Zinc-mediated reductive cyclodimerization of α,β-unsaturated aryl ketones under aqueous conditions

Article abstract of DOI:10.1071/CH07120

Zinc-mediated reductive cyclodimerization of ?,?-unsaturated aryl ketones produces 3,4-trans-diarylcyclopentanols 2 regio- and stereoselectively in good yields in a 1:4 (v/v) mixture of saturated aqueous NH₄Cl and tetrahydrofuran at room temper

Full text of DOI:10.1071/CH07120

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 621–623
Zinc-Mediated Reductive Cyclodimerization of
α,β-Unsaturated Aryl Ketones Under Aqueous Conditions
Anil Kumar,A Satish Kumar,A and Kamal K. KapoorA,B
ADepartment of Chemistry, University of Jammu, Jammu-180006, India.
BCorresponding author. Email: k2kapoor@yahoo.com
Zinc-mediated reductive cyclodimerization of α,β-unsaturated aryl ketones produces 3,4-trans-diarylcyclopentanols 2
regio- and stereoselectively in good yields in a 1/4 (v/v) mixture of saturated aqueous NH4Cl and tetrahydrofuran at room
temperature.
Manuscript received: 24 April 2007.
Final version: 15 June 2007.
Introduction
stabilize the radical anion as suggested in the proposed mech-
anism (Scheme 2), since the reaction did not occur in cases of
methylvinylketone (entry 9) and benzylideneacetone (entry 10).
In another set of experiments, it was noticed that the
reaction did not occur with the use of either zinc powder
or aqueous NH4Cl in THF, and the starting chalcone was
recovered intact, which suggests the application of the com-
bination of both reagents for the success of the reaction. In
order to determine the effect of electron-withdrawing sub-
stituents on the reaction, 3-nitrobenzylideneacetophenone was
subjected to the optimized reaction conditions. It was found that
3-nitrobenzylideneacetophenone was insoluble in THF/H2O
(4/1). Continuation of the reaction in this solvent mixture for
12 h returned the starting material intact (as determined byTLC).
A bid to replace THF with N,N-dimethylformamide (DMF), and
to keep the other parameters the same, did render the starting
material soluble but it generated an unidentifiable mixture of
products along with the starting material after 5 h of reaction.
The relative stereochemistry of the products was assigned by
NOE and a two-dimensional NMR [1H–1H COSY] study. In
the NOESY experiment of compound 2a, a strong NOE effect
between H2 and H4, and between H3 and the hydrogen atom of
the OH group, was observed. As shown in Fig. 1, the experiment
evidences the cis-positions of C5-Hb with C4-H, and C5-Ha with
the hydrogen atom of the OH group. These observations clearly
indicate that the relative stereochemistry in compound 2a is 1,2-
cis, 2,3-trans, and 3,4-trans. The stereochemistry of compound
2a is in agreement with that reported by Takaki et al.[7] using
Yb–HMPA–THF and Zhou et al.[5] using SmI2.
Carbon–carbon bond formation is the essence of organic syn-
thesis, and the reductive dimerization of carbonyl compounds is
a valuable tool for establishing the carbon–carbon bond. In the
past decade, metal-mediated organic reactions in aqueous media
have attracted considerable interest.[1] The reactions in aqueous
media offer several advantages over conventional organometal-
lic reactions in organic solvents in view of practical convenience
and avoidance of the use of anhydrous solvents. Our labora-
tory has recently reported[2] that zinc powder in the presence
of a catalytic amount of mercury(ii) chloride can be used to
initiate the reaction by single electron transfer (SET)[3] from
the zinc surface and effect the reductive cyclodimerization of
α,β-unsaturated ketones.A similar type of reductive cyclodimer-
izationofα,β-unsaturatedketoneshasalsobeencarriedoutusing
SmI2,[4,5] Zn–TiCl4,[6] Yb,[7] tributyltin hydride,[8] and NdCl3–
lithium naphthalide.[9] In our ongoing endeavour to develop
eco-friendly protocols,[10] we contemplated replacing the toxic
mercury(ii) chloride with a mild and non-toxic agent, such as
aqueous NH4Cl. Zinc metal in the presence of aqueous NH4Cl
has previously been reported to catalyze the cyclodimerization
of only 1,1-dicyano alkenes.[11]
Results and Discussion
When benzylideneacetophenone was treated with two
equivalents of zinc in saturated aqueous NH4Cl solution and
tetrahydrofuran (THF) in a 1:4 ratio, formation of 1,3,4-
triphenyl-2-benzoylcyclopentanol 2a (Table 1, entry 1), akin to
our earlier observation[2] with Zn/HgCl2, was observed in 4 h
(Scheme 1). As coupling components, α,β-unsaturated ketones
are reactive enough to undergo reductive dimerization cycliza-
tion in the presence of zinc in aqueous media because of
activation of the carbon–carbon double bond by the attached keto
group. However, in the present reaction, another minor dihydro
product 3a was also obtained. The reaction was extended to a
variety of other substrates and the results are shown in Table 1.
It is evident from Table 1 that the success of the reaction
demands the presence of aryl moieties at both ends of the
α,β-unsaturated ketonic functionality. This is probably to
A possible reaction mechanism involves a radical anion inter-
mediate I, generated by SET from the zinc surface, followed by
coupling and cyclization as shown in Scheme 2.
Out of the possible transition states A and B for cycliza-
tion, the transition state A, which leads to the formation of
3,4-trans 2 is favourable over its counterpart B because of steric
implications. This is corroborated by the fact that the 3,4-trans
compound 2 is the main product, while the 3,4-cis 2 is never
obtained by this method.
In conclusion, the present methodology has advantages
over those previously reported[2,4–9] in view of environmental
© CSIRO 2007
10.1071/CH07120
0004-9425/07/080621

