Regioselective synthesis of functionally congested biaryls through a novel C-C bond formation reaction

Article abstract of DOI:10.1016/j.tetlet.2005.06.034

An expeditious synthesis of unsymmetrical biaryls functionalized with electron-withdrawing or -donating substituents is described and illustrated by the carbanion-induced ring transformation of 2H-pyran-2-ones with malononitrile in excellent yields.

Full text of DOI:10.1016/j.tetlet.2005.06.034

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 5585–5587
Regioselective synthesis of functionally congested biaryls through
a novel C–C bond formation reactionI
Atul Goel* and Fateh Veer Singh
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
Received 11 February 2005; revised 25 May 2005; accepted 6June 2005
Available online 1 July 2005
Abstract—An expeditious synthesis of unsymmetrical biaryls functionalized with electron-withdrawing or -donating substituents is
described and illustrated by the carbanion-induced ring transformation of 2H-pyran-2-ones with malononitrile in excellent yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Biaryl ring systems functionalized with electron donor
or acceptor moieties are not only the central motifs of
a large number of natural products1 and synthetic phar-
maceuticals but are also useful as versatile auxiliaries for
asymmetric syntheses,2 as chiral phases for chromato-
graphy3 and as important substrates for chiral liquid
crystalline materials.4
ability of several aryl-boronic acids, easy work-up and
tolerance of the reaction to aqueous media. Despite
the broad synthetic applicability of the Suzuki reaction,
the expansion of these methods to prepare functionally
congested biaryls places constraints on the choice of re-
agents, catalysts and/or reaction conditions. Therefore,
the necessity for an efficient and concise synthesis of
biaryls having functional group diversity is evident in
natural product chemistry as well as in the discovery
of new reagents for asymmetric synthesis.
While the chemistry of symmetrical and unsymmetrical
biaryls is replete with synthetic methods, most of them
fall into the categories of the inter- and intramolecular
cross coupling of two aromatic rings in the presence of
organometallic complexes. Reductive dimerization of
aryl halides is one of the oldest methods5 for the con-
struction of biaryls using copper bronze as a reducing
agent. Oxidative coupling of electron-rich aromatic phe-
nols also leads to the formation of biaryls in moderate
yields.6 Recently, palladium-catalyzed cross coupling
between the electrophilic compounds Ar–X (X being
mainly Br, I and OTf) and organometallic species Ar–
M (M being Mg, Zn, Sn and B) has become increasingly
popular for the construction of symmetrical and unsym-
metrical biaryl ring systems.7 Among them, the palla-
dium-catalyzed aryl-boronic acid coupling (Suzuki
reaction) has become a general and versatile route to ac-
cess functionalized biaryls due to the commercial avail-
Herein, we report an efficient and convenient procedure
for the preparation of functionally congested biaryls
through the reaction of ethyl 2-cyano-3,3-di(methyl-
sulfanyl)acrylate with either aryl acetones or propiophen-
ones followed by a base-catalyzed ring transformation
of 2H-pyran-2-ones 3 with malononitrile. The beauty
of the procedure lies in the creation of a functionally
crowded aryl ring through lactonization without using
an organometallic reagent or a catalyst.
Our approach to prepare functionalized biaryls 5a–e is
based on the ring transformation of 5-aryl-3-cyano-6-
methyl-4-methylsulfanyl-2H-pyran-2-ones 3a–e by using
malononitrile as a carbanion source. The 2H-pyran-2-
ones 3a–e used as parent precursors were prepared by
the reaction of ethyl 2-cyano-3,3-di(methylsulfanyl)acryl-
ate8,9 1 with substituted aryl acetones 2a–e under alka-
line conditions in high yields (Scheme 1). Lactones,
3a–e have three electrophilic centres; C2, C4 and C6in
which the latter is highly reactive towards nucleophiles
due to extended conjugation and the presence of
the electron withdrawing substitutent at position 3 of
the pyran ring. The biaryl compounds 5a–e were
Keywords: Biaryl; Phenyl acetone; Lactone; Malononitrile; Pyran-2-
one.
q C.D.R.I. Communication No. 6728.
*
Corresponding author. Fax: +91 522 2623405;
agoel13@yahoo.com
e-mail:
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.034

