Notes
J . Org. Chem., Vol. 62, No. 24, 1997 8541
Cl3(thf)6]2[Zn2Cl6]6 was used, however, the pinacol cou-
pling of benzaldehyde occurred predominantly and 1a
was not obtained at all. Since the presence of the
vanadium(II) species in the reaction mixture immediately
induces the pinacol coupling of an aldehyde,7 the com-
bination of Et2Zn and VCl4 or VCl3(thf)3 probably does
not afford a vanadium(II) species but provides some
higher-valent vanadium species. It may be of interest
to know whether only one or both Et groups of Et2Zn add
to carbonyls in these reactions. Thus, we examined the
reaction using 2 equiv of benzaldehyde in the reaction of
run 1 (Table 1). Although during 5 h of reaction at 0 °C
only 40% of 1a besides 38% of the unreacted benzalde-
hyde was obtained, after 24 h of reaction 36% of 1a and
30% of propiophenone were obtained accompanied by 8%
of the starting benzaldehyde and 27% of benzyl alcohol;
in the latter reaction about 1.3 equiv of Et groups have
been transferred.8 This indicates that one of the two
ethyl groups was transferred easily to carbonyls but the
transfer of the second ethyl group proceeds only slowly,
though both ethyl groups can add to carbonyl groups.
It is known that Me2Zn shows extremely low reactivity
toward a carbonyl compound compared to Et2Zn when
combined with an amino alcohol.1 Me2Zn, combined with
a vanadium(III) or a vanadium(IV) compound, however,
was also sufficiently effective for the methylation of
benzaldehyde. Reaction of Me2Zn with benzaldehyde in
the presence of VCl4 afforded 1-phenylethan-1-ol (1b)
quantitatively under similar conditions to those applied
to the system, Et2Zn-VCl4 (Table 1, run 3). Employing
VCl3(thf)3, 1b was also obtained in 91% yield (Table 1,
run 4).
reaction time and a little higher temperature (20 °C) were
needed. In contrast to the reactivity of alkylzinc reagents
activated by amino alcohols, the activity of the Me2Zn-
VCl4 or VCl3(thf)3 system was much higher than that of
the Et2Zn system. Alkylation of acetophenone using
Et2Zn instead of Me2Zn did not proceed at all, and
acetophenone was recovered (Table 1, runs 9 and 10).
Methylation of 4-tert-butylcyclohexanone using the
Me2Zn-VCl4 system resulted in the preferential forma-
tion of the axial alcohol (axial alcohol:equatorial alcohol
) 73:27) (Table 1, run 11). The selectivity did not change
by using VCl3(thf)3 instead of VCl4 (Table 1, run 12) and
is similar to that of methylation with MeLi (axial alcohol:
equatorial alcohol ) 79:21).10 The methylation of an ester
(methyl benzoate) using the ZnEt2-VCl4 or VCl3(thf)3 was
not successful, and the ester was recovered quantitatively
(Table 1, runs 13 and 14).
In the methylation of carbonyl compounds using the
Me2Zn-VCl4 system, the consumption of aldehyde was
much faster than that of ketone. Thus, a competitive
reaction between an aldehyde and a ketone was exam-
ined. When a mixture of benzaldehyde (1.0 equiv) and
acetophenone (1.0 equiv) was reacted with Me2Zn (1.0
equiv) in the presence of VCl4 (1.0 equiv) in THF at 0
°C, only the methylation of benzaldehyde proceeded and
the alcohol 1b was obtained in 80% yield along with
unreacted acetophenone in 98% yield (eq 1).
An aliphatic aldehyde was also treated with Me2Zn-
VCl4 to afford the corresponding methylated alcohol
(Table 1, run 5). In the reaction of an R,â-unsaturated
aldehyde, the 1,2-addition proceeded exclusively (Table
1, run 6). Although it is reported that an alkylzinc
activated by an amino alcohol did not react with ketones,1
two ketones were transformed to the corresponding
alcohols by using Me2Zn-VCl4 (Table 1, runs 7, 8, 11,
and 12). To obtain a satisfactory yield, a prolonged
In the methylation of acetophenone with the Me2Zn/V
system, we have also examined whether both of the
methyl substituents can add to the carbonyl or not. Thus,
2 equiv of acetophenone was treated in THF at ambient
temperature with a methylating reagent prepared from
1 equiv of Me2Zn and 1 equiv of VCl3(thf)3. After 38 h of
reaction, 34% of the alcohol 1b accompanied with 14%
of a coupling product, 2,2-dimethyl-2,2-diphenylbutane
(3) (vide infra), was obtained. The remaining 37% of
acetophenone was unreacted. This indicates that only
0.96 equiv of the available 2 equiv of methyl groups had
been utilized; only one of the two zinc methyls can add
to ketone under the reaction conditions. This propensity
of the methylating reagent is also responsible for the high
chemoselectivity between aldehyde and ketone shown in
the above competitive experiment.
