Enantioselective cathodic reduction of some prochiral ketones in the presence of (-)-N,N′-dimethylquininium tetrafluoroborate at mercury cathode

Article abstract of DOI:10.1016/S0957-4166(03)00169-1

This work describes preparative scale enantioselective cathodic reduction of some prochiral ketones, viz. 3,4-dihydro-1(2H)-naphthaleneone, 2-octanone, 1-phenyl-2-propanone, E-3-octen-2-one, 1-octyn-3-one, 1-undecyn-3-one, 1-tetradecyn-3-one at mercury pool in N,N-dimethyl formamide (DMF)-2-propanol (9.5:0.5), using tetrabutylammonium tetrafluoroborate (TBA·BF₄), as supporting electrolyte and (-)-N,N′-dimethylquininium tetrafluoroborate (DMQ·2BF₄), as a enantioselective inductor. The products obtained were corresponding (S)-alcohols in 24-70% ee.

Full text of DOI:10.1016/S0957-4166(03)00169-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1079–1081
Enantioselective cathodic reduction of some prochiral ketones in
the presence of (−)-N,N%-dimethylquininium tetrafluoroborate at
mercury cathode
Ashok K. Yadav,* Meera Manju and Pukh Raj Chhinpa
Department of Chemistry, University of Rajasthan, Jaipur-302 004, India
Received 31 January 2003; accepted 17 February 2003
Abstract—This work describes preparative scale enantioselective cathodic reduction of some prochiral ketones, viz. 3,4-dihydro-
1(2H)-naphthaleneone, 2-octanone, 1-phenyl-2-propanone, E-3-octen-2-one, 1-octyn-3-one, 1-undecyn-3-one, 1-tetradecyn-3-one
at mercury pool in N,N-dimethyl formamide (DMF)–2-propanol (9.5:0.5), using tetrabutylammonium tetrafluoroborate
(TBA·BF4), as supporting electrolyte and (−)-N,N%-dimethylquininium tetrafluoroborate (DMQ·2BF4), as a enantioselective
inductor. The products obtained were corresponding (S)-alcohols in 24–70% ee. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
in the presence of catalytic amounts of (1R,2S)-(−)-
N,N%-dimethylephedrinium tetrafluoroborate. Our cur-
rent interest in this area is to explore the cathodic
reduction of some prochiral ketones 1–7 in the presence
of DMQ2+ as a chiral inductor, at a mercury pool, in
the presence of 0.1 M TBA·BF4, as supporting elec-
trolyte, in DMF/2-propanol (9.5:0.5). The compounds
obtained were (S)-1,2,3,4-tetrahydro-1-naphthol 1a,
(S)-2-octanol 2a, (S)-phenyl-2-propanol 3a, (S,E)-3-
octen-2-ol 4a, (S)-1-octyn-3-ol 5a, (S)-1-undecyn-3-ol
6a, and (S)-1-tetradecyn-3-ol 7a.
Among the variety of methods1–4 available for stere-
ocontrolled synthesis, the few electrochemical methods
are based on the use of chirally modified electrodes,5–7
the use of a chiral supporting electrolyte,7 chiral
solvent8 and cathodic reduction in the presence of
optically active compounds2,3,6,9,10 and crown ethers,11
etc., Schaefer et al.12 have proposed a refined model for
the transition state of the alkaloid induced enantioselec-
tive electroreduction of 4-methyl coumarin in the pres-
ence of yohimbine. Diastereoselective cathodic
reduction of phenylglyoxalic acid attached to chiral
auxiliaries13 and diastereoselective cathodic cyclization
of 1-(4- and 1-(3-oxoalkyl)pyridinium salts, etc., have
been reported.14 Our efforts, on the cathodic
reduction15 of unconjugated ketones, resulted in
regioselective intramolecular cyclized products, e.g. 6-
hepten-2-one, on cathodic reduction, at mercury pool,
in the presence of (−)-N,N%-dimethylquininium tetra-
fluoroborate (DMQ·2BF4), in DMF/2-propanol, gave
cis-1,2-dimethylcyclohexanol.
2. Results and discussion
In our strategy, we have carried out cathodic reductions
of prochiral ketones 1–7 in DMF/2-propanol (9.5:0.5)
containing 10 mM of DMQ·2BF4 at a mercury pool
cathode, in a divided cell, using a porous diaphragm. A
constant current 100 mA (c.d., 10 mA cm−2) was
passed, until a charge corresponding to 2.2 F mol−1 was
transferred. The products obtained were (S)-alcohols
1a–7a in 80, 70, 72, 75, 72, 65 and 68% yield, respec-
tively, having enantiomeric excesses of 62, 24, 35, 59,
70, 56 and 50%, respectively. The enantiomeric excess
of compounds 1a–7a has been assayed by comparison
with this known value of the maximum specific rotation
and by HPLC analysis of 2-methoxy-2-trifluoromethyl
phenyl acetate (MPTA) ester in petroleum ether–aceto-
nitrile (9.5:0.5), at flow rate 3 mL/min.
Recently, we have reported16 the enantioselective
cathodic reduction of some prochiral ketones and
obtained the corresponding (S)-alcohols in 40–55% ee,
* Corresponding author. Fax: +91-0141-2708621; e-mail: draky@
sify.com
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00169-1

