Preparation of ester-group substituted allylic zinc by palladium-catalyzed umpolung of γ-acyloxy-α,β-unsaturated ester by bis(iodozincio)methane

Article abstract of DOI:10.1246/cl.2010.96

Treatment of γ-acyloxy-α,β-unsaturated ester with bis(iodozincio)methane in the presence of palladium catalyst gave an allylic zinc carrying an ester group; the allylic zinc, which is prepared by this umpolung process, reacts with ketones regioselectively

Full text of DOI:10.1246/cl.2010.96

doi:10.1246/cl.2010.96
96
Published on the web December 26, 2009
Preparation of Ester-group Substituted Allylic Zinc by Palladium-catalyzed Umpolung
of £-Acyloxy-¡,¢-unsaturated Ester by Bis(iodozincio)methane
Shizue Ueno, Mutsumi Sada, and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoutodaigaku-katsura, Nishikyo-ku, Kyoto 615-8510
(Received October 29, 2009; CL-090959; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp)
Treatment of £-acyloxy-¡,¢-unsaturated ester with bis-
bis(iodozincio)methane (3e)7 improved the yield of the adduct
4a without formation of 6 (Entry 6). Optimization of the
reaction conditions using 3e, the yield of the adduct 4a was
raised to 61% (Entries 6-9). Instead of benzoate 1a, the acetate
1b gave the better yield (73%, Entry 10). In these reactions of
Table 1, the corresponding regioisomeric adduct, benzyl 2-(1-
hydroxy-1-phenylethyl)but-3-enoate (5a), was not detected.
(iodozincio)methane in the presence of palladium catalyst
gave an allylic zinc carrying an ester group; the allylic zinc,
which is prepared by this umpolung process, reacts with ketones
regioselectively.
The Reformatsky reaction is one of the most efficient C-C
bond forming reactions. Treatment of ¡-haloester with zinc in
the presence of aldehyde or ketone gives ¢-hydroxy esters in
good yields.1 Its vinylog, however, starting from £-bromo-¡,¢-
unsaturated ester, has been shown to form a mixture of
regioisomers, that is, ¡-vinyl-¢-hydroxy ester and ¤-hydroxy-
¡,¢-unsaturated ester in a low yield.1b,2 Improved Reformatsky
reactions have given the better yields, but have not realized high
regioselectivity of the adducts.3 As shown in Figure 1, the
reaction intermediate is mainly an allylic zinc species, but the
reaction may accompany single electron transfer processes such
as the Barbier reaction. In order to realize selective reaction, it is
necessary to prepare the intermediary allylic zinc without a
single electron transfer. For this purpose, we tried to prepare the
corresponding allylic zinc species by a palladium-catalyzed
umpolung of £-acyloxy-¡,¢-unsaturated ester with various
organozinc reagents.4
PhCHO
Et2Zn
OH
OCOPh
ð1Þ
Ph
cat. Pd(PPh3)4
Zn
Pd
25 °C
OCOPh
94%
OCOPh
The different results using diethylzinc (3a) and bis(iodo-
zincio)methane (3e) in Table 1 can be rationalized by the
following reaction pathway. It is presumed based on Tamaru’s
umpolung of allylic benzoate. As shown in Figure 2, starting
from 1, ³-allyl palladium 7 is formed via an oxidative insertion.
