Generation and suppression of 3-/4-functionalized benzynes using zinc ate base (TMP-Zn-ate): New approaches to multisubstituted benzenes

Article abstract of DOI:10.1021/ja071268u

We present full details of our new methods for preparing functionalized benzynes with lithium di-alkyl(2,2,6,6-tetramethylpiperidino)zincate (R ₂Zn(TMP)Li) through deprotonative zincation as a key reaction. In this system, by choosing appropriate ligands for the zincate, either regioselective zincation of functionalized haloaromatics or the generation of substituted benzynes can be controlled in good yields with excellent chemoselectivity, using the same substrate. Zincation with ^tBu ₂Zn(TMP)Li followed by electrophilic trapping or zincation with Me₂Zn(TMP)Li followed by nucleophilic or diene trapping is shown to be a powerful tool for the chemoselective preparation of 1,2,3-/1,2,4- trisubstituted benzene derivatives. These methods offer far greater generality than previous methods for the synthesis of multifunctionalized benzenes. Computational/theoretical studies of the reaction mechanism of this unique benzyne formation indicated that preferential coordination of the dialkylzinc moiety of zincate to halogen is the reason for the reduced activation energy of the elimination, that is, for the formation of the benzyne. The role of the ligands on Zn in accelerating/decelerating the elimination is also discussed.

Full text of DOI:10.1021/ja071268u

Published on Web 12/20/2007
Generation and Suppression of 3-/4-Functionalized Benzynes
Using Zinc Ate Base (TMP-Zn-ate): New Approaches to
Multisubstituted Benzenes
Masanobu Uchiyama,*,†,‡,§ Yuri Kobayashi,† Taniyuki Furuyama,†,§
Shinji Nakamura,† Yumiko Kajihara,‡ Tomoko Miyoshi,‡ Takao Sakamoto,‡
Yoshinori Kondo,‡ and Keiji Morokuma*,#
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, The Graduate School of Pharmaceutical
Sciences, Tohoku UniVersity, Aobayama, Aoba-ku, Sendai 980-8578, Japan, AdVanced Elements
Chemistry Laboratory, Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa,
Wako-shi, Saitama 351-0198, Japan and the Cherry L. Emerson Center for Scientific
Computation and Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
Received February 22, 2007; E-mail: uchiyama@mol.f.u-tokyo.ac.jp; morokuma@euch.chem.emory.edu
Abstract: We present full details of our new methods for preparing functionalized benzynes with lithium
di-alkyl(2,2,6,6-tetramethylpiperidino)zincate (R2Zn(TMP)Li) through deprotonative zincation as a key
reaction. In this system, by choosing appropriate ligands for the zincate, either regioselective zincation of
functionalized haloaromatics or the generation of substituted benzynes can be controlled in good yields
t
with excellent chemoselectivity, using the same substrate. Zincation with Bu2Zn(TMP)Li followed by
electrophilic trapping or zincation with Me2Zn(TMP)Li followed by nucleophilic or diene trapping is shown
to be a powerful tool for the chemoselective preparation of 1,2,3-/1,2,4-trisubstituted benzene derivatives.
These methods offer far greater generality than previous methods for the synthesis of multifunctionalized
benzenes. Computational/theoretical studies of the reaction mechanism of this unique benzyne formation
indicated that preferential coordination of the dialkylzinc moiety of zincate to halogen is the reason for the
reduced activation energy of the elimination, that is, for the formation of the benzyne. The role of the ligands
on Zn in accelerating/decelerating the elimination is also discussed.
Introduction
various functional groups on the benzynes. Several methods for
generating functionalized benzynes bearing limited substituents
Aromatic rings are key structural elements of organic
molecules, and hence chemo- and regiocontrolled synthesis of
multisubstituted benzenes remains one of the central issues in
organic synthesis. However, the variety of available derivatives
is still quite limited. Inter-/intramolecular reaction, such as
cycloaddition and nucleophilic addition, of substituted benzynes
is, in principle, one of the most effective ways for introducing
multiple functional groups on aromatic rings.1 In particular,
substituents on benzyne can control the regioselectivity of
incoming reagents through electronic, steric, and chelation
effects. Such regioselectivity is important in theoretical chem-
istry as well as for organic synthesis.2 However, functionalized
benzyne chemistry has not been well developed, mainly because
of the lack of efficient preparation methods compatible with
such as alkyl, alkoxy, or halogen groups have been reported.3
These methods require 1,2,3-(or 1,2,4-)trisubstituted benzenes
as precursors (in which two of the substituents are in ortho
positions),3 and therefore application of these conventional
methods to the enhancement of benzynes bearing electrophilic
substituents suffers from significant limitations in two re-
spects: (1) poor availability of the starting highly substituted
benzenes, and (2) restricted compatibility with the remaining
functional groups. Thus, a new method for generating regio-
controlled functionalized benzynes with high functional group
compatibility is highly desirable.
