Pd(II)-Catalyzed Direct Sulfonylation of Unactivated C(sp3)-H Bonds with Sodium Sulfinates

Article abstract of DOI:10.1021/acs.orglett.5b01634

A Pd(II)-catalyzed sulfonylation of unactivated C(sp³)-H bonds with sodium arylsulfinates using an 8-aminoquinoline auxiliary is described. This reaction demonstrates excellent functional group tolerance with respect to both the caboxamide starting material and the sodium arylsulfinate coupling partner, affording a broad range of aryl alkyl sulfones. Moreover, the late-stage modification of complex molecules was achieved via this sulfonylation protocol.

Full text of DOI:10.1021/acs.orglett.5b01634

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed Direct Sulfonylation of Unactivated C(sp3)−H Bonds
with Sodium Sulfinates
Wei-Hao Rao, Bei-Bei Zhan, Kai Chen, Peng-Xiang Ling, Zhuo-Zhuo Zhang, and Bing-Feng Shi*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
S
* Supporting Information
ABSTRACT: A Pd(II)-catalyzed sulfonylation of unactivated
C(sp3)−H bonds with sodium arylsulfinates using an 8-
aminoquinoline auxiliary is described. This reaction demon-
strates excellent functional group tolerance with respect to
both the caboxamide starting material and the sodium
arylsulfinate coupling partner, affording a broad range of aryl
alkyl sulfones. Moreover, the late-stage modification of
complex molecules was achieved via this sulfonylation
protocol.
viewpoint of step and atom economy, an attractive and
ryl alkyl sulfones constitute an important class of
Acompounds that find widespread use as pharmaceuticals complementary alternative would be direct sulfonylation of
C(sp3)−H bonds.5 In 2009, Dong and co-workers reported a
pioneering study on Pd(II)-catalyzed ortho-C(aryl)−H sulfo-
nylation with arylsulfonyl chlorides directed by a pyridine
coordinating group.6a Shortly thereafter, mechanistic experi-
ments from the same group showed the first direct evidence of
C(sp2)−SO2 reductive elimination from high-valent Pd(IV)
intermediates.6b Although these seminal studies demonstrated
the strategic value of directed sulfonylation through a Pd(II)/
Pd(IV) catalytic cycle, reactions of this type have generally been
limited to C(sp2)−H bonds with substrates that are unsuitable
for further elaboration.7 This, in turn, has significantly limited
synthetic applications toward structurally complex molecules.
Over the past decade, transition-metal-catalyzed C(sp3)−H
functionalization has emerged as a powerful means of
incorporating diverse functional groups into complex mole-
cules.7 However, direct sulfonylation of unactivated C(sp3)−H
bonds remained elusive, largely due to the difficulty of
identifying proper sulfonylation reagents that are sufficiently
reactive yet do not interfere with or inhibit the C−H activation
process. Recently, our group and others have demonstrated the
nickel-catalyzed thiolation of C(sp3)−H bonds to form
thioethers8 and the corresponding sulfones could be synthe-
sized followed by oxidation (Scheme 1b).8c These established
methods, however, suffer from several limitations, including the
use of odorous disulfides; a substrate scope restricted to
carboxamides bearing α-quaternary centers; and the need for a
two-step thiolation/oxidation sequence to afford aryl alkyl
sulfones. As part of our continuing efforts on Pd-catalyzed
functionalization of unactivated C(sp3)−H bonds,9 we
hypothesized that sodium sulfinates would be effective for
this purpose for several reasons: (1) sodium sulfinates are
and materials.1 They are also versatile precursors in synthetic
chemistry, including in fragment coupling and in Julia
olefination.2 Therefore, considerable efforts have been devoted
to the synthesis of sulfones.3 The most commonly used
methods for aryl alkyl sulfone preparation are nucleophilic
substitution of carbon electrophiles with sodium sulfinates or
thiophenols followed by oxidation (Scheme 1a).4 These
methods have disadvantages in that they require multistep
sequences to preinstall a leaving group and that they are
incompatible with numerous functional groups. From the
Scheme 1. Synthesis of Aryl Alkyl Sulfones
Received: June 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01634
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
readily accessible and stable to air and moisture; (2) sodium
sulfinates have been extensively used as sulfonyl nucleophiles in
metal-catalyzed allylic substitution;10 and (3) they prefer S-
coordination to the palladium center over O-coordination
because of the soft nature of sulfur. Inspired by the seminal
work of Daugulis on Pd-catalyzed functionalization of
unactivated C(sp3)−H bonds with N,N-bidentate directing
groups,11,12 we report herein a palladium-catalyzed direct
sulfonylation of unactivated C(sp3)−H bonds with sodium
sulfinates for the synthesis of diverse aryl alkyl sulfones
(Scheme 1c). This protocol tolerates a wide range of functional
groups and is compatible with the late-stage sulfonylation of
complex molecules. Notably, this transformation represents the
first example of transition-metal-catalyzed sulfonylation of
unactivated C(sp3)−H bonds.
structure of sulfonylated product 1a was confirmed by single-
crystal X-ray analysis.16
With the optimized conditions in hand, the scope of sodium
sulfinates was examined. As shown in Figure 1, a variety of
To test our hypothesis, we commenced our investigation by
examining the reaction of alanine derivative 1 with PhSO2Na
(Table 1). After extensive screening of various solvents and
a
Table 1. Optimization of the Reaction Conditions
b
entry
additive
yield (%)
1
/
49
55
62
60
65
73
63
55
44
2
Boc-Gly-OH
Boc-Phg-OH
Boc-Phe-OH
