A diversity oriented synthesis of highly functionalized unsymmetrical biaryls through carbanion induced ring transformation of 2H-pyran-2-ones

Article abstract of DOI:10.1016/S0040-4020(02)01066-9

A new route for the synthesis of unsymmetrical biaryls endowed with electron withdrawing and donating substituents is delineated through base catalyzed ring transformation of 2H-pyran-2-ones with malononitrile in a single step. This procedure offers the f

Full text of DOI:10.1016/S0040-4020(02)01066-9

Tetrahedron 58 (2002) 8793–8798
A diversity oriented synthesis of highly functionalized
unsymmetrical biaryls through carbanion induced ring
transformation of 2H-pyran-2-onesq
*
Nidhi Agarwal, Abhishek S. Saxena, Farhanullah, Atul Goel and Vishnu J. Ram
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 23 May 2002; revised 30 July 2002; accepted 22 August 2002
Abstract—A new route for the synthesis of unsymmetrical biaryls endowed with electron withdrawing and donating substituents is
delineated through base catalyzed ring transformation of 2H-pyran-2-ones with malononitrile in a single step. This procedure offers the
flexibility of introducing desired functionalities in aromatic rings, which are difficult to obtain by other classical routes. q 2002 Elsevier
Science Ltd. All rights reserved.
Biaryls with electron donating and withdrawing substituents
occupy a unique place in various classes of organic
compounds not only due to their prevalence as the core
framework of numerous natural products1 but also their use
as chiral reagents,2 as chiral phases for chromatography3
and as a building block of chiral liquid crystals.4 Although
the synthesis of symmetrical and unsymmetrical biaryls has
been extensively investigated by various groups, the key
step in such syntheses is almost always the inter- or intra-
molecular cross-coupling of two aromatic rings in the
presence of metal complexes. However, the process of
achieving symmetrical and unsymmetrical biaryls endowed
with electronegative or electropositive groups is still a
major problem in the synthesis of natural products.
chemistry, most of them suffer with limitations to harsh
reaction conditions or functional group intolerance and/or
difficulty in obtaining various metal complexes.9
4-Aryl-3-cyanoanthranilate and 4-arylanthranilodinitrile
may be considered as biaryls in which one of the two-
phenyl rings is endowed either with carbomethoxy, amino
and nitrile functionalities or amino groups flanked with
dinitrile substituents. There are reports in the literature
where biaryl compounds with an amino function juxtaposed
with nitrile groups have been either synthesized by the
reaction of a,b-unsaturated carbonyl compounds with
malononitrile10 or by the reaction of hydroxy methylene
ketones and enaminoketones with malononitrile11 separ-
ately, but they suffer from low yield of the desired product.
Thus, there is increasing demand to develop an efficient and
convenient synthesis of highly functionalized biaryls
particularly those with electron donor and acceptor
substituents. Here, we describe an expeditious route for
the synthesis of suitably functionalized biaryls through
carbanion induced ring transformation of 2H-pyran-2-ones
using malononitrile as a source of the carbanion.
The reductive dimerization of aryl halides is one of the
oldest methods for the preparation of biaryl compounds.
The classical Ullmann reaction5 has commonly been
employed to generate biaryls with electronegative groups.
The most commonly used process to obtain symmetrical and
unsymmetrical biaryls is through Suzuki cross-coupling
reactions.6 A recent improvement of the Suzuki coupling is
the introduction of phosphine-free catalytic systems.7
Recently, Pd-catalyzed cross-coupling of aromatic halides
with organometallic complexes has been found to be a
versatile route for C–C bond formation.8 Although these
procedures have acquired wide popularity in synthetic
1. Results and discussion
Our strategy to synthesize 4-aryl-3-cyanoanthranilate is
based on the carbanion induced ring transformation of
6-aryl-3-carbomethoxy-4-methylsulfanyl-2H-pyran-2-
ones12 (1) with malononitrile (2). These 2H-pyran-2-ones
may be considered as cyclic ketene hemithioacetals 0and
have been prepared by the reaction of methyl 3,3 -di-
methylthioacrylate with acetophenones as described
earlier.12 The reaction of 1 with malononitrile at room
q CDRI Communication No. 6296.
Keywords: biaryls; 2H-pyran-2-ones; carbanion; coupling reaction; ring
transformation.
