Transition-Metal-Catalyzed Transformation of Sulfonates via S-O Bond Cleavage: Synthesis of Alkyl Aryl Ether and Diaryl Ether

Article abstract of DOI:10.1021/acs.orglett.9b02858

The catalytic conversion of sulfonates, a versatile class of pharmaceutical intermediates, is usually based on C-O bond cleavage. In this paper, however, we discover a rare transformation of sulfonates via S-O bond cleavage catalyzed by transition metal, through which alkyl sulfonates could undergo an intramolecular desulfitative C-O coupling to form aryl alkyl ethers in the presence of a nickel catalyst. Meanwhile, aryl sulfonates perform similarly to give diaryl ethers catalyzed by a palladium complex. This transformation could tolerate a wide range of functionalities. Controlled experiments reveal that the 2-pyridyl group is necessary to promote the reaction as designed. Crossover experiments proved that this transformation might proceed partly in an intermolecular pathway.

Full text of DOI:10.1021/acs.orglett.9b02858

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Catalyzed Transformation of Sulfonates via S−O
Bond Cleavage: Synthesis of Alkyl Aryl Ether and Diaryl Ether
Xuemeng Chen,†,§ Xue Xiao,†,§ Haotian Sun,† Yue Li,† Haolin Cao,† Xuemei Zhang,†
Shengyong Yang,† and Zhong Lian*,†,‡
†Department of Dermatology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School
of Pharmacy, Sichuan University, Chengdu 610041, P.R. China
‡Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for
Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, P.R. China
S
* Supporting Information
ABSTRACT: The catalytic conversion of sulfonates, a versatile
class of pharmaceutical intermediates, is usually based on C−O
bond cleavage. In this paper, however, we discover a rare
transformation of sulfonates via S−O bond cleavage catalyzed
by transition metal, through which alkyl sulfonates could
undergo an intramolecular desulfitative C−O coupling to form
aryl alkyl ethers in the presence of a nickel catalyst. Mean-
while, aryl sulfonates perform similarly to give diaryl ethers
catalyzed by a palladium complex. This transformation could tolerate a wide range of functionalities. Controlled experiments
reveal that the 2-pyridyl group is necessary to promote the reaction as designed. Crossover experiments proved that this
transformation might proceed partly in an intermolecular pathway.
ulfonates are synthetically versatile intermediates in the
In this paper, we report an intramolecular desulfitative
Spreparation of various pharmaceuticals and agrochemicals, transition-metal-catalyzed C−O bond formation via S−O bond
cleavage of sulfonates17 (Scheme 1d). The challenges of this
conversion may involve the following: (a) SO2 can poison the
transition metal through coordination;18 (b) in the oxidative
addition stepof transitionmetalinto sulfonates, thereis acompe-
tition between C−O bond cleavage19 and S−O bond cleavage;16
(c) the reductive elimination of nickel(II) alkoxide complexes is
often cited as being significantly difficult.20
The initial study investigated the desulfination of alkyl sulfo-
nates. To restrain more favorable C−O bond cleavage, a pyri-
dine group was introduced as the directing group in the
sulfonate, facilitating the envisioned S−O bond cleavage.
3-Phenylpropylpyridine-2-sulfonate 1 was used as a model
substrate (Table 1). After screening the reaction parameters, we
found the desulfitative product 2 could be formed in excellent
yield when Ni(COD)2 and SIPr·HCl were employed as catalyst
precursors, KOtBu was used as base, and xylene was used as
solvent at 140 °C. Controlled experiments have revealed some
keyfactorsforthesuccessofthisreaction.Thecatalystwasprovento
be necessary for this desulfination (Table 1, entries 2−4), whereas
the nickel complex was uniquely effective (Table 1, entry 5). When
other nickel complexes (NiCl2, Ni(OTf)2)21 were employed
instead of Ni(COD)2, the desired product 2 was formed in around
70% yield (Table 1, entries 6 and 7). Decreasing the catalyst
loading resulted in a reduced yield (Table 1, entries 8−12).
such as Ropinirole,1 Fingolimod,2 and Pregabalin3 (Scheme 1a).
