Deprotonative cadmation of functionalized aromatics

Article abstract of DOI:10.1039/b809543d

This communication describes the deproto-metalation of a large range of aromatics including heterocycles using a newly developed lithium-cadmium base; the reaction proceeds at room temperature with an excellent chemoselectivity and efficiency, and proved to be regioselective in most cases. The Royal Society of Chemistry.

Full text of DOI:10.1039/b809543d

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COMMUNICATION
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Deprotonative cadmation of functionalized aromaticsw
Jean-Martial L’Helgoual’ch,a Ghenia Bentabed-Ababsa,ab Floris Chevallier,a
Mitsuhiro Yonehara,c Masanobu Uchiyama,*c Aıcha Derdourb and
¨
Florence Mongin*a
Received (in Cambridge, UK) 5th June 2008, Accepted 16th July 2008
First published as an Advance Article on the web 17th September 2008
DOI: 10.1039/b809543d
This communication describes the deproto-metalation of a large
range of aromatics including heterocycles using a newly devel-
oped lithium–cadmium base; the reaction proceeds at room
temperature with an excellent chemoselectivity and efficiency,
and proved to be regioselective in most cases.
(THF), the reactions proved to be chemoselective, but require 1
or 2 equiv of base.
Herein we report an efficient regio- and chemoselective direct
cadmation on functionalized aromatics including very sensitive
heterocycles using a newly designed lithium cadmate base.
Among organometallics, organocadmium reagents have been
mainly prepared by reaction of organic halides with cadmium
metal or by transmetalation, and used as soft nucleophilic
reagents in organic synthesis.8 Wittig et al. documented in
1951 the synthesis of Ph3ZnLi and Ph3CdLi, and their efficiency
to deprotonate fluorene in diethyl ether.9 Quenching with CO2
and subsequent acidic work-up afforded diphenyleneacetic acid
in a low yield of 16% after 10 days reaction time using Ph3ZnLi
whereas a satisfying 64% yield was obtained after 3 days using
Ph3CdLi, a result attributed to the size of the central metal. This
prompted us to study the use of lithium cadmates for the
deproto-metalation of sensitive aromatic substrates.
The deprotonative metalation of aromatic rings has been widely
used as a powerful method for regioselective functionalization.1
Various strong bases such as alkyllithiums and lithium dialkyla-
mides have been largely employed for this purpose because of
their solubility in ethers and alkanes, and also because many of
them are commercially available. However, the use of alkyl-
lithiums on their own as bases has been limited to substrates
with C–H acidity enhanced by directing groups. In addition,
recourse to simple lithium dialkylamides for aromatics bearing
reactive functions (e.g. ester or cyano groups) or sensitive
p-deficient heterocycles required strictly controlled conditions
(extremely low reaction temperatures, in situ trapping...) due to
the high reactivity of the corresponding aryllithiums. The use of
additives for lithium compounds in order to get more efficient or
more chemoselective bases, or else to modify the deprotonation
site, is a challenging area. Representative activation ways are the
formation of chelates between alkyllithiums and N,N,N0,N0-
tetramethylethylenediamine (TMEDA), as well as the formation
of complexes between alkyllithiums and potassium tert-butoxide
