Batch Versus Flow Lithiation–Substitution of 1,3,4-Oxadiazoles: Exploitation of Unstable Intermediates Using Flow Chemistry

Article abstract of DOI:10.1002/chem.201902917

1,3,4-Oxadiazoles are a common motif in pharmaceutical chemistry, but few convenient methods for their modification exist. A fast, convenient, high yielding and general α-substitution of 1,3,4-oxadiazoles has been developed using a metalation-electrophilic trapping protocol both in batch and under continuous flow conditions in contradiction to previous reports which suggest that α-metalation of this ring system results in ring fragmentation. In batch, lithiation is accomplished at an industrially convenient temperature, ?30 °C, with subsequent trapping giving isolated yields of up to 91 %. Under continuous flow conditions, metalation is carried out at room temperature, and subsequent in flow electrophilic trapping gave up to quantitative isolated yields. Notably, lithiation in batch at room temperature results only in ring fragmentation and we propose that the superior mixing in flow allows interception and exploitation of an unstable intermediate before decomposition can occur.

Full text of DOI:10.1002/chem.201902917

A Journal of
Accepted Article
Title: Batch Versus Flow Lithiation-Substitution of 1,3,4-Oxadiazoles:
Exploitation of Unstable Intermediates Using Flow Chemistry
Authors: Jeff Wong, John Tobin, Filipe Vilela, and Graeme Barker
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Batch Versus Flow Lithiation-Substitution of 1,3,4-Oxadiazoles:
Exploitation of Unstable Intermediates Using Flow Chemistry
Jeff Y. F. Wong, John M. Tobin, Filipe Vilela and Graeme Barker*
Abstract: 1,3,4-Oxadiazoles are a common motif in pharmaceutical
chemistry, but few convenient methods for their modification exist. A
fast, convenient, high yielding and general α-substitution of 1,3,4-
oxadiazoles has been developed using a metalation-electrophilic
trapping protocol both in batch and under continuous flow conditions
in contradiction to previous reports which suggest that α-metalation of
this ring system results in ring fragmentation. In batch, lithiation is
accomplished at an industrially convenient temperature, –30 °C, with
subsequent trapping giving isolated yields of up to 91%. Under
continuous flow conditions, metalation is carried out at room
temperature, and subsequent in flow electrophilic trapping gave up to
quantitative isolated yields. Notably, lithiation in batch at room
temperature results only in ring fragmentation and we propose that
the superior mixing in flow allows interception and exploitation of an
unstable intermediate before decomposition can occur.
Scheme 1. Previous oxadiazole lithiations vs. this work
Introduction
comparatively delicate motif, oxadiazoles are typically installed
Oxadiazoles occupy an important role in modern medicinal
late in target synthesis, and subsequent substitutions in adjacent
chemistry,[1] often acting as bioisosteres of carboxylate
positions analogous to isosteric α-amino acid-derived peptide
derivatives including amides,[2] esters,[2] carbamates[3] and
stereocentres are correspondingly rare.
hydroxamic esters[4] as well as attracting attention for their
This paucity of oxadiazole modifications becomes
optoelectronic properties.[5] In almost all cases the 1,3,4-isomer
problematic in light of the harsh conditions used to form the
exhibits pharmacologically favorable activity with respect to
heterocycle, typically from a precursor hydrazide in DMSO or
lipophilicity (log D), hERG inhibition and metabolic stability.[1]
DMF at high temperature.[8] Therefore, there is a clear need to
Examples of bioactive 1,3,4-oxadiazoles include raltegravir with
develop oxadiazole modifications in the heterobenzylic position.
an antiretroviral activity[6] and zibotentan as an endothelin
In this context, we herein disclose a convenient protocol for the α-
receptor antagonist[7] (figure 1). Often thought of as a
lithiation substitution of alkyl-1,3,4-oxadiazoles under both batch
and continuous flow conditions using industrially accessible
temperatures (–30 °C in batch and room temperature in flow),[9]
short reaction times (1.3 s – 1 min) and a readily available non-
nucleophilic base, LDA.
