Azole-N-acetonitriles as carbonyl synthons: A one-pot preparation of heteroaryl amides from halides

Article abstract of DOI:10.1055/s-2004-832849

Azole-N-acetonitrile derivatives were utilized as synthons for an ambident carbonyl moiety via a strategy relying upon sequential base-mediated S _NAr substitution of a 2-halo heterocycle, in situ oxidation, and amine displacement. This strategy allows prompt and efficient synthesis of N-containing heteroaryl amides directly from the corresponding halides via a one-pot process.

Full text of DOI:10.1055/s-2004-832849

LETTER
2323
Azole-N-Acetonitriles as Carbonyl Synthons: A One-Pot Preparation of
Heteroaryl Amides from Halides
Azole-
N
-Aceton
h
itriles as
C
a
o
rbonyl Synth
n
ons gxing Zhang, Zhiwei Yin, John F. Kadow, Nicholas A. Meanwell, Tao Wang*
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institut, 5 Research Parkway, Wallingford, CT 06492, USA
E-mail: wangta@bms.com
Received 17 June 2004
CN
Z
N
O
CN
Abstract: Azole-N-acetonitrile derivatives were utilized as syn-
thons for an ambident carbonyl moiety via a strategy relying upon
sequential base-mediated SNAr substitution of a 2-halo heterocycle,
in situ oxidation, and amine displacement. This strategy allows
prompt and efficient synthesis of N-containing heteroaryl amides
directly from the corresponding halides via a one-pot process.
N
X
N
base
[O]
+
Y
Z
Z
7
Y
Y
Z = NR1R2, 8
Z = Ar, 9
Z = NR1R2, 1
Z = Ar, 3
Z = NR1R2, 10
Z = Ar, 11
X = Cl, Br
Y = C, N, O, S
Scheme 1 Preparation of heteroaryl amides or heteroaryl ketones
via a condensation–oxidation-displacement protocol
Key words: azole-N-acetonitrile, carbonyl synthon, heteroaryl
amide, acyl anion equivalent
However, two issues remain to be addressed. First, it is
readily apparent that in both of these protocols, the sub-
stituent bound to the acetonitrile moiety is retained in the
final product, providing some limitation to the versatility
of the reaction, which only allows constructing amides or
ketones along one dimension. Second, the claim ‘ami-
noacetonitrile derivatives as amide synthons’ is restricted
to N,N-disubstituted aminoacetonitrile derivatives 1.
When N-monosubstituted aminoacetonitriles were ap-
plied, cyano-imine derivatives, rather than primary
amides, were generated.3b Such results showed that the
procedure described in Scheme 1 is only capable of pro-
ducing secondary amides.
Heteroaryl amides are commonly encountered as structur-
al elements in many investigational and marketed drugs.
Two prominent examples of the latter are the antiarthritic
agent Leflunomide and the antiemetic agent Granisetron
(Figure 1).1,2 We have previously demonstrated that N,N-
disubstituted aminoacetonitrile derivatives 1 are effective
and versatile synthons for amides of general composition
23 and that an aryl acetonitrile, represented by 3, can be
viewed as the synthetic equivalent of an aryl carbonyl
moiety 4 (Figure 2).4 For both, a two-step process consist-
ing of base-mediated alkylation of the methylene moiety
and subsequent oxidation results in the generation of the
final carbonyl moiety 10 or 11 after elimination of HCN
from an intermediate cyanohydrin 8 or 9. This process is
summarized in Scheme 1.3,4
As part of an effort to further broaden the utility of this
synthetic protocol it was envisioned that if the amine ele-
ment of structure 1 could be configured to act as a leaving
group, substituted acetonitriles represented by 5 would
function in an ambident fashion, acting sequentially in a
nucleophilic and an electrophilic capacity, thereby deliv-
ering a synthetic equivalent to 6 (Figure 2). This approach
would permit building amides two-directionally, offering
a very efficient method for the preparation of N-contain-
ing heteroaryl amides, including both primary and sec-
ondary amides, directly from the corresponding halides,
respectively. The documented one-pot process, possess-
ing similar capability, has been limited to transition-met-
al-mediated amidation of aryl halide with carbon
monooxide and amine, which generally requires escalated
temperature and/or high pressure.5
CF3
Me
N
HN
NH
O
O
N
N
Me
Me
N
O
Leflunomide
Granisetron
Figure 1 Marketed drugs with amide subunits
O
O
CN
O
CN
ref. 3
CN ref. 4
?
The realization of this protocol relies upon the fact that
acyl derivatives of sp2-hybridized azole nitrogen atoms
(12) are, in contrast to simple amides derived from sp3-
configured nitrogen atoms, chemically labile and well es-
tablished as acylating agents (Figure 3).6 In previous stud-
ies, we have established synthetic access to stable
substituted acetonitriles 8 derived from simple amine de-
rivatives and demonstrated that they could readily be oxi-
dized to amides 10.3,4 Consequently, the extension of this
R
R
N
R
N
R
Ar
N
Ar
1
5
6
4
2
3
Figure 2 Carbonyl synthons
SYNLETT 2004, No. 13, pp 2323–2326
0
3
.1
1
.2
0
0
4
Advanced online publication: 28.09.2004
DOI: 10.1055/s-2004-832849; Art ID: S05604ST
© Georg Thieme Verlag Stuttgart · New York

