Catalytic asymmetric synthesis of β-triazolyl amino alcohols by asymmetric transfer hydrogenation of α-triazolyl amino alkanones

Article abstract of DOI:10.1016/j.tetasy.2017.05.012

The synthesis of optically active β-triazolyl amino alcohols was carried out via ruthenium catalyzed asymmetric transfer hydrogenation of α-triazolyl amino alkanones. This reaction proceeds under mild reaction conditions with up to 99% yield and 99.9% ena

Full text of DOI:10.1016/j.tetasy.2017.05.012

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric synthesis of b-triazolyl amino alcohols by
asymmetric transfer hydrogenation of a-triazolyl amino alkanones
⇑
Vijyesh K. Vyas, Bhalchandra M. Bhanage
Department of Chemistry, Institute of Chemical Technology, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of optically active b-triazolyl amino alcohols was carried out via ruthenium catalyzed
asymmetric transfer hydrogenation of -triazolyl amino alkanones. This reaction proceeds under mild
reaction conditions with up to 99% yield and 99.9% enantiomeric excess (ee). This protocol was applied
to the synthesis of an enantiopure antitubercular agent and its arylated product with retention in enan-
tiomeric purity. The absolute configuration at the stereogenic center of the chiral product as found to be
(S).
Received 14 May 2017
Accepted 23 May 2017
Available online xxxx
a
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
reduction of azido alkanones followed by copper(I)-catalyzed
azide-alkyne [3+2] click cycloaddition to produce optically active
In medicinal chemistry, 1,2,3 and 1,2,4-triazole nuclei have
immense importance as far as their application is concerned in
drug discovery.1 Due to its pharmacologically important structural
unit, the triazole nucleus can be found in many biologically active
compounds and have shown anti-HIV,2a anti-cancer,2b anti-viral2c
and anti-bacterial2d activities. The b-triazolyl alcohols core
structure has been found to be an important structural motif and
a potent pharmacophore in medicinal chemistry and is widely
known for its antifungal and antimalarial properties (Fig. 1).3
Moreover, in recent years this core structure has exhibited antitu-
bercular activity (Fig. 1). Kim et al. synthesized various non-chiral
b-triazolyl amino alcohols derivatives4 and compared their antitu-
bercular activities with the known antitubercular agent econa-
zole.5 It is evident from this work that by altering the substituent
on the triazole nucleus, the pharmacological activity of the antitu-
bercular drug can be tuned. In their work, they synthesized a range
of b-triazolyl amino alcohols, including the corresponding ether
functionalized triazoles, and their activities were evaluated against
mycobacterium tuberculosis. This study revealed some structural
units to be as good as or even better than econazole. By considering
the potential of non-chiral b-triazolyl amino alcohols as a potent
pharmacophore, the synthesis and evaluation of its enantiopure
version is required in order to facilitate its biological screening.
Efforts have been made to construct optically active b-triazolyl
amino alcohols by Hua et al. via the lipase catalyzed asymmetric
triazolyl alcohols (Scheme 1Aa).6 In this work the authors concen-
trated on the asymmetric reduction of
a-azidoalkanones; one of
the derivatives of the product was subjected to click cycloaddition
to produce b-triazolyl amino alcohols. However, there is no
account with regards to the retention of the enantiomeric purity
in the cycloaddition product. Feringa et al. reported a one pot enzy-
matic cycloaddition to produce b-triazolyl amino alcohols with
excellent enantioselectivity, however, the conversion of the start-
ing material into the desired product was poor (Scheme 1Ab).7
Recently, we reported the diastereo- and enantioselective asym-
metric transfer hydrogenation of
a-heteroaryl amino cycloalka-
nones catalyzed by tethered ruthenium complexes driven by
dynamic kinetic resolution (Scheme 1B).8 In continuation of our
interests in asymmetric transfer hydrogenation, we herein have
focused our attention on the enantioselective synthesis of b-tria-
zolyl amino alcohols through asymmetric transfer hydrogenation.
2. Results and discussions
We started our optimization studies with 1-phenyl-2-(4-phe-
nyl-1H-1,2,3-triazol-1-yl)ethan-1-one 1a as a model substrate.
The tethered Ru-TsDPEN complex9 was applied under the opti-
mized reaction conditions to the reduction of
a-heteroaryl amino
cycloalkanones8 and then used for the asymmetric transfer hydro-
genation of 1a. The results were not as promising as reported in the
earlier work, as the reaction proceeded with only 96% ee (Table 1,
entry 1). This led us to use N-sulfonylated-1,2-diamines ligands10
with various ruthenium complexes in the presence of formic
acid/triethylamine as a hydrogen source. Moderate conversion
⇑
Corresponding author.
E-mail addresses: bm.bhanage@ictmumbai.edu.in, bm.bhanage@gmail.com
(B.M. Bhanage).
http://dx.doi.org/10.1016/j.tetasy.2017.05.012
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Vyas, V. K.; Bhanage, B. M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.012

2
V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
antifungal
the temperature with 0.5 mol % of catalyst resulted in lower con-
OH
OH
version and enantiopurity (Table 1, entries 17 and 18). A detailed
time study revealed that 12 h was the optimum reaction time
and gave the best conversion and enantioselectivities (Table 1,
entries 19–22).
N
N
N
N
N
N
N
N
N
F
F
N
N
With the optimized reaction conditions in hand, a range of
F
F
a-triazolyl alkanones were hydrogenated with (R,R)-E Ru-FsDPEN
antimalarial
complex (Table 2). The substrate class was divided in two sets
depending on the substitution patterns. The first set includes sub-
stituent variation on the parent benzene ring. Next, we studied the
effect of electron donating and withdrawing groups on the enan-
tiopurity of the products obtained. Substrates 1a, 1b and 1c with
an electron donating group on the parent nucleus were able to fur-
nish the corresponding products 2a, 2b and 2c with almost similar
levels of enantiopurity, but a minor decrease in conversion in the
case of 2c. Excellent conversions with only a slight decrease in
enantioselectivities were observed in the case of 1d, 1e and 1h
with weak electron withdrawing substituents on the parent
nucleus at the para- and meta-positions. However, a considerable
decrease in enantioselectivity was observed with strongly electron
withdrawing substituents, such as nitro group, at the para- and
meta-positions. Biaryl substrates 1i and 1j were converted into
the corresponding products 2i and 2j with 95.7% and 95.1% ee
respectively. Heteroaryl substrates 1k and 1l furnished the prod-
ucts 2k and 2l with best results in set I, producing 99.9% and
98.6% ee respectively. From the literature, it is evident that by
altering the substituent on triazole nucleus, the pharmacological
activity of the drug molecule can be tuned. Set II includes sub-
strates with various substituents on the triazole nucleus. Sub-
strates 1m and 1n with a substituted phenyl group on the
triazole nucleus gave products 2m and 2n with 97.8% and 97.2%
ee respectively. When the phenyl substituent was replaced by
non-aromatic cyclic substrate, 1o and 1q, and with aliphatic side
chain, substrate 1p, the corresponding products 2o, 2p and 2q
were obtained with excellent yield and enantioselectivity. The next
N
OH
O
N
F
OR
S
O
F
antitubercular
N
N
Cl OH
N
Cl
O
N
N
N
HO
Cl
Cl
Figure 1. Examples of b-1,2,3 and 1,2,4-triazoaryl amino alkanols and b-triazoaryl
amino ether as an active pharmacophore.
was obtained by (R,R)-B with similar enantiomeric excess as (R,R)-
A (Table 1, entry 2). Much better conversion was observed with (R,
R)-C and (R,R)-D with excellent ee in the case of (R,R)-D (Table 1,
entries 3 and 4). Superior results were observed with catalyst (R,
R)-E in terms of conversion (99%) and ee (99%) (Table 1, entry 5).
Hence (R,R)-E complex was used for further optimization studies.
