Solvent and ligand partition reaction pathways in nickel-mediated carboxylation of methylenecyclopropanes

Article abstract of DOI:10.1039/b515684j

Methylenecyclopropanes are carboxylated with gaseous carbon dioxide in the presence of a stoichiometric amount of a nickel complex; the reaction pathways are significantly influenced by the reaction solvent and the amine ligand. The Royal Society of Chemi

Full text of DOI:10.1039/b515684j

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Solvent and ligand partition reaction pathways in nickel-mediated
carboxylation of methylenecyclopropanes
Masahiro Murakami,* Naoki Ishida and Tomoya Miura
Received (in Cambridge, UK) 4th November 2005, Accepted 4th January 2006
First published as an Advance Article on the web 13th January 2006
DOI: 10.1039/b515684j
varied significantly as a function of reaction solvent and amine
ligand (Table 1). When 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,
2.2 equiv) was used as the amine ligand in toluene solvent,
cyclopropane derivative 2a was obtained along with a small
amount of the branched a,b-unsaturated ester 3a6 (73%, 2a : 3a :
4a 5 93 : 7 : 0, entry 1). In contrast, the use of more polar solvents
favoured the formation of 3a (entries 2–5). In particular, the
reaction with DBU in N-methyl-2-pyrrolidinone (NMP) gave 3a in
78% yield as the major product (2a : 3a : 4a 5 6 : 94 : 0). Here, the
formation of the linear c,d-unsaturated ester 4a was not observed.
However, to our surprise, use of 7-methyl-1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (MTBD) instead of DBU altered the reaction
course to favour production of the linear c,d-unsaturated ester 4a;7
the reaction with MTBD in NMP gave 4a in 52% yield exclusively
(entry 8). At a higher CO2 pressure of 5 atm, the yield was
improved (67%, 2a : 3a : 4a 5 0 : 1 : 99, entry 9). Suppression of
the formation of 4a with DBU, and of 2a and 3a with MTBD
suggests different mechanisms operate with DBU and MTBD
(vide infra).
Methylenecyclopropanes are carboxylated with gaseous carbon
dioxide in the presence of a stoichiometric amount of a nickel
complex; the reaction pathways are significantly influenced by
the reaction solvent and the amine ligand.
The incorporation of carbon dioxide into organic compounds
presents an important challenge in chemistry, as reduction of
greenhouse gases has emerged as a pressing global issue. In
addition, due to its abundance as a raw material and innocuous
nature, the development of methods to activate intrinsically inert
carbon dioxide and to fix it into organic compounds becomes of
practical value to synthetic chemists.1 On the other hand, a
number of transition metal-mediated processes involving the
carbon–carbon bond cleavage of methylenecyclopropanes have
been reported.2 Methylenecyclopropanes are unique in that
coordination of their carbon–carbon double bonds to low-valent
transition metals triggers cleavage at either the proximal Csp2–
Csp3 bond or the distal Csp3–Csp3 bond of the cyclopropane
core.3 There has been, however, only one example of carboxylation
of methylenecyclopropanes with carbon dioxide; a palladium-
catalysed reaction at relatively high temperature forms unsaturated
The partitioning of the various reaction pathways can be
explained by assuming the mechanism shown in Scheme 1.
Initially, nickel(0) forms the p-complex I with the carbon–carbon
double bond of methylenecyclopropane and carbon dioxide. For
the formation of the products 2a and 3a, oxidative cyclisation
occurs to give the nickelacycle II.8 Direct hydrolysis of II followed
by methylation with Me3SiCHN2 affords 2a. Alternatively, the
five-membered ring lactones through
a sequence involving
oxidative addition of the distal carbon–carbon bond to palladium,
insertion of carbon dioxide and, finally, reductive elimination
(eqn. 1).4
ð1Þ
Table 1 Nickel-mediated carboxylation of 1a with CO2 under various
conditionsa
It has been reported recently that low-valent nickel species
mediate the coupling of carbon dioxide with various unsaturated
hydrocarbons under mild conditions,5 which encouraged us to
explore a new nickel-mediated carboxylation reaction of methyl-
enecyclopropanes. Notably, it was found that diverse reaction
pathways are partitioned in response to reaction conditions, such
as a reaction solvent and the amine ligand employed, affording
products essentially different from those obtained in the palladium
case mentioned above.
