A novel tandem [2 + 2] cycloaddition-Dieckmann condensation: Facile one- pot process to obtain 2,3-disubstituted-2-cycloalkenones from ynolates [6]

Full text of DOI:10.1021/ja990656w

J. Am. Chem. Soc. 1999, 121, 6507-6508
6507
A Novel Tandem [2 + 2] Cycloaddition-Dieckmann
We previously described the reactions of alkyl-substituted
Condensation: Facile One-Pot Process To Obtain
ynolates with aldehydes at -78 °C which give 2:1 adducts (e.g.,
5
), due to the nucleophilicity of the intermediate enolate 4a higher
2
,3-Disubstituted-2-cycloalkenones from Ynolates
Mitsuru Shindo,* Yusuke Sato, and Kozo Shishido
Institute for Medicinal Resources
2
than that of the ynolate (Scheme 3). This result would indicate
Scheme 3
UniVersity of Tokushima
Sho-machi 1 Tokushima 770-8505, Japan
ReceiVed March 1, 1999
Ynolate anions (1) are ketene anion equivalents, and their
1
chemistry is very attractive. Recently, we have developed a novel
and useful method for the generation of lithium ynolates via the
cleavage of ester dianions prepared from readily available R,R-
2
dibromo esters (2) (Scheme 1) and have demonstrated new
Scheme 1
3
reactions using ynolates. It has been known that the [2 + 2]
4
cycloaddition of ynolates with aldehydes affords highly reactive
intermediates, â-lactone enolates.2,3a,5 This suggests that a well-
the difficulty of tandem reactions utilizing 4a in this system
because the â-lactone enolates would be immediately trapped by
the aldehyde. To achieve a tandem reaction of â-lactone enolates
derived from ynolates, the reactivity of the enolates (4) should
be less than that of the ynolates. After surveying a range of
electrophiles, we have found that ketones (e.g., pentyl phenyl
ketone, 3b) provide â-lactones (6) by the reaction with alkyl-
substituted ynolates at -78 °C, followed by protonation with
designed reaction using ynolates could make one-pot multistep
synthesis possible via intermediate â-lactone enolates, including
those not available via enolization of the corresponding â-lactones.
Herein, we describe a novel methodology of tandem [2 + 2]
cycloaddition-Dieckmann condensation, taking advantage of
these characteristics of ynolates, and demonstrate a facile one-
pot synthesis of synthetically useful 2,3-disubstituted-2-cyclo-
alkenones as an application for the described methodology
4
saturated aqueous NH Cl (Scheme 3). This product could be easily
decarboxylated to form olefin 7, as a 2:1 mixture of isomers, in
(Scheme 2).
6
good overall yield from 3b. If the ketone 3 possessed another
electrophilic center in the molecule, an intramolecular cyclization
would proceed to provide bicyclic â-lactones, leading to the
formation of synthetically useful disubstituted cycloalkenes.
Scheme 2
On the basis of this concept, we selected γ- or δ-keto esters as
substrates, expecting the realization of the tandem [2 + 2]
cycloaddition-Dieckmann condensation. This process is exempli-
fied by the following: To a solution of ynolate (1a), prepared
from R,R-dibromo ester (1.0 mmol) and a solution of t-BuLi (4.0
mmol, 1.4 M in pentane) at -78 °C for 3 h and 0 °C for 0.5 h in
THF, was added a solution of ethyl 5-oxo-5-phenylpentanoate
(
8a, 0.8 mmol) in THF, and the mixture was then stirred for 5 h
at -78 °C. After the usual workup, acid-catalyzed decarboxylation
refluxing in benzene in the presence of a catalytic amount of
(
(
1) Review: Shindo, M. Chem. Soc. ReV. 1998, 27, 367-374.
2) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433-4436. (b) Shindo,
7
(
silica gel: method A) was conducted without purification of
â-lactone (10aa). After filtration and concentration, 2-butyl-3-
phenyl-2-cyclohexenone (11aa) was isolated in a 74% yield along
with 6% of ethyl 5-phenyl-5-decenoate (12), which was derived
from uncyclized â-lactone (9aa) (Scheme 4). This is the first
example of the tandem [2 + 2] cycloaddition-Dieckmann
M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54, 2411-2422.
(
3) (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998, 39,
4
857-4860. (b) Shindo, M.; Oya, S.; Sato, Y.; Shishido, K. Heterocycles
1
998, 49, 113-116.
(
4) Stepwise mechanism cannot be ruled out, but in this manuscript, [2 +
2
] cycloaddition is used as a matter of convenience.
5) (a) Sch o¨ llkopf, U.; Hoppe, I. Angew. Chem., Int.. Ed. Engl. 1975, 14,
65. (b) Hoppe, I.; Sch o¨ llkopf, U. Liebigs Ann. Chem. 1979, 219-226. See
(
7
8
condensation (Table 1).
also ref 1. For examples of â-lactone chemistry, see: (c) Mulzer, J.;
Chucholowski, A. Angew. Chem., Int. Ed. Engl. 1982, 21, 777-778. For
reviews see: (d) Pons, J.-M.; Pommier, A. Synthesis 1993, 441-459. (e)
Mulzer, J. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 342-350.
(6) Mechanistic investigations: Morao, I.; Lecea, B.; Arrieta, A.; Cossio,
F. P. J. Am. Chem. Soc. 1997, 119, 816-825 and references therein.
(7) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185.
1
0.1021/ja990656w CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/25/1999

