Samarium-induced alkyl halide mediated reductive coupling of ketones

Article abstract of DOI:10.1016/S0040-4039(00)00510-4

Reductive coupling of aromatic ketones was achieved by samarium metal in the presence of alkyl halides. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00510-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3793–3796
Samarium-induced alkyl halide mediated reductive coupling
of ketones
Anjan Ghatak, Frederick F. Becker and Bimal K. Banik ∗
The University of Texas, M. D. Anderson Cancer Center, Department of Molecular Pathology, Box 089, 1515 Holcombe Blvd,
Houston, Texas 77030, USA
Received 1 January 2000; accepted 16 March 2000
Abstract
Reductive coupling of aromatic ketones was achieved by samarium metal in the presence of alkyl halides. © 2000
Published by Elsevier Science Ltd. All rights reserved.
Keywords: samarium; reductive coupling; alkyl halides; aromatic ketones.
The use of samarium diiodide as single electron transfer reagent in organic synthesis has been explored
extensively.1 In recent years the chemistry of samarium metal has received increasing attention from the
synthetic community.2 The operational simplicity of using samarium metal over commercially available
samarium diiodide has been demonstrated in our recent publications. We have shown a facile reduction
of the aromatic nitro compounds3 and imines4 by samarium metal in the presence of catalytic amounts
of iodine.
In continuation of our ongoing research into the application of samarium metal in organic synthesis,
we decided to investigate Barbier-type addition of allyl group to ketones in presence of samarium metal.
Treatment of acetophenone (1a) with allyl bromide in the presence of samarium metal unexpectedly
produced the alcohol derivative 2a. No trace of the allyl group was detected in the crude reaction
mixtures. After additional experimentation, we found that with 2.5 equiv. of samarium metal and 0.6
equiv. of allyl bromide, acetophenone was completely converted to the diol 2a in 3 h in 69% yield (dl:
meso=58:42).5 No trace of the alcohol 3a was obtained (Scheme 1).
Kagan et al.6 reported similar pinacol type of coupling of ketones using 1.1 equiv. of samarium
dibromide in tetrahydrofuran. The preparation of air-sensitive samarium dibromide is a two-step synthetic
operation and requires samarium trioxide, hydrobromic acid, methyl formate and lithium dispersion. In
contrast, we have used allyl bromide (0.6 equiv.) and samarium metal as the reactants.
Therefore, we decided to apply this mild and efficient protocol of reductive coupling (pinacolization)
of aromatic ketones to a number of substrates (Table 1). 3-Methoxy acetophenone (1b) under identical
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00510-4
tetl 16789

3794
Scheme 1.
reaction conditions produced the diol 2b as the exclusive product in 59% yield with a dl:meso ratio of
59:41. 4-Methoxy acetophenone (1c) produced the diol 2c in 57% yield and similar diastereoselectivity
along with the simple reduction product 3c in 11% yield. Both 3-chloro-acetophenone (1d) and 4-
chloro-acetophenone (1e) underwent reaction producing the diols 2d and 2e, respectively, in comparable
yields and diastereoselectivity along with small quantities of reduction products. 20-Acetonapthone (1f)
produced the diol 2f in slightly higher diastereoselectivity in 49% yield along with the alcohol 3f in 24%
yield. In case of 60-methoxy-20-acetonapthone (1g), the reaction did not proceed to completion even after
20 h. The major product was the alcohol 3g (20%). The diol 2g was obtained in 15% yield as a single
diastereomer. About 40% unreacted ketone was recovered. From the above results, it is evident that as the
bulk of the aromatic part of the ketone increased, the tendency of forming the simple reduction product
increased.
In order to determine the generality of the reaction, several other ketones were reduced under identical
conditions. For example, when benzophenone (4a) was used as the substrate (Scheme 2), the reductive
coupling product 5a was exclusively formed in 59% yield. Similarly, when the substrate was 4,40-
dichlorobenzophenone (4b), the product was exclusively the diol 5b in 57% yield. On the other hand,
tricyclic fluorenone (6) gave a mixture of fluorenol (8, 37%) along with the dimeric product (7, 23%).
Encouraged by these results above and to investigate whether this type of pinacol coupling is feasible
with other alkyl halides, we selected allyl iodide, 4-bromo-1-butene and ethyl bromoacetate to study the
reaction in detail. Surprisingly, the reaction of acetophenone (1a) with these halides in the presence of
samarium metal under identical conditions afforded 2a in 50–60% yield, although the progress of the
reaction was found to be slower compared to the allyl bromide reaction.
In order to investigate the mechanism of the reaction, acetophenone was treated with samarium metal
and 0.6 equivalent of 1,2-dibromoethane and the diol was obtained in 67% yield as the only isolated
product after 2 h. Kagan et al.6 reported that samarium dibromide cannot be obtained from the reaction
of samarium metal and 1,2-dibromoethane.
Reduction of benzophenone by following Kagan’s method afforded benzhydrol. However, in contrast
to Kagan’s observation we isolated the diols 5a and 5b as the exclusive products from the reductive
coupling of benzophenones 4a and 4b. Reaction of acetophenone (1a) by samarium metal in the presence