1080
A. K. Yada6 et al. / Tetrahedron: Asymmetry 14 (2003) 1079–1081
Compounds 1–7 have been cathodically reduced to
yield (S)-alcohols.
3.2. Work-up
DMF was removed under reduced pressure (50°C at 35
mmHg). About 60 mL water was added and the prod-
ucts were extracted with ether, dried over anhydrous
sodium sulfate and filtered. The solvent was removed
and products 1a–7a were further purified by distilla-
tion/column chromatography over silica gel (G).
The effect of concentration of the inductor viz.
DMQ·2BF4, on cathodic reduction of 1, was studied at
1 ,5, 10, 15 and 25 mM. Product 1a was obtained in
75–80% yield with 50, 55, 62, 64 and 66% ee’s, respec-
tively, establishing that the inductor concentration has
no significant effect on ee and thus suggests strong
adsorption on the surface of electrode.17
3.3. Purification and ee determination of chiral alcohols
1a–7a
In conclusion, the present procedure provides a novel
general methodology for synthesis of (S)-alcohols 1a–
7a in 24–70% ee. These are preliminary investigations
and the mechanistic pathway of the process is under
study and will be addressed later.
3.3.1. (S)-1,2,3,4-Tetrahydro-1-naphthol, 1a. The
product was purified, on silica gel, using a 5:1 mixture
of benzene and ethyl acetate. 80% yield; colourless oil;
[h]2D4=−22.2 (c 3.06, CHCl3) 62% ee based on its maxi-
mum rotation20 [h]1D7=+32.7.
3.3.2. (S)-2-Octanol, 2a. Distillation at 120–140°C at 100
mmHg afforded (S)-2-octanol (and remaining starting
material 1) 70% yield; colourless oil; [h]2D1=−2.4 (c 5.53,
ethanol), 24% ee based on the highest reported21 value
for (S)-2-octanol [h]2D1=+10.1 (c 5.57, ethanol).
3. Experimental
3.1. General
The electrosynthesis has been performed on a Autolab
PGSTAT 100 electrochemical system. TBA·BF4 and
DMQ·2BF4 were synthesized according to reported
methods15,18 and were dried under vacuum and kept in
a desiccator. DMF was dried by a reported method19
and kept over activated molecular sieves (4 A) under
nitrogen gas. 2-Propanol (A.R. grade) and other chem-
icals (L.R. grade) were used as such.
3.3.3. (S)-Phenyl-2-propanol, 3a. Distillation at 120–
135°C (17 mmHg) gave a mixture of starting ketone
and (S)-phenyl-2-propanol in 72% yield; colourless oil;
[h]2D5=+14.7 (c 5.28, benzene) in 35% ee based on
highest reported value22 of (S)-3a, lit. [h]2D5=+41.8 (c
5.26, benzene).
,
3.3.4. (S,E)-3-Octen-2-ol, 4a. Column chromatography
on silica gel using a 5:1 mixture of pentane–ether
followed by distillation [103–118°C, 17 mmHg] gave
(S,E)-3-octen-2-ol; colourless oil; 75% yield. The enan-
tiomeric excess, as well as absolute configuration, was
determined on the basis of the specific rotation value of
saturated derivative. The above obtained alcohol (30 mg,
0.22 mM) was reduced by treatment with potassium
azodicarboxylate (450 mg, 2.3 mM) and acetic acid (140
mg, 2.3 mM) in methanol (5 mL). Column chromatog-
raphy, using pentane–ether (4:1), followed by distillation
gave (S)-2-octanol, as colourless oil [h]2D2=−6.0 (c 5.5,
ethanol) in 59% ee, lit.21 [h]2D1=+10.1 (c 5.57, ethanol).
The electrosynthesis has been carried out as follows:
Catholyte: 0.1
M
tetrabutylammonium tetra-
fluoroborate (TBA·BF4) in DMF/2-propanol (9.5:0.5)
and 10 mM DMQ·2BF4 (70 ml); Anolyte: 0.1 M
TBA·BF4 in DMF/2-propanol (9.5:0.5) in porous
diaphragm (30 ml); Cathode: Mercury pool; Anode: Pt
foil.
0.01 M of ketone 1–7 was added to the catholyte. A
constant current of 100 mA (current density 10 mA
cm−2) was passed until charge corresponding to 2.2 F
mol−1 was transferred.