In this article, we present full details of our new approach to
the preparation of functionalized benzynes (Figure 1) and
† The University of Tokyo.
‡ Tohoku University.
(3) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967. (b) H. Hart. In The Chemistry of Triple-Bonded
Functional Groups; S. Patai, Ed.; John Wiley & Sons Ltd.: Chichester,
U.K., 1994; Suppl. C2, Chapter 18. (c) Gilchrist, T. L. In The Chemistry
of Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester,
U.K., 1983; Suppl. C, Chapter 11. For examples of the preparation of
benzynes, see: (d) Kitamura, T.; Yamane, M.; Inoue, K.; Tokuda, M.;
Fukatsu, N.; Meng, Z.; Fujiwara, Y. J. Am. Chem. Soc. 1999, 121, 11674-
11679. (e) Matsumoto, T.; Hosoya, T.; Katsuki, M.; Suzuki, K. Tetrahedron.
Lett. 1991, 32, 6735-6736. (f) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6,
99-102.
§ RIKEN.
# Emory University.
(1) (a) Knochel, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, England, 1991; Vol. 8, Chapter 4.4 and references
cited therein. (b) Kessar, S. V. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, England, 1991; Vol. 8, Chapter 2.3
and references cited therein.
(2) (a) Johnson, W. T. G.; Cramer, C. J. J. Am. Chem. Soc. 2001, 123, 923-
928. (b) Dkhar, P. G. S.; Lyngdoh, R. H. D. Proc. Indian Acad. Sci., Chem.
Sci. 2000, 112, 97-108 (CAN 133:104683).
9
472
J. AM. CHEM. SOC. 2008, 130, 472-480
10.1021/ja071268u CCC: $40.75 © 2008 American Chemical Society

Generation and Suppression of Benzynes
A R T I C L E S
Table 1. Ligand Screening of Zincate for Direct Generation of Benzynea
entry
FG
Zn-ate
temp
diene
yield (%)
1
2
3
H (1a)
H (1a)
H (1a)
tBu3ZnLi
nBu3ZnLi
Me3ZnLi
room temp
room temp
room temp
A
A
A
0
trace
99 (4a)
4
5
6
H (1a)
Me3ZnLi
Me3ZnLi
Me3ZnLi
0 °C
0 °C
0 °C
A
B
A
96 (4a)
79 (4a-B)
86 (4b)
H (1a)
CONiPr2 (1b)
7
H (1a)
Me4ZnLi2
-78 °C
A
99 (4a)
a Unless otherwise noted, the iodine-zinc exchange reaction was carried out using zincate (2.2 equiv) and substrate 1 (1 equiv) in THF in the presence
of 1,3-diphenylisobenzofuran (2.2 equiv). b Isolated yield. c FG ) functional group.
multiply substituted benzenes.4 A new zinc ate base (lithium
di-methyl(2,2,6,6-tetramethylpiperidino)zincate: Me2Zn(TMP)-
Li), which functions both as a base for directed ortho metalation
on functionalized benzenes and as a promoter for the benzyne
formation, was developed for direct chemo- and regioselective
benzyne formation reaction. This reagent provides a new,
efficient, and simple method for preparing trisubstituted
benzene derivatives, and we describe several synthetic applica-
tions, including preparation of substituted arylsilanes and a
biphenyl derivative. By selecting appropriate ligands for the
zincate, generation and suppression of benzyne formation in
this system can be controlled to afford desired products in
good yield with excellent chemoselectivity, using the same
substrate.
benzyne formation.5,6 However, their use has been limited
because these reagents or the resulting intermediary aromatic
metal species undergo reaction with electrophilic functional
(directing) groups.7 Our approach capitalizes on the high
chemoselectivity of organozincate reagents, which allows flex-
ible design and fine-tuning by modifying the ligation environ-
ment.8 To date, little attention has been paid to benzyne
formation using zinc ate complexes, except for a single report
by Harada et al.,9 because of their mild reactivity. One naturally
expects that the elimination of a metal-stabilized anion and a
leaving group would require high activation energy. However,
in 1999, Harada et al. overcame this drawback of zincates by
the use of a strong leaving group (trifluoromethylsulfonyl
(TfO-)), and the successive homologation reactions with zincate
to afford butylphenylzinc species were reported to proceed
smoothly. However, only a limited number of examples of the
homologation reactions have been examined, and their generality
remains unclear. Thus, we systematically investigated the ability
of organozinc ate complexes to show high reactivity and
selectivity in the benzyne formation reaction without the
occurrence of successiVe homologation reactions.
Direct Benzyne Formation Reaction Through Halogen-
Zinc Exchange Reaction. Optimization of the Ligation
Environment of Zincates and Reaction Conditions. As a
preliminary model reaction, the iodine-zinc exchange reaction
of 2-haloiodobenzenes with various zincates was investigated.
