studies utilizing lithium diethylamide as a base circumvent
this problem.8 On the other hand, Helquist9 and Uguen10 have
described the conversion of methyl 2-R-halomethyloxazole-
4-carboxylates to the corresponding nonbasic organozinc and
organochromium derivatives for subsequent addition to
aldehydes. Unfortunately, our efforts to prepare the analogous
organozinc derivative of 1 (X ) ZnBr or ZnI) led to sluggish
reactions and low product yields. Herein, we communicate
the deployment of samarium Barbier conditions leading to
the successful coupling of a variety of substituted five-
membered heterocycles with aliphatic aldehydes. The in-
tact incorporation of substituted oxazoles or thiazoles
provides encouragement for applications of complex mo-
lecular constructions as an alternative to de novo heterocyclic
synthesis.
Scheme 2. Barbier Coupling of 4 with Aldehyde 6
Initial investigations explored reactions of the R-iodo-2-
methyloxazole 4 as a prelude to our phorboxazole studies.
Multigram quantities of 4 were readily prepared from the
condensation of ethyl dichloroacetimidate (Scheme 1) with
The requisite R-iodomethylene functionality was routinely
introduced by treatment of the precursor alcohol with Ph3P
and iodine (Imid, CH2Cl2, 0 °C) or via radical bromination
with NBS (CHCl3) followed by NaI exchange in acetone.
Experimentation has been focused on model studies to guide
our efforts for total synthesis. Thus, the iodomethylene
substituent is generally positioned at C2 of the parent
heterocycle. Entries 1-3 demonstrate the incorporation of
ester functionality at C4 of the oxazole. Preparatively useful
addition reactions occur (55-87% yields) with aliphatic
aldehydes, which include typical protecting groups for
â-hydroxyl substituents. To gain a better understanding of
this reaction, we examined the 2-iodomethyl benzoxazole
(23) and analogous benzothiazole (26) examples of entries
6-9. Aromatic aldehydes were not useful and gave rise to
competing pinacol coupling. However, aliphatic aldehydes
displayed a range of reactivity exemplified by isobutyral-
dehyde (19) and R-benzyloxyacetaldehyde (21). In the former
case, reductive alkylations routinely exceeded 80% yields.
Several side reactions were observed with R-alkoxyalde-
hydes, including carbonyl reduction to the corresponding
alcohols, as well as reductive elimination to produce benzyl
alcohol as observed in the case of 21. These processes limited
the desired Barbier coupling to 35-45% yields. No signifi-
cant improvements in yields were observed when reactions
were conducted in tetrahydropyran,13 with the addition of
catalytic Ni(II) salts,14 or in the presence of Lewis acids.15
In the case of 2-R-iodomethyloxazoles and thiazoles, it is
tempting to postulate a net two-electron reduction producing
the N-metallo-enamine 37 for precomplexation in the six-
membered array 38 by analogy to carbonyl coupling
processes (Figure 2).
Scheme 1. Preparation of R-Halo-2-methyl-oxazoles
serine methyl ester followed by brief exposure to DBU and
halogen exchange of 5 with sodium iodide. Preliminary
experiments of Scheme 2 established the SmI2-mediated
coupling between 4 and model aldehyde 611 under Barbier
conditions in fewer than 5 min at temperatures ranging from
-78 to 22 °C and provided the â-hydroxyoxazole 7 as an
inseparable mixture of diastereomers (68% yield). Stoichio-
metric quantities of aldehyde and iodide 4 were premixed
in degassed THF and added via cannula to a freshly prepared
solution of excess (2.5 equiv) SmI2. Structural verification
of 7 was provided by oxidation under modified Swern
conditions12 and subsequent deprotection of ketone 8 with
methanol in the presence of catalytic camphorsulfonic acid
to yield the desired cyclic ketal 9.
General characteristics of the samarium diiodide coupling
are summarized in Table 1. Several representative oxazole
and thiazole derivatives have been examined, although our
survey made no attempt to optimize results for each case.
Although this hypothesis may warrant consideration,
limited studies with 4-R-iodomethyl examples (Table 1,
entries 10-14) suggest more broadly defined applications
for this Barbier coupling. The C-4 substituted heterocycles
(6) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner,
M. A. Angew. Chem., Int. Ed. 2003, 42, 1258.
(7) Meyers, A. I.; Lawson, J. P. Tetrahedron Lett. 1981, 22, 3163.
(8) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett.
1999, 1, 87.
(9) Helquist, P.; Gangloff, A. R.; Akermark, B. J. Org. Chem. 1992, 57,
4797.
(10) Uguen, D.; Breuilles, P. Tetrahedron Lett. 1998, 39, 3149.
(11) Nonracemic 6 was prepared according to the method of Carreira:
Carreira, E. M.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 12360.
(12) (a) Tidwell, T. T. Synthesis 1990, 857. (b) Mancuso, A. J.; Huang,
S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(13) Haumann-Gaudinet, B.; Namy, J.-L.; Kagan, H. B. Tetrahedron Lett.
1997, 38, 6585.
(14) Machrouhi, F.; Harmann, B.; Namy, J.-L.; Kagan, H. B. Synlett
1996, 633.
(15) Aoyagi, Y.; Yoshimura, M.; Tsuda, M.; Tsuchibuchi, T.; Kawamata,
S.; Tateno, H.; Asano, K.; Nakamura, H.; Obokata, M.; Ophta, A.; Kodama,
Y. J. Chem. Soc., Perkin Trans. 1 1995, 689.
4100
Org. Lett., Vol. 7, No. 19, 2005