Syntheses, structure, and reactivity of acyclic enetriyne and enetetrayne derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.01.076

Sonogashira coupling of buta-1,3-diynylbenzene with ((2-iodophenyl)ethynyl) trimethylsilane and 1,2-diiodobenzene led to the novel enetriyne, 1-ethynyl-2-(phenylbuta-1,3-diynyl)benzene, and enetetrayne, 1,2-bis(phenylbuta-1,3-diynyl)benzene, respectively.

Full text of DOI:10.1016/j.tetlet.2014.01.076

Tetrahedron Letters 55 (2014) 1569–1572
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Syntheses, structure, and reactivity of acyclic enetriyne and
enetetrayne derivatives
a
a
a
a
John D. Spence a, , Miranda L. Lackie , Nicola A. Clayton , Sergio A. Toscano , Michelle A. Farmer ,
⇑
Esfir Popova a, Marilyn M. Olmstead b
a Department of Chemistry, California State University, Sacramento, 6000 J Street, Sacramento, CA 95819, United States
b Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Sonogashira coupling of buta-1,3-diynylbenzene with ((2-iodophenyl)ethynyl)trimethylsilane and
1,2-diiodobenzene led to the novel enetriyne, 1-ethynyl-2-(phenylbuta-1,3-diynyl)benzene, and
enetetrayne, 1,2-bis(phenylbuta-1,3-diynyl)benzene, respectively. Solid state structural and thermal
analyses are also described. In solution, 1-ethynyl-2-(phenylbuta-1,3-diynyl)benzene was found to
undergo thermal Bergman cyclization to afford 2-(phenylethynyl)naphthalene.
Received 7 November 2013
Revised 14 January 2014
Accepted 18 January 2014
Available online 27 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Buta-1,3-diynylbenzene
Enetriyne
Enetetrayne
Bergman cyclization
Highly conjugated carbon rich compounds derived from (E)-,
(Z)-, and gem-diethynylethenes and tetraethynylethene have found
widespread interest for applications in molecular electronics, non-
linear optics, and light-emitting diodes in addition to their use in
the preparation of larger macrocycles and cages through organome-
tallic coupling reactions.1 Cyclization pathways are also available to
the diethynylethene unit, most notably Bergman2 and related
cycloaromatizations3 of (Z)-hex-3-ene-1,5-diyne units to the corre-
sponding 1,4-didehydrobenzene diradical, providing additional
applications in synthetic and medicinal chemistry as DNA cleaving
agents. It is widely recognized that the naturally occurring ened-
iyne antitumor agents employ strain control to modulate the reac-
tivity of a cyclic enediyne unit leading to their cytotoxic properties.4
In addition to being promoted thermally, photochemical activation
of cyclic5 as well as acyclic enediynes derived from 1,2-bis(phenyl-
ethynyl)benzene6 can be accomplished upon irradiation at 300 nm
to control the timing of resultant Bergman cyclization (Scheme 1).7
(E)-Hex-3-ene-1,5-diyne lacks this reactivity while, with appropri-
ate aryl substituents, cross-conjugated geminal diethynylethene
units can undergo a Hopf-type cyclization8 under thermal condi-
tions,9 radical anionic Bergman-like cyclization under reductive
conditions,10 or photochemical electrocyclic ring closure.11 Tetra-
ethynylethene, despite possessing a bis(enediyne) motif, has not
been reported to undergo cyclization reactions.
Ph
300 nm
Ph
Ph
Ph
Ph
iPrOH
Ph
Scheme 1. Bergman cycloaromatization of 1,2-bis(phenylethynyl)benzene.
Recently, we have been interested in highly conjugated enediy-
nes to examine how extended conjugation affects chemical and
physical properties of the enediyne unit.12 One method to extend
conjugation to the enediyne core is to incorporate additional al-
kyne units through the enediyne alkyne, generating buta-1,3-diy-
nyl derivatives. Such butadiynyl enediyne derivatives have been
previously explored in the literature (Fig. 1), but none have led
to isolation of the corresponding Bergman cyclization product.
Systems studied include the bis(enediyne) 113 with a central but-
adiyne linkage and related cyclic derivatives,14 cyclodec-5-en-
1,3,7,9-tetrayne analogs such as 2,13 dehydrobenzoannulenes15
including 316 and 4,17 bis(buta-1,3-diynyl)pyridines 5,18 and the
related non-conjugated enetetrayne 6.19 Of these systems, only
acyclic 1 was observed to give a Bergman cycloaromatization prod-
uct based on mass spectroscopy data. Skipped enetetrayne 6 was
found to undergo a complex tandem radical cyclization initiated
by formation of a non-benzenoid five-membered ring diradical.
