Mechanism and regioselectivity of the cycloaddition of thiones derived from meldrum's acid, malonates, or other dicarbonyls

Article abstract of DOI:10.1021/jo800945y

(Chemical Equation Presented) Several α,α-dioxothiones were generated in situ and reacted with 1,3-dienes of varying electronic and steric properties. It was found that thiones 10a and 11a reacted well with electron-rich or electron-poor dienes and are complementary in their regioselectivities when steric effects are at play. The calculated preferred mechanistic pathway implies a thiiranium zwitterion intermediate.

Full text of DOI:10.1021/jo800945y

Mechanism and Regioselectivity of the Cycloaddition of Thiones
Derived from Meldrum’s Acid, Malonates, or Other Dicarbonyls
Ste´phane Perreault, Maude Poirier, Pascal Le´veille´, Olivier Rene´, Pascal Joly, Yves Dory,*
and Claude Spino*
De´partement de Chimie, UniVersite´ de Sherbrooke, 2500 Boul. UniVersite´,
Sherbrooke, QC, Canada J1K 2R1
claude.spino@usherbrooke.ca
ReceiVed May 6, 2008
Several R,R-dioxothiones were generated in situ and reacted with 1,3-dienes of varying electronic and
steric properties. It was found that thiones 10a and 11a reacted well with electron-rich or electron-poor
dienes and are complementary in their regioselectivities when steric effects are at play. The calculated
preferred mechanistic pathway implies a thiiranium zwitterion intermediate.
Introduction
electrophilic and thus enlarge sulfur’s orbital coefficient in the
lowest unoccupied molecular orbital (LUMO). The regiochem-
istry of addition from the reaction of 1 with Danishefsky’s diene
2, for example, was interpreted in such a way (Scheme 1).5
Recently, we reported a synthetic approach to the picrasane
framework of anticancer quassinoids in which we used a regio-
and stereoselective hetero-Diels-Alder reaction of R,R-di-
oxothiones 10b,c and 11a (Scheme 1, bottom).4 Diethyl
thiomalonate (10b, Figure 1) reacted with 1,3-diene 5 to afford
a 1:2 mixture of cycloadducts 6b and 7b (Scheme 1). We were
able to reverse the regioselectivity by using a bulkier malonate
10c. Interestingly, thione 11a, derived from Meldrum’s acid,6
led to a much increased ratio of 15:1 for 8a:9a.
Thiones and thioaldehydes have been known to participate
efficiently as dienophiles in Diels-Alder reactions.1 The breadth
of reactions available to manipulate the carbon-sulfur bond
(e.g., desulfurization, elimination, or Pummerer rearrangement)
make cycloadditions of such dienophiles leading to dihydrothi-
apyrans a powerful method to form carbon-carbon bonds.2 Yet,
few examples of the use of thiocarbonyl dienophiles in total
syntheses are documented.3,4 The use of thiocarbonyl dieno-
philes in synthesis is limited perhaps because the level of
regioselectivity observed with unsymmetrical 1,3-dienes is not
always useful and often difficult to predict.1,3 It is documented
that the nature of the substituent on the thione or thioaldehyde
greatly influences the regiochemical outcome of their Diels-Alder
reactions.1 Electron-deficient substituents render the sulfur
Relatively little information exists concerning the mechanism
and selectivity issues of the Diels-Alder reactions of thiones
and thioaldehydes, other than results using electronically very
(1) (a) Boger, D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology
in Organic Synthesis; Wasserman, H. H., Ed.; Academic Press Inc.: San Diego,
1987; Organic Chemistry, a Series Monograph, Vol. 47, pp 120-145. (b)
Weinreb, S. M.; Staib, R. S. Tetrahedron 1982, 38, 3087–3128.
(2) For a review on the use of thiocarbonyl compounds in carbon-carbon
forming reactions, see: Metzner, P. Synthesis 1992, 1185–1199.
(3) Vedejs, E.; Galante, R. J.; Goekjan, P. G. J. Am. Chem. Soc. 1998, 120,
3613–3622.
(5) (a) Vedejs, E.; Perry, D. A.; Houk, K. N.; Rondan, N. G. J. Am. Chem.
Soc. 1983, 105, 6999–7001. (b) Vedejs, E.; Eberlein, T. H.; Mazur, D. J.;
McClure, C. K.; Perry, D. A.; Ruggeri, R.; Schwartz, E.; Stults, J. S.; Varie,
D. L.; Wilde, R. G.; Wittenberger, S. J. Org. Chem. 1986, 51, 1556–1562. (c)
Vedejs, E.; Eberlein, T. H.; Varie, D. L. J. Am. Chem. Soc. 1982, 104, 1445–
1447.
(6) For a review of the use of Meldrum acid derivative in the synthesis of
natural products, see: Ivanov, A. S. Chem. Soc. ReV. 2008, 37, 789–811.
(4) Perreault, S.; Spino, C. Org. Lett. 2006, 8, 4385–4388.
10.1021/jo800945y CCC: $40.75
Published on Web 09/05/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7457–7466 7457

Perreault et al.
SCHEME 1. Diels-Alder Reactions of Thiones and Thioaldehydes
SCHEME 2. Cycloaddition Reactions of Thiones 10a or
11a-c with Isoprene 12
We chose isoprene 12 to initiate our study because it is a
weakly electronically biased diene in Diels-Alder cycloaddi-
tions. In addition, steric effects are minimal in this diene and
as such it was deemed ideal to study the difference in
regioselectivity between various thiones. Thiones 10a-c were
formed by treatment of alkyl bromomalonates with elemental
sulfur following Abelman’s procedure,8 while thiones 11a-c
were generated using the method of Capozzi9 involving the
phthalimide derivatives 19. All thiones studied reacted at room
temperature with isoprene to give regioisomer 13 or 15 as the
major product, in line with what is expected if the CdS bond
is polarized with the negative end at carbon and positive end at
a sulfur (Scheme 2 and Table 1). The structure of the major
regioisomer 15a was unambiguously assigned from a single
crystal X-ray diffraction analysis (see Supporting Information).
