Copper-mediated cross-coupling of functionalized arylmagnesium reagents with functionalized alkyl and benzylic halides

Article abstract of DOI:10.1021/ol0163272

(equation presented) Functionalized arylmagnesium halides, prepared via an iodine-magnesium exchange, undergo a smooth cross-coupling reaction with functionalized primary alkyl iodides and benzylic bromides in the presence of CuCN·2LiCl, either in stoichi

Full text of DOI:10.1021/ol0163272

ORGANIC
LETTERS
2
001
Vol. 3, No. 18
871-2873
Copper-Mediated Cross-Coupling of
Functionalized Arylmagnesium Reagents
with Functionalized Alkyl and Benzylic
Halides
2
Wolfgang Dohle, David M. Lindsay, and Paul Knochel*
Ludwig-Maximilians-UniVersit a¨ t M u¨ nchen, Institut f u¨ r Organische Chemie,
Butenandtstrasse 5-13, Haus F, 81377 M u¨ nchen, Germany
knoch@cup.uni-muenchen.de
Received June 22, 2001
ABSTRACT
Functionalized arylmagnesium halides, prepared via an iodine−magnesium exchange, undergo a smooth cross-coupling reaction with
functionalized primary alkyl iodides and benzylic bromides in the presence of CuCN‚2LiCl, either in stoichiometric (with trimethyl phosphite
as an additive) or catalytic quantities.
4
Transition metal catalyzed cross-coupling reactions are an
important method for forming new carbon-carbon bonds.
Recently, we have reported a general preparation of highly
are known, in most cases the reaction proceeds only at
temperatures higher than 0 °C, implying that organomag-
nesium species bearing sensitive functional groups, such as
a cyano group or an ester function, cannot be used. However,
we have discovered that functionalized arylmagnesium
compounds 1, which are obtained from the corresponding
1
functionalized arylmagnesium halides using an iodine-
2
magnesium exchange reaction. Herein, we wish to report a
procedure allowing a Cu(I)-mediated cross-coupling of
5
6
functionalized arylmagnesium bromides of type 1 with
aryl iodides 3 by reaction with i-PrMgBr in THF (-20
°C, 0.5-1 h), undergo a smooth transmetalation with CuCN‚
2LiCl at -20 °C, leading to the corresponding arylcopper
3
various functionalized alkyl iodides of type 2. Although
7
several Cu(I)-catalyzed cross-coupling reactions between
unfunctionalized arylmagnesium reagents and alkyl halides
reagents. Furthermore, by performing this transmetalation
in the presence of trimethyl phosphite, the resulting aryl-
(1) (a) Diederich, F., Stang, P. J., Eds. Metal-catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Tamao, K. ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Pattenden, G., Eds.; Perga-
mon: Oxford, 1991; Vol. 3, Chapter 2.2, p 435.
(4) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b)
Novak, J.; Salemink, C. A. Synthesis 1983, 597. (c) Onuma, K.; Hashimoto,
H. Bull. Chem. Soc. Jpn. 1972, 45, 2582. (d) Normant, J. F.; Villieras, J.;
Scott, F. Tetrahedron Lett. 1977, 18, 3263. (e) Friedman, L.; Shani, A. J.
Am. Chem. Soc. 1974, 96, 7101. (f) Fouquet, G.; Schlosser, M. Angew.
Chem., Int. Ed. Engl. 1974, 13, 82. (g) Derguini-Boumechal, F.; Lin-
strumelle, G. Tetrahedron Lett. 1976, 17, 3225. (h) Leder, J.; Fujioka, H.;
Kishi, Y. Tetrahedron Lett. 1983, 24, 1463.
(2) (a) Rottl a¨ nder, M.; Boymond, L.; B e´ rillon, L.; Lepr eˆ tre, A.; Varchi,
G.; Avolio, S.; Laaziri, H.; Qu e´ guiner, G.; Ricci, A.; Cahiez, G.; Knochel,
P. Chem. Eur. J. 2000, 6, 767. (b) Abarbri, M.; Thibonnet, J.; B e´ rillon, L.;
Dehmel, F.; Rottl a¨ nder, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618. (c)
Delacroix, T.; B e´ rillon, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 2000,
6
5, 8108. (d) Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.;
Knochel, P. Synlett 2001, 477. (e) Kitagawa, K.; Inoue, A.; Shinokubo, H.;
Oshima, K. Angew. Chem., Int. Ed. 2000, 39, 2481. (f) Tr e´ court, F.; Breton,
G.; Bonnet, V.; Mongin, F.; Marsais, F.; Qu e´ guiner, G. Tetrahedron Lett.
(5) The commercially available isopropylmagnesium chloride (either as
a solution in THF or diethyl ether) is equally suitable for the halogen-
magnesium exchange.
(6) Addition of DMPU or NMP as a cosolvent offers no significant
improvement in the rate or yield of the exchange or cross-coupling. When
diethyl ether is used as solvent, addition to any reactive functional group
(e.g., ester) is observed instead of I-Mg exchange.
1
999, 40, 4339.
3) For Cu(I)-catalyzed cross-coupling between functionalized zinc
reagents and alkyl iodides, see: Tucker, C. E.; Knochel, P. J. Org. Chem.
993, 58, 4781.
(
1
1
0.1021/ol0163272 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/04/2001