The results are summarized in Table 1. We first speculated that
it might be possible to develop benzyne formation reactions by
Figure 1. Summary of the reactions described here (FG ) functional
group).
Detailed second-order Møller-Plesset perturbation (MP2) and
ONIOM2 (MP2:HF) studies were also performed for these
unique benzyne formation reactions. Mechanistic studies on
benzyne formation from o-metallohalobenzenes (metal ) Li,
Na, Mg, ...) are still lacking, despite the fact that knowledge of
the reaction pathways and the elimination mechanism would
aid rational design to improve the yield and selectivity of the
benzyne formation and to develop more efficient metal reagents.
The purposes of our computational/theoretical study were as
follows: (1) to investigate the reaction pathways of benzyne
formation reactions using zincate; (2) to investigate the geo-
metrical features of the transition structure, intermediates, and
products of the present benzyne formation; and (3) to analyze
the role of the ligands on zinc in the generation of benzyne.
t
using Bu3ZnLi,8d the most chemoselective halogen-metal
(4) A part of the results concerning the 3-functionalized benzynes described
here was reported as a preliminary Communication: Uchiyama, M.;
Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.; Ohwada, T.; Kondo,
Y. J. Am. Chem. Soc. 2002, 124, 8514-8515.
(5) For reviews on directed ortho metalation, see; (a) Snieckus, V. Chem. ReV.
1990, 90, 879-933. (b) Gschwend, H. W.; Rodriguez, H. R. Heteroat.
Facilitated Lithiations. Org. React. (N.Y.) 1979, 26, 1-360.
(6) For examples of nonlithio-aromatic species, see: (a) Armstrong, D. R.;
Clegg, W.; Dale, S. H.; Hevia, E.; Hogg, L. M.; Honeyman, G. W.; Mulvey,
R. E. Angew. Chem., Int. Ed. 2006, 45, 3775-3778. (b) Sapountzis, I.;
Lin, W.; Fischer, M.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 4364-
4366.
(7) Upton, C. J.; Beak, P. J. Org. Chem. 1975, 40, 1094-1098.
(8) (a) Review: Uchiyama, M.; Kondo, Y. Synth. Org. Chem. Jpn. 2006, 64,
1180-1190. (b) Kondo, Y.; Takazawa, N.; Yamazaki, C.; Sakamoto, T. J.
Org. Chem. 1994, 59, 4717-4718. (c) Kondo, Y; Matsudaira, T.; Sato, J;
Murata, N.; Sakamoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 736-
738. (d) Kondo, Y; Fujinami, M.; Uchiyama, M.; Sakamoto, T. J. Chem.
Soc., Perkin Trans. 1 1997, 799-800.
Results and Discussion
Organolithiums and Grignard reagents have been widely used
as powerful metalating reagents of aromatic rings and also for
(9) Harada, T.; Chiba, M.; Oku, A. J. Org. Chem. 1999, 64, 8210-8213.
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J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008 473

A R T I C L E S
Uchiyama et al.
for benzyne synthesis, and the deprotonative zincation was
investigated using 3-cyanobromobenzene (6c) as a representative
substrate (see Supporting Information, Figure S-1, for
details).12
While deprotonative metalation of 3-substituted benzenes such
as 6c can take place at three positions, the metalation using
zincate bases proved to occur regioselectively at the C2
position.4 As expected, in the reaction using the newly
designed Me2Zn(TMP)Li, the directed zincation and the sub-
sequent generation of 3-cyanobenzyne (3c) proceeded smoothly
at room temperature, and the resulting benzyne reacted with
1,3-diphenylisobenzofuran to give the corresponding Diels-
Figure 2. Electrophilic trapping of the intermediary zincates (2).
exchange reagent in our group. Despite excellent reactivity and
selectivity in the iodine-zinc exchange reaction (Figure 2), the
reagent did not mediate benzyne formation reaction at all at
room temperature (Table 1, entry 1). Even when the reaction
was carried out at higher temperature (40 °C-reflux), unsatis-
factory results were obtained (yields < 30%). With benzalde-
hyde as the electrophile instead of diene, 2-halobenzhydrol
derivatives were obtained in high yields, and this result
clearly indicates that only regio-/chemoselective zincation
proceeded without the following benzyne formation (Figure 2).
