Rhodium-catalyzed transannulation of 1,2,3-triazoles with nitriles

Article abstract of DOI:10.1021/ja805079v

Stable and readily available 1-sulfonyl triazoles are converted to the corresponding imidazoles in good to excellent yields via a rhodium(II)-catalyzed reaction with nitriles. Rhodium iminocarbenoids are proposed intermediates. Copyright

Full text of DOI:10.1021/ja805079v

Published on Web 10/15/2008
Rhodium-Catalyzed Transannulation of 1,2,3-Triazoles with Nitriles
Tony Horneff,† Stepan Chuprakov,† Natalia Chernyak,‡ Vladimir Gevorgyan,*,‡ and Valery V. Fokin*,†
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037, and Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Received July 2, 2008; E-mail: vlad@uic.edu; fokin@scripps.edu
Discovery of the copper-1 and ruthenium-catalyzed2 azide-alkyne
cycloaddition reactions reinvigorated interest in 1,2,3-triazoles.
However, even a cursory survey of the literature reveals that in
most reports utilizing this chemistry, 1,2,3-triazoles remain reactivity
culs-de-sac: permanent inert connectors that unite molecular frag-
ments with a desired function.3 This is not surprising when one
takes into account the exceptional stability of these nitrogen
heterocycles: they are exceedingly resistant to thermal degradation
and are not affected by severe hydrolytic, reductive, and oxidative
conditions.4 Herein, we wish to report that Rh(II) complexes
catalyze ring opening of N-sulfonyl 1,2,3-triazoles 1 to form Rh-
iminocarbenoids i, which, upon reaction with nitriles, produce
imidazoles 2 in good to excellent yields (eq 1).
When 1-toluenesulfonyl 4-phenyl 1,2,3-triazole 1a was treated
at 80 °C with dirhodium(II) octanoate in the presence of styrene,
trans-cyclopropane carboxaldehyde 7 was obtained in nearly
quantitative yield with >20:1 trans-selectivity10 (eq 4), thus
confirming our hypothesis that reactive rhodium-carbenoid species
could be obtained from sulfonyl triazoles. Evidently, aldehyde 7
originated from the corresponding tosylimine upon hydrolysis
during column chromatography on silica gel.
Encouraged by this result, we attempted a transannulation
reaction of triazole 1a with benzonitrile under a number of
conditions (Table 1). Triazole 1a was readily transformed into the
N-tosyl imidazole 2a in 51% yield when the reaction was performed
in the microwave synthesizer at 140 °C for 15 min using 0.5 mol
% of rhodium(II) acetate dimer. No special precautions to exclude
atmospheric oxygen were taken (entry 1). A screen of other catalysts
revealed that the electron-deficient rhodium(II) heptafluorobutyrate
and trifluoroacetate were significantly less active (entries 2 and 3).
We envisioned that 1-sulfonyl triazoles 1 could serve as
precursors to the diazoimine species 3 that, in turn, could be
converted to metal carbenoids 4 (eq 2). Rhodium carbenoids exhibit
the wealth of reactivity,5 and this method of generating their diazo
progenitors is particularly attractive considering that sulfonyl
triazoles effectively become synthetic equivalents of R-diazo
aldehydes 5, which, understandably,6 cannot be converted to the
corresponding rhodium carbenoids 6.
Table 1. Reaction of 1-(p-Toluenesulfonyl)-4-phenyl-1,2,3-triazole
with Benzonitrile: Effect of the Catalyst, Solvent, and Temperature
A related ring-chain isomerization of 7-halo pyridotriazoles to
(2-pyridyl) diazoalkanes was recently exploited in the rhodium-
catalyzed reactions with alkynes and nitriles yielding indolizines
and imidazopyridines, respectively.7 These transannulation pro-
cesses are remarkably efficient and exhibit excellent scope with
respect to the nitrile and alkyne components.
1-(p-Toluenesulfonyl)triazoles 1 used in our study can be
prepared by tosylation of the parent NH-triazoles8 (eq 3). However,
reactions of NH-triazoles with other sulfonyl chlorides often
produced mixtures of N-1 and N-2 sulfonylated products, requiring
careful tuning of the reaction conditions. Copper-catalyzed cy-
cloaddition of sulfonyl azides with terminal alkynes, instead, is a
more direct and reliable route to the desired 1-sulfonyl triazoles.
Recent improvements in the selectivity of this reaction4e,9 make
it an even more convenient alternative to the NH-triazole
route.
entry
catalyst
solvent
t, °C
time
yield, %a
1
2
3
4
5
6
7
8
Rh2(OAc)4
Rh2(CF3COO)4
Rh2(C3F7COO)4
Rh2(Oct)4
Rh2(S-DOSP)4
-
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,2-DCE
toluene
hexane
THF
140
140
140
140
140
140
160
140
120
100
140
140
140
140
140
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
30 min
30 min
15 min
15 min
15 min
15 min
15 min
51
0b
<5
82
83
0b
0c
77
70
43
73
55
71
0d
9
10
11
12
13
14
15
PhCl
62
a Isolated yield. b Only starting material observed. c Only decom-
position observed. d Besides starting material, (Z)-2-phenyl-4-tosyl-
5,6,7,8-tetrahydro-4H-1,4-oxazocine observed.11
† The Scripps Research Institute.
‡ University of Illinois at Chicago.
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10.1021/ja805079v CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Rh-Catalyzed Transannulations of 1-Sulfonyl Triazoles with Nitriles
a Isolated yield. b General procedure A: Rh2(Oct)4 (0.5 mol %), CHCl3, 15 min at 140 °C/MW. c General procedure B: Rh2(S-DOSP)4 (0.5 mol %),
DCE, 12-24 h at 80 °C (see Supporting Information for details).
Gratifyingly, rhodium(II) octanoate catalyst provided 82% yield
of imidazole 2a, and Rh2(S-DOSP)4 was equally effective (entries
4 and 5). Further elevation of temperature resulted in the formation
of intractable mixtures of products (entry 7), whereas temperatures
below 120 °C led to significantly lower conversion and yields (entry
9 and 10). Halogenated solvents (chloroform, dichloromethane, and
1,2-dichloroethane) were superior to THF, toluene, and hexane
(entries 1, 8, 11-15).
When performed with conventional heating at 80 °C under inert
atmosphere, the reaction proceeded to completion in 15 h and
furnished imidazole 2a in 83% yield. These experiments led to the
formulation of two general procedures (described in detail in
Supporting Information): procedure A, in which the reaction is
performed in the microwave synthesizer at 140 °C in chloroform
and procedure B, which utilizes conventional heating and 1,2-
dichloroethane as a solvent.
appears to be quite insensitive to both steric and electronic variations
of the sulfonyl group. Thus, 4-methoxy- and 2,4,6-triisopropyl, and
4-bromobenzenesulfonyl triazoles were equally reactive furnishing
imidazoles in good yields (entries 17, 18, 24). In contrast, the nature
of the substituent at C4 of the triazole has a significant effect on
the reaction. Aromatic groups were preferred to aliphatic, and more
electron deficient substituents (cf. entries 20 and 21) imparted higher
reactivity to the triazole. Reactivity of 4-benzyl triazole (entry 16)
is another noteworthy example because R-alkyl diazoacetates are
known to undergo ready ꢀ-hydride elimination.12 In our conditions,
this pathway was not dominant, although 26% of 4-methyl-N-(3-
phenylallylidene)benzenesulfonamide (2.4:1 E:Z) was observed.
Benzene ring expansion, another potential side reaction, was not
observed.13
The copper(I)-catalyzed synthesis of 1-sulfonyl triazoles and their
subsequent transannulation with nitriles can be combined into a
one-pot two-step synthesis, thus further simplifying the experimental
procedure (eq 5). The catalytic amount of copper remaining in the
reaction mixture after the first step evidently does not interfere with
the formation or reactivity of the carbenoid. Thus, we successfully
prepared 1-(p-toluenesulfonyl) imidazole 2a by combining tosyl
azide and phenylacetylene in chloroform in the presence of 1 mol
% of the copper(I) thiophene-2-carboxylate catalyst,14 and after 14 h
the reaction mixture was treated with 3 equiv of benzonitrile and
Next, we examined the scope of the reaction with respect to the
nitrile component. As illustrated by the examples shown in Table
2, a broad range of nitriles efficiently participated in the transan-
nulation reaction. For example, aromatic (Table 2, e.g., entries 1-4),
alkyl (entries 5-7, 10, 13, 14, 23), and alkenyl (entries 8, 22) nitriles
were competent reactants, providing 1-sulfonyl imidazole products
in very good yields. Electron-deficient nitriles were less reactive
than electron-rich ones (cf. entries 1 and 2). In addition, the reaction
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J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008 14973