Previous reports of alkyl-1,3,4-oxadiazole metalations are
sparse, stemming from Micetich’s observation that attempted
lithiation-trapping of 2,5-dimethyl-1,3,4-oxadiazole results solely
in ring fragmentation (scheme 1).[10] While neither substrate nor
trapped oxadiazoles were recovered, details of the ring
fragmentation products were not given. Deaton has reported the
α-lithiation of 2-methyl-5-aryl-1,3,4-oxadiazoles followed by
trapping with aldehydes during the synthesis of cathepsin K
inhibitors, however yields were modest, presumably due to
competing ring fragmentation (scheme 1).[11] Katritzky has also
Figure 1. Bioactive 1,3,4-oxadiazoles
reported the metalation of oxadiazolylmethyl-1H-benzotriazoles in
the doubly benzylic position.[12] Ortho-metalation of aryl-1,3,4-
oxadiazoles to manganese[13] and iridium[14] metallacycles has
been demonstrated, though subsequent C-C bond forming
processes have not been reported.
[a]
Mr J. Y. F. Wong, Dr J. M. Tobin, Dr F. Vilela and Dr G. Barker
Institute of Chemical Sciences
Heriot-Watt University
Riccarton, Edinburgh, UK
E-mail: graeme.barker@hw.ac.uk
We have also optimised our new synthetic protocol for use
under continuous flow conditions. Flow chemistry has enjoyed
Supporting information for this article is given via a link at the end of
the document.
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Entry
Base (1.3 eq.)
nBuLi
Temp./°C
–78
–30
–78
–30
–78
–30
rt
Time
Yield[a]
44%
48%
96%
80%
92%
95%
0%
1
2
3
4
1 h
nBuLi
15 min
20 min
1 min
20 min
1 min
10 s
sBuLi
sBuLi
Scheme 2. Previous in-flow deprotonations vs. this work
5
6
LDA
considerable attention from synthetic chemists in recent years,[15]
with multiple examples of group 1 and 2 organometallic reactions
reported,[16] most notably by the groups of Knochel[17] and Ley.[18]
However, formation of new organolithium species in flow has
largely been restricted to halogen-lithium exchange or
deprotonation at sp2 centres. Alezra[19] as well as Cantillo and
Kappe[20] have separately reported LDA-mediated enolate
formation under continuous flow conditions, and Ley reports the
LiHMDS-facilitated heterobenzylic lithiation of methylpyridines.[21]
While these examples detail the formation of chemically stable
organolithiums usable under batch conditions, we herein report
sp3 deprotonation to form an organolithium species which is
unstable under comparable batch conditions. Subsequent in-flow
interception by electrophilic trapping allows synthetic use of this
intermediate and high yields of products could be obtained
(scheme 2).
LDA
7
8
LDA
LDA
rt
1.3 s
40%
[a] as determined by 1H NMR in the presence of dimethylsulfone
Table 1. Optimisation of oxadiazole modification
nucleophilic base LDA: yields of 92% after 20 min at –78 °C and
95% after 1 min at –30 °C were obtained. Raising the
temperature to rt resulted in decomposition of the lithiated
intermediate after 10 s (entry 7) – inspection of the 1H NMR
spectrum of the crude reaction mixture revealed a complex
1,3,4-Oxadiazoles have previously been employed as
amide and ester bioisosteres.[2] Commonly derived from amino
acids, naturally occurring amide and ester protein ligands feature
branching points at the α-position. We therefore proposed to
investigate the possibility of substituting alkyl-1,3,4-oxadiazoles at
the analogous carbon via a metalation-substitution approach.
Results and Discussion
We began our investigations by screening a number of different
organolithium bases at –78 °C and the industrially accessible –
30 °C[9] for lithiation of oxadiazole 1 prior to electrophilic trapping
n
with acetone (table 1). When deprotonating with BuLi (entries 1
and 2), modest conversions to 2 were observed with no remaining
starting material due to competitive nucleophilic attack by nBuLi.1
s
Switching to the more sterically hindered base BuLi led to an
increase in yields, providing 96% and 80% yields after 20 min at
–78 °C and 1 min at –30 °C respectively (entries 3 and 4). We
then investigated the milder and less
Scheme 3. Electrophile scope
mixture of products (not including 1 or 2) which we were unable
to separate, but which we propose arise from the ring
fragmentation observed by Micetich.[10] Reducing the metalation
1 For further details, see ESI.
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time to 1.3 s at rt gave a 40% yield of 2 with no remaining 1 (entry
8), indicating that decomposition happens quickly after lithiation
at room temperature.
