Sulfur(IV)-Mediated Unsymmetrical Heterocycle Cross-Couplings

Article abstract of DOI:10.1002/anie.201915425

Despite the tremendous utilities of metal-mediated cross-couplings in modern organic chemistry, coupling reactions involving nitrogenous heteroarenes remain a challenging undertaking – coordination of Lewis basic atoms into metal centers often necessitate elevated temperature, high catalyst loading, etc. Herein, we report a sulfur (IV) mediated cross-coupling amendable for the efficient synthesis of heteroaromatic substrates. Addition of heteroaryl nucleophiles to a simple, readily-accessible alkyl sulfinyl (IV) chloride allows formation of a trigonal bipyramidal sulfurane intermediate. Reductive elimination therefrom provides bis-heteroaryl products in a practical and efficient fashion.

Full text of DOI:10.1002/anie.201915425

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: S(IV)–Mediated Unsymmetrical Heterocycle Cross-Couplings
Authors: Tian Qin, Min Zhou, and Jet Tsien
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915425
Angew. Chem. 10.1002/ange.201915425
Link to VoR: http://dx.doi.org/10.1002/anie.201915425
http://dx.doi.org/10.1002/ange.201915425

10.1002/anie.201915425
Angewandte Chemie International Edition
COMMUNICATION
Sulfur(IV)–Mediated Unsymmetrical Heterocycle Cross-Couplings
Min Zhou, Jet Tsien and Tian Qin *
by Stockman and Procter in recent years. Stockman and co-
workers developed an approach for the enantioselective
synthesis of diarylmethanes via C(sp3)-C(sp2) ligand coupling.18
Procter and co-workers reported a method for the stereoselective
synthesis of substituted (E,Z)-1,3-dienes via ligand coupling of all-
Abstract: Despite the tremendous utilities of metal-mediated cross-
couplings in modern organic chemistry, coupling reactions involving
nitrogenous heteroarenes remain
a challenging undertaking –
coordination of Lewis basic atoms onto metal centers often
necessitate elevated temperature, high catalyst loading, etc. Herein
we report a sulfur (IV) mediated cross-coupling amendable for the
efficient synthesis of heteroaromatic substrates. Addition of heteroaryl
nucleophiles onto a simple, readily-accessible alkyl sulfinyl (IV)
carbon sulfurane intermediates.19 Peng group described
a
benzyne-mediated desulfurized biaryl synthesis.20 Inspired by
these path-pointing efforts (supra), we surmised that the ability of
sulfuranes to undergo ligand coupling could be harnessed to
provide a unique mode of cross-coupling. It is envisaged that the
basic sulfur center is impervious to metal chelating, potentially
making the process amendable for the coupling of basic
heteroarenes.
chloride allows formation of
a trigonal bipyramidal sulfurane
intermediate. Reductive elimination therefrom provides bis-heteroaryl
products in a practical and efficient fashion.
We set out to identify a suitable sulfur(IV) precursor which
could react with heteroaryl nucleophiles to provide a transitory
sulfurane. Alkyl sulfinates were initially employed to avert compe-
The advent and popularization of transition-metal catalyzed
cross-couplings in the later part of the 20th century heralded
revolutionary changes in the synthesis of biaryls.1 The
fundamental steps of oxidative addition and transmetalation give
rise to metal-aryl complexes, wherein the orbital overlap of aryl
groups enable a new modality of C–C bond formation through
reductive elimination in a three-center ligand coupling process.2
Despite their tremendous utilities3, these venerable reactions are
not without limitations. Cross-coupling of substrates comprising
Lewis basic functionalities (e.g., heteroarenes) has proven to be
difficult, as the basic heteroatoms coordinate to the Lewis acidic
metal center, thwarting reductive elimination (e.g., via catalyst
deactivation).4 Further, a number of heteroaryl nucleophiles are
known to have poor stability under cross-coupling conditions – for
example, boronic acids having azine nitrogen at the α-position are
prone to proto-deborylation.5,6 As an example, a high loading of
palladium (> 10%) was required in the Negishi and Stille7
couplings to access 7, a key intermediate in the preparation of
microbicide BMS-599793 (6), in both discovery8 and process
settings.9 In light of the foregoing, development of an alternative
and practical (and preferably transition-metal-free) method for
cross-coupling, particularly one that is amendable for basic
heterocyclic substrates remains desirable. Recently, the McNally
group reported an elegant approach to access 2,2’-diazines
through a phosphorous mediated cross-coupling.10 Here, we
show that stable and easily accessible sulfinyl (IV) chloride can
facilitate the oxidative cross-coupling of heteroaryl building blocks,
providing an assortment of unsymmetrical heterocycles
expediently.
