Regio- and Stereoselective Synthesis of 1,2-Dihaloalkenes Using In-Situ-Generated ICl, IBr, BrCl, I2, and Br2

Article abstract of DOI:10.1016/j.chempr.2020.03.011

We describe a catalyst-free 1,2-trans-dihalogenation of alkynes with an unprecedented substrate scope and exclusive regio- and stereoselectivity. This versatile dihalogenation system—a combination of NX¹S electrophile and alkali metal halide (MX²) in acetic acid—is applicable for diverse categories of alkynes (electron-rich or poor alkynes, internal and terminal alkynes, or heteroatoms such as O-, N-, S-substituted alkynes). The hydrogen bonding donor solvent acetic acid is essential for the in-situ generation of X¹X² electrophile, including ICl, IBr, BrCl, I₂, and Br₂. Haloalkenes are not only commonly found in biologically active natural products but also have been used extensively in cross-coupling reactions. More specifically, 1,2-dihaloalkenes are especially important synthons because of the presence of two synthetic handles that open a broad avenue to expeditiously generate multisubstituted alkenes. Dihalogenation of alkynes is a straightforward way to prepare 1,2-dihaloalkenes. However, existing alkyne dihalogenation methods either rely on the use of toxic reagents, such as IBr and ICl, lack regio- and stereoselectivity or have limited substrate scope. Thus, the development of a widely applicable and yet efficient alkyne dihalogenation method is still highly desired. Here, we have addressed the aforementioned issues based on an in-situ-generated dihalogenation of reagents, such as ICl and Ibr, by using the readily available N-halosuccinimide (NXS) and alkali metal halides as halogen sources. Our method offers an unprecedented substrate scope, the regio- and stereoselectivity for the synthesis of 1,2-dihaloalkenes. Our simple and mild conditions might find wild applications in the preparation of high-value building blocks for medicines and materials. Dihaloalkenes are important raw materials for pharmaceutical and chemical industries. However, existing preparation methods suffer from a limited substrate scope as well as poor regio- and stereoselectivity. Furthermore, these methods often necessitate highly toxic reagents, such as Cl₂, ICl, and BrCl. Our environmentally friendly 1,2-trans-dihalogenation is based on easy-handling halide sources, such as alkali metal halides. What is more, our method offers an unprecedented substrate scope, the regio- and stereoselectivity for the synthesis of 1,2-dihaloalkenes.

Full text of DOI:10.1016/j.chempr.2020.03.011

Article
Regio- and Stereoselective Synthesis of 1,2-
Dihaloalkenes Using In-Situ-Generated ICl,
IBr, BrCl, I2, and Br2
Xiaojun Zeng, Shiwen Liu, Yuhao
Yang, Yi Yang, Gerald B.
Hammond, Bo Xu
gb.hammond@louisville.edu (G.B.H.)
bo.xu@dhu.edu.cn (B.X.)
HIGHLIGHTS
Catalyst-free dihalogenation of
diverse alkynes
Easy-handling halide sources—
alkali metal halides
In-situ generation of ICl, IBr, BrCl,
I2, and Br2
Dihaloalkenes are important raw materials for pharmaceutical and chemical
industries. However, existing preparation methods suffer from a limited substrate
scope as well as poor regio- and stereoselectivity. Furthermore, these methods
often necessitate highly toxic reagents, such as Cl2, ICl, and BrCl. Our
environmentally friendly 1,2-trans-dihalogenation is based on easy-handling
halide sources, such as alkali metal halides. What is more, our method offers an
unprecedented substrate scope, the regio- and stereoselectivity for the synthesis
of 1,2-dihaloalkenes.
Zeng et al., Chem 6, 1018–1031
April 9, 2020 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.03.011

Article
Regio- and Stereoselective Synthesis
of 1,2-Dihaloalkenes Using In-Situ-
Generated ICl, IBr, BrCl, I2, and Br2
2,
Xiaojun Zeng,1 Shiwen Liu,2 Yuhao Yang,1 Yi Yang,2 Gerald B. Hammond,1,3, and Bo Xu
*
*
SUMMARY
The Bigger Picture
Haloalkenes are not only
We describe a catalyst-free 1,2-trans-dihalogenation of alkynes with an unprec-
edented substrate scope and exclusive regio- and stereoselectivity. This versa-
tile dihalogenation system—a combination of NX1S electrophile and alkali
metal halide (MX2) in acetic acid—is applicable for diverse categories of alkynes
(electron-rich or poor alkynes, internal and terminal alkynes, or heteroatoms
such as O-, N-, S-substituted alkynes). The hydrogen bonding donor solvent ace-
tic acid is essential for the in-situ generation of X1X2 electrophile, including ICl,
IBr, BrCl, I2, and Br2.
commonly found in biologically
active natural products but also
have been used extensively in
cross-coupling reactions. More
specifically, 1,2-dihaloalkenes are
especially important synthons
because of the presence of two
synthetic handles that open a
broad avenue to expeditiously
generate multisubstituted
INTRODUCTION
Halogenated organic compounds are among the most important structural motifs as
they are ubiquitous in natural products,1,2 materials,3 and pharmaceuticals.4 They
are also among the most versatile building blocks.5,6 More specifically, 1,2-dihaloal-
kenes are reliable cross-coupling partners, which have been extensively utilized to
construct a wide range of multisubstituted alkenes and other complex mole-
cules.7–14 Compared with 1,2-dihaloalkenes containing only one kind of halogen
(e.g., dichloroalkenes), dihaloalkenes containing two different halogens are more
exciting and have broader applications.15 For example, dihaloalkenes containing
two different halogens could undergo cross-coupling reactions in a step-wise
manner for the installment of two different molecular fragments.7,16–27 In this regard,
significant efforts have been devoted to the construction of dihaloalkenes. However,
the regio- and stereoselective, yet environmentally friendly synthesis of dihaloal-
kenes with a broad scope is still challenging.28–34
alkenes. Dihalogenation of
alkynes is a straightforward way to
prepare 1,2-dihaloalkenes.
However, existing alkyne
dihalogenation methods either
rely on the use of toxic reagents,
such as IBr and ICl, lack regio-
and stereoselectivity or have
limited substrate scope. Thus, the
development of a widely
applicable and yet efficient alkyne
dihalogenation method is still
highly desired. Here, we have
addressed the aforementioned
issues based on an in-situ-
As taught in any introductory organic chemistry course, the electrophilic addition of
X2, such as Br2 or Cl2, to alkynes is a straightforward method for the synthesis of 1,2-
dihaloalkenes. The electrophilic dihalogenation of alkynes suffers from limited sub-
strate scope as well as poor regio- and stereoselectivity. Furthermore, these
methods need highly toxic reagents, such as Cl2, ICl, and BrCl.35,36 For example,
many electrophilic additions of permanent dipole reagents, such as ICl and IBr, to
alkynes deliver a mixture of cis- and trans- products with poor regioselectivity37,38
or, in other cases, ionic liquids39 are required (Scheme 1A). Chalifoux and co-
workers23 described a trans-addition of ICl to trialkysilyl-substituted alkynes via
neighboring group participation at ꢀ78ꢁC (Scheme 1B). However, this strategy is
limited to silyl-substituted alkynes. Many other dihalogenation systems based on
combinations of N-halosuccinimide (NXS),21,40 I2,41 or Cl242 together with TMSBr,22
TMSCl, HgCl2,43 or HCl33 have been developed (Scheme 1C). A Bu4NI-DCE sys-
tem19,20 has also been explored (Scheme 1D). All these approaches generally
generated dihalogenation of
reagents, such as ICl and Ibr, by
using the readily available N-
halosuccinimide (NXS) and alkali
metal halides as halogen sources.
Our method offers an
unprecedented substrate scope,
the regio- and stereoselectivity
for the synthesis of 1,2-
dihaloalkenes. Our simple and
mild conditions might find wild
1018 Chem 6, 1018–1031, April 9, 2020 ª 2020 Elsevier Inc.

