Carbanion-induced base-catalyzed synthesis of unsymmetrical biaryls from suitably functionalized 2H-pyran-2-ones through ring-transformation reactions

Article abstract of DOI:10.1016/S0040-4039(01)01481-2

A synthesis of unsymmetrical highly functionalized biaryls with an amino substituent juxtaposed with two nitrile groups in one of the phenyl rings is delineated and illustrated by the carbanion-induced ring-transformation of 6-aryl-4-methylsulfanyl-2H-pyr

Full text of DOI:10.1016/S0040-4039(01)01481-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7127–7129
Carbanion-induced base-catalyzed synthesis of unsymmetrical
biaryls from suitably functionalized 2H-pyran-2-ones
through ring-transformation reactions†
Vishnu Ji Ram* and Nidhi Agarwal
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 29 June 2001; accepted 7 August 2001
Abstract—A synthesis of unsymmetrical highly functionalized biaryls with an amino substituent juxtaposed with two nitrile groups
in one of the phenyl rings is delineated and illustrated by the carbanion-induced ring-transformation of 6-aryl-4-methylsulfanyl-
2H-pyran-2-one-3-carbonitrile (1) and 4-sec-amino-6-aryl-2H-pyran-2-one-3-carbonitrile (2) to 2-amino-4-aryl-6-methylsulfanyl-
1,3-benzodinitrile (3) and 2-amino-6-sec-amino-4-aryl-1,3-benzodinitrile (4) using malononitrile as a source of the carbanion, in
moderate yield. © 2001 Elsevier Science Ltd. All rights reserved.
An expedient synthesis of unsymmetrical biaryls, partic-
ularly those with hindered rotation, has always been a
fascinating and challenging undertaking in natural
product chemistry. Arenes with electron donating and
accepting substituents are recognized as molecular sub-
units for displaying non-linear optical properties due to
their high polarisability.1 These molecules not only
exhibit optical properties but also display diverse phar-
macological activities.2–6
product synthesis, it is limited to certain substituents in
the phenyl ring and is restricted by the difficulty in
obtaining Grignard reagents. Thus, the need for an
improved synthesis of unsymmetrical biaryls was real-
ized with the option of introducing substituents of
choice at specific positions either by using the appropri-
ate carbanion reagents or by manoeuvring the sub-
stituent in, for example, a 6-aryl-4-methylsulfanyl-2H-
pyran-2-one-3-carbonitrile (1).
Despite numerous approaches to the synthesis of highly
functionalized symmetrical and unsymmetrical biaryls,
many synthesis have limitations with respect to harsh-
ness or functional group intolerance of the conditions
required.
Our strategy for the synthesis of unsymmetrical biaryls
with electron donating and accepting substituents is
based on the base-catalyzed ring-transformation of 4-
sec-amino-6-aryl-2H-pyran-2-one-3-carbonitrile (2),14
obtained from the reaction of 6-aryl-4-methylsulfanyl-
2H-pyran-2-one-3-carbonitrile (1)15 and a secondary
amine. Our initial endeavors with malononitrile failed
to affect substitution reactions on 1 and led to a ring
transformed compound 3 in lieu of the substituted
product. However, the ring-transformation of 2 with
malononitrile was very facile and yielded a biaryl with
amino substituents juxtaposed with nitrile groups.
Compounds with this ring system had been obtained
earlier in 10–20% yield16 as by-product from the reac-
tion of chalcone and malononitrile. Formation of these
compounds through ring-transformation may possibly
be initiated by nucleophilic attack at C6, a highly
electrophilic center compared to C4 of the lactone ring
due to the extended conjugation and reduction in elec-
trophilicity of C4 center by the presence of secondary
amino group. In this reaction, the initial attack of the
Symmetrical biaryls have been prepared by coupling
aromatic moieties in the presence of different coupling
reagents, for example Ni complexes,7 arylthallium
bis(trifluoroacetate),8 lithium tetrachloropalladate or
ruthenium(IV) tetrakis(trifluoroacetate).9,10 Recently,
palladium-catalyzed cross-coupling between elec-
trophilic compounds ArꢀX (X=Br, I, OTf) and
organometallic species ArꢀM (M being mainly Mg, Zn,
Sn and B) has been found to be a versatile route for
CꢀC bond formation.11,12 Although the synthesis of
unsymmetrical biaryls through oxazoline mediated
coupling13 has acquired wide popularity in natural
* Corresponding author. Fax: 91-0522-223405/223938; e-mail: vjiram
@yahoo.com
† C.D.R.I. Communication No. 6126.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01481-2

7128
V. J. Ram, N. Agarwal / Tetrahedron Letters 42 (2001) 7127–7129
confirmed by X-ray diffraction. These compounds were
prepared by stirring an equimolar mixture of the lac-
tone 2, malononitrile and powdered KOH in DMF for
20–30 h at room temperature. At the end of the reac-
tion, the reaction mixture was poured into ice water
with vigorous stirring and the mixture neutralized with
10% HCl. The crude product was purified by silica gel
column chromatography.
carbanion generated in situ from the malononitrile at
C6 with ring opening is followed by decarboxylation
and cyclization to yield the unsymmetrical biaryl which
has an amino substituent flanked by two nitrile groups
in one of the phenyl rings. There are two possible
modes of cyclization after a ring opening and decar-
boxylation, as depicted in Scheme 1, which would yield
either the 2-amino-6-sec-amino-4-aryl-1,3-benzodini-
trile 4 or the 4-sec-amino-2-aryl-6-imino-1,6-dihydro-
1,1-dinitrile 5 or a mixture of 4 and 5. The product
isolated from the reaction in moderate yield was char-
acterized by spectroscopic and elemental analyses as the
2-amino-6-sec-amino-4-aryl-1,3-benzodinitrile 4. The
structure of one of the compounds, 4a, was further
Acknowledgements
The authors are thankful to ICMR and CSIR for
financial support.
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