Hydrogen bonding network assisted regio- and stereo- controlled hydrohalogenations of sulfonyl alkynes

Article abstract of DOI:10.1016/j.tetlet.2018.09.051

We have developed an efficient synthesis of β-halo Z-sulfonyl alkenes via hydrohalogenations of readily available sulfonyl alkynes. The high hydrogen bonding acidity of linear acetic acid network or aggregate may play a vital role in activation of sulfony

Full text of DOI:10.1016/j.tetlet.2018.09.051

Accepted Manuscript
Hydrogen Bonding Network Assisted Regio- and Stereo- Controlled Hydroha-
logenations of Sulfonyl Alkynes
Bocheng Chen, Xiaowen Xia, Xiaojun Zeng, Bo Xu
PII:
S0040-4039(18)31135-3
https://doi.org/10.1016/j.tetlet.2018.09.051
TETL 50290
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 August 2018
14 September 2018
18 September 2018
Please cite this article as: Chen, B., Xia, X., Zeng, X., Xu, B., Hydrogen Bonding Network Assisted Regio- and
Stereo- Controlled Hydrohalogenations of Sulfonyl Alkynes, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.09.051
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Hydrogen Bonding Network Assisted Regio- and
Stereo- Controlled Hydrohalogenations of Sulfonyl
Alkynes
Leave this area blank for abstract info.
Bocheng Chen, Xiaowen Xia, Xiaojun Zeng* and Bo Xu*
X
O O
O
O
LiX, AcOH
R2
S
S
R1
R2
R1
100 °C, 12 h
2
X = Cl, Br, I
H
1
Z-product
39 examples, up to 98%
Exclusive Z-selectvitiy
Works for Cl, Br, I
Works for both aromatic and aliphatic substrates
Tetrahedron Letters
journal homepage: www.elsevier.com
Hydrogen Bonding Network Assisted Regio- and Stereo- Controlled
Hydrohalogenations of Sulfonyl Alkynes
Bocheng Chen, Xiaowen Xia, Xiaojun Zeng* and Bo Xu*
Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua
University, Shanghai 201620, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We have developed an efficient synthesis of -halo Z-sulfonyl alkenes via
hydrohalogenations of readily available sulfonyl alkynes. The high hydrogen bonding
acidity of linear acetic acid network or aggregate may play a vital role in activation of
sulfonyl alkyne substrates. Our condition offers high stereoselectivity, good chemical
yields, and high functional group tolerance.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Hydrogen Bonding Network
Hydrohalogenations
Sulfonyl Alkynes
-halo Z-sulfonyl alkenes
Alkenyl halides are important targets in medicine, agrochemicals and advanced materials.1 Moreover, alkenyl halides are also
important synthetic building blocks which have been used extensively in cross-coupling chemistry2 such as Suzuki couplings3,
Sonogashira couplings,4 Stille couplings5, and Buchwald-Hartwig aminations.6 More specifically, halogenated sulfonyl alkenes are
especially versatile synthons for synthesis of highly functionalized alkenes due to presence of two synthetic handles.7
As a result, the efficient synthesis of halogenated sulfonyl alkenes has attracted much attention. For example, iron catalyzed
reactions of sulfonyl chlorides with alkynes has been reported for the preparation of chlorinated sulfonyl alkenes (Scheme 1a).7a
Alternatively, halogenated sulfonyl alkenes could be prepared by iron7b (Scheme 1b) catalyzed or copper8 (Scheme 1c) catalyzed
halosulfonylation of terminal alkynes using sulfonylhydrazides. Other common methods are transition metal (such as Co, Ni, Cu)
catalyzed9 or uncatalyzed10 sulfonylation of alkynes using sodium sulfinates and various halide sources (Scheme 1d). -Halo sulfonyl
