Amidation of unactivated ester derivatives mediated by trifluoroethanol

Article abstract of DOI:10.1039/c7ob00593h

A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and chiral esters with retention of chiral integrity.

Full text of DOI:10.1039/c7ob00593h

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COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Amidation of Unactivated Ester Derivatives Mediated by
Trifluoroethanol
Christopher G. McPherson,a Nicola Caldwell,a Craig Jamieson,*a Iain Simpsonb and Allan J. B.
Watsona
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of
unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the
method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and
chiral esters with retention of chiral integrity.
www.rsc.org/
Introduction
and sustainability.
The amide functional group is extensively encountered within
nature and medicinal chemistry, where it is commonly found
in peptide bonds in proteins and small-molecule drugs,
respectively.1,2 Approximately a quarter of registered drugs are
found to contain an amide bond,3 thereby making amide bond
formation one of the most frequently executed
transformations within the pharmaceutical industry.4,5
However, established methods for the synthesis of amides
from carboxylic acids have a number of drawbacks, particularly
with regard to atom economy and sustainability, which
ultimately limit their effective application.6 In recent years,
several catalytic amidation methods have emerged seeking to
improve the atom economy of this process, and thus
minimising environmental impact.7-13
Within our own laboratories,
a programme focused on
catalytic amide bond formation has been developed in recent
years,23-26 with a view to addressing some of the outstanding
issues associated with this important transformation.
In a recent report, we aimed to determine if an exogenous
alcohol-derived additive could be employed to facilitate an
initial transesterification, forming an active ester intermediate
(1, Scheme 1) in situ, and ultimately enabling the direct
reaction of simple ester derivatives with amines.27 Through a
combination of reaction screening, where a range of additives,
bases and solvents were evaluated, and the application of
Design of Experiments (DoE) optimisation methods,28 it was
possible to develop
a
sustainable, inexpensive and
When considering the use of esters as coupling partners,
stoichiometric approaches allowing the direct conversion of
esters to amides have also been developed, overcoming the
protracted reaction times and high temperatures associated
with aminolysis.14,15 In recent years, catalytic approaches
enabling the aminolysis of ester derivatives have been
reported.16-22 However, despite the benefits of these catalytic
approaches, a number of limitations hinder their application.
In some cases only a limited substrate scope have beeen
demonstrated with respect to the acylating species, whereas
other approaches require the use of transition or rare earth
metals, raising potential issues associated with both toxicity
unprotracted procedure for the synthesis of amides from
unactivated ester derivatives and primary or cyclic secondary
amines using
a catalytic quantity (20 mol%) of 2,2,2-
trifluoroethanol (TFE) as an additive (Scheme 1).
Scheme 1. TFE-mediated catalytic amidation procedure.
In the current study, we present the full scope and limitations
of the complete process. We demonstrate the importance of
the choice of base on the outcome of the reaction, as well as
reporting further extension of the methodology in order to
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allow the incorporation of secondary acyclic amines,
previously intractable in the progenitor process. In addition to
this, we demonstrate an improved method for the preparation
of amide substrates based on enantiopure starting materials
with good retention of stereoconfiguration.
Results and Discussion
In our initial study, to investigate the general utility of the
methodology, a range of ester and amine starting materials
were assessed for their applicability in this reaction manifold
(Scheme 2). In our preliminary communication, a broad range
of amides were able to be prepared under the optimum
conditions developed.27 Several aryl esters, substituted with
both electron-withdrawing and electron-donating groups were
successfully coupled with benzylamine, furnishing the
corresponding amides (2-6
However, electron rich aryl esters (
comparatively less competent coupling partners.
)
in good to excellent yields.
6) were noted to be
Aliphatic esters were also tolerated (
7-11), including two
amino acid-derived substrates (11 & 12). However, significant
erosion of enantiopurity was unfortunately observed when
using an α-chiral ester, affording 11 (ee = 8% as determined by
chiral HPLC), which represented a limitation of the first
generation method at this stage. Esters containing heterocyclic
motifs (12-15) were also found to be proficient coupling
partners with pyridine- (12), pyrimidine- (13), and thiophene-
(
14) derived species furnishing good to excellent yields of the
respective amide derivatives.
Variation of the amine coupling partner from benzylamine
allowed further exemplification of the process. Aliphatic
amines could be successfully applied alongside heterocyclic
(
15) and aliphatic (16) esters. The successful coupling of
piperidine (17, 18) and piperazine (19) derivatives extended
the substrate scope, highlighting the applicability of the
approach to cyclic secondary amines. In order to demonstrate
the successful application of our methodology to a medicinally
relevant compound, the experimental Ampakine Farampator
Scheme 2. Representative scope of first generation process reported previously.27
a
b
Isolated yields shown. 8% ee as determined by chiral HPLC. Synthesised from the
(
20), currently in Phase II trials for ADHD,29 was prepared in a
corresponding ethyl ester starting material.
good yield of 60% in one step. Despite the general utility of the
method with the exemplars shown above, tertiary amides
prepared from acyclic secondary amines such as N-
methylbenzylamine (21) and dibenzylamine (22) could not be
In an effort to extend the utility of the process to
accommodate previously problematic substrates such as acylic
secondary amines and chiral ester derivatives, we first sought
to establish the role of pKa of the conjugate acid associated
with the base used. When developing our first generation
process, it was noted that the pKa values of both K3PO4 and
TFE are extremely similar (12.3 and 12.5, respectively). In
order to investigate whether this alignment of base and
additive pKa is a prerequisite for the reaction to proceed
efficiently, a selection of bases, representing a broader range
of pKa values than initially studied, were screened using a
model system (Table 1). Initial attempts focused on retaining
the potassium counterion (Table 1, Entries 1-8). From this it
could be noted that K3PO4 (Entry 6) was the optimal choice
with a 78% conversion obtained, fully consistent with our
prepared using this methodology, highlighting
limitation of the initially developed method.
a second
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previous observations. Potassium tert-butoxide (Entry 8) also system was again examined, and the effects of altering the
furnished the desired amide product but in a comparatively additive, base and solvent analysed via HPLC, the results of
lower conversion of 47%. The phosphate species of the base which are presented in Table 2.
was then retained and the role of the metal counterion was In the first instance, the model amidation was repeated using
next examined. (Table 1, Entries 9-13). The use of Mg3PO4 the conditions optimised for our progenitor process, resulting
(Entry 12) resulted in the only measurable conversion of 16%, in only 1% conversion to the desired amide (Table 2, Entry 1).
with the other counterions proving unsuccessful for reaction Moderate formation of the desired amide, however, was
progression. Cs2CO3 (Entry 14) also led to poor conversion, noted when using K3PO4 in conjunction with cyclopentylmethyl
indicating that potassium was the preferred counterion.
ether (CPME), 1,4-Dioxane and 2-MeTHF (Table 2, Entry 2-4).
Consistent with the extended base screen discussed above, no
A range of organic bases were then explored (Entries 15-19), other base was seen to promote the reaction. One exception
with all but DBU (Entry 18, 61%) proceeding with either no or to this is the use of KOtBu (Table 2, Entries 5-7) where the
minimal conversion to the amide product. From consideration desired amide could be formed in conversions of up to 96%.
of this extended base study, it can be concluded that those However, when the reaction was performed in the absence of
bases with a pKa in line with that of TFE (K3PO4 and DBU) the TFE additive, substantial direct aminolysis was observed
perform considerably better in the reaction manifold than (Table 2, Entry 7). This is consistent with earlier reports of
bases with a pKa either greater or less than 12. The exception using KOtBu to promote amidation of ester derivatives, we
to this is KOtBu which, although furnishes the amide in believe that the KOtBu is facilitating the reaction via radical-
moderate yield, is still less effective than the original base of based process.31,32
choice. Clearly, the choice of counterion is also important with
Table 2. Initial tertiary amide optimisation
other phosphate salts proving ineffective in the reaction. This
observation may be attributable to the solubility of the TFE
adduct in the reaction milieu.
