Hydroxy-β-thiolactams to oxazole-2-thiones. A novel dmso-promoted oxidation

Article abstract of DOI:10.1021/ol802050a

(Chemical Equation Presented) 3-Aryl-3-hydroxy-1-methylazetidine-2-thiones react with HCI in DMSO to give 3-methyl-5-aryloxazole-2-thiones. Substituent effects correlate with rate effects on hydrolyses of acetals of benzaldehyde. An ¹⁷O labeling experiment indicates that the oxygen atom of the product is derived from the hydroxyl group. Trifluoroacetic anhydride/DMSO in CH₂Cl₂ can also promote the reaction. Mechanisms involving a Grob-type fragmentation of an activated substrate, followed by recyclization, or a cyclopropylcarbinyl type of rearrangement can account for this oxidative rearrangement.

Full text of DOI:10.1021/ol802050a

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4975-4978
Hydroxy-ꢀ-Thiolactams to
Oxazole-2-thiones. A Novel
DMSO-Promoted Oxidation
Xavier Creary* and Andrea Losch
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
creary.1@nd.edu
Received September 2, 2008
ABSTRACT
3-Aryl-3-hydroxy-1-methylazetidine-2-thiones react with HCl in DMSO to give 3-methyl-5-aryloxazole-2-thiones. Substituent effects correlate
with rate effects on hydrolyses of acetals of benzaldehyde. An 17O labeling experiment indicates that the oxygen atom of the product is
derived from the hydroxyl group. Trifluoroacetic anhydride/DMSO in CH2Cl2 can also promote the reaction. Mechanisms involving a Grob-type
fragmentation of an activated substrate, followed by recyclization, or a cyclopropylcarbinyl type of rearrangement can account for this oxidative
rearrangement.
A number of years ago we reported on the synthesis of
3-hydroxy-1-methylazetidine-2-thiones (hydroxy-ꢀ-thiolac-
Scheme 1. Formation of Hydroxy-ꢀ-thiolactams from Esters
tams) 1 by reaction of esters with N,N-dimethylthioforma-
mide promoted by excess lithium diisopropylamide (LDA).1
This transformation proceeds via deprotonation of the N,N-
dimethylthioformamide by the LDA followed by condensa-
tion with the ester to form the intermediate acylthioamide
2. In situ deprotonation of 2 by the excess LDA leads to 3,
and subsequent cyclization gives the observed product 1.
These hydroxy-ꢀ-thiolactams 1 were readily converted to
ꢀ-lactams by ozonolysis.1 They could also be converted to
mesylate derivatives and solvolytic reactions of these me-
sylates have been studied in detail.2 During the course of
related studies we have discovered a novel oxidative rear-
rangement of 1 that occurs under acidic conditions in DMSO.
We have prepared the chloride derivative 4 (An )
p-CH3OC6H4) from the corresponding hydroxy-ꢀ-thiolactam
and carried out solvolytic studies in DMSO-d6 containing a
trace of water as well as triethylamine to neutralize the
byproduct HCl. Under these conditions the hydroxy-ꢀ-
thiolactam 5 is formed via a carbocation mechanism.3
However, if the byproduct HCl is not neutralized as it is
formed, further warming smoothly converts 5 to the oxazo-
line-2-thione 6. Indeed, when pure 5 is dissolved in a freshly
prepared solution of 2 M HCl in DMSO, conversion to 6
(1) Creary, X.; Zhu, C. J. Am. Chem. Soc. 1995, 117, 5859.
(2) Creary, X.; Zhu, C.; Jiang, Z. J. Am. Chem. Soc. 1996, 118, 12331.
(3) Creary, X.; Burtch, E.; Jiang, Z. J. Org. Chem. 2003, 68, 1117.
10.1021/ol802050a CCC: $40.75
Published on Web 10/10/2008
2008 American Chemical Society

