Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers

Article abstract of DOI:10.1021/jacs.9b02312

We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.

Full text of DOI:10.1021/jacs.9b02312

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Communication
Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of #-Oxo-
Vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
Liang Gong, Hongbao Sun, Li-Fan Deng, Xia Zhang, Jie Liu, Shengyong Yang, and Dawen Niu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2019
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Journal of the American Chemical Society
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Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of -Oxo-Vinylsulfones to
Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
Liang Gong,‡ Hong-Bao Sun,‡ Li-Fan Deng, Xia Zhang, Jie Liu, Shengyong Yang, Dawen Niu*
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Department of Emergency, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and School of
Chemical Engineering, Sichuan University, Chengdu, China 610041
Supporting Information Placeholder
Scheme 1. Sulfones as electrophiles in cross-coupling
reactions.
ABSTRACT: We demonstrate that readily available and
bench-stable -oxo-vinylsulfones are competent
electrophiles in Ni-catalyzed Suzuki-Miyaura cross-
coupling reactions. The C–sulfone bond in the -oxo-
vinylsulfone motif is cleaved chemoselectively in these
reactions, furnishing C-aryl glycals or acyclic vinyl ethers
in high yields. These reactions proceed under mild
a) Challenges of using arylsulfones as electrophiles in cross-coupling reactions
Main Challenges:
O
O
- RSO2Met
I. non-trivial oxidative insertion step
II. chemoselective oxidative insertion?
S
R3
R1 R3
Met
+
R1
R2
-
III. desulfination process of R2SO2
1
2
3
Previous work: Wenkert, Julia, Denmark, Crudden, Baran, Hu, Li, etc.
conditions and tolerate
a
remarkable scope of
b) Use of -oxo vinylsulfones as electrophiles in cross-coupling reactions (This work)
heterocycles and functional groups. Preliminary
mechanistic studies revealed the importance of an -
heteroatom in facilitating these transformations.
O
O
O
S
O
Ar
Ar B(OH)2
–
– R’SO2
R’
RO
RO
or
+
Ni
Ar BPin
40 to 80 °C
OR
OR
4
5
6
O
O
• Mild conditions
O
S
O
R’
• Broad substrate scope
• Desulfination process suppressed
-Oxygen atom is critical for reactivity
RO
RO
The Suzuki-Miyaura cross-coupling reactions have
become indispensable tools in organic and medicinal
chemistry by enabling the facile and robust union of
molecular fragments via C–C bonds.1 The current
availability and relative stability of various organoboron
nucleophiles imparts great operational simplicity to these
reactions. The most frequently used electrophiles for
Suzuki-Miyaura couplings are organohalides and
sulfonates.2 The discovery and development of
alternative electrophilic partners for Suzuki-Miyaura
reactions is of significance, especially in situations where
the conventional ones are unreactive, unstable, or difficult
to prepare. In this regard, some very recent achievements
include the use of phenolates, ethers or esters,3
ammonium or pyridinium salts,4 nitro compounds,5
amides,6 acid fluorides,7 and activated C–C bonds8 as
electrophiles.9 Such advances have dramatically enriched
the toolboxes of synthetic chemists and enlarged the
accessible chemical space.
OR
4
OR
7
•

this outcome. First, the oxidative insertion of the less
polarized C–SO2R bonds is considered to be more
difficult.11 Second, sulfones contain two C–SO2 bonds
(cf. 1 in Scheme 1a), which have to be distinguished
during the oxidative insertion step. Third, upon oxidative
-
insertion, the resulting sulfinates (RSO2 ) are prone to
undergo desulfination to give R- which can re-enter the
catalytic cycle as nucleophiles, rather than
electrophiles.12
In spite of the above challenges, tremendous progress
has been made in harnessing sulfones as electrophilic
cross-coupling partners. The use of sulfones as the C(sp3)
electrophiles was reported by the Li13a and the Denmark
groups.13b Recent significant developments include those
disclosed by the Crudden group14 to make tertiary or
quaternary carbon-centers, and by the Baran15 and Hu
groups16 to make C–C bonds from highly fluorinated
species. Interestingly, although the use of vinyl or
arylsulfones as C(sp2) electrophiles has a longer history,
research in this realm11 has remained largely dormant
since the seminal studies of the Wenkert17 and the Julia
groups.18 Most of the reported methods employ Grignard
reagents as nucleophiles,19 which greatly limits their
synthetic utility.
