S. Roth et al.
first time, an efficient catalytic system for successful reduc-
tive couplings of ketones with thiols to yield substituted thi-
oethers in good yields has been established.
Subsequently, nitrogen-based nucleophiles were also stud-
ied. It was demonstrated that sulfonamides could be success-
fully introduced as coupling partners for aldehydes and ke-
tones without major changes in reaction conditions to give
the corresponding substituted sulfonamides in good yields.
Overall, a general, efficient metal-free method for reduc-
tive couplings of aldehydes and ketones with a wide range
of nucleophiles, based on triflic acid (1–5 mol%) together
with triethylsilane as reducing agent to form a widely appli-
cable reductive coupling procedure, has been developed.
The reaction only produces either nontoxic hexaethyldisilox-
ane or triethylsilanol as byproducts and does not require
any form of activation, neither of the carbonyl compound
nor of the nucleophile prior to reaction. This, in our opinion,
emphasizes the usefulness of the reaction by minimizing
synthetic effort and producing significantly reduced amounts
of environmentally hazardous waste.
Scheme 4. Proposed generation of the active catalyst.
The catalyst is regenerated and the catalytic cycle is closed.
A proposed catalytic cycle of a general reductive coupling
reaction is given in Scheme 5. Detailed investigations into
the mechanism are currently in progress.
Experimental Section
Only representative procedures and products are shown below. Full ana-
lytical data for all new compounds can be found in the Supporting Infor-
mation.
Scheme 5. Proposed simplified catalytic cycle based on TESOTf as active
catalyst.
Representative procedure for the reductive coupling of aldehydes and
ketones to afford symmetrical ethers
Conclusion
Dibenzyl ether (2): Triethylsilane (0.55 mmol, 1.1 equiv, 50 mL) and tri-
fluoromethanesulfonic acid (1 mol%, 5 mmol, 5 mL, as a 1m stock solu-
tion in nitromethane) were added at ambient temperature to a solution
of benzaldehyde (1, 0.50 mmol, 1.0 equiv, 50 mL) in nitromethane
(0.5 mL) or dichloromethane. The reaction mixture was stirred for 1 min
and directly transferred to a column of silica gel (containing a small layer
of silica-supported sodium hydrogen carbonate to remove traces of acid).
The crude product was purified by column chromatography with a mix-
ture of petroleum ether and ethyl acetate (100:1 to 3:2) as eluent to give
2 (49 mg, 99%) as a colourless oil. 1H NMR (300 MHz, CDCl3): d=4.61
(s, 4H; CH2), 7.31–7.45 ppm (m, 10H; Ar); 13C NMR (75 MHz, CDCl3):
d=72.1 (CH2), 127.6, 127.7, 128.4, 138.3 ppm (Ar).[25]
Reductive coupling of carbonyl compounds with nucleo-
philes has the potential to be a powerful tool for the synthe-
sis of a range of functionalized compounds directly from al-
dehydes or ketones. We have been able to demonstrate here
that a simple Brønsted acid such as triflic acid could be used
as a general efficient catalyst for reductive couplings of car-
bonyl compounds with oxygen-, sulfur- and nitrogen-based
nucleophiles under the same set of reaction conditions. The
reaction can be performed in open air and at ambient tem-
perature.
Representative procedure for the reductive coupling of aldehydes and
ketones with alcohols
(Ethoxymethyl)benzene (26): Ethanol (0.325 mmol, 1.3 equiv, 19 mL),
triethylsilane (0.275 mmol, 1.1 equiv, 44 mL) and trifluoromethanesulfonic
acid (1 mol%, 2.5 mmol, 5 mL, as a 0.5m stock solution in nitromethane)
were added at ambient temperature to a solution of benzaldehyde (1,
0.250 mmol, 1.0 equiv, 25 mL) in nitromethane (0.5 mL). The reaction
mixture was stirred for 16 h and directly transferred to a column of silica
gel (containing a small layer of silica-supported sodium hydrogen carbon-
ate to remove traces of acid). The crude product was purified by column
chromatography with a mixture of petroleum ether and ethyl acetate
(100:0 to 5:1) as eluent to give 26 (32 mg, 97%) as a colourless oil.
1H NMR (300 MHz, CD2Cl2): d=1.23 (t, 3J=7.0 Hz, 3H; CH3), 3.45 (q,
3J=7.0 Hz, 2H; CH2CH3), 4.49 (s, 2H; CH2Ph), 7.23–7.41 ppm (m, 5H;
Ar); 13C NMR (75 MHz, CD2Cl2): d=15.0 (CH3), 66.1 (CH2CH3), 72.9
(CH2Ph), 127.7, 128.0, 128.6, 139.4 ppm (Ar).[8e]
For the first time, a wide range of alcohols as coupling
partners both for aldehydes and for ketones has been stud-
ied. The corresponding ethers were formed in good to excel-
lent yields when aldehydes were treated variously with pri-
mary, secondary or even tertiary alcohols, such as tert-butyl
alcohol. Ketones could be successfully coupled with primary
alcohols, but when secondary alcohols were employed the
yields were considerably lower. The influence of additional
functionalization of the alcohols was also studied, revealing
that the reaction conditions are compatible with the pres-
ence of distal double and triple bonds, as well as of carbox-
ylic acids, esters and amides.
Representative procedure for the reductive coupling of ketones with
thiols
When thiols were applied as nucleophiles, it could be
shown that aldehydes predominantly formed stable thioace-
tals. Ketones, however, formed the desired thioethers in
high yields with either primary or secondary thiols. For the
Ethyl(1-phenylethyl)sulfane (56): Ethanethiol (1.3 mmol, 1.3 equiv,
96 mL), triethylsilane (1.1 mmol, 1.1 equiv, 176 mL) and trifluoromethane-
sulfonic acid (1 mol%, 10 mmol, 10 mL, as a 1m stock solution in nitrome-
12208
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12203 – 12209