Sulfonates can be easily obtained from esterification of corre-
sponding commercial sulfonyl chlorides and hydroxyl com-
pounds.4 Aryl tosylate (ArOTs), a kind of typical and most
common sulfonate, could serve as electrophiles and take part in
various cross-coupling reactions, such as Suzuki−Miyaura
reaction,4d,5 Kumada reaction,6 Stille reaction,7 Heck reaction,8
Hiyama−Denmark reaction,9 Buchwald−Hartwig reaction,8,10
and so on (Scheme 1b, top). For the transformation of alkyl
tosylate, the OTs group was generally considered as a leaving
group to generate alkene via β-H elimination under basic con-
ditions11 or undergo nucleophilic substitution.12 Additionally, in
2002, Fu reported palladium-catalyzed Suzuki cross-couplings of
alkyl sulfonates13 (Scheme 1b, bottom). Notably, all of the con-
versions of sulfonates described above are based on the cleavage
of the C−O bond.
The transformation of sulfonate, proceeded by breaking the
S−O bond, was mainly carried out via a sulfonyl transfer mecha-
nism. For example, sulfonates could react with aryl Grignard
reagent to form sulfones,14 and activated sulfonates could com-
binewithaminestoproducesulfonamide.15 However, transition-
metal-catalyzed transformation of sulfonates via S−O bond
cleavage remains very rare. The Buchwald group discovered a
palladium-catalyzed chlorosulfonylation of arylboronic acids to
synthesize aryl sulfonamides, in which the palladium catalyst
could selectively be oxidatively added into the S−O bond16
(Scheme 1c).
Received: August 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02858
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Organic Letters
Letter
Among the various bases (LiOtBu, NaOtBu, KOtBu, K2CO3,
K3PO4, and KHMDS) attempted, KOtBu22 showed the best per-
formance (Table 1, entries 13−17). Structurally similar ligands
(IPr·HCl, IMes·HCl, SIMes·HCl) revealed less reactivity in this
reaction (Table 1, entries 18−20). Lastly, other solvents (DMF,
DMSO, toluene, dioxane, anisole) were employed instead of
xylene, giving a lower yield of 2 (Table 1, entries 21−25).
With satisfactory reaction conditions established, we next
evaluated the scope of this reaction (Scheme 2). The primary
Scheme 1. Versatility and Transformation of Sulfonates
a
Scheme 2. Substrate Scope of Alkyl Sulfonates
Table 1. Condition Optimization for Desulfitative C−O
a
Coupling of 1
entry
changes from standard condition
yield of 2 (%)
1
2
3
4
95
0
0
no Ni(COD)2
no SIPr·HCl
a
Reaction conditions: Alkyl sulfonates (0.2 mmol), Ni(COD)2
no Ni(COD)2 and SIPr·HCl
other metals instead of Ni
NiCl2 instead of Ni(COD)2
Ni(OTf)2 instead of Ni(COD)2
Ni(COD)2 (1 mol %)
Ni(COD)2 (2 mol %)
Ni(COD)2 (3 mol %)
Ni(COD)2 (5 mol %)
Ni(COD)2 (7 mol %)
LiOtBu instead of KOtBu
NaOtBu instead of KOtBu
K2CO3 instead of KOtBu
K3PO4 instead of KOtBu
KHMDS instead of KOtBu
IPr·HCl instead of SIPr·HCl
IMes·HCl instead of SIPr·HCl
SIMes·HCl instead of SIPr·HCl
DMF instead of xylene
DMSO instead of xylene
toluene instead of xylene
dioxane instead of xylene
anisole instead of xylene
0
(10 mol %), SIPr·HCl (20 mol %), KOtBu (3.0 equiv), and xylene
b
5
trace
69
70
trace
15
34
57
80
0
b
(2.5 mL) at 140 °C for 1 h. 5.0 mmol scale with an argon balloon
6
7
connected to the reaction flask.
c
8
c
9
alkyl sulfonates suggested good reactivity in the desulfination
process (2−10), even in the presence of chloro and bromo
substituents (5 and 6), which were sensitive to the nickel
complex with an electron-rich ligand.23 The secondary alkyl
sulfonates had similar reactivity. Cyclohexyl sulfonate (11) and
its derivatives (12, 13, 14, and 15) also proceeded well.
