2-Furanylboronic acid as an effective catalyst for the direct amidation of carboxylic acids at room temperature

Article abstract of DOI:10.1002/ejoc.201403468

2-Furanylboronic acid has been identified as an inexpensive and effective catalyst for the dehydrative amide formation of carboxylic acids and amines. This transformation can be efficiently carried out at room temperature and is applicable to a wide range of carboxylic acids with primary and secondary amines to afford amides in good to excellent yields.

Full text of DOI:10.1002/ejoc.201403468

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DOI: 10.1002/ejoc.201403468
1
2-Furanylboronic Acid as an Effective Catalyst for the Direct Amidation of
Carboxylic Acids at Room Temperature
Eric Kwok Wai Tam,*[a] Rita,[b] Lionel Yiqian Liu,[c] and Anqi Chen*[a]
Keywords: Synthetic methods / Organocatalysis / Green chemistry / Amides / Amines / Carboxylic acids
2-Furanylboronic acid has been identified as an inexpensive
and effective catalyst for the dehydrative amide formation
of carboxylic acids and amines. This transformation can be
efficiently carried out at room temperature and is applicable
to a wide range of carboxylic acids with primary and second-
ary amines to afford amides in good to excellent yields.
6
11
Introduction
Amides are abundant in nature and chemical products
such as pharmaceuticals, fine chemicals and polymers. Con-
sequently, amide bond formation is recognised as an impor-
tant transformation in a variety of industries, especially in
the pharmaceutical sector, wherein approximately 25% of
drugs contain amide bonds (Figure 1).[1] Despite the crucial
importance of amide formation, the most commonly used
methods, that is, the use of acid derivatives and coupling
reagents, are inefficient and unsustainable for the chemical
industry. This is due to the use of hazardous chemicals and
to the formation of large quantities of by-products that not
only lead to difficulties in product isolation but also has an
adverse environmental impact. Therefore, amide formation
was identified by the industry as a top priority transforma-
tion for the development of more efficient and sustainable
approaches.[2] This need has led to the development of a
plethora of alternative, more efficient methods for amide
formation.[3]
Despite the tremendous progress in the field, the cou-
pling reaction between carboxylic acids and amines remains
by far one of the most common approaches for amide syn-
thesis in both research and the industry, primarily because
of the wide availability of feedstock. However, because of
the strong C–OH bond of the carboxylic acid, the reaction
usually requires a stoichiometric coupling reagent to acti-
vate the carboxylic acid to drive the dehydration reaction
(Figure 2).[3a,3b,3g,4] Given that most coupling reagents are
16
21
26
31
36
Figure 1. Examples of amide-containing drugs.
expensive and could have a molecular weight as high as
that of the amide product, this approach suffers from cost
ineffectiveness, poor atom efficiency, and tedious product
isolation procedures.[5] Therefore, the development of more
41
[a] Institute of Chemical and Engineering Sciences (ICES), Agency
for Science, Technology and Research (A*STAR),
8 Biomedical Grove, Neuros #07-01, 138665 Singapore
E-mail: eric_tam@ices.a-star.edu.sg
chen_anqi@ices.a-star.edu.sg
http://www.ices.a-star.edu.sg
[b] School of Chemical and Life Sciences
Singapore Polytechnic, 500, Dover Road, 139651 Singapore
[c] Department of Chemistry, National University of Singapore,
3 Science Drive 3,117543 Singapore
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403468.
Figure 2. Amide formation using typical coupling reagents.
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E. K. W. Tam, Rita, L. Y. Liu, A. Chen
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efficient, catalytic approaches for the direct coupling of (3a), benchmarking against the previously reported condi-
carboxylic acids and amines that enable sustainable amide tions.[8a] The screening was focused on meta-substituted
formation represents a highly important yet challenging benzeneboronic acids and heteroarylboronic acids, which
86
91
46
51
56
61
66
71
area of chemistry.
have been much less explored. From the screening results
In this field, significant progress has been made recently, (Table 1), five boronic acids (Figure 4), that is, (3-
with several promising catalyst systems being reported.[6–9] cyanophenyl)boronic acid (1d, entry 2), 3-(trifluoromethyl-
Amongst these, the pioneering work by Yamamoto et al. phenyl)boronic acid (1e; entry 3), (3,5-difluorophenyl)-
on electron-deficient arylboronic acids as catalysts for the
coupling of carboxylic acids and amines (referred to as di-
rect amidation) represents one of the most important devel-
opments (Figure 3).[6] The best performing catalyst, (3,4,5-
trifluorophenyl)boronic acid (1a), has been shown to effec-
tively catalyse direct amidation in a refluxing solvent
(Ͼ 120 °C) using 4 Å molecular sieves as a water scavenger.
