Regioselective generation of aryllithiums from substituted bromobenzenes XC6H4Br (X = 4-Br, 4-I, 4-CN, 2-CN)

Article abstract of DOI:10.1002/ejoc.200701126

Selected activated bromobenzenes XC₆H₄Br (X = 4-Br, 4-I, 4-CN, 2-CN) were successfully deprotonated with lithium 2,2,6,6-tetramethylpiperidide (LTMP) in THF at -80°C. Thus, 2,5-dibromo-, 2-bromo-5-iodo-, 5-bromo-2-cyano-, and 3-bromo

Full text of DOI:10.1002/ejoc.200701126

FULL PAPER
DOI: 10.1002/ejoc.200701126
Regioselective Generation of Aryllithiums from Substituted Bromobenzenes
XC6H4Br (X = 4-Br, 4-I, 4-CN, 2-CN)
Sergiusz Lulin´ski,*[a] Janusz Serwatowski,[a] and Magdalena Szczerbin´ska[a]
Keywords: Lithiation / Arenes / Lithium / Halides / Cyanides
Selected activated bromobenzenes XC6H4Br (X = 4-Br, 4-I,
4-CN, 2-CN) were successfully deprotonated with lithium
2,2,6,6-tetramethylpiperidide (LTMP) in THF at –80 °C. Thus,
2,5-dibromo-, 2-bromo-5-iodo-, 5-bromo-2-cyano-, and 3-
bromo-2-cyanophenyllithium were obtained as stable inter-
mediates and could be converted by subsequent reactions
into various functionalized derivatives with good yields. A
competition of directing effects of bromine versus iodine and
cyano groups is discussed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
disilylated derivatives was obtained, whereas 1,4-bis(tri-
methylsilyl)-2,5-dibromobenzene forms selectively with a
high yield by using an excess amount of base and electro-
phile. Importantly, the internal quench implies that only se-
lected electrophiles can be employed, which limits the syn-
thetic value of this method.
Introduction
The metalation of bromoarenes is potentially a useful
method for the diverse functionalization of these important
reagents.[1] However, there are severe limitations for this
protocol. Firstly, only lithium dialkylamides can be used to
effect deprotonation, as alkyllithiums cause Br–Li ex-
change. Bromine is a relatively weak ortho-directing group
and another acidifying substituent is required to allow pro-
ton abstraction.[2–4] Once formed, ortho-bromoaryllithiums
are thermally labile and may release benzynes already at
low temperatures (below –70 °C)[5] unless they are stabilized
by another strongly electron-withdrawing ortho substituent,
for example, halogen, CF3, or OCF3.[6] Alternatively, bro-
mine migration is driven by the formation of a thermody-
namically more-stable isomer, for example, 2,3-dibromo-
phenyllithium initially generated from 1,2-dibromobenzene
rearranges into the 2,6-dibromo isomer at –75 °C,[7] which
is stable in THF up to ca –40 °C.[8] In this context, it should
be noted that the treatment of selected aryl bromides
and bromopyridines with the bulky TMP-zincate
(tBu2ZnTMP)Li provides ortho-metalated derivatives that
do not collapse into arynes.[9]
It was reported previously that 1,4-dibromobenzene (1)
is deprotonated with LTMP at –75 °C, but no further de-
tails were given.[7] It is known that 2,5-dibromophenyllith-
ium (1-Li) decomposes rapidly under metalation conditions
to form a highly reactive aryne, that is, 4-bromo-1,2-dehy-
drobenzene, which forms substituted biphenyls[10] or ani-
lines[8] depending on the composition of the reaction mix-
ture. However, 1-Li proved sufficiently stable to be trapped
by using an in situ quench technique with the use of LDA/
TMSCl in THF at ca –70 °C.[8] Unfortunately, a mixture
