Cross-coupling of non-activated chloroalkanes with aryl grignard reagents in the presence of iron/N-heterocyclic carbene catalysts

Article abstract of DOI:10.1021/ol2031729

An efficient and high-yielding cross-coupling reaction of various primary, secondary, and tertiary alkyl chlorides with aryl Grignard reagents was achieved by using catalytic amounts of N-heterocyclic carbene ligands and iron salts. This reaction is a simple and efficient arylation method having applicability to a wide range of industrially abundant chloroalkanes, including polychloroalkanes, which are challenging substrates under conventional cross-coupling conditions.

Full text of DOI:10.1021/ol2031729

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1066–1069
Cross-Coupling of Non-activated
Chloroalkanes with Aryl Grignard
Reagents in the Presence of Iron/
N-Heterocyclic Carbene Catalysts
Sujit K. Ghorai,† Masayoshi Jin,†,‡ Takuji Hatakeyama,† and Masaharu Nakamura*,†
International Research Center for Elements Science (IRCELS), Institute for Chemical
Research, Kyoto University, Uji, Kyoto 611-0011, Japan, and Process Technology
Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo Co., Ltd.,
1-12-1, Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan
masaharu@scl.kyoto-u.ac.jp
Received December 23, 2011
ABSTRACT
An efficient and high-yielding cross-coupling reaction of various primary, secondary, and tertiary alkyl chlorides with aryl Grignard reagents was
achieved by using catalytic amounts of N-heterocyclic carbene ligands and iron salts. This reaction is a simple and efficient arylation method
having applicability to a wide range of industrially abundant chloroalkanes, including polychloroalkanes, which are challenging substrates under
conventional cross-coupling conditions.
Aryl and alkyl chlorides are abundant industrial feed-
stocks with annual global production on the order of
millions of tons.1 Significant progress has been made in
the development of synthetically valuable cross-coupling
reactions with aryl chlorides. These transformations are
extremely important for preparing aromatic compounds
in academic and industrial settings.2 However, alkyl chlo-
rides remain challenging substrates in cross-coupling reac-
tions, and they are not commonly used as electrophilic
coupling partners3 because the kinetic and thermody-
namic stability of non-activated sp3 carbonÀchlorine bonds
toward transition-metal catalysts hampers efficient bond
reorganizations between the coupling partners.4 Recently,
considerable effort has been devoted to achieving useful
cross-coupling reactions with non-activated alkyl chlo-
rides. Several catalysts have been reported,5 but they are
mostly limited to primary alkyl electrophiles, and only
one method is applicable to secondary alkyl chlorides.5f
(4) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. Rev. 2000, 100,
3187–3204.
(5) Examples of cross-coupling of alkyl chlorides under transtion
metal catalysis other than iron. [Pd]: (a) Frisch, A. C.; Shaikh, N.; Zapf,
A.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 4056–4059. (b) Frisch,
A. C.; Rataboul, F.; Zapf, A.; Beller, M. J. Organomet. Chem. 2003, 683,
403–409. (c) Ackermann, L.; Kapdi, A.; Schulzke, C. Org. Lett. 2010, 12,
2298–2301. [Ni]: (d) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222–4223. (e) Vechorkin, O.;
Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 9756–9766. (f)
† Kyoto University.
‡ Daiichi Sankyo Co., Ltd.
ꢀ
Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360–5361.
(1) Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry; VCH:
New York, 2003.
[Co]: (g) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006,
128, 1886–1889. [Cu]: (h) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.;
Kambe, N. Angew. Chem., Int. Ed. 2007, 46, 2086–2089.
(2) (a) Grushin, V. V.; Alper, H. Top. Organomet. Chem. 1999, 3,
193–226. (b) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–1564.
(3) (a) Review:Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004,
346, 1525–1532. (b) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed.
2005, 44, 674–688. (c) Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006,
79, 663–672. (d) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009,
48, 2656–2670.
(6) Reviews: (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev.
