Trialkylamine-mediated intramolecular acylation of akenes with carboxylic acid chlorides

Article abstract of DOI:10.1248/cpb.58.591

Trialkylamine-mediated intramolecular cyclization of pent-4-enoyl chlorides was studied. Substitution with a tertiary alkyl group at the 2-position gave cyclopent-2-en-1-ones, while substitution with an aromatic group gave enol esters, which were formed by O-acylation of initially formed 3-chlorocyclopentanones with ketenes.

Full text of DOI:10.1248/cpb.58.591

April 2010
Communications to the Editor
Chem. Pharm. Bull. 58(4) 591—592 (2010)
591
(3)
Trialkylamine-Mediated Intramolecular
Acylation of Akenes with Carboxylic
Acid Chlorides
Jun-ichi MATSUO,* Takaya HOSHIKAWA,
Shun SASAKI, and Hiroyuki ISHIBASHI
It should be noted that 3-chlorocyclopentanone 8, which
might be a precursor of 7, was obtained in 45% yield as a
single diastereomer7) and ketene 9 was isolated in 8% yield
after preparative thin-layer chromatography on silica gel.8—10)
The isolation of 8 and 9 suggests that an internal alkyl group
retards the intramolecular cyclization due to its steric effect.
On the other hand, reaction of carboxylic acid chloride 10
bearing a phenyl group at the 2-position did not give the
expected cyclopentenone 11, whereas an enol ester 12 was
obtained in 74% yield as a mixture of diastereomers (drꢁ
54 : 46) (Eq. 4).
School of Pharmaceutical Sciences, Institute of Medical,
Pharmaceutical and Health Sciences, Kanazawa University;
Kakuma-machi, Kanazawa 920–1192, Japan.
Received December 3, 2009; accepted January 14, 2010; published
online January 15, 2010
Trialkylamine-mediated intramolecular cyclization of pent-4-
enoyl chlorides was studied. Substitution with a tertiary alkyl
group at the 2-position gave cyclopent-2-en-1-ones, while substi-
tution with an aromatic group gave enol esters, which were
formed by O-acylation of initially formed 3-chlorocyclopen-
tanones with ketenes.
(4)
Key words intramolecular cyclization; carboxylic acid chloride; alkene;
allyl ketene
During our investigation on Lewis acid-catalyzed in-
Effects of substituents on the aryl group of 2-arylpent-4-
tramolecular [4ꢀ2] cycloaddition of 2-allyl-3-ethoxycy- enoyl chlorides 13 were then investigated to clarify the scope
clobutanones,1—4) we tried to prepare 2-allyl-3-ethoxy-2- and limitations of the formation of a novel dimerization
tritylcyclobutanone 2 by [2ꢀ2] cycloaddition under standard product 14 (Table 1). Substitution of a p-chloro group gave
conditions of employing 2-tritylpent-4-enoyl chloride 1, ethyl enol ester 14a in 59% yield (entry 1) while enol esters 14b, c
vinyl ether, and triethylamine. However, the desired product bearing p-methyl and p-methoxy groups, which were found
2 was not obtained, whereas a cyclopentenone 3 was ob- to be hydrolyzed more easily during purification by column
tained in 75% yield (Eq. 1).
chromatography on silica gel, were obtained in moderate to
low yields (entries 2, 3). Thus, substitution of the aryl group
with an electron-withdrawing group gave enol esters 14 more
efficiently partly because of the increased stability of 14
against hydrolysis.11)
(1)
Methanolysis of the obtained enol ester 14a in the pres-
Intramolecular acylation of olefin has been conventionally ence of an equimolar amount of 4-(dimethylamino)pyridine
carried out by Friedel–Crafts reaction of alkenyl acid chlo- (DMAP) gave methyl ester 15 and cyclopentenone 16 in 90%
rides by using a Lewis acid such as AlCl3,5) but the observed and 64% yields, respectively (Eq. 5).
base-promoted intramolecular cyclization has not been re-
ported to date. We report here the scope and limitations on
the present base-promoted intramolecular acylation of a car-
(5)
bon-carbon double bond of acid chlorides.
Investigation of reaction conditions for conversion of 1 to
3 in the absence of ethyl vinyl ether revealed that 3 was ob-
tained in 79% yield by using 1.2 eq of ethyldiisopropylamine
at 90 °C for 11 h (Eq. 2).6)
Table 1. Cyclization of 2-Arylpent-4-enoyl Chlorides
(2)
The reaction proceeded more smoothly in acetonitrile than
in toluene. Carboxylic acid chloride 4 having a t-butyl group
at the 2-position also gave the corresponding cyclopentenone
5 in 52% isolated yield (90 °C for 3 h).
Next, cyclization of an internal alkenyl group was exam-
ined by using 2-crotyl-2-tritylacetyl chloride 6. The cycliza-
tion of 6 was found to proceed slowly, and cyclopentenone 7
was obtained in low yield (14%) (Eq. 3).
Entry
X
14
% yielda)
1
2
3
Cl
Me
MeO
14a
14b
14c
59b)
50
20
a) Determined by 1H-NMR analysis unless otherwise noted (% yieldꢁmol of
14/2ꢂmol of 13). b) Isolated yield.
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: jimatsuo@p.kanazawa-u.ac.jp