Which is the actual reactive species in this alkylation,
an alkylzinc reagent or an alkylvanadium reagent? It
has been reported that in the alkylation of an aldehyde
using Ti(OiPr)4 and Et2Zn an ethyltitanium reagent
prepared in situ reacts with the aldehyde.2b,c Although
vanadium is also an early transition metal like titanium,
a C-V bond is more unstable compared to a C-Ti bond.
Thus, a nucleophilic attack of an alkylvanadium species
to carbonyl compounds does not readily occur unless
stabilizing additive such as HMPA is present.11 In our
alkylation of carbonyl compounds mediated by a dialkyl-
(6) (a) Cotton, F. A.; Duraj, S. A.; Extine, M. W.; Lewis, G. E.; Roth,
W. J .; Schmulbach, C. D.; Schwotzer, W. J . Chem. Soc., Chem.
Commun. 1983, 1377-1378. (b) Bouma, R. J .; Teuben, J . H.; Beukema,
W. R.; Bansemer, R. L.; Huffman, J . C.; Caulton, K. G. Inorg. Chem.
1984, 23, 2715-2718. (c) Cotton, F. A.; Duraj, S. A.; Roth, W. J . Inorg.
Chem. 1985, 24, 913-917.
(7) For pinacol-type coupling of carbonyl compounds by vanadium(II)
species, see: (a) Freudenberger, J . H.; Konradi, A. W.; Pedersen S. F.
J . Am. Chem. Soc. 1989, 111, 8014-8016. (b) Takahara, P. M.;
Freudenberger, J . H.; Konradi, A. W.; Pedersen, S. F. Tetrahedron Lett.
1989, 30, 7177-7180. (c) Konradi, A. W.; Pedersen, S. F. J . Org. Chem.
1990, 55, 4506-4508. (d) Park, J .; Pedersen, S. F. J . Org. Chem. 1990,
55, 5924-5926. (e) Annunziata, R.; Cinquini, M.; Cozzi, F.; Giaroni,
P. Tetrahedron Asymmetry 1990, 1, 355-358. (f) Annunziata, R.;
Cinquini, M.; Cozzi, F.; Giaroni, P.; Benaglia, M. Tetrahedron 1991,
47, 5737-5758. (g) Raw, A. S.; Pedersen, S. F. J . Org. Chem. 1991,
56, 830-833. (h) Kemp, D. J .; Sowin, T. J .; Doherty, E. M.; Hannick,
S. M.; Codavoci, L.; Henry, R. F.; Green, B. E.; Spanton, S. G.; Norbeck,
D. W. J . Org. Chem. 1992, 57, 5692-5700. (i) Annunziata, R.; Benaglia,
M.; Cinquini, M.; Cozzi, F.; Giaroni, P. J . Org. Chem. 1992, 57, 782-
784. (j) Konradi, A. W.; Pedersen, S. F. J . Org. Chem. 1992, 57, 28-
32. (k) Park, J .; Pedersen, S. F. Tetrahedron 1992, 48, 2069-2080. (l)
Kraynack, E. A.; Pedersen, S. F. J . Org. Chem. 1993, 58, 6114-6117.
(m) Konradi, A. W.; Kemp, S. J .; Pedersen, S. F. J . Am. Chem. Soc.
1994, 116, 1316-1323. (n) Kammermeier, B.; Beck, G.; J acobi, D.;
J endralla, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 685-687. (o)
Kammermeier, B.; Beck, G.; Holla, W.; J acobi, D.; Napierski, B.;
J endralla, H. Chem. Eur. J . 1996, 2, 307-315. (p) Hirao, T.; Hasegawa,
T.; Muguruma, Y.; Ikeda, I. J . Org. Chem. 1996, 61, 366-367.
(8) Formation of propiophenone could be formally explained by a
â-hydride elimination from vanadium alcoholate of 1a 9 liberating a
“V-H” species, which may reduce benzaldehyde to give benzyl alcohol.
The details of the reaction will be reported separately.
(9) Hirao, T.; Misu, D.; Agawa, T. J . Am. Chem. Soc. 1985, 107,
7179-7181.
(10) MacDonald, T. L.; Still, W. C. J . Am. Chem. Soc. 1975, 97,
5280-5281.
(11) Kataoka, Y.; Makihira, I.; Tani, K. Tetrahedron Lett. 1996, 37,
7083-7086.