Synthesis of aminonicotinonitriles and diaminopyridines through base-catalyzed ring transformation of 2H-pyran-2-ones

Article abstract of DOI:10.1021/jo0204496

An efficient and convenient synthesis of 2-amino-6-aryl-4-methylsulfanylnicotinonitriles (2), 2-amino-6-aryl-4-substituted-aminonicotinonitriles (4), and 2-amino-6-aryl-4-substituted-aminopyridines (6) has been delineated and illustrated through base-cata

Full text of DOI:10.1021/jo0204496

ridines with amines or condensation of R,â-unsaturated
carbonyl compounds with malononitriles in the presence
of ammonium acetate10 is prominent. Recently, Fort et
al.11 have described a convenient way to introduce
reactive functionalities at specific positions in the pyri-
dine ring of 4-DMAP through direct R-lithiation with
BuLi-LiDMAE reagent. Though use of palladium-
catalyzed amination12,13 has been shown to be of immense
value as an alternative approach for the preparation of
aminopyridines, most of these procedures suffer with
limitation of functional group intolerance due to harsh
reaction conditions, sluggish reactions, and low yields.
Herein, we report a convenient synthesis of function-
alized aminonicotinonitriles and 2,4-diaminopyridines in
a single step through ring transformation of 2H-pyran-
2-ones in moderate yields. The beauty of the procedure
lies in flexibility of introducing reactive functionalities
at position 2, 3, 4, or 6 of the pyridine ring.
Our synthetic approach to preparing 2-amino-6-aryl-
4-methylsulfanylnicotinonitriles (2a -c) is based on ring
transformation of 6-aryl-3-cyano-4-methylsulfanyl-2H-
pyran-2-ones (1) by using cyanamide as a nucleophilic
source. The 2H-pyran-2-ones (1) used as a parent precur-
sor have been prepared by the reaction of methyl 2-cyano-
3,3-dimethylthioacrylate with acetophenone as described
earlier.14 The lactones, 6-aryl-3-cyano-4-methylsulfanyl-
2H-pyran-2-ones (1) on reaction with secondary amines
were transformed to 6-aryl-3-cyano-4-substituted-amino-
2H-pyran-2-ones15,16 (3 and 5). The lactones 1, 3, and 5
were the key intermediates for the synthesis of 2-amino-
and 2,4-diaminopyridine derivatives (2, 4, and 6). Thus,
2-amino-6-aryl-4-methylsulfanylnicotinonitriles (2a -c)
were prepared by base-catalyzed ring transformation of
1 with cyanamide under an inert atmosphere (Scheme
1). The reaction is possibly initiated by the attack of the
nucleophile (NCNH-) at position C-6, a highly electro-
philic site of the pyran ring due to extended conjugation
and presence of an electron withdrawing substituent (CN
or COOMe) at position 3, followed by the formation of a
cyclic intermediate involving the nitrile functionality of
cyanamide and C-3 of the pyran ring and decarboxylation
to yield 2 (Scheme 1).
Syn th esis of Am in on icotin on itr iles a n d
Dia m in op yr id in es th r ou gh Ba se-Ca ta lyzed
Rin g Tr a n sfor m a tion of 2H-P yr a n -2-on es†
Farhanullah, Nidhi Agarwal, Atul Goel,* and
Vishnu J i Ram*
Medicinal Chemistry Division, Central Drug Research
Institute, Lucknow-226001, India
vjiram@yahoo.com; agoel13@yahoo.com
Received J uly 8, 2002
Abstr a ct: An efficient and convenient synthesis of 2-amino-
6-aryl-4-methylsulfanylnicotinonitriles (2), 2-amino-6-aryl-
4-substituted-aminonicotinonitriles (4), and 2-amino-6-aryl-
4-substituted-aminopyridines (6) has been delineated and
illustrated through base-catalyzed ring transformation of
6-aryl-3-cyano-4-methylsulfanyl/substituted-amino-2H-pyran-
2-ones (1, 3, and 5) with cyanamide and ammonium carbon-
ate separately.
