Synthesis of Optically Active α,β-Unsaturated Triazolyl Alcohols via Chiral Auxiliary-Modified NaBH4 Reduction of the Corresponding Ketones

Article abstract of DOI:10.1055/s-2003-44365

α-Disubstituted pyrrolidine-2-methanols were synthesized starting from L-proline and their application as chiral auxiliary in the asymmetric NaBH₄ reduction of α,β-unsaturated triazolyl ketones was investigated. The corresponding α,β-unsaturated triazolyl alcohol derivatives (Uniconazole and Diniconazole) were obtained in good chemical yields with high ee values (up to 93%).

Full text of DOI:10.1055/s-2003-44365

PAPER
217
Synthesis of Optically Active , -Unsaturated Triazolyl Alcohols via Chiral
Auxiliary-Modified NaBH Reduction of the Corresponding Ketones
4
S
Z
ynthesisof
O
p
h
ticallyActiv
o
e
,
-Unsatu
u
rated Triazolyl Alc
Z
ohols henghong, Tang Yilong, Wang Lixin, Zhao Guofeng, Zhou Qilin, Tang Chuchi*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
P. R. China
Fax +86(22)23503438; E-mail: c.c.tang@eyou.com
Received 12 September 2003; revised 30 October 2003
pair of diastereomer esters. The (E,S)-(–)- or (E,R)-(+)-
enantiomer of 1 is obtained by resolving and decomposing
the diastereomeric ester mixture. The other method is
Abstract: -Disubstituted pyrrolidine-2-methanols were synthe-
sized starting from L-proline and their application as chiral auxiliary
3
in the asymmetric NaBH reduction of , -unsaturated triazolyl ke-
4
asymmetric reduction of the corresponding ketone 2
tones was investigated. The corresponding , -unsaturated triazolyl
alcohol derivatives (Uniconazole and Diniconazole) were obtained (Figure 2) in the presence of a chiral auxiliary. Lithium
2
a
2b,4
in good chemical yields with high ee values (up to 93%).
aluminum hydride or sodium borohydride were used
to reduce the ketone. The most used reductant was sodium
Key words: triazoles, L-proline, asymmetric reduction
(
potassium) borohydride due to economic and safety fac-
tors. The design and synthesis of chiral auxiliary was the
most important factor in the borohydride reduction reac-
tion.
,
-Unsaturated triazolyl alcohol derivatives are an im-
portant type of triazolyl pesticide. Among them, com-
pound 1 possesses not only highly effective, broad
spectrum and systematic fungicidal activity, but also ex-
cellent plant growth regulatory and herbicidal activities.1
This type of compound contains a carbon–carbon double
bond and an asymmetric carbon atom. The E-isomers of 1
exhibit excellent bioactivity, whilst the Z-isomers are
largely inactive. It was found that the (E,S)-(–)-enatiomer
of 1 exhibits an excellent fungicidal activity, while the
Figure 2 Chemical structures of triazolyl keto derivatives 2a,b
(
E,R)-(+)-enantiomer of 1 (Figure 1) exhibits excellent
2
plant growth regulatory activity and herbicidal activity.
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 an improvement
in the economics of the processes of field application and
to the expectation of minimizing the environmental pollu-
tion as well as the improvement in safety. Therefore, the
synthesis of optically active enantiomer of 1 has been
drawing much attention from organic chemists.
Yoneyoshi2b,4a–c reported that the application of chain
chiral amino alcohol hydrochlorides to sodium borohy-
dride reduction of , -unsaturated triazolyl ketone deriv-
atives 2 resulted in the formation of optically active 1 with
good conversion and lower to moderate enantioselectivity
4
d
(
40–72%). Additionally, Liao reported that optically ac-
tive 1 (X = H) could be obtained in 92% yield and 30% ee
via potassium borohydride reduction of 2a (X = H) in the
presence of a chiral phase-transfer catalyst.