*
Corresponding author. Tel.: þ91-522-212416; fax: þ91-522-223405;
e-mail: vjiram@yahoo.com
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01066-9

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N. Agarwal et al. / Tetrahedron 58 (2002) 8793–8798
Scheme 1.
temperature under an inert atmosphere led to the formation
of the ring transformed products methyl 3-amino-2-cyano-
5-methylsulfanyl[1,10-biphenyl]-4-carboxylates (3) in
moderate yield. The results are shown in Scheme 1.
unsymmetrical biaryls in which one of the phenyl rings is
substituted with amino and cyano groups. The precursors
6-aryl-3-cyano-4-sec-amino-2H-pyran-2-ones (7) used for
the ring transformation reactions were prepared by the
reaction of 4 with secondary amines (6) at reflux
temperature. Thus, reaction of 7 with malononitrile in the
presence of alkali at room temperature afforded highl0y
functionalized biaryls such as 3-amino-5-sec-amino-4 -
substituted[1,10-biphenyl]-2,4-dicarbonitriles (8) in
moderate yields (Scheme 3).
To study the influence of electron withdrawing substituents
at position 3 of the pyran ring by replacing carbomethoxy
group with cyano functionality a reaction of 6-aryl-3-cyano-
4-methylsulfanyl-2H-pyran-2-one (4) with malononitrile in
presence of base was carried out and the product 0isolated,
characterized as 3-amino-5-methylsulfanyl-4 -substi-
tuted[1,10-biphenyl]-2,4-dicarbonitriles (5) in good yields
(Scheme 2).
A plausible mechanism for the formation of these products
may be the initial attack of the carbanion generated in
situ from malononitrile at position C6 of the pyran ring, a
highly electropositive center, followed by ring opening,
The reaction was further exploited for the construction of
Scheme 2.

N. Agarwal et al. / Tetrahedron 58 (2002) 8793–8798
8795
Scheme 3.
decarboxylation and re-cyclization to yield unsymmetrical
biaryls (Path A, Scheme 1). This reaction may also proceed
via an inverse electron demand Diels–Alder type cyclo-
addition reaction with malononitrile, followed by elimi-
nation of carbon dioxide to yield biaryl compounds (Path B,
Scheme 1). Since the reaction is performed at ambient
temperature (,258C) under very mild reaction conditions,
Path A seems to be highly probable. The beauty of the
procedure lies in the creation of molecular diversity by
synthesizing highly functionalized cyanoanthranilates and
anthranilo-1,3-dinitriles, which are difficult to obtain in a
single step from easily accessible precursors.
Aldrich. TLC was performed on precoated silica gel plastic
plates and visualized by UV irradiation, exposure to iodine
vapors or spraying with KMnO4 solution. IR spectra of
liquid samples were run neat, and solids as KBr pellets on a
Perkin–Elmer AC-1 instrument. 1H NMR spectra were
recorded at 200 MHz (Brucker WM-200) in CDCl3 with
tetramethylsilane as internal reference. Chemical shifts
and coupling constants J are reported in d (ppm) and
Hz, respectively. Mass spectra were collected at 70 eV
using Jeol JMS-300 spectrometer. Elemental analyses (C,
H, and N) were determined on a Carlo Erba EA-1108 at
RSIC, Central Drug Research Institute, Lucknow 226001,
India.
In summary, our synthetic approach is superior to the
existing procedures in many ways such as (a) mild reaction
conditions, (b) use of inexpensive reagents, (c) versatility
and compatibility of functional groups, and (d) easy work-
up process. Hence, this methodology should prove to be of
value in the preparation of highly functionalized biaryls in
which concurrent or systematic variation in an aryl ring is
required.
2.1. Synthesis of methyl 3-amino-2-cyano-5-(methyl-
sulfanyl)[1,10-biphenyl]-4-carboxylates (3), general
procedure
A mixture of 6-aryl-3-carbomethoxy-4-methylsulfanyl-2H-
pyran-2-one 1 (1 mmol), malononitrile (0.08 g, 1.2 mmol)
and KOH (0.07 g, 1.2 mmol) in dry DMF (12 mL) was
stirred at room temperature for 20 h. After completion of the
reaction, mixture was poured into ice water with vigorous
stirring and finally neutralized with 10% HCl. The solid thus
obtained was filtered and purified on a silica gel column
using chloroform as eluent.