Fully–carbon linked sulfuranes have long been considered
unstable and elusive species.11 C–C ligand coupling was believed
to be a major decomposition pathway. Extensive mechanistic
studies by Trost12 and Oae13 established that that the trigonal
bipyramidal geometries of sulfuranes allowed ligands to be placed
at a dihedral angle of approximately 90°, thereby facilitating ligand
coupling via reductive elimination.14 A series of studies emanating
from the Furukawa and Oae group15, 16 demonstrated that addition
of organometallic nucleophiles onto sulfoxides led to the
formation of ligand coupling products via oxy-sulfurane
intermediates (see Supporting Information for historical summary
of sulfur mediated couplings). However, these hypervalent sulfur
species have found little synthetic utility17 until the seminal works
A
Reductive elimination: transition metals vs sulfur
Ar1(Het)
-X/M’(2)
Ar2(Het)
-X/M’(3)
Ar1
(Het)Ar1
O
(Het)Ar1
(Het)Ar2
alkyl
S
[M]
[S]
90°
S
(L)n
M
M
O
(Het)Ar2
alkyl
LG
5
Ar2
trigonal
bipyramid (4)
w/o
TM
metal
complex
oxidative addition
/transmetalation
1
[this study]
B
Case Study
[Process]: Negishi
10.6 mol% Pd(dppf)Cl2
yield 41-56%
OMe
OMe
M
+
N
N
N
N
N
X
[Discovery]: Stille
10 mol% Pd(PPh3)4/CuI
yield 53%
HN
9
N
HN
8
7
F-C acylation;
amidation
OMe
Develop as a topical
microbicide to prevent HIV
transmission.
N
CN
O
N
DS003,
N
N
BMS-599793 (6)
HN
O
C
. Optimization: Sulfur(IV)-mediated cross-coupling of heteroarenes
(1.0 equiv)
2-PyM
N
10
MgX
-20 °C,
then rt 1 h
MgCl
Li
ZnCl
N
N
Sulfur
(IV)
M
Li
4% 80% N.D.
7% 79% N.D.
-Py
N
(1.5 equiv)
-2
MgCl
-78 °C,
then rt 30 min
11
-Me
ZnCl N.D. N.D. N.D.
6
Me
MgX
12
Me
Entry
Sulfur(IV) Conditions
Yield/%a
iPrSO2Na (13) (1.3) + TFAA
iPrSO2Na (13) (1.3) + TMSCl
1
2
3
4
5
6
trace
trace
iPrSO2Na (13) (1.3) + (COCl)2 (1.5)
iPrSOCl (14) (1.5)
42
77
57
67
MeSOCl (15) (1.5)
EtSOCl (16) (1.5)
tBuSOCl (17) (1.5)
p-MePhSOCl (18) (1.5)
CF3SOCl (19) (1.5)
DABSO (20) (1.5)
7
8
9
53
73
< 5
< 5
10
Mukaiyama reagent PhS(NtBu)Cl (21) (1.5)
(iPrS)2 (22) (0.75) + AcOH (1.5) + SO2Cl2 (2.33)
(CyS)2 (23) (0.75) + AcOH (1.5) + SO2Cl2 (2.33)
11
12
13
32
79(75)b
65
[a] Yield determined by GC-FID with dodecane as an internal standard. [b] Isolated
yield. See Supporting Information for additional details.
dppf
= 1,1′-Bis(diphenylphosphino)ferrocene, TFAA = Trifluoroacetic anhydride,
TMS = Trimethylsilyl, DABSO = 1,4-Diazabicyclo[2.2.2]octane bis(sulfur dioxide)
adduct, Cy = Cyclohexyl.
Figure 1. (A) Synthesis of unsymmetrical heterocyclic biaryls; (B) Case study
of BMS-599793 (6): discovery and process route to access intermediate 7; (C)
Optimization of sulfur (IV) reaction conditions.
[*]
Dr. M. Zhou, J. Tsien, Prof. T. Qin
Department of Biochemistry, The University of Texas Southwestern
Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-
9038, United States
E-mail: Tian.Qin@utsouthwestern.edu
This article is protected by copyright. All rights reserved.

