Mild Method for the Synthesis of Thiazolines from Secondary and Tertiary Amides

Full text of DOI:10.1021/jo971883o

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J . Org. Chem. 1998, 63, 908-909
Mild Meth od for th e Syn th esis of Th ia zolin es
fr om Secon d a r y a n d Ter tia r y Am id es
Andr e´ B. Charette* and Peter Chua
D e´ partement de Chimie, Universit e´ de Montr e´ al,
Qu e´ bec H3C 3J 7, Canada
Received October 14, 1997
Thiazolines are a class of heterocycles that have received
much attention recently due to their presence in numerous
interesting biologically active natural products such as
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2
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curacin A, thiangazole, and mirabazole B (Figure 1). Even
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though numerous methodologies are available,
high
yields for the formation of the thiazoline are sometimes not
obtained, especially with acid-sensitive or racemization-
prone substrates. Herein, we report that at low tempera-
tures in a medium buffered with excess pyridine, iminium
and imino triflates can be generated and reacted with amino
thiols to allow efficient access to thiazolines without any
racemization.
F igu r e 1.
Sch em e 1
Pioneering studies by Ghosez and others have demon-
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12
strated that iminium (2) and imino triflates (3) can be
generated by the treatment of tertiary or secondary amides
with triflic anhydride. We reasoned that subsequent addi-
tion of an amino thiol to these highly electrophilic species
should result in the formation of the thiazoline under
conditions that most functional groups and chiral centers
should tolerate (Scheme 1).
The optimal conditions involved an initial activation of
the amide by adding triflic anhydride to the amide in
(1) (a) Gerwick, W. H.; Proteau, P. J .; Nagle, D. G.; Hamel, E.; Blokin,
A.; Slate, D. L. J . Org. Chem. 1994, 59, 1243-1245. (b) For a leading
reference on Curacin A, see: White, J . D.; Kim, T.-S.; Nambu, M. J . Am.
Chem. Soc. 1997, 119, 103-111 and references therein.
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Wipf, P.; Venkatraman, S. Synlett 1997, 1-10. (b) Boyce, R. J .; Mulqueen,
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(
d) Ehrler, J .; Farooq, S. Synlett 1994, 702-704. (e) Parsons, R. L.;
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B.; Reichenbach, H.; J urkiewicz, E.; Hunsmann, G.; H o¨ fle, G. Liebigs Ann.
Chem. 1992, 357-359.
anhydrous dichloromethane-containing pyridine, which is
present to neutralize any adventitious acid. Pyridine seems
to be the optimal base since using a stronger base than
pyridine generates a conjugate acid that would be too weak
to be an effective general acid catalyst for the addition of
the amine onto the thio imidate or for the elimination of the
amine residue. Addition of triflic anhydride must be slow
since an exotherm can cause triflic anhydride to react with
pyridine to form N-triflylpyridinium triflate, which is not
reactive enough to O-sulfonylate the amide.
Application of these conditions to various amides are
summarized in Table 1. Secondary and tertiary alkyl and
aryl amides are readily converted to thiazolines. The
reaction of the substrate derived from 2-phenylcyclopropane
carboxylic acid seems to be sensitive to the nature of the
amide. The secondary N-methylamide is converted ef-
ficiently (entries 9 and 10), but the tertiary N,N-dimethyl
amide decomposes and fails to give the thiazoline. This may
be attributed to the propensity of the cinnamyl cyclopropane
moiety to undergo carbocationic ring opening. The cyclo-
propyl thiazoline was formed without any detectable epimer-
ization at the R-carbon. In all the cases studied, no
epimerization at the R-carbon of cysteine was detected when
optically pure cysteine ethyl ester was used as the ami-
nothiol.
(3) Carmeli, S.; Moore, R. E.; Patterson, G. M. L. Tetrahedron Lett. 1991,
3
2, 2593-2596.
(4) Walker, M. A.; Heathcock, C. H. J . Org. Chem. 1992, 57, 5566-5568.
(5) (a) Ito, H.; Imai, N.; Takao, K.-I.; Kobayashi, S. Tetrahedron Lett.
1
996, 37, 1799-1800. (b) Pattenden, G.; Thom, S. M. J . Chem. Soc., Perkin
Trans. 1 1993, 1629-1636. (c) Kaneko, T.; Shiba, T.;. Hirotsu, Y. Bull.
Chem. Soc. J pn. 1967, 40, 2945-2949. (d) Baganz, H.; Domaschke, L.
Chem. Ber. 1962, 95, 1842-1843.
(6) (a) Wipf, P.; Xu, W. J . J . Org. Chem. 1996, 61, 6556-6562. (b) Wipf,
P.; Miller, C. P.; Venkatraman, S. Fritch, P. C. Tetrahedron Lett. 1995, 36,
6
7
395-6398. (c) Wipf, P.; Venkatraman, S. J . Org. Chem. 1995, 60, 7224-
229. (d) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397-5400.
(
e) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267-6270. (f) Wipf,
P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907-910. (g) Atkins, G. H.;
Burgess, E. M. J . Am. Chem. Soc. 1968, 90, 4744-4745.
(7) (a) Lai, J . Y.; Yu, J .; Mekonnen, B.; Falck, J . R. Tetrahedron Lett.
1
996, 37, 7167-7170. (b) Gal e´ otti, N.; Montagne, C.; Poncet, J .; J ouin, P.
Tetrahedron Lett. 1992, 33, 2807-2810. (c) Barrett, G. C., Khokhar, A. R.
J . Chem. Soc., C 1969, 1117-1119.
(8) (a) Busacca, C. A.; Dong, Y.; Spinelli, E. M. Tetrahedron Lett. 1996,
3
1
1
7, 2935-2938. (b) White, J . D.; Kim, T.-S.; Nambu, M. J . Am. Chem. Soc.
995, 117, 5612-5613. (c) Fukuyama, T.; Xu, L. J . Am. Chem. Soc. 1993,
15, 8449-8450.
(
9) Vorbr u¨ ggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9353-9372.
(10) Aitken, R. A.; Armstrong, D. P.; Galt, R. H. B.; Mesher, S. T. E. J .
Chem. Soc., Perkin Trans. 1 1997, 935-943. (b) Nishio, T. Tetrahedron
Lett. 1995, 36, 6113-6116.
(11) (a) Falmagne, J . B.; Escudero, J .; Taleb-Saharaoui, S.; Ghosez, L.
Angew. Chem., Int. Ed. Engl. 1981, 20, 879-880. (b) Barbaro, G., Battaglia,
A.; Bruno, C.; Giorgianni, P.; Guerrini, A. J . Org. Chem. 1996, 61, 8480-
8
488.
(12) (a) Sisti, N. J .; Fowler, F. W.; Grierson, D. S. Synlett 1991, 816-
To demonstrate the mildness of these reaction conditions,
several more highly functionalized amides were converted
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18. (b) Sisti, N. J .; Zeller, E.; Grierson, D. S.; Fowler, F. W. J . Org. Chem.
997, 62, 2093-2097. (c) Thomas, E. W. Synthesis 1993, 767-768.
S0022-3263(97)01883-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