Sulfones represent a fundamental functional group in
chemistry.10 The versatility and general stability of
sulfones render them important intermediates that have
been applied in the synthetic schemes of many complex
products. However, when compared with organohalides
or sulfonates,the use of sulfones as electrophiles in cross-
coupling reactions (1+2 to 3, Scheme 1a) is relatively
uncommon. Several factors may have contributed to
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Page 2 of 14
Table 1. Condition optimization for cross-coupling of
We commenced our study by using phenyl boronic acid
8a/b and 9.a
(9) and the sulfonyl glycal 8a as model substrates (Table
1). After screening reaction parameters, we found the
desired aryl glycal 10 could be formed in excellent yield
when Ni(COD)2 and Cy3P•HBF4 (L1) were employed as
catalyst precursors, KOH as base, and THF as solvent at
60 °C (entry 1). Under these conditions, we found
potassium phenylsulfinate (11) was formed in almost
quantitative yield and precipitated out of solution. The
vinyl ether or allyl ether groups in 8a stayed intact under
these reaction conditions. Control experiments have
revealed some key factors for the success of this reaction.
Among the various transition metals (Pd, Fe, Co, Ni, etc.)
attempted, Ni is uniquely effective to promote this
reaction (entry 2 and Table S1 in SI). Besides Ni(COD)2,
other Ni(II) precatalysts could also be employed (entry 3–
4). A gram scale reaction was performed using
NiCl2•glyme with standard Schlenk technique (entry 4).
Lowering the catalyst loading to 5 mol% resulted in
slightly diminished yield of 10 (entry 5). Switching ligand
to L2 delivered 10 in decent yield, but the use of L3
dramatically lowered the reaction efficiency (entries 6–
7). The use of NaOH instead of KOH gave 71% yield of
10 (entry 8), but employing tBuOK afforded 10 in only
11% yield (entry 9). Boronic acid pinacol esters could
also be used as nucleophiles, giving almost identical
yields as did boronic acids (entry 10). In contrast, the use
of trifluoroborates led to almost no desired product (entry
11). An electronically tuned sulfone substrate 8b, which
contains a 4-trifluoromethyl substituent could also be
used (entry 12). This reaction could be conducted in other
solvents such as tBuOH and toluene (entry 13–14).
Interestingly, water could be used as a co-solvent (entry
15). Lastly, the reaction could even proceed at 40 °C,
albeit with somewhat lower yield of 10 (entry 16).
1
2
3
4
5
6
7
8
OBn
OBn
O
O
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
O
S
O
Ph
R
RSO2K
+
Ph B(OH)2
+
KOH (2 equiv)
THF, 60 °C, 13 h
BnO
BnO
9
OBn
OBn
R = Ph, 8a
R = 4-CF3Ph, 8b
10
11
conversion
of 8a
yield
of 10
entry
deviation from “standard conditions”
Cy3P•HBF4
1
2
3
4
5
6
“standard conditions” with 8a
100%
trace
100%
90%
94%
0%
L1
Fe, Co, Pd instead of Ni(COD)2
9
Ni(OTf)2 instead of Ni(COD)2, 80 °C
NiCl2•glyme instead of Ni(COD)2, 80 °C
Ni(COD)2 (5 mol%) and Cy3P•HBF4 (10 mol%)
L2 instead of Cy3P•HBF4, 80 °C
93%
81%c
86%
81%
10
11
12
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Ph
Ph
90%
83%
N
N
L3 instead of Cy3P•HBF4
7
8
26%
87%
12%
71%
11%
90%
NaOH instead of KOH
KOtBu instead of KOH
L2
9
100%
100%
Ph-Bpin instead of Ph-B(OH)2
10
Ph-BF3K instead of Ph-B(OH)2
8b instead of 8a
11
12
13
90%
100%
100%
0%
iPr
iPr
84%
82%
N
N
tBuOH instead of THFb
PhMe instead of THFb
14
15
16
95%
100%
>95%
92%
90%
85%
iPr
iPr
THF/H2O (3:1) used as solvent
reaction performed at 40 °C for 16 h
L3
a Reactions in this Table were performed at 0.05 mmol scale, using 2 equiv. of 9. Yield and
conversion were determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.
b Reaction was performed at 80 °C using Ni(OTf)2. c Isolated yield of a 2 mmol scale reaction.