5586
A. Goel, F. V. Singh / Tetrahedron Letters 46 (2005) 5585–5587
Scheme 1.
synthesized by stirring an equimolar mixture of 2H-
pyran-2-ones 3a–e, malononitrile and powdered KOH
in DMF for 12–15 h at room temperature (Scheme 1).
The reaction was monitored by TLC and thereafter
poured into ice water and neutralized with dilute HCl.
The crude product thus obtained was purified by silica
gel chromatography and characterized by elemental
and spectroscopic analyses.10
phenones 6 in dry DMSO to prepare 5-methyl-4-
methylsulfanyl-2-oxo-6-phenyl-2H-pyran-3-carbonitriles
7a–c in 80–90% yields (Scheme 2). The 2H-pyran-2-ones
7a–c were then reacted with malononitrile in the pres-
ence of a base to afford 3-amino-6-methyl-5-methyl-
sulfanyl-biphenyl-2,4-dicarbonitriles 8a–c in 89–94%
yields.
In summary, we have prepared functionally congested
biaryls through the carbanion-induced ring transforma-
tion of functionalized 2H-pyran-2-ones in excellent
yields. This methodology may be applicable to the syn-
thesis of other complex biaryls, which are difficult to
prepare by classical cross coupling procedures.
The transformation of 5-aryl-2H-pyran-2-ones into
biaryls is possibly initiated by attack of the malononit-
rile carbanion at position C-6of lactone 3, followed
by intramolecular cyclization involving one of the
nitrile functionalities and C-3 of the pyranone ring and
elimination of carbon dioxide to yield 5a–e.
The reaction was further exploited by reacting an
equimolar mixture of ketene dithioacetal 1 with propio-
Acknowledgements
This work was supported by the Council of Scientific
and Industrial Research, New Delhi, India. The authors
thank SAIF, CDRI, Lucknow for providing elemental
analyses and spectroscopic data.
References and notes
1. (a) Torssell, K. G. B. Natural Product Chemistry;
Wiley: Chichester, 1983; (b) Thomson, R. H. The
Chemistry of Natural Products; Blackie and Son: Glasgow,
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2. (a) Noyori, R. Chem. Soc. Rev. 1989, 18, 187–208; (b)
Andersen, N. G.; Maddaford, S. P.; Keay, B. A. J. Org.
Chem. 1996, 61, 9556–9559.
3. Mikes, F.; Boshart, G. J. Chromatogr. 1978, 149, 455–
464.
4. (a) Yamamura, K.; Ono, S.; Tabushi, I. Tetrahedron Lett.
1988, 29, 1797–1798; (b) Yamamura, K.; Ono, S.; Ogoshi,
H.; Masuda, H.; Kuroda, Y. Synlett 1989, 18–19.
5. Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174–
2185.
Scheme 2.

A. Goel, F. V. Singh / Tetrahedron Letters 46 (2005) 5585–5587
5587
6. Taylor, W. I.; Battersby, A. R. In Oxidative Coupling of
Phenols; Dekker: New York, 1967; Vol. 1.
10. General procedure for the synthesis of compound 5: a
mixture of 5-aryl-3-cyano-6-methyl-4-methylsulfanyl-2H-
pyran-2-one 3 (1 mmol), malononitrile (1 mmol) and
powdered KOH (1.2 mmol) in dry DMF (5 mL) was
stirred at room temperature for 12–15 h. At the end the
reaction mixture was poured into ice water with vigorous
stirring and finally neutralized with dilute HCl. The solid
thus obtained was filtered and purified on a silica gel
column using chloroform–hexane (1:2) as eluent. Com-
pound 5a: white solid; yield 94%; mp 192–194 °C; 1H
NMR (200 MHz, CDCl3) d 2.20 (s, 3H, CH3), 2.30 (s, 3H,
SCH3), 5.22 (br s, 2H, NH2), 7.04–7.19 (m, 4H, ArH); IR
(KBr) 2220 (CN), 3352 (NH), 3413 cmÀ1 (NH); MS (FAB)
298 (M++1). Anal. Calcd for C16H12FN3S: C, 64.63; H,
4.07; N, 14.13. Found: C, 64.69; H, 4.10; N, 14.19.
Compound 8a: white solid; yield 94%; mp 220–222 °C; 1H
NMR (200 MHz, CDCl3) d 2.16(s, 3H, CH 3), 2.59 (s, 3H,
SCH3), 5.12 (br s, 2H, NH2), 7.20–7.25 (m, 2H, ArH),
7.47–7.50 (m, 3H, ArH); IR (KBr) 2221 (CN), 3348 (NH),
3407 cmÀ1(NH); MS (FAB) 280 (M++1). Anal. Calcd for
C16H13N3S: C, 68.79; H, 4.69; N, 15.04. Found: C, 68.88;
H, 4.78; N, 15.16.
´
7. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359–1469.
8. Tominaga, Y.; Ushirogochi, A.; Matsuda, Y. J. Hetero-
cycl. Chem. 1987, 24, 1557–1567.
9. General procedure for the synthesis of compound 3: a
mixture of ethyl 2-cyano-3,3-di(methylsulfanyl)acrylate 1
(10 mmol), aryl acetone (11 mmol) and powdered KOH
(12 mmol) in dry DMSO (50 mL) was stirred at room
temperature for 10 h. After completion, the reaction
mixture was poured into ice water with constant stirring.
The precipitate thus obtained was filtered and purified on
a silica gel column using chloroform as eluent. Com-
pound 3c: yellow solid; yield 81%; mp 142–144 °C; 1H
NMR (200 MHz, CDCl3) d 2.05 (s, 3H, CH3), 2.85 (s,
3H, SCH3), 7.42 (d, 1H, J = 7.5 Hz, ArH), 7.49 (s, 1H,
ArH), 7.63 (t, 1H, J = 7.6Hz, ArH), 7.75 (d, 1H,
À1
J = 7.6Hz, ArH); IR (KBr) 1692 (CO), 2212 cm
(CN); MS (FAB) 326(M ++1). Anal. Calcd for
C15H10F3NO2S: C, 55.38; H, 3.10; N, 4.31. Found: C,
55.49; H, 3.13; N, 4.26.