Substitution effect on the regioselective halogen/metal exchange of 3-substituted 1,2,5-tribromobenzenes

Article abstract of DOI:10.1016/j.tetlet.2007.11.124

Regioselective halogen/metal exchange reactions using isopropylmagnesium chloride were studied on 3-substituted 1,2,5-tribromoarenes. Seven examples are given.

Full text of DOI:10.1016/j.tetlet.2007.11.124

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 415–418
Substitution effect on the regioselective halogen/metal exchange
of 3-substituted 1,2,5-tribromobenzenes
Karsten Menzel *, Paul M. Mills, Doug E. Frantz , Todd D. Nelson à, Michael H. Kress §
Merck Research Laboratories, Department of Process Research, Merck & Co., Inc., 466 Devon Park Drive, Wayne, PA 19087, United States
Received 31 May 2007; revised 19 November 2007; accepted 21 November 2007
Abstract
Regioselective halogen/metal exchange reactions using isopropylmagnesium chloride were studied on 3-substituted 1,2,5-tribromo-
arenes. Seven examples are given.
Ó 2007 Published by Elsevier Ltd.
Keywords: 1,2-Dibromobenzene; Grignard reactions; Halogen/metal exchange; Regioselectivity; Carboxylic acids
1. Introduction
2. Results and discussion
Due to the ever increasing need for accessing highly
functionalized benzene rings, the regioselective functional-
ization of di- and tribromoarenes has drawn increased
attention from organic chemists. Regioselective cross
coupling1–4 and halogen/metal exchange reactions5,6 of
1,4- and 1,3-dibromobenzenes are well documented in the
literature. Conversely, only few examples of 1,2-dibromo-
benzene and 1,2,4-tribromobenzene derivatives have been
studied in these same regioselective reactions.7,8 Herein,
we report the results of a site selective halogen/metal
exchange reaction using isopropylmagnesium chloride with
3-substituted 1,2,5-tribromobenzenes.
In general, the functionalization of the ortho-positions
to the bromide in 3,5-substituted bromobenzene derivatives
affords complex regioisomeric mixtures. Based on a recent
report from Krasovskiy and Knochel8a on the regioselec-
tive halogen/metal exchange of 1,2,4-tribromobenzene,
we envisioned that 3,5-substituted 1,2-dibromobenzene
derivatives could be regioselective functionalized in a halo-
gen/metal exchange reaction (Scheme 1). Regioselective
halogen/metal exchange on 1,4- and 1,3-dibromoarenes
using butyllithium has demonstrated low functional group
compatibility even at À78 °C.5,6 In contrast, Knochel and
co-workers showed that isopropylmagnesium chloride
undergoes smooth halogen/ magnesium exchange in the
presence of a variety of functional groups including
cyanides and esters.9 More importantly, these exchange
reactions occur typically between 0 and À40 °C without
significant degradation of the arylmagnesium intermedi-
ates,10 which prompted us to study the effects of substitu-
tion at the 3-position of 1,2,5-tribromobenzenes on the
corresponding halogen/metal exchange reaction with
isopropylmagnesium chloride.
*
Corresponding author at present address: MRL, Merck & Co., Inc.,
Sumneytown Pike, PO Box 4, West Point, PA 19486, United States. Tel.:
+1 215 652 0623.
E-mail address: karsten_menzel@merck.com (K. Menzel).
Present address: Department of Biochemistry, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-
9038, United States.
à
Present address: MRL, Merck & Co., Inc., 126 Lincoln Avenue, PO
A series of 3-substituted 1,2,5-tribromobenzene deriva-
tives (1a–g, Table 1) were prepared following a standard
bromination protocol11,12 and were utilized as starting
Box 2000, Rahway, NJ 07065-0900, United States.
§
Present address: MRL, Merck & Co., Inc., Sumneytown Pike, PO Box
4, West Point, PA 19486, United States.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.124

416
K. Menzel et al. / Tetrahedron Letters 49 (2008) 415–418
Br
Br
H
Br
1) iPrMgCl,
THF, -40 °C
1
H
Br
H
Br
H
Br
H
H
2
2) 1M HCl
4
H
Br
1b
Br
4
Br
5
6
Scheme 1. Halogen/metal exchange on 1,2,4-tribromobenzene and its possible regioisomers studied by Knochel.
agreement with Knochel’s observation,8a the bromide in
2-position of 1,2,4-tribromobenzene (1b) was predomi-
nantly exchanged using isopropylmagnesium chloride,
although we obtained the carboxylic acids 2b:3b as a 1:5
mixture.17 Also the methoxy group with its positive meso-
meric effect was expected to activate the bromide at C-1;
however, treatment of 1c with isopropylmagnesium chlo-
ride furnished a 1:1 mixture of regioisomers. This non-
selective exchange could be rationalized by a competitive
halogen/metal exchange of the bromides at C-2 and C-1
through the mesomeric effect and additional ortho-directing
ability of the methoxy group.
