Rhodium-catalyzed reformatsky-type reaction

Article abstract of DOI:10.1021/ol006268c

(equation presented) A novel Reformatsky-type reaction was developed using RhCl(PPh₃)₃ and diethylzinc. Inter- and intramolecular Reformatsky-type reactions were achieved efficiently under mild reaction conditions to give β-hydroxy esters.

Full text of DOI:10.1021/ol006268c

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2549-2551
Rhodium-Catalyzed Reformatsky-Type
Reaction
Kazuo Kanai, Hitoshi Wakabayashi, and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received June 28, 2000
ABSTRACT
A novel Reformatsky-type reaction was developed using RhCl(PPh3)3 and diethylzinc. Inter- and intramolecular Reformatsky-type reactions
were achieved efficiently under mild reaction conditions to give â-hydroxy esters.
The Reformatsky reaction is a well-recognized carbon-
carbon bond-forming reaction of an R-halo ester with an
aldehyde or a ketone in the presence of zinc metal to give a
â-hydroxy ester (Scheme 1).1
carbon bond, most efforts have been focused on the activation
of zinc or the utilization of other metals, such as magnesium,3
cadmium,4 nickel,5 indium,6 cerium,7 and lithium,8 to facili-
tate the insertion. With activated zincs, such as Rieke-Zn,9
Zn-Cu couple,10 Zn/Ag-graphite,11 and so on, the Refor-
matsky reaction can be conducted under milder reaction
conditions. However, these reagents usually must be freshly
prepared because of their instability to air and moisture.
Although little attention has been focused on the catalytic
version of this type of reaction, there is an interesting variant
which utilized zinc and a catalytic amount of titanocene
dichloride.12 This prompted us to investigate an efficient and
mild transition metal-catalyzed Reformatsky-type reaction.
We would like to disclose herein a new Reformatsky-type
reaction promoted by rhodium catalysis and conducted under
mild reaction conditions.
Scheme 1 The Reformatsky Reaction
A particular advantage of this reaction stems from the fact
that the site of reaction is strictly determined by the halogen
moiety. This may be advantageously used for regioselective
enolate formation in polycarbonyl compounds which are
difficult to achieve by base-induced proton abstraction.2 To
extend the scope of the Reformatsky reaction, variable
parameters have been extensively investigated. Since the
reaction is initiated by insertion of zinc into the halogen-
We first studied the intermolecular reaction as shown in
Table 1.13
(3) (a) Moriwake, T. J. Org. Chem. 1996, 31, 983. (b) Borno, A.; Bigley,
D. B. J. Chem. Soc., Perkin Trans. 2 1983, 1311.
(4) Burkhardt, E.; Rieke, R. D. J. Org. Chem. 1985, 50, 416.
(5) Inaba, S.-I.; Rieke, R. D. Tetrahedron Lett. 1985, 26, 155.
(6) For recent review, see: Cintas, P. Synlett 1995, 1087.
(7) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.;
Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904.
(8) Villieras, J.; Perriot, P.; Bourgain, M.; Normant, J. F. J. Organomet.
Chem. 1975, 102, 129.
(1) For recent reviews of the Reformatsky reaction, see: (a) Fu¨rstner,
A. Synthesis 1989, 571. (b) Rathke, M. W.; Weipert, P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds; New York, 1991; Vol.
2, p 277. (c) Fu¨rstner, A. In Organozinc Reagents; Knochel, P., Jones, P.,
Eds; Oxford University Press: New York, 1999; p 287.
(2) For examples, see: (a) Vedejs, E.; Ahmad, S. Tetrahedron Lett. 1988,
29, 2291. (b) Dener, J. M.; Zhang, L. H.; Rapoport, H. J. Org. Chem. 1993,
58, 1159. (c) Binch, H. M.; Griffin, A. M.; Schwidetzky, S.; Ramsay, M.
V. J.; Gallagher, T.; Lichtenthaler, F. W. J. Chem. Soc., Chem. Commun.
1995, 967.
(9) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 452.
(10) Santaniello, E.; Manzocchi, A. Synthesis 1977, 698.
(11) Csuk, R.; Fu¨rstner, A.; Weidmann, H. J. Chem. Soc., Chem.
Commun. 1986, 775.
(12) Ding, Y.; Zhao G. J. Chem. Soc., Chem. Commun. 1992, 941.
10.1021/ol006268c CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/19/2000