The other structures could easily be inferred from comparison
of 1H NMR data. A look at Table 1 reveals a significant
difference in regioselectivity between Meldrum’s acid-derived
thione 11a and the other thiones (compare entry 2 with entries
1, 3, and 4). The lower levels of regioselectivity obtained with
thiones 11b and 11c (entries 3 and 4) indicate that steric effects
have little influence on the regiochemical outcome of these
reactions. To gain better insight of the particularities of thione
11a, we performed high-level calculations.
TABLE 1. Regioisomeric Ratios Obtained and Calculated in the
Reaction of 12 with Thiones 10a and 11a-c
entry thione yield (%)a exptl ratio of 13:14 or 15:16b calcd ratioc
1
2
3
4
10a
11a
11b
11c
56
53
58
82
3:1
15:1
6:1
1.4:1
6.1:1
3:1
2.0:1
a Isolated yields of pure compounds. b Ratios measured by 1H NMR.
Computational Analysis. The B3LYP functional,10 in con-
junction with the 6-31+G(d) basis set, is known to give
acceptable relative energies and geometries for a broad variety
of pericyclic reactions. We then supplemented this original basis
set with another d diffuse function and even a f diffuse function
to all heavy atoms11 to gain a better representation of the soft
sulfur atom.12 Therefore gas-phase transition structures (TSs)
were optimized using the B3LYP functional and the 6-31+G(f2d)
basis set. Harmonic vibrational frequencies (at the same level
of theory) were employed to characterize optimized geometries
as either first-order saddle structures (one imaginary frequency)
c Calculated from ∆Gq298 italic figures in Figures 2-7.
biased 1,3-dienes, such as Danishefsky’s diene.7 Malonate-
derived thiones8 10a-c and Meldrum’s acid-derived thione 11a4
are highly reactive thiones that should give high regioselectivi-
ties in their Diels-Alder reactions. We herein disclose experi-
mental results and detailed DFT calculations that demonstrate
the exceptional characteristics of these thiones in formal [4 +
2]-cycloadditions. In addition, calculations suggest a new
alternate, perhaps preferred, mechanism of reaction.
FIGURE 1. Structures of thiones 10 and 11.
7458 J. Org. Chem. Vol. 73, No. 19, 2008

Mechanism and RegioselectiVity of the Cycloaddition of Thiones
FIGURE 2. Calculated B3LYP/6-31+G(f2d) free energy profiles computed at 25 °C for the reaction of thione 10a with isoprene 12 leading to
major product 13a. Bond distances (Å), bond orders, and relative energies (kcal/mol) are shown for the TS. The value of the only imaginary
frequency of the TS is indicated together with a vectorial description of atomic motions.
FIGURE 3. Calculated B3LYP/6-31+G(f2d) free energy profiles computed at 25 °C for the reaction of thione 10a with isoprene 12 leading to
minor product 14a. Bond distances (Å), bond orders, and relative energies (kcal/mol) are shown for the TS. The value of the only imaginary
frequency of the TS is indicated together with a vectorial description of atomic motions.
or minima (only real frequency) and to provide after scaling by
0.96513 zero-point vibrational energies (ZPVEs) and enthalpies
and free energies. ZPVE (0 K) corrected relative energies (∆Erel)
were calculated using the electronic energies from optimized
starting thiones 10a and 11a,c and isoprene 12 and TSs (i.e.,
∆ErelTS ) ETS - Ethione - E12). All relative enthalpies ∆Hrel
and free energies ∆Grel were calculated at 25 °C. Salient TS
ZPVE corrected relative energies and geometrical parameters
are summarized in Figures 2-7. Adducts populations (13a-14a,
15a,c-16a,c), calculated using the TS free energies, are
presented in Table 1. The good agreement between synthetic
and calculated regioselectivities for the reactions (Table 1)
allows the experimental findings to be explained through
interpretation of the TS geometries. IRC calculations14 (B3LYP/
6-31+(f2d)) confirmed that all isolated transition structures
indeed belong to the reaction paths. The GAMESS (version 11,
2008) program was used throughout.15 Optimized geometries
(in Cartesian coordinate form) are provided as Supporting
Information as well as IRC pathways as multistructures xyz files.
Examination of the theoretical calculations shows that di-
methyl thiomalonate (10a) reacts with isoprene 12 in a one-
step process to give regioisomeric adducts 13a and 14a through
a Diels-Alder-like transition state (Figures 2 and 3). Despite
being concerted, these reactions appear to be highly unsym-
metrical as shown by the geometry of the transition states. While
C-S distances a and b are relatively short (2.16 and 2.63-2.66
Å, respectively) the C-C distance c is very long (2.95-2.97
Å). Bond order16 analysis of these transition states further reveals
that both bonds a and b “contain” a fair share of electrons,
(7) For kinetic data on the Diels-Alder reactions of several diarylthiones,
see: Rohr, U.; Schatz, J.; Sauer, J. Eur. J. Org. Chem. 1998, 2875–2883.
J. Org. Chem. Vol. 73, No. 19, 2008 7459

Perreault et al.
