Mg-promoted regio- and stereoselective C-acylation of aromatic α,/β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ol016376e

(matrix presented) Treatment of aromatic α/β-unsaturated carbonyl compounds with Mg turnings in the presence of acid anhydrides/TMSCI or acyl chlorides in DMF brought about a facile and efficient cross-coupling to give C-acylation products, which are usef

Full text of DOI:10.1021/ol016376e

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3439-3442
Mg-Promoted Regio- and Stereoselective
C-Acylation of Aromatic r,â-Unsaturated
Carbonyl Compounds
Toshinobu Ohno,† Masahiro Sakai, Yoshio Ishino,† Toshihide Shibata,
Hirofumi Maekawa, and Ikuzo Nishiguchi*
Department of Chemistry, Nagaoka UniVersity of Technology, 1603-1,
Kamitomioka-cho, Nagaoka, Niigata 940-2188, Japan, and Osaka Municipal Technical
Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
nishiiku@Vos.nagaokaut.ac.jp
Received July 2, 2001
ABSTRACT
Treatment of aromatic r,â-unsaturated carbonyl compounds with Mg turnings in the presence of acid anhydrides/TMSCl or acyl chlorides in
DMF brought about a facile and efficient cross-coupling to give C-acylation products, which are useful 1,4-dicarbonyl compounds, in good to
excellent yields in a regio- and stereoselective manner. The reaction may be initiated by electron transfer from magnesium to the substrates.
Conjugate addition of an acyl anion and its equivalents to
R,â-unsaturated carbonyl compounds may be one of the most
attractive and challenging subjects for preparing 1,4-dicar-
bonyl compounds, which are important synthetic intermedi-
ates of useful cyclopentenones, cyclopenta-1,3-diones, buteno-
lides, and furans.1 However, the synthetic utility of the acyl
anion has been considerably limited because of its instability,
difficulties in generation, and treatment.2 Furthermore, ap-
plication of its chemical equivalents in organic synthesis
generally requires troublesome and complicated procedures
for their protection and deprotection.3
We previously reported the electroreductive C-acylation
of R,â-unsaturated esters and nitriles in the presence of acid
anhydrides to form γ-ketoesters and nitriles.4 We report here
Mg-promoted regio- and stereoselective C-acylation of
aromatic R,â-unsaturated carbonyl compounds 1 with acid
anhydrides/TMSCl or acyl chlorides 2 to give the corre-
sponding γ-keto carbonyl compounds 3 in good to excellent
yields. As a result of the high regio- and stereoselectivity,
facile procedure, simple equipment, high potential for large-
scale preparation, and mild reaction conditions, this reaction
seems to be one of the most promising methods for the
synthesis of compounds that may be expected to be formed
from the conjugate addition of an acyl anion to 1.
† Osaka Municipal Technical Research Institute.
(1) (a) Hassner, A. ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 1, pp 541-577. (b) Ellison, R. A.
Synthesis 1973, 397. (c) Ho, T.-L. Synth. Commun. 1974, 4, 265. (d)
Herrmann, J. L.; Schlessinger, R. H. Tetrahedron Lett. 1973, 3275-3278.
(e) Cregge, R. J.; Hermann, J. L.; Richman, J. E.; Romanet R. F.;
Schlessinger, R. H. Tetrahedron Lett. 1973, 2595-2598. (f) Hermann, J.
L.; Richman, J. E.; Romanet R. F.; Schlessinger, R. H. Tetrahedron Lett.
1973, 2599-2602. (g) Jonsson, E. U.; Johnson, C. R. J. Am. Chem. Soc.
1971, 93, 5309-5311. (h) Schneider, P. W.; Bravard, D. C.; McDonaid, J.
W.; Newton, W. E. J. Am. Chem. Soc. 1972, 94, 8641-8642. (i) Chavdarian,
C. G.; Heathcock, C. H. J. Am. Chem. Soc. 1975, 97, 3822-3823. (j)
Miyashita, M.; Yanami, T.; Yoshikoshi, A. J. Am. Chem. Soc. 1976, 98,
4679-4681.
A typical procedure is as follows. To a solution of ethyl
cinnamate (1a, 5 mmol), propionic anhydride(2b, 75 mmol),
and magnesium turnings for a Grignard reaction (15 mmol)5
in freshly distilled N,N-dimethylformamide (DMF, 50 mL)
(2) For recent reports on the generation and reaction of an acyl anion,
see: (a) Seyferth, D.; Weinstein, R. M.; Hui, R. C.; Wang, W.-L.; Archer,
C. M. J. Org. Chem. 1991, 56, 5768-5773. (b) Ryu, I.; Hayama, Y.; Hirai,
A.; Sonoda, N.; Orita, A.; Ohe, K.; Murai, S. J. Am. Chem. Soc. 1990,
112, 7061-7063. (c) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S.
J. Am. Chem. Soc. 1996, 118, 493-494 and references therein.
(3) Larock, R. C., ComprehensiVe Organic Transformation, 2nd ed.;
Wiley-VCH: New York, 1999; pp 1435-1450 and references therein.
(4) (a) Shono, T.; Nishiguchi, I.; Ohmizu, H. J. Am. Chem. Soc. 1977,
99, 7396-7397. (b) Ohno, T.; Aramaki, H.; Nakahiro, H.; Nishiguchi, I.
Tetrahedron 1996, 52, 1943-1952. (c) Kise, N.; Hirata, Y.; Hamaguchi,
T.; Ueda, N. Tetrahedron Lett. 1999, 40, 8125-8128.
10.1021/ol016376e CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/03/2001