2. Experimental
Mps were determined on Bu¨chi-530 apparatus in an open
capillary and are uncorrected. The reagent grade reaction
solvent DMF was further purified and dried following the
literature procedure. Malononitrile was purchased from
2.1.1. Methyl 3-amino-2-cyano-5-(methylsulfanyl)[1,10-
biphenyl]-4-carboxylate (3a). White solid; mp 169–1708C;

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N. Agarwal et al. / Tetrahedron 58 (2002) 8793–8798
[Found: C, 64.54; H, 4.77; N, 9.44. C16H14N2O2S requires
C, 64.41; H, 4.73; N, 9.39%]; nmax (KBr) 3444, 2209,
1672 cm21; dH (200 MHz, CDCl3) 2.45 (s, 3H, SCH3), 3.98
(s, 3H, OCH3), 6.41 (brs, 2H, NH2), 6.55 (s, 1H, ArH), 7.51
(m, 5H, ArH); m/z (EI) 298 (Mþ), 266.
C, 60.19; H, 4.38; N, 14.04%]; nmax (KBr) 3408, 2205,
1665 cm21; dH (200 MHz, CDCl3) 2.45 (s, 3H, SCH3), 3.99
(s, 3H, OCH3), 6.44 (brs, 2H, NH2), 6.53 (s, 1H, ArH), 7.45
(m, 1H, PyH), 7.92 (d, 1H, J¼7.2 Hz, PyH), 8.71 (d, 1H,
J¼7.2 Hz, PyH), 8.77 (s, 1H, PyH); m/z (EI) 299 (Mþ), 267,
219.
2.1.2. Methyl 3-amino-2-cyano-40-fluoro-5-(methyl-
sulfanyl)[1,10-biphenyl]-4-carboxylate (3b). White solid;
mp 185–1868C; [Found: C, 60.81; H, 4.21; N, 8.93.
C16H13FN2O2S requires C, 60.75; H, 4.14; N, 8.85%];
2.1.9. Methyl 2-amino-3-cyano-6-(methylsulfanyl)-4-(4-
pyridinyl)benzoate (3i). Yellow solid; mp 210–2118C;
[Found: C, 60.23; H, 4.48; N, 14.26. C15H13N3O2S requires
C, 60.19; H, 4.38; N, 14.04%]; nmax (KBr) 3416, 2214,
1670 cm21; dH (200 MHz, CDCl3) 2.45 (s, 3H, SCH3), 3.99
(s, 3H, OCH3), 6.44 (brs, 2H, NH2), 6.51 (s, 1H, ArH), 7.46
(d, 2H, J¼7.2 Hz, PyH), 8.74 (d, 2H, J¼7.2 Hz, PyH); m/z
(EI) 299 (Mþ), 267.
n
max (KBr) 3425, 2212, 1670 cm21; dH (200 MHz, CDCl3)
2.44 (s, 3H, SCH3), 3.97 (s, 3H, OCH3), 6.42 (brs, 2H, NH2),
6.53 (s, 1H, ArH), 7.18 (m, 2H, ArH), 7.82 (m, 2H, ArH);
m/z (EI) 316 (Mþ), 288.
2.1.3. Methyl 3-amino-30-chloro-2-cyano-5-(methyl-
sulfanyl)[1,10-biphenyl]-4-carboxylate (3c). White solid;
mp 169–1708C; [Found: C, 57.89; H, 3.97; N, 8.58.
C16H13ClN2O2S requires C, 57.74; H, 3.94; N, 8.41%];
2.1.10. Methyl 2-amino-3-cyano-6-(methylsulfanyl)-4-(2-
thienyl)benzoate (3j). Yellow solid; mp 204–2068C;
[Found: C, 55.32; H, 4.10; N, 9.31. C14H12N2O2S2 requires
C, 55.24; H, 3.97; N, 9.20%]; nmax (KBr) 3447, 2208,
1670 cm21; dH (200 MHz, CDCl3) 2.42 (s, 3H, SCH3), 3.80
(s, 3H, OCH3), 6.42 (brs, 2H, NH2), 6.51 (s, 1H, ArH), 7.21
(m, 1H, CH), 7.32 (d, 1H, J¼7.2 Hz, CH), 7.58 (d, 1H,
J¼7.2 Hz, CH); m/z (EI) 304 (Mþ), 271.
n
max (KBr) 3444, 2209, 1672 cm21; dH (200 MHz, CDCl3)
2.45 (s, 3H, SCH3), 3.98 (s, 3H, OCH3), 6.42 (brs, 2H, NH2),
6.55 (s, 1H, ArH), 7.44 (m, 3H, ArH), 7.49 (s, 1H, ArH); m/z
(EI) 332 (Mþ), 299, 176.
