A novel tandem [2 + 2] cycloaddition-Dieckmann condensation with ynolate anions. Efficient synthesis of substituted cycloalkenones and naphthalenes via formal [n + 1] cycloaddition

Article abstract of DOI:10.1021/jo015929w

A novel tandem [2 + 2] cycloaddition-Dieckmann condensation via ynolate anions is described. Ynolate anions are useful for the formation of reactive β-lactone enolates via a pathway not involving the enolization of the corresponding β-lactones. The [2 + 2] cycloaddition of ynolate anions with δ- or σ-keto esters, followed by Dieckmann condensation, gives bicyclic β-lactones, which are easily decarboxylated to produce synthetically useful 2,3-disubstituted cyclopentenones and cyclohexenones in one pot. This tandem reaction was applied to a novel, one-pot synthesis of highly substituted naphthalenes.

Full text of DOI:10.1021/jo015929w

7818
J . Org. Chem. 2001, 66, 7818-7824
A Novel Ta n d em [2 + 2] Cycloa d d ition -Dieck m a n n Con d en sa tion
w ith Yn ola te An ion s. Efficien t Syn th esis of Su bstitu ted
Cycloa lk en on es a n d Na p h th a len es via F or m a l [n + 1]
Cycloa d d ition
Mitsuru Shindo,* Yusuke Sato, and Kozo Shishido
Institute for Medicinal Resources, University of Tokushima, PRESTO, J apan Science and
Technology Corporation (J ST), Sho-machi 1, Tokushima 770-8505, J apan
shindo@ph2.tokushima-u.ac.jp
Received J uly 15, 2001
A novel tandem [2 + 2] cycloaddition-Dieckmann condensation via ynolate anions is described.
Ynolate anions are useful for the formation of reactive â-lactone enolates via a pathway not involving
the enolization of the corresponding â-lactones. The [2 + 2] cycloaddition of ynolate anions with δ-
or γ-keto esters, followed by Dieckmann condensation, gives bicyclic â-lactones, which are easily
decarboxylated to produce synthetically useful 2,3-disubstituted cyclopentenones and cyclohexenones
in one pot. This tandem reaction was applied to a novel, one-pot synthesis of highly substituted
naphthalenes.
Sch em e 1
In tr od u ction
Stabilized carbanions, like enolate anions, are funda-
mental reactive species that are widely used in synthetic
organic chemistry. Ynolate anions1 with a triple bond in
place of the double bond of enolate anions are ketene
anion equivalents and, as such, are expected to act as
multifunctional carbanions for ketenes which are also
highly reactive species.2 Since Scho¨llkopf first succeeded
in generating lithium ynolates and found that their
cycloaddition with aldehydes and ketones gave â-lactone
enolates,3 there have been many published reports on the
synthesis of ynolates and their reactions.4-10 However,
studies on the versatility of ynolate anions have remained
Sch em e 2
at a rather basic level. To advance ynolate chemistry, it
would be useful if one could develop a general and
convenient methodology for the preparation of ynolates
(1). Recently, we reported a new method for the genera-
tion of lithium ynolates via the cleavage of ester dianions
(2) prepared from readily available R,R-dibromoesters (3)
(Scheme 1).11
(1) For reviews, see: Shindo, M. Chem. Soc. Rev. 1998, 27, 367-
374. Shindo, M. J . Synth. Org. Chem. J pn. 2000, 58, 1155-1166.
Shindo, M. Yakugaku Zasshi 2000, 120, 1233-1246.
(2) Recent reviews on ketene chemistry: Aggarwal, V. K.; Ali, A.;
Coogan, M. P. Tetrahedron 1999, 55, 293-312. Shioiri, T.; Takaoka,
K.; Aoyama, T. J . Heterocycl. Chem. 1999, 36, 1555-1563. Pommier,
A.; Kocienski, P.; Pons, J .-M. J . Chem. Soc., Perkin Trans. 1 1998,
2105-2118. Hyatt, J . A.; Raynold, P. W. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1994; Vol. 45, Chapter 2, p
159-646. Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273-279.
(3) Scho¨llkopf, U.; Hoppe, I. Angew. Chem., Int. Ed. Engl. 1975, 14,
765. Hoppe, I.; Scho¨llkopf, U. Liebigs Ann. Chem. 1979, 219-226.
(4) Woodbury, R. P.; Long, N. R.; Rathke, M. W. J . Org. Chem. 1978,
43, 376.
(5) (a) Kowalski, C. J .; Fields, K. W. J . Am. Chem. Soc. 1982, 104,
321-323. (b) Kowalski, C. J .; Haque, M. S.; Fields, L. W. J . Am. Chem.
Soc. 1985, 107, 1429-1430. (c) Kowalski, C. J .; Haque, M. S. J . Org.
Chem. 1985, 50, 5140-5142. (d) Kowalski, C. J .; Lal, G. S. Tetrahedron
Lett. 1987, 28, 2463-2466. (e) Kowalski, C. J .; Reddy, R. E. J . Org.
Chem. 1992, 57, 7194-7208. (f) Reddy, R. E.; Kowalski, C. J . Org.
