An improved method for the bromination of metalated haloarenes via lithium, zinc transmetalation: A convenient synthesis of 1,2-dibromoarenes

Article abstract of DOI:10.1021/jo052515k

A facile protocol for the synthesis of 1,2-dibromoarenes is described. A standard ortho-lithiation/bromination procedure, when applied to bromoarenes, resulted in poor yields of the corresponding 1,2-dibromoarenes (13-62% yield). However, transmetalation

Full text of DOI:10.1021/jo052515k

plished either by using electrophilic bromination3 or by bromi-
nation of lithiated arenes with reagents such as bromine,4 NBS,5
Br2F4C2,6 or 1,2-dibromoethane.7
An Improved Method for the Bromination of
Metalated Haloarenes via Lithium, Zinc
Transmetalation: A Convenient Synthesis of
1,2-Dibromoarenes
While the above methods are commonly used to access a
wide array of brominated arenes, there are some limitations to
this methodology when applied to the synthesis of 1,2-
dibromoarenes. The electrophilic bromination of bromoarenes
has afforded mixtures of corresponding 1,4- and 1,2-dibro-
mides.8 The complimentary ortho-metalation reaction of bro-
moarenes with LDA or LiTMP9 has afforded the corresponding
ortho-lithiated bromoarenes with high selectivity and yield.
However, the subsequent bromination of the ortho-lithiated
species furnished 1,2-dibromoarenes in low to moderate yields.
A plausible explanation for the poor yields is depicted in Scheme
1.
Karsten Menzel,*,† Ethan L. Fisher,† Lisa DiMichele,‡
Doug E. Frantz,†,1 Todd D. Nelson,† and Michael H. Kress†
Merck Research Laboratories, Department of Process Research,
Merck & Co., Inc., 466 DeVon Park DriVe,
Wayne, PennsylVania 19087, and Merck Research Laboratories,
Department of Process Research, Merck & Co., Inc.,
126 E. Lincoln AVenue, Rahway, New Jersey 07065
karsten_menzel@merck.com
It is well documented that the original deprotonation of 1,3-
bromochlorobenzene (1a) with LiTMP affords the lithiated
intermediate (2a),10 which is stable at -78 °C. Immediately after
bromine addition to this anion is initiated, the reaction mixture
contains both the desired product 4a and unreacted aryllithium
(2a) (pathway A, Scheme 1). It is our supposition that this yet
unreacted anion (2a) is basic enough to abstract a proton from
the newly generated 1,2-dibromoarene (4a).11 Consequently, the
desired 1,2-dibromo-3-chlorobenzene (4a) is contaminated with
polyhalogenated arene 612 and copious amounts of starting
material 1a.13 To support our hypothesis, we reacted 0.5 equiv
of 3-chloro-1,2-dibromo-3-chlorobenzene (4a) with 1.0 equiv
of pregenerated aryllithium (2a) for 1 h at -78 °C. A sample
of the reaction mixture was analyzed by GC/MS after a
subsequent quench of the reaction mixture with d4-acetic acid,
which indicated that deuterated 5 was formed.
ReceiVed December 6, 2005
A facile protocol for the synthesis of 1,2-dibromoarenes is
described. A standard ortho-lithiation/bromination procedure,
when applied to bromoarenes, resulted in poor yields of the
corresponding 1,2-dibromoarenes (13-62% yield). However,
transmetalation of the transient aryllithium intermediate to
an arylzinc species with ZnCl2, followed by bromination,
resulted in dramatically improved yields of the synthetically
useful 1,2-dibromoarenes (68-95% yield).
(3) (a) March, J. Aromatic Electrophilic Substitution. In AdVanced
Organic Chemistry, 4th ed.; Wiley & Sons: New York, 1992; pp 507-
511. (b) Cram, D. J.; Carmarck, R. A.; deGrandpre, M. P.; Lein, G. M.;
Goldberg, I.; Knobler, C. B.; Maverick, E. F.; Trueblood, K. N. J. Am.
Chem. Soc. 1987, 109, 7068.
