Preparation and reactivity of macrocyclic dienynes

Article abstract of DOI:10.1016/j.tetlet.2010.02.013

(1E,5E)-Cyclopentadeca-1,5-dien-3-yne (1c), which represents the first macrocyclic 1,5-dien-3-yne, can be obtained by thermal- or butyllithium-induced fragmentation of the corresponding 1,2,3-selenadiazole 8. The (E,E)-dienyne functionality causes a geometrical strain E_g, which enhances the reactivity in addition (1c→12,13) and cycloaddition (1c→10) reactions and lowers the isomerization barrier to the unstrained (E,Z)-configuration 1d (E_g = 0). A slow process 1c→1d occurs even at ambient temperatures within several weeks.

Full text of DOI:10.1016/j.tetlet.2010.02.013

Tetrahedron Letters 51 (2010) 1952–1954
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation and reactivity of macrocyclic dienynes
*
Herbert Meier , Hans-Joachim Bissinger, Anita Vierengel
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, 55099 Mainz, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
(1E,5E)-Cyclopentadeca-1,5-dien-3-yne (1c), which represents the first macrocyclic 1,5-dien-3-yne, can
be obtained by thermal- or butyllithium-induced fragmentation of the corresponding 1,2,3-selenadiazole
8. The (E,E)-dienyne functionality causes a geometrical strain Eg, which enhances the reactivity in addi-
tion (1c?12,13) and cycloaddition (1c?10) reactions and lowers the isomerization barrier to the
unstrained (E,Z)-configuration 1d (Eg = 0). A slow process 1c?1d occurs even at ambient temperatures
within several weeks.
Received 6 January 2010
Revised 2 February 2010
Accepted 3 February 2010
Available online 11 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Open-chain 1,5-dien-3-ynes are a well-known class of com-
pounds with various applications in organic synthesis. Cyclization
reactions to carbo- and heterocycles and cycloadditions, including
Domino–Diels–Alder reactions, represent prominent examples for
the reactivity of 1,5-dien-3-ynes.1 Moreover, such dienynes are
substructures of many carotenoids. On the contrary, very few cyc-
lic 1,5-dien-3-ynes 1 have been studied.2–5 In particular, the highly
reactive cycloocta-1,5-dien-3-yne (1a)6 and the 12-membered ring
system 1b,7 which contains a further CC double bond, should be
mentioned (Fig. 1).
E, Z
E, Z
(CH2)n
1
1a
Figure 1. Cycloalka-1,5-dien-3-ynes.
1b
Force field calculations and model studies revealed that the bor-
der line between 1,5-dien-3-ynes with and without angle strain
(geometrical strain Eg) depends strongly on the configuration of
the two double bonds.7 Eg = 0 should be realized in 10-, 11-, or
higher ring system for (Z,Z) configurations, in 13-, 14-, or higher
ring system for (E,Z) configurations and in 17-membered and high-
er rings for (E,E) configurations. The larger the macrocyclic rings
are, the more the ring strain can be distributed to bond angles,
bond lengths, etc. This encouraged us to synthesize (1E,5E)-cyclo-
pentadeca-1,5-dien-3-yne (1c).
We started the preparation with 3,14-dihydroxycyclopentadec-
an-1-one (2), a compound, which was used for the preparation of
muscone and exaltone.8 The dehydration of 2 with p-toluenesul-
fonic acid yielded (2E,14E)-cyclopentadeca-2,14-dien-1-one (3) as
a primary product (Scheme 1). The isomeric dienones 5 and 6 are
secondary products, which were generated by acid catalysis
(3?5,6).9 A comparably slower consecutive reaction yielded the
bicyclic enone 4 by a Nazarov10 cyclization (3?4). (2E,13E)-Cyclo-
pentadeca-2,13-dien-1-one (5) was the major component (70–80%
of the mixture 3/4/5/6).11 It could be purified by column chroma-
tography (SiO2, n-hexane/acetone gradient) and was obtained in
a yield of 60–68% related to 2. Dienone 5 was then transformed
into its semicarbazone 7, which exists as syn–anti mixture
(2:1).12 The reaction of 7 and SeO2 afforded 1,2,3-selenadiazole
8,13 which represented the precursor for the desired dienyne 1c.
The fragmentation of 8 could be performed by thermolysis on Cu
powder at 180 °C and 5–10 Pa (yield 54%) or by a very short treat-
ment with n-butyllithium at À70 °C (yield 46%).14 Thermolysis at
higher pressure (ꢀ100 Pa) led to longer contact periods in the
hot zone and to an isomerization of the strained ring system 1c
to the unstrained (E,Z)-dienyne 1d (Eg = 0). The E?Z isomerization
works even at room temperature with a half-life of about 20 d,
which corresponds to a surprisingly low activation barrier for a ste-
reoisomerization of an olefinic double bond. The second (E)-config-
ured double bond is stable, since 1d does not have a geometrical
strain.
When 1,2,3-selenadiazole 8 was refluxed in p-xylylene in the
presence of tetraphenylcyclo pentadienone (9), 32% of the trapping
product 10 was obtained (Scheme 2).15 The isolated alkyne 1c re-
acted even at room temperature to yield 65% 10.
Treatment of 1c with n-BuLi in n-hexane between À70 °C and
room temperature gave a mixture of addition products. In princi-
ple, two types of 1,2-additions, a 1,4-addition and a 1,6-addition
seem to be possible (Scheme 3). Apart from oligomerizations, we
established a chemoselective 1,2-addition to the triple bond, which
yielded an (E,Z,E)-triene, (1c?12) and a regioselective 1,4-addition
to a vinylallene (1c?13). The oily mixture could be separated by
* Corresponding author. Tel.:+49 6131 3922605; fax: +49 6131 3925396.
E-mail address: hmeier@mail.uni-mainz.de (H. Meier).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.013