When a transmetallation between 7 and an organozinc 3 is
not efficient, a self-transmetallation of 7 would form bisallyl
palladium 8. In the case of Tamaru’s reaction using allylic
Table 1. Reactions of (E)-benzyl 4-acyloxybut-2-enoate 1 with
acetophenone (2a) mediated by organozinc 3 and Pd(0) catalysta
OH
Acetophenone (2a)
Organozinc 3
O
O
O
R
Ph
CH3
BnO
BnO
cat. Pd
THF, 40 °C, 12 h
O
1
4a
Tamaru reported formation of an allylic zinc by diethylzinc-
mediated umpolung of a ³-allyl palladium, which was formed
from an allylic benzoate and Pd(0) (eq 1).4b The crucial step is
considered to be transmetallation from the ³-allyl palladium
to the allylic zinc, which is driven by diethylzinc (eq 1, in
parentheses). Following Tamaru’s procedure, a mixture of (E)-
benzyl 4-(benzoyloxy)but-2-enoate (1a)5 and acetophenone (2a)
was treated with diethylzinc (3a) in the presence of a catalytic
amount of Pd(PPh3)4. Although the corresponding adduct 4a6
was formed selectively, it could not be obtained in a reasonable
yield (Entry 1). The main product was a dimer of ³-allyl
palladium intermediate [(E)-dibenzyl 5-vinylhex-2-enedioate
(6)]. Increased amount of diethylzinc did not change the yield
so much (Entry 2). Dimethylzinc (3b, Entry 3), methylzinc
iodide (3c, Entry 4), and zincate (3d, Entry 5) were examined
instead of diethylzinc (3a), but the adduct could not be obtained
in a reasonable yield in all cases. On the contrary, use of
O
O
BnO
BnO
BnO
OH
Ph
5a
H3C
O
6
Entry
R
Organozinc 3
Pd catalyst
4a/%b
1
2
3
4
5
6
7
8
9
Ph (1a, 1.1) Et2Zn (3a, 1.2)
Ph (1a, 2.2) Et2Zn (3a, 2.4)
Ph (1a, 1.1) Me2Zn (3b, 1.2)
Ph (1a, 1.1) MeZnI (3c, 1,2)
Pd(PPh3)4 (0.1)
Pd(PPh3)4 (0.2)
Pd(PPh3)4 (0.1)
Pd(PPh3)4 (0.1)
Pd(PPh3)4 (0.1)
21 (30)c
31 (30)
16 (54)d
24 (64)d
<1 (30)e
48 (23)
18 (17)
Ph (1a, 1.1) tBu3ZnLi (3d,1.2)
Ph (1a, 1.1) CH2(ZnI)2 (3e, 1.2) Pd(PPh3)4 (0.1)
Ph (1a, 1.1) CH2(ZnI)2 (3e, 1.2) Pd(P(2-Furyl)3)2 (0.1)f
Ph (1a, 1.1) CH2(ZnI)2 (3e, 1.2) Pd(P(p-Anisyl)3)2 (0.1)f 15 (25)
Ph (1a, 2,2) CH2(ZnI)2 (3e, 2.4) Pd(PPh3)4 (0.2)
61 (3)
73 (<1)
29 (16)
10 Me (1b, 2.2) CH2(ZnI)2 (3e, 2.4) Pd(PPh3)4 (0.2)
11 CF3 (1c, 2.2) CH2(ZnI)2 (3e, 2.4) Pd(PPh3)4 (0.2)
aTo a mixture of 1, 2a (1.0), and Pd catalyst in THF, organozinc 3
was added dropwise at 25 °C. The ratio of the reactants is shown in
parentheses. The whole was stirred at 40 °C for 12 h. The yields
were determined by 1H NMR using dibromomethane as an internal
standard. The numbers in parentheses are yields of recovered
acetophenone (2a). cThe dimer 6 was obtained in 48% yield.
dTrace amount of 6 (<3%) was observed. eBenzyl 5,5-dimethyl-2-
hexenoate, which is a t-Bu-adduct, was obtained in 37% yield.
fPalladium catalyst was prepared in situ from Pd2dba3 and
triarylphosphine in THF.
Reformatsky Reaction
Zn
Umpolung
R'-Zn
O
b
O
O
RO
Br
ZnX
RO
X
RO
O
PdX
Zn
Barbier Reaction
RO
Figure 1. Plausible pathway of the Reformatsky reaction and
umpolung method.
