Intra- and intermolecular trapping of cyclopentapyrazine carbenes derived from 1,2-dialkynylimidazoles

Article abstract of DOI:10.1016/j.tetlet.2005.11.010

The thermolysis of 1,2-dialkynylimidazoles in benzene solution affords high yields of 7-phenyl-5H-cyclopentapyrazines, which presumably form by solvent trapping of cyclopentapyrazine carbene intermediates. In cases where dialkynylimidazole contains side chains that can participate in intramolecular carbene C-H insertion or olefin addition, these processes compete with solvent addition to afford novel tri- and tetracyclic pyrazines, which can be obtained in good yield when the thermolysis is carried out in hexafluorobenzene.

Full text of DOI:10.1016/j.tetlet.2005.11.010

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 353–356
Intra- and intermolecular trapping of cyclopentapyrazine
carbenes derived from 1,2-dialkynylimidazoles
Asha K. Nadipuram and Sean M. Kerwin*
Division of Medicinal Chemistry, College of Pharmacy, Institute for Cellular and Molecular Biology,
University of Texas at Austin, Austin, TX 78712, USA
Received 19 October 2005; revised 1 November 2005; accepted 2 November 2005
Available online 18 November 2005
Abstract—The thermolysis of 1,2-dialkynylimidazoles in benzene solution affords high yields of 7-phenyl-5H-cyclopentapyrazines,
which presumably form by solvent trapping of cyclopentapyrazine carbene intermediates. In cases where dialkynylimidazole con-
tains side chains that can participate in intramolecular carbene C–H insertion or olefin addition, these processes compete with sol-
vent addition to afford novel tri- and tetracyclic pyrazines, which can be obtained in good yield when the thermolysis is carried out in
hexafluorobenzene.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In our continuing studies of aza-variants of the diradi-
cal-generating Bergman1 and Myers-Saito2 cyclizations,
we prepared the previously unknown 1,2-dialkynyl
imidazoles (1).3 Our expectation that mild thermolysis
(75–100 °C) of 1 in 1,4-cyclohexadiene would lead to
trapping of the 5,8-didehydroimidazo[1,2-a]pyridine
diradicals 2ÅÅ, formed by aza-Bergman cyclization of 1
was not realized. Instead, we obtained mixtures of
cyclopropanes 3 and the 5H-cyclopentapyrazines 4, both
presumably arising from the corresponding cyclopenta-
pyrazine carbene 5 (Scheme 1).4 While the mechanistic
Scheme 1. Thermal rearrangement of 1,2-dialknylimidazoles to cyclo-
details of this rearrangement of 1 to 5 have not been
fully addressed,3 this cyclization is reminiscent of the
carbene-generating cyclizations of enyne carbonyls,5
enyne imines,6 acyl ynimines,7 and 2-ethynylphenyl
di- and triazines.8
pentapyrazine carbenes.
tuted cyclopentapyrazines can be considered as analogs
of phenyl pyrrolo[2,3-b]pyrazines, which are of interest
as cyclin-dependent kinase inhibitors.12,13 Polycyclic
cyclopentapyrazines, such as analogs of the extremely
cytotoxic cephalostatins,14 are also of potential interest,
both in terms of biological activity and as the building
blocks for novel coordination compounds and
materials.15
This rearrangement of 1 to 5 represents a novel
approach to the synthesis of cyclopentapyrazines. While
5-alkyl-substituted cyclopentapyrazines are known as
flavor agents isolated from roasted foodstuffs,9 few
examples of phenyl-substituted,10 and polycyclic11
cyclopentapyrazines have been prepared. Phenyl-substi-
The synthetic utility of carbenes is well appreciated; and
the thermal,7,8 photochemical,16 or metal-catalyzed5,6,8
generation of carbenes or carbenoids from alkynes rep-
resents a growing area of interest. However, there are
relatively few examples of cascade cyclizations involving
carbenes formed by thermal cyclizations.17 Here, we
Keywords: Cyclization; C–H Insertion; Cyclopropanation; Domino
reactions; Thermal rearrangement.
*
Corresponding author. Tel.: +1 512 471 5074; fax: +1 512 232
2606; e-mail: skerwin@mail.utexas.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.010