Noticeably, the stereochemical information (12, 13, 14) was
kept after desulfination. In addition, the success of the
desulfitative C−O coupling at a gram scale (11) demonstrated
the practicality of this method. Cyclopentyl (16) and cyclobutyl
(17) sulfonates were also subjected to the standard conditions.
Othersecondaryalkylsulfonateswithacarbonchain(18and19)
could give the corresponding product in a good yield but in a
moderate yield with an adamantyl group (20). The catalytic
system was proven to be efficient for tertiary alkyl sulfonates
(21), albeit in a reduced yield, due to the steric effect. Sulfonates
with a methyl or trifluoromethyl substituent on the pyridine ring
(22−25) could also undergo this intramolecular desulfitative
coupling reaction. To our delight, compounds containing two
sulfonates could extrude two SO2 molecules to generate the
c
10
11
12
c
c
13
14
15
16
17
18
19
20
21
22
23
24
25
21
0
0
7
50
62
66
25
23
60
73
72
a
Reactions in this table were performed under an Ar atmosphere at
0.2 mmol scale. Yields were determined by GC using dodecane as an
internal standard. Other metals included Pd(dba)2, [Rh(COD)Cl]2,
and Ru3(CO)12. Ni(COD)2/SIPr·HCl = 1:2.
b
c
B
DOI: 10.1021/acs.orglett.9b02858
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Organic Letters
Letter
corresponding diether (26) in a good yield. It is worth noting that
there is no or trace β-H elimination product (terminal alkene)
formed when scoping the substrates in Scheme 2.
We next sought to demonstrate the desulfination of aryl
sulfonates (Scheme 3). Phenylpyridine-2-sulfonate (27) was
desired product (53). This result shows the great potentialof this
method for the late-stage derivatization of pharmaceuticals.
Lastly, the substrate with two sulfonates (54) also afforded the
corresponding product in the standard conditions.
To gain more insight into the mechanism of this intramolecu-
lar desulfitative coupling, some controlled experiments were
carried out. First, electron-deficient substrates (4-CF3, 55
and 56) and 4-pyridine substrates (57 and 58) did not produce
the corresponding desulfitative products in the standard condi-
tions, and the starting sulfonates were recovered. This fact indi-
cated that the nitrogen atom at the ortho-position was necessary
for the S−O bond cleavage (Scheme 4a). In the intramolecular
a
Scheme 3. Substrate Scope of Aryl Sulfonates
a
Scheme 4. Mechanistic Study
a
Standard condition A: Alkyl sulfonates (0.2 mmol), Ni(COD)2
a
Reaction conditions: Aryl sulfonates (0.2 mmol), Pd(dba)2 (5 mol %),
(10 mol %), SIPr·HCl (20 mol %), KOtBu (3.0 equiv), and xylene
(2.5 mL) at 140 °C for 1 h. Standard condition B: Aryl sulfonates
(0.2 mmol), Pd(dba)2 (5 mol %), XantPhos (5 mol %), K3PO4
(1.5 equiv), and toluene (3 mL) at 160 °C for 16 h.
XantPhos (5 mol %), K3PO4 (1.5 equiv), and toluene (3 mL) at
160 °C for 16 h. 4.25 mmol scale.
b
employed as a benchmark substrate. After evaluation of some
parameters, thereactionconditionusingPd(dba)2 (5mol%)and
XantPhos (5 mol %)as precatalyst, K3PO4 as base, andtoluene as
solvent at 160 °C led to the best result, giving the desulfitative
product in 89% yield (28). Scaled up by 21 times to 4.25 mmol,
the reaction gave the desired product (28) in 47% isolated
yield.24 With these reaction conditions in hand, the substrate
scope was then examined. Other aryl sulfonates with electron-
neutral substituents such as naphthyl (29 and 30) could tolerate
this desulfitative coupling. Substrates with electron-rich sub-
stituents including alkyl (31−34), amino (35), and ether groups
(36) were also subjected to the optimized reaction conditions.