Synth. 1993, 71, 146.
This finding has led to our present investigation of
ynolate chemistry.12 First, we focused on the â-lactone
enolates (4) generated by the cycloaddition of ynolate
anions with carbonyl compounds (Scheme 2).3,5,11 It
occurred to us that a well-designed reaction using yno-
lates could make possible one-pot multistep syntheses
involving tandem reactions13 via intermediate â-lactone
enolates. If the â-lactone enolates could be produced via
a method not involving enolization of the corresponding
â-lactones, these reactions would be of greater utility.
Since modern synthetic organic chemistry demands high
(6) Stang, P. J .; Roberts, K. A. J . Am. Chem. Soc. 1986, 108, 7125-
7127.
(7) J ulia, M.; Saint-J almes, V. P.; Verpeaux, J . N. Synlett 1993, 233-
234.
(8) Satoh, T.; Mizu, Y.; Hayashi, Y.; Yamakawa, K. Tetrahedron Lett.
1994, 35, 133-134. Sato, T.; Unno, H.; Mizu, Y.; Hayashi, Y. Tetra-
hedron 1997, 53, 7843-7854.
(11) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433-4436. (b)
Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54, 2411-2422.
(12) (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998,
39, 4857-4860. (b) Shindo, M.; Oya, S.; Sato, Y.; Shishido, K.
Heterocycles 1998, 49, 113-116. (c) Shindo, M.; Oya, S.; Murakami,
R.; Sato, Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 5943-5946. (d)
Shindo, M.; Oya, S.; Murakami, R.; Sato, Y.; Shishido, K. Tetrahedron
Lett. 2000, 41, 5947-5950. (e) Shindo, M.; Sato, Y.; Shishido, K. J .
Org. Chem. 2000, 65, 5443-5445.
(9) Akai, S.; Kitagaki, S.; Naka, T.; Yamamoto, K.; Tsuzuki, Y.;
Matsumoto, K.; Kita, Y. J . Chem. Soc., Perkin Trans. 1 1996, 1705-
1709.
(10) Kai, H.; Iwamoto, K.; Chatani, N.; Murai, S. J . Am. Chem. Soc.
1996, 118, 7634-7635. Iwamoto, K.; Kojima, M.; Chatani, N.; Murai,
S. J . Org. Chem. 2001, 66, 169-174.
10.1021/jo015929w CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/19/2001

[2 + 2] Cycloaddition-Dieckmann Condensation
J . Org. Chem., Vol. 66, No. 23, 2001 7819
Sch em e 3
Sch em e 6
Sch em e 7
Sch em e 4
Sch em e 5
observed. This is due to the much higher nucleophilicity
of the intermediate enolate (6). The ynolate (1a ), by
comparison, has lower nucleophilicity because of the
stabilization of the anion by the phenyl group. This result
illustrates the apparent difficulty of tandem reactions
utilizing aldehydes; namely, the â-lactone enolates gener-
ated would be immediately trapped by the aldehydes. To
realize a tandem reaction of â-lactone enolates derived
from ynolates, the nucleophilicity of the enolates should
be less than that of the ynolates themselves.
Next, we examined reactions of ynolates with ketones.
A diluted THF solution of cyclohexanone was slowly
added to a solution of the ynolates at -78 °C to give only
the 2:1 adduct (10). However, when cyclohexanone was
added in one portion, the desired â-lactone (9) was
isolated in 45% yield (Scheme 6). These results suggest
that the difference in reactivity between the enolate and
the ynolate is smaller than that for benzaldehyde.
Encouraged by these results, we then tried to use more
sterically hindered ketones. Not unexpectedly, reactions
of the ynolate anion (1b) with acetophenone and ben-
zophenone at -78 °C provided the desired 1:1 adducts
(12) without generation of the 2:1 adducts, suggesting
that the nucleophilicity of the ynolate (1b) was higher
than that of the enolates (11) (Scheme 7). The â-lactones
(12) were decarboxylated during workup to give the
olefins (13a ,b). Pentyl phenyl ketone also provided the
â-lactone, which was decarboxylated by refluxing in
benzene in the presence of silica gel to give 13c in good
overall yield.15
Ta n d em [2 + 2] Cycloa d d ition -Dieck m a n n Con -
d en sa tion . In the cycloaddition described above, if the
ketone possesses another electrophilic center in the
molecule, an intramolecular cyclization might proceed
sequentially to provide bicyclic â-lactones, leading to the
formation of synthetically useful disubstituted cyclo-
alkenes. Based on this idea, we selected δ-keto esters as
the substrate, expecting the tandem [2 + 2] cycloaddi-
tion-Dieckmann condensation to take place (Scheme 8).
The keto ester 14 (0.8 mmol) was added at -78 °C to a
solution of the ynolate (1b), prepared from the R,R-
efficiency, ynolate anions are promising reagents in
minimizing synthetic steps as well as in providing new
chemistry.
We describe herein the full details, including scope and
limitations, of a novel tandem [2 + 2] cycloaddition-
Dieckmann condensation via ynolate anions to provide
2,3-disubstituted cycloalkenones (Scheme 3).14 A one-pot
synthesis of highly substituted naphthalenes is also
included as an application of this tandem reaction.