Overall solvent studies revealed that nonpolar and polar aprotic
solvents were able to furnish good to excellent conversion and
enantioselectivities (Table 1, entries 6–11), whereas polar protic
solvents gave only poor to moderate conversion and enantioselec-
tivities (Table 1, entries 12–14). A significant loss in conversion
was observed when the catalyst loading was reduced to 0.5 mol
%, whereas 2 mol % of catalyst loading did not produce better
results compared to 1 mol % (Table 1, entries 15 and 16). Increasing
Previous work
A) Enzymatic reduction of α-azido ketone followed by click cycloaddition
(a) Hua et al.
O
N
OH
OH
N
N
R
N3
N3
lipase
click
cycloaddition
carbonyl
reductase
% ee not accounted
up to 99% ee
(b) Feringa et al.
O
N
OH
N
N
R
R
halohydrin dehalogenase, NaN3, buffer
CuSO4, Na Asc, MonoPhos,
R
<50% conversion
N
O
OH
N
N
X
CT cells suspension, NaN3, buffer,
CuSO4, Na Asc, MonoPhos,
R
<50% conversion
B) Ruthenium catalyzed DKR-asymmetric transfer hydrogenation of rac-α-heteroaryl amino cycloalkanones
OH
O
N
[(R,R)-Teth-TsDpen RuCl]
N
N
N
N
N
formic acid/triethylamine,
DCM, 27 oC, 6 h
n
R
n
R
up to 99.9% ee
cis/trans up to 99/1
n= 1,2,3
This work
X
X
N
O
N
N
OH
Y
R
Y
N
RuCl[(R,R)-FsDPEN]-(p-cymene)
R
R
R
formic acid/triethylamine,
DCM, 27 oC, 12h
up to 99% yield
X= N, CH
Y= N, CH
up to 99.9% ee
Scheme 1. Enzymatic hydrogenation and asymmetric transfer hydrogenation of a-triazoaryl amino ketones.
Please cite this article in press as: Vyas, V. K.; Bhanage, B. M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.012

V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 1
Optimization of the reaction conditionsa
N
N
OH
N
N
O
N
catalyst,
Ph
Ph
N
formic acid/triethylamine
solvent, time, temp.
2b
1a
Ru
N
Ru
N
Ru
N
Ru
Cl
Cl
Ru
N
Cl
TsN
Ph
FsN
Ph
TsN
Ph
TsN
Ph
Cl
TsN
Ph
Cl
N
H
H
H
H
Ph
Ph
H
Ph
H
H
H
H
Ph
Ph
(R,R)-A
(R,R)-B
(R,R)-D
(R,R)-C
(R,R)-E
Entry
Catalyst
Solvent
Catalyst (mol %)
Temp. (°C)
Time (h)
Conv. (%)b
ee (%)b
1
2
3
4
5
6
7
8
(R,R)-A
(R,R)-B
(R,R)-C
(R,R)-D
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
(R,R)-E
DCM
DCM
DCM
DCM
DCM
DCE
Toluene
CH3CN
1,4-Dioxane
THF
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.5
2
0.5
0.5
1
1
1
1
27
27
27
27
27
27
27
27
27
27
27
27
27
27
27
27
40
60
27
27
27
27
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
18
24
24
02
06
12
24
>99
54
82
84
99
99
75
99
80
90
99
30
35
50
60
>99
85
85
30
75
99
99
96
96
95
99
99
94
88
92
91
90
82
79
74
81
99
99
92
87
97
99
99.2
99
9
10
11
12
13
14
15
16
17
18
19
20
21
22
DMF
CH3OH
C2H5OH
(CH3)2CHOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
a
Conditions: 0.5 mmol of 1a, 1 mol % of (R,R)-A–E and 0.5 mL HCOOH/Et3N (5:2) were added into solvent (3.0 mL) and the mixture was stirred at given temperature for
given time.
b
The conversions and ee’s were for the chiral product determined by chiral HPLC.
class of substrates, 1r, 1s, 1t and 1u replaced the 1,2,3-triazole
nucleus with a 1,2,4-triazole nucleus. All four substrates were con-
verted into the corresponding products 2r, 2s, 2t and 2u with com-
parable enantioselectivities in all the cases.
We demonstrated the applicability of this method to the syn-
thesis of enantiopure hydroxyl triazole 4 based drug molecule,
which is two-fold better in terms of activity when compared to
the known drug molecule econazole by asymmetric transfer
hydrogenation of structure 3 with 97.3% enantioselectivity. This
hydroxy triazole 4 was further arylated by 4-chlorobenzyl bromide
to give the ether derivative 5 of compound 4 with excellent enan-
tiopurity (97.5%) and 62% yield (Scheme 2).
In order to determine the absolute configuration at the stere-
ogenic center, compound 2s was recrystallized from n-hexane/
IPA to give needle shaped crystals. These crystals were subjected
to single crystal XRD analysis and the absolute configuration at
the stereogenic centre was found to be (S) (See ESI) (Fig. 2). The
absolute configurations of the other compounds were assigned
by comparing their specific rotations with that of 2s.
and isolated yields. This method provides access to the synthesis
of optically active b-triazolyl amino alcohols and their correspond-
ing aryl ether compounds with retention in the enantiomeric pur-
ity in the latter case. The absolute configurations of the compounds
were found to be (S).
4. Experimental
4.1. General
All reactions were carried out in oven-dried glassware. All
derivatives of acetophenone and ruthenium complexes were pur-
chased from commercial sources. Analytical TLC was performed
with silica gel plates (0.25 mm thickness). Column chromatogra-
phy was performed with silica gel (40–200 mesh). NMR spectra
were recorded with an (1H NMR at 400 MHz, 13C NMR at
125 MHz) spectrometer. Chemical shifts are reported in ppm rela-
tive to tetramethylsilane as the internal standard and the coupling
constants J in Hz. The reaction was monitored by GC and the prod-
ucts were analyzed by GC–MS and IR. HRMS were recorded on a
micro-mass ESI TOF (time of flight) mass spectrometer.
3. Conclusion
In conclusion, we have devised a route to synthesize optically
active b-triazolyl amino alcohols by the ruthenium catalyzed
asymmetric transfer hydrogenation of b-triazolyl amino alcohols.
The optically active compounds with varying substitution pattern
on triazole nucleus were obtained with high enantiomeric excess
4.2. General procedure for the synthesis of a-bromo alkanones
A solution of substituted alkanone (10 mmol) in CH2Cl2 (4 mL)
was added dropwise to a solution of n-bromosuccinimide (2.14 g,
12 mmol, 1.2 equiv) and p-TsOH (0.2 g, 1 mmol, 0.1 equiv) in
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4
V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 2
Substrate studya
X
X
N
O
N
OH
Y
R
Y
N
N
RuCl[(R,R)-FsDPEN]-(p-cymene)
R
R
R
formic acid/triethylamine,
DCM, 27 oC, 12h
1a-1u
(S)-2a-2u
Set I
N
N
N
N
N
OH
OH
N
OH
N
N
MeO
N
2a
2b
2c
98% yield, 99.1% ee (S)
82% yield, 94.3% ee (S)
94% yield, 99.2% ee (S)
N
N
N
OH
N
OH
N
OH
N
N
N
N
2d
2f
2e
96% yield, 96.3% ee (S)
96% yield, 95.3% ee (S)
91% yield, 80.0% ee (S)
F
Cl
Cl
O2N
N
N
N
OH
N
OH
N
OH
N
N
N
N
O2N
2g
2i
2h
94% yield, 96.7% ee (S)
99% yield, 95.7% ee (S)
90% yield, 88.0% ee (S)
N
N
N
OH
N
OH
N
N
OH
N
N
N
2l
2j
2k
O
S
92% yield, 99.9% ee (S)
95% yield, 98.6% ee (S)
97% yield, 95.1% ee (S)
Set II
N
N
OH
N
N
N
OH
N
N
OH
N
N
OMe
2o
2n
2m
99% yield, 97.5% ee (S)
85% yield, 97.2% ee (S)
96% yield, 97.8% ee (S)
N
N
N
OH
N
N
OH
OH
N
N
N
N
5
2p
2q
2r
97% yield, 98.0% ee (S)
99% yield, 98.6% ee (S)
95% yield, 95.2% ee (S)
N
N
OH
OH
OH
N
N
N
N
N
N
N
2s
2u
93% yield, 96.0% ee (S)
2t
S
98% yield, 96.4% ee (S)
94% yield, 96.8% ee (S)
Cl
a
Conditions: 0.5 mmol of 1a, 1 mol % of (R,R)-E and 0.5 mL HCOOH/Et3N (5:2) were added into CH2Cl2 (3.0 mL) and the
mixture was stirred at 27 °C for 12 h. The yields were for the product isolated by preparative chromatography. The ee
values were determined by chiral HPLC. The absolute configurations of all compounds were assigned by comparing the
specific rotation values with the specific rotation of 2s.