We then evaluated the influence of other alkyl ligands on
t
Alder adduct (4c)13 in 80% yield. On the other hand, when -
Bu2Zn(TMP)Li14 was used under the same conditions, only
zincation occurred regio-/chemoselectively without the
formation of benzyne, and the resulting arylzincate (2c-tBu) was
treated with I2 to give 3-bromo-2-iodobenzonitrile (1c) in 82%
yield.
n
zinc upon benzyne formation. In the case of using Bu3ZnLi,
I. Generation of 3-Functionalized Benzyne Using Me2Zn-
(TMP)Li. As shown in Table 2, deprotonative zincation with
Me2Zn(TMP)Li proved effective for the one-pot generation of
various 3-functionalized benzynes.4 Not only alkoxy groups,
but also a variety of electrophilic functional groups, including
amide, cyano, ester, and various halogens (runs 1-8), are
compatible with Me2Zn(TMP)Li, and neither destruction of
functional groups nor self-condensation was observed. The
generation of a disubstituted asymmetric benzyne also caused
no problem (run 10). The trifluoromethyl group works as an
exclusively para-metalating directing group, and the generation
of benzyne proceeded smoothly at the 4-position (run 9),
although the mechanism of this peculiar metalation is not
clear. Thus, this benzyne formation reaction has a high
compatibility with functional groups, presumably because of
the soft nucleophilicity of zincates. Finally, deprotonative
zincation of various halobenzenes (or their analogues) using
Me2Zn(TMP)Li was then investigated to examine the scope of
the present method (runs 11-13); various groups such as fluoro,
chloro, and triflyl (except for iodo15) turned out to work well
as both ortho-directing and -leaving groups in benzyne forma-
tion.
only trace amounts of 4a were obtained at room temperature,
along with byproducts obtained by the homologation reaction
of the intermediary benzyne and zincate (Table 1, entry 2).
Finally, we found that the use of Me3ZnLi produced Diels-
Alder adducts (4a or 4a-B) in satisfactory yields in THF at over
0 °C (Table 1, entries 3-5).10 Other solvents, such as Et2O,
toluene, and CH2Cl2, gave less satisfactory results. It is
noteworthy that this benzyne formation method was also
applicable to the electrophilic functional group-containing
o-bromoiodobenzene (1b) (Table 1, entry 6). Furthermore, when
Me4ZnLi2 was employed in THF, 4a was obtained quantitatively
even at -78 °C (Table 1, entry 7), supporting our previous
findings that dianion-type ate complexes display increased
reactivity relative to the monoanion-type ones.11
In other words, we found a significant switching of the
reactivity of the aryldialkylzincate intermediates (2-R). This
drastic change of reaction modes (metalation (no elimination;
tBu) or generation of benzyne (facile elimination; Me)) depend-
ing on the alkyl-ligation environment is a feature of zincates
and is potentially useful from the synthetic viewpoint.
Direct Benzyne Formation Reaction Through Deproto-
native Zincation Reaction by Using Zinc Ate Base. Develop-
ment of Me2Zn(TMP)Li. Having optimized the ligation
environment of the arylzincates for benzyne formation and
suppression, we next focused on the application to the synthesis
of multiply substituted benzyne and benzene. Taking the
availability of precursors and general applicability into
consideration, deprotonation is expected be advantageous for
the preparation of (multi-)functionalized benzynes. Similar
ligand effects might operate in the deprotonative zincation.
Thus, we designed Me2Zn(TMP)Li as a new zinc ate base
(12) R2Zn(TMP)Li (R ) Me or tBu) can be prepared simply by mixing
dialkylzinc and LTMP in a 1:1 molar ratio in THF at room temperature
for 1 hour. See Supporting Information for details. On the basis of our
computational analysis,14c,d the deprotonation of aromatic compounds using
R2Zn(TMP)Li is endothermic in most cases, so excess zincate (2.2 equiv)
was used for the deprotonation reaction in this study. Iodine or benzaldehyde
was used as a representative electrophile in this study, but intermediary
arylzincate species are known to be able to react with various electrophiles
(see refs 8, 11, and 14).
(13) A series of recent studies has expanded the utility of rigid oxabicyclic
compounds: (a) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004,
126, 1437-1447. (b) Lautens, M.; Fagnou, K.; Yang, D. J. Am. Chem.
Soc. 2003, 125, 14884-14892. (c) Lautens, M.; Fagnou, K.; Hiebert,
S. J. Am. Chem. Soc. 2003, 125, 48-58. (d) Lautens, M.; Schmid, G. A.;
Chau, A. J. Org. Chem. 2002, 67, 8043-8053. (e) Lautens, M.; Hiebert,
S.; Renaud, J-L. J. Am. Chem. Soc. 2001, 123, 6834-6839. (f)
Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170-7171. (g)
Lautens, M.; Renaud, J-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1803-
1804.
(14) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc.
1999, 121, 3539-3540. (b) Imahori, T.; Uchiyama, M.; Sakamoto, T.;
Kondo, Y. Chem. Commun. 2001, 2450-2451. (c) Uchiyama, M.;
Matsumoto, Y.; Nobuto, D.; Furuyama, T.; Yamaguchi, K.; Morokuma,
K. J. Am. Chem. Soc. 2006, 128, 8748-8750. (d) Uchiyama, M.;
Matsumoto, Y.; Usui, S.; Hashimoto, Y.; Morokuma, K. Angew. Chem.,
Int. Ed. 2007, 46, 926-929. (e) Mulvey, R. E.; Mongin, F.; Uchiyama,
M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802-3824. (f) Kondo,
Y.; Morey, J. V.; Morgan, J. C.; Naka, H.; Nobuto, D.; Raithby, P. R.;
Uchiyama, M.; Wheatley, A. E. H. J. Am. Chem. Sol. 2007, 129, ASAP.