Communications
J . Org. Chem., Vol. 63, No. 4, 1998 909
Ta ble 1. Con ver sion of Secon d a r y a n d Ter tia r y Am id es to Th ia zolin esa
Sch em e 2
treatment with excess methylamine in methanol. Amide 10
was then submitted to the standard conditions, but this did
not produce the desired bis(thiazoline) 11 as the final
product. Instead, two other compounds were isolated. The
first compound was the result of tautomerization followed
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by subsequent oxidation of the desired bis(thiazoline) 11.
Small quantities of this unstable ester 13 could be isolated
as a mixture of diastereomers, but this compound eventually
rearranged to a less polar compound upon chromatography.
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This less polar compound turned out to be the thiazole 14,
and it is presumably the product of the aromatization of
ester 13 upon the loss of H2O. Although this unoptimized
reaction failed to give the desired bis(thiazoline) 11, isolable
bis(heterocyclic) compounds were produced in 57% yield,
thus demonstrating that this methodology is capable of
forming contiguous thiazolines.
Whereas the mono(thiazoline) compounds are relatively
stable, bis(thiazoline) compounds made from R-amino acids
with R-protons readily tautomerize to give compounds that
seem to be more sensitive toward oxidation or decomposition.
Applications of this method toward the synthesis of curacin
A, thiangazole, and mirabazole are underway and will be
reported in due course.
Ack n ow led gm en t. This research was supported by the
Natural Science and Engineering Research Council (NSERC)
of Canada, Alfred P. Sloan Foundation, Merck Frosst
Canada, FCAR (Qu e´ bec), and the Universit e´ de Montr e´ al.
A FCAR predoctoral fellowship to P.C. is also gratefully
acknowledged.
to thiazolines (entries 11-13). Using typical reaction condi-
tions, amides bearing functional groups such as a benzoate,
silyl ether, benzyl ether, and acetonide were readily con-
verted to thiazolines.
Su p p or tin g In for m a tion Ava ila ble: Characterization data
and proton and carbon NMR spectra for all compounds (57 pages).
J O971883O
Another interesting application of this methodology would
be the synthesis of molecules containing multiple contiguous
thiazolines such as thiangazole (Scheme 2). Thiazoline ester
(
13) Such facile air oxidation has been observed during the purification
of some tantazoles: Carmeli, S.; Moore, R. E.; Patterson, G. M. L.; Corbett,
T. H.; Valeriote, F. J . J . Am. Chem. Soc. 1990, 112, 8195-8197.
(14) The structure was confirmed by X-ray crystallography.
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was quantitatively converted to N-methyl amide 10 upon