applications in the preparation of
high-value building blocks for
medicines and materials.
Scheme 1. Strategies for the Synthesis of 1,2-Dihaloalkenes
need harsh reaction conditions and are case-specific for a given type of alkyne sub-
strate. Alternatively, 1,2-dihaloalkenes could also be accessed via hydrohalogena-
tions of haloalkynes, where pre-installment of a halogen to an alkyne is needed.
For instance, the nucleophilic addition of alkali metal halides to haloalkynes leads
to Z-dihaloalkenes44 (Scheme 1E), but unfriendly reaction conditions are indispens-
able and regio-isomer formation is common45 (Scheme 1F). Zhu’s group (Scheme
1G) reported a Pa-catalyzed hydrohalogenation of haloalkynes,46 a reaction that
exclusively gives anti-addition products but their method is limited to the synthesis
of iodoalkenes. Recently our group developed the synthesis of (Z)- and (E)-1,2-chlor-
ohaloalkenes via gold catalysis and hydrogen bonding catalysis, respectively47
(Scheme 1H). However, these methods were only applicable to hydrochlorination.
Hitherto, the efficient regio- and stereoselective synthesis of diverse dihaloalkenes
from a wide range of categories of alkynes (electron-rich or -poor alkynes, internal
and terminal alkynes, heteroatoms such as O, N, S-substituted alkynes) by using a
unified yet straightforward and environmentally friendly protocol remains an un-
solved challenge in synthesis.
1Department of Chemistry, University of
Louisville, Louisville, KY 40292, USA
Recently, we developed easily handled and reactive N,N0-Dimethylpropyleneurea
(DMPU)-HX reagents that enable the regio- and stereoselective synthesis of haloal-
kenes.47–51 Nevertheless, the high acidity of HX was incompatible with some func-
tional groups.52,53 An in-situ generated reactive halogenation reagent could be ad-
vantageous in such instances.54–59 Recently, Oestreich and co-workers reported the
hydroiodination of C–C multiple bonds by using in-situ-generated HI or HBr driven
by the aromatization of cyclohexa-1,4-dienes.60,61 We are now glad to report a
2College of Chemistry, Chemical Engineering
and Biotechnology, Donghua University,
Shanghai 201620, China
3Lead Contact
*Correspondence:
gb.hammond@louisville.edu (G.B.H.),
bo.xu@dhu.edu.cn (B.X.)
https://doi.org/10.1016/j.chempr.2020.03.011
Chem 6, 1018–1031, April 9, 2020 1019

Table 1. Optimization of the Reaction Conditions
Entry
1
Electrophilic X+
Nucleophilic Halogen
Solvent
Yields %a (1b:1c:1d)
95 (8:1:0)
ICl (1.2 equiv)
n/a
n/a
DCM
2
Bu4NI (3 equiv)
DCE (80ꢁC)
DCM
Complexb
89 (0:0:100)
85 (0:0:100)
45 (0:0:100)
Trace
3
NIS
TMSCl
4
NIS
PhCOCl
DCM
5
NIS
AcCl
DCM
6
NIS
LiCl
CH3CN
7
NIS
LiCl
HFIP
Trace
8
NIS
LiCl
HOAc
71 (90:10:0)
80 (98:2:0)
81 (97:3:0)
93 (88:12:0)
66 (67:33:0)
40 (61:39:0)
82 (77:23:0)
75 (82:18:0)
9
NIS
LiCl
HOAc-DCMc
HOAc-DCMc
HOAc-DCMc
HOAc-DCMc
HOAc-DCMc
Toluene
10
11
12
13
14e
15e
DIHd
ICl (1.5 equiv)
IOAc
IOAc
NCS
LiCl
n/a
LiCl (2 equiv)
LiCl (4 equiv)
I2
NCS
I2,
HOAc_DCMc
Conditions: alkynes 1a (0.2 mmol), NIS (0.3 mmol, 1.5 equiv), Clꢀ reagent (0.4 mmol, 2 equiv), solvent
(1 mL), 24 h.
aYields were determinated by NMR.
bBoth hydrochlorinated and dichlorinated products were detected.
cHOAc-DCM (0.5:0.5 mL).
dDIH: 1,3-diiodo-5,5-dimethylhydantion.
e5 mol % of thiourea catalyst was used.
versatile dihalogenation system—a combination of NX1S and LiX2 that arises in the
presence of an H-bonding solvent, such as AcOH. This system slowly generates reac-
tive ICl, IBr, BrCl, Br2, and I2 in situ. Because of the mild conditions, our dihalogena-
tion of alkynes has demonstrated unprecedented substrate scope, yielding products
with remarkably high regio- and stereoselectivity (Scheme 1, bottom).
RESULTS
We used the iodochlorination of alkyne 1a as our model reaction (Table 1). We first
evaluated this reaction by using an extensively used iodochlorination reagent—ICl
(Table 1, entry 2). Not surprisingly, a mixture of regio-isomers was detected; this
result was consistent with the reported literature.31 Another reported dihalogenera-
tion system (Bu4NI- dichloroethylene (DCE), 80ꢁC)20 gave a complex mixture of
products (Table 1, entry 2). An additional dihalogenation system [N-Iodosuccini-
mide (NIS)-Trimethylsilyl chloride (TMSCl)]16 gave only the hydrochlorinated prod-
uct (Table 1, entry 3). We found that neither NIS-PhCOCl nor NIS-AcCl gave the
desirable product (Table 1, entries 4–5), suggesting that hydrochlorination occurs
before iodochlorination. Remarkably, the hydrochlorination products could be in-
hibited when LiCl was used (Table 1, entries 6–7) but because of the limited solubility
of LiCl, employing solvents like CH3CN or HFIP led to very low yields. We envisioned
that a hydrogen bond donor solvent, such as HOAc not only would be able to
1020 Chem 6, 1018–1031, April 9, 2020

