Synthesis of 2-(hetero)aryl-5-(trimethylsilylethynyl)oxazoles from (hetero)arylacrylic acids

Article abstract of DOI:10.1021/acs.orglett.5b00009

A three-step method for the synthesis of 2-(hetero)aryl-5-(trimethylsilylethynyl)oxazoles is described. Easily accessible bis(trimethylsilyl)acetylene and acrylic acid derivatives are used as starting materials for the preparation of mono- and disubstituted 5-(trimethylsilyl)pent-1-en-4-yn-3-ones. Oxidative phthalimidoaziridination of these enynones provides the key 2-acyl-1-phthalimidoaziridines that are further utilized in the thermal expansion of the three-membered ring to furnish the target functionalizable oxazoles.

Full text of DOI:10.1021/acs.orglett.5b00009

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑(Hetero)aryl-5-(trimethylsilylethynyl)oxazoles from
(Hetero)arylacrylic Acids
Alena S. Pankova, Alexander Yu. Stukalov, and Mikhail A. Kuznetsov*
Institute of Chemistry, Saint Petersburg State University, Universitetsky pr. 26, 198504 Saint Petersburg, Russia
S
* Supporting Information
ABSTRACT: A three-step method for the synthesis of 2-(hetero)aryl-5-
(trimethylsilylethynyl)oxazoles is described. Easily accessible bis-
(trimethylsilyl)acetylene and acrylic acid derivatives are used as starting
materials for the preparation of mono- and disubstituted 5-
(trimethylsilyl)pent-1-en-4-yn-3-ones. Oxidative phthalimido-
aziridination of these enynones provides the key 2-acyl-1-phthalimido-
aziridines that are further utilized in the thermal expansion of the three-
membered ring to furnish the target functionalizable oxazoles.
s numerous bioactive natural products contain an oxazole
ring, research has focused on the properties and methods
Scheme 1. Representative Synthesis of 5-Alkynyloxazoles4a,b
A
of synthesis of these heterocycles.1 In addition, the scaffold of
2,5-disubstituted oxazole features promising fluorescent proper-
ties, which may be used in optical materials, biomolecular
probes, and sensor elements.2 The availability of easily
functionalized groups at the oxazole ring plays a key role in
the elaboration of this heterocycle, and a terminal triple bond
offers a wealth of practical synthetic transformations toward this
goal. While several methods for the synthesis of alkynyloxazoles
are known,3 5-alkynyl substituted oxazoles have primarily been
obtained by the Sonogashira reaction (Scheme 1).4 These
catalytic processes use mild reaction conditions and show
considerable functional group compatibility. However, the
employed halogen or triflate oxazole electrophiles are often
not commercially available and their preparation is sometimes
tedious, which can increase the total number of synthetic steps
and diminish the overall yield of the desired products. As a
feasible alternative to known methods, we have developed a
novel synthetic route to alkynyloxazoles from easily available
compounds and report our results herein.
Earlier we have shown that oxazoles can be prepared in good
yields by a two-step procedure involving thermolysis of N-
phthalimidoaziridines obtained from α,β-unsaturated ketones.5
It is also known that the acylation of bis(trimethylsilyl)-
acetylene (BTMSA) with acyl chlorides is suitable for the
preparation of trimethylsilylalkynones.6 Based on this knowl-
edge, we decided to explore a novel route to 5-(trimethyl-
silylethynyl)oxazoles from substituted acrylic acids employing
an aziridine as the key intermediate (vide infra).
First, we prepared several substituted cinnamic and 3-
heteroarylacrylic acids 1a−h from the corresponding aldehydes
and malonic acid by the Knoevenagel reaction. In addition, 2-
aryl-3-phenylacrylic acids 2a−c and 3a,b were synthesized from
benzaldehyde and arylacetic acids.7,8 In general, two stereo-
isomers are obtained in this reaction, but (E)-isomer 2 with cis-
orientation of the aryl rings prevails (Table 1). Mixtures of
isomeric phenylacrylic acids 2 and 3 were separated utilizing
their different acidity: treatment of solutions of their salts with
acetic acid (pH ∼5) afforded (E)-isomers, and further
acidification to pH ∼1 with concentrated HCl allowed isolating
(Z)-isomers (see Supporting Information for details). The
reaction with 4-nitrophenylacetic acid gave a better result when
triethylamine was replaced with less basic pyridine,8 and the
heating time was reduced (Table 1, entries 3, 4). While this
allowed an increase in the yield of 2c from 7% to 44%, the
Received: January 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00009
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acyl chloride does not react with bis(trimethylsilyl)acetylene
instead giving the product of intramolecular cyclization (see
Supporting Information for details).