Table 1. Copper(I)-Mediated Cross-Coupling between Functionalized Arylmagnesium Derivatives 1 and Functionalized Alkyl Iodides
2, Leading to Polyfunctional Arylated Products of Type 4
a
Method A: CuCN‚2LiCl (1 equiv), P(OMe)3 (1.9 equiv), 20 °C, 2-8 h. Method B: CuCN‚2LiCl (0.2 equiv), -5 °C, 20-24 h. b Isolated yield of
analytically pure product.
copper species are stable at 20 °C; in the absence of this
additive, extensive formation of homocoupling products
theless, various arylmagnesium compounds bearing an ester
function have been used successfully (Table 1, entries 1-12).
The alkyl iodide can also bear functionality such as an ester
(Table 1, entries 1, 2, 5, 6, 10, 12, 14, and 15), a nitrile
(Table 1, entries 7 and 8), a chloride (Table 1, entries 4, 6,
(
biphenyls) is observed. Thus, under these developed condi-
8
tions, various primary alkyl iodides undergo the expected
cross-couplings within a few hours at room temperature
(method A; Scheme 1, Table 1). It was observed that the
presence of electron-withdrawing substituents, such as an
ester or amide group, on the aryl moiety considerably reduces
their reactivity toward most electrophiles compared with the
corresponding unfunctionalized arylmagnesium species. None-
Scheme 1
(
7) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
988, 53, 2390.
8) Alkyl tosylates do not undergo the reaction.
1
(
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Org. Lett., Vol. 3, No. 18, 2001

to functionalized benzylic bromides such as 5a-d, affording
the desired benzhydryl derivatives 6a-d in 61-72% yields
Scheme 2
1
2
(Scheme 2).
In summary, we have developed a method allowing the
Cu(I)-catalyzed cross-coupling of functionalized arylmag-
nesium compounds with alkyl iodides. Extensions of these
methods are currently underway in our laboratory.
Acknowledgment. We thank BASF AG (scholarship for
W. D.) and the Alexander von Humboldt foundation (fel-
lowship for D.M.L.) for generous support. We also thank
BASF AG (Ludwigshafen), Chemetall GmbH (Frankfurt),
Aventis (Frankfurt), and DEGUSSA-H U¨ LS AG (Hanau) for
generous gifts of chemicals.
1
2, and 14) or even a keto group (Table 1, entry 9). In all
Supporting Information Available: All analytical data
for compounds of Table 1 and Schemes 1 and 2 and
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
cases, the desired cross-coupling products are obtained in
good to excellent yields (56-89%). Nitrogen functionalities,
such as an amide or a tertiary amine, are also well tolerated,
both in the organomagnesium reagent and in the alkyl iodide
(Table 1, entries 11-15).
OL0163272
We have also found that this cross-coupling can be
mediated by substoichiometric quantities of Cu(I). In
particular, using 20 mol % of CuCN‚2LiCl, good yields (55-
3%) of cross-coupled products are obtained after reaction
at -5 °C for 24 h (Table 1, entries 2, 4, 6, and 8).
Additionally, the use of this low-temperature substoichio-
metric protocol results in greatly decreased quantities of
homocoupling products, thus obviating the need for the
9
(11) In the cross-coupling of magnesium reagent 1a and alkyl iodide 2a
using Cu(OAc)2 (20 mol %), the expected product 4a was formed in only
2
0% yield (compared with 60% with CuCN‚2LiCl). When Cu(OAc) (20
6
mol %) was employed as the catalyst, arylmagnesium species 1a and iodide
2
c were coupled to give 4c in 46% yield (compared with 57% using CuCN‚
2LiCl).
(12) Typical procedure: preparation of methyl 4-(4-chlorobutyl)-
benzoate (4b): A dry 10 mL Schlenk flask was charged with methyl
-iodobenzoate (650 mg, 2.481 mmol, 1 equiv) and the flask evacuated
4
then filled with argon and this process repeated a further two times. Dry
THF (2.5 mL) was added, and the solution was cooled to -25 °C in a dry
ice/2-propanol bath; then isopropylmagnesium bromide (1.6 mL, 1.6 M in
THF, 2.560 mmol, 1.03 equiv) was added slowly over 5 min, keeping the
temperature below -20 °C. On completion of the addition, the reaction
mixture was stirred at -20 °C for 30 min. A solution of CuCN‚2LiCl (0.5
mL, 1 M in THF, 0.500 mmol, 0.2 equiv) was then added, followed by
2
trimethyl phosphite additive. Cu(OAc) has also been used
for the cross-coupling of unfunctionalized aryl Grignard
reagents with unfunctionalized alkyl iodides,10 and this led
2
us to evaluate this copper source. However, Cu(OAc) and
11
Cu(OAc) were both inferior to CuCN‚2LiCl. The catalytic
1-chloro-4-iodobutane (440 mg, 2.014 mmol, 0.8 equiv), and the flask placed
CuCN-mediated cross-coupling procedure can also be applied
in a cryostatically controlled cooling bath at -5 °C. Stirring was continued
for 24 h; then the reaction was quenched by the addition of a 9:1 solution
of saturated NH4Cl(aq) and 25% NH3(aq) (3 mL) and poured into water
(15 mL). The aqueous phase was extracted with CH2Cl2 (3 × 20 mL), and
the combined organic extracts were washed with water (20 mL) and dried
over Na2SO4. The solvents were removed in vacuo, and the residue was
purified by flash chromatography (1:1 pentane/CH2Cl2) to give 288 mg of
a colorless oil (63% yield).
(9) In the absence of any Cu species, the reaction proceeds in very low
yield. For example, the cross-coupling between 1a and 2a gave product 4a
in only 6% yield after 72 h at -5 °C.
(
10) Masada, H.; Yasunishi, Y.; Kikuchi, N. Nippon Kagaku Kaishi 1995,
1
0, 844.
Org. Lett., Vol. 3, No. 18, 2001
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