Synthesis of New Aminonicotinate Derivatives from Acetylated Baylis-Hillman Adducts and Enamino Esters via a Consecutive [3+3]-Annulation Protocol

Article abstract of DOI:10.1055/s-0029-1218607

A one-pot, consecutive [3+3]-annulation protocol is described for the synthesis of new aminonicotinate derivatives from acetylated Baylis-Hillman adducts and enamino esters. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218607

PAPER
573
Synthesis of New Aminonicotinate Derivatives from Acetylated Baylis–
Hillman Adducts and Enamino Esters via a Consecutive [3+3]-Annulation
Protocol
S
ynthesis of
New Ami
e
nonicotinat
t
e
D
eriv
t
atives u Ravinder,a Partha Sarathi Sadhu,a Amlipur Santhoshi,a Puli Narender,a Gundimella Y. S. K. Swamy,b
Krishnan Ravikumar,*b Vaidya Jayathirtha Rao*a
a
Fax +91(40)27160757; E-mail: jrao@iict.res.in
Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500607, India
b
E-mail: ravikumar_iict@yahoo.co.in
Received 20 August 2009; revised 5 November 2009
logical importance, the development of simple and
convenient approaches to 2-aminopyridines from easily
available starting materials is very much required.
Abstract: A one-pot, consecutive [3+3]-annulation protocol is de-
scribed for the synthesis of new aminonicotinate derivatives from
acetylated Baylis–Hillman adducts and enamino esters.
In recent years the Baylis–Hillman reaction has attracted
the attention of many organic chemists, because it is a
simple, straightforward method for the generation of at-
tractive densely functionalized molecules.14 Recently, we
have reported the synthesis of Baylis–Hillman adducts
and have converted them into quinolines, 1,8-naphthy-
ridines and 2-pyridones.15 So far, no report exists in the
literature on the synthesis of aminonicotinate derivatives
from Baylis–Hillman adducts. In continuation of our re-
search on the synthesis of heterocyclic compounds and
applications of Baylis–Hillman chemistry,15,16 we now de-
scribe a facile, one-pot synthesis of aminonicotinate de-
rivatives via treatment of acetylated Baylis–Hillman
nitriles with enamino esters by way of a [3+3]-annulation
process.
Key words: Michael addition, cyclization, isomerization, hydro-
lysis, heterocycles
Multisubstituted pyridines represent molecular frame-
works that serve as a platform for developing pharmaceu-
tical agents for various applications. Among these,
aminopyridine and nicotinate analogues constitute an im-
portant class of compounds in organic synthesis and drug
discovery.1 A large number of aminopyridine derivatives
have been reported to exhibit antitumor,2a,b vasodilator2c
and anti-inflammatory2d activities. A few aminopyridine
derivatives have recently been screened as NCX inhibi-
tors.2e Moreover, aminopyridine derivatives are the key
intermediates in the synthesis of the corresponding 1,8-
naphthyridines,3 7-azaindoles,4 oxazolopyridines5 and im-
idazopyridines.6 In addition to pharmaceutical applica-
tions, aminopyridine derivatives have been used as
ligands for transition-metal complexes,7 as fluorescent
dyes8 and also for agricultural products.9
The starting materials, acetylated Baylis–Hillman nitriles
1a–g and enamines 2a,b (Table 1), were synthesized ac-
cording to literature procedures.17 Enamino ester 2a was
treated with sodium hydride in anhydrous tetrahydrofuran
at room temperature, and acetylated Baylis–Hillman ni-
trile 1a was added. The reaction was completed in six
hours and furnished the desired product 3a in good yield
(Table 1). We have examined this reaction by using dif-
ferent bases (K2CO3, Et3N, t-BuOK, NaH) and varying the
equivalents, from one to three, separately. Potassium car-
bonate and triethylamine failed to promote the reaction,
whereas in the case of potassium tert-butoxide the yield
was lower than when sodium hydride was used. So, final-
ly, we concluded that three equivalents of sodium hydride
are suitable to promote the reaction. Encouraged by this
result, we have successfully transformed several represen-
tative acetylated Baylis–Hillman nitriles 1b–g via treat-
ment with enamino ester 2a or 2b into the desired
substituted aminonicotinate derivatives 3b–j in good
yields (Table 1). All of the aminonicotinates synthesized
were characterized by spectroscopic techniques and 3a
was additionally characterized by X-ray crystallographic
studies (Figure 1).
