Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations

Article abstract of DOI:10.1021/acs.joc.1c01310

Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C-H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.

Full text of DOI:10.1021/acs.joc.1c01310

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Exploiting Continuous Processing for Challenging Diazo Transfer
and Telescoped Copper-Catalyzed Asymmetric Transformations
Daniel C. Crowley, Thomas A. Brouder, Aoife M. Kearney, Denis Lynch, Alan Ford, Stuart G. Collins,
and Anita R. Maguire*
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ABSTRACT: Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds,
including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/
debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing
the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-
transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C−H insertion processes
demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly
over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.
(CHT) forms through reversible electrocyclic ring opening/
closing, as evidenced by time-averaged H NMR signals.
Formation of the quaternary bridgehead stereocenter with
excellent enantiofacial control through use of the copper bis-
oxazoline catalysts is very attractive from a synthetic
perspective.
Despite the synthetic versatility of α-diazocarbonyl com-
pounds, their use at scale has been limited by safety concerns
around the potentially hazardous nature of these compounds
and, more particularly, their sulfonyl azide or diazoalkane
precursors.22,23 For example, the practical synthetic utility of
the copper-mediated intramolecular Buchner research in
Scheme 1 is impacted by the requirement to utilize a
diazoalkane, in this instance diazoethane, to generate the α-
diazoketone. To address this challenge, efforts have been made
to establish continuous processing methodologies for in situ
generation and use of diazo compounds and, by extension, for
INTRODUCTION
■
20,21
1
The transition-metal-catalyzed reactions of α-diazocarbonyl
compounds are among the most versatile transformations in
organic synthesis.1−5 In particular, enantioselective rhodium-
and copper-catalyzed processes have attracted significant
attention, facilitating the efficient formation of new C−C
bonds, among other transformations, in a highly diastereose-
lective and enantioselective fashion, including C−H inser-
tion,4,5 aromatic addition reaction,1 and cyclopropanation.6−8
Within our research team, highly enantioselective copper-
catalyzed C−H insertions, employing bis(oxazoline) ligands,
have been reported across a range of substrates leading to
thiopyran S,S-dioxides (up to 98% ee),9 sulfolanes (up to 80%
ee),10 cyclopentanones (up to 82% ee),11 and β- and γ-lactams
(up to 82% ee),12 with particular success using sulfonyl-
substituted α-diazoketones and α-diazoesters. Extension of this
work to copper-mediated desymmetrization proved highly
effective, resulting in formation of the desymmetrized
thiopyran S,S-dioxide in up to 98% ee.13
Special Issue: Enabling Techniques for Organic Syn-
thesis
Furthermore, the same copper−bis(oxazoline) catalysts have
been employed in intramolecular Buchner additions (Scheme
1),14−19 leading to azulenones with excellent enantiocontrol
(up to 95% ee);16 the azulenones exist in a dynamic
equilibrium of the norcaradiene (NCD) and cycloheptatriene
Received: June 4, 2021
© XXXX The Authors. Published by
American Chemical Society
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Scheme 1. Synthetic Route to Azulenones Previously Reported by Maguire14,17,18
Scheme 2. Previous work by Wirth,29 Collins and Maguire,40 Monbaliu,41 and Maguire14
in situ preparation of the requisite diazo-transfer reagents.24−28
Of the reports of the diazo-transfer process in flow, however,
most have employed sulfonyl azides directly as reagents.29−32
The improved safety profile associated with the handling and
use of hazardous compounds in flow chemistry platforms has
been a critical aspect of the increasing emergence of these
technologies. Enhanced process control,24,32−37 due to
automation, in-line reaction monitoring, and the superior
efficiency of mass and heat transfer in continuous processes
principally, a consequence of the high surface-area-to-volume
ratios inherent in pipe or tube reactorstogether with the
specific facility for immediate use of hazardous material,
generated in situ in minimal quantities,38 has enabled synthetic
chemistry approaches that would previously have been
dismissed due to the associated risks at large scale.
Wirth has reported a two-step telescoped process where
batch-generated sulfonyl azide was used for diazo transfer to an
aryl ester 1 which, following liquid−liquid separation, was
flowed into a round-bottom flask containing a rhodium(II)
catalyst, affording a racemic cyclopropanation product 2
(Scheme 2A).29 Wirth’s method included a drying trap with
MgSO4, which notably improved yield, although side product
formation was still observed.
diazo transfer to a range of substrates in good to excellent
yields and including development of a sodium acetylacetonate
6 quench system to remove any unreacted sulfonyl azide from
the reaction outflow following the diazo transfer.39,40 As
illustrated in Scheme 2B, the generation of mesyl azide, diazo
transfer to the β-ketoester 3, and subsequent transformation of
the α-diazo-β-ketoester 4 in a thermal Wolff rearrangement
with trapping of the ketene by methanol has been successfully
telescoped in a continuous flow process establishing that α-
diazocarbonyl compounds can be generated and used in flow
without isolation and handling of either the α-diazocarbonyl
compounds or, critically, the sulfonyl azide precursors.
Subsequently, Monbaliu has described a telescoped process
for the synthesis of BOC-protected methylphenidate, starting
with in situ TsN3 preparation followed by Regitz diazo transfer
and rhodium(II) octanoate catalyzed intermolecular C−H
insertion leading to the product 7 in 19% yield (Scheme 2C).41
An alternative telescoped synthesis was also reported whereby
the thermolysis of a tosyl hydrazone followed by intra-
molecular C−H insertion and β-lactam methanolysis afforded
the deprotected derivative of 7 in a much improved yield of
70%.41
Over the past two decades, there has been tremendous
progress in immobilization of rhodium carboxylate and
carboxamidate catalysts,42−47 with significant contributions
from Davies,48−51 Doyle,52,53 and Hashimoto,54 among others.
To overcome the requirement to synthesize (in advance)
and handle sulfonyl azides, we have demonstrated successful in
situ generation of tosyl or mesyl azide in flow telescoped with
B
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Davies has reported in situ formation of aryl α-diazoesters in
flow, via oxidation of the corresponding hydrazones, followed
by telescoped intermolecular cyclopropanation or C−H
insertion with an immobilized rhodium(II) carboxylate
catalyst.51 Excellent yields and enantioselectivities were
reported which matched the results from the corresponding
batch reactions.
Copper-catalyzed transformations utilizing heterogeneous
immobilized bis(oxazoline) ligands have also been inves-
tigated,55−60 including the immobilization of a (4S)-Ph-
bis(oxazoline) ligand onto laponite clay by electrostatic
interactions, which was used in the intermolecular C−H
insertion into THF. Only a handful of reports, however, have
described immobilized copper-catalyzed transformations of α-
diazocarbonyl compounds performed in flow.61,62 Following
the precedent of Burguete63 for generation of an insoluble
polymer bound (IPB) copper−bis(oxazoline) catalyst 9, our
group has demonstrated its use for enantioselective intra-
molecular Buchner reactions in batch and using continuous
flow processing, in up to 83% ee (Scheme 2D);14 critically, the
immobilized copper catalyst could be washed and reused a
number of times.
diazocarbonyl compounds including α-diazoketones 8, 11−13,
an α-diazolactam 29, α-cyano-α-diazoacetamides 55−62, an α-
diazo-β-ketonitrile 38, and an α-diazosulfonyl ester 63 and
demonstration of their direct use in three enantioselective
copper-mediated transformations, thereby establishing the
feasibility of this approach.
RESULTS AND DISCUSSION
■
α-Diazoketones 8 and 11−13 were selected for the initial
investigations in this work, with a view to telescoping the in
situ generation of these compounds with their direct use in
copper-catalyzed aromatic addition in continuous flow. Prior
to this work, the diazoethane acylation route to α-diazoketones
8 and 11−13, summarized in Scheme 3,14 has been utilized
Scheme 3. Synthesis of α-Diazoketones 8 and 11−13 in
Batch14
To the best of our knowledge, however, a fully telescoped
continuous flow process involving formation of the sulfonyl
azide followed sequentially by diazo transfer and a copper-
catalyzed process has not been reported to date. A key
challenge is to ensure that the reaction outflow from the diazo
transfer is amenable to direct exposure to the enantioselective
transition-metal catalyst. In particular, removal of any reaction
components from the diazo-transfer processsulfonamide,
base, and any unreacted sulfonyl azidethat could negatively
impact on the transition-metal-catalyzed transformation
through metal leaching, catalyst poisoning, or complexation
leading to reduced activity and/or enantioselectivity must be
addressed; in addition, the removal of water is critical to
avoiding competing O−H insertion pathways. Furthermore,
for efficient telescoping, conducting the sulfonyl azide
generation, prior to the diazo transfer, in a solvent which is
compatible with the enantioselective transition metal-catalyzed
step is critically important.
rather than diazo transfer (in order to overcome the
insufficient activation afforded by a single ketone group), but
while effective, this route suffers from a number of challenges;
these include the safety hazards associated with diazoethane
and its precursor, N-ethyl-N-nitrosourea, which limit its
scalability.64 Furthermore, this process affords the α-diazo-
ketones in diethyl ether, while dichloromethane is the usual
choice of solvent for copper-catalyzed aromatic additions.17 An
alternative method that avoids the use of diazoalkanes and
which is more versatile in the choice of solvent was, therefore,
highly desirable, enhancing compatibility with downstream
reactions.
Debenzoylative diazo transfer for preparation of α-
diazoketones 8 and 11−13, as pioneered by Taber,65,66 was
explored (Figure 1); an adaptation of this route for a
In general, it is evident that any telescoped process using
diazo compounds, generated in flow, in a downstream
transition-metal catalysis requires a diazo feed stream that is
(1) in a suitable solvent for the desired transition metal-
catalyzed process, (2) free of any byproducts and reagents
from upstream processes, and (3) sufficiently dry to undergo
water-sensitive transformations.
Our objective was, therefore, to further develop our earlier
telescoped continuous sulfonyl azide synthesis and diazo-
transfer methodologies,39,40 which did not completely fulfill
these criteria (vide infra), to deliver a process that would
enable the in situ generation of α-diazoketones through diazo
transfer to be directly linked with copper-catalyzed down-
stream transformations utilizing IPB copper−BOX catalyst 9.
Specifically, aromatic addition and C−H insertion were the
transformations of interest. As part of this work, we also wished
to develop a versatile route which could be employed for the
synthesis of α-diazoketones such as those illustrated in Scheme
1, possessing a simple methyl substituent, but also for more
diverse α-diazocarbonyl compounds bearing additional sub-
stituents, including α-diazo-β-ketonitriles.
Figure 1. Diazoethane acylation route vs debenzoylative diazo-
transfer route.
continuous flow platform would offer significant advantages
over the diazoethane acylation route, obviating use of
hazardous diazoalkanes and dramatically improving the safety
profile of the process. Dichloromethane is typically employed
as the reaction solvent for these transformations, which would
be compatible with subsequent telescoped aromatic addition
or C−H insertion, while allowing further scope to use
alternative solvents instead. This proposed route would exploit
Herein, we report the successful telescoping of triflyl azide
generation and use in the synthesis of a range of different α-
C
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sulfonyl azide diazo-transfer reagents, which the group has
experience in generating and using in flow.39,40
proved challenging to completely remove the sulfonyl
benzamide byproduct and 11 was afforded in a comparable
36% yield; this result confirmed, however, that conducting this
diazo transfer in continuous flow and passing the effluent
through silica gel had no detrimental impact on the reaction
outcome.
As summarized in Table 1, investigation of a range of bases
was undertaken, none of which led to a better outcome than
DBU. Interestingly, diazo transfer was not observed when
immobilized DBU was used. Use of sodium hydride, which had
proved effective under batch conditions,68 could not be readily
employed in flow.
Synthesis of α-Diazoketones by Debenzoylative
Diazo Transfer. Initial studies focused on debenzoylative
diazo transfer to β-diketone 19 (prepared via the correspond-
ing acyl benzotriazole67) conducted in batch, prior to
investigation in flow. Thus, 2,5-dimethyl-1,5-diphenylhexan-
1,3-dione (19) was transformed to α-diazoketone 11, employ-
ing DBU as base and p-nitrobenzenesulfonyl azide (p-NBSA)
as diazo-transfer reagent in dichloromethane at 0 °C (Scheme
4), in an adaption of Taber’s original route.65 Purification of α-
Scheme 4. Synthesis of α-Diazoketone 11 by Debenzoylative
Diazo Transfer in Batch
An improved yield (54%, Table 1, entry 8) was observed
when the temperature in the reactor coils was elevated to 45
°C. Methanesulfonyl azide (MsN3) proved to be a poor choice
of diazo-transfer reagent for this transformation; however, use
of p-toluenesulfonyl azide (TsN3) (53%, Table 1, entry 10)
gave a result comparable to that of p-NBSA (Table 1, entry 8).
TsN3 was also a more judicious choice of diazo-transfer
reagent than p-NBSA as its sulfonyl benzamide byproduct was
more easily removed during flash chromatography, allowing
clean fractions of α-diazoketone 11 to be more readily
obtained. Using this methodology, employing TsN3 on
continuous flow, the aryl-substituted α-diazoketones 8, 12,
and 13 were afforded in similar yields from their corresponding
1,3-diketones and DBU (Scheme 5).
Despite the encouraging results with these improved
conditions, the yields obtained remained moderate at best
(11, 53%, Table 1, entry 10 cf. 37% in batch, Scheme 4 vs 83%
for diazoethane acylation from the acid chloride, Scheme 3).
As the reaction was envisaged to be part of a telescoped
process, the diazo-transfer reagent would ideally be generated
in the solvent to be used in the downstream diazo transfer and
copper-catalyzed transformations; aromatic addition reactions
are typically conducted in dichloromethane with a significant
decrease in chemo- and enantioselectivity observed with other
solvents.14 In particular, acetonitrile has been found to inhibit
homogeneous copper−bis(oxazoline) catalysis of aromatic
diazoketone 11 proved challenging due to coelution with the
sulfonyl benzamide byproduct resulting in 37% yield, which
was later improved through alteration of the sulfonyl azide
(vide infra).
Extending this process to flow (Table 1, entry 1) was first
undertaken using peristaltic pumps matching the “in batch”
reaction conditions with the exception of temperature; the
reaction was performed at room temperature for convenience
due to the favorable dissipation of heat in continuous flow. A
residence time of 1 h proved sufficient for complete
consumption of the starting material. As the outflow of the
diazo transfer was ultimately envisaged to be directly used in a
transition-metal-catalyzed reaction, it was important to remove
DBU from the reaction stream to prevent complexation with
metal catalysts, compromising the subsequent transformation.
Accordingly, the reactor effluent was flowed through a plug of
silica gel prior to collection. As with the batch process, it
Table 1. Optimization of Debenzoylative Diazo Transfer to Diketone 19 in Flow
entry
1
base
sulfonyl azide
temp (°C)
yield (%)
DBU
p-NBSA
p-NBSA
p-NBSA
p-NBSA
p-NBSA
p-NBSA
p-NBSA
p-NBSA
MsN3
rt
rt
rt
rt
rt
rt
rt
45
45
45
36
b
b
b
18
b
a
2
3
Amberlyst A21
polymer-bound DBU
triethylamine
tetramethylguanidine
1,4-diazabicyclo[2.2.2]octane
N,N-diisopropylethylamine
DBU
a
4
5
6
7
8
9
10
b
54
25
53
DBU
DBU
TsN3
a
b
Solid base was packed in a 6.6 mm diameter glass column, and the combined 1,3-diketone 19/ p-NBSA stream was passed through it. No signals
1
for α-diazoketone product 11 were observed in the H NMR spectrum of the crude product mixture; only unreacted starting material 19 was
recovered.
D
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Scheme 5. Debenzoylative Diazo Transfer to Diketones 18, 20, and 21 in Flow
Scheme 6. Debenzoylative Diazo Transfer to Diketone 19 Using Triflyl Azide (22) in Batch
Scheme 7. Debenzoylative Diazo Transfer to Diketone 19 in Flow Using Triflyl Azide (22)
addition and to be incompatible with the IPB copper catalyst 9,
causing leaching of copper.14 Tosyl azide is prepared in flow in
aqueous acetonitrile,39 or NMP,41 and in batch in aqueous
acetone,69 solvents which are not readily compatible with
transition-metal catalysis downstream.
Triflyl azide (22) is prepared by the reaction of triflic
anhydride with sodium azide. For the purpose of this work, the
“in batch” preparation of triflyl azide (22) was carried out
using a slightly modified version of the procedure reported by
Xu,71 whereby the sulfonyl azide was generated with sodium
azide (5.0 equiv) and triflic anhydride (1.1 equiv relative to
19) in a biphasic (2:1) water/dichloromethane mixture at 0 °C
for 2 h. The layers were separated, and then the dichloro-
methane solution of triflyl azide (22) was used directly in the
diazo-transfer step (Scheme 6).