alkenes could also be prepared from a multicomponent reaction with insertion of sulfur dioxide (Scheme 1e).11 Halogenated sulfonyl
alkenes also could be prepared indirectly from oxidation of haloalkenyl sulfides.12 Despite these important progresses, there are still
challenges for synthesis of halogenated sulfonyl alkenes: 1) most of the above methods work only for aromatic substrates; 2) complex
conditions were used; 3) E-isomers were obtained in most cases.10f-i

previous methods
H
Ar2
O
Fe(acac)2/P-Ligand Cl
Ar2SO2Cl
Ar1
S
(a)
(b)
+
toluene, 110 o
C
1 O
Ar
E-product
H
Ar2
O
X
FeCl3 or FeBr3
TBAP (2 equiv)
S
1 O
Ar
CH3CN, 80 o
C
X = Br, Cl
E-product
Ar1
Ar2SO NHNH
+
2
2
H
Ar2
O
Ar1
CuX, BPO
DMSO, rt
S
(c)
(d)
O
X
X = I, Br, Cl
Z-product
H
Ar2
O
X
NXS or X2
MX
Ar2SO2Na
S
Ar1
+
or
1 O
Ar
[Cu], [Co], [Ni]
E-product
oxidant (CAN or, O2)
H
Ar2
O
DABCO.(SO2)2
CuCl, KI
I
Ar2-N2BF4
Ar1
S
+
(e)
1 O
Ar
E-product
O
O
LiX (3 equiv), THF
X
O
O
S
R
S
R1
R
CH3COOH or CF3COOH
(1.5 equiv)
F3C
(f)
H
Z-product
this work
X = I, Br
X
O
O
O
O
LiX
R2
S
S
R1
R2
R1
(g)
hydrogen bond
donor solvent
(e.g. AcOH)
H
X = Cl, Br, I
2
1
Z-product
Exclusive Z-selectvitiy
Works for Cl, Br, I
Works for both aromatic and aliphatic substrates
Scheme 1. Synthesis of halogenated sulfonyl alkenes.
Recently, we have developed various hydrogen-bonding network or cluster13 assisted transformations such as
(radio)hydrofluorination of ynamides,14 hydrofluorination of alkenes,15 addition of sulfonic acids to haloalkynes,16 metal and halogen-
free Friedel–Crafts acylations17 and chloride-tolerant gold-catalyzed hydrochlorination of alkynes.18 Along this line, and also inspired
by literature reports hydrohalogenations of trifluoromethylsulfonyl alkynes (Scheme 1f),19 allkynylnitriles20 and alkynyl acid
derivatives21 using MX/AcOH (X = Cl, Br, I)19-20, 22 system, we are glad to report a widely applicable hydrogen bond network assisted
regio- and stereo- controlled hydrohalogenations of readily available sulfonyl alkynes (Scheme 1g).

R
O
R
a)
H
O
H
O
H
R
n
cyclic H-bond
aggregates
R
O
H
O
H
better H-bong donor
H
R
O
H
O
R
R
n
linear H-bond aggregates
O
b)
H
O
O
H
O
cyclic H-bond dimer
in gas phase or in dilute solution
H
O
O
H
O
H
O
O
H
O
O
O
n
linear H-bond aggregates
predominant in pure acetic acid
c)
average H-bond
dissociation energy
linear
aggregates
LUMO
1AcOH
2.45 ev
-
2AcOH
3AcOH
4AcOH
1.52 ev
1.11 ev
0.90 ev
12.8 Kcal/mol
13.6 Kcal/mol
14.3 Kcal/mol
cyclic dimer
2AcOH
geometry of linear (AcOH)4
2.19 ev
16.8 Kcal/mol
R1
d)
R2
S
O
O
1
H
O
H
O
O
O
n
hydrogen bonding cluster
enhanced Brønsted acid
LUMO
1
1.64 ev
1.1AcOH 1.29 ev
1.2AcOH 1.23 ev
1.3AcOH 1.22 ev
1.3AcOH
LUMO and geometryof
Scheme 2. Effect of H-bond aggregates. LUMOs and bonding energies were calculated at B97X-D/6-31** level of theory.
Recently Hunter and coworkers23 have reported that formation of a hydrogen bond (H-bond) between two alcohol molecules leads to
polarisation of the hydroxy groups, resulting in an increase in binding affinity for subsequent interactions with the unbound donor and
acceptor sites. As a result, a hydrogen bonding aggregation or network will form preferentially. And self-association of alcohols leads to
formation of cyclic aggregates and linear polymeric chains. The linear aggregate is a much better H-bond donor than monomer and
cyclic H-bong aggregates23 (Scheme 2a).
