Aerobic oxidative C-H olefination of cyclic N-sulfonyl ketimines catalyzed by a rhodium catalyst

Article abstract of DOI:10.1021/ol501152a

A useful method for the synthesis of ortho-olefinated ketimines from readily accessible cyclic N-sulfonyl ketimines and various olefins has been achieved. The reactions proceeded by Rh(III)-catalyzed, N-sulfonyl ketimine-directed C-H cleavage under aerobic conditions. Further synthetic transformations of the olefinic products led to interesting heterocyclic molecules.

Full text of DOI:10.1021/ol501152a

Letter
pubs.acs.org/OrgLett
Aerobic Oxidative C−H Olefination of Cyclic N‑Sulfonyl Ketimines
Catalyzed by a Rhodium Catalyst
Nan-Jin Wang,‡ Shu-Tao Mei,‡ Li Shuai, Yi Yuan, and Ye Wei*
College of Pharmacy, Third Military Medical University, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: A useful method for the synthesis of ortho-
olefinated ketimines from readily accessible cyclic N-sulfonyl
ketimines and various olefins has been achieved. The reactions
proceeded by Rh(III)-catalyzed, N-sulfonyl ketimine-directed
C−H cleavage under aerobic conditions. Further synthetic
transformations of the olefinic products led to interesting
heterocyclic molecules.
ince the pioneering work by Fujiwara and Moritani on
However, the N-sulfonyl imine rarely acts as an efficient
S
oxidative olefination of the aryl C−H bond,1 transition-
directing group for C−H functionalization because of the low
coordination ability of the nitrogen atom which derives from
the electron-withdrawing effect of the conjugated sulfonyl
group. Recently, Li11 successfully established a Ru-catalyzed
C−H activation/annulation protocol for the synthesis of
indenamines from N-Ts imines and internal alkynes. Sub-
sequently, Nishimura12 and Dong13 developed Ir- and Rh-
catalyzed spirocyclic sultam synthesis from cyclic N-sulfonyl
ketimines and 1,3-dienes or internal alkynes, respectively. In
addition, Li14 reported Rh-catalyzed reactions between N-Ts
aldimines and olefins leading to ortho-olefinated benzaldehydes,
in which an excess of copper(II) salt was used as an oxidant and
CNTs was in situ hydrolyzed into CO. Very recently,
Dong15 developed a method for the synthesis of pyridines from
N-sulfonyl ketimines and alkynes with the N−S bond as an
internal oxidant. Despite these advances, the substrate scope in
transition-metal-catalyzed, N-sulfonyl imine directed C−H
functionalization still needs to be expanded further. Herein,
we describe a Rh(III)-catalyzed oxidative C−H olefination of
cyclic N-sulfonyl ketimines with various olefins. This protocol
enables the reactions to occur under an air or O2 atmosphere,
furnishing a diversity of ortho-olefinated compounds.
metal-catalyzed oxidative aryl C−H olefination has attracted
considerable attention from synthetic chemists.2 Although such
a C−H olefination protocol has been applied to various arenes
including simple arenes3 as well as electron-rich4 and -deficient
arenes,5 oxidative aryl C−H olefination with the assistance of
directing groups is undoubtedly of great importance and
usefulness, because the use of directing groups not only
facilitate C−H activation but also improve the regioselectivity
and reaction efficiency. With such a chelation-directed strategy,
a diversity of arenes have successfully been transformed into a
plethora of olefinic molecules over the course of the past few
years.6 Despite these achievements, the development of more
useful and easily transformable directing groups remains highly
desirable.
The N-sulfonyl imine motif widely exists in biologically active
molecules. For example, compounds containing an N-sulfonyl
imine moiety are potential inhibitors of HCV (hepatitis C
virus) NS5b,7 kinase,8 and PFT (protein farnesyltransferase)9
(Figure 1). On the other hand, the N-sulfonyl imines are highly
Initially, the reaction between cyclic N-sulfonyl ketimine 1a,
a readily accessible derivative of saccharin, and methyl acrylate
2a was chosen as a model reaction to optimize the reaction
conditions. After considerable experimentation, we found that
the ortho-olefinated product 3a was obtained in 81% yield in
the presence of [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %),
and Cu(OAc)2 (50 mol %) at 120 °C in dioxane under air
atmosphere within 12 h (entry 1, Table 1).