composed of the starting material, monosilylated and 2,5-
Results and Discussion
We were interested in optimizing the reaction conditions
as to allow the selective synthesis of 2,5-dibromophenyllith-
ium (1-Li) as an intermediate stable on a macroscopic time-
scale,[11] that is, for at least several minutes. This time is
necessary to perform a subsequent reaction with an external
electrophile. It can be prepared readily from 1,2,4-tribromo-
benzene by using Br–Li exchange in THF at –105 °C, but
the reaction suffers from poor selectivity and possible side
reactions, which reduce the yields of the desired 2,5-di-
bromo-substituted benzenes to ca 50%.[12] The attempted
deprotonation of 1 with the use of LTMP activated with
PMDTA in THF at ca –100 °C failed, but the reaction pro-
ceeds effectively over a few minutes at –80 °C. Under these
conditions, 1-Li is stable for at least 1 to 2 h. Typically, slow
decomposition manifested by gradual darkening of the re-
action mixture starts above –70 °C, and the rapid degrada-
tion accompanied with a substantial temperature jump is
observed at ca –60 °C. However, in a few experiments we
observed this rapid decomposition even at ca –75 °C, so it
is advisable not to exceed –80 °C during the lithiation step,
as well as during the subsequent addition of the electro-
phile. Further optimization was performed concerning the
choice of metalating agent. In fact, LTMP alone (i.e., with-
out the addition of PMDTA) works equally well, as evi-
denced by the yields of 2,5-dibromobenzoic acid 1a ob-
tained from trapping with CO2 (Table 1). In contrast,
[a] Warsaw University of Technology, Faculty of Chemistry,
Noakowskiego 3, 00-664 Warsaw, Poland
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S. Lulin´ski, J. Serwatowski, M. Szczerbin´ska
FULL PAPER
LTMP proved better than LDA, as carboxylation followed small amount of the starting material was recovered. This
by acidic hydrolysis afforded 2,5-dibromobenzoic acid in 84 indicates that the lithiation of 1,4-diiodobenzene occurs
and 68% yields, respectively. The synthetic value of 1-Li quite effectively, but the resultant 2,5-diiodophenyllithium
was confirmed, as we synthesized several functionalized is too labile at –80 °C and decomposes rapidly via the aryne
1,4-dibromobenzenes in good yields. The results are sum- pathway (with elimination of LiI), although it can be
marized in Table 1.
trapped even at slightly higher temperature by using an in-
ternal TMSCl quench as demonstrated previously.[13]
Table 1. Lithiation of 1-bromo-4-iodobenzene: Synthesis of substi-
tuted 1,4-dibromobenzenes 1a–h.
Table 2. Lithiation of 1-bromo-4-iodobenzene: Synthesis of 2-sub-
stituted 1-bromo-4-iodobenzenes 2a–c.
Compound Electrophile
E
Yield [%]
Compound
Electrophile
E
Yield [%]
1a
1a
1a
1b
1c
1d
1e
1f
CO2
CO2H
84[a]
82[b]
68[c]
68[a]
61[a]
2a
2b
2c
CO2
Me2NCHO
(MeS)2
CO2H
CHO
MeS
63
65
55[a]
tBuNCO
(CO2Me)2
2-MeOC6H4CHO
Me3SiCl
Bu3SnCl
(MeS)2
CONH-tBu
COCO2Me
[a] Contaminated with 3% 1-bromo-4-iodo-3-(methylthio)benzene
(2d).
2-MeOC6H4CH(OH) 50[a]
Me3Si
Bu3Sn
SMe
I
74[a]
84[a]
75[a]
70[a]
Despite a significant synthetic potential, the lithiation of
bromobenzonitriles has not been extensively investigated.
As expected, 3-bromobenzonitrile lithiates at C-2 with
LTMP owing to a cooperating acidifying effect of two adja-
1g
1h
I2
[a] Lithiation with LTMP. [b] LTMP–PMDTA. [c] LDA.