Our group is interested in the development of novel
methods to make carbohydrate derivatives.20 In a project
aimed at making C-aryl glycals,21 common intermediates
to pharmaceutically important C-glycosides,22 we
became intrigued by the possibility of using 1-sulfonyl
glycals as an alternative to the corresponding 1-iodo-
glycals as the electrophilic cross-coupling partners (4 + 5
to 6, Scheme 1b). The reported preparation of 1-iodo-
glycals requires the use of t-BuLi, and, as with other -
oxo-vinyl halides, many 1-iodo-glycals are inherently
unstable.21a-e In comparison, 1-sulfonyl glycals are
readily obtained in large scale from glycosyl sulfones by
-oxo elimination and show stability toward long-term
storage.23 These features should render them more
attractive substrates in library synthesis. We were aware,
though, besides the intrinsic challenges of using sulfones
as cross-coupling electrophiles mentioned above, to
employ sulfonyl glycal 4 as a synthetic equivalent of 7
presents additional difficulties. First, the presence of an
-oxygen atom in 4 would render the double bond more
electron-rich, and might further deactivate the C–S bond
toward oxidative addition. Second, a number of other
functional groups, including vinyl ethers3,24 and allyl
ethers, could potentially undergo oxidative addition and
interfere with the reaction outcomes. These potential
pitfalls notwithstanding, we established in this work that
1-sulfonyl glycals could serve as convenient electrophilic
partners in the Ni-catalyzed Suzuki-Miyaura reactions, to
produce various C-aryl glycals in high yields. We further
established that acyclic -oxo-vinyl sulfones could
function as electrophilic synthons in these reactions as
well, furnishing acyclic vinyl ethers. Control experiments
have shown that the -oxygen atom played critical roles
to activate these substrates and facilitate the desired
reactions.
With satisfactory reaction conditions established, we
explored the scope of this reaction (Scheme 2). We found
a large variety of boronic acid derivatives could partake
in this reaction. For example, both electron-rich (13a-b,
e-f, j) and electron-deficient aryl rings (13d) were
tolerated. Aryl boronic acids bearing an ortho-substituent
were suitable substrates (13g-i). Vinyl and allyl group
could be installed as well, furnishing conjugate diene 13k
and skipped diene 13l, respectively. Functional groups
including nitriles (13m), esters (13n), free hydroxyls
(13o), ketones (13p), amines (13b), amides (13q), and
carbamates (13af) were all accommodated, attesting to
the mildness of the reaction conditions. Various
heteroaryls including dioxolanes (13j), thiophenes (13r-
s), furans (13t-v), quinolines (13x-y), indoles (13z), aza-
indoles (13aa), pyridines (13w, 13ab-af), and
pyrimidines (13ag) could be readily incorporated,
highlighting the generality and practicality of this
reaction. Lastly, we showed that the aryl pinacol boronic
ester derived from loratadine could be employed in this
transformation, affording 13ah in 55% yield.