Table 1. Synthesis of Acrylic Acids 2 and 3
Oxidative aminoaziridination of enynones 4a−k readily gave
previously unknown 1-phthalimidoaziridines 5a−k in good
yields (Table 3). Since the inversion of an endocyclic nitrogen
atom is slow on the NMR time scale,10 disubstituted aziridines
5a−h exist as mixtures of two invertomers with a significant
a
a
entry
R
base
time (h) (E)-isomer (%)
(Z)-isomer (%)
1
2
3
4
H
Et3N
Et3N
Et3N
Py
5
2a (55)
2b (61)
2c (7)
3a (19)
3b (14)
3c (−)
3c (−)
1
predominance of one of them at 25 °C. H NMR spectra of
OMe
NO2
NO2
5
these compounds contain two pairs of characteristic doublets
assigned to the protons of the aziridine ring. While signals of
the major invertomers appear at δ 3.84−3.94 and 4.47−4.71
ppm, those for the minor ones are at δ 4.06−4.32 and 4.45−
4.76 ppm. The values of the vicinal coupling constants (3J =
5
1.5
2c (44)
a
Isolated yield.
isolation of the (Z)-isomer 3c using our protocol was not
successful.
The acyl chlorides obtained by the treatment of unsaturated
acids 1a−h and 2a−c with oxalyl chloride were used without
purification for the acylation of bis(trimethylsilyl)acetylene to
furnish ketones 4a−k in good yields (Table 2). We also wish to
3
4.7−5.0 Hz for the major invertomers and J = 5.2−5.4 Hz for
the minor ones) indicate the trans-arrangement of the aziridine
protons, which is consistent with the well-known retention of
the initial configuration of the double bond in the course of the
oxidative aminoaziridination.11 Carbon atom signals of the
aziridine ring are observed at δ 44−54 ppm in the 13C NMR
spectra.
Table 2. Synthesis of Enynones 4a−k
As the phthalimide substituent deshields the syn-located
aziridine proton,10 assignment of the spatial structure of
1
invertomers can be based on their H NMR spectra. The
low-field proton doublet of the major invertomer is slightly
broadened as compared to the high-field doublet due to the
long-range interaction with ortho-protons of the aromatic
substituent. It indicates that in the major invertomer the
phthalimide group and R1-substituent are in the anti-position
which appears to be sterically more favorable. The increasing
amount of the minor invertomer for heteroarylaziridines 5f−h
is likely due to the smaller size of the five-membered rings as
compared to the six-membered phenyl ring. Trisubstituted
aziridines 5i−k exist as single invertomers, and a syn-orientation
of the phthalimide group and the aziridine proton is supported
by the characteristic singlet of the latter at δ 5.03−5.19 ppm.
Signals of the methine and quaternary carbons of the aziridine
ring are found at δ ∼56 and ∼63 ppm, respectively.
entry acid
R1
R2
enynone yield (%)
1
1a
1b
1c
1d
1e
1f
4-O2NC6H4
4-ClC6H4
Ph
H
H
H
H
H
H
H
H
Ph
4a
4b
4c
4d
4e
4f
73
84
91
90
82
82
89
77
84
82
66
2
3
4
4-MeC6H4
4-MeOC6H4
2-thienyl
3-thienyl
1-phenylpyrazol-4-yl
Ph
5
6
7
1g
1h
2a
2b
2c
4g
4h
4i
8
9
10
11
Ph
4-MeOC6H4
4-O2NC6H4
4j
Ph
4k
Finally, we have examined the key thermal transformation of
aziridines 5a−k into targeted azoles 6a−k. All experiments
were carried out in toluene solution in sealed vials under TLC
control, and products were isolated by column chromatography
in good yields (Table 4). The structure and composition of
point out that (Z)-acrylic acids 3 exhibit varying reactivity
under our reaction conditions. Thus, no ketone is formed when
3a is subjected to the standard protocol, as the corresponding
Table 3. Synthesis of 1-Phthalimidoaziridines 5a−k
entry
enynone
R1
R2
aziridine
ratio of invertomers
isolated yield (%)
1
4a
4b
4c
4d
4e
4f
4-O2NC6H4
4-ClC6H4
Ph
H
H
H
H
H
H
H
H
Ph
5a
5b
5c
5d
5e
5f
1:0.02
1:0.05
1:0.05
1:0.06
1:0.07
1:0.17
1:0.12
1:0.25
1:0
89
76
72
76
72
65
62
66
78
74
81
2
3
4
4-MeC6H4
4-MeOC6H4
2-thienyl
3-thienyl
1-phenylpyrazol-4-yl
Ph
5
6
7
4g
4h
4i
5g
5h
5i
8
9
10
11
4j
Ph
4-MeOC6H4
4-O2NC6H4
5j
1:0
4k
Ph
5k
1:0
B
DOI: 10.1021/acs.orglett.5b00009
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 4. Synthesis of Oxazoles 6a−k
entry
aziridine
R1
R2
temp (°C)
time, h
oxazole
isolated yield (%)
1
5a
5b
5c
5d
5e
5f
4-O2NC6H4
4-ClC6H4
Ph
H
H
H
H
H
H
H
H
Ph
140
140
130
110
110
100
120
130
110
110
110
6
6a
6b
6c
6d
6e
6f
66
62
