Selenolactonization Mechanism with Selenenyl Halides
Preparative Selenolactonization. Preparation of (()-(4RS,5SR)-
Dihydro-4-(phenylseleno)-5-(2-methylphenyl)furan-2(3H)-one (24).
A flame-dried, 10-mL, Schlenk flask equipped with a stir bar under
an atmosphere of argon was charged with benzeneselenenyl chloride
(211 mg, 1.1 mmol, 1.1 equiv) and 2,6-di-tert-butyl-4-methylpy-
ridine (201 mg, 0.98 mmol, 0.98 equiv). CH2Cl2 (4 mL) was added
via syringe and the resulting solution cooled to -75 °C (bath
temperature) with an external i-PrOH/CO2 cold bath. A solution
of 4-(2-methylphenyl)but-3-enoic acid (176 mg, 1.0 mmol, 1.0
equiv) in CH2Cl2 (4 mL) was added dropwise via cannula to the
orange suspension; the immediate formation of a homogeneous
yellow solution was observed. The reaction mixture was stirred
for 2 h at -75 °C, the cooling bath removed, and the mixture stirred
for an additional 1 h. The resulting dark yellow solution was
transferred to a 25-mL round-bottom flask with CH2Cl2 (3 × 1
mL) and then was concentrated in vacuo to afford 354 mg of a
dark yellow oil. The crude material was preadsorbed onto silica
gel (1 g) and purified by column chromatography (SiO2, 20 g, 20
mm i.d. × 12 cm, hexanes/Et2O, 9:1, 400 mL) to afford 291 mg of
a pale pink liquid. Bulb-to-bulb distillation afforded 266 mg (81%)
of (()-24 as a viscous, pink liquid. Data for (()-24: bp 150 °C (5
b, chloride cleaves the silyl ester in the rate-determining step
to afford a zwitterionic seleniranium carboxylate that rapidly
cyclizes to the observed product. Weinberg and Wooley studied
the transilylation reaction between trimethylsilyl esters and
trialkylsilyl chlorides in THF solution. Their results demon-
strated that additives such as trimethylammonium chloride
promoted this exchange reaction, but only at elevated temper-
atures (reflux).44 This evidence suggests that path b is unlikely
(under the reaction conditions employed) and leads us to suggest
that path a is the more likely mechanism for this reaction.
SCHEME 17
1
× 10-5 mmHg, ABT); H NMR (500 MHz, CDCl3) 7.53-7.56
(m, 2 H, CH(13)), 7.36 (dt, J ) 7.3, 1.4 Hz, 1 H, CH(15)), 7.29
(2H, dt, J ) 7.3, 1.5 Hz, 1 H, 2 H, CH(14)), 7.22-7.25 (m, 3 H,
CH(3,4,5)), 7.17 (d, J ) 7.1 Hz, 1 H, CH(6)), 5.68 (d, J ) 5.0 Hz,
1 H, CH(8)), 3.83 (ddd, J ) 8.0, 6.0, 5.0, 1 H, CH(9)), 3.05 (dd,
J ) 18.2, 8.0 Hz, 1 H, CH2(10a), 2.67 (dd, J ) 18.1, 6.0 Hz, CH2-
(10b), 2.29 (s, 3 H, CH3(1)); 13C NMR (126 MHz, CDCl3) 175.0
(C(11)), 135.9 (C(13)), 135.5 (C(7)), 135.3 (C(2)), 131.0 (C(3)),
129.5 (C(14)), 129.0 (C(15)), 128.7 (C(4)), 126.4 (C(5)), 126.4
(C(12)), 124.7 (C(6)), 83.6 (C(8)), 41.1 (C(10)), 35.8 (C(10)), 19.3
(C(1)); 77Se NMR (143 MHz, CDCl3) 390.1; IR (neat) 3056 (m),
3026 (w), 2923 (w), 1782 (s), 1606 (w), 1578 (m), 1477 (m), 1462
(m), 1438 (m), 1412 (m), 1361 (w), 1301 (w), 1254 (m), 1209 (s),
1157 (m), 1110 (m), 1068 (m), 1048 (m), 1021 (m), 999 (s), 977
(m), 866 (m), 837 (m), 742 (s), 692 (s); MS (EI, 70 eV) 332 ((M•+,
34), 330 (17), 186 (22), 185 (15), 184 (100), 183 (28), 182 (55),
181 (30), 180 (26), 176 (15), 175 (50), 174 (18), 158 (26), 157
(22), 156 (14), 147 (18), 145 (18), 132 (10), 131 (71), 129 (25),
128 (14), 119 (37), 117 (24), 116 (26), 115 (35), 105 (21), 104
(29), 103 (17), 91 (62), 86 (78), 84 (11), 78 (50), 77 (46), 65 (23),
55 (10); TLC Rf 0.14 (hexanes/Et2O, 9:1) [CAM/∆]. Anal. Calcd
for C17H16O2Se (331.27): C, 61.64; H, 4.87. Found: C, 61.90; H,
4.83.
