Ketone-catalyzed photochemical C(sp3)–H chlorination

Article abstract of DOI:10.1016/j.tet.2017.05.008

Photoexcited arylketones catalyze the direct chlorination of C(sp³)–H groups by N- chlorosuccinimide. Acetophenone is the most effective catalyst for functionalization of unactivated C–H groups while benzophenone provides better yields for benzylic C–H functionalization. Activation of both acetophenone and benzophenone can be achieved by irradiation with a household compact fluorescent lamp. This light-dependent reaction provides a better control of the reaction as compared to the traditional chlorination methods that proceed through a free radical chain propagation mechanism.

Full text of DOI:10.1016/j.tet.2017.05.008

Accepted Manuscript
3
Ketone-catalyzed photochemical C(sp )–H chlorination
Lei Han, Jibao Xia, Lin You, Chuo Chen
PII:
S0040-4020(17)30474-X
10.1016/j.tet.2017.05.008
TET 28674
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 January 2017
Revised Date: 19 April 2017
Accepted Date: 2 May 2017
3
Please cite this article as: Han L, Xia J, You L, Chen C, Ketone-catalyzed photochemical C(sp )–H
chlorination, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.008.
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Graphical Abstract
Ketone-catalyzed photochemical C(sp3)–H
chlorination
Leave this area blank for abstract info.
Lei Han, Jibao Xia, Lin You and Chuo Chen*
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX
75390-9038, USA

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Ketone-catalyzed photochemical C(sp3)–H chlorination
Lei Hana, Jibao Xiaa, Lin Youa and Chuo Chena,
aDepartment of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Photoexcited arylketones catalyze the direct chlorination of C(sp3)–H groups by N-
chlorosuccinimide. Acetophenone is the most effective catalyst for functionalization of
unactivated C–H groups while benzophenone provides better yields for benzylic C–H
functionalization. Activation of both acetophenone and benzophenone can be achieved by
irradiation with a household compact fluorescent lamp. This light-dependent reaction provides a
better control of the reaction as compared to the traditional chlorination methods that proceed
through a free radical chain propagation mechanism.
Available online
Keywords:
C–H functionalization
Chlorination
Arylketone
2009 Elsevier Ltd. All rights reserved
.
Photochemistry
Visible light
1. Introduction
Halogenation is a common strategy to enhance the potency or
alter the physical properties of small molecule drugs.1-3 Naturally
occurring halogenated molecules also often display medicinally
useful activities.4,5 Catalysts that promote C–H halogenation are
thus highly valuable. We report herein a catalytic, light-
dependent method for C(sp3)‒H chlorination (Fig. 1).
Figure 1. A catalytic, light-dependent method for C–H chlorination.
Whereas a variety of C‒H fluorination methods6-18 have been
reported, free radical chain reactions remain to be the most
frequently used method for C‒H chlorination. In contrast,
biological C–H chlorination is catalyzed by α-ketoglutarate
(αKG)-dependent non-heme iron (FeNH) halogenases.19-22 A good
example is the sequential chlorination of the BarA-loaded L-
leucine by BarB2 and BarB1 in the biosynthesis of barbamide (1)
(Fig. 2).23,24 Mechanistically, this halogenase-catalyzed C‒H
chlorination reaction is similar to C‒H hydroxylation reactions
catalyzed by the corresponding oxygenases.25-27
The reaction of 2 has inspired Que and co-workers to develop
biomimetic chlorinating complexes.28 They showed that
[Fe(TPA)Cl2](ClO4) (8) promotes C(sp3)‒H chlorination upon
activation with tert-butyl hydroperoxide (Fig. 3) (TPA = tri-(2-
pyridylmethyl)amine). However, mechanistic studies indicated
Figure 2. C–H chlorination in the biosynthesis of barbamide (1) and the
mechanism of C–H chlorination catalyzed by FeNH-αKG halogenase.
———
Corresponding author. Tel.: +1-214-648-5048; fax: +1-214-648-0320; e-mail: Chuo.Chen@UTSouthwestern.edu

