Preparation of azidoaryl- and azidoalkyloxazoles for click chemistry

Article abstract of DOI:10.1016/j.tetlet.2012.08.032

A series of azidoaryl- and azidoalkyl(diphenyl)oxazole scaffolds were warranted for biofilm inhibition studies. Cyclization of azidoaryl- or azidoalkyl esters of benzoin with ammonium acetate in acetic acid gives 2-azidoaryl- or 2-azidoalkyl-4,5-diphenyloxazoles. The azidoaryl esters are prepared from the corresponding azidocarboxylic acids/acid chlorides while the azidoalkyl esters are prepared from the corresponding haloalkyl esters.

Full text of DOI:10.1016/j.tetlet.2012.08.032

Tetrahedron Letters 53 (2012) 5641–5644
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of azidoaryl- and azidoalkyloxazoles for click chemistry q
Catherine M. Loner a, Frederick A. Luzzio b, , Donald R. Demuth a
⇑
a Department of Periodontics, Endodontics and Dental Hygiene, University of Louisville School of Dentistry, 501 S. Preston St. Louisville, Kentucky 40292, USA
b Department of Chemistry, University of Louisville, 2320 So. Brook St. Louisville. Kentucky 40292, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of azidoaryl- and azidoalkyl(diphenyl)oxazole scaffolds were warranted for biofilm inhibition
studies. Cyclization of azidoaryl- or azidoalkyl esters of benzoin with ammonium acetate in acetic acid
gives 2-azidoaryl- or 2-azidoalkyl-4,5-diphenyloxazoles. The azidoaryl esters are prepared from the cor-
responding azidocarboxylic acids/acid chlorides while the azidoalkyl esters are prepared from the corre-
sponding haloalkyl esters.
Received 20 July 2012
Accepted 7 August 2012
Available online 14 August 2012
Keywords:
Azides
Ó 2012 Elsevier Ltd. All rights reserved.
Click chemistry
Oxazoles
Biofilms
Peptidomimetics
Introduction
gets. They are also poorly basic and, despite having a contiguous
array of nitrogen atoms, are not protonated at physiological pH.
Organic azides are utilized as precursors to amines, nitro com-
pounds, and many types of nitrogen heterocycles such as aziri-
dines, azetidines, pyrrolidones, oxazoles, indoles, and triazoles.1
In the area of biological probes, they are employed as readily-pre-
pared reactive intermediates for labeling and bioconjugation.2 In
terms of a functional group found in biologically active molecules,
compounds such as AZT3a or azido-thalidomide3b are excellent
examples of pharmacophores which exhibit the azide moiety as a
necessary component of an active structure. More recently organic
azides are commonly employed as reacting partners with acety-
lenes in the 1,3-dipolar cycloaddition reaction popularly known
as ‘click chemistry’.4 While the dipolar cycloaddition of azides with
terminal acetylenes was established through the pioneering work
of Huisgen, the introduction of so called ‘click chemistry’ by Sharp-
less has served to exemplify its use in biomedical applications such
as drug discovery and structural biology.5 Click chemistry may be
used in conjunction with many types of scaffolds which bear either
the acetylene or azide components. Scaffolds composed of hetero-
cycles6, carbohydrates7, polypeptides8, terpenes,9 or lipids10 are
but a few of the many possible structural families that may be
functionalized for click chemistry. The 1, 2, 3-triazole ‘linker’ units
that result from the dipolar cycloaddition come with a unique set
of properties all their own.11 These units may hydrogen bond
thereby increasing aqueous solubility or affinity for molecular tar-
We are currently interested in the inhibition of biofilm forma-
tion using the techniques of click chemistry. Porphyromonas gingi-
valis is a major pathogen associated with periodontal disease and
this organism colonizes the dental biofilm by interacting with oral
streptococci. We previously showed that this interaction is inhib-
ited 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.12 Consequently,
the design and study of small-molecule, non-peptide based inhib-
itors of the Mfa/AgI/II interaction can encompass the employment
of two synthetic scaffolds joined together via a ‘click’ reaction.
