Hydroxy-rhodium(I) catalyzed regioselective Michael addition of cyclic enones

Article abstract of DOI:10.1016/j.tetlet.2011.12.057

Hydroxy-rhodium catalyzed dimerization of various cyclic enones to the corresponding α-enone adducts is developed. The key feature of this method is that the base-sensitive, highly substituted enones also undergo dimerization and the resultant products ar

Full text of DOI:10.1016/j.tetlet.2011.12.057

Tetrahedron Letters 53 (2012) 1042–1044
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Tetrahedron Letters
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Hydroxy-rhodium(I) catalyzed regioselective Michael addition of cyclic enones
⇑
Gullapalli Kumaraswamy , Dasa Rambabu
Organic & Biomolecular Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydroxy-rhodium catalyzed dimerization of various cyclic enones to the corresponding a-enone adducts
Received 11 November 2011
Revised 13 December 2011
Accepted 14 December 2011
Available online 30 December 2011
is developed. The key feature of this method is that the base-sensitive, highly substituted enones also
undergo dimerization and the resultant products are obtained in moderate to good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Transition metal
Hydroxy-rhodium
Dimerization
Cyclohexenone
Cycloheptenone
Transition metal catalyzed carbon–carbon bond formation is a
powerful approach in organic synthesis.1 Varied families of transi-
tion metal complexes have been shown to catalyze a diverse array
of reactions involving carbon–carbon and carbon-heteroatom bond
formation. Among the variety of transition metal catalyzed reac-
tions, rhodium-catalyzed conjugate addition reactions proceed un-
der mild conditions with high regioselectivity as well as good
yields.2 This strategy provides a complement to the frequently
used technique that involves a base-catalyzed addition procedure
for enones. While examining the rhodium(I)-catalyzed3 stereose-
lective 1,4-addition of an arylboronic acid to a cyclic enone 1a in
the presence of 5 mol % of Rh(cod)2BF4 in dioxane/water heating
at 100 °C for 2 h., surprisingly, after work-up, together with the ex-
pected product 3-phenyl hexanone, a substantial amount of adduct
2a was also isolated (30%).3 When the reaction was performed
without arylboronic acid under similar conditions, it also resulted
in 2a in a similar yield (30%). In another set of reactions, when
the KOH loading was increased to 40 mol %, the reaction proceeded
smoothly to yield the required product in a 90% yield (Scheme 1).
When the molar ratio of the Rh catalyst was reduced to 2 mol %
and with similar KOH loading (40 mol %), the reaction proceeded
smoothly without compromising the yield (90%).4 The same reac-
tion in the absence of the catalyst under otherwise similar condi-
tions did not yield the desired compound 2a. Other important
methods for the synthesis of enone adduct 2a that were reported
in the literature include employing inorganic bases,5 organic
bases,6 and a phase transfer catalytic method.7
O
O
O
2 mol% Rh(cod)2 BF4
40 mol% KOH
1,4-dioxane : H2O (9:1)
°
90 C, 2h
1a
2a, 90% yield
Scheme 1. Hydroxy-rhodium catalyzed regioselective dimerization of cyclohexe-
none.
Among the solvents surveyed, dioxane/water turned out to be
the solvent of choice (Table 1). Aqueous 1,2-dichloroethane and
toluene did not yield the desired product 2a. Interestingly, experi-
ments were conducted with other metal salts (RuCl3, CuCl2, CuCl,
CuBr, CuI and FeCl2, and PdCl2) as the catalyst in combination with
KOH for this transformation, but none could catalyze the desired
reaction, whereas RhCl3ꢀH2O/KOH initiated the reaction and the
corresponding product 2a was obtained albeit in low yield (50%).
The pre-catalyst system generated with 2 mol % of Rh(cod)2BF4/
LiOH also showed comparable activity toward the synthesis of 2a.
To check the generality of this protocol, the experiment was ex-
tended to various enone substrates under optimized conditions,
and the results are summarized in Table 1.
Five-substituted cyclohexenone 1b and 1c smoothly underwent
dimerization and gave the desired products 2b and 2c with 85%
and 70% yields (Table 1, entries 1 & 2), respectively. Similarly, 5-
(4-methylphenyl) cyclohexenone 1d and 5-(4-methoxyphenyl)
cyclohexenone 1e were subjected to standard protocol and the
respective products 2b, 2c were furnished in good yield (Table 1,
⇑
Corresponding author. Tel.: + 91 40 27193154; fax: + 91 40 27193275.
E-mail address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.057