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2004, 104, 6217–6254. (b) Furstner, A.; Martin, R. Chem. Lett. 2005, 34,
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624–629. (c) Czaplik, W. M.; Mayer, M.; Cvengros, J.; von Wangelin,
A. J. ChemSusChem 2009, 2, 396–417. (d) Plietker, B. Synlett 2010,
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r
10.1021/ol2031729
Published on Web 01/30/2012
2012 American Chemical Society

Besides these other metal catalysts, iron catalysts have
recently proved to be remarkably effective for coupling
reactions of non-activated alkyl halides.6À8 Nonetheless,
these iron-catalyzed reactions are mainly applied to alkyl
bromides and iodides. Alkyl chlorides, especially primary
and tertiary ones, remain poor substrates with iron cata-
lysts. This is partly, but critically, owing to the reaction
mechanism of the iron-catalyzed cross-couplings of alkyl
halides, which are most likely radical-mediated.9
Herein, we report a versatile metal-catalyzed cross-
coupling method applicable to a variety of alkyl chlorides
with aryl Grignard reagents. The reactions are easily
carried out with catalytic amounts of FeCl3 and N-hetero-
cyclic carbene (NHC) ligands10,11 by the slow addition
technique developed by us previously8a,m,n (Figure 1).
We began by studying coupling reactions between
1-chlorodecane and phenylmagnesium bromide in the
presence of an iron salt12 and an NHC ligand. Table 1
summarizes the outcomes of the reactions with various
ligands and conditions.13 Use oftheIPrligandand the slow
addition technique were the keys to obtaining the cross-
coupling product in high yield. In the absence of a ligand,
the desired coupling product 2 was obtained in 20% yield
Figure 1. Coupling reaction between alkyl chlorides and aryl
Grignard reagents in the presence of FeCl3 and NHC ligands.
along with significant amounts of alkene and alkane
byproducts; thus, the product selectivity was quite low at
32% (Table 1, entry 1). While the widely used IMes did not
work well (Table 1, entry 2), bulkier NHCs such as ItBu,
IAd, and IPr improved the product selectivity to as high as
80% and caused efficient conversion of 1 (Table 1, entries
(7) Seminal early studies on Fe-catalyzed cross-coupling reaction: (a)
Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487–1489. (b)
Molander, G. A.; Rahn, B. J.; Shubert, D. C.; Bonde, S. E. Tetrahedron
Lett. 1983, 24, 5449–5452. (c) Yanagisawa, A.; Nomura, N.; Yamamoto,
H. Tetrahedron 1994, 50, 6017–6028. (d) Reddy, C. K.; Knochel, P.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1700–1701. (e) Cahiez, G.;
3À5). A superior result was obtained when IPr HCl was
€
Avedissian, H. Synthesis 1998, 1199–1205. (f) Furstner, A.; Leitner,
3
ꢀ
A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856–13863.
used as the NHC precursor (Table 1, entry 6). Further-
more, we found that without the slow addition technique,
the reaction provided 1-decene as the major product in
47% yield and gave the desired product with only 25%
selectivity (Table 1, entry 7). We tried to improve the
reaction further with the NHC ligand SIPr, but it proved
to be less effective than its unsaturated congener IPr
(Table 1, entry 8). On the basis of these results, we selected
(8) Selected papers. Fe-catalyzed cross-coupling reactions of alkyl
halides: (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686–3687. (b) Nagano, T.; Hayashi, T. Org. Lett.
€
2004, 6, 1297–1299. (c) Martin, R.; Furstner, A. Angew. Chem., Int. Ed.
2004, 43, 3955–3957. (d) Bedford, R. B.; Bruce, D. W.; Frost, R. M.;
Goodby, J. W.; Hird, M. Chem. Commun. 2004, 2822–2823. (e) Bedford,
R. B.; Betham, M.; Bruce, D. W.; Danopoulos, A. A.; Frost, R. M.;
Hird, M. J. Org. Chem. 2006, 71, 1104–1110. (f) Dongol, K. G.; Koh, H.;
Sau, M.; Chai, C. L. L. Adv. Synth. Catal. 2007, 349, 1015–1018. (g)
Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew. Chem., Int. Ed.