H. Meier et al. / Tetrahedron Letters 51 (2010) 1952–1954
1953
OH
OH
i
i
O
O
O
O
2H2O
85%
3
2
4
6
i
i
ii
N
O
65%
NH
H2N
7
5
O
60-68%
26% iii
c
c
d
54%
IV
d
b
e
b
a
e
f
a
f
VI
~100%
N
N
V
Se
46%
1c
8
1d
Scheme 1. Preparation of the cyclopentadeca-1,5-dien-3-ynes 1c and 1d. Reagents and conditions: (i) p-TsOH, toluene, 110 °C; (ii) H2N–NH–CONH2ÁHCl, NaOAc, EtOH, 78 °C;
(iii) SeO2, dioxane/H2O (100:1), 25 °C; (iv) Cu, 180 °C, 5–10 Pa; (v) n-BuLi/n-hexane, 5 s at À70 °C; (vi) 25 °C, ca. 30 d or from 8 at 180 °C and 100 Pa.
1c
CO
Table 1
Ph
1H and 13C NMR data of 1c, 1d, 12, and 13 (d values in CDCl3, TMS as internal standard,
d (13C) values within 1.0 ppm are interchangeable)
O
Ph
Ph
Ph
Ph
Ph
Ph
Compd
Olefinic and acetylenic positions
CH2 (CH3)
8
a
b
c
d
e
f
Ph
1c
6.12a
5.50a
5.50
6.12 2.16 (4H), 1.46
(4H), 1.34–1.18
(10H)
N2
,
Se
9
10
CO
Scheme 2. Cycloaddition reaction of isolated or in situ-formed 1c and tetraphe-
nylcyclopentadienone 9.
146.7
6.15b
110.3
5.58b
93.0
93.9
93.0 110.3
5.51c
146.7
33.1, 31.8, 29.7,
28.4, 27.0
1d
12
6.12c 2.23 (2H), 2.16
(2H), 1.48–1.20
(14H)
146.0
110.4
85.9 110.3
144.4
32.9, 29.5, 28.5,
28.2, 28.2, 27.7,
26.8,
26.7, 26.2
5.65
6.15
5.82
6.36
5.58 2.11 (6H),
1.40–1.18
(18H),
0.87 (3H,CH3)
35.8, 31.1, 30.9,
29.8, 27.9,
131.3
128.9
138.9 128.3 125.3
132.3
27.9, 27.4
27.2, 27.0,
26.6, 25.9, 22.5,
14.0 (CH3)
13
5.60
5.80
5.71
4.93
2.09 2.08 (2H), 1.38–
1.17 (22H), 0.87
(3H, CH3)
131.4
126.5
92.7 206.5
96.2
39.7
35.8, 34.8, 31.8,
29.8, 28.7, 28.1,
27.6, 27.3,
27.2, 26.6, 26.3,
22.7, 14.1 (CH3)
a
b
c
3Jtrans = 15.4 Hz.
3Jtrans = 15.3 Hz.
3Jcis = 10.1 Hz.
Scheme 3. Addition reactions of (E,E)-dienyne 1c and n-BuLi.