For the cyclic derivatives, calculations suggest strain build up in
the transition state prevents cycloaromatization of the enediyne.13
The thermal reactivity of 2,3-bis(buta-1,3-diynyl)pyridines was
⇑
Corresponding author. Tel.: +1 (916) 278 4477; fax: +1 (916) 278 4986.
E-mail address: jspence@csus.edu (J.D. Spence).
http://dx.doi.org/10.1016/j.tetlet.2014.01.076
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1570
J. D. Spence et al. / Tetrahedron Letters 55 (2014) 1569–1572
with K2CO3 in THF/MeOH readily afforded enetriyne 7 in a
two-step 49% yield. In a similar fashion, Sonogashira coupling
employing a four-fold excess of buta-1,3-diynylbenzene with
O
O
1,2-diiodobenzene 10 afforded enetetrayne
8 in 55% yield.
1
3
2
4
Enetriyne 7 and enetetrayne 8, isolated as stable solids, were
purified by column chromatography and recrystallized prior to
examining thermal and photochemical properties.
The electronic absorbance spectra of enetriyne 7 and ene-
tetrayne 8 in CHCl3 each gave three prominent absorption bands
above 300 nm, with the longest wavelength absorbance red-
shifted compared to their respective enediyne counterparts. For
enetriyne 7, the longest wavelength absorbance was observed at
340 nm (
served at 243 nm (
absorbance for enetetrayne
= 19,400), with a weak shoulder to the red, and the wavelength
of maximum intensity at 251 nm ( = 41,400). The analogous ened-
e
= 22,400), while the most intense absorption was ob-
= 37,400). Similarly, the longest wavelength
was observed at 352 nm
e
HO
R
R
8
(e
H3C
TMS
e
N
iyne, 1,2-bis(phenylethynyl)benzene, gave one prominent peak
above 300 nm observed at 310 nm with a weak shoulder to the
red, and most intense absorption at 273 nm. Stronger absorbance
to higher excited states, as observed for enetriyne 7 and ene-
tetrayne 8, is a common feature for enediyne chromophores.23
The emission spectra of enetetrayne 8, however, were extremely
weak compared to the parent enediyne 1,2-bis(phenyleth-
ynyl)benzene. Upon excitation at 313 nm, enetetrayne 8 gave a rel-
ative fluorescence quantum yield of only 0.02 compared to 0.57 for
1,2-bis(phenylethynyl)benzene using perylene (Ufl = 0.94) as a ref-
erence. Enetriyne 7 shows no measurable fluorescence.
RO
6
5
7
8
To gain further insight into the structure of the butadiynyl
derivatives we obtained the X-ray crystal structures of enetriyne
7 and enetetrayne 8 illustrated in Figure 2. Selected bond lengths
and angles are provided in Table 1. As illustrated in Figure 2, the
phenylbutadiynyl units of enetetrayne 8 are more widely splayed
than the corresponding alkynyl units of enetriyne 7, leading to a
larger observed cÁÁd distance for 8 (4.297 Å) compared to 7
(4.039 Å). Additionally, the entire molecule of enetriyne 7 is essen-
tially planar with a 6.4° angle between phenyl rings, whereas in
enetetrayne 8 the distal phenyl substituents are twisted by 74.3°
and by 71.6° with respect to the central phenyl ring.
Thermal reactivity of enetriyne 7 and enetetrayne 8 in the solid
state has been investigated by differential scanning calorimetry
(DSC). Although DSC has been shown to be a very crude measure
of relative reactivities for enediynes,24 and gives no information
regarding cyclization pathway, it provides insight into thermal
stability and potential for cyclization in solution. 7 and 8 each
displayed melting endotherms followed by broad exotherms indic-
ative of radical cyclization and subsequent polymerization. For
Figure 1. Examples of buta-1,3-diynyl enediyne derivatives.
not reported. Furthermore, no photochemical studies have been re-
ported for enetetrayne models. In this paper, we describe the syn-
thesis of an acyclic enetriyne 7 and enetetrayne 8 containing
phenylbuta-1,3-diynyl units to examine structure and reactivity
of the extended enediyne unit.