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Scheme 3. Substrate scope of the sulfones.a
Scheme 2. Substrate scope of organoboron
nucleophiles.a
1
2
OBn
OBn
O
O
3
4
5
6
(HO)2B
Het
Het
Het
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
O
S
O
Ph
or
+
KOH (2 equiv)
THF or tBuOH
60 °C, 12 h
BnO
BnO
PinB
OBn
8a
OBn
12
13
7
8
9
R
yield
F
MeO
Me
13a OMe 82%
NMe2
13b
13c
13d
74%
79%
74%
MeO
13e, 82%
F
CF3
R
10
11
12
13
14
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13f, 75%
13g, 72%
13l, 85%b
Me
O
O
13h, 90%
13i, 80%
13j, 82%
13k, 48%b
Me
Me
HO
Me2N
NC
MeOOC
O
Me
13o, 71%
O
13m, 70%
13n, 81%
13p, 73%
13q, 45%
S
S
O
O
O
13r, 83%
13s, 90%
13t, 86%
13u, 75%
13v, 86%
N
N
N
N
N
N
Bn
Bn
13w, 59%
13x, 89%
13y, 87%
13z, 68%
13aa, 86%
MeO
F3C
N
N
MeO
N
N
13ab, 84%
13ac, 90%
13ad, 94%
N
N
N
N
N
N
MeO
N
OMe
EtO
O
N
O
Boc
13ah, 55%b
13ae, 89%
13af, 80%
13ag, 73%
a Reactions were performed at 0.2 mmol. The reported isolated yields are average of two runs. See
SI for experimental details. b Reaction was performed at 80 °C.
To further demonstrate the potential utility of this
reaction, we employed it to synthesize known
pharmaceutical agents and modified amino esters
(Scheme 4). We established that the cross-coupling
between sulfone 23 and boronate 24 proceeded smoothly
to afford 25 in 88% yield. Aryl glycal 25 could then be
converted to ipragliflozin (26a) by a sequence of
The scope of 1-sulfonyl glycals was also investigated
(Scheme 3a). The 1-sulfonyl glycals 15 were prepared by
base induced -elimination from the corresponding
glycosyl sulfones 14. Substrates derived from glucose
(16a-b), galactose (16c), fucose (16d), rhamnose (16e),
arabinose (16f), and xylose (16g) could be employed.
Both alkyl ether and silyl ether protecting groups (16a-b)
were well tolerated by the reaction conditions. Even
sulfones made from disaccharides such as maltose (16h)
were competent reaction partners, affording the
corresponding aryl glycals in excellent yield.
hydroboration/oxidation/deprotection
Alternative treatment of
reactions.
by
25
a
hydrogenation/deprotection process led to 2-deoxy
ipragliflozin (26b). Transition metal catalyzed C–H
borylation is a robust method to prepare aryl boronates
from complex molecules.25 Combining this C–H
borylation reaction with our cross-coupling reaction with
8a, a carbohydrate moiety could be readily installed onto
a tryptophan derivative 27 to furnish 29 via the
intermediacy of 28. Lastly, the cross-coupling between
vinyl sulfone 30 (derived from 4-fluorobenzaldehyde)
and vinyl boronic acid pinacol ester (31) afforded
electron-rich diene 32 in high yield as a mixture of E/Z
isomers. Both isomers underwent smooth Diels–Alder
reaction with diethyl fumarate to give a pair of
diastereomers, which then converge to the same ketone
33 upon hydrolysis.26 Ketone 33 was used as a key
intermediate in the synthesis of 34, a potent human NK1
In addition to the cyclic -oxo-vinyl sulfones listed
above, acyclic variants also could be employed in our
reactions (Scheme 3b). Acyclic -oxo-vinyl sulfones 19
could be prepared in one step from the condensation
between aldehydes 17 and sulfone 18. Their subsequent
coupling with tolyl boronic acid (20) afforded the
corresponding vinyl ethers (21a-d) in good yields as a
mixture of E/Z isomers. Further hydrolysis afforded the
corresponding ketone 22. Compared with conventional
1,2-addition/oxidation sequence that converts aldehydes
to ketones, the method outlined in Scheme 3b affords
ketones that are further extended by one methylene unit.
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Scheme 5. Mechanistic studies.a
Page 4 of 14
Scheme 4. Synthetic applications.a
1
2
3
4
5
6
7
8
9
10
11
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receptor antagonist. With other arylaldehydes used as
starting materials, analogues of 34 could be made by this
route (See Scheme S1 in SI for another example).
provided only low quantities of the arylated products
under identical conditions.