€
2007, 46, 4364–4366. (h) Furstner, A.; Martin, R.; Krause, H.; Seidel, G.;
IPr HCl with the slow addition technique as the condi-
tions for the rest of this study.
3
Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773–8787.
(i) Hatakeyama, T.; Nakagawa, N.; Nakamura, M. Org. Lett. 2009, 11,
4496–4499. (j) Kawamura, S.; Ishizuka, K.; Takaya, H.; Nakamura, M
Chem. Commun. 2010, 46, 6054–6056. (k) Hatakeyama, T.; Hashimoto,
T.; Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono,
T.; Nakamura, M. J. Am. Chem. Soc. 2010, 132, 10674–10676. (l) Jin,
M.; Nakamura, M. Chem. Lett. 2011, 40, 1012–1014. (m) Hatakeyama,
T.; Fujiwara, Y.; Okada, Y.; Itoh, T.; Hashimoto, T.; Kawamura, S.;
Ogata, K.; Takaya, H.; Nakamura, M. Chem. Lett. 2011, 40, 1030–1032.
(n) Hatakeyama, T.; Okada, Y.; Yoshimoto, Y.; Nakamura, M. Angew.
Chem., Int. Ed. 2011, 50, 10973–10976.
(9) Noda, D.; Sunada, Y.; Hatakeyama, T.; Nakamura, M.; Nagashima,
H. J. Am. Chem. Soc. 2009, 131, 6078–6079.
(10) Cazin, C. S. J., Ed.; N-Heterocyclic Carbenes in Transition Metal
Catalysis and Organocatalysis; Springer: New York, 2010; Vol. 32, Cata-
lysis by Metal Complexes.
Table 2 presentsthe scope of the couplingreaction with a
variety of alkyl chlorides. Primary alkyl chlorides were
coupled with various aryl Grignard reagents to give the
corresponding products in good to excellent yields.
Phenyland para-substitutedarylGrignard reagentsgave
the coupling products in 83À92% yields (Table 2, entries
1À6). Excellent yields were obtained with the moderately
sterically demanding 2-tolyl- and 1-naphthylmagnesium
bromides (Table 2, entries 7, 8, and 13). Only the bulky
mesityl Grignard failed to yield product (Table 2, entry 9).
Sterics appear to hinder the reaction in cases of extreme
crowding. As in entries 10 and 11 (Table 2), the steric
hindrance at β-position to the reaction site did not much
affect the chemical yield, suggesting that the substation
proceeded via a non-SN2 mechanism.
(11) Favorable effects of NHC ligands in iron-catalyzed cross-
couplings of haloalkanes were reported previously: (a) Bica, K.; Gaertner,
€
P. Org. Lett. 2006, 8, 733–735. (b) Plietker, B.; Dieskau, A.; Mows, K.;
Jatsch, A. Angew. Chem., Int. Ed. 2007, 47, 198–201. See also ref 8e.
(12) To avoid the risk of trace metal contamination, we used pure
anhydrous FeCl3 (99.99% from Aldrich), even though other iron salts,
such as Fe(acac)3 and FeCl2, were found to be effective. Details are given
in the Supporting Information. For the trace metal contamination in
iron-catalyzed cross-couplings, see: (a) Buchwald, S. L.; Bolm, C. Angew.
Chem., Int. Ed. 2009, 48, 5586–5588. (b) Bedford, R. B.; Nakamura, M.;
Gower, N. J.; Haddow, M. F.; Hall, M. A.; Huwe, M.; Hashimoto, T.;
Okopie, R. A. Tetrahedron Lett. 2009, 50, 6110–6111.
Entries 14À24 (Table 2) show that the cross-coupling of
secondary alkyl chlorides proceeded smoothly to give the
corresponding coupling products in excellent yields. The
only poor reaction was again with the mesityl nucleophile.