The synthetic route toward acyclic enetriyne and enetetrayne
derivatives presented herein employed straightforward Sonogash-
ira cross-coupling20 reactions of buta-1,3-diynylbenzene outlined
in Scheme 2. Due to the relative instability of the terminal buta-
1,3-diynylbenzene, however, a solution of this key intermediate
in toluene was freshly prepared from 2-methyl-6-phenylhexa-
3,5-diyn-2-ol as previously described,21 and immediately used in
subsequent Sonogashira coupling. Pd/Cu-catalyzed coupling
employing a two-fold excess of buta-1,3-diynylbenzene with
((2-iodophenyl)ethynyl)trimethylsilane 922 followed by desilylation
Ph
TMS
1. Pd(PPh3)4, CuI
Et3N, Toluene
2. K2CO3
I
9
THF/CH3OH
(49%)
7
Ph
Pd(PPh3)4, CuI
Et3N, Toluene
I
I
(55%)
10
8
Scheme 2. Synthesis of enetriyne 7 and enetetrayne 8.
Figure 2. X-ray crystal structures of enetriyne 7 and enetetrayne 8.

J. D. Spence et al. / Tetrahedron Letters 55 (2014) 1569–1572
1571
Table 1
220 oC
Selected bond lengths (Å) and bond angles (°) for enetriyne 7 and enetetrayne 8
PhCl, 1,4-CHD
Enetriyne 7
C1–C2
C2–C3
C3–C8
C8–C9
C9–C10
C10–C11
C11–C12
C12–C13
C1–C10 (cÁÁd)
1.1859(18)
1.4385(16)
1.4145(15)
1.4318(15)
1.2072(15)
1.3707(15)
1.2059(15)
1.4309(15)
4.039(2)
C1–C2–C3
C2–C3–C8
C3–C8–C9
C8–C9–C10
C9–C10–C11
C10–C11–C12
C11–C12–C13
178.86(12)
120.23(19)
119.71(10)
179.36(12)
179.23(12)
178.54(12)
177.74(11)
7
11
entrya
[CHD] (M)
0.047
0.47
2.35
0.047
0.47
time (h)
conversion (%)b,c
yield (%)c
-
1
2
3
4
5
6
4
4
4
12
12
12
13
19
30
34
52
82
5 (24)d
12 (40)d
-
Enetetrayne 8
C7–C8
C8–C9
1.209(2)
1.380(2)
1.201(2)
1.438(2)
1.413(2)
1.442(2)
1.198(2)
1.378(2)
1.205(2)
1.438(2)
4.297(3)
C6–C7–C8
C7–C8–C9
C8–C9–C10
C9–C10–C11
C10–C11–C16
C11–C16–C17
179.46(17)
178.84(18)
179.28(17)
176.11(17)
121.36(14)
121.43(14)
12 (24)d
35 (43)d
C9–C10
C10–C11
C11–C16
C16–C17
C17–C18
C18–C19
C19–C20
C20–C21
C9–C18 (cÁÁd)
2.35
a Initial [7] = 4.7 × 10-3 M. b Based on recovered starting material.
c Measured by GC with internal standard. d Based on recovered 7.
Scheme 3. Thermal Bergman cycloaromatization of enetriyne 7.
cyclization were observed. In addition, products derived from
rearrangement of the initial 1,4-diradical and C1–C5 derived
cyclization products, observed in the thermal cyclization of 1,2-
bis(phenylethynyl)benzene,26 were not observed in the thermal
cyclization of 7 or 8.
enetriyne 7, a melting endotherm was observed at 64 °C followed
by a strong exotherm with a peak maximum at 174 °C. The exo-
therm temperature maximum for 7 is nearly 20 °C lower than that
observed for 1-ethynyl-2-phenylethynylbenzene (193 °C), and is
slightly higher than that observed for 1,2-diethynylbenzene
(166 °C). Enetetrayne 8 displays a much higher melting endotherm
at 139 °C, followed immediately by a broad exotherm at 190 °C. In
comparison, 1,2-bis(phenylethynyl)benzene displays a much high-
er exotherm peak temperature at 323 °C. The DSC data suggests
sterics and strain build-up in transition state is not an issue for
thermal Bergman cyclization of acyclic enetriyne 7 and ene-
tetrayne 8 as observed cyclization temperatures are comparable
to 1,2-diethynylbenzene which readily undergoes solution cycliza-
tion to afford naphthalene.24
To determine if enetriyne 7 and enetetrayne 8 are capable of
undergoing Bergman cyclization their solution reactivity was
examined in the presence of a hydrogen atom donor. Heating a
solution of enetriyne 7 in chlorobenzene containing 10–500 fold
excess of 1,4-cyclohexadiene (CHD) at 180 °C for 24 h led primarily
to recovery of unreacted starting material with trace amounts of
cyclized product observed by GCMS and 1H NMR spectroscopy.
