A simple catalytic method for the regioselective halogenation of arenes

Article abstract of DOI:10.1021/ol060747f

This paper describes a mild palladium-catalyzed method for the regioselective chlorination, bromination, and iodination of arene C-H bonds using N-halosuccinimides as oxidants. These transformations have been applied to a wide array of substrates and can provide products that are complementary to those obtained via conventional electrophilic aromatic substitution reactions.

Full text of DOI:10.1021/ol060747f

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2523-2526
A Simple Catalytic Method for the
Regioselective Halogenation of Arenes
Dipannita Kalyani, Allison R. Dick, Waseem Q. Anani, and Melanie S. Sanford*
UniVersity of Michigan, Department of Chemistry, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109-1055
mssanfor@umich.edu
Received March 27, 2006
ABSTRACT
This paper describes a mild palladium-catalyzed method for the regioselective chlorination, bromination, and iodination of arene C−H bonds
using N-halosuccinimides as oxidants. These transformations have been applied to a wide array of substrates and can provide products that
are complementary to those obtained via conventional electrophilic aromatic substitution reactions.
Selectively halogenated arenes [halogen (X) ) Cl, Br, or I]
are extremely valuable starting materials for synthetic
elaboration. Classically, these functional groups have been
used as precursors to organolithium1 and Grignard reagents2
as well as in benzyne generation3 and nucleophilic aromatic
substitution.4 More recently, aryl halides have also found
widespread utility as substrates for Pd-, Ni-, and Cu-catalyzed
cross-coupling reactions to form diverse C-C, C-N, C-O,
and C-S bonds.5,6 In addition, aryl chlorides, bromides, and
iodides serve as important components of a wide array of
biologically active molecules.7
The most common synthetic approach to halogenated
arenes is electrophilic aromatic substitution (EAS),8 using
reagents such as N-halosuccinimides,9a-c X2,9d peroxides/
HX,9e,f peroxides/MX,9g-j or hypervalent iodine reagents/MX
(M ) Li, Na, K, or TMS).9k,l While these transformations
are widely used, they suffer from several notable disadvan-
tages, such as the following: (i) the substrate scope is often
(1) Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275.
(2) Handbook of Grignard Reagents; Silverman, G. S., Rakita, P. E.,
Eds.; Dekker: New York, 1996.
(3) Levin, R. H. React. Intermed. (Wiley) 1985, 3, 1.
(4) Crampton, M. R. Organic Reaction Mechanisms; Wiley: New York,
2003; p 275.
(5) (a) Metal Catalyzed Cross Coupling Reactions; Dieterich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Prim, D.; Campagne, J. M.;
Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041. (c) Beletskaya, I.
P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (d) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (e) Kunz, K.; Scholz,
U.; Ganzer, D. Synlett 2003, 2428.
(6) (a) Hassan, J.; Se´vignon, M.; Gozzi, C., Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (b) Bringmann, G.; Walter, R.; Weirich, R.
Angew. Chem., Int. Ed. 1990, 102, 1006. (c) Hartwig, J. F. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Wiley-Interscience:
New York, 2002, p 1051. (d) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125. (e) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley-Interscience: New York, 2002, p
1097.
(7) Butler, A.; Walker, J. V. Chem. ReV. 1993, 93, 1937.
(8) (a) Taylor, R. Electrophilic Aromatic Substitution; John Wiley: New
York, 1990. (b) De la Mare, P. B. Electrophilic Halogenation; Cambridge
University Press: Cambridge, 1976, Chapter 5. (c) Merkushev, E. B.
Synthesis 1988, 923.
(9) (a) Zhang, Y.; Shibatomi, K.; Yamamoto, H. Synlett 2005, 18, 2837
and references therein. (b) Prakash, G. K. S.; Mathew, T.; Hoole, D.;
Esteves, P. M.; Wang, Q.; Rasul, G.; Olah, G. A. J. Am. Chem. Soc. 2004,
126, 15770. (c) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi,
K.; Horaguchi, T. Chem. Lett. 2003, 32, 932. (d) Firouzabadi, H.; Iranpoor,
N.; Shiri, M. Tetrahedron Lett. 2003, 44, 8781. (e) Vyas, P. V.; Bhatt, A.