FIGURE 4. Calculated B3LYP/6-31+G(f2d) free energy profiles computed at 25 °C for the reaction of thione 11a with isoprene 12 leading to
major product 15a via thiiranium zwitterion intermediate 17a. Bond distances (Å), bond orders, and relative energies (kcal/mol) are shown for the
TSs. The value of the only imaginary frequency of each TS is indicated together with a vectorial description of atomic motions.
whereas bond c is virtually “empty”. This bonding pattern
suggests that a transient thiiranium zwitterion species might
appear along the pathway. Such three membered ring formed
by the sulfur atom and one alkene of isoprene is more easily
generated from the methyl substituted alkene (bond order for
bond b of 0.46 and 0.21 in TSs leading to 13a and 14a,
respectively, Figures 2 and 3). This difference of stability might
be the dominant factor at work, resulting in preferred formation
of adduct 13a. The large asynchronicity of the transition state
is confirmed by the motions of the atoms (imaginary frequency)
of very large amplitude across bond a.
and 18a,c are largely asymmetrical as reflected both in the bond
lengths and bond orders for a and b. Canonical representations
of these ions (Figures 4-7) are in excellent agreement with
these theoretical observations. Bond a is consistently very short
as in the final products 14a,c and 15a,c. Close examination of
the most energetic determining step represented by TS2s
indicates its true nature. This reaction consists in the transfer
of the bond b electrons of the thiiranium zwitterions into bond
c of the adducts. This is indeed strongly supported by TS2s
bonds b and c of identical lengths (2.51-2.57 Å) and similar
bond orders.
Equivalent concerted transition states were not located for
reactions involving isoprene and thiones 11a,c. Rather, multi-
stage mechanisms were found. A first, least energetic step leads
to thiiranium zwitterions intermediates 17a,c and 18a,c (Figures
4-7). The bond length and bond orders of these TS1s match
closely with these of concerted TSs (Figures 2 and 3). It is
noteworthy that all thiiranium zwitterions intermediates 17a,c
Results and Discussion
As discussed above, calculations indicate that the reactions
of thiones 11a and 11c follow a [2 + 1]-cycloaddition pathway
involving a transition state TS1 leading to the thiiranium
zwitterion intermediates 17a or 18c, respectively. The interme-
diates then collapse to the cycloadducts 15a and 15c, respec-
tively, via a second transition state TS2 (Figures 4 and 6). The
reaction involving 10a goes through a very asynchronous [4 +
2]-cycloaddition. Thiiranium ions are known and several
theoretical treatments of them have been disclosed.17 Toma and
co-workers have also found, by calculation, a thiiranium
(8) (a) Abelman, M. M. Tetrahedron Lett. 1991, 32, 7389–7392. (b) Kirby,
G. W.; McGregor, W. M. J. Chem. Soc., Perkin Trans. 1 1990, 3175–3181.
(9) Capozzi, G.; Menichetti, S.; Nativi, C.; Rosi, A.; Valle, G. Tetrahedron
1992, 48, 9023–9032.
(10) Hertwig, R. H.; Koch, W. Chem. Phys. Lett. 1997, 268, 345–351.
(11) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. v. R.
J. Comput. Chem. 1983, 4, 294–301.
(12) Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys. 1984, 80, 3265–
3269.
(17) (a) Chesnut, D. B. Heteroat. Chem. 2005, 16, 263–270. (b) Bravo, F.;
Visto, A.; Alca´zar, E.; Molas, P.; Bo, C.; Castillo´n, S. J. Org. Chem. 2003, 68,
686–691. (c) Taniguchi, N. J. Org. Chem. 2006, 71, 7874–7876. (d) Destro, R.;
Lucchini, V.; Modena, G.; Pasquato, L. J. Org. Chem. 2000, 65, 3367–3370.
(e) Fachini, M.; Lucchini, V.; Modena, G.; Pasi, M.; Pasquato, L. J. Am. Chem.
Soc. 1999, 121, 3944–3950. (dd) Schmid, G. H.; Strukelj, M.; Dalipi, S.; Ryan,
M. D. J. Org. Chem. 1987, 52, 2403–2407. (ee) Sromek, A. W.; Gevorgyan, V.
Top. Curr. Chem. 2007, 274, 77–124. (f) Fox, D. J.; House, D.; Warren, S.
Angew. Chem., Int. Ed. 2002, 41, 2462–2482.
(13) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502–16513.
(14) (a) Gonzales, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161.
(b) keywords used during calculations: $IRC PATH)GS2 STRIDE)0.25 $END.
(15) (a) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon,
M. S.; Jensen, J. J.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.; Windus,
T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993, 14, 1347–1363.
(b) Default OPTTOL)0.0001 value used during calculations.
(16) Mayer, I. J. Comput. Chem. 2007, 28, 204–221.
7460 J. Org. Chem. Vol. 73, No. 19, 2008

Mechanism and RegioselectiVity of the Cycloaddition of Thiones
FIGURE 5. Calculated B3LYP/6-31+G(f2d) free energy profiles computed at 25 °C for the reaction of thione 11a with isoprene 12 leading to
minor product 16a via thiiranium zwitterion intermediate 18a. Bond distances (Å), bond orders and relative energies (kcal/mol) are shown for the
TSs. The value of the only imaginary frequency of each TS is indicated together with a vectorial description of atomic motions.
FIGURE 6. Calculated B3LYP/6-31+G(f2d) free energy profiles computed at 25 °C for the reaction of thione 11c with isoprene 12 leading to
major product 15c via thiiranium zwitterion intermediate 17c. Bond distances (Å), bond orders, and relative energies (kcal/mol) are shown for the
TSs. The value of the only imaginary frequency of each TS is indicated together with a vectorial description of atomic motions.
J. Org. Chem. Vol. 73, No. 19, 2008 7461

Perreault et al.
FIGURE 7. Calculated B3LYP/6-31+G(f2d) free energy profiles computed at 25 °C for the reaction of thione 11c with isoprene 12 leading to
minor product 16c via thiiranium zwitterion intermediate 18c. Bond distances (Å), bond orders, and relative energies (kcal/mol) are shown for the
TSs. The value of the only imaginary frequency of each TS is indicated together with a vectorial description of atomic motions.
