First synthesis of a highly strained cyclodeca-1,5-diyne skeleton via intramolecular Sonogashira cross-coupling

Article abstract of DOI:10.1016/S0040-4039(00)01890-6

Cyclization of alkenyl bromides 6 and 11 containing a terminal alkyne was achieved by using an intramolecular cross-coupling reaction catalyzed by Pd(0) and Cu(I). Under the optimal reaction conditions, cyclodeca-1,5-diyne derivatives 7 and 12 were obtain

Full text of DOI:10.1016/S0040-4039(00)01890-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 81–83
First synthesis of a highly strained cyclodeca-1,5-diyne skeleton
via intramolecular Sonogashira cross-coupling
Wei-Min Dai* and Anxin Wu
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong SAR, China
Received 29 August 2000; revised 9 October 2000; accepted 26 October 2000
Abstract—Cyclization of alkenyl bromides 6 and 11 containing a terminal alkyne was achieved by using an intramolecular
cross-coupling reaction catalyzed by Pd(0) and Cu(I). Under the optimal reaction conditions, cyclodeca-1,5-diyne derivatives 7
and 12 were obtained in 43 and 28% yields, respectively. © 2000 Elsevier Science Ltd. All rights reserved.
The cross-coupling reaction of alkenyl halides or trifl-
ates with 1-alkynes under the Sonogashira conditions1
is a useful method for synthesis of conjugated enynes.2
However, the formation of medium-size rings directly
via the Sonogashira cross-coupling is rare probably due
to the bent triple bond that creates unfavorable ring
strain. Schreiber et al. reported an elegant synthesis of
the dynemicin A skeleton through cross-coupling of an
alkenyl bromide with a 1-alkyne to form a 15-mem-
bered lactone followed by an intramolecular Diels–
Alder reaction.3 Hirama et al. reported a synthesis of
the cyclodeca-1,6-diyne skeleton possessing an exocyclic
double bond by using cross-coupling of an alkenyl
bromide with activated tributyltin acetylide4 under the
Stille direct coupling conditions.5 It was found that the
same cyclization did not take place between alkenyl
bromides and the corresponding 1-alkyne under the
Sonogashira conditions.4a,6 By taking advantage of acti-
vation of both cross-coupling partners, 9- or 10-mem-
bered 1,5-diyne-3-enes were constructed via reaction of
(Z)-bis(trimethylstannyl)ethylene with 1,7-diiodo-1,6-
heptadiyne or 1,8-diiodo-1,7-octadiyne under the Stille
direct coupling conditions.7 We report here the first
example of an intramolecular Sonogashira cross-cou-
a
path b
intramolecular
cross-coupling
X
X
allylic
Y
rearrangement
Y
Y
X = H
Br
Ar
Ar
b
Ar
3: Y = OH, OMe
1
2
Scheme 1.
HO
HO
Pd(PPh3)4, CuI
base, solvent
see Table 1
CHO
Br
5
nBuLi, THF
-78 °C, 30 min
(97%)
Br
Ph
Ph
Ph
4
7
6
Scheme 2.
Keywords: coupling reactions; diynes; alkenyl halides; cyclization.
* Corresponding author. Fax: +852 2358 1594; e-mail: chdai@ust.hk
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01890-6

