TEMPO-Regulated Regio- and Stereoselective Cross-Dihalogenation with Dual Electrophilic X+ Reagents

DOI: 10.1002/cjoc.202100472

Source and publish data:

Chinese Journal of Chemistry p. 3004 - 3010 (2021)

Update date:2022-08-02

Topics: Reagents Stereoselective Regioselective

Authors:

Kong, Yi

Cao, Tongxiang

Zhu, Shifa

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Article abstract of DOI:10.1002/cjoc.202100472

A TEMPO catalyzed cross-dihalogenation reaction was established via redox-regulation of the otherwise complex system of dual electrophilic X⁺ reagents. Formally, the ICl, BrCl, I₂ and Br₂ were generated in-situ, which enabled high regio- or stereoselective access to a myriad of iodochlorination, bromochlorination and homo-dihalogenation products with a wide spectrum of functionalities. With its mild conditions and operational simplicity, this method could enable wide applications in organic synthesis, which was exemplified by divergent synthesis of two pharmaceuticals. Detailed mechanistic investigations via radical clock reaction, pinacol ring expansion and Hammett experiments were conducted, which confirmed the intermediacy of halonium ion. In addition, a dynamic catalytic model based on the versatile catalytic role of TEMPO was proposed to explain the selective outcomes.

Full text of DOI:10.1002/cjoc.202100472

Chinese Journal

of Chemistry

CJC

中国化学 - An International Journal

Accepted Article

Title: TEMPO-regulated regio- and stereoselective cross-dihalogenation with dual

electrophilic X+ reagents

Authors: Yi Kong, Tongxiang Cao,* and Shifa Zhu*

This manuscript has been accepted and appears as an Accepted Article online.

This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100472.

The final Version of Record (VoR) of it with formal page numbers will soon be

published online in Early View: http://dx.doi.org/10.1002/cjoc.202100472.

ISSN 1001-604X • CN 31-1547/O6

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TEMPO-regulated regio- and stereoselective cross-dihalogena-

tion with dual electrophilic X⁺reagents

Yi Kong, Tongxiang Cao,* and Shifa Zhu*

Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China

University of Technology, Guangzhou, 510640, P. R. China.

Keywords

Cross-dihalogenation | TEMPO catalysis | Dual electrophilic addition | Redox-regulation | Hammett plot

Main observation and conclusion

A TEMPO catalyzed cross-dihalogenation reaction was established via redox-regulation of the otherwise complex system of dual elec-

trophilic X⁺reagents. Formally, the ICl, BrCl, I₂and Br₂were generated in-situ, which enabled high regio- or stereoselective access to a

myriad of iodochlorination, bromochlorination and homo-dihalogenation products with a wide spectrum of functionalities. With its

mild conditions and operational simplicity, this method could enable wide applications in organic synthesis, which was exemplified by

divergent synthesis of two pharmaceuticals. Detailed mechanistic investigations via radical clock reaction, pinacol ring expansion and

Hammett experiments were conducted, which confirmed the intermediacy of halonium ion. In addition, a dynamic catalytic model

basing on the versatile catalytic role of TEMPO was proposed to explain the selective outcomes.

Comprehensive Graphic Content

in divergent

drugs

TEMPO-regulated

cross-dihalogenation

Application

synthesis

regio/stereoselective

X²

R²

R¹

X¹

R¹

R²

X¹

X²

TEMPO

dual X⁺addition

•

Z-toremifene

examples

cis-clomifene

broad substrates

selectivity

good

Selected

representive

BzO

TsO

EtO

scale

77%

55%

58%

1.8

74%

73%

91%

87%

O O

OEt

TBSO

88%

42%

CO₂

77%

61%

52%

76%

82%

73%

75%

74%

99%

73%

50%

*E-mail: caotx@scut.edu.cn; zhusf@scut.edu.cn

View HTML Article

Supporting Information

Chin. J. Chem. 2021, 39, XXX－XXX©

2021

SIOC,

CAS,

Shanghai,

WILEY-VCH

GmbH

This article has been accepted for publication and undergone full peer review but has not been

through the copyediting, typesetting, pagination and proofreading process which may lead to

differences between this version and the Version of Record. Please cite this article as doi:

10.1002/cjoc.202100472

First author et al.