2.1.4. Methyl 3-amino-40-chloro-2-cyano-5-(methyl-
sulfanyl)[1,10-biphenyl]-4-carboxylate (3d). White solid;
mp 184–1868C; [Found: C, 57.83; H, 3.98; N, 8.52.
C16H13ClN2O2S requires C, 57.74; H, 3.94; N, 8.41%];
2.2. Synthesis of 3-amino-5-(methylsulfanyl)[1,10-bi-
phenyl]-2,4-dicarbonitriles (5), general procedure
n
max (KBr) 3422, 2208, 1680 cm21; dH (200 MHz, CDCl3)
To a mixture of 6-aryl-3-cyano-4-methylsulfanyl-2H-
pyran-2-one 4 (1 mmol) in dry DMF (12 mL), malononitrile
(0.08 g, 1.2 mmol) and KOH (0.07 g, 1.2 mmol) was added
and stirred at room temperature for 20–30 h. After
completion of the reaction, mixture was poured into ice
water with vigorous stirring and finally neutralized with
10% HCl. The solid thus obtained was filtered and purified
on a silica gel column using chloroform/hexane (3:1) as
eluent.
2.44 (s, 3H, SCH3), 3.98 (s, 3H, OCH3), 6.42 (brs, 2H, NH2),
6.50 (s, 1H, ArH), 7.47 (s, 4H, ArH); m/z (EI) 332 (Mþ),
300, 176.
2.1.5. Methyl 3-amino-40-bromo-2-cyano-5-(methyl-
sulfanyl)[1,10-biphenyl]-4-carboxylate (3e). White solid;
mp 210–2118C; [Found: C, 51.11; H, 3.52; N, 7.48.
C16H13BrN2O2S requires C, 50.93; H, 3.47; N, 7.42%];
n
max (KBr) 3448, 2203, 1670 cm21; dH (200 MHz, CDCl3)
2.43 (s, 3H, SCH3), 3.97 (s, 3H, OCH3), 6.41 (brs, 2H, NH2),
6.49 (s, 1H, ArH), 7.41 (d, 2H, J¼8.2 Hz, ArH), 7.62 (d, 2H,
J¼8.2 Hz, ArH); m/z (EI) 377 (Mþ), 345.
2.1.6. Methyl 3-amino-2-cyano-40-methyl-5-(methyl-
sulfanyl)[1,10-biphenyl]-4-carboxylate (3f). White solid;
mp 209–2108C; [Found: C, 65.43; H, 5.23; N, 9.03.
C17H16N2O2S requires C, 65.35; H, 5.18; N, 8.96%]; nmax
(KBr) 3440, 2212, 1687 cm1; dH (200 MHz, CDCl3) 2.43 (s,
6H, SCH3, CH3), 3.97 (s, 3H, OCH3), 6.40 (brs, 2H, NH2),
6.53 (s, 1H, ArH), 7.28 (d, 2H, J¼8.0 Hz, ArH), 7.43 (d, 2H,
J¼8.0 Hz, ArH); m/z (EI) 312 (Mþ), 280.
2.2.1. 3-Amino-5-(methylsulfanyl)[1,10-biphenyl]-2,4-di-
carbonitrile (5a). White solid; mp 243–2448C (Rep.13
242–2448C); [Found: C, 67.78; H, 4.31; N, 15.79.
C15H11N3S requires C, 67.90; H, 4.17; N, 15.83%]; nmax
(KBr) 3343, 2216 cm21; dH (200 MHz, CDCl3) 2.56 (s, 3H,
SCH3), 5.24 (brs, 2H, NH2), 6.56 (s, 1H, ArH), 7.49–7.53
(m, 5H, ArH); m/z (EI) 265 (Mþ).
2.2.2. 3-Amino-40-methyl-5-(methylsulfanyl)[1,10-bi-
phenyl]-2,4-dicarbonitrile (5b). White solid; mp 230–
2318C; [Found: C, 68.50; H, 4.56; N, 15.24. C16H13N3S
requires C, 68.79; H, 4.69; N, 15.04%]; nmax (KBr) 3370,
2212 cm21; dH (200 MHz, CDCl3) 2.42 (s, 3H, CH3), 2.55
(s, 3H, SCH3), 5.22 (brs, 2H, NH2), 6.55 (s, 1H, ArH), 7.30
(d, 2H, J¼8.1 Hz, ArH), 7.43 (d, 2H, J¼8.1 Hz, ArH); m/z
(EI) 279 (Mþ).
