The "Aryne" route to biaryls featuring uncommon substituent patterns

Article abstract of DOI:10.1002/1521-3773(20021115)41:22<4272::AID-ANIE4272>3.0.CO;2-B

1,2-Didehydroarenes ("arynes") mediate as extremely reactive, short-lived intermediates in selective aryl-aryl coupling processes to form biaryls with unprecedented substituent patterns (see scheme, X = H, F, Cl). Possible applications include the synthesis of novel ligands for asymmetric catalysis.

Full text of DOI:10.1002/1521-3773(20021115)41:22<4272::AID-ANIE4272>3.0.CO;2-B

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12, Union Road, Cambridge CB21EZ, UK; fax: (þ 44)1223-336-033;
or deposit@ccdc.cam.ac.uk).
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Scheme 1. Reported[1] reaction of 1,2- and 1,4-dibromobenzene with
butyllithium to form 1 or 2, respectively.
phenyl (2; 18%).[1] Effective aryl aryl coupling in general
requires the participation of transition elements. When Lau
and co-workers[2] succeeded in raising the yield of 2,2’-
dibromobiphenyl to 81% by a careful optimization of the
reaction conditions, the condensation hypothesis had to be
abandoned. It was tempting to base an alternative mechanism
on the intermediacy of 1,2-didehydrobenzene (1,3-cyclo-
hexadien-5-yne, the so-called ™benzyne∫). However, if such
a species were really involved, 1,4-dibromobenzene would
have to give rise not only to 2, as reported,[1] but also to its 3,4’-
isomer 3. As revealed by gas chromatographic analysis, the
isomers 2 (M ¼ H; 41%) and 3[3] (M ¼ H; 21%) were indeed
formed concomitantly with bromobenzene (14%; Scheme 2).
These findings are in agreement with a metalation, elimina-
tion, addition sequence featuring 4-bromophenyllithium, 2,5-
dibromophenyllithium, and 4-bromo-1,2-didehydrobenzene
as transient entities.
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The ™Aryne∫ Route to Biaryls Featuring
Uncommon Substituent Patterns**
Frÿdÿric Leroux and Manfred Schlosser*
Scheme 2. Postulated mechanism of the coupling of 1,4-dibrombenzene
with butyllithium to account for the formation of a mixture of 2 and 3.
In 1957, Gilman and Gaj[1] disclosed a facile preparation of
2,2’-dibromobiphenyl (1) in 21% yield by treatment of 1,2-
dibromobenzene with half a molar equivalent of butyllithium
(Scheme 1). In support of the surmised condensation process
between dibromobenzene and a phenyllithium intermediate
derived from it by halogen metal permutation, they analo-
gously converted 1,4-dibromobenzene into 4,4’-dibromobi-
The ensuing work developed in three stages. The first
objective was to provide evidence for the suspected aryne
intermediate in the 1,2-dibromobenzene transformation.
Once the essential details of this reaction are understood,
one should be able to make use of this knowledge to construct
first symmetrical and eventually unsymmetrical biaryls. Ac-
cording to our hypothesis, the final step in the formation of 1
should be bromine abstraction from 1,2-dibromobenzene by
the 2’-bromo-2-biphenylyllithium species resulting from the
combination of 2-bromophenyllithium with 1,2-didehydro-
benzene (Scheme 3). If the starting material were replaced
with 1-bromo-2-iodobenzene, iodine transfer would have to
occur. In fact, treatment of this dihalo compound with half a
[*] Prof. Dr. M. Schlosser, Dr. F. Leroux
Institut de chimie molÿculaire et biologique
Ecole Polytechnique Fÿdÿrale
1015 Lausanne (Switzerland)
Fax : (þ 41)21-693-9365
E-mail: manfred.schlosser@epfl.ch
[**] This work was supported by the Swiss National Science Foundation,
Bern (grant 20-63’584-00).