We employed the above protocol for the functionaliza- cent substituents to give an intermediate stable at –75 °C.[15]
tion of 1-bromo-4-iodobenzene (2). We showed previously We found previously that the in situ metalation/disilylation
that the in situ metalation/disilylation of 2 with LDA/ of 4-bromobenzonitrile (3) with LDA/TMSCl gives 2,5-bis-
TMSCl gives a mixture of 2,5- and 2,6-disilylated deriva- (trimethylsilyl)-4-bromobenzonitrile, which might reflect
tives in a ratio of 3:1.[13] Such a result suggests that the comparable ortho-directing ability of bromine with respect
ortho-directing ability of bromine is only slightly stronger to the CN group.[13] Similarly, the in situ lithiation/disilyl-
than that of iodine. However, when we subjected 2 to the ation of 2-bromobenzonitrile (4) is also very effective and
metalation with LTMP/THF at ca –80 °C, followed by elec- provides 3,6-bis(trimethylsilyl)-2-bromobenzonitrile with a
trophilic quench with CO2 and DMF, we isolated 2-bromo- high yield.[13] Indeed, lithiation of 3 with LDA/THF at
5-iodobenzoic acid (2a) and corresponding benzaldehyde –80 °C, followed by carboxylation, afforded a mixture of 5-
2b, respectively, with good yields and free of its regioiso- bromo-2-cyano- (3a) and 2-bromo-5-cyanobenzoic acid
mers resulting from lithiation ortho to iodine (Table 2). It (3b) in a ratio of ca. 2:1 and a total yield of ca. 50%. How-
seems that LTMP as a bulkier base is able to discriminate ever, we found that treatment of 3 with LTMP/THF at
better between two lithiation sites than LDA does. A sim- –80 °C gives selectively 5-bromo-2-cyanophenyllithium (3-
ilar behavior was reported previously for the lithiation of 1- Li), which was carboxylated to give 3a in high yield
bromo-4-chlorobenzene, where LTMP deprotonated prefer- (Scheme 1).[16] This means that the nitrile wins over bro-
entially at the sterically less-hindered position ortho to the mine in its ortho-directing ability with LTMP used as a de-
chlorine atom, whereas LDA generated a comparable pro- protonating agent. In this case, bromine contributes only
portion of regioisomeric 2-bromo-5-chlorophenyllith- with a potent long-range meta-acidifying effect, which obvi-
ium.[14] The formation of the 2-iodo-5-bromophenyllithium ously strongly facilitates proton abstraction from the posi-
byproduct was proved only in the synthesis of 2c, as the tion adjacent to the CN group and increases the stability of
major product was contaminated with a small amount (ca. resultant 3-Li.
3%) of the regioisomeric 1-bromo-4-iodo-3-(methylthio)-
In addition, we observed that the metalation of 4 with
benzene (2d). This indicates that the lithiation of 2 is not LTMP/THF at –80 °C occurs selectively ortho to the CN
perfectly regioselective, but the higher instability of ortho- group to give 3-bromo-2-cyanophenyllithium (4-Li).
iodoaryllithium species with respect to its ortho-bromo ana- Derivatization of 3-Li and 4-Li with B(OMe)3 followed by
logue results in the effective fate of the former intermediate hydrolysis afforded corresponding boronic acids 3c and 4a,
during aging of the reaction mixture. In fact, the attempted respectively, with reasonable yields (Scheme 1). Similar re-
lithiation of 1,4-diiodobenzene with LTMP in THF at sults were obtained recently by using in situ lithiation/
–80 °C, followed by carboxylation, failed to yield the de- boronation of 3 and 4 with LTMP/B(OiPr)3.[17] However, it
sired 2,5-diiodobenzoic acid and simultaneously only a was reported that the obtained neopentylglycol ester of 3c
1798
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Eur. J. Org. Chem. 2008, 1797–1801

Regioselective Generation of Aryllithiums from Substituted Bromobenzenes
2,5-Dibromobenzoic Acid (1a): A solution of 1 (11.8 g, 50 mmol) in
THF (50 mL) was added to a stirred solution of LTMP freshly
prepared from TMP (7.8 g, 55 mmol) and nBuLi (10 , 5.5 mL,
55 mmol) in THF (70 mL) at –80 °C. After ca. 40 min stirring at
ca. –80 °C (internal temperature), a mixture containing lithiate 1-
Li was cooled to ca. –100 °C and saturated with a stream of gas-
eous CO2. The mixture was stirred for 30 min at –75 °C and then
left to warm to ca. –20 °C, followed by careful hydrolysis with
aqueous sulfuric acid (1.5 , 50 mL). The water phase was sepa-
rated and extracted with diethyl ether (2ϫ50 mL). The combined
organic layer was concentrated under reduced pressure. A solid res-
idue was filtered and washed consecutively with water (3ϫ50 mL),
toluene (2 ϫ 25 mL), and hexane (50 mL). Drying in vacuo af-
forded the title compound as a white powder. M.p. 157–159 °C
(ref.[19] 155–156 °C). Yield: 11.7 g (84%). 1H NMR (400 MHz,
Scheme 1. Regioselective ortho-CN lithiation of 4- and 2-bromo-
benzonitrile.
