A novel synthesis of 2,4,4-trisubstituted 2-cyclopentenones by consecutive reaction of 1-chlorovinyl p-tolyl sulfoxides with acetonitrile and its homologues

Article abstract of DOI:10.1016/j.tetlet.2003.08.004

1-Chlorovinyl p-tolyl sulfoxides were synthesized from several kinds of ketones and chloromethyl p-tolyl sulfoxide in three steps in high overall yields. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium (lithium α-carbanion of ace

Full text of DOI:10.1016/j.tetlet.2003.08.004

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7517–7520
A novel synthesis of 2,4,4-trisubstituted 2-cyclopentenones by
consecutive reaction of 1-chlorovinyl p-tolyl sulfoxides with
acetonitrile and its homologues
Tsuyoshi Satoh* and Daisuke Wakasugi
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 11 July 2003; revised 30 July 2003; accepted 1 August 2003
Abstract—1-Chlorovinyl p-tolyl sulfoxides were synthesized from several kinds of ketones and chloromethyl p-tolyl sulfoxide in
three steps in high overall yields. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium (lithium a-carbanion
of acetonitrile) at low temperature gave the adducts in almost quantitative yields. The adducts were then treated with LDA
followed by excess lithium a-carbanion of the homologues of acetonitrile to afford 3,5,5-trisubstituted cyclopentadienyl
enaminonitriles, which were hydrolyzed and heated under acidic conditions to give 2,4,4-trisubstituted 2-cyclopentenones in good
overall yields.
© 2003 Elsevier Ltd. All rights reserved.
The 2-cyclopentenone ring system is obviously one of
the most widely found carbon structures in natural and
unnatural organic compounds. In addition, 2-cyclopen-
tenones are quite important intermediates in synthetic
organic chemistry.1 Many methods, including the
Nazarov cyclization2 and the Pauson–Khand reaction,3
have already been reported for the construction of
2-cyclopentenones; however, in view of the importance
of 2-cyclopentenone derivatives in organic synthesis,
new methods are still very important and welcome.
and chloromethyl p-tolyl sulfoxide to give 1-chlorovinyl
p-tolyl sulfoxides 2, which are treated with excess
cyanomethyllithium to afford cyclopentadienyl enam-
inonitriles 3. The enaminonitriles 3 are heated with
H3PO4 in acetic acid to give 4,4-disubstituted 2-
cyclopentenones 4 in high overall yields (Scheme 1).
As this method is quite useful for the synthesis of
substituted 2-cyclopentenones, we further investigated
the reaction of 2 with several lithium a-carbanions of
the homologues of acetonitrile. However, for example,
the reaction of 2 with lithium a-carbanion of propioni-
trile gave only a complex mixture. Finally, we found a
quite interesting and versatile method for the synthesis
Recently, we reported a new method for the synthesis,
including asymmetric synthesis, of 4,4-disubstituted 2-
cyclopentenones 4.4 The method starts from ketones 1
Scheme 1.
Keywords: 1-chlorovinyl p-tolyl sulfoxide; acetonitrile; enaminonitrile; 2,4,4-trisubstituted 2-cyclopentenone; Thorpe–Ziegler reaction.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.004

