(C) 4-Alkoxymethyl-2,6,7-trithiabicyclo[2.2.2]octane. The solu-
tion of 2,2-bis(mercaptomethyl)-3-alkoxypropanethiol (from step
B) and methyl orthoformate in toluene with several crystals of
TsOH•H2O was refluxed for 24 h, washed with saturated NaHCO3
and water, and dried over Na2SO4. The solvent was removed under
reduced pressure, and the resulting yellow solid was purified by
column chromatography (silica gel, hexane/EtOAc, 20:1).
However, it is not surprising that the relatively low stability
of TTBO radical (E) does not have as large a detrimental effect
on the efficiency of fragmentation as does the back electron
transfer. Enhanced stability of the TTBO radical cations seems
to play a critical role in the fragmentation mechanism. Ad-
ditionally, the overall effect on the quantum efficiency of
fragmentation is mitigated by yet another factor: the acces-
sibility of sulfurs for the sensitizer approach, which enhances
the rates of the initial electron-transfer quenching, kET, of triplet
benzophenone. The LFP experiments consistently show that kET
for the TTBO adducts are greater than for dithiane adducts.
These rates also correlate (i.e., are attenuated) with the steric
crowding introduced by the carbonyl component: the adducts
with benzaldehyde quench the triplet sensitizer with a 40-50%
higher rate than the more crowded adducts of benzophenone
(Table 2).
1-Bromo-2,2-bis(bromomethyl)-3-methoxypropane: Prepared
from 5.13 g (91.5 mmol) of KOH, 7.00 g (20.8 mmol) of 3-bromo-
2,2-bis(bromomethyl)propanol and 13.00 g (91.5 mmol) of io-
domethane in 35 mL of DMSO: 5.49 g, 78%.
2,2-Bis(mercaptomethyl)-3-methoxypropanethiol: Prepared
from 3.23 g (57.7 mmol) of NaSH‚9H2O, 2.6 g (81.3 mmol) of S
powder, 4.88 g (14.4 mmol) of 1-bromo-2,2-bis(bromo-methyl)-
3-methoxypropane, 2.5 g (39.3 mmol) of Cu powder, 13.7 g of Zn
1
dust (216 mmol) and 70 mL of conc. HCl. H NMR (500 MHz,
CDCl3) δ 3.33 (s, 3H), 3.29 (s, 2H), 2.62 (d, 6H, J ) 8.9 Hz), 1.22
The features discussed above account for the superior
quantum yields of sensitized fragmentation in benzophenone
adducts of TTBOs compared with benzophenone adduct of
methyldithiane. Although the benzaldehyde adducts of TTBOs
showed somewhat lesser quantum efficiencies, when compared
with benzaldehyde adduct of methyldithiane (Table 1), adducts
4 with alkoxy substituents were found to be adequate for tagging
as they cleanly produce TTBO tags upon sensitized irradiation.
Only allylic compound 4e produced traces of side product,
which is conceivably the result of Paterno`-Bu¨chi cycloaddition
of the sensitizer to the double bond.
Similar to dithianes, TTBOs 1 and 2 can be detected with
excellent sensitivity using mass-produced analytical instruments,
for example, GCMS. The enhanced stability of their radical
cations accounts for their low detection limit.
In conclusion, 4-substituted trithiabicyclo[2.2.2]octanes are
versatile and readily accessible mass-differentiated tags for the
encoding of combinatorial libraries, which can be photoreleased
with high quantum efficiencies and detected in minute amounts
by ubiquitous analytical techniques.
(t, 3H, J ) 8.9 Hz).
4-Methoxymethyl-2,6,7-trithiabicyclo[2.2.2]octane (2a): Pre-
pared from 2.86 g (14.5 mmol) of 2,2-bismercaptomethyl-3-
methoxypropane-1-thiol, 2.3 g (21.7 mmol) of methyl orthofor-
1
mate: 2.77 g (92%). H NMR (500 MHz, CDCl3) δ 4.60 (s, 1H),
3.37 (s, 3H), 3.19 (s, 2H), 3.05 (s, 6H). 13C NMR (500 MHz,
CDCl3) δ 80.55, 59.43, 39.04, 33.29,30.68.
