Formation of 3-halobenzyne: Solvent effects and cycloaddition adducts

Article abstract of DOI:10.1021/ol049655l

Noncoordinating solvents permit the halogen-metal exchange-induced formation of benzyne (aryne) from di- and trihalobenzene precursors in the presence of cyclopentadiene to give 1,4-dihydro-1,4-methano-naphthalenes. Studies with mixed halide precursors and nonacidic Diels-Alder diene traps reveal that ethereal and hydrocarbon solvents influence the halide leaving group facility, resulting in a reversal of 3-halobenzyne regioselectivity.

Full text of DOI:10.1021/ol049655l

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1589-1592
Formation of 3-Halobenzyne: Solvent
Effects and Cycloaddition Adducts
Jotham W. Coe,* Michael C. Wirtz, Crystal G. Bashore, and John Candler
Pfizer Global Research and DeVelopment, Groton Laboratories, Pfizer, Inc.,
Groton, Connecticut 06340
coejw@groton.pfizer.com
Received February 26, 2004
ABSTRACT
Noncoordinating solvents permit the halogen−metal exchange-induced formation of benzyne (aryne) from di- and trihalobenzene precursors
in the presence of cyclopentadiene to give 1,4-dihydro-1,4-methano-naphthalenes. Studies with mixed halide precursors and nonacidic Diels−
Alder diene traps reveal that ethereal and hydrocarbon solvents influence the halide leaving group facility, resulting in a reversal of 3-halobenzyne
regioselectivity.
Benzynes (arynes) are highly reactive chemical intermediates
that continue to fascinate synthetic and mechanistic chem-
ists.1 As transient species, they are often studied indirectly
through chemical reactions, some of which generate struc-
tures inaccessible by other pathways.2 One early example,
the Diels-Alder cycloaddition of benzyne and cyclopenta-
diene, remains the only direct approach to 1,4-methano-1,4-
dihydronaphthalenes. We became interested in their corre-
sponding 5-halo-derivatives as pharmaceutical intermediates
(e.g., 1). The known preparation of 1 involves the potentially
hazardous nitroanthranilic acid benzyne route (three steps,
18% yield).3 We sought a more controllable, scalable, and
direct synthesis. To our surprise, the reaction of 24 with
cyclopentadiene under halogen-magnesium exchange condi-
tions5 afforded a mixture of fluoride 1 and unwanted iodide
3, the latter of which presumably formed by exchange of
iodide via intermediate 3-fluorobenzyne 5 (Scheme 1; see
Supporting Information [SI]).6
Scheme 1
(1) For recent developments and leading references in benzyne chemistry,
see: Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu, N.; Meng,
Z.; Fujiwara, Y. J. Am. Chem. Soc. 1999, 121, 11674-11679. Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701-730.
(2) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003,
42, 502-528.
We reasoned that n-BuLi would sequester iodide (as
n-BuI) in the halogen-metal exchange step and avoid the
formation of 3. Earlier studies by Hart et al. demonstrated
the successful generation of benzyne by this approach with
highly substituted 1,2-dibromobenzenes in cycloaddition
(3) (a) Snow, R. A.; Cottrell D. M.; Paquette L. A. J. Am. Chem. Soc.
1977, 99, 3734-3744. (b) For methods of generation from other relevant
anthranilic acids, see: Seltzman, H. H.; Berrang, B. D. Tetrahedron Lett.
1993, 34, 3083-3086.
(4) Rausis, T.; Schlosser, M. Eur. J. Org. Chem. 2002, 19, 3351-3358.
10.1021/ol049655l CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/10/2004

