Regioselective synthesis of functionally crowded benzenes at room temperature through ring transformation of 2H-pyran-2-ones

Article abstract of DOI:10.1055/s-2007-984885

An expeditious synthesis of highly substituted benzenes with electron-withdrawing or electron-donating substituents is described and illustrated by carbanion-induced ring transformation of 2H-pyran-2-one with malononitrile in excellent yield. The novelty

Full text of DOI:10.1055/s-2007-984885

2086
LETTER
Regioselective Synthesis of Functionally Crowded Benzenes at Room
Temperature through Ring Transformation of 2H-Pyran-2-ones1
Functionally C
a
rowde
d
Be
t
nzenes
e
through Ri
h
ng Transformation
V
of
2
H
-Pyran-2-on
e
es er Singh, Vijay Kumar, Atul Goel*
Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; E-mail: agoel13@yahoo.com
Received 15 May 2007
Fisher carbene complexes,12 Danheiser alkyne–cyclo-
butenone cyclization,13[4+2]-cycloaddition of metala-
cyclopentadienes and alkynes,14 [2+2+2]- and [4+2]-
cycloaddition reactions in the presence of transition-metal
Abstract: An expeditious synthesis of highly substituted benzenes
with electron-withdrawing or electron-donating substituents is
described and illustrated by carbanion-induced ring transformation
of 2H-pyran-2-one with malononitrile in excellent yield. The
novelty of the reaction lies in the creation of an aromatic ring at catalyst,15 [4+2]-Yamamoto benzannulation of O-alkynyl
benzaldehyde and alkyne,16 [4+2]-annulation of Baylis–
room temperature from a six-membered lactone under mild reaction
Hillman adducts17 and [3+3]-cyclocondensation between
conditions.
bielectrophiles and binucleophiles.18 Although these ben-
Key words: 2H-pyran-2-one, benzene, malononitrile, ring trans-
formation reaction
zannulation approaches afford a wide variety of aromatic
compounds, the utilization of these protocols for the prep-
aration of functionally congested benzenes such as substi-
Benzene compounds functionalized with electron-donor tuted isophthalonitriles places constraints on the choice of
or -acceptor substituents such as alkyl, alkoxy, amino, reagents or conditions. Aromatic compounds with nitrile
nitrile or ester groups are useful scaffolds in organic syn- and amine functionalities not only possess interesting bi-
thesis, and are widely used in industry as well as in the ological activities19 but are also useful synthons for their
laboratory. In particular, the synthesis of highly function- transformation to quinazolines20 and fluorenones.21 Al-
alized benzenes in a regioselective manner is one of the though numerous regio- and stereoselective Diels–Alder
challenging tasks in academic endeavours.2 Direct sub- reactions22 of 2H-pyran-2-ones with electron-deficient
stitutions onto the benzene scaffolds by electrophilic or and electron-rich dienophiles do provide benzene deriva-
nucleophilic substitution reactions,3 metal-catalyzed tives, they require forcing thermal reaction conditions to
coupling reactions4 and metalation–functionalization eliminate the carbon dioxide from the adduct and/or are
reactions5 offer a versatile approach to the synthesis of a associated with a mixture of positional isomers. The wide-
plethora of di- and trisubstituted benzene analogues, but ranging applications and limitations of existing protocols
some of them suffer from low positional selectivity of prompted us to develop a simple, general and efficient
electron-donating or -withdrawing groups and/or from route that could offer flexibility of substituent variations
orienting effects of the substituents when applied to the on benzene scaffold.
synthesis of highly hindered aromatic systems. Substan-
Herein we report an efficient and convenient procedure
tial improvements and developments in metal-catalyzed
for the synthesis of highly functionalized benzene deriva-
cross-coupling reactions have been made in recent years,
tives through the reaction of methyl 2-cyano-3,3-dimeth-
which furnish congested benzene derivatives in a regiose-
ylsulfanylacrylate with substituted acetones followed by
base-catalyzed ring transformation of 2H-pyran-2-ones
using malononitrile as a source of carbanion. The advan-
tage of the procedure lies in the creation of functionalized
lective manner.6 Other general regioselective methods for
the synthesis of functionalized benzenes include directed
ortho-metalation reactions,7 Ir-catalyzed selective boryla-
tion of arenes and heteroarenes at the positions ortho with
benzenes generated through lactonization at room tem-
respect to cyano groups,8 Suzuki–Miyaura couplings of
perature without using an organometallic reagent or a
hindered substrates using Buchwald’s catalyst9 or in the
catalyst.
presence of a bioxazoline-derived nitrogen–heterocyclic
The chemistry of 2H-pyran-2-one derivatives is very
interesting, which find diverse synthetic applications as a
diene component in Diels–Alder reactions. During our
recent studies on 2H-pyran-2-ones, we developed new
protocols for the synthesis of pyridines,23 pyridones,24
dibenzofurans,25 and biaryls26 through nucleophile-in-
duced ring transformation reactions. The topology of 2H-
pyran-2-one ring system in 3a–e is characterized by the
presence of three electrophilic centers; C-2, C-4 and C-6
in which C-6 position is highly prone to nucleophiles due
to the extended conjugation and the presence of the
carbene ligand.10
Numerous alternative synthetic protocols that build up
aromatic moiety from acyclic precursors11 have received
a great deal of attention for the preparation of highly
functionalized benzene derivatives. The construction of
benzene skeleton from acylic precursors include benz-
annulation reactions such as [3+2+1]-Dötz reaction of
SYNLETT 2007, No. 13, pp 2086–2090
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8
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Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984885; Art ID: G14207ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionally Crowded Benzenes through Ring Transformation of 2H-Pyran-2-ones
2087
electron-withdrawing substituent at position 3 of the thereafter poured into ice-water and neutralized with
pyranone ring. Our synthetic approach to preparing highly dilute HCl. The crude product thus obtained was purified
substituted benzenes 5a–e is based on ring transformation on neutral alumina column using chloroform–hexane
of 2H-pyran-2-ones 3a–e by using malononitrile as a (1:9) as eluent and characterized by spectroscopic
carbanion source. The 2H-pyran-2-ones 3a–e used as a analyses.28
parent precursor were prepared by the reaction of methyl
A plausible reaction mechanism for the formation of
2-cyano-3,3-dimethylsulfanylacrylate27 (1) with substi-
highly functionalized benzenes 5a–e is based on Michael–
tuted acetones 2a–e under alkaline conditions in high
Ziegler–Thorpe–retro-Diels–Alder-type reaction of 1
yields (Table 1). The highly functionalized benzene de-
with active methylene compound under mild reaction
conditions as depicted in Table 1. The reaction is initiated
by the Michael addition of an anion, generated from a
molecule of substituted acetones 2, to the ketene-S,S-ace-
rivatives 5a–e were synthesized by stirring an equimolar
mixture of 2H-pyran-2-ones 3a–e, malononitrile and
powdered KOH in DMF for 8–12 hours at room tempera-
ture (Table 1). The reaction was monitored by TLC and
tal 1 followed by intra-molecular cyclization to form a
Table 1 Synthesis of Highly Functionalized Benzene Derivatives 5a–e
SMe
R2
R1
CN
O
O
NC
COOMe
SMe
KOH
CH2(CN)2
R2
+
+
R1
DMSO
4
O
MeS
2
3
1
DMF KOH
O
O
SMe
CN
O
MeS
R2
R2
R1
CN
MeS
O
– CO2
CN
C
–
NH
N
NH2
R2
H
R1
R1
CN
CN
CN
5
Entry
2
3
5
Yield (%)
3
5
SMe
SMe
O
CN
O
CN
a
28
36
35
52
89
NH2
O
CN
SMe
SMe
CN
O
CN
O
b
c
87
90
89
NH2
O
CN
SMe
SMe
CN
O
CN
O
NH2
O
CN
SMe
SMe
O
CN
CN
O
d
NH2
O
CN
SMe
SMe
CN
O
CN
O
e
48
91
O
NH2
CN
Synlett 2007, No. 13, 2086–2090 © Thieme Stuttgart · New York

