Amide formation using in situ activation of carboxylic acids with [Et 2NSF2]BF4

Article abstract of DOI:10.1002/ejoc.201300289

The formation of amides through the in situ activation of carboxylic acids with [Et₂NSF₂]BF₄ is presented. A wide range of carboxylic acids and amines were used to produce the corresponding amides in up to 99 % yield. The reaction of hindered amines was also possible in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under slightly modified conditions. An enantiopure carboxylic acid and amine were both shown to react without racemization. Copyright

Full text of DOI:10.1002/ejoc.201300289

FULL PAPER
DOI: 10.1002/ejoc.201300289
Amide Formation Using In Situ Activation of Carboxylic Acids with
[Et2NSF2]BF4
Olivier Mahé,[a] Justine Desroches,[a] and Jean-François Paquin*[a]
Keywords: Synthetic methods / Amides / Carboxylic acids / Amines / Borates
The formation of amides through the in situ activation of car-
boxylic acids with [Et2NSF2]BF4 is presented. A wide range
of carboxylic acids and amines were used to produce the cor-
responding amides in up to 99% yield. The reaction of hin-
dered amines was also possible in the presence of 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) under slightly modified
conditions. An enantiopure carboxylic acid and amine were
both shown to react without racemization.
under mild conditions, employ a simple protocol in a non-
toxic solvent, and generate easily separable byproducts.
N,N-Diethylamino-S,S-difluorosulfinium tetrafluorobor-
ate (XtalFluor-E),[8] is a commercial deoxofluorinating
agent that was recently developed as a safe alternative to
the well-known diethylaminosulfur trifluoride (DAST) rea-
gent.[9] It is an easily handled crystalline solid with en-
hanced thermal stability. Unlike DAST or its derivatives,
XtalFluor-E does not generate fluoride anions during a de-
oxofluorination. Thus, an external fluoride source, such as
Et3N·3HF, is added for the reaction to proceed efficiently.
Recently, our group[10] and others[11] have capitalized on
this key difference by replacing the fluoride ions with other
types of nucleophiles. We also reported the use of Xtal-
Fluor-E as a dehydrating agent for the syntheses of various
heterocycles.[12] It was during this work[12a] that we ob-
served increased reaction yields when acetic acid was added.
We hypothesized that this was a result of the formation of
an activated ester intermediate that originated from acetic
acid and XtalFluor-E (see Figure 1). We wondered if this
Introduction
Amide bonds are ubiquitous in molecular structures of
all domains of organic chemistry.[1] Their unique properties
(e.g., stability, polarity, conformational diversity, etc.) have
made them “nature’s choice” for key chemical connection
in proteins, and they are found in numerous synthetic and
natural biological compounds. They are also the basis of
some of the most utilized synthetic polymers. Nevertheless,
the development of new methods for the preparation of
amide bonds is still an active field of research because their
formation still remains challenging in various situations.[2]
The ideal way to create an amide bond would be through
the direct condensation of readily available carboxylic acids
and amines (direct amidation). However, this reaction is
thermodynamically impeded by the formation of the corre-
sponding carboxylate-ammonium salt,[3] and requires high
temperature (≈150 °C) to promote the dehydration step.[4]
To overcome this limitation, coupling reagents that can
convert the carboxylic acid partner into an activated deriva-
tive (e.g., acyl halide, mixed anhydride, O-acylurea, etc.)
have been extensively developed, and these derivatives can
then furnish an amide upon reaction with the amine part-
ner.[5]
More recent efforts have focused on the development of
catalytic processes, which are superior in terms of atom
economy.[6,7] Although enormous progress has been made
in this area, numerous issues remain unresolved (i.e., ele-
vated temperatures, removal of water, limited scope, etc.).
Hence, the use of stoichiometric amounts of reagents re-
mains viable provided they are safe and low-cost, operate
[a] Canada Research Chair in Organic and Medicinal Chemistry,
PROTEO, CCVC, Département de chimie, Université Laval,
1045 Avenue de la Médecine, Québec, QC, Canada G1V 0A6
Fax: +1-418-656-7916
E-mail: jean-francois.paquin@chm.ulaval.ca
Homepage: www.chm.ulaval.ca/jfpaquin
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300289.
