Construction of previously inaccessible 2-amino-4-benzyl substituted oxazoles

Article abstract of DOI:10.1016/j.tetlet.2003.11.046

A process for the synthesis of 2-amino-4-benzyl-oxazoles is reported.

Full text of DOI:10.1016/j.tetlet.2003.11.046

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 867–868
Construction of previously inaccessible 2-amino-4-benzyl
substituted oxazoles
Christopher C. Lindsey, Brendan M. OÕBoyle, Stephanie J. Mercede and
Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93106-9510, USA
Received 26 September 2003; revised 3 November 2003; accepted 3 November 2003
Abstract—A process for the synthesis of 2-amino-4-benzyl-oxazoles is reported.
Ó 2003 Elsevier Ltd. All rights reserved.
2-Amino-oxazoles are generally constructed by Harri-
sonÕs procedure, which involves a sodium hydroxide
mediated addition of cyanamide to an a-substituted
a0-hydroxyketone, Figure 1.1 However, when this pro-
cess is applied to an a-aryl-a0-hydroxyketone, the
anticipated product does not form. This observation can
most likely be attributed to an undesired enolization,
which leads to a complicated mixture of condensation
products. Nevertheless, our need for 2-amino-4-benzyl-
oxazoles motivated us to develop a strategy for their
construction.2
oxazole 3 (Scheme 1). However, it is more efficient to
subject the alcohol 3 to immediate silylation (0.5 M in
CH2Cl2, 1.1 equiv imidazole, cat. DMAP, 1.1 equiv
TBSCl). In this manner, siloxyoxazole 4 arises from
benzylamine in a respectable 53% isolated yield after
purification (Hex–EtOAc/85:15).
After considerable experimentation, the acyl derivatives
5–7 were constructed in a single pot from 4 (Scheme 2).
BnNH2
Na2CO3
+
BrCN
Bn
Bn
N
Addition of the crude benzyl-cyanamide 1, procured by
treatment of cyanogen bromide with benzyl amine, to a
dimer of dihydroxyacetone 2 (0.5 M in THF–H2O/1:1
with 0.5 equiv NaOH) affords the isolable 2-amino-
Bn
N
NH
NH
N
H
1
TBSCl,
cat. NaOH
O
O
N
imidazole
DMAP
O
OH
3
2
2
OTBS
4 (53 % from BnNH2)
R
OH
NH
OH
2
O
OH
cat. NaOH
R2
3N
O 1
Scheme 1. Synthesis of the oxazole.
R1
5
4
N
H
R1
H
H
2-amino-oxazole
with 4-position substituted
R1 Ar
Bn
N
Me
O
N
N
Bn
NH
HO
OH
1) NaH, MeI
complicated
mixtures
R1 = Ar
O
N
O
O
R1
2) TBAF, acylating agent
R'
TBSO
4
Figure 1. HarrisonÕs synthesis of 2-amino-oxazoles.
5 R' = -OCH2CH3 (63%)
6 R' = -CH3 (71%)
7 R' = -Ph (47%)
* Corresponding author. Tel.: +1-805-893-5531; fax: +1-805-893-5690;
e-mail: pettus@chem.ucsb.edu
Scheme 2. Formation of acyl derivatives.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.046

868
C. C. Lindsey et al. / Tetrahedron Letters 45 (2004) 867–868
Table 1. Couplings of oxazoles 5–7 with aryl nucleophiles
Bn
N
Me
O
N
Stille couplings
8 Y = H
5 - 7
9 Y = OMOM
10 Y = OBn
Y
Entries
SM
Conditions
Aryl-Nuc
Prd
Yield (%)
1
2
3
4
5
6
7
8
9
6
6
7
7
7
7
5
5
5
0.2 equiv Pd2(dba)3, 3 equiv LiCl
0.2 equiv Pd2(dba)3, 3 equiv LiCl
3 equiv CuBr
1.3 equiv of 11
1.3 equiv of 12
5.0 equiv PhMgBr
1.3 equiv of 11
1.3 equiv of 12
1.3 equiv of 13
1.3 equiv of 13
1.3 equiv of 12
1.3 equiv of 11
8
9
0
0
8
38
30
52
37
62
83
70
0.2 equiv Pd2(dba)3, 3 equiv LiCl
0.2 equiv Pd2(dba)3, 3 equiv LiCl
0.2 equiv Pd2(dba)3, 3 equiv LiCl
0.2 equiv Pd2(dba)3, 3 equiv LiCl
0.2 equiv Pd2(dba)3, 3 equiv LiCl
0.2 equiv Pd2(dba)3, 3 equiv LiCl
8
9
10
10
9
8
Attempts to methylate only the amine functionality in 3
or acylate only the hydroxyl residue in 3 were unsuc-
cessful. However, this problem was eventually solved in
the following fashion. The –OTBS ether 4 (0.2 M in
THF, 0 °C) is first subjected to MeI (1.1 equiv) and NaH
(1.5 equiv). After 3.5 h, the organic layer is separated
and dried over Na2SO4. This crude material is then
concentrated in vacuo and sequentially treated (neat)
with TBAF (1.1 equiv 1.0 M in THF, 0 °C, 2 h) and
ethylchloroformate (1.5 equiv) along with DMAP
(1.5 equiv). Work-up and chromatography affords 5 in a
63% overall yield from 4. The acetate 6 and benzoate 7
are produced in 71% and 47% using similar conditions
with acetic anhydride and benzoyl chloride, respectively.
In principle, palladium mediated couplings of the oxa-
zole carbonate 5 with other nucleophiles5 could lead to a
great many types of 4-substituted oxazoles that could
not be previously addressed by the Harrison condensa-
tion strategy alone. We anticipate future application of
the 2-amino-oxazole 10 as a 2p component in inverse
demand Diels–Alder reactions with o-quinone methides
in lieu of a previous example that has been noted with
furan.6
Acknowledgements
The displacement of these carbonylated materials 5–7 by
various types of metal nucleophiles was then investi-
gated.3 As the ethyl carbonate 5 had initially proven
very difficult to prepare, we began studying the reac-
tivity of the acetate 6 and the benzoate 7 (Table 1). The
acetate 6 proved unreactive (Table 1, entries 1–2).
However, addition of PhMgBr (5.0 equiv, 1.0 M in
THF) to the benzoate 7 (0.67 M in THF, 60 °C) con-
taining CuBr (3.0 equiv) affords the benzylated oxazole
11 in moderate yields (38%, entry 3).3 Unfortunately,
this protocol does not transfer to aryl Grignard species
expressing an ortho substituent on the aryl-ring. How-
ever, the aryl stannanes 11–13, are effective coupling
partners. HegedusÕs coupling conditions (0.2 equiv
Pd2(dba)3, 3.0 equiv LiCl, 1.3 equiv of ArSnMe3, 0.67 M
NMP) are particularly successful providing substituted
oxazoles 8–10 in greater than 60% yield from the start-
ing oxazole carbonate 5 (Table 1, entries 7–9).4 The
benzoate 7 can also be used in these processes, but the
yields of the benzylated oxazole are significantly lower
(Table 1, entries 4–6).
Research grants from the UC Committee on Cancer
Research (19990641) and (SB010064), and the National
Science Foundation (Career-0135031) are appreciated.
References and notes
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Nishida, A.; Fuwa, M.; Naruto, S.; Sugano, Y.; Saito,
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1990, 55, 3019–3023.
SnMe3
H
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OMOM
SnMe3
OBn
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