Conclusion
Mechanistic studies of the selenocyclization reaction have
allowed the determination of the reaction mechanism and
identified the intermediates along the mechanistic path for the
selenocyclization reaction with benzeneselenenyl chloride. The
reaction proceeds via an initial formation of a Markovnikov
â-chloro selenide adduct that ultimately cyclizes to afford the
selenolactone product. Along the reaction pathway this adduct
can also reverse to starting material or form an anti-Markovnikov
adduct. Reversibility of the initial addition reaction was
demonstrated by two crossover experiments that also indicated
that reversibility and cyclization were competitive processes
under the reaction conditions. The key role of the halide
counterion as a base in the reaction was also demonstrated by
reactions contrasting benzeneselenenyl chloride and bromide.
In the absence of a sufficiently basic counterion, the cyclization
is unable to proceed and no product is obtained. This study also
demonstrated through the use of silyl and alkyl ester substrates
that the processes of addition and isomerization were finely
balanced thermodynamically and an equilibrium process that
could be shifted by manipulation of the reaction temperature.
These studies have provided a firm mechanistic foundation
on which to further pursue opportunities for (asymmetric)
catalysis of electrophile-initiated reactions. Such investigations
are ongoing and the results will be reported in due course.
VT-NMR Experiment between (E)-Trimethylsilyl 4-Phenyl-
3-butenoate 15b and Benzeneselenenyl Chloride. An oven-dried
NMR tube was cooled in a desiccator and then charged with
benzeneselenenyl chloride (35.8 mg, 0.187 mmol, 1.1 equiv),
capped with a rubber septum, and attached to a vacuum manifold
via an inlet needle. The tube was purged three times with a vacuum/
argon cycle and then was maintained under an atmosphere of argon.
CD2Cl2 (0.5 mL) was added via syringe, and the tube was vortexed
for 15 s to afford an orange/brown solution. The tube was immersed
in a -75 °C cold bath (bath temperature, acetone/CO2) which
resulted in precipitation of the majority of the benzeneselenenyl
chloride. A solution of (E)-trimethylsilyl 4-phenyl-3-butenoic acid
15b (39.8 mg, 0.17 mmol) in CD2Cl2 (0.25 mL) was added via
cannula, and the tube was momentarily removed from the cooling
bath and revortexed to afford a homogeneous dark yellow solution.
The tube was taken to the precooled (-70 °C) NMR magnet and
inserted. The mixture was aged for 30 min at -70 °C, and then
Experimental Section
General Experimental Procedures. See the Supporting Infor-
mation.
1
both the H NMR (64 scans) and 13C NMR (1024 scans) spectra
(43) For a formally endocyclic process on an sp3 carbon, the leaving
group must be included in the ring. Tenud, M.; Farooq, S.; Seibel, J.;
Eschenmoser, A. HelV. Chem. Acta 1970, 53, 2059-2069.
(44) Weinberg, J. M.; Wooley, K. L. J. Organomet. Chem. 1997, 542,
235-240.
were recorded. The temperature was then increased to -20 °C,
1
and after 30 min of aging, the H NMR (64 scans) spectrum was
recorded. This process was repeated at 0 °C, and then the tube was
removed from the NMR spectrometer and was allowed to stand at
J. Org. Chem, Vol. 71, No. 19, 2006 7305