Pd-mediated synthesis of substituted benzenes fused with carbocycle/heterocycle

Article abstract of DOI:10.1039/b612770c

A new Pd-catalyzed one-pot multicomponent coupling reaction for the construction of benzene ring fused with carbocycle or heterocycle under a Cu-free condition is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b612770c

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Pd-mediated synthesis of substituted benzenes fused with carbocycle/
heterocycle{{
Nalivela Kumara Swamy, Lakshmi Kumar Tatini, J. Moses Babu, Pazhanimuthu Annamalai and
Manojit Pal*
Received (in Cambridge, UK) 4th September 2006, Accepted 7th December 2006
First published as an Advance Article on the web 9th January 2007
DOI: 10.1039/b612770c
A new Pd-catalyzed one-pot multicomponent coupling reaction
for the construction of benzene ring fused with carbocycle or
heterocycle under a Cu-free condition is described.
Polyfunctionalized benzenes fused with a carbocycle or heterocycle
Fig. 2 Synthesis of enynone derivatives.
play an important role in organic chemistry, not only as key
synthons in many bioactive compounds and drugs,1 but also as
useful intermediates widely used in industry as well as the
laboratory. For this reason, there is a continued interest in the
development of new multicomponent coupling reactions that allow
assembly of multiply substituted benzene in a highly regioselective
manner. Among the many different approaches to polysubstituted
benzenes, the transition-metal mediated multicomponent coupling
e.g. [2 + 2 + 2]-cyclotrimerization of alkynes2 or [4 + 2]-
cyclodimerization of conjugated enynes3 is particularly attractive.
Scheme 1 Pd-catalyzed reactions of 2-iodo-2-cyclohexenone (1a) with
terminal alkynes.
Recently, regioselective construction of benzene ring using a
reaction between 2-iodo-2-cyclohexenone (1a) with 2-methyl-3-
Sonogashira coupling–[4 + 2]-benzannulation strategy has been
reported.4 We envisioned that compounds containing the 2-alkynyl
butyn-2-ol (2a) under a similar Cu-free condition (Scheme 1).
Very interestingly, the reaction gave an aromatic compound 3a
enone moiety (A, Fig. 1) in the presence of a terminal alkyne might
but not the Sonogashira product6 4a. Compound 3a showed an
also undergo a transition metal-mediated [4 + 2]-benzannulation,
intense molecular ion peak at m/z 263.0 (M+, 100%) in the mass
affording a general method for the regioselective synthesis of
spectra and gave signals at d 8.09 and 7.91 in the 1H NMR spectra
due to the aromatic protons. Additionally, the signal at d 198.4
benzene fused with carbocyclic/heterocyclic structure, that has
rarely been reported.4a
in the 13C NMR (1662 cm21 in IR) spectra identified 3a as a
This unique intermolecular benzannulation process is particu-
1-tetralone derivative. This was supported by the molecular
larly attractive, because by choosing an appropriate enynone
structure of 3b (R = 1-hydroxy cyclohexyl) confirmed by X-ray
analysis (Fig. 3).7
partner a carbocycle or heterocycle of specific interest can be fused
with the benzene ring, which allows for considerable versatility,
since a variety of enynone derivatives can be generated from the
corresponding a-haloketones (Fig. 2).
Recently, we have reported that the palladium [(PPh3)2PdCl2]
catalyzed reaction of 3-halo (thio)flavones with terminal alkynes
affords the corresponding 3-enynyl (thio)flavones5a,b particularly
under a Cu-free condition.5c More recently, we examined the
Fig. 1 Synthesis of polysubstituted benzenes.
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road,
Miyapur, Hyderabad, 500049, India. E-mail: manojitpal@drreddys.com;
Fax: 91 40 2304 5438; Tel: 91 40 2304 5439
{ DRL publication number 613.
{ Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, crystallography and
in vitro testing. See DOI: 10.1039/b612770c
Fig. 3 X-Ray crystal structure of 3b (ORTEP diagram). Displacement
ellipsoids are drawn at 50% probability level for non-hydrogen atoms.
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Table 1 Pd-mediated synthesis of substituted benzenesa (Continued )
Entry Haloenone Alkyne Product Yield (%)
Table 1 Pd-mediated synthesis of substituted benzenesa
Entry Haloenone Alkyne
1
Product
Yield (%)
3a
75
12
1e
2c
3l
62
13
1e
2b
3m
78
2
1a
1a
3b
80
a
All reactions were carried out by using I (0.9 mmol), 2 (0.27 mmol),
PdCl2(PPh3)2 (0.036 mmol), Et3N (7.2 mmol) in DMF (for entries 1,
6, 8 and 11) or 1,4-dioxane at 80 uC for 3–5 h under nitrogen.