Entry
Base
K3PO4
K3PO4
K3PO4
K3PO4
KOtBu
KOtBu
KOtBu
Solvent
THF
Conversion (%)
Table 1. Further investigation into the nature of the base species.
1
2
1
CPME
37
12
43
96
56
58
3
1,4-Dioxane
2-MeTHF
CPME
4
5
6
7a
THF
CPME
Entry
Base
pKa
Conversion (%)
1
2
KTFA
KH2PO4
KOAc
0
1
1
2
3
6
1
aReaction performed in the absence of TFE.
4
K2HPO4
K2CO3
K3PO4
KOH
KOtBu
Ca3PO4
Cs3PO4
Li3PO4
Mg3PO4
Na3PO4
Cs2CO3
NMO
7
1
5
10
12
16
18
13
13
13
13
13
10
7
2
6
78
5
With modest conversion to the desired amide observed,
further optimisation was undertaken. At this point in the
study, the ester species used in the model reaction was altered
to methyl 4-(trifluoromethyl)benzoate, as the inherent
electron-withdrawing characteristic of which was anticipated
to make the desired amidation reaction more amenable.
Despite examining a more activated substrate, the amidation
reaction was still found to not proceed when run in THF (Table
3, Entry 1). Interestingly, altering the order of addition of the
reaction, allowing a 30 minute window for formation of the
active ester intermediate before addition of the amine,
resulted in the desired amidation proceeding in 70%
conversion (Table 3, Entry 2). This was then subsequently
7
8
47
1
9
10
11
12
13
14
15
16
17
18
19
1
0
16
1
11
13
4
DABCO
Et3N
9
11
12
19
1
DBU
61
8
BEMP
applied to the amidation of methyl benzoate where
a
With further understanding into the choice of base used,
attention then turned to addressing the limitations identified
above. As discussed previously, the incompatibility of acyclic
secondary amines with the previously optimised conditions to
form tertiary amides represents a major gap in the scope of
method. We proposed that altering the additive, base and
solvent may overcome this problem. To this end, a model
significant increase in obtained conversion was again observed
(Table 3, Entry 3). Based on these results, we reason that
concomitant addition of the reactants result in a preferential
formation of
a quaternary ammonium salt between
trifluoroethanol and the amine substrate, precluding
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formation of the target amide due to sequestration of the TFE
catalyst in the insoluble base matrix.
i) CF3CH2OH (20 mol%)
K3PO4 (1 equiv),
1,4-Dioxane(2 M),
125 °C, 30 min
O
O
With the aim of further optimising this observed conversion,
the temperature of the reaction was increased, with the
solvent selected accordingly (Table 3, Entries 4-6). Pleasingly,
this resulted in a 93% isolated yield of the desired amide when
carrying out the reaction in dioxane (Table 3, Entry 5).
Importantly, the corresponding control reactions resulted in
no amide product (Table 3, Entries 7-9), confirming that the
reaction does not proceed via direct aminolysis but instead
requires formation of the TFE-derived active ester species.
R1
O
R1
N
ii) N-methylbenzylamine
(1equiv.)
O
O
N
O
N
N
F3C
NC
23, 71%
24, 93%
25, 43%
O
N
O
O
N
N
Cl
H2N
MeO
Table 3. Tertiary amide optimisation with increased temperature.
26, 62%
27, 0%
28, 71%
O
N
O
O
N
N
OMe
N
OMe
29, 93%
30, 21%
31, 52%
Entry
Solvent
Temperature
C)
Conversion
O
N
O
N
O
N
(°
(%)
0
N
O
1
2a
3a,b
4a
5a
THF
THF
90
90
32, 35%
33, 99%
34, 87%a
70
62
77c
93c
72c
0c
Scheme 3. Investigating the scope of the ester component. aSynthesised from the
THF
90
corresponding ethyl ester starting material.
CPME
125
125
100
125
125
125
1,4-Dioxane
6a
2-MeTHF
1,4-Dioxane
Having investigated the scope of the ester component in
conjunction with a model acyclic secondary amine, attention
was turned to variation of the amine coupling partner (Scheme
4). This was somewhat more limited in scope, as for example,
it was found that increasing the size of the substituent from N-
methylbenzylamine to the corresponding ethyl, isopropyl,
7a,d
8a,e
9a,f
0c
0c
1,4-Dioxane
1,4-Dioxane
a30 min preformation of active ester at reaction temperature. bMethyl benzoate
used as ester substrate. cIsolated yield. dPerformed in the absence of K3PO4.
ePerformed in the absence of TFE. Performed in the absence of both K3PO4 and
butyl and dibenzyl- derivatives (35-38) was not tolerated,
f
presumably due to steric hindrance. Returning to methylated
derivatives, substitution on the aromatic ring in the form of an
o-methoxy was tolerated in modest yield (39).
TFE.
With optimum conditions allowing the coupling of acyclic
secondary amines now established, we first sought to
investigate the scope of the ester component of the reaction
(Scheme 3). Pleasingly, several aryl esters, containing both
electron-withdrawing and electron-donating groups were
successfully coupled with N-methylbenzylamine, furnishing the
corresponding amides (23-30) in good to excellent yields.
Exceptions to this include the coupling of methyl 4-
aminobenzoate
(27), and ring systems bearing ortho
substitution (e.g. 30). Heteroaryl esters were also tolerated
within the reaction in moderate yields (31 and 32). Alkyl esters
(
33 and 34) furnished the corresponding amide products in
excellent yields when evaluated using this second generation
method.
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i) CF3CH2OH (20 mol%)
K3PO4 (1 equiv),
1,4-Dioxane(2M),
125 °C, 30 min
O
O
R2
N
O
ii) Amine (1 equiv.)
R1
O
N
O
N
O
N
35, 0%
36, 0%
37, 0%
O
N
O
N
O
N
MeO
38, 0%
39, 31%
40, 80%
O
O
N
O
N
N
N
41, 34%
42, 0%
43, 59%
O
O
N
O
O
N
S
N
44, 19%
45, 60%
46, 0%
O
N
O
N
O
Scheme 5. Application of stoichiometric TFE additive. a) yield obtained using 20 mol%
O
N
TFE.
O
47, 0%
48, 25%
49, 99%
From the chosen subset, it was apparent that the use of a full
equivalent of TFE does, indeed, in most cases increase the
yield obtained. The para fluoro substrate (50) could be
obtained in good yield of 58% compared to the previous 18%.
Scheme 4. Substrate scope of the acyclic secondary amine component
A range of heteroaryl esters (51-54) demonstrate the same
Pleasingly, homologation of the amine was tolerated in
moderate to good yield (40 and 41). Unfortunately, aniline
derivatives, such as 42, were not competent substrates under
these new conditions, which can be ascribed to their
inherently lower nucleophilicity. A range of heteroaryl derived
marked improvement, and in the case of the furan (32) and
thiophene (54) derivatives, almost full conversion of the ester
to the amide is obtained. For the glycine derived alkyl ester 55
,
a more modest increase in yield to 38% is observed. Pleasingly,
the pyrrolidinone derived ester 56, which was not a competent
substrate when using catalytic quantities of TFE, is now a
viable with a good yield of 62%.
amines
moderate to good yields of the corresponding amides
obtained. By contrast, alkyl amines (46 47 and 48) were in
(43-45) were successful coupling partners with
,
general not compatible with the reaction manifold. In the case
of amines such as 46 and 47 we propose this is attributable to
the volatility of the amine starting material under the high
temperature required for the reaction to proceed. However, as
expected, the electron rich amine 49 was found to undergo
amidation efficiently, forming the expected product in 99%
yield.