We envisioned that hydrogen bonding donor solvents such as acetic acid may have similar behavior as alcohols. In general, cyclic
dimer of acetic acid occurs in gas phase and in dilute solutions of non-hydrogen-bonding solvents (Scheme 2b).24 And the cyclic dimers
should be relatively weak H-bond donor (Scheme 2b). Jorgensen and coworkers have reported that in liquid phase of pure acetic acid,
linear polymeric chains of AcOH are dominant species with only 7% of the AcOH molecular are in cyclic dimers, and there is a
negligible occurrence of non-hydrogen-bonded AcOH molecular.24 The linear acetic acid aggregates should have high H-bond acidity
according to Scheme 2a. Diluted acetic acid is a weak monoprotic acid with pKa value of 4.76 in water. Due to weak Brønsted acidity,
acetic acid may not be able to activate weakly basic electrophiles via proton transfer (specific acid catalysis). But we envisioned due to
dominate presence of linear acetic acid aggregates, pure acetic acid solvent may act as powerful H-bond activator in many
transformations.
Our DFT calculations (Scheme 2c) on AcOH are consistent with Hunter and coworkers’ report on alcohols.23 LUMO of the linear H-
bond aggregates - (AcOH)n decreases and average H-bond dissociation energy increase when the number of molecular in the aggregate
(n) increase. The lower LUMO of linear AcOH aggregates indicates high H-bond acidity and it could activate the electrophiles in
chemical reactions. Indeed, (AcOH)n could activate the sulfonyl alkyne 1 via hydrogen bonding: with increased number of acetic acid in
(AcOH)n, LUMO of 1.(AcOH)n decreases (Scheme 2d). This may lead to increased reactivity towards nucleophilic attack. Hydrogen
bonding network or cluster has advantages of being environmentally-friendly (vs. transition metal) and good functional group tolerance
(vs. strong acids such as TfOH).

Table 1. Optimization of the hydrochlorination of bromoalkyne 1a.a
Cl
O
O
O
MCl, solvent
12 h
O
S
S
Ph
Ph
H
1a
2a
anti-addition
entry solvent
MX
yieldb
0
a Conditions: 1a (0.2 mmol), MX (0.8 mmol, 4 equiv), solvent (1.5 mL), 100 °C, 12 h.
b Yields detected by GC-MS. c Unidentified products detected.
1
DMSO
DMF
LiCl
We used hydrochlorination of sulfonyl alkyne25 1a as our model reaction
(Table 1). Using LiCl as chlorination reagent, there was no reaction when
aprotic solvents such as DMSO and DMF were used (Table 1, entries 1-2).
There was also no reaction when protic solvents such as ethanol and HFIP26
(hexafluoro-2-propanol) were used (Table 1, entries 3-4). Although strong
hydrogen-bond donating solvents such as HFIP could form hydrogen bond
networks or clusters which have been shown to provide significant increases
in the rate of many reactions,16, 27 its H-bond donor ability may be still not
enough to activate electron deficient sulfonyl alkynes. According to our
calculations (Scheme 2), we envisioned that in pure liquid phase, acetic acid
may function as a very strong hydrogen bond donor in hydrochlorination. To
our delight, the hydrochlorination was very efficient using acetic acid as
solvent (Table 1, entry 5). However, the reaction gave a complex mixture
when trifluoroacetic acid was used as solvent. We also evaluated other
2
LiCl
0
3
EtOH
HFIP
LiCl
0
4
5
LiCl
o
CH3COOH
CF3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
LiCl
LiCl
90%
44c
6
7
NaCl
NH4Cl
KCl
56%
83%
81%
88%
trace
trace
8
9
10
11
12
MgCl2
LiCl
DMSO/CH3COOH (10 equiv)
EtOH/CH3COOH (10 equiv)
LiCl
chloride sources such as NaCl, NH4Cl, KCl and MgCl2 (Table 1, entries 7-10), LiCl still gave the best result. Also we found the reaction
did not work when only 10 equiv of AcOH was used ((Table 1, entries 11-12).