3
4
3c
3d
62
50
We then investigated the reaction between 1a and 2a under
various conditions to find the optimum condition for obtaining
this unprecedented reaction product in higher yields. Among the
catalysts we examined, (PPh3)2PdCl2 or PdCl2 in DMF gave best
results while the use of 10% Pd/C–PPh3 or Pd(OAc)2 or (PPh3)4Pd
also afforded 3a albeit in low yields. When the reaction was
performed in the absence of (PPh3)2PdCl2 no product was formed
indicating that the Pd-catalyst is needed for the reaction to
proceed. The best solvent for the reaction was DMF or 1,4-
dioxane and Et3N was the base of our choice. The preparation of
3a is representative: A mixture of 1a (0.9 mmol), (PPh3)2PdCl2
(0.036 mmol) and Et3N (7.2 mmol) in DMF (6 mL) was stirred at
25 uC for 5 min under N2 and 2a (0.27 mmol) was added slowly.
The mixture was stirred at 80 uC for 3 h, and after usual work up
the product was isolated by column chromatography (petroleum
ether–EtOAc) to afford 3a in 75% yield (Table 1, entry 1). We then
tested the optimized conditions with other terminal alkynes
(Table 1, entries 2 and 3). The reaction proceeded well to give
5,7-disubstituted 1-tetralones 3b and 3c. Isomeric products such as
6,7-disubstituted 1-tetralones or dimeric product,4b which may be
formed during the benzannulation process, were not detected.
However, the use of 2-iodocyclopent-2-one afforded 1-indanones
3d and 3c (Table 1, entries 4 and 5) along with unidentified side
products. The use of other appropriate halides afforded quinazo-
line-2,4-dione, xanthen-9-one and thioxanthen-9-one derivatives,
respectively (Table 1, entries 6–13). Notably, the reaction of
1-ethynyl-4-methylbenzene with 1a provided the corresponding
Sonogashira product i.e. 2-p-tolylethynylcyclohex-2-enone in 30%
yield along with other side products.8
2b
2a
5
1b
3e
52
6
7
2a
2b
3f
65
58
1c
3g
8
9
2a
2b
3h
3i
77
67
1d
1d
Mechanistically, the reaction seems to proceed via generating
2-alkynyl enones (A) in situ according to a Cu-free Sonogashira
pathway5a,c followed by regioselective [4 + 2]-benzannulation,3c,9
perhaps aided by the electron-withdrawing effect of the carbonyl
group, involving a second molecule of terminal alkyne (Fig. 1). To
prove the intermediacy of A, the reaction of 1d with 2a was carried
out for 1.5 h, which afforded a 1 : 1 mixture of 3h and
3-alkynylflavone (3hh). However, 3hh was consumed after another
1.5 h producing 3h as the sole product. Additionally, 3hh (prepared
via Sonogashira coupling of 1d with 2a) afforded 3h when reacted
separately with 2a under the same condition (Scheme 2).
10
11
2c
2a
3j
62
52
3k
In summery, a new catalytic approach to benzo derivatives of
carbo- and heterocycles has been developed through the sequential
1036 | Chem. Commun., 2007, 1035–1037
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N. Sadayori, U. Radhakrishnan and Y. Yamamoto, J. Am. Chem.
Soc., 1999, 121, 6391.
4 For a sequential one-pot procedure involving Sonogashira coupling and
homo-benzannulation for the synthesis of 6H-dibenzo[b,d]pyran-6-ones,
see: (a) T. Kawasaki and Y. Yamamoto, J. Org. Chem., 2002, 67, 5138;
(b) C. Xi, C. Chen, J. Lin and X. Hong, Org. Lett., 2005, 7, 347.
5 (a) M. Pal, R. Dakarapu, K. Parasuraman, V. Subramanian and
K. R. Yeleswarapu, J. Org. Chem., 2005, 70, 7179; (b) M. Pal,
K. Parasuraman, V. Subramanian, R. Dakarapu and K. R.
Yeleswarapu, Tetrahedron Lett., 2004, 45, 2305; (c) For our studies on
Cu-free Sonogashira coupling, see: M. Pal, K. Parasuraman, S. Gupta
and K. R. Yeleswarapu, Synlett, 2002, 1976.