7518
T. Satoh, D. Wakasugi / Tetrahedron Letters 44 (2003) 7517–7520
Scheme 2.
of 2,4,4-trisubstituted 2-cyclopentenones 8. The essence
of the reaction is as follows. First, 1-chlorovinyl p-tolyl
sulfoxides 2 are treated with cyanomethyllithium at
−78°C to give the adducts 5 in near quantitative yields.
After purification, 5 are again treated with LDA fol-
lowed by excess lithium a-carbanion of homologues of
acetonitrile 6 to afford the cyclopentadienyl enaminoni-
triles 7, which are heated with H3PO4 to afford the
2,4,4-trisubstituted 2-cyclopentenones 8 in good overall
yields from 2 (Scheme 1).
amount of water for about 30 h to afford the desired
2,4,4-trisubstituted-2-cyclopentenones 12a and 12b in
93 and 83% yields, respectively (Scheme 2).
To ascertain the generality of this procedure, we syn-
thesized two 1-chlorovinyl p-tolyl sulfoxides from 1,4-
cyclohexanedione mono-ethylene ketal and benzo-
phenone and reacted them first with cyanomethyl-
lithium (Table 1). As shown in Table 1, the adducts
were obtained in 99 and 93% yields, respectively. With
these adducts, a-carbanions of propionitrile (entries 1
and 5) and butyronitrile (entries 2 and 6) were reacted.
The desired enaminonitriles were obtained in 55ꢀ76%
yield. The enaminonitriles were converted to the desired
2,4,4-trisubstituted 2-cyclopentenones under the above-
mentioned conditions without any problem in 72ꢀ89%
yield.
A representative example is described for the synthesis
of 2,4,4-trisubstituted 2-cyclopentenones 12 from 1-
chlorovinyl p-tolyl sulfoxide 9 and acetonitrile, propi-
onitrile, and butyronitrile as shown in Scheme 2. A
THF solution of 1-chlorovinyl p-tolyl sulfoxide 9,
derived from cyclopentadecanone and chloromethyl p-
tolyl sulfoxide,5 was added to a solution of three equiv-
alents of cyanomethyllithium in THF at −78°C and the
reaction mixture was stirred for 10 min. This reaction
gave the adduct 10 as a mixture of two diastereomers in
97% yield after silica gel column chromatography. A
solution of 10 was added to a solution of LDA (3
equiv.) at −78°C and the reaction mixture was stirred
for 30 min. To this was added lithium a-carbanion of
propionitrile (4 equiv.), which was generated from pro-
pionitrile and n-BuLi at −78°C, through a cannula and
the whole was slowly allowed to warm to room temper-
ature over 2.5 h. This treatment gave the desired
cyclopentadienyl enaminonitrile 11a in 80% yield. The
same treatment of 10 with butyronitrile afforded 11b in
a similar yield.
Interestingly, (4-methoxyphenyl)acetonitrile (entries 4
and 7) gave the aromatic ring-substituted 2-cyclopen-
tenones in good overall yields; especially in entry 4, the
two-step overall yield was 89%. The result in entry 3 is
much more interesting; by our method a highly hin-
dered triphenylmethyl group can be introduced at the
2-position of the 2-cyclopentenone by using 3,3,3-
triphenylpropionitrle. The generality of this reaction
was confirmed by these results.
Table 2 shows the results for the reaction of the adduct
10 and various kinds of the homologues of acetonitrile.
A long carbon chain can be introduced at the 2-posi-
tion of the cyclopentenone to give 12c in good overall
yield (entry 1). 3-Methylbutyronitrile gave isopropyl
group-substituted 2-cyclopentenone 12d without any
The presumed mechanism of this reaction is illustrated
in Scheme 3. Treatment of the adduct 5 with LDA gives
the lithium a-sulfinyl carbanion 13. Elimination of
lithium chloride from the carbanion 13 results in the
formation of the a-sulfinyl carbenoid 14 upon warming
of the reaction mixture. Lithium a-carbanion of the
homologues of the acetonitrile 6 adds to the elec-
trophilic carbon of the carbenoid 14 to give the a-sulfi-
nyl carbanion of dinitrile 15. Finally, this dinitrile 15
cyclizes under highly basic conditions (the Thorpe–
Ziegler reaction)6 with concomitant elimination of the
p-toluenesulfenyl anion to give the enaminonitrile 7.
The enaminonitriles 11a and 11b were heated under
reflux in acetic acid containing H3PO4 and a small
Scheme 3.

