Oxazoles for click chemistry II: Synthesis of extended heterocyclic scaffolds

Article abstract of DOI:10.1016/j.tetlet.2014.11.014

Abstract New routes to 2,4,5-trisubstituted oxazoles were established whereby the substitution pattern was established by the structure of the starting nonsymmetrical acyloins. 2-Chloromethyl-4, 5-disubstituted oxazoles were prepared by refinements of an earlier described process whereby chloroacetyl esters of symmetrical and nonsymmetrical acyloins were cyclized using an ammonium acetate/acetic acid protocol. After substitution is effected, the azide moiety is then installed by substitution under mild conditions. While dibrominated and iodinated phenyloxazoles are required for further synthetic elaboration, the cyclization reaction was found to be very sensitive to the relative positions of the halogens in the starting materials.

Full text of DOI:10.1016/j.tetlet.2014.11.014

Accepted Manuscript
Oxazoles for click chemistry II: synthesis of extended heterocyclic scaffolds
Pravin C. Patil, Frederick A. Luzzio, Donald R. Demuth
PII:
S0040-4039(14)01896-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.014
TETL 45398
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 October 2014
3 November 2014
3 November 2014
Please cite this article as: Patil, P.C., Luzzio, F.A., Demuth, D.R., Oxazoles for click chemistry II: synthesis of
extended heterocyclic scaffolds, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.11.014
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Oxazoles for click chemistry II: synthesis of
extended heterocyclic scaffolds
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Pravin C. Patil, Frederick A. Luzzio*, Donald R. Demuth
R1
R2
O
R1
O
R1
N
O
R3
R2
O
R3
R2
O
R1=phenyl
R2=alkyl, phenyl
R3=2, 3, 4-azidophenyl, azidomethyl, chloromethyl

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Oxazoles for click chemistry II: synthesis of extended heterocyclic scaffolds
Pravin C. Patila , Frederick A. Luzzioa,  and Donald R. Demuthb
aDepartment of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky, 40292, USA
bDepartment of Periodontics, Endodontics and Dental Hygiene, University of Louisville School of Dentistry, 501 S. Preston St. Louisville, Kentucky, 40292 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
New routes to 2, 4, 5-trisubstituted oxazoles were established whereby the substitution pattern
was established by the structure of the starting nonsymmetrical acyloins. 2-Chloromethyl-4, 5-
disubstituted oxazoles were prepared by refinements of an earlier described process whereby
chloroacetyl esters of symmetrical and non-symmetrical acyloins were cyclized using an
ammonium acetate/acetic acid protocol. After substitution is effected, the azide moiety is then
installed by substitution under mild conditions. While dibrominated and iodinated
phenyloxazoles are required for further synthetic elaboration, the cyclization reaction was found
to be very sensitive to the relative positions of the halogens in the starting materials.
Available online
Keywords:
Oxazoles
Azides
Click Chemistry
Peptidomimetics
Biofilms
2009 Elsevier Ltd. All rights reserved.
together via a “click” reaction. In a prior communication5 we
detailed a route to the inhibitory 4, 5-diaryl-2-azidoaryl- and 4, 5-
diaryl-2-azidoalkyl oxazole scaffolds, and we now describe
extensions of our methodology which enables access to a great
1. Introduction
The oxazole structural motif plays a central role in medicinal
and natural products chemistry.1 Apart from the major classical
name reactions and contemporary strategies used in preparing the
oxazole nucleus, there remains unique opportunities for
elaborating this central framework to provide a plethora of
synthetic targets.2 Moreover, in the area of peptidomimetics,
oxazole-based scaffolds, backbones and amino acid analogues
many substituted oxazoles having diverse functionality and
extended heterocyclic frameworks. Our initial route entailed the
cyclization of azidoalkyl- or azidoaryl esters of benzoin with
ammonium acetate in acetic acid (115°C/3h) thereby affording
the corresponding 2-azidoaryl- or 2-azidoalkyl-4, 5-diphenyl-
oxazoles. We also discovered that cyclizations of benzoin esters
could be accomplished by treatment with thiourea (DMF/150°C);
however, these conditions were not compatible with either alkyl
or aryl azides and provided complex mixtures. Essentially, the
intermediate azido esters were pre-formed before the final
cyclization to the target oxazole and the basic scheme relied on
both the preparation of the starting haloalkyl esters and
substitution of halide with azide. We now report an extension of
the cyclization methodology to 2-(azidophenyl)-4-phenyl-5-
alkyloxazoles 1a-i along with the corresponding 2-azido-methyl-
4-phenyl-5-alkyloxazoles 2a-c. The use of the symmetrical diaryl
acyloin as a starting material was detailed in our previous
communication and the use of which established the basic
strategy and provided the 2-alkyl- or 2-aryl-4, 5-diphenyl
substitution in the target heterocycle.5 The scheme toward the 2-
azidophenyl- and 2-azidomethyl-4-phenyl-5-alkyl-substituted
oxazoles detailed herein required a somewhat different strategy
continue to provide
a diverse array of compounds for
pharmacological evaluation in numerous therapeutic areas.3 We
are presently conducting studies entailing the inhibition of dental
biofilm formation using both the trisubstituted oxazole scaffold
and the techniques of click chemistry. Porphyromonas gingivalis
is a major pathogen associated with periodontal disease and this
organism colonizes the dental biofilm by interacting with oral
streptococci. Demuth and Sissons previously showed that this
interaction is inhibited by a peptide comprised of two distinct
structural motifs which block the interaction of minor fimbrial
antigen (Mfa) of P. gingivalis with the antigen I/II (AgI/II) of
oral streptococci.4 Consequently, the design and study of small-
molecule, non-peptide based inhibitors of the Mfa/AgI/II
interaction can involve the employment of two heterocyclic
scaffolds, one being a substituted oxazole, which may be joined
———
 Corresponding author. Tel.: +0-502-852-7323; fax: +502-852-8149; e-mail:faluzz01@louisville.edu