There are important safety and process considerations when
carrying out the process shown in Scheme 6. Triflyl azide (22)
should never be isolated in pure form, and the organic solvent
should not be removed from its solutions, as this is known to
lead to detonation.74 The separated organic phase was washed
with aqueous sodium bicarbonate to neutralize any triflic acid
that may be present and which could degrade the subsequent
α-diazoketone products. The resulting triflyl azide solution was
added slowly (20−30 min) to a dichloromethane solution of
1,3-diketone 19 and DBU at room temperature, and reaction
progression was monitored by IR spectroscopy. After 2 h,
complete disappearance of the azide stretch (∼2150 cm−1)74
was observed, and the pure α-diazoketone 11 (ν(C=N2): 2061
cm−1) was isolated in 65% yield. The excess of sodium azide
Trifluoromethanesulfonyl azide (22) (triflyl azide, TfN3) is a
powerful diazo-transfer reagent that reacts even with highly
stabilized acceptor molecules.70 In addition to its potent
reactivity, it is versatile due to the variety of organic solvents in
which it can be generated, including dichloromethane, toluene,
hexane, acetonitrile, pyridine, MeOH, and EtOH;70−76 this is a
desirable attribute for diazo transfers that are part of telescoped
processes and which necessitate the α-diazocarbonyl com-
pound to be in a requisite solvent for the “end-of-line”
transformation. However, there are inherent risks associated
with triflyl azide (22) and its byproducts and extreme caution
should be exercised during its preparation and use; it is a toxic
compound and is known to detonate if not handled
correctly.23,74 Where appropriate procedures are followed,
however, it can be used in a safe manner (see the Supporting
Information (SI) for further discussion on safety consid-
erations on using triflyl azide in flow), facilitating the
preparation of many otherwise difficult-to-access diazo
substrates.71,75,76
E
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Scheme 8. Telescoped Generation of Triflyl Azide (22) and Direct Use for Debenzoylative Diazo Transfers in Flow
used in the reaction and remaining in the aqueous layer was
quenched by the literature method.77
azide (22) and subsequent use in debenzoylative diazo transfer
to 1,3-diketones 18−21 proved successful, enabling the use of
triflyl azide as a powerful reagent for diazo transfer while
obviating the need for isolation or handling of this reagent.
Focusing on the generation of triflyl azide in flow, based on the
Xu procedure for batch preparation of triflyl azide (22)71 and
the successful use of a dichloromethane solution of 22 for
diazo transfer in flow (Scheme 7), generation of triflyl azide
(22) in flow was initially implemented in dichloromethane.
Thus, an aqueous solution of sodium azide was pumped to a
T-piece to meet a dichloromethane solution of triflic anhydride
with the combined biphasic stream passed through a reactor
coil for a residence time of 1 h. To avoid the reaction of triflic
anhydride with adventitious water, the dichloromethane
solution was freshly prepared before use, and any hydrolysis
was effectively reduced by charging the reagent solutions at 3
mL min−1 to minimize exposure to air during the transfer. The
reaction stream then joined a stream of saturated aqueous
sodium bicarbonate to remove any triflic acid, and the
combined biphasic effluent was then separated by an in-line
liquid−liquid separator.
The reactant ratios for this process were determined by prior
experiments involving diazo transfer to a known excess of
sodium acetylacetonate hydrate (see the SI for further details),
which indirectly established the efficiency of formation of triflyl
azide (22) as 58% by measuring the extent of diazo transfer to
the β-diketonate 6 to form 23 (as shown, more generally, in
Scheme 9), without having to isolate and quantify the
hazardous sulfonyl azide. The ratio of triflic anhydride to
1,3-diketone 19 required to execute a telescoped synthesis of
α-diazoketone 11 in flow, therefore, was estimated to be 1.7:1,
Given this much improved yield for the debenzoylative diazo
transfer through use of triflyl azide, the diazo-transfer element
of the process was initially trialled in flow (Scheme 7). Triflyl
azide (22) was generated in batch, as described above (Scheme
6); the resulting dichloromethane solution of triflyl azide (22)
was pumped to a T-piece to meet a solution stream of 19 and
DBU, and then the combined stream was pumped through a
coiled reactor for a residence time of 2 h at room temperature.
Use of a peristaltic pump proved effective, while HPLC
(piston) pumps were found to be less effective. The orange
effluent stream was passed through a silica gel plug, collected,
and checked by IR spectroscopy to verify complete
consumption of triflyl azide (22) prior to concentration.
The desired α-diazoketone 11 was afforded in 93% yield
after chromatography. 19F NMR spectra were recorded for the
isolated product to ensure that no residual triflyl azide or other
1
fluorinated byproducts, without observable signals in the H
NMR spectrum, were present. There is one report in the
literature of the byproduct trifluoromethylsulfonyl benzamide
(δF −76.97);78 this compound was not observed or isolated
during this work and was presumably retained on the silica gel.
This increase in yield (up to 93%, from 65% for the batch
process (Scheme 6) and 53% for the tosyl azide mediated
transformation (Table 1, entry 10)) was a significant
breakthrough and effectively represented optimized conditions
for diazo transfer to form 11 in continuous flow. The improved
outcome in flow vs batch can be rationalized due to the
superior process control achieved in flow, in this instance, the
control over reactant ratios and temperature, specifically the
consistent manner in which reagents were combined during
the continuous process.
Scheme 9. Diazo Transfer to Sodium Acetylacetonate 6
Telescoped Debenzoylative Diazo Transfer in Flow.
Having established that use of triflyl azide in flow for diazo
transfer was effective, the next challenge was to telescope the
preparation of this hazardous reagent in flow with the diazo-
transfer step. As illustrated in Scheme 8, the formation of triflyl
F
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respectively. Scheme 8 outlines the continuous flow setup used
for the telescoped synthesis of triflyl azide (22) and
subsequent debenzoylative diazo transfer to 1,3-diketones
18−21, 24, and 25. As was noted for the triflyl azide solution
(vide supra), use of a peristaltic pump was required.
Table 2. Comparison of Methods for Synthesis of α-
Diazoketones 8 and 11−13
flow yield (in flow yield batch yield
batch yield
c,d
a
situ TfN3)
(TsN )
a3
(TfN3)
(%)
(diazoethane)
(%)
a
,b
entry diazo
(%)
(%)
50
53
45
43
The conditions for the preparation of triflyl azide (22) for
this diazo transfer in flow were chosen to deliver similar
reactant ratios and concentrations to those successfully
employed for the process with pregenerated triflyl azide (22)
in Scheme 7. The stream containing the triflyl azide after the
phase separation was mixed with the solution containing the
substrate and DBU and passed through a reactor coil for 2 h.
The effluent from the diazo transfer was again pumped through
a column reactor of silica gel at room temperature (for removal
of polar reaction components), and the collected reaction
solution was checked by IR spectroscopy to ensure complete
consumption of triflyl azide (22). The process was first
implemented for debenzoylative diazo transfer to diketone 19,
and gratifyingly, α-diazoketone 11 was isolated reproducibly in
80% yield, albeit slightly lower than the yield recorded for the
flow process using a “preformed” triflyl azide solution (93%,
Scheme 7). This result, however, was still a considerable
improvement on other batch diazo-transfer processes inves-
tigated with alternative diazo-transfer reagents during this
work. The reduced yield for the telescoped method is most
likely due to the presence of residual water in the organic
stream, compared to the pregenerated solution of triflyl azide
in Scheme 7, which was dried when prepared in batch prior to
use in the diazo transfer. For later telescoped processes,
involving downstream transition-metal catalysis, this observa-
tion was addressed through incorporation of a drying agent
into the process (vide infra).
On the basis of the successful synthesis of α-diazoketone 11
using this telescoped preparation of triflyl azide (22) and
subsequent diazo transfer in flow, this process using identical
conditions was applied to each of the other precursors
identified for this study at the outset, namely 1,3-diketones
18, 20, and 21 (Scheme 8), with good yields achieved for α-
diazoketones 8, 12, and 13 (70−80%, after chromatography).
The flow process was also used to synthesize novel α-
diazoketones 26 and 27 in excellent yields (80% and 91%,
respectively) from their 1,3-diketone precursors 24 and 25
(Scheme 8), indicating that the process is efficient even when
the steric demand of the alkyl substituent at the site of reaction
is increased. The flexibility of this route to α-diazoketones
bearing different substituents on the diazo carbon is a clear
advantage, avoiding generation and use of a series of
diazoalkanes to access differently substituted α-diazoketones.
The precursor diketones 24 and 25 were readily accessed using
the route employed for 19.
1
2
3
4
8
72
80
75
70
69
76
62
11
12
13
65
44
38
a
b
Yield after flash chromatography, based on the 1,3-diketone. TsN3
c
was preprepared in batch. Diazoethane acylation using an acid
chloride. Yield after flash chromatography, based on the acyl
d
chloride.
advantage in addition to the enhanced safety through
generation and use in situ (Table 2, entries 2 and 4).
It was noted that the chromatographic purification of α-
diazoketones 8 and 11−13, synthesized by the telescoped
TfN3 flow methodology, afforded cleaner isolated products
than those obtained from chromatographic purification of the
crude products from the diazoethane acylation route; in
particular, isolated α-diazoketone 8 was afforded in signifi-
cantly improved purity than from the diazoethane acylation
route (Figure 2).
With downstream processes in mind, ease of purification is
an important benefit. Byproducts may prove to be detrimental
to a transition-metal-catalyzed transformation in a telescoped
process; the telescoped diazo-transfer process with triflyl azide
(22) furnished the crude α-diazoketones with minimal
byproducts. The 1H NMR spectra of the crude effluent, before
being passed through the in-line silica gel plug, indicated the
presence of just the α-diazoketone and DBU salts (which are
removed by passage through a silica gel plug) with no other
substantive byproducts.
Notably the telescoped generation of triflyl azide and
debenzoylative diazo transfer can be effected in toluene in
place of dichloromethane, affording α-diazoketone 11 in 68%
yield after chromatography, with just a minor decrease in yield
relative to that in the chlorinated solvent (80%) (Scheme 8).
Both toluene and dichloromethane are compatible with the
downstream copper-mediated transformations. In addition to
the advantage of using a more environmentally friendly
solvent,79,80 there is also a very significant safety benefit, as
the risk of formation of diazidomethane during the formation
of the triflyl azide is completely eliminated. For all of the
processes described herein, the aqueous sodium azide solution
and dichloromethane are typically in contact for less than 2 h;
there are no reported instances of diazidomethane forming at
room temperature in this time frame and there are multiple
examples in the literature of sodium azide and dichloro-
methane being safely used together under similar condi-
tions.71,81,82 An in situ IR study was also undertaken, which
supported this assertion (see the SI).
An important difference between the telescoped generation
of triflyl azide (22) and our previously reported method for
mesyl azide generation in flow40 is that the liquid−liquid
separation, to remove the aqueous stream, is carried out prior
to the diazo-transfer step. This change was made as, in contrast
to the homogeneous aqueous acetonitrile medium used for
mesyl azide generation, a biphasic system (CH2Cl2/toluene/
water) might lead to inefficient mixing between the reagents
during the diazo-transfer step. The aqueous waste from the
liquid−liquid separator can also be safely destroyed in a
The yields obtained for the telescoped flow process with
triflyl azide (22) were generally comparable with those of the
diazoethane acylation route (from the preformed acid
chlorides), although in the case of the 4-fluoro α-diazoketone
13, the yield from the telescoped TfN3 flow process offered a
far superior yield (Table 2, entry 4, 70% vs 38%). Previously,
we reported the synthesis of α-diazoketone 13 in just 38%
yield.14 The yields for the telescoped triflyl azide flow process
were also higher than those recorded when using batch
prepared tosyl azide as diazo-transfer reagent in flow. Notably,
the yields of 11 and 13 obtained using the telescoped TfN3
flow process were higher than those obtained using TfN3 22 in
the corresponding batch reaction, highlighting a synthetic
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1
Figure 2. Comparison of the H NMR spectra of α-diazoketone 8 recorded after chromatography following synthesis in batch with diazoethane
(A) and following synthesis with the telescoped TfN3 methodology in flow (B). Spectra recorded in CDCl3 at 400 MHz (showing residual CHCl3
signal at δH 7.26).
Scheme 10. Synthesis of α-Diazolactam 29 via Telescoped in Situ Generation of Triflyl Azide (22) and Deacylative Diazo
Transfer
Figure 3. Flowchart for the telescoped generation of TfN3 22 and diazo transfer to diketone 19 in flow including the in-line removal of byproducts;
required process inputs and desired output are shown in green; process byproducts are shown in orange; steps involving separation of byproducts
are shown in blue; components of the process without user handling are shown in red.
H
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Scheme 11. Telescoped Syntheses of α-Diazoketones 8 and 11 with Downstream Copper-Catalyzed Asymmetric Aromatic
Addition86,87
continuous manner (see the SI for experimental details), based
on the literature method.77
effluent in a solvent suitable to use in a downstream copper-
catalyzed aromatic addition (see Figure 3 for an overview of
the overall process). Furthermore, excess sodium azide and any
triflic acid were readily removed in the aqueous layer prior to
diazo transfer, and subsequently, the organic effluent from the
diazo transfer was readily purged of both DBU (or, most likely,
its salt 30, Figure 3) and the sulfonyl benzamide byproduct by
passing through a silica gel plug. The sulfonyl benzamide
byproduct and DBU could, each, potentially coordinate to the
copper catalyst downstream, hindering the transition-metal-
catalyzed aromatic additions, and therefore, their removal prior
to flowing into the immobilized catalyst bed was critical for
successful transition-metal-catalyzed transformation. Indeed,
we have established experimentally that residual DBU is not
compatible with the immobilized copper catalyst 9, as passing a
diazo-transfer reaction solution containing DBU and its salts
through the IPB catalyst 9 (by omitting prior passage through
silica gel) was found to lead to high levels of copper leaching
as indicated by a dramatic change of color (green to white)
occurring with concomitant loss of catalytic activity.
The telescoped triflyl azide generation and debenzoylative
diazo-transfer methodology affords a vastly improved safety
profile relative to use of diazoalkane acylation, particularly
when toluene is employed as the reaction solvent. Isolation and
handling of hazardous diazoalkanes and nitrosoureas were
avoided, while the organic azide was synthesized in a safe
continuous manner without isolation or handling. Further-
more, the diazoethane acylation approach, in terms of overall
yield, offers only marginally better results than the telescoped
TfN3 flow process; for example, synthesis of α-diazoketone 11
(Figure 1): 58% yield for diazoethane acylation (over two
steps: carboxylic acid → acyl halide → α-diazoketone) versus
50% for debenzoylative diazo transfer (over three steps:
carboxylic acid → acyl benzotriazole → 1,3-diketone → α-
diazoketone).
The versatility of this telescoped process was further
demonstrated by preparation of α-diazolactam 29 from the
activated lactam 28, utilizing a deacylative diazo-transfer
strategy,83,84 demonstrating that this approach can be
generalized beyond debenzoylation (Scheme 10). In this
instance, the triflyl azide was generated in toluene while the
reagent solution was in dichloromethane indicating the process
remains efficient in a mixed solvent system.
Evidently, the silica gel column has a finite capacity to retain
the polar byproducts; accordingly, the volume of the solution
of α-diazoketone passed over the immobilized copper catalyst
was adjusted to avoid elution of any of the unwanted polar
components.
Telescoped Aromatic Additions of α-Diazoketones.
With the viability of our continuous flow strategy for
generation and in situ use of triflyl azide (22) for
debenzoylative diazo transfer leading to a range of α-
diazocarbonyl compounds established, our attention turned
to telescoping this process with copper-mediated asymmetric
transformations, with an initial focus on intramolecular
aromatic addition.
Two telescoped processes comprising triflyl azide gener-
ation, debenzoylative diazo transfer, and aromatic addition
were investigated, furnishing enantioenriched azulenone 31
and the PTAD adduct 10 derived from azulenone 32 (Scheme
11). In both tranformations, the triflyl azide (22) prepared in
flow was passed over KOH pellets in a round-bottomed flask as
a reservoir and then pumped forward to effect debenzoylative
diazo transfer with either 1,3-diketone 18 or 19.85
Generation of triflyl azide (22) and subsequent debenzoy-
The diazo-transfer effluent was also collected over KOH
lative diazo-transfer reactions in flow provided a crude reaction
pellets, and an appropriate portion of this reaction solution,
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Scheme 12
1
Figure 4. H NMR spectra of the crude reaction mixtures from the aromatic addition of 11 performed in freshly distilled dichloromethane (A),
HPLC-grade dichloromethane (B), and HPLC-grade dichloromethane spiked with water (C). Spectra recorded in CDCl3 at 300 MHz. The ratio of
azulenone 31 to 2,3-diketone 34 was readily determined from the relative integration of the 2H AB quartet of 31 and the 2H singlet of 34.
containing the α-diazoketone 8 or 11, was pumped forward to
undergo aromatic addition, ensuring the capacity of the silica
gel column to retain the polar byproducts, especially the
sulfonyl benzamide salts 30, is not exceeded and thereby
avoiding leaching of the copper catalyst (vide supra).
Following passage through silica gel, the stream containing
α-diazoketone 8 or 11 was directly passed through a packed
bed reactor containing IPB catalyst 9 (10 mol %). The
aromatic addition of α-diazoketone 11 was performed at 45
°C, while the aromatic addition of α-diazoketone 8 was
performed at room temperature.
The process afforded azulenone 31 in 50% yield after
chromatography (over the two steps from the 1,3-diketone
precursor 19). Rather than attempt to isolate and purify the
labile azulenone 32, the reactor effluent containing 32 was
collected into a flask containing PTAD in dichloromethane to
transform it to the stable cycloadduct 10 prior to isolation;
once all the effluent was collected, the contents of the flask
were stirred for 1 h at room temperature and the product
cycloadduct 10 was isolated in 30% yield (over three steps
from 1,3-diketone precursor 18).
triflyl azide generation and subsequent diazo-transfer reaction
produced an effluent, that after treatment with silica gel and
drying agent, was sufficiently clean and anhydrous to undergo
downstream transition metal-catalyzed transformations with no
noticeable impact on enantioselection. While the yields were
slightly lower than those achieved with pure α-diazoketones,
the benefit of achieving these enantioselective transformations
without isolating or handling either the triflyl azide (22) or the
α-diazoketone offsets this. These results demonstrate that the
synthetic power of enantioselective transition-metal-catalyzed
transformations of α-diazoketones can be achieved without
handling either the hazardous precursor sulfonyl azide or the α-
diazoketone and that the solution of the α-diazoketone generated
in flow is sufficiently clean to flow directly into an immobilized
copper catalyst without undermining the enantioselectivity.