Subsequent improvements have been directed towards
decreasing the reaction temperature for effective catalysis
and convenient operation as well as avoiding racemisation
of chiral substrates. For example, Whiting et al. have shown
that bifunctional arylboronic acid 1b enables the coupling
reaction to be carried out in refluxing fluorobenzene at
85 °C.[7] More remarkably, Hall and co-workers have very
recently reported that (o-haloaryl)boronic acids such as 1c
were able to mediate direct amidation at room temperature
in the presence of molecular sieves as a dehydrating agent.[8]
This represents significant progress toward catalytic direct
amidation, although o-iodo arylboronic acid (1c) is not
commercially available and requires the use of equimolar
expensive silver(I) sulfate to introduce the iodide from its
boronic acid precursor.[10]
Table 1. Screening of arylboronic acids for direct amidation.
Entry
Ar
Yield [%][b]
1
2
3
4
Ph
22
95 (92)
91 (92)
86
3-CNC6H4
3-CF3C6H4
3-FC6H4
5
6
7
8
3-HOC6H4
0
78
66
5
52
50
58
7
0
78
81
36
85
63
17
95 (93)
34
35
99 (91)
23
44
92 (88)
55
73
84
51
99 (98)
0
3-MeOC6H4
3-iPrOC6H4
3-BnOC6H4
3-F2CHOC6H4
3-F3COC6H4
3-MeSC6H4
3-Me2NC6H4
3-MeNHSO2C6H4
3,4-F2C6H3
3-F,4-BrC6H3
3-F,4-MeOC6H3
3,4-Cl2C6H3
3-CF3,4-ClC6H3
3,4-(MeO)2C6H3
3,5-F2C6H3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3,5-Me2C6H3
4-ClC6H4
2-furanyl
3-furanyl
2-benzofuranyl
2-thiophenyl
5-Cl(2-thiophenyl)
5-CN(2-thiophenyl)
N-boc-1H-pyrrol-2-yl
1H-indol-5-yl
Figure 3. Representative arylboronic acids for the dehydrative cou-
pling of carboxylic acids and amines.
[c]
2-I,5-MeOC6H3
no catalyst
In our continuing efforts to develop efficient and envi-
ronmentally benign methods for amide formation,[11] our
recent efforts were directed to the discovery of more cost-
efficient, easily accessible arylboronic acids for direct cata-
lytic amidation. In this context, we report herein the finding
of 2-furanylboronic acid 1g as an inexpensive and highly
effective catalyst for direct amidation at ambient tempera-
ture.
[a] Reaction conditions: phenylacetic acid (2a; 0.275 mmol), ben-
zylamine (3a; 0.25 mmol), boronic acid (10 mol-%), 4 Å MS
(freshly activated, 0.5 g), CH2Cl2 (3.5 mL), room temp., 24 h.
[b] Yields were determined by HPLC analysis. Yields given in pa-
rentheses were obtained in 3 h. [c] Hall’s catalyst 1c.
76
Results and Discussion
81
Our investigation commenced with the screening of a
broad range of commercially available arylboronic acids to
identify active catalysts. This was based on the coupling re-
Figure 4. Best performing arylboronic acids identified from screen-
action between phenylacetic acid (2a) and benzylamine ing.
2
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Direct Amidation of Carboxylic Acids
boronic acid (1f; entry 20), 2-furanylboronic acid (1g; en- Table 3. Direct amidation of carboxylic acid 2a with various
amines.[a]
try 23) and (thiophen-2-yl)boronic acid (1h; entry 26) were
found to perform excellently compared with the reported
best catalyst 1c (entry 31). These best performing catalysts
were further evaluated for a shorter reaction time of 3 h
and the yields (given in parentheses in Table 1) were only
marginally lower than with 1c. Based on these results, the
easily accessible, inexpensive 2-furanylboronic acid (1g) was
selected for further optimisation.
96
101
Optimisation of the conditions began with the screening
of solvents (Table 2, entries 1–11). The best solvents for cat-
alyst 1g turned out to be similar to those reported for 1c,[8b]
with CH2Cl2 (entry 1) and toluene (entry 4) being the most
suitable, and diethyl ether (entry 7) also performed well.
106 Higher polarity solvents including tetrahydrofuran (THF),
2-Me-THF, acetonitrile, dioxane and ethanol gave much
lower yields, whereas the use of N,N-dimethylformamide
(DMF) led to transamidation, forming N-benzylformamide
as a side-product.[12]
Table 2. Optimisation of reaction parameters for amidation.
Entry
1g
Solvent
4 Å MS
Concentration Yield[b]
[mol-%]
(g/mmol 3a)
of 2a [m]
[%]
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
CH2Cl2
THF
2-methyl-THF
toluene
DMF
CH3CN
Et2O
dioxane
EtOH
EtOAc
dimethyl carbonate
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
0.75
0.5
1.0
1.0
1.0
1.0
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.079
0.12
99
27
8
98
23
10
89
54
0
9
10
11
12
13
14
15
16
17
18
19
33
0
98
96
92
57
96
98
79
55
0.16
0.22
0.16
[a] Reaction conditions: phenylacetic acid (2a; 1.1 mmol), benzyl-
amine 3a (1.0 mmol), catalyst 1g and 4 Å MS in the specified sol-
vent at room temp. for 24 h. [b] Yields were determined by HPLC
analysis.
