Rhodium-catalyzed spirocyclic sultam synthesis by [3+2] annulation with cyclic N-sulfonyl ketimines and alkynes

Article abstract of DOI:10.1002/chem.201303372

An efficient Rh^III-catalyzed [3+2] annulation of cyclic N-sulfonyl ketimines with internal alkynes was disclosed in the presence of catalytic amounts of AgSbF₆ to form synthetically challenging spirocyclic sultams in high yield under

Full text of DOI:10.1002/chem.201303372

COMMUNICATION
DOI: 10.1002/chem.201303372
Rhodium-Catalyzed Spirocyclic Sultam Synthesis by [3+2] Annulation with
Cyclic N-Sulfonyl Ketimines and Alkynes
Lin Dong,* Chuan-Hua Qu, Ji-Rong Huang, Wei Zhang, Qian-Ru Zhang, and
Jin-Gen Deng[a]
Functionalized sulfonamides such as sultams and sulfami-
dates have been used as key intermediates to synthesize di-
verse biologically active compounds.[1]Strategies for synthe-
sizing sultam derivatives increasingly rely on transition
metal-catalyzed bond formation.[2] In fact, catalytic addition
of organometallic reagents to sulfonamides offers one of the
most reliable methods for constructing sultams with an
a-polysubstituted carbon stereocenter.[3] Synthesizing spiro-
cyclic sultams, however, has proven significantly more diffi-
cult for organic chemists,[4] and a breakthrough came with
the application of metal catalytic [3+2] tandem reaction se-
quences.[5–7] Building on the pioneering work of Takai[5a–c] in
2005, the research groups of Cramer,[5d,e,i] Zhao,[5f,g], and
Cheng[5h] independently showed that metal alkenyl inter-
mediates generated by alkyne insertion can undergo
Grignard-type [3+2] annulation to imine groups
À
(Scheme 1a). Activating the C H bond to generate reactive
organometallic intermediates is an eco-friendly alternative
to conventional catalytic addition methods.
Tandem Grignard-like cyclization has been exploited in
the synthesis of various heterocyclic compounds, with car-
bonyl and imine moieties serving as both directing groups
and electrophiles.[7b,8] However, electron-deficient imines
such as cyclic N-sulfonylimines have rarely been used to
À
direct C H functionalization and Grignard-type cyclization,
presumably because the conjugated sulfonyl group reduces
the electron density on the nitrogen.[6,9] Li and coworkers re-
cently developed the first RuII-catalyzed redox-neutral an-
Scheme 1. Transition-metal-catalyzed [3+2] annulation of imines and in-
nulative coupling of N-sulfonylimines and alkynes using sul-
fonamide as a cocatalyst (Scheme 1b).[9] Nishimura and
coworkers obtained spirocyclic sultams by iridium-catalyzed
[3+2] annulation involving cyclic N-sulfonyl ketimines and
ternal alkynes/alkenes.
cyclic N-sulfonyl ketimines and internal alkynes affords spi-
rocyclic benzosultams through a formal [3+2] annulation,
which requires only catalytic amounts of silver salts. We
speculate that in this atom-economical nucleophilic addition
process, Grignard-type cyclization generates an N-Rh-O in-
termediate, which then undergoes protonolysis to form the
final product (Scheme 1d).[10]
We initially started our investigation by studying the an-
nulative coupling reaction of cyclic N-sulfonyl ketimines 1a
with diphenyl acetylene (2a; Table 1). Under the catalyst of
1,3-dienes (Scheme 1c).[6] Here we describe an alternative
III
À
approach in which Rh -catalyzed C H activation of simple
[a] Prof. Dr. L. Dong, C.-H. Qu,+ J.-R. Huang,+ W. Zhang, Q.-R. Zhang,
Prof. Dr. J.-G. Deng
Key Laboratory of Drug-Targeting and
Drug Delivery System of the Education Ministry
Department of Medicinal Chemistry, West China School of Pharmacy
Sichuan University, Chengdu, 610041 (China)
Fax: (+86)28 85503538
[Cp*RhCl2]2 (5 mol%) and CuACHTUNTRGNENUG(OAc)2 (1.1 equiv), aminoin-
E-mail: dongl@scu.edu.cn
[+] These authors contributed equally.
dane 3aa was formed exclusively in dichloroethane albeit
with low yield at 808C for 15 h (Table 1, entry 1). Other
copper additives such as CuACHTNUGTRENN(UG OTf)2 and CuAHCTUTGNERNN(UGN acac)2 exhibited
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303372.
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Table 1. Optimizations of reaction conditions.[a]