10.1002/anie.201915425
Angewandte Chemie International Edition
COMMUNICATION
24
(1.0 equiv)
-20 °C,
then rt 1 h
Het
• >50 examples
Me
Me
AcOH (1.5 equiv)
SO2Cl2 (2.33 equiv)
Me
Me
O
• 6-member heterocycles
• 5-member heterocycles
• Fused heterocycles
• Lewis basic heterocycles
• Transition metal free
MgX
Het
S
Me
Me
S
S
25
(1.5 equiv)
-40 °C, then rt 30 min
[quantitative]
Het
-78 °C,
then rt 30 min
Cl
14
Het
(22: 0.75 equiv)
[isolated] or [in situ]
MgX
[Cross-Coupling]
$55.8 per mole S
Pyridine & Diazine
A
Me
O
R
Me
N
Cl
R
N
N
N
N
N
N
Me
N
N
Me
N
N
N
O
N
Br
Cl
N
Cl
26: (82%)
27: (69%)
28: (63%)
29: (51%)
R = H;
R = CF3; 30: (65%)a
R = MeO; 31: (86%)a
Me
Me
O
R = 3-Me;
R = 4-Me;
R = 5-Me;
32: (51%)b
12: (75%)a
33: (36%)
34: (45%)a,b
R
N
R
O
TMS
Me
O
N
N
Br
N
N
N
N
N
F
N
N
Br
N
O
N
N
N
CF3
40: (59%)a,b
Br
R = H;
R = 4-Me; 38: (96%)
R = H; Current: 35: (47%)b
(Previous: [Pd] 13%)g
R = Me; 36: (41%)b
37: (94%)
39: (44%)a
41: (57%)b
42: (48%)a,c
O
R
Br
Br
N
N
O
Br
TMS
NR2
N
N
N
N
N
N
CF3
N
N
N
Br
F
N
Cl
N
N
Cl
N
Br
N
Br
NC
43: (39%)a,b
46: (58%)a
47: (62%)a
Br
44: (49%)a
R = 5-F;
R = 3-Br-6-Cl;
NR2 = 1-piperidinyl
49: (40%)b
48: (53%)a,b
45: (67%)
Thiazole, Oxazole & Imidazole
Br
B
Me
Br
Br
N
N
S
N
N
N
N
N
N
S
F
N
S
N
S
Br
Cl
N
Cl
N
Br
N
S
N
S
S
O
Me
Current: 51: (95%)b
(Previous: [Pd
/Cu],65%)g
Current: 55: (70%)b
(Previous: [Negishi],
43%; [Stille], 81%)g
Current: 52: (60%)b
(Previous: [Negishi], 60%)g
54: (35%)b
50: (68%)
53: (67%)
56: (61%)
Fused Rings
C
Br
X
N
R
X
R
Br
C8H17
N
X
N
N
N
Cl
N
N
N
N
N
Cl
N
N
N
N
MOM
Br
Br
Me
R = H; Current: 60: (82%)a,b
(Previous: [Stille] 38%
[MIDA boronate] 74% )g
R = Me; 61: (62%)
57: (96%)
X = CH; Current: 64: (84%)a,b
(Previous: 3 steps, 3.5%)g
X = N; 65: (49%)a,c
X = CH, R = H;
X = CH, R = Me; 58: (92%)
X = N, R = H;
X = S; 66: (89%)b
X = O; 67: (44%)b
62: (56%)a,b
63: (41%)
59: (87%)c
Other Linkages
D
R
N
CO2Et
N
N
N
N
F
N
Me
N
N
N
N
F
S
N
N
N
N
68: Current: (52%)a,b
(Previous:
MeO
N
OMe
MeO
R = H;
R = Me;
N
OMe
Br
F
R
R = H; 71: (62%)f
R = Br; 72: (48%)f
74: (35%)d
[Negishi], 60%)g
69: (43%)
70: (43%)a
73: (56%)e
76: (35%)d
d
75: (31%)
CO2Et
CO2Et
N
Me
Me
N
O
C8H17
O
O
N
N
N
N
O
N
N
N
O
Me
Me
Cl
78: (55%)e
N
79: (39%)b
80: (72%)f
Me
Me
81: (42%)
77: (66%)
Scheme 1. Scope of the sulfur (IV) mediated unsymmetrical heterocyclic couplings. The first Grignard reagent is depicted in green and the second Grignard reagent
in brown. Reaction condition: 14 (1.5 equiv), 24 (0.1 mmol, 1.0 equiv), -20 °C to rt 1 h; 25 (1.5 equiv), -78°C to 30 min. [a] 0.5 mmol scale, 14 was prepared in situ.