111
Having identified the best solvent, we next turned our
attention to other reaction parameters, including the
amount of 4 Å molecular sieves used, substrate concentra-
tion and catalyst loadings (Table 2, entries 12–19). Optimal
conditions were found to be 10 mol-% catalyst loading,
116 0.16 m carboxylic acid 2a in CH2Cl2 and 1 g of 4 Å molec-
ular sieves (MS) per millimole of amine 3a (entry 17).
Whereas increasing the concentration of 2a beyond 0.2 m
substantially reduced the yield (entry 18) (inefficient mixing
observed), reducing the catalyst loading to 5 mol-% almost
[a] Reaction conditions: phenylacetic acid (2a; 1.1 mmol), amine
3a–3n (1.0 mmol), catalyst 1g (10 mol-%), 4 Å MS (1.0 g), CH2Cl2
(7 mL), room temp., 24 h. [b] Isolated yield.
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121 halved the yield (entry 19). Additionally, the order of ad- acid and base extraction without column chromatographic
dition of reagents and the stoichiometry of the carboxylic purification. However, substitution at both α- and β-posi-
acid and the amine were crucial to this direct amidation. tions of amines 3f–i significantly reduced the yields, which
Premixing the carboxylic acid and the arylboronic acid in is also reflected in cyclic and secondary amines 3k–n. These 146
the presence of activated molecular sieves for several min- results imply that the reaction is sensitive to steric hin-
126 utes prior to addition of the amine ensured the formation drance around the amino group. The reaction is not com-
of an activated carboxylic acid intermediate to effectively patible with a free hydroxyl group, as shown in 3j, likely
couple with the amine. This was evident by a control reac- due to the formation of a borate ester,[13] which deactivates
tion in which both substrates 2a and 3a were added concur- the boronic acid catalyst. As reported previously,[8b] less 151
rently with the catalyst, resulting in only 34% yield of nucleophilic amines such as aniline does not undergo amid-
131 amide product. Moreover, a slight excess of the carboxylic ation (not shown).
acid relative to the amine (1.1:1.0 mol ratio) was preferred,
The generality of this direct amidation was further dem-
because an excess of amine (20 mol-%) significantly slowed onstrated on a variety of carboxylic acids with amine 3e.
the reaction. These observations are consistent with pre- As shown in Table 4, the reaction works well with aliphatic 156
viously reported results.[8b]
acids 2a–g without α-substitution, providing the corre-
136
With the optimised conditions in hand, the substrate sponding amides in excellent yields. A variety of functional
scope of direct amidation catalysed by 1g was investigated. groups including ester and bromide were well tolerated.
First, the amidation between phenylacetic acid (2a) with a However, when substituents are present at the α-position
range of primary and secondary amines was studied of the carboxylic acids (2h–k), the yield of amide products 161
(Table 3). In general, primary amines 3a–e gave much better decreases and the trend is aggravated as the steric bulk of
141 yields (generally Ͼ90%) than secondary amines. The isola- the substituent increases (2k–l). These observations echo
tion of the amide products was conveniently achieved by the limitation of steric effects observed in the case of amines
Table 4. Direct amidation of carboxylic acids with amine 3e.[a]
[a] Reaction conditions: carboxylic acid (2a–2o; 1.1 mmol), amine 3e (1.0 mmol), catalyst 1g (10 mol-%), 4 Å MS (1.0 g), CH2Cl2 (7 mL),
room temp., 24 h. [b] Isolated yields.
4
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Direct Amidation of Carboxylic Acids
(see above). Carboxylic acids containing an amino group
166 (2m) and N-heterocyclic motif (2n) gave only moderate
yields of amide products, but benzoic acid (2o) essentially
did not undergo amidation under the reaction conditions,
which has been observed previously.[8]
Although it has been reported that 2-furanylboronic acid
171 is prone to decomposition at ambient temperature or heat-
ing due to protodeboronation,[14] monitoring a solution of
the compound in CD2Cl2 (equivalent to the reaction sol-
vent CH2Cl2) at ambient temperature (ca. 25 °C) by
1H NMR spectroscopic analysis for up to 30 h (reaction
176 time 24 h) did not reveal any appreciable decomposition.
Analysis of a bottle of 2-furanylboronic acid stored at 4 °C
for 11 months did not show any decomposition either, and
the result was well reproduced when it was tested on the
amidation of 2a with 3a.