(15) The iodine-zinc exchange may occur preferentially over the de-
protonation.
(10) In the case of using Me3ZnLi, even when the reaction was carried out at
higher temperature (40°C-reflux), no homologation product (methyl-
adduct) was detected. On the other hand, when the reaction of o-
bromoiodobenzene (1a) with tBu3ZnLi was performed under reflux for 16
hours in the presence of diene (A), the Diels-Alder adduct (4a) was obtained
in 50% yield.
(11) (a) Uchiyama, M.; Furuyama, T.; Kobayashi, M.; Matsumoto, Y.; Tanaka,
K. J. Am. Chem. Soc. 2006, 128, 8404-8405. (b) Uchiyama, M.;
Matsumoto, Y.; Nakamura, S.; Ohwada, T.; Kobayashi, N.; Yamashita,
N.; Matsumiya, A.; Sakamoto, T. J. Am. Chem. Soc., 2004, 126,
8755-8758. (c) Uchiyama, M.; Kondo, Y.; Miura, T.; Sakamoto, T. J.
Am. Chem. Soc. 1997, 119, 12372-12373. (d) Uchiyama, M.; Koike, M.;
Kameda, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1996, 118, 8733-
8734.
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Generation and Suppression of Benzynes
A R T I C L E S
Table 2. Direct Generation of 3-Functionalized Benzyne Using Me2Zn(TMP)Lia
a The reaction was carried out using Me2Zn(TMP)Li (2.2 equiv) and substrate (1 equiv) in THF in the presence of 1,3-diphenylisobenzofuran (2.2 equiv).
b Isolated yield.
t
a
Table 3. Deprotonative Zincation of 3-Substituted Benzynes Using Bu2Zn(TMP)Li
t
a The reaction was carried out using Bu2Zn(TMP)Li (2.2 equiv) and substrate (1 equiv) in THF. b Isolated yield. c FG ) functional group.
II. Synthesis of 1,2,3-Functionalized Benzenes Using
compounds.4,16 The substrate scope and limitations are sum-
marized in Table 3. With amide, cyano, methoxy, and various
halides containing m-bromobenzenes, both the chemical yield
and the regioselectiVity were good to excellent. A 1,2,4-
t
tBu2Zn(TMP)Li. On the other hand, zincation with Bu2Zn-
(TMP)Li followed by electrophilic trapping (with I2) proved a
powerful tool for the preparation of 1,2,3-trisubstituted aromatic
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J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008 475

A R T I C L E S
Uchiyama et al.
Table 4. Direct Generation of 4-Functionalized Benzyne Using Me2Zn(TMP)Lia
a The reaction was carried out using Me2Zn(TMP)Li (2.2 equiv) and substrate (1 equiv) in THF in the presence of 1,3-diphenylisobenzofuran (2.2 equiv).
b Isolated yield. c FG ) functional group.
substituted substrate could be used, and a 1,2,3,4-tetrasubstituted
product was obtained with high chemo-/regioselectivity. The
trifluoromethyl group also functions as an exclusively para-
metalating directing group, affording the 1,2,4-substituted
benzene derivative.
temperature was increased and/or reaction time was extended,
the reaction proceeded slowly but afforded the desired products
(9) in high yields (Figure 3). Additionally, when a strong
directed leaving group, such as a TfO group, was used, the
reaction time was shortened.
Application to Preparation of Various 4-Functionalized
Benzynes and 1,2,4-Functionalized Benzenes. Having
established effective procedures for the generation of 3-func-
tionalized benzynes, we then considered 4-functionalized ben-
zynes. However, deprotonative metalation has so far been
regarded as a difficult reaction to use for the synthesis of
4-substituted benzynes, because of its apparently unfavorable
regioselectivity. In fact, in the reaction of 4-methoxybromoben-
t
zene (7a) with Bu2Zn(TMP)Li and the successive iodination,
the deprotonative zincation proceeded at the ortho position of
the methoxy group (a good directing group) selectively to give
1-methoxy-2-iodo-4-bromobenzene (8a) in a quantitative yield
(eq 1).17
Figure 3. Reaction of 4-haloanisole with Me2Zn(TMP)Li.