Cl
N
Cl
O
N
N
N
N
N
Cl
OH
Cl
O
N
N
N
(a)
(b)
Cl
4
3
5
Cl
Cl
98% yield
97.3 ee
62% yield
97.5% ee
(a) RuCl[(R,R)-FsDPEN]-(p-cymene), formic acid/triethylamine, DCM, 27 oC, 12 h
(b)
NaH, DMF, 0 oC, 4-chloro benzyl bromide
Scheme 2. O-arylation of optically active b-triazoaryl amino alkanols.
CH2Cl2 (10 mL) at 0 °C. The reaction mixture was then heated at
reflux for 4 h. After the addition of H2O (10 mL), the organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(2 Â 15 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure. Col-
umn chromatography on silica gel provided substituted-
a-bro-
moalkanone (80–94% yield).12
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V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
120.7, 113.2, 56.6, 55.9. HRMS Calculated for C17H16N3O2 [M+H]+
294.1237, found 294.1243.
C6
C5
Cl1
4.3.2.4. 1-(4-Fluorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
N2
ethan-1-one 1d11
.
White solid, mp = 160–162 °C, 255 mg,
C1
C4
C10
91% yield. MS (EI, 70 eV) m/z (%): 281 (M+17.20), 224 (39.00),
C8
(cmÀ1): 2982,
N1
~
137 (69.60), 103 (72.10), 77 (100). IR (ATR)
m
C2
1770, 1531, 1234. 1H NMR (400 MHz, CDCl3) d 8.09– 8.02 (m,
2H), 7.94–7.89 (m, 1H), 7.88–7.80 (m, 2H), 7.45–7.38 (m, 2H),
7.36–7.30 (m, 1H), 7.25– 7.16 (m, 2H), 5.85 (s, 2H). 13C NMR
(101 MHz, CDCl3) d 188.7, 166.5 (d, J = 257.7 Hz), 148.2, 131.0,
130.9, 130.3, 128.8, 128.2, 125.8, 121.3, 116.5 (d, J = 22.2 Hz),
55.3.
C7
O1
S
C3
N3
C9
Figure 2. Single crystal XRD of 2s (CCDC 1548034).
4.3.2.5. 1-(4-Chlorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
4.3. Experimental procedure for the synthesis of
amino alkanone
a
-triazoaryl
ethan-1-one 1e4d
.
White solid, mp = 133–135 °C, 267 mg,
90% yield. MS (EI, 70 eV) m/z (%):297 (M+ 15.99), 261 (14.23),
(cmÀ1): 2933,
~
m
186 (41.44), 153 (56.11), 111 (100). IR (ATR)
4.3.1. Typical procedure for
synthesis via click reactions (1a–1q)
To a slurry of substituted -bromo alkanones (1.0 mmol), sub-
a-triazoaryl amino alkanone
1770, 1528, 1239. 1H NMR (400 MHz, CDCl3) d 7.98–7.79 (m, 5H),
7.54 – 7.37 (m, 4H), 7.37 – 7.28 (m, 1H), 5.83 (s, 2H). 13C NMR
(101 MHz, CDCl3) d 189.2, 141.3, 132.2, 130.3, 129.6, 129.5,
128.8, 128.8, 128.2, 125.8, 121.3, 55.3.
a
stituted alkynes (1.0 mmol), sodium azide (1.5 mmol) in water/
PEG-400 (1:1, 10 mL) was added cuprous iodide (0.05 mmol) and
stirred for 2 h at 25–30 °C. The water was then extracted into ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate
and the volatiles evaporated. The crude compound was purified by
column chromatography (EtOAc/hexanes: 25/:75) (88–99%
yield).4d
4.3.2.6. 1-(Naphthalen-1-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
ethan-1-one 1j.
Pale brown solid, mp = 190–192 °C, 300 mg,
96% yield. MS (EI, 70 eV) m/z (%):313 (M+ 8.96), 236 (20.11), 155
(cmÀ1): 2995, 1759,
~
m
(100), 144 (66.78), 105 (48.22). IR (ATR)
1526, 1246. 1H NMR (400 MHz, DMSO) d 8.66–8.57 (m, 2H), 8.44
–8.37 (m, 1H), 8.27–8.20 (m, 1H), 8.07–8.00 (m, 1H), 7.92–7.86
(m, 2H), 7.72– 7.60 (m, 3H), 7.50– 7.41 (m, 2H), 7.38– 7.30 (m,
1H), 6.29 (s, 2H). 13C NMR (101 MHz, DMSO) d 195.5, 146.8,
134.5, 134.0, 131.8, 131.2, 130.0, 130.0, 129.4, 129.1, 128.8,
128.3, 127.2, 125.6, 125.3, 123.6, 57.9, 55.3. HRMS Calculated for
4.3.2. Procedure for the synthesis of triazoaryl amino
cycloalkanols 1r–1u, 3
To a mixture of potassium carbonate (1.5 mmol), 1,2,3- and
1,2,4-triazole (1 mmol) and 5 mL of acetonitrile at 40 °C was added
a solution of
a-bromo alkanones (1.0 mmol) in 5 ml of acetonitrile.
C
20H16N3O [M+H]+ 314.1288, found 314.1291.
The mixture was allowed to react for 5 h at 40 °C and then at reflux
temperature (80 °C) for 16 h. The solid was removed by filtration
and the filtrate was concentrated to dryness leaving a residue. This
was dissolved in dichloromethane and washed twice with water.
The organic extract was dried over sodium sulfate and purified
by column chromatography (60–75% yield).13
4.3.2.7. 2-(4-Cyclohexyl-1H-1,2,3-triazol-1-yl)-1-phenylethan-1-
one 1o.
White solid, mp = 90–92 °C, 244 mg, 91% yield. MS
(EI, 70 eV) m/z (%):269 (M+ 3.68), 213 (17.55), 136 (100), 105
~
(61.35). IR (ATR)
m
(cmÀ1): 2933, 1770, 1448, 1246. 1H NMR
(400 MHz, DMSO) d 8.09–8.00 (m, 2H), 7.81–7.65 (m, 2H), 7.62–
7.53 (m, 2H), 6.09 (s, 2H), 3.40–3.30 (m, 1H), 2.74–2.63 (m, 1H),
2.01– 1.87 (m, 2H), 1.77 – 1.59 (m, 3H), 1.45 – 1.27 (m, 4H). 13C
NMR (101 MHz, DMSO) d 192.7, 134.6, 134.6, 129.4, 128.6, 128.6,
122.6, 56.1, 55.3, 35.1, 33.0, 26.1. HRMS Calculated for C16H20N3O
[M+H]+ 270.1601, found 270.1605.
4.3.2.1. 1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-one
1a4d
.