(4) (a) Hudlicky, M.; Hudlicky, T. Formation of Carbon-Halogen Bond.
In Supplement D: The Chemistry of Halides, Pseudohalides and Azides;
Patai, S., Rappoport, Z., Eds.; The Chemistry of Functional Groups; Wiley
& Sons: Chichester, U.K., 1983; Chapter 22, pp 1021-1172. (b) Sasson,
Y. Formation of Carbon-Halogen Bonds (Cl, Br, I). In Supplements D2:
The Chemistry of Halides, Pseudohalides and Azides; Patai, S., Rappoport,
Z., Eds.; The Chemistry of Functional Groups; Wiley & Sons: Chichester,
U.K., 1995; Chapter 11, pp 535-628.
Polyhalogenated arenes are ubiquitous target molecules in
the field of material science and natural product syntheses.2 The
widespread utility of these subunits necessitates versatile and
convenient methods for their preparation. Traditionally, the
regioselective preparation of bromoarenes has been accom-
(5) (a) Mitchell, R. C.; Lai, Y.-H.; Williams, R. V. J. Org. Chem. 1979,
44, 4733. (b) Ando, W.; Tsumaki, H. Synthesis 1982, 263. (c) Townsend,
C. A.; Davis, S. G.; Christensen, S. B.; Link, J. C.; Lewis, C. P. J. Am.
Chem. Soc. 1981, 103, 6885. (d) Martina, S.; Enkelmann, V.; Wegner, G.;
Schluter, A.-D. Synthesis 1991, 613.
† Merck & Co., Inc., Wayne, Pennsylvania.
‡ Merck & Co., Inc., Rahway, New Jersey.
(1) Current address: Department of Biochemistry, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-
9038.
(6) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424.
(7) Miah, M. A. J.; Snieckus, V. J. Org. Chem. 1985, 50, 5436.
(8) (a) Ferguson, L. N.; Garner, A. Y.; Mack, J. L. J. Am. Chem. Soc.
1954, 76, 1250. (b) Cresp, T. M.; Giles, R. G. F.; Sargent, M. V. Chem.
Comm. 1974, 11. (c) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi,
K.; Horaguchi, T. Chem. Lett. 2003, 32, 932.
(9) (a) Heiss, C.; Schlosser, M. Eur. J. Org. Chem. 2003, 447. (b) Marull,
M.; Schlosser, M. Eur. J. Org. Chem. 2003, 1576. (c) Mongin, F.; Marzi,
E.; Schlosser, M. Eur. J. Org. Chem. 2001, 2771. (d) Schlosser, M.
Organometallics in Synthesis. A Manual, 2nd ed.; Wiley: Chichester, U.K.,
2002.
(10) Mongin, F.; Schlosser, M. Tetrahedron Lett. 1997, 38, 1559.
(11) Mallet, M.; Queguiner, G. Tetrahedron 1985, 41, 3433.
(12) (a) Polybrominated arene formation under strong basic conditions:
Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376 and references therein.
(b) Mongin, F.; Desponds, O.; Schlosser, M. Tetrahedron Lett. 1996, 37,
2767.
(2) (a) Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L.,
Jr.; Wright, A.; Koehn, F. J. Org. Chem. 1988, 53, 3116. (b) Utkina, N.
K.; Denisenko, V. A.; Scholokova, O. V.; Virovaya, M. V.; Gerasimenko,
A. V.; Popov, D. Y.; Krasokhin, V. B.; Popov, A. M. J. Nat. Prod. 2001,
64, 151. (c) Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 1998,
61, 959. (d) Sielcken, O. E.; van Tilborg, M. M.; Roks, M. F. M.; Hendriks,
R.; Drenth, W.; Nolte, R. J. M. J. Am. Chem. Soc. 1987, 109, 4261. (e)
Stock, C.; Hofer, F.; Bach, T. Synlett 2005, 511. (f) Schroter, S.; Stock, C.;
Bach, T. Tetrahedron 2005, 61, 2245. (g) Vorogushin, A. V.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146. (h) Yam, V. W.-W.;
Ko, C.-C.; Zhu, N. J. Am. Chem. Soc. 2004, 126, 12734. (i) Wenderski, T.;
Light, K. M.; Ogrin, D.; Bott, S. G.; Harlan, C. J. Tetrahedron Lett. 2004,
45, 6851. (j) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126, 1437.
