Nickel-butadiene catalytic system for the cross-coupling of bromoalkanoic acids with alkyl grignard reagents: A practical and versatile method for preparing fatty acids

Article abstract of DOI:10.1002/chem.201204222

The knights who say Ni: A practical and convenient synthetic route to fatty acids involves the Ni-catalyzed alkyl-alkyl cross-coupling of bromoalkanoic acids and alkyl Grignard reagents in the presence of 1,3-butadiene as an additive (see scheme). Copyright

Full text of DOI:10.1002/chem.201204222

DOI: 10.1002/chem.201204222
À
Nickel Butadiene Catalytic System for the Cross-Coupling of
Bromoalkanoic Acids with Alkyl Grignard Reagents: A Practical and
Versatile Method for Preparing Fatty Acids
[
a]
[a]
[a]
[a]
Takanori Iwasaki, Kiyokazu Higashikawa, Vutukuri P. Reddy, Willbe W. S. Ho,
[
b]
[b]
[c]
[a]
Yukari Fujimoto, Koichi Fukase, Jun Terao, Hitoshi Kuniyasu, and
[
a]
Nobuaki Kambe*
Fatty acids are essential to natural life because they act as
key components in biological membranes and glycerides, as
well as in various biologically active agents, such as prosta-
boxy functionality with Grignard reagents in the presence of
[8e,12,13]
1,3-butadiene as an additive,
in combination with an
[14]
in situ protection procedure. As an example of a synthetic
application of this method, the regioisomers of elaidic acid
were synthesized through an iterative cross-coupling proce-
dure.
[1]
glandins and endocannabinoids. For the construction of
structurally diverse carbon frameworks of fatty acids, transi-
tion-metal-catalyzed cross-coupling reactions appear to be
the most straightforward and efficient methods for carbonÀ
In our previous studies, we reported that the Ni-catalyzed
cross-coupling reactions of alkyl halides with alkyl Grignard
carbon bond formation and they have been employed in the
synthesis of a wide variety of fatty acids with unsaturated
[8e,12]
reagents in the presence of butadienes
were effective
[
2–4]
bonds.
However, these methods are limited to reactions
for the construction of hydrocarbon skeletons that contained
aprotic polar functionalities, such as ketones, esters, and ni-
2
[3]
[4]
at sp or sp carbon atoms, in which the stereochemistry
of the olefinic moieties that are being introduced must be
controlled. In contrast to these reactions, cross-coupling re-
[8e,12f]
triles.
When alkyl halides that contained a carboxylic
acid group are subjected to this cross-coupling reaction,
without employing tedious protection-deprotection process-
es, the deprotonation of the carboxylic acid group is un-
avoidable. Thus, to develop a simple and straightforward
route to fatty acids with various carbon chains, we examined
the Ni-catalyzed cross-coupling reactions of 6-bromohexano-
ic acid (1a) with excess amounts of nBuMgCl under various
conditions and we found that the expected decanoic acid
was obtained in quantitative yield as the sole product, with
no evidence of any undesirable side reactions, when the re-
action was conducted at 08C for 1 h in the presence of
2.4 equivalents of nBuMgCl (Scheme 1). In this reaction, a
3
[5]
actions between sp -hybridized carbon centers appear to
be a useful and, potentially, more-promising tool, because
they are applicable to the synthesis of both saturated and
unsaturated fatty acids and they are free from the problems
[6–8]
associated with double-bond stereochemistry.
However,
owing to the lower tolerance of the carboxylic group toward
organometallic reagents, including transition-metal com-
[9,10]
[3c,4b,8,11]
plexes,
ic equivalents
protected carboxy groups
or their synthet-
[3a,d,4c]
are often employed. Herein, we report a
convenient and efficient one-pot procedure for the construc-
tion of carbon frameworks of fatty acids by using the nickel-
catalyzed cross-coupling of alkyl halides that contain a car-
[
a] Dr. T. Iwasaki, K. Higashikawa, Dr. V. P. Reddy, W. W. S. Ho,
Prof. Dr. H. Kuniyasu, Prof. Dr. N. Kambe
Department of Applied Chemistry
Graduate School of Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-7390
Scheme 1. Cross-coupling of bromoalkanoic acid 1a with nBuMgCl in
the presence of a Ni catalyst.
E-mail: kambe@chem.eng.osaka-u.ac.jp
stoichiometric amount of nBuMgCl acted as base to form
the magnesium carboxylate salt of compound 1a, which
then underwent cross-coupling at the other terminal carbon
atom with the remaining nBuMgCl.
To avoid consuming the Grignard coupling partner during
the deprotonation process, we tested other Grignard re-
agents for use as the base in the cross-coupling of bromo-
hexanoic acid (1a) with nOctMgCl (2b). The in situ protec-
tion of compound 1a by deprotonation with the base was
[
b] Prof. Dr. Y. Fujimoto, Prof. Dr. K. Fukase
Department of Chemistry, Graduate School of Science
Osaka University, Toyonaka, Osaka 560-0043 (Japan)
[
c] Prof. Dr. J. Terao
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering
Kyoto University, Katsura
Nishikyo-ku, Kyoto 615-8510 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204222.
2956
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2956 – 2960

