H. R. Chobanian et al. / Tetrahedron Letters 48 (2007) 1213–1216
1215
Table 2 (continued)
Entry
Ar–X
Producta
Yieldb (%)
70
CO2Me
OTf
O
O
11
12
O
O
OMe
O
55
F3C
N
Br
F3C
N
a All products gave satisfactory NMR and MS data.
b Isolated microwave yield after column chromatography on silica.
and structurally diverse substrates. The procedure
proved to be quite general and well tolerated for both
aryl and heteroaryl chlorides. Good isolated yields were
realized in all cases (55–88%, Table 2, entries 1–4). For
some substrates, however (entries 5 and 7), a side prod-
uct was identified as the dimer of the aryl ring. An
aryl triflate was also a viable substrate for this reaction
reductive elimination then undergo reductive elimina-
tion giving rise to the desired arylation product and
regeneration of the Pd0 species (Scheme 1).
In summary, we describe another entry into the arena of
palladium-catalyzed arylation of acetone that can be
performed readily under microwave-mediated or ther-
mal conditions. The reaction is shown to be general
for a wide array of aryl and heteroaryl substrates. In
certain cases, spontaneous cyclization yields potentially
useful isocoumarin pharmacophores.
(entry 11). Interestingly,
a subsequent cyclization
occurred after the arylation reaction to afford an iso-
coumarin derivative under the described reaction condi-
tions. A similar cyclization was also observed in entry
12.9
References and notes
In comparison with our previous work utilizing the
Bu3SnOMe/isopropenyl acetate conditions,2 the current
procedure afforded comparable yields in most cases, and
superior in the case of aryl or heteroaryl chloride. The
utilization of microwave irradiation has shortened
reaction times from an average of 2–14 h down to
15 min. The catalyst loading is comparable with previ-
ously published results (6 mol %).10 One significant
advantage was the benign byproducts, which could be
easily removed through aqueous work-up and silica gel
chromatography.
1. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
2. Liu, P.; Lanza, T.; Jewell, J. P.; Jones, C. P.; Hagmann,
W. K.; Lin, L. S. Tetrahedron Lett. 2003, 44, 8869.
3. Ando, T.; Yamawaki, J. Chem. Lett. 1979, 45.
4. Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
15824.
5. Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104,
6831.
6. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685.
7. S-Phos ligand was purchased from Strem Chemicals,
7 Mulliken Way, Dexter Industrial Park, Newburyport,
MA 01950.
8. Chobanian, H. R.; Fors, B. P.; Lin, L. S. Tetrahedron Lett.
2006, 47, 3303.
Mechanistically, we postulate the Pd-catalyzed arylation
of acetone as commencing with in situ generation of the
zinc enolate via reaction of the silyl enol ether (2-tri-
methylsilyloxypropene) and ZnF2.11 Reaction of the
zinc enolate with Ar–Pd–X would produce the trans-
metallated palladium species, which would then undergo
9. For an analogous cyclization, see: Lewis, C. N.; Spargo, P.
L.; Staunton, J. Synthesis 1986, 11, 944.
10. Iwama, T.; Rawal, V. H. Org. Lett. 2006, 8, 5725.
11. General experimental conditions. Microwave: 1 (200 mg,
0.96 mmol), Pd2(dba)3 (70.0 mg, 0.07 mmol), S-Phos
(80.0 mg, 0.20 mmol), ZnF2 (119 mg, 1.10 mmol) and 2-
trimethylsilyloxypropene (188 mg, 1.40 mmol) were mixed
in 4.5 mL of DMF in a 5 mL microwave vial. The vial was
capped and heated in the microwave reactor for 15 min at
150 °C. Once complete, the reaction mixture was diluted
with 1 N HCl (20 mL) and EtOAc (20 mL). The EtOAc
layer was removed, dried over MgSO4, filtered and
concentrated giving rise to an oil. The oil was chromato-
graphed on silica gel (40–70% EtOAc–hexanes) and
concentrated under reduced pressure to yield 178 mg
(86%) of 2 as an orange oil: 1H NMR (500 MHz, CD3OD)
d 9.02, (s, 1H), 8.24 (s, 1H), 7.90 (d, J = 8 Hz, 1H), 7.76 (s,
1H), 7.63 (dd, J = 8.5, 14 Hz, 1H), 7.51 (dd, J = 7.0,
14.5 Hz, 1H), 4.11 (s, 2H), 2.19 (s, 3H). 13C NMR
(500 MHz, CD3OD) d 206.4, 151.7, 142.9, 135.3, 131.2,
128.6, 126.2, 123.3, 44.3, 28.6. LC–MS: m/z 186.24
(M+H)+.
OTMS
OZnF
ZnF2
Ar Pd
X
ArX
Pdo
O
Ar
Pd
Ar
O
O
PdAr
Scheme 1.