Upon increasing the reaction temperature to 220 °C, however, ene-
triyne 7 was found to undergo Bergman cyclization to produce
naphthalene derivative 11 as a function of 1,4-cyclohexadiene con-
centration (Scheme 3). While traces of 11 were observed with
10 equiv of 1,4-cyclohexadiene, increased yields were observed
with 100 and 500 equiv of hydrogen atom donor indicative of a
highly endothermic and reversible Bergman cyclization as previ-
ously observed for benzannelated enediynes.24,25 On a preparative
scale, the cyclization of 7 in the presence of 500 molar equivalents
of 1,4-cyclohexadiene led to the isolation of pure 11 in 11% yield
upon heating for 18 h at 220 °C. Further increase of reaction tem-
perature and amount of hydrogen atom donor, including conduct-
ing the reaction in neat 1,4-CHD, did not lead to any improvement
in the isolated yield of 11. The cyclization of 7 and isolation of 11 is
an improvement compared to the cyclization of compound 1 in
which the product, biphenyl, was only observed by GCMS data
with no isolated yield reported.13 The isolated yield of 11, however,
is lower than the 35% isolated yield of naphthalene from the ther-
mal Bergman cyclization of 1,2-diethynylbenzene.24 Under similar
conditions (100–500 fold excess 1,4-CHD, chlorobenzene, 220 °C),
enetetrayne 8 showed degradation of starting material, however,
no evidence of products derived from single or double Bergman
Irradiation of 7 and 8 in isopropanol at 300 and 350 nm27 led to
rapid conversion of starting material, however, no isolable prod-
ucts were observed for either enetriyne 7 or enetetrayne 8. Trace
amounts of volatile products resulting from addition of a molecule
of solvent were observed by GCMS; however, it is unclear if these
are a result of Bergman cyclization or photoreduction of one of the
alkynyl units followed by solvent addition. Similar results were
obtained in alternative solvents commonly employed in photo-
Bergman cyclizations including acetonitrile, benzene, and tetrahy-
drofuran in the presence or absence of 1,4-CHD as hydrogen atom
donor. As photo-Bergman cyclization is favored through the ex-
cited singlet state,6 the weaker fluorescence of 7 and 8 compared
to 1,2-bis(phenylethynyl)benzene indicates alternative reaction
pathways for 7 and 8 through the triplet excited state.
In effort to promote photo-Bergman cyclization at 350 nm, we
prepared acyclic enetriyne 7 and enetetrayne 8 containing phenyl-
butadiynyl units. With extended conjugation, each derivative
shows absorption bands out to 340–350 nm, though extremely
weak to no fluorescence was observed. The presence of additional
alkyne units reduces the ability of the core enediyne to undergo
Bergman cyclization and favors alternative polymerization or
degradation pathways. Enetriyne 7 is the first reported example
of an extended enediyne containing a butadiynyl unit to afford
the isolated thermal Bergman cyclization product, however, no
photo-Bergman cyclization products were observed for 7 or 8.
Acknowledgments
Funding for this project has been provided by the donors of the
Petroleum Research Fund, administered by the American Chemical
Society (47422-B4), the National Science Foundation (CHE-
0922676), and through the California State University, Sacramento,
SURE program.
Supplementary data
Experimental conditions and spectral data for compounds 7, 8,
and 11. Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data Centre

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J. D. Spence et al. / Tetrahedron Letters 55 (2014) 1569–1572
11. (a) Kaafarani, B. R.; Neckers, D. C. Tetrahedron Lett. 2001, 42, 4099; (b) Kaafarani,
B. R.; Wex, B.; Bauer, J. A. K.; Neckers, D. C. Tetrahedron Lett. 2002, 43, 8227.
12. (a) Spence, J. D.; Hargrove, A. E.; Crampton, H. L.; Thomas, D. W. Tetrahedron
Lett. 2007, 48, 725; (b) Korovina, N. V.; Chang, M. L.; Nguyen, T. T.; Fernandez,
R.; Walker, H. J.; Olmstead, M. M.; Gherman, B. F.; Spence, J. D. Org. Lett. 2011,
13, 3660; (c) Spence, J. D.; Rios, A. C.; Frost, M. A.; McCutcheon, C. M.; Cox, C. D.;
Chavez, S.; Fernandez, R.; Gherman, B. F. J. Org. Chem. 2012, 77, 10329.
