Reactivity of N-(1,2,4-triazolyl)-substituted 1,2,3-triazoles

Article abstract of DOI:10.1021/ol201949h

Synthetically useful rhodium(II) carbenes were obtained from N-(1,2,4-triazolyl)-substituted 1,2,3-triazoles and Rh(II) carboxylates. The electron-withdrawing 1,2,4-triazolyl group reveals the heretofore unknown reactivity of nonsulfonyl 1,2,3-triazoles, which exhibit the reactivity of diazo compounds. The resulting carbenes provide ready asymmetric access to secondary homoaminocyclopropanes (80-95% ee, dr >20:1) via reactions with olefins and also engage in efficient transannulation reactions with nitriles.

Full text of DOI:10.1021/ol201949h

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4870–4872
Reactivity of N-(1,2,4-Triazolyl)-Substituted
1,2,3-Triazoles
Mikhail Zibinsky and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037, United States
fokin@scripps.edu
Received July 19, 2011
ABSTRACT
Synthetically useful rhodium(II) carbenes were obtained from N-(1,2,4-triazolyl)-substituted 1,2,3-triazoles and Rh(II) carboxylates. The electron-
withdrawing 1,2,4-triazolyl group reveals the heretofore unknown reactivity of nonsulfonyl 1,2,3-triazoles, which exhibit the reactivity of diazo
compounds. The resulting carbenes provide ready asymmetric access to secondary homoaminocyclopropanes (80ꢀ95% ee, dr >20:1) via
reactions with olefins and also engage in efficient transannulation reactions with nitriles.
The intrinsic ability of certain electron-deficienttriazoles
to undergo ring-chain isomerism1 opens the possibility of
using them as latent diazo compounds. We have recently
Scheme 1. Azavinyl Carbenes from 1,2,3-Triazoles
demonstrated that 1-sulfonyl-1,2,3-triazoles 1 can indeed
serve as stable and readily available progenitors of N-
sulfonyl azavinyl carbenes 2 (Scheme 1, top).2 Similarly
to transition metal carbenes obtained from diazocarbonyl
compounds,3 azavinyl carbenes are useful and versatile
reactive intermediates. Their generation does not require
preparation and handling of diazo compounds, and their
electronic and steric properties, and hence reactivity, can
be finely tuned by varying the imine functionality at the
vicinal carbon atom.
(1) R-Diazoimines are known to exist in cyclic 1,2,3-triazole form,
except for those bearing a strong electron-withdrawing group at N-1: (a)
Dimroth, O. Ann. 1909, 364, 183. (b) Gilchrist, T. L.; Gymer, G. E. Adv.
Heterocycl. Chem. 1974, 16, 33.
(2) (a) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.;
Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972. (b) Grimster, N.;
Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510. (c)
Reactions of carbenes generated from 1,2,3-triazoles are
experimentally convenient and, because the concentration
of the reactive carbene is low, do not require special
precautions in order to avoid side reactions.
Until now, only sulfonyl triazoles have been shown to
produce transition metal azavinyl carbenes. We report
here a first example of 1,2,3-triazoles3 designedtoundergo
Rh(II)-catalyzed transformations, and we demonstrate
that an electron-deficient heterocycle at the N-1 position
Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. J.
Am. Chem. Soc. 2009, 131, 18034. (d) Chuprakov, S.; Malik, J. A.;
Zibinsky, M.; Fokin, V. V. J. Am. Chem. Soc. 2011, 133, 10352.
(3) (a) Doyle, M. P.; McKervey, M.; Ye, T. Modern catalytic methods
for organic synthesis with diazo compounds: from cyclopropanes to ylides;
Wiley: New York, 1998. (b) Doyle, M. P. In Reactive Intermediate
Chemistry; Moss, R. A., Platz, M. S., Jones, Jr., M., Eds.; Wiley: New York,
2004; pp 561ꢀ592. (c) Davies, H. M. L; Manning, J. R. Nature 2008, 451,
417. (d) Davies, H. M. L.; Beckwith, R. E. Chem. Rev. 2003, 103, 2861.
(e) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010,
110, 704. (f) Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40,
1857.
r
10.1021/ol201949h
Published on Web 08/18/2011
2011 American Chemical Society