[b] Using 25 (3.0 equiv of its precursor). [c] Adding 24 (1.5 equiv of its precursor) at -78 °C then warming to rt slowly and 25 (1.0 equiv) as the limiting reagent. [d]
Using EtSOCl (1.5 equiv). [e] Using 14 (1.3 equiv) and 25 (2.0 equiv). [f] Using tBuSOCl (1.5 equiv) and 25 (2.5 equiv) was added at rt. [g] See SI for literature
routes. The concentration of Grignard reagents were titrated by I2. If it was too dark for titration, the concentration was assumed according to its precursor. For all
the details regarding Grignards preparation, see SI. MIDA = N-methyliminodiacetic acid.
This article is protected by copyright. All rights reserved.

10.1002/anie.201915425
Angewandte Chemie International Edition
COMMUNICATION
-ting coupling reaction. It was reasoned that activation of the
sulfinate oxygen, followed by sequential reactions with 2-pyridyl
Grignard 10 and 11 could afford a coupling product via a sulfurane
intermediate. Sodium isopropyl sulfinate (13) were subjected to a
variety of activating agents21 – nevertheless, only trace amounts
of coupling product were observed in most cases (see Supporting
Information). After rigorous experimentation, it was discovered
that oxalyl chloride could activate sulfinates to form sulfinyl
chlorides, which could then react with 10 and 11 to furnish cross-
coupling product 12 in 42% yield (entry 3). Direct application of
sulfinyl chloride 14 led to an increased yield of 77% with only a
trace amount of first homo-coupling. Application of other alkyl
sulfinyl chlorides (e.g., 15–17, 19) resulted in diminished yields
(entries 5-7, 9), while para-methylphenyl sulfinyl chloride 18
offering the slightly lower yield (entry 8). Furthermore,
isopropylsulfinyl chloride 14 was proved to be a more general
reagent than 18 after the side-by-side comparison reactions for
selected substrates, see Supporting Information for additional
details. This preference for secondary alkyl groups is possibly
attributable to an interplay of the Thorpe–Ingold effect and
sterics.22 Use of the Mukaiyama reagent23 (21) furnished the
product in 32% yield (entry 11). Unsurprisingly, only trace amount
of product was observed when DABSO24 (20) (entry 10) or
isopropylsulfonyl chloride was used. A one-pot procedure was
then developed -- isopropylsulfinyl chloride (14) was prepared in
situ from oxidation of diisopropyl sulfide (22) using Herrmann’s
protocol,25 whereupon treatment with the nucleophiles in the
same pot provided the coupling product in high yield (entry 12).
The in situ formed sulfinyl chloride may be also be stored under
refrigeration (+ 4°C) for future reactions without deterioration for
months. A preliminary survey of nucleophilic heteroaryl reagents
indicated a strong preference for Grignard reagents (Figure 1C,
inset). Notably, neither Pummerer rearrangement byproducts26,27
nor alkyl deprotonation28 was observed under the optimized
reaction conditions.
product was still obtained (such as substrate 76) in the absence
of adjacent Lewis basic atom, albeit in a lower yield.
A distinct advantage of this methodology is the ability to
procure coupling products of Lewis basic heteroarenes building
blocks while obviating complications under transition-metal
mediated reactions due to catalyst poisoning. The compatibility
with halogenated compounds could also allow for modular and
iterative reactions, enabling rapid assembly of highly
functionalized heteroaryl scaffolds. Scheme 2A provides a case-
in-point example emphasizing the applicability and the utility of
the method described herein. Tri-substituted pyridines 85/86 were
expeditiously synthesized using the sulfur(IV) mediated cross-
coupling followed by sequential transition-metal couplings.
Notably, compound 47 en route to 85/86 was synthesized in 5
mmol scale in good yield. The ability to generate organometallic
species (the nucleophiles of the present reaction) under both
A
Gram scale & sequential coupling
Br
Br
“S”
protocol
+
N
NR2
Cl
N
R2N
N
MgX
Cl
N
MgX
83
(1.5 equiv)
NR2 = 4-morpholinyl
82
47, 1.27 g, 72%
(1.0 equiv, 5 mmol)
(0.5 mmol scale, 62%)
Ph
Ph
[Fe]
NR2
N
[Pd]
NR2
N
Alkyl
N
Cl
N
AlkylMgX
PhB(OH)2
Alkyl = iPr;
Alkyl = nHexyl; 86: (81%)
85: (61%)
84: (71%)
B
Deprotonation vs halogen-magnesium exchange
Br
N
I
halogen-
magnesium
exchange
Deproto-
nation
N
I
N
N
N
Cl
N
Cl
N
“S”
protocol
“S”
N
H
protocol
Br
88: (46%)
87
89: (52%)
C
Synthesis of the ALK-5/4 receptor intermediate (91)
Cl
MOM
With the optimal conditions in hand, the substrate scope
was explored. Heterocyclic Grignard reagents, either prepared by
halogen-magnesium exchange29 or deprotonation30, were found
to be compatible with the reaction conditions. Various 2,2’-linked
diazines were generated in high yields accordingly (Scheme 1A).