(e.g. LIC-KOR superbase).
A recent study showed LiTMP and (TMP)2Zn, even if not
associated in the form of a zincate, could behave synergistically,
combining both the efficiency of LiTMP and the chemoselectivity
of (TMP)2Zn.10 In order to seek more efficient and direct
methods for introducing functionalities into heteroaromatic rings,
we focused the deprotonative metalation using the corresponding
mixture with cadmium instead of zinc on the difference of metal
size. First attempts using anisole (1a) as substrate indicated that
an in situ prepared mixture of CdCl2ꢀTMEDA11 (0.5 equiv.) and
LiTMP (1.5 equiv.) was suitable for an efficient reaction, when
used in THF at room temperature. Indeed, subsequent trapping
with iodine after 2 h afforded the expected derivate 2a in 74%
yield, against 30% yield using CdCl2ꢀTMEDA (0.5 equiv.) and
LiTMP (1.5 equiv.). Since (TMP)2Cd (1 equiv.) and LiTMP
(1 equiv.) give much lower conversions when used separately
under the same reaction conditions, both of them play a role in
the reaction mechanism. In order to obtain additional information
about the active species of a basic mixture obtained from a THF
solution of LiTMP and CdCl2ꢀTMEDA (0.33 equiv.), NMR and
DFT studies were carried out. The analysis of the 13C NMR
spectra revealed that LiTMP was not present in solution, suggest-
ing the formation of a lithium cadmate. This was confirmed by the
B3LYP-calculated equilibrium between LiTMP and (TMP)2Cd
on one side and (TMP)3CdLi on the other side, which is in sharp
contrast to the corresponding zinc–lithium mixture obtained from
LiTMP and ZnCl2ꢀTMEDA (Scheme 1).10
By combining soft organometallic compounds with alkali
additives (e.g. LiTMP, TMP = 2,2,6,6-tetramethylpiperidino,
t
or LiCl), bases such as Bu2Zn(TMP)Li,2 iBu3Al(TMP)Li,3
5
(Me3SiCH2)2Mn(TMP)LiꢀTMEDA,4 MeCu(TMP)(CN)Li2
and (TMP)2Znꢀ2MgCl2ꢀ2LiCl6 have been prepared and used
to generate functionalized aromatic compounds.
Mulvey introduced the term alkali metal-mediated metalation
to depict the reactions of ate bases because the reactivity
(‘‘synergy’’) they exhibit cannot be attained by the homometallic
compounds on their own.7 When performed in tetrahydrofuran
a
´
´
Chimie et Photonique Moleculaires, UMR 6510 CNRS, Universite
de Rennes 1, Baˆtiment 10A, Case 1003, Campus Scientifique de
Beaulieu, F-35042 Rennes Cedex, France.
E-mail: florence.mongin@univ-rennes1.fr; Fax: +33-2-23-23-69-55;
Tel: +33-2-23-23-69-31
b
`
´
Laboratoire de Synthese Organique Appliquee, Faculte des Sciences
de l’Universite, BP 1524 Es-Senia, Oran, 31000, Algeria
´
´
c The Institute of Physical and Chemical Research, RIKEN, 2-1
Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
E-mail: uchi_yama@riken.jp; Fax: +81-48-467-2879
Representative results from the metalation-trapping sequences
of benzenes bearing various directing metalation groups (DMG)
using lithium tris(2,2,6,6-tetramethylpiperidino)cadmate (TMP-
cadmate) are summarized in Table 1. Veratrole (1b) was similarly
regioselectively deprotonated. Polar functional groups including
w Electronic supplementary information (ESI) available: Experimental
procedures and characterizations (1H and 13C NMR spectra for all
compounds), and theoretical data (details of computational methods,
cartesian coordinates and Gibbs free energies). See DOI: 10.1039/b809543d
ꢁc
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Chem. Commun., 2008, 5375–5377 | 5375