Within the expansive area of nitrogen/oxygen heterocycles, we
have identified the substituted oxazole framework as a starting
point for peptidomimetic inhibitors of Mfa/AgI/II interaction. Oxaz-
oles and their semi-saturated congeners, the oxazolines have been
proposed as backbone replacements for peptide bonds in pepti-
domimetic chemistry and protein-derived frameworks.13 More-
over, the oxazole framework is also a viable starting point as a
basic scaffold for the construction of chemically diverse pharmaco-
phores. The relative ease of installing an azido group on most mol-
ecules together with the diversity of oxazole substitution has led
us to choose the 4,5-disubstituted oxazole system with a spacer
containing the azido group at the 2-position. The ‘spacer’ can take
the form of either an aromatic ring with 1,3- or 1,4- substitution, or
one or more methylene units which link the azido group to the het-
erocycle. Hence, the azidooxazole coupling partners described
herein can be placed in two structural groups, 2-azidoaryl-4,5-
disubstituted oxazoles 1 and 2-azidoalkyl-4,5-disubstituted oxaz-
oles 2. Our initial experiments in the 2-azidoaryl-4,5-disubstituted
q
Presented by CML at the 242nd National Meeting of the American Chemical
Society, Denver, Colorado, August 28, 2011; ORGN130.
⇑
Corresponding author. Tel.: +1 502 852 7323; fax: +1 502 852 8149.
E-mail address: faluzz01@louisville.edu (F.A. Luzzio).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.032

5642
C. M. Loner et al. / Tetrahedron Letters 53 (2012) 5641–5644
oxazole series entailed the preparation of benzoic or acetic esters
of benzoin with the objective of thiourea-mediated cyclization to
the corresponding 2-phenyl- or 2-methyl-4,5-diphenyloxazoles
1a, 2a (Eq. 1).14 One could also envision these intermediates as
occurring en route to later-stage azido substitution. In experiments
whereby the optimal temperatures required for heterocycle forma-
tion were explored, treatment of the known benzoyl ester of ben-
zoin 6a
Ph
Ph
O
O
O
a.
O
X
X
( )n
Cl
( )n
7a, n=1, X=H
7b, n=1, X=Cl
7c, n=3, X=Br
7d, n=4, X=Br
8a, n=1, X=H
8b, n=1, X=Cl
8c, n=3, X=Br
8d, n=4, X=Br
d.
Ph
Ph
N
b.
Me
O
2a
Ph
Ph
N3
N
Ph
Ph
O
Ph
Ph
Ph
N
O
c.
N3
N
O
( )n
(
)
n
N3
( )n
O
O
O
R
Ph
2b, n=1
2c, n=3
2d, n=4
9b, n=1
9c, n=3
9d, n=4
2
1
, R=N3
ð1Þ
Ph
Ph
O
Ph
Ph
Scheme 2. Synthesis of 2-azidoalkyl-4,5-diphenyloxazoles. Reagents/conditions:
(a) benzoin, pyridine/DMAP, 0 °C; (b) NaN3/DMF/80 °C; (c) NH4OAc/HOAc/118 °C; d.
thiourea/DMF/150 °C.
N
O
(NH2)2CS
DMF/heat
O
R
O
R
1a, 2a
R=Ph
R=alkyl
the analogous 2,4,5-substituted oxazoles. 2-Methyloxazole 2a
would then be submitted to benzylic-type halogenation followed
by substitution with azide ion (Scheme 2). Cyclization of the known
acetylbenzoin 8a19 with thiourea in N,N-dimethylformamide
(150 °C) gave 2-methyl-4,5-diphenyloxazole 2a in 74% yield.20
Halogenation of 2a with N-bromosuccinimide under a variety of
conditions failed to give the expected benzylic bromide intermedi-
ate, thereby precluding installation of azide by nucleophilic substi-
tution. When it became evident that the azide displacement would
not be the last step in obtaining 2b, the alternative route involving
the preparation and cyclization of the azidoacetyl ester was ex-
plored (Scheme 2).
with thiourea in hot N,N-dimethylformamide (DMF) gave 2,4,5-
triphenyloxazole 1a (69%) (Scheme 1).15 Next, the 4-azidobenzoyl
ester 6b was prepared by diazotizing 4-aminobenzoic acid 3b
(NaNO2/HCl/NaN3) in the presence of sodium azide.16 Following
azidation of 3b, the resultant 4-azidobenzoic acid 4b was treated
with thionyl chloride. The direct addition of the acid chloride 5b
to benzoin then afforded the ester 6b.17 However, treatment of azi-
dobenzoyl ester 6b with thiourea/DMF similar to the cyclization of
6a gave only products of decomposition and none of the expected
2-azidophenyl-4,5-diphenyloxazole 1b. Presumably, the highly
reducing nature of thiourea at higher temperatures proved to be
incompatible with the azide functionality of 6b or possibly the
product 1b. Alternatively, the 4-azidobenzoyl ester 6b was treated
with ammonium acetate in acetic acid (118 °C) which did provide
1b in 61% yield after purification by flash-column chromatogra-
phy.18 Using a scheme similar to that which gave 1b, 2-(3-azid-
ophenyl)-4,5-diphenyloxazole 1c was prepared accordingly.
