Copper-catalyzed cross-coupling of functionalized alkyl halides and tosylates with secondary and tertiary alkyl Grignard reagents

Article abstract of DOI:10.1002/anie.201204275

Added value: A copper-based method is highly efficient for the cross-coupling of alkyl electrophiles with secondary and tertiary alkyl Grignard reagents. The method is distinguished by its broad substrate scope and high functional group tolerance. Copyright

Full text of DOI:10.1002/anie.201204275

Angewandte
Chemie
DOI: 10.1002/anie.201204275
Cross-Coupling
Copper-Catalyzed Cross-Coupling of Functionalized Alkyl Halides and
Tosylates with Secondary and Tertiary Alkyl Grignard Reagents**
Peng Ren, Lucas-Alexandre Stern, and Xile Hu*
Efficient alkyl–alkyl cross-coupling reactions had been diffi-
cult to achieve because of the reluctance of alkyl electrophiles
to undergo oxidative addition, and the propensity of metal
alkyl intermediates for b-H elimination.[1] Recent work shows
that these problems can be circumvented by the judicious
choice of catalyst, ligand, and reaction conditions.[2–6] How-
Scheme 1. Cross-coupling of 1 with tBuMgCl (yields determined by GC
analysis).
ever, the coupling of non-activated alkyl electrophiles with
secondary and tertiary alkyl nucleophiles is still challenging
because of the difficulty in achieving transmetalation from
sterically encumbered nucleophiles, and because the isomer-
ization of metal alkyl species is often facile and would lead to
undesired products.[7,8] As a result, these potentially valuable
coupling reactions have not been systematically investigated
and only a few examples have been reported.[3–5,7,9,10] Cahiez
et al. and Kambe et al. showed that non-activated alkyl
halides could be coupled to secondary and tertiary alkyl
Grignard reagents in high yields in the presence of a copper
salt, with or without a diene or alkyne ligand.[4,5,9] Together
these studies provide an important proof of concept. How-
ever, only simple alkyl halides, such as octyl and decyl halides,
were used as the substrates. These reactions demonstrated
limited synthetic utility, because of the high reactivity of alkyl
Grignard reagents towards functional groups. Following our
earlier work on the functional-group-tolerant Kumada cou-
pling of non-activated alkyl halides,[6,11] we decided to study
the copper-catalyzed coupling reactions of functionalized
alkyl electrophiles.[12] Herein, we describe a copper-based
method that is efficient for the coupling of secondary and
tertiary Grignard reagents with alkyl halides and tosylates
containing important and sensitive functional groups. The
high activity, broad substrate scope, and high functional-
group tolerance of the copper catalysis demonstrate its value
in preparative and synthetic useful reactions.
over 90% for reactions in THF, toluene, and ether, but lower
for reactions in N,N’-dimethylformamide (DMF) and
N-methylpyrrolidone (NMP).[13]
A catalyst loading of
0.5 mol% was sufficient to give a yield of 94%. The coupling
reaction could be catalyzed by a soluble copper(I) complex,
such as [(MeN2N)Cu(PPh3)],[14] [{Cu(PPh3)Cl}4], and [Cu-
(Phen)(PPh3)2]NO3, to give the product in a similar yield.[13]
CuCl2 and CuCl2·2H2O were also suitable precatalysts.[13]
Additional information on the influence of solvent, temper-
ature, (pre)catalyst, and the (pre)catalyst loading can be
found in Table S1 in the Supporting Information. It appears
that Cu-catalyzed cross-coupling of 1 with tBuMgCl is highly
efficient under mild reaction conditions, such as a small
amount of CuCl, room temperature, in THF, and without
additive.
Having demonstrated that copper catalysis could be
applied for the coupling of a functionalized alkyl halide and
a tertiary alkyl Grignard reagent, we decided to explore the
scope of this catalysis. For the convenience of experimental
manipulation, the reactions were carried out in THF, at room
temperature, and with 3 mol% of CuCl as catalyst. A large
number of functionalized alkyl electrophiles could be coupled
to secondary and tertiary alkyl Grignard reagents to give the
products in high yields upon isolation (Table 1). The coupling
was generally completed within 1 hour.