SCHEME 3. Competition between Thiones 11a and 11c for 2,3-Butadiene 20
zwitterion intermediate in the hetero-Diels-Alder reaction
between methylvinyl ether (dienophile) and a thione analogous
to 11b (the diene).18,19
We ran a competition experiment opposing thiones 11a and
11c (1.0 equiv each) for their cycloaddition with 2,3-dimeth-
ylbutadiene 20 (1.0 equiv). We chose these two thiones for the
competition experiment because of their small difference in
terms of steric volume and also because they are generated under
identical reaction conditions. We mixed the two thione precur-
sors 19a and 19c in the presence of 20 and added the base
(Scheme 3). Twice as much cycloadduct 21a was formed than
cycloadduct 21c. So, thione 11a is either more reactive than
thione 11c or it is formed faster. Either way, we believe this is
a result of the higher polarization of the CdS bond in 11c.
The higher polarization of thione 11a in comparison to 10a,
11b, and 11c may appear unexpected at first glance. However,
we believe that the reasons behind this increased polarization
parallel those behind the accrued acidity of Meldrum’s acid 22
(18) (a) Legnani, L.; Lunghi, C.; Albini, F. M.; Nativi, C.; Richichi, B.; Toma,
L. Eur. J. Org. Chem. 2007, 3547–3554. For leading articles concerning the use
of thiones as dienes, see: (b) Boccardo, G; Capozzi, G; Giuntini, M; Menichetti,
S.; Nativi, C. Tetrahedron 1997, 53, 17383–17394. (c) Capozzi, G.; Franck,
R. W.; Mattioli, M.; Menichetti, S.; Nativi, C.; Valle, G. J. Org. Chem. 1995,
60, 6416–6426. (d) Capozzi, G.; Menichetti, S.; Nativi, C.; Rosi, A.; Franck,
R. W. Tetrahedron Lett. 1993, 34, 4253–4256.
(19) For a discussion on the cycloaddition of singlet oxygen and the possible
involvement of a related perepoxide zwitterions, see: (a) Adam, W.; Prein, M.
Acc. Chem. Res. 1996, 29, 275–283. (b) Leach, A.; Houk, K. N. Chem. Commun.
2002, 1243–1255. (c) Clennan, E. L. Tetrahedron 2000, 56, 9151–9179.
FIGURE 8. Parallel between the accrued acidity of Meldrum’s acid
and the higher polarization of thione 11a.
7462 J. Org. Chem. Vol. 73, No. 19, 2008

Mechanism and RegioselectiVity of the Cycloaddition of Thiones
SCHEME 4. Regioselectivity of the Cycloadditions of
Thiones 10a, 11a, and 11c with Diene 25
SCHEME 6. Regioselectivity of the Cycloadditions of
Thiones 10a and 11a with Diene 33
Thiones 10b and 11a reacted just as well with electron-poor
dienes. Reaction with 1-carbomethoxy-1,3-butadiene (33) af-
forded in each case a single regioisomer 34a or 36a (Scheme
6). Compound 36a is crystalline and amenable to X-ray
diffraction analysis (see Supporting Information). If one consid-
ers the thione’s sulfur atom as electrophilic, the regiochemical
outcome of the reaction of thione 10a and 11a with 33 may
seem counter-intuitive. However, one arrives at the correct
prediction for the regiochemistry from FMO considerations
(HOMOdiene-LUMOthione). We wanted to see the effect a C2-
ester would have but we could not use 2-carbomethoxy-1,3-
butadiene because it dimerizes too fast.22 We used instead
2-carbomethoxy-1-ethyl-1,3-butadiene (38). Again, thione 11a
led to a lower regioselectivity than expected in its reaction with
38 while thione 10a reacted to give 34a as the major product
in a 11: 1 ratio (Scheme 7). These results, taken together with
the ones shown in Scheme 1 for diene 5, indicate that thiones
10a (or 10b) and 11a are quite complementary. Thiones 10a,b
give reasonable ratios of regioisomers despite detrimental steric
effects (dienes 25 or 38), while thione 11a gives very high
regioselectivities when steric effects are minimal (isoprene 12)
or beneficial (diene 5).
It is beyond the scope of this article to survey the methods
to transform dihydrothiapyrans into useful products. It is worth
mentioning, however, that we have found very mild conditions
to cleave open the dioxanedione moiety of cycloadducts derived
from thione 11a. After several failed hydrolysis attempts using
aqueous acidic media or Lewis acids, we found that catalytic
Ni(acac)2 in refluxing methanol hydrolyzed the dioxanedione
fragment in 8a without causing decomposition of this quite
sensitive molecule (Scheme 8). Concomitant decarboxylation
of the monocarboxylic acid afforded ester 44 in 95% yield.
Alternatively, the ꢀ-hydroxy acid 43 was prepared in quantitative
yield and as a single diastereomer by treating 8a with sodium
borohydride in THF. We could not ascertain the stereochemistry
at the new chiral center in 43.
SCHEME 5. Perfectly Regioselective Reactions of Thiones
10a and 11a with Dienes 30a-c
compared to the acids corresponding to 10a, 11b, and 11c (CH2
instead of CdS).20 Indeed, the acidities of the ꢀ-dicarbonyl
compounds corresponding to 11b and 11c were also found to
be lower than that of Meldrum’s acid itself.20 Dipolar repulsion
and electronic induction of the inner-ring oxygens have been
invoked, among other reasons, as possible causes of this
phenomenon.20 In the same way the acidity of Meldrum’s acid
22 is a reflection of the relative stability of the resulting enolate
23, the higher reactivity and regioselectivity displayed by thione
11a may be a reflection of the relative importance of its
polarization, i.e. of its resonance structure 24 (Figure 8).
We probed the regioselectivity of the cycloadditions of thiones
10a, 10b, 11a, and 11c with several dienes (Schemes 4–7). We
were surprised by the observed regioselectivities of additions
for thiones 10a, 11a, and 11c with diene E-25 to give 26a, and
28a,c (Scheme 4). Normally, one would expect a C1-substituent
in a diene (as in E-25) to better direct the regiochemical outcome
of a cycloaddition than the same substituent at C2 (as in 12).