Starting with 3-aminobenzoic acid 3c, 3-azido-benzoic acid 4c
was prepared using the NaNO2/HCl/NaN3 method followed by di-
rect conversion to the acid chloride 5c. Reaction of 5c with benzoin
afforded 3-azidobenzoyl ester 6c which was cyclized to 1c (80%)
using the ammonium acetate/acetic acid protocol.
Treatment of benzoin chloroacetate 8b21 with sodium azide in
hot DMF (80 °C) gave the azido ester 9b in 22% yield after purifica-
tion by flash-column chromatography. Cyclization of azidoacetyl
ester 9b to 2-azidomethyloxazole 2b was accomplished in 46%
yield by heating 9b with ammonium acetate (15 equiv) in acetic
acid (118 °C). The analogous preparation of the benzoin haloesters
8c and 8d were accomplished from 4-bromobutyryl chloride 7c and
5-bromovaleryl chloride 7d.22 Preparation of haloesters 8c and 8d
was followed by their conversion to the azidoesters 9c (85%) and
9d (56%) using sodium azide/DMF (80 °C).23 Through the employ-
ment of ammonium acetate under conditions similar to the prepa-
ration of 1b and 1c, the intermediate azidoesters 9c and 9d were
cyclized to the 2-azidoalkyloxazoles 2c (64%) and 2d (81%).24 In
summary, we have detailed a general method for the preparation
of both 2-azidoaryl- and 2-azidoalkyloxazoles for employment in
click chemistry. The scheme utilizes azido-substituted esters which
are submitted to a relatively high-temperature aminative hetero-
cyclization. A distinct improvement in the method would entail
the introduction of a heterocyclization in which lower tempera-
tures and neutral, non-reducing conditions are employed thereby
allowing the presence of sensitive functionality and preserving
the azide group. Ongoing synthetic studies currently involve the
preparation of trisubstituted 2-azidooxazoles in which both (or
one of) the 4,5-aryl groups described in the present work are
interchanged with alkyl groups of varying substitution. The oxazole
targets bearing more structural diversity together with their
biological evaluation in biofilm inhibition will be reported by our
laboratory in due course.
The initial experiments in the 2-azidoalkyl-4,5-disubstituted
oxazole series 2b–d entailed the preparation of acetic esters of ben-
zoin with the same objective of thiourea-mediated cyclization to
O
O
R1
b.
Cl
R
R
5a, R=H
3b, R=4-NH2,R1=OH
3c, R=3-NH2,R1=OH
5b, R=4-N3
5c, R=3-N3
a.
4b, R=4-N3,R1=OH
4c, R=3-N3,R1=OH
c.
R
Ph
Ph
Ph
Ph
O
N
d.
O
R
O
O
1a, R=H
1b, R=4-N3
1c, R=3-N3
Acknowledgments
6a, R=H
6b, R=4-N3
6c, R=3-N3
The measurement of high resolution mass spectra by the Texas
A&M University Laboratory for Biological Mass Spectrometry and
Dr. Vanessa Santiago are acknowledged. CML thanks the Depart-
ment of Chemistry for financial support.
Scheme 1. Synthesis of 2-azidoaryl-4,5-diphenyloxazoles. Reagents/conditions: (a)
NaNO2/HCl/NaN3; (b) SOCl2/76 °C; (c) benzoin/pyridine/DMAP/0 °C; d. NH4OAc/
HOAc/118 °C, or thiourea/DMF/150 °C.

C. M. Loner et al. / Tetrahedron Letters 53 (2012) 5641–5644
5643
sodium sulfate. Removal of the drying agent by filtration and rotary
evaporation of the solvent gave a crude solid that was purified by flash
chromatography on silica gel (hexane/EtOAc, 4:1) to obtain 6b (80%) and 6c
(72%). 2-oxo-1,2-diphenylethyl-4-azidobenzoate (6b): Rf: 0.42 (hexane/ethyl
acetate, 4:1); FTIR 2118.00, 1174.79, 1710.42, 1693.73, 1448.18,
References and notes
1. (a) Bräse, S.; Gil, C.; Knepper, K.; Zimmerman, V. Angew. Chem., Int. Ed. 2005, 44,
5188–5240; (b) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297–368.