The pyridine ring, an integral part of various natural
products of therapeutic importance, plays a pivotal role
in catalyzing both biological and chemical reactions.
Pyridine nucleotide, the prosthetic group of many en-
zymes, is involved in various oxidation-reduction pro-
cesses in living organisms. On the other hand, from a
chemical perspective, several dialkylaminopyridines such
as 4-(dimethylamino)pyridine (DMAP), 4-pyrrolidinopy-
ridine (PPY), and their analogues have been extensively
used as catalysts in acylation and alkylation1-4 reactions
as well as efficient ligands for complexation with transi-
tion metals.5 Recently, attention has been focused to
develop new catalysts for esterification of unreactive
alcohols6 and enantioselective acyl transfer.7 Sammakia
et al.8 have developed a new strategy for the design of a
catalyst that has totally separate binding and catalytic
sites that offers greater flexibility and less constraint on
catalytic systems. Further study revealed that the pres-
ence of certain substituents in the vicinity of the ring
nitrogen of pyridine ameliorates the catalytic action.
Among various approaches to the synthesis of 4-ami-
nopyridines, the nucleophilic substitution9 of 4-halopy-
(10) (a) Victory, P.; Borrell, J . I.; Vidal-Ferran, A. Heterocycl. 1993,
36, 769. (b) Manna, F.; Chimenti, F.; Bolasco, A.; Bizzarri, B.; Filippelli,
W.; Filippelli, A.; Gagliardi, L. Eur. J . Med. Chem. 1999, 34, 245. (c)
Sakurai, A.; Midorikawa, H. Bull. Chem. Soc. J pn. 1968, 41, 430.
(11) Cuperly, D.; Gros, P.; Fort, Y. J . Org. Chem. 2002, 67, 238.
(12) (a) Hartwig, J . F. Synlett 1997, 116. (b) Hartwig, J . F. Angew.
Chem., Int. Ed. 1998, 37, 2046. (c) Frost, C. G.; Mendonc¸a, P. J . Chem.
Soc., Perkin Trans. 1 1998, 2615. (d) Belfield, A. J .; Brown, G. R.;
Foubister, A. J . Tetrahedron 1999, 55, 11399.
(13) (a) J aime-Figueroa, S.; Liu, Y.; Muchowski, J .; Putman, D.
Tetrahedron Lett. 1998, 39, 1313. (b) Wagaw, S.; Buchwald, S. L. J .
Org. Chem. 1996, 61, 7240. (c) Wolfe, J . P.; Buchwald, S. L. J . Am.
Chem. Soc. 1997, 119, 6054. (d) Marcoux, J .-F.; Wagaw, S.; Buchwald,
S. L. J . Org. Chem. 1997, 62, 1568.
(14) (a) Tominaga, Y.; Ushirogouchi, A.; Matsuda, Y.; Kobayashi,
G. Chem. Pharm. Bull. 1984, 32, 3384. (b) Tominaga, Y.; Ushirogouchi,
A.; Matsuda, Y. J . Heterocycl. Chem. 1987, 24, 1557. (c) Ram, V. J .;
Verma, M.; Hussaini, F. A.; Shoeb, A. J . Chem. Res. (S), 1991, 98. (d)
Ram, V. J .; Verma, M.; Hussaini, F. A.; Shoeb, A. J . Liebigs. Ann.
Chem. 1991, 1229.
* To whom correspondence should be addressed. Fax: +91-522-
2223405.
† CDRI Communication No. 6312.
(1) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.
(2) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34,
2069.
(3) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129.
(4) Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494.
(5) (a) Mashima, K.; Oshiki, T.; Yrata, H. J . Organomet. Chem. 1998,
569, 15. (b) Takenaka, Y.; Osakada, K. Bull. Chem. Soc. J pn. 2000,
73, 129.
(6) (a) Spivey, A.; Maddaford, A.; Fekner, T.; Redgrave, A. J .;
Frampton, C. S. J . Chem. Soc., Perkin Trans. 1 2000, 3460. (b) Hotsuki,
H.; Sakai, H.; Shinohara, T. Synlett 2000, 116.
