Nickel-catalyzed cross-coupling reaction of alkyl halides with organozinc and grignard reagents with 1,3,8,10-tetraenes as additives

Article abstract of DOI:10.1002/anie.200460246

Essential additives: The addition of bis(1,3-butadienyl) compounds (tetraenes) was essential in the efficient Nicatalyzed cross-coupling of organozinc reagents with alkyl bromides and a tosylate (see scheme, X = C(CO₂Me)₂ or NCH₂Ph). The efficiency of the Ni-catalyzed cross-coupling of an alkyl fluoride with a Grignard reagent was also improved by using these tetraenes.

Full text of DOI:10.1002/anie.200460246

Communications
cross-coupling reaction of alkyl halides with organozinc
[
4–6]
reagents
in a THF/N-methylpyrrolidone (NMP) mixed
solvent containing magnesium bromide. It was also found that
these tetraenes (2) were effective also for the nickel-catalyzed
cross-coupling of alkyl fluorides with Grignard reagents.
Synthetic Methods
First we examined a cross-coupling reaction of alkyl
halides with organozinc reagents that used 1,3-butadiene as
the additive. For example, n-decyl bromide (1 mmol), dieth-
Nickel-Catalyzed Cross-Coupling Reaction of
Alkyl Halides with Organozinc and Grignard
Reagents with 1,3,8,10-Tetraenes as Additives**
ylzinc (2 equivalents, 1m in hexane), NiCl (0.03 equiv), and
2
1,3-butadiene (1 equivalent) were added sequentially to a
solution of THF (8 mL) and NMP (4 mL) at ꢀ788C and the
mixture stirred at 258C for 48 hours. However, this reaction
gave only a trace amount of the cross-coupling product, n-
dodecane (< 1%), as shown in Table 1 (entry 1). Addition of
magnesium bromide increased the yield of n-dodecane to
45%, but side reactions (reduction and HBr elimination)
could not be suppressed (entry 2). Only a trace amount of
dodecane was obtained without 1,3-butadiene even in the
presence of magnesium bromide (entries 3 and 4). The salts
Jun Terao, Hirohisa Todo, Hideyuki Watanabe,
Aki Ikumi, and Nobuaki Kambe*
Transition-metal-catalyzed cross-coupling reactions between
organic halides and organometallic reagents is a powerful tool
for constructing carbon skeletons. Significant advances have
been achieved in this field over the last decade that have
enabled cross-coupling reactions to be effected between alkyl
groups by using either a nickel or palladium catalyst. We
have contributed to this progress by developing a unique
catalytic system that proceeds efficiently under mild condi-
tions by using 1,3-butadiene as an additive in the absence of
phosphane ligands, where bis-p-allylnickel or -palladium
[
1]
[
5]
Bu NBr, Bu NI, and LiBr were also shown to be not
4
4
[
2]
effective as additives (entries 5–7). The yield of dodecane was
increased up to 73% by adding four equivalents of 1,3-
butadiene; however, formation of by-products, n-decane and
decenes, could not completely be suppressed (entries 8 and 9).
Under similar conditions, [Ni(acac) ] (acac = acetylaceta-
2
[
3]
intermediates (1) are proposed to be involved [Eq. (1)].
noate) afforded a slightly better yield of the product
(entry 10), while nickel catalysts bearing phosphane ligands
This system facilitates the cross-coupling of a wide variety of
alkyl tosylates and halides, such as fluorides, chlorides, and
bromides, with Grignard reagents. However, a drawback of
this methodology is the range of functional groups that are
tolerant to this system because of the high reactivity of the
Grignard reagents. Herein, we reveal a solution to this
problem by employing 1,3,8,10-tetraenes (2) that serve as
extremely efficient ligands to promote the nickel-catalyzed
were less efficient (entries 11 and 12). PdCl did not show a
2
high catalytic activity (entry 13). The coupling products were
obtained in yields of only 37 and 7%, respectively (entries 14
[
5]
and 15), when isoprene and p-fluorostyrene were employed
as additives under the same conditions as entry 10.