K.; Ramachandraiah, G.; Bedekar, A. V. Tetrahedron Lett. 2003, 44, 4085.
(f) Lee, K.; Cho, H. K.; Song, C. Bull. Korean Chem. Soc. 2002, 23, 773.
(g) Iskra, J.; Stavber, S.; Zupan, M. Synthesis 2004, 11, 1869. (h) Dewkar,
G. K.; Narina, S. V.; Sudalai, A. Org. Lett. 2003, 5, 4501. (i) Tamhankar,
B. V.; Desai, U. V.; Mane, R. B.; Wadgaonkar, P. P.; Bedekar, A. V.
Synthetic Commun. 2001, 31, 2021. (j) Roche, D.; Prasad, K.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 2000, 41, 2083. (k) Braddock, D. C.;
Cansell, G.; Hermitage, S. A. Synlett 2004, 3, 461. (l) Evans, P. A.; Brandt,
T. A. J. Org. Chem. 1997, 62, 5321.
10.1021/ol060747f CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/19/2006

limited to activated arenes, (ii) side reactions including
benzylic halogenation and overhalogenation of the arene are
common, (iii) only a limited set of arene substitution patterns
can be accessed, and (iv) multiple regioisomeric products
are frequently obtained, resulting in decreased yields and the
requirement for tedious separations.8,9 Another important
route to selectively halogenated arenes involves directed
ortho-lithiation (DoL) followed by a halogen quench.10 DoL
reactions have found application in the construction of a
variety of complex molecules;11 however, their broad utility
remains limited by the requirement for strong bases (which
results in reduced functional group tolerance) and by the
relatively narrow scope of suitable directing groups.
Due to the clear limitations of current methods, the
development of new, simple, and complementary transition
metal-catalyzed reactions for the selective halogenation of
arenes would be highly desirable. In general, examples of
the metal-catalyzed formation of arene C-X bonds remain
rare, predominantly because carbon-halogen bond-forming
reductive elimination is thermodynamically disfavored rela-
tive to aryl halide oxidative addition at most metal centers.12
However, a number of reports have shown that stoichiometric
C-X coupling can be achieved at PdII centers under
oxidizing conditions, using oxidants such as X2,13a-d CuX2,13e,f
peroxides/[TEBA]Cl (TEBA ) triethylbenzylammonium
chloride),13g or PhICl2.13h In addition, several groups have
demonstrated that PdII-catalyzed reactions can be terminated
with an oxidative carbon-halogen bond-forming step.14d,15
We sought to exploit such C-X couplings in the develop-
ment of a general, Pd-catalyzed method for the halogenation
of arene carbon-hydrogen bonds. As summarized in Scheme
1, we hoped to couple Pd-mediated ligand-directed C-H
activation (a well-precedented transformation at PdII cen-
ters)14 with oxidative halogenation of the resulting PdII carbon
bond to release an aryl chloride, bromide, or iodide
Scheme 1. Pd-Catalyzed Ligand-Directed C-H Bond
Halogenation
product.14d,15a We report herein that a variety of commercially
available electrophilic halogenating reagents s particularly
N-chloro-, N-bromo-, and N-iodosuccinimideseffectively
mediate Pd-catalyzed arene halogenation; furthermore, these
transformations can provide complementary products to those
of classical EAS reactions.