2088
F. Veer Singh et al.
LETTER
2H-pyran-2-one intermediate 3. The 2H-pyran-2-one ferent secondary amines. The compound 6-isopropyl-2H-
intermediate is attacked by a malononitrile anion at C-6 pyran-2-one 6 was prepared in high yield by refluxing a
position followed by Thorpe cyclization involving one of solution of lactone 3d with an equivalent of secondary
the nitrile functionalities of malononitrile and C-3 of the amine in methanol for 6–8 hours (Table 2).
pyranone ring to form a bicyclic intermediate and further
by decarboxylation to furnish thefunctionalized benzenes
2-Amino-4-isopropyl-6-sec-amino-isophthalonitriles 7a–c,
were synthesized in excellent yields by stirring a mixture
5a–e in high yields. The reaction was further exploited for
of 2H-pyran-2-ones 6a–c with malononitrile (4) in the
the synthesis of 2-amino-4-isopropyl-6-sec-amino-iso-
presence of a base. All the compounds were characterized
phthalonitriles 7a–c, which are also very difficult to pre-
pare by classical approaches. To obtain the compounds
by spectroscopic analyses.28,29
7a–c, the methylsulfanyl group of 3d was replaced by dif-
Table 2 Preparation of Compounds 6 and 7 from Lactone 3d
N
O
SMe
CN
O
CN
O
N
H
CN
C
N
O
KOH
DMF
CH2(CN)2
–
+
MeOH
O
O
4
N
6
3d
CN
O
N
CN
CN
–
+
N
N
O
– CO2
NH
CN
NH
H
NH2
H
CN
CN
CN
7
Entry
6
7
Yield (%)
N
H
6
7
O
N
O
O
N
O
a
74
72
86
CN
CN
O
N
H
NH2
CN
N
N
O
b
92
CN
CN
O
N
H
NH2
CN
N
N
N
N
N
c
78
89
CN
CN
O
N
H
NH2
O
CN
Synlett 2007, No. 13, 2086–2090 © Thieme Stuttgart · New York

