Facile Syntheses of Oxazolines and Thiazolines with N-Acylbenzotriazoles under Microwave Irradiation

Article abstract of DOI:10.1021/jo0355092

Microwave reactions of 2-amino-2-methyl-1-propanol (2) or 2-aminoethanethiol hydrochloride (4) with readily available N-acylbenzotriazoles 1a-j in the presence of SOCl₂ produced 2-substituted 2-oxazolines 3a-j in 84-98% yields and 2-substituted

Full text of DOI:10.1021/jo0355092

F a cile Syn th eses of Oxa zolin es a n d Th ia zolin es w ith
N-Acylben zotr ia zoles u n d er Micr ow a ve Ir r a d ia tion
Alan R. Katritzky,* Chunming Cai, Kazuyuki Suzuki, and Sandeep K. Singh
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received October 13, 2003
Microwave reactions of 2-amino-2-methyl-1-propanol (2) or 2-aminoethanethiol hydrochloride (4)
with readily available N-acylbenzotriazoles 1a -j in the presence of SOCl2 produced 2-substituted
2-oxazolines 3a -j in 84-98% yields and 2-substituted thiazolines 5a -i in 85-97% yields,
respectively. With use of this method chiral oxazoline 6, bisoxazoline 7, bisthiazoline 8, and 5,6-
dihydro-4H-1,3-oxazines 9 or 10 have also been prepared in 82-96% yields. These results
demonstrate a new application of N-acylbenzotriazoles in the preparation of oxazolines and
thiazolines under mild conditions and short reaction times with microwave irradiation.
In tr od u ction
methods including imidate hydrochlorides,6g ortho esters,6h
imino ether hydrochlorides,6i aldehydes,6j or nitriles.6k-m
Thiazolines have been prepared (i) by the condensation
of amino thiols with nitriles,5a esters,7a imino ethers7b or
imino triflates,7c (ii) from N-acyl-2-aminoethanols6a,7d or
â-hydroxy thioamides,7e-g or (iii) by multistep conversions
from oxazolines.7h
However, there are limitations associated with these
literature methods: direct conversions of carboxylic acids
into the corresponding 2-oxazolines proceed with elimi-
nation of water at high temperatures (160-220 °C),
require long reaction times (12-18 h), and frequently give
low yields.1a,8 Use of nitriles requires a Lewis acid and
proceeds at high temperatures with elimination of
ammonia.6k Other methods utilize complex reagents6c,7f,g
or strongly acidic conditions.6f The problem of long
reaction times in the synthesis of oxazolines has been
solved to some extent by using microwaves,6e,i,m but the
reported procedures that involve domestic ovens suffer
from low reproducibility and lack general applicability.
Oxazolines and thiazolines are important hetero-
cycles.1,2 2-Oxazolines are structural entities in naturally
occurring iron chelators,3a,b cytotoxic cyclic peptides,3c,d
and antimitotic3e and neuroprotective agents.3f Well-
known applications of 2-oxazolines include their use as
synthetic intermediates,4a,b protecting groups,4c and chiral
auxiliaries.4d,e Thiazoline derivatives possess anti HIV-
1,5a antimitotic,5b and bioluminescent activities,5c and
have recently found applications as building blocks in
pharmaceutical drug discovery.5d-f
Reaction of carboxylic acids with amino alcohols is the
most common method for the synthesis of oxazolines.6a-f
Other carboxylate functionalities can be used in similar
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10.1021/jo0355092 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/09/2004
J . Org. Chem. 2004, 69, 811-814
811

Katritzky et al.