A survey of the literature shows that derivatization of a 2-
unsubstituted pyridine moiety in a complex molecule to
the corresponding 2-aminopyridine is often desired but
only achieved in a long sequence and with low efficien-
cy.10 There are several methods available in the literature
for the synthesis of 2-aminopyridine derivatives.11 One of
the most traditional approaches is amination of 2-halopy-
ridines and analogues with ammonia or an equivalent un-
der high temperature (150–250 °C) and pressure.2e,12 The
second approach is the Chichibabin reaction1b,13 where 2-
aminopyridines can be directly obtained from sodium
amide and pyridines. There are some limitations, howev-
er, with the procedures for the synthesis of 2-aminopy-
ridines suffering from the use of high reaction
temperatures and prolonged reaction times, poor regiose-
lectivity and low product yields. Due to the immense bio-
SYNTHESIS 2010, No. 4, pp 0573–0578
x
x
.
x
x
.2
0
1
0
Advanced online publication: 16.12.2009
DOI: 10.1055/s-0029-1218607; Art ID: T16309SS
© Georg Thieme Verlag Stuttgart · New York
A plausible mechanism for the formation of aminonicoti-
nate derivative 3a is shown in Scheme 1. The resonance-

574
M. Ravinder et al.
PAPER
Table 1 One-Pot Synthesis of Aminonicotinate Derivatives from Acetylated Baylis–Hillman Nitriles and Enamino Esters
OAc
R1
R1
NaH
(3 equiv)
CN
+
R
THF,
r.t., 6–8 h
R
H2N
3a–j
N
H2N
2a, b
1a–g
Entry
1
Baylis–Hillman nitrile
Enamino ester
Producta
Yieldb (%)
68
OAc
COOEt
NH2
EtOOC
EtOOC
EtOOC
EtOOC
CN
1a
2a
3a
3b
3c
3d
3e
N
N
N
N
NH2
NH2
NH2
NH2
OAc
CN
CN
2
3
4
5
1b
1c
1d
1e
2a
2a
2a
2a
65
61
70
69
F
F
OAc
OAc
CN
Cl
Br
Cl
Br
OAc
EtOOC
CN
N
NH2
Cl
Cl
OAc
EtOOC
EtOOC
CN
6
1f
2a
3f
68
N
N
NH2
NH2
OAc
Br
Br
CN
7
8
9
1g
1a
1b
2a
2b
2b
3g
3h
3i
65
56
55
OAc
COOMe
NH2
MeOOC
MeOOC
CN
N
NH2
NH2
OAc
CN
N
N
F
F
OAc
MeOOC
CN
10
1d
2b
3j
58
NH2
Cl
Cl
a All products were characterized by NMR, IR and mass spectroscopy.
b Yield of isolated product.
stabilized anion generated by the action of sodium hydride simultaneously to give intermediate I which was not iso-
on the amino group of enamine 2a attacks through its a- lated during the reaction. Thus formed, intermediate I un-
carbon (which is nucleophilic in nature) at the b-carbon of dergoes a proton shift as well as intramolecular
the external double bond of the acetylated Baylis–Hillman cyclization to give the six-membered cyclic intermediate
nitrile 1a via an SN2¢ mechanism, by which C–C bond for- II. In this annulation protocol, the two-carbon and one-
mation takes place and subsequent migration of the dou- nitrogen source from the enamino ester with the three-
ble bond with elimination of the acetate group occurs carbon source from the acetylated Baylis–Hillman nitrile
Synthesis 2010, No. 4, 573–578 © Thieme Stuttgart · New York

PAPER
Synthesis of New Aminonicotinate Derivatives
575
values in d, J in Hz). HRMS (ESI) data were recorded on a QSTAR
XL high-resolution mass spectrometer. GC-MS data were recorded
on an Agilent 6890 series GC-MS system (column: Varian CP-Sil 8
CB, 5% phenyl, 95% PDMS, 30.0 m × 250 mm × 0.30 mm nominal).