It was notable that no signals associated with DBU or DBU
salt 30 were observed in the 1H NMR spectra of the
concentrated crude reaction effluents, indicating that, at least
on the scale investigated, the silica gel column had successfully
removed these byproducts. Despite employing KOH pellets as
drying agent, 2,3-diketone 34 (Scheme 12) was also afforded
as a side product during the aromatic addition of α-
Critically, the isolated products 31 and 10 were afforded
with comparable enantiopurities (60 and 82% ee, cf. 61% ee
and 83% ee) to those reported for the transformations carried
out with IPB 9 in batch and flow but which were not
telescoped, instead using preprepared α-diazoketone.14 These
results were encouraging and demonstrated that the telescoped
1
diazoketone 11, and was clearly observed in the H NMR
spectrum of the crude product mixture and was isolated after
chromatography in 19% yield as a yellow oil.
Use of KOH pellets as a drying agent was undertaken to
combat the impact of residual water in the reaction stream as it
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Scheme 13. Synthesis of α-Diazoketone 36 with the Telescoped Flow Synthesis Using in Situ Generated Triflyl Azide
Scheme 14. Synthesis of α-Diazo-β-ketonitrile 38 via a Telescoped Flow Synthesis Using in Situ Generated Triflyl Azide (22)
passes on to the immobilized copper catalyst. Although the
liquid−liquid separator used following the upstream generation
of triflyl azide successfully partitions the organic and aqueous
phases, the organic layer is not anhydrous at this point. In
order to test the effect that the water content of dichloro-
methane has on aromatic addition, a homogeneous Cu(PF6)−
33 [(4S)-Ph-BOX] catalyzed transformation of α-diazoketone
11 was carried out (Scheme 12) under identical conditions,
but with three different sources of dichloromethane as solvent:
(A) dichloromethane which had been freshly distilled over
calcium hydride, (B) HPLC grade dichloromethane (with
amylene as a stabilizing agent), and (C) HPLC grade
dichloromethane (with amylene as a stabilizing agent), spiked
with a few drops of water per 100 mL of dichloromethane.
Furthermore, the effluent from the diazo-transfer stream was
collected over KOH pellets before being pumped forward to
undergo downstream aromatic additions.
During the phase separation in the liquid−liquid separator, a
small volume of dichloromethane remains after the triflyl azide
separation has been undertaken and the solution progressed
downstream to the diazo transfer. To check the efficiency with
which the hazardous triflyl azide (22) was progressed through
(Scheme 11), quantification of the amount of triflyl azide that
remains in the residual dichloromethane phase in the separator
was undertaken and estimated as approximately 2% of the total
generated; this was readily quenched by addition of sodium
acetylacetonate (6).
Telescoped Regitz-Type Diazo Transfer in Flow. While
the debenzoylative diazo transfer using triflyl azide generated
in flow proved very successful, generalizing this approach to
standard Regitz diazo transfer was investigated to broaden the
synthetic scope and specifically to enable telescoping with a
C−H insertion process (vide infra). Accordingly, Regitz-type
diazo transfer to form the novel α-diazo-β-diketone 36 was
achieved in an excellent yield of 94% (Scheme 13); in this
instance, triethylamine was sufficiently basic to deprotonate β-
hydroxyenone 35. The residence times, reagent ratios, and
temperatures were consistent with the previously performed
telescoped transformations. In the absence of an alkyl
substituent at the α-carbon of the β-hydroxyenone, the
reaction mechanism was seen to proceed entirely through
Regitz diazo transfer, with no evidence for competing
debenzoylation. This result supports the extensive evidence
reported by Regitz, Taber and others that the debenzoylation
pathway is only observed when the α-carbon possesses an alkyl
substituent.65,66,90−93
1
The H NMR spectra of the crude product mixtures of the
three transformations indicated increased formation of the 2,3-
diketone byproduct 34 in the reaction spiked with water
(Figure 4C). The formation of the 2,3-diketone 34 can be
envisaged either by reaction of the carbene with oxygen or by
O−H insertion into water followed by oxidation of the α-
hydroxyketone,88 possibly facilitated by the copper cata-
lyst89the outcome of the spiking experiment indicating
that water is a more likely source in this instance.
In contrast, the corresponding 2,3-diketone product was not
isolated for the telescoped aromatic addition of α-diazoketone
8, although its formation could not be excluded based on the
presence of minor impurity signals in the 1H NMR spectrum of
the cycloadduct 10 prior to chromatography.
As use of a drying agent, following in-line partitioning of the
biphasic stream, to reduce the water content is clearly
advantageous, accordingly, in all the telescoped transforma-
tions described herein, KOH pellets were placed in the
reservoir containing the organic effluent (the solution of triflyl
azide (22)) from the in-line liquid−liquid separation as it is
pumped forward to the diazo-transfer step (Scheme 11).
Diazo Transfer to a β-Ketonitrile and α-Cyanoaceta-
mides. Having demonstrated efficient synthesis of α-
diazoketones via the in situ generation and use of triflyl
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azide in flow, extension to a broader range of α-diazocarbonyl
compounds was undertaken to expand the scope of this
approach with a particular focus on nitrile derivatives which
can be challenging to access in certain instances. Accordingly,
Regitz-type diazo transfer employing our telescoped triflyl
azide generation and diazo-transfer methodology proved
successful when employing β-ketonitrile 37 as the substrate,
affording the desired α-diazo-β-ketonitrile 38 in 85% yield
(Scheme 14); this outcome is comparable with the yields for
α-diazo-β-ketonitriles under batch conditions reported by
Charette, who had also utilized TfN3 22,76 and with the yields
obtained when imidazole-1-sulfonyl azide hydrochloride was
used.94,95 It has also been demonstrated that acylation of
diazoacetonitrile can afford α-diazo-β-ketonitriles;96 however,
this reagent poses its own safety challenges.97 Interestingly, a
debenzoylative diazo-transfer approach to 38 had proved
unsuccessful, with the benzoylated starting material recovered
essentially quantitatively.
Following the successful application of our telescoped triflyl
azide generation and diazo-transfer methodology to a Regitz-
type diazo transfer, for synthesis of α-diazo-β-ketonitrile 38,
our attention was attracted to its potential for preparation of α-
cyano-α-diazoacetamides. The reported synthesis of these α-
diazocarbonyl compounds, by Xu,71 required the use of triflyl
azide (22) (Scheme 15), and therefore, these substrates
appeared to be clear candidates for preparation via our
telescoped flow procedures, without storage or handling of
triflyl azide (22).
cyanoacetamide 47, but without success. This outcome
highlights the importance of developing a safe method for
the generation and use of triflyl azide for diazo transfers which
cannot be readily effected using less reactive sulfonyl azides,
although Xu had reported a single example of diazo transfer to
an α-cyanoacetamide using p-ABSA and DBU.98
The 1H NMR spectra of the crude reaction mixtures
following concentration were relatively clean in all cases, and
the α-cyano-α-diazoacetamides 55−62 were isolated after
chromatography in yields ranging from moderate to excellent
as yellow solids in most cases. These compounds were
relatively stable and could be stored for extended periods in a
freezer without any evidence of deterioration. Using this
protocol, α-cyano-α-diazoacetamides can be readily accessed in
multigram quantities, with the primary limitation being the
scale of triflyl azide (22) handled.
Our telescoped preparation of triflyl azide (22) followed by
Regitz diazo transfer was then applied to generate the α-cyano-
α-diazoacetamides in flow (Table 4). Once again, the organic
effluent from the in-line liquid−liquid separator was collected
in a flask containing potassium hydroxide pellets before being
immediately pumped forward to the diazo-transfer step.
In practice, synthetically useful amounts (3.0 mmol) of the
α-cyano-α-diazoacetamides were prepared and purification by
column chromatography was employed to ensure complete
removal of the byproducts. Excellent yields were achieved
across the series. Furthermore, the quality of the products
isolated was comparable in flow or batch. It was notable that
the yields for the α-cyano-α-diazoacetamides were more
uniform in flow, across the series investigated, than the yields
obtained in batch (Table 4 cf. Table 3), presumably due to
enhanced control of reagent mixing and temperature.
Scheme 15. Synthesis Route to α-Cyano-α-diazoacetamides
Reported by Xu71
Introduction of an in-line silica gel plug was undertaken with
a view to telescoping the diazo transfer with subsequent
transition-metal-catalyzed transformations by removal of the
triethylamine salts in-line at smaller scales (approximately 1
mmol). Evidently, the volume of silica gel used in the plug
must be appropriate to the scale of the reaction to avoid
leaching of the polar byproductstypically, in this work the
reactions were conducted at a 1 mmol scale and using a 100
mm × 10 mm internal diameter glass column of silica gel.
Notably, synthesis of gram quantities of α-cyano-α-diazoace-
tamides using this methodology in flow does not require
inclusion of the silica gel column as chromatographic
purification affords the products in analytically pure form,
with or without the silica gel plug in a flow system.
While triflyl azide (22) is the most common choice of diazo-
transfer reagent for synthesizing α-cyano-α-diazoacetamides,
Reisman has reported using imidazole-1-sulfonyl azide hydro-
chloride as an alternative in batch,95 although the reaction
times reported are much longer (24 h vs approximately 4 h)
and marginally lower yields were reported in comparison to
yields obtained for the telescoped flow process in this work.
Most importantly, however, as mentioned earlier, use of triflyl
The α-cyanoacetamides 47−54 were synthesized by the
route described by Xu (Scheme 16).71 A range of substituted
benzaldehydes were transformed to secondary benzyl amines
39−46 by reductive amination with tert-butylamine or
benzylamine. These amines were then converted to amides
in a DMAP-mediated coupling reaction with cyanoacetic acid.
Compounds 47−54 were prepared on a synthetically useful
scale (2−10 g) and were afforded as pure solids, usually upon
recrystallization from ethanol, and were stable on storage at
room temperature.
A modified version of the method reported by Xu,71 with
triflyl azide (22) and using triethylamine as base, was utilized
for synthesis of α-cyano-α-diazoacetamides 55−62 in batch
(Table 3), as a means of comparing the outcome of their
preparation via our telescoped continuous process. As part of
this work, the potential viability of tosyl azide (TsN3) and
DBU, and also p-acetamidobenzenesulfonyl azide (p-ABSA)
and triethylamine, were assessed for the diazo transfer to α-
Scheme 16. Synthetic Route to α-Cyanoacetamides 47−54
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Table 3. Synthesis of α-Diazo-α-cyanoacetamides 55−62 in Batch with Triflyl Azide (22)
a
entry
substrate
diazo
R1
R2
yield (%)
1
2
3
4
5
6
7
8
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
H
4-Cl
H
4-F
4-Me
4-Br
3,5-dimethyl
4-pyridyl
benzyl
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
66
64
72
65
83
90
58
46
a
Isolated after flash chromatography.
Table 4. Synthesis of α-Cyano-α-diazoacetamides with the Telescoped Flow Synthesis Using in Situ Generated Triflyl Azide
(22)
a
entry
substrate
diazo
R1
R2
yield (%)
1
2
3
4
5
6
7
8
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
H
4-Cl
H
4-F
4-Me
4-Br
3,5-dimethyl
4-pyridyl
benzyl
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
80
95
78
88
83
84
96
76
a
Isolated after flash chromatography.
azide (22) in flow offers clear safety advantages relative to its
generation and use in batch.
key to a fully telescoped process involving triflyl azide
generation, diazo transfer and direct C−H insertion reaction
of α-diazo-β-oxosulfone 63 in continuous flow.
Telescoped C−H Insertion. Earlier work by our team has
demonstrated excellent enantiocontrol in intramolecular C−H
insertions with α-diazo-β-oxosulfones;9,13 the generation and
use of triflyl azide in flow for diazo transfer offers for the first
time the possibility of telescoping the synthesis of α-diazo-β-
oxosulfones with the copper-catalyzed C−H insertion leading
to thiopyran S,S-dioxides. Key to this is the potential to
prepare the α-diazo-β-oxosulfones in a solvent medium which
is compatible with the catalyst and sufficiently clean to avoid
catalyst poisoning or deterioration. Given its successful use for
enantioselective intramolecular Buchner reactions in batch and
using continuous flow processing,14 investigation of the use of
IPB copper−bis(oxazoline) catalyst 9 in the copper-catalyzed
desymmetrization of α-diazo-β-oxosulfone 63 was investi-
gated.13 Use of the immobilized catalyst 9, in this instance, was
A number of heterogeneous batch reactions were initially
conducted to support development of the final continuous
process, as shown in Table 5. These reactions investigated
whether the IPB copper−bis(oxazoline) catalyst 9 would
afford efficient C−H insertion of α-diazo-β-oxosulfone 63, as
observed upon homogeneous copper-catalyzed batch reac-
tions,13 prior to attempting a telescoped diazo-transfer reaction
and C−H insertion step in flow. To examine results of a
homogeneous versus heterogeneous copper-catalyzed C−H
insertion during this investigation, a homogeneous reaction
was also undertaken for comparison using Cu(CH3CN)4PF6
(5 mol %) and the analogous (4R)-Ph bis(oxazoline) ligand 64
(6 mol %), in dichloromethane at reflux (Table 5, entry 5).
M
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Table 5. Heterogeneous Copper-Catalyzed C−H Insertion of α-Diazo-β-oxosulfone 63 in Batch
a
Compound 9 was reused multiple times with addition of fresh catalyst (entries 1−3), collected by filtration once the crude reaction mixture was
b
cooled to room temperature, agitated in fresh dichloromethane for 2 h, collected by filtration, and air-dried overnight. Reaction completion was
determined by IR spectroscopic analysis upon disappearance of the diazo stretch for 63. Conversion was calculated on the basis of comparison of
the integrations for the C(1)H doublet of doublets at δH 3.75 (1H, J 4.7, 3.1 Hz) for 65 and the methyl singlet at δH 3.88 (3H) for 63. Yields after
column chromatography. The enantiopurity was measured by chiral-phase HPLC analysis (for full details, see the SI). Fresh 9 was used to make
c
d
e
f
g
up the difference in polymer catalyst mol % from the previous run. Yield in parentheses was calculated on the basis of the percent conversion from
h
i
1
the H NMR spectrum of the crude reaction material. The major enantiomer has a 1R,4aR,8aS configuration. Homogeneous batch reaction.
j
k
Cu(CH3CN)4PF6 (5 mol %) and (4R)-Ph BOX ligand 64 (6 mol %) used. The major enantiomer has a 1S,4aS,8aR configuration.
Reactions using IPB copper catalyst 9 at 5 and 10 mol % (5
In an attempt to achieve 100% conversion of the α-diazo-β-
oxosulfone 63, 15 mol % of 9 was used (5 mol % fresh catalyst
and 10 mol % reused catalyst) with the reaction mixture heated
under reflux for 48 h (Table 5, entry 3); however, only 78%
conversion was achieved, with a 60% yield of thiopyran 65,
while retaining 93% ee in the insertion product. An interesting
point to note is that the regio- and diastereoselectivity of the
reaction appear unaffected by use of the IPB copper catalyst 9;
in common with similar homogeneously catalyzed reactions,
65 was found to be the major product.13
Although maintaining a high level of stereoselectivity,
achieving reaction completion in dichloromethane under reflux
was challenging with the IPB copper catalyst 9. In order to
facilitate the transition of the copper-catalyzed desymmetriza-
tion process of α-diazo-β-oxosulfone 63 to a continuous flow
platform, the reaction would ideally reach completion in less
than an hour to avoid requiring impractically low flow rates
that would correspond to excessively long residence times.
Accordingly, conducting the IPB copper-catalyzed C−H
insertion of 63 in toluene, a higher boiling (bp 111 °C) and
“greener” solvent compared to dichloromethane (bp 40 °C)
was investigated with a view to reducing the reaction time.
mol % fresh catalyst and 5 mol % of reused catalyst) loadings
in dichloromethane at reflux did not achieve complete
conversion of 63; the heterogeneous reaction was considerably
slower than the homogeneous reaction, which was complete
after 4 h (Table 5, entry 1 cf. entry 5).
After reflux for 24 h at a 10 mol % loading of 9 (Table 5,
entry 2), 83% conversion was observed in the 1H NMR
spectrum of the crude reaction mixture which resulted in a
yield of 59% for 65 with 92% ee after column chromatography.
The decrease in enantioselectivity from 97% ee to 92% ee
observed, upon immobilization of the ligand, when using the
IPB copper catalyst 9 is relatively modest and is in line with
that observed for aromatic addition.14 As expected, the major
enantiomer of 65 isolated from the use of the IPB (4S)-Ph
bis(oxazoline) copper catalyst 9 was the 1R,4aR,8aS
enantiomer, the opposite enantiomer observed to that isolated
from the homogeneous reaction when using the (4R)-Ph
bis(oxazoline) ligand 64. This result highlights that very similar
ligand−substrate interactions occur with the heterogeneous
IPB copper catalyst, compared to the homogeneous copper-
catalyzed reaction.
N
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Scheme 17. Synthesis of α-Diazoketone 63 with the Telescoped Flow Synthesis Using in Situ Generated Triflyl Azide (22)
Scheme 18. Telescoped Process for the Synthesis and C−H Insertion of α-Diazo-β-oxosulfone 63
A heterogeneous reaction of α-diazo-β-oxosulfone 63 was
conducted using toluene under reflux with a fresh sample (10
mol %) of 9 in a manner similar to that employed for the other
entries in Table 5, other than the change of solvent. The
reaction was observed to occur rapidly (30 min) at the elevated
temperature of 111 °C; however, some additional impurity
using the diazo-transfer agent p-ABSA. Thus, the triflyl azide
flow methodology is also very effective for diazo transfer to α-
sulfonyl esters.