(k) Sygula, A.; Rabideau, P. W. J. Am. Chem. Soc. 2000, 122, 6323. (l)
Luly, J.; Rapoport, H. J. Org. Chem. 1981, 46, 2745.
(13) All products have been identified by GC/MS.
10.1021/jo052515k CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/08/2006
2188
J. Org. Chem. 2006, 71, 2188-2191

TABLE 1. Variation of Reaction Conditions Following Pathway B
in Scheme 1a
SCHEME 1. 1,2-Dibromoarene Formation
equiv of
ZnCl2
age timeb
[h]
assay yield
entry
[%]c of 4a
1
2
3
0
1.0
1.0
0.5
0.5
58
95
91
18d
a Standard reaction conditions: 1.2 equiv of TMP in THF at -78 °C,
1.1 equiv of 1.6 M n-BuLi in hexane, 1.0 equiv of 3-bromo-1-chlorobenzene,
2 h age, addition of 1.0 equiv of 1.0 M ZnCl2 in THF, 30 min age, 1.5
equiv of Br2 at -78 °C. b Age time after the addition of ZnCl2 at -78 °C.
c Assay yield after bromination at -78 °C. d 2-Bromo-6-chlorophenylzinc
was allowed to warm to room temperature over 18 h followed by the
addition of bromine.
dramatically increased assay yield (95%) of 4a was obtained if
aryllithium intermediate 2a was transmetalated to zinc species
3a prior to bromination (Scheme 2). A similar assay yield of
1,2-dibromo-3-chlorobenzene (4a) was obtained (91%) if the
reaction mixture was allowed to warm to room temperature over
18 h prior to the addition of bromine. This result suggested that
2-bromo-6-chlorophenylzinc (3a) was much more thermody-
namically stable than 2-bromo-6-chlorophenyllithium (2a).23,24
Finally, these transmetalation/bromination conditions with 1.0
equiv of zinc chloride at -78 °C were used to explore the scope
of 1,2-dibromoarene formation.
To minimize this undesired deprotonation reaction, we
envisioned that transmetalation from lithium to a less basic metal
like zinc would result in arylzinc (3a), which would effectively
preclude latent deprotonation of the desired product 4a after
bromination (pathway B, Scheme 1). We were pleased to find
that by simply adding an anhydrous zinc chloride solution in
THF14 to 2-bromo-6-chlorophenyllithium (2a) followed by
bromination afforded 1,2-dibromo-3-chlorobenzene (4a) in
excellent yield (95% assay yield).15
Direct comparisons of aryllithium bromination to arylzinc
bromination were made and the data are compiled in Table 2.
The direct bromination of the lithiated 1,3-bromohalobenzene
derivatives 1a-d gave moderate assay yields (52-62%) of the
desired aryl bromides 4a-d; however, each of these reactions
contained significant amounts of starting material. In contrast
to both the reaction profiles and assay yields of aryllithiums
2a-d, the bromination of the corresponding arylzinc species
3a-3d afforded brominated arenes 4a-d in excellent assay
yields (90-95%) and isolated yields (84-93%). In addition,
in all of these examples, essentially complete consumption of
starting aryl bromides (1a-d) occurred. The bromination of
1-bromo-2-cyanobenzene (1e) via the ortho-lithiated intermedi-
ate afforded a low assay yield (45%) of aryl bromide 4e and
occurred with low conversion (39% recovered 1e). Marked
improvements occurred to both the conversion (99%) and yield
of dibromide 4e (93% assay yield, 87% isolated yield) by
utilizing the zinc methodology. The bromination of 2- and
3-bromo-1-trifluoromethylbenzene (1f and 1h) once again
afforded low assay yields of the two dibromoarenes 4f and 4h
(32% and 52%, respectively) via the direct bromination of the
corresponding aryllithium intermediates. After transmetalation
