Synthesis of 2,5-diethynyl substituted oxepins from trans-1,4- diethynylcyclohexa-2,5-diene-1,4-diols

Article abstract of DOI:10.1016/j.tetlet.2005.03.044

Reaction of trans-1,4-bis(trimethylsilylethynyl)cyclohexa-2,5-diene-1,4- diol with n-BuLi followed by methanesulfonyl chloride resulted in the formation of a dark red solid, which was identified as 2,5-bis(trimethylsilylethynyl) oxepin. Deprotection of the silyl groups resulted in the formation of 2,5-diethynyloxepin, a red, shock sensitive solid. Reaction of a differentially substituted cyclohexa-2,5-diene-1,4-diol gave a mixture of 2,5-diethynyl substituted oxepins.

Full text of DOI:10.1016/j.tetlet.2005.03.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3221–3224
Synthesis of 2,5-diethynyl substituted oxepins from
trans-1,4-diethynylcyclohexa-2,5-diene-1,4-diols
Arkasish Bandyopadhyay and Sethuraman Sankararaman*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
Received 26 January 2005; revised 2 March 2005; accepted 8 March 2005
Available online 22 March 2005
Abstract—Reaction of trans-1,4-bis(trimethylsilylethynyl)cyclohexa-2,5-diene-1,4-diol with n-BuLi followed by methanesulfonyl
chloride resulted in the formation of a dark red solid, which was identified as 2,5-bis(trimethylsilylethynyl)oxepin. Deprotection
of the silyl groups resulted in the formation of 2,5-diethynyloxepin, a red, shock sensitive solid. Reaction of a differentially substi-
tuted cyclohexa-2,5-diene-1,4-diol gave a mixture of 2,5-diethynyl substituted oxepins.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The reversible thermal valence isomerization of the oxe-
pin 1–benzene oxide 2 system has been studied in detail
(Scheme 1).1 This system exhibits thermochromism as
well as solvatochromism, the benzene oxide form is col-
orless and the oxepin is yellow.2 At low temperatures the
benzene oxide form is predominant and above room
temperature the oxepin form is dominant.
application of this method for the synthesis of an oxepin
with extended acetylenic conjugation.
Recently we reported an efficient method for the synthe-
sis of cis- and trans-isomers of 1,4-diethynyl substituted
cyclohexa-2,5-diene-1,4-diols 3 and 6 from p-benzoquin-
one.5 The cis-isomer of 3 was shown to be a useful
building block for the synthesis of acetylenic macro-
cycles.5 Herein we report the synthesis of 2,5-bis(trimeth-
ylsilylethynyl)oxepin from the trans-isomer, 3. Initially
our intention was to synthesize the bis-methanesulfonate
ester of diol 3, but to our surprise, treatment of diol 3
with 2 equiv of n-BuLi followed by 2 equiv of meth-
anesulfonyl chloride, resulted in the formation of a dark
red solid, identified as 2,5-bis(trimethylsilylethynyl)oxe-
pin 4.
Introduction of functional groups that extend the conju-
gation of the oxepin p system shifts the electronic
absorption maxima well into the visible region.3 Oxepins
bearing functional groups with extended conjugation are
potentially useful as thermochromic systems. Ethynyl
substituted oxepins are unknown and are potentially
useful for the synthesis of oxepins with extended p con-
jugation and polyacetylene polymers bearing oxepin
backbones. The classical methods of oxepin synthesis in-
volve multiple steps.4 Herein we describe the synthesis of
2,5-diethynyl substituted oxepins in two steps and the
Subsequently the procedure was optimized for the for-
mation of oxepin 4. It was found that only one equiva-
lent of methanesulfonyl chloride was sufficient to
produce oxepin 4 in 65% yield (Scheme 2).
Scheme 1. Valence isomerization of oxepin–benzene oxide.
Keywords: Oxepin; Valence isomerization; Extended conjugation;
Acetylene; Thermochromism.
*
Scheme 2. Synthesis of oxepin 4 from 3. Reagents and conditions:
(a) 2.0 equiv n-BuLi, 1.0 equiv CH3SO2Cl, THF, ꢀ78 ꢁC to rt.
Corresponding author. Tel.: +91 44 2257 8252; fax: +91 44 2257
0545; e-mail: sanka@iitm.ac.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.044

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A. Bandyopadhyay, S. Sankararaman / Tetrahedron Letters 46 (2005) 3221–3224
Scheme 5. Deprotection of the TMS group. Reagents and conditions:
(a) K2CO3, MeOH, rt, 30 min, N2.
