Dialkylaminoacetonitrile Derivatives as Amide Synthons. A One-Pot Preparation of Heteroaryl Amides via a Strategy of Sequential SNAr Substitution and Oxidation

Article abstract of DOI:10.1021/jo030233j

Dialkylamino acetonitrile derivatives were utilized as alternative to cyanohydrin synthons for preparation of the corresponding heteroaryl dialkyl amides via a strategy of sequential base-mediated coupling and oxidation. The most advantageous oxidant, NiO₂-H₂O, can readily oxidize 2-substituted aminoacetonitriles to the corresponding amides under both basic and neutral conditions by forming cyanohydrins in situ.

Full text of DOI:10.1021/jo030233j

Dia lk yla m in oa ceton itr ile Der iva tives a s
Am id e Syn th on s. A On e-P ot P r ep a r a tion of
Heter oa r yl Am id es via a Str a tegy of
Sequ en tia l SNAr Su bstitu tion a n d
Oxid a tion
Zhongxing Zhang, Zhiwei Yin, J ohn F. Kadow,
Nicholas A. Meanwell, and Tao Wang*
F IGURE 1. Drugs with heteroaryl amide subunits.
Department of Chemistry, The Bristol-Myers Squibb
Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492
wangta@bms.com
F IGURE 2. Alternative amide synthon.
Received J uly 18, 2003
SCHEME 1
Abstr a ct: Dialkylamino acetonitrile derivatives were uti-
lized as alternative to cyanohydrin synthons for preparation
of the corresponding heteroaryl dialkyl amides via a strategy
of sequential base-mediated coupling and oxidation. The
most advantageous oxidant, NiO2-H2O, can readily oxidize
2-substituted aminoacetonitriles to the corresponding amides
under both basic and neutral conditions by forming cyano-
hydrins in situ.
Heteroaryl amides are both useful synthetic intermedi-
ates and important structural elements of several drugs
and candidates, including the hypnotic agent rilmazafone
and the HIV non-nucleoside reverse transcriptase inhibi-
tor delavirdine (Figure 1).1,2 We have previously demon-
strated that N,N-disubstituted aminoacetonitrile deriva-
tives (1) are effective synthons of the corresponding
amides 2 via a procedure that takes advantage of
umpolung-like properties of 1, as summarized in Figure
2.3 The anion of 1, prepared by deprotonation using
NaHDMS in THF, was reacted with an ester 3 to provide
intermediate 4 (Scheme 1). The intermediate 4 was
deprotonated in situ by the excess base present in the
reaction mixture and the anion oxidized by adding
Clorox, to afford the R-ketoamide 5 in good overall yield.3
We now report the extension of this concept to the
preparation of heteroaryl amides 8 via a sequential SNAr
substitution and oxidation, a convenient one-pot process
summarized in Scheme 2. An important advantage of this
process is that the oxidation of the intermediate 7 to
SCHEME 2
amide 8 could occur under mild, neutral conditions using
NiO2-H2O in THF4,5 at room temperature.
Conceptually, it was anticipated that the strategy
described in Scheme 1 could be extended to the construc-
tion of heteroaryl amides by taking advantage of the
electron-withdrawing effect of the nitrogen atom in
heterocyclic rings to activate a halogen at the adjacent
(1) (a) Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May,
P. D.; Palmer, J . R.; J ohnson, P. D.; Smith, H. W.; Busso, M.; Tan,
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10.1021/jo030233j CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/22/2004
1360
J . Org. Chem. 2004, 69, 1360-1363