622
A. Kumar, S. Kumar, and K. K. Kapoor
Table 1. Zinc-mediated reductive dimerization cyclization of α,β-unsaturated aryl ketones
Entry
Ar1
Ar2
Major
product
Time
[h]
Yield
[%]
Mp [◦C] (lit.[5]
)
2:3
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
C6H5
C6H5
4-MeC6H4
C6H5
Me
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
4
4
80
78
71
72
78
70
63
67
—
—
68
195 (192–194)
193 (192–194)
195 (191–193)
172–174 (172–174)
185–186 (186–188)
171–173 (172–173)
182–184 (186–188)
192–194
—
—
90:10
92:8
4-Cl-C6H4
2-Cl-C6H4
C6H5
4-Me-C6H4
3,4-OCH2O-C6H3
3,4-OCH2O-C6H3
4-OMe-C6H4
H
4.5
4.5
5.0
6.0
5.5
6.0
10.0
12.0
5.0
80:20
88:12
85:15
87:13
90:10
85:15
—
9
10
11
C6H5
C6H5
2j
2k
—
90:10
C6H5CH=CH
205
Ar2
O
Ar1
O
O
Zn/Aq. NH4Cl
THF, r.t.
OH
2
3
1
ꢀ
Ar1
Ar2
Ar1
Ar2
4
5
Ar2
Ha
Ar1
Hb
1
2
3
(Major product)
(Minor product)
Scheme 1. Zinc-mediated reductive cyclodimerization reaction of α,β-unsaturated aryl ketones.
Hꢀ
Ar1
Ar1
O
C
O
C
Ar2
Ar2
HC
C
CH
CH
Zn
SET
Znꢀ
I
1
Proton
abstraction
Coupling
Ar1
Ar2
O
O
Cyclization
pathway A
Ar1
Ar1
Zn
2
or
O
Ar2
Pathway B
Ar2
Ar2
3
II
O
Ar1
Ar2
Ar1
Ar1
H
H
Zn
O
Protonation
Zn
O
3,4-trans 2
O
Ar2
Ar1
Ar2
A
Ar2
O
Ar2
O
H
Ar1
Ar1
Ar1
Zn Protonation
O
3,4-cis 2
Zn
O
Ar2
Ar1
Ar2
H
B
3,4-trans 2 ꢁꢁ 3,4-cis 2
Scheme 2. Proposed mechanism for the cyclodimerization reaction.

