Photoinduced site-selective C(sp3)-H chlorination of aliphatic amides

Article abstract of DOI:10.1021/acs.orglett.0c03297

Herein, we report a new photochemical method for C(sp³)-H chlorination of amides which employs tert-butyl hypochlorite as the chlorinating agent and a household compact fluorescent lamp as the light source. The reaction proceeds via N-heterocyclic carbene SIPr·HCl-promoted N-H chlorination and subsequent photoinduced Hofmann-L?ffler-Freytag chlorine atom transfer. The latter process is facilitated by (diacetoxyiodo)benzene. This protocol exhibits a broad scope and is suitable for site-selective chlorination of methyl hydrogen as well as methylene and methine hydrogen.

Full text of DOI:10.1021/acs.orglett.0c03297

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Letter
Photoinduced Site-Selective C(sp3)−H Chlorination of Aliphatic
Amides
Yanshuo Zhu, Jingcheng Shi, and Wei Yu*
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ABSTRACT: Herein, we report a new photochemical method for C(sp3)−H chlorination of amides which employs tert-butyl
hypochlorite as the chlorinating agent and a household compact fluorescent lamp as the light source. The reaction proceeds via N-
̈
heterocyclic carbene SIPr·HCl-promoted N−H chlorination and subsequent photoinduced Hofmann−Loffler−Freytag chlorine
atom transfer. The latter process is facilitated by (diacetoxyiodo)benzene. This protocol exhibits a broad scope and is suitable for
site-selective chlorination of methyl hydrogen as well as methylene and methine hydrogen.
are more commonly used precursors of N-radicals because of the
hlorine-containing organic compounds not only are
1
Cimportant bulk chemicals in the chemical industry but activating effect of carbonyl and sulfonyl groups. In view of the
importance of halogenated amides, HLF C(sp3)−H chlorina-
also play an essential role as synthetic intermediates or designed
tion of amides has been much investigated since the 1960s. In
early studies, UV light irradiation was employed to convert N-
chloroamides to the corresponding amidyl radicals (Scheme
1A).9,10 Although this protocol is straightforward and has the
merit of simplicity, its scope in synthesis is rather limited because
of the harshness of UV light. Recently, Yu,11 Zhang,12 and our
group13 applied visible light photoredox catalysis to effect the
1,5-chloro transfer of N-chlorosulfonamides. Photoinduced site-
selective chlorination of sulfamate esters and sulfamides via 1,6-
HAT was achieved by Roizen.14 Moreover, two novel methods
for C(sp3)−H chlorination of amides with N-allylsulfonamides
and N-alkyloxy amides as precursors were reported by Studer15
and Leonori.16 Despite these achievements, however, it is still
highly desirable to develop new methods which can enable the
remote chlorination of both amides and sulfonamides in a simple
and highly efficient way. In this concern, herein, we report a
simple metal-free photochemical protocol for HLF chlorination
of amides and sulfonamides with tert-butyl hypochlorite as the
chlorinating reagent (Scheme 1B). This method exhibits a wide
scope; both amides and sulfonamides can be chlorinated at the
δ-position in good yield and high regioselectivity. Notably, the
reaction can be implemented under the irradiation of a
targets in the synthesis of natural products and functional
materials.2,3 Traditionally, organic chlorides are prepared
through functional group transformations from olefins, alcohols,
acids, or their analogues. By comparison, installation of a
chlorine atom to a C−H bond constitutes a more efficient and
straightforward method for the preparation of these valuable
compounds.4 However, although numerous efforts have been
made toward this goal, selective C−H chlorination of synthetic
usefulness still remains a big challenge until now. It has long
been known that free radical reactions are applicable to the
halogenation of the C(sp3)−H bond, but in the past, they are
mostly limited to bromination and chlorination at benzyl
positions.5 Recently, several excellent methods have been
developed to allow C(sp3)−H chlorination to be implemented
under mild conditions with good regioselectivity.6 However,
these methods only work well for chlorinating the methine
carbon or cyclic methylene carbon, whereas the efficacy for site-
selective chlorination of the acyclic methylene and methyl
C(sp3)−H has yet to be improved.
Intramolecular hydrogen atom transfer (HAT) from a C(sp3)
atom to an electrophilic heteroatom-centered radical is a facile
process for the generation of carbon radicals. The intramolecular
HAT is highly regioselective (1,5-HAT in most cases) and thus
provides a viable solution for the selective C(sp3)−H
functionalization of organic compounds.7 In this regard, much
attention has been paid to the N-radical-directed C(sp3)−H
Received: October 1, 2020
functionalization reactions (generally referred to as Hofmann−
8
̈
Loffler−Freytag (HLF) reaction). Whereas aliphatic N-
halogen amines were initially used for the HLF reaction, amides
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© XXXX American Chemical Society
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A