61
49
50
46
28
30
72
69
72
2
2.5
3
3
4
4-MeC6H4
4-MeOC6H4
2-thienyl
3-thienyl
1-phenylpyrazol-4-yl
Ph
7
5
4.5
5
6
7
5g
5h
5i
6
6g
6h
6i
8
6
9
7
10
11
5j
Ph
4-MeOC6H4
4-O2NC6H4
7
6j
5k
Ph
7
6k
Scheme 2. Plausible Mechanism for the Ring Expansion of 2-Acyl-1-phthalimidoaziridines into Oxazoles
obtained oxazoles 6a−k are in agreement with their NMR and
HRMS data. Importantly, the trimethylsilyl substituted triple
bond remained intact in all isolated products. For disubstituted
compounds 6a−h, the signal of the H4 proton is observed at δ
7.29−7.41 ppm and its corresponding carbon atom resonates at
∼133 ppm. Trisubstituted oxazoles 6i−k feature a signal of the
C4 at lower field (δ ∼142−144 ppm).
Surprisingly, 2-thienyl-substituted aziridine 5f underwent a
competitive isomerization and gave a mixture of oxazole 6f and
enhydrazine 11 (Scheme 3). The structure of the latter product
was confirmed by 2D NMR spectroscopy including 13C−1H
and 15N−1H HSQC, 13C−1H HMBC, and NOESY spectra.
Scheme 3. Thermolysis of Aziridine 5f
The transformation of disubstituted aziridines into oxazoles
proceeded under milder conditions if substituent R1 was an
electron-rich aromatic ring or a 2-thienyl substituent (Table 4,
entries 4−6). This can be explained by a more effective
stabilization of the cationic center in the intermediate
azomethine ylides (vide infra). At the same time, yields of
oxazoles 6a−c with NO2, Cl, and H substituents were slightly
higher even at more elevated temperatures. Conversion of
trisubstituted aziridines 5i−k into oxazoles 6i−k appears to be
insensitive to the electronic character of the substituent at the
C2 atom of the aziridine (Table 4, entries 9−11).
Although the mechanism of the ring expansion of 2-
acylaziridines 5 into oxazoles 6 has not been fully elucidated,
one can speculate about the likely steps involved in this
transformation (Scheme 2). Upon heating, the conrotatory ring
opening of the C−C bond in the aziridine gives azomethine
ylides 7 and/or 8. Then two pathways are possible: an
elimination of the phthalimide molecule with the formation of
nitrile ylide 9 followed by its cyclization into oxazole 6, or the
initial formation of oxazoline 10 with the consequent loss of the
phthalimide.5
Nucleophilic ring opening via the C−N bond cleavage is very
typical for aziridines.12 In our case, the observed regioselectivity
can be explained by the influence of the neighboring sulfur
atom whose lone pair can push out the aziridine nitrogen with
the formation of an intermediate zwitter-ion 12. In addition, a
similar enhydrazine was not obtained for 3-thienyl analog 5g
supporting our hypothesis.
C
DOI: 10.1021/acs.orglett.5b00009
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) Walton, D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45−
In summary, we have developed a new synthetic route to 5-
alkynyl-1,3-oxazoles via 2-acylaziridines providing an attractive
alternative to the known methods. Readily available starting
materials and reagents and only three simple steps with good
yields are the main advantages of our synthetic protocol.
Moreover, this method is applicable for various substituent
patterns of the initial compounds that allows introducing one
or two groups into the oxazole ring. Lastly, we note that the
ethynyl substituent with an easily removable TMS group offers
various routes for further useful transformations.
46.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, copies of the
1D and 2D NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: m.kuznetsov@spbu.ru.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Alexey Fedorov (ETH Zurich) for his
help in the preparation of this manuscript and acknowledge the
Russian Scientific Fund (Research Grant 14-13-00126) for
financial support. NMR and HRMS analyses were performed at
the Saint Petersburg State University Center for Magnetic
Resonance and Center for Chemical Analysis and Materials
Research, respectively. This paper is dedicated to Prof. V. I.
Minkin (SFedU, Rostov-on-Don) on the occasion of his 80th
birthday.
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DOI: 10.1021/acs.orglett.5b00009
Org. Lett. XXXX, XXX, XXX−XXX