General Procedure for Preparation of Adducts 3-6. n-BuLi
(1.6 M in hexane) was added to TTBO in 5-10 mL of THF under
nitrogen and stirred for 10-15 min at 25 °C, at which point a 2
mL solution of benzaldehyde or benzo-phenone in THF was added
and stirred for 3 h, quenched with aqueous ammonium chloride,
extracted with CH2Cl2 (2 × 20 mL), and dried over Na2SO4. The
solvent was removed under reduced pressure, and the crude material
was purified by column chromatography on silica gel (hexane/
EtOAc).
Adduct 4a: Prepared from 100 mg (0.48 mmol) of 4-methoxy-
methyl-2,6,7-trithiabicyclo[2.2.2]octane (2a), 0.66 mL (1.06 mmol)
of n-BuLi (1.6 M in hexane), and 76 mg (0.72 mmol) of
benzaldehyde: 47 mg (31%) after purification on silica gel, hexane/
1
EtOAc ) 10:1, then 3:1. H NMR (500 MHz, CDCl3) δ 7.57 (m,
Experimental Section
2H), 7.38 (m, 3H), 5.00 (d, 1H, J ) 3.1 Hz), 3.34 (s, 3H), 3.18
(dd, 2H, J ) 14.9. Hz, J ) 9.01 Hz), 3.05 (dd, 3H, J ) 11.7 Hz,
J ) 2.0 Hz), 2.95 (d, 1H, J ) 3.3 Hz), 2.93 (dd, 3H, J ) 11.7 Hz,
J ) 2.0 Hz). 13C NMR (400 MHz, CDCl3) δ 136.87, 129.00,
128.32, 127.81, 79.83, 78.27, 65.90, 59.39, 34.76, 32.52.
General Procedure for Preparation of TTBOs. (A) 1-Bromo-
2,2-bis(bromomethyl)-3-alkoxypropanes. Fine-powdered KOH
was added to a vigorously stirred solution of 3-bromo-2,2-bis-
(bromomethyl)propanol and an alkyl halide in 35 mL of DMSO.
The temperature was kept below 60 °C using an ice bath. After
the initial exothermic step, the stirred solution was heated at 60 °C
for 2 h and cooled to 20 °C; 100 mL of water was added, and the
aqueous phase was extracted with 3 × 50 mL of CH2Cl2. The
organic layer was dried over Na2SO4 followed by the removal of
the solvent.
Computational Methods. The structures and the energies were
computed with Gaussian 03, Rev. C02, computational package.11
The values in Table 3 and elsewhere in the text represent zpe-
corrected B3LYP/6-311+G(2d,p) energies, obtained for geometries
optimized at the same theory level.
(B) 2,2-Bis(mercaptomethyl)-3-alkoxypropanethiol. NaHS‚
9H2O and elementary sulfur powder were dissolved in DMF upon
warming, heated at 80 °C for 1 h, and cooled to ∼ 40 °C, and then
the 1-bromo-2,2-bis(bromomethyl)-3-alkoxypropane (from step A)
was added. The temperature was raised to 80-90 °C and kept there
for 7-8 h. DMF was removed under reduced pressure, and copper
powder and toluene (30 mL) were added to the resulting crude
product and refluxed overnight. Black copper sulfide was filtered
off, then zinc dust and 20-30 mL of ethanol were added to the
yellow filtrate. Concentrated HCl was added dropwise under stirring.
The resulting solution was stirred for 24 h under nitrogen; the
toluene layer was separated from the ethanol-water mixture,
washed with water (20 mL), and dried over Na2SO4. The solvent
was removed under reduced pressure to furnish oil with a
characteristic smell, which was used without further purification.
Acknowledgment. This work is supported by NSF, CHE-
640838.
Supporting Information Available: Additional experimental
information, spectra, computational details. This material is available
JO702091E
(11) Frisch, M. J.; et al. Gaussian 03, revision C.02; Gaussian, Inc.:
Pittsburgh, PA, 2003.
(12) Sweigart, D. A.; Turner, D. W. J. Am. Chem. Soc., 1972, 94, 5599-
5603.
338 J. Org. Chem., Vol. 73, No. 1, 2008