Transannulation of 1-sulfonyl-1,2,3-triazoles with heterocumulenes

Article abstract of DOI:10.1021/ja400350c

Readily available 1-mesyl-1,2,3-triazoles are efficiently converted into a variety of imidazolones and thiazoles by Rh(II)-catalyzed denitrogenative reactions with isocyanates and isothiocyanates, respectively. The proposed triazole-diazoimine equilibrium results in the formation of highly reactive azavinyl metal-carbenes, which react with heterocumulenes causing an apparent swap of 1,2,3-triazole core for another heterocycle.

Full text of DOI:10.1021/ja400350c

Communication
pubs.acs.org/JACS
Transannulation of 1‑Sulfonyl-1,2,3-triazoles with Heterocumulenes
Stepan Chuprakov, Sen Wai Kwok, and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
not require a slow introduction into the reaction mixture, and a
reaction partner is normally used in only a slight excess.8 Given
ABSTRACT: Readily available 1-mesyl-1,2,3-triazoles are
efficiently converted into a variety of imidazolones and
thiazoles by Rh(II)-catalyzed denitrogenative reactions
with isocyanates and isothiocyanates, respectively. The
proposed triazole−diazoimine equilibrium results in the
formation of highly reactive azavinyl metal-carbenes, which
react with heterocumulenes causing an apparent swap of
1,2,3-triazole core for another heterocycle.
the experimental simplicity of this approach, we envisioned that
the addition of heterocumulenes to azavinyl carbenes i could be
a promising method for the synthesis of different nitrogen-
containing heterocyclic molecules.
Accordingly, we attempted the reaction of 1-tosyl-4-phenyl-
1,2,3-triazole 1a with 1.2 equiv of phenyl isocyanate in the
presence of various Rh(II) carboxylate complexes (1 mol %) at
ambient temperature (Table 1 and Figure 1). It was anticipated
rug discovery research constantly calls for new synthetic
Dmethods for the rapid and reliable construction of
heterocyclic frameworks from easily available precursors.
Synthetic approaches that enable straightforward syntheses of
several different heterocyclic cores from a common inter-
mediate are especially attractive. Recently discovered deni-
trogenative transformations of readily accessible 1,2,3-triazoles
have led to a new family of synthetic methods toward a variety
of valuable organic molecules,1 including nitrogen-containing
heterocycles.2 For example, imidazoles1c,3 and pyrroles3c,4 can
now be accessed through transannulation reactions of 1-
sulfonyl triazoles with nitriles and alkynes, wherein the 1,2,3-
triazole core is transformed into another heterocycle. Here, we
report an efficient synthesis of imidazolones 2 and thiazole
derivatives 3 by a Rh(II)-catalyzed denitrogenative trans-
annulation of 1-sulfonyl-1,2,3-triazoles 1 with isocyanates and
isothiocyanates, respectively (eq 1).
Table 1. Catalyst Screening for Transannulation with Phenyl
Isocyanate
a
L =
Oct
Piv
PTV
PTTL NTTL
NTV
R = p-Tol (1a)
R = Me (1b)
<5%
-
35%
53%
55%
56%
51%
89%
14%
59%
86%
95%
a
Performed on 0.2 mmol scale; NMR yields are shown.
Figure 1. Rhodium(II) carboxylates used in this study.
that the attack of the nitrogen lone pair of isocyanate on the
azavinyl carbene i would form an “ylide-type” intermediate;3
subsequent cyclization9 would lead to imidazolone 2a. To our
delight, the expected heterocyclic product 2a10 was indeed
formed in the reaction mixture in moderate yield under these
conditions, although the reaction proceeded rather sluggishly. It
A formal [3 + 2] cycloaddition of heterocumulenes with
metal-carbenes derived from diazo compounds has not been
extensively studied.5 Moreover, existing literature reports brand
isocyanates,5c isothiocyanates5c and carbodiimides5a,b as in-
competent reaction partners for Rh(II)-carbenes generated
from diazoesters and diazoketones. Only moderate yields of the
corresponding heterocyclic products have been reported, and
the heterocumulene was used in large excess (typically as a
solvent). We and others have recently been successful in
employment of Rh(II) azavinyl carbenes i that are conveniently
generated from 1,2,3-triazoles.1−4,6 Unlike typical diazo
compounds, these readily available7 carbene precursors do
11
12
was found that Rh2(S-PTV)4 6 and Rh2(S-NTV)4
8
catalysts (Figure 1) gave most promising results, although
yields did not exceed 60% (Table 1).13
Received: January 11, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
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a
Table 2. Transannulation of 1-Mesyl-1,2,3-triazoles with Isocyanates
a
Procedure: triazole 1 (1.0 mmol), isocyanate (1.2 mmol), Rh2(S-NTTL)4 (0.005 mmol) were stirred in 5 mL of dry chloroform at room
b
temperature for 1−6 h. Isolated yield.
