Ruthenium- and sulfonamide-catalyzed cyclization between N-sulfonyl imines and alkynes

Article abstract of DOI:10.1021/ol302594w

Ruthenium(II)-catalyzed redox-neutral annulative coupling of N-sulfonyl imines with alkynes has been achieved for the synthesis of indenamines, where a sulfonamide cocatalyst is necessary.

Full text of DOI:10.1021/ol302594w

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5506–5509
Ruthenium- and Sulfonamide-Catalyzed
Cyclization between N‑Sulfonyl Imines
and Alkynes
Peng Zhao, Fen Wang, Keli Han, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China
xwli@dicp.ac.cn
Received September 20, 2012
ABSTRACT
Ruthenium(II)-catalyzed redox-neutral annulative coupling of N-sulfonyl imines with alkynes has been achieved for the synthesis of indenamines,
where a sulfonamide cocatalyst is necessary.
Transition-metal-catalyzed CꢀH bond activation has
been increasingly explored and has been realized as a
widely used strategy in the synthesis of complex structures.1
The advantage of CꢀH activation lies in the harnessing of
ubiquitous yet often unreactive CꢀH bonds. Transition-
metal-catalyzed cyclization via CꢀH activation represents
an efficient method for the construction of carbocycles and
heterocycles.2,3 This method is powerful because no pre-
activation of the CꢀH bond to traditionally used carbonꢀ
halogen and carbonꢀmaingroupmetalbondsisnecessary.
Carbocyclization via CꢀH activation and insertion of a
π-bond leads to very useful synthetic methods, where
mechanistically distinct reactions are successfully com-
bined in a tandem process.
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Recently, catalytic insertion of CꢀH bonds into alkynes
(hydroarylation) has been increasingly explored using
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r
10.1021/ol302594w
Published on Web 10/23/2012
2012 American Chemical Society

rhodium,2 ruthenium,3 iridium,4 cobalt,5 palladium,6 and
nickel7 catalysts. In particular, in 2005 Takai8 reported
pioneering work on the carbocyclization of imines with
alkynes, leading to the synthesis of indenamines. By using
rhodium and ruthenium catalysts, the groups of Bergman
and Ellman,2b Shi,2d,e Li,2i Zhao,2k Cramer,2f Glorius,2j
Cheng,2h and Jeganmohan3f have revealed that cyclome-
talation can be followed by alkyne insertion to generate a
metal alkenyl intermediate that undergoes (intramolecular)
nucleophilic addition to a carbonyl or imine group, leading
to CꢀC bond formation or redox-neutral cyclization
reactions (Figure 1). In addition, Grignard-type addition
of a transition metalꢀcarbon bond into an aldehyde has
been achieved via a Rh(III)-catalyzed CꢀH activation
pathway under chelation assistance.2i,9 Thus in these car-
bocyclization reactions, the role of the directing group is
twofold: it acts as a directing group as well as an electro-
phile. Despite the success, the substrate scope is still
limited, and Rh(III) complexes are mostly used, while less
expensive ruthenium complexes have been less explored.3f
In this context, CꢀH activation and coupling reactions of
readily available arene substrates should provide impor-
tant protocols for accessing diversely functionalized are-
nes, which broadens the utility of CꢀH bond activation,
particularly using cost-effective transition metals such as
ruthenium.
We reasoned that N-sulfonyl imines of benzaldehyde are
bifunctional and can serve this purpose. If CꢀH activation
is achievable, the imine group is sufficiently activated
to allow for intramolecular nucleophilic attack by a
metalꢀC(sp2) bond. However, the cyclometalation of an
N-sulfonyl imine can be problematic because the elec-
tron density on the nitrogen is depleted by a conjugated
sulfonyl group. Indeed, no CꢀH activation of N-sulfonyl
imines has been previously reported, although N-aryl or
N-OR substituted imines have been well studied for CꢀH
activation.2m,10
We initiated our studies with the screening of the reac-
tion conditions for the coupling of PhCHdNTs (1a) with
diphenylacetylene. No reaction occurred with or without
an acetic acid additive when [RhCp*Cl2]2 or [RhCp*-
(MeCN)3](SbF6)2 was applied as a catalyst. In addition,
no reactivity was observed when [Ru(p-cymene)Cl2]/
AgSbF6 (5 mol %/20 mol %) was used as a catalyst in
the presence of AcOH (4 equiv) (dioxane, 120 °C), a set of
conditions that has been used in the ruthenium(II)-cata-
lyzed hydroacylation of alkynes.11 Thus the low reactivity
of PhCHdNTs is likely ascribable to the low donor ability
of this imine group. We reasoned that addition of a
catalytic amount of an amine such as TsNH2 should
reversibly yield a gem-diamine intermediate, which may
allow for cyclometalation and subsequent reactions. Grat-
ifyingly, when TsNH2 (5 mol %) was introduced into these
ruthenium-catalyzed conditions, the expected indenamine
3aa was isolated in 68% yield (eq 1), and an optimal
isolated yield of 81% was achieved when the amount of
TsNH2 was increased to 10 mol %. In contrast, [RhCp*-
(MeCN)3](SbF6)2 and [RhCp*Cl2]2 all failed to catalyze
this reaction when the TsNH2 cocatalyst (10%) was
provided.
With the optimal conditions in hand, we next examined
the scope and generality of this coupling reaction (Scheme 1).
Figure 1. Carbocylization via CꢀH activation.
(8) (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am.
Chem. Soc. 2006, 128, 202. (b) Kuninobu, Y.; Kawata, A.; Takai, K.
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Z.-J. Org. Lett. 2012, 14, 636.
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Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 3645. (b) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064. (c) Parthasarathy, K.;
Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325. (d) Too, P.-C.;
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Org. Lett., Vol. 14, No. 21, 2012
5507