Unfortunately, the ethyl-derived amine 35 remained
incompatible with these conditions, supporting our earlier
observations that more sterically crowded secondary amines
do not undergo the desired amidation. However, the pyridine
derived amine 57 reflects the increased yields seen when
varying the ester substrate, and affords the corresponding
tertiary amide in 70%. In a similar fashion, the thiophene
derived methylamine
(
44
)
also exhibits
a
significant
Despite the success in developing reaction conditions that
were suitable for a number of acyclic secondary amine
substrates, from consideration of the substrate scope above, it
can be noted that a number of exemplars could only be
isolated in sub-optimal yields. In order to address this, we
reasoned that increasing the quantity of the trifluoroethanol
additive from a catalytic amount (20 mol%) to a full equivalent
may lead to increased yields. Accordingly, a subset of the
amide products previously examined were re-evaluated to
investigate this proposal (Scheme 5).
improvement in yield, with 92% of the amide product isolated,
compared to the previous 19%. Finally, an alkyl amine
previously studied was re-evaluated using a full equivalent of
TFE. Amide 58, previously obtained in 12% yield, could now be
isolated in a yield 65%.
Despite having compromised the catalytic nature of the
reactions for these more demanding substrates, this
stoichiometric approach compares favourably with other
established methods of amide coupling, especially given the
low cost of TFE33 as an additive. Accordingly, application of
stoichiometric quantities of TFE is a viable approach for
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substrates that are not compatible with the catalytic reaction
manifold.
100
90
80
70
60
50
40
30
20
10
0
Having successfully adapted the first generation method to
enable the condensation of acyclic secondary amines,
attention was turned to the remaining limitation of our
progenitor process. As discussed above, the amidation of
benzylamine and Boc-Phe-OMe to the corresponding amide
(
11) resulted essentially in complete epimerisation. Altering
the additive used from trifluoroethanol to 4-
0
1
2
3
4
5
6
7
8
9
10 11 12 13
(trifluoromethyl)phenol was found to minimise the extent of
racemisation, affording the amide in a comparable yield of
38% with an ee of 65%. Encouraged by this, we conducted a
more extensive screen of potential bases and additives in
order to identify further enhancements in both the yield and
corresponding enantiomeric excess of the amide product.
Accordingly, the coupling of Boc-Phe-OMe with benzylamine
mediated by 4-(trifluoromethyl)phenol was selected as the
model reaction, with the effect of varying the base initially
investigated (Table 4).
pKa of base
Figure 1. Effect of the pKa of the base compared to the ee of the obtained product.
Table 5. Effect of varying the additive on the yield and ee obtained.
O
O
H
N
H
N
Additive (20 mol%)
KOAc (1 equiv.)
THF (2M)
Boc
O
NH2
Boc
N
H
+
Ph
Ph
90 °C, 22h
11
Table 4. Effect of varying the base on the yield and ee obtained.
Entry
Additive
pKa
-
Yield (%)
28
ee
87
91
89
91
93
79
92
89
89
1
2
3
4
5
6
7
8
9
Picoline n-oxide
HOCt
2
54
HOAt
3
32
HOBt
5
47
Oxyma
NHS
5
50
Entry
Base
KTFA
pKa
0
Yield (%)
46
ee
93
87
92
92
92
85
75
40
16
8
58
1
2
3
4
5
6
7
8
9
4-CF3C6H4OH
HFIP
9
55
KH2PO4
KOAc
2
62
9
35
6
55
TFE
12
31
NMO
7
36
K2HPO4
DABCO
K2CO3
Cs2CO3
DBU
7
48
It can be noted from Table 5 that the nature of the additive
has little effect on the ee obtained, with only N-
hydroxysuccinimide (Table 5, Entry 6) leading to a product with
an ee less than 87 % (Figure 3). The use of HOCt34 (Table 5,
Entry 2) and 4-(trifluoromethyl)phenol (Table 5, Entry 7) led to
comparative yields and ee of the desired product, with 4-
(trifluoromethyl)phenol selected as the optimum additive due
to a marginally superior yield to ee balance.
9
40
10
10
12
46
34
69
From consideration of the data in Table 4, a clear trend can be
discerned between the strength of base and the extent of
racemisation (Figure 2). The use of KTFA (Table 4, Entry 1),
with a pKa of 0, results in minimal racemisation, whereas, if a
base with a pKa of greater 10 is used (Table 4, Entries 7-9), high
levels of racemisation are observed. Based on this, the base
offering the best combination of isolated yield relative to
product ee was deemed to be KOAc and, as such, was retained
for use in the following additive screen (Table 5).
In order to elucidate at which point epimerisation occurred in
the reaction, Boc-Phe-OMe and the corresponding amide
product (11) were individually subjected to the reaction
conditions in the absence of both 4-(trifluoromethyl)phenol
and benzylamine (Table 6).
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Table 6. Epimerisation Study
successfully utilised as a substrate, however the corresponding
amide was obtained in poor yield but with good retention of
enantiopurity.
Conclusions
In summary, we have successfully developed
a novel
organocatalysed approach to amide bond formation, from
readily available unactivated ester starting starting materials.
From initial conditions allowing the coupling of primary and
cyclic secondary amines, further tuning of reaction conditions
allowed the process to be optimised for secondary amines
which had previously proven intractable. A range of tertiary
amides were then successfully synthesised, with the process
tolerant to various functionalities. The original conditions were
also successfully adapted via alteration of the additive and
base from TFE/K3PO4 to 4-(trifluoromethyl)phenol/KOAC,
which successfully incorporated the application of alpha chiral
esters to our amidation protocol. Corresponding chiral amides
were synthesised accordingly with good to excellent retention
of chiral integrity observed.
Entry
Substrate
Initial
ee
ee upon reaction
completion
1
2
Boc-Phe-OMe
100
92
100
92
11
As shown in Table 6, after being subjected to the reaction
conditions, both Boc-Phe-OMe and 11 showed no degradation
in enantiopurity. It can, therefore, be inferred that the
observed level of racemisation in the reaction occurs at the
point of nucleophilic attack of the amine to the activated ester
species.
Having developed optimum conditions providing excellent
levels of stereoretention, a range of
α-chiral esters were
Experimental Section
prosecuted to validate the generality of the transformation
(Scheme 6).
General Methods. All reagents and solvents were used as obtained
unless otherwise stated. Purification was carried out according to
standard laboratory methods.35 BEMP was purified by vacuum
distillation from CaH2 and stored in a septum-sealed oven-dried
flask over previously activated 4 Å molecular sieves and purged with
and stored under nitrogen. Reactions were carried out under
Schlenk conditions using oven-dried glassware, which was
4-CF3C6H4OH (20 mol%)
KOAc (1 equiv.)
O
O
NH2
+
R1
O
R1
N
H
THF (2 M),
90 °C, 22 h
evacuated and purged with
N
2
before use. Thin layer
chromatography was carried out using aluminum-backed silica
plates which were analysed under 254 nm UV light or developed
O
O
O
H
CbzHN
CbzHN
N
N
H
N
H
N
H
Boc
using potassium permanganate solution. Flash chromatography
Ph
was carried out using ZEOprep 60 HYD 40-63 µm silica gel. 1H
NMR spectra were recorded at 400 or 500 MHz, and 13C NMR
spectra were recorded at 101 or 126 MHz. Chemical shifts are
reported in ppm, and coupling constants are reported in hertz with
11, 55%, 92% ee
59, 53%, 100% ee
60, 52%, 96% ee
O
N
O
N
H
O
CbzHN
N
H
CDCl3
referenced at 7.26 (1H) and 77.16 ppm (13C), and DMSO
H
S
OH
OH
referenced at 2.50 (1H) and 39.52 ppm (13C). Variable temperature
NMR experiments were performed at 400 MHz (1H) and 126 MHz
61, 33%, 89% ee
62, 80%, 83% ee
63, 67%, 98% ee
13C) at 298 or 333K. Mass spectrometry data was generated using
O
O
N
H
(
H
N
N
O
H
O
a TOF analyzer. Optical rotations were measured at 589 nm, with
concentrations reported in grams per 100 mL. Conversions were
determined by HPLC using caffeine as an internal standard. Chiral
HPLC data was obtained on an Agilent 1260 Infinity HPLC using a
Chiralpak IA column. The data for products 2 – 20 were reported in
our earlier communication.27
General Method for for Chiral Secondary Amide Substrate Scope
To an oven-dried, purged and sealed Schlenk tube containing 4-
(trifluoromethyl)phenol (46 mg, 0.28 mmol, 0.2 equiv.), KOAc (139
mg, 1.42 mmol, 1 equiv.), ester (1.42 mmol, 1 equiv.) and THF (700
μL) was added benzylamine (155 µL, 1.42 mmol, 1 equiv.). The
reaction mixture was heated at 90 °C for 22 h then diluted with
OH
O
64, 51%, 97% ee
65, 98%, 94% ee
66, 15%, 83% ee
Scheme 6. Substrate scope of enantiopure esters.
