Reactivity of 4H-1-Benzothiopyran-4-one 1-Oxides
J . Org. Chem., Vol. 66, No. 7, 2001 2277
1
chromanone 1a was accomplished by H2O2 in the pres-
ence of chloroperoxidase (CPO)20 or iodosylbenzene and
chiral, nonracemic porphyrin catalyst.22 Very recently two
mild and efficient procedures have been published for the
oxidation of sulfides including 1-thiochromanone (1a ) to
their sulfoxides, one of them utilizes H2O2 in the presence
of titanium derivatives supported on silica,23 whereas
ceric ammonium nitrate (CAN) and hydrated silica gel
were used in the other case.24
differences in the H NMR spectra arise from anisotropy
effects of the sulfoxide functionality. Thus, a marked
downfield shift (0.67-0.8 ppm) is observed for the 3-Hax
(“syn-axial effect”)33 and a smaller upfield shift (0.09-
0.24 ppm) for the 2-H and 3-Heq hydrogen atoms of cis-
5a -c and cis-6a , while a small downfield shift (0.09-
0.24 ppm) of the 3-Heq and 2-methyl and a small upfield
shift (0.08-0.19 ppm) is found for the 2-H hydrogen
atoms of trans-5a -c and trans-5a . On the basis of these
NMR data, we may conclude that the sulfoxides 5 and 6
have similar conformations both in solution and in crystal
phases. Also, the calculated ∆δ ) δtrans - δcis values for
the 2-methyl, C-2, C-3 and C-8a carbon atoms of the
sulfoxides 5a (+1.9, +5.2, +3.2, and +3.6) and 5b (+1.7,
+5.1, +3.1, and +3.5) may be explained by the “gauche
γ steric shift”33 and furnish further support for the
preferred half-chair conformation with pseudoequatorial
methyl groups.
The diastereomeric ratio in Table 2 indicates a low cis
preference, which falls far behind the diastereoselectivity
observed in the sulfoxidation for the 2,3-dihydro-1,5-
benzothiazepin-4(5H)-ones.13h The observed low diaste-
reoselectivity in the sulfoxidation of 2-substituted 1-thio-
chroman-4-ones 2a -c and 3a originates from the poor
steric control during the attack of DMD on the half-chair-
like conformation of the thiochromanone ring, as exem-
plified in the calculated29 conformation (Figure 1) of
2-methyl-1-thiochroman-4-one (2a ).
1-Thioflavanone 1-oxide (6a ) was obtained by treat-
ment with ice-cold H2O2/acetic acid,14,25 sodium perio-
date,18,25 chloramine-T,25 or monoperoxyphthalic acid (1
equiv),15 but in these sulfoxidations also some sulfones
were obtained as byproducts. In view of the simple
procedure, the high efficiency, and good selectivity, DMD
seems to be the oxidant of choice to prepare 1-thiochro-
man-4-one 1-oxides.
A point of interest was the diastereoselectivity in the
sulfoxidation of 2-substituted 1-thiochroman-4-ones 2a -c
and 3a by DMD. Although some sporadic mention has
been made on the formation of diastereomers in the
literature,19c,25-27 neither their separation nor the deter-
mination of the relative configuration has been carried
out. We succeeded in separating the mixtures of the cis
and trans diastereomers of 2a and 2b by column chro-
matography, which allowed the unequivocal assignment
of the NMR signals to the each diastereomer. Although
1
the H NMR28 and 13C NMR spectra showed character-
DMD oxidation of the 1-thiochromones 10a and 11a ,
1-thioflavone (12a ), and their 3-benzyl derivatives 10e
and 12b-d with an excess (3.50-5.28 equiv) of DMD
afforded the corresponding sulfones 16a ,e, 17a , and
18a -d in excellent (82-93%) yields; the complete con-
version to the sulfones required a higher excess of DMD
than in the case of 1-thiochroman-4-ones (Table 1,
Scheme 2).