2. Hein, C. D.; Liu, X.-M.; Wang, D. Pharmaceutical Res. 2008, 25, 2216–2230.
3. (a) Horowitz, J. P.; Chua, J.; Noel, M. J. Org. Chem. 1964, 29, 2076–2078; (b)
Capitosti, S. M.; Hansen, T. P.; Brown, M. L. Org. Lett. 2003, 5, 2865–2867.
4. (a) Huisgen, R. Angew. Chem. 1963, 75, 604–637; (b) Huisgen, R. Angew. Chem.,
Int. Ed. Engl. 1963, 2, 565–598; (c) Huisgen, R. Angew. Chem. 1963, 75, 742–754;
(d) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633–635.
1504.39 cmꢁ1 1H NMR: (400 MHz, CDCl3) d: 6.96 (s, 1H); 6.99–7.33 (m,
;
14H); 7.90-7.92 (d, 2H, J = 7.99); 8.01–8.04 (d, 2H); 13C NMR (100 MHz, CDCl3)
d: 193.62, 165.20, 145.29, 118.81-145.20, 78.06; HRMS calcd for C21H15N3O3
(M+H)+ 358.1192, Found: 358.1195. 2-oxo-1,2-diphenylethyl-3-azidobenzoate
(6c): Rf: 0.53 (hexane/ethyl acetate, 4:1); FTIR 2124.85, 1299.51, 1711.90,
1695.45, 1482.43, 1448.61 cmꢁ1 1H NMR: (400 MHz, CDCl3) d: 7.00 (s, 1H);
;
5. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
2021.
7.08ꢁ7.90 (m, 14H); 13C NMR (100 MHz, CDCl3) d: 193.42, 165.20, 120.16–
140.62, 78.33; HRMS calcd for C21H15N3O3 (M+Li)+ 364.1273, Found: 364.1266.
18. General procedure for preparation of 2-(4-azidophenyl)-4,5-diphenyloxazole (1b)
and 2-(3-azidophenyl)-4,5-diphenyl-oxazole (1c): The azidobenzoic esters 6b or
6c (1 equiv) and ammonium acetate (15 equiv) are combined in glacial acetic
acid (10 mL). The mixture is then heated (oil bath) at reflux (118 °C) for 2 hours
under an atmosphere of nitrogen. The reaction mixture was monitored by TLC
and when complete, the reaction mixture was dissolved in diethyl ether
(110 mL) and washed with NaOH solution (3 ꢀ 100 mL). The diethyl ether layer
is separated and dried over anhydrous sodium sulfate. Removal of the drying
agent by filtration and rotary evaporation of the solvent gave a crude oil that
was purified by flash chromatography on silica gel (hexane/ethyl acetate, 4:1)
to obtain 1b (61%) and 1c (80%) as amorphous solids. 2-(4-azidophenyl)-4,5-
diphenyloxazole (1b): Rf: 0.60 (hexane/ethyl acetate, 4:1); FTIR: 2088.97,
6. (a) Fiandanese, V.; Maurantonio, S.; Punzi, A.; Rafashieri, G. G. Org. Biomol.
Chem. 2012, 10, 1186–1195; (b) Wang, M.; Das, M. R.; Li, M.; Boukerroub, R.;
Szunerits, S. J. Phys. Chem. C 2009, 113, 17082–17086; (c) Buck, S. B.; Bradford,
J.; Gee, K. R.; Agnew, B. R.; Clarke, S. T.; Salic, A. Biotechniques 2008, 44, 927–
929; (d) Comstock, L. R.; Rajski, S. R. J. Org. Chem. 2004, 69, 1425–1428.
7. (a) Stefani, H. A.; Silva, N. C. S.; Manarin, F.; Lüdtke, D. S.; Zukerman-Schpector,
J.; Madureira, L. S.; Tiekink, E. R. T. Tetrahedron Lett. 2012, 53, 1742–1747; (b)
Pèrez-Castro, I.; Caamaño, O.; Fernández, F.; Garcia, M. D.; López, C.; de Clercq,
E. ARKIVOK 2010 (iii) 152–168.
8. (a) Baccile, J. A.; Morrell, M. A.; Falotico, R. M.; Milliken, B. T.; Drew, D. L.; Rossi,
F. M. Tetrahedron Lett. 2012, 53, 1933–1935; (b) Franke, R.; Doll, C.; Eichler, J.
Tetrahedron Lett. 2005, 46, 4479–4482.
9. Sall, C.; Dombrowsky, L.; Bottzeck, O.; Praud-Tabaries, A.; Blache, Y. Bioorg.
Med. Chem. Lett. 2011, 21, 1493–1497.
