Methodology for the synthesis of substituted 1,3-oxazoles

Article abstract of DOI:10.1055/S-0029-1219374

The halogen dance isomerization is a facile and preparatively effective pathway for the synthesis of 2,4,5-trisubstituted 1,3-oxazoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1219374

LETTER
591
Methodology for the Synthesis of Substituted 1,3-Oxazoles
Methodology for
t
a
he Synthesi
v
s
of
S
ubstitu
i
ted 1,3
d
-Oxazoles R. Williams,* Liangfeng Fu
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN 47405-7102, USA
Fax +1(812)8558300; E-mail: williamd@indiana.edu
Received 22 December 2009
Dedicated to Prof. Gerald Pattenden on the occasion of his 70th birthday
azoles via the Cornforth rearrangement.12 Examples of
site-selective ring metalations via complex-induced prox-
imity effects13 (CIPE) have been recorded in [2,4]-
bisoxazoles14 and for 2-methyl-1,3-oxazole-4-carboxylic
acid.15 Furthermore, Stambuli and coworkers have recent-
ly described the selective C-5 deprotonation of 2-meth-
ylthio-1,3-oxazole leading to the production of 2,5-
disubstituted oxazoles, and we have reported related stud-
ies of C-5 deprotonation using 2-phenylsulfonyl-1,3-ox-
azoles.16
Abstract: The halogen dance isomerization is a facile and prepara-
tively effective pathway for the synthesis of 2,4,5-trisubstituted 1,3-
oxazoles.
Key words: oxazoles, halogen dance rearrangement, alkylation
In recent years, structural elucidation studies of biologi-
cally significant natural products have frequently incorpo-
rated novel 1,3-oxazole ring systems within complex
molecular architectures. Numerous examples include
hennoxazole A,1 phorboxazoles A and B,2 diazonamides
A and B,3 rhizopodin,4 telomestatin,5 and the ulapualides.6
In addition, 1,3-oxazole moieties are commonly displayed
within depsipeptides as a result of oxidative cyclodehy-
drations of serine and threonine residues.7 These structur-
al features have inspired widespread inclusion of
substituted 1,3-oxazoles in medicinal chemistry, and par-
ticularly in the design of peptidomimetics. The prolifera-
tion of complex structures for challenging syntheses has
ignited renewed interests in the development of effective
methodologies toward substituted oxazoles. We have pre-
viously described an oxidative cyclodehydration route as
a general strategy for the de novo preparation of 2,4-di-
substituted 1,3-oxazoles.8 Studies toward the elaboration
of the oxazole nucleus have reported cross-coupling reac-
tions of alkenylation and arylation at C-29 as well as Stille
reactions of 2-phenyl-1,3-oxazoles.10
In this letter, we describe the kinetic C-4 deprotonation of
5-bromo-2-phenylthio-1,3-oxazole (1a) which initially
leads to the lithium species 1b. Upon warming to 0 °C, an-
ion 1b undergoes efficient isomerization to afford the
reactive 5-lithio-4-bromo-2-phenylthio-1,3-oxazole (2a).
Reactions of 2a with a variety of electrophiles yield the
trisubstituted oxazoles 3. Transmetalation of the lithium
species 2a provides the zinc reagent 2b for effective
Negishi cross-coupling processes to give products of al-
kenylation and arylation at the C-5 position (Scheme 1).
The nature of the isomerization which leads from the 5-
bromo heterocycle 1a to yield the 4-bromo derivative 2a
is described as the halogen dance (HD) reaction. This
base-induced migration has been studied in aromatic and
heteroaromatic systems.17,18 Strangeland and Sammakia
demonstrated the first example of the halogen dance in a
1,3-thiazole system,19 and Stanetty and coworkers have
recently published the only oxazole example of this halo-
gen migration in their studies of 5-bromo-2-phenyl-1,3-
oxazole.20
Efforts for elaboration of the oxazole nucleus can be
greatly facilitated by site-selective formation of a reactive
carbanion. Kinetic deprotonation of the C-2 hydrogen of
the parent oxazole provides access to a ring-closed carb-
anion as well as the ring-opened isonitrile enolate.11 C-
Acylations of the enolate produce 4,5-disubstituted ox-
In the course of our studies of 2,5- and 2,4-disubstituted
oxazoles, we have found that the base-catalyzed halogen
exchange of 2-phenylthio-5-bromo-1,3-oxazole 121 is a
PhS
O
PhS
PhS
O
O
LDA
Br
M
E
N
N
N
–78 °C to 0 °C
THF
X
Br
Br
3 E = electrophile
R3
1a X = H
1b X = Li
2a M = Li
2b M = ZnBr
ZnBr2
4 E =
R2
R1
Scheme 1
SYNLETT 2010, No. 4, pp 0591–0594
0
1.
0
3.
2
0
1
0
Advanced online publication: 08.02.2010
DOI: 10.1055/s-0029-1219374; Art ID: D37509ST
© Georg Thieme Verlag Stuttgart · New York

