Catalytic asymmetric C-H insertions of rhodium(II) azavinyl carbenes

Article abstract of DOI:10.1021/ja202969z

A highly efficient enantioselective C-H insertion of azavinyl carbenes into unactivated alkanes has been developed. These transition metal carbenes are directly generated from readily available and stable 1-sulfonyl-1,2,3-triazoles in the presence of chiral Rh(II) carboxylates and are used for C-H functionalization of alkanes to access a variety of β-chiral sulfonamides.

Full text of DOI:10.1021/ja202969z

COMMUNICATION
pubs.acs.org/JACS
Catalytic Asymmetric CÀH Insertions of Rhodium(II) Azavinyl
Carbenes
Stepan Chuprakov, Jamal A. Malik, Mikhail Zibinsky, and Valery V. Fokin*
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
ABSTRACT: A highly efficient enantioselective CÀH
insertion of azavinyl carbenes into unactivated alkanes has
been developed. These transition metal carbenes are directly
generated from readily available and stable 1-sulfonyl-1,2,3-
triazoles in the presence of chiral Rh(II) carboxylates and
are used for CÀH functionalization of alkanes to access a
Figure 1. Chiral Rh(II) carboxylates used in this study.
variety of β-chiral sulfonamides.
Our recent success in the development of the rhodium-
catalyzed asymmetric cyclopropanation reaction3b largely capi-
talized on utilizing 1-(alkylsulfonyl) triazoles in combination
with the highly efficient Rh2(S-NTTL)44 complex 6 (Figure 1).
Accordingly, we attempted enantioselective functionalization of
the secondary CÀH bonds of cyclohexane using 1-(methan-
esulfonyl)-substituted triazole 3a in the presence of 0.5 mol % of
said catalyst (eq 3). We were pleased to find that the correspond-
ing CÀH insertion product, chiral imine 4a, was formed in
excellent yield at ambient temperature using a 1:1 (v/v) mixture
of the alkane and chloroform (eq 3).5
The attempted hydrolysis of 4a using K2CO3 in wet methanol
delivered the corresponding carbaldehyde 8a as a racemic
mixture, presumably due to the high acidity of the hydrogen at
the stereocenter. In contrast, one-pot treatment of the inter-
mediate imine with sodium borohydride or lithium aluminum
hydride resulted in a smooth and quantitative reduction of 4a to
afford mesyl-protected amine 5a with 96% ee (eq 3).6 Naturally,
this strategy for CÀH insertion with subsequent in situ reduction
of the imine was adopted for further studies.
irect and chemo- and stereoselective CÀH functionaliza-
D
tion of alkanes remains a formidable challenge for synthetic
organic chemists due to the inherently poor reactivity of CÀH
bonds. The consequent use of highly reactive species imposes
inherent limitations on both chemo- and stereoselectivity of the
reactions. Intermolecular insertions of highly reactive metal-
bound carbenes into sp3 CÀH bonds of unactivated alkanes
have emerged as a promising means for functionalization of these
seemingly inert compounds, and excellent results have been
obtained with rhodium(II)-stabilized donor/acceptor carbenes.1
However, this strategy has been mainly limited to rhodium(II)
carbenes i derived from diazoesters 1 (eq 1).2
We have recently demonstrated that readily available 1-sulfo-
nyl triazoles 3 can serve as direct precursors to related azavinyl
carbenes ii (eq 2).3 The latter share many reactivity features of the
well-studied carbenes i and can be efficiently used to introduce an
aldehyde or amino group into organic molecules.3b,c Herein we
report the first Rh(II)-catalyzed enantioselective intermolecular
CÀH insertion of azavinyl carbenes ii, derived from 1-sulfonyl-
1,2,3-triazoles 3, to access a variety of chiral N-sulfonylamines 5 in
good yield and high enantioselectivity (eq 2).