dissolve LiCl, but would also increase the reactivity of the electrophile. As expected,
a high yield of iodochlorinated product was observed with HOAc, albeit with low
stereoselectivity (Table 1, entry 8). Interestingly, using dichloromethane (DCM) as
the co-solvent significantly improved both the yield and the regioselectivity of the
product (Table 1, entry 9). We tested another electrophilic iodide source (DIH),
but it did not improve the reaction (Table 1, entry 10). Because AcOH might play
an important role in the selectivity of this reaction, we investigated the reaction of
ICl by using AcOH-DCM as the solvent, but we found the E-Z selectivity was still
not good (Table 1, entry 11). Similarly, IOAc gave poor E-Z selectivity (Table 1, entry
12). When more equivalents of LiCl were employed, we obtained a lower yield and
stereoselectivity (Table 1, entry 12). Recently, Ishihara and co-workers34 reported an
efficient thiourea-I2-NCS system for iodochlorination of alkenes. However, the same
condition showed poor E-Z selectivity in the iodochlorination of alkyne 1a when us-
ing Ishihara and co-workers’ thiourea catalyst (Table 1, entry 14). Next, we switched
the solvent to DCM-HOAc, We found that it could slightly improve the stereoselec-
tivity, but offered a lower chemical yield.
We then explored the substrate scope under the optimized conditions (Figure 1).
First, we evaluated the scope of terminal aromatic alkynes (Figure 1, 2–12), obtaining
good yields and excellent regioselectivities. The efficiency of the reaction was not
affected by electron-withdrawing groups (e.g., ester-) or electron-donating groups
(e.g., MeOꢀ, Ph). Even an unprotected phenol group was well tolerated (Figure 1,
9). Heteroaromatics such as pyridine and thiophene were not affected by the reac-
tion conditions (Figure 1, 11 and 12). We next evaluated the scope of terminal
aliphatic alkynes and found that at lower temperatures (ꢀ25ꢁC) the reaction showed
high trans-selectivity62 (Figure 1, 13–22). It should be noted that unprotected hy-
droxyls (Figure 1, 14 and 17), alkene (Figure 1, 15), sulfonate (Figure 1, 18), benzo-
triazoles (Figure 1, 20), indazole(Figure 1, 20), thiophene (Figure 1, 21), or the nitro
group (Figure 1, 22) did not hinder the efficiency of the reaction.
Haloalkynes are versatile, yet readily available, building blocks,46,47,63–69 with which
our highly regioselective iodochlorination protocol should enable to access
extremely valuable trihalogenated alkenes.70 To our delight, both aromatic and
aliphatic haloalkynes gave excellent regioselectivity and chemical yields of trihalo-
genated alkenes. Diverse functional groups, such as acid-sensitive esters (Figure 1,
24), aldehyde (Figure 1, 25), methoxyl (Figure 1, 26), and nitrile (Figure 1, 27) sur-
vived the reaction conditions. Compared with bromoalkynes and iodoalkynes (Fig-
ure 1, 28, 30), chloroalkynes (Figure 1, 31 and 32) were less reactive and required
a longer time as well as more equivalents of NIS-LiCl, but the products were, never-
theless, obtained in good yields and excellent trans-selectivity.
Encouraged by the broad scope of haloalkynes that tolerated our reaction condi-
tions, we examined the scope of electron-deficient alkynes, such as alkynyl ketones
(Figure 1, 33–41). The substitution pattern (ortho, meta, and para) and electronic
properties of aromatic substituents (electron-deficient or electron-rich) played a
small role; good yields were obtained regardless (Figure 1, 33–38). In general, sub-
strates containing electron-rich substitution gave slightly higher yields than those
containing electron-deficient substitutions (Figure 1, 36 and 37). The substitution
groups attached to the carbonyl group played a negligible role in the reactivity;
even the sterically hindered cyclohexyl and tertiary butyl groups were well tolerated
(Figure 1, 39 and 40). A dialkyl ynone was also a suitable substrate (89%, Figure 1,
41). We were pleased to find that the same protocol worked well for alkynyl esters
(Figure 1, 42–49). Moreover, phenylamine (Figure 1, 47) and alkyl alkynyl esters
Chem 6, 1018–1031, April 9, 2020 1021

Figure 1. The Scope of the Iodochlorination of Alkynes
1022 Chem 6, 1018–1031, April 9, 2020

Figure 2. ORTEP Drawings of Obtained Products
(Figure 1, 48 and 49) were good substrates for this reaction. It should be noted that
our protocol displayed much better regioselectivities compared with the reported
method.20 Our iodochlorination system could be extended to other diverse alkyne
types such as highly electron-deficient sulfonyl alkynes (Figure 1, 50–57),71 elec-
tron-rich alkynyl thioethers (Figure 1, 55–57), electron-deficient alkynyl aldehydes
(Figures 1, 65), electron-deficient alkynyl acid (Figure 1, 66), electron-deficient al-
kynyl nitrile (Figure 1, 67), electron-rich ynol ether (Figure 1, 68), and ynamide (Fig-
ure 1, 69). Most of the highly functional dihaloketenes prepared using our protocol
were hitherto unknown.
Despite the wide structural diversity of the above alkynes, our dihalogenation af-
forded products with exclusive or very high regioselectivity. We investigated the re-
gioselectivity of internal alkynes that exhibited small structural biases (R1 and R2) on
each end of the triple bond (Figure 1, 58–64). We were pleased to find that for al-
kynes substituted with an aryl group and an aliphatic group (R1 = aryl, R2 = aliphatic)
(Figure 1, 58–60), the reaction was regiospecific. To our delight, even very chal-
lenging unsymmetrical aryl alkynes (R1 = phenyl substituted with a withdrawing
group—ester or ketone, and R2 = phenyl substituted with an electron-donating
group) furnished regiospecific products (Figure 1, 61 and 62). As expected, our pro-
tocol worked very well for symmetric diaryl and dialkyl alkynes (Figure 1, 63 and 64).
To corroborate the functional group tolerance and wide applicability of our method-
ology, we conducted late-stage dihalogenation of alkynes containing natural
product motifs (Figure 1, 70–73). Alkynes tethered to complex structures such as zal-
toprofen (Figure 1, 70), diacetone-D-glucose (Figure 1, 71), hiestrone (Figure 1, 72)
and L-menthol (Figure 1, 73) gave desired products in excellent yields and selec-
tivity. The structure assignments of our obtained products were further confirmed
by single-crystal X-ray diffraction (see the Oak Ridge Thermal Ellipsoid Plot Program
[ORTEP]) drawings of 10,72 29,73 51,74 and 69,75 Figure 2).
Because the iodochlorination of alkynes using ICl is the most commonly used
method in the literature, we compared the reactivity of the ICl method with our
new in-situ method for various types of alkynes (see Supplemental Information,
Section 23). In general, possibly due to the high reactivity of ICl, a mixture of re-
gio-isomers was obtained in most cases, and we also detected dichlorinated and
diiodinated products in some cases.
Having demonstrated the scope of the iodochlorination of alkynes, we switched our
attention to other dihalogenation systems (Figure 3). Diiodination (NIS-LiI-AcOH),
Chem 6, 1018–1031, April 9, 2020 1023