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Letter
a
Scheme 1. Photoinduced Remote C(sp3)−H Chlorination of
Amides
Table 1. Screening of the Reaction Conditions
b
entry
x/y
solvent
conditions
80 °C, 15 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
CFL, rt, 6 h
in dark, rt, 6 h
CFL, rt, 6 h
yield (%) 2a/3a
1
2
3
4
5
6
7
8
0.1/1.0
0.1/1.0
0.1/1.0
0.1/1.0
0.1/1.0
0.1/1.0
0.1/0.5
0.1/0.2
0.05/0.5
0.1/0
DCE
DCE
DCM
CH3CN
THF
CH3OH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
60/21
91/0
76/7
80/11
cd
,
0/0
0/0
93/0
32/0
90/0
11/0
9
10
11
12
cd
,
0/0.5
0/0
0.1/0.5
0.1/0.5
0.1/0.5
0.1/0.5
0.1/0.5
0.1/0.5
0/96
e
13
f
trace/trace
87/0
78/10
89/0
14
CFL, rt, 6 h
15
16
17
blue LEDs, rt, 6 h
blue LEDs, rt, 18 h
white LEDs, rt, 6 h
43/48
a
The reactions were conducted on a 0.2 mmol scale in 2.0 mL of
household compact fluorescent lamp (CFL) in a tandem pattern
of N-chlorination and 1,5-chlorine atom transfer, which are
enabled by N-heterocyclic carbene (NHC)·SIPr·HCl and
(diacetoxyiodo)benzene (DIB), respectively.
solvent under an argon atmosphere unless otherwise specified. DCE,
b
c
dichloroethane; DCM, dichloromethane. Isolated yield. No reaction
d
e
took place. Most of 1a was recovered. The reaction was performed
f
under an aerobic atmosphere. The reaction was conducted on a 8
mmol scale.
At the initial stage of this study, we envisioned that
carboxamides would be chlorinated at the δ-position with an
electrophilic chlorinating agent. As the previously developed
photocatalytic protocol13 cannot effect the anticipated con-
version of carboxamides, iron catalysis under thermal conditions
was explored next. After extensive screening of the reaction
conditions, we found that by using t-BuOCl as the chlorinating
reagent, FeF3 as catalyst, SIPr·HCl and DIB as the additive,
compound 1a can be transformed into the desired product 2a in
good yield in dichloroethane (DCE) at increased temperature
(Scheme 2). A subsequent control experiment indicated that the
a longer reaction time is needed for a complete conversion
(entries 15 and 16). White LEDs (10 W), on the other hand,
were less effective as the light source (entry 17). DCE proved to
be the optimal solvent. The reaction can be implemented on
gram scale without much loss in yield (entry 14). Control
experiment shows that 1a did not react without SIPr·HCl (entry
11), and only a small conversion was observed when DIB was
absent (entry 10). Air inhibited the reaction completely (entry
13). When the reaction was conducted in the dark under the
otherwise same conditions, 3a was generated as the only product
(entry 12). We also tested the effectiveness of several other
NHCs as well as hypervalent iodine reagents, and the result is
presented in Supporting Information (Tables S1 and S2).
The optimized conditions (Table 1, entry 7) were then
applied to a wide variety of differently substituted carboxamides,
and the result is presented in Scheme 3. This protocol works well
for N-aryl-substituted carboxamides, and δ-chlorination prod-
ucts 2 were obtained in good yield and high selectivity whatever
the electronic nature of the aryl ring. The methyl hydrogen was
chlorinated as well as the methylene and methine hydrogen.
This method is also applicable to N-alkyl-substituted carbox-
amides. It should be noted that in the case of compound 1ac,
which has δ-methylene hydrogen atoms at both the carbonyl
side and the aminyl side, only 2ac was obtained in a yield of 80%.
However, for compounds lacking δ-hydrogen at the aminyl
side, the chlorination can take place as well at the carbonyl side.
As such, compounds 2al−2ao were generated in moderate to
good yields from the corresponding amide precursors (Figure
1).
Scheme 2. FeF3-Catalyzed C(sp3)−H Chlorination of
Carboxamide 1a
reaction took place as well in the absence of FeF3. On the basis of
this result, more conditions were explored without using iron,
and the results are presented in Table 1.
As shown in Table 1, 1a was transformed into 2a in 60% in
DCE at 80 °C under an argon atmosphere with assistance of 0.1
equiv of SIPr·HCl and 1.0 equiv of DIB. N-Chlorination product
3a was generated in 21% at the same time. The reaction was
greatly improved by irradiation with a 45 W white CFL at
ambient temperature. The yield of 2a increased considerably,
and the reaction time was shortened to 6 h. The reaction took
place as well with blue LEDs (10 W) as the light source, although
B
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Scheme 3. Reaction Scope-1
Figure 2. Reaction scope-3. The reaction was carried out on 0.2 mmol
scale. Reaction time: 2.5 h. aThe reaction was carried out on an 8 mmol
scale. bReaction time: 6 h.
Scheme 4. Control Experiment
a
Figure 1. Reaction scope-2. 1.5 equiv of t-BuOCl was used, and the
reaction time was 12 h.
This procedure was equally suitable to chlorinate the
sulfonamides. As shown in Figure 2, variously substituted
sulfonamides (4) reacted under the standard conditions to
afford the corresponding sulfonamides (5) in moderate to
excellent yields. The reaction also took place without using SIPr·
HCl, but the yield was considerably lower (5b, 37%) under the