N-Acylbenzotriazoles9a have hitherto been reported as
versatile reagents for N-acylation,9b formylation,9c trifluoro-
acylation,9d O-acylation,9e C-acylation,9f-h and the syn-
thesis of polycyclic heteroaromatics.9i We now apply
N-acylbenzotriazoles in a mild and general procedure for
the direct synthesis of 2-substituted 2-oxazolines and
2-substituted 2-thiazolines under microwave irradiation
using a single mode cavity synthesizer,10a which ensures
reproducibility and safety. Microwave heating has emerged
as a powerful technique to promote a variety of chemical
reactions.10a-f Microwave reactions are also attractive in
offering reduced pollution and low cost together with
simplicity in processing and handling.11a,b
TABLE 1. P r ep a r a tion of 2-Su bstitu ted 2-Oxa zolin es
w ith N-Acylben zotr ia zoles 1a -ja
product
entry reactants
R
(yield, %)b
1
2
3
4
5
6
7
8
9
1a + 2
1b + 2
1c + 2
1d + 2
1e + 2
1f + 2
1g + 2
1h + 2
1i + 2
1j + 2
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
4-ClC6H4
2-ClC6H4
phenyl
1-naphthyl
2-furyl
3a (98)
3b (95)
3c (90)
3d (90)
3e (98)
3f (86)
3g (95)
3h (95)
3i (84)
3j (91)
Resu lts a n d Discu ssion
2-phenylethenyl
1-(6-methoxy-2-naphthyl)ethyl
P r ep a r a tion of N-Acylben zotr ia zoles. The starting
N-acylbenzotriazoles 1a -k with aryl or heterocyclic
groups were prepared in 74-95% yields from the corre-
sponding carboxylic acids following a recently developed
one-step procedure.12 N-Acylbenzotriazoles 1a -k were
characterized by NMR spectroscopy and by comparison
of melting points with those reported in the literature.
P r ep a r a tion of 2-Oxa zolin es. Microwave reactions
were performed in sealed heavy-walled Pyrex tubes
under controlled conditions in a safe and reproducible
procedure. Single mode microwave irradiation was used
at a fixed temperature, pressure, and irradiation power
during the reaction time by an automatic power control.
Optimization of the reaction conditions was carried out
on the cyclocondensation of 1H-1,2,3-benzotriazol-1-yl-
(4-tolyl)methanone (1a ) and 2-amino-2-methyl-1-propanol
(2) in chloroform and different combinations of temper-
ature, time, and irradiation power were studied to
achieve the maximum chemical yield at the lowest
reaction temperature. Our initial microwave experiment
with the mixture containing 1a and 2-amino-2-methyl-
1-propanol (2) at 80 °C and 50 W irradiation power for
10 min produced the desired oxazoline 3a along with the
uncyclized intermediate, N-(2-hydroxy-1,1-dimethylethyl)-
4-methylbenzamide in a 2:1 ratio as determined by the
1H NMR spectrum of the crude product mixture. SOCl2
has been advantageously used for the cyclization of such
intermediates.13 Accordingly, addition of SOCl2 to the
above reaction mixture and subsequent irradiation for 2
min resulted in complete conversion of the uncyclized
10
a
MW, 50 W, 80 °C, 10 min, CHCl3, then SOCl2, MW, 2 min.
Isolated yield.
b
intermediate into 4,4-dimethyl-2-(4-methylphenyl)oxazo-
line (3a ) without the formation of side products or any
noticeable decomposition. Thus, a two-step one-pot pro-
cedure was developed for the synthesis of 2-substituted
oxazolines from N-acylbenzotriazoles under mild condi-
tions with microwave irradiation. By contrast, thermal
reaction of 1a and the amino alcohol 2 in refluxing
chloroform for 30 min showed the presence of substantial
amounts (30-40%) of starting materials and the forma-
tion of N-(2-hydroxy-1,1-dimethylethyl)-4-methylbenza-
mide along with another side product. Stirring the
reaction mixture at room temperature for 12 h resulted
in a 1:1 ratio of the desired oxazoline 3a and the
uncyclized intermediate, which on addition of SOCl2
cyclized in 2 h to give the oxazoline 3a in 70% yield.
Comparison of the above reaction conditions and results
obtained suggested the use of microwave irradiation as
the energy source for the synthesis of 2-substituted
2-oxazolines from N-acylbenzotriazoles.