For the telescoped three-step continuous process, including
C−H insertion, in situ prepared α-diazo-β-oxosulfone 63
solution was pumped, first, through a glass column reactor
packed with silica gel to remove polar reagents and byproducts
(principally, DBU and DBU salts), followed subsequently by a
glass column reactor packed with the IPB copper catalyst 9 (10
mol %) that was heated to 111 °C, where the final C−H
insertion step occurred (Scheme 18).
The telescoped process resulted in the desymmetrized
product 65 being isolated in 26% yield and 88% ee after
column chromatography. Critically, this outcome showed that
it is possible to utilize the reaction stream containing the α-
diazosulfone 63 directly in the copper-mediated C−H
insertion without any deterioration in the enantiopurity of
the desymmetrized product 65, albeit with a reduced yield.
Thus, the telescoping is feasible not only with copper-mediated
aromatic addition but also with the much more demanding C−
H insertion into an unactivated bond. Although a lower yield
was observed, the enantioselectivity observed is comparable to
1
signals were noticed in the H NMR spectrum of the crude
product mixture, albeit with 65 still observed as the major
product. Gratifyingly, 65 was isolated with a 57% yield and
88% ee after column chromatography. Both the yield and the
enantioselectivity of 65 were reduced somewhat in comparison
to those seen for the dichloromethane reactions using 9 and
for the homogeneous reaction (Table 5, entries 1−5),
however, with clear advantages in terms of reaction time and
efficiency.
On the basis of these encouraging preliminary results using
the IPB copper catalyst 9 in batch, the desymmetrization
reaction was transferred to the three-step telescoped flow
process. Initially, focusing on the diazo-transfer step, the
synthesis of 63 was undertaken in flow in toluene via Regitz-
type diazo transfer following triflyl azide formation (Scheme
17), with 80% yield of α-diazoester 63 obtained after column
chromatography, which was comparable to the batch reaction
O
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Figure 5. Summary of process inputs and outputs.
that obtained when the heterogeneous batch reaction was
conducted in toluene (Table 5, entry 4).
cyano-α-diazoacetamides 55−62, an α-diazo-β-ketonitrile 38,
and an α-diazosulfonyl ester 63, via both Regitz-type diazo
transfer and deacylative/debenzoylative diazo-transfer pro-
cesses in excellent yields (70−96%) and offers versatility in
the solvent employed, in addition to addressing the hazards
associated with handling of this highly reactive sulfonyl azide.
Notably, triflyl azide (22) led to successful diazo transfer to
form α-diazoketones 8 and 11−13 with substantially higher
yields than achieved with tosyl azide in flow. Furthermore,
using this continuous flow protocol the diazo substrates are
generated in solvents that are compatible with downstream
transition-metal-catalyzed processes, such as toluene and
dichloromethane. Telescoping the generation of the triflyl
azide (22) and diazo-transfer process with enantioselective
copper-mediated intramolecular aromatic addition and C−H
insertion processes demonstrates that the reaction stream of
the α-diazocarbonyl compound can be obtained in sufficient
purity to pass directly into the immobilized copper bis-
(oxazoline) catalyst 9 without detrimentally impacting on the
enantioselectivity observed. Thus, azulenones 31 and 32 (as its
PTAD adduct 10) were obtained in 60% ee and 82% ee, in
50% and 30% yield respectively, with little or no decrease in
enantioselectivity observed when the Buchner addition was
telescoped with the diazo-transfer protocol. Furthermore, the
desymmetrisation via copper-mediated C−H insertion to form
the thiopyran S,S-dioxide proved successful in toluene, leading
to the desymmetrized product in 88% ee, comparable with the
enantioselectivity observed using the immobilized copper
catalyst in a batch reaction.
Thus, it appears the generation of triflyl azide (22) and
telescoping this with the diazo transfer to form 63 proceeds
efficiently; however, the outflow of the diazo transfer is a
relatively complex solution containing a stoichiometric amount
of DBU, triflyl sulfonamide and potentially other byproducts
which could detrimentally impact on the IPB copper catalyst.
Observation of enantioselective C−H insertion, albeit at a
reduced efficiency compared to a typical homogeneous
reaction,13 solely by passing the reaction mixture through
silica gel, offers promise that this process can be further
optimized in terms of yield, especially as the extent of the
enantioselectivity was not detrimentally affected (88% ee).
Notably, the synthesis of triflyl azide (22), the diazo transfer to
66, and the copper-mediated C−H insertion can be conducted
in a single telescoped process without detrimental impact on
the stereochemical outcome and, in particular, the enantio-
purity of the thiopyran dioxide 65.
Previous literature reports generated or utilized TsN3 in
solvents which had detrimental effects on the yields of
downstream transition-metal-catalyzed processes, such as
NMP41 or MeCN.39 In addition to the high level of reactivity
of TfN3, one of the primary reasons for selecting TfN3 as
diazo-transfer reagent was due to the ability to generate the
compound in a solvent (toluene or dichloromethane in this
work) which was amenable for use in downstream transition-
metal-catalyzed processes without requiring a solvent swap.
Ultimately, the potential hazard of residual triflyl azide (22) in
the reaction outflow was mitigated by two features: (1) in the
development of the diazo transfer telescoped with triflyl azide
formation, it was established using IR spectroscopy that no
residual triflyl azide (22) was present in the reaction outflow,
for the reagent ratio levels employed; (2) reaction monitoring
of each the reaction effluents by IR spectroscopy prior to
concentration showed no evidence of the characteristic azide
stretch for triflyl azide (22), or indeed sodium azide. As
summarized in Figure 5 the synthetic power of triflyl azide and
the α-diazocarbonyl compounds has been effectively exploited,
in tandem with immobilized copper catalysts, in transforming
achiral starting materials to highly enantioenriched products
while obviating the need to isolate, handle, or store these
compounds.
EXPERIMENTAL SECTION
■
General Procedures. Solvents were distilled prior to use as
follows: dichloromethane was distilled from calcium hydride when
used for transformations of α-diazoketones, ethyl acetate was distilled
from potassium carbonate, tetrahydrofuran was distilled from sodium
benzophenone ketyl in a nitrogen atmosphere and hexane was
distilled prior to use. All commercial reagents were used without
further purification unless otherwise stated. Amines 39−46,71 sulfone
63,13 and pyrrolidinone 28,83 were prepared according to literature
methods. Insoluble polymer bound (IBP) catalyst 9 was prepared
from copper(I) hexafluorophosphate and 2,2′-(1,3-bis(4-
vinylphenyl)propylidene)bis((4S)-4-phenyl-4,5-dihydro-2-oxazole)
polymer as previously reported.14
1H (300 MHz) and 13C (75.5 MHz) NMR spectra were recorded
on a Bruker Avance 300 NMR spectrometer. 1H (400 MHz) and 13
C
(100.6 MHz) NMR spectra were recorded on a Bruker 400 MHz
NMR spectrometer. All spectra were recorded at 300 K in deuterated
chloroform (CDCl3) unless otherwise stated, using tetramethylsilane
(TMS). Chemical shifts (δH and δC) are reported in parts per million
(ppm) relative to TMS and coupling constants are expressed in hertz
(Hz). 19F NMR spectra showed chemical shifts (δF) measured relative
to hexafluorobenzene, which shows a single resonance at −163.0 ppm.
CONCLUSION
■
While triflyl azide (22) is a very powerful reagent for diazo
transfer, its use is limited by the hazards associated with its
handling. Generation and use of triflyl azide in flow leads to
efficient synthesis of a range of α-diazocarbonyl compounds,
including α-diazoketones 8, 11−13, an α-diazolactam 29, α-
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Splitting patterns in 1H spectra are designated as s (singlet), bs (broad
singlet), d (doublet), bd (broad doublet), t (triplet), bt (broad
triplet), q (quartet), qu (quintet), dd (doublet of doublets), dt
(doublet of triplets), dq (doublet of quartets), ddd (doublet of
doublets of doublets), td (triplet of doublets), ddt (doublet of
doublets of triplets), AB (AB system), or (m) multiplet. 13C NMR
spectra were calibrated using the solvent signal, i.e. CDCl3: δC 77.0
ppm, and multiplicities were assigned with the aid of DEPT
experiments. Assignment of 1H signals was aided using 2D NMR
stirred at room temperature for 30 min, after which carboxylic acid (1
equiv) was added in one portion. A white suspension formed
following the addition, which was stirred at room temperature for 2 h.
The suspension was filtered by gravity filtration, and the white solid
collected was washed with dichloromethane (2 × 30 mL). The
combined organic washings and filtrate were collected, dried, and
concentrated under reduced pressure to afford the crude acylbenzo-
triazole.
1′-(1H-Benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-phenylbutan-1′-
1
including H−1H COSY, HSQC and HMBC.
one.99
Infrared spectra were measured using a Perkin−Elmer FTIR
UATR2 spectrometer.
Organic phases were dried using magnesium sulfate or potassium
hydroxide pellets. Flash column chromatography was carried out
using Kieselgel silica gel 60, 0.040−0.063 mm (Merck). Thin-layer
chromatography (TLC) was carried out on precoated silica gel plates
(Merck 60 PF254). Visualization was achieved by UV (254 nm) light
absorption.
This compound was prepared according to the general procedure
using thionyl chloride (1.0 mL, 13.0 mmol), 1(H)-benzotriazole (5.80
g, 48.7 mmol), 3-methyl-3-phenylbutanoic acid (2.03 g, 11.4 mmol)
and dichloromethane (75 mL). The crude product was purified by
flash chromatography on silica gel with hexane/ethyl acetate (80:20)
as eluent which afforded acylbenzotriazole as a colorless oil (2.39 g,
Elemental analysis was carried out by Microanalysis Laboratory,
National University of Ireland, Cork, using Exeter Analytical CE440
elemental analysers. Low-resolution mass spectra (LRMS) were
recorded on a Waters Quattro Micro triple quadrupole instrument in
electrospray ionization (ESI) mode using 50% acetonitrile−water
containing 0.1% formic acid as eluent. High-resolution mass spectra
(HRMS) were recorded on a Waters LCT Premier TofLC−MS
instrument in electrospray ionization (ESI) mode using 50%
acetonitrile−water containing 0.1% formic acid as eluent or on an
Agilent 6530B Accurate Mass Q-TOF LC/MS instrument in
electrospray ionization (ESI) mode using 50% acetonitrile−water
containing 0.1% formic acid as eluent. High resolution (precise) mass
spectra (HRMS) were also recorded on a Waters Vion IMS
instrument (SAA055 K) with Waters Acquity I-class UPLC in
electrospray ionization (ESI) mode using 50% acetonitrile−water
containing 0.1% formic acid as eluent and Leucine Enkephalin as
reference solution. Samples were prepared for either LRMS or HRMS
by employing acetonitrile as solvent and are accurate to within 5 ppm.
Melting points were obtained using a Unimelt Thomas-Hoover
Capillary melting point apparatus and are uncorrected. Enantiopurity
of chiral compounds was determined by chiral stationary phase high-
performance liquid chromatography (HPLC) performed on a
Chiralcel OD-H or Lux Amylose-1 column. HPLC analysis was
performed on a Waters alliance 2690 separations module. All chiral
columns were purchased from Daicel Chemical Industries Limited or
Phenomenex. Optical rotations were measured at 589 nm in a 10 cm
cell on a PerkinElmer 141 polarimeter or on a Rudolph Autopol V
Plus polarimeter; concentrations (c) are expressed in g/100 mL, and
the specific rotation of a compound and is expressed in units of 10−1
deg cm2 g−1.
All continuous processes were performed using a flow chemistry
system consisting of four HPLC pumps and up to four temperature-
controlled tubular reactors (a glass reactor manifold containing a
temperature controlled glass column) and a flow chemistry system
consisting of three peristaltic pumps. To prepare the reactor for
operation pumps were purged with the solvent to be used in the
reaction prior to use. All reaction tubing, coils, inlets and connections
were also purged thoroughly in a similar manner. All pumps were
primed using appropriate solvents and pump backwash reservoirs
were filled. The solvent that was to be used was flushed through all
injectors and reactors. Pumps were run at reaction flow rates to check
for stability, in both reagent and solvent lines, before committing
reagents. Reactors that were to be used were then heated to the
desired temperatures, using the flow chemistry platform, to check
system pressurization. General specifications of flow systems used:
Material of tubing: PFA; Diameter of tubing: 1 mm; Working flow rates:
0.05 mL/min −9.99 mL/min; Tubular reactor working volume: 10 mL;
Temperature range: −70 to +250 °C.
1
75%). νmax/cm−1 (ATR): 2966, 1739, 1596, 1484, 1450, 1365. H
NMR (CDCl3, 400 MHz): δ 8.21 (d, 1H, J = 8.3 Hz, ArH), 8.08 (d,
1H, J = 8.2 Hz, ArH), 7.63−7.55 (m, 1H, ArH), 7.51−7.41 (m, 3H,
ArH), 7.33−7.26 (m, 2H, ArH), 7.21−7.13 (m, 1H, ArH), 3.82 [s,
2H, C(2′)CH2], 1.60 [s, 6H, C(3′)(CH3)2]. 13C{1H} NMR (CDCl3,
100.6 MHz): δ 170.4 (C), 147.6 (C), 146.2 (C), 131.0 (C), 130.2
(CH), 128.3 (CH), 126.2 (CH), 126.1 (CH), 125.5 (CH), 120.1
(CH), 114.6 (CH), 47.7 (CH2), 38.0 (C), 29.2 (CH3). HRMS (ESI)
m/z: [M + H]+ Calcd for C17H18N3O, 280.1450; Found 280.1450.
1′-(1H-Benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-(3′′,4′′,5′′-trime-
thylphenyl)-butan-1′-one.
This compound was prepared according to the general procedure99
using thionyl chloride (2.30 mL, 30.0 mmol), 1(H)-benzotriazole
(14.30 g, 120.0 mmol), 3-methyl-3-(3′,4′,5′-trimethylphenyl)butanoic
acid (6.50 g, 30.0 mmol) and dichloromethane (100 mL). The crude
acyl benzotriazole was isolated as a brown oil [8.31 g, 86%due to the
high viscosity of the sample (and consequent difficulty with solvent
removal in vacuo), it contained residual dichloromethane (δH5.30
ppm)estimated corrected yield 64%] and carried forward without
1
chromatographic purification. H NMR (CDCl3, 400 MHz): δ 8.23
(d, 1H, J 8.3, ArH), 8.08 (d, 1H, J = 8.3 Hz, ArH), 7.63−7.54 (m, 2H,
ArH), 7.51−7.41 (m, 2H, ArH), 7.07 [s, 2H, C(2′′)H and C(6′′)H],
3.78 [s, 2H, C(2′)CH2], 2.23 [s, 6H, C(3′′)CH3 and C(5′′)CH3],
2.08 [s, 3H, C(4′′)CH3], 1.56 [s, 6H, C(3′)(CH3)2].
1′-(1H-Benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-(4′′-chloro-
phenyl)butan-1′-one.
This compound was prepared according to the general procedure99
using thionyl chloride (1.03 mL, 13.8 mmol), 1(H)-benzotriazole
(6.59 g, 55.36 mmol), 3-methyl-3-(4′-chlorophenyl)butanoic acid
(2.94 g, 13.84 mmol), and dichloromethane (75 mL). The crude acyl
benzotriazole was isolated as a colorless oil (3.09 g, 71%) and carried
forward without chromatographic purification. 1H NMR (CDCl3, 400
MHz): δ 8.20 (d, 1H, J = 8.3 Hz, ArH), 8.10 (d, 1H, J = 8.3 Hz,
ArH), 7.65−7.56 (m, 1H, ArH), 7.53−7.45 (m, 1H, ArH), 7.44−7.36
(m, 2H, ArH), 7.30−7.22 (m, 2H, ArH), 3.81 [s, 2H, C(2′)CH2],
1.58 [s, 6H, C(3′)(CH3)2]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ
170.1 (C), 146.2 (C), 146.1 (C), 132.0 (C), 131.0 (C), 130.4 (CH),
128.4 (CH), 127.0 (CH), 126.2 (CH), 120.1 (CH), 114.5 (CH),
47.6 (CH2), 37.6 (C), 29.3 (CH3).
Preparation of 1,3-Diketones. General Procedure for Prep-
aration of Acyl Benzotriazoles.99 Thionyl chloride (1.15 equiv) was
added in one portion to a stirring solution of 1(H)-benzotriazole
(4.25 equiv) in dichloromethane. The resulting yellow solution was
Q
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1′-(1H-Benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-(4′′-fluoro-
phenyl)butan-1′-one.
205.8 (C), 198.0 (C), 144.8 (C), 136.3 (C), 135.7 (C), 133.4 (CH),
132.7 (C), 128.6 (CH), 124.7 (CH), 56.3 (CH), 54.6 (CH2), 36.8
(C), 30.5 (CH3), 27.8 (CH3), 20.8 (CH3), 15.0 (CH3), 13.4 (CH3).
HRMS (ESI) m/z: [M + H]+ Calcd for C23H29O2 337.2162; Found
337.2160.
2,5-Dimethyl-1-phenyl-5-(4′-chlorophenyl)hexane-1,3-dione
This compound was prepared according to the general procedure99
using thionyl chloride (0.66 mL, 5.50 mmol), 1(H)-benzotriazole
(4.00 g, 34.0 mmol), 3-methyl-3-(4′-fluorophenyl)butanoic acid (1.66
g, 8.50 mmol), and dichloromethane (50 mL). The crude acyl
benzotriazole was isolated as a yellow oil [2.30 g, 91%due to the
high viscosity of the sample (and consequent difficulty with solvent
removal in vacuo), it contained residual dichloromethane (δH5.30
ppm)estimated corrected yield 72%] and carried forward without
(20).