COMMUNICATION
performed by stirring compound 1a with one equivalent of
a Grignard reagent at À788C for 10 min in a THF solution
that contained one equivalent of N-methyl-2-pyrrolidone
Table 2. Cross-coupling of alkyl bromides that contain a carboxy group
[
a]
(
1) with n-octyl Grignard reagent 2b.
(
NMP). When methyl- and phenyl Grignard reagents were
used, compound 3ab was obtained in 84% and 56% yield,
respectively (Table 1, entries 1 and 2). In contrast to these
[
b]
Entry
1
Bromocarboxylic acid
1
Yield [%]
54
Table 1. Ni-catalyzed cross-coupling of 6-bromohexanoic acid (1a) with
octylmagnesium chloride by using different Grignard reagents as the
1b
[
a]
base.
[
c]
2
3
4
1c
1d
1e
n.i.
>99
95
[
b]
Entry
Base
2
Yield [%]
5
6
1 f
1g
>99
1
2
3
4
5
6
MeMgBr
PhMgBr
nBuMgCl
iBuMgCl
sBuMgCl
tBuMgCl
2c
2d
2a
2e
2 f
2g
84
56
95
>99
>99
>99
97
7
1h
97
[
(
(
a] Reaction conditions: 6-Bromohexanoic acid (195 mg, 1.0 mmol), THF
[
(
a] Reaction conditions: Compound 1 (1.0 mmol), THF (1.5 mL), NMP
95 mL, 1.0 mmol), tBuMgCl (in THF, 1.0 mmol), À788C, 10 min; then,
1.5 mL), NMP (95 mL, 1.0 mmol), C12
in THF, 1.0 mmol), À788C, 10 min; then, nOctMgCl (in THF, 1.4 mmol),
(1 mol%, 1.3 mg), 08C,
h. [b] GC yield after conversion into the corresponding methyl ester.
H26 as an internal standard, RMgCl
nOctMgCl (in THF, 1.4 mmol), gaseous 1,3-butadiene (22 mL, 1.0 mmol),
NiCl (1 mol%, 1.3 mg), 08C, 1 h. [b] Yield of isolated product. [c] Not
isolated (n.i.).
gaseous 1,3-butadiene (22 mL, 1.0 mmol), NiCl
1
2
2
unsatisfactory results, quantitative yields were obtained
when n-, i-, s-, and tBuMgCl were used as the base (Table 1,
entries 3–6). Among these reagents, tBuMgCl was found to
be a more-suitable base than n-, i-, and sBuMgCl, because
the latter three reagents, when they remained, competed
with the different Grignard reagents that were subsequently
added for the cross-coupling reaction with bromide 1 (see
below). Unfortunately, metal hydrides, such as NaH and
tained in either case. The reaction of branched bromocar-
boxylic acid 1 f proceeded efficiently, thereby affording the
product in excellent yield (Table 2, entry 5). An aromatic
carboxylic acid moiety also remained intact under the re-
AHCTUNGTRENNUNGa ction conditions and the corresponding coupling product
(3hb) was obtained in 97% yield (Table 2, entry 7).
The results for the cross-coupling of 6-bromohexanoic
acid (1a) with various Grignard reagents are summarized in
Table 3. Primary alkyl Grignard reagents afforded their cor-
responding carboxylic acids (3) in good-to-excellent yields
(Table 3, entries 1, 2, and 5–7). Under the same conditions,
iBuMgCl and sBuMgCl yielded their corresponding carbox-
ylic acids in 75% and 52% yields, respectively, and no prod-
uct was obtained with tBuMgCl (Table 3, entries 2–4). These
results indicate that the steric bulkiness of the carbon chains
is an important factor in this reaction. Similar trends were
also observed with Grignard reagents 2j–2l (Table 3, en-
tries 6–8). Secondary Grignard reagent 2l gave the corre-
sponding coupling product in reasonable yield. A more ster-
ically hindered primary Grignard reagent (2m) reacted slug-
gishly, even when 5 mol% of the Ni catalyst was used
(Table 3, entry 9). PhMgBr did not give the desired product,
but reacted at the carboxy carbon to afford the correspond-
ing ketone as the major product (Table 3, entry 10).
CaH , were not suitable and resulted in lower yields of the
2
cross-coupling products. In the absence of NMP, the yield
decreased slightly (by about 5%).
Next, we performed the Ni-catalyzed cross-coupling re-
ACHTUNGTRENNUNGa ctions of various bromocarboxylic acids (1) under our opti-
mized conditions. As shown in Table 2, when a-bromoacetic
acid (1b) was used as the substrate, coupling product 3bb
was obtained in 54% yield (Table 2, entry 1). b-Bromopro-
pionic acid (1c) gave a complex mixture and no coupling
product was isolated (Table 2, entry 2). This result is in
sharp contrast to the successful cross-coupling of the corre-
sponding nickelalactones, which suggests that the mecha-
nisms for these two reactions are different from each
[7]
other. Carboxylic acids that contained a longer methylene
tether could be coupled with Grignard reagent 2b in good-
to-excellent yields (Table 2, entries 3, 4, and 6). Because Ni
catalyzes the cross-coupling of alkyl tosylates and fluorides
Grignard reagents with long alkyl chains are less easily ac-
cessible and are also difficult to handle, owing to their low
solubility in THF. Indeed, when octadecylmagnesium bro-
mide was prepared from 1-bromooctadecane and magnesi-
um metal at a concentration of about 1m in THF by using
[12d,e]
with Grignard reagents,
we examined the reactions of
decanoic-acid derivatives that contained a TsO group or an
F atom on the terminal carbon atom as analogues of com-
pound 1g; however the expected products were not ob-
Chem. Eur. J. 2013, 19, 2956 – 2960
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2957