Report

halogen reagents.

Background and Originality Content

Scheme 1 Importance of organohalides and principle of design for cross-di-

halogenation

It cannot be overstressed how fundamental roles of organohal-

ides played in organic synthesis. They exhibit versatile activities in

different scenarios, such as radical, carbocation and carbanion,

which account for their prevalence in various named reactions since

the early beginning of organic chemistry. In addition, more than

5000 naturally occurring organohalogens have been character-

ized,^[1]which display a range of extraordinary biological activities,

and their synthesis have become a competitive subject in drug dis-

covery (Scheme 1a).^[2]For example, halomon was one of the most

extreme cases of differential cytotoxicity in NCI-60 human tumour

cell line screen and was selected for preclinical drug development.^[3]

Therefore, there is no doubt that exploiting new halogentation

methods based on easy available industry feedstocks would have a

profound effect on organic community. In this vein, dihalogenation

of alkynes has constructive means owing to the versatile reactivity

of organohalide, especially cross-dihalogenation because the re-

sulting products could selectively bridge two different building

blocks.^[4]However, there were only a few methods reported on

cross-dihalogenation of alkynes (Scheme 1b), and most of them suf-

fered from limited substrate scope and hazard conditions.^[5]Fur-

thermore, these reactions were usually companied with some re-

gio- and stereoisomers,^{[5b, 5c, 5e, 5h, 5j]}which might raise several pains-

taking troubles in purification and application. Specifically, at the

early stage some highly toxic reagents, such as HgCl₂, ICl, and BrCl,

were applied, and sometimes the ionic liquid was required.^{[5a, 5b, 5g,}

occurring

Naturally

organohalogens

OAc

Me Br

algoane

anverene

halomon

prefuroplocamioid

works

furoplocamioid

in cross-dihalogenation of

alkynes

R¹

Et₃N•HF X₂R¹

I/Br

R²

HgCl₂

Bu₄NI DCE

4) R¹

CO₂

R²

Cl₄

KF NIS

R²

CO₂

•

R¹

I/Br

HBF₄OEt₂

NBS/TMSCl

[hmim][

]

8) R¹

R²

NR₂

PhSPh, NXS

R²

]

[Py₂][

NR₂

R¹

I/Br

R¹

X²

R²

SiR₃

I/Br

NX²LiX¹

R²

SiR₃

ICl

HOAc, DCM

X¹

COMe

1979-2002

2006-2014

development of TEMPO-regulated cross-dihalogenation with dual X⁺

2018-2020

This Work

reagents

c) Conceptual

complex system

(

)

system

regulated

redox-cat⁺

X¹X²

solvent

BrCl

ICl

X²

X¹

X²

R²

R¹

X¹

redox

R¹

R²

TEMPO

X¹

X²

NXS

X¹

X²

regulation

TEMPO

X²

X¹

I₂Br

X¹

X²

species

redox-cat

¹and

dual X⁺addition

diverse active

tailored

•

good

•

broad substrates

selectivity

Results and Discussion

Optimization Study Initially, the multihalogenated alkenes were

chosen as the targets owing to their superiority in selectively inte-

grating different building blocks from divergent orientations.^[4]So

the haloalkyne 1 with a native bromide was selected as the model

substrate, and NIS/NCS as halogen sources. In the absence of

TEMPO, the alkynyl bromide was drawn into the chaos of untamed

active species to give a statistic distributed mixture of halogenation

(Table 1, entry 1). It is noteworthy that the bromine scrambling

products 1c and 1d indicate that the bromine is able to hop in dif-

ferent oxidation states, such as bromine cation, anion, and even

radical. Gratifyingly, when the postulated redox-regulator, TEMPO,

was introduced, the desired iodochlorination product 1a was iso-

lated in 78% yield and the bromine scrambling products (1c and 1d)

were suppressed efficiently (Table 1, entry 2). These striking con-

trasts indicated that the persistent radical TEMPO had a great ben-

efit to this otherwise complex system, which encouraged us to in-

vestigate other aminoxyl radical (Table 1, entries 3-6). The out-

comes revealed that the selectivity was sensitive to the redox cata-

lyst, which further confirmed that TEMPO actually redefined the

property of system in a unique manner. The solvent of the reaction

exerted a great influence on the efficiency as well (Table 1, entries

7-11). Lowering the reaction temperature did not improve the se-

lectivity, but decreased the reaction rate obviously (Table 1, entry

12). Reducing the catalyst loading had no effect on the selectivity,

but reduced the yield greatly (Table 1, entries 13-14).