4
3
[D6]acetone): δ = 7.93 (d, JH,H = 2.5 Hz, 1 H, Ph), 7.52 (d, JH,H
= 8.5 Hz, 1 H, Ph), 7.45 (dd, JH,H = 8.5, 2.5 Hz, 1 H, Ph) ppm.
13C NMR (100.6 MHz, [D6]acetone): δ = 165.5, 136.0, 135.5, 134.2,
134.1, 120.9, 120.4 ppm.
was contaminated with 10% of the regioisomeric product
arising from the lithiation/boronation ortho to the bromine
atom. Our interpretation of this difference involves a plaus-
ible extensive degradation of the lithiation byproduct 2-
bromo-5-cyanophenyllithium, which is therefore trapped
less effectively with external electrophiles than with major
product 3-Li. Indeed, the yield of 3c prepared by using our
stepwise protocol is lower (65%) than that reported for the
in situ quench,[17] where the 90:10 mixture of two boronated
4-bromobenzonitriles was isolated in 98% yield. The syn-
thesis of 3c is a useful alternative to the Ir-catalyzed bo-
rylation of 3, which produces the synthetically equivalent
pinacol ester of 3c.[18]
2-(tert-Butylaminocarbonyl)-1,4-dibromobenzene (1b): Compound
1-Li was prepared as described above in the synthesis of 1a. It was
then treated with a solution of tBuNCO (5.5 g, 55 mmol) in Et2O
(10 mL) at ca. –80 °C, and the resultant mixture was stirred for ca.
30 min at ca. –75 °C. Further workup was performed as described
for 1a. A crude product was filtered and washed consecutively with
water (3ϫ50 mL) and hexane (2ϫ25 mL). Drying in vacuo af-
forded the title compound as a white powder. M.p. 120–122 °C.
Yield: 11.4 g (68%). 1H NMR (400 MHz, CDCl3): δ = 7.55 (d,
3
4JH,H = 2.0 Hz, 1 H, Ph), 7.39 (d, JH,H = 8.5 Hz, 1 H, Ph), 7.33
(dd, JH,H = 8.5, 2.0 Hz, 1 H, Ph), 5.81 (br., 1 H, NH), 1.44 (s, 9
H, tBu) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 165.3, 140.5,
134.5, 133.6, 132.0, 121.4, 117.7, 52.4, 28.6 ppm. C11H13Br2NO
(335.04): calcd. C 39.43, H 3.91, N 4.18; found C 39.76, H 3.78, N
4.53.
Conclusion
Methyl 2-(2Ј,5Ј-Dibromophenyl)-2-oxoacetate (1c): Compound 1-Li
was prepared as described above in the synthesis of 1a. It was then
treated with a solution of (CO2Me)2 (6.1 g, 52 mmol) in THF
(30 mL) at ca. –85 °C, and the resultant mixture was stirred for ca.
30 min at ca. –75 °C. Further workup was performed as described
for 1a. A crude product was filtered and washed consecutively with
water (3ϫ50 mL) and hexane (2ϫ20 mL) and dried. Recrystalli-
zation from CH2Cl2/hexane (1:1, 50 mL) at –50 °C afforded the
title compound as a pale yellow powder. M.p. 65–66 °C. Yield: 9.8 g
The lithiation of four substituted bromobenzenes can be
performed with LTMP at –80 °C to provide regioselectively
the corresponding bromoaryllithiums as stable intermedi-
ates in good yields. Subsequent derivatization provides con-
venient access to various functionalized bromoarenes, in-
cluding synthetically valuable arylcarboxylic and aryl-
boronic acids.
1
4
(61%). H NMR (400 MHz, CDCl3): δ = 7.77 (d, JH,H = 2.0 Hz,
3
Experimental Section
1 H, Ph), 7.55 (dd, JH,H = 8.5, 2.0 Hz, 1 H, Ph), 7.49 (d, JH,H =
8.5 Hz, 1 H, Ph), 3.96 (s, 3 H, OMe) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 185.5, 162.0, 137.1, 136.8, 135.0, 134.1, 121.8, 120.0,
53.5 ppm. C9H6Br2O3 (321.95): calcd. C 33.58, H 1.88; found C
33.90, H 1.69.
