Synthesis of optically active α,β-unsaturated triazolyl alcohols via asymmetric NaBH4 reduction of the corresponding ketones

Article abstract of DOI:10.1081/SCC-120030684

Chiral ligands 5a-d were synthesized starting from L-proline and their application in the asymmetric NaBH₄ reduction of α,β -unsaturated triazolyl ketones 2 was investigated. The corresponding α,β-unsaturated triazolyl alcohol derivatives (1a,

Full text of DOI:10.1081/SCC-120030684

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Synthesis of Optically Active α,β‐Unsaturated
Triazolyl Alcohols via Asymmetric NaBH4 Reduction
of the Corresponding Ketones
Zhenghong Zhou a , Yilong Tang a , Lixin Wang a , Guofeng Zhao a , Qilin Zhou a & Chuchi
Tang a
a State Key Laboratory of Elemento‐Organic Chemistry, Institute of Elemento‐Organic
Chemistry , Nankai University , Tianjin, 300071, P.R. China
Published online: 21 Aug 2006.
To cite this article: Zhenghong Zhou , Yilong Tang , Lixin Wang , Guofeng Zhao , Qilin Zhou & Chuchi Tang (2004) Synthesis
of Optically Active α,β‐Unsaturated Triazolyl Alcohols via Asymmetric NaBH4 Reduction of the Corresponding Ketones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:8,
1359-1365, DOI: 10.1081/SCC-120030684
To link to this article: http://dx.doi.org/10.1081/SCC-120030684
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 8, pp. 1359–1365, 2004
Synthesis of Optically Active
a,b-Unsaturated Triazolyl Alcohols via
Asymmetric NaBH4 Reduction of the
Corresponding Ketones
Zhenghong Zhou, Yilong Tang, Lixin Wang, Guofeng Zhao,
*
Qilin Zhou, and Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin, P.R. China
ABSTRACT
Chiral ligands 5a–d were synthesized starting from L-proline and their
application in the asymmetric NaBH4 reduction of a,b-unsaturated
triazolyl ketones 2 was investigated. The corresponding a,b-unsaturated
triazolyl alcohol derivatives (1a, uniconazole and 1b, diniconazole) were
obtained in good chemical yield with high ee values (up to 93%).
Key Words: a,b-Unsaturated triazolyl alcohol; L-Proline; Chiral
ligands; Ketones; Asymmetric NaBH4 reduction.
*
Correspondence: Chuchi Tang, State Key Laboratory of Elemento-Organic Chem-
istry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
P.R. China; Fax: þ86-22-23503438; E-mail: c.c.tang@eyou.com.
1359
DOI: 10.1081/SCC-120030684
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Zhou et al.
INTRODUCTION
a,b-Unsaturated triazolyl alcohol derivatives are an important type of
triazolyl pesticides. Among them, compound 1 possesses not only highly
effective, broad spectrum, and systematic fungicidal activity, but also excel-
lent plant growth regulatory and herbicidal activities.[1] In this type of
compound, it contains a carbon–carbon double bond and an asymmetric
carbon. The E-isomers of 1 exhibit excellent bioactivity, whilst the Z-isomers
are largely inactive. It was found that the (E)-(S)-(2)-enatiomer of 1 exhibits
an excellent fungicidal activity, while the (E)-(R) a (þ)-enantiomer of 1 exhi-
bits an excellent plant growth regulatory activity and herbicidal activity.[2]
Based on these facts, the application of the more active single enantiomer
results in application of a smaller amount of the chemical, which leads to
the improvement in economics of the processes of field application and to
the expectation of minimizing the environmental pollution as well as the
improvement in safety. Therefore, the synthesis of optically active enantiomer
of 1 has been drawing much attention from organic chemists.
Two methods were reported for the synthesis of optically active 1. One is
resolution via the formation of diastereomer esters. The reaction of racemate
of 1 with an optically active carboxylic acid in the presence of a base affords a
pair of diastereomer esters. (E)-(S)-(2)- or (E)-(R)-(þ)-enantiomer of 1 is
obtained by resolving and decomposing the said diastereomeric ester mix-
ture.[3] The other method is asymmetric reduction of the corresponding ketone
in the presence of a chiral ligand. Lithium aluminum hydride[2a] or sodium
borohydride[2b,4] was used to reduce the ketone. The most used reductant
was sodium (potassium) borohydride due to economic and safety factors.
The design and synthesis of chiral ligand were the most important factor in
the borohydride reduction reaction.
Yoneyoshi[4a] reported that the application of chiral amino alcohol hydro-
chlorides represented by the general formula 3 into sodium borohydride
reduction of a,b-unsaturated triazolyl ketone derivative 2 resulted in the for-
mation of optically active 1 with good conversion and low to moderate enan-
tioselectivity. Chiral amino alcohol hydrochlorides, represented by the general

