Generation of functionalized asymmetric benzynes with TMP-zincates. Effects of ligands on selectivity and reactivity of zincates

Article abstract of DOI:10.1021/ja0202199

We have developed new methods for preparing functionalized benzynes through deprotonative zincation as a key reaction using R₂Zn(TMP)Li, and we also describes dramatic ligand effects on the benzyne formation. Deprotonative zincation of various meta-substituted bromobenzenes with Me₂Zn(TMP)Li proved effective for the one-pot generation of various 3-functionalized benzynes, particularly those 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-trisubstituted aromatic compounds.⁸ The resultant 1,2,3-trisubstituted benzenes are available as precursors for generation of 3-substituted benzynes by halogen-zinc exchange reactions with Me₃ZnLi. These methods offer far greater generality than previous methods for the synthesis of functionalized asymmetric benzynes, and should be of value in new syntheses of various natural products and functional materials. In addition, these results underline the utility of spectator ligands on the central metal of ate complexes as a tunable functionality in the development of new ate complex-promoted reactions. Copyright

Full text of DOI:10.1021/ja0202199

Published on Web 06/22/2002
Generation of Functionalized Asymmetric Benzynes with TMP-Zincates.
Effects of Ligands on Selectivity and Reactivity of Zincates
Masanobu Uchiyama,*,†,§ Tomoko Miyoshi,‡ Yumiko Kajihara,‡ Takao Sakamoto,‡ Yuko Otani,†
Tomohiko Ohwada,† and Yoshinori Kondo‡
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan, and Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
Aobayama, Aoba-ku, Sendai 980-8578, Japan
Received February 12, 2002
Scheme 1
Benzyne is among the most important intermediates in organic
chemistry and has an unique structure, with two double bonds and
one triple bond in a planar six-membered ring.1 While unsubstituted
benzyne has a symmetric triple bond, substituents on the benzyne
break this symmetry, leading to different reactivities of the
individual carbon atoms (Figure 1), i.e., substituents on benzyne
can control the regioselectivity of incoming reagents through
electronic, steric, and chelation effects. Therefore, such regio-
selectivity is important for organic synthesis2 as well as for
theoretical chemistry.3 However, the potential of functionalized
(asymmetric) benzynes has not yet been realized mainly due to the
lack of efficient generation methods compatible with various
functional groups, particularly electrophilic substituents such as
ester, amide, and cyano groups, on the benzyne.
Table 1. Chemoselective Deprotonative Metalation and
Generation of Benzynes
Figure 1. Asymmetric benzynes.
Several methods for generating functionalized benzynes bearing
restricted substituents such as alkyl, alkoxy, or halogen groups have
been reported.1 These methods require (1,2,3- or 1,2,4-) trisubsti-
tuted benzenes as precursors, in which two of the substituents are
in ortho positions, and they are eliminated upon the generation of
the substituted benzynes.1 However, the applicability of these
conventional methods to generation of benzynes bearing electro-
philic substituents is limited in two respects: (1) poor availability
of the starting highly substituted benzenes, and (2) restricted
compatibility with the remaining electrophilic functional groups.
Thus, a method for generating asymmetric benzynes with high
functional group compatibility is highly desirable.
Taking the availability of precursors and general applicability
into consideration, deprotonative metalation seems to be advanta-
geous to generate (multi-)functionalized benzynes.4 Herein, we will
report new methods to generate functionalized benzynes through
deprotonative zincation as a key reaction, using lithium dialkyltetra-
methylpiperidino-zincates (R2Zn(TMP)Li),5 and we also describe
dramatic effects of the ligands on Zn upon the benzyne formation.
As a model reaction, the deprotonative zincation of 3-cyano-
bromobenzene (1a) with various R2Zn(TMP)Li was first investi-
gated by focusing on the nature of TMP-zincates (Scheme 1). While
deprotonative metalation of meta-substituted benzenes such as 1
can take place in three positions, the metalations with TMP-zincates
* Corresponding author. E-mail: uchiyama@mol.f.u-tokyo.ac.jp.
† The University of Tokyo.
‡ Tohoku University.
§ PRESTO, Japan Science and Technology Corporation (JST).
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J. AM. CHEM. SOC. 2002, 124, 8514-8515
10.1021/ja0202199 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
proved to occur regioselectively at the C2 position.4a Furthermore,
the nature of alkyl ligands on the zincates turned out to influence
dramatically the reactivities of the resultant arylzincates (2). In the
stituted benzynes could be achieved by utilizing the drastic ligand
effects in zincates. While the role of nonreacting (i.e., dummy or
spectator) ligands of ate complexes has been discussed, general
application of their influence has not yet been realized. The present
work underlines the utility of dummy ligands on the central metal
of ate complexes as a tunable functionality in the development of
new ate complex-promoted reactions. On the basis of the simplicity
of the procedure, the absence of a requirement for tedious multistep
synthesis of the precursor, and high chemo-/regioselectivity, we
consider that the present methods represent a valuable extension
of the aryne chemistry.
Acknowledgment. This research was partly supported by grants
from the Japan Society of Promotion of Science.
Supporting Information Available: Experimental procedures and
characterizations (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
t
reaction with Bu2Zn(TMP)Li,5 zincation occurred regio-/chemo-
selectively without the formation of benzyne and the resulting
