Cp2ZrCl2-mediated three-component coupling reactions of CO2, ethylene (or alkynes), and electrophiles leading to carboxylic acid derivatives

Article abstract of DOI:10.1055/s-2005-864807

Zirconacycles 1 and 2 can be simply generated from Cp₂ZrCl ₂, EtMgBr, and an atmospheric pressure of CO₂. The treatment of Cp₂ZrCl₂ with EtMgBr followed by exposure to CO₂ generates zirconacycle 1, which can react with various electrophiles to give a variety of carboxylic acid derivatives. Unsaturated zirconacycles 2 can also generated from Cp₂ZrCl₂, EtMgBr, alkynes, and CO₂. Complexes 2 react with electrophiles to give α,β-unsaturated acids stereoselectively.

Full text of DOI:10.1055/s-2005-864807

LETTER
919
Cp2ZrCl2-Mediated Three-Component Coupling Reactions of CO2, Ethylene
(or Alkynes), and Electrophiles Leading to Carboxylic Acid Derivatives
Carboxylic
Acid
D
o
erivatives hei Yamashita, Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax +81(6)68797396; E-mail: chatani@chem.eng.osaka-u.ac.jp
Received 21 January 2005
COOH
O
Abstract: Zirconacycles 1 and 2 can be simply generated from
Cp2ZrCl2, EtMgBr, and an atmospheric pressure of CO2. The treat-
ment of Cp2ZrCl2 with EtMgBr followed by exposure to CO2 gen-
erates zirconacycle 1, which can react with various electrophiles to
give a variety of carboxylic acid derivatives. Unsaturated zircona-
cycles 2 can also generated from Cp2ZrCl2, EtMgBr, alkynes, and
CO2. Complexes 2 react with electrophiles to give a,b-unsaturated
acids stereoselectively.
R
O
R
Br
COOH
CO2
R
COOH
CuI
R
Br
Ni(0)
Cp2ZrCl2
Cp2Zr
+
O
O
Key words: carbon dioxide, carboxylic acids, Grignard reactions,
metallacycles, nucleophilic additions, alkynes
EtMgBr 0 °C, 1 atm
Br
1
CuI
R
R
COOH
PhI, Ni(0)
Carbon dioxide (CO2) is an attractive C1 building block in
organic synthesis, because it is highly functional, abun-
dant, inexpensive, nontoxic, and nonflammable. The fixa-
tion of CO2 promoted by transition metal complexes has
experienced particularly significant progress.1 The hydro-
genation of CO2 to formic acid or related reactions cata-
lyzed by ruthenium complexes has been the subject of
extensive study.2 Perhaps the most promising reactions in-
volve the reaction of CO2 and epoxides in preparing five-
membered cyclic carbonates3,4 or the copolymerization of
CO2 and epoxides leading to polycarbonates.5 The direct
carboxylation of an aromatic ring (Kolbe–Schmitt reac-
tion) is also of interest in this regard.6
CO2
COOH
Ph
R
R
R
R
Br
COOH
Cp2Zr
O
O
2
Scheme 1
potential as a b-metalocarboxylic acid or a homoenolate is
self evident.15 We succeeded in generating the complex 1
in situ, directly from Cp2ZrCl2 by an improved method.