Resu lts a n d Discu ssion
Cycloa d d ition of Yn ola tes w ith Ca r bon yl Com -
p ou n d s. Scho¨llkopf has reported that the ynolate anion
(1a ) bearing a phenyl substituent reacts with benzalde-
hyde to give the 3,4-disubstituted â-lactone (5) (Scheme
4).3 We have found, however, that the alkyl-substituted
ynolates (e.g., 1b) reacted with an excess of benzaldehyde
to afford the 3,3,4-trisubstituted â-lactone (7, 2:1 adducts)
(Scheme 5). Even when only 1 equiv of the aldehyde was
added, none of the 3,4-disubstituted â-lactone (8) was
(13) For recent reviews on tandem reactions, see: Chapdelaine, M.
J .; Hulce, M. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New
York, 1990; pp 225-653. Ho, T.-L. Tandem Organic Reactions; Wiley:
New York, 1992. Bunce, R. A. Tetrahedron 1995, 51, 13103-13159.
Tietze, L. F. Chem. Rev. 1996, 96, 115-136. Denmark, S. E.;
Thrarensen, A. Chem. Rev. 1996, 96, 137-165. Winkler, J . D. Chem
Rev. 1996, 96, 167-176. Ryu, I.; Sonoda, N.; Curran, D. Chem. Rev.
1996, 96, 177-194. Parsons, P. J .; Penkett, C. S.; Shell, A. J . Chem
Rev. 1996, 96, 195-206.
(14) Preliminary communication: Shindo, M.; Sato, Y.; Shishido, K.
J . Am. Chem. Soc. 1999, 121, 6507-6508.
(15) Danheiser, R. L.; Nowick, J . S. J . Org. Chem. 1991, 56, 1176-
1185.

7820 J . Org. Chem., Vol. 66, No. 23, 2001
Shindo et al.
Sch em e 8
Sch em e 9
carbons.17 As far as we know, there are few reports of
this type of Dieckmann condensation.
We next attempted the direct generation of the reactive
intermediate, the â-lactone enolate, from the correspond-
ing â-lactone (Scheme 9). The â-lactone 18, obtained by
protonation of the lactone enolate 15, was treated with
LDA at -78 °C. When TLC showed that nothing had
occurred, the mixture was then warmed to 0 °C, resulting
in decomposition and recovery of 18. It is possible that
the less-hindered ester, and not the â-lactone (16), was
converted into the enolate (20). This result indicates the
difficulty in directly generating the enolate 15 from the
â-lactone 18. However, using the ynolate anion solved
this problem by allowing the regioselective formation of
the enolate via [2 + 2] cycloaddition prior to Dieckmann
condensation.
To establish the generality of the tandem methodology,
reactions using a variety of δ-keto esters18 were exam-
ined. As shown in Table 2, these esters can serve as
substrates and furnish 2,3-disubstituted cyclohexenones
in good yields (entries 1-5). Primary carbon substituted
ynolates (R ) Me, Bu) afforded the desired products;
however, when the cyclohexyl-substituted ynolate was
used, the uncyclized â-lactone was obtained because the
Dieckmann condensation did not proceed, probably due
to steric hindrance (entry 6).
γ-Keto esters are also suitable substrates for this
tandem reaction to provide synthetically useful 2,3-
disubstituted cyclopentenones (entries 7-11). A keto
diester (24) also gave the desired cyclopentenone (33),
which demonstrates that the method will work with
substrates having other ester functions. A keto ester (25)
did not afford the seven-membered ring, probably due to
the steric strain in the transition state of Dieckmann
condensation. In some cases (e.g., entries 10, 11), the
bicyclic intermediates decomposed during workup. Pre-
sumably, the â-lactones were opened at room tempera-
ture by the attack of water or hydroxide, followed by a
retroaldol reaction. To avoid the possibility of decomposi-
tion, decarboxylation catalyzed by acid should proceed
prior to the ring opening of the â-lactones. Thus, the
reaction mixture of the Dieckmann condensation was
quenched with 3% HCl-EtOH, followed by immediate
refluxing (decarboxylation method B). As a result, the
desired cycloalkenones were successfully obtained in
higher yields (entries 4, 8, 10, 11). With this improved
Ta ble 1. Ta n d em [2 + 2] Cycloa d d ition -Dieck m a n n
Con d en sa tion
reaction time (h)
19 (%)
17 (%)
total (%)
0.5
1.5
3.0
5.0
46
36
17
6
26
46
66
74
72
82
83
80
dibromoester (1.0 mmol) and t-BuLi (4.0 mmol) according
to the usual procedure. TLC showed that the starting
ester had immediately disappeared and that two spots
had appeared simultaneously. After 5 h at -78 °C, the
crude mixture seemed to contain the desired bicyclic
â-lactone (16). Since the products did not respond to
purification with silica gel column chromatography, they
were treated with Danheiser’s method of decarboxylation
(method A: refluxing in benzene for several hours in the
presence of a catalytic amount of silica gel)15 without
purification. After filtration and concentration, 2-butyl-
3-phenyl-2-cyclohexenone (17) was isolated in 74% overall
yield along with ethyl 5-phenyl-5-decenoate (19), which
was derived from the uncyclized â-lactone (18). When the
reaction was quenched after a shorter time, the uncyc-
lized product (19) was obtained in higher yield, as shown
in Table 1. These results show that the â-lactone enolates
(15) are actually the intermediates and that the rate-
determining step is the Dieckmann condensation. This
is the first example of a tandem [2 + 2] cycloaddition-
Dieckmann condensation, although tandem reactions
using Dieckmann condensation, such as the Michael-
Dieckmann reaction, are well known.16 Unlike conven-
tional Dieckmann condensations in which reactions are
thermodynamically controlled to provide cyclic enolized
â-ketoesters, ours is a kinetically controlled reaction
affording nonenolizable keto lactones bearing quaternary
(16) Recent examples of tandem Michael addition-Dieckmann
condensations: Ma, D.; Sun, H. J . Org. Chem. 2000, 65, 6009-6019.