We began our studies by screening a series of electrophilic
reagents for the Pd-catalyzed halogenation of 3-methyl-2-
phenylpyridine (1) in two different solventssAcOH and CH3-
CN.16 Importantly, control reactions (in the absence of
palladium) were first carried out with each reagent and
generally did not yield any halogenated products in AcOH
or CH3CN.17 In contrast, in the presence of catalytic Pd-
(OAc)2, most of these reagents afforded at least traces of
1-Cl, 1-Br, and 1-I, with GC yields ranging from 0% to
87%. Interestingly, PhICl2 (entry 5) afforded low conversion
to the chlorinated product 1-Cl; in contrast, similar iodine-
(III) reagents have served as highly effective oxidants in Pd-
catalyzed C-H activation/acetoxylation and C-H activation/
arylation reactions.14,18 This surprising result is likely due
to the instability of PhICl2 under the reaction conditions.19
The best overall yields in all cases were obtained using
commercially available and inexpensive N-halosuccinimides
as terminal oxidants.20,21 Notably, NIS (entry 13) afforded a
yield of 1-I comparable to that of I2/PhI(OAc)2 (entry 14)s
conditions recently reported for the Pd-catalyzed C-H
activation/iodination of oxazoline derivatives.15a In general,
similar results were obtained in MeCN and AcOH, although
the yield of iodinated product 1-I was reproducibly higher
in MeCN. While the yields shown in Table 1 were obtained
with 5 mol % of Pd(OAc)2, reactions of 1 with N-
halosuccinimides proceeded in comparable reaction times and
GC yields (71%, 54%, and 90% for 1-Cl, 1-Br, and 1-I,
respectively) using as little as 1% catalyst loading.22
(10) Snieckus, V. Chem. ReV. 1990, 90, 879.
(11) For some recent examples, see: (a) Young, D. W.; Comins, D. L.
Org. Lett. 2005, 7, 5661. (b) McCulloch, M. W. B.; Barrow, R. A.
Tetrahedron Lett. 2005, 46, 7619. (c) Pradhan, T. K.; De, A.; Mortier, J.
Tetrahedron 2005, 61, 9007.
(12) For example, Keq for direct reductive elimination of haloarenes from
PdII ranges from ∼10-5 (for Ar-I) to ∼10-2 (for Ar-Cl). See: Roy, A. H.;
Hartwig, J. F. Organometallics 2004, 23, 1533 and references therein.
(13) (a) van Belzen, R.; Elsevier: C. J.; Dedieu, A.; Veldman, N.; Spek,
A. L. Organometallics 2003, 22, 722. (b) Alsters, P. L.; Engel, P. F.;
Hogerheide, M. P.; Marinus, P. H.; Copijn, M.; Spek, A. L.; van Koten, G.
Organometallics 1993, 12, 1831. (c) Kubota, M.; Boegeman, S. C.; Keil,
R. N.; Webb, C. G. Organometallics 1989, 8, 1616. (d) Wong, P. K.; Stille,
J. K. J. Organomet. Chem. 1974, 70, 121. (e) Ba¨ckvall, J. Acc. Chem. Res.
1983, 16, 335. (f) Ba¨ckvall, J. Tetrahedron Lett. 1977, 18, 467. (g) Alsters,
P. L.; Boersma, J.; van Koten, G. Organometallics 1993, 12, 1629. (h)
Lagunas, M.-C.; Gossage, R. A.; Spek, A. L.; van Koten, G. Organome-
tallics 1998, 17, 731.
(16) An initial screen of the reaction of 2-phenylpyridine with NCS in
11 different solvents revealed that the highest yields were obtained in MeCN
and AcOH. As a result, further investigations focused on these two solvents.
(17) The control reaction with PhICl2 in AcOH afforded traces (5% by
GC) of a monochlorinated product.
(18) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
(19) Togo, H.; Sakuratani, K. Synlett 2002, 1966.
(14) (a) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8,
1141. (b) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149. (c) Desai,
L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. (d)
Dick, A. R.; Hull, K. L. Sanford, M. S. J. Am Chem. Soc. 2004, 126, 2300.
(e) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330.
(15) (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2112. (b) Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett. 2004, 45, 1785. (c)
Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R. Organometallics
2004, 23, 5618. (d) El-Qisairi, A. K.; Qaseer, H. A.; Katsigras, G.; Lorenzi,
P.; Trivedi, U.; Tracz, S.; Hartman, A.; Miller, J. A.; Henry, P. M. Org.
Lett. 2003, 5, 439 and references therein. (e) Zhu, G.; Lu, X. J. Organomet.
Chem. 1996, 508, 83 and references therein. (f) Henry, P. M. J. Org. Chem.
1971, 36, 1886. (g) Fahey, D. R. J. Organomet. Chem. 1971, 27, 283.
