Facile generation method for conjugated allenyl esters based on retro-Dieckmann-type ring-opening reactions

Article abstract of DOI:10.1016/j.tetlet.2005.02.138

α-Alkynyl-α-ethoxycarbonyl cyclopentanones 1a-c and cyclohexanones 2a-c were readily synthesized by the reaction of ethyl 2-oxocyclopentanonecarboxylate 6 and ethyl 2-oxocyclohexanonecarboxylate 7 with alkynyllead triacetates 5a-c obtained from lithium acetylides 4a-c and lead tetraacetate. Treatment of 1a-c and 2a-c with 1 N KOH in THF or with n-Bu ₄N⁺OEt^- in EtOH and THF gave the corresponding conjugated allenyl esters 8a-c, 9a-c, 10a-c, and 11a-c in good to excellent yields, respectively.

Full text of DOI:10.1016/j.tetlet.2005.02.138

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2883–2886
Facile generation method for conjugated allenyl esters based
on retro-Dieckmann-type ring-opening reactions
Shigeki Sano, Hisashi Shimizu and Yoshimitsu Nagao*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Received 28 January 2005; revised 17 February 2005; accepted 18 February 2005
Abstract—a-Alkynyl-a-ethoxycarbonyl cyclopentanones 1a–c and cyclohexanones 2a–c were readily synthesized by the reaction of
ethyl 2-oxocyclopentanonecarboxylate 6 and ethyl 2-oxocyclohexanonecarboxylate 7 with alkynyllead triacetates 5a–c obtained
from lithium acetylides 4a–c and lead tetraacetate. Treatment of 1a–c and 2a–c with 1N KOH in THF or with n-Bu4N+OEtÀ in
EtOH and THF gave the corresponding conjugated allenyl esters 8a–c, 9a–c, 10a–c, and 11a–c in good to excellent yields,
respectively.
Ó 2005 Elsevier Ltd. All rights reserved.
Since the allenylic compounds have been particularly
versatile in oxidation, reduction, addition, rearrange-
ment, substitution, polymerization, and inter- and intra-
molecular cyclization reactions, various synthetic
methods for the characteristic allenes have been devel-
oped.1,2 We reported previously the mild alkaline
hydrolysis of diethyl a-acetylamino(or methoxy)-a-
alkynylmalonates (DAM) to generate conjugated allenyl
esters that promote 5-endo-mode heterocyclic cycliza-
tion giving trisubstituted oxazoles, SH-enzyme inhibi-
tion, chiral pyrrolinone formation, and Myers-type
biradical aromatization, each according to a specific cas-
cade reaction.3,4 Here, we describe a new type of facile
synthesis of conjugated allenyl esters utilizing retro-
Dieckmann-type ring-opening reactions of a-alkynyl-a-
(ethoxycarbonyl)cyclopentanones and cyclohexanones.
Scheme 1 illustrates the generation of conjugated allenyl
esters A via Route ‘‘a’’ based on the attack with anionic
nucleophiles (NuÀ = OHÀ and EtOÀ) on the ketone
R
R
•
•
O
Nu
H
O
Nu
•
Nu
"a"
OEt
"b"
"a"
R
OEt
OEt
O
n
O
O
n
Nu = OH , OEt
O
O
H2O
R
H
O
R
R
OEt
Nu
Nu
•
O
H
O
n
O
"b"
Nu
OEt
OEt
n
1 n = 1
2 n = 2
Nu = OH
O
n
n
A
R
R
OEt
O
O
OH
•
H
O
H
n
CO2
H2O
n
O
B
Scheme 1.
Keywords: Cyclopentanone; Cyclohexanone; Retro-Dieckmann reaction; Conjugated allenyl ester; X-ray crystallographic analysis.
*
Corresponding author. Tel.: +8188 633 7271; fax: +8188 633 9503; e-mail: ynagao@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.138

