Kadnikov and Larock
SCHEME 3
lecular trapping of the acylpalladium complex and the
irreversible insertion of the alkyne into the arylpalladium
bond. In most cases, insertion of the alkyne is a much
faster process, and only in the reactions with very
unreactive alkynes (Table 4, entries 10 and 11) does the
intramolecular attack of the carbamate oxygen predomi-
nate.
Con clu sion s
We have successfully extended the palladium-catalyzed
carbonylative annulation of internal alkynes to reactions
with o-iodoaniline derivatives, thus providing a new
synthesis of 3,4-disubstituted 2-quinolones. A crucial
aspect of the synthesis is the choice of the protecting
group on the nitrogen atom of the iodoaniline. The most
effective groups are alkoxycarbonyl, p-toluenesulfonyl,
and trifluoroacetyl. A wide variety of internal alkynes
bearing alkyl, aryl, heteroaryl, hydroxyl, and alkoxyl
substituents has been employed in this process affording
the desired 2-quinolones in 50 to 80% yields. Though the
use of unsymmetrical alkynes leads to the formation of
mixtures of regioisomers with low regioselectivity, these
products are easily separable by column chromatography.
Electron-rich iodoanilines with substituents para to the
amino group are also effective in the carbonylative
annulation. The carbonylative annulation of electron-poor
iodoaniline derivatives affords 2-quinolones in lower
yields than the parent system.
reaction conditions, the reaction of this acylpalladium
complex with an internal alkyne is apparently very
slow.6b Therefore, in the absence of any internal nucleo-
phile capable of trapping the acylpalladium complex, the
acylpalladium complex undergoes decarbonylation to the
original arylpalladium complex, which eventually reacts
with the internal alkyne, and is thus converted into the
coumarin or the 2-quinolone. Further evidence support-
ing this scheme has been obtained during our investiga-
tion of the carbonylative annulation of N-substituted
o-iodoanilines.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Syn -
th esis of 3,4-Disu bstitu ted 2-Qu in olon es. Ethyl N-(2-
iodophenyl)carbamate (0.5 mmol), the alkyne (1.5 mmol),
pyridine (1.0 mmol), n-Bu4NCl (0.5 mmol), and Pd(OAc)2 (5
mol %, 0.025 mmol) were placed in a 4 dram vial and then
dissolved in 5 mL of DMF. The vial was purged with CO for 2
min and then connected to a balloon of CO. The reaction
mixture was stirred at 100 °C for 12 h, allowed to cool to room
temperature, diluted with EtOAc, washed with water, and
concentrated under reduced pressure. The residue was treated
with 5 mL of 1 M ethanolic NaOH at room temperature for 30
min. Then satd aq NH4Cl (15 mL) was added, and the resulting
mixture was extracted with EtOAc. The organic extracts were
combined, washed with satd aq NH4Cl, and water, dried over
anhydrous MgSO4, and concentrated under reduced pressure.
The residue was separated by column chromatography on
silica gel.
3,4-Dip r op yl-2(1H)-qu in olin on e (1): white solid; mp 159-
160 °C; 1H NMR (CDCl3) δ 7.68 (d, J ) 8.0 Hz, 1H), 7.43 (ddd,
J ) 1.2, 6.8, 8.0 Hz, 1H), 7.38 (dd, J ) 1.2, 8.0 Hz, 1H), 7.20
(ddd, J ) 1.4, 6.8, 8.2 Hz, 1H), 2.86-2.90 (m, 2H), 2.74-2.78
(m, 2H), 1.59-1.71 (m, 4H), 1.05-1.12 (m, 6H); 13C NMR
(CDCl3) δ 164.3, 147.6, 137.5, 131.4, 129.2, 124.5, 122.3, 120.4,
116.5, 31.1, 29.3, 23.6, 22.9, 14.8, 14.7; IR (neat, cm-1) 2963,
2868, 1661; MS m/z (rel intensity) 229 (67, M+), 228 (52), 214
(100), 200 (47), 186 (41); HRMS calcd for C15H19NO 229.1467,
found 229.1470.
In most of the reactions employing ethyl N-(2-iodophe-
nyl)carbamate a minor byproduct can be isolated, along
with the desired 2-quinolone. The byproduct is either
isatoic anhydride (36) (in the reactions without ethanolic
NaOH treatment) or ethyl 2-aminobenzoate (37) (in the
reactions with a basic workup). In the reaction with
4-octyne the yield of the byproduct is around 10-12%.
However, in the reactions employing a very unreactive
alkyne, such as 4,4-dimethyl-2-pentyne or 1-phenyl-3,3-
dimethyl-1-butyne (Table 4, entries 10 and 11), ethyl
2-aminobenzoate was isolated in 30 and 39% yields,
respectively. In almost all reactions this byproduct was
detected in the crude product mixtures by 1H NMR
spectroscopy, but it was not isolated in a pure form and
the exact yield was not determined. The mechanism of
formation of these byproducts is shown in Scheme 3.
Insertion of CO into the arylpalladium bond, followed by
intramolecular attack by the oxygen atom of the carbam-
ate group on the carbonyl of the acylpalladium complex,
leads to the intermediate 38. Attack on the oxonium ion
38 by a water molecule and elimination of ethanol lead
to the formation of isatoic anhydride. Upon treatment
with ethanolic NaOH, the more electrophilic ester car-
bonyl group is attacked by an ethoxide anion generating
a carbamic acid anion, which spontaneously loses CO2
giving rise to ethyl 2-aminobenzoate. A similar intramo-
lecular attack of an amide oxygen on an acylpalladium
complex has been previously observed.25
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research, and Kawaken Fine Chemicals Co., Ltd.
and J ohnson Matthey, Inc. for donating palladium
acetate.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of starting materials; characterization data and
1H and 13C NMR spectra for all new compounds. This material
These data support the mechanistic scheme outlined
above. An acylpalladium complex is generated under our
reaction conditions, but it is not very reactive. The ratio
of the products from initial CO insertion and initial
alkyne insertion depends on the rates of the intramo-
(25) Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 1996, 997.
6780 J . Org. Chem., Vol. 69, No. 20, 2004
J O049149+