Figure 1. Activation of carboxylic acids with [Et2NSF2]BF4 for the
synthesis of 1,3,4-oxadiazoles and amides.
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O. Mahé, J. Desroches, J.-F. Paquin
FULL PAPER
intermediate would react with other nucleophiles, in par- to be important in the synthesis of 1,3,4-oxadiazoles.[12a]
ticular amines, leading to the synthesis of amides. Herein, An improvement was observed by employing 15 min of ac-
we report the synthesis of amides through the in situ acti- tivation time (see Table 1, Entry 10). However, an activation
vation of carboxylic acids with XtalFluor-E.[13,14]
time of 2 h followed by a reaction time of 1 h was deter-
mined to be optimal (see Table 1, Entry 12).
Using the optimized conditions, we next investigated the
scope of our reaction by first examining the amine partner
with phenylacetic acid as the carboxylic acid (see Table 2).
A wide range of amines that include cyclic (see Table 2, En-
tries 1–3) and acyclic secondary amines (see Table 2, En-
tries 4–6) were tolerated in the reaction. Notably, an amine
that contained a free alcohol was well tolerated, and the
desired amide was obtained in 62% yield (see Table 2, En-
try 5). Also, the use of N,O-dimethylhydroxylamine hydro-
chloride under slightly modified conditions provided Wein-
reb amide 7 in good yield (see Table 2, Entry 6). Primary
amines that include aliphatic (see Table 2, Entry 7), benzylic
and heterobenzylic (see Table 2, Entries 8 and 9), and allylic
amines (see Table 2, Entry 10) underwent the reaction
equally well. Aromatic amines were also well tolerated as
exemplified by the use of aniline, which gave the amide in
excellent yield (see Table 2, Entry 11). Using the less nucleo-
philic methyl sulfonamide gave the desired product in 68%
yield without purification (see Table 2, Entry 12). However,
sterically hindered amines did not perform well, and low
yields were observed (see Table 2, Entries 13 and 14).
We then focused on the acid partner and used morph-
oline as the amine (see Table 3). Linear aliphatic acids (see
Table 3, Entries 1 and 2) performed well as did the conju-
gated cinnamic acid (see Table 3, Entry 3). Diphenylacetic
acid provided the corresponding amide 19 in a nearly quan-
titative yield (see Table 3, Entry 4). Pivalic acid, however,
gave the amide in a low 34% yield (see Table 3, Entry 5).
For the benzoic acids, the electronic nature of the substitu-
ents had an impact on their reactivity (see Table 3, En-
tries 6–10). For instance, a lower yield of 64% was obtained
with an electron-withdrawing substituent (see Table 3, En-
try 7) compared to the reaction with neutral benzoic acid
(see Table 3, Entry 6), where a 70% yield of the amide was
obtained. On the contrary, benzoic acids that contained an
electron-donating group such as methoxy furnished amides
in excellent yields (see Table 3, Entries 8 and 9). Interest-
ingly, an unprotected phenol was tolerated (see Table 3, En-
try 10). Finally, the use of thiophenecarboxylic acid pro-
vided the corresponding amide 26 in 71% yield (see Table 3,
Entry 11).
Results and Discussion
We first tested our hypothesis with phenylacetic acid,
morpholine, and XtalFluor-E under conditions inspired by
the original deoxofluorination protocol (see Table 1).[9]
Gratifyingly, the desired amide was obtained in 66% yield
using CH2Cl2 as the solvent (see Table 1, Entry 1). The or-
der of addition appears to be important. Indeed, the ad-
dition of the amine last led to a cleaner reaction with an
83% isolated yield (see Table 1, Entry 2). Although a
slightly lower yield was obtained in toluene (see Table 1,
Entry 3), ethyl acetate provided a similar result to those ob-
tained with CH2Cl2 (see Table 1, Entry 4). This is particu-
larly interesting because ethyl acetate is considered a pre-
ferred solvent in the pharmaceutical industry,[15] and there-
fore, it was selected for further optimization of the reaction.