T. Satoh, D. Wakasugi / Tetrahedron Letters 44 (2003) 7517–7520
7519
Table 1. Synthesis of 2,4,4-trisubstituted 2-cyclopentenones from 1-chlorovinyl p-tolyl sulfoxides via the cyclopentadienyl
enaminonitriles
Table 2. Synthesis of various kinds of 2,4,4-trisubstituted 2-cyclopentenones 12 from 1-chlorovinyl p-tolyl sulfoxides derived
from cyclopentadecanone via the cyclopentadienyl enaminonitriles 11
problem in good overall yield (entry 2). As shown in
entry 3, a highly hindered substituent, triphenylmethyl
group, again could be introduced by this reaction;
however, in this case the yield of 12e was shown to be
somewhat lower than that in Table 1, entry 3.
of 2,4,4-trisubstituted 2-cyclopentenones. As it has been
recognized that the transformation of 2-cyclopen-
tenones to 2-substituted 2-cyclopentenones is no easy
task,7 this procedure will become a quite important
method for the synthesis of 2,4,4-trisubstituted 2-
cyclopentenones.
Entry 4 shows that the cyclopentadienyl enaminonitrile
having a conjugated olefin could be obtained without
problem; however, the acidic treatment gave only 24%
yield of 12f. Aromatic group-substituted 2-cyclopen-
tenone 12g was again obtained without problem in
good overall yield.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research No. 11640545 from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan,
which is gratefully acknowledged.
In conclusion, we have presented herein a new, rela-
tively short, and quite versatile procedure for synthesis

7520
T. Satoh, D. Wakasugi / Tetrahedron Letters 44 (2003) 7517–7520
mond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263 and
References
references cited therein.
1. Some recent reviews and a monograph for construction of
cyclic compounds including cyclopentenones: (a) Ho, T.-L.
Carbocyclic Construction in Terpene Synthesis; VCH Pub-
lishers, Inc.: Weinheim, 1988; (b) Thebtaranonth, C.;
Thebtaranonth, Y. Tetrahedron 1990, 46, 1385; (c) Petasis,
N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757; (d)
Booker-Milburn, K. I.; Sharpe, A. J. Chem. Soc., Perkin
Trans. 1 1998, 983.
4. (a) Satoh, T.; Ota, H. Tetrahedron 2000, 56, 5113; (b)
Satoh, T.; Yoshida, M.; Ota, H. Tetrahedron Lett. 2001,
42, 9241; (c) Satoh, T.; Yoshida, M.; Takahashi, Y.; Ota,
H. Tetrahedron: Asymmetry 2003, 14, 281.
5. Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda, K.;
Koyama, M. Tetrahedron 1998, 54, 5557.
6. (a) Baldwin, S. J. Org. Chem. 1961, 26, 3280; (b) Baldwin,
S. J. Org. Chem. 1961, 26, 3288; (c) Schaefer, J. P.;
Bloomfield, J. J. Org. React. 1967, 15, 1; (d) Brown, C. A.
Synthesis 1975, 326; (e) Mundy, B. P.; Ellerd, M. G. Name
Reactions and Reagents in Organic Synthesis; John Wiley
and Sons: New York, 1988; pp. 208–209; (f) Davis, B. R.;
Garratt, P. J. In Comprehensive Organic Synthesis; Trost,
B. M.; Heathcock, C., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, p. 848; (g) Takaya, H.; Naota, T.; Mura-
hashi, S.-i. J. Am. Chem. Soc. 1998, 120, 4244; (h) Flem-
ing, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
7. Rezgui, F.; Amri, H.; Gaied, M. M. E. Tetrahedron 2003,
59, 1369.
2. (a) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986,
86, 857; (b) Habermas, K. L.; Denmark, S. E.; Jones, T.
K. Org. React. 1994, 45, 1.
3. (a) Pauson, P. L. Tetrahedron 1985, 41, 5855; (b) Schore,
N. E. Org. React. 1991, 40, 1; (c) Belanger, D. B.; O’Ma-
hony, D. J. R.; Livinghouse, T. Tetrahedron Lett. 1998, 39,
7637; (d) Belanger, D.; Livinghouse, T. Tetrahedron Lett.
1998, 39, 7641; (e) Ishizaki, M.; Iwahara, K.; Kyoumura,
K.; Hoshino, O. Synlett 1999, 587; (f) Brummond, K. M.;
Kent, J. L. Tetrahedron 2000, 56, 3263; (g) Perez-Serrano,
L.; Blanco-Urgoiti, J.; Casarrubios, L.; Dominguez, G.;
Perez-Castells, J. J. Org. Chem. 2000, 65, 3513; (h) Brum-
8. Bose, D. S.; Jayalakshmi, B. Synthesis 1999, 64.