Three-component synthesis of highly functionalized 5-acetyloxazoles

Article abstract of DOI:10.1002/chem.200900386

A study was conducted to demonstrate three-component synthesis of highly functionalized 5-acetyloxazoles. The two-step procedure allowed a highly flexible substitution pattern at C-2 and C-4 position. The synthesis procedure also allowed the incorporation

Full text of DOI:10.1002/chem.200900386

DOI: 10.1002/chem.200900386
Three-Component Synthesis of Highly Functionalized 5-Acetyloxazoles
Tilman Lechel,[a] Dieter Lentz,[a, b] and Hans-Ulrich Reissig*[a]
The occurrence of the oxazole subunit in architecturally
complex structures and their use in functional materials con-
tributed to an ongoing interest in this class of heterocycles.
More precisely, oxazole derivatives have found industrial ap-
plication as scintillator and laser dyes.[1] Owing to their im-
portant biological activities alkaloids with oxazole moieties
have attracted much attention in drug development as
potent antitumor, antibacterial, antiviral or antifungal
agents.[2] To date, a variety of synthetic methods for oxazoles
has been reported.[1,3,4] One of the most widely used synthe-
ses of 2,5-di- and 2,4,5-trisubstituted oxazoles is the cyclode-
hydration of a-acylamino-ketones known as Robinson–Ga-
briel reaction.[5] Most of the Robinson–Gabriel based meth-
ods require harsh dehydrating agents and the direct intro-
duction of different functional groups in 2-, 4- or 5-position
is quite rare.
In our previous work we reported on the high utility of al-
koxyallenes 1 as C-3 building blocks in the synthesis of het-
Scheme 1. Synthesis of 4-methylpyrimidines 4, 4-hydroxypyridines 6, and
erocyclic compounds as intermediates of natural products or
5-acetyloxazole derivatives 7 via alkoxy-substituted enamides 5 starting
other interesting products.[6] Enamides, such as 5, are readily
from lithiated alkoxyallenes 1, nitriles 2 and carboxylic acids 3.
accessible in one step by a novel three-component synthesis
using lithiated alkoxyallenes, nitriles and carboxylic acids as
key components. The mechanism of the enamide formation
has already been discussed in former publications.[7] Recent-
ly, we have demonstrated that enamides 5 are ideal precur-
sors for the synthesis of highly functionalized 4-methylpyri-
midines[8] 4 and 4-hydroxypyridine derivatives[9] 6 using
either ammonium salts or trimethylsilyl trifluoromethanesul-
fonate and base (Scheme 1). Herein, we describe reaction
conditions that easily convert alkoxy-substituted enamides 5
to 2,4-substituted 5-acetyloxazoles 7.[10] This method easily
allows the incorporation of different substituents in 2- and
4-position of the resulting oxazoles.
Following the reported procedure enamides 5a–i could be
obtained in moderate to good yields. As depicted in Table 1
(entries 1–7) benzyloxy- or trimethylsilylethoxy-protected al-
lenes reacted with benzonitrile and different carboxylic
acids in yields between 21 and 75%. In case of R3 = CF3
(entry 1) enamide 5a could be isolated in 40% together
with the corresponding 4-hydroxypyridine 6 as a side prod-
uct in 36% yield. The different solubilities of the aromatic
or heteroaromatic carboxylic acids (entries 2–5) might be
the reason why the yields vary in a range of 24 and 75% (in
general not optimized). While benzoic acid and 2-thiophene
carboxylic acid could be dissolved in diethyl ether or THF
before adding to the reaction mixture, picolinic acid was
only soluble in DMF and precipitated immediately at
À788C. The reaction was also performed with propiolic acid
and pyruvic acid giving products with an alkynyl or an
acetyl moiety in low yields (21 and 28%, entries 6 and 7).
[a] T. Lechel, Prof. Dr. D. Lentz, Prof. Dr. H.-U. Reissig
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax : (+49)30-8385-5367
E-mail: hans.reissig@chemie.fu-berlin.de
[b] Prof. Dr. D. Lentz
Responsible for X-ray crystal structure analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900386.
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Chem. Eur. J. 2009, 15, 5432 – 5435