Table 1
Regioisomeric ratio and isolated yield of carboxylic acids 2 and 3
Entry
Compound
R
Ratio 2:3
Yielda [%]
1
2
3
4
5
6
7
a
1a
1b
1c
1d
1e
1f
Me
H
OMe
CN
Cl
1:32
1:5
85
78
80
N.D.c
82
1:1
2.3:1b
3:1
CF3
F
6:1
11:1
50
90
1g
Isolated yield of mixture 2:3 (average of two runs).
Ratio was determined after quench of the arylmagnesium intermediate
b
with aqueous HCl.
c
2d could not be isolated due to the formation of 4,6-dibromo-iso-
Compounds, bearing electron withdrawing groups at
C-3, preferentially exchanged the bromide at C-2 in the
presence of isopropylmagnesium chloride as would be
predicted from the inductive effect. Interestingly, the reac-
tivity and extent of exchange of the bromide at C-2 varied
and appears to depend on the extent of electronegativity of
the substituent at C-3 (F > CF3 > Cl > CN).18 High regi-
oselectivity ratios of the carboxylic acids 2:3 were observed
for fluorobenzene (1g) (11:1) and trifluoromethylbenzene
(1f) (6:1), respectively. Substituents at C-3 with a compara-
bly lower electronegativity, like chlorobenzene (1e) and
cyanobenzene (1d) led to decreased regioselective ratios
for 2:3 of 3:1 and 2:1, respectively.
Although there was no spectroscopic evidence that the
bromide at C-5 was exchanged,19 the electron withdrawing
ability of this bromide affected the reaction rate and site
selectivity of the compounds in Table 1. For example, all
of the C-3 substituted 1,2,5-tribromobenzenes studied
(Table 1) underwent smooth exchange at À40 °C in 2 h
and reactions went to completion in the presence of
1.1 equiv isopropylmagnesium chloride. In comparison to
1a, for example, 2,3-dibromotoluene exchanged the bro-
mide at C-2 at À20 °C in 18 h in the presence of 7 equiv
of isopropylmagnesium chloride.8c,20 Additionally, the
presence of a bromide at C-5 led to decreased regioselective
ratios compared to compounds without substitution at that
position.
benzofuran-1,3-dione; the major signal by HPLC related to the formation
of isobenzofuran while the minor signal remained unchanged during the
work up conditions.
materials in a halogen/metal exchange using isopropylmag-
nesium chloride at À40 °C in THF.
Generally, the halogen/metal exchange on 3-substituted
1,2,5-tribromobenzenes 1a–g formed exclusively two
regioisomers as confirmed by LC/MS. The unambiguous
assignments of the regioisomers formed in the halogen/
metal exchange and the regioisomeric ratio were achieved
by converting the arylmagnesium intermediates generated
from 1a–g into the corresponding benzoic acids by the
addition of CO2 as depicted in Scheme 2. The advantage
of the benzoic acid was the simplified purification and the
opportunity to analyze the products by a variety of
NMR experiments.13,14 The NMR experiments confirmed
that under the reaction conditions, two regioisomers were
formed (2 and 3) in various ratios depending upon the
electronics of the substituent in the 3-position.15,16 The
regioisomeric ratios and isolated yields obtained in the
halogen/metal exchange reaction are summarized in
Table 1.
The bromide at C-1 was preferentially exchanged when
electron neutral or donating groups were studied. 3-
Methyl-1,2,5-tribromobenzene (1a) resulted in the forma-
tion of the carboxylic acids 2a:3a as a 1:32 mixture. In
3. Conclusion and summary
Br
CO2H
Br
2
1) iPrMgCl,
2
2
3
3
3
R
Br
R
Br
R
CO2H
THF, -40 °C
1
1
1
We have demonstrated the regioselective halogen/metal
exchange reaction between PrMgCl and various 3-substi-
tuted 1,2,5-tribromobenzenes. As anticipated, we have
found that the electronic nature of the substituent at C-3
greatly influences the regioselectivity in these reactions
and in some cases provides exclusive access to a single
i
5
5
5
2) CO2, HCl
Br
1a-g
Br
2a-g
Br
3a-g
Scheme 2. Site selective halogen/metal exchange on 3-substituted 1,2,5-
tribromobenzenes.