Scope of the Investigation With the optimized reaction condi-

tions (Table 1, entry 2) in hand, the substrate scope was then ex-

plored. As shown in Table 2, various alkynyl bromides with different

electronic substitution groups on the phenyl motif were tested

firstly, which underwent the iodochlorination reaction smoothly to

give 1a-11a in moderate to good yield (29-87%) and the structure

was confirm unambiguously by X-ray crystallographic analysis of

10a. The electronic nature of substituents exerted a dramatic im-

pact on the reaction outcomes with the electron-rich substrates in

better yields than the electron-deficient counterparts. For example,

the 4-tert-butyl, 4-chloro, 4-fluoro substituted iodochlorination

products were obtained in higher than 85% yields, while the 4-tri-

fluoromethyl and 4-cyano substituted products were furnished in

65% and 61%, respectively.

5i, 5j]

Later, a few environmental-benign cross-dihalogenation sys-

tems have been developed, while they only worked well with spe-

cific alkynes.^{[5e, 5h, 6]}Recently, the challenging iodofluorination of al-

kyne was achieved as well.^{[5d, 7]}It is noteworthy that a catalyst-free

protocol for 1,2-trans-dihalogenation of alkynes with broad sub-

strate was reported lately by using a critical hydrogen bonding do-

nor solvent.^[8]As a complement, several hydrohalogenation meth-

ods based on prehalogenated haloalkynes to achieve the cross-hal-

ogenated alkenes were also exploited.^[9]Despite of these contin-

uous efforts and achievements, it is still highly desirable, yet chal-

lenging, to exploit efficient regio- and stereoselective cross-dihalo-

genation protocols.

It is obvious that the precedent works on addition of two differ-

ent halogens across the alkyne or alkene were mostly focused on

using ICl/BrCl or the combination of an electrophilic halogen rea-

gent X₁and a nucleophilic anion X₂in a redox neutral manner

(Scheme 1b). We wonder whether a reductive cross-dihalogenation

strategy with cheap and easily available NXS as halogen sources is

feasible (Scheme 1c). Encouragingly, several reductive dibromina-

tion of alkynes and alkenes were reported,^[10]indicating the feasi-

bility of our postulation. However, to the best of our knowledge, no

reductive cross-dihalogenation reaction was reported, which might

arise from the following challenges. Obviously, diverse active spe-

cies (Scheme 1c), such as halogen species in different forms and

multiple oxidation states, might exist in the same scenario. These

active species could be aggressive in competitively engaging the

substrates, which would lead to awful mixtures of regio- and stere-

oisomers, even compounds with different compositions. Consider-

ing such system might involve a plethora of redox events and a class

of transient species of halogen,^[11]thus we postulated that a redox

versatile catalyst might be able to redefine the behavior of such spe-

cies via redox-regulation (Scheme 1c). Inspired also by Jiao’s

achievement in halogenation by using simple DMSO as catalyst,^[12]

the commercially available persistent aminoxyl radical TEMPO was

supposed to be a promising catalyst for the envisaged reductive

cross-dihalogenation reaction, as this open-shell species is inclined

to engage redox reaction via one or two-electron processes to ac-

cess three discrete oxidation states.^[13]Herein, we report a reduc-

tive cross-dihalogentation protocol by successfully merging the ver-

satile redox ability of TEMPO with the redox nature of electrophilic

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Chin. J. Chem. 2021, 39, XXX－XXX

Running title

Chin. J. Chem.