White solid, mp = 140–142 °C, 247 mg, 94% yield. MS
(EI, 70 eV) m/z (%): 263 (M+ 16.59), 206 (40.75), 130 (94.43), 103
~
(98.65), 77 (100) IR (ATR)
m
(cmÀ1): 2995, 1770, 1520, 1246. 1H
NMR (400 MHz, CDCl3) d 8.05–7.77 (m, 5H), 7.64–7.30 (m, 6H),
5.86 (s, 2H). 13C NMR (101 MHz, CDCl3) d 190.3, 134.6, 133.9,
130.5, 129.1, 128.8, 128.2, 128.1, 125.9, 125.8, 121.5, 55.4.
4.3.2.8. 2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-1-phenylethan-
1-one 1q.
White solid, mp = 88–90 °C, 199 mg, 88% yield.
MS (EI, 70 eV) m/z (%):227 (M+ 5.59), 170 (4.57), 120 (13.47), 105
(cmÀ1): 3268, 2995, 1759, 1246. 1H
~
4.3.2.2.
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(p-tolyl)ethan-1-
White solid, mp = 157–159 °C, 263 mg, 95% yield.
(100), 94 (39.01). IR (ATR)
m
one 1b4d
.
NMR (400 MHz, DMSO) d 8.07–7.99 (m, 2H), 7.79–7.74 (m, 1H),
7.74–7.66 (m, 1H), 7.61–7.53 (m, 2H), 6.07 (s, 2H), 2.02–1.90 (m,
1H), 0.94–0.84 (m, 2H), 0.76–0.65 (m, 2H). 13C NMR (101 MHz,
DMSO) d 192.7, 134.6, 134.5, 129.4, 129.3, 128.6, 122.9, 56.1, 8.1,
6.9. HRMS Calculated for C13H14N3O [M+H]+ 228.1131, found
228.1136.
MS (EI, 70 eV) m/z (%): 277 (M+ 22.54), 227 (48.87), 119 (100), 77
(67.05). IR (ATR)
m
(cmÀ1): 2995, 1768, 1532, 1250. 1H NMR
~
(400 MHz, CDCl3) d 7.95–7.82 (m, 5H), 7.45–7.39 (m, 2H), 7.35–
7.29 (m, 3H), 5.84 (s, 2H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 189.8, 148.1, 145.8, 131.4, 130.5, 129.8, 128.8, 128.26, 128.1,
125.8, 121.2, 55.3, 21.8.
4.3.2.9. 1-(2,4-Dichlorophenyl)-2-(1H-1,2,3-triazol-1-yl)ethan-
4.3.2.3. 1-(3-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
1-one 3.
White solid, mp = 101–103 °C, 166 mg, 65% yield.
ethan-1-one 1c.
Yellow solid, mp = 125–127 °C, 291 mg, 99%
MS (EI, 70 eV) m/z (%): 256 (M+ 23.43), 186 (69.00), 172 (37.09),
yield. MS (EI, 70 eV) m/z (%):293 (M+ 33.47), 263 (18.67), 130
144 (31.90), 110 (100). IR (ATR)
m
(cmÀ1): 2995, 1759, 1240, 861.
~
~
(89.21), 77 (100). IR (ATR)
m
(cmÀ1): 3095, 1770, 1246, 1026. 1H
1H NMR (400 MHz, CDCl3) d 8.21 (s, 1H), 7.95 (s, 1H), 7.62
(d, J = 8.4 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.39–7.33 (m, 1H), 5.60
(s, 2H). 13C NMR (101 MHz, CDCl3) d 192.0, 152.1, 144.8, 139.5,
133.5, 132.7, 131.6, 130.8, 127.9, 57.8. HRMS Calculated for
NMR (400 MHz, DMSO) d 8.52–8.47 (m, 1H), 7.87–7.81 (m, 2H),
7.69–7.63 (m, 1H), 7.56–7.41 (m, 4H), 7.35–7.26 (m, 2H), 6.23 (s,
2H), 3.82 (s, 3H). 13C NMR (101 MHz, DMSO) d 192.9, 159.9,
146.7, 135.8, 131.2, 130.6, 129.4, 128.3, 125.6, 123.5, 121.0,
C
10H8Cl2N3O [M+H]+ 256.0039, found 256.0042.
Please cite this article in press as: Vyas, V. K.; Bhanage, B. M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.012

6
V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.3.3. General procedure for the asymmetric transfer
4.3.3.5. (S)-1-(4-Chlorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-
hydrogenation of rac-
a
-heteroaryl amino cycloalkanones 2a–
yl)ethan-1-ol 2e4d
.
White solid, mp = 148–150 °C, 143 mg,
D
2u
96% yield, 95.3% ee, [
a]
25 = +96.3 (c 0.1, CHCl3). MS (EI, 70 eV)
The
a
-triazoaryl amino alkanone (0.5 mmol), catalyst (2 mg,
m/z (%): 299 (M+, 3.12), 227 (12.21), 159 (25.25), 141 (100), 95
3.2 Â 10À3 mmol), DCM (5 mL) and formic acid/triethylamine
(0.5 ml) azeotrope were added sequentially to the reaction tube
and stirred at 27 °C. The reaction was monitored by TLC. After com-
pletion of the reaction, it was quenched by water (20 mL) and
extracted with ethyl acetate (2 Â 20 mL). The organic layer was
dried over Na2SO4 and concentrated to give a residue. The residue
was purified by a silica gel column eluted with pet ether and ethyl
acetate to give the pure desired product (yield 82–99%).9
(20.27). IR (ATR)
(cmÀ1): 3270 (broad), 2922, 1078, 761. 1H
~
m
NMR (400 MHz, DMSO) d 8.47 (s, 1H), 7.85–7.77 (m, 2H), 7.44–
7.26 (m, 7H), 5.94 (d, J = 4.8 Hz, 1H), 5.04 (dt, J = 8.7, 4.5 Hz, 1H),
4.59 – 4.42 (m, 2H). 13C NMR (101 MHz, DMSO) d 146.4, 141.4,
132.5, 131.3, 129.3, 128.6, 128.4, 128.2, 125.5, 122.5, 71.1, 56.9.
HPLC (OJ-H elute: Hexanes/i-PrOH = 80:20, detector: 210 nm, flow
rate: 0.7 mL/min), tmajor = 30.0 min, tminor = 33.2 min.
4.3.3.6. (S)-1-(4-Nitrophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
4.3.3.1. (S)-1-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-
ethan-1-ol 2f7b
.
White solid, mp = 192–194 °C, 140 mg, 91%
ol 2a7b
99.2% ee, [
.
White solid, mp = 150–152 °C, 124 mg, 94% yield,
D
yield, 80.0% ee, [
a
]
D
25 = +24.3 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):
a]
25 = +86.3 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):265
310 (M+, 2.06), 264 (18.97), 158 (31.55), 152 (100), 77 (87.08). IR
(M+, 11.47), 207 (29.05), 119 (47.61), 105 (83.57), 77 (100). IR
(ATR)
(cmÀ1): 3153 (br), 2917, 1517, 1354, 1084. 1H NMR
~
m
(ATR)
(cmÀ1): 3251 (br), 2930, 1462, 1057. 1H NMR (400 MHz,
(400 MHz, DMSO) d 8.48 (s, 1H), 8.21–8.15 (m, 2H), 7.84–7.76
(m, 2H), 7.67–7.61 (m, 2H), 7.44–7.37 (m, 2H), 7.33–7.25 (m,
1H), 6.17 (d, J = 4.8 Hz, 1H), 5.20 (dt, J = 8.5, 4.5 Hz, 1H), 4.66 –
4.49 (m, 2H). 13C NMR (101 MHz, DMSO) d 150.0, 147.4, 146.4,
131.2, 129.3, 128.2, 127.8, 125.5, 123.8, 122.6, 71.0, 56.6. HPLC
(OD-H elute: Hexanes/i-PrOH = 85:15, detector: 210 nm, flow rate:
0.7 mL/min), tminor = 58.6 min, tmajor = 76.0 min.