Pleasingly, good to excellent levels of stereoretention were
observed across the range of -chiral esters subjected to the
optimised conditions. Amino acid derived amides (59 61) were
α
-
successfully synthesised in moderate yield. Incorporation of a
hydroxyl group in the alpha position was also tolerated
without significant deterioration in the observed enantiomeric
excess, with the corresponding
α-hydroxy amides obtained in EtOAc (10 mL), washed with brine (3 x 10 mL), dried over Na2SO4,
and concentrated to a residue in vacuo which was purified by silica
moderate to good yields (62-64). A dioxolane containing ester
gel chromatography (MeOH/CH2Cl2 or Acetone/Pet. Ether 40 – 60
was successfully coupled, furnishing the desired amide in
excellent yield and stereoretention (65). Ibuprofen was also
°C).
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ARTICLE
Journal Name
General Method for Tertiary Amide Ester Substrate Scope
2835, 1630, 1580, 1398, 1269, 1042, 750, 698 cm-1; 1H NMR (400
MHz, 333 K, DMSO-d6): δH 7.39 – 7.27 (m, 6H), 7.01 – 6.95 (m, 3H),
4.58 (s, 2H), 3.76 (s, 3H), 2.86 (s, 3H); 13C NMR (101 MHz, CDCl3): δC
159.7, 129.7, 128.9, 128.3, 127.7, 126.8, 119.2, 119.0, 115.9, 115.5,
112.6, 112.1, 55.4, 50.9, 37.1, 33.4 (mixture of rotamers); HRMS
(ESI) m/z: [M+H]+ calcd for C16H18NO2 256.1332, found 256.1328.
To an oven-dried, purged and sealed Schlenk tube containing
trifluoroethanol (20 µL, 0.28 mmol, 0.2 equiv.), K3PO4 (301 mg, 1.42
mmol, 1 equiv.) and 1,4-Dioxane (700 μL) was added ester (1.42
mmol, 1 equiv.) and the reaction heated at 125 °C for 30 min. N-
methylbenzylamine (183 µL, 1.42 mmol, 1 equiv.) was then added
and the reaction mixture was heated at 125 °C for a further 22 h. N-benzyl-2-methoxy-N-methylbenzamide (30). Purified by silica gel
Reaction was then diluted with EtOAc (10 mL), washed with brine (3 chromatography (1% MeOH/CH2Cl2), affording the title compound
x 10 mL), dried over Na2SO4, and concentrated to a residue in vacuo as a yellow oil (78 mg, 21%): νmax (neat) 3062, 3029, 3004, 2922,
which was purified by silica gel chromatography (MeOH/CH2Cl2).
2837, 1629, 1601, 1400, 1247, 1024, 754, 700 cm-1; 1H NMR (400
MHz, 333 K, DMSO-d6): δH 7.42 – 6.95 (m, 9H), 4.69 (s, 1H), 4.30 (s,
1H), 3.83 (s, 2H), 3.78 (s, 1H), 2.88 (s, 1H), 2.68 (s, 2H) (mixture of
rotamers); 13C NMR (101 MHz, 333 K, DMSO-d6): δC 168.2, 154.7,
137.1, 136.7, 129.9, 128.2, 127.4, 127.1, 127.0, 126.8, 126.7, 126.2,
120.5, 120.3, 111.4, 55.4, 55.2, 53.3, 49.1, 35.1, 31.6 (mixture of
rotamers); HRMS (ESI) m/z: [M+H]+ calcd for C16H18NO2 256.1332,
N-benzyl-N-methylbenzamide (23).36 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (226 mg, 71%): νmax (neat) 3060, 3029, 2921, 1629,
1398, 1264, 1068, 698 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6):
δH 7.45 – 7.42 (m, 5H), 7.39 -7.36 (m, 2H), 7.29 (t, J = 7.2 Hz, 3H),
4.60 (s, 2H), 2.86 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 172.4, 171.7, found 256.1330.
137.2, 136.7, 136.4, 129.7, 128.9, 128.5, 128.3, 127.7, 127.1, 126.9, N-benzyl-N-methylnicotinamide (31). Purified by silica gel
55.3, 50.9, 37.1, 33.3 (mixture of rotamers); HRMS (ESI) m/z: chromatography (2% MeOH/CH2Cl2), affording the title compound
[M+H]+ calcd for C15H16NO 226.1226, found 226.1224.
as a yellow oil (166 mg, 52%): νmax (neat) 3026, 2919, 1627, 1400,
1074, 1026, 734, 699 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6): δH
8.64 (d, J = 5.4 Hz, 2H), 7.86 (d, J = 7.3 Hz, 1H), 7.47 – 7.28 (m, 6H),
4.62 (s, 2H), 2.90 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 169.8, 169.1,
150.9, 148.1, 147.9, 136.7, 136.1, 135.1, 134.8, 132.2, 129.1, 129.0,
128.4, 127.9, 126.7, 123.5, 55.3, 51.1, 37.1, 33.7 (mixture of
rotamers); HRMS (ESI) m/z: [M+H]+ calcd for C14H15N2O 227.1179,
N-benzyl-N-methyl-4-(trifluoromethyl)benzamide (24).37 Purified by
silica gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow oil (386 mg, 93%): νmax (neat) 3066, 3032,
2926, 1634, 1407, 1325, 1167, 1109, 1072, 852, 700 cm-1; H NMR
1
(500 MHz, 333 K, DMSO-d6): δH 7.79 (d, J = 7.5 Hz, 2H), 7.66 (d, J =
7.7 Hz, 2H), 7.39 – 7.28 (m, 5H), 4.69 – 4.44 (m, 2H), 2.85 (s, 3H); 13
C
NMR (126 MHz, 333 K, DMSO-d6): δC 169.0, 140.3, 136.8, 129.5 (q, found 227.1173.
2JCF = 32.0 Hz), 128.4, 127.3, 127.0, 125.1 (q, 3JCF = 3.6 Hz), 123.7 (q, N-benzyl-N-methyl-2-phenylacetamide (33).37 Purified by silica gel
1JCF = 272.4 Hz), 53.8, 49.8, 36.4, 32.5 (mixture of rotamers); HRMS chromatography (1% MeOH/CH2Cl2), affording the title compound
(ESI) m/z: [M+H]+ calcd for C16H15F3NO 294.1100, found 294.1096.
N-benzyl-4-cyano-N-methylbenzamide (25).38 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (153 mg, 43%): νmax (neat) 3060, 3030, 2924, 2230,
1632, 1402, 1264, 1070, 850, 700 cm-1; 1H NMR (400 MHz, 333 K,
DMSO-d6): δH 7.89 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 7.9 Hz, 2H), 7.39 –
as a yellow oil ( 336 mg, 99%): νmax (neat) 3062, 3029, 2921, 1640,
1400, 1109, 731, 698 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6): δH
7.31 – 7.20 (m, 10H), 4.62 (s, 1H), 4.53 (s, 1H), 3.77 (s, 2H), 2.94 (s,
2H), 2.82 (s, 1H) (mixture of rotamers); 13C NMR (101 MHz, 333 K,
DMSO-d6): δC 170.2, 137.5, 135.5, 128.7, 128.1, 127.9, 127.2, 126.7,
126.0, 52.6, 49.9, 34.8; HRMS (ESI) m/z: [M+H]+ calcd for C16H18NO
7.28 (m, 5H), 4.66 (s, 2H), 2.85 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 240.1383, found 240.1382.