2.1.7. Methyl 2-amino-3-cyano-6-(methylsulfanyl)-4-
(2-pyridinyl)benzoate (3g). Yellow solid; mp 180–
1818C; [Found: C, 60.25; H, 4.42; N, 14.20. C15H13N3O2S
requires C, 60.19; H, 4.38; N, 14.04%]; nmax (KBr) 3431,
2206, 1668 cm21; dH (200 MHz, CDCl3) 2.48 (s, 3H,
SCH3), 3.97 (s, 3H, OCH3), 6.44 (brs, 2H, NH2), 6.89 (s, 1H,
ArH), 7.38 (m, 1H, PyH), 7.79 (m, 2H, PyH), 8.76 (d, 1H,
J¼7.2 Hz, PyH); m/z (FAB) 300 (Mþþ1).
2.2.3. 3-Amino-40-methoxy-5-(methylsulfanyl)[1,10-bi-
phenyl]-2,4-dicarbonitrile (5c). White solid; mp 212–
2138C; [Found: C, 65.36; H, 4.10; N, 13.94. C16H13N3OS
requires C, 65.06; H, 4.43; N, 14.22%]; nmax (KBr) 3336,
2217 cm21; dH (200 MHz, CDCl3) 2.56 (s, 3H, SCH3), 3.88
(s, 3H, OCH3), 5.22 (brs, 2H, NH2), 6.54 (s, 1H, ArH), 7.01
(d, 2H, J¼8.6 Hz, ArH), 7.49 (d, 2H, J¼8.6 Hz, ArH); m/z
(EI) 295 (Mþ).
2.1.8. Methyl 2-amino-3-cyano-6-(methylsulfanyl)-4-(3-
pyridinyl)benzoate (3h). Yellow solid; mp 208–2098C;
[Found: C, 60.26; H, 4.45; N, 14.20. C15H13N3O2S requires

N. Agarwal et al. / Tetrahedron 58 (2002) 8793–8798
8797
2.2.4. 3-Amino-40-bromo-5-(methylsulfanyl)[1,10-bi-
phenyl]-2,4-dicarbonitrile (5d). Yellow solid; mp 260–
2618C; [Found: C, 52.02; H, 2.71; N, 11.94. C15H10BrN3S
requires C, 52.33; H, 2.92; N, 12.20%]; nmax (KBr) 3372,
2213 cm21; dH (200 MHz, CDCl3) 2.56 (s, 3H, SCH3), 5.26
(brs, 2H, NH2), 6.51 (s, 1H, ArH), 7.37 (d, 2H, J¼8.2 Hz,
ArH), 7.65 (d, 2H, J¼8.2 Hz, ArH); m/z (EI) 344 (Mþ).
2.2.5. 3-Amino-40-chloro-5-methylsulfanyl[1,10-bi-
phenyl]-2,4-dicarbonitrile (5e). White solid; mp 210–
2118C; [Found: C, 60.20; H, 3.45; N, 14.18. C15H10ClN3S
requires C, 60.09; H, 3.36; N, 14.10%]; nmax (KBr) 3435,
2213 cm21; dH (200 MHz, CDCl3) 2.56 (s, 3H, SCH3), 5.26
(s, 2H, NH2), 6.52 (s, 1H, CH), 7.26 (d, 2H, J¼8.2 Hz,
ArH), 7.47 (d, 2H, J¼8.2 Hz, ArH); m/z (EI) 299 (Mþ), 266.
2.2.6. 3-Amino-30-chloro-40-fluoro-5-(methylsulfanyl)-
[1,10-biphenyl]-2,4-dicarbonitrile (5f). White solid;
mp 218–2198C; [Found: C, 56.42; H, 2.63; N, 13.41.