(7) (a) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int.
Ed. 2001, 40, 234. (b) Ruble, J . C.; Twedell, J .; Fu, G. C. J . Org. Chem.
1998, 63, 2794. (c) Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1996, 118,
1809.
(15) Ram, V. J .; Nath, M.; Srivastava, P.; Sarkhel, S.; Maulik, P. R.
J . Chem. Soc., Perkin Trans. 1 2000, 3719.
(8) Sammakia, T.; Hurley, T. B. J . Org. Chem. 2000, 65, 974.
(9) Vorbru¨ggen, H. Adv. Heterocycl. Chem. 1990, 49, 117.
(16) Ram, V. J .; Srivastava, P.; Agarwal, N.; Sharon, A.; Maulik, P.
R. J . Chem. Soc., Perkin Trans. 1 2001, 1953.
10.1021/jo0204496 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/11/2003
J . Org. Chem. 2003, 68, 2983-2985
2983

SCHEME 1
SCHEME 2
Similarly, 2-amino-6-aryl-4-substituted-aminonicoti-
nonitriles (4a -k ) were prepared in moderate yield by
ring transformation of 6-aryl-3-cyano-4-substituted-amino-
2H-pyran-2-one (3) by cyanamide under a nitrogen
atmosphere. In this reaction, the initial step is an attack
of cyanamide at position C-6 of the pyran-2-one 3,
followed by decarboxylation and ring opening. The ring-
opened intermediate thus generated in situ re-cyclizes
involving C-3 of the pyran ring and the nitrile functional-
ity of cyanamide to yield 4 as shown in Scheme 2.
To study the effect of an electron-withdrawing CN
substituent at position 3 on catalytic action of 2,4-
diaminopyridine, 2-amino-6-aryl-4-substituted-aminopy-
ridines (6) were synthesized through ring transformation
of 5 by ammonium carbonate in pyridine at reflux
temperature (Scheme 3). The plausible mechanism for
the formation of 6 is possibly initiated by attack of
ammonia, generated in situ from ammonium carbonate
at position 6 of the pyran ring followed by decarboxylation
and ring closure involving the cyano function at position
3 to yield 6-aryl-2,4-diaminopyridines (6a -i). All the
synthesized compounds were characterized by spectro-
scopic and elemental analysis. The 1H NMR of 4a showed
two sharp singlets at δ 3.26, 6.41 for dimethylamino and
methine protons, respectively. A broad singlet at δ 5.16
was assigned for amino protons. The two peaks at ν 3439
and 2195 cm-1 in the IR spectrum revealed the presence
of the amino and the cyano groups, respectively. The
molecular ion peak in the mass spectrum was at m/z 238,
which was in agreement with the proposed structure.
SCHEME 3
Some of the synthesized compounds (2a , 4a ,b,d ,f,g,i,
6a ,c,g) were examined for their catalytic action on
acetylation of tert-butyl alcohol with acetic anhydride as
described previously,2 but none of the compounds was
found superior to DMAP.
In summary, our synthetic approach is superior to the
existing procedures in many ways such as (a) low-
temperature reaction conditions, (b) use of inexpensive
reagents, (c) versatility and compatibility of functional
groups, and (d) easy workup. The synthetic strategy
opens a new avenue for the synthesis of highly function-
alized 2,4-diaminopyridines to develop new efficient
catalysts for acylation reactions.
Exp er im en ta l Section
Gen er a l P r oced u r e: Syn th esis of 2-Am in o-6-a r yl-4-m e-
th ylsu lfa n yln icotin on itr ile (2a -c). A mixture of 6-aryl-3-
cyano-4-methylsulfanyl-2H-pyran-2-ones (1 mmol), cyanamide
(0.05 g, 1.2 mmol), and powdered KOH (0.12 g, 2 mmol) in dry
2984 J . Org. Chem., Vol. 68, No. 7, 2003

DMF (10 mL) was stirred at room temperature under inert
atmosphere for 30-50 h. After completion, the reaction mixture
was poured into ice-water with constant stirring and then
neutralized with 10% HCl. The precipitate thus obtained was
filtered and purified on silica gel column chromatography using
hexane-chloroform (1:1) as eluent.