General Comments: All reactions involving air- and moisture-sensi-
tive reagents were carried out under an argon atmosphere. Et2O
and THF were stored over sodium wire before use. Starting bromo-
benzenes and other important reagents, including tert-butylisocy-
anate, dimethyl oxalate, 2-methoxybenzaldehyde, chlorotrimethyl-
silane, chlorotributyltin, N,N-dimethylformamide, dimethyl di-
sulfide, iodine, nBuLi (10  solution in hexanes), 2,2,6,6-tetrameth-
ylpiperidine, and trimethyl borate were received from Aldrich. The
NMR chemical shifts are given relative to TMS by using known
chemical shifts of residual proton (1H) or carbon (13C) solvent reso-
nances. In the 1H and 13C NMR spectra of tin derivative 1f satellite
α-(2Ј-Methoxyphenyl)-2,5-dibromobenzyl Alcohol (1d): Compound
1-Li was prepared as described above in the synthesis of 1a. It
was then treated with a solution of 2-methoxybenzaldehyde (7.1 g,
50 mmol) in THF (30 mL) at ca. –80 °C, and the resultant mixture
was stirred for ca. 30 min at ca. –75 °C. Further workup was per-
formed as described for 1a. A crude product was filtered and
washed consecutively with water (3ϫ50 mL) and hexane
(2ϫ20 mL) and dried. Recrystallization from toluene/hexane (1:2,
50 mL) afforded the title compound as colorless crystals. M.p. 130–
1
peaks were observed due to H–Sn (119Sn and 117Sn) and 13C–Sn
couplings, respectively. In the 13C NMR spectra of arylboronic ac-
ids 3b and 4a, the resonances of boron-bound carbon atoms were
not observed due to their broadening by a quadrupolar boron nu-
cleus. New compounds gave satisfactory elemental analyses except
for 4a, which formed an air-stable hydrate.
1
132 °C. Yield: 9.3 g (50%). H NMR (400 MHz, CDCl3): δ = 7.77
4
3
(d, JH,H = 2.5 Hz, 1 H, Ph), 7.40 (d, JH,H = 8.5 Hz, 1 H, Ph),
7.32–7.28 (m, 2 H, Ph, PhЈ), 6.94–6.89 (m, 3 H, PhЈ), 6.33 (d, 3JH,H
= 3.0 Hz, 1 H, CHOH), 3.90 (s, 3 H, OMe), 3.12 (d, 3JH,H = 3.0 Hz,
Eur. J. Org. Chem. 2008, 1797–1801
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S. Lulin´ski, J. Serwatowski, M. Szczerbin´ska
FULL PAPER
1 H, CHOH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 157.0, 2-Bromo-5-iodobenzoic Acid (2a): This compound was prepared as
143.5, 133.9, 133.1, 131.9, 131.8, 129.6, 129.3, 127.7, 121.6, 120.7, described for 1a from 1-bromo-4-iodobenzene 2 (5.7 g, 20 mmol).
110.6, 70.4, 55.5 ppm. C14H12Br2O2 (372.05): calcd. C 45.20, H A crude product was dissolved in aqueous NaOH (1 , 30 mL),
3.25; found C 45.45, H 3.41.
and the resultant solution was filtered and washed with toluene
(20 mL) and hexane (20 mL). The product was precipitated with
aqueous HCl (1 , 30 mL), filtered, and washed with water
(2ϫ20 mL). Drying in vacuo afforded the title compound as a
white powder. M.p. 172–174 °C. Yield: 4.1 g (63%). 1H NMR
(400 MHz, [D6]acetone): δ = 11.8 (br., 1 H, COOH), 8.15 (d, 4JH,H
= 2.5 Hz, 1 H, Ph), 7.79 (dd, JH,H = 8.5, 2.5 Hz, 1 H, Ph), 7.51 (d,
3JH,H = 8.5 Hz, 1 H, Ph) ppm. 13C NMR (100.6 MHz, [D6]ace-
tone): δ = 165.7, 142.3, 140.4, 136.8, 135.6, 121.5, 92.4 ppm.