of the 1,2,3-triazole ring can facilitate its conversion to the
carbene species 4 (Scheme 1). This route significantly
expands the repertoire of accessible azavinyl carbenes
and allows practical access to synthetically useful second-
ary amines, which are difficult to obtain by other methods.
Ethyl 1,2,4-triazolyl-1,2,3-triazoles 34 (see Supporting
Information for the preparation procedure) were found to
readily produce azavinyl carbenes 4 that reacted with
olefins. Thus, in the presence of the Rh2(esp)2 complex,5
styrene was converted to cyclopropane carboxaldehyde 5a
in 82% isolated yield (trans/cis ratio 3:1; Scheme 2). The
Rh2(piv)4 catalyst provided the product aldehyde with
similarly low diastereoselectivity as well as a somewhat
lower yield (66%). In contrast, the same reaction carried
out with the Rh2(S-NTTL)4 catalyst gave 5a in 84% yield
and 80% ee with a significantly improved trans/cis ratio
(5:50 > 20:1). The low diastereoselectivity observed in
reactions catalyzed by Rh2(piv)4 and Rh(esp)2 suggests
that it is determined not only by the donorꢀacceptor
electronic properties of these carbenes but also by the steric
demands of the imine group, as compared to the sulfonyl
azavinyl carbenes2d and those derived from diazoacetates.
Optimization of the reaction conditions revealed that Rh2-
(S-NTTL)4 performed better than other catalysts, giving
cyclopropane products with a high 95% ee (dr > 20:1;
65 °C in CHCl3).
Hydrolysis of the intermediate imine confirmed both the
relative and absolute stereochemistry of the cyclopropane
products. These results correlate well with our prior find-
ings for reactions of 1-sulfonyl-1,2,3-triazoles, in which
Rh2(S-NTTL)4 also gave excellent asymmetric induction
inchloroformand1,2-DCE.2b,c Itisworth mentioning that
performing the reaction at an elevated temperature did not
affect its enantio- and diastereoselectivity.
Scheme 3. Rh2(S-NTTL)4-Catalyzed Enantio- and Diastereo-
selective Cyclopropanation of Alkenes with Triazoles 3a
Scheme 2. Cyclopropanation of Styrene with Triazole 3a Cata-
lyzed by Rh(II) Carboxylates
Other chiral Rh(II) carboxylates were then evaluated in
the cyclopropanation reaction (cf. Table S2 of the Sup-
porting Information). However, instead of removing the
5-amino-1,2,4-triazolyl group, we carried out the one-pot
reduction of the intermediate imine in order to access
valuable heterocyclic secondary amine 6a. Most chiral
catalysts showed excellent diastereoselectivity (dr >20:1)
compared to 3:1 obtained for Rh2(esp)2. As for the en-
a All reactions were performed at 75 °C except for compounds 6a
and 6b, which were obtained at 65 °C. bAt 40% conversion.
When other alkenes and triazoles 3 were examined in the
reactionwithRh2(S-NTTL)4, excellent diastereoselectivity
and good enantioselectivity were a general trend for this
type of carbene (Scheme 3).
The only downside of using the Rh2(S-NTTL)4 catalyst
was the increased reaction time(24 h). Electron-rich olefins
(4-methoxystyrene and 1,1-diphenylethylene) produced
substituted 2-pyrrolines instead of cyclopropanes in good
yields.2b Reactions of triazoles 3 with aromatic and ali-
phatic nitriles provide substituted triazolylimidazoles 7.
These compounds are likely formed via the initial attack of
the nitrile nitrogen at the electrophilic carbene center.
Screening of several readily available achiral Rh(II) car-
boxylates and solvents in the reaction of 3a with benzoni-
trile revealed that Rh2(esp)2 was the most effective catalyst
for this transannulation reaction. Although the imidazole
6
antioselectivity, Rh2(S-NTTL)4 and Rh2(S-PTAD)4
emerged as the most promising catalysts after the initial
screening, which was performed in 1,2-DCE at 80 °C.
Rh2(S-DOSP)4 and Rh2(R-NTV)4 provided 6a as an
opposite enantiomer with 38% and 66% ee, respectively.
(4) Xia, F.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.;
Peng, L. Org. Biomol. Chem. 2007, 5, 1695.
(5) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126, 15378.
€
(6) (a) Muller, P.; Bernardinelli, G.; Allenbach, Y. F.; Ferri, M.;
€
Flack, H. D. Org. Lett. 2004, 6, 1725. (b) Muller, P.; Lacrampe, F.;
Bernardinelli, G. Tetrahedron: Asymmetry 2003, 14, 1503.
Org. Lett., Vol. 13, No. 18, 2011
4871

