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Z. Ruan et al. / Tetrahedron Letters 47 (2006) 7649–7651
Table 2. Representative yields of amide 3
O
O
R1
O
CHO
Entry
Acid
Amine
Yield (%)
NaB(OAc)3H
N
H
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
1d
1d
1e
1e
1e
1f
2a
2c
2d
2e
2f
95
88
88
89
94
71
86
70
76
85
98
65
0
O
O
NH2R1COOMe
AcOH/DMF
4
5
O
PhCOCl
DIEA/DCM
2d
2g
2b
2a
2d
2e
2g
2j
R1
O
(n-Bu)4NOH
N
O
THF/MeOH/H2O
40 °C, O/N
O
O
Ph
6
O
N
O
7
OH
R1
Ph
10eq. R2NHR3
20eq. PhSiH3
Resin 7-1 R1:
Resin 7-2
O
2k
2b
2a
2c
2d
2f
0
O
R1:
77
65
89
80
95
65
40
66
76
89
71
92
62
78
88
94
DMF/rt/15h
R2
R2
N
R3
O
R1
R1
Ph
N
2g
2h
2d
2g
2h
2e
2f
N
R3
50% TFA
HN
O
O
O
O
Ph
in DCM
2h
O
9
8
Scheme 2. Solid-phase phenylsilane-mediated amidation couplings.
1f
1f
2g
2d
2g
2i
1g
1g
1g
Table 3. Purity and yield data of amide 9
Entry
Resin
Amine
Purity (%)
Yield (%)
31
32
33
34
35
36
37
38
39
40
41
42
7-1
7-1
7-1
7-1
7-1
7-1
7-2
7-2
7-2
7-2
7-2
7-2
2a
2c
2d
2g
2i
92.8
97
70
89
14
0
86
83
85
86
0
87
90
81
84
75
was necessary to drive the coupling reaction to comple-
tion. Reaction mixtures were dried in vacuo, and puri-
fied by reverse phase preparative HPLC with
micromass detection. Representative results produced
by this synthesis are listed in Table 2.
2k
2a
2c
2d
2g
2i
82
86
75
79
In the majority of cases, reactions proceeded cleanly and
the desired carboxylic amides were obtained in high
yields. However, virtually no amide products were
obtained with sterically-hindered amines or aniline (see
entry 13 with amine 2j and entry 14 with amine 2k).
Phenylsilane-promoted couplings did not appear to lead
to any appreciable racemization as indicated by entry 7.7
2k
0
SPE resin.8 Also, as observed in the solution-phase
library, very few amides were obtained from sterically-
hindered amines or aniline (see entries 36, 41, and 42).
In order to explore the extension of these coupling con-
ditions to solid-phase, two representative acid resins (7-1
and 7-2 in Scheme 2) were prepared from 4-formyl-3-
methoxyphenoxy methyl resin 4 and amino methyl
esters, (NH2R1COOMe) by reductive amidation, acyl-
ation, and deprotection. The acid resins were then
tested with the representative amines described in Table
1. The chemistry was performed on a 0.02 mmol scale of
resin in DMF at room temperature for 15 h with
10 equiv of amines and 20 equiv of PhSiH3. Typical
results are summarized in Table 3.
In summary, an effective method for the preparation of
carboxamides from carboxylic acids, amines, and phen-
ylsilane has been established. The method may be
applied for both solution and solid-phase applications.
Further investigations to explore the scope and limita-
tions of this transformation are ongoing.
References and notes
1. (a) Jones, J. The Chemical Synthesis of Peptides; Oxford
University Press: Oxford, 1991; (b) Bodanszky, M. Princi-
ples of Peptide Synthesis; Springer: Berlin, 1984.
2. (a) Molander, G.; Schmitt, M. J. Org. Chem. 2000, 65,
3767–3770; (b) Lipshutz, B.; Chrisman, W.; Noson, K.;
Papa, P.; Sclafani, J.; Vivian, R.; Keith, J. Tetrahedron
Direct analyzes of the cleaved products 9 (HPLC and
LC/MS) indicated high purity and yields in most cases
based on the initial acid resin loadings. The major impu-
rity was unreacted carboxylic acid, which can be easily
separated by passing crude products through SAX