Chem. Lett. 2010, 39, 96-97
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

97
O
Table 3. Reaction of ketones 2 with allylic zinc prepared by
2
O
R
umpolung of (E)-benzyl 4-acetoxypent-2-enoate (10) with 3e and
BnO
3
1
Pd(0)a
O
1
O
Pd(0)
O
O
O
O
OH
R2 BnO
Ketone 2 (1.0)
CH3
O
O
CH
3 CH2(ZnI)2 3e (2.4)
R'-Zn (3)
BnO
BnO
+
BnO
R1
CH3
BnO
BnO
R2
R1
O
Pd(PPh3)4 (0.2)
THF, 40 °C, 10 h
Pd
O
CH3
HO
Zn
Pd
OBn
11
12
10 (2.2)
OCOR1
7
9
8
Entry
Ketone 2
11/%b
12/%b
O
acetophenone
2a
1
2
3
Cyclohexanone
Acetone
Acetonec
2c
2g
2g
<5 11a
<5 11b
<5 11b
91 12a
89 12b
72 12b
O
2
OH
O
2
BnO
3
BnO
1
CH3
BnO
1
3
BnO
HO
CH3
Ph
aTo a mixture of 1b (2.2 mmol), 2 (1.0 mmol), and Pd catalyst
(0.2 mmol) in THF, dizinc 3e (2.4 mmol) was added dropwise at
25 °C. The whole was stirred at 40 °C. bThe yields were deter-
mined by 1H NMR using dibromomethane as an internal standard.
cThe reaction period was 24 h.
Ph
O
dimer 6
adduct on C1
adduct on C3
4a
5a
Figure 2. Plausible reaction pathway.
Table 2. Reactions of ketones 2 with allylic zinc prepared by
umpolung of (E)-benzyl 4-acetoxybut-2-enoate (1b) with 3e and
Pd(0)a
used as a substrate. As shown in Table 3, treatment of 10 and a
ketone 2 with bis(iodozincio)methane (3e) in the presence of
palladium catalyst gave the adduct in good yields. Unlike
the reactions using primary acetate 1, the products were 12,
which corresponds with 5 in Table 2. As the isomerization from
5g to 4g was observed under longer reaction times in Entries 7
and 8 of Table 2, the reaction period was also prolonged to 24 h
in the reaction of 10 and acetone (Entry 3). In this case,
however, the adduct 12b was obtained in 72% yield without
formation of 11b.
Thus, we have shown umpolung of £-acyloxy-¡,¢-unsat-
urated esters to the corresponding allylic zinc reagents by use
of a gem-dizinc reagent. The reagent reacts with ketones to give
the adducts with high regioselectivity. It has been shown that
gem-dizinc possesses unique reactivity as a dianion equivalent,12
and now we have shown it to function as an efficient reducing
reagent of ³-allyl palladium.
Ketone 2 (1.0)
CH2(ZnI)2 3e (2.4)
O
OH
O
O
O
CH3
BnO
+
R2
BnO
BnO
Pd(PPh3)4 (0.2)
THF, 40 °C, 12 h
R2
R1
R1
HO
5
O
1b (2.2)
4
Entry Ketone 2
4/%b
5/%b
1
2
3
4
5
6
7
8
Acetophenone
Propiophenone
Cyclohexanone
2a
2b
2c
73 4a
47 4b
78 4c
77 4d
80 4e
63 4f
8 4g
<1 5a
<1 5b
<1 5c
<1 5d
<1 5e
<1 5f
74 5g
<1 5g
4-t-Butylcyclohexanone 2d
Cycloheptanone
2-Butanone
Acetone
Acetonec
2e
2f
2g
2g
45 4g
aTo a mixture of 1b (2.2 mmol), 2 (1.0 mmol), and Pd catalyst
(0.2 mmol) in THF, dizinc 3e (2.4 mmol) was added dropwise
at 25 °C. The whole was stirred at 40 °C. bThe yields were
determined by 1H NMR using dibromomethane as an internal
c
References and Notes
standard. The reaction period was 90 h.
1
2
3
a) R. L. Schriner, Org. React. 1942, 1, 1. b) M. W. Rathke, Org.