1278.93, 1608.72, 1493.77, 1087.95 cmꢁ1 1H NMR: (500 MHz, CDCl3) 7.21–
;
8.13 (m, 14H, aromatic); 13C NMR (125 MHz, CDCl3) d: 159.46, 145.61, 142.26,
136.47, 119.34-132.01; HRMS calcd for C21H14N4O (M+H)+ 339.1246, Found:
339.1243. 2-(3-azidophenyl)-4,5-diphenyloxazole (1c): Rf: 0.53 (hexane/ethyl
10. Bori, I. D.; Hung, H.-Y.; Qian, K.; Chen, C.-H.; Morris-Natschke, S. L.; Lee, K.-L.
Tetrahedron Lett. 2012, 53, 1987–1989.
11. Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6, 2696–2718.
12. (a) Daep, C.; James, D.; Lamont, R.; Demuth, D. Infection and Immunity 2006, 74,
5756–5762; (b) Filoche, S.; Wong, L.; Sissons, C. H. J. Dent. Res. 2010, 89, 8–18;
(c) Daep, C.; Lamont, R.; Demuth, D. Infection and Immunity 2008, 76, 3273–
3280; (d) Daep, C.; Novak, E.; Lamont, R.; Demuth, D. Infection and Immunity
2011, 79, 67–74.
13. (a) Walsh, C. T.; Malcolmson, S. J.; Young, T. S. ACS Chem. Biol. 2012, 7, 429–442;
(b) Davis, M. R.; Sing, E. K.; Wahyudi, H.; Alexander, L. D.; Kunicki, J. B.;
Nazarova, L. A.; Fairweather, K. A.; Giltrap, A. M.; Jolliffe, K. A.; McAlpine, S. R.
Tetrahedron 2012, 68, 1029–1051.
acetate, 4:1); FTIR: 2146.37, 1276.93, 1590.12, 1590.35 cmꢁ1
;
1H NMR:
(400 MHz, CDCl3) d: 7.09–7.94 (m, 14H, aromatic); 13C NMR (100 MHz,
CDCl3) d: 159.09, 145.96, 140.87, 136.85, 116.84–132.25; HRMS calcd for
C
21H14N4O (M+H)+ 339.1246, Found: 339.1241.
19. Butler, R. N.; Hanahoe, A. B.; King, W. B. J. Chem. Soc. 1978, 8, 881–884.
20. 2-Methyl-4,5-diphenyloxazole (2a): 2-Oxo-1, 2-diphenylethyl acetate 8a (0.20 g,
0.79 mmol) was dissolved in DMF (10 mL). Thiourea was then added and the
reaction was heated (150°, oil bath) under a nitrogen atmosphere. As the
reaction progressed, the color changed from colorless to a light yellow-orange
and had an odorous smell. The reaction was monitored by TLC and when
complete, the reaction mixture was dissolved in dichloromethane (40 mL) and
then washed with water (3 ꢀ 30 mL). The dichloromethane layer was
separated and dried over anhydrous sodium sulfate. Removal of the drying
agent by filtration and rotary evaporation of the solvent gave a crude oil that
was purified by flash chromatography on silica gel (dichloromethane) to
provide 2a (74%): Rf: 0.098 (hexane/ethyl acetate, 2:1); FTIR 2920.50; 1220.30;
14. (a) Dalko, M.; Dumats, J. U.S. Patent 6333,414 B1, 2001; Chem. Abs.
134:326522.; (b) See also: Turner, C. D.; Liang, S. H. Current Org. Chem. 2011,
15, 2846–2870.
15. 2,4,5-Triphenyloxazole (1a): Benzoyl ester 6a25 (200 mg, 0.63 mmol) was added
to DMF (7.0 mL) followed by thiourea (96.5 mg, 1.26 mmol). The mixture was
heated under a nitrogen atmosphere while stirring (150 °C, oil bath) under an
atmosphere of nitrogen. Heating was continued for 16 h whereupon thin-layer
chromatographic analysis indicated complete consumption of starting material
and formation of product as evidenced by a more mobile spot. The DMF was
removed under high vacuum and the solid residue was flash-chromatographed
on silica gel (hexanes/ethyl acetate, 9:1) which provided 1a (130 mg, 69%) as a
white crystalline solid: mp. 116–118 °C (Lit.26 116–117 °C).
1502.00, 1588.24 cmꢁ1 1H NMR (400 MHz, CDCl3)d: 2.617 (s, 3H); 7.25–7.66
;
(m, 10H, aromatic); 13C NMR (100 MHz, CDCl3) d 160.35, 145.41, 134.82,
126.46-132.14, 13.92; HRMS calcd for C16H13NO (M+H)+ 236.1075, Found:
236.1077.
