Copper-catalyzed coupling reaction of unactivated secondary alkyl iodides with alkyl Grignard reagents in the presence of 1,3-butadiene as an effective additive

Article abstract of DOI:10.1039/c2cc34847k

Cu-catalyzed cross-coupling of unactivated secondary alkyl iodides with alkyl Grignard reagents in the presence of 1,3-butadiene as a ligand precursor was developed. The use of 1,3-butadiene resulted in improved yields of alkyl-alkyl products with improved selectivities.

Full text of DOI:10.1039/c2cc34847k

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COMMUNICATION
Copper-catalyzed coupling reaction of unactivated secondary alkyl
iodides with alkyl Grignard reagents in the presence of 1,3-butadiene as
an effective additivew
Ruwei Shen,a Takanori Iwasaki,a Jun Teraob and Nobuaki Kambe*a
Received 7th July 2012, Accepted 25th July 2012
DOI: 10.1039/c2cc34847k
Cu-catalyzed cross-coupling of unactivated secondary alkyl iodides
with alkyl Grignard reagents in the presence of 1,3-butadiene as a
ligand precursor was developed. The use of 1,3-butadiene resulted in
improved yields of alkyl–alkyl products with improved selectivities.
1,3-butadiene,11c tetraenes11e or an alkyne.12d These reactions
proceed efficiently for a variety of primary alkyl halides, even
alkyl chlorides and fluorides,12 providing a convenient tool for
the construction of carbon–carbon bonds. However, unactivated
secondary alkyl halides continue to be impregnable targets for
coupling by these methods.
Transition-metal catalyzed cross-coupling reactions of organic
halides with organometallic reagents are some of the most
important C–C bond-forming reactions in organic synthesis.1
Among the most challenging of these reactions is the use of
unactivated alkyl halides as coupling electrophiles to form
alkyl–alkyl coupled products, due in part to the fact that
alkylmetal intermediates generated in situ in the catalytic cycle
can undergo b-hydride elimination, as well as participate in other
undesired reactions.2 In the past decade, many new protocols have
been developed to overcome these inherent difficulties in sp3–sp3
cross-coupling via the use of transition metal catalysts (such as
Pd,3 Ni,4 Fe5), and a wide range of primary alkyl halides can now
be successfully used, when suitable conditions are employed.2
Compared to primary alkyl halides, the utilization of secondary
alkyl halides as coupling electrophiles is more interesting6
since these reactions could result in the formation of some
useful synthetic precursors having tertiary carbon centers
and stereogenic centers.7 This has been demonstrated by the
pioneering work of Fu et al. in which the asymmetric catalysis
of racemic activated and unactivated secondary alkyl halides
was achieved.8 However, the coupling of unactivated secondary
halides remains a difficult task and is less developed. Thus, only
a few methods for the alkyl–alkyl coupling of unactivated
secondary alkyl halides have been reported.6,9,10
In this communication, we wish to report on the copper(I)
iodide catalyzed cross-coupling reaction of unactivated secondary
alkyl iodides with alkyl Grignard reagents using 1,3-butadiene as an
additive. We found that 1,3-butadiene showed remarkable effects in
improving both the efficiency and selectivity of the reaction,
resulting in the production of alkyl–alkyl coupled products in good
to high yields.11,12 The copper-catalyzed coupling of unactivated
primary alkyl halides with alkyl Grignards was developed by
us11b,12a,b,d and others.13 However, regarding unactivated secondary
alkyl halides,14 only one report has been published concerning the
coupling of unactivated secondary alkyl sulfonates and halides
with alkyl Grignards catalyzed by a copper thiolate catalyst.14a
Quite recently, Liu et al. reported that a combination of
TMEDA and LiOMe with CuI was effective for cross-coupling
between secondary alkyl derivatives.14b
When a catalytic amount of CuI was added to a solution of
4-phenylbutan-2-yl iodide (1a), n-BuMgCl (1.5 equiv.) and
1,3-butadiene (1 equiv.) in THF at ꢀ78 1C, followed by
stirring at 0 1C for 4 h, the cross-coupled product 2a was
obtained in 90% yield along with a small amount of the
elimination product 3 (1%) and the reduction product 4
(o1%) (Table 1, entry 1). In contrast, a similar reaction in
the absence of 1,3-butadiene gave a mixture of 2a (56%), 3
(15%) and 4 (8%) (entry 2), clearly indicating that the
presence of 1,3-butadiene is crucial for improving the yield
and selectivity of the reaction. At lower concentration of 1,3-
butadiene (0.5 equiv.), the yield was slightly reduced (81%).