1-Mesyl-substituted triazoles have previously been recog-
nized as excellent azavinyl carbene precursors in Rh(II)-
catalyzed reactions.1a,f,k Therefore, we examined their reactivity
in the transannulation with isocyanates. We were pleased to
find that triazole 1b underwent the reaction with phenyl
isocyanate more efficiently than its 1-tosyl-substituted congener
1a, providing generally higher yields of the corresponding
mesyl-substituted product 2b in the presence of various Rh(II)
carboxylates (Table 1, Figure 1).13 It was found that complexes
6−7 bearing amino acid derived ligands were superior catalysts
compared to simple alkane carboxylates 4−5 (Figure 1).
lones 2 in good to excellent yields (Table 2, entries 1−3 and 7−
9). Moreover, 1b underwent this reaction efficiently with
primary and secondary alkyl isocyanates, furnishing N-alkyl-
substituted heterocyclic products 2n−p in high yields (entries
13−15). Notably, allyl isocyanate reacted with complete
chemoselectivity favoring transannulation over cyclopropana-
tion of the double bond (entry 14, Table 2). Next, we examined
the scope of this reaction with respect to various aryl
substituents at the C-4 position of the triazole. Gratifyingly,
substrates possessing electron-rich (entries 6, 12, 17 and 18)
and electron-deficient (entries 4, 5, 10 and 16) aryl groups
showed similar efficiency in this transannulation reaction and
afforded the corresponding imidazolones 2 in high yield (Table
2).
12
Employment of the bulky Rh2(S-NTTL)4 complex 9 in this
reaction allowed for the clean and rapid (1 h) conversion of
triazole 1b to the imidazolone 2b in 95% yield (Table 1).
Having identified the optimal substrate−catalyst combina-
tion, we examined the scope of the reaction (Table 2). 4-Phenyl
triazole 1b reacted smoothly with a wide range of aryl-
substituted isocyanates14 to afford the corresponding imidazo-
Encouraged by the successful transannulation of 1,2,3-
triazoles with isocyanates, our interest turned to the reactivity
of other heterocumulenes15 in this transformation. To this end,
we attempted reaction of phenyl isothiocyanate with triazole 1b
B
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Journal of the American Chemical Society
Communication
a,b
Table 3. Rh(II)-Catalyzed Transannulation of 1-Mesyl-1,2,3-triazoles with Isothiocyanates
a
Procedure: triazole 1 (1.0 mmol), isothiocyanate (1.2 mmol), Rh2(S-NTTL)4 9 (0.005 mmol) were stirred in 5 mL of dry chloroform at room
b
c
temperature. Isolated yields are shown. Recovered starting material.
in the presence of Rh2(S-NTTL)4 catalyst 9. Previous studies
reported that metal-carbenes are likely to be intercepted by the
sulfur atom (rather than by the nitrogen lone pair) of
isothiocyanates; a subsequent cyclization of the putative
sulfur-ylide intermediate furnishes products with an exocyclic
nitrogen atom.5c Indeed, transannulation of 4-phenyl-1,2,3-
triazole 1b with 1.2 equiv of phenyl isothiocyanate at ambient
temperature afforded N-phenyl thiazole imine derivative 3a in
87% isolated yield (Table 3). The identity of 3a was
unambiguously confirmed by the single crystal X-ray analysis,
which additionally labeled this product as Z-imine.16
Examination of the scope of the Rh(II)-catalyzed trans-
annulation with respect to various 1-mesyl-1,2,3-triazoles 1 and
substituted isothiocyanates (Table 3), effectively applying the
reaction conditions developed for isocyanates (vide supra),
revealed that triazole 1b reacted smoothly with a variety of
isothiocyanates under these reaction conditions. In particular,
exceptionally good results were obtained with isothiocyanates
possessing electron-withdrawing substituents. Thus, reaction
with bromo- and trifluoromethyl-substituted aryl isothiocya-
nates as well as with N-benzoyl-substituted compounds
afforded the corresponding thiazole derivatives in excellent
yield (e.g., compounds 3b, 3d−e and 3h, Table 3). Electron-
rich aryl- and alkyl isothiocyanates reacted more reluctantly,
and a significant amount of starting material was recovered even
after prolonged (24 h) reaction times (3f and 3g, Table 3). We
tentatively attribute the observed inhibition to the coordination
of the formed thiazole product to the rhodium(II) catalyst that
blocks the essential reactive site of the latter.