COMMUNICATION
Table 1. Three-component synthesis of enamides 5a–i starting from al-
koxyallenes 1.
cyclopropyl substituent could also be prepared (entries 8
and 9). To compare the reactivity of benzyl and trimethyl-
silylethyl-protected enamides we prepared enamides 5c and
5d (Table 1, entries 3 and 4) with identical substituents R2
and R3. Entries 3 and 4 of Table 2 reveal higher yields of the
corresponding oxazole 7 starting from the trimethylsilyl-
ethyl-protected enamide 5. Attempts to apply fluoride re-
agents, such as HF/pyridine, to trimethylsilylethyl-protected
enamides, such as 5i, were successful, but the yield of 7h
could not be increased.
According to the structure determination of the 2,4-dicy-
clopropyloxazole derivative by X-ray diffraction 7h possess-
es crystallographic Cs symmetry (Figure 1).[11] As a conse-
quence the carbon planes of both cyclopropane rings are ex-
actly in perpendicular orientation with respect to the oxa-
zole ring. These antiperiplanar conformations allow favora-
ble electronic interactions of the heteroaryl moiety with the
cyclopropane rings.
Entry
R1
R2
R3
Product
Yield[a] [%]
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
TMSE
TMSE
TMSE
TMSE
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-C9H19
cPr
CF3
Ph
2-pyridyl
2-pyridyl
2-thienyl
5a
5b
5c
5d
5e
5 f
5g
5h
5i
40[b]
54[8]
27
24
75
21
28
27
75
ꢀ
C CH
acetyl
Ph
TMSE
cPr
[a] Reaction conditions: 1) Alkoxyallene (1.0 or 3.0 equiv), nBuLi (1.1 or
2.7 equiv), Et2O, À408C, 20 min. 2) Nitrile (1.5 or 1.0 equiv), 30 min at
À408C. 3) À788C, 4 h, then carboxylic acid (3.0 or 6.0 equiv), warm up to
RT overnight. TMSE=trimethylsilylethyl, c-Pr=cyclopropyl. [b] In addi-
tion 36% pyridinol 6 isolated as side product.
Changing the nitrile to n-nonylnitrile and treatment with
benzoic acid gave only poor yields (27%, entry 8). Gratify-
ingly, the use of cyclopropylnitrile and cyclopropane carbox-
ylic acid as components afforded the expected product in
high yields (75%, entry 9).
The cyclization of enamides 5a–i to the corresponding ox-
azole derivatives was carried out in a sealed tube with an
excess of trifluoroacetic acid acting as solvent and reagent.
After heating at 808C for 15–20 min the corresponding 5-
acetyloxazoles 7a–h were obtained in moderate to very
good yields (Table 2, entries 1–9, 39–99%). Noteworthy, not
only electron-withdrawing heteroaryl groups can be intro-
duced to the C-2 position in similar yields, but also alkynyl
or acetyl substituents are possible at this ring position (en-
tries 6 and 7). The C-4 position is not restricted to aromatic
substituents as oxazoles with an unbranched alkyl chain or a
Figure 1. X-ray crystal structure of compound 7h.
The formation of oxazole derivatives could be explained
in accordance to the Robinson–Gabriel mechanism for the
cyclodehydration of a-acylaminoketones. In contrast to the
generally accepted mechanism of the Robinson–Gabriel re-
action[12] our preliminary studies with 18O-labelled enamides
showed that the enol oxygen is incorporated into the oxa-
zole ring. This discovery fits to the mechanism assumed for
the conversion of ortho-hydroxy benzeneamides into ben-
zoxazoles.[13]
Next we focused our attention to the substituent at C-5 of
the oxazole. Our method is not restricted to introduce 5-
acetyl substituted oxazoles as demonstrated by the synthesis
of derivative 11. This compound could be prepared by a g-
phenyl substituted (trimethylsilylethoxy)alkyne 9, using the
general reaction conditions for the synthesis of enamides
and oxazoles (Scheme 2). First, Pd-catalyzed coupling of
alkyne 8[14] with iodobenzene yielded alkyne 9 in 72%.
Direct isomerization of this compound with n-butyllithium
Table 2. Synthesis of oxazole derivatives 7a–h.
Entry
R1
R2
R3
Product
Yield[a] (%)
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
TMSE
TMSE
TMSE
TMSE
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-C9H19
cPr
CF3
Ph
2-pyridyl
2-pyridyl
2-thienyl
7a
7b
7c
7c
7d
7e
7 f
7g
7h
74
48
64
99
68
57
39
ꢀ
C CH
acetyl
Ph
51
TMSE
cPr
67, 34[b]