(Table 1, entry 5).[5g,7a–d] Next various silver salts were em-
ployed instead of AgSbF6, however, only AgOTf and
AgCO2CF3 gave the [3+2] annulation product in 79 and
16% yield, respectively (Table 1, entries 6–9). Among the
test of solvents, t-amyl alcohol was also appropriate for the
reaction, but needed harsh conditions (Table 1, entries 10–
12). To our delight, the reaction could occur smoothly even
at room temperature, and 3aa was isolated with 93% yield
in just 4 h (Table 1, entry 13). The high reactivity of this re-
action promoted us to reduce the catalyst loading to
2.5 mol% of [Cp*RhCl2]2, however, the reaction rate drop-
ped dramatically under low temperature. Luckily, the reac-
tion could be completed in 15 h by raising the temperature
back to 808C, in addition the reactivity was still excellent
even when the amount of AgSbF6 was reduced to only
10 mol% (Table 1, entries 14–17).
With the optimal reaction conditions in hand, various al-
kynes were studied for RhIII-catalyzed [3+2] annulation with
N-sulfonyl ketimine (Table 2). The process showed wide
substrate tolerance with internal alkynes. The internal al-
kynes with different electrical properties all reacted smooth-
ly to give the corresponding spirocyclic aminoindanes (3ab–
ad) with good to excellent yields. Likewise, alkyl-substituted
alkyne 2e exhibited the similar high reactivity in this cata-
lytic system. Interestingly, the desired 3af could be con-
structed with 96% yield when electron-deficient 2 f as the
internal alkyne. In addition, disubstituted unsymmetrical al-
kynes reacted well with ketimine 1a to give the isomers in
good yields with poor to moderate regioselectivity.
Additive
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
Cu(OAc)2, AgSbF6
Solvent
T [8C]
t
Yield [%][b]
1[c]
2[c]
3[c]
4[d]
5
6
7
8
9
10
11
12
13
N
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
toluene
t-AmOH
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
110
110
25
25
40
80
80
15 h
15 h
15 h
15 h
15 h
15 h
25 h
25 h
15 h
15 h
15 h
15 h
4 h
14
N.D
N.D
97
97
N.D
79
AgSbF6
Ag2O
AgOTf
AgCOOCF3
Ag2CO3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
16
N.D
N.D
19
99
93
40
97
99
99
14[e]
15[e]
16[e]
17[e,f]
4 d
4 d
15 h
15h
[a] Reaction conditions unless otherwise specified: 1a (0.075 mmol), 2a
(0.05 mmol), [Cp*RhCl2]2 (5 mol%), additive (20 mol%), solvent (1 mL),
under Ar atmosphere. [b] Isolated yield. [c] Additive (1.1 equiv) was
added. [d] CuACHTUNGTRENNUNG(OAc)2 (1.1 equiv), AgSbF6 (20 mol%) were added.
[e] [Cp*RhCl2]2 (2.5 mol%) was added. [f] AgSbF6 (10 mol%) was
added.
More substituted cyclic N-sulfonyl ketimines 1 were ex-
plored next. N-sulfonyl ketimines bearing either electron-
donating or -withdrawing substituents at the para-position of
the ketimine-aryl ring gave the spirocyclic sultams 3ba–da
in excellent yields. In contrast, ortho-substituted aryl sub-
strate 1e afforded 3ea in 89% yield, whereas a mixture of
regioisomers was obtained from the meta-methoxy substrate
1 f in 95% yield. N-sulfonyl ketimines 1g and h showed per-
fect regioselectivity and the corresponding spirocyclic sul-
tams 3ga and ha were all obtained in 99% yield, probably
owing to both the steric and electronic effects. N-sulfonyl
ketimines fused with an array of diversely substituted ben-
zene ring underwent the Rh-catalyzed [3+2] annulation re-
action to deliver the 3ia–ka in good to excellent yields. To
explore the scope, other cycle N-sulfonyl ketimines such as
assorted six-membered ring benzo-fused imine 1l and cyclic
imine 1m were also tolerated in this reaction, the spirocyclic
skeletons 3la and ma could be prepared in 96 and 52%
yield, respectively.
negative reactivity towards the [3+2] annulation reaction
(Table 1, entries 2 and 3). When AgSbF6 and CuACTHNURTGNENG(U OAc)2
were both added to the reaction, excellent conversion of 2a
was observed and spirocyclic sultams 3aa was separated in
97% yield (Table 1, entry 4). In addition, [Cp*RhCl2]2 with
only a catalytic amount of AgSbF6 as an additive gave excel-
lent yield and the structure of the final product 3aa was