(20) Notably, bromination of 1 with NBS (and bromination reactions in
general) proceeded in lower yield than the analogous chlorinations or
iodinations. The yield was independent of the source or quality (recrystal-
lized versus nonrecrystallized) of the NBS. The predominant side products
appeared to be traces of the corresponding dibrominated product along with
mixtures of oxidatively coupled arylpyridines (dimers of 1, heterodimers
of 1 with 1-Br, etc.). Interestingly, no acetoxylated side products were
observed with NBS, even in AcOH.
(21) Low yields with some oxidants may be due to the formation PdX2,
which is both less soluble and less electrophilic than Pd(OAc)2. See ref
15a.
(22) The use of 0.5 mol % of Pd(OAc)2 in the reaction of 1 with NXS
resulted in somewhat lower yields of 1-Cl, 1-Br, and 1-I (60%, 41%, and
77% GC yield, respectively).
2524
Org. Lett., Vol. 8, No. 12, 2006

Table 1. Palladium-Catalyzed Halogenation of
Table 2. Pd(OAc)2-Catalyzed Directed Halogenation of Arenes
2-Methyl-3-Phenylpyridine with Diverse Oxidants
GC yield in GC yield in
AcOH (%)
(isolated
yield, %)
MeCN (%)
(isolated
yield, %)
halogenating
reagent
entry
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
NCS
1-Cl
1-Cl
1-Cl
1-Cl
1-Cl
1-Cl
1-Br
1-Br
1-Br
1-Br
1-Br
1-Br
1-I
60 (65)b
63
56
42
32
21a
53 (56)b
39
32
15
0
0a
64
64
44
37
0
56
51
36
0
15
30a
44
24
42
8
26
15a
87 (79)
71
0
Pb(OAc)4/LiClc
Chloramine-T
K2Cr2O7/LiClc
PhICl2
CuCl2
NBS
Br2/PhI(OAc)2
Pb(OAc)4/LiBrc
K2Cr2O7/LiBrc
Br2
CuBr2
NIS
I2/PhI(OAc)2
K2Cr2O7/LiIc
Pb(OAc)4/LiIc
I2
1-I
1-I
1-I
1-I
0
40
a With 2.4 equiv of halogenating reagent. b Isolated yield obtained from
reaction conducted at 120 °C. c With 2 equiv of LiX.
As summarized in Table 2, the Pd-catalyzed chelate-
directed halogenation of arenes with N-halosuccinimides
could be extended to a variety of substrates. In general, these
halogenation reactions exhibited scope and functional group
tolerance comparable to analogous Pd-catalyzed C-H
activation/acetoxylation14a-d and C-H activation/arylation14e,18
reactions. Pyridines (entries 3-5, 7, 8, 12), oxime ethers
(entries 9, 10), isoquinolines (entry 6), amides (entries 1,
2), and isoxazolines (entry 11) were successfully employed
as directing groups. Additionally, the reactions were tolerant
of aryl halides (entries 10, 12), enolizable oxime ethers
(entries 9, 10), and esters (entry 11), as well as oxidizable
functionalities, such as aromatic aldehydes (entries 3, 4) and
benzylic methylene groups (entries 9, 11). Importantly, these
reactions were readily scalable; for example, a 15 g (82
mmol) scale reaction of substrate 7 with NBS afforded a
yield of 7-Br (56%) comparable to that obtained on the 1.4
mmol scale (entry 7).
a In AcOH. b In MeCN. c At 120 °C. d With 2.5 equiv of NCS.