A. K. Yada6 et al. / Tetrahedron: Asymmetry 14 (2003) 1079–1081
2. Blaser, H. U. Chem. Rev. 1992, 92, 935–952.
1081
3.3.5. (S)-1-Octyn-3-ol, 5a. The product, on separation
by column chromatography on silica gel, using a 5:1
mixture of pentane–ether as a eluent, gave oily 1-octyn-3-
ol; 72% yield. Distillation at 120–125°C (25 mmHg),
afforded a pure sample of 5a [h]2D2=−14.4 (c 0.85, ether)
and 70% ee, based on HPLC analysis of MTPA esters.
Petroleum ether and acetonitrile (99.5:0.5) was used in
HPLC, at flow rate of 3 mL/min, which afforded peak
of esters of (S)-1-octyn-3-ol (tR 3.6 min, 85.6%) and
(R)-1-octyn-3-ol (tR 4.1 min, 15.4%).
3. Nogradi, M. Stereoselective Synthesis; VCH: New
York, Weinheim, 1995.
4. Murray, R. W. Acc. Chem. Res. 1980, 13, 135–141.
5. Brunner, H. Top. Sterochem. 1988, 18, 129.
6. Komori, T.; Nonaka, T. J. Am. Chem. Soc. 1984, 106,
56–59.
7. Tellac, A. Bull. Soc. Chem. Fr. 1985, 743–761.
8. Seebach, D.; Dei, H. A. Angew. Chem., Int Ed. Engl.
1975, 87, 629–630.
9. Horner, L.; Brich, W. Justus Liebigs Ann. Chem. 1978,
1354–1364.
10. Nielsen, M. F.; Batanero, B.; Lohl, T.; Schaefer, H. J.;
Wurthwein, E. U.; Froehlich, R. Eur. J. Chem. 1997, 3,
2011–2024.
11. Horner, L.; Brich, W. Chem. Ber. 1978, 111, 574–578.
12. Hoeweler, U.; Schoo, N.; Schaefer, H. J. Liebigs Ann.
Chem. 1993, 6, 609–614.
3.3.6. (S)-1-Undecyn-3-ol, 6a. Column chromatography
on silica gel gave (S)-(−)-undecyn-3-ol in 65% yield.
Distillation (130–145°C, 5 mmHg) gave, 6a [h]2D2=−8.6
(c 0.86 ether) in 56% ee, based on HPLC analysis of
MTPA ester in petroleum–acetonitrile (99.5:0.5), at flow
rate 3 mL/min. (S)-esters (tR 3.7 min, 78%), (R)-esters
(tR 4.1 min, 22%).
13. Reufer, C.; Zielinski, C.; Schaefer, H. J.; Froehlich, R.
Acta. Chem. Scand. 1999, 53, 1023–1037.
14. Gorny, R.; Ruediger, Schaefer, H. J.; Froehlich, R.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2007–2009.
15. Yadav, A. K.; Singh, A. Synlett 2000, 8, 1199–1201.
16. Yadav, A. K.; Singh, A. Bull. Chem. Soc. Jpn. 2002,
75, 587–588.
3.3.7. (S)-1-Tetradecyn-3-ol, 7a. Column chromatogra-
phy on silica gel gave (S)-1-tetradecyn-3-ol in 68% yield.
Distillation [130–145°C, 3 mmHg] gave 7a [h]2D2=−6.4 (c
0.78 ether) in 50% ee, based on HPLC analysis of MTPA
esters in petroleum–acetonitrile (99.5:0.5), at flow rate 3
mL/min (tR 3.8 min, 75%), (R)-esters (tR 4.2 min, 25%).
17. For example, see: (a) Jubault, M.; Raoult, E.; Pletier,
D. J. Chem. Soc., Chem. Commun. 1980, 953; (b)
Kopilov, J.; Kariv, E.; Miller, L. L. J. Am. Chem. Soc.
1977, 99, 3450–3454.
All products 1a–7a were characterized by 1H NMR and
IR spectra.
18. For example, see: Olmstead, W. N.; Margolin, Z.; Bor-
dwell, F. G. J. Org. Chem. 1980, 45, 3295–3299.
19. Practical Organic Chemistry; Furniss, B. S.; Hannaford,
A. J.; Smith, P. W. G.; Tatchell, A. R., ed.; 1996, p.
409.
Acknowledgements
Financial support from DST, New Delhi, is gratefully
acknowledged.
20. Davies, A. G.; White, A. M. J. Chem. Soc. 1952, 3300–
3303.
21. Hill, R. K. J. Am. Chem. Soc. 1958, 80, 1611–1613.
22. Arcus, C. L.; Hallgarten, P. A. J. Chem. Soc. 1956,
2987–2991.
References
1. Blaser, H. U. Tetrahedron: Asymmetry 1991, 2, 843–
866.