354
A. K. Nadipuram, S. M. Kerwin / Tetrahedron Letters 47 (2006) 353–356
report the results of the thermolysis of 1 in benzene to
give 7-phenyl-5H-cyclopentapyrazines in good yield. In
cases where R2 of 1 is propyl or butenyl, the intramole-
cular cyclization of the intermediate carbene 5 is a com-
petitive side reaction with formal intermolecular C–H
insertion reaction with benzene, affording moderate
yields of polycyclic pyrazines. This intramolecular cycli-
zation is the major reaction path when these thermolyses
are carried out in hexafluorobenzene, leading to good
yields of polycyclic pyrazines.
Table 1. Thermolysis of dialkynylimidazoles in benzene
Series
Conditions
Yield of 7 (%)
Other products (yield)
a
b
c
d
e
f
100 °C, 2 d
100 °C, 4 d
80 °C, 5 d
80 °C, 2 d
90 °C, 8 d
90 °C, 8 d
90 °C, 4 d
88
83
72
38
82
82
49
2. Results and discussion
8 (17%)
1,2-Dialkynyl imidazoles were prepared from 2-iodoim-
idazole through N-alkynylation of the lithium anion
with alkynyl iodonium triflates or tosylates18 (Scheme
2). N-Alkynyl-2-iodoimidazoles 6a,b undergo Sonogash-
ira coupling19 with a variety of terminal acetylenes to af-
ford dialkynyl imidazoles in good yield. In the case of
the coupling products of 6b, treatment with TBAF affor-
ded the desilylated dialkynylimidazoles 1b–g.20 Dialkyn-
ylimidazoles with terminal aryl substituents (1a,b,e,f) are
isolated as stable solids; however, those with alkyl termi-
nal substituents are somewhat unstable, turning dark
upon storage under inert atmosphere in the freezer over
the course of days to weeks.
g
9 (24%)
cyclopentapyrazines 7, which are formed in good
yields.23 In the case of dialkynylimidazole 1d, the iso-
lated yield of 7d was only moderate, and the formation
of polymeric products, which were not further charac-
terized, was noted. In the case of the propyl analogue
1c, the intramolecular insertion product 824 was isolated
along with 7c (1:4.2 ratio). The butenyl analog 1g affor-
ded the tetracyclic cyclopropane 925 along with 7g (1:2
ratio).
Heating solutions of dialkynylimidazoles 1a–g in benz-
ene21 leads to the formation of cyclopentapyrazines
(Table 1).22 Dialkynylimidazoles bearing terminal aryl
substituents on either alkyne (1a,b,e,f) required more
forcing conditions than those with alkyl (1c), alkenyl
(1g), or alkoxyalkyl (1d) substituents, but in all cases,
the reactions required a number of days to reach com-
pletion (Table 1). With the exception of dialkynylimi-
dazoles 1c,d,g, the exclusive products isolated after
flash chromatography (SiO2, 0–15% EtOAc/hexanes)
of the reaction mixtures were the phenyl-substituted
The structures of the phenyl-substituted cyclopentapyr-
azines 7a and 7c were established by high-resolution
mass spectrometry (HRMS), and 2D NMR (COSY,
NOESY, HMBC, and HMQC), which allowed unam-
biguous assignment of all the 1H and 13C NMR re-
sonances. The other phenylcyclopentapyrazines were
characterized by HRMS, 1H, and 13C NMR. The
polycyclic cyclopentapyrazines 8 and 9 were character-
ized by HRMS, H and 13C NMR, and in the case of
1
9, COSY NMR.
We did not detect or isolate any norcaradiene/cyclo-
heptatriene products from these thermolyses in benzene,
indicating that if these are formed as intermediates, they
are rapidly converted to the phenyl-substituted products
under these conditions. Alternatively, the formation of 7
may proceed through stepwise benzene C–H insertion26
by the triplet carbene 5, which is predicted to be lower in
energy than the initially formed singlet.4 Cyclopenta-
pyrazines 7 and 8 were all isolated as the more stable,
conjugated double-bond isomers, which is due to
isomerization during the reaction. We note that when
deuterated 1c (R1 = D) is subjected to thermolysis in
benzene, deuterated 7c (R1 = D, 90% isotopic purity)
is produced, as determined by 1H NMR analysis of
the crude reaction product. However, upon purification,
there is substantial protium/deuterium exchange at the
cyclopentapyrazine 5-position; the chromatographically
isolated 7c contains only 50% deuterium.
Scheme 2. Synthesis of 1,2-dialkynylimidazoles.

