materials and do not allow the use of oxazole derivatives
containing sensitive functional groups. Recently, we have
reported a set of novel sterically hindered TMP-bases
(TMP = 2,2,6,6-tetramethylpiperidyl) complexed by LiCl.8
TMPMgCl LiCl (1)9 and TMPZnCl LiCl (2)10 have pro-
ven to be especially efficient for a broad range of metalations
particularly for sensitive heterocycles.
Herein, we report the full functionalization of oxazole
(3) using successive metalations with TMP-bases 1 and 2
(Scheme 1).
undergoes Negishi cross-couplings11 using Farina’s ligand
((o-furyl)3P)12 with various ortho-, meta-orpara-substituted
aryl iodides, as well as an aryl bromide furnishing the desired
cross-coupling products 4aÀh in 74À94% yield (Table 1,
entries 1À8). The 2-oxazolylzinc reagent also reacts well in
Pd-catalyzed Negishi acylation reactions13 with benzoyl
chloride and 3-chlorobenzoyl chloride, providing the ke-
tones 4i and 4j in 73À86% yield (entries 9 and 10). The
2-zincated oxazole also reacts after transmetalation with
3
3
CuCN 2LiCl14 in a copper(I)-mediated allylation reaction
3
with ethyl 2-(bromomethyl)acrylate15 to furnish the ally-
lated oxazole 4k in 78% yield (entry 11).
Scheme 1. Successive Metalations of Oxazole (3) at Positions 2,
5, and 4 Using TMPMgCl LiCl (1) and TMPZnCl LiCl (2)
3
3
Table 1. 2-Substituted Oxazoles of Type 4 Obtained by Regio-
selective Zincation of Oxazole (3) Using TMPZnCl LiCl (2) and
Quenching with Electrophiles
3
Thus, treatment of oxazole (3) with TMPZnCl LiCl
(2; 1.4 equiv, 0 °C, 1 h)10 leads to the quantitative formation
of the corresponding 2-oxazolylzinc reagent which successfully
3
(6) (a) Meyers, A. I.; Collington, E. W. J. Am. Chem. Soc. 1970, 92,
6676. (b) Dondoni, A.; Fantin, G.; Fagagnolo, M.; Medici, A.; Pedrini, P.
Synthesis 1987, 693. (c) Gilchrist, T. L. Adv. Heterocycl. Chem. 1987, 41, 4.
(d) Iddon, B. Heterocycles 1994, 37, 1321. (e) Crowe, E.; Hossner, F.;
Hughes, M. J. Tetrahedron Lett. 1995, 51, 8889. (f) Vedejs, E.; Luchetta,
L. M. J. Org. Chem. 1999, 64, 1011. (g) Bayh, O.; Awad, H.; Mongin, F.;
ꢀ
ꢀ
Hoarau, C.; Bischoff, L.; Trecourt, F.; Queguiner, G.; Marsais, F.; Blanco,
F.; Abarca, B.; Ballesteros, R. J. Org. Chem. 2005, 70, 5190. (h) Miller, R.
A; Smith, R. M; Marcune, B. J. Org. Chem. 2005, 70, 9074. (i) Pirrung,
M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128, 11772.
(7) (a) Meyers, A. I.; Lawson, J. P. Tetrahedron Lett. 1981, 22, 3163.
(b) Williams, D. R.; Brooks, D. A.; Meyer, K. G.; Pagel, M. Tetradedron
Lett. 1998, 39, 8023. (c) Li, B.; Buzon, R. A.; Zhang, Z. Org. Process Res.
Dev. 2007, 11, 951. (d) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org.
Lett. 2009, 11, 1457.
(8) (a) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004,
2288. (b) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215. (c)
Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333. (d) Ren,
H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543. (e) Krasovskiy,
A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 159.
(9) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
2006, 8, 5673. (c) Garcia-Alvarez, P.; Graham, D. V.; Hevia, E.;
Kennedy, A. R.; Klett, J.; Mulvey, R. E.; O’Hara, C. T.; Weatherstone,
S. Angew. Chem., Int. Ed. 2008, 47, 8079. (d) Mulvey, R. E. Organome-
tallics 2006, 25, 1060. (e) Westerhausen, M. Dalton Trans. 2006, 4755. (f)
Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem.,
Int. Ed. 2007, 46, 3802. (g) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10,
2497. (h) Mosrin, M.; Boudet, N.; Knochel, P. Org. Biomol. Chem. 2008,
6, 3237. (i) Piller, F. M.; Knochel, P. Synthesis 2011, 1751.
a Isolated yield of analytically pure product. b Pd-catalyzed cross-
coupling using 3 mol % Pd(dba)2 and 6 mol % P(o-furyl)3. c The aryl
bromide was used as an electrophile for Pd-catalyzed cross-coupling
using 4 mol % Pd(PPh3)4. d Pd-catalyzed acylation reaction using
4 mol % Pd(PPh3)4. e CuCN 2LiCl was used for the reaction with this
3
electrophile.
(10) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. (b)
Bresser, T.; Knochel, P. Angew. Chem., Int. Ed. 2011, 50, 1914. (c) Duez,
S.; Steib, A. K.; Manolikakes, S. M.; Knochel, P. Angew. Chem., Int. Ed.
2011, 50, 7686. (d) Klier, L.; Bresser, T.; Nigst, T. A.; Karaghiosoff, K.;
Knochel, P. J. Am. Chem. Soc. 2012, 134, 13584. (e) Unsinn, A.; Ford,
M. J.; Knochel, P. Org. Lett. 2013, 15, 1128. (f) Crestey, F.; Zimdars, S.;
Knochel, P. Synthesis 2013, 45, 000A. (g) Monzon, G.; Knochel, P.
Synlett 2010, 304.
(12) (a) Farina, V.; Baker, S. R.; Benigni, D. A.; Sapino, C., Jr.
Tetrahedron Lett. 1988, 29, 5739. (b) Farina, V.; Baker, S. R.; Benigni,
D. A.; Hauck, S. I.; Sapino, C., Jr. J. Org. Chem. 1990, 55, 5833.
(13) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J. A.;
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(14) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(15) Villieras, J.; Rambaud, M. Synthesis 1982, 924.
(11) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E.; Kobayashi, M. J. J. Org. Chem. 1980,
45, 5223. (c) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
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