Ratioc
Entry Solvent
Amine
Yield (%)b 2a
:
3a
:
4a
1
2
3
4
5
6
7
8
9
a
toluene
THF
DMF
DBU
DBU
DBU
73
77
68
66
78
93
40
23
4
6
0
0
0
0
7
60
77
96
94d
0
0
0
1
0
0
0
0
0
A solution of benzylidenecyclopropane (1a, 1.1 equiv), Ni(cod)2
(1 equiv, cod 5 cycloocta-1,5-diene) and an amine ligand
(2.2 equiv) was stirred at 0 uC for 4 h under an atmosphere of
carbon dioxide (1 atm). An aqueous workup followed by
methylation with Me3SiCHN2 afforded a mixture of methyl esters
of the carboxylated products. The distribution of these products
CH3CN DBU
NMP
toluene
THF
NMP
NMP
DBU
MTBD 27
MTBD 40
MTBD 52
MTBD 67e
. 99
. 99
. 99
99
Conditions: 1a (1.1 equiv), CO2 (1 atm), Ni(cod)2 (1.0 equiv),
amine (2.2 equiv), solvent, 0 uC, 4 h; hydrolysis with diluted HCl;
Department of Synthetic Chemistry and Biological Chemistry, Kyoto
University, Katsura, Kyoto, 615-8510, Japan.
E-mail: murakami@sbchem.kyoto-u.ac.jp; Fax: +81 75 383 2748;
Tel: +81 75 383 2747
b
then methylation with TMSCHN2, MeOH.
Combined yields.
Ratio determined by 1H NMR. E : Z 5 94 : 6. CO2 (5 atm).
c
d
e
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Chem. Commun., 2006, 643–645 | 643

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incorporated at the expected positions (eqn. 2), whereas no
deuterium incorporation was observed with 4a (eqn. 3). In
contrast, when MTBD(d3) having a CD3 group was used as the
base, the vinylic position of product 4a was deuterated (eqn. 4).
These contrasting results shown in eqns. 3 and 4 can be explained
by assuming that the intermediate nickelacycle VI abstracts a
proton from the methyl group of MTBD prior to an aqueous
workup.
ð2Þ
ð3Þ
Scheme 1 Proposed mechanism for the carboxylation reaction of 1a.
intermediate II may undergo b-carbon elimination to give the six-
membered nickelacycle IV, probably through the dissociated ionic
complex III, which would allow a syn (or synclinal) conformation
of the nickel–carbon linkage with the cleaving carbon–carbon
bond.9 Hydrolysis and methylation then leads to the production of
3a. We assume that b-carbon elimination occurs more easily with
the ionic intermediate III than with the nickelacycle II and that a
polar solvent such as NMP facilitates the formation of the ionic
intermediate to favour the formation of 3a.10,11 On the other hand,
when MTBD is used as the amine ligand, the proximal carbon–
carbon bond cis to the phenyl group of 1a undergoes oxidative
addition giving the nickelacycle V.12,13 Insertion of carbon dioxide
into the nickel–sp3 carbon linkage gives VI. The corresponding E
product 4a is selectively produced by subsequent protonolysis and
methylation.14
ð4Þ
Under these optimised conditions, a structurally diverse set of
methylenecyclopropanes 1 was examined (Table 2).{ The reactions
of (arylmethylidene)cyclopropanes 1b–1f in toluene produced the
corresponding cyclopropane derivatives 2b–2f with moderate to
good selectivities, except in the case of 1d (entries 1–5). The
chlorophenyl moiety of 1f remained intact in the presence of
nickel(0). The alkylidenecyclopropane derivative 1g gave the ring-
opening product 3g as the major product, even when toluene was
used as solvent (entry 6).15 All the reactions in NMP gave the
branched a,b-unsaturated esters 3 selectively (entries 7–12). The
We quenched the reactions forming 2a, 3a and 4a with DCl/
D2O (2 M) in order to support the intermediacy of II, IV and VI.