Tatsuta, K.; Yoshimoto, T.; Gunji, H.; Okado, Y.; Takahashi, M. Chem.
Lett. 2000, 646-647. Rodriguez, J . Synlett 1999, 505-518. Covarru-
bias-Zuniga, A.; Gonzalez-Lucas, A. Tetrahedron Lett. 1998, 39, 2881-
2882. 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 1997, 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.; Ko¨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, 4997-4999. Bunce, R. A.; Harris, C. R. J . Org. Chem. 1992,
57, 6981-6985.
(17) In this case, the kinetically generated â-lactone enolates reacted
with the ester irreversibly without proton exchange. See also House,
H. O. Modern Synthetic Reactions, 2nd edition; W. A. Benjamin, Inc.:
Menlo Park, 1972; p 740.
(18) Most of the starting keto esters or the corresponding carboxylic
acids are commercially available.

[2 + 2] Cycloaddition-Dieckmann Condensation
J . Org. Chem., Vol. 66, No. 23, 2001 7821
Ta ble 2. Syn th esis of 2,3-Disu bstitu ted -2-cycloa lk en on es via th e Ta n d em Rea ction
entry
ynolate
R
keto ester
R′
n
time (h)a
decarboxylationb
cycloalkenone
yield (%)
1
2
3
4
5
6
7
8
9
1b
1c
1b
1b
1c
1d
1b
1b
1b
1c
1c
1c
Bu
Me
Bu
14
14
21
21
21
14
22
22
23
22
24
25
Ph
Ph
Me
Me
Me
Ph
Ph
Ph
Me
Ph
2
2
2
2
2
2
1
1
1
1
1
3
5
A
A
A
B
A
A
A
B
A
B
B
A
17
26
27
27
28
29
30
30
31
32
33
34
74
89
78
89
54
0c
63
89
83
84
60
0
1.5
1.5
1.5
1.5
48
Bu
Me
c-Hex
Bu
Bu
Bu
Me
Me
Me
1.5d
1.5
1.5
1.5
2
10
11
12
EtO2C(CH2)2-
Ph
2
a
b
Time of the tandem reaction at -78 °C. Method A: A solution of the â-lactone in benzene was refluxed in the presence of silica gel.
Method B: The tandem reaction mixture was quenched with 3% HCl-EtOH, and the resulting solution was refluxed. c The uncyclized
olefin was obtained in 85% yield. -40 °C.
d
Sch em e 10
decarboxylation procedure, a facile one-pot synthesis of
2,3-disubstituted cycloalkenones was achieved.
Using this transformation, we carried out, in good
yield, concise syntheses of both dihydrojasmone (35),19
by the reaction of the pentyl-substituted ynolate with
ethyl 4-oxopentanoate, and a potential intermediate (36)
for R-cuparenone (37), by the one-pot reaction of the
methyl-substituted ynolate with ethyl 4-oxo-4-(4-meth-
ylphenyl)butanoate (Scheme 10).20
This process can also be applied to the synthesis of
fused rings. The cyclic keto ester 38 reacts with the
ynolate to afford, in good yield, 1-methylhexahydronaph-
thalen-2-one (39), the Robinson annulation product
(Scheme 11). This tandem process is an efficient alterna-
tive to the classical annulation.
The bicyclic â-lactones (e.g., 40) possess contiguous
quaternary carbons, of which the stereochemistry is
strictly defined. To exploit the stereocenters, we tried to
convert the â-lactone into other functionalities without
losing the stereochemistry (Scheme 12). Attempts at
direct methanolysis and aminolysis resulted in genera-
tion of the diketo ester 41 and the diketo amide 42,
respectively. These products, which lost their stereo-
centers at the angular positions of the â-lactone, are
thought to arise from nucleophilic addition of methanol
and benzylamine followed by a retroaldol reaction.
To prevent the retroaldol reaction, the ketone was
reduced by NaBH4 to give the alcohol 43, then subjected
to aminolysis by benzylamine. As expected, the compound
(44) bearing the two quaternary stereogenic centers
derived from the â-lactone (40) was generated in good
nucleus is an important skeleton in organic chemistry
yield. These results clearly demonstrate the synthetic
because it is not only found in biologically active natural
utility of the bicyclic â-lactones (e.g., 40).
