Sterically hindered lithium dialkylcuprates for the generation of highly functionalized mixed cuprates through a halogen-copper exchange

Article abstract of DOI:10.1002/1521-3773(20020902)41:17<3263::AID-ANIE3263>3.0.CO;2-8

Even aldehyde and ketone functions are tolerated in mixed organocuprates prepared by copper-halogen exchange using (Me₃CCH₂)₂CuLi (Neopent₂CuLi) or (PhMe₂CCH₂)₂CuLi (Neophyl₂CuLi). The steric hindrance of the neopentyl and neophyl groups is essential to ensure the chemoselectivity of the reaction (see scheme), and therefore allows a general preparation of polyfunctionalized organocuprates.

Full text of DOI:10.1002/1521-3773(20020902)41:17<3263::AID-ANIE3263>3.0.CO;2-8

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afford the desired mixed cuprate 4a, which reacts with
electrophiles such as allyl bromide, acid chlorides, or 2-
cyclohexen-1-one to afford the desired products 5a d in yields
of 70 95% (Table 1, entries 1 4). Functionalized aromatic
bromides such as diethyl 2-bromoterephthalate smoothly
undergo Br/Cu exchange with Neopent2CuLi (1; THF,
ꢀ408C, 30 min) to provide the lithiumcuprate 4b, which upon
allylation furnishes the diester 5e (Table 1, entry 5).
Sterically Hindered Lithium Dialkylcuprates
for the Generation of Highly Functionalized
Mixed Cuprates through a Halogen Copper
Exchange**
Claudia Piazza and Paul Knochel*
Dedicated to Professor Jean-Francois Normant
Remarkably, ketone functions are compatible with the
I/Cu-exchange reaction. Treatment of 2-iodobenzophenone
with 1 (ꢀ40!08C, 30 min) leads to the desired mixed cuprate
(4c). Allylation or methylation (methyl iodide) leads to the
products 5 f and 5g, respectively (Table 1, entries 6 and 7).
Similarly, 4-iodophenyl tert-butyl ketone is converted into the
cuprate 4d and subsequently allylated (Table 1, entry 8).
Attempts to convert 4-iodoacetophenone into the corre-
sponding cuprate led to extensive deprotonation. However,
the use of Neophyl2CuLi (2) allows the preparation of the
corresponding cuprate 4e in approximately 80% yield (THF,
ꢀ30!258C, 1 h). This cuprate can be acylated (PhCOCl) or it
can undergo a Michael addition to 2-cyclohexen-1-one,
leading to the products 5j and 5k, respectively (Table 1,
entries 10 and 11). Finally, even an aldehyde function is
compatible with the iodine copper exchange. Treatment of 2-
iodobenzaldehyde with 1 (1.1 equiv, ꢀ40!ꢀ208C, 4 h) pro-
vides the cuprate 4 f, which is allylated to give 2-allylbenzal-
dehyde (5m) in 80% yield (Table 1, entry 13; see also
entry 12). The bulky lithium cuprates 1 and 2 also allow
the use of functionalized alkenyl iodides as substrates.
The reaction of 2-iodo-3-methyl-2-cyclohexenone (6) with
Neopent2CuLi (1) furnished the corresponding alkenylcup-
rate 7 (Scheme 2). The presence of the methyl group at C3 in 6
as well as the bulky nature of the cuprate 1, disfavor 1,4-
addition and favor I/Cu exchange. After allylation, the
cyclohexenone 8 is obtained in 74% yield (Scheme 2).
In summary, we have shown that sterically hindered
cuprates 1 and 2 allowa highly chemoselective I/Cu exchange.
With this method, newfunctionalized cuprates that bear ester,
ketone, or even aldehyde functions can be prepared and used
in synthesis. Further investigations for the preparation of new
polyfunctionalized alkenyl and heterocyclic copper reagents
are underway.