K. Menzel et al. / Tetrahedron Letters 49 (2008) 415–418
417
5. Halogen/metal exchange of 1,4-dibromobenzene derivatives using
alkyllithium: (a) Dabrowski, M.; Kubicka, J.; Lulinski, S.; Serwa-
towski, J. Tetrahedron 2005, 61, 6590; (b) Parham, W. E.; Piccirilli, R.
M. J. Org. Chem. 1977, 42, 257; (c) Voss, G.; Gerlach, H. Chem. Ber.
1989, 122, 1199; (d) Gilman, H.; Langham, W.; Moore, F. W. J. Am.
Chem. Soc. 1940, 62, 2327.
6. Halogen/metal exchange of 1,3-dibromobenzene derivatives using
alkyllithium: (a) Sunthankar, S. V.; Gilman, H. J. Org. Chem. 1951,
16, 8; (b) Barluenga, J.; Montserrat, J. M.; Florez, J. J. Org. Chem.
1993, 58, 5976; (c) Han, Y.; Walker, S. D.; Young, R. N. Tetrahedron
Lett. 1996, 37, 2703; (d) Hoye, T. R.; Mi, L. Tetrahedron Lett. 1996,
37, 3097.
regioisomer. In general, electron withdrawing groups tend
to activate the bromide at C-2 for exchange, while electron
neutral and donating groups direct the Grignard reagent
predominantly to the bromide at C-1. Additionally, a bro-
mide at C-5 affected the overall reactivity of the compound
and the regioselective ratios compared to compounds with-
out substitution at C-5.
4. Experimental
7. Using alkyllithium: (a) Piette, J. L.; Renson, L. Bull. Soc. Chim. Belg.
1970, 79, 353; (b) Hardcastle, I. R.; Hunter, R. F.; Quayle, P.
Tetrahedron Lett. 1994, 35, 3805; (c) Schlosser, M.; Heiss, C. Eur. J.
Org. Chem. 2003, 447.
8. Halogen/metal exchange of 1,2-dibromobenzene derivatives using
isopropylmagnesium chloride: (a) Krasovskiy, A.; Knochel, P.
Angew. Chem., Int. Ed. 2004, 43, 3333; (b) Cottet, F.; Castagnetti,
E.; Schlosser, M. Synthesis 2005, 798; (c) Menzel, K.; Mills, P. M.;
Dimichele, L.; Frantz, D. E.; Nelson, T. D.; Kress, M. H. Synlett
2006, 1948.
4.1. General information
All starting materials were prepared according to Doyle
et al.11 and gave satisfactory 1H and 13C NMR spectra. All
reactions were carried out under an inert gas atmosphere,
using Schlenk techniques.
5. Typical procedures
9. Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int.
Ed. 2000, 39, 4414.
5.1. General procedure for the halogen/metal exchange
reaction: 2-bromo-6-fluorobenzoic acid (2g)
10. Aryllithium compounds tend to decompose at higher temperatures via
a dehydrobenzene pathway: (a) Dabrowski, M.; Kubicka, J.; Lulinski,
S.; Serwatowski, J. Tetrahedron Lett. 2005, 46, 4175; (b) Hoffmann,
R. W. Dehydrobenzene and Cycloalkynes; Academic Press: New York,
1967; (c) Wickham, P. P.; Hazen, K. H.; Guo, H.; Jones, G.; Reuter
Hardee, K.; Scott, W. J. J. Org. Chem. 1991, 56, 2045; (d) Wenwei, L.;
Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44,
4258.
In a Schlenk flask 782 mg (2.35 mmol) of 3-fluoro-1,2,5-
tribromobenzene was dissolved in 5 mL of THF under
nitrogen. The reaction mixture was cooled to À40 °C and
charged slowly with 1.30 mL (2.58 mmol, 1.98 M) of
iPrMgCl in THF. The reaction mixture was aged for 2 h
at À40 °C before a slow stream of CO2 was passed through
the reaction mixture for 1 h at À40 °C. The reaction mix-
ture was added to 10 mL of 1 M NaOH and the organic
layer was extracted two times with a total of 20 mL of
1 M NaOH. The combined aqueous layer was acidified
using 3 M HCl and extracted three times with a total
amount of 30 mL EtOAc. The organic phase was dried
over Na2SO4, filtered and concentrated in vacuum. The
white residue was purified by flash column chromato-
graphy (EtOAc/hexane 10:1). Compound 2g: 1H NMR
(CDCl3, 300 MHz): 10.29 (br s, 1H), 7.74–7.73 (m, 1H),
7.50 (dd, J = 1.65 Hz, 8.82 Hz, 1H); 3g: 1H NMR (CDCl3,
300 MHz): 10.29 (br s, 1H), 7.78–7.77 (m, 1H), 7.61 (dd,
J = 2.31 Hz, 8.13 Hz, 1H).
