Highly functionalized pyridines synthesis from N-sulfonyl ketimines and alkynes using the N-S bond as an internal oxidant

Article abstract of DOI:10.1021/ol500345n

The N-S bond-based internal oxidant offers a distinct approach for the synthesis of highly functionalized pyridines. A novel Rh(III)-catalyzed one-pot process undergoes an efficient C-C/C-N bond formation along with desulfonylation under very mild conditions. The method is quite simple, general, and efficient.

Full text of DOI:10.1021/ol500345n

Letter
pubs.acs.org/OrgLett
Highly Functionalized Pyridines Synthesis from N‑Sulfonyl Ketimines
and Alkynes Using the N−S Bond as an Internal Oxidant
Qian-Ru Zhang, Ji-Rong Huang, Wei Zhang, and Lin Dong*
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, and State
Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
S
* Supporting Information
ABSTRACT: The N−S bond-based internal oxidant offers a
distinct approach for the synthesis of highly functionalized
pyridines. A novel Rh(III)-catalyzed one-pot process undergoes
an efficient C−C/C−N bond formation along with desulfonyla-
tion under very mild conditions. The method is quite simple,
general, and efficient.
ighly functionalized pyridines represent an important
class of hererocycles that are widely implicated in natural
the best of our knowledge, N−S bonds have not been reported
to function as internal oxidants in C−H activation protocols. In
addition, more reactive electrophiles such as cyclic N-
sulfonylimines have rarely been developed as directing groups
for pyridines synthesis by C−N bond formation along with
desulfonylation.9−12 Herein, we report a novel approach which
comprises Rh(III)-catalyzed C−H activation of simple N-
sulfonyl ketimines and internal alkynes to afford the highly
functionalized pyridines, where the N−S bond could work as an
internal oxidant (Scheme 1, approach 3). The one-pot process
undergoes an efficient C−N bond formation and concomitant
desulfonylation under very mild conditions.
We commenced our investigation by studying the coupling
of cyclic N-sulfonyl ketimine 1a with diphenyl acetylene 2a
(Table 1). Using [Cp*RhCl2]2 as a catalyst, Cu(OAc)2 did
work, but 3aa was formed in only a low yield (Table 1, entry 1).
Meanwhile, among various silver salts, CF3SO3Ag and AgBF4
provided better yields (Table 1, entries 2−5). Additional
solvents were screened for the reaction, in which HOAc
exhibited good reactivity and improved the yield to 45% (Table
1, entries 6−9). To our surprise, the reaction can be carried out
with excellent efficiency in the presence of HOAc in DCE
(Table 1, entries 10 and 11). Among the study of other acids,
CF3COOH and pivalic acid were also appropriate for the
reaction and gave 3aa in 64% and 79% yields, respectively
(Table 1, entries 12 and 13). In addition, the lower catalyst
loading still gave a good yield even when the temperature was
reduced to only 60 °C (Table 1, entries 14 and 15). Indeed,
when the amount of diphenyl acetylene 2a was lowered to 1.2
equiv, a good yield of 3aa was achieved (Table 1, entry 16). To
our delight, the reactivity was still excellent even when the
AgBF4 was lowered to 0.5 equiv; however, 0.3 equiv of AgBF4
gave rise to a lower yield (Table 1, entries 17 and 18). This
suggests that the N−S bond supports its role as an internal
H
products, functional materials, and medicinal chemistry.1 While
methods for the synthesis of this motif have been developed
over the past several decades,2,3 there is increased interest in
this field due to the continued importance of the pyridine core
in various fields. Thus, the development of new approaches to
pyridines is highly desirable.