The above optimized microwave reaction conditions
were applied to the synthesis of a variety of 2-substituted
2-oxazolines 3a -j (Table 1). These results illustrate the
general applicability of this method for the preparation
of 2-substituted 2-oxazolines under mild conditions (80
°C) and short reaction times (12 min). Use of N-acylben-
zotriazoles also avoids some earlier observed complica-
tions in microwave reactions, such as dimerization or the
exclusive formation of amides from carboxylic acids.6i
P r ep a r a tion of Th ia zolin es. The procedure devel-
oped for the synthesis of oxazolines was successfully
applied to the preparation of thiazolines. Thus, condensa-
tion of N-acylbenzotriazoles 1a -f,h ,i with 2-aminoet-
hanethiol hydrochloride (4) in the presence of Et3N under
microwave irradiation at 80 °C and 50 W irradiation
power for 10 min, followed by the addition of SOCl2 and
subsequent irradiation for 2 min furnished the desired
2-substituted 2-thiazolines 5a -f,h ,i in excellent yields
(Table 2). Again, no formation of any side product was
detected in the crude reaction mixtures as determined
(9) (a) Katritzky, A. R.; Shobana, N.; Pernak, J .; Afridi, A. S.; Fan,
W.-Q. Tetrahedron 1992, 48, 7817. (b) Katritzky, A. R.; He, H.-Y.;
Suzuki, K. J . Org. Chem. 2000, 65, 8210. (c) Katritzky, A. R.; Chang,
H.-X.; Yang, B. Synthesis 1995, 503. (d) Katritzky, A. R.; Yang, B.;
Semenzin, D. J . Org. Chem. 1997, 62, 726. (e) Katritzky, A. R.; Pastor,
A.; Voronkov, M. V. J . Heterocycl. Chem. 1999, 36, 777. (f) Katritzky,
A. R.; Pastor, A. J . Org. Chem. 2000, 65, 3679. (g) Katritzky, A. R.;
Suzuki, K.; Singh, S. K.; He, H.-Y. J . Org. Chem. 2003, 68, 5720. (h)
Katritzky, A. R.; Suzuki, K.; Singh, S. K. Croat. Chim. Acta 2003, in
press. (i) Katritzky, A. R.; Huang, T.-B.; Voronkov, M. V. J . Org. Chem.
2000, 65, 8069.
(10) (a) Hayes, B. L. Microwave Synthesis: Chemistry at the Speed
of Light; CEM Publishing: Matthews, NC, 2002. (b) Perreux, L.; Loupy,
A. Tetrahedron 2001, 57, 9199. (c) Lidstro¨m, P.; Tierney, J .; Wathey,
B.; Westman, J . Tetrahedron 2001, 57, 9225. (d) Caddick, S. Tetrahe-
dron 1995, 51, 10403. (e) Fini, A.; Breccia, A. Pure Appl. Chem. 1999,
71, 573. (f) Katritzky, A. R.; Singh, S. K. Arkivoc 2003, 13, 68.
(11) (a) Varma, R. S. Green Chem. 1999, 1, 43. (b) Tanaka, K.; Toda,
F. Chem. Rev. 2000, 100, 1025.
1
by TLC analysis and H NMR spectra. Our method also
avoids multistep preparation of starting materials or the
requirement of special reagents.5a,6c,7b,d,f,g
(12) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, in
press.
(13) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J . Org. Chem. 1978,
43, 1372.
Further, we used this method to prepare the chiral
oxazoline 6 by the reaction of (2S)-2-amino-3-phenyl-1-
812 J . Org. Chem., Vol. 69, No. 3, 2004

Facile Syntheses of Oxazolines and Thiazolines
TABLE 2. P r ep a r a tion of 2-Su bstitu ted 2-Th ia zolin es
column chromatography on silica gel with hexanes/ethyl
acetate (3:2) to give 3a (70%).