A series of symmetrically substituted diarylalkynes readily
coupled with 1a to give indenamides 3aaꢀ3ad in good
isolated yield (75ꢀ88%). Aliphatic alkynes are also applic-
able but generally with lower reactivity (46ꢀ76%). When
PhCtCMe was used, a mixture of two inseparable regio-
isomers (3ah and 3ah0) was obtained in a 6:1 ratio, where
the phenyl group is oriented vicinal to the NHTs group in
the major product (3ah). Moreover, the regioselectivity
decreased as the steric bulk of the alkyl group (R) in
PhCtCR increases (3ai, 3aj, and 3ak), with a small
regioselectivity of 2:1 being obtained for PhCtCnBu
(3ak). A silylated alkyne can be applied but with clean
desilylation under the reaction conditions. Thus product
3al was isolated in 70% yield when PhCtCSiMe3 was
coupled with 1a. Here the PhCtCSiMe3 acts as a surro-
gate for the terminal alkyne that is inapplicable in this
reaction.
bearing halogen (3baꢀ3da), methyl (3ea), and CF3(3fa)
groups at the para position of the benzene ring all under-
went smooth coupling without significant variation of the
isolated yield (69ꢀ87%). In contrast, N-Ts imine with a
para OMe group gave rather low conversion and no
analytically pure product can be isolated, indicating that
a para electron-donating group lowered the reactivity.
Substituents at the ortho position are also tolerated, and
the steric effect caused by ortho substitution has no detri-
mental effect as in the isolation of 3gaꢀ3ia in good yield
(63ꢀ82%). When a meta substituent was introduced, the
CꢀH functionalization occurred selectively at the less
hindered site (3ja and 3ka). In addition to the N-Ts
substituent, other N-sulfonyl groups such as arenesulfonyl
and methanesulfonyl are also effective (eq 2).
Scheme 1. Coupling of N-Sulfonyl Imines with Alkynesa,b
Derivatization of the indenamine product was carried
out next. When catalyzed by a Cu(OAc)2ꢀphenathroline
system (20 mol % and20 mol %), O2 (1 atm) oxidation of
3aa afforded indenone 4aa in 82% yield (eq 3). In addition,
a one-pot synthesis of 4aa can be achieved. After the
annulative coupling of 1a with diphenylacetylene was
completed, the solvent was removed and was replaced by
DMF. Addition of Cu(OAc)2•H2O and stirring at 100 °C
afforded 4aa in comparably high yield (85%). Two-step
oxidation of analogousindenamines toindenones has been
recently reported.12 Furthermore, a single step synthesis of
thistype ofindenoneproducthas been recently reportedby
Shi by employing a Rh(III)-catalyzed CꢀH activation
strategy.2d Furthermore, when a mixture of 3ah and 3ah0
was subjected to the copper-catalyzed aerobic oxidation
conditions, aldehyde-functionalized indenone 5ah was iso-
lated as a major product in 67% yield (eq 4). Here the
allylic methyl was oxidized to an aldehyde group.
To probe the mechanism of this reaction, the KIE was
measured from the competition of 1a and 1a-d5 with
diphenylacetylene, and a value of kH/kD = 1.6 was ob-
tained. While this value is indeterminate and no solid
conclusion on CꢀH activation can be drawn, further
information in this regard was obtained when a labeling
a Reaction conditions: imine (0.4 mmol), alkyne (0.6 mmol), [Ru(p-
cymene)Cl2]2 (0.02 mmol), AgSbF6 (0.08 mmol), AcOH (1.6 mmol), 1,4-
b
dioxane (4 mL), 120 °C, 20 h. Isolated yield after column chromato-
graphy. c Only the structure of the major isomeric product was shown. d
PhCtCSiMe3 was used.
The scope of the imine substrate was defined next us-
ing diphenylacetylene as a coupling partner. N-Ts imines
(12) Wang, S.-Y.; Zhu, Y.-X.; Wang, Y.-G.; Lu, P. Org. Lett. 2009,
11, 2615.
5508
Org. Lett., Vol. 14, No. 21, 2012