Herein we report the design and synthesis of some new
chiral auxiliaries and their application in the synthesis of
optically active , -unsaturated triazolyl alcohol deriva-
tives 1 via asymmetric NaBH reduction of the corre-
4
sponding prochiral ketones 2.
Methyl N-tert-butoxycarbonyl-L-prolinate was synthe-
5
sized starting from L-proline via esterification and amino
Figure 1 Chemical structures of triazolyl hydroxy derivatives 1a,b
6
group protection. Substituted N-tert-butoxycarbonyl pro-
tected pyrrolidine-2-methanols 3 were prepared through
the Grignard reaction of N-protected methyl L-prolinate in
moderate yield, which was similar to the procedure re-
Two methods were reported for the synthesis of optically
active 1. One is resolution via the formation of diastere-
omer esters. The reaction of racemic 1 with an optically
active carboxylic acid in the presence of a base affords a
7
ported by Soai. Substituted pyrrolidine-2-methanols hy-
drochlorides 4 were obtained via the deprotection of the
corresponding 3 with a solution of anhydrous hydrogen
chloride in ethyl acetate in high yield (Scheme 1).
SYNTHESIS 2004, No. 2, pp 0217–0220
x
x
.
x
x
.2
0
0
3
Advanced online publication: 09.12.2003
DOI: 10.1055/s-2003-44365; Art ID: F08103SS
Georg Thieme Verlag Stuttgart · New York
The analytical and spectral data of the intermediates 3 and
target compounds 4 are listed in Tables 1 and 2, respec-
©

2
18
Z. Zhenghong et al.
PAPER
Table 2 Compounds 4a–d Prepared
Compounda
Mp (°C)
>290
>295
>290
145
[ ]57820 (MeOH)
+70.4 (c = 0.50)
+89.3 (c = 0.46)
+70.6 (c = 0.32)
17.6 (c = 0.17)
Yield (%)
4
4
4
a
b
c
91
89
84
90
Scheme 1
4
d
a
Satisfactory microanalyses obtained: C 0.21, H 0.13, N 0.12.
1
tively. H NMR spectra of chiral auxiliaries 4 were not re-
corded due to their poor solubility in chloroform as
hydrochlorides.
er than that of the electron-withdrawing fluorine substitut-
Optically active 1 was obtained with good enantioselec- ed one 4c. Therefore, the use of the auxiliary 4b led to the
tivity and chemical yield through sodium borohydride re- highest ee value (93%) for both of the substrates (entries
duction of ketone 2 in the presence of chiral auxiliary 4. 6 and 17). Based on these results, both the electronic and
In all cases, the S-enantiomer of 1 was obtained as the ma- steric effects of the substituent R have influence on the
jor product. The optimal mole ratio of chiral auxiliary and enantioselectivity. However, it is still unclear which one
sodium borohydride was 1:1 and the chiral auxiliary ami- is the dominant factor. Additionally, it is worth noting that
no alcohols were recoverable. The results of the reaction chiral auxiliary 4 has a good chemical stability. Prelimi-
carried out at different reaction temperatures and solvents nary investigation revealed that it could easily be recov-
are summarized in Table 3.
ered with its steric configuration retained and reused.
As shown in Table 3, the reaction temperature had a mod- In conclusion, this work has resulted in the discovery of a
erate influence on the reaction. Since the reaction ran new class of auxiliaries containing a pyrrolidine ring for
quite slowly below 0 °C, the yield at 0 °C was less than the asymmetric NaBH
that at higher temperature. However, better enantioselec- triazolyl ketones 2. Compared with the acyclic chiral ami-
reduction of (E)- , -unsaturated
4
tivity was obtained at 0 °C. Moreover, solvent was also no alcohols in literature,2
b,4a–c
the corresponding (E)- , -
found to be an essential factor to the enantioselectivity of unsaturated triazolyl alcohols 1 were obtained with higher
the reaction. Better results were observed when the reac- enantioselectivity. These findings are helpful in the large-
tion was carried out in 1,2-dichloroethane and toluene scale manufacture of the single enantiomer of Unicaona-
rather than in the polar solvent THF. The nature of the zole (1a) and Diniconazole (1b), which will promote the
chiral auxiliary 4 had a more significant influence on the field application of the single isomer of the two pesticides.