For example, pyridine, pyrimidine, and pyrazine-based
nucleophiles all reacted smoothly in this cross-coupling reaction.
Cross-couplings of thiazole, oxazole, and imidazole were also
successfully demonstrated (Scheme 1B, 50–56). It is of note that
boronic acids of these 5-membered heteroaromatics are
generally unstable – as such, Stille coupling using toxic stannane
reagents is the go-to method for these coveted heteroarenes.14
Fused heterocycles such as azaindoles, quinolines, isoquinolines,
benzothiazole, and benzoxazole could also be successfully
coupled under the present conditions (Scheme 1C). Due to the
rapid reaction rate and low temperature, a gamut of functionalities
remained unscathed. These include ether (31–33), alkene (41),
alkyne (37–38, 45), acetal (35–36), nitrile (43), ester (76–77), and
amide (49). It is particularly noteworthy that aryl halides which are
generally labile under transition-metal catalyzed cross-couplings
were found to be compatible with the present reaction, allowing
the possibility for further modification. Aside from the 2,2’-linked
products (supra), the reaction manifold is amenable for the
preparation of bis-heteroaryls with other linkages (Scheme 1D).
On the other hand, organometallic nucleophiles derived from
certain heterocycles such as quinoxaline were found to be
unstable under the reaction conditions (see Supporting
Information for complete list). Substrates having a neighboring
nitrogen atom typically provide products in higher yields, akin to
the reports by Oae and Furukawa.16d-e,16i Nevertheless, coupling
XMg
N
N
“S” protocol,
HCl quench
Me
N
N
N
+
BrMg
N
11
Me
H
91
90
Cl
Previous: [Stille]
Current: “S” protocol, 58%
(3.0 equiv of
its precursor)
(1.0 equiv)
D
Synthesis of the BMS-599793 intermediate (7)
OMe
XMg
MOM
N
“S” protocol;
deprotection
N
MgCl
N
N
N
N
+
HN
Previous:
Med Chem: [Stille], 53%
Process: [Negishi], 41-56%
N
92
7
93
(1.0 equiv)
OMe
(2.0 equiv of
its precursor)
Current: “S” protocol, 42%
E
Preliminary Mechanistic inquiry
2-(Me)Py
12:
sulfurane (97)
BrMg
iPr
O
2-Py
N
Me
MgX
64%;
62%;
64%
S
94
O
S
2-Py
N
Het
R2
+
N
2-Py
MgX
iPr
O
-78 °C
to rt
S
98:
iPr
iPr
R3
< 1%;
< 1%;
5%
2-(Me)Py
95
30 min
or
R1
+
R2
R3
2-Py
O
iPr
MgX
N
Me
S
99:
ND;
7%;
2%
S
O
MgBr
2-(Me)Py
SNAr
96
Scheme 2. (A) Gram scale and sequential transition metal-catalyzed coupling.
(B) Diverse coupling products derived from the same heterocycle via
deprotonation and halogen-magnesium exchange. (C) Synthesis of the ALK-5/4
receptor intermediate. (D) Synthesis of the BMS-599793 intermediate. (E)
Preliminary mechanistic inquiry. For experimental details, see Supporting
Information. MOM = Methoxymethyl.
This article is protected by copyright. All rights reserved.

10.1002/anie.201915425
Angewandte Chemie International Edition
COMMUNICATION
11. e) J. Terao, N. Kambe, Acc. Chem. Res. 2008, 41, 1545. f) E. I.
Negishi, Bull. Chem. Soc. Jpn. 2007, 80, 233. g) T. Hiyama, E. Shirakawa,
Top. Curr. Chem. 2002, 219, 61. h) K.Sonogashira, J. Organomet. Chem.
2002, 653, 46. i) J. K. Stille, Angew. Chem. Int. Ed. 1986, 25, 508. j) K.
Fugami, M. Kosugi, Top. Curr. Chem. 2002, 219, 87.
directed metalation and halogen-metal exchange further bolsters
the versatility of this method. For example, 2-pyridyl 3-
iodopyrazine 88 and 2-pyridyl pyrazine 89 were selectively and
divergently obtained from 87 through TMPMgCl·LiCl (TMP =
2,2,6,6-tetramethylpiperidinyl) deprotonation30 or nBuMgCl
exchange29 followed by the present cross-coupling protocol
(Scheme 2B). It is worth noting that the iodo group was found
intact under the deprotonation conditions to access 88.