Aminonicotinate Derivatives 3a–j; General Procedure
To a well-stirred solution of NaH (60% in paraffin oil; 240 mg, 6
mmol) in anhyd THF (15 mL) was added the enamino ester 2a or
2b (2 mmol) dissolved in anhyd THF (5 mL) at r.t. under N2 atmo-
sphere, and the mixture was stirred for 15 min at the same tempera-
ture. Then, an acetylated Baylis–Hillman nitrile 1a–g (2.2 mmol)
dissolved in anhyd THF (5 mL) was added slowly and the mixture
was stirred at r.t. until the reaction was completed. After comple-
tion, the solvent was removed under reduced pressure and the resi-
due was diluted with ice-cold H2O (15 mL) and extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed
with H2O (10 mL), dried (Na2SO4), concentrated under reduced
pressure and purified by silica gel column chromatography
(EtOAc–hexane, 1:9 followed by 1:4) to afford pure compound
3a–j.
Ethyl 6-Amino-5-benzyl-2-methylnicotinate (3a)
Yield: 68%; white solid; mp 137–139 °C.
IR (KBr): 3436, 3326, 3130, 1695, 1655, 1597, 1470, 1243 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.88 (s, 1 H), 7.30–7.13 (m, 5 H),
4.71 (s, 2 H), 4.28 (q, J = 7.6 Hz, 2 H), 3.83 (s, 2 H), 2.65 (s, 3 H),
1.37 (t, J = 7.6 Hz, 3 H).
Figure 1 ORTEP diagram of compound 3a
13C NMR (75 MHz, CDCl3): d = 166.6, 159.0, 158.2, 141.1, 137.5,
128.9, 128.2, 126.9, 115.5, 115.3, 60.4, 37.1, 24.2, 14.3.
GC-MS (EI, 70 eV): m/z (%) = 270 (100) [M+], 254, 241, 225, 197,
180, 152, 127, 105, 91, 77, 43.
HRMS (ESI): m/z calcd for C16H19N2O2 [M + H]+: 271.1446; found:
271.1456.
gives the [3+3]-cyclized product II. Subsequently, dou-
ble-bond migration takes place and gives aminonicotinate
3a in good yield after the usual workup. The beauty of this
reaction is that three chemical transformations [i.e., addi-
tion, cyclization, isomerization (proton shifts)] take place
in one pot leading to the aminonicotinate derivative.
Ethyl 6-Amino-5-(4-fluorobenzyl)-2-methylnicotinate (3b)
Yield: 65%; white solid; mp 131–133 °C.
In summary, we have developed a straightforward, conve-
nient and practical synthesis of aminonicotinate deriva-
tives from acetylated Baylis–Hillman nitriles and
enamino esters, via a [3+3]-annulation protocol, in mod-
erate to good yields. We believe this reaction has enough
scope for further investigations.
IR (KBr): 3487, 3313, 3112, 2980, 1708, 1647, 1598, 1507, 1260
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.85 (s, 1 H), 7.12 (q, J = 8.3 Hz,
2 H), 6.97 (t, J = 8.3 Hz, 2 H), 4.59 (br s, 2 H), 4.28 (q, J = 6.8 Hz,
2 H), 3.80 (s, 2 H), 2.65 (s, 3 H), 1.37 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.6, 163.4, 160.1, 159.3, 158.1,
141.0, 133.2, 133.1, 129.8, 129.7, 115.9, 115.6, 115.2, 115.2, 60.4,
36.3, 24.4, 14.3.
Melting points were determined on a Mel-Temp apparatus and are
uncorrected. IR spectra were recorded using a Thermo Nicolet Nex-
us 670 FTIR spectrometer. 1H and 13C NMR spectra were recorded
on either a Bruker Avance 300-MHz or a Varian Inova 400-MHz
FT spectrometer, using TMS as an internal standard (chemical shift
GC-MS (EI, 70 eV): m/z (%) = 288 (100) [M+], 273, 259, 243, 215,
198, 171, 146, 133, 120, 109, 100, 51.
OAc
O–
NC
Ph
1a
EtO2C
EtO2C
–
EtO2C
NaH (3 equiv)
THF, r.t.