Reaction conditions: [a] TFA (excess), sealed tube, 808C, 15–20 min.
[b] HF/Py (3.0 equiv), 08C, 1 min.
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H.-U. Reissig et al.
In conclusion, we have developed a novel and fast three-
component synthesis to 2,4-disubstituted 5-acetyloxazoles
using a-lithiated alkoxyallenes, nitriles and carboxylic acids
as precursors. The two-step procedure allows a highly flexi-
ble substitution pattern at C-2 and C-4 position (Scheme 4).
The acetyl group at C-5 can be further functionalized em-
ploying standard reactions. Scope and limitations of this
method leading to highly substituted oxazole derivatives is
currently under investigation.
Scheme 2. Synthesis of enamide 10 and oxazole 11 starting from g-phenyl
substituted (trimethylsilylethoxy)alkyne 9.
Scheme 4. Highly flexible substitution pattern in all positions.
at À408C to the a-lithiated alkoxyallene and subsequent
treatment with pivalonitrile and trifluoroacetic acid gener-
ates the enamide 10 in 42% yield. The cyclization was
either possible with trifluoroacetic acid under the general
conditions or with HF/pyridine to provide the expected
product 11 in 59 or 42% yield, respectively.
Experimental Section
Synthesis of enamide 5i (typical procedure): Trimethylsilylethoxyallene
(4.00 g, 25.6 mmol) was dissolved in Et2O (52 mL) and n-butyllithium
(9.73 mL, 24.3 mmol, 2.5m in hexanes) was added at À408C. After
25 min at À508C to À408C cyclopropane nitrile (0.95 mL, 12.8 mmol)
was added. The solution was stirred at À408C for 30 min and then cooled
down to À788C. After stirring for 4 h at this temperature cyclopropane
carboxylic acid (4.06 mL, 51.2 mmol) was added and the mixture was
warmed up overnight to room temperature. The mixture was quenched
with satd. aq. NaHCO3 solution (40 mL) and extracted twice with Et2O
(40 mL). The combined organic layers were dried with Na2SO4, filtered
and concentrated. Column chromatography (silica gel, EtOAc/hexane
1:10) provided 5i as colorless oil (2.98 g, 75%).
Oxazoles with the 5-acetyl group are not easily available
by other methods.[15] Only a few deal with the synthesis of
related oxazol-5-yl ketones.[16] This functional group enables
the preparation of a variety of other oxazole derivatives.
The trifluoromethyl-substituted oxazoles 7a and 11 were
smoothly reduced using sodium borohydride to give the cor-
responding alcohols 12a–b in very good yields (82–93%).
Subsequent dehydration employing Hibbert conditions fur-
nished 5-alkenyl-substituted oxazoles 13a–b in 74 and 88%
yield (Scheme 3). NMR spectroscopy confirmed the trans-
configuration of compound 13b. These oxazole derivatives
can be starting point for further synthetic elaboration.
Grignard addition of vinylmagnesium bromide to oxazole
7a afforded compound 14 in good yield (75%), which
should be a suitable precursor for further studies leading to
Diels–Alder products. Treatment of 7a with hydroxylammo-
nium chloride provided oxime 15 as the singular isomer in
64% yield.
Synthesis of oxazole 7h (typical procedure): Enamide 5i (144 mg,
0.465 mmol) was added in a sealed tube and dissolved in TFA (2.0 mL).
The reaction mixture was placed in a preheated oil bath (808C). After
stirring for 15 min at this temperature water (4.0 mL) was slowly added
to the reaction mixture and extracted three times with CH2Cl2 (4.0 mL).
The combined organic layers were dried with Na2SO4, filtered and con-
centrated. Column chromatography (silica gel, EtOAc/hexane 1:10) pro-
vided 7h as colorless solid (60 mg, 67%).
Acknowledgements
Support by the Deutsche Forschungsgemeinschaft (SFB 765), the Fonds
der Chemischen Industrie and the Bayer Schering Pharma AG is most
gratefully acknowledged.
Keywords: cumulenes
·
cyclization
·
heterocycles
·
multicomponent reactions · oxazoles
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Highly Functionalized 5-Acetyloxazoles
COMMUNICATION
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Received: February 11, 2009
Published online: April 22, 2009
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