No epoxidation of double bond was observed; even the
addition of further batches of DMD left the 1-thio-
chromone and 1-thioflavone 1,1-dioxides intact. This
preferred attack of DMD on the heteroatom in the
presence of a double bond is well-documented;35 also the
persistence of the R,â- or â,γ-unsaturated sulfones toward
DMD has been demonstrated.36
When the substrates 10a ,e, 11a , and 12a ,d were
treated only with a slight excess (1.2 equiv) of DMD, both
1H NMR analysis of the reaction mixture (Table 2) and
the yields of isolated materials (Table 1) revealed a high
proportion of sulfone and considerable amounts of un-
reacted sulfide; the expected sulfoxides were found only
as minor products. A literature survey indicated that
the sulfones of 1-thiochromones and 1-thioflavones are
readily available by oxidation with hot H2O2 in acetic
acid,3b,11,14,37,38 hot peracetic acid,39 hot monoperoxy-
istic shifts for each diastereomer, the NMR data alone
were insufficient to establish the relative configuration
unambiguously, since the preferred conformations of the
diastereomers are unknown. For this purpose, PM3
calculations29 were conducted on the diastereomeric
sulfoxides, which revealed a conformation with pseudo-
equatorial methyl groups for both isomers, the sulfoxide
oxygen atom is pseudoaxial in the cis30 and pseudoequa-
torial in the trans30 diastereomer.
Definitive configurational assignment was provided by
X-ray analysis of the two isomers of 5b.31 Thus, the more
polar major diastereomer is the cis sulfoxide (cis-5b),
while the less polar minor one is the trans sulfoxide
(trans-5b). On the basis of the relative configurations of
the cis,trans-5b, all the remaining diastereomers32 were
assigned with the help of the NMR data. The observed
(21) MacKenzie, N. E.; Thomson, R. H. J . Chem. Soc., Perkin Trans.
1 1982, 395.
(22) Groves, C. T.; Viski, P. J . Org. Chem. 1990, 55, 3628.
(23) Fraile, J . M.; Garc´ıa, J . I.; La´zaro, B.; Mayoral, J . A. J . Chem.
Soc., Chem. Commun. 1998, 1805.
(24) Ali, M. H.; Leach, D. R.; Schmitz, C. E. Synth. Commun. 1998,
28, 2969.
(25) Ba´lint, J . Ph.D. Thesis, Kossuth Lajos University, Debrecen,
Hungary, 1978.
(26) Still, I. W. J .; Brown, W. L.; Colville, R. J .; Kutney, G. W. Can.
J . Chem. 1984, 62, 586.
(27) Chauhan, M. S.; Still, I. W. J . Can. J . Chem. 1975, 53, 2880.
(28) 1H NMR spectra of cis-5a and cis-5b allowed first order analysis
only at g360 MHz.
(29) Software package VAMP 5.0: Rauhut, G.; Chandrasekhar, J .;
Alex, A.; Steinke, T.; Clark, T. University of Erlangen-Nu¨rnberg,
Germany, 1993.
(30) The cis prefix refers to the isomer in which the sulfoxide oxygen
and the alkyl/aryl group at the position 2 are on the same side of the
heteroring; the trans-5a -c have the 1R*,2S*, while the trans-6a has
the 1R*,2R* relative configuration, the difference is due to the change
in the priority of the substituents at the C-2 atom.
(31) For crystallographic data, see: (a) Peters, K.; Peters, E.-M.;
Adam, W.; Ko¨ve´r, P.; Le´vai, A.; Patonay, T. Z. Kristallogr. NCS 2000,
215, 217 for cis-5b. (b) Peters, K.; Peters, E.-M.; Adam, W.; Ko¨ve´r, P.;
Le´vai, A.; Patonay, T. Z. Kristallogr. NCS 2000, 215, 219 for trans-
5b.
(32) The 1-thioflavanone 1-oxide diastereomers were separated by
fractional crystallization and the relative configuration of the cis-6a
was determined by X-ray analysis, which led to the same assignment,
cf. Somogyi, L. Phosphorous, Sulfur Silicon 1998, 143, 191.
(33) Lett, R.; Marquet, A. Tetrahedron 1974, 30, 3379.
(34) Zoller, U. Cyclic Sulfones and Sulfoxides. In The Synthesis of
Sulphones, Sulphoxides and Cyclic Sulphides, The Chemistry of
Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley: Chicester,
1994.
(35) For recent reviews on dioxirane chemistry, see: (a) Adam, W.;
Hadjiarapoglou, L. Top. Curr. Chem. 1993, 164, 45. (b) Curci, R.; Dinoi,
A.; Rubino, M. F. Pure Appl. Chem. 1995, 67, 811. (c) Adam, W.; Smerz,
K. Bull. Soc. Chim. Belg. 1996, 105, 581. (d) Kazakov, V. P.; Voloshin,
A. I.; Kazakov, D. V. Russ. Chem. Rev. 1999, 68, 253.
(36) Adam, W.; Golsch, D.; Hadjiarapoglou, L.; Le´vai, A.; Nemes,
Cs.; Patonay, T. Tetrahedron 1994, 50, 13113.