Next, we examined the scope of this rhodium-catalyzed CÀH
insertion into cyclohexane with respect to the substitution
pattern of the triazole. First, various aryl substituents at C-4 of
the triazole were examined (Table 1). It was found that 1-mesyl-
substituted triazoles with both electron-withdrawing and elec-
tron-donating aryl groups at C-4 underwent CÀH insertion to
afford amines 5aÀf with excellent enantioselectivity. Triazole
with a p-methoxyphenyl electron-donating group reacted noticeably
Received: April 1, 2011
Published: May 27, 2011
r
2011 American Chemical Society
10352
dx.doi.org/10.1021/ja202969z J. Am. Chem. Soc. 2011, 133, 10352–10355
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Asymmetric CÀH Functionalization of Cyclohexane with 1-Sulfonyl Triazolesa
a All reactions were carried out on a 1.0 mmol scale in a mixture of 2.5 mL of cyclohexane and 2.5 mL of chloroform. Conditions A: Rh2(S-NTTL)4 (6,
0.5 mol %), room temperature, 1À24 h. Conditions B: Rh2(S-PTAD)4 (7, 0.5 mol %), 40 °C, 2À7 h. b Performed at room temperature.
faster than the parent phenyl-substituted compound. However, the
yield of the corresponding product 5b was somewhat lower, and
formation of carbene dimers was observed. In contrast, the methoxy
group was tolerated at the meta-position of the aryl substituent in
the triazole to produce the corresponding CÀH insertion product
5f in excellent yield. Similarly, triazoles with electron-withdrawing
groups at C-4 reacted smoothly to furnish products 5d and 5e in
good yields and with excellent enantioselectivity.
and 86% yield, respectively, and 93% ee for both compounds
(Table 2, entries 1À2). In accord with earlier reports,2 the insertion
occurred at the tertiary site of adamantane, furnishing product 5o in
95% yield and 94% ee (entry 3). Gratifyingly, CÀH functionaliza-
tion of 2-methylbutane proceeded selectively at the tertiary site
(C-2), leaving the sterically encumbered secondary CÀH bonds at
C-3 intact,9 and delivering product 5p in 87% yield and 92% ee
(entry 4). Moreover, the reaction of the homologous 2-methyl-
pentane, which has accessible methylene CÀH bonds, produced a
mixture of products with remarkably high (5:1)10 selectivity toward
insertion into tertiary CÀH bonds (C-2 vs C-4, entry 5) forming
sulfonamide 5q in 63% yield and 91% ee. The last two entries
demostrate considerably higher levels of enantiocontrol in tertiary
CÀH insertions compared to previously reported protocols.11
The significantly higher chemoselectivity toward the insertion
into tertiary over secondary CÀH bonds observed for azavinyl
carbenes, as compared to the carboxylic ester congeners (vide
supra), prompted us to further evaluate the reactivity of the
former using kinetic isotope effect studies.
To this end, we subjected triazole 3a to the CÀH insertion
reaction conditions using a 1:1 mixture of cyclohexane and its
fully deuterated analog (eq 4). The observed value of the
deuterium KIE, calculated from product distribution, was very
close to the previously reported kH/kD for the CÀH insertion of
carboxylic ester-substituted carbenes (KIE = 2.0 for phenyl
diazoacetate2b). While these preliminary studies should not be
used to draw direct parallels between the two classes of carbenes,
Following the initial studies, the scope of this transformation
with respect to the sulfonyl moiety of the triazole was examined.
As illustrated by the results summarized in Table 1, isopropyl-
sulfonyl and 2-(trimethylsilyl)-ethylsulfonyl7 derivatives 5g
and 5h could be obtained using this method in good yield
and high enantioselectivity. Arylsulfonyl-substituted triazoles,
however, underwent CÀH insertion in the presence of Rh2
(S-NTTL)4 sluggishly. In contrast, the use of the less sterically
8
demanding, commercially available Rh2(S-PTAD)4 complex 7
(Figure 1) resulted in smooth formation of the corresponding
arylsulfonyl-protected amines 5iÀl at 40 °C or at room temperature.