reactions.7 However, only three examples with cyclopenta-
diene are known.8,9 Herein we reveal that n-BuLi-induced
halogen-metal exchange in the presence of cyclopentadiene
in noncoordinating solVents effects the formation of the
desired benzyne-derived products. Moreover, in addition to
circumventing the iodide exchange reaction and affording
acceptable cycloaddition yields, hydrocarbon solvents also
profoundly shift the lithium halide leaving group facility.
When a mixture of 2,6-difluoroiodobenzene (2, 1 equiv)
and cyclopentadiene (1.5 equiv) in THF (0.2 M) was treated
with n-BuLi (1 equiv) at 0 °C, starting iodide 2 was recovered
unchanged (>90%, Scheme 2, eq 1). Proton transfer from
consumed, and the 5-aryl-1,4-dihydro-1,4-methano-naphtha-
lene byproduct 10 was readily separated (∼11% yield, GC-
MS).12
In petroleum ether and other hydrocarbon solvents (pen-
tane, hexane, heptane, and cyclohexane), a precipitate,
presumably LiF, forms upon n-BuLi addition. The reaction
mixtures thicken considerably and require mechanical stirring
on a larger scale. In contrast, toluene better dissolves all
trihalobenzene precursors and affords readily stirred reaction
mixtures.13 In toluene, however, substrate 2 gave lower
isolated yields of 1 (28%, Table 1) than did the corresponding
Table 1. 1,4-Dihydro-1,4-methano-naphthalenes
Scheme 2
entry substrate
X
Y
Z
solvent
product yield
1
2
3
4
5
6
7
8
2
2
2
11
12
15
16
17
F
F
F
Cl
Br
H
H
H
I
I
I
I
I
F
F
F
Cl
Br
F
THF
hydrocarbons
toluene
1
1
1
13
14
18
18
18
0
41%
28%
42%
69%
27%
56%
89%
toluene
toluene
toluene
toluene
Br
I
Br Br
Cl
toluene
chloro- and bromo-substrates 1114 and 12,15 respectively
(entries 3-5). Similar conversions of 1,2-dihalobenzenes
afforded the parent 1,4-dihydro-1,4-methano-naphthalene 18.
As with the trihalogenated precursors 2, 11, and 12, the
isolated yields of 18 improve in the sequence from 15, 16,
and 17 (entries 6-8). This trend correlates well with literature
precedent regarding the relative reactivity of lithiated o-
haloaryllithium intermediates (Br > Cl > F).16
Although acceptable yields under mild, convenient condi-
tions were in hand, the conversion of 17 to 18 illustrated
the high efficiency possible: equimolar 17, cyclopentadiene,
and n-BuLi gave 18 in 89% of theory on a 100 g scale.
Indeed, the results in Table 1 and the literature precedent16
suggested that by judicious choice of halogens, more reactive
o-haloaryllithium species should more efficiently form
3-fluorobenzyne 5 and its cycloaddition products.17 We
cyclopentadiene was more rapid than halogen-metal ex-
change with 2 in THF.9,10 However, under otherwise identical
conditions in petroleum ether, 1 was produced as the only
halo-1,4-dihydro-1,4-methano-naphthalene in 35-41% yield
(eq 2, Scheme 2).11 Starting iodide 2 was completely
(5) (a) Wittig, G.; Knauss, E. Chem. Ber. 1958, 91, 895-907. (b) Muir,
D. J.; Stothers, J. B. Can. J. Chem. 1993, 71, 1290-1296.
(6) (a) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65,
5334-5341. (b) Pansegrau, P. D.; Rieker, W. F.; Meyers, A. I. J. Am. Chem.
Soc. 1988, 110, 7178-7184. (c) Wang, A.; Maguire, J. A.; Biehl, E. J.
Org. Chem. 1998, 63, 2451-2455. (d) Okano, M.; Amano, M.; Tagaki, K.
Tetrahedron Lett. 1998, 39, 3001-3004.
(7) (a) Hart, H.; Lai, C.-Y.; Nwokogu, G. C.; Shamouilian, S.; Teuerstein,
A.; Zlotogorski, C. J. Am. Chem. Soc. 1980, 102, 6651-6652. (b) Hart,
H.; Shamouilian, S. J. Org. Chem. 1981, 46, 4874-4876. (c) Nwokogu,
G. C.; Hart, H. Tetrahedron Lett. 1983, 24, 5725-5726. (d) Hart, H.;
Nwokogu, G. C. Tetrahedron Lett. 1983, 24, 5721-5724. (e) Blatter, K.;
Schlu¨ter, A.-D. Chem. Ber. 1989, 122, 1351-1356.
(8) (a) Hart, H.; Lai, C.; Nwokogu, G. C.; Shamouilian, S. Tetrahedron
1987, 43, 5203-5224. (b) Koenig, B.; Knieriem, B.; Rauch, K.; de Meijere,
A. Chem. Ber. 1993, 126, 2531-2534.
(9) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300-
305. Beak, P.; Musick, T. J.; Chen, C.-W. J. Am. Chem. Soc. 1988, 110,
3538-3542.
(10) We chose to study this process at 0 °C, expecting that the formation
of benzyne from lithiated species would be more rapid than proton transfer
processes. The formation of benzyne from meta-dihalolithiobenzenes in
isolated systems is known to proceed rapidly above -15 °C; see: Saednya,
A.; Hart, H. Synthesis 1996, 1455-1458.
(11) These yields are comparable to those in previously reported Grignard
approaches to unsubstituted products. See ref 5.
(12) This common byproduct in benzyne reactions is derived by addition
of 2,6-difluorophenyllithium (8) to 3-fluorobenzyne (5) to form biaryl-
lithium species 9, from which elimination of LiF and Diels-Alder
cycloaddition form 10.
(13) 1,2-Difluoro-3-iodo-benzene is immiscible in hydrocarbons. See SI.
(14) See SI and: Bennetau, B.; Rajarison, F.; Dunogues, J.; Babin, P.
Tetrahedron 1993, 49, 10843-10854.
(15) Du, C. J. F.; Hart, H.; Ng, K. K. D. J. Org. Chem. 1986, 51, 3162-
3165.
(16) (a) Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1956, 78, 2217-
2222. (b) Bunnett, J. F.; Kearley, Jr. F. J. J. Org. Chem. 1971, 36, 184-
186. (c) Chen, L. S.; Chen, G. J.; Tamborski, C. J. Organomet. Chem. 1980,
193, 283-292.
1590
Org. Lett., Vol. 6, No. 10, 2004