6508 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
Communications to the Editor
Scheme 4
with 3% HCl-EtOH, followed by immediate refluxing of the
resulting bicyclic â-lactones (decarboxylation method B). As a
result, the desired products (11) were successfully obtained in
higher yields (entry 4, 7, 9, 10). By this improved procedure, a
facile one-pot synthesis of 2,3-disubstituted cycloalkenones was
achieved. The utility of this transformation has been demonstrated
by the accomplishment of the concise syntheses of dihydrojas-
9
mone (11ed) and a potential intermediate of R-cuparenone
(
(
11be).10 A keto-diester (8f) also gave the desired cyclopentenone
11bf), which demonstrates that the method will work with
substrates having other ester functions.
â-Lactone 13, obtained by protonation of the lactone enolate
9
aa, did not give 10aa by treatment with LDA at -78 °C, but
decomposed (Scheme 5). This indicates that the direct generation
Scheme 5
Table 1. Tandem [2 + 2] Cycloaddition-Dieckmann
Condensation: Synthesis of 2,3-Disubstituted-2-cycloalkenones
of the enolate 9aa from the â-lactone 13 is very difficult. Use of
the ynolate anion has indeed solved this problem, however,
allowing regioselective formation of the enolate via [2 + 2]
cycloaddition, prior to Dieckmann condensation.
In conclusion, we have developed a novel tandem [2 + 2]
cycloaddition-Dieckmann condensation via ynolate anions and
achieved a facile synthesis of 2,3-disubstituted-2-cycloalkenones
in good yields. The salient feature of ynolate anions as a ketene
anion equivalent includes the selective formation of reactive
intermediates such as enolate anions via a course different from
enolization of the corresponding carbonyl compounds. This result
demonstrates that ynolate anions have much potential as players
in new reaction sequences, especially tandem reactions.
tandem
reaction
decar-
ynolate
keto ester
R′
temp/ time/ boxyl-
°C
yield/
%
a
entry
1
R
8
n
h
ation
11
1
2
3
4
5
6
7
8
9
1a Bu
8a Ph
8a Ph
2
2
2
2
2
1
1
1
1
1
1
1
-78
-78
5
3
A
A
A
B
A
A
B
A
B
B
A
B
11aa
11ba
11ab
11ab
74
89
78
89
1b Me
1a Bu
1a Bu
1b Me
1a Bu
1a Bu
1a Bu
1b Me
1b Me
Acknowledgment. This work was supported by Grants-in-Aid for
Scientific Research on Priority Areas (No. 283, “Innovative Synthetic
Reactions”) from the Ministry of Education, Science, Sports and Culture,
Government of Japan, and the Eisai Award in Synthetic Organic
Chemistry, Japan.
8b Me
8b Me
8b Me
8c Ph
8c Ph
8d Me
8c Ph
8e Tol
-78 1.5
-78 1.5
-78 1.5
-40 1.5
-78 1.5
-78 1.5
-78 1.5
-78 1.5
-78 1.5
11bb 54
11ac
11ac
11ad
11bc
63
89
83
84
Supporting Information Available: Synthetic procedures and char-
acterization data for 11aa-11bf (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
1
1
1
0
1
2
11beb 76
1e pentyl 8d Me
1b Me 8f EtO
2 2
CH )
11ed
11bf
80
60
JA990656W
2
C-
-78
2
(
(8) A review for Dieckmann condensation: Davis, D. R.; Garratt, P. J. In
ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-
mon: Oxford, 1991; Vol. 2, pp 795-863. Recent examples for tandem Michael
addition-Dieckmann condensation: Tatsuta, K.; Yamazaki, T.; Mase, T.;
Yoshimoto, T. Tetrahedron Lett. 1998, 39, 1771-1772. Kobayashi, K.; Maeda,
K.; Uneda, T.; Morikawa, O.; Konishi, H. J. Chem. Soc., Perkin Trans. 1,
a
Method A: A solution of 10 in benzene was refluxed in the
presence of silica gel. Method B: A reaction mixture of 10 was
quenched with 3% HCl-EtOH and the resulting solution was refluxed.
Dihydrojasmone.
b
1
997, 443-446. Maiti, S.; Bhaduri, S.; Achari, B.; Banerjee, A. K.; Nayak,
N. P.; Mukherjee, A. K. Tetrahedron Lett. 1996, 44, 8061-8062. Groth, U.;
Halfgang, W.; K o¨ hler, T.; Kreye, P. Liebigs Ann. Chem. 1994, 885-890.
Honda, T.; Mori, M. Chem. Lett. 1994, 1013-1016. Periasamy, M.; Reddy,
M. R.; Radhakrishnan, U.; Devasagayaraj, A. J. Org. Chem. 1993, 58, 4997-
To establish the generality of the tandem reaction, we examined
reactions using a variety of δ-keto esters (8). As shown in the
table, they can serve as substrates and yield 2,3-disubstituted
4
999. Bunce, R. A.; Harris, C. R. J. Org. Chem. 1992, 57, 6981-6985.
2
-cyclohexenones in good yields (entry 1-5). When γ-keto esters
(
9) For recent examples of synthesis of dihydrojasmone, see: Shono, T.;
were used, 2,3-disubstituted cyclopentenones were also obtained
in high yields (entry 6-11). Since some of the bicyclic intermedi-
ates (e.g., 10bc, 10be) were decomposed during the workup, the
reaction mixture of the Dieckmann condensation was quenched
Yamamoto, Y.; Takigawa, K.; Maekawa, H.; Ishifune, M.; Kashimura, S.
Chem. Lett. 1994, 1045-1048. Mathew, J. J. Org. Chem. 1990, 55, 5294-
5
297. Ho, T.-L. Chem. Ind. 1988, 762.
(10) Cossy, J.; Gille, B.; Bouzbouz, S.; Bellosta, V. Tetrahedron Lett. 1997,
38, 4069-4070.