Gallium-mediated allyl transfer from bulky homoallylic alcohol to aldehydes via retro-allylation: Stereoselective synthesis of both erythro- and threo-homoallylic alcohols

Article abstract of DOI:10.1021/ol0515199

(Chemical Equation Presented) Retro-allylation of bulky gallium homoallylic alkoxides occurs to generate (Z)- and (E)-crotylgallium reagents stereospecifically, starting from erythro- and threo-homoallylic alcohols, respectively. The (Z)- and (E)-crotylgallium reagents immediately reacted with aromatic aldehydes to afford the corresponding erythro and threo-homoallylic alcohols, respectively.

Full text of DOI:10.1021/ol0515199

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3577-3579
Gallium-Mediated Allyl Transfer from
Bulky Homoallylic Alcohol to Aldehydes
via Retro-allylation: Stereoselective
Synthesis of Both erythro- and
threo-Homoallylic Alcohols1
Sayuri Hayashi, Koji Hirano, Hideki Yorimitsu, and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received June 29, 2005
ABSTRACT
Retro-allylation of bulky gallium homoallylic alkoxides occurs to generate (Z)- and (E)-crotylgallium reagents stereospecifically, starting from
erythro- and threo-homoallylic alcohols, respectively. The (Z)- and (E)-crotylgallium reagents immediately reacted with aromatic aldehydes to
afford the corresponding erythro- and threo-homoallylic alcohols, respectively.
Allylation of carbonyl compounds is among the most
important reactions in organic synthesis.2 Thus, preparation
of allylic metals has been well investigated, including
reductive metalation of allylic halide (or pseudohalide) by
low-valent metal, transmetalation of highly reactive allylic
metal to another metal, and direct allylic deprotonation by a
strong base. Recently, we have developed a novel and mild
method for the preparation of allylic zirconium reagents by
allylic C-H bond activation of alkene and applied it to
carbonyl allylation.3 Here we report a new method for the
generation of allylic gallium reagents4 by gallium-mediated
retro-allylation reaction of bulky homoallylic alcohols.5
Treatment of bulky homoallylic alcohol (1a, 1.2 mmol)
with methylmagnesium iodide (1.2 mmol) in dioxane af-
forded the magnesium alkoxide of 1a. Gallium trichloride
(1.2 mmol) and benzaldehyde (1.0 mmol) were sequentially
added at 25 °C. After the mixture was stirred for 0.5 h,
extractive workup followed by silica gel column purification
provided homoallylic alcohol 2a in excellent yield. Unfor-
tunately, no erythro/threo selectivity was observed. A
substoichiometric amount of gallium trichloride also effected
the crotylation6 reaction, affording 2a in 79% yield. On the
(1) Throughout this manuscript, we have adopted the unambiguous
erythro/threo nomenclature proposed by Noyori: Noyori, R.; Nishida, I.;
Sakata, J. J. Am. Chem. Soc. 1981, 103, 2106-2108.
(2) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (b)
Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-2793.
(3) (a) Fujita, K.; Yorimitsu, H.; Oshima, K. Chem. Rec. 2004, 4, 110-
119. (b) Fujita, K.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Am. Chem.
Soc. 2004, 126, 6776-6783. (c) Fujita, K.; Yorimitsu, H.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 2004, 69, 3302-3307.
(4) (a) Yamaguchi, M. In Main Group Metals in Organic Synthesis;
Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 1., Chapter 7. (b) Araki, S.; Ito, H.; Butsugan, Y. Appl. Organomet.
Chem. 1988, 2, 475-478. (c) Tsuji, T.; Usugi, S.; Yorimitsu, H.; Shinokubo,
H.; Matsubara, S.; Oshima, K. Chem. Lett. 2002, 2-3. (d) Takai, K.; Ikawa,
Y. Org. Lett. 2002, 4, 1727-1729.
10.1021/ol0515199 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/15/2005