C7H4BrIO2 (326.91): calcd. C 25.72, H 1.23; found C 26.00, H 1.52.
1,4-Dibromo-2-(trimethylsilyl)benzene (1e): Compound 1-Li was
prepared as described above in the synthesis of 1a. It was then
treated with TMSCl (5.6 g, 52 mmol) at ca. –80 °C, and the result-
ant mixture was stirred for ca. 30 min at ca. –75 °C. Further
workup was performed as described for 1a. A crude oily product
was dissolved in hexane (50 mL), and the resultant solution was
washed with water (50 mL), dried with MgSO4, and concentrated.
Fractional distillation in vacuo afforded the title compound as a
colorless oil. B.p. 73–76 °C (0.5 Torr). Yield: 11.4 g (68%). 1H
2-Bromo-5-iodobenzaldehyde (2b): This compound was prepared as
described for 2a by using DMF (2.2 g, 30 mmol) as the electrophile.
A crude product was recrystallized from hexane (15 mL) to give
the title compound as pale yellow crystals. M.p. 105–107 °C. Yield:
4.05 g (65%). 1H NMR (400 MHz, CDCl3): δ = 10.22 (s, 1 H,
4
NMR (400 MHz, CDCl3): δ = 7.52 (d, JH,H = 2.5 Hz, 1 H, Ph),
3
7.39 (d, JH,H = 8.5 Hz, 1 H, Ph), 7.31 (dd, JH,H = 8.5, 2.5 Hz, 1
H, Ph), 0.41 (s, 9 H, SiMe3) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 144.0, 138.6, 134.3, 133.5, 128.7, 121.4, –0.8 ppm. C9H12Br2Si
(308.09): calcd. C 35.09, H 3.93; found C 35.18, H 3.99.
4
CHO), 8.17 (d, JH,H = 2.5 Hz, 1 H, Ph), 7.72 (dd, JH,H = 8.5,
2.5 Hz, 1 H, Ph), 7.36 (d, 3JH,H = 8.5 Hz, 1 H, Ph) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 190.3, 143.8, 138.5, 135.3, 134.6, 126.6,
92.9 ppm. C7H4BrIO (310.91): calcd. C 27.04, H 1.30; found C
27.28, H 1.70.
1,4-Dibromo-2-(tributylstannyl)benzene (1f): Compound 1-Li was
prepared as described above in the synthesis of 1a. It was then
treated with Bu3SnCl (16.3 g, 50 mmol) at ca. –80 °C, and the re-
sultant mixture was stirred for ca. 30 min at ca. –75 °C. Further
workup was performed as described for 1e. Fractional distillation
in vacuo afforded the title compound as a colorless oil. B.p. 139–
143 °C (0.5 Torr). Yield: 22.0 g (84%). 1H NMR (400 MHz,
1-Bromo-4-iodo-2-(methylthio)benzene (2c): This compound was
prepared from 2 as described for 1g. A crude product was recrys-
tallized from hexane (15 mL) to give the title compound as color-
less crystals. M.p. 47–48 °C. Yield: 3.6 g (55%). 1H NMR
4
3
CDCl3): δ = 7.40 (d, JH,H = 2.5 Hz, 1 H, Ph), 7.35 (d, JH,H
=
8.0 Hz, 1 H, Ph), 7.26 (dd, JH,H = 8.0, 2.0 Hz, 1 H, Ph), 1.59–1.53
(m, 6 H, CH2CH2CH2CH3), 1.40–1.31 (m, 6 H, CH2CH2CH2CH3),
4
(400 MHz, CDCl3): δ = 7.33 (d, J = 2.0 Hz, 1 H, Ph), 7.28 (dd, J
3
= 8.5, 2.0 Hz, 1 H, Ph), 7.20 (d, J = 8.5 Hz, 1 H, Ph), 2.45 (s, 3
3
1.18 (t, 6 H, CH2CH2CH2CH3), 0.91 (t, JH,H = 7.0 Hz, 9 H,
H, SMe) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 142.2, 134.4,
133.9, 133.2, 121.1, 92.9, 15.7 ppm. C7H6BrIS (329.00): calcd. C
25.55, H 1.84; found C 25.93, H 1.56. The product was contami-
nated with 3% of 1-bromo-4-iodo-3-(methylthio)benzene 2d: 1H
CH2CH2CH2CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
149.8, 140.2, 133.2, 132.7, 131.4, 121.6, 28.9, 27.3, 13.7, 10.9 ppm.