In another experiment, we subjected sulfone 8a to a
THF solution containing a stoichiometric amount of
Ni(COD)2 and PCy3 at 45 °C but without a boronic acid
component, and found phenylated product 10 was formed
in 76% yield (Scheme 5b). This result suggests that both
the oxidative insertion of 8a by Ni(0) and the
desulfination of the resulting phenyl sulfinate (cf. 41 in
Scheme 5c) are viable and facile processes. With the
above information, we proposed a plausible reaction
mechanism as depicted in Scheme 5c. Substrate 39 first
undergoes an regioselective C–S bond insertion by Ni(0)
to afford 41, presumably facilitated by the transient
formation of 40. Vinyl nickel species 41 could either
undergo a desulfination/reductive elimination sequence
to give 42, or a transmetallation step to furnish 43
followed by reductive elimination to give 44 as product.
The success of our reaction suggests that the
transmetallation process could outcompete the
desulfination step.
The facility with which our cross-coupling proceeds is
surprising. We performed some preliminary studies to
probe into the mechanism of this reaction. We first
prepared a pair of substrates 35a and 35b that differ only
by O atom vs. a CH2 group, respectively (Scheme 5a).
When subjecting these two substrates to our standard
conditions, we found that 35a was cleanly converted to
36a, while the all-carbon analog 35b remained inert.
Thus, instead of deactivating vinyl sulfones, the presence
of an -oxygen atom appears to activate these substrates.
This result led us to propose that the -oxygen atom in
35a might facilitate the oxidative insertion step by
precoordinating with the Ni catalyst.27 This hypothesis
could also explain the high regioselectivity of the
oxidative insertion step: the C–S bond adjacent to the
oxygen atom is cleaved selectively. To further
corroborate this hypothesis, we then prepared and
compared the reactivity of sulfones 37a-c. Among these
substrates, 37a, which possess a coordinating -nitrogen
atom, underwent smooth coupling with tolyl boronic acid
(20). Sulfone 37b also contains a nitrogen atom in the
aromatic ring, but it is para to the sulfone moiety.
Accordingly, both 38b and the all-carbon analog 38c
In summary, we have shown that -oxo-vinylsulfones
are competent electrophilic partners in the Ni-catalyzed
Suzuki-Miyaura cross-coupling reactions, and developed
general methods to prepare pharmaceutically relevant
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Electrophiles in Cross-Coupling Reactions. Adv. Organomet. Chem.
aryl glycals and synthetically important acyclic vinyl
2016, 66, 143–222. (d) Tobisu, M.; Chatani, N., Cross-Couplings
Using Aryl Ethers via C-O Bond Activation Enabled by Nickel
Catalysts. Acc. Chem. Res. 2015, 48, 1717–1726. (e) Tollefson, E. J.;
Hanna, L. E.; Jarvo, E. R. Stereospecific nickel-catalyzed cross-
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48, 2344–2353. (f) Su, B.; Cao, Z. C.; Shi, Z.-J. Exploration of earth-
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chemical bond activations. Acc. Chem. Res. 2015, 48, 886–896. (g)
Cornella, J.; Zarate, C.; Martin, R., Metal-catalyzed activation of ethers
via C–O bond cleavage: a new strategy for molecular diversity. Chem.
Soc. Rev. 2014, 43, 8081–8097. (h) Yu, D.-G.; Li, B.-J.; Shi, Z.-J.
Exploration of New C−O Electrophiles in Cross-Coupling Reactions.
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1
2
3
4
5
6
7
8
ethers. These reactions employ readily available starting
materials and reagents, proceed under mild conditions,
and tolerate a remarkable scope of functional groups and
heterocycles. Mechanistic studies provide insights into
the reaction pathway, and suggest the presence of an -
heteroatom in -oxo-vinylsulfones was critical for their
reactivities in these cross-coupling reactions.
9
ASSOCIATED CONTENT
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Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
(4) Yadav, M. R.; Nagaoka, M.; Kashihara, M.; Zhong, R. L.;
Miyazaki, T.; Sakaki, S.; Nakao, Y. The Suzuki-Miyaura Coupling of
Nitroarenes. J. Am. Chem. Soc. 2017, 139, 9423−9426.