characterized by X-ray crystallography (Figure 1),[11] which
revealed that CuACHTUNGTRENNUNG(OAc)2 was not necessary and the mecha-
nism might be Grignard-type cyclization in this system
To additionally establish the scope of our approach, acy-
clic N-sulfonylimine 4 has been applied. As expected, it
could also react smoothly with diphenyl acetylene 2a to de-
liver the desired [3+2] product 5 in 55% yield under the
standard conditions in 13 h (Scheme 2).
We propose a plausible catalytic cycle in Scheme 3.[12] The
À
combination of ortho C H activation of cyclic N-sulfonyl
ketimine 1a and coordination of the imine nitrogen by Rh
leads to formation of five-membered rhodacycle I with
Figure 1. ORTEP representation of 3aa
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Spirocyclic Sultam Synthesis
COMMUNICATION
Table 2. Substrate scope of alkynes and cyclic N-sulfonyl ketimines.[a,b]
Scheme 3. A plausible mechanism for the reaction.
goes Grignard-type migration through intramolecular imine
À
insertion into the Rh C linkage, affording in
A
ter
E
di-
ate III.[9] The Rh center of intermediate III is stabilized by
an N/O chelator. Finally, protonation by acid forms the nu-
cleophilic addition product 3aa and regenerates the catalyst
to allow the reaction cycle to continue.[8a,e] In this way, the
catalytic cycle does not require any other additives.
In summary, we have disclosed an efficient RhIII-catalyzed
[3+2] annulation of cyclic N-sulfonyl ketimines with internal
alkynes in the presence of catalytic amounts of AgSbF6 to
form synthetically challenging spirocyclic sultams in high
yield under mild conditions. In this way, we have extended
the scope of Grignard-type cyclization to cyclic N-sulfonyl
ketimines and alkynes in the presence of RhIII-catalyst. We
are working to develop this useful reaction further.
Experimental Section
General Procedure for the Preparation of the Spirocyclic Sultams: 3-phe-
nylbenzo[d]isothiazole 1,1-dioxide (1a; 18.2 mg, 0.075 mmol, 1.5 equiv),
diphenyl acetylene (2a; 8.9 mg, 0.05 mmol, 1.0 equiv), [Cp*RhCl2]2
(0.8 mg, 2.5 mol%, 0.025 equiv) and AgSbF6 (1.8 mg, 10 mol%,
0.1 equiv) were stirred in DCE (1.0 mL) under Argon at 808C for 15 h.
TLC analyses of the mixture confirmed formation of 3aa. Flash chroma-
tography on silica gel (EtOAc/PE=1:10) gave 3aa as a white solid
(21.0 mg, 99%).
[a] Reaction conditions unless otherwise specified: 1 (0.075 mmol), 2
(0.05 mmol), [Cp*RhCl2]2 (2.5 mol%), AgSbF6 (10 mol%), DCE (1 mL),
808C, under Ar atmosphere for 15–16 h. [b] Yields are reported for the
isolated products. [c] Performed with 1 (0.05 mmol) and 2 (0.1 mmol).
[d] Major isomers are shown.
Acknowledgements
We are grateful for the financial support from the NSFC (21202106), Si-
chuan University Scientific Research Foundation, Sichuan University
“985 project-Science and technology innovation platform for novel drug
development” and the Open Research Fund from State Key Laboratory
of Breeding Base of Systematic Research, Development and Utilization
of Chinese Medicine Resources
Scheme 2. Reaction of acyclic N-sulfonylimine 4 with 2a.
simulACHTUNGTRENNUNGtaACHTUNGTRENNUNGneous loss of a proton. Subsequent regioselective
À
À
alkyne insertion into the Rh C bond yields an alkyne-coor-
dinating seven-membered ring intermediate II, which under-
Keywords: alkyne
cyclization · rhodium · spirocyclic sultams
·
C H activation
·
Grignard-type
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www.chemeurj.org

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group:
P 21/n, Bond precision: C-C=0.0022 A, Wavelength=
0.71073, Cell: a=13.739(3), b=9.2407(16), c=16.769(3) ꢂ, alpha=
90, beta=105.278(2), gamma=908, Temperature: 153 K, Dcalcd
:
1.363 gcmÀ3. CCDC 943583 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
[12] An alternative mechanism also could not be excluded: the hydroary-
lation leads to a styrene species, and then Lewis acid catalyzes
Prins-type reaction to give the product.
Received: August 28, 2013
Published online: November 4, 2013
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Chem. Eur. J. 2013, 19, 16537 – 16540