EtO
– NaOAc
[3+3]
NH–
NH
NH
NH2
2a
H
H
EtO2C
EtO2C
EtO2C
Ph
Ph
Ph
workup
N
N
H
NH
NH
N
NH2
I
II
3a
Scheme 1
Synthesis 2010, No. 4, 573–578 © Thieme Stuttgart · New York

576
M. Ravinder et al.
PAPER
HRMS (ESI): m/z calcd for C16H18N2O2F [M + H]+: 289.1352;
HRMS (ESI): m/z calcd for C16H18N2O2Cl [M + H]+: 305.1056;
found: 289.1342.
found: 305.1049.
Ethyl 6-Amino-2-methyl-5-(4-methylbenzyl)nicotinate (3c)
Yield: 61%; white solid; mp 122–124 °C.
Ethyl 6-Amino-5-(3-bromobenzyl)-2-methylnicotinate (3g)
Yield: 65%; white solid; mp 124–126 °C.
IR (KBr): 3483, 3299, 3105, 2985, 1705, 1642, 1559, 1261 cm–1.
IR (KBr): 3485, 3303, 3142, 2977, 1700, 1643, 1558, 1258 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.89 (s, 1 H), 7.10 (d, J = 8.1 Hz,
2 H), 7.04 (d, J = 8.1 Hz, 2 H), 4.61 (br s, 2 H), 4.29 (q, J = 7.2 Hz,
2 H), 3.79 (s, 2 H), 2.66 (s, 3 H), 2.32 (s, 3 H), 1.37 (t, J = 7.2 Hz, 3
H).
1H NMR (300 MHz, CDCl3): d = 7.87 (s, 1 H), 7.37 (d, J = 7.9 Hz,
1 H), 7.30 (s, 1 H), 7.16 (t, J = 7.7 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 1
H), 4.65 (br s, 2 H), 4.30 (q, J = 7.2 Hz, 2 H), 3.81 (s, 2 H), 2.65 (s,
3 H), 1.37 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 165.9, 158.9, 157.6, 138.9,
135.9, 135.0, 128.9, 128.5, 116.1, 112.4, 59.5, 34.6, 24.1, 20.5,
14.1.
13C NMR (75 MHz, CDCl3): d = 166.5, 159.5, 158.0, 141.2, 140.0,
131.2, 130.4, 130.1, 126.8, 123.0, 115.6, 114.4, 60.4, 36.6, 24.4,
14.3.
GC-MS (EI, 70 eV): m/z (%) = 284 (100) [M+], 269, 255, 239, 211,
GC-MS (EI, 70 eV): m/z (%) = 348 (100) [M+], 319, 303, 275, 240,
194, 178, 167, 152, 141, 119, 105, 91, 77, 51.
226, 195, 181, 169, 153, 127, 115, 97, 77, 52.
HRMS (ESI): m/z calcd for C17H21N2O2 [M + H]+: 285.1603; found:
HRMS (ESI): m/z calcd for C16H18N2O2Br [M + H]+: 349.0551;
285.1604.
found: 349.0569.
Ethyl 6-Amino-5-(4-chlorobenzyl)-2-methylnicotinate (3d)
Yield: 70%; pale yellow solid; mp 175–177 °C.
Methyl 6-Amino-5-benzyl-2-methylnicotinate (3h)
Yield: 56%; white solid; mp 144–147 °C.
IR (KBr): 3477, 3308, 3141, 2982, 1714, 1643, 1561, 1258 cm–1.
IR (KBr): 3482, 3307, 3133, 2946, 1709, 1646, 1559, 1262 cm–1.
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 7.69 (s, 1 H), 7.24 (d,
J = 8.6 Hz, 2 H), 7.15 (d, J = 8.6 Hz, 2 H), 5.65 (s, 2 H), 4.21 (q,
J = 7.0 Hz, 2 H), 3.77 (s, 2 H), 2.58 (s, 3 H), 1.33 (t, J = 7.0 Hz, 3
H).
13C NMR (75 MHz, DMSO-d6): d = 165.8, 158.9, 158.0, 139.2,
138.2, 130.7, 130.4, 128.2, 115.4, 112.3, 59.6, 34.2, 24.2, 14.1.
GC-MS (EI, 70 eV): m/z (%) = 304 (100) [M+], 289, 275, 259, 243,
231, 214, 196, 181, 167, 152, 125, 112, 99, 77, 52.