Ester and amide groups were readily tolerated (Table 1,
entries 1–4). A substrate containing a carboxylic acid group
was successfully coupled when more than two equivalents of
a Grignard reagent was used (Table 1, entry 5). Presumably
one equivalent of the Grignard reagent first deprotonated the
carboxylic acid group to form a carboxylate group, which did
not interfere with the cross-coupling. Likewise, a substrate
containing an alcohol group was coupled in a high yield under
similar reaction conditions (Table 1, entry 6). As expected,
the more robust ether and thioether groups were tolerated
(Table 1, entries 7–10). Nitrile-containing substrates were
coupled as well (Table 1, entries 11 and 12). An acetal
group was tolerated, which is notable as upon transformation
of this group useful aldehyde-containing compounds can be
obtained (Table 1, entry 13). Gratifyingly, substrates contain-
ing important heterocyclic groups, such as indole, furan,
The coupling of ester-containing alkyl bromide 1 with
tBuMgCl was used as the test reaction (Scheme 1). In the
absence of a catalyst, no coupling product was formed. In the
presence of a simple copper salt, such as CuCl, the coupling
proceeded smoothly at room temperature. The yields were
[*] P. Ren, L. A. Stern, Prof. Dr. X. L. Hu
Laboratory of Inorganic Synthesis and Catalysis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
ISIC-LSCI, BCH 3305, Lausanne 1015 (Switzerland)
E-mail: xile.hu@epfl.ch
Homepage: http://lsci.epfl.ch
[**] This work is supported by the Swiss National Science Foundation
(project number 20021_126498).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204275.
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Table 1: Scope of Cu-catalyzed alkyl–alkyl coupling.[a]
Yield[b]
[%]
Entry
Alkyl X
Product
Yield[b]
[%]
À
À
Entry
Alkyl X
Product
1
2
3
4
82
77
75
73
15
16
17
18
84
84
83
87
5
6
76[c]
91[c]
19
20
74
75[d]
7
81
21
93
8
82
90
80
22
23
24
85
76
94
9
10
11
12
82
75
25
26
90
93
13
14
86
82
27
78
[a] See the Supporting Information for experimental details. [b] Yield of the isolated product. [c] 2.2 equiv of Grignard reagent was used. [d] 4 equiv of
NMP was used as additive.
piperidine, thiophene, and pyridine groups, were coupled in
high yields (Table 1, entries 14–19). The coupling of ketone-
containing substrates was more challenging. Under the
standard reaction conditions, the yields were about 30–
50%.[13] However, it was found that NMP promoted the
coupling of ketone-containing substrates. For example, with
four equivalents of NMP as additive, the yield of a substrate
containing an aliphatic ketone moiety was increased from
51% to 75% (Table 1, entry 20). The limit of the group
tolerance of the coupling method was also probed, and these
investigations indicated that aldehyde, nitro, and succinimide
groups were not compatible with this method (see the
Supporting Information, Table S2).[13]
Not only alkyl iodides and bromides, but also alkyl
tosylates could be coupled (Table 1, entries 18 and 19).
Because tosylates are often easily prepared from the corre-
sponding alcohols, this success significantly increases the
synthetic utility of the present coupling method. Alkyl
chlorides could not be coupled. Thus, for a molecule contain-
ing both a bromide and a chloride, selective coupling of the
alkyl bromide was achieved (Table 1, entry 21). Likewise,
because secondary alkyl halides could not be coupled,
selective coupling of a primary alkyl bromide was accom-
plished for a molecule that also contained a secondary alkyl
bromide (Table 1, entries 22–23). The coupling of an alkyl
electrophile is selective in the presence of an aryl bromide
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moiety, which is on the same molecule (Table 1, entry 24).
This feature could be useful for the sequential and selective
functionalization of alkyl and aryl electrophiles. The nucle-
ophilic coupling partners are not limited to iPrMgCl or
tBuMgCl. Various acyclic and cyclic Grignard reagents could
be used. Although the present work focuses on the coupling
of secondary and tertiary alkyl Grignard regents, the same
method can be used for the coupling of primary alkyl
Grignard regents with high yields (Table 1, entries 25–27).
We attempted to develop enantioselective coupling reac-
tions of a primary alkyl halide with a secondary alkyl
Grignard reagent using a chiral copper catalyst. Two test
reactions were investigated [Scheme 2, Eq. (2) and (3)]. Five
chiral ligands commonly used for copper catalysis were
coupling of cyclopropylmethyl bromide with tBuMgCl
yielded only neopentylcyclopropane, but not 5,5-dimethyl-
hex-1-ene [Scheme 3, Eq. (4)]. The coupling of 6-bromo-1-
hexene with tBuMgCl yielded only 7,7-dimethyloct-1-ene, but
Scheme 3. Cross-coupling reactions to probe the reaction mechanism
(yields determined by GC analysis).
not neopentylcyclopentane [Scheme 3, Eq. (5)]. These results
indicate that the activation of alkyl electrophile does not
occur through a radical mechanism. Given that alkyl tosylates
can be coupled in high yields, an SN2 mechanism is more
likely; this finding is consistent with the work of Kambe et al.
on similar reactions.[4]
In conclusion, we have developed a highly efficient
method for the cross-coupling of non-activated and function-
alized alkyl halides and tosylates with secondary and tertiary
alkyl Grignard reagents.[15] The copper-based method is
remarkably practical and general. The wide scope, and
especially the tolerance to a large number of important yet
sensitive functional groups, make this method attractive for
the streamlined synthesis of functional molecules.[16]
Received: June 1, 2012
Published online: && &&, &&&&
Keywords: alkylation · copper · cross-coupling ·
.