TABLE 1. Oxid a tive Con d ition s for F or m a tion of Am id e
8 fr om In ter m ed ia te 7
TABLE 2. On e-P ot P r ep a r a tion of Heter oa r yl Am id e via
a n SNAr -Oxid a tion Str a tegy
entry
oxidanta
bleach
NaBO3-4H2O
TMSOOTMS
Fe2O3
K3Fe(CN)6
VO(acac)2
CAN
yieldb,c (%) entry oxidanta yieldb,c (%)
1
2
3
4
5
6
7
8
9
36
36
62
24
32
6
12 BaO2
13 MgO2
14 CaO2
15 SrO2
16 ZnO2
17 Li2O2
41
21
48
34
46
33
42
22
33
63
13
16
7
18 Na2O2
19 MnO2
FeCl3
m-CPBA
4
8
8
20 H2O2-urea
21 NiO2-H2O
22 CCl3-CCl3
10 CuCl2
11 CuO
a
b
3 equiv of oxidant was used. LC-MS yield. c Other species
include intermediate 7a and unknown products.
carbon atom. Potential substrates in this process in-
clude the heterocycles pyridine, pyrazine, pyrimidine,
pyridazine, triazine, imidazole, pyrazole, oxazole, and
thiazole derivatives in which the halogen atom R to the
nitrogen atom is disposed toward facile displacement by
nucleophiles via an SNAr substitution process. This
process is depicted in Scheme 2 and relies upon the
presence of excess base to generate the anion of inter-
mediate 7 in situ, a process facilitated by the increased
acidity of 7 compared to 1. Direct in situ oxidation of 7
and subsequent collapse of the hydroxylated product with
the release of cyanide would be expected to provide the
heteroaryl amide 8.
The concept was initially examined under the condi-
tions analogous to those established earlier for the
reaction of 1 with esters.3 Thus, N,N-diethylacetonitrile
(1a ) was treated with an excess of NaHMDS and then
exposed to 2,3-dichloropyrazine (6a ) followed by the
addition of excess bleach as the oxidant. However, this
protocol afforded a mixture of the desired amide 8a and
the unoxidized intermediate 7a (Table 1), prompting
further optimization. Toward this objective, a panel of
commercially available oxidants was evaluated in this
process, as summarized in Table 1. The anion derived
from 7a , generated in situ, was exposed to a variety of
oxidants and the progress and outcome of these reactions
monitored by LC-MS. From this survey, TMSO-OTMS
and NiO2-H2O provided the best results, affording amide
8a in yields of 62% and 63%, respectively, based on LC-
MS analysis and after similar reaction times.
Having established TMSO-OTMS and NiO2-2H2O as
the optimal oxidants, extension of this one-pot procedure
to a variety of heterocyclic halides was examined in order
to generate the corresponding heteroaryl amides. The
results, summarized in Table 2, demonstrate the syn-
thetic utility of this protocol which proceeds in yields
ranging from 38% to 79%.
SCHEME 3
intermediate anion of 7. However, protonation of the
intermediate anion of 7 may occur prior to oxidation. This
process is particularly relevant for reagents containing
water, such as NiO2-H2O and NaBO3-4H2O or those
added as aqueous solutions, as with bleach (Table 1). To
examine this facet of reactivity, intermediate 7a was
isolated and exposed to the two most effective oxidants,
TMSO-OTMS and NiO2-H2O. In the absence of any
base, NiO2-H2O oxidized intermediate 7a to amide 8a
in a yield of 67%, as determined by LC-MS, after simply
stirring the mixture in THF at room temperature over-
night (Scheme 3). In contrast, exposure of 7a to TMSO-
OTMS resulted in only unchanged starting material.
However, when NaHMDS was introduced to generate the
The sequential SNAr-oxidation procedure as conceived
and described relies upon the direct oxidation of the
J . Org. Chem, Vol. 69, No. 4, 2004 1361

