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I. Nishiguchi et al. / Tetrahedron Letters 43 (2002) 635–637
Table 1. Mg-promoted C-acylation of aromatic carbonyl
compounds (1) with acid chlorides (2)
rides 2 depending on a decrease in bulkiness of the
substituent R2 under the reaction conditions.
Entry
Aromatic carbonyl
compound (1)
Acid
chloride (2)
Product (3)
In order to obtain useful information for the reaction
mechanism of the present reductive cross-coupling,
some control experiments were accomplished. First, it
was found that a difference in the addition mode led to
a large effect on product yield. Thus, the dropwise
addition of a DMF solution of propionyl chloride (2a)
into a suspension of m-chlorobenzaldehyde (1d) and
Mg metal in DMF afforded 1-propioxy-1-(m-
chlorophenyl)butan-2-one (3e) and dimeric 1,2-(m-
chlorophenyl)pinacol derivative (5e) in 55 and 32%
yields, respectively, while the dropwise addition of a
DMF solution of 1d into a solution of 2a and Mg metal
in DMF brought about exclusive formation of 3e (Y=
98%) accompanying none of 5e, as shown in Scheme 1.
X
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
H
H (1a)
C2H5 (2a)
C2H5 (2a)
C3H7 (2b)
C3H7 (2b)
C2H5 (2a)
C3H7 (2b)
C2H5 (2a)
C3H7 (2b)
C2H5 (2a)
CH3 (2c)
C2H5 (2a)
C3H7 (2b)
i-C3H7 (2d) 93 (3m)
t-C4H9 (2e) 99 (3n)
C2H5 (2a)
C2H5 (2a)
C2H5 (2a)
C2H5 (2a)
C2H5 (2a)
C2H5 (2a)
61 (3a)
71 (3b)
77 (3c)
79 (3d)
98 (3e)
84 (3f)
65 (3g)
76 (3h)
51 (3i)
56 (3j)
58 (3k)
61 (3l)
m-OCH3
m-OCH3
m-F
m-Cl
m-Cl
p-Cl
p-Cl
p-CH3
H
H
H
H
H
H (1b)
H (1b)
H (1c)
H (1d)
H (1d)
H (1e)
H (1e)
H (1f)
CH3 (1g)
CH3 (1g)
CH3 (1g)
CH3 (1g)
CH3 (1g)
C2H5 (1h)
i-C3H7 (1i)
C6H5 (1j)
CH3 (1k)
CH3 (1l)
CH3 (1m)
9
10
11
12
13
14
15
16
17
18
19
20
Secondly, use of propionic anhydride instead of propi-
onyl chloride as an acylating agent in the reaction of 1d
resulted in the formation of three types of products,
C-acylation product 3e, simply hydrogenated benzylic
alcohol ester 4e, and dimeric product 5e in 42, 15 and
33% yields, respectively. Furthermore, treatment of
phenacyl derivatives 6 possessing an acetoxy or a
methoxy group with Mg metal in the presence of
aliphatic acid chlorides (2a,e) under similar conditions
led to selective formation of the corresponding enol
esters 7 as the main products in satisfactory yields
(Scheme 2).
H
H
H
49 (3o)
30 (3p)
89 (3q)
91 (3r)
73 (3s)
70 (3t)
m-Cl
p-Cl
m-OCH3
Reaction conditions: Substrate 1 (10 mmol), acid chloride 2 (100
mmol), Mg (50 mmol), DMF (50 mL), temp. 5–15°C, one night,
under a N2 atmosphere.
Although detailed reaction mechanisms of the present
Mg-promoted C-acylation of carbonyl compounds 1
are not clear as yet, these experimental facts indicate
that the reductive coupling proceeds through radical
anion intermediates 8A and 8B, generated by electron
transfer from Mg metal to aromatic carbonyl com-
pounds 1a–m and 6a–d. In the case that the substituent
Y is an alkyl group, the intermediates 8A are subjected
to subsequent electrophilic attack of acid chlorides 2
followed by the second electron transfer from Mg-metal
to generate the O-anions 9, and dimerization of 8B
affords the O,O%-dianions 10. On the other hand, elimi-
nation of Y from 8A followed by the second electron
transfer takes place predominantly to give the enolate
anions 11 when Y is a methoxy or an acetoxy group
(Scheme 3).
brought about a considerable increase in yield of the
desired products 3, whereas electron-donating groups
on the aromatic ring of 1 gave a decrease in that of 3,
providing a good correlation in Hammett’s plot (yield
of 3 versus s) possessing a positive z-value (a series of
entries 1, 2, 4, 5, 7, 9, and that of entries 10, 18, 19, 20).
Furthermore, steric hindrance around the carbonyl car-
bon atoms of 1 gave a significant influence on the yield
of 3. Thus, as the substituent R1 of 1 is more bulky, the
yield of 3 distinctly decreased (entries 11, 15, 16). On
the other hand, it may be quite noteworthy that an
increase in bulkiness of the substituent R2 of aliphatic
acid chlorides 2 brought about a remarkable increase in
yield of the products 3 (entries 10–14). This unexpected
phenomenon may suggest some instability of acid chlo-
COC2H5
CH
OCOC2H5
OCOC2H5
H
Mg
+
CHO
C2H5COCl
C
H
C
+
DMF
Cl
Cl
Cl
Cl
H5C2OCO
1d
2a
3e
5e
Dropwise Addition of 1d into
a DMF solution of 2a and Mg
98%
0%
Dropwise Addition of 2a into
a DMF solution of 1d and Mg
55%
32%
Scheme 1. Effect of the addition mode.