592
D. R. Williams, L. Fu
LETTER
PhS
PhS
PhS
O
O
O
1a (X = H)
Br
Br
Li
Li
N
N
N
N
–78 °C to 0 °C
X
5
Br
Br
1b X = Li
2a
PhS
O
6
H
Scheme 2
facile process with considerable synthetic utility. Thus, isomerization of the 5-bromo compound 1a to yield the
treatment of 1a with LDA at –78 °C leads to deprotona- corresponding 4-bromo-1,3-oxazole (Table 1, entry 1),
tion at C-4 providing 1b which subsequently undergoes which serves as an important precursor for the regiocon-
rapid halogen exchange with starting 1a. This process trolled synthesis of 2,4-disubstituted oxazoles. Addition-
generates the intermediates 5 and 6 thereby facilitating a ally, the regioselective introductions of 5-iodo, 5-stannyl,
final bromine transfer to produce the more stable lithium and 5-silyl functionality (Table 1, entries 2–4) advance
reagent 2a (Scheme 2). After stirring at 0 °C (45 min), so- new opportunities for site-specific reactivity in these het-
lutions of 2a were cooled to –78 °C for the introduction of erocycles. Our efforts have also recorded the transmetala-
various electrophiles. Upon warming to 22 °C, reaction tion of 2a to provide 2b via the addition of anhydrous
mixtures were quenched, and the products were purified ZnBr2 in THF at 0 °C. As a result, these studies provide
by flash silica gel chromatography prior to full character- for cross-coupling reactions with aryl and alkenyl iodides
ization. A survey of our results is complied in Table 1, and (entries 10–13 of Table 1) affording 67% to 80% yields of
illustrates useful yields in a number of alkylation process- highly functionalized 2,4,5-trisubstituted 1,3-oxazoles.22
es including condensations with aldehydes and ketones
(entries 5–9 of Table 1). Our conditions permit facile
Table 1 Preparation of 5-Substituted 4-Bromo-2-(Phenylthio)oxazole 2
PhS
PhS
O
O
1) LDA, –78 °C to 0 °C
Br
E
N
N
2) then: E+, –78 °C to r.t.
1
3
H
Br
Entry
1
Cond.a
A
Electrophile
H2O
Product
PhS
Yield (%)
88
O
H
I
N
Br
O
PhS
N
I
2
3
4
A
A
A
87
83
89
N
O
O
Br
O
PhS
N
n-Bu3SnCl
SnBu3
Br
O
PhS
N
TIPSOTf
TIPS
OH
Br
O
PhS
N
O
5
6
A
A
82
72
O
H
O
Br
O
PhS
N
HCHO
OH
Br
Synlett 2010, No. 4, 591–594 © Thieme Stuttgart · New York