Thus, the treatment of Cp2ZrCl2 with EtMgBr in THF at
–78 °C followed by exposure to CO2 at 0 °C gave com-
plex 1, which was used in further reactions without isola-
tion (Equation 1). It is noteworthy that complex 1 can be
converted into various unsaturated carboxylic acid deriv-
atives by coupling with a variety of electrophiles. Some
representative examples are summarized in Scheme 1,
and the results on the reaction with allylic electrophiles
are shown in Table 1. Treatment of 1 with allyl bromide
resulted in no reaction. However, the use of CuI (1.2
equiv) as the promoter gave 5-hexenoic acid (3) in 29%
yield.16,17 The addition of DMPU (2 equiv) improved the
yield to 76%. A reaction with cinnamyl bromide gave 6,
indicating that the reaction proceeds by an SN2¢ mecha-
nism. The reaction at 20 °C slightly improved the yield of
Recently, the nickel-mediated or catalytic incorporation
of CO2 into unsaturated hydrocarbons, such as alkynes,7
allenes,8 1,3-butadienes,9 and diynes10 have been exten-
sively studied. However, due to the relatively inert nature
of CO2, the number of efficient processes for chemical
fixation remain limited, compared with gaseous CO.11
Thus, a new type of transformation of CO2 continues to
pose a significant synthetic challenge. We wish to report
here on a simple method for the generation of a zir-
conocene–CO2–ethylene complex
1 and new zir-
conocene–CO2–alkyne complexes 2, and their use in the
synthesis of unsaturated carboxylic acids (Scheme 1).12
Zirconacycles, including zirconacyclopentadienes, zir-
conacyclopentenes, and zirconacyclopentanes, are recog-
nized as useful intermediates in organic synthesis.13 Alt
reported that the zirconacycle 1 can be prepared from
Cp2Zr(C2H4)(PMe3) and CO2.14 However, to the best of
our knowledge, synthetic applications in which this com-
plex is used have not been reported, although its high
CO2
0 °C
EtMgBr
Cp2ZrCl2
Cp2Zr
O
THF
–78 °C, 1 h
O
1
Equation 1
SYNLETT 2005, No. 6, pp 0919–0922
0
6.
0
4.
2
0
0
5
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864807; Art ID: U02105ST
© Georg Thieme Verlag Stuttgart · New York

920
K. Yamashita, N. Chatani
LETTER
6. A reaction with propargyl bromide resulted in allenyl- isomers was low. Our attention was next focused on the
ation to give 8 in 65% yield. The reaction of cyclohex- generation of an unsaturated zirconium–CO2 complex,
enone with 1 resulted in selectively 1,4-conjugate addition such as 2. It is well known that ethylene, on a zirconium
to give 9 in good yield.
complex can be replaced by other molecules, such as
alkynes, aldehydes, nitriles, and isocyanates, to generate
other zirconacycles.19 Thus, complex 2 was obtained sim-
ply by the treatment of Cp2ZrCl2 with EtMgBr, the addi-
tion of an alkyne, and exposure of the reaction mixture to
CO2, as shown in Scheme 2.20 The use of 3-hexyne gave
2-ethyl-2-pentenoic acid (12a) in 70% isolated yield upon
acidic treatment. A terminal alkyne gave the correspond-
ing unsaturated carboxylic acid 12d regioselectively in
good yield.
A nickel complex also promotes the coupling reactions.18
The reaction of 1 with cinnamyl bromide in the presence
of Ni(cod)2 (0.5 equiv) resulted in a-allylation to give
product 10, in contrast to CuI, where g-allylation took
place. Palladium complexes also led to the selective for-
mation of a-allylation product 10, but the efficiency was
lower than when the nickel catalyst was used (17%).
The use of PrMgBr in place of EtMgBr, followed by
treatment with allyl bromide gave the expected carboxylic
acids in low yield and the ratio of the normal and branched
Table 1 The Reaction of 1 with Various Electrophilesa
Electrophile
Promoterb
Product
Yield (%)c,d
76
Br
COOH
CuI, DMPU
3
CuI, DMPUCuI
44
70
Br
Br
Br
COOH
COOH
4
CuI
CuI
67 (57:43)
Br
e
Me
5
43 (92:8)
51 (93:7)f
COOH
Ph
Br
Ph
6
CuI
CuI
24f
65
COOH
HO
O
7
COOH
Br
8
CuI
57
O
O
COOH
COOH
9
Ni(cod)2
Ni(cod)2
66
Br
3
Ph
45 (2:>98)
COOH
Ph
Br
10
PhI
Ni(cod)2
37
COOH
Ph
11
a Reaction conditions: Cp2ZrCl2 (1 mmol), 3.0 M EtMgBr in Et2O (2.2 mmol), electrophile (1.2 mmol), 60 °C, 12 h.
b CuI (1.2 mmol), DMPU (2 mmol), Ni(cod)2 (0.5 mmol).
c Isolated yield.
d The number in parenthesis is the ratio of g-allylation and a-allylation product.
e A 86:14 mixture of crotyl bromide and 3-bromo-but-1-ene was used.
f The reaction was carried out at 20 °C.