Figure 1. Biologically active molecules containing a N-sulfonyl imine
moiety.
valuable synthons for the construction of a variety of nitrogen-
containing molecules.10 We can envision that exploring a N-
sulfonyl imine as a directing group in the C−H functionaliza-
tion can not only prepare various compounds related to the
biologically active molecules but also provide a platform for the
synthesis of structurally diverse and complex molecules.
The key results obtained during the optimization process are
summarized in Table 1. Thus, a catalytic amount of AgSbF6 is
Received: April 21, 2014
Published: May 9, 2014
© 2014 American Chemical Society
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Letter
Table 1. Optimization of Reaction Conditions
Scheme 1. Rh-Catalyzed Oxidative Olefination of N-Sulfonyl
Ketimines with Methyl Acrylate
a
a
entry
change from the standard conditions
no change
yield (%)
1
81
<5
55
40
14
42
0
2
without AgSbF6
3
AgBF4 instead of AgSbF6
4
AgOTf instead of AgSbF6
5
20 mol % Cu(OAc)2 instead of 50 mol % Cu(OAc)2
80 °C instead of 120 °C
toluene instead of dioxane
6
7
8
t-AmylOH instead of dioxane
DCE instead of dioxane
51
<5
0
9
10
11
12
13
DMF instead of dioxane
2 equiv of Ag2CO3 instead of Cu(OAc)2/air
2 equiv of AgOAc instead of Cu(OAc)2/air
2 equiv of PhI(OAc)2 instead of Cu(OAc)2/air
54
29
24
a
b
See Supporting Information for reaction details. 3 equiv of HOAc
c
were used. 3 equiv of PivOH were used.
a
Isolated yields.
Scheme 2. Rh-Catalyzed Oxidative Olefination of Cyclic N-
a
Sulfonyl Ketimines with Various Olefins
crucial to this transformation. The reaction only gave a trace
amount of the desired product in the absence of AgSbF6 (entry
2). By replacing AgSbF6 with AgBF4 or AgOTf, the reaction
occurred albeit with lower yields of 3a (entries 3 and 4).
Reducing the amount of Cu(OAc)2 from 50 to 20 mol %
resulted in a very low yield (entry 5). In addition, the reaction
took place at 80 °C affording a 42% yield of 3a (entry 6).
Among the various solvents, only t-AmylOH (tert-amyl
alcohol) showed a moderate yield (entry 8), and other solvents
such as toluene, DCE (1,2-dichloroethane), and DMF (N,N-
dimethylformamide) all exhibited negative results (entries 7, 9,
and 10). A screening of other oxidants indicated that Ag2CO3
provided 3a in 54% yield (entry 11). However, poor results
were obtained when the reaction was carried out with AgOAc
or PhI(OAc)2 as the oxidant (entries 12 and 13).
We applied the optimized conditions to the reactions of
methyl acrylate 2a with an array of different N-sulfonyl
ketimines (Scheme 1). The coupled products bearing o- and
p-methyl, p-trifluoromethyl as well as naphthyl groups were
obtained in 52−85% yields (3ba−3da, 3fa, and 3ga). In the
case of a m-methyl ketimine substrate, the C−C bond
formation took place exclusively at the less-hindered site
(3ca). Although the ketimine substrate with a p-methoxy group
only gave 3ea in 14% yield under the standard reaction
conditions, the addition of 3 equiv of acetic acid strongly
promoted the reaction, providing a 63% yield of the desired
product. Strangely, for substituted furan, the olefination
reaction proceeded sluggishly under the reaction conditions
for 3ea. However, 3ja was obtained in a synthetically useful
yield when switching acetic acid to pivalic acid. Although the
exact role of the acetic acid and pivalic acid in the reactions
remains unclear, it has been known that acidic conditions are
beneficial to the C−H cleavage.16−18 More importantly,
thiophenes also smoothly underwent the oxidative olefination,
affording the products in good yields (3ha−3ia). Notably,
under Li’s conditions, the N-Ts aldimines of heterocycles such
as furan coupled with olefins sluggishly, with <10% of the
desired product formation.14
a
b
See Supporting Information for reaction details. Reactions were
carried out under 1 atm of O2.
