Hydrolysis of R-Alkyl-R-(methylthio)methylene Meldrum’s Acids
8-Me and 8-Et the CdC bond is essentially coplanar with the
carbonyl groups (see dihedral angles) yet the CdC bonds are
still somewhat elongated relative to that in 8-H. Probably this
is because here the planar structure requires the C-C and C-R
bonds to be in an eclipsed orientation which elongates the Cd
C bond and makes the compounds less stable. Evidence for the
eclipsed interaction, i.e., the repulsion between R and the syn
carbonyl carbon, is seen in the CdC-C(O) angles which are
117.9°, 122.2° and 122.0° for R ) H, Me and Et, respectively.
An additional factor that may or may not be important is the
influence of the R substituent on the π-donor effect of the MeS
group. π-donation leads to stabilization of the substrate and an
elongation of the CdC bond. If steric hindrance were to
diminish the π-donor effect by twisting the CdS bond, this
could reduce the elongation of the CdC bond and enhance the
reactivity of the substrate. As noted above, the observed trend
in the CdC bond lengths is in the opposite direction and hence,
if this factor plays a role at all, the effect on CdC bond length
is more than offset by the bond lengthening factor discussed
above.
Experimental Section
Materials. Compounds 8-R (R ) alkyl) were prepared by
substituting one SCH3 group of 5-[1,1-bis(methylthio)methylene]-
2,2-dimethyl-1,3-dioxane-4,6-dione, 8-SMe, by an alkyl group.
8-SMe was prepared according to Hunter and McNab21 from
Meldrum’s acid and carbon disulfide, followed by methylation of
the dithiolate anion formed with methyl iodide. Crystallization from
1:3 THF/petroleum ether gave yellow needles, mp 119-120 °C
(lit.21 mp 116-118 °C), H NMR (CDCl3) δ: 1.70 (6H, s) and
1
2.61 (6H, s).
8-Me was prepared according to Hunter and McNab21 by reacting
8-SMe with MeMgBr and crystallization of the product from EtOH.
Mp: 118-120 °C (lit.21 mp 116-117.5 °C). 1H NMR (CDCl3) δ:
1.71 (6H, Me) and 2.51 (3H, Me), 2.88 (3H, SMe).
8-s-Bu. To a stirred solution of 8-SMe (1.00 g, 4 mmol) in dry
THF (15 mL) were added isobutyl-MgBr (2.1 mL, 4.20 mmol)
dropwise during 10 min, and the reaction mixture was stirred for
an additional 2 h under nitrogen. Aqueous 5% HCl solution was
added, the organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 25 mL). The combined organic layer
was washed with water (3 × 25 mL), dried (MgSO4), and
evaporated. The crude remainder was chromatographed on silica
gel column using EtOAc-petroleum ether (40-60 °C) eluant. Two
main fractions were observed. The minor fraction: 8-H (5%) and
1
8-s-Bu mp 96-98 °C (0.48 g, 47%). H NMR (CDCl3) δ: 1.05
(6H, d), 1.69 (6H, s), 1.97 (1H, hept), 2.50 (3H, s), 3.10 (2H, d).
Anal. C, 55.78; H, 6.89; S, 12.33. Calcd for C12H18O4S: C, 55.81;
H, 6.97; S, 12.40.
8-t-Bu. To a stirred solution of 8-SMe (1.00 g, 4 mmol) in dry
THF (15 mL) at -10 °C was added a t-BuLi solution in diethyl
ether (2.1 mL, 4.2 mmol) dropwise during 10 min, and stirring
under nitrogen was continued for 1 h. Aqueous HCl solution (5%,
13 mL) was added to the reaction mixture, the organic layer was
separated, the aqueous layer was extracted with CH2Cl2 (3 × 25
mL), and the combined organic layer was washed with water (3 ×
25 mL), dried (MgSO4), and evaporated in vacuo. The crude residue
was crystallized from ethanol, giving 0.63 g (61%) of pure 8-t-Bu.
