Bergman cycloaromatization of imidazole-fused enediynes: The remarkable effect of N-aryl substitution

Article abstract of DOI:10.1016/j.tetlet.2004.02.152

A series of N-aryl substituted 'imidazole-fused' (Z) 3-ene-1,5-diynes was prepared and kinetic parameters for their Bergman cycloaromatization reactivities were determined. N-Arylation enhanced rates relative to N-alkyl derivatives by up to sevenfold (ANOVA p<0.0001). The greatest enhancement was exhibited by the N-phenyl derivative (sevenfold at 145°C).

Full text of DOI:10.1016/j.tetlet.2004.02.152

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3621–3624
Bergman cycloaromatization of imidazole-fused enediynes:
the remarkable effect of N-aryl substitution
Zhengrong Zhao, Yunshan Peng, N. Kent Dalley, John F. Cannon and Matt A. Peterson*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA
Received 7 January 2004; accepted 10 February 2004
Abstract—A series of N-aryl substituted ‘imidazole-fused’ (Z) 3-ene-1,5-diynes was prepared and kinetic parameters for their
Bergman cycloaromatization reactivities were determined. N-Arylation enhanced rates relative to N-alkyl derivatives by up to
sevenfold (ANOVA p < 0:0001). The greatest enhancement was exhibited by the N-phenyl derivative (sevenfold at 145 °C).
Ó 2004 Elsevier Ltd. All rights reserved.
Since its discovery in the early 1970s, the Bergman
cycloaromatization reaction1 (Fig. 1) has been the subject
of extensive experimental and theoretical investigation.2
Interest in this process has been stimulated by the crit-
ical role the Bergman cyclization plays in the biological
activities of naturally occurring enediyne antitumor
antibiotics,3 and by its potential use in synthetic meth-
ods for polycyclic aromatic compounds4 and polymeric
materials.5 Large numbers of synthetic analogues of
DNA-cleaving agents (e.g., calicheamicins, esperamic-
ins, dynemicins, neocarzinostatin, and kedarcidin) have
been prepared in efforts to improve upon the properties
of the parent compounds,3 and numerous related (Z)
3-ene-1,5-hexadiynes have been studied in order to
determine factors that influence the rate of Bergman
cycloaromatization. From these latter studies it is clear
that several factors contribute to the energy barriers
involved in cycloaromatization. Among these are the
so-called ‘c,d’ distance (the distance between the terminal
alkynyl carbons),6 electronic factors,7 and differences in
strain energies for transition state and ground state
geometries.8
Attempts to modulate electronic contributions to Berg-
man cycloaromatization barriers have focused on direct
substitution of the ene moiety in monocylic (Z) enediy-
nes,7b;c or substitution at ortho7a or para7b positions in
benzannelated enediynes. Of the heterocyclic enediynes
reported to date, the ‘imidazole-fused’ enediynes (4,5-
bis-(alkynyl)imidazoles)9 have received comparatively
little attention, and only one report dealing with syn-
thetic methods has appeared in the literature.9b The
Bergman reactivity of these compounds was apparently
never studied. We became interested by the possibility
that imidazole-fused enediynes might provide an
unusually versatile platform for probing electronic
effects due to their possession of three sites for potential
functionalization (imidazole positions 1–3). Function-
alization at any of these positions might reasonably be
expected to influence the electronics of the imidazole
ring, providing previously unexplored avenues for
modulating rates of Bergman cycloaromatizations.10
Here we report our findings relative to the effect of N1
substitution.
R3
R4
H
R1
R2
R3
R4
R1
R2
R3
R4
R1
R2
k2
k1
k-1
2H
H
1
2
3
N-Alkyl and N-aryl substituted 4,5-bis-ethynylimidaz-
oles were prepared according to the route depicted in
Scheme 1.11 Sonogashira12 coupling of 4 with TMS-
acetylene gave 5 in 85% yield. N-Alkylation followed by
removal of the TMS groups gave 6a–e (45–87%, two
steps). N-Arylation was accomplished employing the
copper-catalyzed method of Collman and Zhong13 to
provide 7a–j (47–67%, two steps). Conversion of
Figure 1. Bergman cycloaromatization.