Notably, the electronic nature of the aryl groups at the sulfonyl
substituents had little or no effect on the overall reaction outcome.
We further explored this novel protocol for CÀH functiona-
lization by examining its scope with respect to the alkane
component (Table 2). Not surprisingly, secondary CÀH bonds
of cyclopentane and cyclooctane were efficiently functionalized
using mesyl-substituted triazole 3a as the azavinyl carbene
source, producing the corresponding amines 5m and 5n in 75
10353
dx.doi.org/10.1021/ja202969z |J. Am. Chem. Soc. 2011, 133, 10352–10355

Journal of the American Chemical Society
COMMUNICATION
Table 2. Rh(II)-Catalyzed CÀH Insertion with 1-Mesyl-Substituted Triazole 1a: Scope of Alkanesa
a Conditions: triazole 3a (1.0 mmol), Rh2(S-NTTL)4 (6, 0.5 mol %), alkane (2.5 mL), and chloroform (2.5 mL), 2À3 h at room temperature. One-pot
subsequent reduction of imine was carried out using 0.5 mL of 2.5 M solution of LiAlH4 in THF at 0 °C. b Isolated yield. c Determined by chiral HPLC.
d 12% of the C-4 insertion product was also observed.
they point to electronic similarities of carboxylic ester and
imineÀsubstituted rhodium(II) carbenes.
carbene carbon (C4 of the parent triazole) functional groups. These
variations, especially the introduction of the imine functionality in
place of the traditional carboxylic ester group in diazo carbonyl
compounds, appear to have a profound influence on the reactivity of
the carbene and allow further derivatization of the products.
In summary, this work demonstrates that azavinyl carbenes derived
from 1,2,3-triazoles can be efficiently used for highly enantioselective
CÀH functionalization of simple unactivated alkanes. Insertions into
secondary and tertiary CÀH bonds afford the corresponding chiral
sulfonamide products in very good yields and with high enantiomeric
excess. Further studies of this CÀH insertion reaction and its
applications are currently underway in our laboratories.
We attribute the dramatic increase in the selectivity toward
insertion into tertiary CÀH bonds observed for azavinyl carbenes
to the lower steric demand of the aldimine group compared to the
carboxylic ester.
Similar to other methods that use convenient and easily available
1-sulfonyl 1,2,3-triazoles12 as direct precursors for rhodium(II)
carbene complexes,3a,b the CÀH insertion protocol described here
is practical and experimentally simple. The inherent ability of
diazoimines to exist in equilibrium that favors the closed 1,2,
3-triazole form13 obviates any special slow addition techniques that
are often employed to ensure a low concentration of the highly
reactive carbenes and parent diazocompounds in the reaction
mixture. Since the triazole form is the predominant tautomer,
concentration of the diazo species remains very low at any given
time. From the synthetic viewpoint, this method provides direct
accesstoβ-chiralaminederivatives,14 expanding the rangeofuseful
products that can be directly accessed from 1,2,3-triazoles.
As a corollary of their straightforward synthesis, the electronic
and steric properties of azavinyl carbenes can be easily tuned by
the variation of both the imine (N1 of the parent triazole) and the
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, character-
b
ization data, NMR spectra, and crystallographic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
fokin@scripps.edu
’ ACKNOWLEDGMENT
This work was supported by grants from the National Institute
of General Medical Sciences, National Institutes of Health
(GM-087620) and National Science Foundation (CHE-0848982).
10354
dx.doi.org/10.1021/ja202969z |J. Am. Chem. Soc. 2011, 133, 10352–10355

Journal of the American Chemical Society
COMMUNICATION
’ DEDICATION
This paper is dedicated to Prof. K. Barry Sharpless on the
occasion of his 70th birthday.