HRMS (ESI): m/z calcd for C16H18N2O2Cl [M + H]+: 305.1056;
1H NMR (300 MHz, CDCl3): d = 7.88 (s, 1 H), 7.30–7.12 (m, 5 H),
4.65 (br s, 2 H), 3.82 (s, 5 H), 2.65 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 167.0, 159.4, 158.3, 141.0, 137.5,
128.9, 128.3, 126.9, 115.5, 115.1, 51.5, 37.2, 24.4.
GC-MS (EI, 70 eV): m/z (%) = 256 (100) [M+], 241, 225, 195, 180,
153, 127, 115, 103, 91, 77, 51.
HRMS (ESI): m/z calcd for C15H17N2O2 [M + H]+: 257.1290; found:
257.1296.
found: 305.1046.
Methyl 6-Amino-5-(4-fluorobenzyl)-2-methylnicotinate (3i)
Yield: 55%; pale yellow solid; mp 151–154 °C.
Ethyl 6-Amino-5-(4-bromobenzyl)-2-methylnicotinate (3e)
Yield: 69%; pale yellow solid; mp 187–189 °C.
IR (KBr): 3486, 3305, 3157, 2955, 1713, 1640, 1559, 1243 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.75 (s, 1 H), 7.13 (q, J = 8.6 Hz,
2 H), 6.96 (t, J = 8.6 Hz, 2 H), 5.23 (s, 2 H), 3.79 (s, 3 H), 3.77 (s, 2
H), 2.75 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 163.4, 160.2, 159.5, 158.1,
140.9, 133.2, 133.1, 129.8, 129.7, 115.9, 115.6, 115.3, 115.2, 51.6,
36.3, 24.4.
GC-MS (EI, 70 eV): m/z (%) = 274 (100) [M+], 259, 243, 213, 171,
147, 133, 109, 83, 52.
HRMS (ESI): m/z calcd for C15H16N2O2F [M + H]+: 275.1195;
found: 275.1199.
IR (KBr): 3475, 3307, 3141, 2982, 2931, 1712, 1642, 1562, 1256
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.85 (s, 1 H), 7.42 (d, J = 8.3 Hz,
2 H), 7.04 (d, J = 8.3 Hz, 2 H), 4.54 (br s, 2 H), 4.28 (q, J = 6.8 Hz,
2 H), 3.78 (s, 2 H), 2.65 (s, 3 H), 1.37 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 165.9, 159.0, 158.0, 139.3,
138.6, 131.1, 130.8, 119.1, 115.3, 112.3, 60.0, 34.3, 24.2, 14.2.
GC-MS (EI, 70 eV): m/z (%) = 348 (100) [M+], 319, 303, 275, 240,
224, 206, 195, 181, 169, 153, 127, 102, 90, 77, 52.
HRMS (ESI): m/z calcd for C16H18N2O2Br [M + H]+: 349.0551;
found: 349.0540.
Methyl 6-Amino-5-(4-chlorobenzyl)-2-methylnicotinate (3j)
Yield: 58%; pale yellow solid; mp 175–177 °C.
Ethyl 6-Amino-5-(2-chlorobenzyl)-2-methylnicotinate (3f)
Yield: 68%; white solid; mp 164–166 °C.
IR (KBr): 3476, 3310, 3118, 2941, 1720, 1645, 1563, 1257 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.86 (s, 1 H), 7.28 (d, J = 8.3 Hz,
2 H), 7.10 (d, J = 8.3 Hz, 2 H), 4.60 (br s, 2 H), 3.83 (s, 3 H), 3.79
(s, 2 H), 2.66 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 159.6, 158.1, 141.1, 136.0,
132.8, 129.6, 129.0, 115.3, 114.9, 51.6, 36.4, 24.4.
GC-MS (EI, 70 eV): m/z (%) = 290 (100) [M+], 275, 259, 231, 216,
196, 178, 152, 125, 97, 77, 52.
HRMS (ESI): m/z calcd for C15H16N2O2Cl [M + H]+: 291.0900;
found: 291.0899.
IR (KBr): 3479, 3312, 3141, 2981, 2929, 1711, 1647, 1563, 1254
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.83 (s, 1 H), 7.39 (q, J = 5.3 Hz,
1 H), 7.20–7.13 (m, 2 H), 6.98 (q, J = 5.3 Hz, 1 H), 4.78 (br s, 2 H),
4.26 (q, J = 6.8 Hz, 2 H), 3.90 (s, 2 H), 2.65 (s, 3 H), 1.35 (t, J = 6.8
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.6, 159.3, 158.1, 141.2, 135.2,
134.1, 129.8, 129.6, 128.3, 127.2, 115.6, 114.1, 60.4, 34.1, 24.4,
14.3.