Having determined optimal metalation conditions, the wide
electrophile scope was demonstrated. Good isolated yields were
obtained after trapping with acetone, benzophenone,
benzaldehyde, MeI, BnBr, Me2SO4, allyl bromide, and TMSBr
(scheme 3). Attempted trapping with TMSCl gave only 51% of
silylated product 8. Trapping with MeOD-d4 gave deuterated
Scheme 4. β-Carbonyl derivative instability
oxadiazole d-1 with 76% D incorporation. Attempts to trap with
electrophiles to give β-carbonyloxadiazoles were less successful,
with only a 24% isolated yield of amide 9 obtained after trapping
with iPrNCO, and we were unable to isolate the expected products
after trapping with BzCl, MeOCOCl or DMF. We propose that
rather than inefficient trapping with these electrophiles, the
products are unstable. Indeed, oxidation of a diastereopure
sample of alcohol 4 (obtained from electrophilic trapping using
PhCHO) with Dess-Martin periodinane led to initial formation of
the expected ketone product (as observed by 1H NMR of the
crude reaction mixture), which then decomposed to an
unidentifiable complex mixture of products before purification
could be carried out (scheme 4). Lithiation using 2.3 eq. LDA
followed by 3.4 eq. MeOCOCl gave disubstituted product 10 in
43% yield via interception of the unstable monosubstituted
product by a second deprotonation-trapping event (scheme 4).
Scheme 5. Substrate scope.
Next, we turned our attention to the substrate scope
(scheme 5) and began by investigating the effect of altering the
alkyl chain undergoing metalation. Exchanging n-propyl for either
ethyl (11) or n-octyl (12) chains maintained the efficiency of the
reaction, with yields of 62% and 71% obtained respectively. We
then probed functional group tolerance, and found that aryl (13,
75% yield of trapped product), haloaryl (15, 81%), ether (16, 84%),
trifluoromethyl (14, 74%), acetal (17, 91%) and dimethylamino (18,
85%) motifs were pleasingly all compatible with the methodology.
Di-N-Boc aminoalkyloxadiazole 22 also underwent efficient
metalation, although in this case migration of a Boc group to give
23 in 61% yield outcompeted trapping with an external
electrophile. We then investigated the compatibility of a second
oxadiazole substituent which could conceivably undergo
Figure 2. X-ray structure of product 3.
An X-ray crystal structure of benzophenone trapped product
3 indicated favorable hydrogen bonding between a β-hydroxyl
substituent and the oxadiazole N3 position (figure 2). This
observation led us to hypothesize that a decomposition pathway
of β-carbonyloxadiazoles exists via formation of the enol tautomer.
Indeed, when enol formation is disfavored (e.g. in product 9) or
impossible (10), β-carbonyl bearing products can be obtained.
metalation:
substitution to give 19 in 71% yield with no evidence of aryl
metalation observed. To our delight, when second
deprotonatable alkyl substituent is present, metalation trapping
phenylpropyloxadiazole
underwent
efficient
a
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occurs with complete selectivity at the less sterically hindered
position, thought in these cases slightly higher yields were
obtained using LiTMP rather than LDA (75% vs. 60% for 20 and
79% vs. 55% for 21). No trace of product arising from metalation
(δH 3.50 ppm).[24] In contrast, the protons of C-lithated carbanions
display considerably upfield shifts, with the benzylic protons of
benzyllithium 27 at δH –0.77 ppm in THF-d8 and 2-lithioaziridines
such as 28 in the range δH 1.20-0.90 ppm.[23a, 25]
Next, we turned our attention to optimizing lithiation-
substitutions under continuous flow conditions. While we have
shown that the reaction did not proceed in high yields at room
temperature in batch due to decomposition of the lithiated
intermediate (table 1, entries 7 and 8), we proposed that the
superior mixing, heat transfer and control of reaction timing under
continuous flow conditions would allow fast metalation then
interception of the unstable intermediate with an electrophile
before decomposition could take place. This is similar to the “flash
chemistry” approach developed by Nagaki and Yoshida to
intercept unstable reaction products or intermediates.[26] For
example, ketone products may be obtained after treatment of
acylchlorides with organolithiums without further reaction to the
tertiary alcohol, and esters may be isolated after trapping
organolithiums with Boc2O.[27] However, in–flow generation of
unstable organolithium species has largely been limited to
carbolithiation[28] and halogen-lithium exchange[29] processes;
deprotonations are limited to a single example at an sp2 center,[30]
or benzylic lithiations at low temperatures (≥–98 °C).[31] In this
context, we have developed the first room temperature
organolithium-mediated deprotonation to form an unstable
Figure 3. Lithiation of 1 followed by in situ 1H NMR
at the other alkyl position was observed.