C15H9ClFN3S requires C, 56.69; H, 2.85; N, 13.22%]; nmax
(KBr) 3342, 2218 cm21; dH (200 MHz, CDCl3) 2.57 (s, 3H,
SCH3), 5.27 (brs, 2H, NH2), 6.49 (s, 1H, ArH), 7.53–7.56
(m, 3H, ArH); m/z (EI) 317 (Mþ).
requires C, 73.82; H, 5.83; N, 20.34%]; nmax (KBr) 2212,
3428 cm21; dH (200 MHz, CDCl3) 2.43 (s, 3H, CH3), 3.22
(s, 6H, NCH3), 5.44 (s, 2H, NH2), 7.26–7.38 (m, 4H, ArH);
m/z (EI) 276 (Mþ), 262, 250.
2.3.3. 3-Amino-40-chloro-5-(1-pyrrolidinyl)[1,10-bi-
phenyl]-2,4-dicarbonitrile (8c). Pale yellow solid; mp
200–2018C; [Found: C, 67.21; H, 4.87; N, 17.66.
C18H15ClN4 requires C, 66.92; H, 4.68; N, 17.42%]; nmax
(KBr) 2216, 3430 cm21; dH (200 MHz, CDCl3) 2.04 (t,
4H, J¼6.6 Hz, NCH2), 3.69 (t, 4H, J¼6.6 Hz, NCH2), 5.20
(s, 2H, NH2), 5.95 (s, 1H, CH), 7.26 (d, 2H, J¼8.2 Hz,
ArH), 7.42 (d, 2H, J¼8.2 Hz, ArH); m/z (EI) 322 (Mþ), 296,
268.
2.3.4. 3-Amino-40-bromo-5-(1-pyrrolidinyl)[1,10-bi-
phenyl]-2,4-dicarbonitrile (8d). Yellow solid; mp
.2608C; [Found: C, 58.99; H, 4.32; N, 15.60.
C18H15BrN4 requires C, 58.81; H, 4.11; N, 15.31%]; nmax
(KBr) 2215, 3430 cm21; dH (200 MHz, CDCl3) 2.04 (t, 4H,
J¼6.6 Hz, NCH2), 3.69 (t, 4H, J¼6.6 Hz, NCH2), 5.20 (s,
2H, NH2), 5.95 (s, 1H, CH), 7.26–7.32 (m, 2H, ArH), 7.38–
7.45 (m, 2H, ArH); m/z (EI) 367 (Mþ), 335, 297.
2.2.7. 3-Amino-5-(methylsulfanyl)-40-nitro[1,10-bi-
phenyl]-2,4-dicarbonitrile (5g). Yellow solid; mp 270–
2718C; [Found: C, 58.25; H, 3.48; N, 17.88. C15H10N4O2S
requires C, 58.05; H, 3.24; N, 18.05%]; nmax (KBr) 3364,
2213 cm21; dH (200 MHz, CDCl3) 2.56 (s, 3H, SCH3), 5.24
(brs, 2H, NH2), 6.54 (s, 1H, ArH), 7.46 (d, 2H, J¼8.6 Hz,
ArH), 7.64 (d, 2H, J¼8.6 Hz, ArH); m/z (EI) 310 (Mþ).
2.3.5. 3-Amino-40-chloro-5-[4-(2-methoxyphenyl)-1-
piperazinyl][1,10-biphenyl]-2,4-dicarbonitrile (8e). Yellow
solid; mp 181–1828C; [Found: C, 67.72; H, 5.12; N, 16.04.
C25H22ClN5O requires C, 67.58; H, 4.99; N, 15.83%]; nmax
(KBr) 2212, 3392 cm21; dH (200 MHz, CDCl3) 3.15 (t, 2H,
J¼4.8 Hz, NCH2), 3.25 (t, 2H, J¼4.8 Hz, NCH2), 3.61
(t, 2H, J¼4.8 Hz, NCH2), 3.73 (t, 2H, J¼4.8 Hz, NCH2),
3.98 (s, 3H, OCH3), 5.23 (s, 2H, NH2), 6.28 (s, 1H, CH),
6.91–6.97 (m, 4H, ArH), 7.01–7.26 (m, 4H, ArH); m/z (EI)
443 (Mþ).
2.2.8. 2-Amino-4-(methylsulfanyl)-6-(1-naphthyl)iso-
phthalonitrile (5h). Colorless oil; [Found: C, 72.60; H,
4.20; N, 13.41. C19H13N3S requires C, 72.35; H, 4.15; N,
13.32%]; nmax (neat) 3349, 2206 cm21; dH (200 MHz,
CDCl3) 2.49 (s, 3H, SCH3), 5.25 (brs, 2H, NH2), 6.62 (s, 1H,
ArH), 7.46–7.57 (m, 5H, ArH), 7.92–7.95 (m, 2H, ArH);
m/z (EI) 315 (Mþ).