G. Kumaraswamy, D. Rambabu / Tetrahedron Letters 53 (2012) 1042–1044
1043
Table 1
Hydroxy-rhodium catalyzed dimerization of various cyclic enones to the corresponding
a-enone adducts
Entry
Substrate
Producta,b
Time/h
2
% Yield
85
O
O
O
1
2b
1b
O
O
O
O
2
3
3
3
70
Ph
Ph
Ph
1c
2c
O
O
85d
Php-Me
p-MePh
p-MePh
1d
2d
O
O
O
88d
65d
68d
Ph(Meo-p)
4
5
6
2
3
3
(p-Meo)Ph
(p-Meo)Ph
1e
2e
O
O
O
O
O
2f
O
1f
O
CO2Et
Ph
O
O
EtO2C
Ph
EtO2C
Ph
1g
2g
O
O
O
7
2
73
1h
2h
O
8
9
1i
O
NRc
NRc
1j
a
b
c
All reactions were carried out in 1 mmol scale with 2 mol % of Rh(cod)2BF4, in dioxane/H2O (9:1).
Yields refer to isolated after column chromatography.
NR = No reaction.
d
Diastereoselectivity was not determined.
entries 3 & 4). Heteroaromatic five-substituted cyclohexenone 1f
as well resulted in Baylis–Hillman adduct 2f in moderate yield (Ta-
ble 1, entry 5). Ester containing 5,6-disubstituted cyclohexenone
1g tolerated the reaction conditions and the desired product 2g
was afforded in a 68% yield (Table 1, entry 6). However, we did
5 mol % of Rh(cod)2BF4 and 10 mol % of L1 in dioxane/water heating
90 °C for 1 h resulted in 2a as racemic in an 83% yield. Replacing L1
and Rh(cod)2BF4 with Cat-1 under otherwise identical conditions
that lead to the desired product 2a with 15% ee and a 75% yield.
Slight increase in the ee value of 2a (25% ee)8 was observed, while
employing 10 mol % of L29 along with 5 mol % of Rh(cod)2BF4 under
typical conditions (Scheme 2).
not succeed in obtaining dimerized
a-enone adducts of cyclo-
pentenone 1i and 4,4-dimethyl cyclohexenone 1j under the opti-
mized conditions (Table 1, entries 8 & 9). In the case of 1i, the
substrate appears to undergo polymerization under the reaction
conditions. In the case of 1j, presumably, the proton abstraction
of Rh-enolate of dimeric intermediate (C, Scheme 3) could not be
achieved due to restricted conformation thereby making the cata-
lytic cycle unfeasible.
Having identified the suitable conditions, we have focused our
efforts on obtaining asymmetric induction in the above reaction
by means of chiral diphosphines L1, Cat-1 and chiral diene L2 as
chiral inducers. To this end, cyclic enone 1a in the presence of
A plausible mechanism to rationalize the observed transforma-
tion is shown in Scheme 3.
Initially, the cationic Rh(I) in the presence of KOH generates Rh-
OH A which could insert enone double bond 1a resulting in vinyl-
ogous Rh-enolate B. The Rh-enolate B on electrophilic attack on a
second molecule of enone could generate C, followed by the
abstraction of proton giving rise to D which upon b-hydroxyeli-
mination leads to the Baylis–Hillman adduct 2a.
In conclusion, we have developed a practical procedure for the
synthesis of cyclic
a-enone adducts. This efficient protocol is