1,2,3-triazoles produced the corresponding thiazoles 3 in good
to excellent yields (3i and 3k−o, Table 3). Moreover, substrate
possessing an alkenyl moiety at the C-4 position also
participated in this reaction affording 5-alkenyl thiazole 3j,
albeit in a moderate yield.17
Further modification of heterocyclic transannulation prod-
ucts 2 and 3 could offer additional synthetic opportunities
expanding the repertoire of useful drug-like molecules that can
be accessed starting from 1-sulfonyl-1,2,3-triazoles. A sulfonyl
group is often used to protect N−H moiety of nitrogen-
containing heterocycles and can easily be removed using a
number of methods.18 We found that the mesyl group of the
imidazolone 2b can be efficiently removed by treatment with
magnesium in refluxing methanol producing the parent
diphenyl NH-imidazolone19 10 in good yield (Scheme 1).
Similarly, treatment of thiazole imine 3m with 1-hydroxybenzo-
Scheme 1. Desulfonylation of Mesyl-Protected
Transannulation Products
Examination of the scope of this reaction with respect to
various substituents at the C-4 position of the triazole revealed
that a range of 1-mesyl-substituted 4-aryl and 4-heteroaryl
C
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Journal of the American Chemical Society
Communication
(6) Selander, N.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 2477.
(7) (a) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952. (b) Yoo, E.
J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.;
Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730.
(8) Typically, to avoid the carbene dimerization side reactions, a
dilute solution of a diazo compound is added over several hours to a
mixture of rhodium catalyst and a large excess of another reagent.
Certain 1,2,3-triazoles, however, undergo tautomerization in solution
to form α-diazoimines in presumably low concentration. See:
(a) Dimroth, O. Ann. Chem. 1909, 364, 183. (b) Gilchrist, T. L.;
Gymer, G. E. Adv. Heterocycl.Chem. 1974, 16, 33. See also ref 3.
(9) Although unlikely, alternative concerted [3 + 2] cyclization path
and [4 + 2] cycloaddition, followed by reductive elimination, may also
be operating in this transformation.
(10) Structure of compound 2a was confirmed by X-ray
crystallography (CCDC 888986). See Supporting Information (SI)
for details.
(11) (a) Hashimoto, S.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami,
S. Tetrahedron Lett. 1993, 34, 5109. (b) Tsutsui, H.; Abe, T.;
Nakamura, S.; Anada, M.; Hashimoto, S. Chem. Pharm. Bull. 2005, 53,
1366.
triazole (HOBt) at room temperature resulted in clean
desulfonylation, nearly quantitatively furnishing 2-(arylami-
no)-thiazole 11 (Scheme 1).
The new method for the construction of imidazolones and
thiazoles via a Rh(II)-catalyzed transannulation reaction of 1-
sulfonyl-1,2,3-triazoles with heterocumulenes is practical and
reliable. This formal [3 + 2] cycloaddition reaction features
metal-stabilized azavinyl carbenes as reactive intermediates,
which are conveniently generated from stable and readily
available 1-mesyl-1,2,3-triazoles. Together with a straightfor-
ward synthesis of triazoles, this new method offers a modular
sequence for the formal addition of “S−C−N” and “N−C−N”
fragments to the acetylenic triple bonds leading to useful
families of five-membered nitrogen-containing heterocycles.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, NMR spectra,
and crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) (a) Muller, P.; Allenbach, Y. F.; Robert, E. Tetrahedron:
̈
Asymmetry 2003, 14, 779. (b) Muller, P.; Bernardinelli, G.; Allenbach,
̈
Y. F.; Ferry, M.; Flack, H. D. Org. Lett. 2004, 6, 1725.
AUTHOR INFORMATION
Corresponding Author
fokin@scripps.edu
■
(13) See SI for a complete catalyst screening table.
(14) One notable exception includes ortho-substituted aryl
isocyanates, employment of which resulted in sluggish and low-
yielding reactions, presumably due to the increased steric hindrance at
the reaction center. Similarly, triazoles possessing sterically demanding
groups at the C-4 reacted with isocyanates hesitantly.
Notes
The authors declare no competing financial interest.
(15) Attempts to utilize carbodiimides in this reaction were
unsuccessful.
ACKNOWLEDGMENTS
■
This work was supported by the National Institute of General
Medical Sciences, National Institutes of Health (GM-087620)
and National Science Foundation (CHE-0848982). We also
thank Dr. Arnold L. Rheingold and Dr. Curtis E. Moore for X-
ray analysis.
(16) The structure has been deposited with the Cambridge
Crystallographic Data Centre (CCDC 888987). See SI for details.
(17) Presumably, the highly reactive 1-alkenyl carbene undergoes a
number of side-reactions (e.g., carbene dimerization); this results in
the observed diminished yield in the transannulation reaction.
(18) Wuts, P. G. M.; Greene, T. W. In Protective Groups in Organic
Synthesis, 4th ed.; Wiley: New York, 2007; pp 872−894.
(19) Lee, S. H.; Yoshida, K.; Matsushita, H.; Clapham, B.; Koch, G.;
Zimmermann, J.; Janda, K. D. J. Org. Chem. 2004, 69, 8829.
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