2.3.6. 3-Amino-40-bromo-5-[4-(2-methoxyphenyl)-1-
piperazinyl][1,10-biphenyl]-2,4-dicarbonitrile (8f). Yellow
solid; mp 215–2168C; [Found: C, 61.66; H, 4.78; N, 14.52.
C25H22BrN5O requires C, 61.42; H, 4.53; N, 14.39%]; nmax
(KBr) 2215, 3424 cm21; dH (200 MHz, CDCl3) 3.29 (t, 4H,
J¼4.8 Hz, NCH2), 3.65 (t, 4H, J¼4.8 Hz, NCH2), 3.92 (s,
3H, OCH3), 5.27 (s, 2H, NH2), 6.32 (s, 1H, CH), 6.95–7.05
(m, 4H, ArH), 7.30 (d, 2H, J¼8.2 Hz, ArH), 7.45 (d, 2H,
J¼8.2 Hz, ArH); m/z (EI) 488 (Mþ), 473, 393.
2.3. Synthesis of 3-amino-5-sec-amino-40-substituted-
[1,10-biphenyl]-2,4-dicarbonitriles (8a–i), general
procedure
A mixture of 7 (1 mmol), malononitrile (0.08 g, 1.2 mmol)
and KOH (0.07 g, 1.2 mmol) in dry DMF (10 mL) was
stirred at room temperature in nitrogen atmosphere for 28 h.
On completion, the reaction mixture was poured into ice
water and neutralized with 10% HCl. Crude product was
filtered and purified on silica gel column by using CHCl3/
hexane (1:1) as eluent.
2.3.7. 3-Amino-40-fluoro[1,10-biphenyl]-5-[4-(2-pyri-
dinyl)-1-piperazinyl-2,4-dicarbonitrile (8g). Yellow
solid; mp 219–2208C; [Found: C, 69.45; H, 4.92; N,
21.33. C23H19FN6 requires C, 69.27; H, 4.80; N, 21.15%];
n
max (KBr) 2216, 3435 cm21; dH (200 MHz, CDCl3) 3.53 (t,
4H, J¼4.9 Hz, NCH2), 3.78 (t, 4H, J¼4.9 Hz, NCH2), 5.23
(s, 2H, NH2), 6.25 (s, 1H, CH), 7.12–7.26 (m, 4H, ArH),
7.48–7.53 (m, 2H, PyH), 8.20–8.25 (m, 2H, PyH); m/z (EI)
398 (Mþ), 323, 307.
2.3.1. 3-Amino-40-fluoro[1,10-biphenyl]-5-dimethyl-
amino-2,4-dicarbonitrile (8a). Yellow solid; mp 210–
2118C; [Found: C, 68.31; H, 4.75; N, 20.22. C16H13FN4
requires C, 68.56; H, 4.67; N, 19.99%]; nmax (KBr) 2205,
3432 cm21; dH (200 MHz, CDCl3) 3.22 (s, 6H, NCH3), 5.22
(s, 2H, NH2), 6.07 (s, 1H, CH), 7.14–7.45 (m, 4H, ArH);
m/z (EI) 280 (Mþ), 266, 237.
2.3.8. 3-Amino-5-{4-[bis-(4-fluorophenyl)methyl]-1-
piperazinyl}-40-chloro[1,10-biphenyl]-2,4-dicarbonitrile
(8h). Colorless oil; [Found: C, 69.12; H, 4.59; N, 13.24.
C31H24ClF2N5 requires C, 68.90; H, 4.47; N, 13.02%]; nmax
(neat) 2212, 3495 cm21; dH (200 MHz, CDCl3) 2.29 (t, 2H,
J¼4.8 Hz, NCH2), 2.42 (t, 2H, J¼4.8 Hz, NCH2), 2.84 (t,
2H, J¼4.8 Hz, NCH2), 3.59 (t, 2H, J¼4.8 Hz, NCH2), 4.38
(s, 1H, CH), 5.79 (s, 2H, NH2), 6.89 (s, 1H, CH), 6.95–7.10
2.3.2. 3-Amino-5-dimethylamino-40-methyl[1,10-bi-
phenyl]-2,4-dicarbonitrile (8b). Yellow solid; mp 185–
1868C; [Found: C, 73.99; H, 6.02; N, 20.58. C17H16N4

8798
N. Agarwal et al. / Tetrahedron 58 (2002) 8793–8798
1988, 29, 1797. (b) Yamamura, K.; Ono, S.; Ogoshi, H.;
Masuda, H.; Kuroda, Y. Synlett 1989, 18.