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Vinylpyridinium and ammonium Tetrafluoroborate Salts: New
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Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. Harnessing Alkyl Amines
as Electrophiles for Nickel-Catalyzed Cross Couplings via C−N Bond
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Basch, C. H.; Santana, S. O.; Watson, M. P. Harnessing
Alkylpyridinium Salts as Electrophiles in Deaminative Alkyl–Alkyl
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Takise, R.; Muto, K.; Yamaguchi, J. Cross-coupling of aromatic esters
and amides. Chem. Soc. Rev. 2017, 46, 5864–5888. (c) Szostak, M.;
Meng, G.; Shi, S. Cross-Coupling of Amides by N–C Bond Activation.
Synlett 2016, 27, 2530−2540. (d) Hie, L.; Fine Nathel, N. F.; Shah, T.
K.; Baker, E. L.; Hong, X.; Yang, Y. F.; Liu, P.; Houk, K. N.; Garg, N.
K. Conversion of amides to esters by the nickel-catalysed activation of
amide C-N bonds. Nature 2015, 524, 79−83. (e) Weires, N. A.; Baker,
E. L.; Garg, N. K. Nickel-catalysed Suzuki-Miyaura coupling of
amides. Nat Chem. 2016, 8, 75−79.
AUTHOR INFORMATION
Corresponding Author
niudawen@scu.edu.cn
Author Contributions
‡These authors contributed equally.
Funding Sources
No competing financial interests have been declared.
This work is supported by funding from National Natural
Science Foundation (Nos. 21772125 and 21602145), and
start-up funding from Sichuan University.
ACKNOWLEDGMENT
We acknowledge Prof. Jason C. Chruma for proofreading
this manuscript and helpful suggestions.
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[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-
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Hydrazines: a Palladium-Catalyzed C-glycosylation. J. Org. Chem.
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4
5
6
7
8
methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one:
A
Potent Human NK1 Receptor Antagonist with Multiple Clearance
Pathways. J. Med. Chem. 2013, 56, 5940−5948. An analogue of 34 has
also been synthesized by this route. See SI for details.
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(23) Qiu, D.; Schmidt, R. R. A Convenient Synthesis of Pyranoid Ene
Lactones from Phenyl Glycosyl Sulfones. Synthesis, 1990, 875–877.
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Catalyzed Cross-Coupling Reaction of Alkenyl Methyl Ethers with
Aryl Boronic Esters. Org. Lett. 2009, 11, 4890–4892.
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Preference in Ni-Catalyzed Cross-Coupling of Halophenols with Alkyl
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For Table of Contents Only
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O
O
Ni(COD)2
Cy3P•HBF4
O
S
O
Ar
Ar B(OH)2
Ph
RO
RO
or
+
+
PhSO2K
KOH, 40–80 °C
Ar BPin
OR
OR
6
7
> 50 examples
18 heteroaryls
cyclic or acyclic
8
9
Ar =
CO2Me
NHBoc
F3C
N
N
MeO
N
N
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60
N
N
TIPS
N
N
MeO
N
OMe
N
EtO
O
Boc
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a) Challenges of using arylsulfones as electrophiles in cross-coupling reactions
Main Challenges:
O O
S
- RSO2Met
I. non-trivial oxidative insertion step
II. chemoselective oxidative insertion?
R3
R1 R3
Met
+
R1
R2
-
III. desulfination process of R2SO2
1
2
3
Previous work: Wenkert, Julia, Denmark, Crudden, Baran, Hu, Li, etc.