170.4, 169.7, 140.8, 140.7, 136.6, 136.0, 132.5, 129.2, 129.0, 128.4, N-benzyl-N-methyl-2-(pyridin-2-yl)acetamide (34). Purified by silica
128.1, 127.9, 127.8, 127.6, 126.6, 118.2, 113.6, 55.1, 51.0. 36.9, gel chromatography (2% MeOH/CH2Cl2), affording the title
33.5 (mixture of rotamers); HRMS (ESI) m/z: [M+H]+ calcd for compound as an orange oil (293 mg, 87%): νmax (neat) 3060, 3029,
C16H15N2O 251.1179, found 251.1178.
3008, 2924, 1642, 1435, 1400, 1111, 756, 733, 700 cm-1; 1H NMR
(400 MHz, 333 K, DMSO-d6): δH 8.49 (s, 1H) 7.73 (t, J = 6.8 Hz, 1H),
7.32 (d, J = 7.8 Hz, 3H), 7.24 (d, J = 7.0 Hz, 3H), 4.69 (s, 1H), 4.54 (s,
1H), 3.94 (s, 1H), 3.91 (s, 1H), 2.99 (s, 2H), 2.82 (s, 1H) (mixture of
rotamers); 13C NMR (101 MHz, 333 K, DMSO-d6): δC 169.5, 156.0,
148.6, 136.0, 128.3, 128.1, 127.2, 126.9, 126.6, 126.4, 123.5, 121.4,
N-benzyl-4-chloro-N-methylbenzamide (26).37 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow solid (229 mg, 62%): νmax (neat) 3055, 3030, 2913, 1632,
1409, 1087, 1074, 1016, 843, 739, 698 cm-1; 1H NMR (400 MHz, 333
K, DMSO-d6): δH 7.50 – 7.45 (m, 4H), 7.39 – 7.35 (m, 2H), 7.31 –
7.27 (m, 3H), 4.59 (s, 2H), 2.86 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 52.7, 49.9, 42.6, 35.0, 33.1 (mixture of rotamers); HRMS (ESI) m/z:
171.3, 170.7, 136.9, 136.5, 135.9, 134.7, 128.9, 128.7, 128.5, 128.4, [M+H]+ calcd for C15H17N2O 241.1335, found 241.1335.
127.8, 126.7, 55.3, 51.1, 37.1, 33.5 (mixture of rotamers); HRMS
(ESI) m/z: [M+H]+ calcd for C15H15ClNO 260.0837, found 260.0831.
General Method for Tertiary Amide Amine Substrate Scope
N-benzyl-4-methoxy-N-methylbenzamide (28).39 Purified by silica To an oven-dried, purged and sealed Schlenk tube containing
gel chromatography (1% MeOH/CH2Cl2), affording the title trifluoroethanol (20 µL, 0.28 mmol, 0.2 equiv.), K3PO4 (301 mg, 1.42
compound as a yellow oil (258 mg, 71%): νmax (neat) 2958, 2919, mmol, 1 equiv.) and 1,4-Dioxane (700 μL) was added methyl
2839, 1625, 1608, 1396, 1249, 1174, 1029, 841, 700 cm-1; H NMR benzoate (178 µL, 1.42 mmol, 1 equiv.) and the reaction heated at
1
(400 MHz, 333 K, DMSO-d6): δH 7.43 - 7.35 (m, 4H), 7.30 – 7.26 (m, 125 °C for 30 min. Amine (1.42 mmol, 1 equiv.) was then added and
3H), 6.99 – 6.96 (m, 2H), 4.60 (s, 2H), 3.80 (s, 3H), 2.88 (s, 3H); 13C
the reaction mixture was heated at 125 °C for a further 22 h.
NMR (101 MHz, CDCl3): δC 171.8, 160.8, 137.2, 129.1, 128.9, 128.4, Reaction was then diluted with EtOAc (10 mL), washed with brine (3
127.6, 126.9, 113.8, 55.4, 51.2, 37.3, 33.6 (mixture of rotamers); x 10 mL), dried over Na2SO4, and concentrated to a residue in vacuo
HRMS (ESI) m/z: [M+H]+ calcd for C16H18NO2 256.1332, found which was purified by silica gel chromatography (MeOH/CH2Cl2).
256.1325.
N-benzyl-3-methoxy-N-methylbenzamide (29).38 Purified by silica gel N-(2-methoxybenzyl)-N-methylbenzamide (39). Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (338 mg, 93%): νmax (neat) 3062, 3029, 3004, 2935, as a yellow solid (113 mg, 31%): νmax (neat) 3017, 2924, 2842, 1629,
8 | J. Name., 2012, 00, 1-3
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ARTICLE
1241, 1024, 756, 728 cm-1; 1H NMR (500 MHz, 333 K, DMSO-d6): δH DMSO-d6): δH 7.44 – 7.43 (m, 3H), 7.38 7.36 (m, 2H), 4.56 (s, 1H),
3.44 (s, 2H), 3.30 (s, 6H), 2.96 (s, 3H); 13C NMR (126 MHz, CDCl3): δC
7.42 (s, 5H), 7.30 – 7.26 (m, 1H), 7.18 (s, 1H), 7.01 – 6.96 (m, 2H),
4.54 (s, 2H), 3.76 (s, 3H), 2.86 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 172.6, 171.8, 136.5, 129.7, 128.5, 127.1, 103.5, 103.1, 54.8, 53.2,
172.7, 171.7, 136.8, 136.6, 129.6, 129.3, 128.8, 128.4, 127.8, 127.0, 50.0, 39.6, 34.5 (mixture of rotamers); HRMS (ESI) m/z: [M+H]+
120.8, 120.7, 110.4, 55.5,55.2, 50.7, 45.5, 37.5, 33.4 (mixture of calcd for C12H18NO3 224.1281, Found 224.1281.
rotamers); HRMS (ESI) m/z: [M+H]+ calcd for C16H18NO2 256.1332,
General Method for Tertiary Amide Substrate Scope Using a Full
Equivalent of TFE
found 256.1332.
N-methyl-N-phenethylbenzamide (40).40 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (271 mg, 80%): νmax (neat) 3060, 3027, 2928, 1629,
1400, 1070, 700 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6): δH 7.43
– 7.38 (m, 3H), 7.28 - 7.19 (m, 7H), 3.54 (s, 2H), 2.86 (s, 5H); 13C
NMR (101 MHz, CDCl3): δC 172.3, 171.4, 139.2, 138.0, 136.7, 129.5,
129.3, 129.0, 128.9, 128.7, 128.4, 127.0, 126.6, 53.1, 49.5, 38.4,
34.9, 33.6, 33.2 (mixture of rotamers); HRMS (ESI) m/z: [M+H]+
calcd for C16H18NO 240.1383, found 240.1379.
To an oven-dried, purged and sealed Schlenk tube containing
trifluoroethanol (100 µL, 1.42 mmol, 1 equiv.), K3PO4 (301 mg, 1.42
mmol, 1 equiv.) and 1,4-Dioxane (700 μL) was added ester (1.42
mmol, 1 equiv.) and the reaction heated at 125 °C for 30 min.
Amine (1.42 mmol, 1 equiv.) was then added and the reaction
mixture was heated at 125 °C for a further 22 h. Reaction was then
diluted with EtOAc (10 mL), washed with brine (3 x 10 mL), dried
over Na2SO4, and concentrated to a residue in vacuo which was
purified by silica gel chromatography (MeOH/CH2Cl2).
N-methyl-N-(3-phenylpropyl)benzamide (41). Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as an orange oil (121 mg, 34%): νmax (neat) 3060, 3027, 2930, 2861,
1629, 1400, 1072, 700 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6):
δH 7.42 – 7.37 (m, 3H), 7.35 – 7.33 (m, 2H), 7.27 – 7.23 (m, 2H), 7.18
– 7.14 (m, 2H), 3.35 (s, 2H), 2.92 (s, 3H), 2.54 (s, 4H), 1.87 (m, 2H);
13C NMR (101 MHz, CDCl3): δC 172.1, 171.5, 141.8, 140.9, 136.8,
129.5, 128.6, 128.5, 128.2, 127.0, 126.7, 126.2, 51.0, 47.4, 37.6,
33.4, 32.9, 32.8, 29.9, 28.8 (mixture of rotamers); HRMS (ESI) m/z:
[M+H]+ calcd for C17H20NO 254.1539, found 254.1533.