2884
S. Sano et al. / Tetrahedron Letters 46 (2005) 2883–2886
n-BuLi
Pb(OAc)4
(1.03 mol eq)
(1.03 mol eq)
H
R
Li
R
(AcO)3Pb
5a-c
R
THF, -78 ˚C, 1 h
CH2Cl2
3a-c
4a-c
O
1a 98%
1b 74%
1c 58%
2a 96%
2b 56%
2c quant
R
CO2Et
6 n = 1
7 n = 2
O
(0.67 mol eq)
n
OEt
CH2Cl2, -50 ˚C, 1.5 h
n
O
1a-c n = 1
2a-c n = 2
a: R =
Me, b: R = n-Pr, c: R =
Scheme 2.
R
H
O
moiety of cycloalkanones followed by Ôretro-Dieck-
mann-type ring-openingÕ (direct allenyl anion formation
and/or enolization) or the generation of conjugated a-
allenylcycloalkanones B via Route ‘‘b’’ by alkaline
hydrolysis (NuÀ = OHÀ) of the ethoxycarbonyl group
followed by decarboxylation. However, we envisaged
exclusive formation of the former via Route ‘‘a’’ due
to the more favorable electrophilicity of the ketone
moiety of cycloalkanones compared with that of the
ester carbonyl group.
R
O
8a 94%
8b 76%
8c 83%
9a 61%
9b 71%
9c 65%
1N KOH
OH
•
O
THF
0 ˚C, 15 min
OEt
OEt
n
n
O
1a-c n = 1
2a-c n = 2
8a-c n = 2
9a-c n = 3
a: R =
, b: R = n-Pr, c: R =
Me
Scheme 3.
The precursor compounds, a-alkynyl-a-(ethoxycar-
bonyl)cyclopentanones 1a–c and cyclohexanones 2a–c,
were readily accessible from ethyl 2-oxocyclopentane-
1-carboxylate 6 and ethyl 2-oxocyclohexane-1-carboxyl-
ate 7 by utilizing the Hashimoto-modified Pinhey reac-
tion procedure as follows (Scheme 2).5–7 Lithium
acetylide 4a, obtained by lithiation of 4-ethynyltoluene
3a with 1.03 mol equiv of n-butyllithium in THF at
À78 °C, was added into a stirring suspension of
1.03 mol equiv of dried lead tetraacetate in CH2Cl2 at
À50 °C by utilizing a cannula system. The mixture was
stirred at À50 °C for 10 min and then at room tempera-
ture for 15 min to generate p-tolylethynyllead triacetate
5a, to which was added a CH2Cl2 solution of 0.67 mol
equiv of ethyl 2-oxocyclopentane-1-carboxylate 6 or
ethyl 2-oxocyclohexane-1-carboxylate 7. After stirring
at room temperature for 1.5 h, the usual workup of
the reaction mixture gave 1a in 98% yield or 2a in 96%
yield based on 6 or 7, respectively.8 Other compounds
1b,c, and 2b,c were synthesized in good to excellent
yields by exploiting a procedure similar to that used
for 1a and 2a, as shown in Scheme 2.
shown in Scheme 3.10 The structure of 8a was precisely
determined by the X-ray crystallographic analysis, as
shown in Figure 1.11 A similar alkaline hydrolysis of
1b,c, and 2a–c with 1N KOH in THF at 0 °C expedi-
tiously furnished the corresponding carboxylic acids 8b
(76% yield), 8c (83% yield), 9a (61% yield), 9b (71%
yield), and 9c (65% yield), respectively. These structures
were determined by the similarity of their spectroscopic
data to those of 8a.10
The allene formation reactions commenced with 1N
KOH in EtOH, which we first used successfully for the
cascade reaction of DAM, giving the conjugated allenyl
esters.9 Namely, treatment of 1a with 1N KOH in
EtOH at 0 °C afforded a mixture of 5-ethoxycarbony-
7-(p-tolyl)-5,6-heptadienoic acid 8a in 32% yield
and ethyl 5-ethoxycarbonyl-7-(p-tolyl)-5,6-heptadienoate
10a in 27% yield. In order to obtain carboxylic acid 8a
with high selectivity, compound 1a was treated with
1N KOH in THF at 0 °C for 15 min. Thus, compound
8a was obtained as a crystalline product (colorless plates
from AcOEt–n-hexane, mp 86–88 °C) in 94% yield, as
Figure 1. Computer-generated drawing from the X-ray coordinates of
compound 8a.