Scheme 3. Mechanism of formation of oxepin 4 from 3.
2,5-diethynyloxepins 9 and 10, each in 90% yield
(Scheme 5).6 The red crystalline solid oxepin 4 was sta-
ble for several months and no decomposition was ob-
served under ambient conditions. Upon cooling the
solid, and the red color of the oxepin 4 gradually chan-
ged to yellow below ꢀ20 ꢁC and turned to pale yellow at
ꢀ78 ꢁC. Upon warming the solid back to room temper-
ature the reverse color changes were observed. This ther-
mochromic behavior was observed over several cycles of
cooling to ꢀ78 ꢁC and warming to room temperature.
We attribute the thermochromic behavior of 4 to the
well known reversible thermal valence isomerization to
5, similar to that observed for 1 and 2. Similarly the dark
red solution of oxepin 4 in acetone-d6 also reversibly
changed color to yellow with lowering of the tempera-
ture and exhibited thermochromism over several cycles.
The solution of 4 in acetone-d6 was stable for several
months and no decomposition could be observed by
1H NMR spectroscopy and TLC. However a red col-
ored solution of 4 in CDCl3 slowly changed color to pale
yellow when stored at ambient temperature and the
decomposition of 4 could be followed by 1H NMR spec-
troscopy. After 3 days, isomerization of 4 was complete
and yielded 2,5-bis(trimethylsilylethynyl)phenol 11 as
the only product (Scheme 6). The isomerization of 4 to
11 could be accelerated by the addition of a small
amount of trifluoroacetic acid. Repeated cooling and
warming of the CDCl3 solution between ꢀ78 ꢁC and
room temperature also accelerated the isomerization.
Interestingly the cis-isomer of diol 3 under identical
reaction conditions failed to yield any oxepin, only the
starting diol was recovered after aqueous work up.
Based on these observations a probable mechanism of
formation of oxepin 4 is shown in Scheme 3. Formation
of 4 is explained on the basis of an intramolecular SN20
substitution reaction of the intermediate mono sulfonate
ester which results in the formation of the benzene oxide
derivative 5. Thermal electrocyclic ring opening of 5
leads to the formation of 4 (Scheme 3).1 The SN20 substi-
tution reaction is stereoelectronically favored in the case
of the trans-isomer over the cis-isomer which explains
the lack of oxepin formation in the latter case.
When a differentially substituted diol was reacted in the
same way, a mixture of oxepins were obtained as illus-
trated in the case of diol 6. Treatment of trans diol 65
with n-BuLi followed by CH3SO2Cl yielded a 1:1 mix-
ture of oxepins 7 and 8 (Scheme 4). The oxepins were
separated by column chromatography and thoroughly
characterized by spectroscopic data.6 The structural
assignment of these two regioisomeric oxepins is based
on the chemical shift values of the acetylenic carbons
from the 13C NMR spectra. In oxepin 7 the chemical
shift values of the ethynyl carbons of the trimethylsilyl-
ethynyl group are 100.8 and 94.7 whereas that of the
diethoxypropynyl group are 88.1 and 84.9, respectively.
In the case of oxepins 4 and 8 the chemical shift values
of the acetylenic carbons on the 2-position are 105.1 and
97.4 for 4 and 105.5 and 97.4 for 8, respectively.
1
The H NMR spectrum of 4 was recorded at various
temperatures in acetone-d6 in an attempt to measure
the dynamics of the valence isomerization of 4 and 5.
However, the spectra recorded from room temperature
to ꢀ90 ꢁC did not reveal any changes. The NMR spec-
tral changes due to the valence isomerization of the
Removal of the trimethylsilyl groups in 4 and 8 using
K2CO3 in MeOH readily yielded the corresponding
Scheme 4. Synthesis of differentially substituted oxepins. Reagents and
conditions: (a) 2.0 equiv n-BuLi, 1.0 equiv CH3SO2Cl, THF, ꢀ78 ꢁC to
rt.
Scheme 6. Rearrangement of oxepin 4 to phenol 11.