With the optimized conditions in hand, we first evaluated the scope of hydrogen bonding assisted hydrochlorinations of sulfonyl
alkynes (Table 2). We evaluated the effect of different [R1, R2] combinations in the sulfonyl alkynes 1 on the efficiency of reactions
(Table 2). Diverse [R1, R2] combinations, such as [R1 = aryl, R2 = alkyl] (Table 2, 2a-2i), [R1 = aryl, R2 = aryl] (Table 2, 2l), [R1 = alkyl,
R2 = alkyl] (Table 3, 2k), [R1 = aryl, R2 = alkenyl] (Table 2, 2j) all gave good yields of hydrochlorination product 2. The substitution
pattern and electronic properties of aromatic substituents (electron-deficient or rich) on R1 played a small role; good yields were
obtained regardless (Table 2, 2a-2i, 2l). Diverse functional groups such as halides (Table 2, 2b, 2g), nitrile (Table 2, 2d), ester (Table 2,
2f) and nitrile group (Table 2, 2d) were well tolerated.
Table 2. Substrate scope for hydrochlorination of sulfonyl alkynes 1.
Cl
O
R1
O
O
4eq LiCl, AcOH
100°C overnight
O
R1
S
R2
S
R2
H
2
1
Cl
Cl
O
Cl
O
O
O
O
O
S
S
S
Ph
Ph
H
H
H
Br
2b
, 85%,
2a
, 79%
2c
, 89%
Cl
Cl
O
O
Cl
O
O
H
O
O
S
R3
S
S
Ph
OAc
Ph
Ph
Cl
H
H
, 96%, R3 = CN
, 92%, R3 = Ph
2d
2e
2f
, 86%
2g
, 88%
Cl
O
Cl
O
Cl
O
O
O
O
S
S
S
OBz
Ph
H
H
H
2h
2j, 83%
, 98%
2i
, 95%
Cl
Cl
O
O
Cl
O
O
O
O
S
S
S
OMe
Ph
Ph
H
H
H
2k
, 82%
2l
, 86%
2l
, 94%
a Conditions: 1 (0.2 mmol), LiCl (0.8 mmol, 4 equiv), AcOH (1.5 mL), 100 °C, 12 h.
We next investigated the scope of the hydrogen bonding assisted hydrobrominations of sulfonyl alkynes 1 (Table 3). Very similar to
hydrochlorination of sulfonyl alkynes, diverse [R1, R2] combinations, such as [R1 = aryl, R2 = alkyl] (Table 3, 3b, 3c, 3d), [R1 = aryl, R2
= aryl] (Table 2, 3m, 3j), [R1 = alkyl, R2 = alkyl] (Table 3, 3a), [R1 = aryl, R2 = alkenyl] (Table 3, 3i) all gave good yields of
hydrobromination product 3. Our conditions exhibited high compatibility with acid sensitive acetyl group (Table 3, 3l), nitrile group
(Table 3, 3f) and cyclopropyl group (Table 3, 3e).
Table 3. Substrate scope for hydrobromination of sulfonyl alkynes 1.

Br
O
O
R1
O
O
4eq LiBr, AcOH
S
R2
S
R2
R1
100 °C, overnight
H
3
1
Br
Br
O
Br
O
O
O
O
O
S
MeO
S
S
H
H
H
Br
3b
, 98%
3c
, 85%
Br
3a
, 85%
Br
O
O
O
O
Br
O
R3
O
S
S
Ph
Ph
S
H
H
H
, 90%, R3 = CN
, 92%, R3 = Ph
3f
3e
, 83%
3d
, 86%,
3g
Br
O
O
Br
O
Br
O
O
O
S
R4
S
S
Ph
Ph
H
H
H
, 81%, R4 = Ph
3k
3j
, 90%, R4 = Me
3i
, 76%
3h
, 90%
Br
Br
O
O
O
O
S
S
OMe
OBz
Ph
H
H
3m
3l
, 82%
, 92%
a Conditions: 1 (0.2 mmol), LiBr (0.8 mmol, 4 equiv), AcOH (1.5 mL), 100 °C, 12 h.
Table 4. Substrate scope for hydroiodination of sulfonyl alkynes 1.