to zinc, the brominated products 4f and 4h were formed in 70%
and 90% yield, respectively. 3-Bromotrifluoromethylbenzene
(1h) was selectively deprotonated in the 4-position and afforded
1,2-dibromo-4-trifluoromethylbenzene (4h) as a single product
after bromination.25 The sterically demanding bromo and
trifluoromethyl substituents prevented the ortho-lithiation in the
2-position with the sterically hindered base LiTMP. Bromination
of 2-bromo-3-lithium pyridine (2i) afforded 2,3-dibromopyridine
Spectroscopic data confirmed the transmetalation from aryl-
lithium16 to arylzinc17 upon the addition of zinc chloride. 13C
NMR data recorded on 2-bromo-6-fluorophenyllithium (2b)18
and 2-bromo-6-fluorophenylzinc (3b)19 indicated a high-field
chemical shift of the metal-bearing carbon from 170.2 ppm (d,
2
2JCF ) ∼137 Hz)20 to 159.8 ppm (d, JCF ) 77 Hz),
2
respectively.21 Additionally, the JF-C(ipso) coupling constant
reflected the presence of the metal species as compared to 24.2
Hz in 1b.22
The above hypothesis was further substantiated by a series
of experiments that are summarized in Table 1.
Only a 58% assay yield of compound 4a was obtained when
the aryllithium species 2a was brominated with bromine. A
(14) The anhydrous ZnCl2 solution can be substituted by an anhydrous
ZnBr2 solution that afforded 3-chloro-1,2-dibromo-3-chlorobenzene (4a) in
94% assay yield.
(15) At the same time only small amounts of side products (1a and 6)
according to Scheme 1 were observed.
(16) 13C NMR data confirmed that within 20 min the deprotonation
reaction primarily formed the lithiated product 2b.
(17) For examples of lithium-zinc transmetalation and Negishi-type
cross-coupling reactions, see: (a) Karig, G.; Spencer, J. A.; Gallagher, T.
Org. Lett. 2001, 3, 835 and references therein. (b) Examples for the cross-
coupling reaction of (2-bromophenyl)(iodo)zinc were described in ref 24.
(18) 1,3-Bromofluorobenzene (1b) was chosen for the NMR experiment,
because the formation of 2-bromo-6-fluorophenyllithium (2b) appeared as
a homogeneous reaction mixture under the standard reaction conditions.
(19) Breitmaier, E.; Voelter, W. Carbon-13 Spectroscopy of Organic
Compounds; VCH: Weinheim, Germany, 1987; Chapter 5, p 258.
(20) A similar 2JF-C(ipso) value was observed for 2-chloro-6-fluorophen-
yllithium: Ramirez, A.; Candler, J.; Bashore, C. G.; Wirtz, M. C.; Coe, J.
W.; Collum, D. B. J. Am. Chem. Soc. 2004, 126, 14700.
(21) The same trend as for 13C NMR chemical shifts of aryllithium and
arylzinc was reported: Gauthier, D. R., Jr.; Szumigala, R. H.; Dormer, P.
G.; Armstrong, J. D., III; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4,
375.
2
(22) For a discussion about JC-F values and electronic charges at the
13C atom see: Doddrell, D.; Barfield, M.; Adcock, W.; Aurangzeb, M.;
Jordan, D. J. Chem. Soc., Perkin Trans. 2 1976, 402.
J. Org. Chem, Vol. 71, No. 5, 2006 2189

SCHEME 2. Arylzinc Pathway to 1,2-Dibromoarenes
TABLE 2. Preparation of 1,2-Dibromoarenes
a Starting material. b Reagents and conditions: 1.2 equiv of 2,2,6,6-tetramethylpiperidine, 1.1 equiv of n-BuLi, 1.0 equiv.of 3-bromoarene, 2 h age, 1.5
equiv of Br2, THF, -78 °C. c Assay yield by HPLC. d Reagents and conditions: 1.2 equiv of 2,2,6,6-tetramethylpiperidine, 1.1 equiv of n-BuLi, 1.0 equiv
of bromoarene, 2 h age, 1.2 equiv of ZnCl2, 30 min age, 1.5 equiv of Br2, THF, -78 °C. e Isolated yield in parentheses.