proceeds readily at room temperature. This process has some
generality and examination of Table 1 shows that other aryl-
Scheme 3. Mechanism 1 for Formation of Oxazole-2-thiones
Table 1. Product Yields and Relative Rates of conversion of 1
to 7 with HCl in DMSO
entry
R
% yield
relative rate
1
2
3
4
5
6
p-CH3OC6H4
p-CH3C6H4
C6H5
p-ClC6H4
t-Bu
84
70
62
40
71
81
14
3.2
1.0
0.26
1.1
5.3
1-adamantyl
and alkyl-substituted hydroxy-ꢀ-thiolactams 1 also undergo
this oxidative rearrangement to give N-methyl oxazoline-2-
thiones of general structure 7. Although the reduced product
was not characterized by spectroscopic methods, it is quite
apparent from the smell of reaction mixture that dimethyl
sulfide is formed. Compounds of general type 7 have been
previously prepared by reaction of tetraazapentalene deriva-
tives with R-haloketones.4 The substrate 7 (R ) Ph) has also
been prepared by a multistep process starting with the
hydrochloride salt of R-aminoacetophenone and CSCl2 or
CS2.5 This novel oxidative ring expansion of 1 in DMSO
promoted by HCl compliments these existing methods for
preparation of compounds of type 7.
A second mechanistic suggestion shown in Scheme 4
involves protonation of the thiocarbonyl group of 1 followed
Scheme 4. Mechanism 2 for Formation of Oxazole-2-thiones
Scheme 2
.
Conversion of Hydroxy-ꢀ-thioalctams to
Oxazole-2-thiones
by trapping of 11 with DMSO. Loss of dimethyl sulfide and
ring expansion to the electron-deficient oxygen would
generate highly stabilized cation 13. Proton loss would give
14, which would be expected to rapidly dehydrate under the
acidic conditions.
Rate data can often give insight into a reaction mechanism.
Therefore relative rates of reaction of 1 were determined by
competition methods and are summarized in Table 1.
Immediately apparent is the fact that overall rate effects are
small. The p-CH3O derivative, although the fastest reacting
substrate, is only 4.5 times more reactive than the p-CH3
derivative. The p-CH3 derivative is only 3.2 times faster than
the unsubstituted p-H system. By way of contrast, relative
solvolysis rates of mesylate derivatives of 1 show large
substituent effects, with relative rates of p-CH3O, p-CH3, and
p-H derivatives being 4.6 × 105, 73, and 1.0, respectively
(F+ ) -6.6).2
Simple correlation of reaction rates of 1 with σ or σ+
substituent constants is not satisfactory. However, Figure 1
shows an excellent correlation between reactivity of 1 and
the rate of acid catalyzed hydrolysis of acetals of general
structure 15,6 which proceed by way of extensively delo-
calized cations 17. This linear free energy relationship
The origin of these oxidized products 7 is of interest. A
number of reasonable mechanisms come to mind, the first
of which is illustrated in Scheme 3. The first process involves
HCl catalyzed ionization of 1 and capture of the intermediate
carbocation 8 by DMSO to generate the oxosulfonium ion
9. The adduct 9 could lose dimethyl sulfide (the oxidation
process) with concomitant ring expansion via thiocarbonyl
migration to the developing electron-deficient oxygen. This
would give an aryl stabilized (as well as oxygen stabilized)
carbocation 10. Deprotonation of 10 would give the observed
product 7.
(4) Matsumura, N.; Tomura, M.; Mori, O.; Takamura, Y.; Yoneda, S.
Tetrahedron Lett. 1989, 30, 2259–62.
(5) Kjellin, G.; Sandstrom, J. Acta Chem. Scand. 1969, 23, 2879–87.
4976
Org. Lett., Vol. 10, No. 21, 2008