Conclusions
Through extensive screening of commercially available 201
arylboronic acids, we have identified 2-furanylboronic acid
as a readily available, inexpensive and efficient catalyst for
the direct amidation of carboxylic acids and amines at
ambient temperature using 4 Å molecular sieves as a de-
hydrating agent. The reaction is applicable to the direct 206
amidation of a wide range of aliphatic carboxylic acids with
aliphatic primary and secondary amines, providing the
amide compounds in good to excellent yields. The amide
products can be easily isolated by acid and base extraction
without column chromatographic purification. However, it 211
has been observed that the reaction is limited to aliphatic
substrates and that it is sensitive to steric hindrance at the
α-position of both carboxylic acid and amine substrates.
Another point to note is that although CH2Cl2 was found
to be the most suitable solvent at this discovery stage, it is 216
disfavoured from a sustainability point of view.[16] Hence,
an alternative solvent should be sought when the reaction
is carried out on larger scales. The findings of this study
provide useful information for the understanding of aryl-
boronic acid catalysed direct amidation and for the develop- 221
ment of more effective, next-generation catalysts.
181
A mechanism for the 2-furanylboronic acid catalysed
amidation is shown in Figure 5 based on the most recent
experimental[8] and computational[15] studies. The catalytic
cycle begins with the formation of an acyl intermediate I
between boronic acid 1g and the carboxylic acid 2. This
186 fast step[15] could be favoured by intramolecular hydrogen-
bonding and by the coordination of the formed water mol-
ecule to the electron-deficient boron atom. The activated
acyl group in I then reacts with amine 3, leading to an or-
thoaminal transition state II, which rearranges to transition
191 state III, favoured by a hydrogen-bonding network and
minimised steric interactions with cis-aligned R1 and R2.
In the final step, water is eliminated from III in the rate-
determining step[15] with amide product 4 being released
and catalyst 1g enters a fresh cycle. Molecular sieves are
196 used in the reaction as a dehydration agent to remove water
formed in the reaction and possibly also functions as a
water reservoir to hydrolyse bis- and tri-acyl borates that
are inactive to the active mono-acyl borate I.[8]
Experimental Section
General Information: All chemicals were obtained from commercial
sources and were used as received. Dried solvents (acetonitrile,
CH2Cl2, DMF, dioxane, THF, diethyl ether and toluene) were
drawn from a Glass Contour solvent purification system. An-
hydrous grade 2-methyltetrahydrofuran was purchased from a com-
mercial source. All reactions requiring anhydrous conditions were
carried out under argon atmosphere using oven-dried glassware.
1H and 13C NMR spectra were recorded with a Bruker 400 MHz
instrument with a CryoProbe. Chemical shifts are reported in parts
per million (ppm) using the undeuterated peak of CDCl3 (7.26 for
proton and 77.2 for carbon) as a reference. Mass spectra were run
with the electrospray ionization time-of-flight (ESI-TOF) mode
with an Agilent 6210 mass spectrometer. HPLC analysis was car-
ried out with an Agilent 1260 infinity analytical system with a bi-
nary pump, using a Poroshell 120 EC-C18 column (Ø4.6ϫ75 mm)
with 1,3-dimethoxybenzene as an internal standard.
226
231
236
General Procedure for 2-Furanylboronic Acid (1g) Catalysed Amide
Formation: A 10 mL glass tube was charged with carboxylic acid
(1.1 mmol), 2-furanylboronic acid (1g; 11.2 mg, 10 mol-%), acti-
vated 4 Å molecular sieves (1.0 g), and anhydrous dichloromethane
(7 mL). The mixture was stirred vigorously for 10 min before amine
(1.0 mmol, 1.0 equiv.) was added. The resulting mixture was stirred
at room temperature for 24 h. The reaction mixture was filtered
through a pad of Celite, and the filtrate was washed with 0.1 m
HCl solution, followed by saturated sodium carbonate solution and
brine. The organic phase was dried with anhydrous MgSO4, fil-
tered, and concentrated to provide pure amide products.
241
246
Compound Characterization Data
251
256
N-Benzyl-2-phenylacetamide (4aa):[17] Yield 221 mg (98%); white
1
solid. H NMR (400 MHz, CDCl3): δ = 7.44–7.24 (m, 8 H), 7.22–
7.16 (m, 2 H), 6.00 (br. s, 1 H), 4.41 (d, J = 5.8 Hz, 2 H), 3.61 (s,
2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.1, 138.2, 134.9,
129.5, 129.1, 128.7, 127.6, 127.5, 127.4, 43.8, 43.7 ppm.
Figure 5. Proposed mechanism for direct amidation catalysed by 2-
furanylboronic acid (1g).
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E. K. W. Tam, Rita, L. Y. Liu, A. Chen
N-(4-Chlorobenzyl)-2-phenylacetamide (4ab):[18] Yield 251 mg CDCl3): δ = 169.2, 135.4, 128.6, 128.5, 126.6, 47.2, 42.8, 41.1, 26.1,
FULL PAPER
(97%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.32 (m,
2 H), 7.32–7.23 (m, 5 H), 7.14–7.06 (m, 2 H), 5.66 (br. s, 1 H), 4.37
(d, J = 6.0 Hz, 2 H), 3.63 (s, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.0, 136.9, 134.8, 133.4, 129.6, 129.3, 129.0, 128.9,
127.7, 44.1, 43.1 ppm.