Synlett 2005, No. 6, 919–922 © Thieme Stuttgart · New York

LETTER
Carboxylic Acid Derivatives
921
(3) For recent reviews, see: Darensbourg, D. J.; Holtcamp, M.
W. Coord. Chem. Rev. 1996, 153, 155.
R
R'
CO2
EtMgBr
R
R'
Cp2ZrCl2
(4) Recent papers, see: (a) Paddock, R. L.; Nguyen, S. T. J. Am.
Chem. Soc. 2001, 123, 11498. (b) Shen, Y.-M.; Duan, W.-
L.; Shi, M. J. Org. Chem. 2003, 68, 1559. (c) Shen, Y.-M.;
Duan, W.-L.; Shi, M. Adv. Synth. Catal. 2003, 345, 337.
(d) Lu, X.-B.; Liang, B.; Zhang, Y.-J.; Tian, Y.-Z.; Wang,
Y.-M.; Bai, C.-X.; Wang, H.; Zhang, R. J. Am. Chem. Soc.
2004, 126, 3732.
(5) (a) Nakano, K.; Nozaki, K.; Hiyama, T. J. Am. Chem. Soc.
2003, 125, 5501. (b) Lu, X.-B.; Wang, Y. Angew. Chem. Int.
Ed. 2004, 43, 3574. (c) Byrne, C. M.; Allen, S. D.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2004,
126, 11404.
Cp2Zr
O
THF
–78 °C, 1 h
0 °C
x h
O
50 °C
1 h
2
H+
a: R = Et, R' = Et
b: R = Ph, R' = Ph
c: R = Ph, R' = Et
d: R = Ph, R' = H
0.5 h 70%
R
R'
3 h 68%
H
1 h 62% (63:37)
0.5 h 72% (96:4)
COOH
12a–d
Scheme 2
(6) (a) Rahim, M. A.; Matsui, Y.; Matsuyama, T.; Kosugi, Y.
Bull. Chem. Soc. Jpn. 2003, 76, 2191. (b) Qin, Z.; Thomas,
C. M.; Lee, S.; Coates, G. W. Angew. Chem. Int. Ed. 2003,
42, 5484. (c) Olah, G. A.; Torok, B.; Joschek, J. P.; Bucsi, I.;
Esteves, P. M.; Rasul, G.; Prakash, G. K. S. J. Am. Chem.
Soc. 2002, 124, 11379.
The use of allyl bromide as an electrophile gave 2,3-dieth-
ylhexa-2,5-dienoic acid (13) in 61% yield (Scheme 3).21
The treatment of 2 with NBS/CuI and I2 underwent halo-
genation to give 14 and 15, respectively in good yields.22
Br
(7) Takimoto, M.; Shimizu, K.; Mori, M. Org. Lett. 2001, 3,
3345.
Et
Et
Et
Et
CuI
(8) Takimoto, M.; Kawamura, M.; Mori, M. Org. Lett. 2003, 5,
2599.
(9) (a) Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2001, 123,
2895. (b) Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2002,
124, 10008.
Cp2Zr
O
COOH
60 °C, 12 h
O
2
13 61%
Et
Br
Et
CuI, NBS
r.t., 1 h
(10) (a) Tsuda, T.; Kiyoi, T.; Miyane, T.; Saegusa, T. J. Am.
Chem. Soc. 1988, 110, 8570. (b) Louie, J.; Gibby, J. E.;
Farnworth, M. V.; Tekavec, T. N. J. Am. Chem. Soc. 2002,
124, 15188. (c) Tekavec, T. N.; Arif, A. M.; Louie, J.
Tetrahedron 2004, 60, 7431.
(11) For a review on CO, see: Colquhoun, H. M.; Thompson, D.
J.; Twigg, M. V. Carbonylation: Direct Synthesis of
Carbonyl Compounds; Plenum Press: New York, 1991.