It is noteworthy that this cross-coupling reaction pro-
ceeded very rapidly and quantitatively when 2,2-bis(penta-
2
,4-dienyl)malonic acid dimethyl ester (2a) was employed as
an additive in place of 1,3-butadiene, with complete suppres-
sion of the formation of decane and decenes (entry 16). The
[
*] Dr. J. Terao, H. Todo, H. Watanabe, A. Ikumi, Prof. Dr. N. Kambe
Department of Molecular Chemistry and Science and
Technology Center for Atoms, Molecules, and Ions Control
Graduate School of Engineering, Osaka University
Yamadaoka 2-1, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7390
NiCl catalyst also gave a satisfactory result under identical
2
conditions (entry 17). The excellent performance of tetraene
2
a is demonstrated readily as the reaction was completed
within 1 h at 258C with only 9 mol% of 2a and 1.3 equivalents
of diethylzinc (entry 18). N,N-Bis(penta-2,4-dienyl)benzyla-
mine (2b) also showed high activity (entry 19). The yield of
dodecane decreased when the amount of magnesium bromide
was decreased (entry 18).
E-mail: kambe@chem.eng.osaka-u.ac.jp
[
**] This research was supported financially in part by a Grant-in-Aid for
Scientific Research. We thank the Instrumental Analysis Center,
Faculty of Engineering, Osaka University, for high-resolution mass-
spectrometric measurements and elemental analysis.
Reactions of various alkyl halides and a tosylate with
organozinc reagents were examined with 2a as an additive
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
6
180
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200460246
Angew. Chem. Int. Ed. 2004, 43, 6180 –6182

Angewandte
Chemie
[
a]
Table 1: Nickel-catalyzed cross-coupling reaction of nC H -Br with diethylzinc.
recovered. Cyclohexyl tosylate also
1
0
21
[
b]
gave butylcyclohexane in a yield of
only 5% after treatment with dibu-
tylzinc.
Product yield [%]
[c]
Entry
Catalyst
Additive (equiv)
C H (1)
t [h]
Dodecane
Decane
Decenes
1
2
3
4
5
6
7
8
9
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
1
<1
45
0
2
<1
3
16
69
73
84
23
20
5
49
45
69
7
14
2
3
2
3
55
5
<1
0
<1
11
<1
46
3
4
6
We have shown that nickel cat-
alyzes cross-coupling reactions of
alkyl fluorides with Grignard
reagents in the presence of 1,3-
butadiene. However, this reaction
is less efficient than those of the
alkyl bromides, as they afford only
moderate yields of the coupling
C H (1), MgBr (3)
4
6
2
none
MgBr (3)
2
C H (1), Bu NBr (3)
4
6
4
NiCl2
C H (1), Bu NI (3)
4
6
4
23
0
NiCl2
NiCl2
NiCl2
C H (1), LiBr (3)
4
6
C H (2), MgBr (3)
9
2
3
4
6
2
C H (4), MgBr (3)
4
6
2
10
11
12
13
14
15
16
17
18
19
[Ni(acac)2]
[NiCl (PPh ) ]
C H (4), MgBr (3)
4
6
2
[
3b]
C H (4), MgBr (3)
40
31
5
37
<1
0
products. For example, treatment
of n-nonyl fluoride with 1.5 equiv-
alents of nPrMgBr in the presence
of 3 mol% of [Ni(acac)2] and
2
3
2
4
6
2
[NiCl (dppp)]
C H (4), MgBr (3)
2
4
6
2
PdCl2
C H (4), MgBr (3)
4
6
2
3
3
[Ni(acac)
2
]
isoprene (4), MgBr
p-fluorostyrene (4), MgBr (3)
2
(3)
[Ni(acac)2]
[Ni(acac)2]
NiCl2
[Ni(acac)2]
[Ni(acac)2]
7
23
0
2
3
0 mol% of 1,3-butadiene gave
2a (2), MgBr (3)
>99
>99
>99
>99
2
dodecane in a yield of only 11%
(Table 3, entry 1). Increasing the
amount of 1,3-butadiene improved
the yield moderately; however, sat-
isfactory yields could not be
2a (2), MgBr (3)
0
0
0
0
0
0
2
[
[
d,e]
d]
2a (0.09), MgBr (3)
2b (0.09), MgBr (3)
2
1
2
[
(
(
a] Conditions unless otherwise stated: n-Decyl bromide (1 mmol), catalyst (3 mol%), additive
equivalents based on the substrate), diethylzinc(2 equiv, 1 m in hexane), mixed solution of THF
8 mL) and NMP (4 mL), 258C, 48 h. [b] Determined by GC analysis. [c] A mixture of 1-decene and 2- attained (Table 3, entries 2–4).