The examination of various amine/XtalFluor-E ratios (see
Table 1, Entries 4–6) revealed that a ratio Ͼ1 was essential
to obtain good results. It was possible to decrease the quan-
tity of XtalFluor-E to 1 equiv. without any change in the
yield (see Table 1, Entry 7). As for the amine, 1.8 equiv. was
the minimum amount required to maintain yields above
80% (see Table 1, Entries 8 and 9). Finally, we examined
the influence of premixing the carboxylic acid and Xtal-
Fluor (in the absence of the amine) as this had been shown
Table 1. Selected optimization results for the amidation of phen-
ylacetic acid (1) with morpholine.[a]
Entry
Morpholine XtalFluor-E Solvent Activation
%
[x equiv.]
[y equiv.]
time [h]
Yield[b]
1[c]
2
3
4
5
2
2
2
2
1.5
1
1.5
1.5
1.5
1.5
1.5
1.5
1
CH2Cl2
CH2Cl2
toluene
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
0
0
0
0
0
0
0
0
0
66
83
76
80
58
38
80
85
69
87
94[e]
96
99
6
7
We next examined in more detail the conditions needed
for hindered amines (i.e., tert-butylamine and diisopropyl-
amine, in particular). Under the standard conditions, those
amines provided low yields of the desired amides (see
Table 2, Entries 13 and 14). In both cases, the major iso-
lated product was N,N-diethyl-2-phenylacetamide, the
amide obtained from the diethylamine released by Xtal-
Fluor-E under the reaction conditions.[9b] In deoxofluorin-
ation reactions, employing 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as a base has been shown to prevent the release
of diethylamine.[9b] Therefore, we examined its use as an
additive in the formation of amides from hindered amines.
2
8
9
1.8
1.5
1.8
1.8
1.8
1.8
1
1
1
1
1
1
10[d]
11[d]
12[d]
13[d]
0.25
1
2
9
[a] See Exp. Section for details of the reaction conditions. Unless
otherwise noted, the amine was added to a solution of the acid
and XtalFluor-E. [b] Yield of isolated 2 after purification by flash
chromatography. [c] The acid was added to a solution of the amine
and XtalFluor-E. [d] 1 h of reaction time after activation. [e] Esti-
1
mation of yield by H NMR analysis of the crude mixture.
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Amide Formation Using In Situ Activation of Carboxylic Acids
Table 2. Amidation of phenylacetic acid (1) with various amines.[a]
Table 3. Amidation of various carboxylic acids with morpholine.[a]
[a] See Exp. Section for details of the reaction conditions. [b] Yield
of isolated amide after purification by flash chromatography.
[c] iPr2EtN was also added. See the Supporting Information for
details. [d] Crude yield, no flash chromatography was necessary.
[a] See Exp. Section for details of the reaction conditions. [b] Yield
of isolated amide after purification by flash chromatography.