2324
Z. Zhang et al.
LETTER
chemistry to aminoacetonitriles 13 derived from an azole that as an activated carbonyl derivative would react with
of the type depicted in Figure 3 became the objective, an exogenous amine to provide the heteroaryl amide 16.
with the concept summarized in Scheme 2.
CN
CN
N
N
base
X
O
CN
+
N
N
Y
7
Y
R
R
N
N
5
14
Y = C, N, O, S
13
12
O
N
N
N
O
N
N
N
N
HNR1R2
N
[O]
N
NR1R2
N
Y
N
Y
N
N
15
N
16
N
N
N
Scheme 2 Preparation of heteroaryl amides via a condensation–
N
N
oxidation–displacement protocol
Figure 3 Amide derived from aminoacetonitrile
In order to explore the viability of the proposed ipso-dis-
placement–oxidation sequence, a series of three commer-
cially available azole-N-acetonitrile derivatives 5 were
examined using the quinoxaline chloride 7a as the other
reaction partner in conjunction with a concomitant survey
of potential oxidants. A mixture of 5a, 5b, or 5c and 7a in
THF at room temperature was treated with 2.5 equivalents
It was anticipated that an anion generated from an azole-
N-acetonitrile 5 using a strong base, such as NaHMDS,
would react with a heteroaryl halide 7 via an ipso-dis-
placement process to form the substituted aminoacetoni-
trile derivative 14. The subsequent oxidation of 14 to the
corresponding cyanohydrin would set the stage for elimi-
nation of HCN to afford an acylated azole derivative 15
Table 1 Investigation of Possible Leaving Groups and Oxidants
N
N
N
N
N
1) NaHMDS
NC
+
N
N
OH
OMe
2) Oxidant
N
N
Cl
N
3) MeOH-H2O
7a
CN
5
17a
14a
O
18a
O
N
N
N
CN
N
NH2
N
N
N
N
O
19a
CN
N
N
N
20a
N
N
N
N
Cl
N
N
Cl
5a, 14aa
5b, 14ab
5c 14ac
Entry
Oxidant
Product (LC-MS yield, %)
Product (LC-MS yield, %)
Product (LC-MS yield, %)
from 5a
from 5b
from 5c
1
2
AcOOH
19a (80)
19a (85)
19a (61)
t-BuOOH
14aa (87)
14ab (89)
19a (4)
14ac (89)
3
4
TMSO-OTMS
Bleach
14aa (46)
19a (46)
18a (31)
19a (47)
14ac (18)
19a (32)
19a (15)
20a (21)
20a (36)
Complicated mixture
5
6
mCPBA
19a (80)
19a (70)
19a (66)
NiO2–H2O
14aa (53)
18a (2)
14ab (45)
20a (19)
NA
19a (10)
20a (10)
7
Na2O2
14aa (82)
14ab (91)
NA
Synlett 2004, No. 13, 2323–2326 © Thieme Stuttgart · New York