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lithium species in the presence of a more stable aryllithium
compound which will then act as the trapping reagent. For
example, when a solution of 2-bromo-6-fluorophenyllithium
was treated with one equivalent of 1,2-dibromobenzene at
ꢁ758C, 2,2’-dibromo-6-fluorobiphenyl[10] (8; Scheme 5, X ¼
F) was obtained in 79% yield. The 2-bromophenyllithium
Scheme 3. Reaction of 1,2-dibrombenzene or 1-bromo-2-iodobenzene
with butyllithium to form 1 or 4, respectively.
molar equivalent of butyllithium afforded 2-bromo-2’-iodo-
biphenyl[4] (4; X ¼ I, Scheme 3) in 81% yield.
To demonstrate the general applicability of the new aryl
aryl linking mode, 9,10-dibromophenanthrene[5] was convert-
ed into 10,10’-dibromo-9,9’-bisphenanthryl[6] (5; 63%), 1-
bromo-3-fluoro-2-iodobenzene[7] into 2-bromo-3’,6-difluoro-
2’-iodobiphenyl[8] (6; 64%), and 1-bromo-3-chloro-2-iodo-
benzene[9] into 2-bromo-3’,6-dichloro-2’-iodobiphenyl (7;
62%; Scheme 4). The crucial steps in all these reactions were,
first the nucleophilic addition of the organolithium precursor
to the transient aryne species released from it by b-elimina-
tion of a lithium halide and, second, stabilization of the
resulting 2-biaryl lithium intermediate by in situ transfer of
bromine or iodine from the starting material.
Scheme 5. Trapping of the labile haloaryllithium intermediates by more
stable aryl lithium compounds.
species formed by halogen metal permutation from 1,2-
dibromobenzene is labile at temperatures above ꢁ1258C,
did not survive the experimental conditions but instantane-
ously released benzyne, which was trapped by the thermally
less sensitive aryllithium component. A similar reaction
between the labile 2,6-dibromophenyllithium (made from
1,3-dibromo-2-iodobenzene[7]) and 1,2-dibromobenzene gave
2,2’,6-tribromobiphenyl[11] (9) in 43% yield.
This aryl aryl coupling method can be modified by
generating the aryne from a thermally labile 2-haloaryl-
Biaryl species carrying three or four ortho-substituents can
be resolved into antipodal atropisomers. Therefore, our
results provide mechanistic insight and at the same time
provide an entry to axially dissymmetric bisphosphanes and
other ligands for enantioselective catalysis. 6’-Fluoro-1,1’-
biphenylene-2,2’-bis(dicyclohexylphosphane)[12] (10) was pre-
pared in 66% yield by consecutive treatment of 2,2’-dibromo-
6-fluorobiphenyl (8) with butyllithium and chlorodicyclohex-
ylphosphane (Scheme 6). Its 13C NMR DEPT spectrum
Scheme 6. Formation of the biaryl atropisomeric 10.
([D8]toluene, 258C) showed signals arising from the cyclo-
hexyl methine units as four different doublets (JC,P ꢀ 17 Hz),
thus exhibiting stereotopicity. This signal pattern did not
change noticeably when the sample was heated to 1258C.
Thus, the barrier to torsional isomerization must exceed
22 kcalmolꢁ1 and may well fall in the range of 25
30 kcalmolꢁ1 if one bases the estimate on the findings of
Jendralla et al.[13] with 6,6’-difluoro-2,2’-biphenylenebis(di-
phenylphosphane), the planarization of which is hampered
Scheme 4. Formation of the biaryls 5, 6, and 7.
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(86%); elemental analysis (%) calcd for C6H3BrClI (317.35): C 22.71,
H 0.95; found C 22.82, H 0.93. c) 1,3-Dibromo-2-iodobenzene: The
synthesis was carried out analogously to ref. [7a] from 1,3-dibromo-
benzene (12 mL, 24 g, 0.10 mol); colorless platelets; m.p. 99 1008C
(from ethanol); yield: 33 g (91%); elemental analysis (%) calcd for
C6H3Br2I (361.80): C 19.92, H 0.84; found C 19.97, H 0.80.
[8] 6: colorless needles (from ethanol); m.p. 100 1018C; 1H NMR
(CDCl3, 400 MHz): d ¼ 7.50 (td, J ¼ 8.1, 0.9 Hz, 1H), 7.39 (dt, J ¼ 7.9,
5.2 Hz, 1H), 7.28 (dt, J ¼ 8.2, 5.7 Hz, 1H), 7.14 (dt, J ¼ 8.6, 1.1 Hz, 1H),
7.10 (dt, J ¼ 8.0, 1.5 Hz, 1H), 7.02 ppm (dd, J ¼ 7.5, 1.1 Hz, 1H);
elemental analysis (%) calcd C12H6BrF2I (394.98): C 36.49, H 1.53;
found C 36.50, H 1.29.