2
Tetrahedron
Scheme 1. Synthesis of 2-azidophenyl-4-phenyl-5-alkyloxazoles
(n=2, 5, 7) from non-symmetrical acyloins:
Scheme 3. Synthesis of 2-azidomethyl-4-phenyl-5-alkyloxazoles
(n=2,5,7):
a
O
O
b
O
O
a
b
N
O
O
5a-c
Cl
( )n
( )n
( )n
5a-c
OTs
OH
Cl
( )n
O
( )n
3a: n=2
3b: n=5
3c: n=7
4a-c
9a-c
10a-c
c
c
d
d
O
N
O
O
R
e
O
N
O
O
( )n
O
R
( )n
1a-i
N3
6a-i
N3
( )n
( )n
O
Reagents/Conditions:
1a, 6a: n=2, R=2-azidophenyl
1b, 6b: n=2, R=3-azidophenyl
1c, 6c: n=2, R=4-azidophenyl
1d, 6d: n=5, R=2-azidophenyl
1e, 6e: n=5, R=3-azidophenyl
1f, 6f: n=5, R=4-azidophenyl
1g, 6g: n=7, R=2-azidophenyl
1h, 6h: n=7, R=3-azidophenyl
1i, 6i: n=7, R=4-azidophenyl
2a: n=2
2b: n=5
2c: n=7
11a: n=2
11b: n=5
11c: n=7
(a) Oxone/4-iodotoluene,
p-TsOH/MeCN/16h, 60oC.
(b) LiOH/H2O/DMF/16h,
5oC to rt.
Reagents/Conditions: (a) chloroacetyl chloride/TEA/DMAP/CH2Cl2/
5oC to rt, 16h. (b) NH4OAc/HOAc/115oC, 3h. (c) NaN3/DMF/rt, 2h.
(d) NaN3/DMF/rt, 2h.(e) NH4OAc/HOAc/115oC, 3h.
(c) TEA/DMAP/CH2Cl2/16h,
5oC to rt.
(d) NH4OAc/HOAc/3h, 115oC
chloroacetyl ester of benzoin (NH4OAc/HOAc/115ºC, 3h) gave
2-chloromethyl-4, 5-diphenyl-oxazole 7, albeit in modest yield.
Substitution of 7 with azide ion (NaN3/DMF/rt, 3h) gave the
azidomethyloxazole 8. Thus, nucleophilic substitution of 7 with
azide ion under mild conditions was a viable alternative to
cyclization of the corresponding azidoacetyl ester as reported
earlier (Scheme 2). The chloroacetyl esters of the
nonsymmetrical acyloins 9a, 9b and 9c were cyclized in similar
fashion thereby providing the corresponding 4-phenyl-5-alkyl-2-
(chloromethyl) oxazoles 10a-c (Scheme 3).8 Conversion to the
corresponding 2-azidomethyl compounds 2a-c was accomplished
by treating 10a-c with sodium azide in DMF (rt).8 For
comparison, the conversion of chloroesters 9a-c to the
corresponding azidoesters 11a-c (NaN3/DMF) according to our
previous route was conducted smoothly.8 The azidoesters 11a-c
were then cyclized to the azidomethyloxazoles 2a-c
(NH4OAc/HOAc).8 When an excess of ammonium acetate/acetic
acid was used during the cyclization of the chloroacetyl ester of
benzoin (Scheme 2), solvolysis to the corresponding 2-
acetoxymethyl oxazole 12 was a competing reaction (7/33%,
12/16%). Decreasing the concentration of ammonium acetate in
acetic acid while carefully monitoring the reaction progress
increased the yield of the chloromethyloxazole 7 to 62% and
decreased the formation of ester 12 to 5%.8 Interestingly, the
and required the preparation and employment of non-symmetrical
acyloins 5a-c as starting materials. Aromatic- aliphatic ketones
were employed in the preparation of non-symmetrical acyloins
through a two-step procedure involving oxidation-tosylation
(Scheme 1). Hence, α-tosylation of ketones 3a-c (oxone/4-
iodotoluene/p-toluenesulfonic acid/acetonitrile/ 16h, 60ºC)
provided the tosylates 4a-c.6,7 Base-mediated hydrolysis
(LiOH/H2O/DMF/16h, 5ºC to rt) of the intermediate tosylates 4a-
c afforded the nonsymmetrical acyloins 5a-c.7,8 The acyloins 5a-
c were then acylated with the appropriate acid chloride to afford
the intermediate acyclic esters 6a-i.8 The acyclic esters 6a-i were
then cyclized with ammonium acetate in acetic acid (3h/115ºC)
to provide the trisubstituted oxazoles 1a-i.8
During earlier studies of the synthesis of the 2-azidomethyl-4,
5-diphenyloxazole 8 we discovered that cyclization of the
Scheme 2: Cyclization of benzoin chloroacetate
R1
R2
O
O
R1
R2
R1
R2
N
N
a
O
+
O
OAc
O
Cl
product
acetoxy
ester
12
could
be
hydrolyzed
Cl
7
12
(K2CO3/EtOH/reflux, 2h 97%) which provided the
hydroxymethyl oxazole 13 in excellent yield.8 The construction
of extended oxazole scaffolds might utilize the aldehyde 14 as a
viable intermediate for Wittig or organometallic reaction, and to
this end, 13 was oxidized to 14 with the Dess-Martin periodinane
R1,R2=C6H5
b
R1
R2
N
O
N3
R1
R2
R1
R2
O
H
N
N
8
O
13
O
14
OH
Reagents/Conditions: (a) NH4OAc/HOAc/115oC, 3h.
(b) NaN3/DMF/rt, 3h.
R1,R2=C6H5