Decreasing the catalyst CuI from 3 mol% to 1 mol% had no effect
and a good yield of the product was also obtained (entry 3). We
also examined other additives (see ESIw for details). The use of
isoprene gave 2a in 85% yield (entry 4), however, other dienes and
alkynes11c gave moderate yields of 2a, accompanied by a significant
amount of by-products 3 and 4 (entries 5–7).
We previously reported on the development of efficient
catalytic systems for cross-coupling reactions of alkyl halides
with Grignard or organozinc reagents using Ni, Pd as well
as Cu catalysts in the presence of p-carbon ligands, such as
a Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan.
E-mail: kambe@chem.eng.osaka-u.ac.jp; Fax: +81-6-6879-7390;
Tel: +81-6-6879-7390
b Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
We next examined the reactions of the secondary alkyl
iodide 1a with various Grignard reagents in the presence of CuI
and 1,3-butadiene. A variety of RMgX reagents were successfully
coupled with 1a to give the corresponding alkyl–alkyl coupled
w Electronic supplementary information (ESI) available: Experimental
details, additional experimental results, characterization data, 1H and
13C NMR spectra and related references. See DOI: 10.1039/c2cc34847k
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9313–9315 9313

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Table 1 Cu-catalyzed cross-coupling of 1a with n-BuMgCla
Table 2 Cu-catalyzed cross-coupling of secondary alkyl iodides with
alkyl Grignard reagents in the presence of 1,3-butadienea
Entry
Additive (1 equiv.)
2ab (%) 3b,c (%)
4b (%)
Entry R1
R2
R3MgX
Yieldb (%)
1
1,3-Butadiene
None
1,3-Butadiene
Isoprene
1,3-Pentadiene
2,3-Dimethyl-1,3-butadiene
90(82)
56
89
85
74
1
15
1
2
3
o1
8
o1
o1
1
1
2
3
4
PhCH2CH2
n-C6H13
n-Pr
Cyclohexyl iodide
PhCH2CH2
PhCH2CH2
PhCH2CH2
n-C6H13
n-Pr
Me
n-Pr
n-BuMgCl
n-BuMgCl
n-BuMgCl
2h, 85
2i, 87c
2j, 81c
2
3d
4
Neopentyl MgCl 2k, 65c
5
5
Allyl EtMgBr
i-Pr n-BuMgCl
Allyl n-BuMgCl
Me
i-Pr
i-Pr
2l, 70
2m,80
2n, 89
2o, 93c
2p, 42c
6e
69
5
2
6d
7
7
69
12
6
8
Allyl MgCl
n-BuMgCl
a
See ESI for details. In each case, ca. 9–13% yield of n-octane resulting
b
from homocoupling of n-BuMgCl was detected as the by-product. GC
9
i-Pr
i-Pr
10d
Neopentyl MgCl 2q, 17c
c
yield based on 1a. Isolated yield in parentheses. Combined GC yields
a
b
See ESI for details. Isolated yield. GC yield. 3 mol% CuI.
c
d
d
e
of the olefin by-products from 1a. 1 mol% CuI. ca. 10% of 1a was
recovered.
The function of 1,3-butadiene may be to stabilize the
cuprate intermediates, thus preventing b-hydride elimination
and reduction (hydrodehalogenation) reactions that could
occur during the catalytic cycle.16 It has been proposed
that cross-coupling reactions involving an alkyl iodide
and an organometallic reagent may follow a radical pathway.