[9] 7: colorless needles (from ethanol); m.p. 136 1388C; 1H NMR
(CDCl3, 400 MHz): d ¼ 7.57 (dd, J ¼ 8.0, 0.7 Hz, 1H), 7.52 (dd, J ¼
8.1, 1.6 Hz, 1H), 7.48 (dd, J ¼ 8.0, 0.8 Hz, 1H), 7.41 (t, J ¼ 7.9 Hz, 1H),
7.25 (t, J ¼ 8.2 Hz, 1H), 7.06 ppm (dd, J ¼ 7.5, 1.2 Hz, 1H); elemental
analysis (%) calcd for C12H6BrCl2I (427.89): C 33.68, H 1.41; found C
33.80, H 1.27.
by two P F interactions. The bisphosphane 10 should race-
mize at ambient temperature only slowly, if at all.
A related approach to the synthesis of asymmetric biaryls is
16]
presently pursued by Buchwald and co-workers.[14
These
authors isolated 2’-substituted 2-biphenylylphosphanes in
18 58% yield after having heated a solution of 1-bromo-2-
chlorobenzene in tetrahydrofuran under reflux in the pres-
ence of magnesium turnings and an ortho-substituted
Grignard reagent (such as 2-tolylmagnesium bromide, 2-
anisylmagnesium bromide, or 2-(dimethylamino)phenylmag-
nesium chloride), before quenching the mixture with chlo-
rodi-tert-butylphosphane or chlorodicyclohexylphosphane.
Received: May 24, 2002 [Z19382]
[10] 8: colorless needles (from ethanol); m.p. 68 708C; 1H NMR (CDCl3,
400 MHz): d ¼ 7.70 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.48 (td, J ¼ 7.9, 1.0 Hz,
1H), 7.40 (dt, J ¼ 7.8, 1.3 Hz, 1H), 7.3 (m, 3H), 7.13 ppm (dt, J ¼ 8.6,
1.1 Hz, 1H); elemental analysis (%) calcd for C12H7Br2F (329.99): C
43.68, H 2.14; found C 44.00, H 2.10.
[11] 9: colorless needles (from ethanol); m.p. 95 978C; 1H NMR (CDCl3,
400 MHz): d ¼ 7.69 (d, J ¼ 8.1 Hz, 1H), 7.64 (dd, J ¼ 8.1, 0.7 Hz, 2H),
7.42 (tt, J ¼ 7.5, 0.9 Hz, 1H), 7.29 (ddt, J ¼ 7.8, 1.8, 0.7 Hz, 1H), 7.18 (dd,
J ¼ 7.6, 1.6 Hz, 1H), 7.12 ppm (dd, J ¼ 8.1, 0.7 Hz, 1H); elemental
analysis (%) calcd for C12H7Br3 (390.90): C 36.87, H 1.81; found C
36.82, H 1.66.
[12] 10: colorless needles (from ethyl acetate/hexanes (1:5)); m.p. 184
1868C; 1H NMR (CDCl3, 400 MHz): d ¼ 7.5 (m, 1H), 7.3 (m, 4H), 7.1
(m, 1H), 1.7 (m, 24H), 1.2 ppm (m, 20H); 13C NMR ([D8]toluene,
101 MHz): d ¼ 162.7 (d, J ¼ 10.6 Hz), 160.2 (d, J ¼ 10.4 Hz), 143.8 (d,
J ¼ 5.2 Hz), 143.8 (d, J ¼ 5.0 Hz), 139.6 (d, J ¼ 22.4 Hz), 137.1 (d, J ¼
19.6 Hz), 133.6 (d, J ¼ 5.2 Hz), 133.4 (s), 133.1 (s), 128.5 (d, J ¼
22.4 Hz), 128.2 (d, J ¼ 12.2 Hz), 115.9 (d, J ¼ 23.6 Hz), 37.8 (d, J ¼
18.4 Hz), 36.8 (d, J ¼ 17.2 Hz), 34.6 (d, J ¼ 16.6 Hz), 34.4 (d, J ¼
16.8 Hz), 31 (m), 30.9 (d, J ¼ 14.2 Hz), 30.5 (d, J ¼ 9.3 Hz), 30.4 (d,
J ¼ 8.4 Hz), 28 (m), 27.4 ppm (s); elemental analysis (%) calcd for
C36H51FP2 (564.75): C 76.56, H 9.10; found C 76.43, H 9.04.