Highly functionalized organometallic compounds are key
intermediates for the preparation of polyfunctionalized
molecules.[1] Recently, we have shown that iodine magnesium
exchange allows the preparation of polyfunctionalized aryl-
magnesium reagents[2] that bear ester, nitrile, amino, or nitro
groups; however, more sensitive functionalities, for example,
ketone or aldehyde groups are usually not compatible with the
ꢀ
presence of a C Mg bond. Herein we report a solution to this
problem by using newsterically hindered organocuprates for
performing an iodine copper or bromine copper exchange.
Corey and Posner[3] have shown that the reaction of lithium
dialkylcuprates with aryl iodides leads to an iodine copper
exchange and to a competitive cross-coupling reaction. Kondo
et al. have shown that the use of lithium dimethylcuprate
allows an iodine copper exchange with a functionalized aryl
iodide that bears an ester group.[4] In this case, an excess of
Me2CuLi (2 equiv) has to be used to quench the methyl iodide
formed in the I/Cu-exchange reaction. In contrast, the readily
prepared lithium dineopentylcuprate (Neopent2CuLi, 1) and
(PhMe2CCH2)2CuLi, (Neophyl2CuLi, 2)[5] rapidly react with
various functionalized iodides of type 3 to give mixed
organocuprates of type 4, which selectively transfer the aryl
group[6] to electrophiles (Eþ), thus leading to products of type
5 (Scheme 1). This approach allows a general preparation of
polyfunctionalized organocuprates.[7,8]
E
X
CuR Li
E+
R2CuLi (1 or 2)
THF
FG
FG
FG
3: X = Br,I
4
5
FG = ester, ketone, aldehyde; R= Me3CCH2 (1) or PhMe2CCH2 (2)
Scheme 1. Preparation of highly functionalized arylcopper reagents.
Experimental Section
The steric hindrance of 1 and 2 is essential for ensuring
the chemoselectivity of the I/Cu exchange.[9] Thus, ethyl
4-iodobenzoate (3a) undergoes a smooth iodine copper
exchange with Neopent2CuLi (1; 1.1 equiv, ꢀ308C, 2 h) to
Typical procedure (5j): A dry and argon-flushed 10-mL flask, equipped
with a magnetic stirrer and a septum, was charged with 4-iodoacetophe-
none (240 mg, 1.0 mmol). Dry THF (2 mL) was added and the solution was
added slowly into
a dry, argon-flushed 25-mL flask that contained
previously prepared Neophyl2CuLi (2; 1.2 mmol) and cooled to ꢀ308C.
The mixture was warmed quickly to room temperature. The I/Cu exchange
was complete within 1 h (checked by GC analysis of reaction aliquots), and
benzoyl chloride (0.1 mL, 0.9 mmol) was added to the mixed organo-
cuprate (4e). After stirring for 30 min at room temperature, the reaction
mixture was quenched with saturated NH4Cl solution (2 mL) and poured
into water (25 mL). The aqueous phase was extracted with diethyl ether
(3 î 30 mL). The organic fractions were washed with brine (30 mL), dried
(MgSO4), and concentrated in vacuo. Purification by flash chromatography
(pentane/diethyl ether 9:1) yielded 4-acetylbenzophenone (5j) as a light-
yellowoil (155 mg, 77%).
[*] Prof. Dr. P. Knochel, C. Piazza
Institut f¸r Organische Chemie, Ludwig-Maximilians-Universit‰t
Butenandtstrasse 5-13, Haus F, 81377 M¸nchen (Germany)
Fax : (þ 49)89-2180-7680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Deutsche Forschungsgemeinschaft (Leibniz program)
for financial support. We thank BASF AG (Ludwigshafen), Chemetall
GmbH (Frankfurt), and Degussa AG (Hanau) for the generous gift of
chemicals.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Received: April 25, 2002 [Z19175]
Angew. Chem. Int. Ed. 2002, 41, No. 17
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Reaction of functionalized lithium cuprates 4 with electrophiles to give 5.