N. Kambe et al.
Table 3. Cross-coupling of compound 1a with various Grignard re-
[
a]
ACHTUNGTRENNUNGa gents.
[
b]
Entry
RMgX
(CH 13MgCl
iBuMgCl
sBuMgCl
tBuMgCl
2
Yield [%]
1
2
3
4
CH
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
)
2h
2e
2 f
2g
95
75
52
n.d.
5
6
7
8
2i
2j
83
92
95
Scheme 2. Cross-coupling through a reverse-addition procedure.
2k
2l
2m
2d
76
25
[
c]
9
1
[
d]
0
n.d.
[
(
1
(
a] Reaction conditions: 6-Bromohexanoic acid (1.0 mmol), THF
1.5 mL), NMP (95 mL, 1.0 mmol), tBuMgCl (in THF, 1.0 mmol), À788C,
0 min; then, compound 2 (in THF, 1.4 mmol), gaseous 1,3-butadiene
22 mL, 1.0 mmol), NiCl (1 mol%, 1.3 mg), 08C, 1 h. [b] Yield of isolat-
ed product. [c] 5 mol% NiCl . [d] Not detected (n.d.); 6-bromo-1-phenyl-
2
2
hexan-1-one (44% yield) was obtained as the major product.
standard procedures, the resulting mixture became a thick
slurry and was difficult to handle with a syringe. In such a
case, a reverse-addition procedure was found to be effective
for carrying out the cross-coupling efficiently: A solution of
compound 1a and tBuMgCl in THF was transferred by
means of a cannula into a solution of the Grignard reagents
Scheme 3. Synthesis of elaidic acid and its regioisomers.
(
2b, 2n, or 2o) at À788C, which were generated by the re-
Aa ctions of octyl, octadecyl, and cis-octadec-9-enyl bromides
C
H
T
U
N
G
T
R
E
N
N
U
N
G
work-up, followed by direct bromination of the siloxy group
[
16]
with two equivalents of magnesium in THF, respectively.
The cross-coupling reactions were performed by adding
with Br PPh .
The second coupling reactions of com-
2
3
pounds 6a–6e with alkyl Grignard reagents that had an ap-
propriate chain length afforded elaidic acid (7a), as well as
a series of its regioisomers (7b–7e) that contained a trans-
olefin unit at the w-5 to w-8 positions.
NMP, 1,3-butadiene, and NiCl to the mixtures. After stir-
2
ring at 08C for 1 h, the corresponding carboxy acids (3ab,
3
an, and 3ao) were obtained in good-to-excellent yields, as
shown in Scheme 2. Notably, the carbon chain of the readily
available oleic acid could be incorporated into cis-15-tetra-
cosenoic acid (3ao, nervonic acid) through the cis-octadec-
In summary, various fatty acids have been prepared
through the alkylÀalkyl cross-coupling of bromoalkyl car-
boxylic acids with Grignard reagents by using a nickelÀbuta-
9-enyl bromide that is formed from the successive reduction
diene catalytic system. These cross-coupling reactions pro-
ceeded efficiently and exclusively in a convenient one-pot
procedure, combined with prior deprotonation by tBuMgCl
as a base. Nervonic acid was synthesized by using this
method with the incorporation of the unsaturated carbon
skeleton of the easily available oleic acid as part of its
carbon framework. The synthetic utility of this procedure
was demonstrated in the synthesis of elaidic acid and its re-
gioisomers through sequential Ni-catalyzed three-compo-
nent cross-coupling reactions by using (E)-6-bromohex-3-
enyl-1-ol as a synthetic building block of a double-bond
unit. This method provides a simple and convenient route to
carboxylic acids with various carbon chains and will open up
and bromination of oleic acid with complete retention of the
double-bond stereochemistry.
Finally, we attempted the synthesis of the w-5 to w-8 re-
[15]
gioisomers of elaidic acid by using an iterative cross-cou-
pling approach with (E)-1-bromo-6-(tert-butyldimethylsilox-
y)hex-3-ene (4) as a trans-olefin building block (Scheme 3).
The first cross-coupling reaction was performed by using [6-
(
(
tert-butyldimethylsiloxy)hex-3-en-1-yl]magnesium bromide
5), which was generated in situ from compound 4, and a
series of w-bromocarboxylic acids with a C –C methylene
5
9
carbon tether. The corresponding coupling products (6a–6e)
were obtained in good-to-excellent yields after the usual
2958
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Chem. Eur. J. 2013, 19, 2956 – 2960