With the products 2a and 3a obtained, deuterium atoms were
Table 2 Nickel-mediated carboxylation of 1 with CO2
Ratioc
Entry
1 (R)
Conditionsa
Yield (%)b
2
:
3 (E : Z)d
:
4
1
2
3
4
5
6
7
8
1b (4-MeC6H4)
1c (2-MeC6H4)
1d (4-MeOC6H4)
1e (4-FC6H4)
1f (4-ClC6H4)
1g (Ph(CH2)2)
1b
1c
1d
1e
1f
1g
1b
1c
1d
1e
1f
A
A
A
A
A
A
B
75
77
78
79
79
70
70
72
79
81
87
68
58
55
40
66
64
37
78
92
51
89
93
20
1
3
1
1
8
0
0
0
0
0
0
0
22
0
0
0
0
0
0
0
0
0
0
0
0
8
49 (91 : 9)
11
7
80 (63 : 35)
99 (93 : 7)
97 (97 : 3)
99 (91 : 9)
99 (93 : 7)
B
9
B
10
11
12
13
14
15
16
17
18
a
Be
Be
B
92 (93 : 7)
. 99 (56 : 44)
C
C
C
C
C
C
3
4
1
1
0
6
97
96
99
99
. 99
94
1g
Common conditions: 1 (1.1 equiv), CO2, Ni(cod)2 (1.0 equiv), amine (2.2 equiv), 0 uC, 4 h; then workup. Conditions A: 1 atm of CO2, DBU,
b
in toluene; conditions B: 1 atm of CO2, DBU, in NMP; conditions C: 5 atm of CO2, MTBD, in NMP. Combined yields. Ratio determined
c
by 1H NMR. Obtained as a mixture of E and Z isomers. The ratio given in parentheses if determined. 6 h.
d
e
644 | Chem. Commun., 2006, 643–645
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pp. 1185–1205; (c) I. Nakamura and Y. Yamamoto, Adv. Synth. Catal.,
2002, 344, 111.
3 For an example of regiochemical control of the site of cleavage by
reaction conditions, see: M. Suginome, T. Matsuda and Y. Ito, J. Am.
Chem. Soc., 2000, 122, 11015.
4 (a) Y. Inoue, T. Hibi, M. Satake and H. Hashimoto, J. Chem. Soc.,
Chem. Commun., 1979, 982; (b) P. Binger and H.-J. Weintz, Chem. Ber.,
1984, 117, 654.
5 (a) H. Hoberg, Y. Peres and A. Milchereit, J. Organomet. Chem., 1986,
307, C38; (b) S. Saito, S. Nakagawa, T. Koizumi, K. Hirayama and
Y. Yamamoto, J. Org. Chem., 1999, 64, 3975; (c) J. Louie, J. E. Gibby,
M. V. Farnworth and T. N. Tekavec, J. Am. Chem. Soc., 2002, 124,
15188; (d) M. Aoki, M. Kaneko, S. Izumi, K. Ukai and N. Iwasawa,
Chem. Commun., 2004, 2568; (e) M. Takimoto, T. Mizuno, Y. Sato and
M. Mori, Tetrahedron Lett., 2005, 46, 5173 and references therein.
6 A mixture of stereoisomers.
7 Production of 4a was not observed with other amines like
DBN, TMEDA, 2,29-bipyridyl, 1,2-dimethylimidazole and 2-methyl-2-
oxazoline.
8 For an example of the nickel-mediated oxidative cyclisation on ethylene,
see: H. Hoberg, Y. Peres, C. Kru¨ger and Y.-H. Tsay, Angew. Chem., Int.
Ed. Engl., 1987, 26, 771.
9 For examples of b-carbon elimination with cyclopropylmethyl–nickel
species, see: (a) P. Binger, Angew. Chem., Int. Ed. Engl., 1972, 11, 309;
(b) S. Saito, M. Masuda and S. Komagawa, J. Am. Chem. Soc., 2004,
126, 10540.
10 The branched ester 3a was obtained as the major product (72%, 2a : 3a :
4a 5 20 : 80 : 0) when the reaction was carried out initially in toluene for
4 h and then CH3CN was added to the reaction mixture which was
further stirred for an additional 4 h prior to an aqueous workup.