TABLE 3. Oxid a tion of N,N-Disu bstitu ted
Am in oa ceton itr iles to Am id e by Nick el P er oxid e
anion, both oxidants functioned effectively to provide
amide 8a in similar yields (Scheme 3).
The observation that the formation of a discrete anion
was not required for oxidation with NiO2-H2O provided
access to additional avenues of reactivity since the
intermediate 7 can be constructed via alternate proto-
cols.6,7 Most commonly, derivatives of 7 can readily be
obtained by the reaction of an aldehyde and an amine in
the presence of a source of cyanide.6 The preparation of
amides 8 from intermediate of type 7 has generally relied
upon the oxidation of the anionic form of intermediate
7, generated under strongly basic conditions, using either
oxygen gas or air in a process that requires extended
reaction times.6a,d,8 The neutral conditions associated with
NiO2-H2O-mediated oxidation of 7 provide a more con-
venient and mild reaction protocol that enhances the
utility of the overall synthetic strategy.
To demonstrate the scope of this process, several
aminoacetonitrile derivatives, either synthesized or ob-
tained from commercial sources, were exposed to NiO2-
H2O in THF. The results are compiled in Table 3 and
reveal that these reactions generally proceed smoothly
and efficiently to completion after 12 h. The only excep-
tion is entry 5, which required heating the reaction
mixture to 50 °C in order to drive the reaction to
completion. It is noteworthy that these mild conditions
are compatible with heterocyclic nitrogen atoms, both
aromatic and saturated, and isolated olefinic bonds
(Table 3, entry 3).
Possible mechanistic pathways for the NiO2-H2O-
mediated oxidation of derivatives of 7 are proposed in
Scheme 4. In path A, single electron-transfer from the
nitrogen atom of substrate to NiO2 would generate the
radical cation 10. The subsequent loss of a hydrogen
radical, possibly assisted by the adjacent nitrogen atom,
would produce the cation 11a , stabilized as 11b. The
reaction of 11a /11b with water would furnish the cyano-
hydrin 13, anticipated to decompose by elimination of
HCN,10 to provide the observed product, amide 8. The
a
b
d
Isolated yield. LC-MS yield. c Two hours at 50 °C. Three
weeks at room temperature.
SCHEME 4. P ossible Mech a n istic P a th w a ys of
NiO2-H2O Oxid a tion
(6) (a) Enders, D.; Amaya, A. S.; Pierre, F. New J . Chem. 1999, 23,
261. (b) Enders, D.; Kirchhoff, J .; Mannes, D.; Raabe, G. Synthesis
1995, 659. (c) J onas, R.; Pruecher, H.; Wurziger, H. Eur. J . Med. Chem.
1993, 28, 141. (d) Chuang, T.-H.; Yang, C.-C.; Chang, C.-J .; Fang, J .-
M. Synlett 1990, 733. (e) Boeckman, R. K., J r.; Breining, S. R.;
Arvanitis, A. Tetrahedron 1997, 53, 8941. (f) Mai, K.; Patil, G.
Tetrahedron Lett. 1984, 25, 4583. (g) Heydari, A.; Fatemi, P.; Alizadeh,
A.-A. Tetrahedron Lett. 1998, 39, 3049. (h) Katritzky, A. R.; Szajda,
M.; Bayyuk, S. Synthesis 1986, 804.
(7) (a) Besson, L.; Le Bail, M.; Aitken, D. J .; Husson, H.-P.; Rose-
Munch, F.; Rose, E. Tetrahedron Lett. 1996, 37, 3307. (b) Corrie, J . E.
T.; Gradwell, M. J .; Papageorgiou, G. J . Chem. Soc., Perkin Trans. 1
1999, 2977. (c) Sigman, M. S.; J acobsen, E. N. J . Am. Chem. Soc. 1998,
120, 5315. (d) Cossu, S.; Conti, S.; Giacomelli, G.; Falorni, M. Synthesis
1994, 1429. (e) Andres, C.; Pedrosa, R.; Pedrosa, R.; Perez-Encabo, A.;
Vicente, M. Synlett 1992, 45. (f) Fuchigami, T.; Ichikawa, S. J . Org.
Chem. 1994, 59, 607. (g) Yang, T.-K.; Yeh, S.-T.; Lay, Y.-Y. Heterocycles
1994, 38, 1711. (h) Michel, S.; Le Gall, E.; Hurvois, J .-P.; Moinet, C.;
Tallec, A.; Uriac, P.; Toupet, L. Liebigs Ann. Recl. 1997, 259. (i)
Sundberg, R. J .; Theret, M.-H.; Wright, L. Org. Prep. Proced. Int. 1994,
26, 386.
(8) (a) Yuste, F.; Origel, A. E.; Brena, L. J . Synthesis 1983, 109. (b)
Rozwadowska, M. D.; Brozda, D. Can. J . Chem. 1980, 58, 1239. (c)
Dominguez, E.; Martinez de Marigorta, E.; Carrillo, L.; Fananas, R.
Tetrahedron 1991, 47, 9253. (d) Royer, J .; Husson, H.-P. Heterocycles
1993, 36, 1493. (e) Leblanc, J .-P.; Gibson, H. W. J . Org. Chem. 1994,
59, 1072.
intermediate 11a /11b could also form via path B, initi-
ated by an abstraction of the hydrogen atom R to the
cyano group in 7 by NiO2-H2O to afford the carbon-based
radical 12.5 While combination of two molecules of 12
would provide a pathway for dimerization,4a,9 electron
transfer from the radical 12 to NiO2 would lead to the
intermediate cation 11a /11b. There is also the possibility
that hydroxyl radical, derived from nickel peroxide, could
combine with the carbon radical 12 to afford the cyano-
hydrin 13 directly (path C).5d
Support for the formation of cation 11a /11b, via path
A or path B, was obtained by treating N,N-diethylamino-
(9) (a) Sugita, J . Nippon Kagaku Zasshi 1967, 88, 1235. (b) Sugita,
J . Nippon Kagaku Zasshi 1967, 88, 668. (c) Golding, B. T.; Hall, D. R.
J . Chem. Soc. D 1970, 1574. (d) Hawkins, E. G. E.; Large, R. J . Chem.
Soc., Perkin Trans. 1 1974, 280.
(10) The reaction and the subsequent workup should be undertaken
with care in a well-ventilated hood due to the possibility of HCN
liberation.
1362 J . Org. Chem., Vol. 69, No. 4, 2004