2
Tetrahedron
ACCEPTED MANUSCRIPT
that the Fenton-type free radical chain reaction is also operative
irradiation of a mixture of cyclohexane and benzophenone in
and there is little or no turnover of the catalyst.29,30 Later, Groves
and co-workers found that Mn(TMP)Cl (9) catalyzes C(sp3)‒H
chlorination by bleach in the presence of a catalytic amount of
carbon tetrachloride gave cyclohexyl chloride and benzpinacol in
good yields. However, there is no report of the development of a
catalytic system for this C‒H chlorination reaction. We have
demonstrated that triplet arylketones are functionally similar to
tetra-n-butylammonium
chloride
(TMP
=
tetramesitylporphyrin).31,32 However, heme mimetics could also
promote aromatic C(sp2)–H oxidation leading to low selectivity
for aromatic substrates. For example, Fuji and co-workers found
that Fe(TPFP)(NO3) (10) catalyzed chlorination of electron-rich
arenes by ozone and tetra-n-butylammonium chloride upon
activation by a catalytic amount of trifluoroacetic acid (TPFP =
tetrakis(pentafluorophenyl)porphyrin).33
the metal-oxo species of 5
and can catalyze C(sp3)‒H
fluorination.6,7 We now show that catalytic C(sp3)‒H chlorination
can also be achieved through this photochemical reaction.
2. Results and discussion
Our work started with optimization of the catalyst system for
benzylic chlorination using ethylbenzene (11) as the standard
substrate (Table 1). Because benzophenone ketyl radical is rather
stable and susceptible to deactivation by dimerization, we first
tested if acetophenone could offer a better catalyst turnover
number. However, irradiation of 11 with UV light in carbon
tetrachloride in the presence of 5 mol % of acetophenone gave
only 12% yield of benzylic chloride 12 along with 7% of the
homobenzylic chloride 13 (entry 1). Whereas there was nearly no
reaction when irradiated with violet light for 24 h (entry 2),
switching the chlorine atom donor to N-chlorosuccinimide (NCS)
led to a quick reaction and 11 was consumed completely to give
12 together with 13 and the dichlorination product 14 (entry 3).
The reaction proceeded well but slower when a household
compact fluorescence lamp (CFL) was used as the light source
(entry 4). Nonetheless, acetophenone, benzophenone, 9-
fluorenone, xanthone, and thioxanthone can all catalyst C‒H
chlorination by NCS upon activation by CFL-irradiation (entries
4‒8). Among these arylketones, benzophenone and 9-fluorenone
provide the best reaction rates and selectivity (entries 5 and 6).
We have also examined the effectiveness of a series of other
chlorinating reagents, but did not observe improvement in
reactivity or selectivity by using N-chlorophthalimide,
trichloroisocyanuric acid, 1,3-dichloro-5,5-dimethylhydantoin,
chloramine T, dichloramine T, and CBMG.
Figure 3. Examples of reported C–H chlorination complexes.
A variety of directing groups have been developed to better
control the regioselectivity of C‒H chlorination. For example,
Sanford and co-workers showed that a pyridine group can direct
and facilitate catalytic halogenation of benzylic C(sp3)‒H groups
by palladium.34,35 Yu and co-workers also demonstrated that an
oxazoline group facilitates palladium-catalyzed C(sp3)‒H
halogenation,36,37 and 2-nitrobenzenesulfonamide is an excellent
directing group for copper-catalyzed C(sp3)‒H bromination.38
Additional directing groups for palladium-catalyzed C(sp3)–H
halogenation include 2-pyridylsulfoximine,39 amide,40 and 8-
aminoquinoline.41 However, C(sp3)‒H halogenation without
over-oxidation is still challenging. Notably, C(sp2)‒H
chlorination can be achieved more easily by using, for example,
chlorobis(methoxycarbonyl)guanidine (CBMG)42 developed by
Baran and co-workers as chlorinated arenes are less electron-rich
and thus less reactive than their precursors toward aromatic
substitution.
Table 1. Effects of the catalyst, chlorine donor, and light source
on the benzylic chlorination of 11
Baran and co-workers have demonstrated that site-selective
halogenation can be realized by trifluoroethyl N-halocarbamate-
mediated Hofmann–Löffler–Freytag reaction.43 Unlike the N-
chloroamine-mediated method, the N-cyclization product is not
formed with the carbamate group. Ball and co-workers also
showed that a peroxide group can be used as an internal oxidant
to achieve copper-catalyzed regioselective C(sp3)–H chlorination
without over-oxidation.44 Intermolecular oxidative radical
halogenation has also been achieved by Alexanian, Vanderwal,
and co-workers by N-haloamides.45,46 They showed that N-
chloro-N-(tert-butyl)-3,5-bis(trifluoromethyl)benzamide
chlorinates sclareolide selectively and effectively. Addition of
cesium carbonate helped suppress dichlorination. Thus, a large
excess of substrates is not needed to prevent over-oxidation.
However, one potential safety concern for performing large-scale
free radical chain reactions is that the chain propagation process
may lead to a runaway reaction. To date, the most practical
method for introducing a chlorine atom onto an aliphic chain is
arguably the silver-catalyzed decarboxylative chlorination
reaction developed by Li and co-workers, although pre-
installation of a carboxylic acid group is required.47
Entry Catalyst Cl source Light source
11
81% 12% 7%
>95%
0% 68% 12% 20%
15% 70% 13% 2%
0% 74% 7% 19%
0% 72% 7% 21%
6% 70% 15% 8%
12 13 14
a
1
2
3
4
5
6
7
8
CCl4a
CCl4
NCS
NCS
NCS
NCS
NCS
NCS
350 nmb
419 nmc
419 nmc
CFLd
‒
‒
A
A
A
A
B
C
D
E
‒
‒
CFLd
CFLd
CFLd
CFLd
21% 67% 10% 2%
a
b
No acetonitrile, carbon tetrachloride is used as the solvent. 16×
c
RPR-3500Å lamps (24 W, 300–420 nm). 16× RPR-4190Å lamps
(24 W, 375–465 nm). d 1× compact fluorescence lamp (19 W).
Walling discovered serendipitously in 1965 that
photoreduction of triplte benzophenone by cyclohexane in the
presence of internal standard Freon 112 (CFCl2CFCl2) led to the
formation of cyclohexyl chloride.48 He subsequently found that
carbon tetrachloride is a better chlorine atom donor. UV-
We next used benzophenone as the standard catalyst to
explore the scope of this reaction (Table 2). Introduction of an
electron-withdrawing group to the benzene ring at the ortho,
meta, or para position did not affect the reaction significantly