enantioselectivity of the reaction. For example, when 2a
was employed as the substrate moderate selectivity was
obtained when R was an alkyl group (ethyl, 4d) in the aux-
1
H NMR was recorded in CDCl on a Bruker AC-P200 instrument
3
using TMS as an internal standard. Specific rotations were mea-
iliary 4. However, higher enantioselectivity was observed sured on a Perkin-Elmer 241MC polarimeter. Elemental analyses
when a phenyl group (4a) replaced the alkyl group, while were conducted on a Yanaco CHN Corder MT-3 automatic analyz-
er. Melting points were determined on a T-3 melting point apparatus
and are uncorrected. All solvents were dried and redistilled.
this difference is not obvious when 2b was employed as
the substrate. Moreover, the introduction of a substituent
(
methyl or fluorine, namely 4b or 4c) at the para position
(
–)-(S)-N-tert-Butoxycarbonyl-2-[bis(4-methylphenyl)hydroxy-
of the benzene ring led to a dramatic increase in the enan-
tioselectivity. Furthermore, the ee value of the electron-
methyl]pyrrolidine (3b); Typical Procedure
To a solution of 4-methylphenylmagnesium bromide [prepared
donating methyl substituted auxiliary 4b was a little high- from Mg (14.4 g, 0.60 mol) and 4-methylphenyl bromide (68.4 g,
Table 1 Compounds 3a–d Prepared
Compounda
Mp (°C)
153–155
[ ]57820 (CHCl ) Yield (%)
1
H NMR (CHCl ) , J (Hz)
3
3
3
3
3
a
179.0
c = 0.40)
75
55
84
79
1.42 (s, 9 H, t-C H ), 1.46–2.07 (m, 4 H, 2 CH ), 2.85–3.40 (m, 2 H,
CH ), 4.87 (q, 1 H, J = 8.6, CH), 7.24–7.40 (m, 10 Harom)
4
9
2
(
(
(
(
2
b
c
148–149
160.2
c = 0.42)
1.42 (s, 9 H, t-C H ), 1.46–2.12 (m, 4 H, 2 CH ), 2.33 (s, 6 H, 2 CH ),
2.89–3.42 (m, 2 H, CH ), 4.87 (m, 1 H, CH), 7.04–7.27 (m, 8 Harom)
4
9
2
3
2
151–152
141.7
c = 0.52)
1.42 (s, 9 H, t-C H ), 1.47–2.10 (m, 4 H, 2 CH ), 2.86–3.36 (m, 2 H,
CH ), 4.88 (q, 1 H, J = 8.4, CH), 6.93–7.36 (m, 8 Harom)
4
9
2
2
3d
viscous liquid
24.4
0.81–1.04 (m, 6 H, 2 CH ), 1.40 (s, 9 H, t-C H ), 1.21–2.11 (m, 8 H, 4
CH ), 2.88–3.46 (m, 2 H, CH ), 4.78 (q, 1 H, J = 8.1, CH)
3
4
9
c = 1.02)
2
2
a
Satisfactory microanalyses obtained: C 0.13, H 0.09, N 0.15.