With optimized conditions in hand, we studied the scope of
this new protocol, and representative results are summarized in
Table 4. Substrates containing methoxy, bromo, trifluoromethyl,
phenyl, and tert-butyl groups on the benzene ring can be utilized
by employing Me2Zn(TMP)Li, affording 4-substituted benzynes
(10) through displacement of the phenyl anion equilibrium (runs
1 and 5-8). No double benzyne formation was observed in run
5, although the double benzyne formation often occurs in
alkyllithium- or Grignard reagent-mediated reactions of 1,4-
dihalobenzene derivatives.1,2 In the case of substrates having
However, we hypothesized that the generation of 4-substituted
benzynes could be realized by using the zincate shift reaction
from the ortho position of the directed metalation group (DMG)
to that of leaving group (eq 2). As expected, when the reaction
(17) In the deprotonation reaction of 7a with Me2Zn(TMP)Li under similar
reaction conditions, 8a was also obtained as a single product.
(16) Generally, when traditional reagents, such as alkyllithiums and lithium
amides, are used, the desired 1,2,3-trisubstituted benzene derivatives are
not obtained in high yields under usual conditions because of the instability
of these reagents and/or intermediary aryllithium species with various
electrophilic substituents or neighboring bromine (including the formation
of benzyne). Indeed, the 2,6-disubstituted iodobenzene derivatives shown
in Table 3 are all new compounds.
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Generation and Suppression of Benzynes
A R T I C L E S
t
Table 5. Deprotonative Zincation of Functionalized 4-Substituted Benzenes Using Bu2Zn(TMP)Lia
t
a The reaction was carried out using Bu2Zn(TMP)Li (2.2 equiv) and substrate (1 equiv) in THF. b Isolated yield. c FG ) functional group.
effective and advantageous. These methods offer far greater
generality than previous methods for the synthesis of function-
alized asymmetric benzynes and multifunctionalized aromatic
compounds (Figure 4).
Silylzincation and Carbozincation of Functionalized Un-
symmetrical Benzynes. We then demonstrated, as shown in
Table 6 and eq 3, that the unsymmetrically functionalized
benzyne intermediates we have obtained can be utilized as an
electrophilic foundation for further functionalization of the
benzene rings. After extensive experimentation, we found that
Me2Zn(SiMe2Ph)Li is the best complex for iodine-zinc ex-
Figure 4. Two alternative methods for generation of functionalized
benzynes.
change, benzyne formation, and successive silylzincation reac-
electron-withdrawing groups such as cyano, ester, and 1,3-
tion19 with high chemoselectivity. In 3-substituted benzynes,
oxazolyl groups,18 a strong directed leaving group, such as a
when a coordinative group (DMG) such as methoxy, meth-
TfO moiety, was required for the benzyne formation to proceed
oxymethyl, or carbonyl group is present, the silylzincation occurs
chemoselectively (runs 2-4).
regiospecifically at the meta carbon atom, mainly because of
On the other hand, the deprotonative zincation of 4-substituted
the coordination of DMG to the cation moiety of the zincate
t
benzenes using Bu2Zn(TMP)Li was found to be regio- and
(which results in the stabilization of the resultant zincate)20 (runs
chemoselective with no formation of benzyne, and the reaction
was tolerant of both electron-donating group, such as methoxy,
and electron-withdrawing groups, such as cyano, 1,3-oxazolyl,
ester, bromo, and trifluoromethyl groups (Table 5).
2-5). On the other hand, the regiocontrol of incoming reagents
is more difficult in 4-substituted benzynes (runs 6-8). In the
case of 4-trifluorobenzyne, the inductive effect of the functional
group seems to be more important for the regioselectivity of
In summary, deprotonative zincation of various 3-/4-
substituted halobenzenes using Me2Zn(TMP)Li proved effective
for the one-pot generation of various 3-/4-functionalized ben-
zynes, particularly those with electrophilic substituents, such
as ester, amide, and cyano. On the other hand, zincation with
tBu2Zn(TMP)Li, followed by electrophilic trapping (with I2)
proved a powerful tool for the preparation of 1,2,3-/1,2,4-
trisubstituted aromatic compounds without the formation of
benzyne. As mentioned in Table 1, the resultant trisubstituted
benzenes (1 or 8) are available as precursors for the generation
of 3-/4-substituted benzynes by iodine-zinc exchange reaction.
Thus, we have provided two new tools for generating various
functionalized benzynes and heterynes (Figure 4). Facile method
A (direct benzyne synthesis from halobenzenes) should make
reactions involving benzynes more synthetically useful. With
dienes having any acidic proton, method B (stepwise benzyne
synthesis using halogen-metal exchange reaction) would be
the silylzincation (run 8).
This methodology should be also applicable for synthesis of
4-substituted biphenyl derivatives, that is, cross biaryl coupling
(eq 3).21
Computational/Theoretical Investigation of Generation
and Suppression of 3-/4-Functionalized Benzynes Using Zinc
Ate Base (TMP-Zn-ate). Theoretical calculations were per-
formed to investigate the reaction pathway and to understand
the origin of the reactivity and unique selectivity achieved
through changing the alkyl ligand on zincates in the organozin-
cate-mediated benzyne formation reaction.