(12) A related nickel complex has been reported. See:
(a) Hoberg, H.; Peres, Y.; Krüger, C.; Tsay, Y.-H. Angew.
Chem., Int. Ed. Engl. 1987, 26, 771. (b) Hoberg, H.;
Ballesteros, A.; Sigan, A.; Jegat, A.; Milchereit, A. Synthesis
1991, 395.
COOH
14 73%
Et
Br
Et
I2
COOH
r.t., 1 h
15 71%
Scheme 3
In summary, we report on the development of some new
transformations of CO2 with EtMgBr (as an ethylene
source) and electrophiles mediated by Cp2ZrCl2.23 A vari-
ety of carboxylic acid derivatives can be obtained from 1
and electrophiles. Related unsaturated complexes 2 are
also easily generated and lead to a,b-unsaturated carbox-
ylic acids stereoselectively. The reaction employs CO, at
atmospheric pressure and mild reaction conditions.
(13) Takahashi, T.; Li, Y. In Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002,
50–85.
(14) Alt, H. G.; Denner, C. E. J. Organomet. Chem. 1990, 390,
53.
(15) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima,
I. J. Am. Chem. Soc. 1987, 109, 8056.
(16) (a) Takahashi, T.; Kotora, M.; Kasai, K.; Suzuki, N.;
Nakajima, K. Organometallics 1994, 13, 4183.
(b) Lipshutz, B. H.; Segi, M. Tetrahedron 1995, 51, 4407.
(17) The reaction was carried out in a 20 mL two-necked flask
equipped with a condenser and an inlet tube. To a solution of
Cp2ZrCl2 (1 mmol, 292 mg) in THF (10 mL) under an
atmosphere of dry nitrogen was added EtMgBr (3.0 M
solution in Et2O, 2.2 mmol, 740 mL) at –78 °C. After the
mixture was stirred for 1 h at the same temperature, carbon
dioxide was bubbled from CO2 balloon and the reaction
mixture was allowed to warm to 0 °C. After the mixture was
stirred for 30 min, CuI (1.2 mmol, 228.6 mg) and allyl
bromide (1.2 mmol) was added to the reaction mixture,
which was stirred at 60 °C for 12 h. Then, the reaction
mixture was quenched with 1 N HCl and extracted with
Et2O. The organic layer was extracted with 4 N NaOH aq
and the aqueous layer was neutralized with 6 N HCl, washed
with Et2O and brine, dried over MgSO4. A crude product was
obtained after evaporation of the residue in vacuo.
5-Bromohex-5-enoic Acid (4): colorless oil. 1H NMR
Acknowledgment
This work was supported, in part, by grants from Monbusho (The
Ministry of Education, Science, Sports, and Culture) and Japan
Society for the Promotion of Science. N.C. wishes to thank to The
Kansai Electronic Power Co. Inc. for financial support.
References
(1) (a) Yin, X.; Moss, J. R. Coord. Chem. Rev. 1999, 181, 27.
(b) Walther, D.; Ruben, M.; Rau, S. Coord. Chem. Rev.
1999, 182, 67.
(2) (a) Inoue, Y.; Izumida, H.; Sasaki, Y.; Hashimoto, H. Chem.
Lett. 1976, 863. (b) Jessop, P. G.; Ikariya, T.; Noyori, R.
Chem. Rev. 1995, 95, 259. (c) Munshi, P.; Main, A. D.;
Linehan, J. C.; Tai, C.-C.; Jessop, P. G. J. Am. Chem. Soc.
2002, 124, 7963.
Synlett 2005, No. 6, 919–922 © Thieme Stuttgart · New York

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K. Yamashita, N. Chatani
LETTER
(CDCl3): d = 1.91 (tt, J = 7.3, 7.3 Hz, 2 H, CH2), 2.39 (t,
J = 7.3 Hz, 2 H, CH2CO), 2.49 (t, J = 7.3 Hz, 2 H, CH2C=),
was stirred for 1 h, the reaction mixture was quenched with
1 N HCl and extracted with Et2O. The organic layer was
extracted with 4 N NaOH aq and aqueous layer was
neutralized with 6 N HCl, washed with Et2O and brine, dried
over MgSO4. The solvent was evaporated in vacuo and
afforded products.