This compound was prepared according to the procedure described
for 19 from lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in
THF, 25.0 mL, 25.0 mmol), propiophenone (3.05 mL, 23.0 mmol),
and 1′-(1H-benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-(4′′-chloro-
phenyl)butan-1′-one (7.22 g, 23.0 mmol) in THF (100 mL). The
crude product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (97:3) as eluent which afforded diketone 20 as a
1
chromatographic purification. H NMR (CDCl3, 400 MHz): δ 8.21
(d, 1H, J = 8.3 Hz, ArH), 8.09 (d, 1H, J = 8.2 Hz, ArH), 7.66−7.56
(m, 1H, ArH), 7.53−7.34 (m, 3H, ArH), 6.98 (t, 2H, J = 8.7 Hz,
ArH), 3.80 [s, 2H, C(2′)CH2], 1.59 [s, 6H, C(3′)(CH3)2].
2,5-Dimethyl-1,5-diphenylhexane-1,3-dione (19).67
1
colorless oil (6.43 g, 85%). νmax/cm−1 (ATR): 2966, 1715, 1674. H
NMR (CDCl3, 400 MHz): δ 7.82−7.73 [m, 2H, C(2′′)H and C(6′′)
H], 7.64−7.55 [m, 1H, C(4′′)H], 7.49−7.39 [m, 2H, C(3′′)H and
C(5′′)H], 7.21−7.09 [m, 4H, C(2′)H, C(3′)H, C(5′)H and C(6′)
H], 4.13 [q, 1H, J = 7.0 Hz, C(2)H], 2.79 [s, 2H, C(4)H2], 1.38, 1.33
[2 × s, 2 × 3H, C(5)(CH3)2], 1.30 [d, 3H, J = 7.0 Hz, C(2)HCH3].
13C{1H} NMR (CDCl3, 100.6 MHz): δ 205.0 (C) 197.5 (C), 146.6
(C), 135.8 (C), 133.7 (CH), 131.6 (C), 128.8 (CH), 128.6 (CH),
128.3 (CH), 126.9 (CH), 57.1 (CH), 53.4 (CH2), 36.8 (C), 29.8
(CH3), 28.4 (CH3), 13.4 (CH3). HRMS (ESI) m/z: [M + H]+ Calcd
for C20H22O235Cl 329.1303; Found 329.1294.
Lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 17.7
mL, 17.7 mmol) was diluted in freshly distilled tetrahydrofuran (60
mL) and cooled to −80 °C (Bath temp). A tetrahydrofuran solution
(10 mL) of propiophenone (2.2 mL, 16.8 mmol) was added slowly
over 15 min. The reaction mixture was stirred at −80 °C for 1 h after
which a tetrahydrofuran solution (15 mL) of 1′-(1H-benzo[d]-
[1,2,3]triazol-1-yl)-3′-methyl-3′-phenylbutan-1′-one (4.68 g, 16.8
mmol) was added in one portion. The reaction mixture was allowed
to warm slowly to room temperature overnight. The reaction mixture
was diluted with aqueous hydrochloric acid (3.2 M, 30 mL) and
stirred for 10 min. The layers were separated and the aqueous layer
was extracted with diethyl ether (2 × 25 mL). The organic layers were
combined, dried, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (95:5) as eluent which afforded diketone 19 as a
2,5-Dimethyl-1-phenyl-5-(4′-fluorophenyl)hexane-1,3-dione
(21).
This compound was prepared according to the procedure described
for 19 from lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in
THF, 8.2 mL, 8.2 mmol), propiophenone (1.02 mL, 7.70 mmol) and
1′-(1H-benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-(4′′-fluorophenyl)-
butan-1′-one (2.30 g, 7.70 mmol) in THF (75 mL). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (97:3) as eluent which afforded diketone 21 as a
colourless oil (1.47 g, 62%). νmax/cm−1 (ATR): 2967, 1715, 1676. 1H
NMR (CDCl3, 400 MHz): δ 7.80−7.74 [m, 2H, C(2′′)H and C(6′′)
H], 7.61−7.54 [m, 1H, C(4′′)H], 7.47−7.39 [m, 2H, C(3′′)H and
C(5′′)H], 7.24−7.16 [m, 2H, C(2′)H and C(6′)H], 6.93−6.85 [m,
2H, C(3′)H and C(5′)H], 4.11 [q, 1H, J = 7.0 Hz, C(2)H], 2.78 [s,
2H, C(4)H2], 1.39, 1.34 [2 × s, 2 × 3H, C(5)(CH3)2], 1.28 [d, 3H, J
= 7.0 Hz, C(2)HCH3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 205.1
(C), 197.6 (C), 161.0 (C, d, 1JCF = 244.4 Hz), 146.7 (C, d, 4JCF = 3.2
Hz), 135.8 (C), 133.6 (CH), 128.8 (CH), 128.6 (CH), 127.0 (CH, d,
1
colorless oil (2.75 g, 56%). νmax/cm−1 (ATR): 2929, 1709, 1677. H
NMR (CDCl3, 400 MHz): δ 7.77−7.70 (m, 2H, ArH), 7.60−7.52 (m,
1H, ArH), 7.46−7.37 (m, 2H, ArH), 7.32−7.22 (m, 4H, ArH), 7.20−
7.12 (m, 1H, ArH), 4.03 [q, 1H, J = 7.0 Hz, C(2)H], 2.79 [s, 2H,
C(4)H2], 1.41, 1.34 [2 × s, 2 × 3H, C(5)(CH3)2], 1.24 [d, 3H, J =
7.0 Hz, C(2)HCH3]. 13C{1H} NMR (100.6 MHz): δ 205.3 (C),
197.8 (C), 148.1 (C), 135.9 (C), 133.5 (CH), 128.7 (CH), 128.6
(CH), 128.3 (CH), 126.0 (CH), 125.4 (CH), 56.8 (CH), 54.2
(CH2), 37.3 (C), 29.8 (CH3), 28.1 (CH3), 13.4 (CH3). HRMS (ESI)
m/z: [M + H]+ Calcd for C20H23O2 295.1698; Found 295.1710.
2,5-Dimethyl-1-phenyl-5-(3′,4′,5′-trimethylphenyl)hexane-1,3-
dione (18).
2
3JCF = 7.7 Hz), 114.9 (CH, d, JCF = 20.9 Hz), 57.1 (CH), 53.7
(CH2), 36.8 (C), 30.0 (CH3), 28.5 (CH3), 13.4 (CH3). 19F{1H}
NMR (CDCl3, 376.5 MHz) δ −117.7; HRMS (ESI) m/z: [M + H]+
Calcd for C20H22O2F 313.1598; Found 313.1592.
This compound was prepared according to the procedure described
for 19 from lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in
THF, 25.0 mL, 25.0 mmol), propiophenone (3.10 mL, 22.8 mmol)
and 1′-(1H-benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-(3′′,4′′,5′′-
trimethylphenyl)butan-1′-one (7.33 g, 22.8 mmol) in THF (100
mL). The crude product was purified by flash chromatography on
silica gel with hexane/ethyl acetate (97:3) as eluent which afforded
diketone 18 as a colorless oil (4.91 g, 64%); νmax/cm−1 (ATR): 2965,
1715, 1675. 1H NMR (CDCl3, 400 MHz): δ 7.70−7.65 [m, 2H,
C(2′′)H and C(6′′)H], 7.58−7.53 [m, 1H, C(4′′)H], 7.42−7.37 [m,
2H, C(3′′)H and C(5′′)H], 6.90 [s, 2H, C(2′)H and C(6′)H], 3.98
[q, 1H, J = 7.1 Hz, C(2)H], 2.77 [AB, 2H, JAB = 22.5 Hz, HA δ = 2.84,
HB δ = 2.71, C(4)H2], 2.18 [s, 6H, C(3′)CH3 and C(5′)CH3], 2.08
[s, 3H, C(4′)CH3], 1.37, 1.33 [2 × s, 2 × 3H, C(5)(CH3)2], 1.23 [d,
3H, J = 7.0 Hz, C(2)HCH3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ
2-Ethyl-5-methyl-1,5-diphenylhexane-1,3-dione (24).
This compound was prepared according to the procedure described
for 19 from lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in
THF, 15.0 mL, 15.0 mmol), butyrophenone (1.93 g, 13.0 mmol), and
1′-(1H-benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-phenylbutan-1′-one
(3.63 g, 13.0 mmol) in THF (100 mL). The crude product was
purified by flash chromatography on silica gel with hexane/ethyl
acetate (97:3) as eluent which afforded diketone 24 as a colorless oil
(3.41 g, 85%). νmax/cm−1 (ATR): 2965, 1716, 1673. 1H NMR
(CDCl3, 400 MHz): δ 7.81−7.74 (m, 2H, ArH), 7.60−7.53 (m, 1H,
R
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ArH), 7.48−7.39 (m, 2H, ArH), 7.30−7.20 (m, 4H, ArH), 7.19−7.11
and the aqueous layer was extracted with diethyl ether. The combined
organic layers were dried and concentrated under reduced pressure.
The crude product was purified by flash chromatography on silica gel
with hexane/ethyl acetate (90:10) as eluent which afforded ketonitrile
37 as a colorless oil (1.86 g, 38%). νmax/cm−1 (ATR): 2967, 2259,
1731. 1H NMR (CDCl3, 400 MHz): δ 7.33−7.24 (m, 4H, ArH), 3.06
[s, 2H, C(2)H2CN], 2.88 [s, 2H, C(4)H2], 1.43 [s, 6H, C(5)-
(CH3)2]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 195.9 (C), 145.5
(C), 132.3 (C), 128.7 (CH), 126.9 (CH), 113.6 (C), 55.0 (CH2),
37.3 (C), 33.4 (CH2), 28.8 (CH3). HRMS (ESI) m/z: [M + H]+
Calcd for C13H15NO35Cl 236.0931; Found 236.0948.
(m, 1H, ArH), 3.94 [t, 1H, J = 6.8 Hz, C(2)H], 2.76 [AB, 2H, JAB
=
14.0 Hz, HA δ = 2.79, HB δ = 2.74, C(4)H2], 1.83 (qd, 2H, J = 7.3, 7.2
Hz, CH2CH3) 1.40, 1.35 [2 × s, 2 × 3H, C(5)(CH3)2], 0.77 (t, 3H, J
= 7.4 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 204.5
(C), 197.0 (C), 148.0 (C), 136.5 (C), 133.5 (CH), 128.74 (CH),
128.67 (CH), 128.3 (CH), 125.9 (CH), 125.5 (CH), 65.0 (CH),
54.0 (CH2), 37.2 (C), 29.9 (CH3), 28.2 (CH3), 22.1 (CH2), 12.3
(CH3). HRMS (ESI) m/z: [M + H]+ Calcd for C21H25O2 309.1849;
Found 309.1850.
2-(Cyclohexylmethyl)-5-methyl-1,5-diphenylhexane-1,3-dione
(25).
Preparation of α-Cyanoacetamides. General Procedure for
Preparation of α-Cyanoacetamides.71 A round-bottom flask was
charged with amine (39−46) (1.0 equiv), 2-cyanoacetic acid (1.02
equiv), and dichloromethane (60 mL) at 0 °C. The flask was then
charged with a solution of N,N′-dicyclohexylcarbodiimide (1.02
equiv) and 4-dimethylaminopyridine (0.01 equiv). The reaction
mixture was stirred for 1 h at room temperature. During this period, a
white precipitate formed which was subsequently removed by suction
filtration. The solvent was removed from the filtrate under reduced
pressure. The product was recrystallized from ethanol.
This compound was prepared according to the procedure described
for 19 from lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in
THF, 10.0 mL, 10.0 mmol), 3-cyclohexyl-1-phenylpropan-1-one (1.73
g, 8.0 mmol), and 1′-(1H-benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-
phenylbutan-1′-one (2.23 g, 8.0 mmol) in THF (75 mL). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (95:5) as eluent which afforded diketone 25 as a
colorless oil (1.77 g, 59%). νmax/cm−1 (ATR): 2921, 2850, 1716,
N,N-Dibenzyl-2-cyanoacetamide (47).71
1
1673. H NMR (CDCl3, 400 MHz): δ 7.82−7.74 [m, 2H, ArH],
This compound was prepared according to the general procedure71
from N,N-dibenzylamine (39) (9.47 g, 48.0 mmol), 2-cyanoacetic
acid (4.09 g, 50.0 mmol), N,N′-dicyclohexylcarbodiimide (9.90 g,
50.0 mmol), and 4-dimethylaminopyridine (0.31 g, 2.80 mmol) in
dichloromethane (60 mL). Colorless crystals (4.43 g, 75%). Mp:
112−115 °C (lit.71 mp 117−119 °C). νmax/cm−1 (ATR): 2260 (CN),
1657 (CO). 1H NMR (CDCl3, 400 MHz): δ 7.45−7.10 (m, 10H, 10
× ArH), 4.66 (s, 2H, NCH2), 4.44 (s, 2H, NCH2), 3.53 (s, 2H,
CH2CN). 13C{1H} NMR (CDCl3, 100.6 MHz): 162.5 (C), 136.0
(C), 134.9 (C), 129.4 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH),
128.0 (CH), 126.2 (CH), 113.9 (C), 50.7 (CH2), 49.6 (CH2), 25.3
(CH2).
7.61−7.54 [m, 1H, ArH], 7.48−7.39 (m, 2H, ArH), 7.30−7.21 (m,
4H, ArH), 7.19−7.12 (m, 1H, ArH), 4.18 [t, 1H, J = 6.8 Hz, C(2)H],
2.77 [AB, 2H, JAB = 14.2 Hz, HA δ = 2.80, HB δ = 2.75, C(4)H2],
1.76−1.44 (m, 7H), 1.40, 1.34 [2 × s, 2 × 3H, C(5)(CH3)2], 1.20−
0.93 [m, 4H], 0.86−0.67 [m, 2H]. 13C{1H} NMR (CDCl3, 100.6
MHz): δ 204.5 (C), 197.0 (C), 148.0 (C), 136.3 (C), 133.5 (CH),
128.8 (CH), 128.7 (CH), 128.3 (CH), 125.9 (CH), 125.5 (CH),
61.1 (CH), 53.9 (CH2), 37.2 (C), 35.92 (CH2), 35.89 (CH), 33.4
(CH2), 33.0 (CH2), 30.0 (CH3), 28.3 (CH3), 26.3 (CH2), 26.09
(CH2), 26.07 (CH2). HRMS (ESI) m/z: [M + H]+ Calcd for
C26H33O2 377.2475; Found 377.2468.
3-Hydroxy-5-methyl-1,5-diphenylhex-2-en-1-one (35).
N-tert-Butyl-2-cyano-N-(4′-chlorobenzyl)acetamide (48).71
This compound was prepared according to the procedure described
for 19 from lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in
THF, 10.0 mL, 10.0 mmol), acetophenone (1.08 g, 9.0 mmol), and
1′-(1H-benzo[d][1,2,3]triazol-1-yl)-3′-methyl-3′-phenylbutan-1′-one
(2.51 g, 9.0 mmol) in THF (75 mL). The crude product was purified
by flash chromatography on silica gel with hexane/ethyl acetate
(99:1) as eluent which afforded hydroxyenone 35 as a colorless oil
(1.08 g, 43%). νmax/cm−1 (ATR): 2967, 1601. 1H NMR (CDCl3, 400
MHz): 16.12 (br s, 1H, OH), 7.72−7.60 (m, 2H, ArH), 7.57−7.17
(m, 8H, ArH), 5.66 [s, 1H, C(2)H], 2.69 [s, 2H, C(4)H2], 1.49 [s,
6H, C(5)(CH3)2]. HRMS (ESI) m/z: [M + H]+ Calcd for C19H21O2
281.1536; Found 281.1530.
This compound was prepared according to the general procedure71
from N-(4′-chlorobenzyl)-2-methylpropan-2-amine (40) (3.44 g, 17.4
mmol), 2-cyanoacetic acid (1.61 g, 19.3 mmol), N,N′-dicyclohex-
ylcarbodiimide (3.90 g, 19.3 mmol), and 4-dimethylaminopyridine
(0.11 g, 0.90 mmol) in dichloromethane (40 mL). Colorless crystals
(2.62 g, 57%). Mp: 127−130 °C (lit.71 mp 125−127 °C). νmax/cm−1
(ATR): 2259 (CN), 1658 (CO). 1H NMR (CDCl3, 400 MHz) 7.41−
7.36 [m, 2H, C(3′)H and C(5′)H], 7.14 [d, 2H, J = 8.5 Hz, C(2′)H
and C(6′)H], 4.54 (s, 2H, CH2N), 3.41 (s, 2H, CH2CN), 1.46 [s, 9H,
C(CH3)3]. 13C{1H} NMR (CDCl3, 100.6 MHz) 162.8 (C), 136.0
(C), 133.7 (C), 129.5 (CH), 126.6 (CH), 114.3 (C), 59.4 (C), 48.6
(CH2), 28.4 (CH3), 27.8 (CH2).
5-Methyl-5-(4′-chlorophenyl)-3-oxohexanenitrile (37).
N-Benzyl-N-tert-butyl-2-cyanoacetamide (49).71
This compound was prepared according to a procedure for synthesis
of β-ketonitriles.100 A 250 mL round-bottom flask was charged with
acetonitrile (1.2 mL, 22.0 mmol) and freshly distilled THF (30 mL).