Syn t h esis of 6-Ar yl-4-(4-a r yl-1-p ip er a zin yl)-2-p yr id i-
n a m in e (6a -i). A mixture of 6-aryl-3-cyano-4-substituted-
amino-2H-pyran-2-ones (5, 1 mmol) and ammonium carbonate
(10 mmol) in pyridine (15 mL) was refluxed for 25-35 h. After
completion, the solvent was distilled off. The residue was diluted
with water and extracted with chloroform. The organic layer was
evaporated to dryness, and crude product obtained was purified
on silica gel column using chloroform-hexane (1:1) as eluent.
6-(4-F lu or op h en yl)-4-[4-(2-m et h oxyp h en yl)-1-p ip er a zi-
n yl]-2-p yr id in a m in e (6a ): yield 21%; colorless oil; IR (neat)
3405 cm-1; 1HNMR (200 MHz, CDCl3) δ 3.22 (t, J ) 4.8 Hz, 4H),
3.64 (t, J ) 4.8 Hz, 4H), 3.90 (s, 3H), 6.03 (s, 1H), 6.46 (s, 1H),
6.89 (brs, 2H), 6.93-7.20 (m, 6H), 7.71-7.86 (m, 2H); MS m/z
(EI+) 378 (M+, 34.6). Anal. Calcd for C22H23FN4O: C, 69.82; H,
6.13; N, 14.80. Found: C, 70.17; H, 6.21; N, 14.93.
2-Am in o-4-(m eth ylsu lfan yl)-6-ph en yln icotin on itr ile (2a):
yield 42%; white solid; mp 149-150 °C; IR (KBr) 3422, 2195
1
cm-1; HNMR (200 MHz, CDCl3) δ 2.62 (s, 3H), 5.21 (brs, 2H),
6.71 (s, 1H), 7.45-7.48 (m, 5H); MS m/z (FAB) 242 (M+ + 1).
Anal. Calcd for C13H11N3S: C, 64.70; H, 4.59; N, 17.41. Found:
C, 64.76; H, 4.63; N, 17.52.
Syn th esis of 2-Am in o-6-a r yl-4-d ia lk yla m in on icotin on i-
tr ile (4a -k ). A mixture of 6-aryl-3-cyano-4-substituted-amino-
2H-pyran-2-ones (3, 1 mmol), cyanamide (0.05 g, 1.2 mmol), and
powdered KOH (0.12 g, 2 mmol) in dry DMF (10 mL) was stirred
at room temperature under inert atmosphere for 40-50 h. After
completion, the reaction mixture was poured into ice-water with
constant stirring and then neutralized with 10% HCl. The
precipitate thus obtained was filtered and purified on silica gel
column chromatography using hexane-chloroform (1:1) as elu-
ent.
Ack n ow led gm en t. N.A. is thankful to CSIR for the
senior research fellowship.
Su p p or tin g In for m a tion Ava ila ble: Characterization
2-Am in o-4-(dim eth ylam in o)-6-ph en yln icotin on itr ile (4a):
yield 51%; white solid; mp 159-160 °C; IR (KBr) 3439, 2195
data (melting point, elemental analyses) and spectroscopic data
1
(IR, H NMR, and MS) for all the new compounds 2b,c, 3b-
1
cm-1; HNMR (200 MHz, CDCl3) δ 3.26 (s, 6H), 5.16 (brs, 2H),
k , 4b-k , 5g-i, and 6b-i. This material is available free of
6.41 (s, 1H), 7.41-7.52 (m, 3H), 7.82-7.89 (m, 2H); MS m/z (EI+)
238 (M+, 63.3). Anal. Calcd for C14H14N4: C, 70.5; H, 5.92; N,
23.51. Found: C, 70.58; H, 5.95; N, 23.40.
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J O0204496
J . Org. Chem, Vol. 68, No. 7, 2003 2985