592
Vol. 58, No. 4
cation, Culture, Sports, Science and Technology, Japan.
References and Notes
1) Matsuo J., Sasaki S., Hoshikawa T., Ishibashi H., Chem. Commun., 46,
934—936 (2010).
2) Matsuo J., Sasaki S., Tanaka H., Ishibashi H., J. Am. Chem. Soc., 130,
11600—11601 (2008).
3) Matsuo J., Sasaki S., Hoshikawa T., Ishibashi H., Org. Lett., 11,
3822—3825 (2009).
4) Matsuo J., Negishi S., Ishibashi H., Tetrahedron Lett., 50, 5831—5833
(2009).
5) Review: Groves J. K., Chem. Soc. Rev., 1, 73—97 (1972).
6) Yields of intramolecular cyclized products described here are based on
the corresponding carboxylic acids. Conversion of carboxylic acids to
carboxylic acid chlorides was carried out by using oxalyl chloride.
7) The stereochemistry of compound 8 was determined by NOE experi-
ments.
8) Biali S. E., Gozin M., Rappoport Z., J. Phys. Org. Chem., 2, 271—280
(1989).
Chart 1. Proposed Mechanism for Trialkylamine-Promoted Intramolecu-
lar Acylation of Alkenes with Carboxylic Acid Chlorides
9) Olah G. A., Wu A., Farooq O., Synthesis, 1989, 568 (1989).
10) Kaprinidis N. A., Woning J., Schuster D. I., J. Org. Chem., 57, 755—
757 (1992).
11) The electron-withdrawing group might increase the acidity at the a-
position of 20.
12) Allyl trityl ketene was isolated in 32% yield by treatment of 1 with
ethyldiisoproylamine at 90 °C for 5 min. Cyclization of isolated allyl
trityl ketene in the absence of any additives took place very slowly (in
acetonitrile, 90 °C, 7 d) to afford 3 in only 31% yield. On the other
hand, cyclization of allyl trityl ketene in the presence of diisopropyl-
ethyamine hydrochloride took place smoothly to afford 3 in 67% yield
(in acetonitrile, 90 °C, 11 h).
13) Otherwise, ring cleavage of a bicyclo[2.1.0]pentan-2-one derivative,
which might be formed by intramolecular [2ꢀ2] cycloaddition of 18,
may proceed to give 20, though bicyclo[2.1.0]pentan-2-ones were not
isolated in this study.
A proposed mechanism for the present amine-mediated in-
tramolecular cyclization is shown in Chart 1. Treatment of
carboxylic acid chloride 17 with trialkylamine gives ketene
18, and intramolecular attack of the alkenyl group to the
ketene carbonyl group which is activated by ammonium
ion12) gives 3-chloropentanone 20 via a transition state 19.13)
When R is an alkyl group, dehydrochlorination with a base
proceeds to give cyclopentenone 21. The presence of an aryl
group as R makes ketone 20 more enolizable, and enol ester
22 is formed by O-acylation of 20 with ketene 18.
In summary, we have found that treatment of pent-4-enoyl
chlorides with trialkylamine gave intramolecular cyclized
products. The structure of products strongly depended on the
substituent at the 2-position: a tertiary alkyl group14) gave cy-
clopentenones, whereas an aryl group gave enol esters. The
present study gives new aspects in the chemistry of allyl
ketenes.15,16)
14) Substitution with diphenylmethyl or benzyl groups at the 2-position (R
of 17) gave the corresponding cyclopentenones 21 in 14% and 7%
yields, respectively. Therefore, substitution of a tertiary alkyl group is
required for efficient cyclization to a cyclopentenone derivative 21.
15) Staudinger H., Schneider H., Schotz P., Strong P. M., Helv. Chim. Acta,
6, 291—303 (1923).
16) Sponsler M. B., Dougherty D. A., J. Org. Chem., 49, 4978—4984
(1984).
Acknowledgments This study was financially supported by a SUNBOR
grant and a Grant-in-Aid for Scientific Research from the Ministry of Edu-