LETTER
Azole-N-Acetonitriles as Carbonyl Synthons
2325
Table 2 One-Pot Synthesis of N-Containing Heteroaryl Amides
O
2) HNR1R2
NC
1) NaHMDS
N
Ar
N
+
X
Ar
NR1R2
THF
3) AcOOH
Cl
7
16
Cl
5a
Me2NH
Yield
(%)
n-PrNH2
Yield
(%)
PhNH2
Yield
(%)
69
O
72
O
37
O
N
N
Cl
N
N
N
N
NHPr
NHPh
NMe2
7a
N
N
16a 69%
16c 37%
16b 72%
78
87
70
74
63
50
32
41
31
O
O
N
O
N
N
S
N
S
Cl
7b
S
S
NHPr
NHPh
NMe2
16f 32%
16d 78%
16e 74%
O
O
O
N
N
O
N
O
N
O
Cl
7c
O
NMe2
NHPh
16i 41%
NHPr
16g 87%
16h 63%
N
Cl
O
O
O
N
N
N
N
N
NHPr
N
NHPh
N
NMe2
Ph
7d
Ph
Ph
Ph
16j 70%
16l 31%
16k 50%
of NaHMDS followed 30 minutes later by the addition of In order to avoid the competition for the acylated azole by
an excess of oxidant. The reaction mixture was quenched HMDS, a revised protocol in which an amine was added
by the addition of MeOH and H2O and the product mix- prior to the oxidant was developed. The results of a survey
tures identified by LC-MS. The results are compiled in of this process, conducted using four heteroaryl chlorides
Table 1. Somewhat surprisingly, the amide 19a emerged and three amine derivatives that provided a series of het-
as the preferred product in most of cases instead of the eroaryl amides 16, are summarized in Table 2.8,9 Primary
expected acid 17a or ester 18a. This result substantiated (products 16b, 16e, 16h, 16k, Table 2) and secondary
the feasibility of the proposed protocol but suggested that (products 16a, 16d, 16g, 16j, Table 2) aliphatic amines
either HMDS or derived ammonia had successfully and participated effectively, generally providing the products
effectively competed with MeOH and H2O as the nucleo- in greater than 50% yield. The poorly nucleophilic amine
phile towards the acylated azole intermediate.7 With re- aniline produced anilides in only moderate yields, 30–
spect to potential oxidants, AcOOH (entry 1, Table 1) and 40% (products 16c, 16f, 16i, 16l, Table 2).
mCPBA (entry 5, Table 1) provided the cleanest results
with the other agents examined performing significantly
less effectively. Competitive dimerization occurred dur-
In summary, we have demonstrated the feasibility of
azole-N-acetonitriles derivatives as carbonyl synthons10
based on a protocol that takes advantage of sequential am-
ing oxidation with either NiO2 or bleach, producing com-
bident chemical reactivity. The synthetic sequence allows
pound 20a and implicated the involvement of radical-
for versatility in the selection of both the heteroaryl halide
that participates in the initial displacement reaction and
the amine moiety that intercepts the acylated azole inter-
based mechanisms in these specific examples (entries 4
and 6, Table 1).
Based on the observed yield, ease of handling and com- mediate. The extension of this methodology to the synthe-
mercial availability, peracetic acid was selected as the sis of hydrocarbon-based aromatic amides from aryl
preferred oxidant for subsequent studies of the scope of halides using transition metal-mediated cross-coupling to
the process. 2,3-Dichloroimidazole was selected as the re- effect the SNAr step of the process is under active investi-
action partner in further studies although all of the hetero- gation.
cycles probed, 2,3-dichloro imidazole, 1,2,4-triazole and
benzotriazole, behaved similarly and were suitable sub-
strates for the process.
Acknowledgment
The authors would like to thank Mr. Alan Xiang-dong Wang for
valuable discussion, and Dr. Li Pan and Dr. Xiaohua Stella Huang
for assistance in obtaining exact mass and NMR spectral data.
Synlett 2004, No. 13, 2323–2326 © Thieme Stuttgart · New York