~
m
DMSO) d 8.48 (s, 1H), 7.86–7.75 (m, 2H), 7.45–7.22 (m, 8H), 5.85
(d, J = 4.7 Hz, 1H), 5.01 (dt, J = 8.6, 4.4 Hz, 1H), 4.58–4.42 (m, 2H).
13C NMR (101 MHz, DMSO) d 146.3, 142.5, 131.3, 129.3, 128.7,
128.1, 128.0, 126.5, 125.5, 122.5, 71.8, 57.2. HPLC (OJ-H elute: Hex-
anes/i-PrOH = 80:20, detector: 210 nm, flow rate: 0.7 mL/min),
tmajor = 33.9 min, tminor = 37.2 min.
4.3.3.2. (S)-2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(p-tolyl)ethan-
4.3.3.7. (S)-1-(3-Nitrophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
1-ol 2b4d
99.1% ee, [
.
White solid, mp = 160–162 °C, 136 mg, 98% yield,
ethan-1-ol 2g.
White solid, mp = 142–144 °C, 139 mg, 90%
a]
D
25 = +54.1 (c 0.1. CHCl3). MS (EI, 70 eV) m/z (%):279
yield, 88.0% ee, [
a]
25 = +40.5 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):
D
(M+, 12.16), 207 (31.20), 130 (43.59), 103 (86.14), 77 (100). IR
310 (M+, 1.59), 264 (11.66), 158 (30.11), 152 (39.40), 77 (100). IR
(ATR)
(cmÀ1): 3305 (br), 2920, 1440, 1080. 1H NMR (400 MHz,
(ATR)
(cmÀ1): 3148 (br), 2923, 1524, 1349, 1085. 1H NMR
~
m
~
m
CDCl3) d 7.82–7.69 (m, 3H), 7.41–7.14 (m, 7H), 5.17 (d, J = 8.7 Hz,
1H), 4.61 (dd, J = 14.0, 3.2 Hz, 1H), 4.42 (dd, J = 14.0, 8.8 Hz, 1H),
3.37 (s, 1H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) d 147.4,
138.3, 137.1, 130.4, 129.5, 128.8, 128.1, 125.8, 125.6, 121.1, 72.8,
57.4, 21.1. HPLC (OJ-H elute: Hexanes/i-PrOH = 80:20, detector:
210 nm, flow rate: 0.7 mL/min), tmajor = 26.3 min, tminor = 31.6 min.
(400 MHz, DMSO) d 8.48 (s, 1H), 8.24 (d, J = 3.9 Hz, 1H), 8.16 –
8.08 (m, 1H), 7.83–7.76 (m, 3H), 7.67–7.57 (m, 1H), 7.45–7.36
(m, 2H), 7.32 – 7.26 (m, 1H), 6.18 (d, J = 4.9 Hz, 1H), 5.22 (dt,
J = 8.6, 4.5 Hz, 1H), 4.69–4.51 (m, 2H). 13C NMR (101 MHz, DMSO)
d 148.2, 146.4, 144.7, 133.3, 131.2, 130.2, 129.3, 128.2, 125.5,
122.9, 122.6, 121.2, 70.8, 56.7. HPLC (OD-H elute: Hexanes/
i-PrOH = 80:20, detector: 210 nm, flow rate: 0.7 mL/min),
4.3.3.3. (S)-1-(3-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-
tmajor = 51.1 min,
C
tminor = 73.2 min.
HRMS
Calculated
for
1-yl)ethan-1-ol 2c.
White solid, mp = 140–142 °C, 121 mg,
16H15N4O3 [M+H]+ 311.1139, found 311.1145.
82% yield, 94.3% ee, [
a
]
D
25 = +63.7 (c 0.1, CHCl3). MS (EI, 70 eV) m/
z (%): 295 (M+, 8.30), 264 (13.12), 158 (40.01), 137 (100), 107
4.3.3.8. 1-(3-Chlorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
ethan-1-ol 2h.
~
m
(88.28). IR (ATR)
(cmÀ1): 3317 (br), 2955, 1370, 1078. 1H NMR
White solid, mp = 176–178 °C, 140 mg, 94%
(400 MHz, DMSO) d 8.47 (s, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.41 (t,
J = 7.5 Hz, 2H), 7.34–7.18 (m, 2H), 6.95 (d, J = 5.6 Hz, 2H), 6.81 (d,
J = 8.2 Hz, 1H), 5.85 (s, 1H), 4.99 (t, J = 5.9 Hz, 1H), 4.59–4.38 (m,
2H), 3.70 (s, 3H). 13C NMR (101 MHz, DMSO) d 159.6, 146.3,
144.1, 131.3, 129.7, 129.3, 128.1, 125.5, 122.5, 118.6, 113.6,
111.9, 71.8, 57.2, 55.4. HPLC (OJ-H elute: Hexanes/i-PrOH = 80:20,
detector: 210 nm, flow rate: 0.7 mL/min), tmajor = 9.5 min,
tminor = 10.9 min. HRMS Calculated for C17H18N3O2 [M+H]+
296.1394, found 296.1400.
yield, 96.7% ee, [
a]
D
25 = +96.3 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):
299 (M+, 5.06), 227 (17.25), 159 (52.77), 141 (82.59), 77 (100) IR
(cmÀ1): 3271 (br), 2922, 1079, 761. 1H NMR (400 MHz,
~
m
(ATR)
DMSO) d 8.48 (s, 1H), 7.86–7.79 (m, 2H), 7.46–7.30 (m, 7H), 6.01
(d, J = 4.8 Hz, 1H), 5.06 (dt, J = 8.6, 4.4 Hz, 1H), 4.64–4.45 (m, 2H).
13C NMR (101 MHz, DMSO) d 146.4, 145.0, 133.4, 131.3, 130.6,
129.3, 128.2, 127.9, 126.4, 125.5, 125.2, 122.6, 71.2, 56.9. HPLC
(OD-H elute: Hexanes/i-PrOH = 80:20, detector: 250 nm, flow rate:
0.7 mL/min), tmajor = 35.5 min, tminor = 45.8 min. HRMS Calculated
for C16H15ClN3O [M+H]+ 300.0898, found 300.0903.
4.3.3.4. (S)-1-(4-Fluorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-
yl)ethan-1-ol 2d.
White solid, mp = 180–182 °C, 127 mg,
D
4.3.3.9. (S)-1-(Naphthalen-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-
96% yield, 96.3% ee, [
a
]
25 = +31.8 (c 0.1, CHCl3). MS (EI, 70 eV) m/
yl)ethan-1-ol 2i.
White solid, mp = 170–172 °C, 157 mg, 99%
z (%): 283 (M+, 15.25), 226 (17.61), 159 (24.57), 117 (100), 103
yield, 95.7% ee, [
a
]
25 = +102.1 (c 0.1, CHCl3). MS (EI, 70 eV) m/z
D
(79.78). IR (ATR)
(cmÀ1): 3288 (broad), 2922, 1220, 1078, 763.
(%): 315 (M+, 10.66), 238 (50.03), 171 (36.44), 157 (100), 77
~
m
1H NMR (400 MHz, DMSO) d 8.46 (s, 1H), 7.85–7.74 (m, 2H), 7.42
– 7.07 (m, 7H), 5.89 (d, J = 4.7 Hz, 1H), 5.04 (dd, J = 8.1, 4.3 Hz,
1H), 4.59–4.40 (m, 2H). 13C NMR (101 MHz, DMSO-d6) d 159.77
(d, J = 201.8 Hz), 146.35, 138.64, 131.29, 129.31, 128.49 (d,
J = 8.4 Hz), 128.16, 125.50, 122.51, 115.40 (d, J = 21.4 Hz), 71.14,
57.09. HPLC (OJ-H elute: Hexanes/i-PrOH = 85:15, detector:
210 nm, flow rate: 0.7 mL/min), tmajor = 27.5 min, tminor = 29.9 min.