arylzincate (2a-2) was treated with I2 to give 1-bromo-2-cyano-3-
iodobenzene (6a) in 82% yield. On the other hand, when Me2Zn-
(TMP)Li was used under the same conditions in the presence of
diene (4a), the Diels-Alder adduct (5a) was obtained in 80% yield,6
which indicates the generation of 3-cyanobenzyne (3a) through
ready “elimination” of the arylzincate (2a). This drastic change of
reaction modes (chemoselective metalation (inert “elimination”;
t-Bu) or generation of benzyne (facile elimination; Me)) dependent
on the alkyl-ligation environment is a feature of zincates, interesting
and potentially useful from the synthetic viewpoint.
Then, deprotonative zincations of various meta-substituted
bromobenzenes with R2Zn(TMP)Li were investigated (Table 1).
Deprotonative zincation with Me2Zn(TMP)Li proved effective for
the one-pot generation of various 3-functionalized benzynes. On
References
(1) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967. (b) Hart, H. In The Chemistry of Triple-Bonded
Functional Groups, Supplement C2; Patai, S., Ed.; John Wiley & Sons
Ltd: Chichester, UK, 1994; Chapter 18. (c) Gilchrist, T. L. In The
Chemistry of Functional Groups, Supplement C2; Patai, S., Rappoport,
Z., Eds.; Wiley: Chichester, UK, 1983, Chapter 11. Recent examples for
the preparation of benzynes: (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.
t
the other hand, zincation with Bu2Zn(TMP)Li followed by elec-
trophilic trapping (with I2) proved a powerful tool for the preparation
of 1,2,3-trisubstituted aromatic compounds.7 The resultant 1,2,3-
trisubstituted benzenes (6) are available as precursors for generation
of 3-substituted benzynes by halogen-zinc exchange reactions (vide
infra).
The trifluoromethyl group works as an exclusively para-
metalating directing group, and the metalation and the generation
of benzyne proceeded smoothly at the 4-position (Entry 8).
To expand the applicability of the present method, deprotonative
zincation of various halobenzenes (or their analogues) with Me2Zn-
(TMP)Li was then investigated (Entries 10-13); various groups
such as fluoro, chloro, and triflate (except for iodo8) turned out to
work well as both ortho-directing and leaving groups in benzyne
formation.
(2) (a) Knochel, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, UK, 1991; Vol. 8, Chapter 4.4 and references
therein. (b) Kessar, S. V. In ComprehensiVe Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 8, Chapter 2.3 and
references therein.
(3) (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.
(4) Alkyllithiums and lithium dialkylamides have been widely used as
powerful bases for regioselective metalation of aromatic rings: (a)
Snieckus, V. Chem. ReV. 1990, 90, 879-933. (b) Gschwend, H. W.;
Rodriguez, H. R. Heteroatom Facilitated Lithiations. In Org. React. (N.Y.)
1979, 26, 1-360. However, their use has been limited because these bases
or the resulting intermediary aryllithium species react with electrophilic
(directing) groups: Upton, C. J.; Beak, P. J. Org. Chem. 1975, 40, 1094-
1098.
(5) Recently we reported a directed zincation of functionalized aromatics using
tBu2Zn(TMP)Li, which greatly extends the compatibility of metalation:
(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. 2450-2551.
Similar benzyne intermediates can reasonably be formed by the
halogen-zinc exchange reaction of o-dihalobenzene analogues
(Scheme 2).9,10 In the reaction of o-bromoiodobenzene (FG ) H;
6j) with Me3ZnLi,10a,b the metalation and following “elimination”
proceeded smoothly, and the resulting benzyne reacted with dienes
(4a,b) to give the corresponding bicyclo compounds (5j, 7) in high
t
yields.6 On the other hand, when Bu3ZnLi10c was used under the
(6) A series of recent studies has expanded the utility of rigid oxabicyclic
compounds, see: (a) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem.
Soc. 2001, 123, 6834-6839. (b) Lautens, M.; Fagnou, K. J. Am. Chem.
Soc. 2001, 123, 7170-7171. (c) Lautens, M.; Renaud, J.-L.; Hiebert, S.
J. Am. Chem. Soc. 2000, 122, 1803-1804.
same conditions, zincation proceeded without the formation of
benzyne, and the arylzincate was trapped by an electrophile, e.g.,
benzaldehyde, to give the corresponding 2-halobenzhydrol deriva-
tives (8j-l) in high yields. These results supports the intermediary
formation of arylzincates (2) in deprotonative zincation by TMP-
zincates. As a matter of course, 3-substituted benzynes can also be
generated by using the iodine-zinc exchange reactions of the 1,2,3-
trisubstituted benzenes (6) shown in Table 1; the reaction of N,N-
diisopropyl-3-bromo-2-iodobenzamide (FG ) CONiPr2; 6c) with
Me3ZnLi proceeded smoothly, and the benzyne reacted with diene
(4a) to give the desired bicyclo compound (5c) in 86% yield. Thus,
we have provided two new tools, which would be applicable for
generating various functionalized benzynes and heterynes.
(7) The 2,6-disubstituted iodobenzene derivatives shown in Table 1 are all
new compounds.
(8) The iodine-zinc exchange may occur preferentially over the deprotonation.
(9) Recently, the iodine-zinc exchange of 2-iodophenyl triflate with n-Bu3ZnLi
was reported to give butylphenylzinc species, and a benzyne intermediate
was proposed to be involved: Harada, T.; Chiba, M.; Oku, A. J. Org.
Chem. 1999, 64, 8210-8213.
(10) For examples of halogen-zinc exchange reactions on aromatics with
zincates, see: (a) Kondo, Y.; Takazawa, N.; Yamazaki, C.; Sakamoto, T.
J. Org. Chem. 1994, 59, 4717-4718. (b) Uchiyama, M.; Koike, M.;
Kameda, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1996, 118,
8733-8734. (c) Kondo, Y.; Fujinami, M.; Uchiyama, M.; Sakamoto, T.
J. Chem. Soc., Perkin Trans. 1 1997, 799-800. (d) Uchiyama, M.;
Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934-4946.
In conclusion, a chemo-/regioselective directed zincation of meta-
functionalized haloaromatics and a versatile generation of 3-sub-
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