3
(entries 1‒6). However, chlorination of ethylbenzene derivatives
with an electron-donating group led to benzylic chlorides that are
not stable under the reaction conditions. Primary and tertiary
benzylic C‒H groups could also be chlorinated smoothly (entries
7 and 8). Remarkably, an ester group at the β-position can be
tolerated (entry 9). Chloride 30 did not undergo elimination
under the reaction conditions.
photochemical reaction does not require the use of a large
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excess of the substrate to suppress over-chlorination.
Acetophenone, for example, catalyzed monochlorination of 31 in
good yields even when a 1:1 or 1:1.2 ratio of substrate to oxidant
was used (entries 6 and 7).
Table 3. Effects of the catalyst on the chlorination of 31
Table 2. Scope of the benzophenone-catalyzed photochemical
benzylic C–H chlorination
Product
(Isolated yield)
b
Entry
1
Substrate
Time
24 h
β-Clb 1,2-Cl2
Entry
Catalyst
Cl equiv
0.8
0.8
0.8
0.8
0.8
1.0
1.2
NMR yield
98%a
7%
17%
23%
12%
27%
24%
–
19%
19%
ND
4%
ND
ND
–
1
2
3
4
5
6
7
A
B
C
D
E
A
A
93%a
(72%)
97%a
91%a
77%a
2
3a
4
24h
9 h
85%b
(63%)
82%b
a Calculated based on NCS. b Calculated based on 31.
The utility of this photochemical reaction has also been briefly
investigated (Table 4). Whereas only a slight excess of the
substrate is needed to achieve monochlorination of simple
hydrocarbons (entries 1 and 2), dichlorination of the tert-butyl
group occurred even at low conversion, eroding the yields for
monochlorination products (entries 3 and 4). Additionally,
chlorination of propionic acid (39) and isovaleric acid (40)
occurred at various positions (entries 5 and 6), and chlorination
of sclareolide and cholesterol resulted in complex mixtures of
products. The α-chlorination of 39 by NCS likely proceeded
through an uncatalyzed, non-radical pathway. However, there
was no significant amount of electrophilic chlorination product in
the reaction of 40 with NCS possibly due to increased steric
hindrance around the α-position.
(71%)
24 h
9 h
(64%)
5
(65%)
6
24 h
5 h
(60%)
Table 4. Scope of the benzophenone-catalyzed photochemical
aliphatic C–H chlorination
7a
(94%)
Cl N3
Isolated yielda
or conversion
8a
48 h
48 h
3%c
ND
ND
ND
Entry Substrate
1
Product
Time
24 h
28
(59%)
95%
9
(79%)
2
3
4
24 h
9 h
95%
70%
82%
a
b
1
Using 1.2 equiv NCS. Determined by H NMR and ND denotes
not detected. c Together with 9% γ-chlorination product.
For non-benzylic chlorination, cyclododecane (31) was used
as the standard substrate for catalyst screen (Table 3).
Acetophenone, benzophenone, 9-fluorenone, xanthone, and
thioxanthone all catalyzed the reaction well, giving good yields
of cyclododecyl chloride (32) (entries 1‒5). It is noteworthy that,
unlike most innate C(sp3)‒H chlorination reactions, this
9 h