82
W.-M. Dai, A. Wu / Tetrahedron Letters 42 (2001) 81–83
pling for synthesis of the highly strained cyclodeca-1,5-
diyne skeleton.
(entry 2). Therefore, the ‘normal reaction protocol’
(Et3N, THF and room temperature)8b,e used for inter-
molecular cross-coupling failed for cyclization of 6.
In our previous study, cyclodeca-1,5-diyne 2 (Ar=Ph,
X=anthraquinone-2-carbonyloxy, Y=OH) was trans-
formed into the 10-membered enediyne 1 (Y=EtO) via
acid-catalyzed allylic rearrangement.8 We prepared al-
cohol 2 (Ar=Ph, X=OH, Y=OTHP) via acetylide
addition to an aldehyde in 10% yield along with 20% of
the undesired intermolecular addition byproduct (path
a in Scheme 1).8a In order to improve the efficiency of
cyclization, we turned our attention to path b by using
an intramolecular cross-coupling of the alkenyl bro-
mide with the 1-alkyne within 3 for construction of 2
with X=H.
Next, we checked the reaction temperature and time for
cyclization of 6 in neat Et2NH (entries 4–7). At 50–
60°C for 2.5 h, the desired product 7 was obtained in
11% yield. The yield of 7 increased to 35% on heating
at 80–90°C for 1.5 h. However, prolonged reaction at
50–60°C or at 80–90°C for 4 h led to decomposition of
7. Addition of THF as the co-solvent for reaction at
50–55°C in entry 8 had a little effect on the yield of 7
(entry 8 versus entry 4). These results indicated that a
high temperature (80–90°C) is preferred for cyclization
of 6 but the product 7 decomposes spontaneously so
that the isolated yield of 7 is time-dependent.
Scheme 29 illustrates the two-step synthesis of (E)-4-
(phenylmethylidene)cyclodeca-1,5-diyn-3-ol 7. Starting
from commercially available a-bromocinnamaldehyde 4
and 1,7-octadiyne 5, alcohol 6 was obtained in 97%
yield via mono-deprotonation of 5 by using 1 equiv. of
n-BuLi followed by addition to aldehyde 4 (Scheme 2).
Cyclization of 6 was carried out in the presence of 10
mol% Pd(PPh3)4 and 20 mol% CuI under high dilution
conditions. We systematically examined the effects of
amine base, solvent, temperature and reaction time on
the yield of 7. The results are summarized in Table 1.
When the cross-coupling reaction was carried out at
room temperature (20°C) in neat Et3N or Et2NH, no
reaction occurred with recovery of 6 (entries 1 and 3).
The same reaction run in the presence of a solvent such
as THF or CH3CN at room temperature gave an
oxidative coupling byproduct in 25–26% yield, result-
ing from dimerization of the terminal alkyne moiety in
6 (entries 9 and 10). The same byproduct was formed
when the reaction was carried out in refluxing Et3N
By keeping reaction temperature at 80–90°C for 1.5 h,
we optimized the ratio of Et2NH and CH3CN (entries
11–14). Reduction of Et2NH from neat to 25% in
CH3CN improved the yield of 7 from 35 to 41% (entry
6 versus entry 11). The best yield of 43% was obtained
when a 1:5 mixture of Et2NH and CH3CN was used
(entry 12). On further dilution to a 1:10 ratio, the yield
dropped sharply to 18% (entry 14). Increase in the
concentration of 6 from 0.02 to 0.05 M reduced the
yield of 7 (entry 13). We also used other secondary and
primary amines to replace Et2NH in the cyclization of
6 under the optimal conditions. All experiments re-
sulted in lower yields of 7 (entries 15–18).
With the success in the cyclization of the alcohol 6
through the intramolecular Sonogashira cross-coupling
reaction, we explored cyclization of ether 8 (Scheme 3).9
Methylation of 6 with MeI and KOH in DMSO gave
compound 8 in 68% yield. The latter compound cy-
Table 1. Effects of base, solvent, temperature (T) and time (t) on cyclization of 6 to form 7a
Entry
Base, solvent
T (°C),b t (h)
7 (%)
Entry
Base, solvent
T (°C),b t (h)
7 (%)
1
2
3
4
5
6
7
8
9
Et3N (neat)
Et3N (neat)
20, 24
90, 1
20, 48
50–60, 2.5
50–60, 4
80–90, 1.5
80–90, 4
50–65, 4
20, 12
0
10
11
12
13
14
15
16
17
18
Et2NH–CH3CN (1:3)
Et2NH–CH3CN (1:3)
Et2NH–CH3CN (1:5)
20, 10
(25)d
41
43
28
18
12
23
25
4
(26)d
0
80–90, 1.5
80–90, 1.5
80–90, 1.5
80–90, 1.5
80–90, 1.5
80–90, 1.5
80–90, 1.5
80–90, 1.5
Et2NH (neat)
Et2NH (neat)
Et2NH (neat)
Et2NH (neat)
Et2NH (neat)
Et2NH–THF (1:1)
Et3N–THF (1:15)
11
(Dec.)
35
Et2NH–CH3CN (1:5)c
Et2NH–CH3CN (1:10)
iPr2NH–CH3CN (1:3)
Piperidine–CH3CN (1:5)
Morpholine–CH3CN (1:5)
(CH3O)2CHCH2NH2ꢀCH3CN (1:5)
(Dec.)
9
(26)d
a The reaction was carried out at 0.02 M of 6 in the presence of 10 mol% Pd(PPh3)4 and 20 mol% CuI.
b Oil bath temperature.
c At 0.05 M of 6.
d Yield of oxidative coupling byproduct of terminal alkyne 6.
MeO
MeO
MeI, KOH
Pd(PPh3)4,CuI,
6
DMSO, 20 °C, 5 h
(68%)
Et2NH (neat),
55-60 °C, 2 h (11%)
Br
Ph
Ph
8
9
Scheme 3.