C O M M U N I C A T I O N S
Scheme 1
Supporting Information Available: Experimental procedures,
characterization data, copies of 1H NMR and 13C NMR. This material
is available free of charge via the Internet at http://pubs.acs.org.
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We have not yet performed extensive investigations of the
mechanism of this transannulation reaction. However, it is probably
mechanistically related to the analogous annulation of nitriles with
diazoketones reported by Helquist and Akermark,15 and we propose
the following mechanistic possibilities (Scheme 1). In pathway A,
a nucleophilic attack of a nitrile at the Rh-carbenoid i16 leads to
the ylide 10, which upon cyclization (path A1) into a zwitterion
11, and subsequent metal loss, produces imidazole 2. Alternatively,
ylide 10 may give rise to the Rh-carbenoid 12 via a 1,3-Rh-shift
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cycloaddition of i with a nitrile (path B) cannot be ruled out at this
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imidazole heterocycle are formed in a two-step sequence which
begins from alkynes, sulfonyl azides, and nitriles.18 Dinitrogen is
the only byproduct of the reaction. In addition, we have demon-
strated for the first time that stable and readily accessible N-sulfonyl
1,2,3-triazoles are convenient precursors to reactive metal car-
benoids and can be viewed as surrogates of the R-diazo imines.
Rhodium carbenoids obtained in this fashion are synthetic equiva-
lents of the putative R-formyl carbenoids and should be useful
analogs of the better known donor-acceptor substituted carbenoid
family. Mechanistic studies and investigation of the scope of their
reactivity are currently underway in our laboratories.
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Acknowledgment. We thank Dr. Jessica Raushel (TSRI) for
help with the CuTC-catalyzed synthesis of sulfonyl triazoles and
Mr. Frank W. Hwang (UIC) for technical assistance. This work
was supported by the National Institutes of Health (Grant GM-
64444, VG; DA-19372, VVF) and the Skaggs Institute for Chemical
Biology and Pfizer, Inc. (SC, VVF).
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