An improved amide coupling procedure for the synthesis of N-(pyridin-2-yl)amides

Article abstract of DOI:10.1016/j.tetlet.2009.02.071

Dehydrative amide couplings with 2-pyridylamines suffer from variable yields. A mild and high-yielding synthesis of N-(pyridin-2-yl)amides employing 2-aminopyridine-N-oxides is presented as a solution.

Full text of DOI:10.1016/j.tetlet.2009.02.071

Tetrahedron Letters 50 (2009) 1986–1988
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An improved amide coupling procedure for the synthesis of
N-(pyridin-2-yl)amides
*
Allyn T. Londregan , Gregory Storer, Ceshea Wooten, Xiaojing Yang, Joseph Warmus
Pfizer Global Research and Development, Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Dehydrative amide couplings with 2-pyridylamines suffer from variable yields. A mild and high-yielding
synthesis of N-(pyridin-2-yl)amides employing 2-aminopyridine-N-oxides is presented as a solution.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 January 2009
Revised 9 February 2009
Accepted 10 February 2009
Available online 14 February 2009
The amide bond is an ubiquitous connection in proteins and
peptides and is found in a large number of small-molecule chemo-
therapeutics.1 Unsurprisingly, the preparation of amide bonds is
among the most common synthetic transformations in organic
chemistry. Most methods employ the dehydrative coupling of car-
boxylic acids with amines. The literature is replete with coupling
reagents and additives2 which facilitate this transformation. When
the acylations are attempted with weakly nucleophilic amines,
however, they are often met with long reaction times and harsh
conditions.3 During the course of our studies, we required a high-
yielding and reproducible procedure for the coupling of carboxylic
acid derivative 1 with 2-aminopyridine 2 (Scheme 1). Although
there is ample literature precedent for carboxylic acid couplings
with 2-aminopyridines, the yields tend to be quite variable and
more often than not, require transformation to the acid chloride
prior to coupling.4 In our hands, we obtained very poor yields
(<5%) of 3 when using standard coupling protocols (EDCI, BOP,
HATU, or acid chloride) with 2, presumably due to the decreased
nucleophilicity of the amine. Neither heating nor the addition of
rate enhancers, such as DMAP (used with the acid chloride and
EDCI), afforded any additional product. We were able to overcome
this intrinsic limitation by replacing 2 with 2-aminopyridine-N-
oxide 4. In the case of coupling between 1 and 4, a nearly quanti-
tative yield of N-oxide-(pyridin-2-yl)amide 5 was observed in 1 h.
A simple catalytic hydrogenation afforded the desired N-(pyridin-
2-yl)amide 3 in excellent yield. Upon further investigation, we
found this coupling protocol to be readily reproducible and appli-
cable to a variety of different carboxylic acid derivatives.
elected to use the BOP reagent. Dehydrative couplings mediated
by BOP proceed quickly and are usually high-yielding.5 These con-
ditions, however, showed at best a 25% conversion (entry 7) at 48 h
to the desired N-(pyridin-2-yl)amides. In some cases, no reaction
was observed when using 2-aminopyridine under condition A. In
contrast, all coupling reactions between 2-aminopyridine-N-oxide
and the carboxylic acids (condition B) were complete in 1 h. Subse-
quent catalytic hydrogenation of the N-oxide proceeded smoothly,
typically in 15 h. Yields ranged from 76–97% for the two-step se-
quence. Amino acid derivatives 6–9 worked very well in the reac-
tion, as did aromatic (10 and 12) and aliphatic (11) acids. As shown
in entry 8, substituted 2-aminopyridine-N-oxides were also effec-
tive partners in the coupling reaction. Although not presented in
Table 1, the replacement of BOP with EDCI in entry 5 also afforded
the desired N-(pyridin-2-yl)amide in excellent yield (86%, two
steps). This would suggest that the improved method is compatible
with alternative coupling reagents.
The direct reaction of amine and acid chloride is a common pro-
cedure for amide bond formation and on first inspection would
N
2
R
R
NH2
O
O
H
N
a, b, c, or d
N
N
H
S
S
R
O
O
O
O
H
N
3
5
f
S
OH
O
N
O
O
4
Comparisons of this new methodology versus a traditional cou-
pling procedure were conducted with a number of carboxylic acids.
As indicated in Table 1, the difference between the two methods is
extreme. For a standard coupling condition (condition A), we
1
H
N
NH2
N
O
N
H
O
e
Scheme 1. Reagents and conditions: (a) EDCI, DMAP, no rxn; (b) BOP, DIEA, no rxn;
(c) HATU, DIEA, no rxn; (d) oxalyl chloride, NEt3, DMAP <5%; (e) BOP, DIEA or HATU,
DIEA 100%; (f) H2, 30 psi, Pd/C, 76–93%.
* Corresponding author. Tel.: +1 860 715 6150; fax: +1 860 686 0001.
E-mail address: allyn.t.londregan@pfizer.com (A.T. Londregan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.071