S. Sano et al. / Tetrahedron Letters 46 (2005) 2883–2886
2885
3. Nagao, Y.; Sano, S. J. Synth. Org. Chem., Jpn. 2003, 61,
1088–1098, and references cited therein.
R
O
4. Nagao, Y. Yakugaku Zasshi 2002, 122, 1–27, and refer-
ences cited therein.
5. Moloney, M. G.; Pinhey, J. T.; Roche, E. G. J. Chem.
Soc., Perkin Trans. 1 1989, 333–341.
6. Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353–
1382.
7. Hashimoto, S.; Miyazaki, Y.; Shinoda, T.; Ikegami, S. J.
Chem. Soc., Chem. Commun. 1990, 1100–1102.
OEt
powdered
KOH
n
O
n
-Bu4N+OH
1a-c n = 1
2a-c n = 2
EtOH
excess
EtOH
(1.1 mol eq)
n
-Bu4N+Br
H2O
small
THF
EtOH - THF
(1 : 2.5)
H2O
(1.25 mol eq)
0 ˚C, 15 min
KBr
n
-Bu4N+OEt
rt, 12 h
8. The spectroscopic data of 1a and 2a are as follows:
Compound 1a: pale yellow oil; 1H NMR (400 MHz,
CDCl3): d 1.32 (3H, t, J = 7.3 Hz), 2.10–2.16 (2H, m), 2.34
(3H, s), 2.39–2.44 (2H, m), 2.46–2.54 (1H, m), 2.65–2.73
(1H, m), 4.27 (2H, q, J = 7.3 Hz), 7.10 (2H, d, J = 7.8 Hz),
7.34 (2H, d, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3): d
14.06, 19.92, 21.49, 36.76, 36.94, 56.58, 62.45, 83.83, 85.20,
119.40, 128.93, 131.82, 138.62, 168.63, 208.12; IR (neat)
2981, 2228, 1763, 1741, 1510 cmÀ1; EI-MS calcd for
C17H18O3 MW 270.1256, found m/e 270.1263 (M+).
Compound 2a: pale yellow oil; 1H NMR (200 MHz,
CDCl3): d 1.33 (3H, t, J = 7.1Hz), 1.75–2.55 (7H, m),
2.88–3.04 (1H, m), 4.30 (2H, dq, J = 2.4 and 7.1Hz), 7.12
(2H, d, J = 8.1Hz), 7.35 (2H, d, J = 8.1Hz); 13C NMR
(100 MHz, CDCl3): d 14.06, 21.49, 21.60, 27.45, 37.36,
38.72, 56.59, 62.14, 84.36, 87.78, 119.44, 129.02, 131.69,
138.73, 168.67, 203.15; IR (neat) 2943, 2227, 1743, 1725,
1511 cmÀ1; EI-MS calcd for C18H20O3 MW 284.1412,
found m/e 284.1404 (M+). Anal. Calcd for C18H20O3: C,
76.02; H, 7.09. Found: C, 75.64; H, 7.19.
R
H
O
10a 94%
10b 71%
10c 63%
11a 92%
11b 64%
11c 48%
a: R =
Me
OEt
•
O
OEt
b: R =
c: R =
n-Pr
n
10a-c n = 2
11a-c n = 3
Scheme 4.
Finally, we have attempted a new type of mild retro-
Dieckmann-type ring-opening reaction of 1a–c and
2a–c with n-Bu4N+OEtÀ generated in situ by treatment
of powdered KOH with excess EtOH–THF in the pres-
ence of n-Bu4N+BrÀ as a phase transfer catalyst in the
solid–liquid system12,13 as follows (Scheme 4). After
treatment of 1.1 mol equiv of powdered KOH and
1.25 mol equiv of n-Bu4N+BrÀ in a solution of EtOH
and THF at room temperature for 12 h, the mixture
was supplemented with a solution of 1a at 0 °C in
THF. After stirring at 0 °C for 15 min, the usual workup
of the reaction mixture gave the desired compound 10a
as a pale yellow oil in 94% yield. The similar treatment
of 1b,c, and 2a–c furnished the corresponding allenyl
diesters 10b (71% yield), 10c (63% yield), 11a (92%
yield), 11b (64% yield), and 11c (48% yield), respectively.
The structures of all products were assigned based on
the similarity of their spectroscopic data to those of
8a–c and 9a–c, except for the data of the carboxyl
group.14 Thus, we have achieved formation of ethyl
esters 10a–c and 11a–c without the use of NaOEt.
9. Nagao, Y.; Kim, K.; Sano, S.; Kakegawa, H.; Lee, W.-S.;
Shimizu, H.; Shiro, M.; Katunuma, N. Tetrahedron Lett.
1996, 37, 861–864.
10. The spectroscopic data of 8a and 9a are as follows:
Compound 8a: colorless plates (AcOEt/n-hexane), mp 86–
88 °C; 1H NMR (400 MHz, CDCl3): d 1.24 (3H, t,
J = 7.3 Hz), 1.79–1.87 (2H, m), 2.34 (3H, s), 2.37–2.46
(4H, m), 4.20 (2H, q, J = 7.3 Hz), 6.54 (1H, t, J = 2.9 Hz),
7.14 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz); 13C
NMR (100 MHz, CDCl3): d 14.20, 21.19, 22.96, 28.19,
33.33, 61.13, 98.60, 103.44, 127.13, 129.18, 129.52, 137.70,
166.58, 179.30, 211.82; IR (KBr) 2981, 2361, 1943, 1709,
1514 cmÀ1; EI-MS calcd for C17H20O4 MW 288.1362,
found m/e 288.1366 (M+). Anal. Calcd for C17H20O4: C,
70.81; H, 6.99. Found: C, 75.86; H, 7.11. Compound 9a:
colorless plates (AcOEt), mp 64–71 °C; 1H NMR
(400 MHz, CDCl3): d 1.25 (3H, t, J = 7.3 Hz), 1.52–1.59
(2H, m), 1.65–1.72 (2H, m), 2.34 (3H, s), 2.29–2.42 (4H,
m), 4.20 (2H, q, J = 7.3 Hz), 6.52 (1H, t, J = 2.9 Hz), 7.13
(2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz); 13C NMR
(100 MHz, CDCl3): d 14.27, 21.23, 24.16, 27.40, 28.50,
33.71, 61.10, 98.37, 103.84, 127.14, 129.53, 131.64, 137.65,
166.77, 179.53, 211.89; IR (KBr) 2935, 1943, 1738, 1709,
1514 cmÀ1; EI-MS calcd for C18H22O4 MW 302.1518,
found m/e 302.1512 (M+).
In conclusion, we have demonstrated methods for the
facile and mild synthesis of the conjugated allenyl esters
based on the retro-Dieckmann-type ring-opening reac-
tions employing 1N KOH and n-Bu4N+OEtÀ; these
methods will be available as new trigger reactions for
various bioorganic and chemical cascade reactions.3,4,15
Acknowledgements
11. The crystallographic data of 8a is as follows: C17H20O4,
˚
M = 288.34, monoclinic, P21/c (#14), a = 10.521(5) A,
This work was supported by a Grant-in-Aid for Scien-
tific Research (B) (2) (No. 16390008) from the Japan
Society for the Promotion of Science. We also extend
our thanks to Professor Masafumi Goto (Kumamoto
University) for the X-ray crystallographic analysis.
˚
˚
b = 5.327(7) A, c = 28.906(4) A, b = 100.00(2)°, V =
3
1595(2) A , Z = 4, Dcalcd = 1.200 g cmÀ3
,
l(Mo Ka) =
˚
0.85 cmÀ1
.
12. Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Cataly-
sis. In Monographs in Modern Chemistry; Ebel, H. S., Ed.;
Chemie: Florida, 1980.
13. Ooi, T.; Maruoka, K. J. Synth. Org. Chem., Jpn. 2003, 61,
1195–1206.
References and notes
14. The spectroscopic data of 10a and 11a are as follows:
Compound 10a: pale yellow oil; 1H NMR (400 MHz,
CDCl3): d 1.22 (3H, t, J = 7.3 Hz), 1.25 (3H, t, J = 7.3 Hz),
1.80–1.87 (2H, m), 2.30–2.43 (4H, m), 2.34 (3H, s), 4.10
1. Schuster, H. F.; Coppola, G. M. Allenes in Organic
Syntheses; Wiley: New York, 1984.
2. Smadja, W. Chem. Rev. 1983, 83, 263–320.