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amide, ester, nitrile and even ketone (substrates 1c, 1d, 1e and 1f,
respectively) are tolerated in the reaction. Aromatic halides 1g
and 1h are chemoselectively converted to the metalated deriva-
tives, with a complete regioselectivity for the position far from
the heavy halogen atom. Bromo ester 1i behaved similarly to give
after trapping the iodide 2i.
We next demonstrated that TMP-cadmate was suitable for
the chemoselective metalation of a large range of aromatic
heterocycles, giving in general higher yields than using Zn10,12
(Table 2). The reaction with both p-excessive (substrates 1j, 1k
and 1l) and p-deficient (substrates 1m, 1n, 1o, 1p and 1q)
heterocycles was found to proceed smoothly at room temp.
The expected iodides formed regioselectively, except 3-iodo-
pyridazine (2o), which was accompanied by the 4-iodo deri-
vative 20o (about 60 : 40 ratio for 2o : 20o).
Starting from pyrazine (1q), the 2,5-diodo derivative 3q was
isolated concomitantly in 20% yield using 0.5 equiv. of TMP-
cadmate, probably through dideprotonation, whereas it was
avoided using 1/3 equiv. The formation of dimetalated derivatives
being described using zincate13 or manganate4,14 type bases, the
use of a larger amount of TMP-cadmate (1 equiv.) was attempted
to deprotonate 1q. Under the same reaction conditions, the
diiodide 3q was isolated in 58% yield. The method was success-
fully extended to five-membered substrates 1r, 1s, 1t and 1l
(Table 3).
Scheme 1 Bond lengths at the B3LYP/6-31G*&SVP(Zn) level in A.
Table 1 Deprotonative cadmation of functionalized benzenes
In summary, highly chemo- and regioselective deprotona-
tive cadmation of functionalized aromatics including hetero-
cycles was realized using a newly developed TMP-Cd-ate base.
The latter is compatible with very sensitive substrates such as
diazines for which classical lithium bases can hardly be used,
even at very low temperatures.15 The aromatic lithium cad-
mates were evidenced using iodine as electrophile. Trapping of
Entry Substrate (1)
Product (2)
Yield (%)
Table 2 Deprotonative cadmation of aromatic heterocyclesa
1
1a
1b
2a 74 (30)a
Entry
1
Substrate (1)
Product (2)
Yield (%)
97 (73)b
1j
2j
2
2b 79
2
3
1k
1l
2k
2l
84 (69)b
68 (68)b
3
4
5
6
7
1c
1d
1e
1f
2c 91
2d 62
2e 68
2f 66
2g 97
4
5
6
1m
1n
1o
2m
2n
2o
97 (52)b
63 (57)b
55c
20o
2p
2q
41c
1g
7
8
1p
1q
71 (57)b
63d (59)b
8
9
a
1h
1i
2h 83
2i 60
a
Reactions carried out using CdCl2ꢀTMEDA (0.5 eq.) and LiTMP
(1.5 eq.). Using ZnCl2ꢀTMEDA (0.5 eq.) and LiTMP (1.5 eq.).10,12
b
c
d
Using CdCl2ꢀTMEDA (1 eq.) and LiTMP (3 eq.). Using CdCl2ꢀ
Using ZnCl2ꢀTMEDA (0.5 eq.) and LiTMP (1.5 eq.).
TMEDA (0.33 eq.) and LiTMP (1 eq.).
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Table 3 Deprotonative dicadmation of aromatic heterocyclesa
Notes and references
1 For excellent reviews, see: (a) H. W. Gschwend and H. R.
Rodriguez, Org. React., 1979, 26, 1–360; (b) V. Snieckus, Chem.
Rev., 1990, 90, 879–933.
Entry
1
Substrate (1)
Product (3)
Yield (%)
58
1q
1r
3q
3r
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E. Hevia, G. W. Honeyman and R. E. Mulvey, Angew. Chem.,
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2
50
3
4
1s
1t
3s
3t
74
81
5
1l
3l
60
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a
Reactions carried out using CdCl2ꢀTMEDA (1 eq.) and LiTMP (3 eq.).
the furylcadmate was attempted using other electrophiles:
benzoyl chloride8b to afford the ketone 4u, and 4-bromo-
anisole to give the expected coupling16 product 5u under
palladium catalysis, as depicted in Scheme 2.
´
4 J. Garcia-Alvarez, A. R. Kennedy, J. Klett and R. E. Mulvey,
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7 For reviews, see: (a) R. E. Mulvey, Organometallics, 2006, 25,
1060–1075; (b) R. E. Mulvey, F. Mongin, M. Uchiyama and Y.
Kondo, Angew. Chem., 2007, 119, 3876–3899 (Angew. Chem., Int.
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P. O’Brien and M. A. Malik, Sci. Synth., 2004, 3, 91–131.
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Nethaji, Dalton Trans., 2006, 2714–2718.
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Scheme 2 Other trapping reactions of heterocyclic cadmates.
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R. E. Mulvey and C. T. O’Hara, Angew. Chem., 2006, 118,
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M. Hogg, G. W. Honeyman, A. R. Kennedy and R. E. Mulvey,
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14 L. M. Carrella, W. Clegg, D. V. Graham, L. M. Hogg, A. L.
Kennedy, J. Klett, R. E. Mulvey, E. Rentschler and L. Russo,
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2007, 46, 4662–4666).
Comparisons with previously described combinations of LiTMP
on the one hand, and Zn,2 Al,3 Mn4 and Cu5 organometallic
compounds on the other hand, showed the basic mixture we here
described is both more efficient and/or more chemoselective.
Due to the toxicity of cadmium compounds we are attempt-
ing to develop basic mixtures with cadmium salts as catalysts
rather than in stoichiometric quantities. In addition, work in
order to develop new mixed lithium–metal bases of ate type
that are still efficient and chemoselective but less toxic are in
parallel under investigation, profiting from the present study.
15 N. Ple, A. Turck, K. Couture and G. Queguiner, J. Org. Chem.,
´ ´
1995, 60, 3781–3786.
16 To our knowledge, cross-coupling reactions using cadmium com-
pounds have only been described starting from organocadmium
chlorides: (a) E.-i. Negishi, T. Takahashi, S. Baba, D. E. Van Horn
and N. Okukado, J. Am. Chem. Soc., 1987, 109, 2393–2401; (b) N.
Bumagin, A. B. Ponomarev and I. P. Beletskaya, Zh. Org. Khim.,
1987, 23, 1345–1353. See also: (c) J. A. Miller and R. P. Farrell,
Tetrahedron Lett., 1998, 39, 7275–7278.
We gratefully acknowledge the financial support of Region
´
Bretagne (to J. M. L.), MESRS of Algeria (to G. B.), and
Hoansha and KAKENHI (Young Scientist (A), Houga, and
Priority Area No. 452 and 459) (to M. U.). The calculations were
performed on the RIKEN Super Combined Cluster (RSCC).
ꢁc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 5375–5377 | 5377