Entry
1
Cuprate 4[a]
Electrophile
allyl bromide
Product 5
Yield [%][b]
4a
4a
5a
5b
95
90[c]
2
3
PhCOCl
87
95[c]
4a
tBuCOCl
5c
83
4
5
4a
4b
cyclohexenone
allyl bromide
5d
5e
70
76
6
7
4c
4c
allyl bromide
MeI
5 f
5g
80
80
8
4d
4d
4e
allyl bromide
cyclohexenone
PhCOCl
5h
5i
93
9
60
10
5j
77[c]
11
4e
cyclohexenone
5k
68[c]
12
13
4 f
4 f
CH3COCl
5l
70
80
allyl bromide
5m
[a] R1 ¼ neopentyl; R2 ¼ neophyl. [b] Yields of isolated analytically pure products. [c] Yields obtained by performing the I/Cu exchange with 2.
3264
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Angew. Chem. Int. Ed. 2002, 41, No. 17

COMMUNICATIONS
approaches, an organosulfone-mediated approach is very
effective for allylation,[2] vinylation,[3] and azidation[4]
[Eq. (1), AIBN ¼ 2,2’-azobisisobutyronitrile]. However,
the reported methods did not work well with primary
alkyl iodides and xanthates owing to inefficient iodine-
atom transfer and xanthate-group transfer, respectively.
Recently, we also reported a tin-free acylation approach
Scheme 2. Iodine copper exchange with 2-iodo-3-methyl-2-cyclohexenone.
[1] A. Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem. 2000,
112, 4584; Angew. Chem. Int. Ed. 2000, 39, 4414.
[2] A. E. Jensen, W. Dohle, I. Sapountzis, D. M. Lindsay, V. A. Vu, P.
Knochel, Synthesis 2002, 4, 565.
AIBN
SO2Et
R
(1)
RX
+
X= I, xanthate
[3] E. J. Corey, G. H. Posner, J. Am. Chem. Soc. 1968, 90, 5615.
[4] Y. Kondo, T. Matsudaira, J. Sato, N. Muraka, T. Sakamoto, Angew.
Chem. 1996, 108, 818; Angew. Chem. Int. Ed. Engl. 1996, 35, 736.
[5] Commercial neopentyl iodide was treated with tBuLi (2 equiv, Et2O,
ꢀ788C!RT, 1 h) to give neopentyllithium, which upon reaction with
CuCN (0.5 equiv, 08C, 10 min) furnished the cuprate 1. PhMe2CCH2Cl
(neophyl chloride) was converted into neophyllithium by reaction with
lithium metal in dry hexane (heated overnight at reflux). The mixture
was then transferred through a cannula into a 50-mL Schlenk tube, and
the hexane was removed under vacuum. Dry diethyl ether was added
and the mixture was centrifuged (2000 rpm, 30 min). Before use, the
clear solution of neophyllithium thus obtained was titrated with
menthol and o-phenantroline as indicator. Treatment with CuCN
(0.5 equiv, room temperature, 10 min) gave the corresponding copper
reagent 2.
using methanesulfonyl oxime ether, in which primary alkyl
iodides and xanthates caused the same problem as a result of
the small energy difference between the methyl radical and
the primary alkyl radical [Eq. (2), V-40 ¼ 1,1’-azobis(cyclo-
hexane-1-carbonitrile)].[5]
V-40
tBuC6H5, 140 oC
OBn
OBn
(2)
RI
+
MeSO2
N
R
N
As our extensive efforts to generate primary alkyl radicals
from primary alkyl iodides and xanthates were unsuccessful,
we have been interested in developing a new reliable method
to generate primary alkyl radicals by using newtypes of
radical precursors that do not require an atom- or a group-
transfer step. In this regard, we have studied the possibility of
using an alkyl allyl sulfone as a radical precursor. Alkyl allyl
sulfones have been widely used as radical acceptors to transfer
an allyl group to a radical precursor.[6] Although alkyl allyl
sulfones have been used once as the radical precursor in an
allylation reaction,[2a] primary alkyl allyl sulfones have not
been examined. To the best of our knowledge, S-alkoxycar-
bonyl dithiocarbonates are the only generators of primary
[6] Previously, we have shown that the neopentyl group does not readily
ꢀ
participate in the formation of newC C bonds: P. Jones, K. C. Reddy, P.
