Two unusual, competitive mechanisms for (2-ethynylphenyl)triazene cyclization: Pseudocoarctate versus pericyclic reactivity

Article abstract of DOI:10.1021/ja017227u

The cyclization of (2-ethynylphenyl)triazenes in ODCB at 200 °C gives exclusively cinnolines, whereas addition of CuCl to 1,2-dichloroethane solutions of the triazenes at 50 °C results in the sole formation of isoindazoles. DFT calculations and deuterium

Full text of DOI:10.1021/ja017227u

Published on Web 02/01/2002
Two Unusual, Competitive Mechanisms for (2-Ethynylphenyl)triazene
Cyclization: Pseudocoarctate versus Pericyclic Reactivity
David B. Kimball,† Rainer Herges,‡ and Michael M. Haley*,†
Department of Chemistry, UniVersity of Oregon, Eugene, Oregon 97403-1253, and Institut fu¨r Organische Chemie,
UniVersita¨t Kiel, 24098 Kiel, Germany
Received October 4, 2001
Scheme 1
Aryl triazenes have been studied over 130 years for their
interesting structural, anticancer, and reactivity properties.1 They
have been used in medicinal2 and combinatorial chemistry,3 in
natural product synthesis,4 as organometallic ligands,5 and as
precursors to heterocycles.6 Recently we reported an unusual
temperature dependence for the conversion of (2-ethynylphenyl)-
triazenes (1) into heterocycles.7 Heating 1i at 170 °C in o-
Scheme 2
dichlorobenzene (ODCB) gave a ca. 1:1 ratio of an isoindazole
aldehyde (2) and a cinnoline (3) in 95% combined yield (Scheme
1). Heating 1 to 200 °C in ODCB, however, resulted in exclusive
formation of 3 in excellent yields (>90%).
To study the generality of these cyclizations for the practical
synthesis of heterocycles, we sought to determine the mechanisms
for both transformations. The conditions used and the products
generated do not support the well-understood mechanisms for
isoindazole or cinnoline synthesis,8 and their concurrent production
from the same starting material in the same pot is unique. For the
isoindazole product, several factors, such as high temperature and
neutral conditions, suggested that cyclization produced carbene 4
(Scheme 2) that could either dimerize or be quenched by oxygen
to generate 2. This cyclization is best described through a
Table 1. Yield of Isoindazole 2 via Cu-Promoted Cyclization of 1
pseudocoarctate transition state,9,10 where cyclization and formation
of the carbene are simultaneous.11 Rearrangements similar to this
are known,12 although in the majority of cases they proceed in the
opposite direction to give ring-opened products.13
entry
R
isoindazole 2
entry
R
isoindazole 2
a
b
c
d
e
H
95%
90%
96%
91%
98%
f
Cl
F
95%
94%
83%
60%a
54%b
Me
g
h
i
t-Bu
C≡CH
Br
CO2Me
CN
NO2
Evidence of carbene 4 was provided by transition state stabiliza-
tion and trapping studies. Use of Cu salts is known to promote and
stabilize carbene (carbenoid) generation;14 thus, stirring a mixture
of CuCl (10 mol %) and 1e in CH2Cl2 at room temperature resulted
in slow (96 h) yet nearly quantitative conversion to isoindazole
2e. Modifying these conditions by heating the mixture of triazene
and CuCl (5 equiv) to 50 °C in 1,2-dichloroethane for 12-36 h
gave high yields of 2 for nearly every R group on the arene (Table
1). In the case of strongly electron-withdrawing groups (entries i
and j), the yields of 2 were lower as dimer formation (5) was a
competitive side reaction.
To provide additional support for 4, cyclization to the iso-
indazole was done in the presence of carbene trapping agents
(Scheme 2). Addition of CuCl to a deoxygenated solution of triazene
1c and 2,3-dimethyl-2-butene (20 equiv) in CH2Cl2 gave, after
stirring overnight at room temperature, 65% yield of cyclopropane
6. Intramolecular trapping could be effected by affixing a (1,1′-
biphenyl)-2-yl group at the terminus of the acetylenic moiety.
Cyclization as above furnished fluorene 7, the product of intra-
molecular C-H insertion by the carbene, in 55% yield.
j
a Plus 34% yield of 5 (R ) CN). b Plus 37% yield of 5 (R ) NO2).
tion of the parent triazene (-NH2) are depicted in Figure 1.
Interestingly, a pericyclic reaction to give a planar, six-membered
intermediate15 is the product of thermodynamic control, even though