N-benzyl-N-methylfuran-2-carboxamide (32).37 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as an orange oil (304 mg, 99%): νmax (neat) 3112, 3062, 3030, 2922,
1621, 1493, 1400, 1070, 746, 700 cm-1; 1H NMR (500 MHz, 333 K,
DMSO-d6): δH 7.80 (s, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.28 (dd, J = 10.1,
7.7 Hz, 3H), 7.00 (s, 1H), 6.60 (dd, J = 3.1, 1.6 Hz, 1H), 4.72 (s, 2H),
3.06 (s, 3H); 13C NMR (126 MHz, CDCl3): δC 160.6, 148.1, 144.1,
137.0, 128.8, 128.3, 127.6, 127.1, 116.6, 111.4, 54.3, 52.0, 35.9,
34.4 (mixture of rotamers); HRMS (ESI) m/z: [M+H]+ calcd for
C13H14NO2 216.1019, found 216.1015.
N-methyl-N-(thiophen-2-ylmethyl)benzamide (44). Purified by silica
gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow oil (304 mg, 92%): νmax (neat) 3062, 2924,
1629, 1398, 1068, 700 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6):
δH 7.47 – 7.40 (m, 6H), 7.04 (s, 1H), 7.00 (dd, J = 5.1, 3.4 Hz, 1H)
4.74 (s, 2H), 2.90 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 174.1, 139.8,
136.2, 128.6, 127.1, 126.1, 125.7, 50.6, 45.9, 37.0, 32.9 (mixture of
rotamers); HRMS (ESI) m/z: [M+H]+ calcd for C13H14NOS 232.0791,
found 232.0787.
N-methyl-N-(pyridin-2-ylmethyl)benzamide (43).41 Purified by silica
gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow oil (190 mg, 59%): νmax (neat) 3058, 3010,
2926, 1629, 1398, 1072, 702 cm-1; 1H NMR (400 MHz, 333 K, DMSO-
d6): δH 8.57 – 8.55 (m, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (s, 5H),
7.31 – 7.28 (m, 2H), 4.66 (s, 2H), 2.95 (s, 3H); 13C NMR (101 MHz,
CDCl3): δC 172.7, 171.7, 157.3, 156.9, 150.0, 149.4, 137.0, 130.2,
129.8, 128.5, 127.2, 127.0, 122.6, 122.3, 121.0, 57.1, 53.1, 38.0,
33.8 (mixture of rotamers); HRMS (ESI) m/z: [M+H]+ calcd for
C14H15N2O 227.1179, found 227.1175.
N-(furan-2-ylmethyl)-N-methylbenzamide (45). Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a brown oil (183 mg, 60%): νmax (neat) 3116, 3060, 2922, 1630,
1400, 1068, 1014, 700 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6):
δH 7.60 (dd, J = 1.8, 0.8 Hz, 1H), 7.47 – 7.40 (m, 5H), 6.43 (dd, J = 3.2,
1.9 Hz), 6.35 (s, 1H), 4.54 (s, 2H), 2.89 (s, 3H); 13C NMR (101 MHz,
CDCl3) δC 172.2, 171.5, 150.9, 150.3, 142.8, 142.5, 136.2, 129.3,
128.5, 127.2, 110.5, 108.8, 108.6, 48.5, 43.8, 37.3, 33.0 (mixture of
rotamers); HRMS (ESI) m/z: [M+H]+ calcd for C13H14NO2 216.1019,
found 216.1016.
N-(cyclohexylmethyl)-N-methylbenzamide (48). Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (83 mg, 25%): νmax (neat) 2921, 2850, 1629, 1448,
1402, 1288, 1070, 700 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6):
δH 7.44 – 7.40 (m, 3H), 7.35 – 7.32 (m, 2H), 3.23 (s, 2H), 2.90 (s, 3H),
1.70 – 1.55 (m, 7H), 1.22 – 1.17 (m, 4H); 13C NMR (126 MHz, CDCl3):
δC 172.5, 171.8, 167.7, 137.2, 137.1, 135.1, 131.4, 129.4, 129.2,
128.7, 128.5, 127.2, 127.0, 57.7, 53.7, 46.4, 38.5, 38.2, 36.5, 36.0,
33.3, 31.1, 30.9, 30.6, 26.6, 26.5, 26.4, 26.1, 26.0, 25.9 (mixture of
rotamers); HRMS (ESI) m/z: [M+H]+ calcd for C15H22NO 232.1696,
N-benzyl-4-fluoro-N-methylbenzamide (50).39 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (200 mg, 58%): νmax (neat) 3064, 3029, 2922, 1630,
1604, 1400, 1225, 1068, 847, 700 cm-1; 1H NMR (400 MHz, 333 K,
DMSO-d6): δH 7.53 - 7.49 (m, 2H), 7.39 – 7.35 (m, 2H), 7.31 – 7.22
(m, 5H), 4.60 (s, 2H), 2.87 (s, 3H)
13C NMR (101 MHz, CDCl3): δC
;
1
170.7, 163.5 (d, JCF = 249.5 Hz), 137.0, 136.7, 132.4, 129.4, 129.0,
2
128.4, 127.8, 126.7, 115.6 (d, JCF = 21.8 Hz), 55.4, 51.1, 37.2, 33.6;
HRMS (ESI) m/z: [M+H]+ calcd for C15H15FNO 244.1132, found
244.1127.
N-benzyl-N,6-dimethylnicotinamide (51). Purified by silica gel
chromatography (2% MeOH/CH2Cl2), affording the title compound
as a yellow oil (181 mg, 53%): νmax (neat) 3030, 2922, 1629, 1599,
1402, 1074, 754, 700 cm-1; 1H NMR (500 MHz, 333 K, DMSO-d6): δH
8.53 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 –
7.29 (m, 4H), 4.62 (s, 2H), 2.90 (s, 3H), 2.51 (s, 3H); 13C NMR (101
MHz, CDCl3): δC 170.1, 169.4, 160.1, 147.6, 147.3, 136.7, 136.2,
135.5, 135.2, 129.2, 129.0, 128.9, 128.3, 127.8, 126.6 123.0, 55.3,
51.1, 37.1, 33.6, 24.5 (mixture of rotamers); HRMS (ESI) m/z:
[M+H]+ calcd for C15H17N2O 241.1335, found 241.1330.
found
232.1693.
N-benzyl-N-methylpyrazine-2-carboxamide (52). Purified by silica
gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow oil (130 mg, 40%): νmax (neat) 3058, 3025,
2924, 1632, 1085, 1019, 701 cm-1; 1H NMR (400 MHz, 333 K, DMSO-
d6): δH 8.87 (d, J = 13.8 Hz, 1H), 8.72 (d, J = 9.9 Hz, 1H), 8.66 (d, J =
N-(2,2-dimethoxyethyl)-N-methylbenzamide (49). Purified by silica
gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow oil (314 mg, 99%): νmax (neat) 2935, 2835,
1
1632, 1400, 1126, 1072, 1027, 702 cm-1; H NMR (500 MHz, 333 K,
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14.0 Hz, 1H), 7.37 – 7.26 (m, 5H), 4.73 (s, 1H), 4.60 (s, 1H), 2.96 (s, 32.8, 30.5, 29.2, 20.2, 19.7, 14.0, 13.7 (mixture of rotamers); HRMS
1H), 2.93 (s, 2H) (mixture of rotamers); 13C NMR (101 MHz, CDCl3): (ESI) m/z: [M+H]+ calcd for C12H18NO 192.1383, found 192.1379.