A. K. Nadipuram, S. M. Kerwin / Tetrahedron Letters 47 (2006) 353–356
355
Scheme 3. Thermolysis of 1,2-dialkynylimidazoles in hexafluorobenzene favors intramolecular cyclization.
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When solutions of dialkynyl imidazoles 1c and 1g in
hexafluorobenzene were heated, the intramolecular trap-
ping products were isolated in much higher yields than
in benzene solvent (Scheme 3). However, even in the
case of hexafluorobenzene, intermolecular addition to
solvent occurs to give minor amounts of the fluorinated
cycloheptatriene adducts 10c and 10g.27 The assignment
of the structures of these hexafluorinated cycloheptatri-
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spectra to those reported for similar systems.28 While
clearly not inert to carbene 5, hexafluorobenzene solvent
has a diminished propensity to undergo addition with
the carbene, which is not unexpected.28,29 Importantly,
this provides a convenient method to favor the intra-
molecular cyclization, leading to ratios of intra- to inter-
molecular products as high as 4.5:1 in the case of 1g.
In summary, thermolysis of dialkynylimidazoles in benz-
ene affords good yields of 7-phenyl-cyclopentapyrazines,
and represents a novel entry into the cyclopentapyrazine
ring system. Further evidence for a carbene intermediate
5 in the thermolysis of 1 has been obtained through iden-
tification of products derived from intramolecular C–H
insertion and cyclopropanation. The formation of these
polycyclic pyrazines 8 and 9 is the major pathway when
these thermolyses are carried out in hexafluorobenzene.
This provides a synthetically useful cascade cyclization
process for the rapid assembly of structurally complex
cyclopentapyrazines.
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Acknowledgements
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This work was supported by a Grant from the Robert
Welch Foundation (F-1298).
References and notes
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24. Spectral data for 8: H NMR (400 MHz, CDCl3): d 8.25
(d, J = 3.2 Hz, 1H), 8.14 (d, J = 3.2 Hz, 1H), 3.36 (s, 2H),
2.82–2.74 (m, 4H), 2.43 (quintet, J = 6.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d 163.66, 158,89, 155.87,
146.72, 141.06, 137.32, 38.33, 35.33, 30.86, 27.10; HRMS
159.0928 (Calcd 159.0922, C10H11N2).
20. Representative spectral data (1g): 1H NMR (400 MHz,
CDCl3): d 7.05 (d, J = 1.5 Hz, 1H), 6.94 (d, J = 1.5 Hz,
1H), 5.87 (ddt, J = 17.2, 10.4, 6.4 Hz, 1H), 5.10
(dq J = 16.8, 1.6 Hz, 1H), 5.03 (dq, J = 10.2, 1.2 Hz,
1H), 3.12 (s, 1H), 2.54 (t, J = 7.2 Hz, 2H), 2.36
(q, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d
136.09, 135.67, 129.05, 121.77, 116.09, 95.16, 71.00, 69.40,
61.38, 32.04, 19.09; HRMS (CI) m/z 171.0925 (Calcd
171.0922, C11H11N2).
1
25. Spectral data for 9: H NMR (500 MHz, CDCl3): d 8.24
(d, J = 3 Hz, 1H), 8.03 (d, J = 3 Hz, 1H), 6.66 (br s, 1H),
2.64–2.60 (m, 2H), 2.49–2.44 (m, 2H), 2.36–2.32 (m, 1H),
2.24–2.10 (m, 1H), 1.68 (t, J = 5 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 164.95, 160.79, 159.64, 140.81,
136.66, 118.08, 44.77, 33.36, 29.27, 21.87, 19.44; HRMS
171.0924 (Calcd 171.0922, C11H11N2).
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21. Caution: benzene is toxic and a carcinogen.
22. General procedure: dialkynylimidazoles 1a–g (30 mg) in
degassed benzene (4.5 mL) were heated in sealed reaction
vials in an 80–100 °C oil bath with TLC monitoring until
the starting material was consumed. The solvent was
evaporated and the reaction products were purified by
flash chromatography.
27. Data for 10c: Melting point 58–60 °C; 1H NMR (400 MHz,
CDCl3): d 8.42 (d, J = 3.2 Hz, 1H), 8.17 (d, J = 3.2 Hz,
1H), 6.85 (br s, 1H), 2.48 (t, J = 7.2 Hz, 2H), 1.81 (sextet,
J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H); partial 13C NMR
(100 MHz, CDCl3): d 158.20, 156.35, 155.26, 145.16,
139.96, 129.81, 31.64, 20.44, 13.85; 19F NMR (282 MHz,
CDCl3 referenced to C6F6 = À163 ppm): d À123.07 (dt,
J = 8, 4 Hz, 2F), À148.71 (m, 2F), À151.88 (m, 2F);
HRMS 345.0814 (Calcd 345.0826, C16H10F6N2).
23. Representative spectral data (7g): 1H NMR (300 MHz,
CDCl3): d 8.34 (d, J = 3 Hz, 1H), 8.22 (d, J = 3 Hz, 1H),
7.50–7.46 (m, 4H), 7.41–7.37 (m, 1H), 5.82 (ddt, J = 17.1,
10.2, 6.6 Hz, 1H), 5.09–4.08 (m, 2H), 3.57 (s, 2H), 2.80 (t,
J = 7.8 Hz, 2H), 2.41 (q, J = 7.8 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d 158.47, 158.05, 150.36, 141.87,
138.58, 138.51, 137.24, 132.63, 129.21, 128.49, 127.83,
115.68, 39.27, 33.26, 28.93; HRMS (CI) m/z 249.1390
(Calcd 249.1392, C17H17N2).
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