I
O
R1
O
O
4eq LiI, AcOH
O
S
R2
S
R2
R1
100 °C overnight
H
4
1
I
O
I
O
I
O
O
O
O
MeO
S
S
S
Ph
H
H
H
Br
4c
, 87%
4b
, 82%
4a
, 92%
I
I
I
O
O
O
S
O
O
O
S
S
Ph
Ph
H
H
H
4f
, 93%
O
4e
, 81%
4d
, 88%
I
I
O
O
O
I
O
O
S
S
S
OMe
R3
Ph
Ph
H
H
H
4m
, 85%, R3 = Ph
, 88%, R3 = CN
4l
, 82%
4g
4h
, 89%
I
O
O
I
O
O
S
S
R3
Ph
H
H
, 91%, R3 = Ph
4k
4j
4i
, 78%
, 92%, R3 = Me
4k
a Conditions: 1 (0.2 mmol), LiI (0.8 mmol, 4 equiv), AcOH (1.5 mL), 100 °C, 12 h.
We next investigated the scope of the hydrogen bonding assisted hydroiodination of sulfonyl alkynes 1 (Table 4). We also evaluated
the effect of different [R1, R2] combinations in the sulfonyl alkynes 1 (Table 3). Very similar to hydrochlorinations and
hydrobrominations of sulfonyl alkynes, diverse [R1, R2] combinations all gave good yields of hydroiodination product 4 and our
conditions exhibited high functional group compatibility. And the structure assignment and stereochemistry of our obtained product was
confirmed by the single-crystal X-ray diffraction of a typical product (see the ORTEP drawing of 4k28 in Table 4).

X
O
S
O
O
O
MX
S
(eq-1)
Ph
AcOH
Ph
2a
H
1a
conversion
LiCl (1 equiv), 80 oC, 1 h
LiCl (2 equiv), 80 oC, 1 h
LiCl (4 equiv), 80 oC, 1 h
8%
12%
15%
LiCl (4 equiv), rt, 4 h
LiBr (4 equiv), rt, 4 h
LiI (4 equiv), rt, 4 h
5%
40%
80%
To gain some insight of the mechanism, we conducted simple kinetic studies (eq-1). The rate of the reactions increased with the
concentration of nucleophiles (LiCl), the rate also increased when a more nucleophilic MX was used (rate: LiI>LiBr>LiCl).
)
n
OAc
H
(
n
)
OAc
H
(
O
O
O
O
O
S
O
Cl
O
O
1
S
S
(HOAc)n
R1
R1
2
R2
S
R1
R1
R2
R2
R2
H
1
Cl-
AdE3 mechanism
-regioselectivity
anti-steoroselectivity
NBO charge density of
1.
(HOAc)3:
C1: -0.408
C2: 0.182
Scheme 3. Proposed mechanism.
The proposed mechanism is shown in Scheme 3. Because the sulfonyl alkynes 1 are relatively electron deficient, the direct
protonation of 1 via proton transfer is difficult (specific acid catalysis), so we propose an AdE3 mechanism29 (Scheme 3). This
mechanism is consistent with the kinetic data that the rate of reaction increases with concentration of nucleophile (eq-1).30 The
exclusive formation of the E-isomer (anti-addition) was also consistent with the AdE3 mechanism. The regio-selectivity found can be
rationalized by the fact that the NBO charge density of C1 is significantly higher than C2 (in 1.(HOAc)3) due to electron withdrawing of
a sulfonyl group (Scheme 3). The exclusive anti-addition is in contrast with formation of Z/E mixture in the literature reports of
hydrohalogenations of allkynylnitriles20 and alkynyl acids or esters using MX/AcOH system.21a, b
In summary, we have developed a widely applicable, highly efficient synthesis of Z- halo sulfonyl alkenes via hydrohalogenations of
sulfonyl alkynes. Other applications of hydrogen bonding network assisted catalytic systems are currently being investigated in our
laboratories.
Acknowledgments
We are grateful to the National Science Foundation of China for financial support (NSFC-21472018 and NSFC-21672035).
References and notes
1. (a) Nunnery, J. K.; Engene, N.; Byrum, T.; Cao, Z.; Jabba, S. V.; Pereira, A. R.; Matainaho, T.; Murray, T. F.; Gerwick, W. H. J. Org. Chem. 2012, 77, 4198-
4208; (b) Akiyama, T.; Takada, K.; Oikawa, T.; Matsuura, N.; Ise, Y.; Okada, S.; Matsunaga, S. Tetrahedron 2013, 69, 6560-6564; (c) Chung, W.-j.; Vanderwal,
C. D. Angew. Chem. Int. Ed. 2016, 55, 4396-4434; (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442-4489; (e) Jana, R.;
Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417-1492; (f) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945-2964.