b) Use of α-oxo vinylsulfones as electrophiles in cross-coupling reactions (This work)
O
O
O
S
O
Ar
Ar B(OH)2
–
– R’SO2
R’
RO
RO
or
+
Ni
Ar BPin
40 to 80 °C
OR
OR
4
5
6
O
O
• Mild conditions
O
S
O
R’
• Broad substrate scope
RO
RO
• Desulfination process suppressed
OR
4
OR
7
• α-Oxygen atom is critical for reactivity
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OBn
OBn
O
O
(HO)2B
PinB
Het
Het
Het
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
O
S
O
Ph
or
+
KOH (2 equiv)
THF or tBuOH
60 °C, 12 h
BnO
BnO
OBn
OBn
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8a
12
13
R
yield
F
MeO
Me
13a OMe 82%
NMe2
13b
13c
13d
74%
79%
74%
MeO
F
CF3
R
13e, 82%
13g, 72%
13l, 85%b
13f, 75%
Me
O
O
13h, 90%
13i, 80%
13j, 82%
13k, 48%b
Me
Me
HO
Me2N
NC
MeOOC
O
Me
O
13m, 70%
13n, 81%
13o, 71%
13p, 73%
13q, 45%
S
S
O
O
O
13r, 83%
13s, 90%
13t, 86%
13u, 75%
13v, 86%
N
N
N
N
N
N
Bn
Bn
13w, 59%
13x, 89%
13y, 87%
13z, 68%
13aa, 86%
MeO
F3C
N
N
MeO
N
N
13ab, 84%
13ac, 90%
13ad, 94%
N
N
N
N
N
N
MeO
N
OMe
EtO
O
N
O
Boc
13ah, 55%b
13ae, 89%
13af, 80%
13ag, 73%
a Reactions were performed at 0.2 mmol. The reported isolated yields are average of two runs. See
SI for experimental details. b Reaction was performed at 80 °C.
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a) Scope of 1-sulfonyl glycals
Ph B(OH)2
6
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
7
8
9
+
O
Ph
9
O
SO2Ph
OR
O
SO2Ph
RO
KOH (2 equiv)
THF, 60–80 °C, 12 h
LDA
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RO
RO
16
14
15
O
O
O
Me
O
TBSO
O
BnO
BnO
tBu Si
tBu
TBSO
O
BnO
OTBS
OTIPS
OBn
OBn
(from galactose)
(from glucose)
16a, 82%b
(from glucose)
(from fucose)
16d, 70%
16c, 72%
16b, 60%
BnO
BnO
Bn
Me
O
O
O
O
O
O
BnO
BnO
BnO
O
BnO
OBn
OBn
OBn
OBn
OBn
(from xylose)
16g, 83%
(from rhamnose)
(from arabinose)
(from maltose)
16f, 77%b
16e, 86%
16h, 92%
b) Scope of acyclic α-oxo vinyl sulfones
Tol B(OH)2
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
H3O+
MeO
Tol
O
R
Tol
MeO
SO2Ph
20
+
P(=O)(OEt)2
KOH (2 equiv)
THF, 60 °C, 8 h
R
MeO
SO2Ph
O
18
21
22
R
LDA
R
17
R =
19c
Me
Me
TIPSO
Ph
Me
Me
Me
21a
83%, 1:1.2 E/Z
21b
70%, 1:1.3 E/Z
21c
90%, 1:1 E/Z
21d
78%, 1:1.7 E/Z
a Reported isolated yields are average of two runs. E/Z ratios were determined by 1H NMR analysis of
the crude reaction mixture after extractive workup. Reactions in Scheme 3a were run at 0.1–0.15
mmol; reactions in Scheme 3b were run at 0.3 mmol. b tBuOH was used as solvent. See SI for
experimental details.
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a) Synthesis of ipragliflozin and 2-deoxy ipragliflozin
5
6
7
8
O
Ar
O
SO2Ph
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
TBSO
F
TBSO
TBSO
+
TBSO
S
PinB
KOH, THF, 80 °C, 12 h
OTBS
25 (88%)
9
OTBS
23
24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
= Ar
F
O
Conditions A
S
HO
HO
or
R
26a, R = OH, ipragliflozin
Conditions B
OH
26b, R = H, 2-deoxy ipragliflozin
b) C–H borylation/Suzuki-Miyaura coupling sequence
CO2Me
CO2Me
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
NHBoc
NHBoc
+
8a
KOH
tBuOH, 60 °C, 12 h
N
O
R
N
BnO
BnO
TIPS
TIPS
27, R = H
Conditions C
OBn
28, R = BPin
29 (45%)
c) Formal synthesis of a human NK1 antagonist
CO2Et
CO2Et
SO2Ph
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
MeO
MeO
O
Conditions D
BPin
+
KOH
tBuOH, 80 °C, 6 h
F
F
F
31
30
32
33
80%, E/Z 1:1b
HO
N
F3C
O
ref. 26
O
a potent human
NK1 receptor antagonist
CF3
F
34
a Unless otherwise noted, isolated yields are reported. See SI for experimental details. b Yield and E/Z
ratio were determined by 1H NMR analysis. Conditions A: (1) BH3•THF; (2) 30% H2O2, 3 M NaOH; (3)
TBAF. Overall yield = 49%. Conditions B: (1) Pd/C, H2 (balloon); (2) TBAF. Overall yield = 85%.