21. 1-Oxo-1, 2-diphenylethyl-2-chloroacetate (8b): Benzoin (0.50 g, 2.37 mmol) and
4-dimethylaminopyridine
(0.29 g,
2.37 mmol)
were
dissolved
in
16. General procedure for preparation of 4- and 3-azidobenzoic acid (4b, 4c): (Adapted
from a procedure by Molina, P.; Diaz, I.; Tarraga, A. Tetrahedron 1995, 51, 5617-
5630). 3-amino- or 4-aminobenzoic acid (3b or 3c, 1 equiv) was dissolved in
aqueous HCl solution (10%) and cooled to 0 °C (ice bath). Aqueous sodium
nitrite (20%, 1.2 equiv) was then added and the reaction mixture was allowed
to stir at room temperature (15 min). A 20% aqueous solution of sodium azide
(1.2 equiv) then was added at room temperature which resulted in a vigorous
dichloromethane (20 mL) and the solution was allowed to stir at 0 °C.
Commercially-available chloroacetyl chloride 7b (0.21 mL, 2.60 mmol) was
added dropwise by syringe. The reaction mixture was then stirred under
nitrogen at 0 °C (4 h) while monitoring by TLC. Upon completion of the
reaction, the reaction mixture was dissolved in diethyl ether (100 mL) and
washed with water (2 ꢀ 90 mL), 5% aqueous HCl (1 ꢀ 90 mL), and 5% aqueous
sodium bicarbonate (1 ꢀ 90 mL). The diethyl ether layer was separated and
dried over anhydrous sodium sulfate. After removal of the drying agent by
filtration and removal of solvent by rotary evaporation, the product
chloroacetyl ester 8b was obtained in 95% yield and found to be of
reasonable purity as evidenced by 1H NMR and TLC. Rf: 0.51 (hexane/ethyl
reaction and creating
a foaming precipitate (Caution!) which filled the
headspace of the reaction flask. The foam precipitate, which was the
azidobenzoic acid product, was collected by vacuum filtration while washing
the filter cake with water. Excess solvent was removed by slow rotary
evaporation prior to vacuum filtration. The slightly yellow-white solids were
stored damp in the refrigerator and were of sufficient purity to use in the next
step (4b: mp 189–190 °C, Lit.27 188.5–190 °C; 4c: mp 176–178 °C, Lit.28176–
177 °C). Prior to the treatment with thionyl chloride to produce 5b/5c, the
azidobenzoic acids were dried at room temperature under high vacuum.
17. General procedure for preparation of 2-oxo-1,2-diphenylethyl-4-azidobenzoate
(6b) and 2-oxo-1, 2-diphenylethyl-3-azidobenzoate (6c) through acid chlorides 5b
and 5c: The azidobenzoic acid 4b or 4c (1 e0071uiv) was dissolved in thionyl
chloride (4.5 equiv). The mixture is heated to reflux (75 °C), and allowed to stir
(5 h). The reaction mixture was then allowed to stir overnight at room
temperature. Thionyl chloride was then removed by adding dichloromethane
(10 mL) and concentrating with the rotary evaporator under aspirator vacuum.
The addition of dichloromethane and vacuum rotary evaporation was repeated
(3ꢀ) to give the acid chlorides 5b or 5c as oils. The azidobenzoyl chlorides (5b/
5c) were used in the next esterification step without further purification.
Benzoin (1 equiv), triethylamine (1 equiv), and 4-dimethylaminopyridine
(0.1 equiv) are dissolved in dichloromethane (10 mL) at 0 °C (ice water bath).
The azidobenzoyl chloride (5b or 5c, 1 equiv) dissolved in dry dichloromethane
(5 mL) was gradually introduced dropwise into the reaction flask while
stirring. The reaction mixture was allowed to stir (3 h) at room temperature
while monitoring by TLC. Upon completion of the reaction, the reaction
mixture was dissolved in diethyl ether (100 mL) and washed with 5% aqueous
HCl solution (4 ꢀ 50 mL) followed by 5% aqueous sodium bicarbonate
(2 ꢀ 100 mL). The organic layer was separated and dried over anhydrous
acetate, 4:1); FTIR 2960, 1734, 1694, 1597, 1495, 1224 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) d: 7.25–7.91 (m, 10H); 6.94 (s, 1H); 3.96–4.11 (dd, 2H);
13C NMR (125 MHz, CDCl3) d: 192.62, 167.91, 128.71–134.17, 78.75, 50.11.