Compound 91, an advanced intermediate to access anaplastic
lymphoma kinase (ALK) 4/5 inhibitor developed by Novartis, was
obtained from the corresponding pyridyl Grignard 11 and
azaindole partner 90 in a single step after acidic quench -- a Stille
coupling31 was previously required to access the same
compound.32 As noted in Figure 1B, en route to BMS-599793 (6)
under process setting, a Negishi coupling utilizing a high load of
palladium catalyst (10.6 mol%) was necessary to access
intermediate 7.8 With the sulfur-mediated cross-coupling, this
critical compound was prepared from pyrazine Grignard 92 and
6-azaindole Grignard 93 in 42% yield (Scheme 2D) in the absence
of transition metal catalysts or ligands. The yield stayed consistent
when the sequence of Grignard addition was reversed (see the
Supporting Information).
[4]
[5]
a) L.-C. Campeau, K. Fagnou, Chem. Soc. Rev. 2007, 36, 1058. b) E.
Tyrrell, P. Brookes, Synthesis 2003, 469. c) M. G. Banwell, T. E.
Goodwin, S. Ng, J. A. Smith, D. J. Wong, Eur. J. Org. Chem. 2006, 3043.
a) P. A. Cox, M. Reid, A. G. Leach, A. D. Campbell, E. J. King, G. C.
Lloyd-Jones, J. Am. Chem. Soc. 2017, 139, 13156. b) P. A. Cox, A. G.
Leach, A. D. Campbell, G. C. Lloyd-Jones, J. Am. Chem. Soc. 2016, 138,
9145.
[6]
For reviews, see: a) S. Darse, J.-P. Genet, Chem. Rev. 2008, 108, 288.
b) G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275. For an
example using a-azineboronic ester, see: c) J. Z. Deng, D. V. Paone, A.
T. Ginnetti, H. Kurihara, S. D. Dreher, S. A. Weissman, S. R. Stauffer, C.
S. Burgey, Org. Lett. 2009, 11, 345. Selected masked boronic acid
coupling methods, see: d) D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am.
Chem. Soc. 2009, 131, 6961. e) K. L. Billingsley, S. L. Buchwald, Angew.
Chem. Int. Ed. 2008, 47, 4695. Other stable non-boron electrophiles,
see: f) T. Markovic, P. R. D. Murray, B. N. Rocke, A. Shavnya, D. C.
Blakemore, M. C. Willis, J. Am. Chem. Soc. 2018, 140, 15916. g) L.-C.
Campeau, S. Rousseaux, K. Fagnou, J. Am. Chem. Soc. 2005, 127,
18020.
To probe the mechanism of this transformation, a series of
the sulfoxides (94–96) were prepared and treated with Grignards
(Scheme 2E). The hetero-coupling product 12 was found to be
the dominant species in all cases, possibly owing to favorable
orbital overlap within the sulfurane intermediate (97).16d-e,16i
However, the formation of byproducts 98 and 99 may suggest a
partial SNAr mechanism33 leading to C(sp2)–C(sp3) coupling
product.
[7]
[8]
T. Wang, J. F. Kadow, N. A. Meanwell, K.-S. Yeung, Z. Zhang, Z, Yin, Z.
Qui, D. H. Deon, C. A. James, E. H. Ruediger, C. Bachband,
US7915283B2, 2011.
a) S. M. Schader, S. P. Colby-Germinario, P. K. Quashie, M. Oliverira,
R.-I. Ibanescu, D. Moisi, T. Mespléde, M. A. Waiberg, Antimicrob. Agents
Chemother. 2012, 56, 4527. b) ref 7. Alternative reported synthesis to
compound 6 was shown as below:
In summary, capitalizing on the unique reactivity of
sulfuranes,
a sulfinyl (IV) chloride–mediated cross-coupling
between heteroarene Grignard reagents has been developed.
Complementary to the venerable Kumada, Negishi, or Stille
couplings, this reaction is uniquely suited for the preparation of
Lewis basic substrates which are difficult to couple under classical
conditions. A large number of functional groups are tolerated
under the reaction condition, allowing modular and rapid access
to molecular complexity.
SnBu3
N
N
N
30 mol% Pd(PPh3)4
Cl
OMe
OMe
N
+
N
150 °C, 5 h
13%
N
HN
HN
R
6
R
CN
O
R =
N
O
Acknowledgements
Financial support was provided by the Robert A. Welch
Foundation (Grant I-2010-20190330) and the Eugene McDermott
Scholar Endowed Scholarship. We thank Prof. Phil S. Baran, Drs.