(92.47). IR (ATR)
(cmÀ1): 3389 (br), 2922, 1233, 1059. 1H NMR
~
m
(400 MHz, DMSO) d 8.53 (s, 1H), 7.89 (dd, J = 9.4, 3.4 Hz, 4H),
7.84–7.78 (m, 2H), 7.58–7.40 (m, 5H), 7.34–7.28 (m, 1H), 6.01 (d,
J = 4.6 Hz, 1H), 5.21 (dt, J = 8.5, 4.4 Hz, 1H), 4.71–4.50 (m, 2H). 13C
NMR (101 MHz, DMSO) d 146.4, 140.0, 133.2, 133.0, 131.3, 129.3,
128.3, 128.2, 128.0, 126.6, 126.4, 125.5, 125.2, 124.8, 122.6, 77.0,
57.1. HPLC (OJ-H elute: Hexanes/i-PrOH = 75:25, detector:
250 nm, flow rate: 1.0 mL/min), tmajor = 49.1 min, tminor = 57.6 min.
HRMS Calculated for C20H18N3O [M+H]+ 316.1444, found 316.1448.
HRMS Calculated for
284.1200.
C16H15FN3O [M+H]+ 284.1194, found
Please cite this article in press as: Vyas, V. K.; Bhanage, B. M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.012

V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
4.3.3.10. (S)-1-(Naphthalen-1-yl)-2-(4-phenyl-1H-1,2,3-triazol-
Hexanes/i-PrOH = 80:20, detector: 250 nm, flow rate: 0.7 mL/
min), tmajor = 51.4 min, tminor = 57.3 min.
1-yl)ethan-1-ol 2j.
White solid, mp = 195–197 °C, 152 mg,
D
97% yield, 95.1% ee, [
a
]
25 = +92.3 (c 0.1, CHCl3). MS (EI, 70 eV)
m/z (%): 315 (M+, 4.75), 237 (64.09), 170 (26.51), 157 (100), 77
4.3.3.15.
(S)-2-(4-Cyclohexyl-1H-1,2,3-triazol-1-yl)-1-pheny-
~
m
(83.33). IR (ATR)
(cmÀ1): 3331 (br), 2922, 1246, 1077. 1H NMR
lethan-1-ol 2o.
White solid, mp = 103–105 °C, 134 mg, 99%
(400 MHz, DMSO) d 8.54 (s, 1H), 7.94–7.81 (m, 6H), 7.62–7.53
(m, 1H), 7.50–7.40 (m, 4H), 7.35–7.26 (m, 1H), 6.03 (d, J = 4.7 Hz,
1H), 5.23 (dt, J = 8.5, 4.4 Hz, 1H), 4.72 – 4.55 (m, 2H). 13C NMR
(101 MHz, DMSO) d 146.4, 140.0, 133.2, 133.0, 131.3, 129.3,
128.3, 128.2, 128.0, 126.6, 126.4, 125.5, 125.2, 124.8, 122.6, 72.0,
57.1. HPLC (OJ-H elute: Hexanes/i-PrOH = 80:20, detector:
250 nm, flow rate: 0.7 mL/min), tmajor = 49.1 min, tminor = 57.7 min.
HRMS Calculated for C20H18N3O [M+H]+ 316.1444, found 316.1450.
yield, 97.5% ee, [
a]
25 = +48.7 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):
D
271 (M+, 14.44), 189 (53.65), 164 (19.41), 107 (100), 77 (65.09). IR
~
m
(ATR)
(cmÀ1): 3221 (br), 2850, 1448, 1064, 1034. 1H NMR
(400 MHz, DMSO) d 7.66 (s, 1H), 7.36–7.16 (m, 5H), 5.75 (s, 1H),
4.93 (s, 1H), 4.37 (t, J = 7.4 Hz, 2H), 2.60 (dt, J = 15.3, 8.4 Hz, 1H),
1.97– 1.80 (m, 2H), 1.74 – 1.56 (m, 3H), 1.39 – 1.13 (m, 5H). 13C
NMR (101 MHz, DMSO) d 152.0, 142.6, 128.6, 127.9, 126.4, 121.6,
71.9, 56.9, 35.0, 33.0, 26.1, 26.0. HPLC (OJ-H elute: Hexanes/
i-PrOH = 80:20, detector: 210 nm, flow rate: 0.7 mL/min),
4.3.3.11. (S)-2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(thiophen-2-
tminor = 13.0 min,
C
tmajor = 14.5 min.
HRMS
Calculated
for
yl)ethan-1-ol 2k.
White solid, mp = 132–134 °C, 124 mg,
D
16H22N3O [M+H]+ 272.1757, found 272.1766.
92% yield, 99.9% ee, [
a]
25 = +48.6 (c 0.1, CHCl3). MS (EI, 70 eV) m/
z (%): 271 (M+, 28.43), 145 (55.12), 117 (100), 77 (70.91). IR
4.3.3.16. (S)-2-(4-Hexyl-1H-1,2,3-triazol-1-yl)-1-phenylethan-1-
~
m
(ATR)
(cmÀ1): 3335 (broad), 3128, 1237, 766. 1H NMR
ol 2p.
Yellow oil, 132 mg, 97% yield, 98.0% ee, [a]
25 = +39.1
D
(400 MHz, CDCl3) d 7.77 (s, 1H), 7.71–7.62 (m, 2H), 7.38–7.22 (m,
4H), 7.07 – 6.98 (m, 2H), 5.52 (dt, J = 7.9, 3.4 Hz, 1H), 4.72 (dd,
J = 13.9, 3.4 Hz, 1H), 4.52 (dd, J = 13.9, 8.7 Hz, 1H), 4.10 (s, 1H).
13C NMR (101 MHz, CDCl3) d 147.3, 143.5, 130.1, 128.8, 128.1,
127.1, 125.5, 125.4, 124.6, 121.2, 69.1, 57.4. HPLC (OJ-H elute: Hex-
anes/i-PrOH = 75:25, detector: 250 nm, flow rate: 1.0 mL/min),
(c 0.1, CHCl3). MS (EI, 70 eV) m/z (%): 273 (M+, 3.71), 229 (55.70),
167 (64.10), 110 (86.02), 79 (100). IR (ATR)
(cmÀ1): 3340 (br),
~
m
2921, 1459, 1074. 1H NMR (400 MHz, DMSO) d 7.68 (s, 1H), 7.33
– 7.22 (m, 4H), 5.76 (d, J = 4.7 Hz, 1H), 4.93 (dt, J = 7.6, 4.7 Hz,
1H), 4.44–4.33 (m, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1.52 (t, J = 7.3 Hz,
2H), 1.29–1.17 (m, 6H), 0.86–0.79 (m, 3H). 13C NMR (101 MHz,
CDCl3) d 147.9, 140.4, 128.6, 128.2, 125.8, 122.2, 72.7, 57.2, 31.5,
29.3, 28.8, 25.4, 22.5, 14.0. HPLC (OJ-H elute: Hexanes/i-
PrOH = 85:15, detector: 210 nm, flow rate: 0.7 mL/min),
tmajor = 40.7 min,
C
tminor = 45.8 min.
HRMS
Calculated
for
14H14N3OS [M+H]+ 272.0852, found 272.0862.
4.3.3.12.
ethan-1-ol 2l.
(S)-1-(Furan-2-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)
tminor = 11.2 min,
C
tmajor = 12.3 min.
HRMS
Calculated
for
White solid, mp = 122–124 °C, 121 mg, 95%
16H24N3O [M+H]+ 274.1919, found 274.1924.
yield, 98.6% ee, [
a]
25 = +50.0 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):
D
255 (M+, 32.68), 190 (70.18), 146 (57.08), 117 (78.31), 102 (100).