While this seems to be the case for thione 10a (5:1 with E-25
vs 3:1 with 12), thiones 11a and 11c led to a lower ratio of
regioisomers in their reaction with diene E-25 than with
isoprene. In each case, however, the major isomer was the one
predicted on the basis of FMO theory. The fact that thiones
11a and 11c give the same ratio suggests that steric effects could
be responsible for the lower-than-expected regioselectivity.
Yet, steric effects were not at all important in the cycload-
ditions between thiones 10a or 11a and electron-rich dienes
30a-c (Scheme 5). Both thiones led to a single regioisomer
with all three dienes 30a-c.21 Perhaps the strong influence
exerted by the ether oxygen on the regiochemistry overrode
steric effects in these cases.
(20) (a) Arnett, E. M.; Harrelson, J. A., Jr J. Am. Chem. Soc. 1987, 109,
809–812. (b) Wang, X.; Houk, K. N. J. Am. Chem. Soc. 1988, 110, 1870–1872.
(c) Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1988, 110, 1872–1874. (d)
Byun, K.; Mo, Y.; Gao, J. J. Am. Chem. Soc. 2001, 123, 3974–3979. (e)
Nakamura, S.; Hirao, H.; Ohwada, T. J. Org. Chem. 2004, 69, 4309–4316. (f)
Lee, I.; Han, I. S.; Kim, C. K.; Lee, H. W. Bull. Korean Chem. Soc. 2003, 24,
1141–1149.
(21) The instability of the final products in these cases prevented their
purification. However, the proton NMR spectra of the crude cycloadducts leave
no doubt that only one isomer was formed in each case (see Supporting
Information).
(22) (a) Sydnes, L. K.; Skattebøl, L.; Chapleo, C. B.; Leppard, D. G.;
Svanholt, K. L.; Dreiding, A. S. HelV. Chim. Acta 1975, 58, 2061–2073. (b)
Spino, C.; Crawford, J. Can. J. Chem. 1993, 71, 1094–1097, and references
therein.
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Perreault et al.
SCHEME 7. Regioselectivity of the Cycloadditions of Thiones 10a and 11a with Diene 33
SCHEME 8. Mild Conditions for the Cleavage of the Dioxanedione Moiety
gel column eluting with 10% ethyl acetate in hexanes to give 13a
and 14a (110 mg, 56% of 3:1 mixture) as a colorless oil. 1H NMR
(CDCl3, 300 MHz): δ 5.61-5.57 (m, 1H of 13a), 5.56-5.51 (m,
1H of 14a), 3.78 (s, 6H), 3.21-3.17 (m, 2H of 14a), 3.09 (s, 2H
of 13a), 2.80-2.76 (m, 2H of 220), 2.67 (s, 2H of 221), 1.75 (s,
3H). IR (CHCl3, cm-1): 3045, 2996, 2954, 2920, 1737, 1267. LRMS
(m/z, relative intensity): 230 (M+, 70), 155 (45), 139 (40), 111 (100).
HRMS calcd for C10H14O4S 230.0613, found 230.0615.
Dihydrothiopyrans 15a and 16a. Reaction of isoprene 12 (156
µL, 1.55 mmol) with 2,2-dimethyl-5-(phtalimide-N-sulfenyl)-
[1,3]dioxane-4,6-dione (19b) (100 mg, 0.31 mmol) according to
general procedure A. The crude product (15:1 mixture of 15a and
16a) was purified by flash chromatography on a silica gel column
eluting with 10% ethyl acetate in hexanes to give 15a and 16a (41
mg, 55% of 15:1 mixture) as a white solid. 1H NMR (CDCl3, 300
MHz): δ 5.76 (br s, 1H of 16a), 5.64 (br s, 1H of 15a), 3.36-3.32
(m, 1H of 16a), 3.20 (s, 1H of 15a), 2.89-2.84 (m, 1H of 15a),
2.72 (s, 1H of 215), 2.01 (s, 3H of 16a), 2.00 (s, 3H of 214), 1.85
(s, 3H of 15a) 1.82 (s, 3H of 16a), 1.76 (s, 3H). 13C NMR (CDCl3,
75.5 MHz): δ 164.9 (s), 129.0 (s), 119.8 (d), 106.2 (s), 44.3 (s),
30.7 (t), 29.5 (q), 29.4 (t), 27.4 (q), 23.9 (q). IR (CHCl3, cm-1):
2993, 2936, 2912, 1732. LRMS (m/z, relative intensity): 242 (M+,
3), 184 (20), 156 (85), 140 (40), 111 (100). HRMS calcd for
C11H14O4S 242.0613, found 242.0616. Mp: 83-85 °C.
2,2-Dimethyl-5-(phtalimide-N-sulfenyl)-[1,3]dioxane-4,6-di-
one (19a). N-(Chlorosulfenyl)phtalimide23 (1.72 g, 8.1 mmol) was
dissolved in THF (10.0 mL) and the solution was cooled to -10
°C. A solution of 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum’s
acid) (700 mg, 4.9 mmol) in THF (5.0 mL) was then added over
a 15 min period. The mixture was stirred 1 h at -10 °C. The solid
obtained was filtered, washed with cold THF and dried under
vacuum to give 19a (1.44 g, 92%) as a white solid. 1H NMR
(CDCl3, 300 MHz): δ 7.95-7.92 (m, 2H), 7.85-7.80 (m, 2H), 1.86
(s, 6H). 13C NMR (CDCl3, 75.5 MHz): δ 166.4 (s), 161.0 (s), 135.2
(d), 134.3 (s), 131.6 (s), 124.5 (d), 124.3 (s), 123.6 (s), 107.7 (s),
58.5 (s), 28.3 (q). IR (neat, cm-1): 3202, 3061, 1744, 1714. LRMS
(m/z, relative intensity): 356 (C16H8N2O4S2, 10), 324 (C16H8N2O4S,
10), 147 (C8H5NO2, 100). Mp: 189 °C (degradation).