In substrates containing two readily accessible ortho-C-H
bonds, only modest yields of the monohalogenated products
were obtained (e.g., Table 2, entry 3), due to competitive
formation of the corresponding di-ortho-halogenated com-
pound. These di-ortho-halogenated products could be isolated
cleanly and in good yields by the use of excess (∼2.5 equiv)
oxidant under otherwise identical conditions (for example,
Table 2, entry 4). The tendency for facile bis-ortho-
halogenation could be attenuated in several ways. For
example, placing a meta substituent on the arene ring resulted
in selective monohalogenation at the less sterically hindered
ortho position (entries 1, 8, 10).14b The second ortho-
halogenation was slowed dramatically in these systems,
presumably due to unfavorable steric interactions during
palladation of the more hindered ortho-C-H bond. Similar
results were obtained with the naphthyl-substituted substrate
5, in which chlorination occurs at the less hindered 3′ position
despite the fact that the 1′ position is more nucleophilic. This
high sensitivity to the steric environment of the aromatic ring
Org. Lett., Vol. 8, No. 12, 2006
2525

appears to be general for a variety of Pd-catalyzed directed
C-H activation/oxidative functionalization reactions.14a,b,e
In biaryl systems, dihalogenation could also be controlled
by placing a substituent adjacent to the biaryl junction (for
example, the 3-methyl group of pyridine substrates 1 and
12 or the fused phenyl ring of isoquinoline substrate 6). After
the first C-H activation/halogenation reaction takes place,
this substituent experiences unfavorable steric interactions
with the halogen, making it energetically unfavorable for the
two aryl rings to achieve coplanarity (which is required for
palladation to take place).23 As a result, a second C-H
activation/halogenation reaction is dramatically slowed or
completely inhibited. This is exemplified by the fact that
the isolated monohalogenated products 1-Cl, 1-Br, and 1-I
showed very low reactivity toward a second functionaliza-
tion; in fact, even under forcing conditions (5 mol % of Pd-
(OAc)2, 2 equiv of NXS, AcOH, 120 °C), these reactions
afforded <35% conversion to the corresponding dihaloge-
nated compounds. The lowest conversion (<5%) was
obtained with 1-I, consistent with the large size of this
substituent exacerbating the unfavorable steric interactions
at the biaryl junction.23
An important feature of these palladium-catalyzed directed
C-H activation/halogenation reactions is that they can
frequently outcompete alternative and more conventional
uncatalyzed transformations. As shown in eq 1, the electron-
rich substrate 13 reacts with NCS under our standard reaction
conditions to afford product 13-Cl24 with or without the Pd-
(OAc)2 catalyst. This is because both electrophilic aromatic
substitution and pyridine-directed halogenation favor the
same product. However, in substrate 14, there is a mismatch
in the products favored by the catalyzed versus the uncata-
lyzed reactions. Under the uncatalyzed conditions, electro-
philic aromatic substitution predominates, leading to the
selective formation of product 14-Cl isomer (eq 2). However,
in the presence of Pd(OAc)2, the relative rate of catalytic
C-H activation/halogenation is significantly faster than that
of the corresponding uncatalyzed EAS reaction. As a result,
chlorinated product 14-Cl is obtained cleanly as a single
isomer (eq 2). This further augments the utility of this
methodology because it allows access to halogenated prod-
ucts that are complementary to those obtained using tradi-
tional synthetic methods.
In summary, we have shown that Pd-catalyzed chelate
directed C-H activation/halogenations proceed efficiently
using simple, inexpensive, and readily available N-halosuc-
cinimides as terminal oxidants. These transformations pro-
vide access to a wide array of selectively chlorinated,
brominated, and iodinated arenes. Further exploration of the
full scope of these reactions, as well as their extension to
alkane and alkene substrates is underway and will be reported
in due course.
Acknowledgment. We thank the NIH NIGMS (RO1-
GM073836-01), the University of Michigan, the Camille and
Henry Dreyfus Foundation, and the Arnold and Mabel
Beckman Foundation for support. Unrestricted support from
Amgen, Boehringer Ingelheim, Eli Lilly, and Merck Research
Laboratories is also gratefully acknowledged. Additionally,
A.R.D. thanks Eli Lilly for a graduate fellowship, and
W.Q.A. is grateful for a Margaret and Henry Sokol under-
graduate summer research fellowship.
Supporting Information Available: Experimental details
and spectroscopic and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue,
Y. Org. Lett. 2001, 3, 2579 and references therein; (b) Chatani, N.; Ie, Y.;
Kakiuchi, F.; Murai, S. J. Org. Chem. 1998, 62, 2604.
(24) GC analysis of the isolated product showed ∼10% of a regioisomeric
product both with and without Pd.
OL060747F
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