product was formed in all of the tested solvents, 1,2-
dichloroethane (1,2-DCE) and chloroform (Table S1 of
Supporting Information) gave consistently high yields.
Interestingly, the lowest temperature at which the reaction
occurs is 65°C. However, it is unclear which particular step
requires an elevated temperature: 1,2,3-triazole ring open-
ing, the formation of the Rh-carbene complex, or the
addition of a nitrile. Slightly higher temperatures resulted
in shorter reaction times and comparable yields.
in the presence of 1 mol % of Rh2(S-NTTL)4 at 70 °C
(Scheme 5). After 90 min, full consumption of styrene was
observed, and the ratio of the corresponding cyclopropanes
9 and 6a0 was 3:1, indicating that the N-sulfonyl triazole 8
reacted with styrene more readily than triazole 3a. An
identical experiment performed at ambient temperature
exhibited a similar trend (after 24 h, 10% of styrene was
consumed, and 9:6a0 ratio was 3:1). Another control reaction
of sulfonyl triazole with 1 equiv of styrene at ambient
temperature demonstrated a slightly faster consumption of
styrene (15% after 24 h). These results point to the generally
lower reactivity of triazolyl triazoles 3a compared to N-
sulfonyl triazoles such as 8 and do not support the notion of
possible catalyst deactivation by 3a via the coordination of
the nitrogen atoms to the Rh center.7
Scheme 4. Rh2(esp)2-Catalyzed Transannulation of Triazoles 3
with Nitriles
Scheme 5. Relative Reactivity of 3a and N-Sulfonyl Triazole 8
In summary, a new family of azavinyl carbenes obtained
form 1,2,3-triazoles containing a carbon substituent at the
N-1 position is now available. These species display high
thermal stability, excellent reactivity, and high chemo- and
stereoselectivity in reactions witholefinsand nitriles. These
N-(1,2,4-triazolyl) azavinyl carbenes are versatile reactive
intermediates that provide access to highly substituted
imidazoles and chiral cyclopropanes containing complex
heterocyclic secondary amines.
At 85 °C, both aliphatic and aromatic nitriles produced
imidazoles 7 in good yield (Scheme 4). Despite the multiple
attempts to react 4-alkyl (R1 = t-Bu, n-C6H13, CH3OCH2ꢀ)
substituted 1,2,3-triazoles with nitriles, we were unable to
isolate the corresponding imidazoles in synthetically useful
yields. The failure of this reaction is most likely due to the
β-hydride shift of the carbene intermediate. Rather surpris-
ingly, the adduct of p-trifluoromethyl phenylacetylene was
also found to be a poor carbene precursor for the transan-
nulation reaction.
Acknowledgment. We gratefully acknowledge financial
support from the National Institutes of Health, National
Institutes of General Medical Sciences (R01-GM087620).
Supporting Information Available. Experimental con-
ditions, optimization procedures, NMR and X-ray data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The relative reactivity of new triazolyl-triazoles 3 was
compared with 1-sulfonyl-1,2,3-triazoles in a competition
experiment, wherein sulfonyl triazole 8 (1 equiv), triazole 3a
(1equiv), and styrene (1 equiv) were reacted in chloroform
(7) Davies, H. M. L.; Townsend, R. J. J. Org. Chem. 2001, 66, 6595.
4872
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