Table 1 Optimization of the reaction conditions^a

Table 2 Substrate scope of iodochlorination^a

R₂N-O

mol%)

TEMPO

mol%)

(1.1

(20

NCS

NIS

eq)

(1.1 eq),

NIS

NCS

eq)

(1.1

(1.1 eq),

solvent

DCE

rt, 24 h

(0.2 M),

24 h

(0.2 M),

MeO

4-Methoxy-TEMPO

TEMPO

4-Oxo-TEMPO

ABNO

4-Hydroxy-TEMPO

MeO

1a 78%^a

scale

2a 41%^a

3a, 83%^a

4a, 87%^a

5a, 78%^a

6a, 85%^a

Ratio^c

1a 1b 1c 1d 1e

1.8

74%^a

Yield

(1a %)^b

Entry

Cat.

Solvent

MeO

CF₃

O₂

DCE

23 14

20 32

7a 86%^a

8a 65%^a

9a 51%^a

10a 61%^a

11a 29%^a

12a 80%^a

TEMPO

BzO

EtO

TsO

TBSO

4-Hydroxy-TEMPO

4-Methoxy-TEMPO

4-Oxo-TEMPO

ABNO

DCE

13a, 80%^a

14a 80%^a

15a 91%^a

16a 55%^a

17a 25%^a

18a, 87%^a

DCE

15 29

14 10

19a, 77%

20a, 73%

21a, 60%

22a, 47%

23a, 97%

24a, 86%, E:Z 10:1

DCE

CO₂Et

TEMPO

DCM

CHCl₃

Toluene

THF

, 58%

MeO

TEMPO

25a, 95%,

E:Z

10:1

26a, 55%

27a

28a, 68%

29a 84%

30a 88%

TEMPO

₃C

12^d

TEMPO

45 39

21 74

63 33

X-ray of 10a

31a, 49%

32a, 88%

33a, 61%

34a, 71%

35a, 52%

TEMPO

MeCN

DCE

Reaction conditions: Unless otherwise specified, the reactions were run

with alkyne or haloalkyne (0.2 mmol), 20 mol% TEMPO, NIS (0.24 mmol) and

TEMPO

NCS (0.24 mmol) in DCE(0.2 M) at 30 C for 24 h; Isolated yields. ^bCompa-

TEMPO 10%

DCE

nied with isomers d and the ratio of a:d > 10:1.

TEMPO 5%

DCE

^aUnless otherwise noted, all reactions were carried out with compound 1

(0.2 mmol), Cat (20 mol%) under conditions indicated in the scheme. ^bI-

solated yield, but companied with isomers 1d; the ratio was confirmed by

quantitative ¹³C NMR spectroscopy (1a: 1d =12.0: 1), which almost identical

to the ratio of GC-MS (1a: 1d =13: 1). ^cRatios were determined by analysing

the integral areas of GC-MS chromatography. ^d0 ^oC for 24 h.

both alkyl and aryl groups could take part in this transformation

smoothly, affording the desired cross-dihalogenation products in

moderate to excellent yields (39-93%) and selectivity. Of note, the

terminal alkyne was effective substrate as well. In addition, a wide

spectrum of functionalities, such as ester, nitrile, nitro, sulfone, sul-

fonate, silyl ether etc. were also tolerated.

It's more obvious that the 4-nitro substituted substrate 11 only

gave the desired product 11a in 29% yield. These results implied

that a positive charge may be build-up in the transition state of

these reactions. Alkynyl bromides containing other type arenes,

such as naphthalene and thiophene, could also participate in this

reaction to give product 12a-13a in good yields. The alkyalkynyl

bromide could be efficiently converted to the desired products 14a-

17a in 25-91% yield. The propiolate derived bromoalkyne 18 under-

went the reaction smoothly to give 18a in 87% yield. Besides, chlo-

roalkyne and iodoalkyne were tested as well, which gave the iodo-

chlorination products 19a and 20a in 77% and 73% yields, respec-

tively. The internal alkynes were also effective substrates, which

could transfer to the desired products 21a and 22a in good yields.

Then, the feasibility of unsymmetrical alkynes was discussed as well,

and the iodochlorinated products 23a-26a were obtained in mod-

erate to excellent yield (55-97%). This strategy was also applicable

to terminal alkynes. Both electron-donating and electron-with-

drawing arylalkynes were well-tolerated, giving the products 27a-

35a in 52-88% yields. It is noted that this reaction tolerated a wide

spectrum scope of functionalities, such as ester, nitrile, nitro, sul-

fone, sulfonate, thiophene, silyl ether etc.