was added trimethylsilyl chloride (TMSCl, 15 mmol) in
several portions at 5-10 °C with magnetic stirring under a
nitrogen atmosphere. The resulting solution was stirred for
15 h at room temperature. After a routine workup of the
reaction mixture, ethyl 3-phenyl-4-oxohexanoate (3b) was
isolated in a 84% yield by column chromatography.
Table 1. Mg-Promoted Regioselective Carbon-Acylation of
Aromatic Alkenoic Acid Derivatives 1a
Scheme 1
This Mg-promoted cross-coupling was remarkably ac-
celerated by the addition of TMSCl6,7 when acid anhydrides
were used as the acylating agents.
Thus, the reaction of 1a without any TMSCl after 2 h
resulted in the exclusive recovery (90%) of 1a and minor
formation (5%) of the product 3b, whereas that in the
presence of 3 molar equiv of TMSCl after 2 h led to the
major formation (62%) of 3b and minor recovery (30%) of
1a. Under the optimized conditions where the relative
proportions of 1:Mg:TMSCl:2 was 1:3:3:15, a variety of
acylated products 3a-l were obtained in good to excellent
yields from the present Mg-promoted C-acylation of aromatic
R,â-unsaturated carbonyl compounds 1a-d with the corre-
sponding acylating agents 2, as shown in Table 1.8 The
reaction proceeded smoothly with acylating agents 2 bearing
various functional substituents such as a chloro or a carbo-
methoxy group.
Because of the ready availability of various acid chlorides,
it is interesting that the use of acyl chlorides9 instead of a
combination of acid anhydrides and TMSCl as the acylating
agents did not appear to affect the reaction, and the
corresponding acylated products were obtained in good
yields. Furthermore, the reaction of ethyl cinnamate (1a) with
cyclic acid anhydrides led to the facile formation of useful
keto R,ω-dicarboxylic acid monoesters. On the other hand,
the similar reactions by electroreductive methods using acyl
chlorides or cyclic acid anhydrides resulted in a low yield
of the acylated products and the formation of complex
product mixtures.4
a The reaction was carried out at 5-10 °C for 15 h in a DMF solution
of a substrate 1, an acylating agent 2 (15 molar equiv), Mg turnings (3
molar equiv) and TMSCl (3 molar equiv, when 2 is acid anhydride). b The
phenyl group was substituted by a 1-naphthyl group. c The phenyl group
was substituted by a 2-naphthyl group.
treatment of 3-alkylated coumarins 5a-d with acid anhy-
drides 2/TMSCl gave exclusively one stereoisomer 6a-d-
[A] (isomer ratios of 6a-d[A]/6a-d[B], 92-98/8-2)10,11
of the acylated products (6a-d) with a cis-configuration
between the 3-alkyl group and the 4-acyl group, as shown
in Table 2.
Moreover, high stereoselectivity is another noteworthy
feature of the present Mg-promoted coupling. Thus, similar
On the other hand, the electroreduction of coumarin 5a in
a DMF solution containing propionic anhydride, TMSCl, and
tetraethylammonium tosylate using a divided cell equipped
with carbon rods as an anode and a cathode, followed by
the same workup procedure as that in the Mg-promoted
reaction, resulted in the formation of stereoisomeric mixtures
(yield 18%) of 6a[A] and 6a[B] (61/39) along with the
(5) Magnesium turnings for a Grignard reaction can be used without
any pretreatment.
(6) Although the detailed role of TMSCl is still unclear as described in
our recent paper on Mg-promoted reductive cross-coupling of ethyl
â-arylacylates with aldehydes, three main roles may be postulated, i.e.,
activation of the surface of magnesium metal, stabilization of anionic
intermediates generated by electron transfer from magnesium, and activation
of electrophiles by coordination to the oxygen atom of carbonyl compounds.
(7) Ohno, T.; Ishino, Y.; Tsumagari, Y.; Nishiguchi, I. J. Org. Chem.
1995, 60, 458-460.
(8) All of the products obtained in this study were characterized by a
variety of spectroscopic methods (1H NMR, 13C NMR, MS, IR) and
elemental analysis, as shown in Supporting Information.
(9) Since acyl chlorides may also be able to activate the surface of
magnesium metal, the reaction using acyl chlorides as acylating agents took
place smoothly in the absence of TMSCl.
(10) The stereochemistry of 6[A] and 6[B] was determined by detailed
analysis of the coupling constants J3H-4H between protons at the 3- and
4-positions in their 1H NMR spectra as reported in the literature.11 For
example, the values of J3H-4H for 6a[A] and 6a[B] are 4.88 and 3.91 Hz.
(11) Alberola, A.; Calvo, B.; Ortega, A. G.; Vicente, M.; Granda, S. G.;
Maelen, J. F. J. Chem. Soc., Perkin Trans. 1 1991, 203-209.
3440
Org. Lett., Vol. 3, No. 22, 2001