experiment was performed using 1a-d5 and diphenylacety-
lene (eq 5). In the isolated product, significant H/D ex-
change (48% H) at the ortho0 position of the phenyl group
Scheme 2. Proposed Catalytic Cycle
1
was observed on the basis of H NMR analysis.13 This
result suggests that the ortho CꢀH activation is reversible,
and importantly this reversible process should be faster
than subsequent steps in the catalytic cycle. Therefore, the
CꢀH cleavage is not involved in the rate-determining step.
A proposed catalytic cycle is given in Scheme 2. Nucleo-
philic addition of TsNH2 to the PhCHdNTs gives a
diamine A which is coordinatively activated. Deprotona-
tion and cyclometalation afford an active ruthenium(II)
intermediate B. Alkyne insertion into the RuꢀC bond
generates a seven-membered metalacycle C, which is pro-
posed to undergo reversible protonolysis of the RuꢀN
bond to give D. Elimination of a TsNH2 gives an imine-
bound metalacycle (E) that should undergo Grignard-like
migratory insertion of the Ru-alkenyl bond to yield an
amide intermediate F. The final product 3 was released
upon protonolysis of the RuꢀN bond. The protonolysis
can be facilitated by the acetic acid additive in this
reaction.9,11 In addition, the acetate group can also act as
a bridging base to facilitate the CꢀH activation via a con-
certed metalationꢀdeprotonation (CMD) mechanism.14
This working hypothesis is also consistent with the poor
reactivity of (4-OMeC6H4)CHdNTs. With the introduc-
tion of a donating OMe group into the para position, both
the nucleophilic addition of TsNH2 and the subsequent
migratory insertion of the RuꢀC bond into the imine are
kinetically disfavored. In line with this observation, the N-
tosylimine derivative of 2-furaldehyde failed to undergo
the same reaction, likely due to electronic effects.
system, the primary sulfonamideplaysanimportantrolein
activating the imine substrate toward cyclometalation. A
broad scope of the imine and the alkyne substrates has
been demonstrated, and the indenamine product can be
furtheroxidizedtoindenonesundersimpleconditions. The
operational simplicity of the coupling reaction, the pre-
valence of sulfonamide functionality in pharmaceuticals,
and the derivatization of the direct products likely make
this synthetic method useful in synthetic chemistry and in
mechanistic studies.
Acknowledgment. We thank the Dalian Institute of
Chemical Physics, Chinese Academy of Sciences for finan-
cial support.
In summary, we have developed a ruthenium(II)-cata-
lyzed annulative coupling of N-sulfonyl imines of benzalde-
hydes with alkynes, leading to indenamines. In this coupling
Supporting Information Available. Synthetic proce-
dure, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Control experiments revealed that the incorporation of hydro-
gen cannot be ascribable to postreaction H/D exchange of this product
because no H/D exchange occurred when 3aa and acetic acid-d4 (10
equiv) were allowed to react under the same conditions.
(14) For a recent review, see: Ackermann, L. Chem. Rev. 2011, 111,
1315.
The authors declare no competing financial interest.
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