The flask was cooled to 0 °C and potassium tert-pentoxide (25% w/v
in toluene, 1.7 M, 13.0 mL, 22.0 mmol) was added slowly to the
solution. While still at 0 °C, the flask was then charged with methyl 3-
methyl-3-(4′-chlorophenyl)butanoate (4.73 g, 20.8 mmol) in THF
(30 mL). The cooling bath was removed, and the flask was warmed to
room temperature and after 2 h the solution was diluted with aqueous
sat. ammonium chloride (40 mL). The organic layer was separated
This compound was prepared according to the general procedure71
from N-(benzyl)-2-methylpropan-2-amine (41) (6.81 g, 42.0 mmol),
2-cyanoacetic acid (3.66 g, 43.0 mmol), N,N′-dicyclohexylcarbodii-
mide (8.87 g, 43.0 mmol) and 4-dimethylaminopyridine (0.25 g, 2.10
mmol) in dichloromethane (60 mL). Colorless crystals (8.50 g, 88%).
Mp: 97−100 °C (lit.71 mp 97−99 °C). νmax/cm−1 (ATR): 2260
1
(CN), 1657 (CO). H NMR (CDCl3, 400 MHz): δ 7.44−7.16 (m,
5H, 5 × ArH), 4.57 (s, 2H, CH2N), 3.43 (s, 2H, CH2CN), 1.48 [s,
S
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9H, C(CH3)3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 162.9 (C),
137.4 (C), 129.3 (CH), 127.8 (CH), 125.2 (CH), 114.5 (C), 59.3
(C), 49.2 (CH2), 28.4 (CH3), 27.9 (CH2).
2260 (CN), 1659 (CO). 1H NMR (CDCl3, 400 MHz): δ 6.93 [s, 1H,
C(4′)H], 6.77 [s, 2H, C(2′)H and C(6′)H], 4.49 (s, 2H, NCH2),
3.43 (s, 2H, CH2CN), 2.32 [s, 6H, C(3′)CH3 and C(5′)CH3], 1.48
[s, 9H, C(CH3)3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 163.0 (C),
139.0 (C), 137.3 (C), 129.4 (CH), 122.9 (CH), 114.6 (C), 59.3 (C),
49.1 (CH2), 28.4 (CH3), 27.9 (CH2), 21.4 (CH3). HRMS (ESI) m/z:
[M + H]+ Calcd for C16H23N2O 259.1805; Found 259.1802.
N-tert-Butyl-2-cyano-N-(pyridin-4′-ylmethyl)acetamide (54).
N-tert-Butyl-2-cyano-N-(4′-fluorobenzyl)acetamide (50).71
This compound was prepared according to the general procedure71
from N-(4′-fluorobenzyl)-2-methylpropan-2-amine (42) (6.24 g, 34.0
mmol), 2-cyanoacetic acid (3.03 g, 36.0 mmol), N,N′-dicyclohex-
ylcarbodiimide (7.35 g, 36.0 mmol), and 4-dimethylaminopyridine
(0.210 g, 1.73 mmol) in dichloromethane (60 mL). Colorless crystals
(4.44 g, 52%). Mp: 101−105 °C (lit.71 mp 98−101 °C). νmax/cm−1
This compound was prepared according to the general procedure71
from N-(pyridin-4′-ylmethyl)-2-methylpropan-2-amine (46) (6.99 g,
42.6 mmol), N′,N′-dicyclohexylcarbodiimide (8.87 g, 43.0 mmol),
cyanoacetic acid (3.66, 43.0 mmol), and 4-dimethylaminopyridine
(0.24 g, 1.9 mmol) in dichloromethane (60 mL). The crude residue
was not recrystallized but was washed with warm diethyl ether to
afford pure acetamide 54 as a pale brown solid (8.09 g, 82%). Mp:
108−111 °C. νmax/cm−1 (ATR): 2977, 2256, 1660, 1602, 1412, 1362,
1191. HRMS (ESI) m/z: [M + H]+ Calcd for C13H18N3O 232.1444;
Found 232.1440. Two sets of signals exist due to the presence of rotamers.
1
(ATR): 2260 (CN), 1651 (CO). H NMR (CDCl3, 400 MHz): δ
7.21−7.06 (m, 4H, 4 × ArH), 4.55 (s, 2H, NCH2), 3.44 (s, 2H,
CH2CN), 1.46 [s, 9H, C(CH3)3]. 13C{1H} NMR (CDCl3, 75.5
MHz): δ 162.9 (C), 162.2 (C, d, 1JCF = 247.0 Hz), 133.1 (C, d, 4JCF
=
3.2 Hz), 126.9 (CH, d, 3JCF = 8.2 Hz), 116.3 (CH, d, 2JCF = 21.7 Hz),
114.4 (C), 59.4 (C), 48.6 (CH2), 28.4 (CH3), 27.8 (CH2). 19F{1H}
NMR (CDCl3, 376.5 MHz): δ −114.4.
N-tert-Butyl-2-cyano-N-(4′-methylbenzyl)acetamide (51).71
1
Major rotamer (83%): H NMR (CDCl3, 400 MHz): δ 8.65 [d,
2H, J = 3.0 Hz, C(2)H and C(6)H], 7.17 [d, 2H, J = 5.7 Hz, C(3)H
and C(5)H], 4.58 (s, 2H, CH2N), 3.40 (s, 2H, CH2CN), 1.47 [s, 9H,
C(CH3)3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 162.8 (C), 150.7
(CH), 147.0 (C), 120.5 (CH), 114.1 (C), 59.6 (C), 48.4 (CH2), 28.5
(CH3), 27.9 (CH2).
This compound was prepared according to the general procedure71
from N-(4′-methylbenzyl)-2-methylpropan-2-amine (43) (3.00 g,
17.0 mmol), 2-cyanoacetic acid (1.53 g, 18.0 mmol), N,N′-
dicyclohexylcarbodiimide (3.71 g, 18.0 mmol), and 4-dimethylami-
nopyridine (0.10 g, 0.81 mmol) in dichloromethane (45 mL).
Colorless crystals (1.57 g, 57%). Mp: 162−165 °C (lit.71 mp 159−
161 °C). νmax/cm−1 (ATR): 2259 (CN), 1661 (CO). 1H NMR
(CDCl3, 400 MHz): δ 7.20 [d, 2H, J = 8.0 Hz, 2 × ArH], 7.07 [d, 2H,
J = 8.0 Hz, 2 × ArH], 4.53 (s, 2H, CH2N), 3.44 (s, 2H, CH2CN),
2.36 [s, 3H, C(4′)(CH3)], 1.47 [s, 9H, C(CH3)3]. 13C{1H} NMR
(CDCl3, 100.6 MHz): δ 163.0 (C), 137.5 (C), 134.3 (C), 129.9
(CH), 125.2 (CH), 114.6 (C), 59.3 (C), 48.9 (CH2), 28.4 (CH3),
27.9 (CH2), 21.0 (CH3).
1
Minor rotamer (17%): H NMR (CDCl3, 400 MHz): δ 8.55 [d,
2H, J = 5.9 Hz, C(2)H and C(6)H], 7.47 [d, 2H, J = 5.8 Hz, C(3)H
and C(5)H], 3.94 (s, 2H, CH2N), 3.23 (s, 2H, CH2CN),1.23 [s, 9H,
C(CH3)3]. 13C{1H} NMR (CDCl3, 75.5 MHz) 166.7 (C), 150.0
(CH), 124.9 (CH), 117.4 (C), 56.5 (C), 44.4 (CH2), 27.3 (CH2),
26.0 (CH3); signal for C(1) not observed.
Synthesis of α-Diazoketones via Debenzoylative Diazo
Transfer. 3-Diazopentan-2,4-dione (23).101
N-tert-Butyl-2-cyano-N-(4′-bromobenzyl)acetamide (52).71
An aqueous solution of sodium azide (10 mL, 1.95 g, 30.0 mmol, 3.0
mL min−1) was pumped through a micromixer T-piece where it met a
dichloromethane solution of trifluoromethanesulfonic anhydride (10
mL, 0.85 mL, 5.0 mmol, 3.0 mL min−1); the combined stream passed
through a reactor coil (4 × 10 mL, rt). After all reagent solutions had
been charged, the combined flow rate was changed to 0.2 mL min−1
to give a residence time of 1 h. The reactor effluent passed through a
T-piece where it met a stream of saturated aqueous sodium
bicarbonate (0.1 mL min−1). The reaction stream was passed through
a back-pressure regulator (8 bar). The biphasic effluent was then
separated by an in-line liquid−liquid separator. The organic effluent
(25 mL) was added to flask containing a suspension of sodium 2,4-
pentanedionate (0.631 g, 5.0 mmol) 6 in dichloromethane (10 mL).
The resulting suspension was stirred at room temperature for 24 h.
The suspension was then washed with water (20 mL), dried and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography on silica gel with hexane/ethyl acetate
This compound was prepared according to the general procedure71
from N-(4′-bromobenzyl)-2-methylpropan-2-amine (44) (5.78 g,
23.8 mmol), 2-cyanoacetic acid (2.04 g, 25.0 mmol), N,N′-
dicyclohexylcarbodiimide (4.95 g, 25.0 mmol), and 4-dimethylami-
nopyridine (0.12 g, 1.20 mmol) in dichloromethane (60 mL).
Colorless crystals (5.10 g, 69%). Mp: 112−115 °C (lit.71 mp 115−
117 °C). νmax/cm−1 (ATR): 2260 (CN), 1661 (CO). 1H NMR
(CDCl3, 400 MHz): δ 7.54 (d, 2H, J = 8.4 Hz, 2 × ArH), 7.08 (d, 2H,
J = 8.3 Hz, 2 × ArH), 4.52 (s, 2H, CH2N), 3.40 (s, 2H, CH2CN),
1.46 [s, 9H, C(CH3)3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 162.8
(C), 136.5 (C), 132.5 (CH), 127.0 (CH), 121.7 (C), 114.2 (C), 59.5
(C), 48.7 (CH2), 28.4 (CH3), 27.8 (CH2).
(90:10) as eluent and isolated as a yellow oil (0.400 g, 65%). νmax
/
1
cm−1 (ATR): 2127, 1663. H NMR (CDCl3, 300 MHz): δ 2.44 (s,
N-tert-Butyl-2-cyano-N-(3′,5′-dimethylbenzyl)acetamide (53).
6H, C(O)CH3).
General Flow Procedure for Telescoped Generation of TfN3 22
and Direct Use for Diazo Transfer. An aqueous solution of sodium
azide (10 mL, 3.0 M, 10 equiv, 3.0 mL min−1) was pumped through a
micromixer T-piece where it met a dichloromethane solution of
trifluoromethanesulfonic anhydride (10 mL, 0.5 M, 1.67 equiv, 3.0
mL min−1); the combined stream passed through a reactor coil (4 ×
10 mL, rt). After all reagent solutions had been charged, the
combined flow rate was changed to 0.2 mL min−1 to give a residence
time of 1 h. The reactor effluent passed through a T-piece where it
met a stream of saturated aqueous sodium bicarbonate (0.1 mL
This compound was prepared according to the general procedure71
from N-(3′,5′-dimethylbenzyl)-2-methylpropan-2-amine (45) (3.18 g,
16.6 mmol), 2-cyanoacetic acid (1.55 g, 17.7 mmol), N,N′-
dicyclohexylcarbodiimide (3.97 g, 17.7 mmol), and 4-dimethylami-
nopyridine (0.11 g, 0.90 mmol) in dichloromethane (60 mL).
Colorless crystals (2.95 g, 69%). Mp: 160−164 °C. νmax/cm−1 (ATR):
T
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min−1). The reaction stream was passed through a back-pressure
regulator (8 bar). The biphasic effluent was then separated by an in-
line liquid−liquid separator. The organic effluent (25 mL) was
directly fed to another pump. The pump delivered the separated triflyl
azide solution (25 mL, 0.17 mL min−1) to a T-piece where it met a
solution of the relevant acceptor substrate (25 mL, 0.12 M, 1 equiv,
[base] 0.128 M, 1.1 equiv, 0.17 mL min−1) which was then passed
through a reactor coil (4 × 10 mL, rt, τ = 2 h) and subsequently
through a glass column packed with silica gel (100 mm × 10 mm
internal diameter) and then finally passed through a back pressure
regulator (8 bar). The reactor effluent was analyzed by IR
spectroscopy and concentrated under reduced pressure affording
the crude α-diazoketone which was subsequently purified by flash
chromatography on silica gel with hexane/ethyl acetate as eluent.
For the synthesis of compounds 55−62, the triflyl azide solution
was collected over KOH prior to use in diazo transfer.
MHz): δ 192.5 (C), 147.6 (C), 131.8 (C), 128.2 (CH), 127.0 (CH),
63.6 (C), 50.3 (CH2), 38.0 (C), 29.1 (CH3), 8.1 (CH3).
2-Diazo-5-methyl-5-(4′-fluorophenyl)hexan-3-one (13).14
This compound was prepared according to the general flow procedure
from a dichloromethane solution of 2,5-dimethyl-1-phenyl-5-(4′-
fluorophenyl)hexane-1,3-dione (21) and DBU (25 mL, 0.12 M,
[DBU] 0.128 M), aqueous sodium azide (10 mL, 3.0 M), and a
dichloromethane solution of trifluoromethanesulfonic anhydride (10
mL, 0.5 M). The crude product was purified by flash chromatography
on silica gel with hexane/ethyl acetate (95:5) as eluent affording α-
diazoketone 13 as a yellow oil (0.491 g, 70%). νmax/cm−1 (ATR):
1
2967, 2066, 1625. H NMR (CDCl3, 300 MHz): δ 7.33−7.28 [m,
2-Diazo-5-methyl-5-(3′,4′,5′-trimethylphenyl)hexan-3-one (8).14
2H, 2 × ArH], 7.02−6.96 [m, 2H, 2 × ArH], 2.68 [s, 2H, C(4)H2],
1.81 [s, 3H, C(1)H3], 1.46 [s, 6H, C(5)(CH3)2]. 13C{1H} NMR
(CDCl3, 75.5 MHz): δ 192.8 (C), 161.2 (C, d, 1JCF 244.2), 143.6 (C),
3
2
127.1 (CH, d, JCF 7.8), 114.8 (CH, d, JCF 20.9), 63.7 (C), 50.7
(CH2), 38.0 (C), 28.8 (CH3), 8.1 (CH3).
5-Diazo-2-methyl-2-phenylheptan-4-one (26).
This compound was prepared according to the general flow procedure
from 2,5-dimethyl-1-phenyl-5-(3′,4′,5′-trimethylphenyl)hexane-1,3-
dione (18) and DBU (25 mL, 0.12 M, [DBU] 0.128 M), aqueous
sodium azide (10 mL, 3.0 M), and a dichloromethane solution of
trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (95:5) as eluent affording α-diazoketone 8 as a
yellow oil (0.558 g, 72%). νmax/cm−1 (ATR): 2963, 2061, 1712, 1624,
1445, 1346. 1H NMR (CDCl3, 300 MHz): δ 6.98 [s, 2H, C(2′)H and
C(6′)H], 2.68 [s, 2H, C(4)CH2], 2.28 [s, 6H, C(3′)CH3 and
C(5′)CH3], 2.14 [s, 3H, C(4′)CH3], 1.83 [s, 3H, C(1)H3], 1.43 [s,
6H, C(5)(CH3)2]. 13C{1H} NMR (CDCl3, 75.5 MHz): δ 193.4 (C),
145.0 (C), 136.1 (C), 132.7 (C), 124.7 (CH), 63.8 (C), 50.7 (CH2),
37.9 (C), 28.5 (CH3), 20.9 (CH3), 15.1 (CH3), 8.3 (CH3).
This compound was prepared according to the general flow procedure
from a dichloromethane solution of 2-ethyl-5-methyl-1,5-diphenyl-
hexan-1,3-dione (24) and DBU (25 mL, 0.12 M, [DBU] 0.128 M),
aqueous sodium azide (10 mL, 3.0 M), and a dichloromethane
solution of trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The
crude product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (90:10) as eluent affording α-diazoketone 26 as a
yellow oil (0.552 g, 80%). νmax/cm−1 (ATR): 2928, 2067, 1609. H
1
NMR (CDCl3, 300 MHz): δ 7.39−7.27 [m, 4H, ArH], 7.24−7.15 [m,
1H, ArH], 2.67 [s, 2H, C(3)H2], 2.22 [q, 2H, J = 7.3 Hz, C(6)H2],
1.48 [s, 6H, C(2)(CH3)2], 0.94 [t, 3H, J = 7.4 Hz, C(7)H3]. 13C{1H}
NMR (CDCl3, 100.6 MHz): δ 192.4 (C), 147.9 (C), 128.2 (CH),
126.1 (CH), 125.6 (CH), 69.5 (C), 51.0 (CH2), 38.5 (C), 28.6
(CH3), 16.0 (CH3), 11.2 (CH2). HRMS (ESI) m/z: [M + Na]+
Calcd for C14H18N2ONa 253.1311; Found 253.1312.
2-Diazo-5-methyl-5-phenylhexan-3-one (11).14
This compound was prepared according to the general flow procedure
from 2,5-dimethyl-1,5-diphenylhexane-1,3-dione (19) and DBU (25
mL, 0.12 M, [DBU] 0.128 M), aqueous sodium azide (10 mL, 3.0 M)
and a dichloromethane solution of trifluoromethanesulfonic anhy-
dride (10 mL, 0.5 M). The crude product which was purified by flash
chromatography on silica gel with hexane/ethyl acetate (85:15) as
1-Cyclohexyl-2-diazo-5-methyl-5-phenylhexan-3-one (27).