25.5, 24.4 ppm.
1-Morpholino-2-phenylethan-1-one (4am):[12b] Yield 140 mg (68%);
1
white solid. H NMR (400 MHz, CDCl3): δ = 7.37–7.30 (m, 2 H),
261
7.29–7.22 (m, 3 H), 3.74 (s, 2 H), 3.65 (s, 4 H), 3.54–3.40 (m, 4
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.7, 134.9, 128.9,
128.6, 127.0, 66.9, 66.6, 46.6, 42.3, 40.9 ppm.
321
N-(4-Methoxybenzyl)-2-phenylacetamide (4ac):[19] Yield 197 mg
(77%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.31 (m,
2 H), 7.31–7.24 (m, 3 H), 7.11 (m, 2 H), 6.82 (m, 2 H), 5.61 (br. s,
N-Benzyl-N-methyl-2-phenylacetamide (4an):[20] Yield 124 mg
(52%); colourless liquid; mixture of two rotamers (1.4:1.0). 1H
266 1 H), 4.34 (d, J = 5.7 Hz, 2 H), 3.78 (s, 3 H), 3.61 (s, 2 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 170.7, 159.2, 135.0, 130.4, 129.6,
129.2, 129.0, 127.5, 114.2, 55.4, 44.0, 43.3 ppm.
NMR (400 MHz, CDCl3): δ (major rotamer) = 7.36–7.18 (m, 9 H), 326
7.14–7.05 (m, 1 H), 4.61 (s, 2 H), 3.79 (s, 2 H), 2.90 (s, 3 H) ppm;
1H NMR (400 MHz, CDCl3): δ (minor rotamer) = 7.36–7.18 (m,
9 H), 7.14–7.05 (m, 1 H), 4.53 (s, 2 H), 3.76 (s, 2 H), 2.96 (s, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.6, 171.3, 137.5,
N-Hexyl-2-phenylacetamide (4ad):[20] Yield 200 mg (91%); white so-
lid. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.32 (m, 2 H), 7.32–
271
7.23 (m, 3 H), 5.34 (br. s, 1 H), 3.56 (s, 2 H), 3.29–3.01 (m, 2 H),
1.47–1.33 (m, 2 H), 1.33–1.13 (m, 6 H), 0.92–0.78 (m, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 171.0, 135.3, 129.6, 129.2, 127.5,
44.1, 39.8, 31.5, 29.6, 26.6, 22.6, 14.1 ppm.
136.7, 135.3, 135.1, 129.1, 129.0, 128.9, 128.8, 128.7, 128.2, 127.8,
127.5, 127.0, 126.9, 126.6, 53.9, 51.2, 41.4, 41.0, 35.4, 34.2 ppm.
331
N-Phenethylhexanamide (4be):[26] Yield 191 mg (87%); yellow solid.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.27 (m, 2 H), 7.25–7.16
(m, 3 H), 5.44 (br. s, 1 H), 3.52 (q, J = 6.8 Hz, 2 H), 2.82 (t, J =
6.9 Hz, 2 H), 2.15–2.08 (m, 2 H), 1.59 (quint, J = 7.6 Hz, 2 H),
1.36–1.21 (m, 4 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 173.3, 139.1, 128.9, 128.8, 126.6, 40.7, 36.9,
35.9, 31.6, 25.6, 22.5, 14.0 ppm.
N-Phenethyl-2-phenylacetamide (4ae):[21] Yield 236 mg (99%); white
1
276 solid; H NMR (400 MHz, CDCl3): δ = 7.31–7.08 (m, 8 H), 7.03–
6.96 (m, 2 H), 5.70 (br. s, 1 H), 3.45 (s, 2 H), 3.40 (q, J = 6.9 Hz,
2 H), 2.68 (t, J = 6.9 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 170.9, 138.7, 135.0, 129.3, 128.9, 128.7, 128.5, 127.2, 126.4,
43.7, 40.7, 35.5 ppm.
336
N-Phenethylundec-10-enamide (4ce): Yield 270 mg (94%); white so-
lid. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.28 (m, 2 H), 7.25–
7.13 (m, 3 H), 5.81 (m, 1 H), 5.37 (br. s, 1 H), 4.99 (dq, J = 17.1,
1.6 Hz, 1 H), 4.93 (m, 1 H), 3.56–3.48 (m, 2 H), 2.82 (t, J = 6.9 Hz,
2 H), 2.15–2.08 (m, 2 H), 2.08–1.99 (m, 2 H), 1.63–1.56 (m, 2 H),
1.41–1.27 (m, 10 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 173.2,
139.3, 139.1, 128.9, 128.8, 126.6, 114.3, 40.6, 37.0, 35.9, 33.9, 29.4,
29.2, 29.1, 25.9 ppm. HRMS (ESI): m/z calcd. for C19H30NO [M
+ H]+ 288.2322; found 288.2323.