11. The synthesis of the starting material was prepared according to:
Doyle, M. P.; van Lente, M. A.; Mowat, R.; Fobare, W. F. J. Org.
Chem. 1980, 45, 2570.
12. Selected data for compounds 1a and 1c–g: 1a: 1H NMR (CDCl3,
300 MHz): 7.71 (d, J = 1.88 Hz, 1H), 7.46 (d, J = 2.15 Hz, 1H), 2.43
(s, 3H); 1c: 1H NMR (CDCl3, 300 MHz): 7.49 (d, J = 1.91 Hz, 1H),
7.18 (d, J = 1.97 Hz, 1H), 3.88 (s, 3H); 1d: 1H NMR (CDCl3,
300 MHz): 8.03 (d, J = 1.88 Hz, 1H), 7.77 (d, J = 2.08 Hz, 1H); 1f: 1H
NMR (CDCl3, 300 MHz): 8.14 (s, 1H), 7.90 (s, 1H); 1g: 1H NMR
(CDCl3, 300 MHz): 7.75 (t, J = 1.91 Hz, 1H), 7.45 (dd, J = 2.13 Hz,
8.04 Hz, 1H).
13. Compound 3a was identified by derivatization to the methyl ester.
The methyl ester was subjected to NOE experiment and a strong NOE
was observed with the ortho proton signal. 2,5-Dibromo-3-methyl-
benzoic acid methyl ester 1H NMR (CDCl3, 300 MHz): 7.74 (d,
J = 2.14 Hz, 1H), 7.64 (d, J = 2.15 Hz, 1H), 3.83 (s, 3H), 2.44 (s, 3H);
13C NMR (CDCl3, 75 MHz): 166.2, 142.1, 136.4, 136.0, 130.2, 121.4,
120.7, 53.3, 23.2.; 2/3b was confirmed by hydrolyzing the arylmag-
nesium intermediate with 1 M hydrochloric acid and comparing the
product mixture with the commercial products: 1,4- and 1,3-dibromo-
benzene.; 2/3c, e–g were identified by a proton coupled 13C NMR
experiment, where the carbonyl carbon was observed as a singlet for
carboxylic acid 2 and a doublet (ꢀJ = 7.5 Hz) for 3.
References and notes
1. Cross coupling reactions of 1,4-dibromobenzene derivatives: Dirk, S.
M.; Proce, D. W.; Chanteau, S.; Kosynki, D. V.; Tour, J. M.
Tetrahedron 2001, 57, 5109.
2. Cross coupling reactions of 1,3-dibromobenzene derivatives: Allen,
D. W.; Nowell, I. W.; March, L. A.; Taylor, B. F. J. Chem. Soc.,
Perkin Trans. 1 1984, 2523.
3. Cross coupling reactions of 1,2-dibromobenzene derivatives: (a)
Singh, R.; Just, G. J. Org. Chem. 1989, 54, 4453; (b) Staab, H. A.;
Hone, M.; Krieger, C. Tetrahedron Lett. 1988, 29, 1905; (c) Cheng, X.;
Hou, G.-H.; Xie, J.-H.; Zhou, Q.-L. Org. Lett. 2004, 6, 2381; 1,2-
dibromofuran derivative: (d) Stock, C.; Hofer, F.; Bach, T. Synlett
2005, 511.
4. For a general review on site selective transition metal catalyzed
reactions of polyhalogenated heteroaromatic ring systems: Schroter,
S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
14. For the regioselective analysis of highly substituted benzene deriva-
tives by NMR, see: Dimichele, L.; Menzel, K.; Mills, P.; Frantz, D.;
Nelson, T. Magn. Reson. Chem. 2006, 44, 1041.
15. There was no spectroscopic evidence observable that the bromide in
5-position underwent the halogen/metal exchange. Similar observa-
tion was published, that is: Sunthankar, S. V.; Gilman, H. J. Org.
Chem. 1951, 16, 8.