1044
G. Kumaraswamy, D. Rambabu / Tetrahedron Letters 53 (2012) 1042–1044
O
O
O
5 mol% Rh (cod)2 BF4
10 mol% of L2
*
1,4-dioxane: H2O (9:1)
90 °C, 2h
2a
1a
85% yield, 25% ee
OMe
Ar
P
P
Ar
Ar
P
P
Ar
Ar
Ar
Ar
Rh
Ar
H
O
P
P
Ar
Rh
Ar
Ar
Ar
O
H
L2
Cat-1
L
1 = Ar = 4-tolyl
Scheme 2. Asymmetric hydroxy-rhodium catalyzed regioselective dimerization of cyclohexenone.
from the CSIR (New Delhi) is gratefully acknowledged. Thanks
are also due to Dr. G.V.M. Sharma for his support.
Rh(cod)2 BF4
KOH
O
O
Supplementary data
O
Supplementary data associated (analytical data and copies of
spectra’s of 2a–h) with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.12.057.
[Rh-OH]
2a
A
1a
O[Rh]
O
O
References and notes
O[Rh]
O
Rh
1. (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reaction, 2nd
ed.; Wiley-VCH: Weinheim, Germany, 2004; (b Beller, M.; Bolm, C. Transition
Metals for Organic Synthesis: Building Blocks and Fine Chemicals; Wiley-VCH:
New York, 1998.
2. (a) Yoshida, K.; Hayashi, T. Rh-Catalyzed Conjugated Additions. In Modern Rh-
catalyzed Organic reaction; Wiley-VCH: Weinheim, 2005; pp 55–77; (b) Krause,
A.; Hoffmann-Roder Synthesis 2001, 171–196; (c) Hayashi, T.; Yamasaki, K.
Chem. Rev. 2003, 103, 2829–2844; (d) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033–8061; (e) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169–196.
3. Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.; Sridhar, B.; Jagadeesh, B.;
Sridhar, B. J. Org. Chem. 2009, 74, 8468–8471.
OH
OH
OH
B
D
D'
[Rh]
O
O
H
4. Typical reaction procedure for the synthesis of 2a: Two-necked flask (10 mL)
OH
equipped with
a septum, magnetic stir bar, condenser, and a three-way
C
stopcock connected to nitrogen-balloon system and subjected to evacuated
protocol was charged with Rh(I)(cod)2BF4 (9 mg, 0.02 mmol). To this, 2 ml of
1,4-dioxane and water (9:1) was added followed by cyclohexenone (1 mmol).
The resulting reaction mixture was stirred for 5 min and KOH solution (2 M,
Scheme 3. A plausible mechanism of regioselective dimerization of cyclohexenone.
20 lL, 0.41 mmol) is added. The combined contents were heated to 90 °C for
2 h. Thereafter, the reaction was cooled to ambient temperature and filtered
through a plug of Celite and washed with EtOAc (3 ꢁ 5 mL). The filtrate was
concentrated under reduced pressure to give crude residue which was purified
by silica gel column chromatography eluting with hexane/EtOAc (9:1)
furnished 2a 174 mg (90%) as dense liquid.
initiated with 2 mol % of Rh(I) catalyst and it also facilitates rapid
synthesis of various dimerized enone adducts possessing pharma-
cophores which could be screened for biological activity.10 Pres-
ently, this methodology, presently restricted to the dimerization
of six and seven-membered cyclic enones, to the best of our knowl-
edge, there is no report wherein, the Rh-OH pre-catalyst perform-
5. (a) Leonard, N. J.; Musliner, W. J. J. Org. Chem. 1966, 31, 639–642; (b) Reingold, I.
D.; Butterfield, A. M.; Daglen, B. C.; Walters, R. S., Jr.; Allen, K.; Scheuring, S.;
Kratz, K.; Gembicky, M.; Baran, P. Tetrahedron Lett. 2005, 46, 3835–3837; (c)
Yanagisawa, A.; Shinohara, A.; Takashi, H.; Arai, T. Synlett 2007, 141–145.
6. (a) Jenner, G. Tetrahedron Lett. 2000, 41, 3091–3094; (b) Hwu, J. R.; Hakimelani,
G. H.; Chou, C.-T. Tetrahedron Lett. 1992, 33, 6469–6472; (c) Ramachary, D. B.;
Rumpamondal Tetrahedron Lett. 2006, 47, 7689–7693.
ing the carbon–carbon bond formation a- to enone. Further work is
under progress for efficient enantioselective catalytic version.
7. Ceccarelli, R.; Insogna, S.; Bella, M. Org. Biomol. Chem. 2006, 4, 4281–4284.
8. The enantioselectivity of 2a (½a D25
ꢃ2.0, c = 1, CH2Cl2) was determined by
ꢂ
Acknowledgments
optical rotation and comparison of value from literature.7
9. Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem., Int.
Ed. 2008, 47, 7669–7672.
We are grateful to Dr. J.S. Yadav, Director, IICT, for his constant
encouragement. Financial support was provided by the DST, New
Delhi, India (Grant No: SR/S1/OC-08/2011) and fellowship to D.R.
10. The racemic enone adduct 2a exhibited synergic herbicidal effect along with
atrazine; Kaufman, H. A.; Napier, R. P. German Patent DE 2016666, 1970, 1105.