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Synthesis of a,b-Unsaturated Triazolyl Alcohols
1361
formula 4, were also used as ligands in the aforementioned reaction.[4b]
The corresponding product 1 was obtained in moderate enantioselectivity
(40–72%ee) with good conversion. Moreover, Liao[4c] reported that optically
active 1 (X55H) could be obtained with 92% yield and 30%ee via potassium
borohydride reduction of 2 (X55H) in the presence of a chiral phase transfer
catalyst.
Substituted 2-pyrrolidine methanol hydrochlorides 5 were prepared
starting from L-proline via esterification, amino group protection, Grignard
reaction, and deprotection. Optically active 1 was obtained with good
enantioselectivity and chemical yield through sodium borohydride reduction
of ketone 2 in the presence of chiral ligand 5. The optimal mole ratio of chiral
ligand and sodium borohydride was 1 : 1 and the chiral ligand amino alcohols
were recoverable. The results of the reaction carried out in different reaction
temperature and solvent were summarized in Table 1.
As shown in Table 1, the reaction temperature had a moderate influence
on the reaction. Since the reaction ran quite slowly below 08C, the yield at 08C
was less than that at higher temperature. However, better enantioselectivity
was obtained at 08C. Moreover, solvent was also found to be an essential
factor to the enantioselectivity of the reaction. Better results were observed
when the reaction was carried out in 1,2-dichloroethane and toluene rather
than in polar solvent THF.
The nature of the chiral ligand amino alcohols had a significant influence
on the enantioselectivity of the reaction. For example, moderate selectivity
was obtained when R was an alkyl group (ethyl, 5d) in the ligand 5 containing
a pyrrolidine ring. However, higher enantioselectivity was observed when the

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Zhou et al.
alkyl group was replaced the phenyl group (5a). Moreover, the introduction of
a substituent (methyl or fluorine) at the para-position of the benzene ring led
to a dramatic increase in the enantioselectivity. Additionally, ee value of the
electron donating methyl substituted ligand (5b) was a little higher than that of
the electron withdrawing fluorine substituted one (5c). Based on these results,
both the electronic and steric effects of the substituent R had influence on the
enantioselectivity. However, it is still unclear which one is the dominant
factor.
In conclusion, this work has resulted in the discovery of some new ligands
for the asymmetric NaBH4 reduction of (E)-a,b-unsaturated triazolyl ketones
2. The corresponding (E)-a,b-unsaturated triazolyl alcohols 1 were obtained
with high enantioselectivity and yield. These findings may promote the
large-scale manufacture of the single enantiomer of uniconazole (1a) and
diniconazole (1b). The chiral ligand used could be easily recovered with its
steric configuration maintained. Moreover, the relationship between the
enantioselectivity and the structure of the ligands 5 was preliminarily investi-
gated. This will provide very useful information for the further design and syn-
thesis of new types of ligands.
EXPERIMENTAL
1H NMR were recorded in CDCl3 on a Bruker AC-P200 instrument using
TMS as an internal standard. Specific rotations were measured on a Perkin–
Elmer 241MC polarimeter. Elemental analyses were conducted on a Yanaco
CHN Corder MT-3 automatic analyzer. Melting points were determined on a
T-3 melting point apparatus. All temperatures were uncorrected. All of the
solvent was used after dried and redistillation.
General Procedure for the Asymmetric NaBH4 reduction of
a,b-Unsaturated Triazolyl Ketones 2
To a suspension of chiral ligand 5 (0.75 mmol) in 6 mL of 1,2-dichloro-
ethane was added a solution of 0.029 g (0.75 mmol) of sodium borohydride
in 1 mL of DMF at 2208C under a nitrogen atmosphere. The resulting mixture
was returned from 2208C to room temperature in 2 hr. Then to the suspension
was added a solution of a,b-unsaturated triazolyl ketone 2 (0.5 mmol) in 2 mL
of solvent. The mixture was stirred for 48 hr at room temperature. Then 10 mL
of 2 N hydrochloric acid was added and the stirring was continued for 1 hr.
The organic layer was separated and the aqueous layer was extracted with
methylene chloride (3 ꢀ 15 mL). The combined organic phase was washed

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Synthesis of a,b-Unsaturated Triazolyl Alcohols
1365
with water and dried over sodium sulfate. After removal of solvent the crude
product was purified by column chromatography on silica gel (200–300
meshes, 4 : 1 petroleum ether/ethyl acetate as the eluent) to afford 1 as a
white solid.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (No.
20002002 and 20272025) and the Ph.D. Programs Foundation of Ministry
of Education of China for generous financial support of our program.
REFERENCES
1. Funaki, Y.; Oshita, H.; Yamamoto, S.; Tanaka, S.; Kato, T. Ger. Pat.
3010560, 1980.
2. (a) Funaki, Y.; Yoneyoshi, Y.; Ishiguri, Y.; Izumi, K. Eur. Pat. 54431,
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Pat. 171175, 1986; (c) Takano, H.; Oguri, Y.; Kato, T. Antifungal and
plant growth regulating activities of enantiomers of (E)-1-(2,4-dichloro-
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(S-3308L).
Nippon Noyaku Gakkaishi 1986, 11 (3), 373; (d) Takano, H.; Kato, T.
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Tanaka, S. Stereochemistry and bioactivities of azole pesticides. Kagaku
to Seibutsu 1986, 24 (3), 180.
3. Priesnitz, U. Ger. Pat. 3515869, 1987.
4. (a) Yoneyoshi, Y.; Suzukamo, G.; Hamada, K.; Nishioka, T. WO 03884,
1984; U.S. Pat. 4749809, 1988; Eur. Pat. 142566, 1984; (b)
Yoneyoshi, Y.; Suzukamo, G.; Sakito, Y.; Nishioka, T. WO 04401,
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Chin. J. App. Chem. 1998, 15 (5), 39.
Received in Japan September 30, 2003

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