281 (؎)-N-(Heptan-2-yl)-2-phenylacetamide (4af):[22] Yield 140 mg
(60%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.33 (m,
2 H), 7.32–7.20 (m, 3 H), 5.06 (br. s, 1 H), 4.01–3.89 (m, 1 H), 3.55
(s, 2 H), 1.38–1.14 (m, 8 H), 1.04 (d, J = 6.6 Hz, 3 H), 0.85 (t, J =
6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.3, 135.4,
341
346
286
129.5, 129.1, 127.4, 45.5, 44.3, 36.8, 31.7, 25.6, 22.7, 21.0,
14.1 ppm.
(؎)-2-Phenyl-N-(1-phenylethyl)acetamide (4ag):[23] Yield 132 mg
(55%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.32 (m,
2 H), 7.32–7.22 (m, 6 H), 7.22–7.15 (m, 2 H), 5.62 (br. s, 1 H), 5.12
(quint, J = 7.1 Hz, 1 H), 3.58 (s, 2 H), 1.40 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.1, 143.2, 135.1,
129.5, 129.2, 128.8, 127.5, 127.4, 126.1, 48.9, 44.1, 21.9 ppm.
N-Phenethylhex-5-ynamide (4de): Yield 157 mg (73%); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.28 (m, 2 H), 7.25–7.16
(m, 3 H), 5.50 (br. s, 1 H), 3.53 (q, J = 6.9 Hz, 2 H), 2.82 (t, J =
6.9 Hz, 2 H), 2.30–2.18 (m, 4 H), 1.94 (t, J = 2.6 Hz, 1 H), 1.83
(quint, J = 7.0 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
172.0, 138.7, 128.6, 128.5, 126.4, 83.3, 68.9, 40.4, 35.5, 34.9, 24.0,
17.6 ppm. HRMS (ESI): m/z calcd. for C14H18NO [M + H]+
216.1383; found 216.1378.
291
351
356
N-Cyclopropyl-2-phenylacetamide (4ah): Yield 87 mg (50%); white
1
solid. H NMR (400 MHz, CDCl3): δ = 7.40–7.19 (m, 5 H), 5.52
296 (br. s, 1 H), 3.54 (s, 2 H), 2.67 (tq, J = 7.1, 3.6 Hz, 1 H), 0.78–0.69
(m, 2 H), 0.44–0.37 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 172.7, 134.9, 129.5, 129.2, 127.5, 43.9, 22.9, 6.8 ppm. HRMS
(ESI): m/z calcd. for C11H14NO [M + H]+ 176.1070; found
176.1068.
(E)-N-Phenethylhex-3-enamide (4ee): Yield 174 mg (80%); yellow
1
solid. H NMR (400 MHz, CDCl3): δ = 7.26 (m, 2 H), 7.24–7.12
(m, 3 H), 5.81 (br. s, 1 H), 5.63–5.52 (m, 1 H), 5.48–5.36 (m, 1 H),
3.48 (q, J = 6.9 Hz, 2 H), 2.87 (d, J = 7.1 Hz, 2 H), 2.78 (t, J =
6.9 Hz, 2 H), 2.01 (q, J = 6.9 Hz, 2 H), 0.94 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.5, 138.9, 137.9,
128.8, 128.6, 126.5, 121.6, 40.6, 40.5, 35.6, 25.5, 13.4 ppm. HRMS
(ESI): m/z calcd. for C14H20NO [M + H]+ 218.1539; found
218.1547.
(4ai):[18]
Yield
361
366
301
N-(Adamantan-1-ylmethyl)-2-phenylacetamide
144 mg (51%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.40–
7.33 (m, 2 H), 7.32–7.24 (m, 3 H), 5.39 (br. s, 1 H), 3.59 (s, 2 H),
2.89 (d, J = 6.3 Hz, 2 H), 1.91 (br. s, 3 H), 1.71–1.64 (m, 3 H), 1.58–
1.51 (m, 3 H), 1.33 (d, J = 2.4 Hz, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.3, 135.3, 129.6, 129.2, 127.6, 51.1, 44.2, 40.2, 37.0,
33.9, 28.3 ppm.
306
Methyl 9-Oxo-9-(phenethylamino)nonanoate (4fe): Yield 300 mg
(98%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.32–7.25 (m,
2 H), 7.23–7.14 (m, 3 H), 5.57 (br. s, 1 H), 3.64 (s, 3 H), 3.53–3.46
(m, 2 H), 2.81 (d, J = 7.0 Hz, 2 H), 2.28 (dt, J = 7.5, 2.3 Hz, 2 H),
2.12–2.06 (m, 2 H), 1.66–1.50 (m, 4 H), 1.32–1.22 (m, 6 H) ppm.