Ming Yan, and Jacob T. Edwards for helpful discussions and
assistance in manuscript preparation. We thank Professors Chuo
Chen, Jef De Brabander, Joseph Ready, Uttam Tamber, Myles
Smith, and J. R. Falck for insightful discussions and the generous
use of their reagents and equipment.
[9]
S. Pikul, H. Cheng, A. Cheng, C. D. Huang, A. Ke, L. H. Kuo, A.
Thompson, S. Wilder, Org. Process Res. Dev. 2013, 17, 907.
[10] a) B. T. Boyle, M. C. Hilton, A. McNally, J. Am. Chem. Soc. 2019, 141,
15441. b) M. C. Hilton, X. Zhang, B. T. Boyle, J. V. Alegre-Requena, R.
S. Paton, A. McNally, Science 2018, 362, 799. c) J. L.; Koniarczyk, J. W.
Greenwood, J. V. Alegre-Requena, R. S. Paton, A. McNally, Angew.
Chem. Int. Ed. 2019, 58, 14882.
[11] a) W. A. Sheppard, J. Am. Chem. Soc. 1971, 93, 5597.
[12] a) R. W. LaRochelle, B. M. Trost, J. Am. Chem. Soc. 1971, 93, 6077. b)
B. Trost, R. LaRochelle, R. Atkins, J. Am. Chem. Soc. 1969, 91, 2175. .
c) B. M. Trost, H. C. Arndt, J. Am. Chem. Soc. 1973, 95, 5288.
Keywords: heterocycle • cross-coupling • sulfurane
Reference:
[13] Y. H. Khim, S. Oae, Bull. Chem. Soc. Jpn. 1969, 42, 1968.
[1]
a) Trends in Cross-Coupling: Theory and Applications; (Eds: T. Colacot)
The Royal Society of Chemistry: 2015. b) Science of Synthesis: Cross
Coupling and Heck-Type Reactions; Workbenh Edition (Eds: G.
Molander, J. P. Wolfe, M. Larhed), Thieme, 2013.
[14] J. Moc, A. Dorigo, K. Morokuma, Chem. Phys. Lett. 1993, 204, 65.
[15] SOCl2 mediated homocoupling: S. Oae, Y. Inubushi, M. Yoshihara,
Phosphorus Sulfur Silicon Relat. Elem. 1995, 103. 101.
[2]
[3]
J. F. Hartwig, Organotransition metal chemistry-from bonding to catalyst.
University Science Books: 2010. Chapter 8.
[16] For selected reviews, see: a) S. Oae, N. Furukawa, Adv. Heterocycl.
Chem. 1990, 48, 1. b) S. Oae, Y. Uchida, Acc. Chem. Res. 1991, 24,
202. c) S. Oae, Pure Appl. Chem. 1996, 68, 805. For benzyl pyridine
synthesis, see: d) S. Oae, T. Kawai, N. Furukawa, Tetrahedron Lett.
1984, 25, 69. e) S. Oae, T. Kawai, N. Furukawa, F. Iwasaki, J. Chem.
Soc., Perkin Trans 2, 1987, 405. f) T. Kawai, Y. Kodera, N. Furukawa, S.
For reviews on metal-catalyst cross-couplings, see: a) J. Hassan, M.
Sévignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359.
b) R. F. Heck, Acc. Chem. Res. 1979, 12, 146. c) N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457. d) N. Miyaura, Top. Curr. Chem. 2002, 219,
This article is protected by copyright. All rights reserved.

10.1002/anie.201915425
Angewandte Chemie International Edition
COMMUNICATION
Oae, M. Ishida, S. Wakabayashi, Phosphorus Sulfur Relat. Elem.1987,
34, 139. g) S. Wakabayashi, M. Ishida, T. Takeda, S. Oae, Tetrahedron
Lett. 1988, 29, 4441. For phenyl pyridine synthesis, see: h) S. Oae, T.
Kawai, N. Furukawa, Phosphorus Sulfur Relat. Elem.1987, 34, 123. For
bipyridine synthesis, see: i) N. Furukawa, T. Shibutani, H. Fujihara,
Tetrahedron Lett. 1987, 28, 5845. For allylpyridine and styrylpyridine,
see: j) S. Oae, Takeda, T.; S. Wakabayashi, Tetrahedron Lett. 1988, 29,
4445. For pyridine homocoupling, see: k) S. Oae, T. Kawai, N. Furukawa,
Tetrahedron Lett. 1984, 25, 2549. For ligand exchange through sulfurane
intermediate, see: l) N. Furukawa, T. Shibutani, K. Matsumura, H.
