A Mild and convenient synthesis of 4-tosyl-4,5-dihydrooxazoles

Article abstract of DOI:10.2174/157017809788489855

A facile and mild synthesis of 4-tosyl-4,5-dihydrooxazoles is described. The reaction between tosyl methyl isocyanide (TosMIC) and cinnamic or aromatic aldehydes is catalyzed by triethylamine, affording trans-5-styryl- or 5-aryl-4-tosyl-4,5-dihydrooxazole

Full text of DOI:10.2174/157017809788489855

Letters in Organic Chemistry, 2009, 6, 293-296
293
A Mild and Convenient Synthesis of 4-Tosyl-4,5-dihydrooxazoles
Xavier Companyó, Albert Moyano* and Ramon Rios*,#
Department of Organic Chemistry, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain
Received October 23, 2008: Revised March 04, 2009: Accepted March 04, 2009
Abstract: A facile and mild synthesis of 4-tosyl-4,5-dihydrooxazoles is described. The reaction between tosyl methyl iso-
cyanide (TosMIC) and cinnamic or aromatic aldehydes is catalyzed by triethylamine, affording trans-5-styryl- or 5-aryl-4-
tosyl-4,5-dihydrooxazoles in quantitative yields without further purification. The mild reaction conditions allowed for the
first time the use of cinnamaldehyde derivatives with excellent results.
Keywords: TosMIC, Catalytic reaction, ꢀ,ꢁ-Unsaturated aldehydes, Oxazolines, 4,5-Dihydrooxazoles.
The discovery of new reaction protocols that allow us to
build complex molecular scaffolds in an efficient way from
readily available starting materials and in mild conditions
remains a challenging goal in chemical synthesis. The aldol-
type condensation of aldehydes and isocyanides containing
an electron-withdrawing group at the ꢀ-carbon atom pro-
vides an important method for the preparation of syntheti-
cally useful 4,5-disubstituted-4,5-dihydrooxazoles. The
chemistry of tosyl methyl isocyanide (TosMIC) [1] has been
extensively elaborated by the Dutch chemist A. M. van Le-
usen and his school. TosMIC constitutes by far the most ver-
satile synthon derived from methyl isocyanide and exhibits a
multifaceted chemistry that is of great utility in organic syn-
thesis [2].
good yields; however, when less drastic conditions were
used the precursor 4-tosyl-4,5-dihydrooxazoles were ob-
tained only in moderate yields (Scheme 1).
When we attempted to apply van Leusen’s procedure
(TosMIC, K2CO3, refluxing methanol) to an ꢀ,ꢁ-unsaturated
aldehyde (cinnamaldehyde), the oxazole product was ob-
tained in much lower yield, and chromatographic purifica-
tion was necessary to isolate the desired compound from a
complex reaction mixture. On the other hand, when the reac-
tion was performed at room temperature, the conversion after
24 h, monitored by NMR, was very low, and the formation
of numerous side-products was again apparent (Scheme 2).
With this chemo-information in mind, we decided to de-
velop a new, organocatalytic approach to the synthesis of 4-
tosyl-4,5-dihydrooxazoles that could be safely applied to
ꢀ,ꢁ-unsaturated aldehydes. In initial experiments we
screened different reaction conditions for the reaction of
TosMIC 1 with cinnamic aldehyde 2a (Table 1). The reac-
Since the pioneering discovery of A. M. van Leusen [3]
of the reaction between aldehydes and TosMIC mediated by
alkali metal bases in 1972, few other methods for the synthe-
sis of 4-tosyl-4,5-dihydrooxazoles have been reported. In
O
CHO
O
N
N
TosMIC,
TosMIC,
Ph
80%
MeOH, K2CO3, r.t.
MeOH, K2CO3, reflux
Ph
Tosyl
91%
Scheme 1. Van Leusen synthesis of 4,5-dihydrooxazoles (2-oxazolines) and of oxazoles.
organometallic chemistry there are several examples such as
the silver catalyzed reaction developed by Ito and coworkers
[4]. In 2002, Motoyama and coworkers disclosed a very ele-
gant synthesis of 4-tosyl-4,5-dihydrooxazoles using metal
catalysts such as Ag, Au or Pt [5]. However, to the best of
our knowledge there are no methods that allow us to build 4-
tosyl-4,5-dihydrooxazoles without the use of metals or in
mild conditions.
tion did not proceed in the absence of base (entries 1-3), and
very low yields were achieved in chloroform solution when
one molar equivalent of triethylamine was added to the reac-
tion mixture (entry 4). To our delight, when methanol was
used as a solvent at room temperature in the presence of ei-
ther a stoichiometric (entry 5) or of a catalytic amount of
triethylamine (entry 6), the reaction furnished the desired 4-
tosyl-5-styryl-4,5-dihydrooxazole 3a in quantitative yield
and, as expected, with very high trans-diastereoselectivity
(only one isomer was detected by NMR). Moreover, since
both the solvent and triethylamine are volatile, the work-up
of the reaction is a simple evaporation of the solvent from
the reaction mixture that affords the compound 3a in essen-
tially pure form.
In the van Leusen original paper [3], the reaction fur-
nished the elimination product (a 5-substituted oxazoline) in
*Address correspondence to these authors at the Department of Organic
Chemistry, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barce-
lona, Spain; Tel: +(34) 934021245; Fax: +(34) 933397878;
E-mails: amoyano@ub.edu, rios.ramon@icrea.cat
#Dr. Ramon Rios is ICREA Junior Researcher at the University of
Barcelona
Next, we decided to screen different ꢀ,ꢁ-unsaturated
aldehydes in order to study the scope of this convenient
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