3
(CHCl3/reflux, 2h, 97%).8 The cyclization of the tricyclic esters
to provide the triaryloxazoles using ammonium acetate in acetic
acid is not without limitations and certain substitution patterns on
either the benzoin portion or the benzoyl ester portion may
nullify any yield of desired product. For example, the 2-azido-, 3-
azido- or 4-azidobenzoyl ester of 4, 4´-dibromobenzoin 15a-c
cyclized under normal conditions (NH4OAc/HOAc, 115ºC) to
afford the corresponding 2-azidopheny-(4,4'-dibromodiphenyl)
oxazoles 16a-c, but the 2-azido, 3-azido or 4-azidobenzoyl esters
of 2,2´-dibromobenzoin 17a-c do not cyclize to give the expected
azidophenyl-2,2'-(dibromodiphenyl) oxazoles. Another example
of steric influence resides in a comparison of the cyclization
reactions of the 4-iodobenzoyl ester 18 and 2-iodobenzoyl ester
20 of benzoin. Treatment of the 4-iodobenzoyl ester 18 under
normal cyclization conditions affords a clean yield (95%) of the
4-iodophenyloxazole 19, while under the same conditions, the
ortho-iodobenzoyl ester 20 gave none of the expected oxazole.
Spectrometry and Dr. Vanessa Santiago are acknowledged.
Financial support from the NIH/NIDCR through grant
1RO1DE023206 (DRD and FAL) is gratefully acknowledged.
Supplementary Information
The 1H, 13C, FTIR and HRMS data for 6a-i, 1a-i, 9a-c, 10a-c,
11a-c, 2a-c, 16a-c, 7, 12, 18 and 19 and experimental procedures
for compounds 4a-c, 5a-c, 6a-i, 1a-i, 9a-c, 10a-c, 2a-c, 11a-c, 7,
12, 13, 14 and 16a-c can be found in the online version at
http://dxdoi.org/
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Oxford, 2012; Vol. 24, pp 328-329.
Br
Br
Br
Br
O
O
N
O
O
N3
2. (a) Senadi, G. C.; Hu, W.-P.; Hsiao, J.-S.; Vandavasi, J. K.; Chen,
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N3
15a: N3=2; Br=4,4'
15b: N3=3; Br=4,4'
15c: N3=4; Br=4,4'
16a: N3=2; Br=4,4'
16b: N3=3; Br=4,4'
16c: N3=4; Br=4,4'
17a: N3=2; Br=2,2'
17b: N3=3; Br=2,2'
17c: N3=4; Br=2,2'
No Cyclized Product
R1
R2
O
O
O
R1
R2
I
I
N
O
18: R1,R2=C6H5,
I=para
19: R1,R2=C6H5,
I=para
20: R1,R2=C6H5,
I=ortho
No Cyclized Product
In summary, we have detailed a synthetic route to 2, 4, 5-
trisubstituted oxazoles which are differentially substituted at the
4- and 5- positions with phenyl groups and alkyl groups
respectively. The route utilizes non-symmetrical acyloins as
starting materials and has the advantage of not involving
installation of an appendage on a pre-formed oxazole. In contrast
to cyclizing azidoalkyl esters to azidoalkyloxazoles, our newly-
developed strategy utilizes direct cyclization of haloalkyl esters
to haloalkyloxazoles so that they may be either transformed to
azides or further elaborated using other nucleophiles. We found
the chloromethyloxazoles to be a valuable intermediate for the
preparation of many more oxazole-based scaffolds and these
studies will be reported in due course.
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Acknowledgments
8. See Supplementary Information for general procedures.
The measurement of high resolution mass spectra by the
Texas A&M University Laboratory for Biological Mass