Otherwise, steric or electronic factors did not significantly
(13) Other NHC or phosphine ligands as well as an excess amount of
TMEDA were not effective. See the Supporting Information for details.
Org. Lett., Vol. 14, No. 4, 2012
1067

Table 1. Iron-Catalyzed Cross-Coupling Reaction of 1-Chloro-
decane with Phenylmagnesium Bromide
Table 2. Cross-Coupling Reaction of Various Alkyl Chlorides
with Arylmagnesium Halidesa
product yield (%)b
RSMd
entrya ligand
2
3
4
coupling selectivity (%)c
1
1
2
3
4
5
6
7
8
none
20
18
18
6
24
31
11
14
16
8
32
39
82
81
80
85
25
68
31
0
IMes 31
ItBu
IAd
78
72
78
85
23
59
0
3
0
IPr
3
0
IPre
IPre,f
SIPr
7
0
47
7
21
21
0
0
a Reactions were carried out on a 0.5À1.0 mmol scale under the
conditions described in Figure 1. b Yields were determined by GC
analysis using undecane as an internal standard. c % Selectivity of the
coupling product 2 in all the products. d Recovery of starting material.
e NHC free carbene was prepared in situ by mixing equimolar amounts
of NHC HCl and PhMgBr at 0 °C for 5 min. f PhMgBr was added at
3
0 °C in a single aliquot and heated to 40 °C for 1.5 h.
affect the selectivity, probably because a secondary car-
bonÀchlorine bond is more susceptible to homolytic cleav-
age than a primary one. Phenylmagnesium chloride also gave
the desired products in good yields, showing that the bromide
ion derived from the Grignard reagent had no role in the
coupling reactions (Table 2, entries 2 and 15). While reactions
with tertiary alkyl chlorides were somewhat inconsistent,
cross-couplings with adamantyl chloride gave the correspond-
ing products in high yields (Table 2, entries 26À28). Again, the
electronic effects of the aryl substituents were negligible.
Unfortunately, tert-butyl chloride gave the cross-coupling
product in only 12% yield, although the chloride substrate
was consumed smoothly (Table 2, entry 25).
The present method could be further applied to poly-
chlorinated alkanes such as 1,3-dihalogenated compounds
(Table 2, entries 29À31). In the presence of iron catalyst
and Grignard reagents, these polychlorinated alkanes
usually provide elimination and cyclization products.14 It
is interesting to note that the coupling reaction of 2,4,6-
trichloroheptane, a model compound of polyvinyl chloride
(PVC),15 gave the triply arylated product in good yield,
suggesting a role of this reaction in polymer functionalization.
To gain mechanistic insight into the cross-coupling
reaction, we conducted a stereochemical study using
diastereomerically pure R,β-[D2]-β-adamantylethyl chlo-
ride 55h with PhMgBr under the standard conditions
a The reactions were carried out on a 1À3 mmol scale for monochloro
compounds, 0.5 mmol scale for dichloro compounds, and 0.33 mmol
scale for trichloro compounds under slow addition conditions. b 1.5 equiv
of Grignard reagent was used per atom of chlorine present in the molecule
unless otherwise noted. c Isolated yield. d 2.0 equiv of Grignard was used
per atom of chlorine present in the molecule. e PhMgCl was used instead
of PhMgBr. f GC yield with undecane as an internal standard. g ca. 99%
of recovery of the starting material. h NMR yield determined with
1,1,2,2-tetrachloroethane as an internal standard. i 1.6 equiv of Grignard
reagent was used.
(14) (a) Kharasch, M. S.; Weiner, M.; Nudenberg, W.; Bhattacharya,
A.; Wang, T.-I.; Yang, N. C. J. Am. Chem. Soc. 1962, 83, 3232–3234. (b)
Rollick, K. L.; Nugent, W. A.; Kochi, J. K. J. Organomet. Chem. 1982,
225, 279–299.
(15) Schilling, F. C.; Schilling, M. L. Macromolecules 1988, 21, 1530–
1532.