LETTER
Functionally Crowded Benzenes through Ring Transformation of 2H-Pyran-2-ones
2089
(13) (a) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.;
In summary, we have developed a new methodology for
the synthesis of highly functionalized benzenes through
carbanion-induced ring transformation of functionalized
2H-pyran-2-ones in excellent yields. This is an important
methodology that offers the flexibility of introducing the
electron-donor or electron-acceptor groups in the molecu-
lar architecture of benzene scaffolds. Our approach is
highly simple, economical and does not require any
specialized reagents or catalysts.
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Acknowledgment
This work was supported by the Department of Science and
Technology (DST), New Delhi. F.V.S. thanks CSIR, New Delhi,
for a senior research fellowship. V.K. thanks UGC, New Delhi, for
a junior research fellowship. The authors are thankful to SAIF,
CDRI, Lucknow for providing spectroscopic analysis.
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(28) General Procedure for the Synthesis of 5 and 7: A mixture
of 5-alkyl-/5,6-dialkyl-3-cyano-4-methylsulfanyl-2H-
pyran-2-ones 3 or 6-isopropyl-4-sec-amino-2H-pyran-2-
ones 6 (1 mmol), malononitrile (1.2 mmol) and powdered
KOH (1.2 mmol) in anhyd DMF (5 mL) was stirred at r.t. for
8–12 h. After completion of the reaction, 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 neutral alumina column using
CHCl3–hexane (1:9) as eluent. 5a: yield: 89%; white solid;
mp 236–238 °C. 1H NMR (200 MHz, CDCl3): d = 2.48 (s, 3
H, Me), 2.54 (s, 3 H, SMe), 5.10 (br s, 2 H, NH2), 6.42 (s, 1
H, ArH). 13C NMR (50.0 MHz, CDCl3 + DMSO): d = 19.95,
26.68, 96.73, 98.40, 118.95, 119.83, 120.87, 152.67, 155.72,
158.00. IR (KBr): 2213 (CN), 3353, 3442 (NH2) cm–1. MS
(FAB): m/z = 204 [M+ + 1]. HRMS: m/z calcd for C10H9N3S:
203.0532; found: 203.0517. 7a: yield: 86%; white solid; mp
190–192 °C. 1H NMR (200 MHz, CDCl3): d = 1.27 (d, J =
6.8 Hz, 6 H, 2 × Me), 3.15–3.37 (m, 5 H, CH, 2 × CH2),
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F. Veer Singh et al.
LETTER
3.83–3.91 (m, 4 H, 2 × CH2), 5.10 (br s, 2 H, NH2), 6.17 (s,
1 H, ArH). 13C NMR (75.5 MHz, CDCl3): d = 21.38, 32.24,
49.76, 65.40, 85.02, 87.90, 102.70, 114.73, 115.00, 152.77,
157.62, 157.92. IR (KBr): 2210 (CN), 3353 (NH), 3412
(NH) cm–1. MS (ESI): m/z = 271 [M+ + 1]. HRMS: m/z calcd
for C15H18N4O: 270.1481; found: 270.1483.
the reaction mixture was washed with ice-cooled H2O. The
crude was purified on a silica gel column using CHCl3 as
eluent. 6a: yield 74%; white solid; mp 162–164 °C. 1H NMR
(200 MHz, CDCl3): d = 1.23 (d, J = 6.8 Hz, 6 H, 2 × Me),
2.00–2.10 (m, 4 H, 2 × CH2), 2.62–2.73 (m, 1 H, CH), 3.54–
3.62 (m, 2 H, CH2), 4.02–4.10 (m, 2 H, CH2), 5.71 (s, 1 H,
CH). 13C NMR (75.5 MHz, CDCl3): d = 20.36, 34.00, 49.89,
66.99, 73.24, 94.52, 117.63, 161.92, 163.11, 172.59. IR
(KBr): 1704 (CO), 2207 (CN) cm–1. MS (ESI): m/z = 249
[M+ + 1].
(29) General Procedure for the Synthesis of 6: A mixture of
compound 3d (1.0 mmol) and secondary amine (1.2 mmol)
was refluxed in MeOH (20 mL) for 6–8 h. After completion
of the reaction, MeOH was evaporated under vacuum, and
Synlett 2007, No. 13, 2086–2090 © Thieme Stuttgart · New York

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