React. 1975, 22, 423.
J. English, Jr., J. D. Gregory, J. R. Trowbridge, II, J. Am. Chem. Soc.
1951, 73, 615.
a) S. Matsubara, N. Tsuboniwa, Y. Morizawa, K. Oshima, H. Nozaki,
Bull. Chem. Soc. Jpn. 1984, 57, 3242. b) A. Otaka, A. Yukimasa,
J. Watanabe, Y. Sasaki, S. Oishi, H. Tamamura, N. Fujii, Chem.
Commun. 2003, 1834.
benzoate (eq 1), the bisallyl palladium would not allow
reductive elimination, as it is stable. In the present case however,
electron withdrawing groups in 8 accelerate the reductive
elimination to give the dimer 6.8 In order to prevent the
formation of the dimer 6, the transmetallation to allylic zinc
species (from 7 to 9) should be accelerated by using a stronger
nucleophilic reagent. For this purpose, the dianion equivalent 3e
is considered to be more suitable.
The reaction was applied to other ketones as shown in
Table 2. In most cases, adduct 4 was obtained selectively,9 and
regioisomer 5 was not detected. When the reaction was applied
to acetone, 5g was obtained as a major product (Entry 7). The
extended reaction period, however, gave 4g as a sole product
(Entry 8). In Entries 7 and 8, the adduct 5g is formed initially,
and then isomerizes into adduct 4g, which is thermodynamically
more favored, under the reaction conditions.10 In the reaction of
using acetophenone (2a), the reaction was quenched after the
whole was stirred for 3.5 h. In the resulting mixture, the adduct
corresponding 5a was not detected. Use of an aldehyde instead
of a ketone for this transformation resulted in methylenation of
the aldehyde.11
4
a) G. Zanoni, A. Pontiroli, A. Marchetti, G. Vidari, Eur. J. Org. Chem.
2007, 3599. b) Y. Tamaru, A. Tanaka, K. Yasui, S. Goto, S. Tanaka,
Angew. Chem., Int. Ed. Engl. 1995, 34, 787. c) Y.-H. Chen, F. E.
McDonald, J. Am. Chem. Soc. 2006, 128, 4568.
M. Sada, S. Ueno, K. Asano, K. Nomura, S. Matsubara, Synlett 2009,
724.
5
6
(E)-Benzyl 5-hydroxy-5-phenylhex-2-enoate (4a): 1H NMR (CDCl3,
300 MHz): ¤ 7.5-7.2 (m, 10H), 6.90 (dt, J = 15.6, 7.2 Hz, 1H), 5.91
(dt, J = 15.6, 1.2 Hz, 1H), 5.15 (s, 2H), 2.76 (ddd, J = 14.1, 7.2,
1.2 Hz, 1H), 2.69 (ddd, J = 14.1, 7.2, 1.2 Hz, 1H), 1.89 (bs, 1H), 1.60
(s, 3H).
7
H. Yoshino, N. Toda, M. Kobata, K. Ukai, K. Oshima, K. Utimoto, S.
Matsubara, Chem.®Eur. J. 2006, 12, 721.
8
9
A. Goliaszewski, J. Schwartz, Organometallics 1985, 4, 417.
J. Nokami, K. Yoshizane, H. Matsuura, S. Sumida, J. Am. Chem. Soc.
1998, 120, 6609.
10 K.-T. Tan, S.-S. Chng, H.-S. Cheng, T.-P. Loh, J. Am. Chem. Soc.
2003, 125, 2958.
11 S. Matsubara, J. Synth. Org. Chem., Jpn. 2007, 65, 194.
12 K. Nomura, T. Hirayama, S. Matsubara, Chem. Asian J. 2009, 4,
1298.
To examine the effect of introduction of a methyl group at
the £-position of 1, (E)-benzyl 4-acetoxypent-2-enoate (10) was
Chem. Lett. 2010, 39, 96-97
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/