(Scheme 1). 1H NMR analysis revealed that the reaction
center completely epimerized to give a 1:1 mixture of
diastereomers, suggesting a radical intermediate. This
1068
Org. Lett., Vol. 14, No. 4, 2012

was in stark contrast with the Cu-catalyzed cross-coupling
reactions between alkyl chlorides and Grignard reagents
reported by Kambe and Terao, where the reactions pro-
ceeded with almost complete inversion of the stereochem-
istry at the reaction center, inferring an SN2 mechanism.5h
Scheme 2. Plausible Mechanism for the Iron-Catalyzed Cross-
Coupling Reaction
Scheme 1. Cross-Coupling Reaction of Diastereomerically Pure
Alkyl Chloride to Study the Mechanism
On the basis of these observations and results reported
previously by us and the other researchers, a plausible
mechanism is postulated in Scheme 2. Initial reduction of
FeCl3 with an aryl Grignard reagent gives an iron(II) inter-
mediate.8h We actually observed an induction period for the
coupling reaction during the addition of ca. 5 equiv of
ArMgBr to FeCl3, in which 3 equiv were used for the partial
reduction of FeCl3 to generate the biaryl and the other
2 equiv were used to generate two NHC ligands from the
corresponding imidazolium salt.16 As shown in Scheme 2, the
iron(II) intermediate can be best described as a neutral
diaryliron possessing two NHC ligands,17 such as A. While
Amay or may not be a reactive intermediate, we are currently
assuming that a ferrate(II) intermediate B is the catalytically
active species because of its higher reducing potential than the
neutral species.18 Thus, homolytic cleavage of the sp3 car-
bonÀchlorine bond and recombination of the resulting
elusive radical with an aryl ligand occur in a solvent cage to
give the coupling product while regenerating A.
effective for arylating polychloroalkanes that would form
byproducts under other conditions. This direct arylation
uses catalytic amounts of IPr and FeCl3 with our slow
addition method. Instead of requiring more costly bromo-
and iodoalkanes, our techniqueworks withlesscostlyalkyl
chlorides, extending the utility of the catalytic cross-cou-
pling of non-activated alkyl halides.
Acknowledgment. This research was supported in part
by a grant from the Japan Society for the Promotion of
Science (JSPS) through the “Funding Program for Next
Generation World-Leading Researchers (NEXT Program),”
initiated by the Council for Science and Technology Policy
(CRTP). Financial support from Daiichi Sankyo Co., Ltd.,
is also gratefully acknowledged. S.K.G. thanks the Japan
Society for the Promotion of Science (JSPS) for a postdoc-
toral fellowship. We appreciate experimental support pro-
vided by Mr. T. Kawabata (Kyoto University), Dr. S. Yasuda
and Dr. C. Liang (The University of Tokyo), and helpful
suggestions from Prof. E. Nakamura (The University of
Tokyo). The deuterium-decoupled 1H NMR spectra were
taken by Dr. K. Kushida (Varian Technologies, Japan,
Co., Ltd.), and we gratefully acknowledge the measurement.
In summary, we have developed an efficient iron-cata-
lyzed cross-coupling reaction and demonstrated its scope
with various primary, secondary, and tertiary alkyl chlo-
rides and aryl Grignard reagents. The method was also
(16) See the Supporting Information for details of the time course
study.
(17) Xiang, L.; Xiao, J.; Deng, L. Organometallics 2011, 30, 2018–
2025.
Supporting Information Available. Detailed experimen-
tal procedures, characterization, and physical data for the
products (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) Uchiyama, M.; Matsumoto, Y.; Nakamura, S.; Ohwada, T.;
Kobayashi, N.; Yamashita, N.; Matsumiya, A.; Sakamoto, T. J. Am.
Chem. Soc. 2004, 126, 8755–8759. See also ref 8h. Bedford proposed an
SET/radical mechanism for cross-coupling of alkyl halides with aryl
Grignard reagents in the presence of monodentate phosphine ligands as
well as NHC ligands: see ref 8e.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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