A. Bandyopadhyay, S. Sankararaman / Tetrahedron Letters 46 (2005) 3221–3224
3223
parent oxepin 1 could be observed only below ꢀ110 ꢁC.7
In the present study the NMR spectrum could not be re-
corded below ꢀ90 ꢁC due to poor solubility. The iso-
merization of 4 to 11 in CDCl3 and also in the
presence of acid is due to the acid catalyzed isomeriz-
ation of the benzene oxide form 5.
The equilibrium between 4 and 5 is favored toward 5 at
low temperatures and hence repeated cooling and warm-
ing of the solution in CDCl3 accelerates the isomeriz-
ation. The trace amount of HCl present in CDCl3 is
responsible for the isomerization (Scheme 7).1,8
In non-acidic solvents such as acetone, THF, and ether
oxepin 4 is quite stable. Oxepin 9 was found to be unsta-
ble and shock sensitive. Attempts to remove the solid
oxepin using a metal spatula led to exothermic decom-
position and formation of smoke. Our attempts to use
oxepin 9 as an acetylenic building block for the synthesis
of oxepins with extended acetylenic conjugation were
unsuccessful as 9 was unstable and slowly polymerized
at room temperature both in the solid state as well as
in solution to yield a dark red colored polymer. At-
tempted Sonogashira coupling of 9 with iodobenzene
failed to yield 2,5-bis(phenylethynyl)oxepin. Similarly
attempted Cadiot–Chodkiewicz coupling of 9 with b-
bromophenylacetylene also failed to yield 2,5-bis(phen-
ylbutadiynyl)oxepin 14. In the above reactions oxepin
9 decomposed to give an intractable polymeric material.
Unlike 9, oxepin 10 was found to be stable in the solid
state as well as in solution.
Scheme 8. Synthesis of oxepin 14 with extended conjugation. Reagents
and conditions: (a) 2.0 equiv b-bromophenylacetylene, CuBr, piper-
idine, NH2OHÆHCl, MeOH, rt, 45 min, 32%; (b) same as in (a) but
with phenylacetylene, (c) 2.0 equiv n-BuLi, 1.0 equiv CH3SO2Cl, THF,
ꢀ78 ꢁC to rt, 30%.
synthesis of oxepins with extended acetylenic conjugation
has also been developed. The effect of ethynyl substitu-
ents on the stability and reactivity of various oxepins is
currently under investigation.
Oxepin 14 could be readily obtained from diol 13
(Scheme 8). The starting diol 13 was obtained by the
Cadiot–Chodkiewicz coupling of diol 125 with b-bro-
mophenylacetylene. Alternatively diol 13 was obtained
by the Cadiot–Chodkiewicz coupling of the bromodiol
15 with phenylacetylene. The bromodiol 15 was pre-
pared by bromination of 12 using N-bromosuccinimide.
The availability of diols 12 and 15 makes the methodol-
ogy shown in Scheme 8 viable and attractive for the syn-
thesis of oxepins with extended acetylenic conjugation.
Acknowledgements
We thank Volkswagen Stiftung, Germany for financial
support and Professor H. Hopf, Institute of Organic
Chemistry, University of Braunschweig, Germany for
support and useful discussions. We thank the Sophisti-
cated Analytical Instrument Facility, IIT Madras for
spectroscopic data, Dr. U. Papke, Institute of Organic
Chemistry, University of Braunschweig, Germany for
HRMS data and Dr. M. Srinivasan, IIT Madras for a
sample of diol 6.
In conclusion we have reported a new method for the
synthesis of the hitherto unknown 2,5-diethynyl disub-
stituted oxepins from the corresponding 1,4-diethynyl-
cyclohexa-2,5-diene-1,4-diols in a single step. From
differentially substituted diols such as 6, a mixture of
isomeric oxepins was obtained that was readily separable
by column chromatography. A new methodology for the
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tetlet.
2005.03.044. Supplementary material contains experi-
mental procedures and characterization data of all the
compounds described in this paper.
References and notes
1. Vogel, E.; Gunther, H. Angew. Chem., Int. Ed. Engl. 1967,
6, 385–401; for a review on arene oxide–oxepin valence
isomerization, see: Boyd, D. R.; Jerina, D. M. In Small
Ring Heterocycles; Hassner, A., Ed.; Wiley: New York,
1984; Vol. 42, pp 197–282.
2. Vogel, E.; Boll, W. A.; Gunther, H. Tetrahedron Lett. 1965,
6, 609–615.
Scheme 7. Mechanism of rearrangement of 4 to 11.