2886
S. Sano et al. / Tetrahedron Letters 46 (2005) 2883–2886
(2H, q, J = 7.3 Hz), 4.20 (2H, dq, J = 1.0 and 7.3 Hz), 6.53
2.41(4H, m), 2.34 (3H, s), 4.09 (2H, q, J = 7.3 Hz), 4.20
(2H, dq, J = 1.0 and 7.3 Hz), 6.51 (1H, t, J = 2.9 Hz), 7.13
(2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz); 13C NMR
(100 MHz, CDCl3): d 14.46, 14.52, 21.47, 24.78, 27.76,
28.80, 34.32, 60.42, 61.28, 98.55, 104.22, 127.37, 129.22,
129.77, 137.83, 166.97, 173.79, 212.12; IR (neat) 2981,
1943, 1737, 1514 cmÀ1; EI-MS calcd for C20H26O4 MW
330.1831, found m/e 330.1826 (M+).
(1H, t, J = 2.9 Hz), 7.14 (2H, d, J = 7.3 Hz), 7.17 (2H, d,
J = 7.3 Hz); 13C NMR (100 MHz, CDCl3): d 14.21, 14.27,
21.23, 23.34, 28.33, 33.72, 60.28, 61.10, 98.54, 103.64,
127.18, 129.31, 129.54, 137.67, 166.60, 173.28, 211.89; IR
(neat) 2980, 1944, 1736, 1709, 1259 cmÀ1; EI-MS calcd for
C19H24O4 MW 316.1675, found m/e 316.1687 (M+). Anal.
Calcd for C19H24O4: C, 72.13; H, 7.65. Found: C, 72.05;
H, 7.71. Compound 11a: pale yellow oil; 1H NMR
(400 MHz, CDCl3): d 1.21 (3H, t, J = 7.3 Hz), 1.24 (3H,
t, J = 7.3 Hz), 1.50–1.57 (2H, m), 1.65–1.72 (2H, m), 2.26–
15. Shibuya, M.; Wakayama, M.; Naoe, Y.; Kawakami, T.;
Ishigaki, K.; Nemoto, H.; Shimizu, H.; Nagao, Y.
Tetrahedron Lett. 1996, 37, 865–868.