Next, we investigated attempting to optimize an
enantioselective lithiation-substitution procedure. Unfortunately,
after assaying a range of chiral lithium amide bases and a range
s
of chiral diamine ligands in the presence of BuLi, we were only
able to obtain high yields of near racemic (best er = 55:45)
products, and a “poor man’s Hoffman test” suggested that the
lithiated intermediate might be configurationally unstable (see
ESI).[22] Instead, we hypothesized that the lithiated intermediate
24 may preferentially adopt its azaenolate form taut-24 in solution,
precluding stereoselective substitution. To probe this, a sample of
Entry
[1]/M
0.39
0.39
0.39
0.23
0.23
tR1/s
5.6
14.0
28
Yield[a]
39%
41%
34%
45%
86%
RSM[a]
24%
22%
16%
0%
1
2
3
4
5
28
2.8
0%
[a] as determined by 1H NMR in the presence of dimethylsulfone
Table 2. Optimisation of continuous flow metalation.
Figure 4. 1H NMR shifts of lithium enolates and lithium carbanions
intermediate followed by fast in-flow trapping before
decomposition can take place as it would under batch conditions.
1 was metalated at –67 °C in THF-d8 and the reaction followed by
1H NMR spectroscopy (figure 3).[23] Before addition of base, the
heterobenzylic protons of 1 appear at δH 2.79 ppm. After addition
of LDA, two signals are clearly visible at δH 2.79 and δH 2.75 ppm,
corresponding to residual 1 and the alkenyl proton of azaenolate
taut-24. While this may at first glance appear unusually upfield for
an sp2 center proton, this does correspond to the spectrum for the
analogous enolate of dimethylacetamide 25 as reported by
Rathke (δH 3.16 and 2.93 ppm) and enolate 26 reported by Still
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We began by investigating the effect of metalating
oxadiazole 1 with LDA under continuous flow conditions at rt and
pumping the resulting solution into a flask containing a rapidly
stirring solution of benzophenone in THF at rt (table 2). Reactor
residence time (tR1) for the metalation step was varied by
changing the flow rate. When utilizing a 0.39 M solution of
oxadiazole 1 in THF (analogous stoichiometry to our optimized
batch conditions), a significant amount of starting material was
recovered, even after extended reactor residence times (entries
1-3). For example, after tR1 = 28 s, only a 34% yield of 3 was
obtained, with 16% 1 remaining. Inspection of the 1H NMR
spectrum of the crude product revealed that the significant mass
loss was due to competitive ring fragmentation. Reduction of the
reduced ring fragmentation, and an 86% yield of 3 was obtained
with no remaining 1 (entry 5).
With high-yielding continuous flow metalation conditions in
hand, we decided to investigate subsequent in-flow electrophilic
trapping. To our delight, metalation of oxadiazole 1 with LDA in
THF at rt with a reactor residence time (tR1) of 1.3 s followed by
trapping with acetone (tR2 = 2.8 s) afforded product 2 in 82% yield,
comparable with the batch yield of 86% (scheme 6). A selection
of oxadiazoles and electrophiles was then chosen to demonstrate
the scope of the reaction under continuous flow conditions
(scheme 6) and in each case yields were comparable to the
equivalent batch synthesis at –30 °C. Notably, acetal-containing
oxadiazole 18 was obtained in quantitative yields. As an exception
to this rule, we found that when flow metalation-trapping was
attempted with a slowly reacting electrophile, TMSBr, only a trace
amount of product 8 was obtained.
Scheme 7. Large scale flow lithiation-substitution
We also wished to demonstrate the utility of our flow
protocol on a larger scale and determine the productivity rate
(scheme 7). Thus, under our standard continuous flow conditions,
12.5 mmol of oxadiazole 1 was metalated and trapped over 5 min
to give an 85% yield of 2. This corresponds to a productivity rate
of 28.8 g/h, or alternatively 7.9 h would be required to produce a
mole of product.
Finally, we wished to demonstrate the utility of the in-flow
lithiation-substitution with a formal synthesis of a sub-nanomolar
cathepsin K inhibitor developed to combat osteoporosis.[11] Thus,
oxadiazole 25 was subjected to our standard in-flow metalation
conditions before in-flow trapping with pivaldehyde to give key
inhibitor synthetic intermediate 26 in 95% yield (scheme 8).