C18H30Br2Sn (524.95): calcd. C 41.18, H 5.76; found C 41.35, H
5.70.
3
NMR (400 MHz, CDCl3): δ = 7.59 (d, JH,H = 8.5 Hz, 1 H, Ph),
4
7.13 (d, JH,H = 2.5 Hz, 1 H, Ph), 6.96 (dd, JH,H = 8.5, 2.5 Hz, 1
1,4-Dibromo-2-(methylthio)benzene (1g): Compound 1-Li was pre-
pared as described above in the synthesis of 1a. It was then treated
with (MeS)2 (4.9 g, 52 mmol at ca. –80 °C, and the resultant mix-
ture was stirred for ca. 30 min at ca. –75 °C. Further workup was
performed as described for 1a. A crude oily product was dissolved
in diethyl ether (80 mL), and the resultant solution was washed
with water (50 mL), dried with MgSO4, and concentrated. Frac-
tional distillation in vacuo afforded a crude product as a low-melt-
ing solid. B.p. 90–95 °C (0.5 Torr). Recrystallization from cold hex-
ane (30 mL, –20 °C) furnished the title compound as colorless crys-
tals. M.p. 62–63 °C (ref.[12] 59–60 °C). Yield: 10.7 g (75%). 1H
H, Ph), 2.46 (s, 3 H, SMe) ppm.
5-Bromo-2-cyanobenzoic Acid (3a): This compound was prepared
as described for 1a from 4-bromobenzonitrile 3 (9.1 g, 50 mmol).
A crude product was washed with water (2ϫ20 mL), toluene
(2ϫ20 mL) and hexane (20 mL). Drying in vacuo afforded the title
compound as a white powder. M.p. 169–171 °C (dec.). Yield: 9.3 g
(82%). 1H NMR (400 MHz, [D6]acetone): δ = 8.30 (d, JH,H
=
4
2.5 Hz, 1 H, Ph), 8.02 (dd, JH,H = 8.5, 2.5 Hz, 1 H, Ph), 7.88 (d,
3JH,H = 8.5 Hz, 1 H, Ph) ppm. 13C NMR (100.6 MHz, [D6]ace-
tone): δ = 164.1, 137.3, 136.9, 135.2, 134.9, 127.6, 117.4, 112.7 ppm.
C8H4BrNO2 (226.03): calcd. C 42.51, H 1.78, N 6.20; found C
42.71, H 2.11, N 6.18.
3
NMR (400 MHz, CDCl3): δ = 7.35 (d, JH,H = 8.5 Hz, 1 H, Ph),
4
7.17 (d, JH,H = 2.0 Hz, 1 H, Ph), 7.10 (dd, JH,H = 8.5, 2.0 Hz, 1
H, Ph), 2.47 (s, 3 H, SMe) ppm.
5-Bromo-2-cyanophenylboronic Acid (3c): This compound was pre-
pared as described for 3a by using B(OMe)3 (6.3 g, 60 mmol) as the
electrophile. A crude product was washed with water (2ϫ20 mL),
toluene (3ϫ20 mL), and hexane (20 mL). Drying in vacuo afforded
the title compound as a white powder. M.p. 280–285 °C (dec.).
Yield: 7.3 g (65%). 1H NMR (400 MHz, [D6]acetone): δ = 8.63 [br.,
1,4-Dibromo-2-iodobenzene (1h): Compound 1-Li was prepared as
described above in the synthesis of 1a. It was then treated with I2
(14.0 g, 55 mmol) at ca. –90 °C, and the resultant mixture was
stirred for ca. 30 min at ca. –80 °C. Further workup was performed
as described for 1a. A crude oily product was diluted with diethyl
ether (80 mL), and the resultant solution was washed with aqueous
Na2S2O3 (1 , 30 mL) and water (50 mL), dried with MgSO4, and
concentrated. Fractional distillation in vacuo afforded a crude
product as yellow oil. B.p. 95–105 °C (0.5 Torr). Recrystallization
from cold hexane (30 mL, –50 °C) furnished the title compound as
almost colorless crystals. M.p. 38–39 °C (ref.[20] 38–39 °C). Yield:
4
B(OH)2], 8.02 (d, JH,H = 2.0 Hz, 1 H, Ph), 7.78 (dd, JH,H = 8.5,
2.0 Hz, 1 H, Ph), 7.70 (d, 3JH,H = 8.5 Hz, 1 H, Ph) ppm. 13C NMR
(100.6 MHz, [D6]acetone): δ = 138.4, 135.8, 134.1, 127.3, 119.3,
116.1 ppm. 11B NMR (64.2 MHz, [D6]acetone): δ = 28.0 ppm.