1954
H. Meier et al. / Tetrahedron Letters 51 (2010) 1952–1954
5. See also: Heber, D.; Rösner, P.; Tochtermann, W. Eur. J. Org. Chem. 2005, 4231–
4247.
6. Echter, T.; Meier, H. Chem. Ber. 1985, 118, 182–197.
7. Meier, H.; Hanold, N.; Molz, T.; Bissinger, H. J.; Kolshorn, H.; Zountsas, J.
Tetrahedron 1986, 42, 1711–1719.
8. Tsuji, J.; Yamada, T.; Shimizu, I. J. Org. Chem. 1980, 45, 5209–5252.
9. Büchi, G.; Wüest, H. Helv. Chim. Acta 1979, 62, 2661–2672.
column chromatography (SiO2, n-pentane) and gave first 15% pure
13 and then 12% pure 12. Within the detection limit of 3%, we
could exclude the presence of 11 and 14 in the product mixture.16
The unstrained dienyne 1d has a much lower reactivity. It did
not add n-BuLi at room temperature, in n-hexane at 60 °C a lot of
oligomers and 15% of 13 were formed.
10. Nazarov, I. N. Usp. Khim. 1951, 20, 71–103. and Usp. Khim. 1949, 18, 377–401.
11. The portion of 5 in a basic medium is lower.
The hydrocarbons 1c, 1d, 12, and 13 are colorless oils. Their 1H
and 13C NMR data are listed in Table 1.17 The reactivity of these
highly unsaturated compounds makes them together with the
known macrocyclic 1,3-dien-5-ynes18,19 interesting candidates
for the synthesis of further macrocyclic systems.
12. Yield 65%; mp 166 °C. 1H NMR (CDCl3): d 8.39 (s, 1H, NH of anti configuration)/
8.07 (s, 1H, NH of syn configuration, proved by NOE measurement), 6.24–5.91
(m, 2H, 2-H, 3-H), 5.15–5.50 (m, 2H, 13-H, 14-H), 3.06 (m, 2H, 15-H), 2.25–1.92
(m, 4H, 4-H, 12H), 1.18–1.28 (m, 14H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H).
13. 7,8,9,10,11,12,13,14-Octahydro-(4E,15E)-6H-cyclo-pentadeca-1,2,3-selenedia-
zole: oil, yield 26%. 1H NMR (CDCl3): d 6.72 (dt, 3J = 16.0 Hz, 4J = 1.4 Hz, 1H, 4-
H), 6.53 (dt, 3J = 15.6 Hz, 4J = 1.4 Hz, 1H, 16-H), 6.40 (dt, 3J = 16.0 Hz, 3J = 7.0 Hz,
1H, 5-H), 6.10 (dt, 3J = 15.6 Hz, 3J = 7.0 Hz, 1H, 15-H), 2.35 (m, 2H, 6-H), 2.24 (m,
2H, 14-H), 1.62–1.10 (m, 14H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H).
14. To the fragmentation processes see Ref. 4–7.
Acknowledgments
We are grateful to the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie for financial support.
15. Mp 226 °C, 1H NMR (CDCl3): d 6.98 (m, 10H, aromat. H), 6.77 (m, 10H, aromat.
H), 6.18 (d, 3Jtrans = 16.2 Hz, 2H, 5-H, 17-H), 5.21 (dt, 3Jtrans = 16.2 Hz, 3J = 6.8 Hz,
2H, 6-H, 16-H), 1.83 (m, 4H, 7-H, 15-H), 1.38–1.23 (m, 12H, 8-H, 9-H, 10-H, 11-
H, 12-H, 13-H, 14-H). EI MS (70 eV): m/z (%) = 559 (100) [M+H+].
16. With the same limit of detection, we could exclude the generation of 1-butyl-
cyclopentadeca-1,3,5-triene and 1-butyl-cyclopentadeca-1,2,4-triene. Both
should be thermodynamically more stable isomers of 13.
References and notes
1. Altogether more than 2000 hits of (E,E)-, (E,Z)- and (Z,Z)-alka-1,5-dien-3-ynes
are listed in reaction data banks.
2. Hopf, H. Classics in Hydrocarbon Chemistry; Wiley-VCH: Weinheim, 2000.
Chapter 8.
3. Stang, P. J.; Diederich, F. Modern Acetylenic Chemistry; Wiley-VCH: Weinheim,
1995.
4. Meier, H.. In Advances in Strain in Organic Chemistry; Halton, B., Ed.; JAI: London,
1991; Vol. 1, pp 215–272.
17. E and Z configurations of the olefinic double bonds in 1c, 1d, 12, and 13 can be
3
easily distinguished by the vicinal coupling constants: Jtrans = 15.4 0.2 Hz,
3Jcis = 10.1 0.1 Hz. The central double bond in 12 has Z configuration, which
was proved by a positive NOE between 4-H and a-CH2 on C-3.
18. Hopf, H.; Krüger, A. Chem. Eur. J. 2001, 7, 4378–4385.
19. Prall, M.; Krüger, A.; Schreiner, P. R.; Hopf, H. Chem. Eur. J. 2001, 7, 4386–4394.