(4i) in only 13% assay yield, while after transmetalation to zinc
the desired product 4i was formed in 90% yield. Finally, methyl
benzoate 4g was formed in 68% yield via the arylzinc species
compared to a 26% assay yield by direct bromination of the
aryllithium intermediate.26
bromination conditions were applied to bromoarenes, the
corresponding 1,2-dibromoarenes were formed in low to moder-
ate yields. The poor yields were rationalized by a deprotonation
pathway. However, transmetalation from aryllithium to the
arylzinc species with ZnCl2 effectively suppressed the formation
of side products and dramatically improved yields of the
synthetically useful 1,2-dibromoarenes.
In conclusion, we have discovered a facile protocol for the
synthesis of 1,2-dibromoarenes. When typical ortho-lithiation/
2190 J. Org. Chem., Vol. 71, No. 5, 2006

of ZnCl2 in THF (2.75 mL, 2.75 mmol) was added dropwise and
allowed to stir for an additional 30 min. Bromine (0.21 mL, 4.12
mmol) was added dropwise at a rate to keep the temperature below
-50 °C. The reaction was monitored by HPLC (typical reaction
time <30 min) and the completed reaction was allowed to warm
to 25 °C and quenched with H2O. The product was extracted two
times into tert-butyl methyl ether and the combined organic layers
were washed with 1 M HCl (aq) followed by H2O. The organic
layer was dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography with hexanes to
afford 0.62 g of 2,3-dibromobenzonitrile as a colorless liquid (2.38
mol, 87%). 1H NMR (CDCl3, 300 MHz) δ 7.85 (dd, J ) 8.20 Hz,
1.40 Hz, 1H), 7.62 (dd, J ) 7.70 Hz, 1.50 Hz, 1H), 7.29 (t, J )
8.00 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 137.7, 133.0, 128.6,
128.0, 126.7, 117.9, 116.8; GC/MS (m/z) 261, 180, 100, 75; melting
point 106.1 °C.
Experimental Section
To n-butyllithium in hexanes (1.95 mL, 1.55 M, 3.02 mmol) at
-20 °C was added a solution of 2,2,6,6-tetramethylpiperidine (0.51
mL, 3.02 mmol) in THF (4.75 mL). After aging for 30 min, the
solution was cooled to -78 °C and a solution of 3-bromobenzoni-
trile (0.5 g, 2.7 mmol) in THF (2.8 mL) was added dropwise so as
to maintain the temperature at <-70 °C. After 2 h, a 1.0 M solution
(23) Typically, ortho-lithiated bromoarenes are plagued by low thermo-
dynamic stability, which can lead to debromination via a benzyne
pathway: (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes;
Academic Press: New York, 1967. (b) Wickham, P. P.; Hazen, K. H.; Guo,
H.; Jones, G.; Reuter, K. H.; Scott, W. J. J. Org. Chem. 1991, 56, 2045. (c)
Lecroux, F.; Schlosser, M. Angew. Chem., Int. Ed. 2002, 41, 4272. (d)
Sapountzis, I.; Lin, W.; Fischer, M.; Knochel, P. Angew. Chem., Int. Ed.
2004, 43, 4364. (e) Hickey, M.; Allwein, S. P.; Nelson, T. D.; Kress, M.
H.; Sudah, O. S.; Moment, A. J.; Rodgers, S. D.; Kaba, M.; Fernandez, P.
Org. Res. Proc. DeV. 2005, 9, 764.
(24) Okano, M.; Amano, M.; Takagi, K. Tetrahedron Lett. 1998, 39,
3001.
(25) The same regioselectivity in the deprotonation step with LiTMP
has been observed: ref 12(b).
(26) The lithiated methyl-3-bromobenzoate (2g) underwent self-conden-
sation as the major side product after bromination was initiated.
Supporting Information Available: Experimental procedures
for the synthesis of compounds 4a-i, as well characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052515K
J. Org. Chem, Vol. 71, No. 5, 2006 2191