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After optimizing the order of addition of the substrates, we and amines. Though the exact mechanism has not been elu-
found that adding DBU to the acid prior to the sequential cidated, our results suggest the intermediate formation of
addition of XtalFluor-E and the amine, without any acti- an activated ester between the acid and XtalFluor-E (see
vation period, provided improved yields (see Scheme 1). Figure 1),[16–18] which is in contrast to the acyl fluoride that
Hence, the yield with tert-butylamine was improved from is generated when Deoxofluor is employed.[13]
23 to 49% (see Table 2, Entry 13), and the yield with diiso-
propylamine was 60% instead of 18% (see Table 2, En-
Experimental Section
try 14). Interestingly, the latter amine could not be used
with Deoxofluor, as the sole product observed was the cor-
responding bis(methoxyethyl)amide.[13]
General Methods: All reactions were carried out under a nitrogen
or argon atmosphere with dry solvents (with the exception of
EtOAc, which was directly used from the bottle) under anhydrous
conditions. The 1H NMR spectroscopic data were recorded at
500 MHz or 400 MHz, and the 13C NMR spectroscopic data were
recorded at 100 MHz at ambient temperature. The samples were
dissolved in CDCl3 or [D6]DMSO using tetramethylsilane, residual
CHCl3 or DMSO as the internal standard. High resolution mass
spectra were obtained using electrospray ionization (ESI). All start-
ing materials were obtained from commercial sources with the ex-
ception of the 2-methyl-5-phenylvaleric acid, which was synthe-
sized.[19]
General Procedure for the Amidation Reaction: Protocol A (premix-
ing of acid + XtalFluor-E): The acid (1 mmol) in ethyl acetate
(3 mL) provided a solution/suspension (0.33 m). To this mixture at
room temperature under argon was added XtalFluor-E (230 mg,
1 mmol, 1 equiv.). The resulting mixture was stirred at room tem-
perature for 2 h. The amine (1.8 mmol, 1.8 equiv.) was then slowly
added (dropwise or portionwise), which generally resulted in an
exothermic reaction. After 1 h of vigorous stirring at room tem-
perature, a solution of NaHCO3 (5% in water) was slowly added
at room temperature, and the reaction was stirred until the emission
Scheme 1. Improvement of the reaction conditions for hindered
amines.
Finally, we investigated the use of enantiopure partners
to validate that the stereochemical integrity was conserved
during the process (see Scheme 2). Hence, under the stan-
dard reaction conditions, phenylacetic acid (1) and (S)-α- of gas was no longer observed. The aqueous phase was extracted
with EtOAc (3ϫ), and the combined organic extracts were washed
with brine, dried with sodium sulfate, and evaporated under re-
duced pressure. The crude material was purified by flash
chromatography to give the desired product.
methylbenzylamine (Ͼ99%ee) provided the corresponding
amide 27 in excellent yield. Similarly, the reaction of Cbz-
l-phenylalanine (28) with aniline gave amide 29 in 75%
yield. In this latter case, the use of DBU provided a cleaner
reaction. Importantly, in both cases, no racemization was
observed as determined by chiral HPLC analysis. These re-
sults suggest that XtalFluor-E could potentially be used for
the synthesis of peptides.
General Procedure for the Amidation Reaction: Protocol B (no pre-
mixing): The acid (1 mmol) in ethyl acetate (3 mL) provided a solu-
tion/suspension (0.33 m). To this mixture at room temperature un-
der argon were added XtalFluor-E (230 mg, 1 mmol, 1 equiv.) and
DBU (150 μL, 1 mmol, 1 equiv.). This solution was cooled to 0 °C,
and the amine (1.8 mmol, 1.8 equiv.) was added dropwise. The mix-
ture was stirred at room temperature overnight (16 h), and a solu-
tion of NaHCO3 (5% in water) was slowly added at room tempera-
ture. The reaction mixture was stirred until the emission of gas was
no longer observed. The aqueous phase was extracted with EtOAc
(3ϫ), and the combined organic extracts were washed with brine,
dried with sodium sulfate, and evaporated under reduced pressure.
The crude material was purified by flash chromatography to give
the desired product.
1-Morpholino-2-phenylethanone (2): By following protocol A, phen-
ylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and morpholine (157 μL,
1.8 mmol, 1.8 equiv.) provided the crude product, which was iso-
lated by flash chromatography (ethyl acetate/hexane, 50:50) to give
the desired product (196 mg, 96%) as a white solid. Spectral data
of 2 were identical with those previously reported.[20,21]
Scheme 2. Formation of amide using enantiopure partners.