2. (a) Wu, W.; Jiang, H. Acc. Chem. Res. 2014, 47, 2483-2504; (b) JohanssonꢀSeechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int.
Ed. 2012, 51, 5062-5085.
3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
4. (a) Negishi, E.-i.; Anastasia, L. Chem. Rev. 2003, 103, 1979-2018; (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467-4470.
5. (a) Espinet, P.; Echavarren, A. M. Angew. Chem. Int. Ed. 2004, 43, 4704-4734; (b) Stille, J. K. Angew. Chem. Int. Ed. 1986, 25, 508-524.
6. (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534-1544; (b) Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564-12649.
7. (a) Xiaoming, Z.; Laurean, I.; Nakamura, E. Org. Lett. 2012, 14, 954-956; (b) Li, X.; Shi, X.; Fang, M.; Xu, X. J. Org. Chem. 2013, 78, 9499-9504.
8. Wan, J.-P.; Hu, D.; Bai, F.; Wei, L.; Liu, Y. RSC Advances 2016, 6, 73132-73135.
9. (a) Taniguchi, N. Tetrahedron 2018, 74, 1454-1460; (b) Taniguchi, N. J. Org. Chem. 2015, 80, 7797-7802; (c) Taniguchi, N. Tetrahedron 2014, 70, 1984-
1990; (d) Taniguchi, N. Synlett 2012, 23, 1245-1249; (e) Taniguchi, N. Synlett 2011, 1308-1312; (f) Taniguchi, N. Tetrahedron 2009, 65, 2782-2790.
10. (a) Huang, X.; Duan, D.; Zheng, W. J. Org. Chem. 2003, 68, 1958-1963; (b) Hou, Y.; Zhu, L.; Hu, H.; Chen, S.; Li, Z.; Liu, Y.; Gong, P. New J. Chem. 2018,
42, 8752-8755; (c) Amiel, Y. J. Org. Chem. 1971, 36, 3697-702; (d) Truce, W. E.; Wolf, G. C. J. Org. Chem. 1971, 36, 1727-32; (e) Ravi, K.; Vikas, D.; Maddi,
S. R. Adv. Synth. Catal. 2017, 359, 2847-2856; (f) Gao, Y.; Wu, W.; Huang, Y.; Huang, K.; Jiang, H. Org. Chem. Front. 2014, 1, 361-364; (g) Gilmore, K.;
Gold, B.; Clark, R. J.; Alabugin, I. V. Aust. J. Chem. 2013, 66, 336-340; (h) Wei, W.; Wen, J.; Yang, D.; Jing, H.; You, J.; Wang, H. RSC Advances 2015, 5,
4416-4419; (i) Sun, Y.; Abdukader, A.; Lu, D.; Zhang, H.; Liu, C. Green Chem. 2017, 19, 1255-1258.
11. Yuanchao, X.; Yunyan, K.; Jie, W. Chem. Eur. J. 2017, 23, 6996-6999.
12. Bao, Y.; Yang, X.; Zhou, Q.; Yang, F. Org. Lett. 2018, 20, 1966-1969.
13. (a) Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48-76; (b) Jeffrey, G. A. Crystallography Reviews 2003, 9, 135-176; (c) Pihko, P. M., Hydrogen bonding in
organic synthesis. Wiley-VCH: Weinheim, 2009.
14. Zeng, X.; Li, J.; Ng, C. K.; Hammond, G. B.; Xu, B. Angew. Chem. Int. Ed. 2018, 57, 2924-2928.
15. Lu, Z.; Zeng, X.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2017, 139, 18202-18205.
16. Zeng, X.; Liu, S.; Shi, Z.; Xu, B. Org. Lett. 2016, 18, 4770-4773.
17. Liu, G.; Xu, B. Tetrahedron Lett. 2018, 59, 869-872.

18. (a) Ebule, R.; Liang, S.; Hammond, G. B.; Xu, B. ACS Catal. 2017, 7, 6798-6801; (b) Zeng, X.; Liu, S.; Hammond, G. B.; Xu, B. ACS Catal. 2017, 904-909;
(c) Judit, O.-M.; Antonio, D.-C.; Mercedes, B.; Antonio, L.-P.; Avelino, C. Angew. Chem. Int. Ed. 2017, 56, 6435-6439.