In conclusion, we have shown by experiments that thiones
10a and 11a are useful thiones in cycloadditions with electron-
rich or electron-poor dienes. Calculations show a stepwise
mechanism involving a thiiranium zwitterionic intermediate.
Thiones 10a and 11a are complementary in that they can give
different levels of regioselectivity depending on the electronics
and sterics of the substrate. Lastly, it is possible to cleave open
the dioxanedione moiety in cycloadducts derived from 11a using
very mild conditions. Cycloadducts from such reactions can be
useful synthetic intermediates, and we are currently using this
methodology in the synthesis of complex terpenes of the
quassinoids family.
Experimental Section
General Procedure A for the Cycloaddition Reactions of
Dienes 12, 20, 30, 33, and 38 with Thiones 11a-c. Diene (1.2-5.0
equiv) was added to a solution (or suspension) of thione precursor
(1.0 equiv) in dichloromethane (0.2 M) at room temperature.
Pyridine (1.1 equiv) was added, and the reaction mixture was stirred
overnight at room temperature. The reaction mixture was quenched
with saturated aqueous NH4Cl. The phases were separated, and the
aqueous phase was extracted three times with dichloromethane. The
organic layers were combined, washed once with water, washed
once with brine, dried over anhydrous magnesium sulfate, and
evaporated under reduced pressure. The crude product was purified
by flash chromatography on a silica gel column.
General Procedure B for the Cycloaddition Reactions of
Dienes 12, 20, 30, 33, and 38 with Thiones 10a,b. A solution of
dimethylbromomalonate (90%, available from Aldrich, 1.0 equiv)
or diethylbromomalonate (available from Aldrich, 1.0 equiv) in
dichloromethane (0.2 M) was added over a period of 3 h with a
syringe pump to a mixture of diene (1.2 to 5.0 equiv), triethylamine
(1.5 equiv), and sulfur powder (2.0 equiv) in dichloromethane (0.2
M) at room temperature. The reaction mixture was stirred overnight
at room temperature, filtered on Celite, and evaporated under
reduced pressure. The crude product was purified by flash chro-
matography on a silica gel column.
Dihydrothiopyrans 26a and Its Regioisomer 27a. Reaction of
trans-1,3-pentadiene (E)-25 (425 µL, 4.26 mmol) with dimethyl-
bromomalonate (200 mg, 0.85 mmol) according to general proce-
dure B. The crude product (5:1 mixture of 26a and 27a) was purified
by flash chromatography on a silica gel column eluting with 3%
Dihydrothiopyrans 13a and 14a. Reaction of isoprene 12 (425
µL, 4.25 mmol) with dimethylbromomalonate (200 mg, 0.85 mmol)
according to general procedure B. The crude product (3:1 mixture
of 13a and 14a) was purified by flash chromatography on a silica
7464 J. Org. Chem. Vol. 73, No. 19, 2008

Mechanism and RegioselectiVity of the Cycloaddition of Thiones
ethyl acetate in hexanes to give 26a (87 mg, 44%) and a 1:1 mixture
of 26a/27a (43 mg, 22%) as colorless oils.
26a. H NMR (CDCl3, 300 MHz): δ 5.84-5.70 (m, 2H), 3.79
cm-1): 2958, 2927, 2874, 1729, 1695. LRMS (m/z, relative
intensity): 238 (M+, 100), 223 (65), 83 (100). HRMS calcd for
C13H18O2S 238.1027, found 238.1030. Mp: 91-92 °C.
1
(s, 3H), 3.77 (s, 3H), 3.17 (dq, 1H, J ) 17.6 and 2.2 Hz), 3.07-2.97
(m, 1H), 2.97 (dd, 1H, J ) 17.6 and 5.0 Hz), 1.07 (d, 3H, J ) 6.6
Hz). 13C NMR (CDCl3, 75.5 MHz): δ 168.8 (s), 168.5 (s), 132.4
(d), 120.7 (d), 60.8 (s), 53.2 (q), 33.3 (d), 25.6 (t), 17.1 (q). IR
(CHCl3, cm-1): 3035, 3008, 2962, 1734, 1253. LRMS (m/z, relative
intensity): 230 (M+, 40), 155 (85), 111 (100). HRMS calcd for
C10H14O4S 230.0613, found 230.0617.
Dihydrothiopyrans 34a and Its Regioisomer 35a. Reaction of
diene 33 (60 mg, 0.43 mmol) with dimethylbromomalonate (41
mg, 0.28 mmol) according to general procedure B. The crude
product (11: 1 mixture of 34a and 35a) was purified by flash
chromatography on a silica gel column eluting with 10% to 20%
ethyl acetate in hexanes to give 34a (42 mg, 50%), 35a (2 mg,
2%) and a mixture of 34a /35a (5 mg, 6%) as colorless oils.
34a. 1H NMR (CDCl3, 300 MHz): δ 6.97 (dd, 1H, J ) 5.0 and
3.3 Hz), 3.82 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 3.63 (t, 1H, J )
6.3 Hz), 3.39 (ddd, 1H, J ) 19.2, 3.3 and 1.7 Hz), 3.26 (dd, 1H,
J ) 19.2 and 5.0 Hz), 1.61-1.51 (m, 2H), 0.88 (t, 3H, J ) 7.1
Hz). 13C NMR (CDCl3, 75.5 MHz): δ 168.6 (s), 168.2 (s), 167.3
(s), 134.5 (s), 132.0 (d), 61.8 (s), 53.4 (q), 52.1 (q), 38.4 (d), 26.5
(t), 26.0 (t), 11.8 (q). IR (CHCl3, cm-1): 3035, 3000, 2953, 2878,
2842, 1738, 1728, 1710, 1265. LRMS (m/z, relative intensity): 302
(M+, 1), 270 (100), 213 (40), 183 (40). HRMS calcd for C13H18O6S
302.0824, found 302.0828.