decenes. [d] n-Decyl bromide (1 mmol), diethylzinc (1.3 equiv, 1m in hexane), mixed solution of THF These poor yields were probably
0
(
8.4 mL) and NMP (4.2 mL), 258C, 1 h. [e] The yields were decreased to 41 and 11% when the amount
because the Ni center will react
with more than two equivalents of
of MgBr was decreased to 1.3 and 0.65 equivalents, respectively.
2
(
Table 2). This catalytic system tolerates unsaturated heter-
Table 3: Affect of the additive on the cross-coupling of alkyl fluorides.
oatom functional groups, such as nitriles, ketones, amides, and
esters (entries 1–4). The use of the secondary alkyl zinc
reagent iPr Zn (entry 5) or an aryl zinc reagent (entry 6) also
2
afforded the corresponding products in good yields. An alkyl
tosylate was also shown to undergo this cross-coupling
reaction under the same conditions (entry 7). Secondary
alkyl halides and tosylates were found to react sluggishly. For
example, treatment of 2-octyl bromide with diethylzinc
afforded decane in a yield of only 3%, along with octane
Entry
[Ni(acac)
2
] [mol%]
Additive (mol%)
Yield [%]
1
2
3
4
5
3
3
3
3
1,3-butadiene (30)
1,3-butadiene (100)
1,3-butadiene (200)
1,3-butadiene (30)
2b (15)
11
58
65
67
94
0.6
(
6%) and octenes (3%), and 82% of 2-octyl bromide was
1
,3-butadiene in the presence of a
Table 2: Nickel-catalyzed cross-coupling reaction of alkyl halides and a tosylate with organozinc
reagents using tetraene 2a.
high concentration of 1,3-butadiene
and will form complexes composed
of C -butadiene-oligomer units.
[
a]
0
[b]
Entry
RX
R Zn
Product
Yield [%]
2
12
The formation of these units will
then predominantly result in a low
1
2
nOct Zn
96
87
2
[
7]
nOct Zn
concentration of 1. To prepare the
bis-p-allylnickel complex structure
exclusively, we applied tetraene 2b
as an additive and found that the
yield was dramatically improved by
the use of only 0.6 mol% of nickel
catalyst and 15 mol% of 2b
(entry 5).
2
3
91
87
4
5
nPr Zn
2
[
c]
iPr Zn
2
79
A plausible reaction pathway is
shown in Scheme 1. A bis-p-allyl-
nickel structure 3 is constructed by
[
[
c]
c]
6
7
nPrBr
Ph Zn
86
83
2
Et Zn
2
0
0
the oxidative cycloaddition of Ni
[
a] Conditions: RX (1 mmol), R Zn (1.3 equiv), NiCl (3 mol%), 2a (9 mol%), MgBr (3 mmol), mixed
2
2
2
solution of THF (8.4 mL) and NMP (4.2 mL), 258C, 1 h. [b] Yield of isolated product. [c] GC yield. with two butadiene moieties of a
Angew. Chem. Int. Ed. 2004, 43, 6180 –6182
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6181

Communications
[
[
1] a) For the history and recent development of transition-metal-
catalyzed cross-coupling reactions, see: International Symposium
on 30 years of the Cross-coupling Reaction, J. Organomet. Chem.
2002, 653, 1 – 291; b) Metal-catalyzed Cross-coupling Reactions
(Eds.: F. Diederich, P. J. Stang), Wiley-VCH, New York, 1998.