Mp: 137-139 °C. 1H NMR (CDCl3) δ: 1.40 (s, 9H), 2.17 (s, 3H),
2.41 (6H). MS (m/z): 201 (M - Bu), 57 (Bu). Anal. C, 55.70; H,
7.04; S, 12.33. Calcd for C12H18O4S: C, 55.81; H, 6.97; S, 12.40.
8-Et, mp 73-75 °C, was prepared in 68% yield, similarly to
the preparation of 8-t-Bu, using EtMgMBr instead of t-BuMgBr.
1H NMR (CDCl3) δ: 1.27 (3H, t), 1.69 (6H, s), 2.50 (3H, s), 3.26
(2H, q). Anal. Calcd for C10H14O4S: C, 52.40; H, 6.27. Found: C,
52.17; H, 6.09.
Why are the kinetic results different from the gas-phase
calculations? As a general proposition, it is unlikely that the
relative contributions of the opposing factors would be exactly
the same in solution and in the gas phase. More specifically,
the solution phase results relate to the difference between
transition state and reactant state energies while the gas phase
calculations relate to the energy differences between the
intermediate and the reactants. It is likely that the transition
state is more sensitive to steric crowding than the intermediate
because, at the transition state, the electrophilic carbon retains
considerable sp2-character and planarity, while in the intermedi-
ate it is sp3 hybridized allowing more space for the surrounding
groups. Regarding the very low rates for 8-Ph, apart from steric
crowding at the transition state, π-donation by the phenyl group
may contribute to the low reactivity of this compound.
8-H. When the procedure described for the preparation of 8-t-
Bu was used but with isopropyl-MgBr instead of t-BuMgBr and
the crude product was recrystallized from ethanol, pure 8-H (0.59
g, 73%) mp: 134-135 °C (lit.21 mp 116-117.5 °C) was obtained.
1H NMR (CDCl3) δ: 1.72 (6H, s), 2.65 (3H, s), 8.97 (1H, s).
Anal: C, 47.67; H, 4.63. Calcd for C8H10O4S: C, 47.52; H, 4.95.
The same procedure gave 8-H when the reaction was conducted
at -40 or -72 °C and when i-PrLi was used instead of i-PrMgBr.
Attempts To Obtain 8-i-Pr. (a) The reactions of i-PrMgBr and
i-PrLi with 8-SMe described above gave 8-H. Changing the solvent
to ether or dry toluene or adding 8-SMe to the i-PrMgBr solution
still gave 8-H.
(b) A solution of i-PrMgBr in THF (2M, 1.2 mL, 2.4 mmol)
was added dropwise at -70 °C to a stirred suspension of CuCN
(0.49 g, 2.4 mmol) in THF (12 mL). The temperature increased to
-20 °C within 30 min. The stirring continued for 10 min and the
dark brown solution was recooled to -70 °C. A solution of 8-SMe
(0.496 g, 20 mmol) in dry THF (12 mL) was added dropwise to
the reaction mixture. After additional stirring for 30 min at -70
°C the mixture was warmed to -25 °C, stirred for 1 h, and warmed
Conclusions. The main motivation for the present study was
to examine steric effects on an SNV reaction without the
potential influence of additional factors such as π-donor and
other electronic effects. The hydrolysis of 8-R with R ) H and
a variety of alkyl groups seemed a good choice to probe the
effect of transition state crowding on the rate of nucleophilic
attack. Our kinetic results confirm that crowding at the transition
state is an important effect but also show that for very large R
groups destabilization of the substrate reverses the decreasing
trend in the rate constants. Our theoretical calculations indicate
that this destabilization results mainly from a sterically induced
twisting and elongation of the CdC double bond.
Our kinetic results also reveal that no intermediate ac-
cumulates to detectable levels, not even at very high pH where
addition of OH- to 8-R is expected to be thermodynamically
favorable. This is because conversion of T-OH to products is
faster than its formation. Furthermore, it was found that in acidic
solution the partitioning of T-OH between return to reactants
and conversion to products depends on the size of R: for R )
H product formation is slower than return to reactants while
for all the other R groups the opposite holds.
(21) Hunter, G. A.; McNab, H. J. Chem. Soc., Perkin Trans. 1 1995,
1209.
J. Org. Chem, Vol. 71, No. 13, 2006 4801