’ REFERENCES
(1) For reviews, see: (a) Davies, H. M. L.; Morton, D. Chem. Soc. Rev.
2011, 40, 1857. (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L.
Chem. Rev. 2010, 110, 704. (c) Davies, H. M. L.; Manning, J. R. Nature
2008, 451, 417. (d) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003,
103, 2861. (e) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977.(f) Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with Diazo Compounds:
From Cyclopropanes to Ylides; Wiley: New York, 1998.
(2) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997,
119, 9075. (b) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am.
Chem. Soc. 2000, 122, 3063.
(3) (a) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.;
Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972. (b) Chuprakov, S.;
Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. J. Am. Chem. Soc. 2009,
131, 18034. (c) Grimster, N.; Zhang, L.; Fokin, V. V. J. Am. Chem. Soc.
2010, 132, 2510. For related 2-pyrydyl analogues, see:(d) Davies,
H. M. L.; Townsend, R. J. J. Org. Chem. 2001, 66, 6595. (e) Chuprakov,
S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463. (f) Chuprakov, S; Hwang,
F. W.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 4757.
(4) For recent applications, see:(a) M€uller, P.; Allenbach, Y. F.;
Robert, E. Tetrahedron: Asymmetry 2003, 14, 779. (b) M€uller, P.;
Bernardinelli, G.; Allenbach, Y. F.; Ferry, M.; Flack, H. D. Org. Lett.
2004, 6, 1725. (c) Marcoux, D.; Charette, A. B. Angew. Chem., Int. Ed.
2008, 47, 10155. (d) Marcoux, D.; Azzi, S.; Charette, A. B. J. Am. Chem.
Soc. 2009, 131, 6970. (e) DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.;
Fox, J. M. J. Am. Chem. Soc. 2011, 133, 1650. See also refs 3b, 3c.
(5) Similarly to the previously reported Rh-catalyzed CÀH insertion
with diazoesters, dry and degassed solvents were used to ensure the
efficiency of the reaction. See Supporting Information for details. See
also ref 2b.
(6) The absolute configuration of 5a was unambiguously assigned by
single crystal X-ray crystallographic analysis (CCDC 813723), and the
homogeneity of the crystalline materials was confirmed by chiral HPLC.
See Supporting Information for details.
(7) Generally, removal of an alkylsulfonyl protecting group to
liberate an amine requires harsh conditions. In contrast, the 2-(trimethy-
lsilyl)ethanesulfonyl (SES) group can be easily removed by treatment
with a fluoride ion. See: Weinreb, S. M.; Demko, D. M.; Lessen, T. A.;
Demers, J. P. Tetrahedron Lett. 1986, 27, 2099.
(8) (a) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006,
8, 3437. (b) Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org. Lett.
2007, 9, 2625. (c) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787.
(9) Similar chemoselectivity was reported for carbenes derived from
aryl and vinyl diazoacetates. See ref 2b.
(10) Approximately a 1:1 ratio of regioisomers was reported for the
related reaction of phenyldiazoacetate and 2-methylpentane. See ref 2b.
(11) For the Rh2(S-DOSP)4-catalyzed reaction, 68 and 26% ee were
reported for the insertion into tertiary sites of 2-methylbutane and
2-methylpentane, respectively.
(12) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952.
(13) (a) Dimroth, O. Ann. 1909, 364, 183. (b) Gilchrist, T. L.;
Gymer, G. E. Adv. Heterocycl. Chem. 1974, 16, 33.
(14) β-Chiral amines can also be accessed indirectly by asymmetric
1,4-addition of C-nucleophiles to nitroolefins followed by reduction of
the nitro group. For recent reviews, see: (a) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713. (b) Berner, O. M.; Tedeschi, L.; Enders, D.
Eur. J. Org. Chem. 2002, 1877.
10355
dx.doi.org/10.1021/ja202969z |J. Am. Chem. Soc. 2011, 133, 10352–10355