Grignard reaction · homogeneous catalysis
Scheme 2. Cross-coupling reactions employing chiral ligands (yields
determined by GC analysis).
[1] a) M. R. Netherton, G. C. Fu, Adv. Synth. Catal. 2004, 346, 1525 –
1532; b) A. C. Frisch, M. Beller, Angew. Chem. 2005, 117, 680 –
695; Angew. Chem. Int. Ed. 2005, 44, 674 – 688; c) J. Terao, N.
Kambe, Acc. Chem. Res. 2008, 41, 1545 – 1554; d) N. Kambe, T.
Iwasaki, J. Terao, Chem. Soc. Rev. 2011, 40, 4937 – 4947; e) A.
Rudolph, M. Lautens, Angew. Chem. 2009, 121, 2694 – 2708;
Angew. Chem. Int. Ed. 2009, 48, 2656 – 2670; f) X. L. Hu, Chem.
Sci. 2011, 2, 1867 – 1886.
[2] a) A. Devasagayaraj, T. Studemann, P. Knochel, Angew. Chem.
1995, 107, 2952 – 2954; Angew. Chem. Int. Ed. Engl. 1995, 34,
2723 – 2725; b) R. Giovannini, T. Studemann, G. Dussin, P.
Knochel, Angew. Chem. 1998, 110, 2512 – 2515; Angew. Chem.
Int. Ed. 1998, 37, 2387 – 2390; c) G. Cahiez, C. Chaboche, C.
Duplais, A. Giulliani, A. Moyeux, Adv. Synth. Catal. 2008, 350,
1484 – 1488; d) C. Valente, S. Baglione, D. Candito, C. J. OꢀBrien,
M. G. Organ, Chem. Commun. 2008, 735 – 737; e) M. R. Nether-
ton, C. Y. Dai, K. Neuschutz, G. C. Fu, J. Am. Chem. Soc. 2001,
123, 10099 – 10100; f) J. R. Zhou, G. C. Fu, J. Am. Chem. Soc.
2003, 125, 14726 – 14727; g) B. Saito, G. C. Fu, J. Am. Chem. Soc.
2007, 129, 9602 – 9603; h) B. Saito, G. C. Fu, J. Am. Chem. Soc.
2008, 130, 6694 – 6695; i) Z. Lu, G. C. Fu, Angew. Chem. 2010,
122, 6826 – 6828; Angew. Chem. Int. Ed. 2010, 49, 6676 – 6678;
j) S. L. Zultanski, G. C. Fu, J. Am. Chem. Soc. 2011, 133, 15362 –
applied in conjunction with a soluble copper salt—Cu(OTf)2.
As shown in Scheme 2, the yields of the coupling reactions
were high regardless of the ligands employed. However, none
of the five ligands gave rise to enantioselectivity, even at
À608C. It is possible that the copper complexes containing
these ligands cannot differentiate the two substituents of the
secondary alkyl Grignard reagents. It is also possible that the
active catalyst is an organocopper species without a chiral
ligand attached. Further work is warranted to probe the origin
of the lack of enantioselectivity, and to eventually develop an
enantioselective coupling method.
A few experiments were conducted to probe the mech-
anism of the coupling reactions. The Cu-catalyzed coupling of
1 with tBuMgCl had the same yields in the absence and
presence of an excess (100 equiv) amount of Hg.[13] This result
suggests that a homogeneous copper species rather than
heterogeneous copper particles is the active catalyst. The
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.
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15364; k) A. Wilsily, F. Tramutola, N. A. Owston, G. C. Fu, J.
Am. Chem. Soc. 2012, 134, 5794 – 5797; l) P. Ren, O. Vechorkin,
K. vonAllmen, R. Scopelliti, X. L. Hu, J. Am. Chem. Soc. 2011,
133, 7084 – 7095; m) C. T. Yang, Z. Q. Zhang, Y. C. Liu, L. Liu,
Angew. Chem. 2011, 123, 3990 – 3993; Angew. Chem. Int. Ed.
2011, 50, 3904 – 3907; n) S. P. Singh, J. Terao, N. Kambe,
Tetrahedron Lett. 2009, 50, 5644 – 5646.
T. Thaler, K. Takatsu, C. Zhang, H. Zipse, B. F. Straub, P. Mayer,
P. Knochel, J. Am. Chem. Soc. 2011, 133, 4774 – 4777.
[9] a) G. Cahiez, O. Gager, J. Buendia, Synlett 2010, 299 – 303; b) J.
Terao, A. Ikumi, H. Kuniyasu, N. Kambe, J. Am. Chem. Soc.
2003, 125, 5646 – 5647.