This compound was prepared according to the general flow procedure
from 2-(cyclohexylmethyl)-5-methyl-1,5-diphenylhexane-1,3-dione
(25) and DBU (25 mL, 0.12 M, [DBU] 0.128 M), aqueous sodium
azide (10 mL, 3.0 M) and a dichloromethane solution of
trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (95:5) as eluent affording α-diazoketone 27 as a
eluent affording α-diazoketone 11 as a yellow oil (0.519 g, 80%). νmax
/
cm−1 (ATR): 2964, 2061, 1621, 1348, 1266, 1054. 1H NMR (CDCl3,
300 MHz): δ 7.37−7.18 [m, 5H, ArH], 2.69 [s, 2H, C(4)H2], 1.80 [s,
3H, C(1)H3], 1.47 [s, 6H, C(5)(CH3)2]. 13C{1H} NMR (CDCl3,
75.5 MHz): δ 193.0 (C), 148.0 (C), 128.2 (CH), 126.1 (CH), 125.5
(CH), 63.8 (C), 50.7 (CH2), 38.4 (C), 28.5 (CH3), 8.2 (CH3).
2-Diazo-5-methyl-5-(4′-chlorophenyl)hexan-3-one (12).14
yellow oil (0.812 g, 91%). νmax/cm−1 (ATR): 2922, 2060, 1627. H
1
NMR (CDCl3, 400 MHz): 7.39−7.27 [m, 4H, ArH], 7.23−7.16 [m,
1H, C(4′)H], 2.69 [s, 2H, C(4)H2], 2.03 [2H, d, J = 7.1 Hz, C(2)
H2], 1.78−1.38 [m, 11H, contains singlet at 1.48 ppm for
C(5)(CH3)2], [C(5)(CH3)2], 1.32−0.99 [m, 4H], 0.90−0.69 [2H,
m]. 13C{1H} NMR (CDCl3, 100.6 MHz) 192.6 (C), 147.8 (C), 128.2
(CH), 126.1 (CH), 125.6 (CH), 67.0 (C), 50.8 (CH2), 38.5 (C),
36.7 (CH), 32.6 (CH2), 30.4 (CH2), 28.8 (CH3), 26.2 (CH2), 26.0
(CH2). HRMS (ESI) m/z: [M + Na]+ Calcd for C19H26N2ONa
321.1937; Found 321.1940.
This compound was prepared according to the general flow procedure
from a dichloromethane solution of 2,5-dimethyl-1-phenyl-5-(4′-
chlorophenyl)hexane-1,3-dione(20) and DBU (25 mL, 0.12 M,
[DBU] 0.128 M), aqueous sodium azide (10 mL, 3.0 M), and a
dichloromethane solution of trifluoromethanesulfonic anhydride (10
mL, 0.5 M). The crude product was purified by flash chromatography
on silica gel with hexane/ethyl acetate (95:5) as eluent affording
affording α-diazoketone 12 as a yellow oil (0.564 g, 75%). νmax/cm−1
1-(4-Chlorophenyl)-3-diazopyrrolidin-2-one (29).83
1
(ATR): 2965, 2061, 1621, 1353, 1279, 1011. H NMR (CDCl3, 300
MHz): δ 7.30−7.26 [m, 4H, ArH], 2.68 [s, 2H, C(4)H2], 1.82 [s, 3H,
An aqueous solution of sodium azide (10 mL, 3.0 M, 10 equiv, 3.0 mL
min−1) was pumped through a micromixer T-piece where it met a
C(1)H3], 1.45 [s, 6H, C(5)(CH3)2]. 13C{1H} NMR (CDCl3, 75.5
U
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toluene solution of trifluoromethanesulfonic anhydride (10 mL, 0.5
M, 1.67 equiv, 3.0 mL min−1); the combined stream passed through a
reactor coil (4 × 10 mL, rt). After all reagent solutions had been
charged, the combined flow rate was changed to 0.2 mL min−1 to give
a residence time of 1 h. The reactor effluent passed through a T-piece
where it met a stream of aqueous sodium bicarbonate (5% w/v, 0.9
mL min−1). The reaction stream was passed through a back-pressure
regulator (8 bar). The biphasic effluent was then separated by an in-
line liquid−liquid separator. The organic effluent (25 mL) was
directly fed to another pump. The pump delivered the separated triflyl
azide solution (25 mL, 2.0 mL min−1) to a T-piece where it met a
solution of ethyl-2-hydroxy-2-(2-oxo-1-(4-chlorophenyl)pyrrolidin-3-
ylidene)acetate (28)83 and DBU in dichloromethane (25 mL, 0.12 M,
[DBU] 0.128 M, 1.1 equiv relative to 28, 2.0 mL min−1) and was then
passed through a reactor coil (4 × 10 mL, rt). When both reagent
solutions had been charged, the combined flow rate was reduced to
0.5 mL min−1 to give a residence time of 1 h, after which the reactor
effluent subsequently passed through a back pressure regulator (8
bar). The reactor effluent was analyzed by IR spectroscopy and
concentrated under reduced pressure to give the crude product which
was subsequently purified by chromatography on silica gel (treated by
adding 1% weight of triethylamine to the dry silica prior to packing)
using hexane:chloroform:ethanol (50:49:1) as eluent affording α-
diazoamide 29 as a bright orange crystalline solid (0.48 g, 73%). Mp:
(95:5) as eluent, affording azulenone 31 as a pale yellow oil (0.095 g,
50%, 60% ee).86 [α]D20 +13.86 (c 1.05, CHCl3). νmax/cm−1 (ATR):
3042, 2926, 1747 (CO), 1715 (CO). 1H NMR (CDCl3, 300 MHz): δ
6.43−6.23 [m, 3H, C(4)H, C(5)H and C(6)H], 6.14−6.07 [m, 1H,
C(7)H], 4.18 [d, 1H, J = 8.0 Hz, C(8)H], 2.28 [B of AB, 1H, JAB
=
17.3 Hz, one of C(2)H2], 2.20 [A of AB, 1H, JAB = 17.3 Hz, one of
C(2)H2], 1.31, 1.14 [2 × s, 2 × 3H, C(3)(CH3)2], 0.76 [s, 3H,
C(8a)CH3]. 13C{1H} NMR (CDCl3, 75.5 MHz): δ 218.5 (C), 127.1
(CH), 126.8 (CH), 125.3 (CH), 119.7 (CH), 109.6 (C), 84.9 (CH),
50.1 (CH2), 40.7 (C), 38.6 (C), 28.8 (CH3), 28.6 (CH3), 11.4
(CH3). Also isolated as a side product during the aromatic addition
reaction of α-diazoketone 11 was the side product:
5-Methyl-5-phenylhexane-2,3-dione (34).88
1
The compound was observed in the H NMR spectrum of the crude
product mixture in a ratio of 1:0.3 (30:34). The 2,3-diketone 34 was
isolated after chromatography on silica gel with hexane/ethyl acetate
as a yellow oil (0.039 g, 19%). νmax/cm−1 (film) 2967, 1713. 1H NMR
(CDCl3, 300 MHz): δ 7.37−7.25 (m, 4H, ArH), 7.22−7.15 (m, 1H,
ArH), 3.09 [s, 2H, C(4)H2], 1.98 [s, 3H, C(1)H3], 1.45 [s, 6H,
C(5)(CH3)2]. 13C{1H} (CDCl3, 100.6 MHz): δ 199.1 (C), 198.1
(C), 147.2 (C), 128.3 (CH), 126.3 (CH), 125.7 (CH), 47.9 (CH2),
37.5 (C), 29.0 (CH3), 23.0 (CH3). HRMS (ESI) m/z: [M + H]+
Calcd for C13H17O2 205.1223; Found 205.1223.
1
131−135 °C. νmax/cm−1 (ATR): 2089 (N2), 1664 (CO). H NMR
(CDCl3, 400 MHz): δ 7.53 (d, 2H, J = 9.0 Hz, ArH), 7.29 (d, 2H, J =
9.0 Hz, ArH), 3.80 [dd, 2H, J = 7.6 Hz, 7.0 Hz, C(4)H2 or C(5)H2],
3.22 [dd, 2H, J = 8.2 Hz, 7.2 Hz, C(4)H2 or C(5)H2]. 13C {1H} NMR
(CDCl3, 100.6 MHz,): δ 166.9 (C), 138.6 (C), 128.8 (CH), 128.7
(C), 119.9 (CH), 54.0 (C), 44.8 (CH2), 17.9 (CH2). HRMS (ESI)
m/z: [M + Na+] Calcd for C10H8N3O35ClNa 244.0248; Found
244.0218.
1,2,3b,4-Tetrahydro-1,1,3a,4,11,12-hexamethyl-7-phenyl-4,10-
etheno-6H,10H-cyclopenta[1,3]cyclopropa[1,2-d][1,2,4]triazolo-
[1,2-a]pyridazine-3,6,8(3aH,7H)-trione (10).14
Telescoped Aromatic Additions of α-Diazoketones. 3,8a-
Dihydro-3,3,8a-trimethylazulen-1(2H)-one (31).14
An aqueous solution of sodium azide (10 mL, 30 mmol, 3.0 M, 3.0
mL min−1) was pumped through a micromixer T-piece where it met a
dichloromethane solution of triflic anhydride (10 mL, 5 mmol, 0.5 M,
3.0 mL min−1); the combined biphasic stream was passed through a
reactor coil (4 × 10 mL, rt). After all reagent solutions had been
charged, the combined flow rate was changed to 0.2 mL min−1 to give
a residence time of 1 h for triflyl azide generation. The reactor effluent
for the first step passed through a T-piece where it met a stream of
saturated aqueous sodium bicarbonate (0.1 mL min−1). The
combined stream was passed through a back pressure regulator (8
bar). The biphasic effluent was then separated by an in-line liquid−
liquid separator and the dichloromethane effluent (25 mL),
containing triflyl azide (22), was collected over KOH pellets. The
separated dichloromethane triflyl azide solution (25 mL, 0.17 mL
min−1) was pumped to a T-piece where it met a dichloromethane
solution of 2,5-dimethyl-1-phenyl-5-(3′,4′,5′-trimethylphenyl)hexane-
1,3-dione (18) and DBU (25 mL, 3 mmol, 0.12 M, [DBU] 0.128 M,
0.17 mL min−1), and the combined stream was then passed through a
reactor coil (4 × 10 mL, rt, 120 min residence time). The diazo-
transfer effluent (75 mL) was also collected over KOH pellets, and a
25 mL portion, containing the α-diazoketone 8, was pumped forward
to undergo aromatic addition; this 25 mL solution was passed through
a silica gel plug (glass column, 100 mm × 10 mm internal diameter, rt,
0.75 mL min−1) to remove polar components. Immediately after
eluting from the silica gel plug, the effluent was passed through a
packed bed reactor containing IPB catalyst 9 (0.417 g, 10 mol %
based on 18, glass column, 150 × 66 mm internal diameter, 0.75 mL
min−1, rt). The reactor effluent containing azulenone 32 was collected
in a flask containing PTAD (0.175 g, 1.0 mmol) in dichloromethane
(10 mL). Once all the effluent was collected, the contents of the flask
were stirred for 1 h at room temperature. The reaction solution was
analyzed by IR spectroscopy and concentrated under reduced
pressure to give the crude product, which was purified by flash
chromatography on silica gel with hexane/ethyl acetate (97:3) as
eluent afforded the adduct 10 as a white solid (0.121 g, 30%, 82%
ee).87 Mp: 176−178 °C. [α]D20 −64.38 (c 0.08, CHCl3). νmax/cm−1
An aqueous solution of sodium azide (10 mL, 30 mmol, 3.0 M, 3.0
mL min−1) was pumped through a micromixer T-piece where it met a
dichloromethane solution of triflic anhydride (10 mL, 5 mmol, 0.5 M,
3.0 mL min−1); the combined biphasic stream was passed through a
reactor coil (4 × 10 mL, rt). After all reagent solutions had been
charged, the combined flow rate was changed to 0.2 mL min−1 to give
a residence time of 1 h for triflyl azide generation. The reactor effluent
for the first step passed through a T-piece where it met a stream of
saturated aqueous sodium bicarbonate (0.1 mL min−1). The
combined stream was passed through a back pressure regulator (8
bar). The biphasic effluent was then separated by an in-line liquid−
liquid separator and the dichloromethane effluent (25 mL),
containing triflyl azide (22), was collected over KOH pellets. The
separated dichloromethane triflyl azide solution (25 mL, 0.17 mL
min−1) was pumped to a T-piece where it met a dichloromethane
solution of 2,5-dimethyl-1,5-diphenylhexane-1,3-dione (19) and DBU
(25 mL, 3 mmol, 0.12 M, [DBU] 0.128 M, 0.17 mL min−1) and the
combined stream was then passed through a reactor coil (4 × 10 mL,
rt, 120 min residence time). The diazo-transfer effluent (75 mL) was
also collected over KOH pellets, and a 25 mL portion, containing the
α-diazoketone 11, was pumped forward to undergo aromatic addition;
this 25 mL solution was passed through a silica gel plug (glass
column, 100 mm × 10 mm internal diameter, rt, 0.75 mL min−1) to
remove polar components. Immediately after eluting from the silica
gel plug, the effluent was passed through a packed bed reactor
containing IPB catalyst 9 (0.417 g, 10 mol % based on 19, glass
column, 150 × 66 mm internal diameter, 0.75 mL min−1, 45 °C). The
reactor effluent was analyzed by IR spectroscopy and concentrated
under reduced pressure to give the crude product, which was purified
by flash chromatography on silica gel with hexane/ethyl acetate
V
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(ATR): 2966, 2927, 1757, 1727, 1699, 1504, 1396. 1H NMR (CDCl3,
300 MHz): δ 7.47−7.31 (m, 5H, ArH), 5.13 [s, 1H, C(10)H], 2.13
[B of AB, 1H, J = 17.9 Hz, one of C(2)H2], 2.02 [s, 3H, C(12)CH3],
1.95 [A of AB, 1H, J = 17.8 Hz, one of C(2)H2], 1.84 [d, 3H, J = 1.1
Hz, C(11)CH3], 1.75 [d, 3H, J = 1.1 Hz, C(4)CH3], 1.69 [s, 1H,
C(3b)H], 1.30, 1.24 [2 × s, 2 × 3H, C(1)(CH3)2], 1.12 [s, 3H,
C(3a)CH3]. 13C NMR (CDCl3, 100.6 MHz): δ 211.7 (C), 156.1 (C),
155.4 (C), 131.5 (C), 130.7 (C), 129.6 (C), 129.0 (CH), 128.1
(CH), 125.4 (CH), 66.2 (C), 57.3 (CH), 48.5 (CH2), 43.5 (C), 41.0
(C), 36.4 (C), 34.5 (CH), 27.1 (CH3), 23.9 (CH3), 21.1 (CH3), 16.8
(CH3), 13.3 (CH3), 7.6 (CH3). HRMS (ESI) m/z: [M + H]+ Calcd
for C24H27N3O3 406.2125; Found 406.2121.
N-tert-Butyl-2-cyano-2-diazo-N-(4′-chlorobenzyl)acetamide
(56).71
This compound was prepared according to the general flow procedure
from N-tert-butyl-2-cyano-N-(4-chlorobenzyl)acetamide (48), trie-
thylamine (25 mL, 0.12 M, [NEt3] 0.128 M), aqueous sodium azide
(10 mL, 3.0 M), and a dichloromethane solution of trifluorometha-
nesulfonic anhydride (10 mL, 0.5 M). The crude product was purified
by flash chromatography on silica gel with hexane/ethyl acetate
(80:20) as eluent affording α-diazoacetamide 56 as a yellow crystalline
Telescoped Regitz-Type Diazo Transfer in Flow. 2-Diazo-5-
methyl-1,5-diphenylhexane-1,3-dione (36).
solid (0.829 g, 95%). Mp: 108−110 °C (lit.71 mp 109−113 °C). νmax
/
cm−1 (ATR): 2213 (CN), 2118 (CN2) 1634 (CO). 1H NMR
(CDCl3, 300 MHz): δ 7.34 (d, 2H, J = 8.4 Hz, ArH), 7.16 (d, 2H, J =
8.4 Hz, ArH), 4.67 (s, 2H, NCH2), 1.41 [s, 9H, C(CH3)3]. 13C{1H}
NMR (CDCl3, 75.5 MHz): 160.9 (C), 137.0 (C), 133.3 (C), 128.9
(CH), 127.4 (CH), 109.7 (C), 60.4 (C), 54.8 (C), 49.2 (CH2), 28.5
(CH3).
This compound was prepared according to the general flow procedure
from a dichloromethane solution of 3-hydroxy-5-methyl-1,5-diphe-
nylhex-2-ene-1-one (35), triethylamine (25 mL, 0.12 M, [NEt3] 0.128
M), aqueous sodium azide (10 mL, 3.0 M) and a dichloromethane
solution of trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The
crude product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (95:5) as eluent affording α-diazoketone 36 as a
N-Benzyl-N-tert-butyl-2-cyano-2-diazoacetamide (57).71
1
yellow oil (0.864 g, 94%). νmax/cm−1 (ATR): 2967, 2118, 1640. H
NMR (CDCl3, 400 MHz): δ 7.58−7.51 [m, 1H, C(4′′)H], 7.50−7.38
(m, 6H, ArH), 7.32−7.25 (m, 2H, ArH), 7.20−7.14 [m, 1H, C(4′)
H], 3.38 [s, 2H, C(4)H2], 1.51 [s, 6H, C(5)(CH3)2]. 13C{1H} NMR
(CDCl3, 100.6 MHz): δ 191.8 (C), 185.2 (C), 148.0 (C), 137.4 (C),
132.6 (CH), 128.8 (CH), 128.2 (CH), 127.4 (CH), 125.9 (CH),
125.7 (CH), 84.0 (C), 52.5 (CH2), 38.3 (C), 29.2 (CH3). HRMS
(ESI) m/z: [M + Na]+ Calcd for C19H18N2O2Na 329.1260; Found
329.1262.