5.44 (d, J = 1.9 Hz, 1 H, CH=), 5.60–5.61 (m, 1 H, CH=). 13
NMR (CDCl3): d = 22.6 (CH2), 32.3 (CH2CO), 40.3
C
(CH2C=), 117.6 (CH2=), 133.1 (C=), 179.6 (CO). IR (neat):
2944 (s), 2913 (s), 2753 (m), 2670 (m), 1720 (s), 1704 (s),
1629 (s), 1452 (s), 1430 (s), 1411 (s), 1245 (s), 1201 (s),
1180 (s), 1118 (s), 1060 (w), 1035 (w), 1002 (w), 925 (s),
890 (s), 779 (m), 644 (w), 605 (w), 555 (w), 532 (m). MS:
m/z calcd for C6H1081BrO2: 194.9844; found: 194.9859.
2,3-Diethylhexa-2,5-dienoic Acid (13): colorless oil. 1H
NMR (CDCl3): d = 1.05 (t, J = 7.6 Hz, 3 H, CH3), 1.06 (t,
J = 7.6 Hz, 3 H, CH3), 2.16 (q, J = 7.6 Hz, 2 H, CH2), 2.35
(q, J = 7.6 Hz, 2 H, CH2), 3.17 (d, J = 6.6 Hz, 1 H,
=CCH2C=), 5.01 (dd, J = 8.5, 1.9 Hz, 1 H, CH2=), 5.06 (dd,
(18) Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.;
Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393.
J = 15.4, 1.9 Hz, 1 H, CH2=), 5.75–5.90 (m, 1 H, CH=). 13
C
(19) (a) Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.;
Negishi, E. Tetrahedron Lett. 1993, 34, 687. (b) Li, Y.;
Matsumura, H.; Yamanaka, M.; Takahashi, T. Tetrahedron
2004, 60, 1393.
(20) For related complexes, see: Takahashi, T.; Xi, C.; Ura, Y.;
Nakajima, K. J. Am. Chem. Soc. 2000, 122, 3228.
(21) The reaction was carried out in a 20 mL two-necked flask
equipped with a condenser and a three-way cock. To a
solution of Cp2ZrCl2 (1 mmol, 292.3 mg) in THF (10 mL)
under an atmosphere of dry nitrogen was added EtMgBr (3.0
M solution in Et2O, 2.2 mmol, 740 mL) at –78 °C. After the
mixture was stirred for 1 h at the same temperature reaction
mixture was allowed to warm to 0 °C, and alkyne (1.0 mmol)
was added. After the mixture was stirred, the flask was
changed with CO2 and warmed to 50 °C. After the mixture
NMR (CDCl3): d = 12.8 (CH3), 14.1 (CH3), 22.8 (CH2), 26.3
(CH2), 38.4 (=CCH2C=), 115.8 (CH2=), 129.2 (COC=),
136.1 (CH=), 151.6 (C=), 174.5 (CO). IR (neat): 3077 (s),
2971 (s), 2935 (s), 2877 (s), 1681 (s), 1637 (s), 1617 (s),
1455 (m), 1403 (s), 1376 (m), 1301 (s), 1251 (s), 1191 (s),
1122 (w), 1049 (w), 997 (m), 948 (m), 912 (s), 788 (m), 746
(w) cm–1. MS: m/z calcd for C10H16O2: 168.1150; found:
168.1157.
(22) Takahashi, T.; Xi, C.; Ura, Y.; Nakajima, K. J. Am. Chem.
Soc. 2000, 122, 3228.
(23) Six reported on the Ti-mediated reaction of alkynes with
CO2 and several electrophiles, such as Br2, I2, NBS, and
aldehydes. See: (a) Six, Y. J. Chem. Soc, Perkin Trans. 1
2002, 1159. (b) Six, Y. Eur. J. Org. Chem. 2003, 1157.
Synlett 2005, No. 6, 919–922 © Thieme Stuttgart · New York