otherwise same conditions. The chlorination can take place at
the sulfonyl side as well as at the aminyl side. In the case that
both positions have available hydrogen atoms, the hydrogen δ to
the nitrogen atom at the aminyl chain was chlorinated
exclusively (5s), consistent with the observed selectivity for
carboxamides. Phosphamides can react in the same way like
carboxamides and sulfonamides (5w and 5x).
As shown in Table 1, SIPr·HCl and DIB play a crucial role in
the reaction. To elucidate the function of SIPr·HCl and DIB, a
control experiment was conducted, which is illustrated in
Scheme 4. The result demonstrates that SIPr·HCl is essential for
initial chlorination of the nitrogen atom in 1a (Scheme 4, (1)
and (2)), whereas DIB has no effect in this step. The catalytic
effect of SIPr·HCl is closely related to the chloride anion. In
addition to SIPr·HCl, we also tested several other NHCs, among
which only those with a chloride counteranion (NHC·HCl) can
enable the reaction (Table S1). We presume that SIPr·HCl
might react with t-BuOCl to generate a small amount of Cl2,
which is a more powerful chlorinating agent than t-BuOCl.
Indeed, we detected the formation of Cl2 (with KI-starch test
a
Trace of 2a was detected.
paper and wet blue litmus paper) when SIPr·HCl was mixed
with t-BuOCl in DCE and found that when n-Bu4NCl was used
in place of SIPr·HCl, 2a was generated from 1a in a yield of 84%
(Scheme S1). The beneficial effect of DIB lies in that it can
facilitate the second HLF chlorination step. Irradiation of 3a in
the presence of DIB resulted in the formation of 2a in excellent
yield (Scheme 4, (4)), whereas only a small amount of 2a was
produced when DIB was removed from the reaction condition
(Scheme 4, (3)).
To gain more insight into the reaction mechanism, a radical-
inhibiting experiment was conducted with 1a (Scheme 5). It was
found that the reaction was completely inhibited by 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) or 2,6-di-tert-butyl-4-
methylphenol (BHT). Moreover, when 1ap and 4y were used as
the substrates, the reaction only afforded 2ap and 5y,
C
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In conclusion, we have developed a new photochemical
method for the site-selective chlorination of amides by
employing tert-butyl hypochlorite as the chlorinating agent
and a household CFL as the light source. The reaction takes
place via N−H chlorination of amides followed by photo-
induced HLF chlorine atom transfer. The success of the present
protocol hinges on the use of SIPr·HCl to promote the N−H
chlorination and (diacetoxyiodo)benzene to facilitate the
generation of the amidyl radical via N−Cl cleavage. A wide
variety of carboxamides and sulfonamides can be chlorinated
under the present conditions in good yield and high efficiency.
We hope that this method will find applications in practical
synthesis.
Scheme 5. Mechanistic Investigation
respectively; no methyl migration was observed. This result is
consistent with a radical chain mechanism for the observed
chlorine atom transfer.13,14
On the basis of the above-mentioned results, a plausible
mechanism is proposed to account for the present chlorination
reactions (Scheme 6). Taking 1a as an example, the reaction is
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03297.
■
sı
Methods and experimental procedures; UV−vis absorp-
tion spectroscopy measurement; optimization of reaction
conditions; characterization data; NMR spectra (PDF)
Scheme 6. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Author
■
Wei Yu − State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou, Gansu 730000, China; orcid.org/
0000-0002-3131-3080; Email: yuwei@lzu.edu.cn
Authors
Yanshuo Zhu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu 730000, China
Jingcheng Shi − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu 730000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03297
Notes
The authors declare no competing financial interest.
initiated by the N-chlorination of 1a through assistance of SIPr·
HCl. The thus-formed 3a undergoes N−Cl cleavage under
irradiation to give amidyl radical A. The cleavage of the N−Cl
bond, which generally requires UV light, is greatly assisted by
DIB. The beneficial effect of DIB might be caused by its
interaction with 3a through halogen bonding between Cl···I,17
which would result in weakening of the N−Cl bond. That the
UV−vis spectrum of the mixture of 3a and PhI(OAc)2 is red-
shifted to some extent relative to those of 3a and PhI(OAc)2
lends support to this hypothesis (Figure S3). It is also possible
that DIB acted as the radical initiator through photoinduced O−
I cleavage, but this initiation is not expected to be efficient as
strong UV light is still needed to break the O−I bond.18
Moreover, this latter mechanism seems contradictory to the fact
that iodosylbenzene exhibited a similar beneficial effect like DIB
(Table S2).
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (No. 21772077) and State Key Laboratory of Applied
Organic Chemistry for financial support.
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