3224
A. Bandyopadhyay, S. Sankararaman / Tetrahedron Letters 46 (2005) 3221–3224
3. Vogel, E.; Beermann, D.; Balci, E.; Altenbach, H.-J.
Tetrahedron Lett. 1976, 17, 1167–1170; Sondheimer, F.;
Shani, A. J. Am. Chem. Soc. 1964, 86, 3168–3169;
McManus, M. J.; Berchtold, G. A.; Boyd, D. A.; Kennedy,
D. A.; Malone, J. F. J. Org. Chem. 1986, 51, 2784–2787.
4. Vogel, E.; Schubert, R.; Boll, W. A. Angew. Chem., Int. Ed.
Engl. 1964, 3, 510; Prinzbach, H.; Arguelles, M.; Druckery,
E. Angew. Chem., Int. Ed. Engl. 1966, 5, 1039.
(CH), 79.4 (C), 76.5 (CH); MS (EI, 70 eV) 142 (M+, 32),
114 (30), 92 (25), 63 (100). (Caution: the solid oxepin 4
appears to be shock sensitive. When the solid was scratched
with a metal spatula, in an attempt to remove it from the
flask, an exothermic decomposition with the formation of
smoke was observed and a black residue was left in the
flask. Upon storing the solid at room temperature the
oxepin decomposed slowly to an insoluble material over a
period of a few days.) Oxepin 10: (red solid, 92%), IR
5. Srinivasan, M.; Sankararaman, S.; Hopf, H.; Varghese, B.
Eur. J. Org. Chem. 2003, 660–665; Sankararaman, S.;
Srinivasan, M. Org. Biomol. Chem. 2003, 1, 2388–2392.
6. General procedure for the synthesis of oxepins: n-BuLi
(0.04 mol, 25 ml of a 1.6 M solution in hexane) was added
at ꢀ78 ꢁC to a stirred solution of the trans-isomer of the
cyclohexa-2,5-diene-1,4-diol (0.02 mol) in THF (100 ml)
under a N2 atmosphere. The resulting solution was stirred
for 30 min at the same temperature. Methanesulfonyl
chloride (1.55 ml, 0.02 mol) was added and stirring was
continued for another 3 h during which time the reaction
mixture was allowed to warm to room temperature. It was
then cooled to 0 ꢁC and quenched by the addition of ice-
cold water (200 ml). The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3 · 50 ml).
The combined organic extract was washed with ice-cold
water (100 ml) and ice-cold saturated brine solution
(100 ml). After drying over MgSO4 the solvent was
removed and a dark red solid was obtained. The crude
product was subjected to column chromatography on silica
gel with hexane as the eluant to obtain pure oxepin as a
dark red crystalline solid (65%). Oxepin 4: mp 103–105 ꢁC;
IR (KBr) 2957, 2141, 1626, 1595, 1246, 1181 cmꢀ1; UV–vis
(hexane) kmax (loge) 206 (4.40), 238 (4.30), 284 (4.07), 348
1
(neat) 2227 cmꢀ1; H NMR (400 MHz, acetone-d6) d 6.51
(1H, d, J = 6.3 Hz), 6.15 (1H, d, J = 6.3 Hz), 6.08 (1H, d,
J = 4.8 Hz), 5.72 (1H, d, J = 4.8 Hz), 5.41 (1H, s), 3.83–
3.51 (4H, m), 2.95 (1H, s), 1.18 (6H, t, J = Hz); 13C NMR
(100 MHz, acetone-d6) d 143.2 (CH), 135.4 (CH), 133.8 (C),
125.7 (C), 122.1 (CH), 119.3 (CH), 91.3 (CH), 84.5 (C),
83.9 (C), 81.5 (CH), 80.8 (C), 61.4 (CH2), 14.4 (CH3);
Oxepin 7: (red oily liquid, 0.12 g, 13%) IR (neat) 2975,
1
2931, 2898, 2144 cmꢀ1; H NMR (400 MHz, acetone-d6) d
6.49 (1H, d, J = 6.4 Hz), 6.09 (1H, d, J = 6.4 Hz), 6.05 (1H,
d, J = 5.4 Hz), 5.68 (1H, d, J = 5.4 Hz), 5.38 (1H, s), 3.52–
3.65 (4H, quartet of AB pattern, J = 6.83, 7.33 Hz), 1.16
(6H, t, J = 6.84 Hz), 0.10 (9H, s); 13C NMR (100 MHz,
acetone-d6) d 143.3 (CH), 135.3 (CH), 134.8 (C), 125.1 (C),
121.8 (CH), 119.0 (CH), 100.8 (C), 94.7 (C), 92.1 (CH),
88.1 (C), 84.9 (C), 61.1 (CH2), 15.1 (CH3), ꢀ0.3 (CH3);
HRMS (ESI, MeOH) calcd for C18H24O3SiNa: 339.1392.