with methyl or tert-butyl substituents underwent olefination
smoothly to give the desired products in synthetically useful
yields (3ka and 3la). Among different acrylates, ethyl acrylate
and n-butyl acrylate reacted with 1a excellently, giving rise to
the corresponding products in 80% and 85% yields, respectively
(3ab and 3ac). However, phenyl acrylate reacted with 1a
sluggishly and only gave 3ad in 45% yield. In contrast to the
acrylates, other electron-poor olefins such as cinnamaldehyde,
acrylonitrile, and methyl methacrylate did not give the
corresponding olefinated products at all, which indicated that
the coupling reactions largely depended on the electronic or
steric effect of the olefins. Besides the activated olefins,
nonactivated olefins such as styrene were also applicable in
the Rh(III)-catalyzed oxidative olefination reactions when the
oxidant was switched from Cu(OAc)2/air to Cu(OAc)2/O2.
The oxidative conditions were compatible with a variety of
functional groups including trifluoromethyl, nitro, cyano, and
ester, delivering the olefinic compounds in moderate to
We next performed the coupling reactions of N-sulfonyl
ketimines 1 with a variety of olefins (Scheme 2). Ketimines
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Letter
excellent yields (3ae−3ai). In addition, the reaction of cyclic
ketimine 3m with methyl acrylate under the standard
conditions also proceeded to give the desired product 3ma in
76% yield.
Scheme 5. Possible Catalytic Cycle
To demonstrate the utility of the ortho-olefinated products,
further synthetic transformations were conducted (Scheme 3).
Scheme 3. Synthetic Transformations of 3
decomposed into Rh(I)X by loss of HX. Finally, the Rh(III) is
regenerated by oxidation of the Rh(I)X with the aid of
Cu(OAc)/air or Cu(OAc)/O2 to fulfill the catalytic cycle.
In summary, we have developed a useful method for the
synthesis of a wide range of ortho-olefinated cyclic N-sulfonyl
ketimines that served as useful starting materials for the rapid
construction of interesting heterocyclic molecules. Further
studies focusing on the transition-metal-mediated C−H bond
functionalization of N-sulfonyl ketimines and their applications
for the construction of heterocyclic skeletons are currently
underway.
In the presence of nucleophiles such as benzyl mercaptan and
MeOH, polycyclic products 4a and 4b were easily prepared in
69% and 95% yields, respectively. Such reactions would have
proceeded through intermolecular nucleophilic attack of the
CN bond and subsequent intramolecular Michael addition of
the resulting sulfonamide to the CC bond. In addition, the
reaction of 3aa with NaBH4 delivered polycyclic product 4c in
good yield under mild reaction conditions. Interestingly,
spirocyclic sultam 4d was obtained in a synthetically useful
yield with TfOH as a catalyst, which might be formed through a
Prins-type reaction.19
ASSOCIATED CONTENT
■
To probe the possible mechanism, we performed some
isotope labeling experiments (Scheme 4). First, an H/D
S
* Supporting Information
Detailed experimental procedures, characterization of products,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 4. Deuteration Experiments
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: weiye712@hotmail.com.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the NSFC (No. 21302220), and Third
Military Medical University is greatly appreciated.
■
exchange experiment was conducted between 1a and deuterium
oxide (Scheme 4a). In the presence of 10 equiv of D2O, it was
found that 83% D was incorporated into the two ortho
positions of the ketimine aryl ring. Next, an intermolecular
competition reaction between 1a and 1a-d5 was performed,
showing a significantly primary kinetic isotope effect of 5.7
(Scheme 4b).20 The above-mentioned data suggested that a
reversible C−H activation process is involved in the Rh(III)-
catalyzed olefination.21,22
On the basis of the above results and recent achievements in
Rh(III)-catalyzed oxidative C−H olefination,6i,n−p,s,u,14 we
suggested a possible catalytic cycle shown in Scheme 5. First,
cyclic N-sulfonyl ketimine 1 reacted with a rhodium catalyst to
form a five-membered rhodacycle species A13,23 with
elimination of HX through chelation-directed C−H activation.
Subsequently, olefin 2 inserted into the C−Rh bond to give an
intermediate B that is prone to β-H elimination, delivering the
desired product 3 and HRh(III)X2 species. The latter then
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