GC-MS (EI, 70 eV): m/z (%) = 304 (49) [M+], 269 (100), 259, 241,
225, 195, 181, 167, 152, 125, 112, 99, 77, 51.
X-ray Crystallography of Compound 3a18
A colorless cube crystal of compound 3a was obtained from CHCl3.
Synthesis 2010, No. 4, 573–578 © Thieme Stuttgart · New York

PAPER
Synthesis of New Aminonicotinate Derivatives
577
C16H18N2O2, M = 270.32, monoclinic, space group P21/n,
a = 12.7513(2) Å, b = 7.4527(1) Å, c = 17.7352(3) Å,
b = 111.069(4)°, V = 1572.7(5) Å3, r = 1.142 g/cm3, F(000) = 576.
X-ray diffraction data were collected using a Bruker SMART CCD
area detector at 293 K, using graphite monochromated Mo Ka radi-
ation (l = 0.71073 Å). Integration and scaling of intensity data were
accomplished using SAINT.19a The structure was solved by direct
methods and refined by the full-matrix least-squares procedure
based on F19b using the program SHELX-97.19b Non-hydrogen at-
oms were refined with anisotropic displacement parameters and hy-
drogen atoms were included in the models at their calculated
positions in a riding model approximation. The molecular geometry
and graphics were computed using the programs PARST19c and
ORTEP-3.19d The ORTEP view of the molecule is shown in
Figure 1.
(5) (a) Myllymäki, M. J.; Koskinen, A. M. P. Tetrahedron Lett.
2007, 48, 2295. (b) Bemis, J. E.; Vu, C. B.; Xie, R.; Nunes,
J. N.; Ng, P. Y.; Disch, J. S.; Milne, J. C.; Carney, D. P.;
Lynch, A. V.; Jin, L.; Smith, J. J.; Lavu, S.; Iffland, A.;
Jirousek, M. R.; Perni, R. B. Bioorg. Med. Chem. Lett. 2009,
19, 2350.
(6) (a) Andaloussi, M.; Moreau, E.; Chavignon, O.; Teulade, J.
C. Tetrahedron Lett. 2007, 48, 8392. (b) Hamama, W. S.;
Zoorob, H. H. Tetrahedron 2002, 58, 6143. (c) Adib, M.;
Sheibani, E.; Zhu, L.-G.; Mirzaei, P. Tetrahedron Lett. 2008,
49, 5108.
(7) (a) Deeken, S.; Proch, S.; Casini, E.; Braun, H. F.; Mechtler,
C.; Marschner, C.; Motz, G.; Kempe, R. Inorg. Chem. 2006,
45, 1871. (b) Kempe, R.; Brenner, S.; Perdita, A.
Organometallics 1996, 15, 1071. (c) Kawasaki, M.; Suzuki,
Y.; Terashima, S. Chem. Lett. 1984, 239.
(8) Araki, K.; Mutai, T.; Shigemitsu, Y.; Yamada, M.;
Nakajima, T.; Kuroda, S.; Shimao, I. J. Chem. Soc., Perkin
Trans. 2 1996, 613.
(9) Henrie, R. N. II WO 8702665, 1987; Chem. Abstr. 1988,
109, 230807.
Acknowledgment
The authors thank the Director, IICT and the Head of the Division
Organic-II for encouragement. M.R., P.S.S. and A.S. thank CSIR,
New Delhi for fellowships.
(10) (a) Lam, P. Y. S.; Clark, C. G.; Li, R.; Pinto, D. J. P.; Orwat,
M. J.; Galemmo, R. A.; Fevig, J. M.; Teleha, C. A.;
Alexander, R. S.; Smallwood, A. M.; Rossi, K. A.; Wright,
M. R.; Bai, S. A.; He, K.; Luettgen, J. M.; Wong, P. C.;
Knabb, R. M.; Wexler, R. R. J. Med. Chem. 2003, 46, 4405.
(b) Song, Y. H.; Clizbe, L.; Bhakta, C.; Teng, W.; Li, W.;
Wong, P.; Huang, B.; Sinha, U.; Park, G.; Reed, A.;
Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett.