On e-P ot Syn th esis of High ly Su bstitu ted Na p h -
th a len es by Ta n d em Rea ction . The naphthalene
products,21 but is also frequently used as a stereocontrol
unit.22 However, the regioselective synthesis of highly
substituted naphthalenes is not easily accomplished
using conventional approaches.23 On the basis of the
(19) For recent examples of syntheses of dihydrojasmone: Bellina,
F.; Ciucci, D.; Rossi, R.; Vergamini, O. Tetrahedron 1999, 55, 2103-
2112. Shono, T.; Yamamoto, Y.; Takigawa, K.; Maekawa, H.; Ishifune,
M.; Kashimura, S. Chem. Lett. 1994, 1045-1048. Solrokin, V. L.;
Kulinkovich, O. G. Zh. Org. Khim. 1993, 29, 1119-1121. Mathew, J .
J . Org. Chem. 1990, 55, 5294-5297. Ho, T.-L. Chem. Ind. 1988, 762
and references cited in these papers.
(20) Cossy, J .; Gille, B.; BouzBouz, S.; Bellosta, V. Tetrahedron Lett.
1997, 38, 4069-4070. Recent examples of syntheses of R-cuparen-
ones: Nakashima, H.; Sato, M.; Taniguchi, T.; Ogasawara, K. Tetra-
hedron Lett. 2000, 41, 2639-2642. Avila-Zarraga, J . G.; Maldonado,
L. A. Chem. Lett. 2000, 512-513 and references cited in these papers.
results described above, we envisioned preparing naph-
thalenes (46) via the tandem reaction of ynolate anions
(21) For examples, see: Deshpande, A. M.; Argade, N. P.; Natu, A.
A.; Eckman, J . Bioorg. Med. Chem. 1999, 7, 1237-1240. Mathe-
Allainmat, M.; Gall, M. L.; J ellimann, C.; Andrieux, J .; Langlois, M.
J . Bioorg. Med. Chem. 1999, 7, 2945-2952. Also see ref 3e.
(22) For examples of binaphthyls, see: Shibasaki, M.; Sasai, H.;
Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256. Pu, L.
Chem. Rev. 1998, 98, 2405-2494.

7822 J . Org. Chem., Vol. 66, No. 23, 2001
Shindo et al.
Sch em e 11
Sch em e 13
Sch em e 12
Sch em e 14
Sch em e 15
(1) with 2-acylphenylacetates (45) as the δ-keto esters
(Scheme 13).
The substrate (45) was prepared according to Meyers’
improved procedure,24 as shown in Scheme 14. 1-In-
danone was reacted with MeMgBr in ether to give the
adduct (47), which was dehydrated (catalytic TsOH, CH2-
Cl2), oxidized (catalytic RuCl3, NaIO4 in hexane, aceto-
nitrile, and H2O),25 and esterified (EtOH, catalytic H2SO4)
to afford (45) in good to moderate overall yields.
The substrates having the sterically hindered substit-
uents R, however, were obtained in only moderate yields
because of the difficulty in adding the Grignard reagents
to indanone in the first step. As a result, they were
synthesized via another route, as shown in Scheme 15.
2-Bromobenzaldehyde was coupled with trimethylsilyl-
acetylene via the Sonogashira reaction to give the product
(48),26 which was reacted with the Grignard reagent to
afford the secondary alcohol (49). The alcohol was
oxidized by PDC to produce the ketone (50), which was
hydroborated, and upon oxidation,27 gave the keto car-
boxylic acid (51) without reduction of the ketone. Finally,
the desired substrate (45) was synthesized by esterifi-
cation in better overall yields.
(23) For recent examples of the construction of naphthalenes: (a)
Padwa, A.; Austin, D. J .; Chiacchio, U.; Kassir, J . M.; Rescifina, A.;
Xu, S. L. Tetrahedron Lett. 1991, 32, 5923-5926. (b) Nishi, Y.; Tanabe,
Y. Tetrahedron Lett. 1995, 36, 8803-8806. (c) Turnbull, P.; Moor, H.
W. J . Org. Chem. 1995, 60, 644-649. (d) Yadav, K. M.; Mohanta, P.
K.; Ila, H.; J unjappa, H. Tetrahedron 1996, 52, 14049-14056. (e)
Andersen, N. G.; Maddaford, S. P.; Keay, B. A. J . Org. Chem. 1996,
61, 2885-2887. (e) Cotelle, P.; Catteau, J . P. Tetrahedron Lett. 1997,
38, 2969-2972. (f) Koning, C. B.; Michael, J . P.; Rousseau, A. L.
Tetrahedron Lett. 1997, 38, 893-896. (g) Koning, C. B.; Michael, J .
P.; Rousseau, A. L. J . Chem. Soc., Perkin Trans. 1 2000, 787-797. (h)
Kao, C.-L.; Yen, S. Y.; Chern, J .-W. Tetrahedron Lett. 2000, 41, 2207-
2210. (i) Iwasawa, N.; Shido, M.; Maeyama, K.; Kusama, H. J . Am.