4.3.3.17.
(S)-2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-1-pheny-
(cmÀ1): 3309 (br), 2922, 1240, 1081. 1H NMR
lethan-1-ol 2q.
White solid, mp = 105–107 °C, 124 mg, 99%
~
m
IR (ATR)
(400 MHz, CDCl3) d 7.71 (s, 1H), 7.63–7.54 (m, 2H), 7.42–7.36 (m,
1H), 7.34–7.22 (m, 3H), 6.36–6.27 (m, 2H), 5.27 (t, J = 4.5 Hz, 1H),
4.82 – 4.69 (m, 2H), 4.57 (dd, J = 13.9, 8.6 Hz, 1H). 13C NMR
(101 MHz, CDCl3) d 152.7, 147.2, 142.6, 130.0, 128.7, 128.1,
125.4, 121.3, 110.5, 107.6, 66.6, 54.7. HPLC (OD-H elute: Hex-
anes/i-PrOH = 80/20, detector: 250 nm, flow rate: 0.7 mL/min),
yield, 98.6% ee, [
a
]
25 = +55.2 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):
D
229 (M+, 19.72), 185 (11.63), 107 (67.71), 94 (100), 77 (47.41). IR
(ATR)
m
(cmÀ1): 3272 (br), 3000, 1246, 1069. 1H NMR (400 MHz,
~
CDCl3) d 7.37 – 7.12 (m, 6H), 5.16 – 5.07 (m, 1H), 4.49 (d,
J = 14.0 Hz, 1H), 4.32 (dd, J = 13.9, 8.6 Hz, 1H), 3.63 (s, 1H), 2.01–
1.66 (m, 1H), 0.82 (dd, J = 56.8, 6.8 Hz, 4H). 13C NMR (101 MHz,
CDCl3) d 149.9, 140.3, 128.7, 128.3, 125.8, 121.2, 72.8, 57.3, 7.6,
6.5. HPLC (OJ-H elute: Hexanes/i-PrOH = 80:20, detector: 210 nm,
flow rate: 0.7 mL/min), tminor = 11.9 min, tmajor = 12.9 min. HRMS
Calculated for C13H16N3O [M+H]+ 230.1288, found 230.1293.
tmajor = 27.6 min,
tminor = 33.2 min.
HRMS
Calculated
for
C14H14N3O2 [M+H]+ 256.1081, found 256.1089.
4.3.3.13. (S)-1-Phenyl-2-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)ethan-
1-ol 2m4a
97.8% ee, [
.
White solid, mp = 156–158 °C, 133 mg, 96% yield,
a]
D
25 = +57.8 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%): 279
4.3.3.18.
2r3a
ee, [
(S)-1-Phenyl-2-(1H-1,2,4-triazol-1-yl)ethan-1-ol
(M+, 10.61), 251 (24.59), 206 (58.83), 115 (100), 104 (49.06). IR
.
a
White solid, mp = 122–124 °C, 89 mg, 95% yield, 95.2%
(ATR)
(cmÀ1): 3272 (br), 2920, 1455, 1079. 1H NMR (400 MHz,
]
25 = +69.7 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%): 189 (M+,
~
m
D
(cmÀ1):
~
CDCl3) d 7.72 (s, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.43–7.29 (m, 5H),
7.18 (d, J = 7.8 Hz, 2H), 5.21 (dd, J = 8.8, 3.1 Hz, 1H), 4.62 (dd,
J = 14.0, 3.2 Hz, 1H), 4.42 (dd, J = 14.0, 8.8 Hz, 1H), 3.49 (s, 1H),
2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) d 147.5, 140.1, 137.9,
129.4, 128.8, 128.5, 127.5, 125.9, 125.5, 120.8, 72.9, 57.4, 21.3.
HPLC (OJ-H elute: Hexanes/i-PrOH = 80:20, detector: 250 nm, flow
rate: 0.7 mL/min), tmajor = 29.3 min, tminor = 37.7 min.
11.43), 161 (21.53), 107 (100), 77 (43.05). IR (ATR)
m
3202 (br), 2951, 1469, 1071. 1H NMR (400 MHz, CDCl3) d 7.94 (s,
1H), 7.79 (s, 1H), 7.39–7.21 (m, 5H), 5.04 (dd, J = 8.6, 3.5 Hz, 1H),
4.41– 4.28 (m, 2H), 4.24 (d, J = 8.5 Hz, 1H). 13C NMR (101 MHz,
CDCl3) d 151.6, 143.9, 140.3, 128.7, 128.3, 125.8, 72.2, 56.8. HPLC
(OD-H elute: Hexanes/i-PrOH = 80:20, detector: 210 nm, flow rate:
0.7 mL/min), tminor = 12.6 min, tmajor = 13.4 min.
4.3.3.14. (S)-2-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-
4.3.3.19. (S)-1-(4-Chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-
phenylethan-1-ol 2n4a
.
White solid, mp = 110–112 °C,
1-ol 2s3a
96.4% ee, [
.
White solid, mp = 120–122 °C, 109 mg, 98% yield,
125 mg, 85% yield, 97.2% ee, [
a]
D
25 = +96.3 (c 0.1, CHCl3). MS (EI,
a
]
D
25 = +83.4 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%): 223
70 eV) m/z (%): 295 (M+, 9.61), 236 (32.09), 187 (55.42), 107
(M , 17.08), 140 (42.87), 111 (100), 68 (53.31). IR (ATR)
m
(cmÀ1):
+
~
~
m
(100), 77 (51.30). IR (ATR)
(cmÀ1): 3212 (br), 2927, 1455, 1072,
3200 (br), 2922, 1464, 1075, 760. 1H NMR (400 MHz, CDCl3) d
7.98 (s, 1H), 7.85 (s, 1H), 7.34 – 7.23 (m, 4H), 5.06 (dd, J = 8.6,
3.3 Hz, 1H), 4.32 (dd, J = 13.9, 3.2 Hz, 1H), 4.21 (dd, J = 14.0,
8.4 Hz, 1H), 4.14 (s, 1H). 13C NMR (101 MHz, CDCl3) d 151.8,
143.9, 138.6, 134.2, 128.9, 127.1, 71.7, 56.6. HPLC (OJ-H elute: Hex-
anes/i-PrOH = 85:15, detector: 210 nm, flow rate: 0.7 mL/min),
tminor = 10.7 min, tmajor = 11.5 min.
1081. 1H NMR (400 MHz, DMSO)
d 8.47 (s, 1H), 7.80 (d,
J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.29 (dd, J = 8.1, 3.7 Hz,
3H), 6.88 (d, J = 8.2 Hz, 2H), 5.75 (d, J = 4.6 Hz, 1H), 4.96 (dt,
J = 8.9, 4.6 Hz, 1H), 4.51 – 4.38 (m, 2H), 3.70 (s, 3H). 13C NMR
(101 MHz, DMSO) d 159.1, 146.3, 134.4, 131.3, 129.3, 128.1,
127.7, 125.5, 122.5, 114.0, 71.4, 57.2, 55.5. HPLC (OJ-H elute:
Please cite this article in press as: Vyas, V. K.; Bhanage, B. M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.012

8
V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.3.3.20. (S)-1-(Naphthalen-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-
Acknowledgements
1-ol 2t3b
96.8% ee, [
.
White solid, mp = 134–136 °C, 112 mg, 94% yield,
a
]
D
25 = +64.6 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%): 239
VKV is thankful to the Department of Science and Technology
(DST), New Delhi, India, for providing Senior Research Fellowship
(SRF). VKV is grateful to Dr. Sawant from Department of Pharma-
ceuticals at ICT for carrying out NMR analysis. Author also thankful
to Miss Debamitra Chakravarty for carrying out single crystal XRD
analysis and Mr. Shashikant Gatkal for providing HRMS analysis
from Savitribai Phule Pune University, Pune.
