Popov et al.
JOCArticle
SCHEME 1. Arene Deprotonation/Electrophilic Quench
conditions or use of strong alkyllithium bases and cryogenic
conditions.9 By employing in situ trapping conditions, either
tBuOLi or weak K3PO4 bases can be used under relatively
mild temperatures (50-130 °C). Polychloro- and polyfluoro-
arenes can be halogenated in moderate to high yields (entries 8
and 11-15). Cyano (entry 10) and nitro (entry 9) groups are
tolerated. Selective mono- (entry 13) or polyhalogenation
(entries 10, 12, and 14) is possible by changing the reaction
stoichiometry. The following substrates were not efficiently
halogenated: 1,3-dinitrobenzene, 1,3,5-trinitrobenzene, 1,3-
difluorobenzene, pyrimidine, and pyridazine. Either low con-
versions (<10%) or substrate decomposition was observed.
2.2. Reactions with Sulfur Electrophiles. We also show that
sulfur electrophiles can be employed for in situ trapping of
arylmetals (Table 2). One can employ either elemental sulfur
or diphenyldisulfide as the trapping agent. The reaction
scope is somewhat limited compared with the halogenation
reaction. Electron-rich heterocycles such as benzoxazole and
N-phenyl-1,2,4-triazole react with sulfur in the presence of
tBuOLi base to afford the respective thiones (entries 1 and 2).
Phenylsulfenylation can be effected by the reaction with
diphenyldisulfide (entries 3-7). Benzothiazole, N-phenyl-
benzimidazole, N-methyl-1,2,4-triazole, and N-phenylpyra-
zole can be converted to the corresponding (S)-phenyl
derivatives. The reaction of 2-chlorothiophene with PhSSPh
afforded 2,5-bis(phenylthio)thiophene. Less acidic pyrazole
derivative requires the use of a stronger tBuOK base for high
conversion to the product. The limitations of the reaction are
as follows. Dibutyl disulfide reacts with benzothiazole to
form the benzothiazolethione by butylsulfenylation/dealky-
lation. Alkyl aryl ether containing substrates such as tetra-
fluoroanisole are dealkylated by RS- that is formed in the
reaction mixture. Polyfluoroarenes such as 1,3,5-trifluoro-
benzene undergo nucleophilic substitution of fluorides in
addition to the desired reaction.
2.3. Reactions with Carbonyl Electrophiles. An impressive
advance in aryl anion in situ trapping by non-enolizable
ketones and aldehydes has been demonstrated previously by
Kondo.6 However, expensive phosphazene bases were
employed, and only benzophenone and pivalaldehyde elec-
trophiles were employed. A thermal reaction of N-alkylimi-
dazoles with aldehydes affording addition products at the
2-position has been reported by Roe.10 A similar iridium-
catalyzed reaction between imidazoles, aldehydes, and
dimethylethylsilane producing 2-substituted imidazoles was
published by Murai.11 Hlasta has shown that imidazoles,
thiazoles, and triazoles can react with aldehydes in the
presence of acid chlorides and triethylamine to give 2-sub-
stituted azoles.12 A more general method that would allow
functionalization of a variety of substrates by employing
cheaper reagents would be useful.
SCHEME 2. Deprotonative Functionalization of Arene
Carbon-Hydrogen Bonds
values below 35.7a The reaction was shown to proceed via an
aryllithium or arylpotassium intermediate formed in situ by
the reaction of the arene with either K3PO4 or tBuOLi
metalating agent (Scheme 2A). It occurred to us that electro-
philic trapping of arylmetals formed under the copper-
catalyzed arylation conditions may result in a convenient
method for functionalization of acidic arenes (Scheme 2B).
Preliminary results describing arene in situ halogenation
were recently disclosed.7b We report here a method for
arylmetal in situ trapping with halogen, sulfur, and carbonyl
electrophiles.
2. Results and Discussion
2.1. Halogenation. Minor modifications of the copper-
catalyzed arylation conditions7b allowed the development
of an efficient process for in situ sp2 C-H bond halogena-
tion. The reactions are carried out in DMF or mixed DMF/
xylenes solvent at 50-130 °C (Table 1). Halogen electrophile
needs to be optimized for each reaction. Carbon tetrachlo-
ride and tetrabromide (entries 1, 2, 6, 7, 9, and 10) as well as
dibromotetrafluoroethane (entries 3-5), iodine (entries
11-12 and 15), and ICl (entries 8, 13, and 14) can be
employed. Electron-rich heterocycles such as benzothiazole
(entries 1 and 2), N-phenyltriazole (entry 3), caffeine (entry
4), and 5-phenyloxazole (entry 5) are halogenated in the most
acidic positions.8 Electron-poor pyridine oxides are also
halogenated under the optimized conditions (entries 6 and
7). For pyridine oxide reaction with carbon tetrabromide,
dibromination-deoxygenation product is obtained in 30%
yield.
(9) Review: (a) Slocum, D. W.; Shelton, P.; Moran, K. M. Synthesis 2005,
3477. (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) Deacon,
G. B.; Smith, R. N. M. Aust. J. Chem. 1982, 35, 1587. (d) Hellmann, M.;
Bilbo, A. J.; Pummer, W. J. J. Am. Chem. Soc. 1955, 77, 3650. (e) Mongin, F.;
Marzi, E.; Schlosser, M. Eur. J. Org. Chem. 2001, 2771. (f) Burukin, A. S.;
Vasil’ev, A. A.; Struchkova, M. I.; Kachala, V. V.; Zlotin, S. G. Russ. Chem.
Bull. 2005, 54, 964. (g) Boga, C.; Del Vecchio, E.; Forlani, L.; Todesco, P. E.
J. Organomet. Chem. 2000, 601, 233.
Halogenation of electron-poor arenes is also successful.
Typically, such reactions require either harsh electrophilic
(7) (a) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008,
130, 15185. (b) Do, H.-Q.; Daugulis, O. Org. Lett. 2009, 11, 421.
(8) (a) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007,
63, 1568. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(10) Roe, A. M. J. Chem. Soc. 1963, 2195.
(11) Fukumoto, Y.; Sawada, K.; Hagihara, M.; Chatani, N.; Murai, S.
Angew. Chem., Int. Ed. 2002, 41, 2779.
(12) Deng, Y.; Hlasta, D. J. Tetrahedron Lett. 2002, 43, 189.
8310 J. Org. Chem. Vol. 74, No. 21, 2009