2] For a recent study and a review of transition-metal-catalyzed
cross-coupling reactions of alkyl halides with organometallic
reagents, see: a) D. J. Cµrdenas, Angew. Chem. 2003, 115, 398 –
401; Angew. Chem. Int. Ed. 2003, 42, 384 – 387; b) T.-Y. Luh, M.
Leung, K.-T. Wong, Chem. Rev. 2000, 100, 3187 – 3204. Several
important papers concerning cross-coupling reactions using alkyl
halides were subsequently reported; see, for example: c) J. H.
Kirchhoff, M. R. Netherton, I. D. Hills, G. C. Fu, J. Am. Chem.
Soc. 2002, 124, 13662 – 13663; d) A. C. Frisch, N. Shaikh, A. Zapf,
M. Beller, Angew. Chem. 2002, 114, 4218 – 4221; Angew. Chem.
Int. Ed. 2002, 41, 4056 – 4059; e) T. Tsuji, H. Yorimitsu, K.
Oshima, Angew. Chem. 2002, 114, 4311 – 4313; Angew. Chem. Int.
Ed. 2002, 41, 4137 – 4139; f) K. Menzel, G. C. Fu, J. Am. Chem.
Soc. 2003, 125, 3718 – 3719; g) J.-Y. Lee, G. C. Fu, J. Am. Chem.
Soc. 2003, 125, 5616 – 5617; h) J. Zhou, G. C. Fu, J. Am. Chem.
Soc. 2003, 125, 12527 – 12530; i) M. Eckhardt, G. C. Fu, J. Am.
Chem. Soc. 2003, 125, 13642 – 13643; j) J. Zhou, G. C. Fu, J. Am.
Chem. Soc. 2003, 125, 14726 – 14727; k) S. L. Wiskur, A. Korte,
G. C. Fu, J. Am. Chem. Soc. 2004, 126, 82 – 83; l) J. Zhou, G. C. Fu,
J. Am. Chem. Soc., 2004, 126, 1340 – 1341; m) M. Nakamura, K.
Matsuo, S. Ito, E. Nakamura, J. Am. Chem. Soc. 2004, 126, 3686 –
Scheme 1. A plausible reaction pathway.
[
8]
1
,3,8,10-tetraene. An organomagnesium or -zinc reagent
1
3
attacks the bis-p-allyl complex 3 to generate the h ,h -
octadienediylnickelate complex 4, which then reacts with
alkyl halides to give a complex 5. Subsequent reductive
elimination affords the coupling product along with 3 to
complete the catalytic cycle. Selective and efficient formation
0
[7]
of 3 from Ni and 2 would, in comparison to 1,3-butadiene,
facilitate the generation of complex 4 and so accelerate the
subsequent oxidative addition process that leads to 5.
In conclusion, it was found that tetraenes 2 exerted
dramatic effects that improved the cross-coupling reactions of
organozinc reagents with alkyl halides catalyzed by nickel.
This reaction proceeds efficiently by the use of primary and
secondary alkyl or aryl zinc reagents under mild conditions.
The use of tetraene 2b as an additive also resulted in high
yields of products in the cross-coupling of an alkyl fluoride
with a Grignard reagent.
3687; n) T. Nagano, T. Hayashi, Org. Lett. 2004, 6, 1297 – 1299;
o) R. Martin, A. Fꢀrstner, Angew. Chem. 2004, 116, 4045 – 4047;
Angew. Chem. Int. Ed. 2004, 43, 3955 – 3957.
[3] a) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu, N. Kambe, J.
Am. Chem. Soc. 2002, 124, 4222 – 4223; b) J. Terao, A. Ikumi, H.
Kuniyasu, N. Kambe, J. Am. Chem. Soc. 2003, 125, 5646 – 5647;
c) J. Terao, Y. Naitoh, H. Kuniyasu, N. Kambe, Chem. Lett. 2003,
32, 890 – 891.
[
4] For Ni-catalyzed cross-coupling reactions of alkyl halides with
alkyl zinc reagents, see: a) A. Devasagayaraj, T. Stꢀdemann, P.