[10] a) D. H. Burns, J. D. Miller, H. K. Chan, M. O. Delaney, J. Am.
Chem. Soc. 1997, 119, 2125 – 2133; b) J. G. Donkervoort, J. L.
Vicario, J. Jastrzebski, R. A. Gossage, G. Cahiez, G. van Koten, J.
Organomet. Chem. 1998, 558, 61 – 69; c) J. Breitenfeld, O.
Vechorkin, C. Corminboeuf, R. Scopelliti, X. L. Hu, Organo-
metallics 2010, 29, 3686 – 3689.
[3] a) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu, N. Kambe, J.
Am. Chem. Soc. 2002, 124, 4222 – 4223; b) J. Terao, H. Todo, H.
Watanabe, A. Ikumi, N. Kambe, Angew. Chem. 2004, 116, 6306 –
6308; Angew. Chem. Int. Ed. 2004, 43, 6180 – 6182.
[4] J. Terao, H. Todo, S. A. Begum, H. Kuniyasu, N. Kambe, Angew.
Chem. 2007, 119, 2132 – 2135; Angew. Chem. Int. Ed. 2007, 46,
2086 – 2089.
[5] G. Cahiez, C. Chaboche, M. Jezequel, Tetrahedron 2000, 56,
2733 – 2737.
[6] O. Vechorkin, X. L. Hu, Angew. Chem. 2009, 121, 2981 – 2984;
Angew. Chem. Int. Ed. 2009, 48, 2937 – 2940.
[7] R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417 –
1492.
[11] a) O. Vechorkin, V. Proust, X. L. Hu, J. Am. Chem. Soc. 2009,
131, 9756 – 9766; b) O. Vechorkin, A. Godinat, R. Scopelliti,
X. L. Hu, Angew. Chem. 2011, 123, 11981 – 11985; Angew. Chem.
Int. Ed. 2011, 50, 11777 – 11781.
[12] After the submission of this paper, Liu et al. published an
efficient Cu-catalyzed cross-coupling of secondary alkyl electro-
philes with secondary alkyl Grignard reagents, see: C. T Yang,
Z. Q. Zhang, J. Liang, J. H. Liu, X. Y. Lu, H. H. Chen, L. Liu, J.
Am Chem. Soc. 2012, 134, 11124 – 11127.
[8] For representative examples of cross-coupling reactions of
secondary and tertiary alkyl nucleophiles with aryl and alkynyl
electrophiles, see: a) L. Hintermann, L. Xiao, A. Labonne,
Angew. Chem. 2008, 120, 8370 – 8374; Angew. Chem. Int. Ed.
2008, 47, 8246 – 8250; b) S. W. Smith, G. C. Fu, Angew. Chem.
2008, 120, 9474 – 9476; Angew. Chem. Int. Ed. 2008, 47, 9334 –
9336; c) C. Han, S. L. Buchwald, J. Am. Chem. Soc. 2009, 131,
7532 – 7533; d) D. L. Sandrock, L. Jean-Gerard, C. Y. Chen, S. D.
Dreher, G. A. Molander, J. Am. Chem. Soc. 2010, 132, 17108 –
17110; e) A. Joshi-Pangu, C. Y. Wang, M. R. Biscoe, J. Am.
Chem. Soc. 2011, 133, 8478 – 8481; f) C. Lohre, T. Droge, C. Y.
Wang, F. Glorius, Chem. Eur. J. 2011, 17, 6052 – 6055; g) S. Seel,
[13] See the Supporting Information.
[14] P. Ren, I. Salihu, R. Scopelliti, X. L. Hu, Org. Lett. 2012, 14,
1748 – 1751.
[15] Liu et al. reported a similar method for the borylation of primary
alkyl electrophiles, see: C. T. Yang, Z. Q. Zhang, H. Tajuddin,
C. C. Wu, J. Liang, J. H. Liu, Y. Fu, M. Czyzewska, P. G. Steel,
T. B. Marder, L. Liu, Angew. Chem. 2012, 124, 543 – 547; Angew.
Chem. Int. Ed. 2012, 51, 528 – 532.
[16] For an application of Cu-catalyzed alkyl – alkyl coupling in total
synthesis, see: J. Dufour, L. Neuville, J. P. Zhu, Chem. Eur. J.
2010, 16, 10523 – 10534.
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Cross-Coupling
P. Ren, L. A. Stern,
X. L. Hu*
&&&& — &&&&
Copper-Catalyzed Cross-Coupling of
Functionalized Alkyl Halides and
Tosylates with Secondary and Tertiary
Alkyl Grignard Reagents
Added value: A copper-based method is
highly efficient for the cross-coupling of
alkyl electrophiles with secondary and
tertiary alkyl Grignard reagents. The
method is distinguished by its broad
substrate scope and high functional
group tolerance.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!