To our delight, this methodology proved to be highly efficient in
the presence of halides (37−39), which were good coupling
partners in the cross-coupling reactions.25 Other electron-poor
substrates with CF3 (40), acetyl (41), ester (42), phenyl (43),
cyano(44),ornitrogroups(45)couldproceedinthisdesulfitative
process well. Moreover, the desired products with a heterocyclic
moiety (46 and 47) were formed via a desulfination pathway.
We also evaluated the functional group tolerance in the pyridine
ring. The results were positive, proven by the corresponding
products in good yields (48−52). This methodology was further
applied to a drug-like molecule, leading to the formation of the
desulfitative coupling of both aryl and alkyl sulfonates, we found
that electron-deficient substrates (59 and 62) reacted faster than
electron-rich substrates (60 and 63) (Scheme 4b). These results
suggested the oxidative addition step might be rate-determining.
It was observed that compound 63 failed to proceed with the
desulfination in the controlled experiment because the catalyst
might be not active enough to start with sulfonate 63 after the
desulfination of compound 62 (Scheme 4b, bottom).
Two alkyl sulfonates with different substituents (59 and 64)
were set up in one pot, and four different ethers (2, 11, 25,
and 61) were produced26 (Scheme 4c, top). Similarly, two aryl
sulfonates with different substituents were also added in one pot,
resulting in three desulfitative crossover products except for
2-phenoxypyridine (28)26 (Scheme 4c, bottom). These two
crossoverexperimentssuggestedthisintramoleculardesulfitative
coupling reaction might proceed partly in an intermolecular
pathway.27
Based on the results above and the literature,16,27 a plausible
mechanism was proposed (Scheme 5). The low-valent metal was
oxidatively added into the S−O bond of sulfonate I, directed by
the 2-pyridyl group to form intermediate II, which was in
equilibrium with ion pair III. The alkoxide/phenoxide in III
C
DOI: 10.1021/acs.orglett.9b02858
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02858.
Additional experimental details (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lianzhong@scu.edu.cn.
ORCID
Shengyong Yang: 0000-0001-5147-3746
Zhong Lian: 0000-0003-2533-3066
Author Contributions
§X.C. and X.X. contributed equally.
Notes
(14)Eroglu, F.;Kahya, D.;Erdik, E. J. Organomet. Chem. 2010, 695(2),
267−270.
(15) Colombe, J. R.; DeBergh, J. R.; Buchwald, S. L. Org. Lett. 2015, 17
(12), 3170−3173.
The authors declare no competing financial interest.
(16) DeBergh, J. R.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc.
2013, 135 (29), 10638−10641.
ACKNOWLEDGMENTS
■
We acknowledge Prof. Bill Morandi (ETH), Prof. Søren Kramer
(Technical University of Denmark), and Prof. Ying Xia (Sichuan
University) for helpful suggestions. This work is supported by
funding from start-up funding from Sichuan University.
(17) Review on desulfitative C−C couplings: (a) Takahashi, F.; Nogi,
K.; Yorimitsu, H. Phosphorus, Sulfur Silicon Relat. Elem. 2019, 194, 742−
745. Papers on desulfitative couplings: (b) Takahashi, F.; Nogi, K.;
Yorimitsu, H. Org. Lett. 2018, 20, 6601−6605. (c)Yu, T. Y.;Zheng, Z. J.;
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(18) Burch, R.; Crittle, D. J.; Southward, B. W. L.; Sullivan, J. A. Catal.
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condenser and an argon balloon, the yield decreased to around 10%, as
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E
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