16. Selected spectroscopic data for 2 and 3: 2b (Heiss, C.; Marzi, E.;
Schlosser, M. Euro. J. Org. Chem. 2003, 4625): 1H NMR (MeOH-d4,
300 MHz): 7.89 (d, J = 2.36 Hz, 1H), 7.59 (s, 1H), 7.49 (d,
J = 2.38 Hz, 1H); 2c: 1H NMR (MeOH-d4, 300 MHz): 7.40 (d,
J = 1.25 Hz, 1), 7.31 (d, J = 1.59 Hz, 1H), 3.85 (s, 3H); 13C NMR
(MeOH-d4, 75 MHz): 167.4, 157.4, 126.5, 123.5, 119.0, 113.9, 55.8; 2d

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K. Menzel et al. / Tetrahedron Letters 49 (2008) 415–418
derivative (isobenzofurandione): melting point: 121 °C (121.5 °C,
(MeOH-d4, 300 MHz): 7.36 (d, J = 2.23 Hz, 1H), 7.24 (d, J =
2.13 Hz, 1H), 3.89 (s, 3H); 13C NMR (MeOH-d4, 75 MHz): 167.3,
157.3, 137.0, 124.1, 121.1, 116.9, 109.1, 56.2; 3d: 1H NMR (MeOH-d4,
Ullmann, K. Chem. Ber. 1911, 44, 427); 1H NMR (MeOH-d4,
300 MHz): 9.05 (br s, acidic proton), 8.13 (d, J = 1.53 Hz, 1H), 7.95
(d, J = 1.34 Hz, 1H); 13C NMR (MeOH-d4, 75 MHz): 166.6, 166.3,
140.1, 136.3, 129.1, 128.1, 125.3, 118.1; 2e (Mongin, F.; Schlosser, M.
Tetrahedron Lett. 1997, 38, 1559: 1H NMR (MeOH-d4, 300 MHz):
7.81 (d, J = 1.65 Hz, 1H), 7.70 (d, J = 1.66 Hz, 1H); 2f: 1H NMR
(MeOH-d4, 300 MHz): 8.16 (d, J = 1.23 Hz, 1H), 8.01 (d,
J = 1.43 Hz, 1H), acidic proton was not observed; 13C NMR
(MeOH-d4, 75 MHz): 166.5, 138.8 (two signals), 134.3, 129.4 (q,
J = 30 Hz)), 128.3 (q, J = 7.5 Hz), 123.1, 120.7; 2g (Mongin, F.;
Schlosser, M. Tetrahedron Lett. 1996, 37, 6551): 1H NMR (CDCl3,
300 MHz): 10.29 (br s, 1H), 7.74–7.73 (m, 1H), 7.50 (dd, J = 1.65 Hz,
8.82 Hz, 1H); 3a: 1H NMR (MeOH-d4, 300 MHz): 7.57 (d,
J = 2.16 Hz, 1H), 7.54 (d, J = 2.14 Hz, 1H), 2.39 (s, 3H); 13C NMR
(MeOH-d4, 75 MHz): 169.1, 143.3, 138.1, 136.5, 131.4 122.5, 121.7,
23.8; 3b: 1H NMR (MeOH-d4, 300 MHz): 7.89 (d, J = 2.36 Hz, 1H),
7.56 (s, 1H), 7.52 (d, J = 2.39 Hz, 1H); 13C NMR (MeOH-d4,
75 MHz): 167.8, 136.9, 136.4, 135.9, 134.9, 122.0, 121.1; 3c: 1H NMR
1
300 MHz); 3e: H NMR (MeOH-d4, 300 MHz): 7.84 (d, J = 2.34 Hz,
1H), 7.74 (d, J = 2.35 Hz, 1H); 3f: 1H NMR (CDCl3, 300 MHz); 3g:
1H NMR (CDCl3, 300 MHz): 10.29 (br s, 1H), 7.78–7.77 (m, 1H),
7.61(dd, J = 2.31 Hz, 8.13 Hz, 1H).
i
17. Similar regioisomeric ratio (15:85; 2:3) was observed if PrMgClÁLiCl
as the reagent in THF was used.
18. Suresh, C. H.; Koga, N. J. Am. Chem. Soc. 2002, 124, 1790.
19. Similar observations in 2-substituted 1,4-dibromobenzene derivatives
were made: (a) Voss, G.; Geralch, H. Chem. Ber. 1989, 122, 1199; (b)
Iida, T. T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Lett.
2001, 42, 4841; (c) Parham, W. E.; Piccirilli, R. M. J. Org. Chem.
1977, 42, 257; (d) Gilman, W. L.; Moore, F. W. J. Am. Chem. Soc.
1940, 62, 2327.
20. An acceleration of exchange using excess of Grignard reagents was
described by: Hoffmann, R. W.; Holzer, B.; Knopff, O.; Harms, K.
Angew. Chem., Int. Ed. 2000, 39, 3072.