22. General procedure for preparation of bromoacyl esters (8c and 8d) through acid
chlorides (7c, 7d: 5-bromovaleric acid (1 equiv) or 4-bromobutyric acid
(1 equiv) was dissolved in thionyl chloride (4.5 equiv). The reaction mixture
was then heated (75 °C, oil bath) under a nitrogen atmosphere overnight. The
excess thionyl chloride was removed by adding dichloromethane (25 mL)
followed by rotary evaporation under aspirator vacuum. The addition of the
dichloromethane and rotary evaporation was repeated (3ꢀ) which yielded the
crude acid chloride as an oil. The 5-bromobutyryl chloride 7c or the 4-
bromovaleryl chloride 7d were used without further purification in the next
step. Benzoin (1 equiv) was dissolved in pyridine (12 mL) followed by cooling
the solution to 0 °C (ice water bath). The acid chloride 7c, 7d (1 equiv) was then
added dropwise to the stirred solution while cooling and stirring. The reaction
flask was capped, and after 30 min, the cooling bath was removed. The reaction
mixture was then stirred (4 h) at room temperature while monitoring by TLC.
After the starting materials were consumed, the reaction mixture was then
dissolved in dichloromethane (300 mL) and washed with 5% aqueous HCl
(5 ꢀ 120 mL). The organic layer was then separated and dried over anhydrous
sodium sulfate. Flash chromatography on silica gel (hexane/ethyl acetate, 6:1)
afforded esters 8c (70%) and 8d (23%) as oils. 2-oxo-1,2-diphenylethyl-4-bromo-
butanoate (8c): Rf: 0.49 (hexane/ethylacetate, 4:1); FTIR: 3063.60, 1708.60,
1692.03, 1588.70, 1531.70 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 2.21–2.23 (t,
;

5644
C. M. Loner et al. / Tetrahedron Letters 53 (2012) 5641–5644
24. General Procedure for preparation of the azidoalkyl oxazoles (2b, 2c, 2d): The azido
2H); 2.60–2.69 (m, 2H); 3.45–3.47 (t, 2H); 6.85 (s, 1H); 7.28–8.01 (m, 10H); 13
C
NMR (100 MHz, CDCl3) d: 193.66, 172.08, 134.56, 133.57, 128.70-129.43,
esters 9b, 9c or 9d (1 equiv) were dissolved in glacial acetic acid (10 mL).
Ammonium acetate (15 equiv) was then added and the reaction mixture was
heated (118 °C, oil bath) under a nitrogen atmosphere (2 h). The reaction
mixture was monitored by TLC, and when complete as evidenced by the
disappearance of the ester, the reaction mixture was dissolved in diethyl ether
(100 mL) and washed with aqueous sodium hydroxide (3 ꢀ 100 mL). The
organic layer was separated and dried over anhydrous sodium sulfate. Flash
chromatography on silica gel (hexane/ethyl acetate, 8:1) afforded 2b (46%), 2c
(64%) and 2d (81%). 2-(azidomethyl)-4,5-diphenyloxazole (2b): Rf: 0.58 (hexane/
77.85, 32.55, 32.34, 27.83; FTIR: 3063.60, 1708.60, 1692.03, 1588.70,
1531.70 cmꢁ1
.
2-oxo-1,2-diphenylethyl-5-bromopentanoate (8d): Rf: 0.47
(hexane/ethyl acetate, 4:1); FTIR: 1734.38, 1693.88, 1597.38, 1448.37 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d: 1.81–1.87 (m, 2H); 1.91–1.98 (m, 2H); 2.44–2.59
(m, 2H); 3.40–3.43 (t, 2H); 6.85 (s, 1H), 7.35–7.93 (m, 10H); 13C NMR
(100 MHz, CDCl3) d: 193.75, 172.63, 134.59, 133.49, 128.07–128.83, 60.25,
44.55, 33.09, 31.76, 23.38.
23. General procedure for conversion of the halogenated esters 8b, 8c or 8d to azido
esters (9b, 9c or 9d): The halogenated ester 8b, 8c or 8d (1 equiv) was dissolved
in DMF. Sodium azide (1.1 equiv) was then added and the reaction mixture was
ethyl acetate, 4:1); FTIR 2098, 1444.19, 1569.48, 1604.78, 1251.13 cmꢁ1 1H
;
NMR (400 MHz, CDCl3) d: 4.44 (s, 2H); 7.18–7.59 (m, 10H); 13C NMR (125 MHz,
CDCl3) d: 157.23, 146.77, 135.52, 126.69-131.80, 46.75. HRMS calcd for
heated (80 °C, oil bath) under
a nitrogen atmosphere (4 h). The reaction
mixture was monitored by TLC and when complete, the DMF was removed
under high vacuum. The crude oil was purified by flash chromatography on
silica gel (hexane/ethyl acetate, 9:1) to obtain 9b (22%) 9c (85%) and 9d (56%).