Computational Methods and Chemical Models. All cal-
culations were done using the Gaussian 03 program package.22
(18) For review see: Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837-
860.
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J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008 477

A R T I C L E S
Uchiyama et al.
Table 6. Silylzincation of Functionalized Benzynes Using Me2Zn(SiMe2Ph)Lia
a The reaction was carried out using Me2Zn(SiPhMe2)Li (3.3 equiv) and substrate (1 equiv) in THF. b Isolated yield. c Treated with 7 equiv of allyl
bromide after silylzincation and stirred for 24 h at room temperature. d FG ) functional group.
We employed Me2Zn(2-BrAni)Li (Ani ) anisole) and tBu2Zn-
(2-BrAni)Li as chemical models for the arylzincate intermedi-
ates. The molecular structures and harmonic vibrational fre-
quencies for Me2Zn(2-BrAni)Li (13) were obtained using
second-order Møller-Plesset perturbation theory (MP2).23 We
used Ahlrichs’ SVP24 all-electron basis set for the Zn and Br
atoms and 6-31G* for the other atoms (denoted as 631SVPs in
the text). Geometry optimization and vibrational analysis were
performed at the same level. All stationary points were
optimized without any symmetry assumptions and characterized
by normal coordinate analysis at the same level of theory (the
number of imaginary frequencies, NIMAG, was 0 for minima
and 1 for TSs). All the transition states structures and the
reaction coordinates (Hessian eigenvectors with negative eigen-
values) were examined visually. The intrinsic reaction coordinate
(IRC) method25 was used to track minimum energy paths from
transition structures to the corresponding local minima.
We used the ONIOM2 (MP2/631SVPs:HF/3-21G) method
for the geometry optimization for tBu2Zn(2-BrAni)Li (14). The
ONIOM method divides the complex 14 into high- (C2Zn(2-
BrAni)Li) and low-level layers (CH3) connected at the interface
by the link H atoms. For the final ONIOM optimized geometries,
we performed single point energy calculations using MP2/
631SVPs.26
I. Pathway of Generation of Benzyne. We first investigated
the reaction pathway of the benzyne formation from Me2Zn-
(2-BrAni)Li (13) as a basic model reaction. Figure 5 shows the
reaction course and the energy profile of the generation of the
benzyne from 13 at the MP2/631SVPs level. The intermediate
13 involves a pseudotetrahedral arrangement around the Zn atom
and Li bridging between the zincate and ortho MeO group.
Among several possibilities for benzyne formation from 13, we
identified one TS, TS1, which involves a trigonal planar
arrangement around Zn. To reach this TS, the orientation of
the Zn atom has to change drastically so that the Lewis acidity
of the Zn atom can effectively enhance the leaving ability of
the Br atom, and the Zn-C2 bond cleaves with an overall energy
loss of 23.5 kcal/mol (MP2/631SVPs). The degree of shortening
of the C1-C2 bond length (1.28 Å) in the TS (9%), as well as
(19) (a) Nakamura, S.; Uchiyama, M. J. Am. Chem. Soc. 2007, 129, 28-29.
(b) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc. 2005,
127, 13116-13117. (c) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am.
Chem. Soc. 2004, 126, 11146-11147.
(20) Comparison of the relative energies of the intermediary zincates based on
MP2/631SVPs calculation. (See Computational Methods for details)
(21) When THF was used as a solvent, the yield of 12a was reduced, though
no non-methylated protonation product could be detected.
(22) Frisch, M. J.; et al. Gaussian 03, revision B.04; Gaussian, Inc.: Pittsburgh,
PA, 2003.
(25) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363-368. (b) Gonzalez, C.;
Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154-2161. Gonzalez, C.;
Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523-5527.
(26) (a) Kwon, O.; Mckee, M. L. J. Phys. Chem. A 2001, 105, 10133-10138.
(b) Irle, S.; Rubin, Y.; Morokuma, K. J. Phys. Chem. A 2002, 106, 680-
688.
(23) Møller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618-622.
(24) Scha¨fer, A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571-2577.
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478 J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008

Generation and Suppression of Benzynes
A R T I C L E S
Figure 5. Intermediates, complexes, and TSs in the benzyne formation of Me2Zn(2-BrAni)Li. Bond lengths and energy changes at the MP2/631SVPs level
are shown in Å and kcal/mol, respectively.
II. Suppression of the Benzyne Formation. It has been
experimentally clarified that a tBu ligand on Zn inhibits benzyne
t
formation and hence the zincation with a Bu-Zn-ate, and
subsequent electrophilic trapping provides a powerful tool for
the synthesis of 1,2,3-/1,2,4-trisubstituted aromatic compounds
without the formation of benzyne. To examine the reaction
selectivity in relation to the nature of the ligand on Zn, we next
examined the benzyne formation of tBu2Zn(2-BrAni)Li (14) by
using the ONIOM2 (MP2/631SVPs:HF/3-21G) method.
t
We can expect a priori that two Bu ligands strongly hinder
the metal (Zn or Li) site from accessing the Br atom, because
of the bulkiness of the tBu ligand, and indeed, this was the case
Figure 6. Dissociation of benzyne-zincate complex (CP1 or CP2).