(m, 8H, ArH), 7.32–7.41 (m, 4H, ArH); m/z (FAB) 540
(Mþþ1).
5. Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174.
6. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513. (b) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki,
A. J. Am. Chem. Soc. 1985, 107, 972. (c) Suzuki, A.; Miyaura,
N. Chem. Rev. 1995, 95, 2457.
2.3.9. 3-Amino-5-{4-[bis-(4-fluorophenyl)methyl]-1-
piperazinyl}-40-methoxy[1,10-biphenyl]-2,4-dicarbo-
nitrile (8i). Colorless oil; [Found: C, 71.98; H, 5.23; N,
13.30. C32H27F2N5O requires C, 71.71; H, 5.07; N,
13.12%]; nmax (neat) 2205, 3432 cm21; dH (200 MHz,
CDCl3) 2.42 (t, 2H, J¼4.8 Hz, NCH2), 2.63 (t, 2H, J¼
4.8 Hz, NCH2), 3.38 (t, 2H, J¼4.8 Hz, NCH2), 3.48 (t, 2H,
J¼4.8 Hz, NCH2), 3.88 (s, 3H, OCH3), 4.28 (s, 1H, CH),
5.18 (s, 2H, NH2), 5.90 (s, 1H, CH), 6.94–7.08 (m, 8H,
ArH), 7.27–7.39 (m, 4H, ArH); m/z (EI) 535 (Mþ), 473,
393.
7. (a) Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron Lett.
1994, 35, 3277. (b) Wallow, T. I.; Novak, B. M. J. Org. Chem.
1994, 59, 5034. (c) Moreno-Manas, M.; Pajuelo, F.; Pleixats,
R. J. Org. Chem. 1995, 60, 2396.
8. (a) Billington, D. C. In Comprehensive Organic Synthesis.
Coupling Reactions between sp3 Carbon Centers, Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 3.
Chapter 2.1. (b) Taylor, S. K.; Bennett, S. G.; Heinz, K. J.;
Lashley, L. K. J. Org. Chem. 1981, 46, 2194.
9. Sainsbury, M. Tetrahedron 1980, 36, 3327.
Acknowledgements
10. (a) Victory, P.; Borrell, J. I.; Vidal-Ferran, A.; Montenegro, E.;
Jimeno, M. L. Heterocycles 1993, 36, 2273. (b) Victory, P.;
Alvarez-Larena, A.; Germain, G.; Kessels, R.; Piniella, J. F.;
Vidal-Ferran, A. Tetrahedron 1995, 51, 235. (c) Murugan, P.;
Shanmugasundaram, P.; Ramakrishnan, V. T.; Srividya, N.;
Ramamurthy, P. Indian J. Chem. 1998, 37B, 737.
N. Agarwal and A. S. Saxena are thankful to CSIR for the
senior research fellowship.
References
11. Khaidem, I. S.; Singh, S. L.; Singh, L. R.; Khan, M. Z. R.
Indian J. Chem. 1996, 35B, 911.
1. (a) Torssell, K. G. B. Natural Product Chemistry. Wiley:
Chichester, 1983. (b) Thomson, R. H. The Chemistry of
Natural Products. Blackie: Glasgow, 1985.
12. (a) Tominaga, Y.; Ushirogochi, A.; Matsuda, Y. J. Heterocycl.
Chem. 1987, 24, 1557. (b) Ram, V. J.; Verma, M.; Hussaini,
F. A.; Shoeb, A. J. Chem. Res. (S) 1991, 98. (c) Ram, V. J.;
Verma, M.; Hussaini, F. A.; Shoeb, A. Liebigs. Ann. Chem.
1991, 1229.
2. Noyori, R. Chem. Soc. Rev. 1989, 18, 187.
3. Mikes, F.; Boshart, G. J. Chromatogr. 1978, 149, 455.
4. (a) Yamamura, K.; Ono, S.; Tabushi, I. Tetrahedron Lett.
13. Peseke, K. J. Prakt. Chem. 1981, 323, 499.