therefore explored mixed halide precursors of 3-fluoro-
benzyne such as 19 (Scheme 3).
from 5) was formed with high selectivity (Scheme 4, entries
1, 3), whereas in toluene, adduct 24 (derived from 21) was
obtained (Scheme 4, entries 2, 4).21 Isolated and GC yields
of the major product were independent of the method of entry
to lithiated intermediate 20 from both 19 and 22.
Scheme 3
The effects of other ethereal and hydrocarbon solvents on
regioselectivity are summarized in Table 2. Polar solvents
Table 2. Product Ratio (GC) as a Function of Solvent
A solution of 1918 and cyclopentadiene (1.5 equiv) in
petroleum ether at 0 °C treated with n-BuLi gave 13 in 50%
yield with less than 5% of the expected adduct 1 (Scheme
3). Fluoride instead of chloride elimination was entirely
unexpected16,19 and stimulated our interest as to the role of
solvents in the formation of 3-halobenzyne. To investigate
this question we used a nonacidic dienophile that would be
inert to halogen-metal exchange in THF (vide infra).
Spiro[2.4]hepta-4,6-diene (1,1-cyclopropylcyclopenta-di-
ene, or CPCP) was chosen as the Diels-Alder trap.20 As
shown in Scheme 4, intermediate 2-chloro-6-fluorophenyl-
THF
DME
95
94
35
29
27
16
3
5
6
Me4THF
MTBE
Et2O
toluene
pentane
65
71
73
84
94
favor the 3-fluorobenzyne-derived adduct 23. Dimethoxy-
ethane (DME) differs little from THF. 2,2,5,5-Tetramethyl-
THF (Me4THF), which has a dielectric constant comparable
to that of THF but is sterically hindered, gives product ratios
similar to those obtained in Et2O and methyl tert-butyl ether
(MTBE). Toluene and pentane favor the 3-chlorobenzyne-
derived product 24.
Scheme 4
The effects of THF/pentane solvent mixtures appear in
Figure 1. A shift to chloride elimination was observed with
increasing THF concentration (see Figure 1 and SI). A
maximum ratio of 98:2 (23:24) was obtained at dilute
substrate concentration in neat THF (0.05 M).22 In related
experiments, 3-fluorobenzyne-derived products were not
favored beyond 35% as Me4THF/pentane concentration was
lithium (20) was generated in the presence of CPCP (3 equiv)
by either halogen-metal exchange with 19 or by direct
metalation of 3-fluorochlorobenzene (22). These reactions
were induced by treatment with n-BuLi (1 equiv) in the
indicated solvent (0.5 M) at 0 °C. In THF, adduct 23 (derived
(17) More reactive (unstable) benzyne precursors lacking the 3-halogen
substituent give high yields with other dienophiles (e.g., furan). See refs 6
and 7 and: Caster, K. C.; Keck, C. G.; Walls, R. D. J. Org. Chem. 2001,
66, 2932-2936.
(18) 1-Chloro-3-fluoro-2-iodobenzene (19) was prepared by metalation
of 3-fluoro-chlorobenzene and reaction with iodine: Bennetau, B.; Rajarison,
F.; Dunogue`s, J.; Babin, P. Tetrahedron 1993, 49, 10843-10854.
(19) For a discussion of the stability of 2,6-dihalophenyllithium, see ref
16b. For halide selectivity in related o-halo-zincate benzyne precursors,
see: Uchiyama, M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Kondo, Y.;
Otani, Y.; Ohwada, T. J. Am. Chem. Soc. 2002, 124, 8514-8515.
(20) Dienes such as furan or N-substituted pyrroles were considered;
however, CPCP ensures minimal diene involvement as a solvent additive.
Figure 1. Effects of increasing THF concentration in pentane (0.5
M) with 22 and n-BuLi.
Org. Lett., Vol. 6, No. 10, 2004
1591