For example, Oshima et al.9j,k,17 and Hu et al.9g reported that
the Co and Ni catalyzed coupling of alkyl iodides that contain
an olefin functionality often produced cyclic products. They
suggested that free alkyl radicals are readily formed from alkyl
iodides, leading to the subsequent cyclization. However, in
our case, the reaction of 1-phenyloct-7-en-3-yl iodide (1b)
with MeMgCl gave the coupling product 2f exclusively in
high yield and formation of a cyclopentane ring from a
possible intramolecular radical cyclization was not detected
(eqn (1)).17 This is in sharp contrast to the lithium cuprate
mediated methylation of the haloalkyl olefins, where cyclization
was the exclusive reaction.18 These data suggest that free
radical species are not involved in our Cu–butadiene catalytic
system.17–20
products in good to high yields, as shown in Scheme 1. In
addition to n-BuMgCl, the methyl Grignard reagent also gave
a satisfactory yield of the product 2b. When the reactions of
allyl or pent-4-enyl Grignard reagents with 1a were carried
out, terminal alkenes 2e and 2f were formed in high yields,
implying the potent usefulness of this method as a convenient
tool for introducing an alkene functionality. The use of 2-(1,3-
dioxolan-2-yl)ethylmagnesium bromide gave a moderate yield
of the corresponding coupling product 2g. It is noteworthy
that the sterically bulky iso-butyl- and neopentyl Grignard
reagents also reacted smoothly with 1a, giving the coupling
products 2c and 2d in 82% and 79% yields, respectively. However,
the isopropyl Grignard reagent gave a complex mixture.
Representative examples of various combinations of secondary
alkyl iodides with Grignard reagents are shown in Table 2.
Reactions of 2-iodooctane and 4-iodoheptane with n-BuMgCl
both gave the expected coupling products in high yields (entries 2
and 3). A homoallyl iodide was also applicable to the reaction
(entries 5 and 7). The iodocyclohexane reacted with the bulky
neopentyl Grignard to give the coupled product in moderate yield
(entry 4). The reaction also proceeded efficiently to give 2m in
80% yield when a branched alkyl iodide was employed (entry 6).
However, more sterically hindered 2,4-dimethylpentan-3-yl iodide
gave poor yields of the coupled products (entries 9 and 10). The
corresponding bromides, though more reactive than chlorides or
tosylates,12d resulted in no reaction.
ð1Þ
As proposed earlier, this reaction appears to proceed by
ionic mechanisms via the formation of magnesiocuprates from
the Grignard reagent and copper catalyst, which then react
with the alkyl iodide to give the cross-coupling product.15
In a synthetic application of the present reaction, we attempted to
prepare dienes and an enyne and the results are summarized in
Scheme 2. Terminal dienes such as 1,6-, 1,8-, 1,10-, and 1,11-dienes
were produced in high yields using the current method without
any by-products arising from radical cyclization.21 In addition, an
alkynylalkyl iodide was also coupled with allylmagnesium chloride
to give the 1,6-enyne 2v in moderate yield. When the formed
dienes 2r and 2s were subjected to Ru-catalyzed metathesis, the
corresponding 5- and 7-membered cycloalkenes were obtained in
good yields (eqn (2)).
Scheme 1 Cross-coupling of 1a with various RMgX.
9314 Chem. Commun., 2012, 48, 9313–9315
c
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G. C. Fu, J. Am. Chem. Soc., 2005, 127, 10482; (f) J. Caeiro,
J. P. Sestelo and L. A. Sarandeses, Chem.–Eur. J., 2008, 14, 741;
(g) P. M. Lundin, J. Esquivias and G. C. Fu, Angew. Chem., Int.
Ed., 2009, 48, 154.
9 For sp3–sp3 coupling of unactivated secondary halides, see: Ni:
(a) J. R. Zhou and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 14726;
(b) T. J. Anderson, G. D. Jones and D. A. Vicic, J. Am. Chem.
Soc., 2004, 126, 8100; (c) B. Saito and G. C. Fu, J. Am. Chem. Soc.,
2007, 129, 9602; (d) V. B. Phapale, E. Bunuel, M. Garcia-Iglesias
and D. J. Cadenas, Angew. Chem., Int. Ed., 2007, 46, 8790;
´
(e) O. Vechorkin, Z. Csok, R. Scopelliti and X. Hu, Chem.–Eur.
J., 2009, 15, 3889; (f) Z. Lu and G. C. Fu, Angew. Chem., Int. Ed.,
2010, 49, 6676; (g) P. Ren, O. Vechorkin, K. von Allmen,
R. Scopelliti and X. L. Hu, J. Am. Chem. Soc., 2011, 133, 7084;
(h) X. Yu, T. Yang, S. Wang, H. Xu and H. Gong, Org. Lett.,
2011, 13, 2138; Co: (i) C. K. Reddy and P. Knochel, Angew. Chem.,
Int. Ed., 1996, 35, 1700; (j) T. Tsuji, H. Yorimitsu and K. Oshima,
Angew. Chem., Int. Ed., 2002, 41, 4137; (k) H. Ohmiya, T. Tsuji,
H. Yorimitsu and K. Oshima, Chem.–Eur. J., 2004, 10, 5640;
(l) G. Cahiez, C. Chaboche, C. Duplais, A. Giulliani and
A. Moyeux, Adv. Synth. Catal., 2008, 350, 1484; (m) W. Zhou,
J. W. Napoline and C. M. Thomas, Eur. J. Inorg. Chem., 2011,
2029; Ag: (n) H. Someya, H. Ohmiya, H. Yorimitsu and
K. Oshima, Org. Lett., 2008, 10, 969.
Scheme 2 Cross-coupling reaction for the synthesis of enynes and
dienes.