δC 167.1, 166.8, 150.0, 149.9, 145.7, 145.6, 145.4, 142.7 (2), 136.5,
General Method for for Chiral Secondary Amide Substrate Scope
To an oven-dried, purged and sealed Schlenk tube containing 4-
(trifluoromethyl)phenol (46 mg, 0.28 mmol, 0.2 equiv.), KOAc (139
mg, 1.42 mmol, 1 equiv.), ester (1.42 mmol, 1 equiv.) and THF (700
μL) was added benzylamine (155 µL, 1.42 mmol, 1 equiv.). The
reaction mixture was heated at 90 °C for 22 h then diluted with
EtOAc (10 mL), washed with brine (3 x 10 mL), dried over Na2SO4,
and concentrated to a residue in vacuo which was purified by silica
gel chromatography (MeOH/CH2Cl2 or Acetone/Pet. Ether 40 – 60
°C).
136.4, 128.9, 128.4, 128.0, 127.8, 127.5, 54.8, 51.6, 36.6, 33.8
(mixture of rotamers); HRMS (ESI) m/z: [M+H]+ calcd for C13H12N3O
226.0986, found 226.0976.
N-benzyl-N-methyl-1H-pyrrole-2-carboxamide (53).42 Purified by
silica gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as an orange solid (218 mg, 71%): νmax (neat) 3231,
1
1589, 1400, 1134, 788, 730, 721, 691 cm-1; H NMR (400 MHz, 333
K, DMSO-d6): δH 11.31 (s, 1H), 7.38 – 7.26 (m, 5H), 6.90 (td, J = 2.7,
1.4 Hz, 1H), 6.48 (s, 1H), 6.11 (dt, J = 3.6, 2.5 Hz, 1H) 4.75 (s, 2H),
3.11 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 163.0, 137.3, 128.9,
127.5, 121.5, 112.8, 109.8, 52.5, 36.2 (mixture of rotamers); HRMS
(ESI) m/z: [M+H]+ calcd for C13H15N2O 215.1179, Found 215.1179.
N-benzyl-N-methylthiophene-2-carboxamide (54). Purified by silica
gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow oil (313 mg, 95%): νmax (neat) 3086, 3029,
2921, 1608, 1396, 1029, 700 cm-1; 1H NMR (400 MHz, 333 K, DMSO-
d6): δH 7.74 (dd, J = 5.0, 1.1 Hz, 1H), 7.44 (d, J = 3.0 Hz, 1H), 7.41 –
7.36 (m, 2H), 7.31 – 7.27 (m, 3H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H), 4.73
(s, 2H), 3.08 (s, 3H); 13C NMR (101 MHz, CDCl3): δC 164.9, 137.9,
136.9, 129.2, 129.0, 127.7, 126.9, 53.5, 35.7; HRMS (ESI) m/z:
[M+H]+ calcd for C13H14NOS 232.0791, found 232.0786
benzyl (R)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate (59).45
Purified by silica gel chromatography (0.5% MeOH/CH2Cl2),
affording the title compound as a white solid (235 mg, 53%): νmax
(neat) 3284, 3060, 3034, 2978, 2932, 1684, 1644, 1526, 1258, 1228,
1048, 698 cm-1; 1H NMR (400 MHz, CDCl3): δH 7.37 – 7.22 (m, 10H),
6.55 (s, 1H), 5.43 (s, 1H), 5.08 – 5.01 (m, 2H), 4.46 – 4.36 (m, 2H),
4.29 – 4.26 (m, 1H), 1.42 – 1.37 (m, 3H); 13C NMR (101 MHz, CDCl3):
δC 172.3, 156.2, 138.0, 136.2, 128.9, 128.7, 128.4, 128.2, 127.8,
127.7, 67.2, 50.8, 43.7, 18.8; HRMS (ESI) m/z: [M+H]+ calcd for
C18H21N2O3 313.1547, found 313.1545; ee = 100%; [α]D20 -10.2 (c =
1.0, EtOH).
tert-butyl (2-(benzyl(methyl)amino)-2-oxoethyl)carbamate (55).43
Purified by silica gel chromatography (1% MeOH/CH2Cl2), affording
the title compound as a yellow oil (152 mg, 38%): νmax (neat) 3406,
1
2978, 2934, 1711, 1653, 1368, 1163, 1052, 702 cm-1; H NMR (500
benzyl (S)-(1-(benzylamino)-4-methyl-1-oxopentan-2-yl)carbamate
(60).46 Purified by silica gel chromatography (1% MeOH/CH2Cl2),
affording the title compound as a white solid (262 mg, 52%): νmax
(neat) 3315, 3271, 3066, 2958, 2932, 1684, 1645, 1530, 1236, 1055,
696 cm-1; 1H NMR (400 MHz, CDCl3): δH 7.38 – 7.25 (m, 10H), 6.52 (s,
1H), 5.30 (d, J = 7.7 Hz, 1H), 5.13 – 5.05 (m, 2H), 4.49 – 4.38 (m, 2H),
4.25 – 4.24 (m ,1H), 1.75 – 1.65 (m, 2H), 1.58 – 1.54 (m, 1H), 0.99 –
0.94 (m, 6H) ; 13C NMR (101 MHz, CDCl3): δC 172.2, 156.4, 138.0,
136.2, 128.9, 128.7, 128.4, 128.2, 127.8, 127.7, 67.2, 53.8, 43.7,
41.9, 41.6, 24.8, 23.1, 22.1; HRMS (ESI) m/z: [M+H]+ calcd for
MHz, 333 K, DMSO-d6): δH 7.33 – 7.22 (m, 5H), 4.52 (s, 2H), 3.85 (d,
J = 4.9 Hz, 2H), 3.68 (d, J = 6.2 Hz, 1H), 2.90 – 2.78 (m, 3H), 1.39 (s,
9H) (mixture of rotamers); 13C NMR (126 MHz, 333 K, DMSO-d6): δC
170.5, 168.7, 155.4, 137.3, 128.4, 128.1, 127.3, 127.0, 126.7, 126.4,
78.0, 77.1, 51.2, 50.2, 41.6, 33.4, 27.9 (mixture of rotamers); HRMS
(ESI) m/z: [M+H]+ calcd for C15H23N2O3 279.1703, found 279.1696.
N-benzyl-N-methyl-2-(2-oxopyrrolidin-1-yl)acetamide (56). Purified
by silica gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow solid (216 mg, 62%): νmax (neat) 2954, 2917,
1
2876, 1684, 1645, 754, 705 cm-1; H NMR (400 MHz, 333 K, DMSO-
20
d6): δH 7.36 – 7.22 (m, 5H), 4.57 – 4.51 (m, 2H), 4.12 (s, 2H), 3.42 -
3.39 (m, 2H), 2.92 -2.82 (m, 3H), 2.27 – 2.19 (m, 2H), 1.99 – 1.95 (m,
2H) (mixture of rotamers); 13C NMR (101 MHz, 333 K, DMSO-d6): δC
174.0, 167.1, 128.4, 128.1, 127.3, 126.8, 126.4, 54.5, 51.5, 50.1,
47.0, 43.5, 33.6, 29.7, 17.3 (mixture of rotamers); HRMS (ESI) m/z:
[M+H]+ calcd for C14H19N2O2 247.1441, found 247.1445.
N-methyl-N-(pyridin-3-ylmethyl)benzamide (57). Purified by silica
gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow oil (225 mg, 70%): νmax (neat) 3057, 3030,
2924, 1627, 1400, 1070, 1027, 787, 715, 702 cm-1; 1H NMR (400
MHz, 333 K, DMSO-d6): δH 8.51 (dd, J = 4.7, 1.5 Hz, 2H), 7.70 (s, 1H),
7.44 (s, 5H), 7.39 (dd, J = 7.8, 4.8 Hz, 1H), 4.64 (s, 2H), 2.89 (s, 3H);
13C NMR (101 MHz, CDCl3): δC 171.9, 149.6, 149.2, 148.8, 136.2,
135.9, 134.6, 132.8, 130.0, 128.6, 127.1, 123.9, 52.9, 48.6, 37.2,
33.2 (mixture of rotamers); HRMS (ESI) m/z: [M+H]+ calcd for
C14H15N2O 227.1179, found 227.1176.