Cyclodimerization of Aryl Ketones
623
H5b), 2.95 (1H, dd, J 14.4, 11.4, H5a), 3.64 (3H, s, OMe), 3.65
(1H, m, H4), 3.74 (3H, s, OMe), 4.01 (1H, dd, J 10.5, 11.0, H3),
4.47 (1H, d, J 12.0, H2), 5.15 (1H, s, OH), 6.62 (2H, d, Ph),
6.78 (2H, d, Ph), 7.60–7.00 (14H, m, Ph). δC (CDCl3, 100 MHz)
205.1 (C=O), 158.4, 158.1, 145.5, 137.7, 136.1, 133.4, 132.0,
128.8, 128.5, 128.2, 128.1, 126.9, 124.8, 113.9, 113.7, 84.0 (C1),
63.7 (C2), 58.8 (C3), 55.1 (OMe), 55.1 (s, OMe), 51.4 (C5), 50.7
(C4). m/z 478.2132 (M+). Calc. for C32H30O4: 4718.2144.
Ph
H
H
O
Ph
3
2
OH
Ph
1
Ph
4
5
H
Ha
Hb
1,2-cis-2,3-trans-3,4-trans-2-Cinnamoyl-1-styryl-3,4-
diphenylcyclopentanol 2k
White needles, mp 205◦C. νmax (KBr)/cm−1 3440, 1668
(CO), 1631, 1600. δH (CDCl3, 400 MHz) 2.6 (1H, dd, J 14.4,
5.6, H5b), 2.8 (1H, dd, J 14.4, 11.0, H5a), 3.58 (1H, ddd, J
9.9, 5.6, 11.0, H4), 3.65 (1H, d, J 11.9, H2), 3.88 (1H, dd, J
9.9, 11.9, H3), 5.06 (1H, s, OH), 6.24 (1H, d, J 16.0, Hvinyl),
6.40 (1H, d, J 15.8, Hvinyl), 6.81 (1H, d, J 15.8, Hvinyl), 7.40–
7.10 (21H, m, Ph, Hvinyl). δC (CDCl3, 100 MHz) 203.1 (C=O),
144.1, 143.9, 140.5, 136.6, 134.0, 133.7, 130.7, 128.8, 127.7,
127.4, 127.0, 126.6, 126.7, 126.5, 126.3, 82.8, 65.2, 59.1, 51.6,
48.3. m/z 470.2259 (M+). Calc. for C34H30O2: 470.2246.
Fig. 1. Observed NOE interactions for 2a.
consciousness, selectivity, mildness, easy handling, and good
yields.
Experimental
General Procedure for the Synthesis of Functionalized
Cyclopentanols
Benzylidene acetophenone 1a (10 mmol) and zinc powder
(22 mmol) were added to a mixture of saturated aqueous NH4Cl
and THF (1:4, 12.5 mL) and stirred at room temperature for
4 h followed by the addition of EtOAc (50 mL). The resultant
mixture was filtered through a Celite pad, washed with cold
water (3 × 15 mL), brine (1 × 20 mL), and dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure on
a rotary evaporator. The residue was charged on a silica column
and eluted with petroleum spirits and ethyl acetate (ratio 19:1)
to yield 2a (80%) as a solid white residue, and 3a (9%).
Acknowledgment
One of the authors (SK) thanks CSIR, New Delhi, for financial assistance
in the form of an SRF.
References
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Spectroscopic Data for Selected Compounds
These compounds are all racemic and the name corresponds to
the relative stereochemistry.
1,2-cis-2,3-trans-3,4-trans-2-Benzoyl-1,3,4-
triphenylcyclopentanol 2a
White solid, mp 195◦C. νmax (KBr)/cm−1 3440 (OH), 1640
(C=O). δH (CDCl3, 400 MHz) 2.58 (1H, dd, J 14.4, 6.1, H5b),
3.00 (1H, dd, J 14.4, 10.7, H5a), 3.77 (1H, ddd, J 10.7, 10.2, 6.1,
H4), 4.10 (1H, dd, J 11.7, 10.2, H3), 4.55 (1H, d, J 11.7, H2),
5.25 (1H, s, OH), 7.10–7.65 (20H, m, aromatic H). δC (CDCl3,
100 MHz) 204.9, 1452, 143.9, 139.8, 137.5, 133.2, 128.4, 128.3,
128.29, 128.1, 128.0, 127.8, 127.5, 126.9, 126.8, 126.3, 124.8
(aromatic), 84.2 (C1), 76.3 (C2), 63.5 (C3), 59.5 (C4), 51.3 (C5).
m/z 418.1921 (M+). Calc. for C30H26O2: 418.1933.
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4, 593.
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Commun. 2006, 36, 2727. doi:10.1080/00397910600764766
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doi:10.1016/S0040-4039(00)01540-9
1,2-cis-2,3-trans-3,4-trans-2-Benzoyl-1-phenyl-3,4-
di(4-methoxyphenyl)cyclopentanol 2h
White solid, mp 192–194◦C. νmax (KBr)/cm−1 3440 (OH),
1652 (CO). δH (CDCl3, 400 MHz) 2.51 (1H, dd, J 14.4, 6.3,