Transition-metal-catalyzed C−H activation has been realized
as an efficient strategy for synthesis of heterocyclic scaffolds.4
Recently, a number of approaches were well studied where C−
H activation with internal oxidants prepared nitrogen-
containing heterocycles.5−8 For example, isoquinoline and
pyridine synthesis from α,β-unsaturated oximes and internal
alkynes/alkenes were demonstrated via Rh(III)-catalyzed
transformation, in which the N−O bond of the oxime acts as
an internal oxidant (Scheme 1, approach 1).6 In a recent report
Zhu demonstrated that the N−N bond-based internal oxidant
approach offers indole synthesis (Scheme 1, approach 2).8
Despite this progress, however, restricted internal oxidant
protocols have been utilized for C−N cyclization. Especially, to
Scheme 1. Rhodium(III)-Catalyzed C−H Activation with
Internal Oxidants
Received: February 1, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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a
Table 1. Optimization of the Reaction Conditions for
Synthesis of 3aa
Table 2. Substrate Scope of Alkynes
a
b
entry
additive
acid [equiv]
solvent
t (h) yield (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2
AgSbF6
CF3SO3Ag
CH3CO2Ag
AgBF4
−
−
−
−
−
−
−
−
DCE
DCE
DCE
DCE
DCE
DMF
THF
tBuOH
HOAc
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
46
46
46
46
46
46
46
23
12
12
12
12
12
12
12
12
12
12
16
mess
31
9
32
trace
20
27
45
73
80
64
79
87
87
86
85
65
AgBF4
a
AgBF4
Reaction conditions unless otherwise specified: 0.1 mmol of 1a, 0.12
mmol of 2, 2.5 mol % of [Cp*RhCl2]2, 50 mol % of AgBF4, 0.5 mmol
of HOAc, 1 mL of DCE, 60 °C, Ar atmosphere. Yields are reported for
the isolated products. Ratios of regioisomers are given within
AgBF4
AgBF4
−
10
11
12
13
14
15
16
17
18
AgBF4
HOAc/2
HOAc/5
CF3CO2H/5
pivalic acid/5
HOAc/5
HOAc/5
HOAc/5
HOAc/5
HOAc/5
1
parentheses and were determined by H NMR analysis. Major
isomers are shown. 0.5 mL of HOAc, 0.5 mL of DCE. 1.0 equiv of
AgBF4.
AgBF4
b
c
AgBF4
AgBF4
c
AgBF4
Table 3. Substrate Scope and Limitations of N-Sulfonyl
Ketimines Patterns
cd
,
AgBF4
a
cde
,
,
AgBF4
cdef
, , ,
AgBF4
cdeg
,
, ,
AgBF4
a
Reaction conditions unless otherwise specified: 0.1 mmol of 1a, 0.2
mmol of 2a, 5 mol % of [Cp*RhCl2]2, 1.0 equiv of additive, 1 mL of
b
c
solvent, 110 °C, Ar atmosphere. Isolated yield. 2.5 mol % of
d
e
f
[Cp*RhCl2]2. 60 °C. 0.1 mmol of 1a, 0.12 mmol of 2a. 50 mol % of
g
AgBF4. 30 mol % of AgBF4.
oxidant in the catalytic cycle. The structure of the final product
3aa was characterized by X-ray crystallography (Figure 1).13,14
Figure 1. X-ray crystal structure of 3aa.
Utilizing optimal reaction conditions, various alkynes were
studied with N-sulfonyl ketimine 1a (Table 2). The process
showed wide substrate tolerance with internal alkynes. With
substituted diaryl acetylenes even for an alkyl-disubstituted
alkyne, the corresponding products can be obtained in good
yields (3ab−3ad). However, with electron-deficient 2e as the
internal alkyne, the desired product 3ae was obtained in a low
yield. To study the regioselectivity of this reaction, a few
disubstituted unsymmetrical alkynes were employed to give the
isomers in good yields with poor regioselectivity (3af−3ah),
whereas no product was obtained when 2i was employed.
Subsequently, a range of substituted cyclic N-sulfonyl
ketimines 1 were employed and the corresponding pyridine
derivatives were constructed effectively (Table 3). The β-
a
Reaction conditions unless otherwise specified: 0.1 mmol of 1, 0.12
mmol of 2a, 2.5 mol % of [Cp*RhCl2]2, 50 mol % of AgBF4, 0.5 mmol
of HOAc, 1 mL of DCE, 60 °C, Ar atmosphere. Yields are reported for
the isolated products. 1.0 equiv of AgBF4. 0.12 mmol of 1, 0.1 mmol
of 2a, 0.5 mL of HOAc, 0.5 mL of DCE. 5 mol % of [Cp*RhCl2]2,
0.5 mL of HOAc, 0.5 mL of DCE.
b
c
d
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position of the olefin unit bearing electron-withdrawing
substituents at the para-position of the aryl ring gave the
products in good yields (3ba, 3ca). In addition, a methoxy at
the para-, meta-, or ortho-position could react smoothly to
afford the products with good yields (3da−3fa). Similarly, 1g
also provided the product 3ga in 91% yield. However, a 3,4-
dicholoro-substituted substrate only produced the correspond-
ing pyridine 3ha in 34% yield, probably because of the electrical
effect. Moreover, other 3,4-disubstituted aryl substrates 1i−1k
proceeded smoothly to produce the product in good yields
(3ia−3ka).