2326
Z. Zhang et al.
LETTER
(6) (a) Nicolaou, K. C.; Baran, P. S. Angew. Chem. Int. Ed.
References
2002, 41, 2678. (b) Katrizky, A. R.; He, H.-Y.; Suzuki, K. J.
Org. Chem. 2000, 65, 8210. (c) Evans, D. A.; Borg, G.;
Scheidt, K. A. Angew. Chem. Int. Ed. 2002, 41, 3188.
(d) Adam, W.; Humpf, H.-U.; Korb, M. N.; Schreier, P.
Tetrahedron: Asymmetry 1997, 8, 3555. (e) Kashima, C.;
Shirahata, Y.; Tsukamoto, Y. Heterocycles 1998, 49, 459.
(f) Bu, X.; Deady, L. W.; Finlay, G. J.; Baguley, B. C.;
Denny, W. A. J. Med. Chem. 2001, 44, 2004. (g) Bhat, B.;
Sanghvi, Y. S. Tetrahedron Lett. 1997, 38, 8811. (h) Jursic,
B. S. Synth. Commun. 1993, 23, 361. (i) Katritzky, A. R.;
Levell, J. R.; Pleynet, D. P. M. Synthesis 1998, 153.
(7) This assumption was further confirmed with an addition of
excess of EtOH prior to oxidation under the same condition.
The formation of 19a (51%) and the ethyl ester (31%) was
detected by LC-MS.
(1) (a) Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.;
May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.;
Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.;
Althaus, I. W.; Downey, K. M. J. Med. Chem. 1994, 37,
999. (b) Natsugari, H.; Ikeura, Y.; Kiyota, Y.; Ishichi, Y.;
Ishimaru, T.; Saga, O.; Shirafuji, H.; Tanaka, T.; Kamo, I.;
Doi, T.; Otsuka, M. J. Med. Chem. 1995, 38, 3106.
(c) Kumar, S.; Singh, R.; Singh, H. Bioorg. Med. Chem. Lett.
1993, 3, 363. (d) Kawakubo, H.; Okazaki, K.; Nagatani, T.;
Takao, K.; Hasimoto, S.; Sugihara, T. J. Med. Chem. 1990,
33, 3110. (e) Tanaka, A.; Sakai, H.; Motoyama, Y.;
Ishikawa, T.; Takasugi, H. J. Med. Chem. 1994, 37, 1189.
(f) Perry, R.; Wilson, B. D. J. Org. Chem. 1996, 61, 7482.
(g) Ben-David, Y.; Portnoy, M.; Milstein, D. J. Am. Chem.
Soc. 1989, 111, 8742.
(8) General Procedure for the Preparation of Heteroaryl
Amides: NaHMDS (2.5 mL, 1.0 M in THF, 2.5 mmol) was
added into a solution of 2-chloro-benzooxazole (153 mg, 1.0
mmol), and (4,5-dichloro-imidazol-1-yl)-acetonitrile (264
mg, 1.5 mmol) in dry THF (15 mL). After stirring for 10 h at
r.t. dimethylamine (1.5 mL, 2 M in THF, 3.0 mmol) and
HOOAc (0.84 mL, 32 wt.% in HOAc, 4.0 mmol) were
subsequently added and the mixture stirred a further 10 h at
r.t. The reaction mixture was quenched with sat. Na2SO3
solution and neutralized by sat. NaHCO3 solution, the
aqueous layer extracted with EtOAc (3 × 20 mL) and the
combined organic layer dried over MgSO4. Concentration in
vacuo afforded a residue which was purified by silica gel
chromatography to provide benzoxazole-2-carboxylic acid
dimethylamide (16g, 165 mg, 87%). 1H NMR (500 MHz,
CDCl3): d = 7.71 (d, 1 H, J = 8.0 Hz), 7.52 (d, 1 H, J = 8.0
Hz), 7.33 (m, 2 H), 3.39 (s, 3 H), 3.10 (s, 3 H). 13C NMR (125
MHz, CDCl3): d = 157.6, 155.2, 149.9, 140.3, 127.0, 125.2,
121.2, 111.4, 38.8, 36.4. HRMS: m/z [M + H]+ calcd for
C10H11N2O2: 191.0821; found: 191.0824.
(2) (a) Kaplan, M. J. Curr. Opin. Investig. Drugs 2001, 2, 222.
(b) Adams, V. R.; Valley, A. W. Ann. Pharmacotherapy
1995, 29, 1240.
(3) (a) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. Org. Lett. 2002, 4, 1103. (b) Zhang, Z.; Yin, Z.;
Kadow, J. F.; Meanwell, N. A.; Wang, T. J. Org. Chem.
2004, 69, 1360.
(4) Yin, Z.; Zhang, Z.; Kadow, J. F.; Meanwell, N. A.; Wang, T.
J. Org. Chem. 2004, 69, 1364.
(5) (a) Meyers, A. I.; Robichaud, A. J.; McKennon, M. J.
Tetrahedron Lett. 1992, 33, 1181. (b) Ozawa, F.; Soyama,
H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa, K.;
Yamamoto, T.; Yamamoto, A. J. Am. Chem. Soc. 1985, 107,
3235. (c) Brunet, J. J.; Sidot, C.; Loubinoux, B.; Caubere, P.
J. Org. Chem. 1979, 44, 2199. (d) Schoenberg, A.; Heck, R.
F. J. Org. Chem. 1974, 39, 3327.
(9) The reaction and the subsequent work-up should be
undertaken with care in a well-ventilated hood due to the
possibility of HCN liberation.
(10) Johnson, J. S. Angew. Chem. Int. Ed. 2004, 43, 1326.
Synlett 2004, No. 13, 2323–2326 © Thieme Stuttgart · New York