ð2Þ
10 Iodocyclopropanes show high reactivity due to their sp2 property,
see: A. B. Charette and A. Giroux, J. Org. Chem., 1996, 61, 8718.
11 (a) J. Terao and N. Kambe, Bull. Chem. Soc. Jpn., 2006, 79, 663;
(b) J. Terao and N. Kambe, Acc. Chem. Res., 2008, 41, 1545;
(c) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu and N. Kambe,
J. Am. Chem. Soc., 2002, 24, 4222; (d) J. Terao, Y. Naitoh,
H. Kuniyasu and N. Kambe, Chem. Lett., 2003, 890;
(e) J. Terao, H. Todo, H. Watanabe, A. Ikumi and N. Kambe,
Angew. Chem., Int. Ed., 2004, 43, 6180; (f) S. P. Singh, J. Terao and
N. Kambe, Tetrahedron Lett., 2009, 50, 5644; (g) S. P. Singh,
T. Iwasaki, J. Terao and N. Kambe, Tetrahedron Lett., 2011,
52, 774; (h) T. Iwasaki, A. Tsumura, T. Omori, H. Kuniyasu,
J. Terao and N. Kambe, Chem. Lett., 2011, 1024.
12 (a) J. Terao, H. Todo, H. Watabe, A. Ikumi, Y. Shinohara and
N. Kambe, Pure Appl. Chem., 2008, 80, 941; (b) J. Terao, A. Ikumi,
H. Kuniyasu and N. Kambe, J. Am. Chem. Soc., 2003, 125, 5646;
(c) J. Terao, H. Watabe and N. Kambe, J. Am. Chem. Soc., 2005,
127, 3656; (d) J. Terao, H. Todo, S. A. Begum, H. Kuniyasu and
N. Kambe, Angew. Chem., Int. Ed., 2007, 46, 2086; (e) J. Terao,
S. A. Begum, Y. Shinohara, M. Tomita, Y. Naitoh and N. Kambe,
Chem. Commun., 2007, 855; (f) J. Terao, M. Nakamura and
N. Kambe, Chem. Commun., 2009, 6011.
13 (a) G. Cahiez, C. Chaboche and M. Jezequel, Tetrahedron, 2000,
56, 2733; (b) G. Cahiez, O. Gager and J. Buendia, Synlett, 2010,
299; Cu/Mn catalyst: (c) J. G. Donkervoort, J. L. Vicario, J. T. B.
H. Jastrzebski, R. A. Gossage, G. Cahiez and G. van Koten,
J. Organomet. Chem., 1998, 558, 61.
14 (a) D. H. Burns, J. D. Miller, H.-K. Chan and M. O. Delaney,
J. Am. Chem. Soc., 1997, 119, 2125; (b) C.-T. Yang, Z.-Q. Zhang,
J. Liang, J.-H. Liu, X.-Y. Lu, H.-H. Chen and L. Liu, J. Am. Chem.
Soc., 2012, 134, 11124. For cross-coupling using allylic Grignard
reagents, see: (c) M. Sai, H. Someya, H. Yorimitsu and K. Oshima,
Org. Lett., 2008, 10, 2545; (d) M. Sai, H. Yorimitsu and K. Oshima,
Bull. Chem. Soc. Jpn., 2009, 82, 1194.
15 (a) J. K. Kochi, J. Organomet. Chem., 2002, 653, 11; (b) B. H. Lipshutz
and S. Sengupta, Organic Reactions, ed. L. A. Paquette, John Wiley
and Sons, New York, 1992, vol. 41, pp. 141–142.
16 For discussion on some organo magnesiocuprates, see: (a) ref. 15b,
p. 184; (b) H. Westmijze, H. Kleijn and P. Vermeer, Recl. Trav.
Chim. Pays–Bas., 1980, 98.