[13] H. Jendralla, C.-h. Li, E. Paulus, Tetrahedron: Asymmetry 1994, 5,
1297 1320.
[1] H. Gilman, B. J. Gaj, J. Org. Chem. 1957, 22, 447 449.
[2] T. K. Dougherty, K. S. Y. Lau, F. L. Hedberg, J. Org. Chem. 1983, 48,
5273 5280.
[3] F. H. Case, J. Am. Chem. Soc. 1938, 60, 424 427.
[4] 4: colorless needles (from ethanol); m.p. 88.5 898C; 1H NMR (CDCl3,
400 MHz): d ¼ 7.94 (d, J ¼ 7.9 Hz, 1H), 7.66 (d, J ¼ 8.0 Hz, 1H), 7.39
(dt, J ¼ 12.8, 7.5 Hz, 2H), 7.2 (m, 3H), 7.08 ppm (dt, J ¼ 7.6, 1.4 Hz,
1H); elemental analysis (%) calcd for C12H8BrI (359.00): C 40.15, H
2.25; found C 40.13, H 2.29.
[5] J. Schmid, G. Ladner, Ber. Dtsch. Chem. Ges. 1904, 37, 4402 4405.
[6] 5: colorless needles (from ethanol); m.p. 344 3488C (dec.); 1H NMR
([D6]DMSO, 400 MHz): d ¼ 9.10 (d, J ¼ 8.2 Hz, 2H), 9.05 (d, J ¼
8.5 Hz, 2H), 8.46 (d, J ¼ 8.0 Hz, 2H), 7.91 (sym m, 4H), 7.77 (t, J ¼
7.9 Hz, 2H), 7.46 (t, J ¼ 7.6 Hz, 2H), 7.13 ppm (d, J ¼ 8.1 Hz, 2H);
elemental analysis (%) calcd for C28H16Br2 (512.24): C 65.65, H 3.15;
found C 65.59, H 3.37.
[7] a) 1-Bromo-3-fluoro-2-iodobenzene: Diisopropylamine (14 mL, 10 g,
0.10 mol) and 1-bromo-3-fluorobenzene (11 mL, 18 g, 0.10 mol) were
consecutively added to a solution of butyllithium (0.10 mol) in
tetrahydrofuran (150 mL) and hexanes (50 mL) in a methanol/dry-
ice bath. After 2 h at ꢁ758C iodine (25 g, 0.1 mmol) in THF (50 mL)
was added, the solvents were evaporated and the residue dissolved in
diethyl ether (100 mL). After washing with a 10% aqueous solution of
sodium thiosulfate (2 î 50 mL), the organic layer was dried. Upon
distillation, a colorless oil was collected; b.p. 108 1098C (10 Torr);
n2D0 ¼ 1.6354; yield: 24 g (78%); elemental analysis (%) calcd for
C6H3BrFI (300.89): C 23.95, H 1.00; found C 24.07, H 1.08. b) 1-
Bromo-3-chloro-2-iodobenzene: Analogously to ref. [7a], the syn-
thesis was carried out from 1-bromo-3-chlorobenzene (12 mL, 19 g,
0.10 mol); colorless needles; m.p. 75 768C (from ethanol); yield: 27 g
[14] H. Tomori, J. M. Fox, S. L. Buchwald, J. Org. Chem. 2000, 65, 5334
5341.
[15] C. Parrish, S. L. Buchwald, J. Org. Chem. 2001, 66, 3820 3827.
[16] S. Kaye, J. M. Fox, F. A. Hicks, S. L. Buchwald, Adv. Synth. Catal.
2001, 343, 789 794.
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