4
Tetrahedron
diethyl ether, filtrated, concentrated and purified by preparative
ACCEPTED MANUSCRIPT
thin-layer chromatography.
86%
5
6
24 h
24 h
1
(1-Chloroethyl)benzene (12). H NMR (400 MHz, CDCl3) δ
conversion
7.45 (d, J = 8.1 Hz, 2H), 7.41–7.30 (m, 3H), 5.12 (q, J = 6.8 Hz,
1H), 1.88 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
128.8, 128.6, 128.3, 126.5, 58.8, 26.5; MS (EI) calcd for C8H9Cl
[M+] 140.0, found 140.1.
76%
conversion
1
1-Chloro-4-(1-chloroethyl)benzene (16). H NMR (400 MHz,
a
b
1
CDCl3) δ 7.36 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 5.06
(q, J = 6.8 Hz, 1H), 1.83 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 141.5, 134.1, 128.9, 128.1, 57.9, 26.6; MS (EI)
calcd for C8H8Cl2 [M+] 174.0, found 174.0.
Calculated based on NCS. Product distribution determined by H
NMR.
The lower selectivity of triplet ketone-catalyzed C(sp3)‒H
1
chlorination comparing to the corresponding fluorination reaction
suggests that the rate limiting step for chlorination is C‒H
abstraction. We suspect that the transfer of a chlorine atom from
NSC to the alkyl radical resulted from C‒H abstraction is a facile
process, leading to kinetic C‒H functionalization. In contrast, the
transfer of a fluorine atom from Selectfluor to the alkyl radical49
is likely slower than C‒H abstraction. Thermodynamic products
were thus formed due to reversible C‒H abstraction. Supportive
to this hypothesis is the observation that dichlorination of
ethylbenzene (11) gave (1,2-dichloroethyl)benzene (14) (Table 1)
1-Chloro-3-(1-chloroethyl)benzene (18). H NMR (400 MHz,
CDCl3) δ 7.43–7.40 (m, 1H), 7.32–7.26 (m, 3H), 5.03 (q, J = 6.8
Hz, 1H), 1.83 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
144.9, 134.6, 130.1, 128.5, 126.9, 124.9, 57.8, 26.6; MS (EI)
calcd for C8H8Cl2 [M+] 174.0, found 174.0.
1
1-Chloro-2-(1-chloroethyl)benzene (20). H NMR (400 MHz,
CDCl3) δ 7.53–7.07 (m, 4H), 5.59 (q, J = 6.8 Hz, 1H), 1.84 (d, J
= 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.1, 132.5,
129.7, 129.4, 128.0, 127.5, 54.6, 25.8; MS (EI) calcd for C8H8Cl2
[M+] 174.0, found 174.0.
4-(1-Chloroethyl)benzonitrile (22). 1H NMR (400 MHz,
CDCl3) δ 7.65 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 5.08
(q, J = 6.8 Hz, 1H), 1.83 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 147.9, 132.6, 127.5, 118.6, 112.2, 57.3, 26.4; MS
(EI) calcd for C9H8ClN [M+] 165.0, found 165.0.
whereas
difluorination
of
11
provided
(1,1-
difluoroethyl)benzene.6 Based on the C‒H bond strength, 1,1-
dihalogenation should be favored in both cases. The C−H bond
dissociation energies for H−CH3, H−CH2F, and H−CH2Cl, are
104.9, 101.3, and 100.1 kcal/mol, respectively.50 Finally, we have
confirmed that benzophenone-catalyzed chlorination of 11 is not
a free radical chain reaction (Fig. 4). The reaction stopped
immediately after the light was turned off.
1
Methyl 4-(1-chloroethyl)benzoate (24). H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 5.10
(q, J = 6.8 Hz, 1H), 3.92 (s, 3H), 1.85 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.7, 147.7, 130.1, 130.1, 126.7,
57.9, 52.4, 26.6; MS (EI) calcd for C9H11ClO2 [M+] 198.0, found
198.1.
4-(Chloromethyl)-1,1'-biphenyl (26). 1H NMR (400 MHz,
CDCl3) δ 7.62–7.57 (m, 4H), 7.50–7.41 (m, 4H), 7.42–7.34 (m,
1H), 4.65 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 141.5, 140.6,
136.6, 129.2, 129.0, 127.7, 127.6, 127.3, 46.2; MS (EI) calcd for
C13H11Cl [M+] 202.1, found 202.1.
1
(1-Azido-1-chloropropyl)benzene (28). H NMR (500 MHz,
CDCl3) δ 7.44–7.27 (m, 5H), 1.95–1.74 (m, 2H), 0.93 (t, J = 7.3
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 133.6, 131.2, 128.1,
128.1, 126.9, 67.9, 34.3, 10.8; MS (EI) calcd for C9H10ClN3 [M+]
195.1, found 195.0.
Figure 4. Benzophenone-catalyzed chlorination of 11 by NCS is a light-
dependent process.
3. Conclusion
Methyl 3-chloro-3-(4-chlorophenyl)propanoate (30). 1H NMR
(400 MHz, CDCl3) δ 7.42–7.27 (m, 4H), 5.31 (m, 1H), 3.70 (s),
3.09 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.9, 138.9,
134.7, 129.2, 128.5, 57.2, 52.3, 44.7; MS (EI) calcd for
C10H10ClO2 [M+] 232.0, found 232.0.
Triplet arylketones effectively catalyze kinetic C(sp3)‒H
chlorination by NCS. For simple substrates, good yields can be
obtained without using a large excess of the substrates.
Additionally, there is no competing aromatic chlorination. Unlike
free radical chain reactions, this light-dependent reaction allows
for control of degree of chlorination by irradiation time.
However, the regioselectivity of this reaction is low, in particular
for more complex substrates, limiting its utility to
functionalization of simple organic compounds.
1
Chlorocyclododecane (32). H NMR (400 MHz, CDCl3) δ
4.21–4.03 (m, 1H), 2.01–1.84 (m, 2H), 1.83–1.64 (m, 2H), 1.63–
1.46 (m, 2H), 1.44–1.18 (m, 16H); 13C NMR (100 MHz, CDCl3)
δ 60.4, 34.0, 23.9, 23.8, 23.5, 23.5, 22.0; MS (EI) calcd for
C12H23Cl [M+] 202.1, found 202.1.
Chlorocyclodecane (34). 1H NMR (400 MHz, CDCl3) δ 4.47–
4.13 (m, 1H), 2.13–2.02 (m, 2H), 2.01–1.90 (m, 2H), 1.75–1.64
(m, 2H), 1.63–1.37 (m, 12H); 13C NMR (100 MHz, CDCl3) δ
62.2, 34.3, 25.3, 24.9, 24.3, 23.0; MS (EI) calcd for C10H19Cl [M+]
174.1, found 174.1.
4. Experimental
General procedure for triplet ketone-catalyzed C(sp3)–H
chlorination. To a 4 mL clear vial charged with the reaction
substrate, N-chlorosuccinimide, ketone catalyst in anhydrous
acetonitrile (0.2 M) was degassed and irradiated with a 19 W
compact fluorescent lamp at room temperature for 24 h. The
solvent was then removed and the residue was dissolved in

