1
240
L. J. Gooßen et al.
LETTER
Table 2 Substrate Scope of the New Cross-Coupling Reaction (continued)
Producta
Ligand
Yield (%)
Producta
Ligand
Yield (%)
O
O
NHAc
5
l
DPPF
65
69
5w
P(p-MeOPh)
3
74
87
O
O
AcNH
5
x
5
m
P(p-MeOPh)3
P(p-MeOPh)3
Conditions: 1 mmol carboxylic acid, 1.2 mmol boronic acid, 1.5 mmol dimethyl dicarbonate, 2.5 mmol water, 3 mol% Pd(OAc) , 7 mol%
2
ligand, 50 °C, 16 h. All yields correspond to isolated yields.
a
Aryl groups originating from the boronic acids are placed on the right side of the keto groups.
Many functional groups are tolerated; carboxylic acids The reactions in Table 2 were performed following the above pro-
1
cedure. All products were isolated and characterized by means of H
and C NMR as well as by GC-MS and HRMS.
and boronic acids containing chloro, keto, cyano, ester, ni-
tro, or protected amino groups were successfully convert-
ed. Some heterocyclic ketones were synthesized as well.
1
3
Due to the formation of only volatile byproducts from the Acknowledgement
activating agent, the purification of the reaction products
is very easily performed.
We thank Prof. Dr. M. T. Reetz for generous support and constant
encouragement, and the DFG, the FCI, and the BMBF for financial
support.
In summary, the disclosed new variant of a palladium-cat-
alyzed cross-coupling reaction between carboxylic acids
and boronic acids further extends the advantages of this References
reaction over traditional ketone syntheses. Using an opti-
(1) (a) March, J. Advanced Organic Chemistry, 3rd ed.; Wiley:
mized catalyst system, the reaction proceeds in high
yields even at low temperatures. Many functionalized ke-
tones are thus conveniently accessible from readily avail-
able, non-toxic chemicals and the purification of the
products is particularly easy. These combined features
render the new reaction protocol valuable for many appli-
cations in combinatorial chemistry and drug discovery.
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(
(
(
(
Representative Experimental Procedure
Synthesis of 6-Oxo-6-phenyl-hexanoic acid methyl ester 5h: A
2
0 mL flask was charged with adipic acid monomethyl ester 1h
(174.2 mg, 1.00 mmol), benzeneboronic acid 4a (146.3 mg, 1.20
mmol), palladium acetate (6.7 mg, 0.03 mmol) and tri-p-methoxy-
phenylphosphine (24.7 mg, 0.07 mmol). THF (4 mL), dimethyl di-
carbonate 2 (268.0 mg, 2.00 mmol) and water (45 L, 2.50 mmol)
were added by syringe, the reaction mixture was purged with argon
and stirred at 20 °C overnight. After removal of the volatiles in
vacuo, the residue was filtered through a small plug of aluminum
oxide using hexane–dichloromethane as eluent. After removal of
40, 3109. (b) Bumagin, N. A.; Korolev, D. N. Tetrahedron
Lett. 1999, 40, 3057. (c) Liebeskind, L.; Srogl, J. J. Am.
Chem. Soc. 2000, 122, 11260.
5) (a) Rubottom, G. M.; Kim, C. J. Org. Chem. 1983, 48, 1550.
(b) Ahn, Y.; Cohen, T. Tetrahedron Lett. 1994, 35, 203.
1
the volatiles, 5h (207 mg, 88%) was obtained as a colorless oil. H
(
c) Fujisawa, T.; Iida, S.; Uehara, H.; Sato, T. Chem. Lett.
983, 1267.
(6) Gooßen, L. J.; Ghosh, K. Angew. Chem. Int. Ed. 2001, 40,
458; Angew. Chem. 2001, 113, 3566.
(7) Gooßen, L. J.; Ghosh, K. Chem. Commun. 2001, 20, 2084.
NMR (300 MHz, CDCl3): = 7.92 (cm, 2 H), 7.57–7.36 (m, 3 H),
1
4
1
.09 (q, J = 6 Hz, 2 H), 2.96 (t, J = 6 Hz, 2 H), 2.40–2.25 (m, 2 H),
.84–1.59 (m, 4 H), 1.22 (t, J = 5 Hz, 3 H) ppm; 13C NMR (75 MHz,
3
CDCl3): = 199.6, 173.3, 136.8, 133.8, 128.4, 127.9, 60.2, 38.0,
+
3
4.0, 24.5, 23.5, 14.1 ppm; MS (EI): m/z (%) = 234 (4) [M ], 189
(8) Kakino, R.; Narahashi, H.; Shimizu, I.; Yamamoto, A.
Chem. Lett. 2001, 1242.
(
7), 143 (17), 120 (44), 105 (100), 77 (32), 51 (6); HRMS (EI): cal-
+
cd. for C H O [M ]: 234.125594; found 234.125439.
1
4
18
3
(
9) Kakino, R.; Yasumi, S.; Shimizu, I.; Yamamoto, A. Bull.
Chem. Soc. Jpn. 2002, 75, 137.
Synlett 2002, No. 8, 1237–1240 ISSN 0936-5214 © Thieme Stuttgart · New York