Conditions C: [Ir(COD)(OMe)]2, 1,10-phenanthroline, B2Pin2, HBPin, 78% (An 8:1 ratio of C6- to C5-
position functionalized product is formed.). Conditions D: (1) diethyl fumarate, m-xylene; (2) 6 N HCl,
CH3CN. Overall yield = 68%.
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9
a) The significance of α-heteroatom in the cross-coupling of sulfones.
B(OH)2
Me
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
X
yield
X
SO2Ph
X
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
O
36a
36b
76%
KOH (2 equiv)
CH
trace
2
THF, 60 °C, 12 h
Me
20
35a/b
36
38
X
Y yield
B(OH)2
Me
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
X
SO2Ph
b
38a N CH
38b CH N
38c CH CH
70%
X
+
29%
Y
KOH (2 equiv)
tBuOH, 60 °C, 12 h
Y
trace
Me
20
37a/b/c
b) Facile oxidative insertion and desulfination of 8a by Ni(0).
OBn
OBn
O
O
Ni(COD)2 (100 mol%)
PCy3 (200 mol%)
O
S
O
THF, 45 °C, 12 h
BnO
BnO
w/o aryl boronic acids
OBn
OBn
8a
c) A plausible reaction pathway.c
10, 76%
Ni(0)
O
SO2R
O
SO2R
39
40
Ni(0)
O
Ar
O
R
O
Ni
SO2R
44
41
ArB(OH)2 + KOH
42
O
Ni
Ar
RSO2K
43
a Unless otherwise noted, yields are determined by 1H NMR using 1,3,5-trimethoxybenzene as
internal standard. b Isolated yield. c For the sake of simplicity, ligands on Ni are omitted and all
steps are drawn as irreversible.
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9
OBn
OBn
Ni(COD)2 (10 mol%)
Cy3P•HBF4 (20 mol%)
O
O
O
S
O
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
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38
39
40
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45
46
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49
50
51
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57
58
59
60
R
RSO2K
+
Ph B(OH)2
+
KOH (2 equiv)
THF, 60 °C, 13 h
BnO
BnO
9
OBn
OBn
R = Ph, 8a
R = 4-CF3Ph, 8b
10
11
conversion
yield
of 10
entry
deviation from “standard conditions”
of 8a
Cy3P•HBF4
1
2
3
4
5
6
“standard conditions” with 8a
100%
trace
100%
90%
94%
0%
L1
Fe, Co, Pd instead of Ni(COD)2
Ni(OTf)2 instead of Ni(COD)2, 80 °C
NiCl2•glyme instead of Ni(COD)2, 80 °C
Ni(COD)2 (5 mol%) and Cy3P•HBF4 (10 mol%)
L2 instead of Cy3P•HBF4, 80 °C
93%
81%c
86%
81%
Ph
Ph
90%
83%
N
N
L3 instead of Cy3P•HBF4
7
8
26%
87%
12%
71%
11%
90%
NaOH instead of KOH
KOtBu instead of KOH
L2
9
100%
100%
Ph-Bpin instead of Ph-B(OH)2
10
Ph-BF3K instead of Ph-B(OH)2
11
12
13
90%
100%
100%
0%
iPr
iPr
8b instead of 8a
84%
82%
N
N
tBuOH instead of THFb
PhMe instead of THFb
14
15
16
95%
100%
>95%
92%
90%
85%
iPr
iPr
THF/H2O (3:1) used as solvent
L3
reaction performed at 40 °C for 16 h
a Reactions in this Table were performed at 0.05 mmol scale, using 2 equiv. of 9. Yield and
conversion were determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.
b Reaction was performed at 80 °C using Ni(OTf)2. Isolated yield of a 2 mmol scale reaction.
c
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