2-Phenyl-1-(pyrrolidin-1-yl)ethanone (3): By following protocol A,
phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and pyrrolidine
(150 μL, 1.8 mmol, 1.8 equiv.) provided the crude product, which
was isolated by flash chromatography (ethyl acetate/hexane, 40:60)
to give the desired product (182 mg, 96%) as a colorless oil. Spec-
Conclusions
In summary, we showed that XtalFluor-E is a useful rea-
gent for the preparation of amides from carboxylic acids tral data of 3 were identical with those previously reported.[20]
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Amide Formation Using In Situ Activation of Carboxylic Acids
2-Phenyl-1-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethanone (4): By
following protocol A, phenylacetic acid (136 mg, 1.0 mmol,
1 equiv.) and 1,4-dioxa-8-azaspiro[4.5]decane (231 μL, 1.8 mmol,
1.8 equiv.) provided the crude product, which was isolated by flash
chromatography (gradient of ethyl acetate/hexane, from 0:100 to
40:60) to give the desired product (255 mg, 97%) as a yellow oil.
Spectral data of 4 were identical with those previously reported.[22]
amine (159 μL, 1.8 mmol, 1.8 equiv.) provided the crude product,
which was isolated by flash chromatography (ethyl acetate/hexane,
40:60) to give the desired product (209 mg, 97%) as an off-white
solid. Spectral data of 10 were identical with those previously re-
ported.[24]
N-Allyl-2-phenylacetamide (11): By following protocol A, phen-
ylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and allylamine (135 μL,
1.8 mmol, 1.8 equiv.) provided the crude product, which was iso-
lated by flash chromatography (ethyl acetate/hexane, 50:50) to give
the desired product (164 mg, 94%) as a white solid. Spectral data
of 11 were identical with those previously reported.[25]
N-Benzyl-N-methyl-2-phenylacetamide (5): By following proto-
col A, phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and N-meth-
ylbenzylamine (232 μL, 1.8 mmol, 1.8 equiv.) provided the crude
product, which was isolated by flash chromatography (gradient of
ethyl acetate/hexane, from 0:100 to 40:60) to give the desired prod-
uct (225 mg, 94%) as a pale yellow oil. Signals from two rotamers
(58:42) were observed in the NMR spectra. Spectral data of 5 were
identical with those previously reported.[21]
N,2-Diphenylacetamide (12): By following protocol A, phenylacetic
acid (136 mg, 1.0 mmol, 1 equiv.) and aniline (164 μL, 1.8 mmol,
1.8 equiv.) provided the crude product, which was isolated by flash
chromatography (100% dichloromethane) to give the desired prod-
uct (201 mg, 95%) as a pale brown solid. Spectral data of 12 were
identical with those previously reported.[21]
N-(2-Hydroxyethyl)-N-methyl-2-phenylacetamide (6): By following
protocol A, phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and 2-
(methylamino)ethanol (144 μL, 1.8 mmol, 1.8 equiv.) provided the
crude product, which was isolated by flash chromatography (ethyl
acetate/hexane, 50:50 and then 100% ethyl acetate) to give the de-
sired product (120 mg, 62%) as a yellow oil. Signals from two rota-
mers (55:45) were observed in the NMR spectra. IR [attenuated
N-(Methylsulfonyl)-2-phenylacetamide (13): The title compound
was obtained by following a modified version of protocol B on a
1.0 mmol scale of phenylacetic acid. [No DBU was added, and
XtalFluor-E (1.5 equiv.) was used]. During the workup, the com-
bined organic extracts were washed with a 2% aqueous HCl solu-
tion (2ϫ). The desired product (145 mg, 68%) was isolated as a
white solid without further purification; m.p. 146–148 °C. IR
total reflectance (ATR), ZnSe): ν = 2921, 2852, 1742, 1625, 1462,
˜
1377, 1076, 728, 698 cm–1. 1H NMR (400 MHz, CDCl3, major rot-
amer): δ = 7.33–7.18 (m, 5 H), 4.87 (t, J = 5.4 Hz, 1 H), 3.73 (s, 2
H), 3.39 (t, J = 5.6 Hz, 2 H), 3.35 (t, J = 6.1 Hz, 2 H), 2.84 (s, 3
(ATR, ZnSe): ν = 3220, 1724, 1445, 1315, 1102, 939, 888, 707 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 8.01 (s, 1 H), 7.43–7.29 (m, 3
H), 7.29–7.23 (m, 2 H), 3.70 (s, 2 H), 3.27 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.8, 132.1, 129.7, 129.6, 128.4, 44.0,
41.6 ppm. HRMS (ESI): calcd. for C9H12NO3S [M + H]+ 214.0532;
found 214.0529.