SCHEME 5
tolerant of a range of oxidatively sensitive functionality.
The extension of this methodology to the synthesis of
hydrocarbon-based aromatic amides from aryl halides is
under active investigation.
Exp er im en ta l Section
Gen er a l Meth od s. Heterocyclic halides 6 (Tables 1 and 2),
substituted acetonitriles 7i-k (Table 3), N,N-diethylamino-
acetonitrile 1, and oxidative agents (Table 1) are commercially
available and were used as received. 1H and 13C NMR spectra
were obtained at 500 MHz with samples dissolved in CD3OD or
CDCl3.
Gen er a l P r oced u r es for th e P r ep a r a tion of Heter oa r yl
Am id es As Exem p lified by th e P r ep a r a tion of Com p ou n d
8c. Gen er a l P r oced u r e for th e P r ep a r a tion of Heter oa r yl
Am id es Usin g TMSO-OTMS. NaHMDS (8.2 mL, 1.0 M in
THF, 8.2 mmol) was added to a solution of 2-chlorobenzoxazole
(0.4 mL, 3.5 mmol) and N,N-diethylaminoacetonitrile (0.55 mL,
4.2 mmol) in dry THF (50 mL). After the mixture was stirred
for 10 h at room temperature, TMSO-OTMS (1.4 g, 7.8 mmol)
was added and the resulting mixture stirred a further 10 h at
room temperature. The reaction mixture was quenched with
saturated Na2SO3 solution, the aqueous layer was extracted with
EtOAc (3 × 50 mL), and the combined organic layers were dried
over MgSO4. Concentration in vacuo afforded a residue which
was purified by silica gel chromatography to provide benzox-
azole-2-carboxylic acid, diethylamide 8c (420 mg, 55%).
Gen er a l P r oced u r e for th e P r ep a r a tion of Heter oa r yl
Am id es Usin g NiO2-H2O. NaHMDS (12 mL, 1.0 M in THF,
12 mmol) was added to a solution of 2-chlorobenzoxazole (0.57
mL, 5.0 mmol) and N,N-diethylaminoacetonitrile (0.84 mL, 6.5
mmol) in dry THF (80 mL). After the mixture was stirred for 10
h at room temperature, NiO2-H2O (2.2 g, 20 mmol) was added
and the resulting mixture stirred a further 10 h at room
temperature. Insoluble solids were filtered off and washed with
MeOH. Concentration of filtrate in vacuo afforded a residue
which was purified by silica gel chromatography to provide
benzoxazole-2-carboxylic acid, diethylamide 8c (720 mg, 66%).
acetonitrile (7d ) with NiO2-H2O in the presence of
n-propylamine (Scheme 5). Under these conditions, the
amidine 14 was formed in 84% yield, as determined by
LC-MS, along with small amounts of the amides 8d (4%)
and 15 (8%). The formation of 14 and 15 is consistent
with the interception of the intermediate cation 11a /11b
by n-propylamine. Path C is considered to be unlikely
for two major reasons. First, alkylamine radical forma-
tion has not been observed at room temperature, which
implies a low possibility of producing 17 via the direct
combination of radicals.4a,4i Second, while hydroxyl radi-
cal is readily formed from nickel peroxide,5d its direct
combination with carbon radical 12 to afford cyanohydrin
13 is presumably not competitive with cation formation,
based on the observed products in the presence of
n-propylamine.
Ack n ow led gm en t. We thank Mr. Alan Xiang-dong
Wang for valuable discussions. We are also very grateful
to Dr. Li Pan for assistance in obtaining exact mass
spectral data.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
and HRMS data of compounds 7a , 8a -l, and 14. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, the utility of dialkylaminoacetonitrile
derivatives as umpolung-based amide synthons11 has
been applied to the preparation of N,N-disubstituted
heteroaryl amides.12 Mild, neutral conditions to effect the
oxidation of a dialkylaminoacetonitrile to the correspond-
ing amide using NiO2-H2O were discovered that are
J O030233J
(12) N-Monosubstituted aminoacetonitrile derivatives are oxidized
to the corresponding cyanoimines, as summarized in the example
shown below:
(11) (a) Larock, R. C. In Comprehensive Organic Transformation;
Wiiley-VCH: New York, 1989; p 865. (b) Hase, T. A. In Umpoled
Synthons: A Survey of Sources and Uses in Synthesis; Wiley-Inter-
science: New York, 1987.
J . Org. Chem, Vol. 69, No. 4, 2004 1363