6 For Sonogashira coupling of 2-halo-2-cyclohexenone with terminal
alkynes in the presence of Cu-salt, see: (a) T. Yao, X. Zhang and R. C.
Larock, J. Am. Chem. Soc., 2004, 126, 11164. See also:(b) M. W. Miller
and C. R. Johnson, J. Org. Chem., 1997, 62, 1582, and references cited
therein.
Scheme 2 Pd-catalyzed reactions of 1d with terminal alkyne 2a.
coupling–benzannulation of a-haloenone with terminal alkynes.
This one-pot Cu-free process was found to be general when alkyl
substituted alkynes were used affording an array of compounds of
potential biological significance,10 the preparation of which may be
tedious via other methods.
We thank Dr R. Rajagopalan, Prof. J. Iqbal, for their
encouragement and analytical group for spectral data.
7 Crystallographic data for 3b: single crystal from chloroform,
C23H30O3?CHCl3, M = 461.86, monoclinic, space group P21/c, a =
3
˚
˚
12.653(6), b = 16.148(7), c = 11.478(5) A, b = 93.125(6)u, V = 2341(1) A ,
Z = 4, Dc = 1.310 Mg m23, T = 298 K, m = 4.119 cm21, 26740
processed reflections, 5278 unique reflections, 2930 observed reflections,
Rint = 3.87%, and R = 0.090 for the 2930 ‘observed’ reflections and
wR2 = 0.167 for all 5278 unique reflections. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b612770c.
8 One of the side products isolated was identified as 2-(2,4-di-p-tolylbut-1-
en-3-ynyl)cyclohex-2-enone (see ESI{).
Notes and references
1 See, for example: (a) S. Gobbi, A. Rampa, A. Bisi, F. Belluti, P. Valenti,
A. Caputo, A. Zampiron and M. Carrara, J. Med. Chem., 2002, 45,
4931; (b) I. K. Kostakis, P. Magiatis, N. Pouli, P. Marakos, A.-L.
Skaltsounis, H. Pratsinis, S. Leonce and A. Pierre, J. Med. Chem., 2002,
45, 2599; (c) Q. Chao, L. Deng, H. Shih, L. M. Leoni, D. Genini,
D. A. Carson and H. B. Cottam, J. Med. Chem., 1999, 42, 3860; (d)
X. Wang, K. F. Bastow, C.-M. Sun, Y.-L. Lin, H.-J. Yu, M.-J. Don,
T.-S. Wu, S. Nakamura and K.-H. Lee, J. Med. Chem., 2004, 47, 5816.
2 For selected references, see: (a) V. Snieckus, Chem. Rev., 1990, 90, 879;
(b) M. Lautens, W. Klute and W. Tam, Chem. Rev., 1996, 96, 49; (c)
S. Saito and Y. Yamamoto, Chem. Rev., 2000, 100, 2901; (d)
Y. Yamamoto, J.-I. Ishii, H. Nishiyama and K. Itoh, J. Am. Chem.
Soc., 2004, 126, 3712.
9 The benzannulation may proceed via the interaction of A with the Pd(0)
species producing a p-complex intermediate B, which might act as a
nucleophilic diene and undergo (formal) Diels–Alder reaction.
Alternatively, this reaction may involve a metallacycle such as C as an
intermediate.
3 (a) S. Saito, Y. Chounan, T. Nogami, T. Fukushi, N. Tsuboya,
Y. Yamada, H. Kitahara and Y. Yamamoto, J. Org. Chem., 2000, 65,
5350; (b) V. Gevorgyan, N. Tsuboya and Y. Yamamoto, J. Org. Chem.,
2001, 66, 2743; (c) S. Saito, M. M. Salter, V. Gevorgyan, N. Tsuboya,
K. Tando and Y. Yamamoto, J. Am. Chem. Soc., 1996, 118, 3970, and
references therein; (d) V. Gevorgyan, A. Takeda, M. Homma,
.
10 Compounds 3i and 3m showed anticancer activity with an average GI50
of 14.6 and 7.1 mM, respectively, on a tested panel of cancer cell lines
[e.g. HT29 (colon), H460 (lung), LoVo (colon)] (see ESI{).
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Chem. Commun., 2007, 1035–1037 | 1037