Scheme 8. Formal synthesis of a cathepsin K inhibitor
Conclusions
In conclusion, we have developed a fast and convenient lithiation-
Scheme 6. Oxadiazole lithiation-substitution in flow
substitution
protocol
for
alkyl-1,3,4-oxadiazoles
and
concentration of the 1 feedstock solution was able to remedy this
problem, with a 45% yield of 3 obtained with no remaining 1 after
tR1 = 28 s (entry 4). Reducing the residency time to 2.8 s greatly
demonstrated its utility with a wide range of substrates and
electrophiles both in batch and under continuous flow conditions.
Our approach addresses key limitations of previous attempts to
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effect oxadiazole metalation, namely competitive decomposition
of the metalated intermediate and extremely limited substrate and
electrophile scope. In batch, our conditions (–30 °C for 1 min then
electrophilic trapping) are amenable for use on a process scale
and gave up to 91% isolated yields, while under flow conditions
room temperature may be used, giving up to quantitative yields.
The success of our approach rested on the use of a non-
nucleophilic lithium amide base (LDA or LiTMP) and either cooling
to –30 °C in batch or the use of a fast deprotonation-trapping
strategy in flow to avoid decomposition of reaction intermediates.
Keywords: heterocycles • lithiation • synthetic methods •
alkylation
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Experimental Section
Typical procedures for batch and flow lithiation-substitutions of an
alkyl-1,3,4-oxadiazole are given below. For full details and all data,
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[7]
[8]
General Lithiation-Substitution Procedure in Batch:
LDA (1.3 eq.) was added dropwise to a stirred solution of
oxadiazole (1.0 eq.) in THF at –30 °C. The resulting solution was
stirred at –30 °C for 1 min then electrophile (2.0 eq.) was added.
The resulting solution was stirred at –30 °C for 10 min then
allowed to warm to rt over 16 h. Saturated NH4Cl(aq) solution was
added and the layers separated, extracting the aqueous with Et2O
(×3). The combined organic layers were dried (MgSO4) and
evaporated under reduced pressure to give the crude product.
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General Lithiation-Substitution Procedure in Continuous
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All continuous flow reactions were carried out using the easy-
Photochem flow reactor from Vapourtec Ltd. A 0.25 M solution of
oxadiazole in THF and a 0.5 M solution of LDA in THF were driven
through two separate peristaltic pumps at 10 mLmin–1 at rt. The
solutions were pumped through 1 mm I.D. PTFE tubing and mixed
at a T-junction. The resulting solution was passed through a
length of tubing (10 mLmin–1, 0.28 mL, tR1 = 1.3 s) before mixing
at a second T-junction with a 1.0 M solution of electrophile
pumped at 10 mLmin–1 through a third peristaltic pump. The
resulting solution was passed through a second length of tubing
(10 mLmin–1, 0.47 mL, tR2 = 2.8 s) and collected as the product
solution. After the flow had reached a steady state, the product
solution was collected for 15 s. A saturated solution of NH4Cl(aq)
was added to the collected product solution and the layers were
separated, extracting the aqueous with Et2O (×3). The combined
organic layers were dried (MgSO4) and evaporated under
reduced pressure to give the crude product.
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Acknowledgements
We gratefully acknowledge Heriot-Watt University for a DTP PhD
Scholarship (to JYFW) and OGIC and Iron Ocean Ltd. For PDRA
funding (JMT). Mass spectrometry data was acquired at the
EPSRC National Mass Spectrometry Facility at Swansea
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Entry for the Table of Contents
FULL PAPER
Jeff Y. F. Wong, John M. Tobin, Filipe
Vilela and Graeme Barker*
Page No. – Page No.
Batch Versus Flow Lithiation-
Substitution of 1,3,4-Oxadiazoles:
Exploitation of Unstable
A convenient new substitution of alkyl-1,3,4-oxadiazoles, a key pharmaceutical
motif, is described. The reaction tolerates a wide scope of substrates and can be
carried out in either batch or continuous flow conditions. In batch cooling to –30 °C
is required to avoid decomposition of an unstable intermediate while in flow this
may be quickly intercepted and synthesis carried out at room temperature.
Intermediates Using Flow Chemistry
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