2-Phenyl-1-(pyrrolidin-1-yl)ethan-1-one (4ak):[24] Yield 113 mg
(60%); colourless liquid. 1H NMR (400 MHz, CDCl3): δ = 7.36–
7.19 (m, 5 H), 3.66 (s, 2 H), 3.56–3.37 (m, 4 H), 1.98–1.78 (m, 4
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.7, 135.1, 129.1,
128.7, 126.8, 47.0, 46.1, 42.5, 26.3, 24.5 ppm.
13C NMR (101 MHz, CDCl3): δ = 174.0, 173.2, 138.9, 128.5, 128.3, 371
126.2, 51.2, 40.5, 36.4, 35.6, 33.8, 28.9, 28.8, 28.7, 25.5, 24.7 ppm.
HRMS (ESI): m/z calcd. for C18H28NO3 [M + H]+ 306.2064; found
306.2063.
311
2-Phenyl-1-(piperidin-1-yl)ethan-1-one (4al):[25] Yield 91 mg (45%);
1
colourless liquid. H NMR (400 MHz, CDCl3): δ = 7.37–7.19 (m,
5 H), 3.73 (s, 2 H), 3.61–3.53 (m, 2 H), 3.43–3.31 (m, 2 H), 1.66– 7-Bromo-N-phenethylheptanamide (4ge): Yield 280 mg (90%); white
316 1.43 (m, 4 H), 1.39–1.30 (m, 2 H) ppm. 13C NMR (101 MHz, solid. H NMR (400 MHz, CDCl3): δ = 7.34–7.28 (m, 2 H), 7.25–
376
1
6
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Job/Unit: O43468
/KAP1
Date: 05-01-15 17:45:33
Pages: 9
Direct Amidation of Carboxylic Acids
7.17 (m, 3 H), 5.42 (br. s, 1 H), 3.56–3.49 (m, 2 H), 3.39 (t, J = nership for Green and Sustainable Manufacture, and the Institute
6.8 Hz, 2 H), 2.82 (t, J = 6.9 Hz, 2 H), 2.12 (t, J = 7.5 Hz, 2 H), of Chemical and Engineering Sciences (ICES), Agency for Science,
436
1.89–1.78 (m, 2 H), 1.61 (quint, J = 7.5 Hz, 2 H), 1.48–1.38 (m, 2
Technology and Research (A*STAR), Singapore. The authors
H), 1.38–1.22 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = thank Dr. Charles W. Johannes (Institute of Chemical and Engi-
381
173.0, 139.0, 128.8, 128.7, 126.6, 40.6, 36.6, 35.8, 33.9, 32.6, 28.4,
27.9, 25.5 ppm. HRMS (ESI): m/z calcd. for C15H23Br79NO [M +
H]+ 312.0958; found 312.0957. HRMS (ESI): m/z calcd. for
C15H23Br81NO [M + H]+ 314.0938; found 314.0938.
neering Sciences, Singapore) and Dr. Helen Sneddon (GSK, Ste-
venage, UK) for valuable suggestions.
[1]
[2]
441
446
451
456
A. K. Ghose, V. N. Viswanadhan, J. J. Wendoloski, J. Comb.
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D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey,
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N-Phenethylcyclopentanecarboxamide (4he): Yield 167 mg (77%);
1
386 white solid. H NMR (400 MHz, CDCl3): δ = 7.33–7.27 (m, 2 H),
7.25–7.15 (m, 3 H), 5.54 (br. s, 1 H), 3.51 (dt, J = 6.9, 5.9 Hz, 2
H), 2.81 (t, J = 6.9 Hz, 2 H), 2.50–2.37 (m, 1 H), 1.86–1.65 (m, 6
H), 1.60–1.47 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
176.3, 139.2, 128.9, 128.7, 126.6, 46.0, 40.7, 35.9, 30.5, 26.0 ppm.
391 HRMS (ESI): m/z calcd. for C14H20NO [M + H]+ 218.1539; found
218.1539.
[3]
(1R,4R)-4-Methyl-N-phenethylcyclohexane-1-carboxamide
(4ie):
1
Yield 146 mg (60%); white solid. H NMR (400 MHz, CDCl3): δ
= 7.34–7.28 (m, 2 H), 7.25–7.16 (m, 3 H), 5.40 (br. s, 1 H), 3.55–
396 3.47 (m, 2 H), 2.81 (t, J = 6.9 Hz, 2 H), 1.93 (m, 1 H), 1.87–1.69
(m, 4 H), 1.48–1.24 (m, 3 H), 0.95–0.83 (m, 5 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 176.2, 139.1, 128.9, 128.7, 126.5, 45.4, 40.5,
35.8, 34.6, 32.1, 29.7, 22.6 ppm. HRMS (ESI): m/z calcd. for
C16H24NO [M + H]+ 246.1852; found 246.1853.