Fortunately, N-sulfonyl ketimines bearing heteroaryl groups
were also compatible, producing 3la and 3ma in 52% and 87%
yields, respectively. The conjugated diene aryl substituent gave
3na in only 47% yield with some side reactions. Notably, the 6-
pyridine alkenyl derivative 3oa could be prepared in 34% yield
in this reaction.14 Importantly, N-sulfonyl ketimines fused with
an array of diversely substituted benzene rings were also
tolerated under the standard conditions, furnishing the
pyridines in good to excellent yields (3pa, 3qa). Encouraged
by the good tolerance toward various functional groups, the
scope of six-membered ring benzo-fused imines 1r−1t was
further examined. Surprisingly, the Rh catalyst was also effective
for these various imines to generate the expected pyridines
which contain the phenolic hydroxyl group (3ra−3ta).
To investigate the mechanism of this reaction, deuterium-
labeling experiments were carried out (Scheme 2). When 1a
without CH3CO2H gave 3aa with a deuterium content of 13%,
meanwhile the content of deuterium in the recovered 1a was
increased from 89% to 95% (eq 7). All of these data imply that
the first step of C−H activation is reversible and the proton
used for the protonolysis in the catalytic system can be either
from the solvent HOAc or produced in the first C−H bond
metalation step (eqs 5−7). In particular, when 1ra was treated
in CD3CO2D, deuterium at the 6-position of the phenyl group
in 3ra was observed in 37%, which indicates that the rhodacycle
might exist at a later stage of the catalytic cycle (eq 8).14
A plausible mechanism for the reaction is proposed in
Scheme 3. In the first step, the rhodium catalyst coordinates to
Scheme 3. A Plausible Mechanism
Scheme 2. Deuterium-Labeling Experiments
the imine nitrogen of cyclic N-sulfonyl ketimine 1a and
subsequent ortho C−H activation yields the five-membered
rhodacycle I with loss of a proton. Then coordination of an
alkyne to a rhodium species gives intermediate II. Sub-
sequently, alkyne regioselective insertion provides an alkyne
coordinating seven-membered ring intermediate III. Inter-
mediate III reductive elimination would afford the transition
state Rh(I) species IV, which could simultaneously undergo
insertion of a SO bond and cleavage of the N−S bond.
During this step, Rh(I) species IV may be oxidized to give
seven-membered Rh(III) species V at the same time S(VI) was
reduced to S(IV), which suggests the N−S bond is acting as an
internal oxidant. And then, a five-membered rhodacycle VI was
formed by elimination of SO2. Finally, protonolysis of the C−
Rh bond of VI may occur to form 3aa and regenerate the
[Rh(III)Cp*] species.
In summary, this appears to be the first example of
developing Rh(III)-catalyzed C−H activation with the N−S
bond of N-sulfonyl ketimines acting as a distinct internal
oxidant to synthesize highly functionalized pyridines. And
importantly, the reaction is accomplished through new C−C/
C−N bond formation, and S−N/S−C (or S−O) bond
cleavage, along with desulfonylation under very mild con-
ditions. Studies on the catalytic mechanism and the full
potential of this methodology are currently underway in our
laboratory.
was conducted in CD3CO2D in the absence of alkynes,
deuterium was observed at the ortho-position, which indicated
the possibility of the reaction pathway via oxidative addition of
an ortho C−H bond (eq 4). In contrast, the same reaction was
conducted in the presence of 2a, and the product 3aa was
observed with 65% deuterium (eq 5). Yet, when the reaction of
isotopically labeled 1a and 2a was performed in CH3CO2H
with standard conditions, no obvious deuterium content in
product 3aa was obtained (eq 6). Furthermore, the reaction
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Letter
(g) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2012,
77, 2501. (h) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66.
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(8) For selected examples on the N−N bond as an internal oxidant,
see: Liu, B.; Song, C.; Zhou, S.; Zhu, J. J. Am. Chem. Soc. 2013, 135,
16625.
(9) For selected examples, see: (a) Wilson, M. W.; Ault-Justus, S. E.;
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, structural proofs, and NMR spectra
of the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dongl@scu.edu.cn.
Notes
The authors declare no competing financial interest.
(11) (a) Donohoe, T. J.; Bower, J. F.; Basutto, J. A.; Fishlock, L. P.;
Procopiou, P. A; Callens, C. K. A. Tetrahedron 2009, 65, 8969.
(b) Zhao, P.; Wang, F.; Han, K.; Li, X. Org. Lett. 2012, 14, 5506.
(c) Nishimura, T.; Ebe, Y.; Hayashi, T. J. Am. Chem. Soc. 2013, 135,
2092.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the NSFC
(21202106), Sichuan University “985 project-Science and
technology innovation platform for novel drug development”.
(12) Dong, L.; Qu, C.-H.; Huang, J.-R.; Zhang, W.; Zhang, Q.-R.;
Deng, J.-G. Chem.Eur. J. 2013, 19, 16537.
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