Chem. Soc. 2000, 122, 10226-10227. (j) Kiselyov, A. S. Tetrahedron
Lett. 2001, 42, 3053-3056. (k) Kajikawa, S.; Nishino, H.; Kurosawa,
K. Tetrahedron Lett. 2001, 42, 3351-3354.
The ynolate (1), prepared from the R,R-dibromoester
(1.0 mmol) and t-BuLi (4.0 mmol), was reacted with ethyl
(26) Austin, W. B.; Bilow, N.; Kelleghan, W. J .; Lau, K. S. Y. J . Org.
Chem. 1981, 46, 2280-2286
(27) Zweifel, G.; Backlund, S. J . J . Am. Chem. Soc. 1977, 99, 3184-
3185. Morris, J .; Wishka, D. G. J . Org. Chem. 1991, 56, 3549-3556.
Mashall, J . M.; Peterson, J . C.; Lebioda, L. J . Am. Chem. Soc. 1984,
106, 6006-6015. J enmalm, A.; Berts, Wei.; Li, Y.-L.; Luthman, K.;
Cso¨regh, I.; Hacksell, U. J . Org. Chem. 1994, 59, 1139-1148.
(24) Wu¨nsch, T.; Meyers, A. I. J . Org. Chem. 1990, 55, 4233-4235.
(25) Carlsen, P. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936-3938

[2 + 2] Cycloaddition-Dieckmann Condensation
J . Org. Chem., Vol. 66, No. 23, 2001 7823
Ta ble 3. On e-P ot Syn th esis of
3,4-Disu bstitu ted -2-n a p h th ols
Sch em e 17
entry
R
R′
conditions
yield (%)
1
2
3
4
5
6
7
8
Me
Me
Et
i-Pr
Ph
-78 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 42 h
-78 °C, 2 h
76
85
88
72
82
93
72
57
Me
Me
Me
Me
Bu
Bu
1-naphthyl -78 °C then rt, 18 h
Me
Ph
-78 °C, 0.5 h
-78 °C, 43 h
rt, 1.5 h
c-Hex Me
Sch em e 16
electron density of the phenyl ring. As expected, the
desired 2-naphthol (58b) was produced exclusively in 89%
yield (Scheme 17).
(2-acetylphenyl)acetate (45, R′ ) Me, 0.8 mmol) in THF,
and the mixture was stirred for 30 min at -78 °C. After
the usual workup and purification, 3,4-dimethyl-2-
naphthol (46, R, R′ ) Me) was isolated in 76% yield. Since
no â-lactone (52) was detected in the NMR and IR spectra
of the crude mixture, decarboxylation of the â-lactone and
subsequent enolization must have proceeded during the
workup. This is a novel methodology for the synthesis of
substituted naphthalenes.
To establish the generality of this process, we examined
reactions using several kinds of 2-acylphenylacetates. As
shown in Table 3, the desired 3,4-disubstituted 2-naph-
thols were successfully obtained in good yields. The
ynolates can also react with sterically hindered ketones
to afford the corresponding sterically congested naph-
thols, although they required longer reaction times and/
or higher temperatures (entries 2, 3, 8). J udging from
TLC analysis, the rate-determining step seems to be the
Dieckmann condensation. A 1,1′-binaphthyl compound
was also efficiently synthesized (entry 5).
Next, a one-pot methyl etherification of the naphthols
was attempted because of the instability of some of the
naphthols. Initially, MeI and HMPA were added to the
basic reaction mixture at -78 °C, and it was allowed to
warm to room temperature over 18 h for decarboxylation.
The desired methyl ether (61a ) was isolated, along with
the olefin (63, R ) Me), in 46% and 26% yield, respec-
tively. The side product was thought to arise from a retro-
Dieckmann condensation induced by lithium ethoxide at
room temperature, followed by ring opening of the
resulting â-lactone enolate (62). To prevent the competi-
tive, undesired retro-Dieckmann condensation, the reac-
tion was quenched and acidified with acetic acid at -78
°C and allowed to warm to room temperature. Then, an
excess of dimethyl sulfate, potassium carbonate, and
DMF was added. As expected, the desired methyl ether
(61a ) was isolated in 76% yield. Using this procedure,
trisubstituted naphthalene ethers (61) were obtained in
good yields (Scheme 18).
The synthesis of the highly substituted naphthalenes
was more challenging. As shown in Scheme 16, ethyl 2-(2-
benzoylphenyl)propionate (53) proved to be a good sub-
strate for this one-pot process and gave 1,3,4-trisubsti-
tuted-2-naphthol (54) in good yield.
2-Acetyl-5-methoxyphenylacetate (55), easily prepared
by Friedel-Crafts acylation of ethyl 3-methoxyphenyl-
acetate, afforded the desired trisubstituted 2-naphthol
(58) in only 20% yield, along with 61% of the olefin (57).