3795
Table 1
Reductive coupling of ketones with samarium metal and allyl bromide
Scheme 2.
of catalytic amounts of bromine failed to produce any alcohol derivatives indicating that the free halogen
has no role in the present reaction.
The present methodology for the reductive coupling of ketones offers distinct advantages over the
existing methods by Kagan6 and Flowers.7 These include a single step reaction of a wider number of
substrates with relatively stable reagents. Though the mechanism of the reaction is not clear at present,
we are reasonably confident that it does not take place though samarium dibromide.
In conclusion, we have developed a mild, efficient and mechanistically interesting reductive coupling
method8 of ketones to produce the corresponding diols in good yield and moderate selectivity.

3796
Acknowledgements
We gratefully acknowledge the funding support received for this research project from The Golden
Family Fund for Cancer Research and NIH Cancer Center Support Grant, 5-P30-CA16672-25, in
particular the shared resources of the Pharmacology and Analytic Center Facility and Centralized
Histopathology Laboratory.
References
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2. (a) Murakami, M.; Hayashi, M.; Ito, Y. Synlett 1994, 179. (b) Yanada, R.; Bessho, K.; Yanada, K. Chem. Lett. 1994, 1279.
(c) Yanada, R.; Bessho, K.; Yanada, K. Synlett 1995, 443. (d) Yanada, R.; Negoro, N.; Bessho, K.; Yanada, K. Synlett 1995,
1261. (e) Yanada, R.; Negoro, N.; Yanada, K.; Fujita, T. Tetrahedron Lett. 1996, 37, 9313. (f) Yanada, R.; Negoro, N.;
Yanada, K.; Fujita, T. Tetrahedron Lett. 1997, 38, 3271. (g) Negoro, N.; Yanada, R.; Okaniwa, M.; Yanada, K.; Fujita, T.
Synlett 1998, 835. (h) Yanada, R.; Negoro, N.; Okaniwa, M.; Miwa, Y.; Taga, T.; Yanada, K.; Fujita, T. Synlett 1999, 537.
(i) Ogawa, A.; Takeuchi, H.; Hirao, T. Tetrahedron Lett. 1999, 40, 7113. (j) Yanada, R.; Negoro, N.; Okaniwa, M.; Ibuka,
T. Tetrahedron 1999, 55, 13947.
3. Banik, B. K.; Mukhopadhyay, C.; Venkatraman, M. S.; Becker, F. F. Tetrahedron Lett. 1998, 39, 7243.
4. Banik, B. K.; Zegrocka, O.; Banik, I.; Hackfeld, L.; Becker, F. F. Tetrahedron Lett. 1999, 40, 6731.
5. We thank Dr. Ogawa for the helpful discussions on the diastereoselectivity of the products through e-mail.
6. Lebrun, A.; Namy, J.-L.; Kagan, H. B. Tetrahedron Lett. 1993, 34, 2311.
7. Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A. Tetrahedron Lett. 1997, 38, 8157. Flowers et al. carried out
pinacol coupling of a single substrate by samarium diiodide in the presence of additives.
8. Representative experimental procedure: a mixture of acetophenone (1a) (0.1 g, 0.83 mmol) and allyl bromide (0.06 g, 0.49
mmol) in MeOH (5 ml) was added to samarium metal (0.31 g, 2.07 mmol) at room temperature under argon. After a few
minutes, an exothermic reaction occurred and the color of the mixture turned to blackish-green and gradually to yellowish-
green. After the ketone was consumed (3 h), the reaction mixture was diluted with CH2Cl2, 0.5 ml saturated NaHCO3
solution added and passed through a pad of Celite. The filtrate was dried (Na2SO4), concentrated and residue subjected to
silica gel chromatography. The diol 2a was obtained in 69% yield (0.069 g) as a mixture of diastereomers (dl:meso=58:42).