aldehyde moiety predominated over that of ester (entry 5).
The reaction with ketone gave the corresponding tertiary
alcohol 2g in modest yield (entry 6).
Scheme 1
Other allylic gallium reagents were readily prepared (Table
2). Completion of unsubstituted allyl transfer took more time
Table 2. Allylation, Methallylation, and Prenylation of
Benzaldehyde
basis of the regioselectivity of the reaction, the reaction
mostly proceeded via a mechanism completely different from
the Lewis acid-mediated allyl transfer reactions reported by
Nokami and Loh.7 Formation of crotylgallium species by
retro-crotylation is most probable.
entry
1
R
R1
R2
time
2
yield
1
2
3
4
1b
1c
1d
1e
iPr
iPr
iPr
Me
H
H
Me
Me
H
Me
H
13 h
0.5 h
11 h
1 h
2h
2i
2j
2j
68%
94%
32%
78%
A variety of aldehydes underwent the crotylation reaction
(Table 1). Not only aromatic aldehydes but also aliphatic
H
yet provided the anticipated product 2h in good yield (entry
1). Methallylation proceeded as smoothly as the crotylation
to furnish 2i in excellent yield (entry 2). Intriguingly,
prenylation was not efficient starting from diisopropyl-
substituted 1d. However, dimethyl substitution at the oxy-
genated carbon dramatically enhanced the prenylation (entry
4). Delicate steric factors around the hydroxy groups play a
key role in these allyl transfer reactions.
Having noticed the delicate steric effect, we further
examined the crotylation reaction by using other crotyl
sources. Fortunately, we found that homoallylic alcohol 1f,
which bears mesityl and methyl groups at its oxygenated
carbon, effected crotyl transfer reaction in ether at -20 °C.
Gratifyingly, the reaction exhibited stereospecificity when
diastereomerically pure 1f was used; the reactions of erythro-
1f8 and threo-1f with benzaldehyde afforded erythro- and
threo-2a, respectively (Scheme 2). Both isomers of 1f were
Table 1. Crotylation of Various Carbonyl Compounds via
Retro-crotylationa
entry
RCOR′
time
1.5 h 2b 88%
1 h 2c 72%
0.5 h 2d 99%
2e 70%b
2
yield erythro/threo
1
2
3
4
5
6
p-CH3C6H4CHO
PhCH2CH2CHO
c-C6H11CHO
(E)-PhCHdCHCHO 3 h
p-MeOCOC6H4CHO 2.5 h 2f 85%
cyclohexanone 0.5 h 2g 59%
48:52
55:45
12:88
54:46
42:58
a Performed as described in the second paragraph by using 1.2 equiv of
GaCl3. b Performed in ether at 0 °C. Conversion of cinnamaldehyde under
the standard conditions resulted in a lower yield because of the concomitant
formation of 4-methyl-1-phenyl-1,3,5-hexatriene.
ones participated in the crotylation reaction. Crotylation of
cyclohexanecarbaldehyde proceeded with high threo selec-
tivity (entry 3). Selective 1,2-addition took place in the
reaction of cinnamaldehyde (entry 4). The allylation of an
Scheme 2
(5) Retro-allylations from lithium, magnesium, and zinc alkoxides were
observed. Among them, Knochel reported threo selectivity. (a) Benkeser,
R. A.; Siklosi, M. P.; Mozdzen, E. C. J. Am. Chem. Soc. 1978, 100, 2134-
2139. (b) Gerard F.; Miginiac, P. Bull. Chim. Soc. Fr. 1974, 2527-2533.
(c) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186-195. We have
serendipitously found similar behavior of zirconium homoallylic alkoxides.
See ref 3c. Under harsh conditions, retro-allylation took place by the action
of tin: (d) Peruzzo, V.; Tagliavini, G. J. Organomet. Chem. 1978, 162,
37-44. (e) Giesen, V. Dissertation, University Marburg, Germany, 1989.
Ruthenium-catalyzed deallylation was reported: (f) Kondo, T.; Kodoi, K.;
Nishinaga, E.; Okada, T.; Morisaki, Y.; Watanabe, Y.; Mitsudo, T. J. Am.
Chem. Soc. 1998, 120, 5587-5588.
(6) For convenience, throughout the manuscript, crotylation, methally-
lation, and prenylation are defined as introductions of 1-methyl-2-propenyl,
2-methyl-2-propenyl, and 1,1-dimethyl-2-propenyl groups, respectively, into
a carbonyl group. On the other hand, crotyl, methallyl, and prenyl groups
denote herein 2-butenyl, 2-methyl-2-propenyl, and 3-methyl-2-butenyl
groups, respectively.
prepared by treatment of mesityl methyl ketone with crotyl
Grignard reagent and readily separated from each other by
column purification on silica gel. Other aromatic aldehydes
underwent the stereospecific crotylation reaction (Table 3).
The reactions with dihydrocinnamaldehyde and cinnamal-
dehyde resulted in lower stereoselectivity (See Supporting
Information).
3578
Org. Lett., Vol. 7, No. 16, 2005