* Corresponding author. Fax: +1-801-422-0153; e-mail: matt_
peterson@byu.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.152

3622
Z. Zhao et al. / Tetrahedron Letters 45 (2004) 3621–3624
fused enediynes to phenyl substitution may be explained
TMS
R
N
R
N
H
H
N
I
I
by significant population of nonplanar conformations of
N-aryl derivatives 7a–j. The p–system of the phenyl ring
of nonplanar conformers would not be conjugated with
the imidazole p–system. Conjugative and field effects
may not be transmitted to the enediyne moiety when the
phenyl ring and imidazole moieties are not in the same
plane. Monte Carlo calculations15 indicate that the
phenyl ring and imidazole moieties are approximately
20° out of planarity for minimum energy conformations
of compounds 7a–j.16
N
b or c
a
d
N
N
5
N
6a–e
7a–j
N
4
8a–e
9a–j
TMS
Scheme 1. Reagents and conditions: (a) TMSCBCH, (Ph3P)4Pd, CuI.
(b) i. Alkylhalide, K2CO3, DMF; ii. NH4F, MeOH. (c) i. ArylB(OH)2,
[Cu(OH)TMEDA]2Cl2, CH2C12; (ii) NH4F, MeOH. (d) 10 equiv 1,4-
cyclohexadiene, benzene-d6.
To investigate possible similarities between imidazole-
fused enediynes and the analogous benzannelated
congeners, 6b was treated with varying concentrations
of 1,4-cyclohexadiene (1,4-CHD) and the reaction
kinetics were determined (Table 2).14 The concentration
of 1,4-CHD did not significantly affect the rate of dis-
appearance of 6b, in sharp contrast to the concentration
dependence observed for the reaction of 1,2-diethynyl-
benzene.17 The kinetic behavior exhibited by 6b para-
lleled behavior exhibited by (Z) 3-ene-1,5-hexadiyne and
cyclodec-3-ene-1,5-diyne (1, R1¼R2¼H, R3¼R4¼CH2–
CH2–) where Bergman cycloaromatization has been
shown to be independent of the concentration of 1,4-
CHD.1;17a;b This observation indicates that k1 is rate
determining for imidazole-fused enediynes, and suggests
compounds 6a–e and 7a–j to the corresponding cyclo-
aromatized products 8a–e and 9a–j11was followed by 1H
NMR,14 and kinetic parameters for these studies are
presented in Table 1. N-Aryl substitution enhanced the
rates relative to the N-alkyl derivatives in all cases
(ANOVA p < 0:0001). The greatest enhancement was
observed for the N-phenyl derivative 7a (Table 1, entry
6). At 145 °C, the rate for 7a was from four to seven
times greater than rates for N-alkyl derivatives (entries
1–5). Substituents on the phenyl ring did not seem to
have a pronounced effect, and Hammet plots for com-
pounds 7a–j did not show linear free-energy relation-
ships. This is in contrast to benzannelated enediynes
where substitution on the phenyl ring significantly
impacts rates, and linear free-energy relationships have
been reported.7d The relative insensitivity of imidazole-
by analogy that k2 > k as has been calculated for
ꢀ1
cyclodec-3-ene-1,5-diyne.
Table 1. Kinetic parameters for Bergman cycloaromatization of imidazole-fused enediynes 6a–e and 7a–j
a
Entry
1
Compound
R
T (°C)
k (10ꢀ5 sꢀ1
)
t1=2 (h)
6a
Methyl
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
125
145
0.42 ꢁ 0.05
2.5 ꢁ 0.3
0.51 ꢁ 0.06
2.2 ꢁ 0.2
0.41 ꢁ 0.02
2.0 ꢁ 0.07
0.35 ꢁ 0.02
1.3 ꢁ 0.2
0.36 ꢁ 0.02
1.6 ꢁ 0.2
2.2 ꢁ 0.04
9.7 ꢁ 0.4
1.3 ꢁ 0.07
4.8 ꢁ 0.18
1.5 ꢁ 0.09
4.2 ꢁ 0.4
1.7 ꢁ 0.2
4.6 ꢁ 0.03
1.9 ꢁ 0.06
4.8 ꢁ 0.06
1.0 ꢁ 0.04
4.7 ꢁ 0.2
1.6 ꢁ 0.06
5.2 ꢁ 0.2
1.3 ꢁ 0.1
4.7 ꢁ 0.1
1.4 ꢁ 0.2
3.9 ꢁ 0.2
0.89 ꢁ 0.1
3.0 ꢁ 0.1
46
7.7
38
2
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
n-Butyl
8.8
47
3
Benzyl
9.7
55
4
p-Methoxybenzyl
p-Nitrobenzyl
Phenyl
15
54
5
12
10
6
2.0
15
7
p-Fluorophenyl
p-Chlorophenyl
p-Bromophenyl
p-Iodophenyl
p-Methoxyphenyl
p-Methoxycarbonylphenyl
m-Nitrophenyl
p-Ethylphenyl
p-tert-Butylphenyl
4.0
13
8
4.1
11
9
4.2
10
10
11
12
13
14
15
4.0
19
4.1
12
7g
7h
7i
3.7
15
4.1
14
4.9
22
7j
7.4
a Kinetic data were measured in triplicate and all first order plots gave excellent linear correlations ðR > 0:990Þ.