This compound was prepared according to the general flow procedure
from N-tert-butyl-2-cyano-N-(benzyl)acetamide (49), triethylamine
(25 mL, 0.12 M, [NEt3] 0.128 M), aqueous sodium azide (10 mL, 3.0
M), and a dichloromethane solution of trifluoromethanesulfonic
anhydride (10 mL, 0.5 M). The crude product was purified by flash
chromatography on silica gel with hexane/ethyl acetate (80:20) as
eluent affording α-diazoacetamide 57 as a yellow crystalline solid
(0.599 g, 78%). Mp: 88−92 °C (lit.71 mp 89−91 °C). νmax/cm−1
(ATR): 2214 (CN), 2121 (CN2) 1634 (CO). 1H NMR (CDCl3, 300
MHz): δ 7.42−7.18 (m, 5H, 5 × ArH), 4.71 (s, 2H, CH2N), 1.43 [s,
9H, C(CH3)3]. 13C{1H} NMR (CDCl3, 75.5 MHz): δ 160.9 (C),
138.4 (C), 128.7 (CH), 127.5 (C), 126.0 (CH), 109.8 (C), 60.3 (C),
49.7 (CH2), 28.5 (CH3).
5-(4′-Chlorophenyl)-2-diazo-5-methyl-3-oxohexanenitrile (38).
N-tert-Butyl-2-cyano-2-diazo-N-(4′-fluorobenzyl)acetamide
This compound was prepared according to the general flow procedure
from a dichloromethane solution of 5-methyl-5-(4-chlorophenyl)-3-
oxohexanenitrile (37), triethylamine (25 mL, 0.12 M, [NEt3] 0.128
M), aqueous sodium azide (10 mL, 3.0 M), and a dichloromethane
solution of trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The
crude product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (90:10) as eluent affording α-diazoketone 38 as a
yellow oil (0.667 g, 85%). νmax/cm−1 (ATR) 2969, 2222 (CN), 2125,
1668. 1H NMR (CDCl3, 400 MHz): δ 7.32−7.27 (m, 4H, ArH), 2.90
[s, 2H, C(4)H2], 1.48 [s, 6H, C(5)(CH3)2]. 13C{1H} NMR (CDCl3,
100.6 MHz): δ 188.2 (C), 145.4 (C), 132.2 (C), 128.5 (CH), 127.0
(CH), 108.6 (C), 58.6 (C), 51.5 (CH), 38.1 (C), 28.9 (CH3). HRMS
(ESI) m/z: [M + Na]+ Calcd for C13H12N3O35ClNa 284.0561; Found
284.0559.
(58).71
This compound was prepared according to the general flow procedure
from N-tert-butyl-2-cyano-N-(4-fluorobenzyl)acetamide (50), trie-
thylamine (25 mL, 0.12 M, [NEt3] 0.128 M), aqueous sodium
azide (10 mL, 3.0 M), and a dichloromethane solution of
trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (80:20) as eluent affording α-diazoacetamide 58
as a yellow crystalline solid (0.724 g, 88%). Mp: 105−107 °C. νmax
/
N,N-Dibenzyl-2-cyano-2-diazoacetamide (55).71
cm−1 (ATR): 2213 (CN), 2121 (CN2) 1635 (CO). 1H NMR
(CDCl3, 400 MHz): δ 7.22−7.13 (m, 2H, 2 × ArH), 7.11−7.01 (m,
2H, 2 × ArH), 4.67 (s, 2H, NCH2), 1.42 [s, 9H, C(CH3)3]. 13C{1H}
NMR (CDCl3, 100.6 MHz): δ 162.0 (C, 1JCF = 246.0 Hz), 160.9 (C),
134.1 (C, 4JCF = 3.2 Hz), 127.6 (CH, 3JCF = 8.1 Hz), 115.7 (CH, 2JCF
= 21.7 Hz), 109.8 (C), 60.4 (C), 49.1 (CH2), 28.5 (CH3). 19F{1H}
NMR (CDCl3, 376.5 MHz): δ −114.9.
This compound was prepared according to the general flow procedure
from N,N-(dibenzyl)-2-cyanoacetamide (47), triethylamine (25 mL,
0.12 M, [NEt3] 0.128 M), aqueous sodium azide (10 mL, 3.0 M), and
a dichloromethane solution of trifluoromethanesulfonic anhydride (10
mL, 0.5 M). The crude product was purified by flash chromatography
on silica gel with hexane/ethyl acetate (80:20) as eluent affording α-
diazoacetamide 55 as a yellow oil (0.697 g, 80%). νmax/cm−1 (ATR)
2214 (CN), 2117 (CN2), 1626 (CO). 1H NMR (CDCl3, 400 MHz):
δ 7.38−7.19 (m, 10H, ArH), 4.59 (s, 4H, 2 × NCH2). 13C{1H} NMR
(CDCl3, 100.6 MHz): δ 159.9 (C), 135.5 (C), 128.9 (CH), 128.1
(CH), 127.7 (CH), 109.7 (C), 50.3 (CH2).
N-tert-Butyl-2-cyano-2-diazo-N-(4′-methylbenzyl)acetamide
(59).71
This compound was prepared according to the general flow procedure
from N-tert-butyl-2-cyano-N-(4-methylbenzyl)acetamide (51) (and
triethylamine (25 mL, 0.12 M, [NEt3] 0.128 M), aqueous sodium
W
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azide (10 mL, 3.0 M), and a dichloromethane solution of
trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (80:20) as eluent affording α-diazoacetamide 59
as a yellow crystalline solid (0.673 g, 83%). Mp: 86−88 °C (lit.71 mp
85−86 °C). νmax/cm−1 (ATR) 2213 (CN), 2117 (CN2), 1634 (CO).
1H NMR (CDCl3, 300 MHz): δ 7.17 [d, 2H, J = 8.0 Hz, C(3′)H and
C(5′)H], 7.09 [d, 2H, J = 8.1 Hz, C(2′)H and C(6′)H], 4.67 (s, 2H,
CH2N), 2.34 [s, 3H, C(4′)(CH3)], 1.42 [s, 9H, C(CH3)3]. 13C{1H}
NMR (CDCl3, 75.5 MHz): δ 160.8 (C), 137.1 (C), 135.3 (C), 129.4
(CH), 125.9 (CH), 109.8 (C), 60.2 (C), 49.5 (CH2), 28.5 (CH3),
21.1 (CH3).
88−91 °C. νmax/cm−1 (ATR): 2982, 2214, 2125, 1635. 1H NMR
(CDCl3, 400 MHz): δ 8.61 [d, 2H, J = 6.0 Hz, C(2)H and C(6)H],
7.19 [d, 2H, J = 5.6 Hz, C(3)H and C(5)H], 4.70 (s, 2H, CH2N),
1.43 [s, 9H, C(CH3)3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 161.1
(C), 150.0 (CH), 148.2 (C), 121.1 (CH), 109.5 (C), 60.6 (C), 48.9
(CH2), 28.5 (CH3). HRMS (ESI) m/z: [M + Na]+ Calcd for
C13H15N5ONa 280.1169; Found 280.1169.
Methyl 2-((2′-Cyclohexylethyl)sulfonyl)-2-diazoacetate (63).13
N-tert-Butyl-2-cyano-2-diazo-N-(4′-bromobenzyl)acetamide
This compound was prepared according to the general flow procedure
from methyl 2-((2′-cyclohexylethyl)sulfonyl)acetate 66 and DBU (25
mL, 0.12 M, [DBU] 0.128 M), aqueous sodium azide (10 mL, 3.0
M), and a dichloromethane solution of trifluoromethanesulfonic
anhydride (10 mL, 0.5 M). The crude product was purified by flash
chromatography on silica gel with hexane/ethyl acetate (80:20) as
eluent affording α-diazosulfonyl ester 63. Yellow oil (0.658 g, 80%).
νmax/cm−1 (ATR): 2124 (CN2), 1713 (CO), 1331, 1294, 1144 (SO2).
1H NMR (CDCl3, 300 MHz): δ 3.88 (s, 3H, CH3), 3.46−3.34
[symmetrical m, 2H, C(1′)H2], 1.81−1.58 [m, 7H, C(2′)H2 and
cyclohexane ring CH2], 1.46−1.06 (m, 4H, cyclohexane ring CH and
cyclohexane ring CH2), 1.05−0.84 (m, 2H, cyclohexane ring CH2).
13C{1H} NMR (CDCl3, 75.5 MHz): δ 160.5 (C), 72.8 (C), 54.7
(60).71
This was prepared according to the general flow procedure from N-
tert-butyl-2-cyano-N-(4-bromobenzyl)acetamide (52), triethylamine
(25 mL, 0.12 M, [NEt3] 0.128 M), aqueous sodium azide (10 mL, 3.0
M), and a dichloromethane solution of trifluoromethanesulfonic
anhydride (10 mL, 0.5 M). The crude product was purified by flash
chromatography on silica gel with hexane/ethyl acetate (80:20) as
eluent affording α-diazoacetamide 60 as a yellow crystalline solid
(0.844 g, 84%). Mp: 109−111 °C (lit.71 mp 109−110 °C). νmax/cm−1
(ATR): 2213 (CN), 2119 (CN2), 1634 (CO). 1H NMR (CDCl3, 400
MHz): δ 7.50 [d, 2H, J = 8.4 Hz, C(3′)H and C(5′)H], 7.10 [d, 2H, J
= 8.4 Hz, C(2′)H and C(6′)H], 4.65 (s, 2H, CH2N), 1.41 [s, 9H,
C(CH3)3]. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 160.9 (C), 137.6
(C), 131.9 (CH), 127.7 (CH), 121.3 (C), 109.7 (C), 60.4 (C), 54.8
(C), 49.3 (CH2), 28.5 (CH3).
(CH2), 53.0 (CH3), 36.4 (CH), 32.8 (CH2), 29.6 (CH2), 26.2
(CH2), 25.9 (CH2).
Telescoped C−H Insertion. Methyl (1R,4aR,8aS)-Octahydro-
1H-isothiochromene-1-carboxylate 2,2-Dioxide (65).13
N-tert-Butyl-2-cyano-2-diazo-N-(3′,5′-dimethylbenzyl)-
acetamide (61).
An aqueous solution of sodium azide (10 mL, 30 mmol, 3.0 M, 3.0
mL min−1) was pumped through a micromixer T-piece where it met a
toluene solution of triflic anhydride (10 mL, 5 mmol, 0.5 M, 3.0 mL
min−1); the combined stream passed through a reactor coil (4 × 10
mL, rt). After all reagent solutions had been charged, the combined
flow rate was changed to 0.2 mL min−1 to give a residence time of 1 h.
The reactor effluent passed through a T-piece where it met a stream
of saturated aqueous sodium bicarbonate (0.1 mL min−1). The
reaction stream was passed through a back pressure regulator (8 bar).
The biphasic reactor effluent was then separated by an in-line liquid−
liquid separator. The toluene layer (25 mL) was collected over KOH
pellets and was directly fed to another pump. The pump delivered the
separated triflic azide solution (25 mL, 0.165 mL min−1) to a T-piece
where it met a DBU and toluene solution of 66 (25 mL, 3 mmol, 0.12
M, [DBU] 0.128 M, 0.165 mL min−1) which then passed through a
reactor coil (4 × 10 mL, rt, 120 min residence time), and then passed
through a back pressure regulator (8 bar). The reactor effluent (100
mL) was collected over KOH pellets, from which a a 25 mL portion,
containing α-diazo-β-sulfonyl ester solution 63 was pumped forward
to undergo C−H insertion; this 25 mL solution was passed through a
silica gel plug (glass column, 100 mm × 10 mm internal diameter, rt,
0.5 mL min−1) to remove polar components. Immediately after
eluting from the silica gel plug, the effluent was passed through a
packed bed reactor containing IPB catalyst 9 (0.313 g, 10 mol %
based on 66, glass column, 150 × 66 mm internal diameter, 0.5 mL
min−1, 111 °C). The reactor effluent was analyzed by IR spectroscopy
and concentrated under reduced pressure. The crude product mixture
was purified by flash chromatography on silica gel, employing ethyl
acetate/hexane (10:90 to 40:60) as eluent and afforded methyl
(1R,4aR,8aS)-octahydro-1H-isothiochromene-1-carboxylate 2,2-diox-
ide (65) as a white solid (47 mg, 26%, 88% ee (determined by chiral
phase HPLC)). Mp: 123−125 °C. νmax/cm−1(ATR): 1731 (CO),
1315, 1288, 1229, 1167, 1109 (SO2). 1H NMR (CDCl3, 300 MHz): δ
3.80 (s, 3H, CH3), 3.77−3.58 [m containing dd at 3.75, 2H, J = 4.7
This compound was prepared according to the general flow procedure
from N-tert-butyl-2-cyano-N-(3,5-dimethylbenzyl) acetamide (53),
triethylamine (25 mL, 0.12 M, [NEt3] 0.128 M), aqueous sodium
azide (10 mL, 3.0 M), and a dichloromethane solution of
trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (80:20) as eluent affording α-diazoacetamide 61
as a yellow crystalline solid (0.818 g, 96%). Mp: 105−107 °C. νmax
/
cm−1 (ATR): 2213 (CN), 2119 (CN2), 1634 (CO). 1H NMR
(CDCl3, 300 MHz): δ 6.90 [s, 1H, C(4′)H], 6.79 [s, 2H, C(2′)H and
C(6′)H], 4.63 (s, 2H, NCH2), 2.31 [s, 6H, C(3′)CH3 and
C(5′)CH3], 1.42 [s, 9H, C(CH3)3]. 13C{1H} NMR (CDCl3, 75.5
MHz): δ 160.8 (C), 138.3 (C), 138.2 (C), 129.1 (CH), 123.8 (CH),
109.8 (C), 60.3 (C), 49.7 (CH2), 28.6 (CH3), 21.4 (CH3). HRMS
(ESI) m/z: [M + Na]+ Calcd for C16H20N4ONa 307.1529; Found
307.1533.
N-tert-Butyl-2-cyano-2-diazo-N-(pyridin-4′-ylmethyl)acetamide
(62).
This compound was prepared according the general flow procedure
from N-tert-butyl-2-cyano-N-(pyridin-4′-ylmethyl)acetamide (54),
triethylamine (25 mL, 0.12 M, [NEt3] 0.128 M), aqueous sodium
azide (10 mL, 3.0 M), and a dichloromethane solution of
trifluoromethanesulfonic anhydride (10 mL, 0.5 M). The crude
product was purified by flash chromatography on silica gel with
hexane/ethyl acetate (80:20 to 40:60) as eluent affording α-
diazoacetamide 62 as a yellow crystalline solid (0.587 g, 76%). Mp:
X
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Hz, 3.1 Hz, C(1)H and HB of C(3)H2], 2.96 (overlapping dddd, 1H, J
= 14.0 Hz, 3.2 Hz, HA of C(3)H2), 2.14−1.62 (m, 8H, C(4)H2, C(4a)
H, C(8a)H and cyclohexane ring CH2), 1.36−1.14 (m, 2H,
cyclohexane ring CH2), 1.11−0.92 (m, 2H, cyclohexane ring CH2).
13C{1H} NMR (CDCl3, 75.5 MHz): δ 166.9 (C), 68.9 (CH), 52.8
(CH3), 48.5 (CH2), 43.0 (CH), 33.6 (CH), 32.9 (CH2), 31.1 (CH2),
30.9 (CH2), 25.5 (CH2), 25.4 (CH2).
Regional Development Fund (D.L., SFI SSPC2 12/RC/2275
5 and SFI SSPC3 Pharm5 12/RC/2275_2), and equipment
provided though a SFI research infrastructure award for
process flow spectroscopy (ProSpect) (SFI 15/RI/3221) is
gratefully acknowledged. Dr. Brian Feerick and Paul McDowell
are acknowledged for their contributions. We acknowledge the
contribution of Janssen Pharmaceutical for the kind loan of
one of the flow chemistry reactors used in this work.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01310.
■
sı
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Authors
Daniel C. Crowley − School of Chemistry, Analytical and
Biological Chemistry Research Facility, University College
Cork, Cork, Ireland
Thomas A. Brouder − School of Chemistry, Analytical and
Biological Chemistry Research Facility, University College
Cork, Cork, Ireland
Aoife M. Kearney − School of Chemistry, Analytical and
Biological Chemistry Research Facility, University College
Cork, Cork, Ireland
Denis Lynch − School of Chemistry, Analytical and Biological
Chemistry Research Facility, Synthesis and Solid State
Pharmaceutical Centre, University College Cork, Cork,
Ireland
Alan Ford − School of Chemistry, Analytical and Biological
Chemistry Research Facility, University College Cork, Cork,
Ireland
Stuart G. Collins − School of Chemistry, Analytical and
Biological Chemistry Research Facility, Synthesis and Solid
State Pharmaceutical Centre, University College Cork, Cork,
Ireland
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Desymmetrization by Asymmetric Copper-Catalyzed Intramolecular
C−H Insertion Reactions of α-Diazo-β-oxosulfones. J. Org. Chem.
2019, 84, 7543−7563.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01310
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ACKNOWLEDGMENTS
■
Financial support from the Irish Research Council (IRC)
(D.C., GOIPG/2015/2972; T.A.B., GOIPG/2015/3188; and
A.M.K., GOIPG/2018/112)), Synthesis and Solid State
Pharmaceutical Centre (SSPC) supported by Science
Foundation Ireland and cofunded under the European
Y
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20
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20
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