294 Letters in Organic Chemistry, 2009, Vol. 6, No. 4
Companyó et al.
O
N
O
TosMIC,
N
TosMIC,
CHO
Ph
Ph
MeOH, K2CO3, r.t.,
24 h; 25% yield (by 1H-NMR)
MeOH, K2CO3, reflux,
12 h; 60% yield after
chromatographic purification
Ph
Tosyl
Scheme 2. Application of the van Leusen procedure to cinnamaldehyde.
Table 1. Optimized Conditions for the Synthesis of (E)-4-Tosyl-5-styryl-4,5-dihydrooxazole 3aa
C-
Solvent,
r.t.
O
Ph
N
TolO2S
N+
CHO
1
2a
Ph
Base
SO2Tol
3a
Entry
Solvent
Base
Yield (%)b
Drc
1
2
3
4
5
6
CDCl3
MeOH
Toluene
CDCl3
MeOH
MeOH
-
0
0
-
-
-
-
0
-
Et3N (1equiv.)
Et3N (1equiv.)
10
100
100
>25:1
>25:1
>25:1
Et3N (10 mol%)
aExperimental conditions: A mixture of cinnamaldehyde 2a (0.25 mmol), base, and tosyl methyl isocyanide 1 (0.25 mmol) in the solvent indicated (1mL) was stirred at room
temperature overnight. The product 3a was isolated after evaporation of the reaction mixture.
bIsolated yield.
cDetermined by 1H-NMR analysis of crude reactions.
Table 2. Cinnamic Aldehyde Scopea
O
C-
MeOH
r.t., 12h
N
Ar
TolO2S
N+
CHO
Ar
1
2a-g
SO2Tol
3a-g
Et3N (10 mol%)
Entry
Product
3a
Ar
Yield (%)b
Drc
1
Ph
100
>25:1
2
3
3b
3c
100
100
>25:1
>25:1
O2N
NC
4
5
6
7
3d
3e
3f
100
100
100
100
>25:1
>25:1
>25:1
>25:1
Cl
Me
Br
3g
Br
aExperimental conditions: A mixture of aldehyde 2a-g (0.25 mmol), Et3N (10%, 0.025 mmol), and tosyl methyl isocyanide 1 (0.25 mmol) in MeOH (1mL) was stirred at room
temperature overnight. The pure products 3a-g were isolated after evaporation of the solvent.
bIsolated yield.
cDetermined by 1H-NMR analysis of the crude reaction mixtures.

Synthesis of 4-Tosyl-4,5-dihydrooxazoles
Letters in Organic Chemistry, 2009, Vol. 6, No. 4
295
Table 3. Aromatic Aldehyde Scopea
O
N
C-
MeOH
r.t
ArCHO
TolO2S
N+
Ar
1
2h-n
SO2Tol
Et3N 10%
3h-n
Entry
Product
3h
Ar
Yield (%)b
Drc
1
Ph
100
>25:1
2
3
3i
3j
100
100
>25:1
>25:1
O2N
NC
Cl
4
5
6
3k
3l
100
100
100
>25:1
>25:1
>25:1
Br
3m
Br
7
3n
100
>25:1
NO2
aExperimental conditions: A mixture of aldehyde 2h-n (0.25 mmol), Et3N (10%, 0.025 mmol), 1 (0.25 mmol) in MeOH (1mL) was stirred at room temperature overnight. Products
3h-n were isolated after evaporation of the solvent.
bIsolated yield.
cDetermined by 1H-NMR analysis of the crude reaction mixture.
methodology. Remarkably, we obtained the final compounds
3 in quantitative yields in all of the examples investigated
(Table 2). There are no differences for different substitution
of the phenyl ring in cinnamic aldehydes. In all the examples
we observe an extremely high (>25:1 d.r.) diastereoselectiv-
ity, probably arising from the greater thermodynamic stabil-
ity of the trans isomer and from the ready epimerization of
the C4 stereogenic center.
These 4-tosyl-4,5-dihydrooxazoles 3 can be easily trans-
formed to the corresponding 5-substituted oxazoles 4 by
simply heating in toluene as exemplified in Scheme 3 for
(E)-5-styryl-1,3-oxazole 4a.
In summary, we have developed a mild and convenient
methodology to synthesize 5-substituted-4-tosyl-4,5-
dihydrooxazoles from aromatic or ꢀ,ꢁ-unsaturated aldehydes
and TosMIC, that takes place in quantitative yields and with
very high trans-diastereoselectivities. Moreover, the work-
up of the reaction is a simple evaporation of the solvent that
gives the desired products in essentially pure form without
any further purification.
In order to expand the scope of the process, we applied
the previously optimized reaction conditions to several aryl
aldehydes. To our delight, in all the examples the products
were obtained in quantitative yield and with essentially com-
plete diastereoselectivity (Table 3) [6].
O
N
O
N
toluene, reflux
Ph
Ph
SO2Tol
3a
4a
quantitative yield
Scheme 3. Synthesis of oxazoles.

