L. M. Fleury, B. L. Ashfeld / Tetrahedron Letters 51 (2010) 2427–2430
2429
Table 4
Next, we examined the effect that the substitution on the allyl
moiety had on the regiochemical outcome of the allylation (Table
5). In particular, we were intrigued to see whether allylmetal re-
agents generated in situ would undergo addition to ketone 1a in
an SE2 or SE20 fashion. Treatment of prenyl bromide (2b) and ke-
tone 1a to our titanocene-catalyzed Grignard generation protocol
resulted in clean SE20 1,2-addition, despite the sterically hindered
gem-dimethyl motif, to provide the corresponding alcohol in 91%
yield (entry 1). Crotyl (2c) and cinnamyl (2d) bromides also under-
went SE20 addition, resulting in homoallyl alcohols in 89% and 91%
yield, respectively (entries 2 and 3). Substitution at the 2-position
of the allyl motif, as demonstrated by methallyl bromide (2e), did
not diminish the efficiency of the allylation event (entry 4).
In conclusion, we have demonstrated that Würtz-coupling
byproducts in the stoichiometric generation of allyl Grignard re-
agents can be avoided under very mild conditions through the cat-
alytic activation and subsequent reductive transmetallation of the
corresponding allyl halide in the presence of 1 mol % Cp2TiCl2 and
unactivated magnesium turnings. The conditions described herein
allow for the in situ allylation of a wide variety of carbonyl deriv-
atives, including aldehydes, ketones, and esters, in excellent yield
within minutes at room temperature. This protocol effectively cir-
cumvents the traditional use of carcinogenic activators and often
exothermic conditions required for Grignard reagent generation.
Further, examination of the scope, mechanistic studies to elucidate
the effect of phosphine additives on the metallation process, and
the development of an enantioselective protocol are in progress,
and will be reported in due course.
Diallylation of estersa
Br
O
2a
OH
11
R1
OR2
R1
Cp2TiCl2 (1 mol%), Mg
THF, rt
10
Entry
Ester
Yield (%)
1
2
3
4
(E)-PhCH@CHCO2Me (10a)
2-Me-C6H4CO2Me (10b)
(E)-4-MeO–C6H4CH@CHCO2Me (10c)
(E)-4-Cl–C6H4CH@CHCO2Me (10c)
96
93
92
97
a
Reaction conditions: 0.4 mmol 10, 1.0 mmol 2a, 1 mol % Cp2TiCl2, and
1.2 mmol Mg in THF (0.1 M) at room temperature for 30–90 min.
In an effort to establish the scope and versatility of the titano-
cene-catalyzed Grignard generation, a series of aldehydes were
examined for their propensity to provide the corresponding homo-
allylic alcohols by treatment with allyl bromide (2a) (Table 2). Both
electron-rich and electron-deficient benzaldehyde derivatives
proved to be excellent substrates providing benzylic alcohols in
high yield (entries 1–7).
a,b-Unsaturated aldehydes underwent
1,2-allylation to yield the corresponding allylic alcohols (entries
8 and 9), and aliphatic aldehydes also proved to be viable sub-
strates (entries 10 and 11).
The titanocene-catalyzed allyl halide activation protocol proved
just as reliable for the allylation of ketones, providing exceptional
yields of the desired homoallylic alcohols (Table 3).13 Benzyl deriv-
atives (electron rich and electron deficient) and
a,b-unsaturated
ketones underwent allylation in excellent yields (entries 1–10).
The allylation of ketone 1d is particularly noteworthy in that the
presence of the free ortho-phenol moiety did not hinder the allyla-
tion event (entry 3). Aliphatic ketones were also viable substrates
as is evidenced by the allylation of 4-t-butylcyclohexanone to pro-
vide alcohol 3l in 94% yield and a syn/anti ratio of 1.3:1 (entry 11).
This diastereomeric outcome is consistent with the addition of an
allyl Grignard reagent and not an allyltitanocene(IV) species.14,15
We next examined the titanocene-catalyzed generation of allyl
Grignard reagents in the presence of ester derivatives (Table 4).
This class of substrates is particularly interesting due to their resis-
tance to nucleophilic attack by allyltitanocene(IV) reagents. A ser-
Acknowledgment
The authors would like to thank the University of Notre Dame
for their generous financial support of this research.
Supplementary data
Supplementary data (detailed experimental procedures and
spectral data for all new compounds) associated with this article
ies of
a,b-unsaturated esters were examined, and in each case an
References and notes
excellent yield (P92%) of the diallylation product was observed.
Regardless of the substrate or relative amount of allyl halide and
magnesium used, the diallylation products were obtained exclu-
sively. These results lend support to our hypothesis that the active
allylmetal reagent is not an allyltitanocene(IV) derivative, but
rather the more reactive allyl Grignard species.
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Table 5
Effect of allyl substitutiona
R3
R3
O
HO Me
Cp2TiCl2 (1 mol%), Mg
THF, rt
R1
Br
+
Ph
Ph
Me
R1 R2
R2
2
3
1a
Entry
Allyl bromide
R1
R2
R3
Yield (%)
1
2
3
4
2b
2c
2d
2e
Me
Me
Ph
H
Me
H
H
H
H
H
Me
91
89b
91b
95
6. (a) Rieke, R. D.; Hudnall, P. M. J. Am. Chem. Soc. 1972, 94, 7178; (b) Burns, T. P.;
Rieke, R. D. J. Org. Chem. 1987, 52, 3674; (c) Rieke, R. D.; Xiong, H. J. Org. Chem.
1991, 56, 3109.
7. Hoffmann, R. W.; Knopff, O.; Kusche, A. Angew. Chem., Int. Ed. 2000, 39, 1462.
8. (a) DeWolfe, R. H.; Young, W. G. Chem. Rev. 1956, 56, 753; (b) Hutchison, D. A.;
Beck, K. R.; Benkeser, R. A.; Grutzner, J. B. J. Am. Chem. Soc. 1973, 95, 7075; (c)
H
a
Allylation reactions were carried out using 0.8 mmol 1a, 0.96 mmol 2a, 1 mol %
Cp2TiCl2, and 1.2 mmol Mg turnings in THF (0.1 M) at room temperature for 20 min.
b
syn/anti = 1:1.