NickelÀButadiene Catalytic System for Preparing Fatty Acids
COMMUNICATION
new fields of fatty acid chemistry in both biological and ma-
terials disciplines.
Vꢂvrovꢂ, T. Holas, A. Hrabꢂlek, Bioorg. Med. Chem. 2006, 14,
7
681–7687. For the stoichiometric reactions of alkylcuprates with w-
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[
7] Five-membered nickelalactones have a b-metalated propionate
Experimental Section
structure and have been used as carbon nucleophiles in coupling re-
actions with alkyl iodides to afford aliphatic carboxylic acids; see:
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General procedure for the cross-coupling of bromocarboxylic acid with
Grignard reagents: tBuMgCl (2g; 0.72m in THF, 1.4 mL, 1.0 mmol) was
added into a Schlenk tube that contained a bromocarboxylic acid (1;
1
.0 mmol), NMP (95 mL, 1.0 mmol), and THF (1.0 mL) at À788C and the
mixture was stirred for 10 min under nitrogen atmosphere. The
Grignard reagent (2; in THF, 1.4 mmol), gaseous 1,3-butadiene (22.4 mL,
atm, 1.0 mmol), and NiCl (1.3 mg) were added at the same tempera-
a
CastaÇo, A. M. Echavarren, Organometallics 1994, 13, 2262–2268.
3
1
2
[8] For cross-coupling reactions between sp carbon atoms that contain
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reaction was quenched by the addition of aqueous HCl and the resulting
solution was extracted with CH
2 2
Cl (3ꢁ30 mL). The combined extract
was dried over Na SO , concentrated under vacuum, and purified by
2
4
column chromatography on silica gel to afford the desired product.
Acknowledgements
8
964–8967; Angew. Chem. Int. Ed. 2012, 51, 8834–8837. With alkyl
This work was supported by a Grant-in-Aid for Scientific Research (S)
Grignard reagents, see: e) S. P. Singh, J. Terao, N. Kambe, Tetrahe-
dron Lett. 2009, 50, 5644–5646.
(
20225004), a Grant-in-Aid for Young Scientists (B) (22750094), and a
Grant-in-Aid for Scientific Research on Innovative Areas (2015) from
the Ministry of Education, Culture, Sports and Technology, Japan. T.I. ac-
knowledges the NOVARTIS Foundation (Japan) for the Promotion of
Science, Asahi Kasei Pharma Co., Ltd., and the Frontier Research
Center of Osaka University. We also thank the Instrumental Analysis
Center of the Faculty of Engineering, Osaka University, for providing as-
sistance with the HRMS analysis.
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Keywords: additives · alkylation · CÀC coupling · fatty
acids · nickel
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