w ith N-Acylben zotr ia zoles 1a -f,h ,ia
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Oxa zo-
lin es 3a -j or 2-Th ia zolin es 5a -i w ith N-Acylben zotr ia -
zoles 1a -j u n d er Micr ow a ve Ir r a d ia tion . A dried heavy-
walled Pyrex tube containing a small stir bar was charged with
2-amino-2-methyl-1-propanol (2) or 2-aminoethanethiol hy-
drochloride (4) (2 mmol), N-acylbenzotriazole (1 mmol), and
CHCl3 (0.5 mL) (reactions with 4 were carried out in the
presence of Et3N). The tube containing the reaction mixture
was sealed with an aluminum crimp cap fitted with a silicon
septum and then it was exposed to microwave irradiation (50
W) for 10 min at a temperature of 80 °C. The buildup of
pressure in the closed reaction vessel was carefully monitored
and was found to be typically in the range of 4-10 psi. After
the irradiation, the reaction tube was cooled with high-
pressure air through an inbuilt system in the instrument until
the temperature had fallen below 30 °C (ca. 2 min). SOCl2 (6
mmol) was added and the reaction mixture was again exposed
to microwave irradiation (50 W) for 2 min at 80 °C. After being
cooled to room temperature, the reaction mixture was ex-
tracted with CHCl3. Aqueous workup gave a residue that was
purified by column chromatography on silica gel with hexanes/
ethyl acetate (3:2) to give 2-oxazolines 3a -j or 2-thiazolines
5a -i.
product
entry
reactants
R
(yield %)b
1
2
3
4
5
6
7
8
1a + 4
1b + 4
1c + 4
1d + 4
1e + 4
1f + 4
1h + 4
1i + 4
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
4-ClC6H4
5a (95)
5b (97)
5c (94)
5d (97)
5e (91)
5f (85)
5h (95)
5i (91)
2-ClC6H4
phenyl
2-furyl
2-phenylethenyl
a
MW, 50 W, 80 °C, 10 min, Et3N, CHCl3, then SOCl2, MW, 2
b
min. Isolated yield.
propanol and 1H-1,2,3-benzotriazol-1-ylphenylmethanone
(1f) in 82% yield. Bisoxazoline 7 and bisthiazoline 8 were
prepared by the reactions of 1,1′-(1,4-phenylenedicarb-
onyl)bis-1H-benzotriazole (1k ) with 2 and 4, respectively,
in 94% and 95% yields. This procedure also works well
for the preparation of 5,6-dihydro-4H-1,3-oxazines; reac-
tions of 1c and 1d with 3-amino-1-propanol under similar
conditions furnished 5,6-dihydro-4H-1,3-oxazines 9 and
10 in 84% and 96% yields, respectively.
4,4-Dim et h yl-2-(4-m et h ylp h en yl)-4,5-d ih yd r o-1,3-ox-
1
a zole (3a ):19 colorless oil; yield, 98%; H NMR δ 7.82 (d, J )
8.3 Hz, 2H), 7.19 (d, J ) 8.3 Hz, 2H), 4.08 (s, 2H), 2.38 (s,
3H), 1.37 (s, 6H); 13C NMR δ 162.1, 141.4, 128.9, 128.1, 125.2,
79.0, 67.4, 28.4, 21.5.
4,4-Dim eth yl-2-(4-m eth oxyp h en yl)-4,5-d ih yd r o-1,3-ox-
1
a zole (3b):20 colorless oil; yield, 95%; H NMR δ 7.88 (d, J )
8.9 Hz, 2H), 6.90 (d, J ) 8.9 Hz, 2H), 4.08 (s, 2H), 3.84 (s,
3H), 1.37 (s, 6H); 13C NMR δ 161.9, 161.9, 129.9, 120.5, 113.6,
79.0, 67.4, 55.3, 28.4.
Con clu sion s
In summary, we have introduced a general method for
the direct preparation of a variety of 2-substituted
oxazolines and thiazolines in excellent yields from readily
available N-acylbenzotriazoles, under mild conditions
using microwaves in a safe and reproducible procedure.
4,4-Dim e t h yl-2-(4-n it r op h e n yl)-4,5-d ih yd r o-1,3-ox-
1
a zole (3c):6m colorless oil; yield, 90%; H NMR δ 8.25 (d, J )
8.4 Hz, 2H), 8.10 (d, J ) 8.4 Hz, 2H), 4.16 (s, 2H), 1.40 (s,
6H); 13C NMR δ 160.2, 149.3, 133.9, 129.2, 123.4, 79.5, 68.2,
28.3.