C21H27N2O3 355.2016, found 355.2016; ee = 96%; [α]D -16.0 (c =
1.2, EtOH), lit [α]D22 -14.1 (c = 1.2, EtOH).
benzyl(S)-(1-(benzylamino)-4-(methylthio)-1-oxobutan-2-
yl)carbamate (61).47 Purified by silica gel chromatography (0.5%
MeOH/CH2Cl2), affording the title compound as a white solid (174
mg, 33%): νmax (neat) 3280, 2915, 1690, 1642, 1534, 1256, 1238,
1
1050, 1029, 698 cm-1; H NMR (400 MHz, CDCl3): δH 7.37 – 7.23 (m,
10H), 6.52 (s, 1H), 5.54 (d, J = 7.2 Hz, 1H), 5.10 (d, J = 11.6 Hz, 2H),
4.49 – 4.35 (m, 3H), 2.61 - 2.45 (m, 2H), 2.15 – 1.95 (m, 6 H); 13C
NMR (101 MHz, CDCl3): δC 171.0, 137.9, 128.9, 128.7, 128.4, 128.3,
127.9, 127.8, 67.3, 54.1, 43.8, 31.7, 30.3, 15.3; HRMS (ESI) m/z:
[M+H]+ calcd for C20H25N2O3S 373.1580, found 373.1580; ee = 89%;
[α]D20 12.4 (c = 1.0, EtOH).
(R)-N-benzyl-2-hydroxy-2-phenylacetamide (62).48 Purified by silica
gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a white solid (273 mg, 80%): νmax (neat) 3406, 3285,
3183, 1647, 1539, 1455, 1068, 758, 707 cm-1; 1H NMR (400 MHz,
CDCl3): δH 7.39 – 7.24 (m, 8H), 7.17 (d, J = 7.4 Hz, 2H), 6.67 (s, 1H),
5.02 -5.01 (m, 1H), 4.44 – 4.34 (m, 2H), 3.89 - 3.86 (m, 1H); 13C NMR
N-butyl-N-methylbenzamide (58).44 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (176 mg, 65%): νmax (neat) 2958, 2932, 2872, 1629,
1402, 1072, 702 cm-1; 1H NMR (400 MHz, 333 K, DMSO-d6): δH 7.44
– 7.41 (m, 3H), 7.36 – 7.33 (m, 2H), 3.32 (s, 2H), 2.91 (s, 3H), 1.53
(m, 2H), 1.23 (s, 2H), 0.85 (s, 3H); 13C NMR (101 MHz, CDCl3): δC
172.1, 171.4, 137.0, 129.4, 128.5, 127.0, 126.8, 51.2, 47.3, 37.6, (101 MHz, CDCl3): δC 172.2, 139.6, 137.8, 128.9, 128.8, 128.8, 127.7,
10 | J. Name., 2012, 00, 1-3
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ARTICLE
126.9, 74.3, 43.5; HRMS (ESI) m/z: [M+H]+ calcd for C15H16NO2
242.1176, found 242.1174; ee = 83%; [α]D20 -26.6 (c = 0.23, MeOH),
lit [α]D20 -5.6 (c = 0.23, MeOH).
Notes and references
1. N. Sewald and H. D. Jakubke, Peptides: Chemistry and
Biology, 2nd edition., Wiley-VCH: Weinheim, 2009.
(S)-N-benzyl-2-hydroxy-3-phenylpropanamide (63).49 Purified by
silica gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a white solid (241 mg, 67%): νmax (neat) 3366, 2919,
1629, 1534, 1091, 1074, 702 cm-1; 1H NMR (400 MHz, CDCl3): δH
7.34 – 7.23 (m, 8H), 7.19 (d, J = 6.8 Hz, 2H), 6.82 ( br. s, 1H), 4.49 –
4.33 (m, 3H), 3.25 (dd, J = 13.9, 4.1 Hz, 1H), 2.94 (dd, J = 13.9, 8.2
Hz, 1H), 2.70 (s, 1H); 13C NMR (101 MHz, CDCl3): δC 172.6, 138.0,
136.9, 129.7, 128.9, 128.8, 127.9, 127.7, 127.2, 73.0, 43.2, 41.0;
HRMS (ESI) m/z: [M+H]+ calcd for C16H18NO2 256.1332, found
256.1333; ee = 98%; [α]D20 -55.7 (c = 3.4, EtOAc), lit [α]D20 -44.4 (c =
3.4, EtOAc)
(S)-N-benzyl-2-hydroxypropanamide (64).50 Purified by silica gel
chromatography (1% MeOH/CH2Cl2), affording the title compound
as a yellow oil (129 mg, 51%); %): νmax (neat) 3310, 1644, 1532,
1273, 1122, 698 cm-1; 1H NMR (400 MHz, CDCl3): δH 7.34 – 7.24 (m,
5H), 7.04 (s, 1H), 4.42 (d, J = 5.9 Hz, 2H), 4.24 (qd, J = 6.8, 4.8 Hz,
1H), 3.53 (d, J = 4.7 Hz, 1H), 1.42 (d, J = 6.8 Hz, 3H); 13C NMR (101
MHz, CDCl3): δC 174.9, 138.0, 128.8, 127.8, 127.7, 115.7, 68.5, 43.2,
21.4; HRMS (ESI) m/z: [M+H]+ calcd for C10H14NO2 180.1019, found
180.1015; ee = 97%; [α]D20 -4.2 (c = 0.25, CHCl3), lit [α]D26 -21.5 (c =
0.25, CHCl3)
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(R)-N-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxamide
(65).
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Purified by silica gel chromatography (15% acetone/Pet. ether 40 –
60 °C), affording the title compound as an off-white solid (329 mg,
98%): νmax (neat) 3332, 2988, 2932, 1649, 1537, 1221, 1029,
839,735, 702 cm-1; 1H NMR (400 MHz, CDCl3): δH 7.36 – 7.32 (m, 2H),
7.30 – 7.26 (m, 3H), 6.89 (br. s, 1H), 4.54 (dd, J = 7.6, 5.3 Hz, 1H),
4.48 (d, J = 6.0 Hz, 2H), 4.31 (dd, J = 8.7, 7.6 Hz, 1H), 4.15 (dd, J =
8.8, 5.3 Hz, 1H), 1.44 (s, 3H), 1.38 (s, 3H); ); 13C NMR (101 MHz,
CDCl3): δC 171.2, 137.9, 128.9, 127.7, 127.7, 111.1, 75.21, 67.9, 43.1,
26.3, 25.1; HRMS (ESI) m/z: [M+H]+ calcd for C13H18NO3 236.1281,
found 236.1280; ee = 94%; [α]D20 +16.0 (c = 1.0, EtOH).
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(S)-N-benzyl-2-(4-isobutylphenyl)propanamide (66).51 Purified by
silica gel chromatography (1% MeOH/CH2Cl2), affording the title
compound as a yellow solid (61 mg, 15%): νmax (neat) 3299, 3030,
2950, 2921, 2867, 1640, 1537, 1454, 1230, 737, 696 cm-1; H NMR
1
(400 MHz, CDCl3): δH 7.27 – 7.19 (m, 5H), 7.14 -7.10 (m, 4H), 6.61 (s,
1H), 4.39 (d, J = 5.8 Hz, 2H), 3.58 (q, J = 7.2 Hz, 1H), 2.45 (d, J = 7.2
Hz, 2H), 1.91 – 1.78 (m, 1H), 1.55 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.6
Hz, 6H); 13C NMR (101 MHz, CDCl3): δC 174.5, 141.0, 138.6, 138.5,
129.8, 128.7, 127.5, 127.5, 47.0, 45.1, 43.7, 30.3, 22.5, 18.6; HRMS
(ESI) m/z: [M+H]+ calcd for C20H26NO 296.2009, found 296.2005; ee
= 83%; [α]D20 +3.0 (c = 0.88, DCM), lit [α]D25 +7.2 (c = 0.88, DCM).
9347
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We thank the EPRSC, AstraZeneca and the University of
Strathclyde for financial support. HRMS data were generated
by the EPSRC UK National Mass Spectrometry Facility at
Swansea University, UK
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