17 Radical cyclization of methylene tethered iodoalkenes like 1b in
Co-catalyzed Heck type reaction: W. Affo, H. Ohmiya, T. Fujioka,
Y. Ikeda, T. Nakamura, H. Yorimitsu, K. Oshima, Y. Imamura,
T. Mizuta and K. Miyoshi, J. Am. Chem. Soc., 2006, 128, 8068.
18 E. C. Ashby and D. Coleman, J. Org. Chem., 1987, 52, 4554.
19 Many of the reported transition-metal catalyzed alkylations of
unactivated secondary halide involve a radical mechanism.2d,6,9,10,15a
20 For a Grignard reagent mediated radical cyclization of iodoalkenes,
see: A. Inoue, H. Shinokubo and K. Oshima, Org. Lett., 2000, 2, 651.
21 (a) E. C. Ashby, Pure Appl. Chem., 1980, 52, 545; (b) A. Inoue,
H. Shinokubo and K. Oshima, Synlett, 1999, 1582.
In conclusion, the findings reported herein demonstrate that CuI,
aided by 1,3-butadiene, catalyzes the cross-coupling of unactivated
secondary alkyl iodides with a variety of alkyl Grignard reagents
giving rise to alkyl–alkyl coupled products in good to high yields
under mild conditions. The reaction is convenient and practical,
and expensive noble metals or ligands are not required. The
present catalytic system provides a useful method for the synthesis
of 1,n-dienes or enynes.
This work was supported by a Grant-in-Aid for Scientific
Research (S) No. 20225004 and Grant-in-Aid for Young
Scientists (B) No. 22750094 from the Ministry of Education,
Culture, Sports and Technology, Japan and General Sekiyu
Foundation.
Notes and references
1 (a) Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich and
P. J. Stang, Wiley-VCH, Weinheim, Germany, 1998; (b) Metal-
Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and
F. Diederich, Wiley-VCH, Weinheim, Germany, 2nd Completely
Revised and Enlarged edn, 2004, vol. 1–2.
2 Recent reviews: (a) D. J. Cardenas, Angew. Chem., Int. Ed., 2003,
42, 384; (b) M. R. Netherton and G. C. Fu, Adv. Synth. Catal.,
2004, 346, 1525; (c) A. C. Frisch and M. Beller, Angew. Chem., Int.
Ed., 2005, 44, 674; (d) N. Kambe, T. Iwasaki and J. Terao, Chem.
Soc. Rev., 2011, 40, 4937; (e) X. L. Hu, Chem. Sci., 2011, 2, 1867.
3 Representative reports: (a) M. R. Netherton, C. Dai, K. Neuschtz
and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 10099; (b) J. Zhou and
G. C. Fu, J. Am. Chem. Soc., 2003, 125, 12527; (c) K. Arentsen,
S. Caddick, F. G. N. Cloke, A. P. Herring and P. B. Hitchcock,
Tetrahedron Lett., 2004, 45, 3511; (d) N. Hadei, E. A. B. Kantchev,
C. J. O’Brien and M. G. Organ, Org. Lett., 2005, 7, 3805;
(e) G.-R. Peh, E. A. B. Kantchev, J.-C. Er and J. Y. Ying,
Chem.–Eur. J., 2010, 16, 4010.
4 Representative examples: (a) A. Devasagayaraj, T. Studemann and
P. Knochel, Angew. Chem., Int. Ed., 1995, 34, 2723; (b) O. Vechorkin
and X. L. Hu, Angew. Chem., Int. Ed., 2009, 48, 2937.
5 K. G. Dongol, H. Koh, M. Sau and C. L. L. Chai, Adv. Synth.
Catal., 2007, 349, 1015.
6 A. Rudolph and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 2656.
7 F. Glorius, Angew. Chem., Int. Ed., 2008, 47, 8347.
8 For unactivated secondary alkyl electrophiles, see: (a) B. Saito and
G. C. Fu, J. Am. Chem. Soc., 2008, 130, 6694; (b) N. A. Owston
and G. C. Fu, J. Am. Chem. Soc., 2010, 132, 11908; (c) Z. Lu,
A. Wilsily and G. C. Fu, J. Am. Chem. Soc., 2011, 133, 8154; for
activated secondary alkyl electrophiles, see: (d) C. Fischer and
G. C. Fu, J. Am. Chem. Soc., 2005, 127, 4594; (e) F. O. Arp and
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9313–9315 9315