2-(4-Ch lor op h en yl)-4,4-d im et h yl-4,5-d ih yd r o-1,3-ox-
1
a zole (3d ):21 colorless oil; yield, 90%; H NMR δ 7.87 (d, J )
8.7 Hz, 2H), 7.37 (d, J ) 8.7 Hz, 2H), 4.11 (s, 2H), 1.38 (s,
6H); 13C NMR δ 161.2, 137.3, 129.5, 128.5, 126.6, 79.2, 67.7,
28.4.
2-(4-Meth ylph en yl)-4,5-dih ydr o-1,3-th iazole (5a): brown-
ish microcrystals (from diethyl ether); mp 40-42 °C (lit.24 mp
41-42 °C); yield, 95%; 1H NMR δ 7.72 (d, J ) 8.1 Hz, 2H),
7.21 (d, J ) 8.1 Hz, 2H), 4.44 (t, J ) 8.4 Hz, 2H), 3.40 (t, J )
8.4 Hz, 2H), 2.39 (s, 3H); 13C NMR δ 168.3, 141.4, 130.6, 129.1,
128.3, 65.1, 33.6, 21.4.
2-(4-Meth oxyp h en yl)-4,5-d ih yd r o-1,3-th ia zole (5b): col-
orless needles (from chloroform); mp 51-53 °C (lit.25 mp 53-
54 °C); yield, 97%; 1H NMR δ 7.78 (d, J ) 8.8 Hz, 2H), 6.91 (d,
J ) 8.8 Hz, 2H), 4.42 (t, J ) 8.2 Hz, 2H), 3.83 (s, 3H), 3.38 (t,
J ) 8.2 Hz, 2H); 13C NMR δ 167.6, 161.8, 129.9, 126.0, 113.7,
65.0, 55.3, 33.6.
Exp er im en ta l Section
Melting points are uncorrected. All of the reactions under
microwave irradiation were conducted in heavy-walled Pyrex
tubes sealed with aluminum crimp caps fitted with a silicon
septum. Microwave heating was carried out with a single mode
cavity Discover Microwave Synthesizer (CEM Corporation,
NC), producing continuous irradiation at 2455 MHz. 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded in
CDCl3 (with TMS for 1H and chloroform-d for 13C as the
internal reference).
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Oxa zo-
lin es with N-Acylben zotr iazoles by Con ven tion al Meth od.
A solution of 2-amino-2-methyl-1-propanol (2) (2 mmol) and
1H-1,2,3-benzotriazol-1-yl(4-methylphenyl)methanone (1a ) (1
mmol) in CHCl3 (10 mL) was stirred at 25 °C for 12 h. SOCl2
(6 mmol) was added and the reaction mixture was stirred for
2 h. Aqueous workup gave a residue that was purified by
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J . Org. Chem, Vol. 69, No. 3, 2004 813

Katritzky et al.
2-(4-Nitr op h en yl)-4,5-d ih yd r o-1,3-th ia zole (5c): color-
less needles (from chloroform); mp 150-152 °C (lit.25 mp 146-
2,2′-(1,4-P h en ylen e)bis[4,5-d ih yd r o-1,3-th ia zole] (8):27
prepared by the reaction of 4 (2 equiv) and 1k (1 equiv)
according to the general procedure; colorless needles (from
1
148 °C); yield, 94%; H NMR δ 8.27 (d, J ) 8.8 Hz, 2H), 8.00
1
(d, J ) 8.8 Hz, 2H), 4.53 (t, J ) 8.5 Hz, 2H), 3.51 (t, J ) 8.5
Hz, 2H); 13C NMR δ 166.6, 149.2, 138.7, 129.2, 123.7, 65.5,
34.2
chloroform); mp 106-108 °C; yield, 94%; H NMR δ 7.88 (s,
4H), 4.49 (t, J ) 8.4 Hz, 4H), 3.45 (t, J ) 8.5 Hz, 4H); 13C
NMR δ 167.8, 135.5, 128.4, 65.3, 33.8.