LETTER
Methodology for the Synthesis of Substituted 1,3-Oxazoles
593
Table 1 Preparation of 5-Substituted (continued) 4-Bromo-2-(Phenylthio)oxazole 2 (continued)
PhS
PhS
O
O
1) LDA, –78 °C to 0 °C
Br
E
N
N
2) then: E+, –78 °C to r.t.
1
3
H
Br
Entry
7
Cond.a
A
Electrophile
Product
PhS
Yield (%)
79
O
OH
OH
O
N
Br
O
PhS
N
O
8
9
A
B
74
87
Br
I
PhS
N
O
H
Br
O
PhS
N
I
10
11
C
C
80
67
Br
O
PhS
N
I
H
OTHP
H
Br
O
OTHP
O
PhS
N
12
13
C
C
72
77
O
I
I
Br
O
PhS
N
CO2Et
CO2Et
Br
a Conditions A: A concentrated solution of 5-bromo-2-phenylthio-1,3-oxazole (1, 1.0 equiv) in THF was added dropwise into a freshly prepared
solution of LDA (1.5 equiv) in THF at –78 °C. After stirring at –78 °C for 10 min, the mixture was warmed to 0 °C using an ice bath and main-
tained at 0 °C for 45 min. Upon cooling to –78 °C, THF solutions of electrophilic reagents (1.5 equiv) were introduced with continued stirring
for 15 min. Reactions were then allowed to warm to 22 °C and were quenched with aq sat. NH4Cl. Extraction (Et2O), drying the organic extracts
over MgSO4, and flash silica gel chromatography led to the purified products. Conditions B: Following the metalation of oxazole 1, anhyd
HMPA (10 equiv) was added at –78 °C. Alkyl iodide (1.5 equiv) in THF was then introduced at –78 °C, and the reaction mixture was warmed
to 22 °C with stirring overnight. Isolation and purification as described in conditions A. Conditions C: Following the metalation of oxazole 1
as previously described, anhyd ZnBr2 (1.2 equiv) in THF was added at 0 °C, and the mixture was allowed to warm to 22 °C with continued
stirring for 1 h. A solution of aryl or alkenyl iodide (1.5 equiv) and Pd(PPh3)4 (10 mol%) in dry DMF was then added, and the reaction mixtures
were stirred at 22 °C, or at 45 °C in the case of entry 12, for 18–24 h. Isolation and purification as described for conditions A above.
In summary, our studies have shown that the halogen
dance isomerization is a synthetically viable process that
can be used to develop molecular complexity in the prep-
aration of 2,4,5-trisubstituted 1,3-oxazoles. Selective re-
placement reactions of the 2-phenylthio and 4-bromo
substituents of our products will enhance the generality
and scope of our observations. Applications for the devel-
opment of this chemistry in natural product synthesis are
currently under way in our laboratories.
Acknowledgment
We acknowledge the support of Indiana University and partial sup-
port of the National Institutes of Health (GM042897).
References and Notes
(1) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.;
Gravalos, D. G. J. Am. Chem. Soc. 1991, 113, 3173.
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8126.
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D. R. Williams, L. Fu
LETTER
(3) For structure revision of diazonamide A, see: Li, J.; Burgett,
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34, 7705.
(13) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew.
Chem. Int. Ed. 2004, 43, 2206.
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Schlosser, M. Eur. J. Org. Chem. 2001, 1371.
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(21) Preparation of Starting Oxazole 1
A CH2Cl2 solution of 2-phenylthio-1,3-oxazole (1.0 equiv)
and anhyd Et3N (1.5 equiv) was stirred at 0 °C, and bromine
(1.5 equiv) in CH2Cl2 (1:1 by volume) was introduced by
slow dropwise addition. The reaction mixture was allowed to
warm slowly to 22 °C, and stirring was continued overnight.
The reaction was quenched with aq sat. NaHCO3 and was
extracted with CH2Cl2. Organic phases were combined and
washed with aq NaHSO3 and then dried over anhyd Na2SO4.
Evaporation of solvent and flash silica gel chromatography
(8:1 hexane–EtOAc) provided 5-bromo-2-phenylthio-1,3-
oxazole (75% yield).
(10) Hämmerle, J.; Spina, M.; Schnürch, M.; Mihovilovic, M. D.;
Stanetty, P. Synthesis 2008, 3099.
(11) For leading references, see: (a) Vedejs, E.; Luchetta, L. M.
J. Org. Chem. 1999, 64, 1011. (b) Whitney, S. E.; Rickborn,
B. J. Org. Chem. 1991, 56, 3058.
(22) Yields of Table 1 are provided for purified products which
were characterized by 1H NMR and 13C NMR spectroscopy,
IR spectroscopy, and HRMS analysis.
Synlett 2010, No. 4, 591–594 © Thieme Stuttgart · New York