Figure 3. Scope of the Dihalogenation of Alkynes
1024 Chem 6, 1018–1031, April 9, 2020

Scheme 2. Iodo-Functionalization of Alkynes and Large-Scale Synthesis
iodobromination (NIS-LiBr-AcOH), dibromination (NBS-LiBr-AcOH) and chlorobromina-
tion (NBS-LiCl-AcOH) gave the desired products with exclusive trans- stereochemistry
and in good chemical yields (Figure 3). Aromatic and aliphatic terminal alkynes, haloal-
kynes, sulfonyl alkynes, alkynyl thioether, alkynyl ether, alkynyl ketone, alkynyl ester as
well as functionalized internal alkynes proved to be suitable substrates. Moreover,
acid-sensitive groups such as tert-butyldiphenylsilyl ether (Figure 3, 80), and phenolic
ether (Figure 3, 83) were compatible with our mild conditions. A lower temperature
(ꢀ40ꢁC) was needed for chlorobromination (NBS-LiCl-AcOH), possibly because of the
high reactivity of BrCl generated in situ. Our protocol is a safer and more selective alter-
native to literature methods that rely on the use of toxic Br2, IBr, and BrCl. The structure
assignments of our obtained products were further confirmed by single-crystal X-ray
diffraction (see the ORTEP drawings of 8276 and 9177).
Recently, the haloacetoxylation of alkenes78–81 and alkynes82 employing electro-
philic X+ and HOAc was reported. We did not detect any competitive acetate addi-
tion reactions in our experiments possibly because HOAc is a weaker nucleophile
than LiX in our dihalogenation reaction. We took solace in finding that the iodoace-
toxylated alkene 9883 (Scheme 2, Equation 2a) was cleanly prepared using NaOAc as
the nucleophile. Encouraged by our success, we investigated other common nucle-
ophiles. Although LiSCN delivered the desirable product 9984 in a moderate yield
(Scheme 2; Equation 2b), other nucleophiles such as LiSeCN, KF, TMSCN and
NaN3 only gave a trace amount of desired products (Scheme 2, Equations 2c–2f).
To demonstrate the general applicability of our developed robust methods, a
commercially available phenylacetylene was extended up to gram-scale under the
optimized conditions, which offered desirable products in 80% yield (Scheme 2,
Equation 2g), and maintain excellent selectivity ( E/Z> 20/1).
Figure 4 shows our proposed mechanism. We and others have reported that linear H-
bond aggregates85 of (AcOH)n are the dominant species in neat AcOH or a highly
concentrated AcOH solution, and (AcOH)n is a strong and tunable hydrogen bond donor
Chem 6, 1018–1031, April 9, 2020 1025

Figure 4. Proposed Mechanism and Geometries of Unsymmetrical Iodoniums
LUMOs were calculated at uB97X-D/6-311++G** level of theory.
system. We postulated that the interaction of (AcOH)n with NIS and LiCl led to the gen-
eration of ICl and succinimide A; the strong H-bond interaction between succinimide A,
ICl and (AcOH)n was the driving force that displaced the equilibrium tothe right. The text-
book mechanism for dihalogenation of an alkyne is the formation of a cyclic iodonium in-
termediate, followed by an SN2-like backside attack of chloride nucleophile to obtain the
trans-addition product.86
Usually, steric and electrophilic factors determine the regioselectivity of electrophilic
addition to unsymmetric alkynes. However, most literature protocols have only
showcased a narrow alkyne substrate scope; thus, a comprehensive yet rational
study of the regioselectivity of electrophilic additions to unsymmetric alkynes is lack-
ing. Because our protocol works for unprecedently diverse categories of unsymmet-
ric alkynes, we now have a rare opportunity to conduct a systematic study of the
regioselectivity of the addition. We speculated that the geometry of the cyclic iodo-
nium intermediate is the determining factor of the regioselectivity seen. For an
alkyne with R1 and R2 on each end of the triple bond, an unsymmetrical iodonium in-
termediate will form, and the nucleophilic chloride anion will prefer to attack the car-
bon with the weaker (longer) bond with the iodine atom.32 As a result, we predicted
that the regioselectivity would be determined by the equilibrium geometry of the
corresponding iodonium, which could be easily be obtained using DFT calculations
(Figure 4). From these calculations, the geometry of the unsymmetrical iodonium de-
pended on R1 and R2’s relative ability to stabilize the neighboring positive charge,
which, in turn, is determined by a combination of conjugation and hyperconjugation
effects. According to the calculations (Figure 4), the neighboring positive charge sta-
bilization ability of groups follows this approximate order: R2N-, OR-, SR- >> Ar- >
Alkyl > H-> I- > Br- > Cl- > CHO-, COOR-, COR- > RSO2. Thus, if the neighboring
positive charge stabilization ability of R1 is higher, in an alkyne substituted with R1,
and R2 that reacts with NIS/LiCl/AcOH, the nucleophilic chloride will bind to the car-
bon closer to the R1. From our calculations of LUMOs and geometries of
1026 Chem 6, 1018–1031, April 9, 2020