Z. Zhao et al. / Tetrahedron Letters 45 (2004) 3621–3624
3623
Table 2. Effect of concentration of 1,4-cyclohexadiene on Bergman
cycloaromatization of 6b at 145 °Ca
critical range suggested to be required for Bergman
cycloaromatization of simple monocyclic enediynes at
37 °C.6
nBu
N
nBu
N
nBu
N
k1
k-1
k2
In our hands, compound 12 proved to be impossible to
prepare via the route depicted in Scheme 2. A number of
different conditions were examined, and each failed to
give the desired product. Yields for the imidazole-fused
cycloundec- and cyclododec-3-ene-1,5-diynes 13 and 14
were also disappointingly low (16% and 27%, respec-
tively). To determine if these yields were at least partly
due to quenching of the butyllithium via deprotonation
of imidazole C-2, we prepared compound 15 as a model
system. Compound 15 was obtained in 67% yield and
products arising from C-2 alkylation were not detected.
An X-ray crystal structure for 5 (Fig. 2)18 reveals that the
2H
N
N
N
10
6b
11
[1,4-CHD] (M)
k (10ꢀ5 sꢀ1
)
t1=2 (h)
0.3
0.7
1.3
2.3
2.2
2.0
2.1
2.3
8.8
9.4
9.2
8.3
a Kinetic data were measured in triplicate and all first order plots gave
excellent linear correlations ðR > 0:990Þ.
ꢀ
c,d distance (4.62 A) and bond angles (h1 ¼ h2 ¼ 129:4°)
CH3
N
CH3
N
CH3
N
are greater than in 1,2-diethynylbenzene (calculated
ꢀ
values for 1,2-diethynylbenzene are: c,d distance¼4.13 A,
b
a
and h1 ¼ h2 ¼ 121:3°).15 These features may contribute
to less favorable energy barriers for ring closure in
imidazole-fused enediynes owing to increased ring strain.
N
N
6a
N
n
n
16 n = 2
17 n = 3
12 n = 1
13 n = 2
14 n = 3
c
The Bergman reactivities of compounds 13 and 14 were
also determined. Compound 14 did not react at
T 6 180 °C. Compound 13 had half-lives of 114 and 35 h
at 145 and 165 °C, respectively. In comparison, com-
pound 6a had half-lives of 7.7 and 3.7 h at the same
temperatures, respectively. This behavior parallels
behavior exhibited by benzannelated enediynes (e.g.,
3,4-benzo-cycloundec-3-ene-1,5-diyne reacts less rapidly
than its monocyclic congener 1,2-diethynylbenzene).17c
However, it is interesting to note the significant retar-
dation in cyclization rate for compound 13 relative to
3-chloro-cycloundec-3-ene-1,5-diyne at similar temper-
ature (t1=2 ¼ 2 h at 170 °C, vs 35 h at 165 °C for 13).
CH3
CH3
N
N
15
CH3
Scheme 2. Reagents and conditions: (a) i. n-BuLi (2.0 equiv), HMPA,
THF; ii. I(CH2)nI (n ¼ 4–6). (b) 10 equiv 1,4-cyclohexadiene, benzene-
d6. (c) i. n-BuLi (2.0 equiv), HMPA, THF; ii. CH3I (excess).
To probe additional factors that might influence the rate
of Bergman cyclization of imidazole-fused enediynes, we
attempted to prepare bicyclic analogues 12–14 (Scheme
2). The calculated15 c,d-distance for imidazole-fused
ꢀ
cyclodec-3-ene-1,5-diyne 12 is 3.41 A. This is near the
In summary, N-aryl and N-alkyl substituted imidazole-
fused enediynes undergo thermally promoted Bergman
cycloaromatization. All compounds examined underwent
smooth conversion to their corresponding benzimidazole
products,11 and N-aryl substitution enhanced rates by up
to sevenfold at 145 °C. Although the cause for this rate
enhancement is uncertain, the absence of any clear linear
free-energy relationship for the N-aryl derivatives suggests
that steric effects may be an important factor.7a The rate of
reaction did not depend on the concentration of trapping
agent (in contrast to benzannelated enediynes), and the
presumably more reactive imidazole-fused cyclodec-3-
ene-1,5-diyne 12 was apparently too strained to allow
preparation via the route investigated. Imidazole-fused
enediynes hold considerable potential as synthetic
reagents for novel polymeric materials and/or pharma-
ceuticals (e.g., ribosylated derivatives may mimic purine
nucleosides) and this work provides a foundation for
exploring these potential applications.