1
27a. H NMR (CDCl3, 300 MHz): δ 5.85-5.73 (m, 1H), 5.70
(dq, 1H, J ) 11.0 and 2.2 Hz), 3.80 (s, 3H), 3.78 (s, 3H), 3.64-3.53
(m, 1H), 2.86 (dm, 1H, J ) 17.6 Hz), 2.69 (dm, 1H, J ) 17.6 Hz),
1.32 (d, 3H, J ) 7.1 Hz). IR (CHCl3, cm-1): 3034, 3007, 2962,
1733, 1252. LRMS (m/z, relative intensity): 230 (M+, 30), 198 (50),
155 (75), 111 (100). HRMS calcd for C10H14O4S 230.0613, found
230.0608.
Dihydrothiopyrans 28a and Its Regioisomer 29a. Reaction of
trans-1,3-pentadiene (E)-25 (155 µL, 1.55 mmol) with 2,2-dimethyl-
5-(phtalimide-N-sulfenyl)-[1,3]dioxane-4,6-dione (19a) (100 mg,
0.31 mmol) according to general procedure A. The crude product
(3:2 mixture of 28a and 29a) was purified by flash chromatography
on a silica gel column eluting with 5% ethyl acetate in hexanes to
give 28a (134 mg, 35%) and 29a (70 mg, 19%) as white solids.
1
35a. H NMR (CDCl3, 300 MHz): δ 7.11 (t, 1H, J ) 4.4 Hz),
3.82-3.73 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.10
(ddd, 1H, J ) 18.5, 4.4 and 1.7 Hz), 2.87 (ddd, 1H, J ) 18.5, 4.4
and 1.8 Hz), 1.91-1.77 (m, 1H), 1.47-1.36 (m, 1H), 1.02 (t, 3H,
J ) 7.1 Hz). LRMS (m/z, relative intensity): 302 (M+, 1), 270 (60),
241 (60), 213 (100). HRMS calcd for C13H18O6S 302.0824, found
302.0828.
1
28a. H NMR (CDCl3, 300 MHz): δ 5.98-5.91 (m, 1H), 5.68
(dq, 1H, J ) 10.7 and 2.2 Hz), 3.54 (dq, 1H, J ) 17.3 and 2.2
Hz), 3.46-3.39 (m, 1H), 3.17 (ddt, 1H, J ) 17.3, 5.7 and 1.6 Hz),
1.97 (s, 3H), 1.74 (s, 3H), 1.07 (d, 3H, J ) 7.1 Hz). 13C NMR
(CDCl3, 75.5 MHz): δ 166.2 (s), 161.8 (s), 131.3 (d), 121.5 (d),
105.9 (s), 48.9 (s), 35.8 (d), 28.9 (q), 27.8 (q), 26.2 (t), 16.5 (q).
IR (CHCl3, cm-1): 3034, 3000, 2973, 1771, 1592, 1290. LRMS
(m/z, relative intensity): 242 (M+, 1), 184 (60), 156 (100), 111 (100),
97 (90). HRMS calcd for C11H14O4S 242.0613, found 242.0607.
Mp: 74-76 °C.
Dihydrothiopyrans 36a and Its Regioisomer 37a. Reaction of
diene 33 (65 mg, 0.46 mmol) with 2,2-dimethyl-5-(phtalimide-N-
sulfenyl)-[1,3]dioxane-4,6-dione (19a) (100 mg, 0.31 mmol) ac-
cording to general procedure A. The crude product (3: 2 mixture
of 36a and 37a) was purified by flash chromatography on a silica
gel column eluting with 10% to 25% ethyl acetate in hexanes to
give 36a and 37a (55 mg, 56% of 3:2 mixture) as a white solid. 1H
NMR (CDCl3, 300 MHz): δ 7.28 (t, 1H of 37a, J ) 5.0 Hz), 7.11
(td, 1H of 36a, J ) 4.6 and 1.5 Hz), 3.95-3.90 (m, 1H of 37a),
3.79 (s, 3H of 37a), 3.77 (s, 3H of 36a), 3.68-3.64 (m, 1H of
36a), 3.52 (dd, 2H of 36a, J ) 4.6 and 1.5 Hz), 3.10 (dd, 2H of
37a, J ) 5.0 and 1.1 Hz), 2.07 (s, 3H of 37a), 1.91 (s, 3H of 36a),
1.88-1.77 (m, 2H of 36a), 1.82 (s, 3H of 36a), 1.75 (s, 3H of
37a), 1.69-1.52 (m, 2H of 37a), 1.01 (t, 3H of 37a, J ) 7.1 Hz),
0.93 (t, 3H of 37a, J ) 7.7 Hz). IR (CHCl3, cm-1): 2953, 2878,
1776, 1738, 1729, 1710, 1291. LRMS (m/z, relative intensity): 283
((M - OMe)+, 1), 282 ((M - MeOH)+, 2), 228 (20), 212 (50),
199 (100), 155 (70). HRMS calcd for C13H15O5S (M - OMe)
283.0640, found 283.0631. Mp: 118-119 °C.
1-Ethyl-2-carbomethoxy-l,3-butadiene 38. To a stirred solution
of 2,5-dihydro-1,1-dioxyde-3-(methylcarboxylate)thiophene (avail-
able from Aldrich, 840 mg, 4.76 mmol) in THF (50 mL) at -78
°C was added a 1.60 M solution of n-BuLi in hexanes (6.20
mL, 9.92 mmol). The solution was stirred for 30 min at -78 °C
and iodoethane (0.55 mL, 6.86 mmol) was added. The mixture
was stirred 45 min at -78 °C and quenched with 1 N HCI. The
phases were separated and the aqueous phase was extracted twice
with diethyl ether. The organic layers were combined, washed
once with brine, dried over anhydrous magnesium sulfate and
evaporated under reduced pressure to give a yellowish oil. A
solution of this oil in toluene (10 mL) was stirred at 110 °C for
3 h. The solution was evaporated under reduced pressure and
the crude product was purified by flash chromatography on a
silica gel column eluting with 5% ethyl acetate in hexanes to
give 38 (240 mg, 36% for 2 steps, Z/E ) 6:1) as a colorless oil.