Figure 5. NMR Investigations
(A–F) 1H NMR spectra of (A) NIS; (B) NIS and HOAc; (C) LiCl: NIS (1: 1) in HOAc after 1 h. (D)
succinimide in CDCl3 and HOAc. (E) NIS In HOAc-DCM (F) NIS, LiCl in HOAc-DCM.
unsymmetrical iodonium (Figure 4), this model explained the regioselectivity very
well. We also found that the reaction system with a higher LUMO (iodonium) has a
faster reaction rate in general. As a general rule, the iodine atom is added to the al-
kynyl carbon substituted with an electron-withdrawing group (e.g., ester and ketone)
and the chlorine atom is added to the alkynyl carbon substituted with an electron-
donating group (e.g., RS-, RO-, and R2N-). It should be noted that for electron-defi-
cient alkyne substrates, the reaction might also go through a Michael addition of a
chloride followed by electrophilic iodination. But we think that this pathway is rela-
tively unlikely. For example, the addition of LiCl in acetic acid to sulfonyl alkynes
needs a very high temperature (100ꢁC)56 and our reaction is conducted at 0ꢁC or
lower temperatures.
To further verify our proposed mechanism, we studied the activating role of HOAc
by using NMR spectroscopy. Figure 5A shows that the peak marked with Ha corre-
sponded to the CH2 signal of NIS, located at 3.03 ppm in CDCl3. There was a small
upfield shift of the methylene group, from 3.03 to 2.97 ppm, when HOAc was added
(Figure 5B), indicating an H-bond interaction between the HOAc and NIS. Interest-
ingly, the signal corresponding to CH2 was completely shifted to 2.77 ppm when LiCl
was added (Figure 5C) and succinimide was detected in a quantitative yield (Fig-
ure 5D). To follow up this result, we carried out two control experiments. When
NIS (0.3 mmol) was added to the mixture solvent DCM/HOAc (0.5/0.5 mL) and
stirred vigorously for 10 min at room temperature, however, the bench stable NIS
was undissolved (Figure 5E). Surprisingly, the reaction mixture turned to a brownish
color immediately after LiCl (0.4 mmol) was added (Figure 5F); this color is very
similar to the color of a solution of ICl in DCM/HOAc. The formation of succinimide
and the color change was a strong indication of ICl formation in situ.
To illustrate the synthetic potential of the products that we obtained using our pro-
tocol, we conducted eight representative transformations of our dihaloalkene prod-
ucts (Scheme 3). Taking advantage of the reactivity difference between alkenyl
chloride and iodide, we were able to synthesize E-enynes 100, b-chloro-a, b-unsat-
urated nitriles 102, phenylhexa-3,5-diyn-1-ol 103, and 2-ethynylbenzofurans 104 by
using a sequence of cross-coupling reactions. Our dihaloalkene products also could
be reduced to alcohol which is consistent with our reported compound 58. More-
over, the halo-thioalkane products enable oxidant to sulfone 101 or sulfoxide 105
Chem 6, 1018–1031, April 9, 2020 1027

Scheme 3. Synthetic Applications
with the dihaloalkene functionality untouched. The structural assignments of prod-
ucts 10187 and 10588 were further confirmed by single-crystal X-ray diffraction.
In summary, we have discovered an efficient method for the regio-selective dihalo-
genation of 13 different classes of alkynes. The in-situ generated electrophilic X1X2
reagents replaced toxic alternatives such as ICl, IBr. We transformed the dihalogen-
ated products into synthetically useful tri- or tetrasubstituted alkenes via tandem
cross-coupling reactions. Further exploration of the in-situ generated X1X2 electro-
philes is currently under investigation in our laboratory.
DATA AND CODE AVAILABILITY
Crystal structure data of compounds 10 (CCDC: 1912785), 29 (CCDC: 1948339), 51
(CCDC: 1912792), 69 (CCDC: 1948338), 82 (CCDC: 1966560), 91 (CCDC: 1966562),
1028 Chem 6, 1018–1031, April 9, 2020

101 (CCDC: 1912791), and 105 (CCDC: 1966561) have been deposited in the Cam-
bridge Structural Database.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.03.011.
ACKNOWLEDGMENTS
We are grateful to the National Institutes of Health for financial support
(R01GM121660). B.X. is grateful to the National Science Foundation of China
(NSFC-21672035 and NSFC-21871046) for financial support. We acknowledge
with gratitude the help provided by Dr. Mark S. Mashuta (Manager X-ray Crystallo-
graphic Facilities, Chemistry Department, University of Louisville) for his helpful in-
sights regarding our crystallographic data.
AUTHOR CONTRIBUTIONS
X.Z., G.B.H., and X.B. conceived the research. X.Z., S.L.,Yuhao Yang, and Yi Yang
carried out experiments and analyzed results. X.Z., G.B.H., and X.B. wrote the manu-
script with input from all the authors.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: June 5, 2019
Revised: December 25, 2019
Accepted: March 13, 2020
Published: April 9, 2020
REFERENCES
1. Gribble, G.W. (1998). Naturally occurring
organohalogen compounds. Acc. Chem. Res.
31, 141–152.
catalyzed coupling of haloalkynes and
a,b-unsaturated carbonyls. J. Org. Chem. 76,
4071–4074.
13. Poulsen, T.B., Dickmeiss, G., Overgaard, J.,
and Jørgensen, K.A. (2008). Organocatalytic
asymmetric synthesis of versatile g-lactams.
Angew. Chem. Int. Ed. Engl. 47, 4687–4690.
2. Landry, M.L., and Burns, N.Z. (2018). Catalytic
enantioselective dihalogenation in total
synthesis. Acc. Chem. Res. 51, 1260–1271.
8. Desrat, S., Remeur, C., Ge´ ny, C., Rivie` re, G.,
Colas, C., Dumontet, V., Birlirakis, N., Iorga,
B.I., and Roussi, F. (2014). From meiogynin A to
the synthesis of dual inhibitors of Bcl-xL and
Mcl-1 anti-apoptotic proteins. Chem.
14. Selina, A.A., Zhachkina, A.E., Karlov, S.S.,
Churakov, A.V., and Zaitseva, G.S. (2004).
Iodochlorination of silyl- and
3. Lin, R., Amrute, A.P., and Pe´ rez-Ramırez, J.
´
germylphenylacetylenes. Heteroatom Chem.
15, 169–174.
(2017). Halogen-mediated conversion of
hydrocarbons to commodities. Chem. Rev.
117, 4182–4247.
Commun. (Camb.) 50, 8593–8596.
9. Zeng, X., Hu, Q., Qian, M., and Negishi, E.-i.
(2003). Clean inversion of configuration in the
Pd-catalyzed cross-coupling of 2-bromo-1,3-
dienes. J. Am. Chem. Soc. 125, 13636–13637.
15. Gilbert, N., Casault, P., Ladouceur, F., Ricard,
S., and Daoust, B. (2018). 1,2-Dihaloalkenes in
metal-catalyzed reactions. Synthesis 50, 3087–
3113.
4. Agarwal, V., Miles, Z.D., Winter, J.M.,
Eusta´quio, A.S., El Gamal, A.A., and Moore,
B.S. (2017). Enzymatic halogenation and
dehalogenation reactions: pervasive and
mechanistically diverse. Chem. Rev. 117, 5619–
5674.
10. Sun, C., Camp, J.E., and Weinreb, S.M. (2006).
Construction of b-haloenamides via direct
copper-promoted coupling of lactams with
2-chloro and 2-bromo vinyliodides. Org. Lett.
8, 1779–1781.
16. Yauchi, Y., Ide, M., Shiogai, R., Chikugo, T., and
Iwasawa, T. (2015). Regio- and stereoselective
synthesis of vicinal (Z)-dihaloalkenylsilanes
from silyl ethynylarenes. Eur. J. Org. Chem.
2015, 938–943.
5. Petrone, D.A., Ye, J., and Lautens, M. (2016).
Modern transition-metal-catalyzed carbon–
halogen bond formation. Chem. Rev. 116,
8003–8104.
11. Jiang, B., Tian, H., Huang, Z.G., and Xu, M.
(2008). Successive copper(I)-catalyzed cross-
couplings in one pot: a novel and efficient
starting point for synthesis of carbapenems.
Org. Lett. 10, 2737–2740.
17. Chen, D., Chen, X., Lu, Z., Cai, H., Shen, J., and
Zhu, G. (2011). Palladium-catalyzed dienylation
of haloalkynes using 2,3-butadienyl acetates: a
facile access to (1Z)-1,2-dihalo- 3-vinyl-1,3-
dienes. Adv. Synth. Catal. 353, 1474–1478.
6. Johansson Seechurn, C.C.C., Kitching, M.O.,
Colacot, T.J., and Snieckus, V. (2012).
Palladium-catalyzed cross-coupling: a
historical contextual perspective to the 2010
nobel prize. Angew. Chem. Int. Ed. Engl. 51,
5062–5085.
12. Negishi, E.-i., Alimardanov, A., and Xu, C.
(2000). An efficient and stereoselective
synthesis of xerulin via Pd-catalyzed cross
coupling and lactonization featuring (E)-
iodobromoethylene as a novel two-carbon
synthon. Org. Lett. 2, 65–67.
18. Chen, X., Kong, W., Cai, H., Kong, L., and Zhu,
G. (2011). Palladium-catalyzed highly regio-
and stereoselective synthesis of (1E)- or (1Z)-
1,2-dihalo-1,4-dienes via haloallylation of
alkynyl halides. Chem. Commun. (Camb.) 47,
2164–2166.
7. Chen, D., Cao, Y., Yuan, Z., Cai, H., Zheng, R.,
Kong, L., and Zhu, G. (2011). Synthesis of cis-
1,2-dihaloalkenes featuring palladium-
Chem 6, 1018–1031, April 9, 2020 1029