5
1
28. Leising, R. A.; Zang, Y.; Que, L., Jr. J. Am. Chem. Soc. 1991,
(1-Chloro-2-methylpropan-2-yl)benzene (36). H NMR (400
ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 7.46–7.27 (m, 5H), 3.66 (s, 2H), 1.44 (s, 6H); 13
C
113, 8555–8557.
29. Kim, J.; Harrison, R. G.; Kim, C.; Que, L., Jr. J. Am. Chem. Soc.
1996, 118, 4373–4379.
30. MacFaul, P. A.; Ingold, K. U.; Wayner, D. D. M.; Que, L., Jr. J.
Am. Chem. Soc. 1997, 119, 10594–10598.
NMR (100 MHz, CDCl3) δ 146.1, 128.5, 126.6, 126.0, 56.5,
39.9, 26.6; MS (EI) calcd for C10H13Cl [M+] 168.1, found 168.2.
1
4-(1-Chloro-2-methylpropan-2-yl)benzonitrile (38). H NMR
(400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4
Hz, 2H), 3.65 (s, 2H), 1.45 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 151.5, 132.2, 127.0, 118.9, 110.5, 55.4, 40.5, 26.6.; MS (EI)
calcd for C11H12ClN [M+] 193.1, found 193.1.
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We thank NIH/NIGMS (R01-GM079554), the Welch
Foundation (I-1868), and UT Southwestern for financial support.
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