2002, 12, 2043.
(11) (a) Sakurai, A.; Midorikawa, H. Bull. Chem. Soc. Jpn. 1968,
41, 430. (b) Farhanullah; Agarwal, N.; Goel, A.; Ram, V. J.
J. Org. Chem. 2003, 68, 2983. (c) Brun, E. M.; Gil, S.;
Mestres, R.; Parra, M. Synthesis 2000, 273. (d) Takaoka,
K.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1996, 37,
4973. (e) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.;
Davies, I. W. J. Org. Chem. 2007, 72, 4554. (f) Goel, A.;
Singh, F. V.; Sharon, A.; Maulik, P. R. Synlett 2005, 623.
(g) Teague, S. J. J. Org. Chem. 2008, 73, 9765.
(h) Hamper, B. C.; Tesfu, E. Synlett 2007, 2257.
(12) (a) Taylor, E. C.; Corvetti, A. J. J. Org. Chem. 1954, 19,
1633. (b) Gudmundsson, K. S.; Johns, B. A. Org. Lett. 2003,
5, 1369.
References
(1) (a) Scriven, E. F. V. In Comprehensive Heterocyclic
Chemistry, Part 2, Vol. 2; Boulton, A. J.; McKillop, A., Eds.;
Pergamon: New York, 1984, 165–314. (b) Leffler, M. T.
Org. React. 1942, 1, 91. (c) McGill, C. K.; Rappa, A. Adv.
Heterocycl. Chem. 1988, 44, 1. (d) Landriscina, M.;
Prudovsky, I.; Carreira, C. M.; Soldi, R.; Tarantini, F.;
Maciag, T. J. Biol. Chem. 2000, 275, 32753. (e) Henry, G.
D. Tetrahedron 2004, 60, 6043. (f) Scipione, L.; De Vita,
D.; Musella, A.; Flammini, L.; Bertoni, S.; Barocelli, E.
Bioorg. Med. Chem. Lett. 2008, 18, 309. (g) Lawton, G. R.;
Ranaivo, H. R.; Chico, L. K.; Ji, H.; Xue, F.; Martásek, P.;
Roman, L. J.; Watterson, M.; Silverman, R. B. Bioorg. Med.
Chem. 2009, 17, 2371. (h) Lechat, P.; Tesleff, S.; Bownan,
W. C. Aminopyridines and Similarly Acting Drugs;
Pergamon: Oxford, 1982. (i) Zhang, J.; Pettersson, H. I.;
Huitema, C.; Niu, C.; Yin, J.; James, M. N. G.; Eltis, L. D.;
Vederas, J. C. J. Med. Chem. 2007, 50, 1850.
(2) (a) Cocco, M. T.; Congiu, C.; Lilliu, V.; Onnis, V. Bioorg.
Med. Chem. 2007, 15, 1859. (b) Amr, A.-G. E.; Mohamed,
A. M.; Mohamed, S. F.; Abdel-Hafez, N. A.; Hammam, A.
E.- F. G. Bioorg. Med. Chem. 2006, 14, 5481. (c) Girgis, A.
S.; Kalmouch, A.; Ellithey, M. Bioorg. Med. Chem. 2006,
14, 8488. (d) Murata, T.; Shimada, M.; Sakakibara, S.;
Yoshino, T.; Masuda, T.; Shintani, T.; Sato, H.; Koriyama,
Y.; Fukushima, K.; Nunami, N.; Yamauchi, M.; Fuchikami,
K.; Komura, H.; Watanabe, A.; Ziegelabauer, K. B.; Bacon,
K. B.; Lowinger, T. B. Bioorg. Med. Chem. Lett. 2004, 14,
4019. (e) Kuramochi, T.; Kakefuda, A.; Yamada, H.;
Tsukamoto, I.; Taguchi, T.; Sakamoto, S. Bioorg. Med.
Chem. 2005, 13, 4022.
(13) Chichibabin, A. E.; Zeide, O. A. J. Russ. Phys. Chem. Soc.
1914, 46, 1216.
(14) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811. (b) Sing, V.; Batra, S. Tetrahedron 2008,
64, 4511. (c) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull.