19. Lemay, A.B., Vulic, K.S., and Ogilvie, W.W.
(2006). Single-isomer Tetrasubstituted Olefins
from regioselective and stereospecific
palladium-catalyzed coupling of b-chloro-
a-iodo-a,b-unsaturated esters. J. Org. Chem.
71, 3615–3618.
32. Bellina, F., Colzi, F., Mannina, L., Rossi, R., and
Viel, S. (2003). Reaction of alkynes with iodine
monochloride revisited. J. Org. Chem. 68,
10175–10177.
47. Zeng, X., Liu, S., Hammond, G.B., and Xu, B.
(2018). Hydrogen-bonding-assisted Bronsted
acid and gold catalysis: access to both (E)- and
(Z)-1,2-haloalkenes via hydrochlorination of
haloalkynes. ACS Catal. 8, 904–909.
33. Barluenga, J., Rodriguez, M.A., and Campos,
P.J. (1990). Electrophilic additions of positive
iodine to alkynes through an iodonium
48. Zeng, X., Lu, Z., Liu, S., Hammond, G.B., and
Xu, B. (2017). Metal-free, Regio-, and stereo-
controlled hydrochlorination and
20. Ho, M.L., Flynn, A.B., and Ogilvie, W.W. (2007).
Single-isomer Iodochlorination of alkynes and
chlorination of alkenes using
mechanism. J. Org. Chem. 55, 3104–3106.
hydrobromination of Ynones and Ynamides.
J. Org. Chem. 82, 13179–13187.
34. Horibe, T., Tsuji, Y., and Ishihara, K. (2018).
Thiourea–I2 as lewis Base–Lewis acid
cooperative catalysts for Iodochlorination of
alkene with in situ-generated I–Cl. ACS Catal.
8, 6362–6366.
tetrabutylammonium iodide and
dichloroethane. J. Org. Chem. 72, 977–983.
49. Okoromoba, O.E., Han, J., Hammond, G.B.,
and Xu, B. (2014). Designer HF-based
fluorination reagent: highly regioselective
synthesis of fluoroalkenes and gem-
21. Ide, M., Yauchi, Y., and Iwasawa, T. (2014).
Regio-, and stereoselective iodobromination
of ynamides for synthesis of (E)-1-bromo-2-
iodoenamides. Eur. J. Org. Chem. 2014, 3262–
3267.
35. Grushin, V.V. (2010). The organometallic
fluorine chemistry of palladium and rhodium:
studies toward aromatic fluorination. Acc.
Chem. Res. 43, 160–171.
difluoromethylene compounds from alkynes.
J. Am. Chem. Soc. 136, 14381–14384.
50. Li, Z., Ebule, R., Kostyo, J., Hammond, G.B.,
and Xu, B. (2017). HBr–DMPU: the first aprotic
organic solution of hydrogen bromide.
Chemistry 23, 12739–12743.
22. Ide, M., Yauchi, Y., Shiogai, R., and Iwasawa, T.
(2014). Regio- and stereoselective synthesis of
(E)-1-bromo-2-iodoalkenes through
36. Iodine monochloride. In Encyclopedia of
Reagents for Organic Synthesis.
iodobromination of internal alkynes.
Tetrahedron 70, 8532–8538.
37. Mukherjee, A., Pati, K., and Liu, R.S. (2009). A
convenient synthesis of tetrabenzo
51. Ebule, R., Liang, S., Hammond, G.B., and Xu, B.
(2017). Chloride-tolerant gold(I)-catalyzed
regioselective hydrochlorination of alkynes.
ACS Catal. 7, 6798–6801.
23. Sproul, K.C., and Chalifoux, W.A. (2015). Highly
regio- and diastereoselective formation of
tetrasubstituted (Z)-1,2-dihaloalkenes from the
halogenation of trimethylsilyl alkynes with ICl.
Org. Lett. 17, 3334–3337.
[de,hi,mn,qr]naphthacene from readily
available 1,2-di(phenanthren-4-yl)ethyne.
J. Org. Chem. 74, 6311–6314.
52. Compain, G., Jouvin, K., Martin-Mingot, A.,
Evano, G., Marrot, J., and Thibaudeau, S.
(2012). Stereoselective hydrofluorination of
ynamides: a straightforward synthesis of novel
a-fluoroenamides. Chem. Commun. (Camb.)
48, 5196–5198.
38. Mao, W., Zhang, J., Li, X., Li, C., and Tian, H.
(2017). Regioisomerically pure multiaryl
24. Li, J., Yang, W., Yang, S., Huang, L., Wu, W.,
Sun, Y., and Jiang, H. (2014). Palladium-
catalyzed cascade annulation to construct
functionalized b- and g-lactones in ionic
liquids. Angew. Chem. Int. Ed. Engl. 53, 7219–
7222.
coronene derivatives: highly efficient synthesis
via bay-extended perylene tetrabutylester.
Chem. Commun. (Camb.) 53, 5052–5055.
39. Bortolini, O., Bottai, M., Chiappe, C., Conte, V.,
and Pieraccini, D. (2002). Trihalide-based ionic
liquids. Reagent-solvents for stereoselective
iodination of alkenes and alkynes. Green
Chem. 4, 621–627.
53. Fosu, S.C., Hambira, C.M., Chen, A.D., Fuchs,
J.R., and Nagib, D.A. (2019). Site-selective C–H
functionalization of (hetero)arenes via
transient, non-symmetric iodanes. Chem 5,
417–428.
25. Li, J., Hu, W., Li, C., Yang, S., Wu, W., and Jiang,
H. (2017). Palladium-catalyzed cascade