solvent-dependent change in product-determining steps.23 We
suspect that solvent association with intermediates and the
departing lithium halide greatly impacts the reaction course.
Related effects have been observed in cycloaddition reactions
of LiBr-free and complexed forms of cyclopentyne.24
In conclusion, solvent and halide influence the generation
and reactions of 3-halogen-substituted benzyne. In THF,
proton transfer from cyclopentadiene to n-BuLi occurs faster
than halogen-metal exchange with 2. Noncoordinating
solvents permit a straightforward preparation of 1,4-methano-
1,4-dihydronaphthalenes25 and 5-substituted derivatives from
symmetrical 2,6-dihaloaryliodides. Initial probes with mixed
halide precursors reveal a solvent-dependent regioselectivity.
Scheme 5
increased, suggesting that polar solvent effects are attenuated
by steric influences (see Table 2 and SI).
Acknowledgment. We wish to thank Drs. J. Lyssakatos,
R. B. Ruggeri, M. P. DeNinno, B. T. O’Neill, T. V. Magee,
B. N. Rogers, J. Benbow, R. Robinson, A. Ramirez, L.
Reiter, and J. L. Rutherford and Profs. D. B. Collum, E. J.
Corey, S. V. Ley, and D. Kemp for lively discussion and
encouragement.
The solvent effect extends to competitive fluoride versus
bromide elimination. Reactions of iodo-arene 25 under
halogen-metal exchange conditions (n-BuLi, 1.05 equiv,
Scheme 5) produced fluoro adduct 23 in THF, derived by
LiBr departure. In pentane, LiF departs to give 26. Experi-
ments with 2-chloro-6-bromophenyllithium revealed that a
slight preference for the expulsion of LiBr versus LiCl in
THF was eroded only slightly when the reaction was
performed in pentane (see SI).
Our efforts to optimize yields of 3-fluorobenzyne-derived
products showed that the solvent alters the product distribu-
tion in systems with available competing elimination path-
ways. Mixed halide substrates exhibit a dramatic ∼200:1
selectivity shift in hydrocarbons versus THF, suggesting a
Supporting Information Available: Tables, figures, and
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL049655L
(23) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 4008-4009.
(24) Gilbert, J. C.; Hou, D.-R. J. Org. Chem. 2003, 68, 10067-10072.
Wang, X.; Rabbat, P.; O’Shea, P.; Tillyer, R.; Grabowski, E. J. J.; Reider,
P. J. Tetrahedron Lett. 2001, 41, 4335-4338.
(25) Representative procedure for benzyne Diels-Alder cycloaddition
with cyclopentadiene: 1,2-Dibromobenzene (17, 100 g, 429 mmol) and
cyclopentadiene (28.4 g, 429 mmol) were stirred in toluene (510 mL) at 0
°C under N2. To this solution was added n-BuLi (241 mL, 1.78 M in
hexanes, 429 mmol) dropwise over 30 min during which the reaction
solution became first yellow then cloudy white. After an additional 10 min
at 0 °C, the mixture was allowed to warm to room temperature, stirred
overnight, and treated with H2O (200 mL) and extracted with hexanes (3
× 150 mL). The organic layer was dried over MgSO4, filtered, and
concentrated to an oil that was purified by chromatography on silica gel
eluting with hexanes to provide a clear, colorless oil (54.3 g, 89%).
(21) The same product ratios were observed when the experiments were
carried out at -78 °C (metalation by n-BuLi for 2 h in the presence of
CPCP (3 equiv)) followed by slow warming to 20 °C.
(22) Butyl adducts resulting from nucleophilic addition of n-BuLi to
3-halobenzyne followed by elimination of lithium halide and subsequent
Diels-Alder trap of 3-butylbenzyne with CPCP were observed in high
dilution experiments. GC yields of these side products can be as much as
10-20% with increasing dilution.
1592
Org. Lett., Vol. 6, No. 10, 2004