2-(4-Ch lor op h en yl)-4,5-d ih yd r o-1,3-th ia zole (5d ): color-
less needles (from chloroform); mp 50-52 °C (lit.26 mp 53-55
°C); yield, 97%; 1H NMR δ 7.77 (dd, J ) 6.9, 1.8 Hz, 2H), 7.38
(dd, J ) 6.9, 1.8 Hz, 2H), 4.45 (t, J ) 8.4 Hz, 2H), 3.43 (t, J )
8.4 Hz, 2H); 13C NMR δ 167.3, 137.1, 131.7, 129.6, 128.7, 65.2,
33.9.
2-(4-Nitr op h en yl)-5,6-d ih yd r o-4H-1,3-oxa zin e (9): pre-
pared by the reaction of 3-amino-1-propanol and 1c according
to the general procedure; colorless needles (from chloroform);
mp 143-144 °C (lit.31 mp 145-146 °C); yield, 84%; 1H NMR δ
8.22-8.19 (m, 2H), 8.07-8.03 (m, 2H), 4.40 (t, J ) 5.5 Hz, 2H),
3.65 (t, J ) 5.8 Hz, 2H), 2.01 (qn, J ) 5.8 Hz, 2H); 13C NMR
δ 153.8, 148.9, 139.9, 127.8, 123.1, 65.4, 42.8, 21.7.
(4S)-4-Ben zyl-2-ph en yl-4,5-dih ydr o-1,3-oxazole (6):30 pre-
pared by the reaction of (2S)-2-amino-3-phenyl-1-propanol and
1f according to the general procedure; colorless oil; yield, 82%;
[R]20D -12 (c 1.53, CHCl3); 1H NMR δ 7.97-7.93 (m, 2H), 7.50-
7.37 (m, 3H), 7.33 -7.19 (m, 5H), 4.63-4.53 (m, 1H), 4.36-
4.30 (m, 1H), 4.13 (dd, J ) 8.5, 7.3 Hz, 1H), 3.23 (dd, J ) 13.5,
5.0 Hz, 1H), 2.72 (dd, J ) 13.5, 8.9 Hz, 1H); 13C NMR δ 163.9,
137.9, 131.3, 129.2, 128.6, 128.5, 128.1, 127.7, 126.4, 71.8, 67.8,
41.8.
2-(4-Ch lor op h en yl)-5,6-d ih yd r o-4H-1,3-oxa zin e (10):32
prepared by the reaction of 3-amino-1-propanol and 1d ac-
1
cording to the general procedure; colorless oil; yield, 96%; H
NMR δ 7.84-7.80 (m, 2H), 7.35-7.30 (m, 2H), 4.35 (t, J ) 5.5
Hz, 2H), 3.59 (t, J ) 5.8 Hz, 2H), 1.97 (qn, J ) 5.8 Hz, 2H);
13C NMR δ 154.7, 136.3, 132.6, 128.3, 128.2, 65.2, 42.6, 21.8.
Ack n ow led gm en t. We thank Dr. Michael J . Collins
for very helpful discussions and the CEM Corporation
for providing the Discover Microwave Synthesizer.
2,2′-(1,4-P h en ylen e)b is[4,5-d ih yd r o-4,4-d im et h yl-1,3-
oxa zole] (7):6f prepared by the reaction of 2 (2 equiv) and 1k
(1 equiv) according to the general procedure; colorless oil; yield,
1
95%; H NMR δ 7.97 (s, 4H), 4.13 (s, 4H), 1.40 (s, 12H); 13C
Su p p or tin g In for m a tion Ava ila ble: General procedure
for the preparation of N-acylbenzotriazoles 1a -k and char-
acterization data for compounds 1a -k , 3e-j, and 5e-i. This
material is available free of charge via the Internet at
http://pubs.acs.org.
NMR δ 161.6, 130.5, 128.2, 79.2, 67.8, 28.4.
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814 J . Org. Chem., Vol. 69, No. 3, 2004