reaction of haloalkynes with unactivated
alkenes for assembly of functionalized
oxetanes. Org. Chem. Front. 4, 373–376.
40. Endo, N., Kanaura, M., and Iwasawa, T. (2016).
Elucidation of reaction process through
b-halogen elimination in CuCN-mediated
cyanation of (E)-1-bromo-2-iodoalkene.
Tetrahedron Lett. 57, 483–486.
54. Gray, E.E., Nielsen, M.K., Choquette, K.A.,
Kalow, J.A., Graham, T.J.A., and Doyle, A.G.
(2016). Nucleophilic (radio)fluorination of
a-diazocarbonyl compounds enabled by
copper-catalyzed H–F insertion. J. Am. Chem.
Soc. 138, 10802–10805.
26. Blomquist, A.T., Burge, R.E., and Sucsy, A.C.
(1952). Many-membered carbon rings. V.
cyclodecyne, cis- and trans-cyclodecene and
related compounds1. J. Am. Chem. Soc. 74,
3636–3642.
41. Uemura, S., Miyoshi, H., and Okano, M. (1979).
Regio- and stereospecific Z-iodo- and
Z-bromochlorination of alkylphenylacetylenes
via Z-chlorotelluration. Chem. Lett. 8, 1357–
1358.
55. Dai, W., Geib, S.J., and Curran, D.P. (2019).
Ring opening reactions of NHC-boriranes with
in situ generated HCl: synthesis of a new class
of NHC-boralactones. J. Am. Chem. Soc. 141,
3623–3629.
27. Wang, L., Zhu, H., Che, J., Yang, Y., and Zhu, G.
(2014). Synthesis of cis-1,2-
dichlorovinylsulfones via Fe-catalyzed regio-
and stereoselective addition of sulfonyl
chlorides to aromatic chloroalkynes.
Tetrahedron Lett. 55, 1011–1013.
42. Zefirov, N.S., Sereda, G.A., Sosonuk, S.E., Zyk,
N.V., and Likhomanova, T.I. (1995). Versatile
iodination of olefins by potassium
56. Chen, B., Xia, X., Zeng, X., and Xu, B. (2018).
Hydrogen bonding network assisted regio-
and stereo- controlled hydrohalogenations of
sulfonyl alkynes. Tetrahedron Lett. 59, 3950–
3954.
dichloroiodate(I). Synthesis 1995, 1359–1361.
28. Tendil, J., Verney, M., and Vessiere, R. (1974).
Additions electrophiles sur les esters
acetyleniques et alleniques—IV. Tetrahedron
30, 579–584.
43. Barluenga, J., Martı´nez-Gallo, J.M., Na´jera, C.,
and Yus, M. (1987). Stereoselective
bifunctionalization of alkynes by means of the
mercury(II) salt–iodine combination. J. Chem.
Soc. Perkin Trans. 1, 1017–1019.
57. Schevenels, F.T., Shen, M., and Snyder, S.A.
(2017). Isolable and readily handled
halophosphonium pre-reagents for hydro- and
deuteriohalogenation. J. Am. Chem. Soc. 139,
6329–6337.
29. Schuh (ne´ e Muller), K., and Glorius, F. (2007). A
¨
domino copper-catalyzed C-N and C-O cross-
coupling for the conversion of primary amides
into oxazoles. Synthesis 2007, 2297–2306.
44. Chen, Z., Jiang, H., Li, Y., and Qi, C. (2010).
Highly efficient two-step synthesis of (Z)-2-halo-
1-iodoalkenes from terminal alkynes. Chem.
Commun. 46, 8049–8051.
58. Derosa, J., Cantu, A.L., Boulous, M.N., O’Duill,
M.L., Turnbull, J.L., Liu, Z., De La Torre, D.M.,
and Engle, K.M. (2017). Palladium(II)-catalyzed
directed anti-hydrochlorination of unactivated
alkynes with HCl. J. Am. Chem. Soc. 139, 5183–
5193.
30. Pagni, R.M., Kabalka, G.W., Boothe, R.,
Gaetano, K., Stewart, L.J., Conaway, R., Dial,
C., Gray, D., Larson, S., and Luidhardt, T. (1988).
Reactions of unsaturated compounds with
iodine and bromine on.gamma. alumina.
J. Org. Chem. 53, 4477–4482.
45. Zefirov, N.S., Samsoniya, N.S., Kutateladze,
T.G., and Zhdankin, V.V. (1991). (Difluoroiodo)
benzene - boron trifluoride as a reagent for the
preparation of 1,4-diketones from O-silyl
derivatives of enols. Zh. Organ. Khim. 27,
220–222.
59. Zeng, X., Li, J., Ng, C.K., Hammond, G.B., and
Xu, B. (2018). Radio)fluoroclick reaction
31. Heasley, V.L., Buczala, D.M., Chappell, A.E.,
Hill, D.J., Whisenand, J.M., and Shellhamer,
D.F. (2002). Addition of bromine chloride and
iodine monochloride to carbonyl-conjugated,
acetylenic ketones: synthesis and mechanisms.
J. Org. Chem. 67, 2183–2187.
46. Zhu, G., Chen, D., Wang, Y., and Zheng, R.
(2012). Highly stereoselective synthesis of (Z)-
1,2-dihaloalkenes by a Pd-catalyzed
enabled by a hydrogen-bonding cluster.
Angew. Chem. Int. Ed. Engl. 57, 2924–2928.
hydrohalogenation of alkynyl halides. Chem.
Commun. 48, 5796–5798.
60. Chen, W., Walker, J.C.L., and Oestreich, M.
(2019). Metal-free transfer hydroiodination of
1030 Chem 6, 1018–1031, April 9, 2020