Fujihara, S. Oae, Tetrahedron Lett. 1986, 27, 3899.
[22] a) R. M. Beesley, C. K. Ingold, J. F. Thorpe, J. Chem. Soc., Trans. 1915,
107, 1080. b) J. O’Neill, T. Riesebeck, J. Cornella, Angew. Chem. Int.
Ed. 2018, 57, 9103.
[23] For selected reviews, see: a) T. Mukaiyama, Angew. Chem. Int. Ed.
2004, 43, 5590. b) J. Matsuo, Synth. Org. Chem. Jpn. 2004, 62, 574.
[24] H. Woolven, C. Gonzalez-Rodríguez, I. Marco, A. L. Thompson, M. C.
Willis, Org. Lett. 2011, 13, 4876.
[25] a) J.-H. Youn, R. Herrmann, Tetrahedron Lett. 1986, 27, 1493. b) F. Izzo,
M. Schäfer, R. Stockman, U. Lücking, Chem. Eur. J. 2017, 23, 15189.
[26] For selected reviews, see: a) L. H. S. Smith, S. C. Coote, H. F. Sneddon,
D. J. Procter, Angew. Chem. Int. Ed. 2010, 49, 5832. b) S. K. Bur, A.
Padwa, Chem. Rev. 2004, 104, 240. c) K. Colas, A. Mendoza, Synlett
2018, 29, 1329.
[17] For a review on the application of sulfur chemistry, see: D. Kaiser, I.
Klose, R. Oost, J. Neuhaus, N. Maulide, Chem. Rev. 2019, 119, 8701.
For selected examples of sulfurane ligand coupling reactions in
synthesis, see: b) R. W. Baker, D. C. R. Hockless, G. R. Pocock, M. V.
Sargent, B. W. Skelton, A. N. Sobolev, E. Twiss (née Stanojevic), A. H.
White, J. Chem. Soc. Perkin Trans. 1 1995, 2615. c) R. W. Baker, J. N.
H. Reek, B. J. Wallace, Tetrahedron Lett. 1998, 39, 6573. d) R. W. Baker,
S. O. Rea, M. V. Sargent, E. M. C. Schenkelaars, T. S. Tjahjandarie, A.
Totaro, Tetrahedron 2005, 61, 3733. f) J. Melzig, C. Rauhut, N. Naredi-
Rainer, P. Knochel, Chem. Eur. J. 2011, 17, 5362.
[27] For selected example, see: K. Colas, R. Martín-Montero, A. Mendoza,
Angew. Chem. Int. Ed. 2017, 56, 16042.
[28] Y. Gaoni, J. Org. Chem. 1982, 47, 2565.
[29] A. Krasovskiy, P. Knochel, Angew. Chem. Int. Ed. 2004, 43, 3333.
[30] A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. Int. Ed. 2006,
45, 2958.
[18] W. M. Dean, M. Šiaučiulis, T. Storr, W. Lewis, R. A. Stockman, Angew.
Chem. Int. Ed. 2016, 55, 10013.
[31] C. Cordovilla, C. Bartolome, J. M. Martínez-Ilarduya, P. Espinet, ACS
Catal. 2015, 5, 3040.
[19] M. Šiaučiulis, A. P. Pulis, D. J. Procter, Angew. Chem. Int. Ed. 2019, 58,
8779.
[32] a) L. Catherine, R. Alexander, N. Johannes, WO2009/087225 A2. b) The
isolate yield was not reported for this Stille coupling.
[20] D.-L. Chen, Y. Sun, M. Chen, X. Li, L. Zhang, X. Huang, Y. Bai, F. Luo,
B. Peng, Org. Lett. 2019, 21, 3986.
[33] J. Wei, H. Liang, C. Ni, R. Sheng, J. Hu, Org. Lett. 2019, 21, 937.
[21] D. C. Lenstra, V. Vedovato, E. F. Flegeau, J. Maydom, M. C. Willis, Org.
Lett. 2016, 18, 2086.
This article is protected by copyright. All rights reserved.

10.1002/anie.201915425
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Heterocycle Cross-Couplings via Sulfur. Addition of heteroaryl nucleophiles
onto a simple, readily-accessible alkyl sulfinyl (IV) chloride allows formation of a
trigonal bipyramidal sulfurane intermediate. Reductive elimination therefrom
provides bis-heteroaryl products in a practical and efficient fashion.
Min Zhou, Jet Tsien, and Tian Qin*
Sulfur(IV)–Mediated Unsymmetrical
Heterocycle Cross-Couplings
This article is protected by copyright. All rights reserved.