Found 339.1422. Oxepin 8: (red oily liquid, 0.28 g, 30%),
IR (neat) 2926, 2936, 2253 cmꢀ1 1H NMR (400 MHz,
;
acetone-d6) d 6.48 (1H, d, J = 6.4 Hz), 6.11 (1H, d,
J = 6.4 Hz), 6.06 (1H, d, J = 5.4 Hz), 5.67 (1H, d,
J = 5.4 Hz), 5.40 (1H, s), 3.56–3.65 (4H, quartet of AB
pattern, J = 9.7, 6.8 Hz), 1.16 (6H, t, J = 6.8 Hz), 0.17 (9H,
s); 13C NMR (100 MHz, acetone-d6) d 143.2 (CH), 135.1
(CH), 133.9 (C), 126.4 (C), 122.2 (CH), 119.2 (CH), 105.5
(C), 97.4 (C), 91.9 (CH), 84.6 (C), 80.9 (C), 61.4 (CH2), 15.2
(CH3), ꢀ0.3 (CH3); HRMS (ESI, MeOH) calcd for
C18H24O3SiNa: 339.1392. Found 339.1388. 11: 1H NMR
(400 MHz, CDCl3) d 7.23 (1H, d, J = 7.8 Hz), 7.02 (1H, s),
6.94 (1H, d, J = 7.8 Hz), 5.82 (1H, br, OH), 0.26 (9H, s),
0.23 (9H, s); 13C NMR (100 MHz, CDCl3) d 156.2 (C),
131.3 (CH), 125.1(C), 124.0 (CH), 117.8 (CH), 109.9 (C),
104.2 (C), 98.5 (C), 96.3 (C), ꢀ0.11 (CH3); MS (EI, 70 eV)
286 (M+, 20), 285 (80), 271 (35), 270 (100), 128 (20), 73
(30).
1
(3.98) nm; H NMR (400 MHz, acetone-d6) d 6.43 (1H, d,
J = 6.4 Hz), 6.04 (1H, d, J = 6.9 Hz), 6.01 (1H, d,
J = 5.4 Hz), 5.61 (1H, d, J = 5.4 Hz), 0.15 (9H, s), 0.13
(9H, s); 1H NMR (400 MHz, CDCl3) d 6.45 (1H, d,
J = 6.3 Hz), 5.78 (2H, d, J = 5.9 Hz), 5.41 (1H, d,
J = 5.3 Hz), 0.02 (9H, s), 0.00 (9H, s); 13C NMR
(100 MHz, CDCl3) d 142.4 (CH), 134.7 (CH), 134.4 (C),
125.8 (C), 121.3 (CH), 118.8 (CH), 105.1 (C), 100.3 (C),
97.4 (C), 94.8 (C), 0.00 (CH3), ꢀ0.21 (CH3); MS (EI, 70 eV)
286 (M+, 100), 271 (55), 255 (10), 149 (22), 128 (10), 73
(18); HRMS calcd for C16H22Si2O: 286.1209. Found
286.1197. Oxepin 9: 1H NMR (400 MHz, CDCl3) d 6.42
(1H, d, J = 6.4 Hz), 5.95 (1H, d, J = 6.5 Hz), 5.92 (1H, d,
J = 5.4 Hz), 5.58 (1H, d, J = 5.4 Hz), 3.05 (1H, s), 2.93 (1H,
s); 13C NMR (100 MHz, CDCl3) d 142.2 (CH), 134.8 (CH),
133.6 (C), 125.0 (C), 121.5 (CH), 118.6 (CH), 83.4 (C), 79.7
7. Gunther, H. Tetrahedron Lett. 1965, 6, 4085–4090.
8. Kaubisch, N.; Daly, J. W.; Jerina, D. W. Biochemistry
1972, 11, 3080–3088; Boyd, D. R.; Berchtold, G. A. J. Am.
Chem. Soc. 1979, 101, 2470–2474.