19. Xiang, J.; Jiang, W.; Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1997, 119, 4123-4129.
20. Guan, Z.; Liu, Z.; Shi, W.; Chen, H. Tetrahedron Lett. 2017, 58, 3602-3606.
21. (a) Taniguchi, M.; Kobayashi, S.; Nakagawa, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986, 27, 4763-6; (b) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57,
709-13; (c) Wenbo, L.; Lihua, G.; Zhenting, Y.; Junliang, Z. Adv. Synth. Catal. 2015, 357, 2651-2655; (d) Lu, X.-Y.; Zhu, G.-X.; Ma, S.-M. Chin. J. Chem .
1993, 11, 267-271.
22. (a) de la Pradilla, R. F.; Morente, M.; Paley, R. S. Tetrahedron Lett. 1992, 33, 6101-6102; (b) Zhu, G.; Chen, D.; Wang, Y.; Zheng, R. Chem. Commun. 2012,
48, 5796-5798; (c) Derosa, J.; Cantu, A. L.; Boulous, M. N.; O’Duill, M. L.; Turnbull, J. L.; Liu, Z.; De La Torre, D. M.; Engle, K. M. J. Am. Chem. Soc. 2017,
139, 5183-5193.
23. Henkel, S.; Misuraca, M. C.; Troselj, P.; Davidson, J.; Hunter, C. A. Chem. Sci. 2018, 9, 88-99.
24. Briggs, J. M.; Nguyen, T. B.; Jorgensen, W. L. J. Phys. Chem. 1991, 95, 3315-3322.
25. Zeng, X.; Liu, S.; Hammond, G. B.; Xu, B. Chem. Eur. J. 2017, 23, 11977-11981.
26. Berkessel, A.; Adrio, J. A. J. Am. Chem. Soc. 2006, 128, 13412-13420.
27. (a) Liu, W.; Wang, H.; Li, C.-J. Org. Lett. 2016, 18, 2184-2187; (b) Colomer, I.; Batchelor-McAuley, C.; Odell, B.; Donohoe, T. J.; Compton, R. G. J. Am.
Chem. Soc. 2016, 138, 8855–8861; (c) Tian, Y.; Xu, X.; Zhang, L.; Qu, J. Org. Lett. 2016, 18, 268-271.
28. The crystallographic data of 4k has been deposited to Cambridge Crystallographic Data Centre (CCDC 1847449).
29. (a) Carey, F. A.; Sundberg, R. J., Advanced Organic Chemistry, Part A: Structure and Mechanisms. In Advanced Organic Chemistry, Part A: Structure and
Mechanisms, 5th ed.; Springer: 2007; Vol. A, pp 536-540; (b) Ashtekar, K. D.; Vetticatt, M.; Yousefi, R.; Jackson, J. E.; Borhan, B. J. Am. Chem. Soc. 2016,
138, 8114-8119; (c) Zeng, X.; Lu, Z.; Liu, S.; Hammond, G. B.; Xu, B. J. Org. Chem. 2017, 82, 13179-13187.
30. (a) Weiss, H. M.; Touchette, K. M.; Andersen, F.; Iskhakov, D. Org. Biomol. Chem. 2003, 1, 2148; (b) Weiss, H. M.; Touchette, K. M.; Angell, S.; Khan, J.
Org. Biomol. Chem. 2003, 1, 2152; (c) Weiss, H. M.; Touchette, K. M. J. Chem. Soc., Perkin Trans. 2 1998, 1523-1528.
Click here to remove instruction text...
1. Metal-free hydrohalogenations.
2. Hydrogen bonding network assisted.
3. Stereo-Controlled synthesis of halogenated sulfonyl alkenes.
X
O O
S
O
O
LiX, AcOH
R2
S
R1
R2
R1
100 °C, 12 h
2
X = Cl, Br, I
H
1
Z-product
39 examples, up to 98%
Exclusive Z-selectvitiy
Works for Cl, Br, I
Works for both aromatic and aliphatic substrates