C–C multiple bonds. J. Am. Chem. Soc. 141,
1135–1140.
(E)- and (Z)-alkenyl sulfonates. Org. Lett. 18,
4770–4773.
coiodination of alkenes and enolethers with
oxygenated nucleophiles. Tetrahedron Lett.
48, 8747–8751.
61. Chen, W., and Oestreich, M. (2019). Metal-free
transfer hydrobromination of C–C triple bonds.
Org. Lett. 21, 4531–4534.
70. Barluenga, J., Rodriguez, M.A., Campos,
P.J., and Asensio, G. (1988). Synthesis of 2-
functionalized 1,1-diiodo-1-alkenes.
80. Monenschein, H., Sourkouni-Argirusi, G.,
Schubothe, K.M., O’Hare, T., and Kirschning, A.
(1999). Reactions of alkenes, alkynes, and
alkoxyallenes with new polymer-supported
electrophilic reagents. Org. Lett. 1, 2101–2104.
Generation and reactions of 1-iodo-1-lithio-
1-alkenes and 1,1-dilithio-1-alkenes. J. Am.
Chem. Soc. 110, 5567–5568.
62. Herges, R., Papafilippopoulos, A., Hess, K.,
Chiappe, C., Lenoir, D., and Detert, H. (2005).
cis-bromination of alkynes without cationic
intermediates. Angew. Chem. Int. Ed. Engl. 44,
1412–1416.
71. Yang, Z., Chen, X., Kong, W., Xia, S., Zheng, R.,
Luo, F., and Zhu, G. (2013). An operationally
simple approach to (E)-a-halo vinyl sulfides and
their applications for accessing stereodefined
trisubstituted alkenes. Org. Biomol. Chem. 11,
2175–2185.
81. Rao, D.S., Reddy, T.R., Babachary, K., and
Kashyap, S. (2016). Regioselective vicinal
functionalization of unactivated alkenes with
sulfonium iodate(i) reagents under metal-free
conditions. Org. Biomol. Chem. 14, 7529–7543.
63. Wu, W., and Jiang, H. (2014). Haloalkynes: a
powerful and versatile building block in
organic synthesis. Acc. Chem. Res. 47, 2483–
2504.
82. Hokamp, T., Storm, A.T., Yusubov, M., and
Wirth, T. (2018). Iodine monoacetate for
efficient oxyiodinations of alkenes and alkynes.
Synlett 29, 415–418.
72. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1912785).
64. Hein, J.E., Tripp, J.C., Krasnova, L.B.,
Sharpless, K.B., and Fokin, V.V. (2009).
Copper(I)-catalyzed cycloaddition of organic
azides and 1-iodoalkynes. Angew. Chem. Int.
Ed. Engl. 48, 8018–8021.
73. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1948339).
83. Xia, X.F., Gu, Z., Liu, W., Wang, N., Wang, H.,
Xia, Y., Gao, H., and Liu, X. (2014). Selective
oxygenation of alkynes: a direct approach to
diketones and vinyl acetate. Org. Biomol.
Chem. 12, 9909–9913.
65. Trofimov, A., Chernyak, N., and Gevorgyan, V.
(2008). Dual role of alkynyl halides in one-step
synthesis of alkynyl epoxides. J. Am. Chem.
Soc. 130, 13538–13539.
74. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1912792).
84. Lu, L.-H., Zhou, S.-J., Sun, M., Chen, J.-L., Xia,
W., Yu, X., Xu, X., and He, W.-M. (2019). Metal-
and solvent-free ultrasonic multicomponent
synthesis of (Z)-b-iodo vinylthiocyanates. ACS
Sustainable Chem. Eng. 7, 1574–1579.
66. Jiang, G., Fang, S., Hu, W., Li, J., Zhu, C.,
Wu, W., and Jiang, H. (2018). Palladium-
catalyzed sequential C(sp2)-H alkynylation/
annulation of 2-phenylphenols with
haloalkynes using phenolic hydroxyl as the
traceless directing group. Adv. Synth. Catal.
360, 2297–2302.
75. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1948338).
76. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1966560).
85. Henkel, S., Misuraca, M.C., Troselj, P.,
Davidson, J., and Hunter, C.A. (2018).
Polarisation effects on the solvation properties
of alcohols. Chem. Sci. 9, 88–99.
77. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1966562).
67. Xie, L., Wu, Y., Yi, W., Zhu, L., Xiang, J., and He,
W. (2013). Gold-catalyzed hydration of
Haloalkynes to a-halomethyl ketones. J. Org.
Chem. 78, 9190–9195.
86. Smith, M., and March, J. (2007). March’s
Advanced Organic Chemistry Reactions,
Mechanisms, and Structure, Sixth Edition
(Wiley-Interscience).
78. Pimenta, L.S., Gusevskaya, E.V., and Alberto,
E.E. (2017). Intermolecular halogenation/
esterification of alkenes with N-
68. Zou, H., He, W., Dong, Q., Wang, R., Yi, N.,
Jiang, J., Pen, D., and He, W. (2016). First
catalyzed hydration of halo-alkynes by a
recyclable catalytic-system. Eur. J. Org. Chem.
2016, 116–121.
87. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1912791).
halosuccinimide and acetic acid catalyzed by
1,4-diazabicyclo[2.2.2]octane. Adv. Synth.
Catal. 359, 2297–2303.
69. Zeng, X., Liu, S., Shi, Z., and Xu, B. (2016).
Hydrogen bonding cluster-enabled addition of
sulfonic acids to haloalkynes: access to both
79. Ribeiro, R.d.S., Esteves, P.M., and de Mattos,
M.C.S. (2007). Triiodoisocyanuric acid: a new
and convenient reagent for regioselective
88. Its crystallographic data have been deposited
to Cambridge Crystallographic Data Centre
(CCDC 1966561).
Chem 6, 1018–1031, April 9, 2020 1031