1
H) ppm. H NMR (400 MHz, CDCl3, minor rotamer): δ = 7.33–
7.18 (m, 5 H), 4.66 (t, J = 5.4 Hz, 1 H), 3.68 (s, 2 H), 3.55–3.45
(m, 4 H), 3.02 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.5 (major), 170.2 (minor), 136.3 (major), 135.9 (minor), 129.1
(major), 129.0 (minor), 128.2 (2 C), 126.2 (2 C), 58.6, 51.7, 49.9,
39.9, 39.4, 36.6, 33.3 ppm. HRMS (ESI): calcd. for C11H16NO2 [M N-(tert-Butyl)-2-phenylacetamide (14): By following protocol B,
+ H]+ 194.1176; found 194.1177.
phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and tert-butylamine
(189 μL, 1.8 mmol, 1.8 equiv.) provided the crude product, which
was isolated by flash chromatography (gradient of ethyl acetate/
hexane, from 0:100 to 40:60) to give the desired product (94 mg,
49%) as a white solid. Spectral data of 14 were identical with those
previously reported.[26]
N-Methoxy-N-methyl-2-phenylacetamide (7): The title compound
was obtained by following protocol A with slight modifications.
Phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) in ethyl acetate
(2.5 mL) gave a solution (0.4 m). To this mixture at room tempera-
ture under argon was added XtalFluor-E (230 mg, 1.0 mmol,
1 equiv.). The resulting mixture was stirred at room temperature
for 2 h. Then, it was added to a 1:1 solution of N,O-dimethyl-
hydroxylamine hydrochloride (176 mg, 1.8 mmol, 1.8 equiv.) and
N,N-diisopropylethylamine (314 μL, 1.8 mmol, 1.8 equiv.) in
EtOAc (0.5 mL). The resulting mixture was stirred at room tem-
perature for 1 h. The reaction was quenched, and the workup was
carried out as described in protocol A. Flash chromatography (gra-
dient of ethyl acetate/hexane, from 0:100 to 40:60) gave the desired
product (157 mg, 88%) as a colorless oil. Spectral data of 7 were
identical with those previously reported.[23]
N,N-Diisopropyl-2-phenylacetamide (15): By following protocol B,
phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and N,N-diisoprop-
ylamine (253 μL, 1.8 mmol, 1.8 equiv.) provided the crude product,
which was isolated by flash chromatography (gradient of ethyl acet-
ate/hexane, from 0:100 to 40:60) to give the desired product
(131 mg, 60%) as a white solid. Spectral data of 15 were identical
with those previously reported.[27]
1-Morpholino-5-phenylpentan-1-one (16): By following protocol A,
5-phenylvaleric acid (178 mg, 1.0 mmol, 1 equiv.) and morpholine
(157 μL, 1.8 mmol, 1.8 equiv.) provided the crude product, which
was isolated by flash chromatography (ethyl acetate/hexane, 50:50)
to give the desired product (241 mg, 97%) as a colorless oil. Spec-
tral data of 16 were identical with those previously reported.[28]
2-Phenyl-N-hexylacetamide (8): By following protocol A, phen-
ylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and hexylamine (238 μL,
1.8 mmol, 1.8 equiv.) provided the crude product, which was iso-
lated by flash chromatography (ethyl acetate/hexane, 30:70) to give
the desired product (218 mg, 99%) as an off-white solid. Spectral
data of 8 were identical with those previously reported.[21]
2-Methyl-1-morpholino-5-phenylpentan-1-one (17): By following
protocol A, 2-methyl-5-phenylvaleric acid (192 mg, 1.0 mmol,
1 equiv.) and morpholine (157 μL, 1.8 mmol, 1.8 equiv.) provided
the crude product, which was isolated by flash chromatography
(ethyl acetate/hexane, 50:50) to give the desired product (204 mg,
N-Benzyl-2-phenylacetamide (9): By following protocol A, phen-
ylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and benzylamine
(197 μL, 1.8 mmol, 1.8 equiv.) provided the crude product, which
was isolated by flash chromatography (ethyl acetate/hexane, 40:60)
to give the desired product (216 mg, 96%) as a white solid. Spectral
data of 9 were identical with those previously reported.[21]
78%) as a pale yellow oil. IR (ATR, ZnSe): ν = 2924, 2854, 1640,
˜
1452, 1229, 1114, 1030, 746, 699 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 7.32–7.23 (m, 2 H), 7.22–7.12 (m, 3 H), 3.71–3.50 (m,
6 H), 3.43 (s, 2 H), 2.69–2.52 (m, 3 H), 1.78–1.68 (m, 1 H), 1.66–
1.54 (m, 2 H), 1.48–1.37 (m, 1 H), 1.11 (d, J = 6.7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 175.0, 142.1, 128.4, 128.3, 125.8,
N-(Furan-2-ylmethyl)-2-phenylacetamide (10): By following proto-
col A, phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and furfuryl-
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67.0, 66.8, 45.9, 42.0, 35.8, 35.1, 33.4, 29.1, 17.4 ppm. HRMS
(ESI): calcd. for C16H24NO2 [M + H]+ 262.1802; found 262.1806.
m.p. 141–143 °C. IR (ATR, ZnSe): ν = 3073, 2923, 2853, 1600,
˜
1438, 1269, 1137, 1025, 845, 746 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.13 (s, 1 H), 7.22–7.16 (m, 1 H), 6.94–6.91 (m, 1 H),
6.86–6.79 (m, 2 H), 3.93–3.32 (m, 8 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.0, 157.0, 135.5, 129.7, 118.0, 117.7, 114.6, 66.8,
48.3, 42.8 ppm. HRMS (ESI): calcd. for C11H14NO3 [M + H]+
208.0968; found 208.0976.
(E)-1-Morpholino-3-phenylprop-2-en-1-one (18): By following pro-
tocol A, cinnamic acid (148 mg, 1.0 mmol, 1 equiv.) and morph-
oline (157 μL, 1.8 mmol, 1.8 equiv.) provided the crude product,
which was isolated by flash chromatography (ethyl acetate/hexane,
50:50) to give the desired product (201 mg, 93%) as a white solid.
Spectral data of 18 were identical with those previously reported.[29]
Morpholino(thiophen-2-yl)methanone (26): By following protocol A,
2-thiophenecarboxylic acid (128 mg, 1.0 mmol, 1 equiv.) and
morpholine (157 μL, 1.8 mmol, 1.8 equiv.) provided the crude
product, which was isolated by flash chromatography (gradient of
ethyl acetate/hexane, from 0:100 to 40:60) to give the desired prod-
uct (133 mg, 67%) as a yellow oil. Spectral data of 26 were identical
with those previously reported.[33]
1-Morpholino-2,2-diphenylethanone (19): By following protocol A,
diphenylacetic acid (212 mg, 1.0 mmol, 1 equiv.) and morpholine
(157 μL, 1.8 mmol, 1.8 equiv.) provided the crude product, which
was isolated by flash chromatography (gradient of ethyl acetate/
hexane, from 0:100 to 40:60) to give the desired product (220 mg,
99%) as an off-white solid; m.p. 119–121 °C. IR (ATR, ZnSe): ν =
˜
1
2916, 2830, 1633, 1458, 1431, 1274, 1110, 1039, 741, 694 cm–1. H
(S)-2-Phenyl-N-(1-phenylethyl)acetamide (27): By following proto-
col A, phenylacetic acid (136 mg, 1.0 mmol, 1 equiv.) and (S)-α-
methylbenzylamine (232 μL, 1.8 mmol, 1.8 equiv.) provided the
crude product, which was isolated by flash chromatography (ethyl
acetate/hexane, 30:70) to give the desired product (216 mg, 90%)
as a white solid. Spectral data of 27 were identical with those pre-
viously reported.[21,34] Chiral HPLC analysis [Chiralpack OD-H
Daicel chiral column, iPrOH/heptane (10:90), flow rate of 0.8 mL/
min, 20 °C, λ = 220 nm][34] showed no racemization during the
amidation process; tR = 16 min (R enantiomer) and tR = 18.5 min
(S enantiomer).
NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m, 4 H), 7.29–7.20 (m, 6
H), 5.17 (s, 1 H), 3.74–3.62 (m, 4 H), 3.49–3.34 (m, 4 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.5, 139.3, 129.0, 128.7, 127.2,
66.9, 66.5, 54.9, 46.5, 42.6 ppm. HRMS (ESI): calcd. for
C18H20NO2 [M + H]+ 282.1489; found 282.1494.
2,2-Dimethyl-1-morpholinopropan-1-one (20): By following proto-
col A, trimethylacetic acid (102 mg, 1.0 mmol, 1 equiv.) and
morpholine (157 μL, 1.8 mmol, 1.8 equiv.) provided the crude
product, which was isolated by flash chromatography (ethyl acetate/
hexane, 40:60) to give the desired product (56 mg, 33%) as a white
solid. Spectral data of 20 were identical with those previously re-
ported.[30]
(S)-Benzyl-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)carbamate
(29): By following protocol B, (CBz)-(l)-Phe-OH (299 mg,
1.0 mmol, 1 equiv.) and aniline (164 μL, 1.8 mmol, 1.8 equiv.) pro-
vided the crude product, which was isolated by flash chromatog-
raphy (gradient of ethyl acetate/hexane, from 0:100 to 40:60) to give
the desired product (281 mg, 75%) as a white solid. Spectral data of
29 were identical with those previously reported.[35] Chiral HPLC
analysis [Chiralpack AD-H Daicel chiral column, iPrOH/heptane
(10:90), flow rate of 0.8 mL/min, 20 °C, λ = 254 nm][35] showed
no racemization during the amidation process; tR = 27.8 min (S
enantiomer) and ; tR = 35.8 min (R enantiomer).
Morpholino(phenyl)methanone (21): By following protocol A, ben-
zoic acid (122 mg, 1.0 mmol, 1 equiv.) and morpholine (157 μL,
1.8 mmol, 1.8 equiv.) provided the crude product, which was iso-
lated by flash chromatography (gradient of ethyl acetate/hexane,
from 0:100 to 40:60) to give the desired product (134 mg, 70%)
as a pale yellow oil. Spectral data of 21 were identical with those
previously reported.[31]
(4-Chlorophenyl)(morpholino)methanone (22): By following proto-
col A, 4-chlorobenzoic acid (157 mg, 1.0 mmol, 1 equiv.) and
morpholine (157 μL, 1.8 mmol, 1.8 equiv.) provided the crude
product, which was isolated by flash chromatography (ethyl acetate/
hexane, 70:30) to give the desired product (144 mg, 64%) as a white
solid. Spectral data of 22 were identical with those previously re-
ported.[31]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra and HPLC traces.
Acknowledgments
This work was supported by the Canada Research Chair Program,
the Natural Sciences and Engineering Research Council of Canada,
the Canada Foundation for Innovation, and the Université Laval.
OmegaChem is acknowledged for the generous gift of the Xtal-
Fluor-E. The authors thank Alexandre L’Heureux (OmegaChem)
for the useful discussions.
(4-Methoxyphenyl)(morpholino)methanone (23): By following proto-
col A, 4-methoxybenzoic acid (152 mg, 1.0 mmol, 1 equiv.) and
morpholine (157 μL, 1.8 mmol, 1.8 equiv.) provided the crude
product, which was isolated by flash chromatography (ethyl acetate/
hexane, 50:50) to give the desired product (187 mg, 85%) as a pale
yellow oil. Spectral data of 23 were identical with those previously
reported.[31]
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ether ) to give the desired product (152 mg, 73%) as a white solid;
4330
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: February 26, 2013
Published Online: May 23, 2013
Eur. J. Org. Chem. 2013, 4325–4331
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4331