This is probably due to ring opening of the â-lactone
enolate (56) accelerated by the electron-donating group
in the para position, since it is known that at a higher
temperature (e.g., at room temperature), enolates are
easily converted into olefins via electrocyclic reactions.28
Thus, the substrate 55b having a pivaloyloxy group in
place of the methoxy group was used to decrease the
Con clu sion
We have developed a novel tandem [2 + 2] cycloaddi-
tion-Dieckmann condensation of ynolates to efficiently
synthesize 2,3-disubstituted cyclopentenones and cyclo-
hexenones. This tandem reaction can be formally re-
garded as an [n + 1] cycloaddition (n ) 4, 5). Moreover,
this tandem reaction was applied to one-pot syntheses
of highly substituted naphthalenes. Since these products,
especially sterically hindered naphthalenes, are difficult
to synthesize via short routes using conventional meth-
ods, this approach should be useful for organic synthesis.
We also demonstrated that the â-lactone enolates, gener-
ated by cycloaddition of ynolates with ketones, are useful
reactive intermediates. Additionally, this result also
shows the high versatility of ynolates.
Exp er im en ta l Section
(28) Pioneering work of this type of reaction: Mulzer, J .; Kerkmann,
T. J . Am. Chem. Soc. 1980, 102, 3620-3622. See also refs 5a, 12a,
and 12e.
(29) Feigenbaum, A.; Fort, Y.; Pete, J .; Scholler, D. J . Org. Chem.
1986, 51, 4424-4432.
Gen er a l. 1H NMR were measured in CDCl3 solution and
referenced to TMS (0.00 ppm). 13C NMR were measured in
CDCl3 solution and referenced to CDCl3 (77.0 ppm). All

7824 J . Org. Chem., Vol. 66, No. 23, 2001
Shindo et al.
Rep r esen ta tive P r oced u r e (Meth od B). Syn th esis of
2-Bu tyl-3-p h en yl-2-cyclop en ten on e (30) fr om Lith iu m
Yn ola te (1b) (Ta ble 2, En tr y 8). To a solution of ethyl 2,2-
dibromohexanoate (302 mg, 1.0 mmol) in 6 mL of dry THF at
-78 °C under argon was added dropwise a solution of tert-
butyllithium (2.72 mL, 4.0 mmol, 1.47 M in pentane). The
yellow solution was stirred for 3 h at -78 °C and allowed to
warm to 0 °C. After 30 min, the resulting colorless reaction
mixture was cooled to -78 °C. Then a solution of ethyl 4-oxo-
4-phenylbutanoate (22) (165 mg, 0.80 mmol) in THF (2 mL)
was added to the reaction mixture. After stirring for 1.5 h at
-78 °C, 3% HCl in ethanol (5 mL) was added, and the mixture
was refluxed. After 2 h, the reaction mixture was cooled to
room temperature and concentrated. The residue was diluted
with ethyl acetate and neutralized with saturated NaHCO3
solution. The resulting mixture was extracted with ethyl
acetate. The organic phase was washed with saturated NaCl
solution, dried over MgSO4, filtered, and concentrated to afford
a yellow oil, which was chromatographed over silica gel (2-
5% ethyl acetate in hexane) to yield 153 mg (89%) of 30 as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ: 0.74 (t, J ) 7.2
Hz, 3H), 1.25-1.50 (m, 4H), 2.37 (t, J ) 7.2 Hz, 2H), 2.52 (t,
J ) 4.8 Hz, 2H), 2.88-2.91 (t, J ) 4.8 Hz, 2H), 7.45-7.47 (m,
5H). 13C NMR (75 MHz, CDCl3) δ: 13.6 (q), 22.8 (t), 23.6 (t),
29.6 (t), 30.3 (t), 34.0 (t), 127.0 (d), 128.5 (d), 129.1 (d), 136.5
Sch em e 18
(s), 141.1 (s), 166.8 (s), 209.4 (s). IR (neat): 1696, 1624 cm-1
.
MS m/z: 214 (M+), 128 (100%). HRMS (EI): calcd for C15H18
O
(M+), 214.1358; found, 214.1323.
reactions were performed in oven-dried glassware under a
positive pressure of argon, unless otherwise noted. Reaction
mixtures were stirred magnetically. Solutions of alkyllithium
reagents were transferred by syringe or cannula and were
introduced into reaction vessels through rubber septa.
Rep r esen ta tive P r oced u r e (Meth od A). Syn th esis of
2-Bu t yl-3-p h en yl-2-cycloh exen on e (17)29 fr om Bu t yl-
Su bstitu ted Lith iu m Yn ola te (Ta ble 2, En tr y 1). To a
solution of ethyl 2,2-dibromohexanoate (302 mg, 1.0 mmol)11b
in 6 mL of dry THF, cooled to -78 °C under argon, was added
dropwise a solution of tert-butyllithium (2.70 mL, 4.0 mmol,
1.48 M in pentane). The yellow solution was stirred for 3 h at
-78 °C and allowed to warm to 0 °C. After 30 min, the
resulting colorless reaction mixture was cooled to -78 °C, and
a solution of ethyl 5-oxo-5-phenylpentanoate (14) (176 mg, 0.80
mmol) in THF (2 mL) was added dropwise. After 5 h at -78
°C, a saturated NH4Cl solution was added, and the resulting
mixture was extracted with ethyl acetate. The organic phase
was successively washed with saturated solutions of NaHCO3
and NaCl, dried over MgSO4, filtered, and concentrated to
afford a yellow oil. This crude mixture was dissolved in
benzene (10 mL), and 100 mg of 100-270 mesh chromato-
graphic silica gel was added. The reaction mixture was heated
at reflux for 10 h and then allowed to cool to room temperature
before filtering. The filtrate was concentrated to afford a yellow
oil, which was chromatographed over silica gel (2-5% ethyl
acetate in hexane) to yield 136 mg (74%) of 17 as a colorless
oil and 13 mg (6%) of 19 as a colorless oil.