W.-M. Dai, A. Wu / Tetrahedron Letters 42 (2001) 81–83
83
HO
HO
CHO
Br
Pd(PPh3)4, CuI
5
Br
nBuLi, THF
-78 °C, 1 h (80%)
Et2NH-CH3CN (1:5)
80-90 °C, 1.5 h (28%)
1-Naph
1-Naph
1-Naph
10
12
11
Scheme 4.
clized, in the presence of 10 mol% Pd(PPh3)4 and 20
mol% CuI in neat Et2NH at 55–60°C for 2 h, to give 9
in 11% yield. The lower yield might be due to the
methoxy group in 8, which serves as a better leaving
group than the hydroxyl group in 6. Thus, decomposi-
tion through side-reactions of the allylic or propargylic
methyl ether with Pd(0)10 or Pd(II)11 species generated
in the reaction significantly reduced the yield of 9. This
was also true for the corresponding allylic acetate that
decomposed entirely on heating in neat Et2NH.
hedron Lett. 1975, 4467. (b) Sonogashira, K. In Compre-
hensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 3, pp. 521–549.
2. Tsuji, J. Palladium Reagents and Catalysts; John Wiley &
Sons: Chichester, 1995; pp. 168–178.
3. Porco, J. A.; Schoenen, F. J.; Stout, T. J.; Clardy, J.;
Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 7410.
4. (a) Hirama, M.; Fujiwara, K.; Shigematsu, K.;
Fukazawa, Y. J. Am. Chem. Soc. 1989, 111, 4120. (b)
Hirama, M.; Gomibuchi, T.; Fujiwara, K.; Sugiura, Y.;
Uesugi, M. J. Am. Chem. Soc. 1991, 113, 9851. (c)
Tokuda, M.; Fujiwara, K.; Gomibuchi, T.; Hirama, M.;
Uesugi, M.; Sugiura, Y. Tetrahedron Lett. 1993, 34, 669.
5. (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771. (b)
Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(c) Mitchell, T. N. Synthesis 1992, 803.
To expand the intramolecular cross-coupling reaction,
we synthesized the 1-naphthyl analogue 12 (Scheme 4).9
Addition of the mono-lithium acetylide derived from
1,7-octadiyne 5 and n-BuLi with 10 provided alcohol 11
in 80% yield. The Pd(0)ꢀCu(I) catalyzed cyclization of
11 was carried out under the optimal conditions used
for 6 to give compound 12 in 28% isolated yield. The
diminished yield of 12 compared to 7 may arise from
the bulky 1-naphthyl group, which may cause unfavor-
able steric interaction during the oxidative addition of
the alkenyl bromide to the Pd(0) catalyst.
6. The Sonogasgira reaction has failed to form a 10-mem-
bered enediyne. Cre´visy, C.; Beau, J.-M. Tetrahedron
Lett. 1991, 32, 3171.
7. Representative examples of 10-membered enediyne syn-
thesis, see: (a) Shair, M. D.; Yoon, T.; Danishefsky, S. J.
J. Org. Chem. 1994, 59, 3755. (b) Takahashi, T.;
Sakamoto, Y.; Yanada, H.; Usui, S.; Fukazawa, Y.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1345. (c) Clive, D.
L. J.; Bo, Y.; Tao, Y.; Daigneault, S.; Wu, Y.-J.;
Meignan, G. J. Am. Chem. Soc. 1996, 118, 4904. (d)
Nantz, M. H.; Moss, D. K.; Spence, J. D.; Olmstead, M.
M. Angew. Chem., Int. Ed. 1998, 37, 470. For 9-mem-
bered enediyne synthesis, see: (e) Tanaka, H.; Yamada,
H.; Matsuda, A.; Takahashi, T. Synlett 1997, 381.
8. (a) Dai, W.-M.; Fong, K. C.; Lau, C. W.; Zhuo, L.;
Hamaguchi, W.; Nishimoto, S. J. Org. Chem. 1999, 64,
682. Also see: (b) Dai, W.-M.; Fong, K. C.; Danjo, H.;
Nishimoto, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 779.
(c) Dai, W.-M.; Fong, K. C. Tetrahedron Lett. 1996, 37,
8413. (d) Dai, W.-M.; Lee M. Y. H. Tetrahedron Lett.
1998, 39, 8149. (e) Dai, W.-M.; Wu, J.; Fong, K. C.; Lee,
M. Y. H.; Lau, C. W. J. Org. Chem. 1999, 64, 5062. (f)
Dai, W.-M.; Lee, M. Y. H. Tetrahedron Lett. 1999, 40,
2397.
In summary, we have established an intramolecular
cross-coupling reaction of alkenyl bromides with 1-
alkynes for an expeditious synthesis of the highly
strained cyclodeca-1,5-diyne skeleton. Key factors to
our success are use of a secondary amine base, a high
reaction temperature (80–90°C) and short reaction
times. With this intramolecular cross-coupling ap-
proach, we synthesized compound 7 in two steps and in
42% overall yield from commercial materials. More-
over, alcohols 7 and 12 are useful precursors for the
synthesis of 10-membered enediynes capable of cleaving
DNA and inhibiting cancer cell growth.8a Application
of this cyclization to the synthesis of related com-
pounds is underway in our laboratory.
Acknowledgements
9. All new compounds were fully characterized by IR, 1H
NMR, 13C NMR, MS and HRMS.
10. Tsuji, J. Palladium Reagents and Catalysts; John Wiley &
Sons: Chichester, 1995; pp. 290–422.
We thank Department of Chemistry, HKUST for
financial support. A post-doctoral fellowship to A. Wu
is also acknowledged.
11. (a) Kataoka, H.; Watanabe, K.; Goto, K.; Tetrahedron
Lett. 1990, 31, 4181. (b) Kataoka, H.; Wataneba, K.;
Miyazaki, K.; Tahara, S.; Ogu, K.; Matsuoka, R.; Goto,
K. Chem. Lett. 1990, 1705. (c) Mahrwald, R.; Schick, H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 593.
References
1. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetra-
.
.