Table 3 Substrate scope of bromochlorination^a

TEMPO

(1.2 eq),

mol%)

(20

DBDMH

DCDMH

(1.2

rt, 24 h

eq)

MeCN(0.2 M),

1b 1c 92:8, 76% 37b 37c 91:9, 47%

4b 4c 92:8, 55%

5b:5c 94:6, 52%

6b 6c 94:6, 77%

7b 7c 96:4, 58%

OBz

₃C

MeO₂C

8b 8c 95:5, 70%

9b 9c 93:7, 39%

10b 10c 90:10, 93%

14b 14c 95:5, 52%

38b 38c 90:10, 76%

TsO

OTBS

17b 17c 90:10, 52%

16b 16c 90:10, 61%

19b 19c 92:8, 82%

41b:41c 95:5, 53%

22b:22c 95:5, 53%

OEt

40b:40c 95:5, 42%

24b:24c 94:6, 77%

25b:25c 95:5, 88%

26b:26c 94:6, 61%

27b:27c 92:8, 39%

Reaction conditions: Unless otherwise specified, the reactions were run

with alkyne or haloalkyne (0.2 mmol), 20 mol% TEMPO, DBDMH (0.24 mmol)

and DCDMH (0.24 mmol) in MeCN (0.2 M) at 30 ^oC for 24 h; isolated yields;

DBDMH: 1,3-dibromo-5,5-dimethylhydantoin; DCDMH: 1,3-dichloro-5,5-di-

methylhydantoin.

Having realized the iodochlorination protocol, we then pro-

ceeded to extend this strategy to more challenging bromochlorina-

tion reaction. Initially, when NIS was replaced by NBS under other-

wise identical conditions, the bromochlorination product 1b and di-

bromonation product 1c were obtained in 2:1 ratio, which might

arise from a narrow redox-window between NBS and NCS. So other

electrophilic halogen sources were tested and satisfactory results

could be obtained when DBDMH and DCDMH were applied (see

Supporting Information for details). The newly optimized condi-

tions were found also robust and efficient for bromochlorination.

As exhibited in Table 3, a large number of substrates bearing

Encouraged by the above achievements, we further advanced

to test the possibility of this strategy in homo-dihalogenation reac-

tion (Table 4). Firstly, the effect of electronic nature of the aryl

groups was discussed, which showed that the electron-rich sub-

strates usually worked better than the electron-deficient one,

which was congruent with that observed in the iodochlorination re-

action. It is worth to note that diiodonation products were also ac-

cessible. For instance, the alkynyl chloride and bromide underwent

this reaction smoothly to give 19e and 1e in 73% and 50% yield,

respectively.

Chin. J. Chem. 2021, 39, XXX－XXX

www.cjc.wiley-vch.de

First author et al.

Report

Table 4 Substrate scope of dihalogenation ^a

Scheme 2 Application in divergent synthesis of drugs.

TEMPO

mol%) NXS

(2.4

eq)

(40

DCE, rt , 24 h

OMe

1. BBr₃, -78 ^oC to -20^oC,

KOH

)

THF/MeOH

Pd(PPh₃

, PCy₃

Pd(OAc)₂

24 h

B(OH)₂

DCM ,

KOH

B(OH)₂

27c

28c

74%

33c, R 4-F, 59%

34c, R 4-CF₃, 55%

₂CO₃

110 ^o12 h

2. Et

THF/H

80 ^o2 h

₂N(C_{2 4}Cl)•HCl,

₂O, C,

4-OMe, 76%

acetone, 60 ^o1 h

2 steps 54%

yield

29c, R 4-Me, 68%

30c, R 4- Bu, 79%

32c, R 4-Cl, 71%

36c,

4-CN, 94%

4-CHO, 50%

2-Br, 87%

2 steps 73%

yield

isomer

(single

used directly)

41c

42c

60 cis-clomifene

43c, 65%

45c, 67%

1. BBr₃, -78 ^oC to

DCM, 2 h

-r.t.