A. T. Londregan et al. / Tetrahedron Letters 50 (2009) 1986–1988
1987
Table 1
Comparison of coupling procedures for the synthesis of N-(pyridin-2-yl)amides
Entry
Substrate
Product
Conditions
Conversiond(%)
Yielde (%)
O
O
O
TsHN
TsHN
1
Aa
Bb
0
>95
n/df
93
OH
OH
N
H
N
N
6
6a
O
TsHN
TsHN
N
H
2
3
4
5
A
B
14
>95
n/d
90
7
Ph
O
Ph
O
7a
TsHN
TsHN
A
B
4
>95
n/d
81
OH
N
H
N
CH3
8
8a CH3
O
O
BocHN
BocHN
A
B
10
>95
n/d
93
OH
N
H
N
9
9a
O
O
OH
N
H
N
A
15
>95
60
n/d
97
55
B
10
Cc
10a
O
O
H3C
H3C
6
A
B
20
>95
5
94
OH
N
H
N
11
11a
O
O
O
O
OH
OH
N
H
N
N
7
8
A
B
25
>95
n/d
76
12
12a
CH3
O
O
Ag
Bg
0
>95
n/d
84
t-Bu
13
t-Bu
13a
N
H
O
O
N
TsHN
TsHN
9
Ah
Bh
0
0
n/d
n/d
N
H
OH
6
6b
a
Substrate (1.0 equiv), 2-aminopyridine 2 (1.1 equiv), BOP (1.2 equiv), DIEA (2.5 equiv), DMF, 48 h, rt.
b
c
d
e
f
(a) Substrate (1.0 equiv), 2-aminopyridine-N-oxide 4 (1.1 equiv), BOP (1.2 equiv), DIEA (2.5 equiv), DMF, 1 h. (b) H2, 10% Pd/C, MeOH, 30 psi, 15 h.
2-Aminopyridine 2 (1.0 equiv), benzoyl chloride (1.0 equiv), NEt3 (2.0 equiv), DMAP (0.1 equiv), CH2Cl2, 24 h, 40 °C.
HPLC measured at reaction completion. Measured over two steps for condition B.
Isolated yield after purification. Yield over two steps for condition B.
Not determined.
g
h
2-Amino-5-methylpyridine and 2-amino-5-methylpyridine-N-oxide used in place of 2 and 4, respectively.
4-Aminopyrdine and 4-aminopyridine-N-oxide used in place of 2 and 4, respectively.
seem to be a viable approach to 6a–13a. As we observed in Scheme
1 (vide supra), the reaction of tosyl-protected amino acid chlorides
with 2-aminopyridine was unsuccessful. In fact, the instability of
tosyl-protected amino acid chlorides has been previously reported6
and limits their use in amide syntheses. Our new methodology
provides a clear advantage when using such systems. The corre-
sponding acid chlorides of entries 5–8, however, do not suffer from
the aforementioned instability. For a comparison, we examined the
synthesis of 10a using benzoyl chloride and 2-aminopyridine (con-
dition C). Despite the use of DMAP in the reaction, we observed
only a 60% conversion to the desired product after 24 h at 40 °C.
It is noteworthy that under these conditions, the use of a highly
reactive acid chloride was less effective than our new method
(55% vs 97%).
results in ester 14, which undergoes nucleophilic attack by the
oxide in 2 to form intermediate 15. A subsequent intramolecular
attack of the pendant amine on the newly formed ester results in
the formation of 16. The fast rate of this reaction can partly be
attributed to its intramolecular nature. As would be expected for
O
O
NH2
O
R
N
H
O
N
O
N
H
BtO
R
N
H
N
O
N
N
N
R
O
14
16
2
15
A possible mechanism for this new transformation is shown in
Scheme 2. Activation of a carboxylic acid derivative with BOP
Scheme 2. Proposed mechanism for the coupling reaction of acid derivatives with
2-aminopyridine-N-oxide and BOP.

1988
A. T. Londregan et al. / Tetrahedron Letters 50 (2009) 1986–1988
this proposed mechanism, the independent synthesis of ester 14,
followed by treatment with 2, produces 16 in analogous fashion.
When the reaction is attempted with 4-aminopyridine-N-oxide in
place of 2, no reaction is noted (see entry 9 in Table 1). This obser-
vation lends further support to an intramolecular 5-exo mecha-
nism, which is not possible in the case of other aminopyridine
isomers.
In summary, a high-yielding and mild synthesis of N-(pyridin-
2-yl)amides from 2-aminopyridine-N-oxides has been presented.
The reaction most likely proceeds via a novel intramolecular ami-
nolysis. The methodology is applicable to a number of different
carboxylic acids.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.071.
References and notes
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Acknowledgments
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We would like to thank David Price and Steven Wright for their
helpful discussions in the preparation of this manuscript.