C7H5BBrNO2 (225.84): calcd. C 37.23, H 2.23, N 6.20; found C
37.42, H 2.49, N 6.16.
1
4
12.7 g (70%). H NMR (400 MHz, CDCl3): δ = 7.99 (d, JH,H
=
3-Bromo-2-cyanophenylboronic Acid Monohydrate (4a·H2O): This
compound was prepared as described for 3b from 2-bromobenzo-
nitrile 4 (3.65 g, 20 mmol). A crude product was washed with water
3
2.5 Hz, 1 H, Ph), 7.46 (d, JH,H = 8.5 Hz, 1 H, Ph), 7.32 (dd, JH,H
= 8.5, 2.5 Hz, 1 H, Ph) ppm.
1800
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1797–1801

Regioselective Generation of Aryllithiums from Substituted Bromobenzenes
[6]
a) F. Mongin, O. Desponds, M. Schlosser, Tetrahedron Lett.
1996, 37, 2767–2770; b) F. Mongin, M. Schlosser, Tetrahedron
Lett. 1996, 38, 6551–6554; c) M. Schlosser, E. Castagnetti, Eur.
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S. Lulin´ski, J. Serwatowski, J. Org. Chem. 2003, 68, 5384–5387.
a) M. Uchiyama, T. Miyoshi, Y. Kajihara, T. Sakamoto, Y.
Otani, T. Ohwada, Y. Kondo, J. Am. Chem. Soc. 2002, 124,
8514–8515; b) T. Imahori, M. Uchiyama, T. Sakamoto, Y.
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(2ϫ10 mL), toluene (2ϫ10 mL), and hexane (10 mL). Drying in
vacuo afforded 4a·H2O as colorless crystals. M.p. 264–267 °C
1
(dec.). Yield: 3.7 g (75%). H NMR (400 MHz, [D6]acetone): δ =
3
7.85–7.81 (m, 2 H, Ph), 7.57 (t, JH,H = 8.0 Hz, 1 H, Ph), 3.18 (br.,
[7]
2 H, H2O) ppm. 13C NMR (100.6 MHz, [D6]acetone): δ = 134.7,
133.94, 133.93, 126.6, 119.3, 118.1 ppm. 11B NMR (64.2 MHz,
[8]
[9]
[D6]acetone): δ = 28.0 ppm. C7H5BBrNO2·H2O (243.85): calcd. C
34.48, H 2.89, N 5.74; found C 35.04, H 3.08, N 5.86.
Acknowledgments
[10]
F. Leroux, M. Schlosser, Angew. Chem. Int. Ed. 2002, 41, 4272–
4274.
This work was supported by the Warsaw University of Technology
and by the Polish Ministry of Science and Higher Education (Grant
No. N N205 055633). The support by Aldrich Chemical Co., Mil-
waukee, WI, U.S.A., through continuous donation of chemicals
and equipment is gratefully acknowledged.
[11]
[12]
J. P. Clayden, Organolithiums: Selectivity for Synthesis, Perga-
mon, Oxford, 2002, p. 174.
S. Lulin´ski, J. Serwatowski, A. Zaczek, Eur. J. Org. Chem. 2006,
5167–5173.
[13]
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details were provided. See: T. Imahori, Y. Kondo, J. Am. Chem.
Soc. 2003, 125, 8082–8083.
M. Lysén, H. M. Hansen, M. Begtrup, J. L. Kristensen, J. Org.
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W. E. Parham, R. M. Piccirilli, J. Org. Chem. 1977, 42, 257–
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Received: November 28, 2007
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Published Online: February 13, 2008
Eur. J. Org. Chem. 2008, 1797–1801
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1801