Repr esen tative P r ocedu r e for th e Syn th esis of 2-Naph -
th ol (46, R, R′ ) Me) fr om Lith iu m Yn ola te (1c) (Ta ble
3, En tr y 1). To a solution of ethyl 2,2-dibromohexanoate (260
mg, 1.0 mmol) in 6 mL of dry THF at -78 °C under argon
was added dropwise a solution of tert-butyllithium (2.80 mL,
4.0 mmol, 1.43 M in pentane). The yellow solution was stirred
for 3 h at -78 °C and allowed to warm to 0 °C. After 30 min,
the resulting colorless reaction mixture was cooled to -78 °C.
Then a solution of ethyl 2-acetylphenylacetate (45, R′ ) Me)
(165 mg, 0.80 mmol) in THF (2 mL) was added to the reaction
mixture. After stirring for 0.5 h at -78 °C, a solution of
saturated aqueous NH4Cl was added, and the mixture was
extracted with ethyl acetate. The organic phase was succes-
sively washed with saturated solutions of NaHCO3 and NaCl,
dried over MgSO4, filtered, and concentrated to afford a yellow
oil, which was chromatographed over silica gel (2-5% ethyl
acetate in hexane) to yield 105 mg (76%) of 46 (R, R′ ) Me) as
a yellow solid, which was recrystallized from a mixture of ethyl
acetate and hexane to give brown prisms (mp 114.2-115.0 °C).
1H NMR (300 MHz, CDCl3) δ: 2.40 (3H, s), 2.61 (3H, s), 4.94
(1H, s), 6.98 (1H, s), 7.35 (2H, m), 7.62 (1H, dd, J ) 2.1, 7.2
Hz), 7.95 (1H, dd, J ) 2.1, 7.2 Hz). 13C NMR (75 MHz, CDCl3)
δ: 12.6 (q), 14.8 (q), 107.2 (d), 123.3 (d), 123.9 (d), 124.4 (s),
125.2 (d), 126.5 (d), 128.4 (s), 132.9 (s), 133.5 (s), 152.2 (s).
IR (CHCl3): 3598, 1176 cm-1. MS m/z: 172 (M+, 100%), 173
(M + 1), 157 (M+ - CH3). Anal. Calcd for C12H12O: C, 83.69;
H, 7.02. Found: C, 83.49; H, 7.19.
1
17. H NMR (CDCl3, 400 MHz) δ: 0.74 (t, J ) 7.3 Hz, 3H),
1.14 (tq, J ) 7.3 Hz, 7.3 Hz, 2H), 1.21-1.29 (m, 2H), 2.04-
2.15 (m, 4H), 2.51 (t, J ) 6.4 Hz, 2H), 2.59 (t, J ) 6.4 Hz, 2H),
7.17 (d, J ) 6.8 Hz, 2H), 7.30-7.40 (3H, m). IR (neat): 1668,
1616 cm-1. MS m/z: 228 (M+, 100%), 229 (M + 1).
Ack n ow led gm en t. This work was partially sup-
ported by Grants-in-Aid for Scientific Research on
Priority Areas (No. 283, “Innovative Synthetic Reac-
tions”) from the Ministry of Education, Science, Sports,
and Culture, Government of J apan, and the Eisai award
in Synthetic Organic Chemistry, J apan.
Eth yl 5-P h en yl-5-d ecen oa te (19). 1H NMR (CDCl3, 400
MHz) δ: 0.82 (t, J ) 7.0 Hz, 2.5H), 0.88-0.98 (m, 0.5H), 1.21-
1.32 (m, 7H, including t, J ) 7.0 Hz, 2.5H), 1.57-1.72 (m,
2.3H), 1.92 (dt, J ) 7.3 Hz, 7.3 Hz, 1.7H), 2.26 (t, J ) 7.5 Hz,
2H), 2.36 (t, J ) 7.5 Hz, 2H), 4.10 (q, J ) 7.0 Hz, 2H), 5.44 (t,
J ) 7.3 Hz, 0.83H), 5.69 (t, J ) 7.3 Hz, 0.17H), 7.12 (d, J )
7.0 Hz, 1H), 7.20-7.46 (m, 4H). IR (neat): 1736 cm-1. MS
m/z: 274 (M+), 129 (100%). HRMS (EI): calcd for C18H26O2
(MH+), 274.1933; found, 274.1906.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O015929W