Acknowledgements
We thank the Elsa Pardee Foundation, the BYU Cancer
Center, and BYU development funds for partial support
of this work.
Figure 2. Crystal structure for compound 5 (hydrogens omitted for
clarity).18

3624
Z. Zhao et al. / Tetrahedron Letters 45 (2004) 3621–3624
(13) UV (MeOH) max 219, 270, 286 nm, min 231, 284 nm;
References and notes
1H NMR (CDCl3, 300 MHz) d 7.27 (s, 1H), 3.60 (s, 3H),
2.54 (t, J ¼ 6:3 Hz, 2H), 2.48 (t, J ¼ 6:3 Hz, 2H), 2.02
(pent, J ¼ 7:2 Hz, 2H), 1.72–1.64 (m, 4H); 1H NMR
(benzene-d6, 300 MHz) d 6.63 (s, 1H), 2.59 (s, 3H), 2.25–
2.18 (m, 4H), 2.01–1.90 (m, 2H), 1.40–1.28 (m, 4H); 13C
NMR (CDCl3, 75 MHz) d 137.3, 133.1, 115.7, 105.2, 97.2,
79.8, 71.7, 32.8, 25.9, 24.4, 19.4, 19.3, 19.2; MS (FAB) m=z
199.1233 ([Mþ1]þ [C13H15N2]¼199.1235); (14) UV
1. (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972,
94, 660; (b) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
2. See for example: Grissom, J. W.; Gunawardena, G. U.;
Klingber, D.; Huang, D. Tetrahedron 1996, 52, 6453.
3. Enediyne Antibiotics as Antitumor Agents; Borders, D. B.,
Doyle, T. W., Eds.; Marcel Dekker: New York, 1995.
4. (a) Bowles, D. M.; Anthony, J. E. Org. Lett. 2000, 2, 85;
(b) Grissom, J. W.; Calkins, T. L.; McMillen, H. A.; Jiang,
Y. J. Org. Chem. 1994, 59, 5833.
5. (a) Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson, C.
Macromolecules 2001, 34, 4104; (b) John, J. A.; Tour, J.
M. J. Am. Chem. Soc. 1994, 116, 5011.
6. (a) Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184; (b)
Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E.
J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866; (c)
Nicolaou, K. C.; Ogawa, Y.; Zuccarello, G.; Kataoka, H.
J. Am. Chem. Soc. 1988, 110, 7247.
7. (a) Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org.
Lett. 2002, 4, 1119; (b) Jones, G. B.; Warner, P. M. J. Am.
Chem. Soc. 2001, 123, 2134; (c) Jones, G. B.; Plourde, G.
W., II. Org. Lett. 2000, 2, 1757; (d) Choy, N.; Kim, C.-S.;
Ballestro, C.; Artigas, L.; Diez, C.; Lichtenberger, F.;
Shapiro, J.; Russell, K. C. Tetrahedron Lett. 2000, 41, 6955.
8. Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P. J. Am.
Chem. Soc. 1990, 112, 4986.
1
(MeOH) max 219, 268, 283 nm, min 211, 231, 281 nm; H
NMR (CDCl3, 300 MHz) d 7.31 (br s, 1H), 3.60 (s, 3H),
2.54 (t, J ¼ 6:0 Hz, 2H), 2.48 (t, J ¼ 6:0 Hz, 2H), 1.83–1.80
(m, 4H), 1.70–1.63 (m, 4H); 1H NMR (benzene-d6,
300 MHz) d 6.61 (s, 1H), 2.57 (s, 3H), 2.26 (t, J ¼ 6:3 Hz,
2H), 2.24 (t, J ¼ 6:3 Hz, 2H), 1.73–1.67 (m, 4H), 1.43–1.34
(m, 4H); 13C NMR (CDCl3, 75 MHz) d 136.3, 131.3, 122.2,
102.7, 94.8, 75.5, 70.0, 32.5, 27.4, 26.4, 26.3, 19.8, 19.5; MS
(FAB) m=z 213.1374 ([MH]þ [C14H17N2]¼213.1392); (16)
UV (MeOH) max 251, 258, 280, 290 nm, min 234, 255, 267,
287 nm; 1H NMR (CDCl3, 300 MHz) d 8.0 (s, 1H), 7.55 (s,
1H), 7.15 (s, 1H), 3.84 (s, 3H), 2.96–2.91 (m, 4H), 1.90–1.78
(m, 2H), 1.75–1.65 (m, 4H); 1H NMR (benzene-d6,
300 MHz) d 7.84 (s, 1H), 7.26 (s, 1H), 6.79 (s, 1H), 2.84–
2.76 (m, 4H), 2.68 (s, 3H), 1.70–1.62 (m, 4H), 1.59–1.50 (m,
2H); 13C NMR (CDCl3, 75 MHz) d 142.7, 141.0, 140.0,
139.0, 119.5, 109.4, 37.3, 37.0, 32.7, 29.3, 29.2; MS (EI) m=z
200.1302 (Mþ[C13H16N2]¼200.1314).
12. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 16, 1975, 4467.
9. (a) Zhao, Z. Masters Thesis, Brigham Young University,
Provo, UT, 2003; (b) Kim, G.; Kang, S.; Ryu, Y.; Keum,
G.; Joon Seo, M. Synth. Commun. 1999, 29, 507.
13. Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233.
14. Kinetics were followed by 1H NMR. Integrations for
resonances specific to the starting material were compared
to resonances specific to the products or anthracene as an
internal standard.
15. Molecular modeling calculations were performed using
MacSpartan Pro, Wave Function, Inc. Monte Carlo
conformational searches employed MMFF94 parameters,
and geometry optimizations were performed at the semi-
empirical level (PM3).
16. Similar dihedral angles have been reported for 3-aryl
substituted (Z) 3-ene-1,5-hexadiynes (see Ref. 7b).
17. (a) Koseki, S.; Fujimara, Y.; Hirama, M. J. Phys. Chem. A
1999, 103, 7672; (b) Kaneko, T.; Takahashi, M.; Hirama,
M. Tetrahedron Lett. 1999, 40, 2015; (c) Semmelhack, M.
F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038.
18. X-ray data for 5: The unit cell is trigonal, space group
10. Theoretical calculations indicate that the energy barrier for
imidazolium-fused enediynes is 2.8 kcal/mol greater than
for the corresponding imidazole-fused enediyne (see Ref. 7b).
11. All compounds gave clean 1H and 13C NMR spectra
consistent with the assigned structures, and molecular
formulas were confirmed by high resolution mass spec-
trometry (Mþ within ꢁ10 ppm of theory). Characterization
data for representative compounds follow: (5) UV (MeOH)
max 223, 275, 291 nm, min 239, 287 nm; 1H NMR (CDCl3,
300 MHz) d 12.95 (br s, 1H), 7.62 (s, 1H), 0.22 (s, 18H); 13
NMR (CDCl3, 75 MHz) d 135.6, 123.4, 101.0, 94.9, 0.001,
MS (FAB) m=z 283.1056
(MNaþ
C
ꢀ0.373;
[C13H20N2NaSi2]¼283.1063); (7a) UV (MeOH) max 220,
1
264 nm, min 244 nm; H NMR (CDCl3, 300 MHz) d 7.68
(s, 1H), 7.54–7.49 (m, 5H), 3.59 (s, 1H), 3.37 (s, 1H); H
1
NMR (benzene-d6, 300 MHz) 7.00 (s, 1H), 6.90–6.87 (m,
3H), 6.79–6.77 (m, 2H), 2.95 (s, 1H), 2.94 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 137.3, 135.5, 132.1, 129.8, 128.5,
127.9, 124.8, 88.4, 81.6, 76.0, 71.2; MS (EI) m=z 192.0680
(Mþ [C13H8N2]¼192.0688); (9a) UV (MeOH) max 241 nm;
1H NMR (CDCl3, 300 MHz) d 8.20 (br s, 1H), 7.94–7.90
ꢀ
ꢀ
P3221, with a ¼ b ¼ 10:986ð2Þ A, and c ¼ 13:724ð10Þ A,
3
ꢀ
V ¼ 1435:5ð11Þ A , Z ¼ 3. There were 889 independent
reflections (Rint ¼ 0:0599) with R1 ¼ 0:0515 for [I > 2sðIÞ].
Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
2317SH. 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
email: deposit@ccdc.cam.ac.uk].
1
(m, 1H), 7.60–7.54 (m, 6H), 7.37–7.35 (m, 2H); H NMR
(benzene-d6, 300 MHz) 8.10 (m, 1H), 7.70 (br s, 1H), 7.19–
7.11 (m, 4H), 6.98–6.94 (m, 2H), 6.85–6.83 (m, 2H); 13C
NMR (CDCl3, 75 MHz) d 130.3, 128.3, 124.3, 123.1, 120.7,
110.8; MS (EI) m=z 194.0837 (Mþ [C13H10N2]¼194.0844);