2-Oxo-1,2-diphenylethyl-2-azidoacetate (9b): Rf: 0.49 (hexane/ethyl acetate,
C
16H13N4O (M+H)+ 277.1089, Found: 277.1090. 2-(3-azidopropyl)-4,5-
diphenyl-oxazole (2c): Rf: 0.30 (hexane/ethyl acetate, 8:1); FTIR 2094.21,
1218.91, 2933.26, 1570.34, 1501.98, 1218.91 cmꢁ1 1H NMR: (500 MHz,
;
CDCl3) d: 2.16–2.19 (m, 2H); 3.02–3.06 (t, 2H); 3.49–3.51 (t, 2H); 7.35–7.67
(m, 10H); 13C NMR (125 MHz, CDCl3) d: 162.68, 145.69, 134.22, 126.54-131.34,
50.55, 26.31, 25.18; HRMS calcd for C18H16N4O (M+H)+ 305.1402, Found:
305.1407. 2-(4-azidobutyl)-4,5-diphenyl-oxazole (2d): Rf: 0.50 (hexane/ethyl
4:1); FTIR 2104.56, 1173.01, 1747.90, 1692.58, 1597.22, 1448.76 cmꢁ1 1H
;
NMR: (500 MHz, CDCl3) d: 7.38–7.94 (m, 10H); 6.97 (s, 1H); 4.03–4.10 (dd,
2H); HRMS calcd for C16H13N3O3 (M+Li)+ 302.1117, Found 302.1121. 2-oxo-1,2-
diphenylethyl-4-azidobutanoate (9c): Rf: 0.44 (hexane/ethylacetate, 4:1); FTIR:
acetate, 4:1); FTIR 2936.78, 2091.06, 1218.94, 1570.01, 1501.95, 1157.14 cmꢁ1
;
2096.16, 1448.47, 1734.69, 1693.83, 1580.74, 1496.07 cmꢁ1
;
1H NMR
1H NMR: (500 MHz, CDCl3) d: 1.77–1.80 (m, 2H); 1.96–2.0 (m, 2H); 2.92–2.95
(t, 2H); 3.36–3.39 (t, 2H); 7.336–7.668 (m, 10H); 13C NMR (125 MHz, CDCl3) d:
162.99, 145.35, 132.23, 126.47-128.92, 51.04, 28.35, 27.65, 24.27; HRMS calcd
for C19H18N4O (M+H)+ 319.1559, Found: 319.1564.
(500 MHz, CDCl3) d: 1.82–1.92 (t, 2H); 2.41–2.60 (m, 2H); 3.28–3.38 (t, 2H);
6.82 (s, 1H); 7.25–7.98 (m, 10H, aromatic); 13C NMR (125 MHz, CDCl3) d:
193.65, 172.23, 134.55, 133.56, 128.69–129.19, 77.86, 50.54, 30.95, 24.33;
HRMS calcd for C18H17N3O3 (M+H)+ 324.1348, Found: 324.1346. 2-oxo-1,2-
diphenylethyl-5-azidopentanoate (9d): Rf: 0.22 (hexane/ethyl acetate, 4:1); FTIR
25. Cutulic, S. P. Y.; Findlay, N. J.; Zhou, S. Z.; Chrystal, E. J. T.; Murphy, J. A. J. Org.
Chem. 2009, 74, 8713–8718.
26. Davidson, D.; Jelling, M. J. Org. Chem. 1937, 2, 328–334.
27. Goddar-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–3800.
28. Boyer, J. H.; Elizey, S., Jr. J. Org. Chem. 1958, 23, 127–129.
2092.58, 1224.81, 1734.84, 1694.21, 1597.46, 1448.81 cmꢁ1
;
1H NMR:
(500 MHz, CDCl3) d: 1.52–1.61 (m, 2H); 1.62–1.71 (m, 2H); 2.32–2.49 (m,
2H); 3.14–3.22 (t, 2H); 6.782 (s, 1H); 7.24–7.85 (m, 10H); 13C NMR (125 MHz,
CDCl3) d: 193.76, 172.64, 134.60, 133.55, 128.66–129.36, 77.66, 51.02, 33.33,
28.13, 22.04. HRMS calcd for C19H19N3O3 (M+H)+ 338.1505, Found: 338.1500.