, PCy₃

₄, KOH

)

Pd(OAc)₂

Pd(PPh₃

THF/MeOH

B(OH)₂

TsO

KOH

2 steps

ref: 62

B(OH)₂

110 ^o12 h

THF/H

80 ^o2 h

2. Et

₂CO₃

₂O,

2 steps 49%

₂N(C_{2 4}Cl)•HCl,

acetone, 60 ^o2 h

44c 55%

46c, 52%

47c, 66%

48c, 64%

22c 99%

yield

2 steps 80%

62 E/Z 2.6:1

yield

OMe

CO₂Et

63, Z-toremifene

25c, 82%

19c, 73%

1c, 75%

19e, 73%

1e, 50%

Mechanistic Study To investigate the reaction mechanism, sev-

Reaction conditions: Unless otherwise specified, the reactions were run

with alkyne or haloalkyne (0.3 mmol), 40 mol% TEMPO and NBS or NIS

(0.72mmol) in DCE (0.2 M) at 30 ^oC for 24 h; Isolated yields.

eral control reactions were then performed (Scheme 3). Firstly, the

radical clock reactions were carried out with vinylcyclopropane 64,

and no ring opening products were observed, but instead the dihal-

ogenated product 64c was isolated in good yield (Scheme 3, eq.1).

These results indicated that no bromine radical was involved in the

product generation event. Then, the Pinnacol rearrangement pre-

cursor 65 was designed and tested as well. As expected, the desired

ring expansion ketone 66 was obtained in 44% yield as the single

isomer, which indicated the intermediacy of iodinium ion (Scheme

3, eq. 2). To get more mechanistic evidences, the Hammett studies

were conducted consequently. The large, negative Hammett-slope

(ρ = -4.34) indicated a bromonium was formed with a high degree

of positive charge development during dibromination of styrene.

Similarly, when alkyne was used for dibromination and iodochlorin-

ation reactions, the Hammett-plot gave a negative ρ (ρ = -2.09 and

-2.48, respectively) value as well. All these investigations confirmed

that the halonium ion involved process was predominated in prod-

uct forming reaction. In addition, the TEMPO could be recovered in

64% yield, which indicated that the TEMPO mainly acts as catalyst.

Finally, several alkenes were tested as substrates for iodochlo-

rination and bromochlorination (Table 5). The results indicated that

this strategy could serve as viable method to access this class of

products. Considering catalytic stereoselective dihalogenation of

alkenes were extensively investigated and recent years have wit-

nessed significant advances in enantioselective version, further ex-

plored the substrate scope was not implemented.^[14]

Table 5 Cross-dihalogenation of alkenes^a

X¹

TEMPO, X¹X²

sol

rt, 24 h

X²

(0.2 M),

₃C

50a, 80%^a

51a, 23%^a

52a, 81%^a

53a, 64%^a

54a, 85%^a

55a 34%^a

57b, 41%^b

54b, 62%

50b, 70%

51b, 68%

55b, 74%

(14:1)

56b, 54%^b

(8:1)

(10:1)

(12:1)

Scheme 3 Mechanistic investigation.

Reaction conditions: Unless otherwise specified, the reactions were run

with alkenes (0.3 mmol), 20 mol% TEMPO, NIS (0.33 mmol) and NCS (0.33

mmol) in DCE (0.2 M) at 30 ^oC for 24 h; ^bAlkenes (0.3 mmol), 30 mol% TEMPO,

DBDMH (0.36 mmol) and DCDMH (0.36 mmol) in toluene (0.2 M) at 30 ^oC

for 24 h; DBDMH: 1,3-dibromo-5,5-dimethylhydantoin; DCDMH: 1,3-di-

chloro-5,5-dimethylhydantoin.

Radical clock test.