1H NMR (CDCl3, 300 MHz): δ 6.73 (t, 1H of E, J ) 7.7 Hz),
6.46 (dd, 1H of E, J ) 17.6 and 11.5 Hz), 6.33 (dd, 1H of Z, J
) 17.6 and 10.5 Hz), 5.95 (t, 1H of Z, J ) 7.7 Hz), 5.55 (dd,
1H of E, J ) 17.6 and 1.7 Hz), 5.37 (d, 1H of E, J ) 11.5 Hz),
5.25 (d, 1H of Z, J ) 17.6 Hz), 5.09 (d, 1H of Z, J ) 10.5 Hz),
3.81 (s, 3H of Z), 3.76 (s, 3H of E), 2.36-2.25 (m, 2H), 1.04 (t,
3H of Z, J ) 7.1 Hz), 0.90 (t, 3H of E, J ) 7.1 Hz). IR (CHCl3,
1
29a. H NMR (CDCl3, 300 MHz): δ 5.93 (dm, 1H, J ) 10.5
Hz), 5.84 (dm, 1H, J ) 10.5 Hz), 3.75-3.66 (m, 1H), 3.14 (dq,
1H, J ) 18.0 and 2.7 Hz), 2.56 (dm, 1H, J ) 18.0 Hz), 2.02 (s,
3H), 1.75 (s, 3H), 1.37 (d, 3H, J ) 7.1 Hz). 13C NMR (CDCl3,
75.5 MHz): δ 165.7 (s), 164.3 (s), 129.0 (d), 125.1 (d), 106.4 (s),
49.9 (s), 34.5 (d), 29.6 (t), 29.4 (q), 27.5 (q), 18.6 (q). IR (CHCl3,
cm-1): 3034, 3000, 2977, 1737, 1592, 1294. LRMS (m/z, relative
intensity): 242 (M+, 2), 156 (95), 140 (85), 111 (85), 97 (100).
HRMS calcd for C11H14O4S 242.0613, found 242.0609. Mp: 69-70
°C.
Dihydrothiopyrans 28c and Its Regioisomer 29c. Reaction of
trans-1,3-pentadiene (E)-25 (155 µL, 1.55 mmol) with 5,5-dimethyl-
2-(phtalimide-N-sulfenyl)cyclohexane-1,3-dione (16d) (99 mg, 0.31
mmol) according to general procedure A. The crude product (3: 2
mixture of 28c and 29c) was purified by flash chromatography on
a silica gel column eluting with 10% ethyl acetate in hexanes to
give 28c (40 mg, 53%) and 29c (24 mg, 31%) as white solids.
1
28c. H NMR (CDCl3, 300 MHz): δ 5.76-5.66 (m, 2H), 3.45
(d, 1H, J ) 14.8 Hz), 3.30-3.22 (m, 1H), 3.22-3.02 (m, 2H),
3.01 (d, 1H, J ) 14.8 Hz), 2.44 (dd, 1H, J ) 14.8 and 2.7 Hz),
2.26 (dd, 1H, J ) 14.8 and 2.7 Hz), 1.12 (s, 3H), 1.05 (d, 3H, J )
7.1 Hz), 0.90 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): δ 203.2 (s),
200.7 (s), 133.9 (d), 119.2 (d), 64.0 (s), 50.9 (t), 49.4 (t), 31.1 (d),
30.5 (s), 30.2 (q), 26.1 (t), 26.1 (q), 16.7 (q). IR (CHCl3, cm-1):
2961, 2885, 1725, 1695. LRMS (m/z, relative intensity): 238 (M+,
70), 223 (30), 83 (100). HRMS calcd for C13H18O2S 238.1027,
found 238.1030. Mp: 43-44 °C.
1
29c. H NMR (CDCl3, 300 MHz): δ 5.96-5.89 (dm, 1H, J )
10.4 Hz), 5.59 (dm, 1H, J ) 10.4 Hz), 3.66 (d, 1H, J ) 14.3 Hz),
3.44-3.34 (m, 1H), 3.23 (d, 1H, J ) 13.8 Hz), 2.84 (dq, 1H, J )
18.4 and 2.7 Hz), 2.36 (dd, 1H, J ) 13.8 and 2.7 Hz), 2.32 (dq,
1H, J ) 18.4 and 2.7 Hz), 2.25 (dd, 1H, J ) 14.3 and 2.7 Hz),
1.29 (d, 3H, J ) 7.1 Hz), 1.18 (s, 3H), 0.79 (s, 3H). 13C NMR
(CDCl3, 75.5 MHz): δ 202.8 (s), 127.2 (d), 63.7 (s), 50.9 (t), 49.0
(t), 34.6 (d), 31.0 (s), 30.4 (q), 26.1 (q), 24.0 (t), 19.5 (q). IR (CHCl3,
J. Org. Chem. Vol. 73, No. 19, 2008 7465

Perreault et al.
cm-1): 3019, 2399, 1520, 1423, 1221, 1210. LRMS (m/z, relative
intensity): 140 (M+). HRMS calcd for C8H12O2 140.0837, found
140.0840.
1
and H NMR spectra for all new compounds; X-ray crystal-
lographic data for compounds 15a and 36a in CIF format; video
clips of cycloaddition reactions with isoprene. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Universite´ de Sherbrooke
and the Natural Sciences and Engineering Research Council
(NSERC) for financial support.
JO800945Y
Supporting Information Available: Characterization data
for all new compounds not included in the experimental section
(23) Bombala, M. U.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1979, 3013–
3016.
7466 J. Org. Chem. Vol. 73, No. 19, 2008