Scheme 3
Table 3. Selective Synthesis of erythro- and threo-Homoallylic
Alcohols
entry
1f
erythro p-CF3C6H4
threo p-CF3C6H4
erythro o-ClC6H4
threo o-ClC6H4
Ar
2
yield erythro/threo of 2
1
2
3
4
5
6
2k 84%
2k 92%
2l
2l
96:4
2:98
99:1
3:97
98:2
2:98
87%
83%
erythro p-CH3C6H4 2b 95%a
threo
p-CH3C6H4 2b 64%a
a Reaction time was 30 h.
We are tempted to assume the reaction mechanism as
follows (Scheme 3). Upon the retro-crotylation reaction of
erythro-1f, a chair transition state 3a would be the most
stable, because of steric reasons, in comparison to other
possible transition states, including another chair transition
state 3b and twist-boat transition states. Formation of a (Z)-
crotylgallium reagent is thus favored. The (Z)-crotylgallium
reagent probably reacts so rapidly with benzaldehyde in the
same pot that its isomerization into the (E)-form is negligible.
The crotylation would proceed via a cyclic transition state,
which selectively provides erythro-2a. Starting from threo-
1f, an (E)-crotylgallium reagent would be predominantly
generated via 4a and led to threo-2a.
should always be prepared in advance of the crotylation
reaction.2 Our new method utilizes stable and easy-to-handle
homoallylic alcohols as the precursors. Selective generations
of (E)- and (Z)-crotylgallium were established in situ via the
gallium-mediated retro-allylation and can be applied to other
allylation reactions.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research, Young Scientists, and COE
Research, from the Ministry of Education, Culture, Sports,
Science and Technology, Government of Japan. We thank
Prof. Masaki Shimizu for helping with the X-ray crystal-
lographic analysis.
Stereoselective preparations of crotylmetals represent an
important challenge. Stereochemically defined crotylmetals
(7) Representative examples: (a) Nokami, J.; Yoshizane, K.; Matsuura,
H.; Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609-6610. (b) Nokami, J.;
Anthony, L.; Sumida, S. Chem. Eur. J. 2000, 6, 2909-2913. (c) Nokami,
J. J. Synth. Org. Chem. Jpn. 2003, 61, 992-1001. (d) Tan, K.-T.; Chng,
S.-S.; Cheng, H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 2958-2963.
(e) Lee, C.-L. K.; Lee, C.-H. A.; Tan, K.-T.; Loh, T.-P. Org. Lett. 2004, 6,
1281-1283. Also see: (f) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J.
Org. Lett. 2001, 3, 3815-3818. (g) Crosby, S. R.; Harding, J. R.; King, C.
D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4, 577-580. (h) Samoshin,
V. V.; Smoliakova, I. P.; Hank, M. M.; Gross, P. H. MendeleeV Commun.
1999, 219-221. (i) Horiuchi, Y.; Taniguchi, M.; Oshima, K.; Utimoto, K.
Tetrahedron Lett. 1994, 35, 7977-7980.
Supporting Information Available: Experimental de-
tails, additional examples for Table 3, an ORTEP diagram
1
of a derivative of erythro-1f, and H NMR spectra of the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Relative configuration of erythro-1f was determined by X-ray
crystallographic analysis after derivatization. See Supporting Information.
OL0515199
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