Synthesis 2004, No. 2, 217–220 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active , -Unsaturated Triazolyl Alcohols
219
Table 3 Experimental Data of the Asymmetric NaBH Reduction of 2 in the Presence of Chiral Auxiliary 4
4
Entry
Substrate
2a
Auxiliary
4a
Solvent
Temp (°C)
25
Yield of 1 (%)a ee (%)b
Config.c
1
2
3
4
5
6
7
8
9
ClCH CH Cl
92
96
69
87
99
92
86
90
94
87
83
90
99
99
98
96
97
99
99
90
99
92
94
90
99
96
96
34
21
91
89
90
93
88
84
64
64
44
28
88
86
60
79
93
90
80
86
84
84
90
59
85
74
67
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2
2
2a
4a
toluene
25
2a
4b
4b
4b
4b
4c
ClCH CH Cl
0
2
2
2a
ClCH CH Cl
25
2
2
2a
ClCH CH Cl
50
2
2
2a
toluene
25
2a
ClCH CH Cl
0
2
2
2a
4c
ClCH CH Cl
25
2
2
2a
4c
ClCH CH Cl
50
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
0
2a
4c
toluene
25
1
2a
4c
THF
25
2
2a
4d
4a
ClCH CH Cl
25
2
2
3
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
ClCH CH Cl
25
2
2
4
4a
toluene
25
5
4a
THF
25
6
4b
4b
4b
4b
4b
4b
4c
ClCH CH Cl
0
2
2
7
ClCH CH Cl
25
2
2
8
ClCH CH Cl
50
2
2
9
ClCH CH Cl
reflux
25
2
2
0
toluene
1
THF
25
2
ClCH CH Cl
25
2
2
3
4c
toluene
25
4
4c
THF
25
5
4d
4d
4d
ClCH CH Cl
25
2
2
6
toluene
25
7
THF
25
a
b
c
Isolated yield.
Determined by HPLC on a chiralcel OD column (95:5 hexane–propan-2-ol, 0.9 mL/min).
Determined by comparison with the literature values.2c,d
0
.40 mol) in THF] was added dropwise a solution of methyl N-tert-
(–)-(S)-2-[Bis(4-methylphenyl)hydroxymethyl]pyrrolidine Hy-
drochloride (4b); Typical Procedure
Compound 3b (19.1 g, 0.05 mol) was dissolved in EtOAc (100 mL)
and anhyd gaseous HCl was bubbled into the reaction mixture with
vigorous stirring until the reactant 3b had disappeared (monitored
by TLC). After removal of the solvent under reduced pressure, the
butoxycarbonyl-L-prolinate (22.90 g, 0.10 mol) in THF (50 mL) at
°C. The resulting mixture was stirred overnight at r.t. Then the re-
0
action was quenched by addition of 1 N aq HCl (100 mL) and stirred
for a further 30 min. The mixture was extracted with CH Cl (4 × 80
2
2
mL) and the combined extracts were washed with brine and dried
Na SO ). After removal of solvent, the yellow residue was recrys-
(
pale yellow residue was washed with anhyd Et O to afford 14.0 g of
2
4
2
tallized from petroleum ether–EtOAc to provide 20.9 g of 3b as a
4b as a white solid (Table 2).
white solid (Table 1).
Synthesis 2004, No. 2, 217–220 © Thieme Stuttgart · New York

2
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Z. Zhenghong et al.
PAPER
Optically Active 1; General Procedure
To a suspension of chiral auxiliary 4 (0.75 mmol) in 1,2-dichloroet-
hane (6 mL) was added a solution of NaBH (0.029 g, 0.75 mmol)
References
(
1) Funaki, Y.; Oshita, H.; Yamamoto, S.; Tanaka, S.; Kato, T.
4
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2
103386.
lowed to come to r.t. in 2 h. Then, to the suspension was added a so-
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and the stirring was continued for 1 h. The organic layer was sepa-
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2
1
The combined organic phases were washed with H O and dried
2
(
Na SO ). After removal of solvent, the crude product was purified
2 4
1
by column chromatography on silica gel (200–300 mesh, 4:1 petro-
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Acknowledgment
We thank the National Natural Science Foundation of China (No.
2
0002002 and 20272025) and the Ph.D. Programs Foundation of
(
(
Ministry of Education of China for generous financial support of
our program.
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(
(
(
1
2
7) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem.
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Synthesis 2004, No. 2, 217–220 © Thieme Stuttgart · New York