Knochel, Angew. Chem. 1995, 107, 2723 – 2725; Angew. Chem. Int.
Ed. Engl. 1995, 34, 2723 – 2725; b) R. Giovannini, T. Stꢀdemann,
G. Dussin, P. Knochel, Angew. Chem. 1998, 110, 2512 – 2515;
Angew. Chem. Int. Ed. 1998, 37, 2387 – 2390; c) R. Giovannini, P.
Knochel, J. Am. Chem. Soc. 1998, 120, 11186 – 11187; d) M. Piber,
A. E. Jensen, M. Rottlꢁnder, P. Knochel, Org. Lett. 1999, 1, 1323 –
Experimental Section
Heptadecan-5-one: A solution of nOct Zn (0.33m in THF, 3.9 mL,
2
1
1
.3 mmol) was added to a solution of 1-bromononan-5-one (221 mg,
1326; e) R. Giovannini, T. Stꢀdemann, A. Devasagayaraj, G.
.0 mmol), MgBr (552 mg, 3.0 mmol), NiCl (4 mg, 0.03 mmol), 2a
2
2
Dussin, P. Knochel, J. Org. Chem. 1999, 64, 3544 – 3553; f) A. E.
Jensen, P. Knochel, J. Org. Chem. 2002, 67, 79 – 85; g) ref. [2j].
5] It is reported that alkyl zinc reagents undergo Ni-catalyzed cross-
(24 mg, 0.09 mmol), and NMP (4.2 mL) in THF (4.6 mL) at 258C
under nitrogen. After stirring the mixture for 1 h, 1m HCl (ca. 2 mL)
was added to the solution at 08C and the mixture was warmed to
[
coupling with alkyl bromides by the combined use of Bu NI and
4
2
58C. Saturated aqueous NaHCO solution (20 mL) was then added,
3
p-fluorostyrene as additives; see: ref [4f].
6] For Pd-catalyzed cross-coupling reaction of alkyl halides with
alkyl zinc reagents, see: ref. [2h].
[7] For structures and stabilities of nickel complexes involved in
cyclo-oligomerization of 1,3-butadiene, see: S. Tobisch, Adv.
Organomet. Chem. 2003, 49,167 – 224, and references therein.
[8] For Ni-mediated cyclization of 1,3,8,10-tetraenes, see: a) P. A.
Wender, M. J. Tebbe, Synthesis 1991, 1089 – 1094, and references
therein; b) M. Takimoto, M. Mori, J. Am. Chem. Soc. 2002, 124,
10008 – 10009.
and the product was extracted with diethyl ether (20 mL), dried over
[
MgSO , and evaporated to give the crude product. Purification by
4
silica gel column chromatography with hexane/diethyl ether (15:1) as
an eluent afforded 233 mg (87%) of octadecan-5-one. H NMR
1
(
400 MHz, CDCl ): d = 2.39 (t, J = 7.6 Hz, 2H), 2.38 (t, J = 7.4 Hz,
3
2
0
4
2
H), 1.59–1.51 (m, 4H), 1.34–1.21 (m, 22H), 0.90 (t, J = 8.4 Hz, 3H),
.88 ppm (t, J = 8.8 Hz, 3H); C NMR (100 MHz, CDCl ): d = 211.1,
2.7, 42.4, 31.8, 29.60, 29.57, 29.56, 29.54, 29.40, 29.35, 29.28, 29.20,
1
3
3
5.9, 23.8, 22.6, 22.3, 14.1, 13.8 ppm; MS (EI) m/z (relative intensity,
+
%
) 268 (M , 0.4), 211 (25), 113 (20), 101 (33), 85 (74), 71 (39), 58
(
100); HR-MS: calcd for C H O: 268.2766, found 268.2758;
18 36
elemental analysis (%): calcd for C H O: C 80.53, H 13.52; found:
1
8
36
C 80.46, H 13.40.
Received: April 7, 2004
Keywords: alkyl halides · cross-coupling · Grignard reagents ·
.
nickel · organozinc reagents
6
182
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 6180 –6182