Knochel, Tetrahedron 1998, 54, 1471; see also: S. H. Bertz, M. Eriksson,
G. Miao, J. P. Snyder, J. Am. Chem. Soc. 1996, 118, 10906.
[7] For the preparation of functionalized organocuprates by the direct
insertion of activated copper, see: a) G. W. Ebert, R. D. Rieke, J. Org.
Chem. 1984, 49, 5281; b) R. D. Rieke, R. H. Wehmeyer, T. C. Wu, G. W.
Ebert, Tetrahedron 1989, 45, 443; c) G. W. Ebert, J. W. Cheasty, S. S.
Tehrani, E. Aouad, Organometallics 1992, 11, 1560; d) G. W. Ebert,
D. R. Pfennig, S. D. Suchan, T. A. Donovan, Tetrahedron Lett. 1993, 34,
2279.
[8] a) B. H. Lipshutz, S. Sengupta, Org. React. 1992, 41, 135; b) R. J. K.
Taylor, Organocopper Reagents, Oxford University Press, Oxford,
1994; c) N. Krause, Modern Organocopper Chemistry, Wiley-VCH,
Weinheim, 2002.
[9] For a chemoselective halogen lithium exchange, see: Y. Kondo, M.
Asai, T. Uchiyama, T. Sakamoto, Org. Lett. 2001, 3, 13.
ꢀ
alkyl radicals from alcohols, but they cannot be applied to C
C-bond formations owing to the rapid formation of the
corresponding xanthates.[7] We have found that alkyl allyl
sulfones are highly efficient and reliable radical precursors for
the generation of primary alkyl radicals under tin-free
ꢀ
conditions and can be successfully applied to various C C-
bond-formation reactions.
Initially, we focused on radical cyanation,[8] and began our
study with a primary alkyl iodide and methanesulfonyl
cyanide.[9] The reaction of 4-phenoxybutyl iodide with meth-
anesulfonyl cyanide (2 equiv) and V-40 (0.2 equiv) in tert-
butylbenzene at 1408C for 5 h afforded 4-phenoxybutyl
cyanide in only 21% yield together with recovered 4-
phenoxybutyl iodide (77%). Notably, methanesulfonyl cya-
nide was completely consumed, with acetonitrile as the major
product [Eq. (3)].[10] However, allyl sulfone 1 was an effective
ꢀ
Tin-Free Radical-Mediated C C-Bond
Formations with Alkyl Allyl Sulfones as
Radical Precursors**
Sunggak Kim* and Chae Jo Lim
The synthetic importance of tin-free radical reactions has
been well recognized in recent years.[1] Among several
[*] Prof. Dr. S. Kim, C. J. Lim
Center for Molecular Design and Synthesis
and Department of Chemistry, School of Molecular Science
Korea Advanced Institute of Science and Technology
Taejon 305-701 (Korea)
V-40
tBuC6H5, 140 oC
(3)
+
MeSO2CN
RI
RCN + CH3CN
21%
R=PhO(CH2)4
Fax : (þ 82)42-869-8370
precursor for radical cyanation, and our approach is outlined
in Scheme 1. We envisaged that the addition of a p-toluene-
sulfonyl radical to 1 would produce an alkyl sulfonyl radical as
well as p-tolyl allyl sulfone 4. Although the alkyl sulfonyl
E-mail: skim@mail.kaist.ac.kr
[**] We thank CMDS and BK21 project for financial support.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 17
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4117-3265 $ 20.00+.50/0
3265