as is the case for conventional Reformatsky conditions. In
the absence of either RhCl(PPh3)3 or diethylzinc, recovery
of the starting material was observed after 1 h at 0 °C. This
suggests that Rh(I) efficiently catalyzes the reaction.
Encouraged by the results obtained above, we next focused
our attention on the intramolecular reaction. As shown in
Table 2, the reaction developed above also effected intramo-
Table 1. Intermolecular Reaction
Table 2. Intermolecular Reaction
Aromatic and aliphatic aldehydes or ketones reacted
smoothly with ethyl bromoacetate or ethyl 2-bromopropi-
onate in the presence of Wilkinson’s catalyst and diethylz-
inc14 to give â-hydroxy esters15 in moderate to good yields.
It is noteworthy that no ethyl adduct was produced and the
reactions were usually completed within 5 min under the
conditions described above. When ethyl 2-bromopropionate
was used as the R-halo ester, essentially no diastereoselec-
tivity16 was observed under the conditions employed (entries
2, 4, 6, and 11). With 2-cyclohexenone as a Reformatsky
acceptor, only 1,2-adducts were obtained (entries 10 and 11),
lecular carbon-carbon bond formation, as expected, provid-
ing secondary and tertiary cycloalkanols in good to excellent
yields under similar reaction conditions. For the reactions
forming five-membered rings (entries 1 and 2), high dias-
tereoselectivities were observed, giving cis-hydroxy ester 5a
as the major product. This result should be attributed to the
sterically and electronically more favored rigid conformation
of the transition state including zinc as depicted in Figure
1.17
(13) Representative procedure for the intermolecular Reformatsky-
type reaction: To a stirred solution of RhCl(PPh3)3 (5 mol %) in THF at
0 °C were added R-halo ester 1, carbonyl compound 2, and a ca. 1.0 M
hexane solution of Et2Zn (2.2 molar equiv). After stirring for 5 min at 0
°C, saturated aqueous NaHCO3 was added. The reaction was filtered, and
the filtrate was partitioned between Et2O and brine. The organic extract
was dried (Na2SO4), and the residue was purified by column chromatography
on silica gel.
(14) In entry 1, Table 1, the reaction gave 3a in a 32% yield, and
unreacted benzaldehyde was recovered (66%) with 1.1 molar equiv of
diethylzinc.
Figure 1. Transition state for zinc enolate providing cis-hydroxy
ester 5a.
(15) 3a: Picotin, G.; Miginiac, P. J. Org. Chem. 1987, 52, 4796. 3b:
Hart, J. D.; Krishnamurthy, R. J. Org. Chem. 1992, 57, 4457. 3c: Carreira,
E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837. 3d:
Kiyooka, S.; Shahid, K. A.; Hena, M. A. Tetrahedron Lett. 1999, 40, 6447.
3e: Araki, S.; Ito, H.; Butsugan, Y. Synth. Commun. 1988, 18, 453. 3f: See
ref 7. 3g: Martin, J.; Pinhey, J. T. Molecules 1998, 3, M59. 3h: Couffignal,
R.; Gaudemar, M. J. Organomet. Chem. 1973, 60, 209. 3i: Enholm, E. J.;
Jiang, S.; Abboud, K. J. Org. Chem. 1993, 58, 4061. 3j: Conan, A.; Sibille,
S.; Perichon, J. J. Org. Chem. 1991, 56, 2018. 3k: Ruano, J. L. G.; Barros,
D.; Maestro, M. C.; Araya-Maturana, R.; Fischer, J. J. Org. Chem. 1996,
61, 9462.
On the other hand, in entries 3 and 4, reactions forming
six-membered rings, the stereoselections were diminished
remarkably. From the results obtained above, it is also
apparent that zinc also plays an important role in the
stereocontrol of the reaction as previously reported.17
(16) Under the conventional Reformatsky reaction conditions, the syn:
anti product ratios are 37:63 for 3b and 67:33 for 3f (refs 1 and 17).
(17) Heathcock, C. H.; In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, p 144.
2550
Org. Lett., Vol. 2, No. 16, 2000

On the basis of the detailed mechanistic investigation of
the ethylzinc enolate formation from 2-bromo-4,4-dimethyl-
3-pentanone and diethylzinc by Heathcock,18 a plausible
mechanism was proposed as depicted in Scheme 2, where
oxidative addition of R-halo ester 1 into Rh(I) initiates the
reaction. After formation of a rhodium(III) complex, trans-
metalation with diethylzinc produces ethylzinc enolate 7 and
Rh(I), by which the reaction could be catalyzed again.
Nucleophilic addition of 7 to carbonyl compound 2 would
then afford zinc alkoxide 8, which upon hydrolysis should
give â-hydroxy ester 3.
Scheme 2. Proposed Mechanism for the Rhodium-Catalyzed
Reformatsky-Type Reaction
Thus, we have developed a mild and efficient Refor-
matsky-type reaction catalyzed by RhCl(PPh3)3 and diethyl-
zinc which can be conducted under mild reaction conditions.
Extension of this methodology is now under investigation
in this laboratory.
Acknowledgment. Support was provided by a Grant-in-
Aid from the Ministry of Education, Sciences, Sports, and
Culture of Japan.
(18) Hansen, M. M.; Bartlett, P. A.; Heathcock, C. H. Organometallics
1987, 6, 2069. Palmer and Reid reported the generation of n-propylzinc
ester enolate from (-)-menthyl bromoacetate and di-n-propylzinc. HoweVer,
their condition for preparing zinc enolate was relatiVely Vigorous compared
to ours deVeloped aboVe, see: Palmer, M. H.; Reid, J. A. J. Chem. Soc.
1962, 1762.
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL006268C
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