(Figure 7). The activation energy for benzyne formation in
tBu-zincate 14 is sufficiently high, and in accordance with the
experimental facts, is much higher than the barrier of the Me-
zincate (13).29
the elongation of the C1-Br (2.60 Å) and C2-Li (2.12 Å) bonds,
clearly suggest that the TS is rather late. Since the elimination
reaction is facilitated by the push-pull synergy of two hetero-
bimetals in the zincate, the activation energy seems to be
reasonably low. The interaction between dialkylzinc moiety and
bromine is crucial for smooth benzyne formation.
Conclusion
The zinc ate base, Me2Zn(TMP)Li, has been developed as a
novel multifunctional base reagent, allowing highly chemo- and
regioselective deprotonative zincation of meta-/para-function-
alized aromatic compounds, and successive 3-/4-benzyne forma-
tion. This simple and straightforward method provides direct
and efficient access to various unsymmetrical functionalized
benzynes, which are valuable synthetic intermediates. We also
demonstrated Diels-Alder cycloaddition, silylzincation, and
phenylzincation with the resultant functionalized benzynes. On
After the TS, the Br anion migrates to the Zn atom, and the
resultant new zincate (Me2Zn(Br)Li) becomes attached to the
benzyne residue to produce a weak complex (CP1) through
cation-p (benzyne; endocyclic p orbital) interaction. As judged
from the C1-C2 bond length (1.27 Å) in the CP, we can consider
the CP to be the benzyne complex. Dissociation of the benzyne-
zincate complex (CP1)27 into a naked benzyne and Me2Zn(Br)-
Li occurs with ca. 20 kcal/mol endothermicity (Figure 6), which
indicates lower stability than TS1 (Figure 5). These findings
suggest that the reactivity and selectivity of the benzyne
intermediate can be tuned through modification of the metal
complex (zincate) moiety, in accordance with experimental
observations.28 Although the stabilization energies from TS to
CP are rather small (ca. 5 kcal/mol), it is probable that CP1
reacts smoothly with a diene or a nucleophile to gain further
stabilization.
t
the other hand, zincation with Bu2Zn(TMP)Li followed by
electrophilic trapping is a powerful tool for the chemoselective
preparation of 1,2,3-/1,2,4-trisubstituted aromatic compounds.
A detailed theoretical/computational mechanistic investigation
of the reaction pathway of benzyne formation in this system
was conducted, and the structure of the benzyne-zincate
complex and the origin of the remarkable selectivity for
generation/suppression of benzyne depending upon the ligands
Figure 7. Reaction pathway of benzyne formation of the di-tert-butylarylzincate intermediate (14). Bond lengths at the ONIOM2(MP2/631SVPs:HF/3-
21G) level and energy changes at the MP2/631SVPs//ONIOM2(MP2/631SVPs:HF/3-21G) level are shown in Å and kcal/mol, respectively.
9
J. AM. CHEM. SOC. VOL. 130, NO. 2, 2008 479

A R T I C L E S
Uchiyama et al.
on the zincate have been elucidated. With the comprehensive
mechanistic knowledge acquired in this research, improvement
of the reaction system and the logical design of a new
chemoselective base reagents are in progress in our laboratory.
a JSPS Research Fellowship for Young Scientists (to T.F.). M.
U. is also the recipient of a Visiting Fellowship at the Cherry
L. Emerson Center of Emory University. The calculations were
performed on the RIKEN Super Combined Cluster (RSCC). We
thank Prof. T. Ohwada and Prof. Y. Otani (The University of
Tokyo) for their valuable comments.
Acknowledgment. This research was partly supported by the
Astellas Foundation, the Sumitomo Foundation, a Grant-in-Aid
for Young Scientists (A) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (to M. U.), and
Supporting Information Available: Complete ref 22; details
of the experimental procedures, spectral and theoretical data
(Cartesian coordinates and total electron energies for the
optimized stationary points at each level of theory). This material
is available free of charge via the Internet at http://pubs.acs.org.
(27) We identified another complexes CP2 in which a benzyne and the zincate
coordinate through cation-p (benzyne; exocyclic p bond) interaction. The
energy difference between CP1 and CP2 is only 1.2 kcal/mol and hence
they may be in equilibrium.
(28) Retbøll, M.; Edwards, A. J.; Rae, A. D.; Willis, A. C.; Bennett, M. A.;
Wenger, E. J. Am. Chem. Soc. 2002, 124, 8348-8360.
(29) Garc´ıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J.
Am. Chem. Soc. 2006, 128, 1066-1067.
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