13. Elbaum, D.; Nguyen, T. B.; Jorgensen, W. L.; Schreiber, S. L. Tetrahedron 1994,
50, 1503.
as supplementary publication no. CCDC 964855 for 7 and CCDC
964854 for 8. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
076.
14. Blanchette, H. S.; Brand, S. C.; Naruse, H.; Weakley, T. J. R.; Haley, M. M.
Tetrahedron 2000, 56, 9581.
References and notes
15. Spitler, E. L.; Johnson, C. A., II; Haley, M. M. Chem. Rev. 2006, 106, 5344.
16. Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614.
17. (a) Haley, M. M.; Brand, S. C.; Pak, J. J. Angew. Chem. Int., Ed. Engl. 1997, 36, 836;
(b) Wan, W. B.; Brand, S. C.; Pak, J. J.; Haley, M. M. Chem. Eur. J. 2000, 6, 2044.
18. Sorokoumov, V. N.; Popik, V. V.; Balova, I. A. Mendeleev Commun. 2011, 21, 19.
19. (a) Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1997, 38,
3943; (b) Ueda, I.; Sakurai, Y.; Kawano, T.; Wada, Y.; Futa, M. Tetrahedron Lett.
1999, 40, 319.
20. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
21. West, K.; Wang, C.; Batsanov, A. S.; Bryce, M. R. J. Org. Chem. 2006, 71, 8541.
22. Yasuike, S.; Kiharada, T.; Tsuchiya, T.; Kurita, J. Chem. Pharm. Bull. 2003, 51,
1283.
1. Nielsen, M. B.; Diederich, F. Chem. Rev. 2005, 105, 1837.
2. (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660; (b) Bergman, R. G.
Acc. Chem. Res. 1973, 6, 25.
3. (a) Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V. Chem. Rev. 2013, 113, 7089;
(b) Peterson, P. W.; Mohamed, R. K.; Alabugin, I. V. Eur. J. Org. Chem. 2013, 2505.
4. (a) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.; Shen, B. Chem.
Rev. 2005, 105, 739; (b)Enediyne Antibiotics as Antitumor Agents; Borders, D. B.,
Doyle, T. W., Eds.; Marcel Dekker: New York, 1995; (c)Neocarzinostatin: The
Past, Present, and Future of an Anticancer Drug; Maeda, H., Edo, K., Ishida, N.,
Eds.; Springer: New York, 1997.
5. Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.; Cecil, T. L. J. Am.
Chem. Soc. 1996, 118, 3291.
6. Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.
7. For a recent review, see Breiner, B.; Kaya, K.; Roy, S.; Yang, W.-Y.; Alabugin, I. V.
Org. Biomol. Chem. 2012, 10, 3974.
8. For a review, see Zimmerman, G. Eur. J. Org. Chem. 2001, 457.
9. Hopf, H.; Berger, H.; Zimmerman, G.; Nüchter, U.; Jones, P. G.; Dix, I. Angew.
Chem. Int., Ed. Engl. 1997, 36, 1187.
23. Kauffman, J. F.; Turner, J. M.; Alabugin, I. V.; Breiner, B.; Kovalenko, S. V.;
Badaeva, E. A.; Masunov, A.; Tretiak, S. J. Phys. Chem. A 2006, 110, 241.
24. Zeidan, T. A.; Kovalenko, S. V.; Manoharan, M.; Alabugin, I. V. J. Org. Chem. 2006,
71, 962.
25. (a) Koseki, S.; Fujimura, Y.; Hirama, M. J. Phys. Chem. A 1999, 103, 7672; (b)
Kaneko, T.; Takahashi, M.; Hirama, M. Tetrahedron Lett. 1999, 40, 2015.
26. Lewis, K. D.; Matzger, A. J. J. Am. Chem. Soc. 2005, 127, 9968.
27. Photolysis experiments were conducted in a Rayonet photochemical reactor
10. (a) Eshdat, L.; Berger, H.; Hopf, H.; Rabinovitz, M. J. Am. Chem. Soc. 2002, 124,
3822; (b) Treitel, N.; Eshdat, L.; Sheradsky, T.; Donovan, P. M.; Tykwinski, R. R.;
Scott, L. T.; Hopf, H.; Rabinovitz, M. J. Am. Chem. Soc. 2006, 128, 4703.
equipped with 16 3000 Å or 3500 Å lamps.
degassed solution of 7 or 8 (20 mg sample in 100 mL solvent) was irradiated for
3–12 h.
A quartz vessel containing a