Boc-Val-OH
Boc-Tle-OH
Boc-lle-OH
3
4
5
6
7
Figure 1. Scope of sodium sulfinates. Reaction conditions: 1 (0.2
mmol), ArSO2Na (0.4 mmol), Pd(OAc)2 (10 mol %), MesCO2H (20
mol %), and Ag2CO3 (0.4 mmol) in DCM (2.0 mL) at 90 °C for 24 h.
Isolated yields.
8
Ac-lle-OH
9
(BnO)2PO2H
MesCO2H
c
10
11
12
13
14
15
75(72)
2,4-Dimethyl-BzOH
2,6-Dimethyl-BzOH
2-Ph-BzOH
54
69
45
35
30
sodium arylsulfinates bearing both electron-donating (1b−1e,
R = Me, OMe, iPr and tBu) and -withdrawing groups (1f−1i, R
= F, Cl, Br, and CF3) were tolerated and gave the desired
sulfonylated products in good yields. It is noteworthy that
halides, such as fluoride, chloride, and bromide, survived under
the standard reaction conditions, giving the sulfonylated
products in moderate to good yields (1f−1h). This offers the
opportunity for further elaboration of these versatile functional
groups by traditional cross-coupling. A more sterically hindered
sodium sulfinate, sodium 2-naphthylsulfinate, also reacted
smoothly with 1 to give the desired product in 59% yield.
Unfortunately, no sulfonylation products were obtained when
sodium alkyl sulfinates were used as the coupling partners.
The scope of aliphatic carboxamide substrates was next
examined (Figure 2). Generally, the reaction preferentially
functionalizes β-methyl C(sp3)−H bonds over other potential
sites. The reaction was sensitive to steric hindrance; substrates
with linear aliphatic chains at the α-position gave lower yields
(2a−4a), while substrates bearing sterically bulky groups at the
α-position afforded the desired products in higher yields (7a
and 8a). Notably, a TIPS-protected terminal alkyne, which
could be used to attach biologically important fluorescent tags
via click chemistry, was compatible with this protocol (5a).
Substrates bearing aryl groups (9a−17a) were more reactive
than those with aliphatic chains. A number of functional groups,
1-AdCO2H
TsOH·H2O
a
Reaction conditions: 1 (0.1 mmol), PhSO2Na (0.2 mmol), Pd(OAc)2
(10 mol %), additive (20 mol %), and Ag2CO3 (0.2 mmol) in DCM
b
(1.0 mL) at 90 °C for 24 h under N2. Yield determined by 1H NMR
c
using CH2Br2 as the internal standard. Isolated yield in parentheses.
oxidants, the desired product 1a was obtained in 49% yield
when the reaction was conducted in DCM at 90 °C using
Ag2CO3 as the oxidant (entry 1; see the Supporting
Information for further details). Recently, several elegant
studies have shown that simple carboxylic acids,13 amino
acids,14 and other types of organic acids15 promote catalytic
C(sp3)−H bond functionalization when used as additives.
Encouraged by these precedents, we then surveyed the effect of
a series of organic acids. To our delight, the sulfonylation
reaction was facilitated by a variety of mono-N-protected α-
amino acids (entries 2−8, 55−73% yields). Notably,
MesCO2H, a sterically bulky benzoic acid, proved to be the
most effective additive, affording the desired product 1a in 72%
isolated yield without any detectable formation of the
desulfinative arylation product (entry 10). Other organic
acids were less efficient than MesCO2H (entries 11−15). The
B
DOI: 10.1021/acs.orglett.5b01634
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Organic Letters
Letter
Scheme 2. Late-Stage C(sp3)−H Sulfonylation of Natural
Products
In conclusion, we have reported the first example of Pd(II)-
catalyzed sulfonylation of an unactivated C(sp3)−H bond with
sodium sulfinates. The reaction is characterized by a broad
substrate scope, excellent functional group tolerance, and high
regioselectivity. This transformation has been successfully
applied to the late-stage sulfonylation of complex molecules
and thus provides a powerful tool for the synthesis of aryl alkyl
sulfones.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, CIF information, and spectral data for all
new compounds. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01634.
Figure 2. Scope of aliphatic amides. Reaction conditions: 2−18 (0.2
mmol), PhSO2Na (0.4 mmol), Pd(OAc)2 (10 mol %), MesCO2H (20
mol %), and Ag2CO3 (0.4 mmol) in DCM (2.0 mL) at 90 °C for 24 h.
Isolated yields.
■
S
such as fluoro, chloro, bromo, and trifluoromethyl substituents,
were tolerated on the aromatic ring. In addition, the electron-
rich naphthyl group (17a) remained intact under the optimized
conditions. However, the protocol can only be applied to the
sulfonylation of β-methyl C(sp3)−H bonds under the
optimized reaction conditions. Notably, the sulfonylation of
γ-C(sp2)−H bond was also feasible, albeit in lower yield (18a,
35%).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bfshi@zju.edu.cn.
Notes
The authors declare no competing financial interest.
Next, we demonstrated the viability of this C(sp3)−H
sulfonylation protocol in the late-stage modification of natural
products. Carboxamide 19, a derivative of β-citronellol, was
successfully converted into the corresponding sulfone 19a in
34% yield (Scheme 2a). Moreover, derivatives of (−)-santonin
(20) and cholic acid (21) were also reacted smoothly with
sodium sulfinate to afford the corresponding products 20a and
21a in moderate yields (Schemes 2b and 2c).
To further demonstrate the practicality of this protocol, the
removal of the quinolinyl auxiliary was conducted as shown in
eq 1. The corresponding carboxylic acid 9b was easily obtained
from the sulfonylated product 9a through a mild, two-step
sequence in 65% yield.17
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (2015CB856600), the NSFC (21422206, 21272206),
and the Fundamental Research Funds for the Central
Universities is gratefully acknowledged.
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