Korean Chem. Soc. 2005, 26, 1481. (d) Basavaiah, D.; Rao,
P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (e) Shi, Y.-
L.; Shi, M. Eur. J. Org. Chem. 2007, 2905. (f) Masson, G.;
Housseman, C.; Zhu, J. Angew. Chem. Int. Ed. 2007, 46,
4614.
(15) (a) Narender, P.; Gangadasu, B.; Ravinder, M.; Srinivas, U.;
Swamy, G. Y. S. K.; Ravikumar, K.; Jayathirtha Rao, V.
Tetrahedron 2006, 62, 954. (b) Narender, P.; Srinivas, U.;
Ravinder, M.; Ramesh, Ch.; Ananda Rao, B.; Harakishore,
K.; Gangadasu, B.; Murthy, U. S. N.; Jayathirtha Rao, V.
Bioorg. Med. Chem. 2006, 14, 4600. (c) Narender, P.;
Srinivas, U.; Gangadasu, B.; Biswas, S.; Jayathirtha Rao, V.
Bioorg. Med. Chem. Lett. 2005, 15, 5378. (d) Narender, P.;
Ravinder, M.; Sadhu, P. S.; Raju, B. C.; Ramesh, Ch.;
Jayathirtha Rao, V. Helv. Chim. Acta 2009, 92, 959.
(e) Ravinder, M.; Sadhu, P. S.; Jayathirtha Rao, V.
Tetrahedron Lett. 2009, 50, 4229.
(3) (a) Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.;
McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P.
J. Org. Chem. 2003, 68, 467. (b) Hamada, Y.; Takeuchi, I.
Chem. Pharm. Bull. 1971, 19, 1857. (c) Zhichkin, P.; Beer,
C. M. C.; Rennells, W. M.; Fairfax, D. J. Synlett 2006, 379.
(d) Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.;
Reider, P. J. Org. Lett. 2001, 3, 1101.
(4) (a) Cottineau, B.; O’Shea, D. F. Tetrahedron Lett. 2005, 46,
1935. (b) Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett.
2001, 42, 6441.
Synthesis 2010, No. 4, 573–578 © Thieme Stuttgart · New York

578
M. Ravinder et al.
PAPER
(18) X-ray crystallographic data for compound 3a have been
(16) (a) Gangadasu, B.; Narender, P.; Bharath Kumar, S.;
Ravinder, M.; Ananda Rao, B.; Ramesh, Ch.; Raju, B. C.;
Jayathirtha Rao, V. Tetrahedron 2006, 62, 8398. (b) Sadhu,
P. S.; Ravinder, M.; Arun Kumar, P.; Jayathirtha Rao, V.
Photochem. Photobiol. Sci. 2009, 8, 513. (c) Gangadasu,
B.; Janaki Ram Reddy, M.; Ravinder, M.; Bharath Kumar,
S.; Raju, B. C.; Pranay Kumar, K.; Murthy, U. S. N.;
Jayathirtha Rao, V. Eur. J. Med. Chem. 2009, 44, 4661.
(17) (a) Basavaiah, D.; Gowriswari, V. V. L. Synth. Commun.
1987, 17, 587. (b) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org.
Lett. 2002, 4, 4723. (c) Suárez, M.; Armas, M. D.; Ramírez,
O.; Alvarez, A.; Alvarez, R. M.; Molero, D.; Seoane, C.; Liz,
R.; Armas, H. N. D.; Blaton, N. M.; Peeters, O. M.; Martín,
N. New J. Chem. 2005, 29, 1567. (d) Cho, H.; Ueda, M.;
Mizuno, A.; Ishihara, T.; Aisaka, K.; Noguchi, T. Chem.
Pharm. Bull. 1989, 37, 2117.
deposited at The Cambridge Crystallographic Data Centre
(CCDC no. 734177). These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html or on
application to The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; Fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk.
(19) (a) SAINT (Version 6.28a) and SMART (Version 5.625);
Bruker AXS Inc.: Madison USA, 2001. (b) Sheldrick, G.
M. SHELXS-97 and SHELXL-97 Programs for Crystal
Structure Solution and Refinement; University of Göttingen:
Germany, 1997. (c) Nardelli, M. J. Appl. Crystallogr. 1995,
28, 659. (d) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7.
Synthesis 2010, No. 4, 573–578 © Thieme Stuttgart · New York