Scheme 5. Acetal Hydrolysis Mechanism
the same intermediate thiocarbonyl adduct 12 suggested in
Mechanism 2. Loss of dimethyl sulfide, with simultaneous
Grob-type fragmentation7 could generate the protonated
ketone 19. Subsequent proton transfer, followed by cycliza-
tion of 20, would ultimately generate the appropriately
labeled product 7.
Figure 1. Correlation of rates of reaction of 1 in HCl/DMSO-d6
with rates of acid-catalyzed hydrolyses of 15.
Scheme 6.
17O Labeling Study
suggests a similar stabilization demand in the transition state
for the reaction of 1, i.e., neighboring oxygen stabilization
of a cationic intermediate as well as aryl stabilization.
In order to determine the source of the oxygen atom in
the oxazoline-2-thione 7, the reaction was carried out on the
labeled substrate 17O-1 (R ) Ph). The product of this reaction
shows an 17O NMR signal (Figure 2) at δ 250 (H217O as an
While protonation of the thioamide by (CH3)2SOH+ seems
reasonable, the possibility exists that the electrophilic sulfur
atom in this species is the actual catalytic species. Reaction
of such an electrophile at the sulfur atom of 1 could generate
21 (Mechanism 4). Grob-type fragmentation would generate
the thio-acylium ion 22. Subsequent proton loss and cycliza-
tion would lead to the appropriately 17O-labeled 7. Alterna-
tively, cyclization of 21 to the strained system 24, as in
Mechanism 5, could lead to the observed product via a
cyclopropylcarbinyl-homoallylic cation type of rearrange-
ment of 24.8
In order to support or rule out the suggestion that
electrophilic sulfur of (CH3)2SOH+ promotes the rearrange-
ment, hydroxythiolactams 1 were added to a mixture of
trifluoroacetic anhydride and DMSO in methylene chloride
at -78 °C. This mixture is known to generate
+
(CH3)2SOCOCF3 , a reagent known to be a source of
electrophilic sulfur.9 Reaction of 1 (R ) Ph) gave a complex
mixture from which 7 (R ) Ph) could be isolated in 35%
Figure 2.
17O NMR spectra of 17O-1 (R ) Ph) and the product
17O-7 (R ) Ph) formed on reaction in HCl/DMSO-d6.
(6) (a) Young, R. P.; Bogseth, R. C.; Rietz, E. G. J. Am. Chem. Soc.
1980, 102, 6268. (b) Jensen, J. L.; Herold, L. R.; Lenz, P. A.; Trusty, S.;
Sergi, V.; Bell, K.; Rogers, P. J. Am. Chem. Soc. 1979, 101, 4672.
(7) (a) Grob, C. A.; Baumann, W. HelV. Chim. Acta 1955, 38, 594. (b)
Weyerstahl, P.; Marsshall, H. Comp. Org. Syn. 1991, 6, 1044.
(8) For a discussion of this type of rearrangement, see: (a) Story, P. R.;
Clark, B. C., Jr. In Carbonium Ions; Olah, G. A., Schleyer, P. v. R., Eds.;
Wiley-Interscience: New York, 1972; Vol. III, pp 1007-1098. (b) Olah,
G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. ReV. 1992, 92, 69. (c) Olah,
G. A.; Reddy, V.; Prakash, In Chemistry of the Cyclopropyl Group, Part
2; Rappoport, Z., Ed.; John Wiley & Sons: New York, 1995; pp 813-
859.
external standard). The 17O of the starting material (δ 42)
has therefore been incorporated into the product 17O-7 (R )
Ph). Hence the DMSO, as in Mechanisms 1 and 2, cannot
be the source of the oxygen atom in 7. Therefore the more
obvious Mechanisms 1 and 2 can be eliminated.
With the failure of Mechanisms 1 and 2 to survive labeling
scrutiny, other suggestions are worthwhile. Three such
possibilities are shown in Scheme 7. Mechanism 3 involves
(9) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165. (b) Omura, K.;
Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957.
Org. Lett., Vol. 10, No. 21, 2008
4977

Scheme 7
.
Alternative Mechanisms for Formation of
Oxazole-2-thiones
Scheme 8. (CF3CO)2O/DMSO-Promoted Rearrangement of 1
do not rule out the protic acid promoted mechanisms (such
as Mechanism 3).
In summary, hydroxy-ꢀ-thiolactams 1 undergo an oxida-
tive ring expansion promoted by HCl in DMSO to give
oxazoline-2-thiones 7. An 17O-labeling study shows that the
hydroxyl oxygen ends up in the oxazoline-2-thione ring. The
oxidative rearrangement of 1 to 7 can also be promoted by
(CF3CO)2O/DMSO mixtures. Grob type fragmentation mech-
anisms as well as cyclopropylcarbinyl to homoallylic rear-
rangement type mechanisms are consistent with the available
data. Investigations continue into the scope and mechanism
of this unusual reaction.
yield after chromatography. Also formed was 12% of the
ꢀ-lactam 25 (R ) Ph), another oxidation product.
The hydroxy-ꢀ-thiolactam 1 (R ) p-ClC6H4) also gave 7
(R ) p-ClC6H4) and 25 (R ) p-ClC6H4) in 28% and 27%
yields respectively after chromatography. The thiolactam 1
(R ) p-CH3OC6H4) gave an extremely complex product
mixture in which a small amount of 7 (R ) p-CH3OC6H4)
could be identified spectroscopically. In contrast to these aryl
substituted thiolactams, the alkyl-substituted systems 1 (R
) 1-adamantyl) and 1 (R ) t-Bu) gave reasonably clean
reactions from which 7 could be isolated in 58% and 57%
yields respectively after chromatography. It is suggested that
reaction of 1 with trifluoroacetic anhydride/DMSO results
in formation of 21 (or the equivalent hypervalent sulfur
intermediate 26). Subsequent rearrangement, as in Mecha-
nism 4 or Mechanism 5, gives the product 7. While these
results suggest that electrophilic sulfur in [Me2SX]+ can
indeed promote the oxidative rearrangement of 1 to 7, they
Acknowledgment. This work was partially supported by
the National Science Foundation. We thank Professor
Richard Taylor (University of Notre Dame) for helpful
discussions and the suggestion of the possibility of electro-
philic sulfur promoted processes.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802050A
4978
Org. Lett., Vol. 10, No. 21, 2008