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a) A. L. L. García, Synlett 2007, 1328–1329; b) M. M. Joullié,
K. M. Lassen, ARKIVOC (Gainesville, FL, U.S.) 2010, 189–
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J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Bio-
mol. Chem. 2006, 4, 2337–2347.
401
(؎)-N-Phenethyl-2-phenylpropanamide (4je):[27] Yield 195 mg
(77%); white solid. 1H NMR (400 MHz, CDCl3): δ = 7.35–7.14 (m,
8 H), 7.01–6.96 (m, 2 H), 5.31 (br. s, 1 H), 3.54–3.44 (m, 2 H),
3.42–3.33 (m, 1 H), 2.69 (dt, J = 6.8, 1.6 Hz, 2 H), 1.49 (d, J =
7.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 174.2, 141.4,
138.9, 129.0, 128.8, 128.7, 127.8, 127.4, 126.5, 47.3, 40.8, 35.7,
18.4 ppm.
[5]
[6]
461
466
471
476
481
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ganic Synthesis and Medicine, Wiley-VCH, Weinheim, Ger-
many, 2005.
406
[7]
N-Phenethyl-2,2-diphenylacetamide (4ke):[28] Yield 53 mg (17%);
white solid. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.15 (m, 13 H),
7.06–7.02 (m, 2 H), 5.54 (br. s, 1 H), 4.87 (s, 1 H), 3.56 (q, J =
411 6.8 Hz, 2 H), 2.78 (t, J = 6.8 Hz, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.9, 139.6, 138.8, 129.1, 128.9, 128.8, 127.4, 126.6,
59.5, 41.0, 35.7 ppm.
[8]
[9]
2-(4-Aminophenyl)-N-benzylacetamide (4me): Yield 114 mg (45%);
yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.29–7.16 (m, 3 H),
416
421
7.08–7.02 (m, 2 H), 6.96–6.90 (m, 2 H), 6.66–6.59 (m, 2 H), 5.40
(br. s, 1 H), 3.49–3.39 (m, 4 H), 2.72 (t, J = 6.9 Hz, 2 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 171.8, 145.7, 138.9, 130.6, 128.8,
128.6, 126.5, 124.6, 115.7, 43.1, 40.8, 35.7 ppm. HRMS (ESI): m/z
calcd. for C16H19N2O [M + H]+ 255.1492; found 255.1488.
[10]
[11]
3-(1H-Indol-3-yl)-N-phenethylpropanamide (4ne):[29] Yield 192 mg
1
(66%); white solid. H NMR (400 MHz, CDCl3): δ = 8.14 (br. s, 1
H), 7.63 (d, J = 7.9 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.33–7.23
(m, 4 H), 7.18 (t, J = 7.4 Hz, 1 H), 7.09–7.02 (m, 2 H), 6.99 (s, 1
H), 5.49 (br. s, 1 H), 3.50 (q, J = 6.8 Hz, 2 H), 3.15 (t, J = 7.3 Hz,
486
491
496
501
426 2 H), 2.72 (t, J = 6.9 Hz, 2 H), 2.59 (t, J = 7.3 Hz, 2 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 173.1, 138.9, 136.5, 128.8, 128.7,
127.2, 126.6, 122.2, 121.9, 119.5, 118.8, 114.9, 111.4, 40.7, 37.5,
35.7, 21.5 ppm.
Supporting Information (see footnote on the first page of this arti-
1
431
cle): Copies of H and 13C NMR spectra for all compounds.
[12]
[13]
Acknowledgments
This work was supported by GlaxoSmithKline (GSK), Singapore
Economic Development Board (EDB) under GSK-Singapore Part-
Eur. J. Org. Chem. 0000, 0–0
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/KAP1
Date: 05-01-15 17:45:33
Pages: 9
E. K. W. Tam, Rita, L. Y. Liu, A. Chen
FULL PAPER
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Received: November 12, 2014
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Published Online: ᭿
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van Rantwijk, V. K. Svedas, R. A. Sheldon, Tetrahedron:
Asymmetry 2000, 11, 4593–4600.
8
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Job/Unit: O43468
/KAP1
Date: 05-01-15 17:45:33
Pages: 9
Direct Amidation of Carboxylic Acids
536
Amides
E. K. W. Tam,* Rita, L. Y. Liu,
A. Chen* ........................................... 1–9
2-Furanylboronic Acid as an Effective
Catalyst for the Direct Amidation of Carb-
oxylic Acids at Room Temperature
Commercially available, inexpensive 2-fu-
ranylboronic acid has been identified as an
effective catalyst for the direct dehydrative
amide formation of carboxylic acids and
amines. This transformation can be ef-
ficiently carried out at room temperature
and is applicable to a wide range of carb-
oxylic acids with primary and secondary
amines to afford amides in good to excel-
lent yields.
541
546
Keywords: Synthetic methods / Organocat-
alysis
/
Green chemistry
/
Amides
/
Amines / Carboxylic acids
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9