pseudocoarctate cyclization to yield the five-membered ring has a
lower barrier. Formation of 4, however, is reversible, which is
consistent with exclusive production of 3 at higher temperatures.
NBO analysis16 showed a notable development of negative charge
at C4, going from -0.03 in 1 to -0.22 in 8. The calculated singlet/
triplet gap is 13.6 kcal mol-1. Thus, 8 is most likely a zwitterion
with some diradical character.17
From these results one could predict the first step after formation
of 8 to be protonation at the partially anionic carbon rather than
hydrogen abstraction. This was confirmed by using hydrogen donor
reagents with differing polarities. Whereas dihydroanthracene-d4
(5 equiv) gave products with no incorporation of deuterium, reaction
of 1e with benzhydrol-d2 (4 equiv) gave 3e where deuteration
occurred at both the 4-position and 3-position (3:2). No products
arising from nucleophilic attack by the benzhydrol oxygen were
observed, and relative integration of the protons on benzophenone
with those on the cinnoline product showed equimolar formation
of both. The deuterium on C3/4 arises from the hydroxyl proton as
To shed light on the mechanism for 3 and the nature of the
intermediates, we performed DFT calculations on a variety of
possible cyclization pathways. The reaction energetics for cycliza-
† University of Oregon.
‡ Universita¨t Kiel.
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10.1021/ja017227u CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
1 and thus give 3. Indeed, deprotonation of 12 and subsequent
heating of the resultant anion to 205 °C in ODCB overnight gave
6-chlorocinnoline (3f) in 51% yield.
The evidence presented herein strongly supports the reversible
generation of carbene 4 as the kinetic intermediate and its
transformation into the thermodymanically more stable zwitterion
8, both of which can furnish useful heterocycles. In addition, the
high-yielding, Cu-catalyzed transformation of 1 into 2 represents
the first practical synthetic application of a coarctate-type cycliza-
tion.13 Further experiments to show the general utility of these
cyclizations as well as to elucidate -NEt2 loss are in progress and
will be elaborated shortly.
Acknowledgment. We thank the National Science Foundation,
the Petroleum Research Fund, administered by the American
Chemical Society, the Fonds der Chemischen Industrie and the
Alexander von Humboldt Foundation for financial support.
Supporting Information Available: Selected spectral data for
compounds 1, 5-7 and 12; NBO analysis for the formation of 8; ACID
plots and Cartesian coordinates for cyclization of 1 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
Figure 1. Calculated stationary points for the cyclization of the parent
(2-ethynylphenyl)triazene (-NH2); relative energies (kcal mol-1) calculated
at the B3LYP/6-31G*(ZPE) level of theory.
Scheme 3
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whereas benzhydrol-d (-OH) gave no deuterated cinnoline.
The above results suggest the mechanism depicted in Scheme
3. Pericyclic ring closure would directly yield 8, a 3-dehydrocin-
nolinium ylide, similar to a 3-dehydropyridinium ylide recently
described by Shevlin and co-workers.18 Alternatively, Hopf-type
dienyne cyclization19 might produce allene 9. Zwitterionic species
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allenes;22 however, 9 was not found to be a minimum on the energy
hypersurface. Protonation of 8 should lead to 10. Leakage of the
label to C3 in 3′ can be explained by invoking another zwitterionic
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loss at this time.21
Both experimental and theoretical evidence suggest reversible
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regenerate 1 and produce the thermodynamically more stable
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tosylhydrazone 12 (Scheme 4). Alkali metal salts of such hydra-
zones fragment at 200 °C to furnish carbenes.22 For our system,
generation of 4 at this temperature should induce rearrangement to
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