(M+, 8.41), 157 (100), 127 (71.65), 68 (54.10). IR (ATR)
m
(cmÀ1):
~
3202 (br), 2923, 1442, 1071. 1H NMR (400 MHz, CDCl3) d 7.96 (s,
1H), 7.84 – 7.74 (m, 4H), 7.51 – 7.36 (m, 3H), 5.19 (dd, J = 8.6,
3.3 Hz, 1H), 4.56 (s, 1H), 4.38 (dd, J = 14.0, 3.4 Hz, 1H), 4.28 (dd,
J = 14.0, 8.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) d 151.6, 143.9,
137.6, 133.2, 128.6, 128.0, 127.7, 126.4, 126.3, 124.9, 123.4, 72.3,
56.8. HPLC (OJ-H elute: Hexanes/i-PrOH = 80/20, detector:
250 nm, flow rate: 0.7 mL/min), tminor = 14.5 min, tmajor = 15.9 min.
A. Supplementary data
Copies of 1H, 13C NMR, HRMS and HPLC spectra of substrate and
products. This material is available free of charge via the Internet at
http://pubs.acs.org. Supplementary data associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetasy.2017.05.012.
4.3.3.21. (S)-1-(Thiophen-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-
ol 2u.
ee, [
White solid, mp = 138–140 °C, 90 mg, 93% yield, 96.0%
a]
25 = +44.2 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%): 195 (M+,
D
~
9.19), 127 (50.98), 113 (100), 83 (46.75). IR (ATR)
m
(cmÀ1): 3267
(br), 2921, 1481, 1081. 1H NMR (400 MHz, CDCl3) d 8.01 (s, 1H),
7.86 (s, 1H), 7.31 – 7.23 (m, 1H), 7.01 – 6.92 (m, 2H), 5.36 (dd,
J = 8.0, 3.7 Hz, 1H), 4.45 (d, J = 17.5 Hz, 1H), 4.41–4.31 (m, 2H).
13C NMR (101 MHz, CDCl3) d 151.8, 144.0, 143.6, 127.0, 125.4,
124.4, 68.6, 56.7. HPLC (OJ-H elute: Hexanes/i-PrOH = 90:10, detec-
tor: 210 nm, flow rate: 0.7 mL/min), tminor = 8.7 min, tmajor = 9.1 -
min. HRMS Calculated for C8H10N3OS [M+H]+ 196.0539, found
196.0543.
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4.3.3.22.
(S)-1-(2,4-Dichlorophenyl)-2-(1H-1,2,3-triazol-1-yl)
ethan-1-ol 45.
White solid, mp = 130–132 °C, 126 mg, 98%
yield, 97.3% ee, [
a
]
D
25 = +51.0 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%):
258 (M+, 31.42), 174 (49.22), 144 (100), 68 (48.21). IR (ATR)
~
m
(cmÀ1): 3302 (br), 2918, 1462, 1079, 759. 1H NMR (400 MHz,
CDCl3) d 8.04 (s, 1H), 7.97 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.39 (d,
J = 2.1 Hz, 1H), 7.26 (dd, J = 8.4, 2.1 Hz, 1H), 5.41 (d, J = 7.3 Hz,
1H), 4.52 (dd, J = 14.0, 2.4 Hz, 1H), 4.21 (dd, J = 14.1, 7.7 Hz, 1H),
3.80 (d, J = 3.7 Hz, 1H). 13C NMR (101 MHz, DMSO) d 146.8, 139.1,
131.5, 129.8, 127.3, 124.5, 123.6, 122.9, 64.0, 50.1. HPLC (OJ-H
elute: Hexanes/i-PrOH = 90:10, detector: 210 nm, flow rate:
0.7 mL/min), tminor = 30.1 min, tmajor = 31.9 min.
4.4. O-Arylation of optically active b-triazoaryl amino alkanols
To a stirred solution of 1-(2,4-dichlorophenyl)-2-(1H-1,2,3-tria-
zol-1-yl)ethan-1-ol 4 (0.2 mmol) in dimethylformamide (DMF)
(0.5 mL) at 0–5 °C was added sodium hydride (60% oil, 0.3 mmol)
in small portions over 10 min. After stirring for 30 min, 4-chloro
benzyl bromide (0.3 mmol) was added and then stirring was con-
tinued at 27 °C for 4 h. The reaction mixture was quenched with
ice cold water (1 mL) and extracted with ethyl acetate
(3 Â 5 mL). The combined organic layers were dried over sodium
sulphate and concentrated under reduced pressure to obtain the
crude product, which was purified by preparative chromatography
to produce 1-(2-((4-chlorobenzyl)oxy)-2-(2,4-dichlorophenyl)
ethyl)-1H-1,2,3-triazole (5) in 50% yield (38 mg).
8. Vyas, V. K.; Bhalchandra, B. M. Org. Lett. 2016, 18, 6436–6439.
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J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986–987; (b) Cheung, F.
K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. Y.; Wills, M. J. Org. Chem. 2005, 70,
3188–3197; (c) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem.
Soc. 2005, 127, 7318–7319; (d) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem.
2006, 71, 7035–7044; (e) Cheung, F. K.; Lin, C.; Minissi, F.; Crivillé, A. L.;
Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett. 2007, 9, 4659–4662; (f) Martins, J.
E. D.; Morris, D. J.; Tripathi, B.; Wills, M. J. Organomet. Chem. 2008, 693, 3527–
3532; (g) Soni, R.; Collinson, J.-M.; Clarkson, G. C.; Wills, M. Org. Lett. 2011, 13,
4304–4307; (h) Jolley, K. E.; Hancock, A. Z.-G. F.; Dyke, A.; Grainger, D. M.;
Medlock, J. A.; Nedden, H. G.; Paih, J. J. M. L.; Roseblade, S. J.; Seger, A.; Siva-
kumar, V.; Morris, D. J.; Wills, M. Adv. Synth. Catal. 2012, 354, 2545–2555; (i)
Nedden, H.; Zanotti-Gerosa, A.; Wills, M. Chem. Rec. 2016, 16, 2619–2639.
10. Representative papers for asymmetric transfer hydrogenation by Ru-TsDPEN
complex (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562–7563; (b) Fujii, A.; Hashiguchi, S.; Uematsu, N.;
4.4.1. (S)-1-(2-((4-Chlorobenzyl)oxy)-2-(2,4-dichlorophenyl)
ethyl)-1H-1,2,3-triazole 55
Pale yellow solid, mp = 120–122 °C, 47 mg, 62% yield, 97.5% ee,
[a
]
D
25 = +44.6 (c 0.1, CHCl3). MS (EI, 70 eV) m/z (%): 382 (M+, 1.24),
~
m
257 (26.08), 173 (100), 144 (94.78), 125 (45.91). IR (ATR)
(cmÀ1): 3260 (br), 2926, 1467, 1085, 765. 1H NMR (400 MHz,
DMSO) d 8.33 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.44–7.24 (m, 6H),
5.56 (s, 2H), 5.01 (dt, J = 7.4, 4.6 Hz, 1H), 4.55–4.43 (m, 2H). 13C
NMR (101 MHz, DMSO) d 146.5, 140.8, 139.6, 133.1, 132.6, 130.7,
129.4, 128.6, 128.4, 128.3, 125.5, 122.5, 71.0, 56.7, 54.9. HPLC
(OJ-H elute: Hexanes/i-PrOH = 87/13, detector: 250 nm, flow rate:
0.7 mL/min), tminor = 45.3 min, tmajor = 48.0 min.
Please cite this article in press as: Vyas, V. K.; Bhanage, B. M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.012

V. K. Vyas, B. M. Bhanage / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
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Please cite this article in press as: Vyas, V. K.; Bhanage, B. M. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.012