Scheme 3
Table 2. Mg-Promoted Stereoselective Carbon-Acylation of
Coumarin Derivatives
plausible mechanisms (Scheme 4). The first electron transfer
from magnesium to a coumarin 5 gives the corresponding
anion radical 10. Electrophilic attack of the 4-position of
the anion radical 10 by acid anhydrides may take place from
the same side of the Mg2+ cation that interacts somewhat
with the acid anhydrides, followed by the almost concerted
second electron transfer from magnesium to give a carbanion
center at the 3-position of the generated carbanion 11.
Subsequent protonation to 11 then occurs from the opposite
side of the Mg2+ cation and the 4-acyl group, leading to
exclusive formation of the single stereoisomers 6a-d[A].
The limited formation of the enol ester 8a in the Mg-
promoted coupling and the formation of a stereoisomeric
isolated yield (%)
entry
R1
R2
R3
6a
7
6[A]:6[B]
a
b
c
d
Me
Et
Me
Ph
H
H
Me
Me
Et
Et
Et
Me
33
40
41
63
43
19
97:3
98:2
98:2
92:8
a Total yield of 6[A] and 6[B].
formation of a dimerization product (7a, yield 34%), an enol
propionate (8a, yield 21%), and a dihydrocoumarin (9a, yield
12%), indicating nonstereoselective acylation in this elec-
trochemical method. A similar nonstereoselectivity was also
observed in the electroreductive acylation of 1-carbethoxy-
cyclohexene.4a
Scheme 4. Proposed Reaction Mechanism of Mg-Promoted
Carbon-Acylation of Coumarins
Scheme 2
Furthermore, treatment of the 2-propioxy-3-methyl-4-
propionylbenzopyrane(8a) with 10% aqueous H2SO4 also
gave a stereoisomeric mixture of 6a[A] and 6a[B] (58/42),
indicating that the stereoselectivity of the Mg-promoted
C-acylation did not arise in the stereoselective hydrolysis of
8a during the workup but rather in the course of the reaction
(Scheme 3).
On the basis of these experimental results, the following
reaction scheme may be proposed as one of the most
Org. Lett., Vol. 3, No. 22, 2001
3441

mixture of 6a[A] and 6a[B] upon acid-catalyzed hydrolysis
of 8a may support regioselective C-acylation at the 4-posi-
tions of anion radicals of 5a-d followed by almost concerted
second electron transfer from magnesium to give the more
stable C3-carbanion 11 rather than the less stable C4-
carbanion through the enol esterification of radical anions
of 5a-d with acid anhydride followed by almost concerted
second electron transfer.
acyl anion to the starting activated olefins, although the
present Mg-promoted reaction does not involve an acyl anion
itself as a reactive species.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Area (10208205)
from the Ministry of Education. Science, Sports and Culture,
Japan.
In conclusion, Mg-promoted cross-coupling of aromatic
R,â-unsaturated carbonyl compounds 1 with acyl chlorides
or acid anhydrides/TMSCl brought about facile, efficient,
regio- and stereoselective C-acylation to give useful 1,4-
dicarbonyl compounds 2 in good to excellent yields and had
some desirable features in comparison with the electrochemi-
cal methods.4 These acylated products are identical to those
formed by the conjugated addition of a difficult-to-generate
Supporting Information Available: Experimental pro-
cedure for the reaction of 1 and 5 with acid anhydride/
trimethylsilyl chloride or acyl chloride and spectroscopic data
for the products 3a-l, 6a-d, 7a,b, 8a, and 9a. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL016376E
3442
Org. Lett., Vol. 3, No. 22, 2001