11 Direct rearrangement of II to IV cannot be ruled out. See: P. Binger,
M. J. Doyle and R. Benn, Chem. Ber., 1983, 116, 1.
12 Nickel catalysts generally prefer cleavage of the proximal carbon–carbon
bond by insertion whereas palladium catalysts prefer that of the distal
one: (a) R. Noyori, Y. Kumagai, I. Umeda and H. Takaya, J. Am.
Chem. Soc., 1972, 94, 4018; (b) S. A. Bapuji, W. B. Motherwell and
M. Shipman, Tetrahedron Lett., 1989, 30, 7107.
13 Regioselective insertion of Zr(II) into the proximal carbon–carbon bond
cis to the phenyl group of 1a has been observed: P. Binger, P. Mu¨ller,
S. Podubrin, S. Albus and C. Kru¨ger, J. Organomet. Chem., 2002, 656,
288.
use of MTBD as the amine ligand resulted in highly selective
formation of the E linear c,d-unsaturated esters 4, although the
yields were moderate (entries 13–18).
In conclusion, we have described the nickel-mediated carbox-
ylation of methylenecyclopropanes with carbon dioxide. Three
types of carboxylated products, which are all different from that
obtained by the palladium-catalysed reaction,4 are prepared
exclusively or preferentially depending on the reaction solvent
and the amine ligand employed.
This work was supported by a grant from the Programmed
R&D of the Research Institute of Innovative Technology for
Earth, Japan. N.I. thanks the Japan Society of Promotion of
Science for a fellowship.
Notes and references
{ General procedure: To a stirred suspension of Ni(cod)2 (82.5 mg,
0.30 mmol) in a freshly distilled solvent (3 mL) in a Schlenk-type flask
under a nitrogen atmosphere at 0 uC was added an amine ligand
(0.66 mmol). The mixture was degassed by a freeze–pump–thaw method,
and then carbon dioxide was introduced. Substrate 1 (0.33 mmol) was
added to the resulting pale yellow suspension at 0 uC. After the reaction
mixture was stirred at 0 uC for 4 h, diluted HCl aq. (2 M) was added to the
reaction mixture. The aqueous layer was extracted with ethyl acetate. The
combined organic layer was washed with brine, dried over Na2SO4 and
concentrated. The residue was treated with TMSCHN2 in Et2O/MeOH.
The solvent was removed under reduced pressure and the residue was
purified by preparative thin-layer chromatography (hexane : ethyl acetate)
to give the product.
1 Reviews: (a) X. Yin and J. R. Moss, Coord. Chem. Rev., 1999, 181, 27;
(b) D. Walther, M. Ruben and S. Rau, Coord. Chem. Rev., 1999, 182,
67; (c) M. Aresta, J. N. Armor, M. A. Barteau, E. J. Beckman, A. T. Bell,
J. E. Bercaw, C. Creutz, E. Dinjus, D. A. Dixon, K. Domen,
D. L. Dubois, J. Eckert, E. Fujita, D. H. Gibson, W. A. Goddard,
D. W. Goodman, J. Keller, G. J. Kubas, H. H. Kung, J. E. Lyons,
L. E. Manzer, T. J. Marks, K. Morokuma, K. M. Nicholas, R. Periana,
L. Que, J. Rostrup-Nielson, W. M. H. Sachtler, L. D. Schmidt, A. Sen,
G. A. Somorjai, P. C. Stair, B. R. Stults and W. Tumas, Chem. Rev.,
2001, 101, 953.
14 Product 4a can result from carboxylation of 1-phenylbuta-1,3-diene, to
which 1a may possibly isomerise in the presence of nickel(0). The present
reaction conditions, however, caused no carboxylation reaction of
1-phenylbuta-1,3-diene prepared independently.
2 Reviews: (a) P. Binger and H. M. Bu¨ch, Top. Curr. Chem., 1987, 135,
77; (b) T. Ohta and H. Takaya, in Comprehensive Organic Synthesis, eds.
B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, Vol. 5,
15 The contrasting results obtained with 1g and (arylmethylidene)-
cyclopropanes 1a–1f are accounted for by assuming the more stable
nature of the nickel–benzylic carbon linkage of II.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 643–645 | 645