BnO₂C

64c, 73%

BnO₂C

TEMPO, NBS

DCE , 30 ^o24 h

(1)

BnO₂C

rearrangement

Pinnacol

Cl^-

OTBS

TBSO

TEMPO, NCS, NIS

TBSO

DCE , 30 ^o24 h

(2)

65a, 0%

66, 44%

Hammett studies

0.5

Clomiphene and Toremifene share a tetra-substituted ethylene

unit with different substituents, which are good platform to test the

diversity-oriented synthetic utility of this methodology. More im-

portantly, Clomiphene is the effective elements of the first line drug

Clomiphene citrate for polycystic ovary syndrome associated infer-

tility.^[15]Toremifene has been used in the treatment of breast can-

cer for more than 20 years,^[16]which could interact with and desta-

bilize the Ebola virus glycoprotein as well.^[17]Notably, recent re-

search has proved that toremifene can block the spike protein and

NSP14 of SARS-CoV-2, offering a drug candidate for COVID-19.^[18]

As demonstrated in Scheme 2, these two important drugs were

synthesized by leveraging the chemo-distinguishable product 1a as

starting material (Scheme 2). Capitalizing on the Suzuki–Miyaura

coupling reaction, two phenyl groups were selectively introduced

to give 59 as a single stereoisomer. After deprotection, the amine

segment was effective introduced to give the cis-clomifene 60 in 73%

yield of two steps. Similarly, the triphenylethylene 61 was obtained

as a single isomer from the same starting material 1a by adjusting

the installation order of aryl. While under the BBr₃condition, a Z/E

mixture was obtained from 61, which probably owe to the electro-

philic BBr₃interact with the C=C double bond. According to the lit-

erature, the alkylation intermediate 62 could be transformed to

toremifene in two steps.^[19]

p-Me

p-OMe

1.5

0.5

p-Me

0.5

p-Cl

p-H

-0.5

-1

p-H

p-F

-0.5

-1

p-CF₃

p-H

p-CF₃

p-CN

0.7

y = -2.48x + 0.24

R² = 0.97

y = -4.34x + 0.30

R² = 0.94

-0.5

-1

y = -2.09x + 0.27

R² = 0.94

-1.5

p-Cl

0.3

p-CN

-1.5

-2

-0.3

-0.2

-0.1

0.1

0.2

-0.3

-0.1

0.1

0.3

0.5

-0.3

-0.1

0.1

0.3

0.5

0.7

As shown in Scheme 4, a dynamic multisite cooperative cata-

lytic model was proposed, wherein different site of the network

plays a particular role respectively. When TEMPO was introduced

into the reaction system, a redox network of TEMPO was estab-

lished via self-disproportionation reaction or other redox events,

such as single electron transfer/hydrogen abstraction with halogen

reagents or solvent.^{[13b], [20]}The resulting three species of TEMPO in

different oxidation acted like the “guard” watching over and regu-

lating the redox behavior of the transient species in this system.

Taking the iodiochlorination reaction as an example, the TEMPO

might be able to abstract a halogen atom from NIS to give TEMPO-

I, which was observed by HRMS (Scheme 4, site A). In addition, the

TEMPO could serve as a scavenger of halogen radical,^{[11a, 21]}which

somehow ensured the observed good selectivity. When the NCS

confronted with TEMPO^-, a redox event might occur preferentially

to give a chloride owning to its greater oxidative ability (Scheme 4,

site B).^[22]In addition, if any I^-was produced somehow, which could

be oxidized into I₂by TEMPO⁺as their matched oxidative poten-

tial.^[13b]It is noteworthy that as lately reported the TEMPO⁺could

interact with NXS to generate an oxoammonium halide (Scheme 4,

site C),^[23]which could also catalyze this reaction but with unsatis-

fied regio- and stereoselectivity. Theoretically, these electrophilic I⁺

www.cjc.wiley-vch.de

Chin. J. Chem. 2021, 39, XXX－XXX

Running title

Chin. J. Chem.

spices, like TEMPO-I, oxoammonium iodide, could interact with al-

kyne or alkene to form a halonium ion, which were then attacked

by chloride to give the iodichlorination product (Scheme 4, central

part). However, as the [TEMPO][OTf] and NIS were less effective

and gave inferior selectivity (see SI for details), we preferred to that

the TEMPO-I was actually the productive catalytic species. Besides,

the contribution from other Lewis base or solvent associated elec-

trophilic halogen spices could also be possible.^[24]

mixture of DCE (0.2 M). The reaction mixture was stirred at room

temperature for 24 h. Upon completion, the solvent was removed

under reduced pressure and the crude product was subjected to

silica gel column chromatography to afford the desired products (1c,

19c, 22c, 25c, 27c-36c, 41c-48c, 1e, 19e).