296 Letters in Organic Chemistry, 2009, Vol. 6, No. 4
Companyó et al.
EXPERIMENTAL SECTION
1H NMR (400 MHz, CDCl3, TMSint): ꢀ (ppm) = 7.84 (s,
1H), 7.50-7.28 (m, 5H), 7.11 (d, J=10.2 Hz, 1H), 7.07 (s,
1H), 6.91 (d, J=10.2 Hz, 1H).
Representative Procedure for the Synthesis of 4-Tosyl-
4,5-dihydrooxazoles: Synthesis of trans-(E)-5-(4-Nitro-
styryl)-4-tosyl-4,5-dihydrooxazole 3b
13C-NMR (100 MHz, CDCl3): ꢀ (ppm) = 150.5, 150.4,
136.4, 130.5, 129.0, 128.6, 126.8, 124.3, 113.1.
HRMS (ESI): Calcd. for C11H10NO [(M+H)+], 172.0762;
found, 172.0757.
In a small vial, 49 mg of TosMIC 1 (0.25 mmol, 1
equiv), 44 mg of 3-(4-nitrophenyl)-2-propenal 2b (0.25
mmol, 1 equiv), and 2.5 mg (0.025 mmol) of Et3N were dis-
solved in 1 mL of MeOH. The reaction was stirred at room
temperature overnight. Next, the solvent and triethylamine
were removed at reduced pressure to afford the pure com-
pound 3b (93 mg) in quantitative yield.
1H NMR (CDCl3, 400 MHz): 8.21 (d, J = 9.0 Hz, 2H),
7.86 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.40 (d, J
= 8.6 Hz, 2H), 7.10 (s, 1H), 6.84 (d, J = 15.8 Hz, 1H), 6.32
(dd, J = 6.9 Hz, J’ = 15.8 Hz, 1H), 5.72 (t, J = 6.9 Hz, 1H),
4.99 (d, J = 6.2 Hz, 1H), 2.44 (s, 3H).
13C NMR (CDCl3, 100MHz): 159.4, 146.1, 141.6, 133.2,
132.0, 130.2, 129.7, 128.9, 127.7, 127.5, 124.3, 90.6, 78.6,
22.0.
HRMS (ESI): Calcd. for C18H17N2O5S [(M+H)+],
373.0853; found, 373.0864; calcd. for C18H17N2NaO5S
[(M+Na)+], 395.0672; found, 395.0679.
ACKNOWLEDGEMENT
We thank the Spanish Ministry of Science and Innova-
tion for financial support (Project AYA2006-15648-C02-01).
REFERENCES
[1]
a) For an extensive review, see: van Leusen, D.; van Leusen, A. M.
Org. React., 2001, 57, 417. b) For a more recent review, see:
Tandon, V. K.; Rai, S. Sulfur Rep., 2003, 24, 307.
[2]
For some recent references, see: a) Sanchez-Garcia, D.; Borrell, J.
I.; Nonell, S. Org. Lett., 2009, 11, 77. b) Baumann, M.; Baxendale,
I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett., 2006, 8,
5231. c) Samanta, S. P.; Kylaenathi, I.; Yli-Kauhaluoma, J. Bioorg.
Med. Chem. Lett., 2005, 15, 3717. d) Mendiola, J.; Balza, A.;
Alvarez-Builla, J.; Vaquero, J. J. J. Org. Chem. 2004, 69, 4974. e)
Tandon, V. K.; Vidisha, G.; Kumar, M.; Singh, K. A.; van Nispen,
S. P. J. M.; van Leusen, A. M. Heterocycles, 2004, 62, 357.
van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett., 1972, 23, 2369.
Sawamura, M.; Hamashima, H.; Ito, Y. J. Org. Chem., 1990, 55,
5935.
Motoyama, Y.; Kawakami, H.; Shimozono, K.; Aoki, K.;
Nishiyama, H. Organometallics, 2002, 21, 3408.
[3]
[4]
[5]
[6]
Representative Procedure for the Synthesis of 5-
Substituted Oxazoles: Synthesis of (E)-5-Styryloxazole 4a
In a round-bottomed flask, a solution of compound 3a
(82 mg, 0.25 mmol) in toluene (4 mL) was heated at reflux
for 3 h. Next, the crude was directly purified by column
chromatography on silica gel (hexanes-ethyl acetate) to af-
ford compound 4a (43 mg, quantitative yield).
For a study on the diastereoselectivity of the reaction between
TosMIC and aromatic aldehydes, see: Solladié-Cavallo, A.;
Quazzotti, S.; Colonna, S.; Manfredi, A. Tetrahedron Lett., 1989,
30, 2933.