Supporting Information

The supporting information for this article is available on the

WWW under https://doi.org/10.1002/cjoc.2021xxxxx.

Scheme 4 Proposed catalytic model for cross-dihalogenation.

site A

TEMPO-I

produce

e^-

redox

process

competitive pathway

potential pathway

TEMPO

Acknowledgement

productive pathway

R²

R¹

We appreciate financial support from the NSFC (21871096,

22071062, 22001077), Ministry of Science and Technology of the

People’s Republic of China (2016YFA0602900), Guangdong Science

HR-MS:

[M+H]⁺

e^-

282.0360

Found: 282.0351

R²

R¹

R²

R¹

and

Technology

Department

(2018B030308007,

Cl^-

oxoammonium

iodide

2021A1515012331), China Postdoctoral Science Foundation

(2018M643062, 2019T120723).

R¹

I^-

TEMPO⁺

TEMPO

site B

R²

I^-

site C

scavenge

Cl^-

e^-

provide

References

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In summary, we have established a TEMPO-catalyzed cross-di-

halogenation system, wherein the ICl, BrCl, I₂and Br₂were formally

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General procedure for iodichlorination with alkynes, haloal-

kynes and alkenes

A 5 mL glass vial with a screw cap was charged with alkyne or

alkene (1.0 eq), TEMPO (20 mol%), NIS (1.1 eq), NCS (1.1 eq) and a

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A 5 mL glass vial with a screw cap was charged with alkyne (1.0

eq), TEMPO (20 mol%) or (30 mol% for alkenes), DBDMH (1.2 eq),

DCDMH (1.2 eq) and a solvent mixture of MeCN (0.2 M) or toluene

(0.2 M for alkenes). The reaction mixture was stirred at room tem-

perature for 24 h. Upon completion, the solvent was removed un-

der reduced pressure and the crude product was subjected to silica

gel column chromatography to afford the desired products (1b, 4b-

10b, 14b, 16b, 17b, 19b, 22b, 24b-27b, 37b, 38b, 40b, 41b, 50b,

51b, 54b-57b).

General procedure for dihalogenation with alkynes and

haloalkynes

A 5 mL glass vial with a screw cap was charged with alkyne or

alkene (1.0 eq), TEMPO (40 mol%), NBS or NIS (2.4 eq) and a solvent

Chin. J. Chem. 2021, 39, XXX－XXX

www.cjc.wiley-vch.de

First author et al.

Report

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(The following will be filled in by the editorial staff)

Manuscript received: XXXX, 2021

Manuscript revised: XXXX, 2021

Manuscript accepted: XXXX, 2021

Accepted manuscript online: XXXX, 2021

Version of record online: XXXX, 2021

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First author et al.

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Entry for the Table of Contents

TEMPO-regulated regio- and stereoselective cross-dihalogenation with dual electrophilic X⁺reagents

Yi Kong, Tongxiang Cao,* and Shifa Zhu*

Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX

TEMPO-regulated

cross-dihalogenation

regio/stereoselective

X²

R²

R¹

X¹

R¹

R²

X¹

X²

TEMPO

dual X⁺addition

•

good

•

broad substrates

selectivity

A TEMPO catalyzed cross-dihalogenation reaction was established via redox-regulation of the otherwise complex system of dual electrophilic X⁺reagents.

Formally, the ICl, BrCl, I₂and Br₂were generated in-situ, which enabled high regio- or stereoselective access to a myriad of iodochlorination, bromochlo-

rination and homo-dihalogenation products with a wide spectrum of functionalities. With its mild conditions and operational simplicity, this method

could enable wide applications in organic synthesis, which was exemplified by divergent synthesis of two pharmaceuticals. Detailed mechanistic inves-

tigations via radical clock reaction, pinacol ring expansion and Hammett experiments were conducted, which confirmed the intermediacy of halonium

ion. In addition, a dynamic catalytic model basing on the versatile catalytic role of TEMPO was proposed to explain the selective outcomes.

www.cjc.wiley-vch.de

Chin. J. Chem. 2021, 39, XXX－XXX

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DOI: 10.1002/cjoc.202100472

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Article abstract of DOI:10.1002/cjoc.202100472

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