Chiral (S)-(+) 1-substituted aryl-4-(1-phenyl) ethylformamido-5-amino-1,2, 3-triazole: A new class of chiral ligands for the silver(I)-promoted enantioselective allylation of aldehydes

Article abstract of DOI:10.1080/00397910500503595

Some novel chiral ligands, (S)-(+) 1-substituted aryl-4-(1-phenyl) ethylformamido-5-amino-1,2,3-triazoles, were prepared starting from 1-substituted aryl-4-ethoxycarbonyl-5-amino-1,2,3-triazoles and other reagents. They were used as catalytic chiral ligan

Full text of DOI:10.1080/00397910500503595

Synthetic Communicationsw, 36: 1063–1070, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500503595
Chiral (S)-(1) 1-Substituted
Aryl-4-(1-phenyl) Ethylformamido-5-
amino-1,2,3-triazole: A New Class of Chiral
Ligands for the Silver(I)-Promoted
Enantioselective Allylation of Aldehydes
Mindong Chen
Department of Environmental Sciences and Engineering, Nanjing
University of Information Science & Technology, Nanjing, China and
College of Pharmacy, China Pharmaceutical University, Nanjing, China
Youfei Zheng, Shuxian Fan, Guizhi Gao, Lei Yang,
Lu Tian, and Yiping Du
Department of Environmental Sciences and Engineering, Nanjing
University of Information Science & Technology, Nanjing, China
Feng Tang and Weiyi Hua
College of Pharmacy, China Pharmaceutical University, Nanjing, China
Abstract: Some novel chiral ligands, (S)-(þ) 1-substituted aryl-4-(1-phenyl) ethylfor-
mamido-5-amino-1,2,3-triazoles, were prepared starting from 1-substituted aryl-4-
ethoxycarbonyl-5-amino-1,2,3-triazoles and other reagents. They were used as
catalytic chiral ligands in the silver (I)-promoted enantioselective allylation reaction
of aldehydes with allyltributyltin.
Keywords: Catalytic, chiral ligands, triazole
Received in Japan July 28, 2005
Address correspondence to Mindong Chen, Department of Environmental Sciences
and Engineering, Nanjing University of Information Science & Technology, Nanjing
210044, China. E-mail: chenmd@nuist.edu.cn or chenmd99@sina.com.cn
1063

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M. Chen et al.
1. INTRODUCTION
Catalytic asymmetric synthesis is a valuable method for the preparation of
optically active substances.[1] In this context, the stereoselective addition of
organometallics to a carbonyl group has been extensively studied; in particu-
lar, the enantioselective allylation of carbonyl compounds is a challenging
problem in organic synthesis. Although numerous important examples of
the reaction using a stoichiomeric amount of chiral diamine have been
reported,[2] there is no method available for a catalytic process using chiral
amine with v-triazole. Recently Yanagisawa et al. reported a new catalytic
enantioselective allylation reaction of aldehydes with allyltributyltin using a
BINAP–silver(I) complex as a catalyst.[3] To the best of our knowledge,
these are the few cases using a chiral silver(I) complex in a catalytic asym-
metric reaction. This interesting result prompted us to design and synthesize
other chiral ligands that are suitable for making chiral silver(I) complexes
for catalytic asymmetric reactions. We wanted to try some chiral ligands
containing a nitrogen atom because it is well known that nitrogen can easily
coordinate to various metals such as Co, Cu, Zn, and other metals, giving
stable chiral metal complexes.[4] Based on this concept, using (S)-(þ)-1-
phenylethylamine as a chiral scaffold, we start to prepare a series of the
chiral (S)-(þ) 1-substituted aryl-4-(1-phenyl) ethylformamido-5-amino-
1,2,3-triazole from 1-substituted aryl-4-ethoxycarbonyl-5-amino-1,2,3-
triazoles and other reagents. In this article, we report the results of using
them as catalytic chiral ligands for silver(I) to promote enantioselective allyla-
tion reaction of various aldehydes with allyltributyltin.
2. RESULTS AND DISCUSSION
1-Substituted aryl-4-ethoxycarbonyl-5-amino-1,2,3-triazoles 1 react with
sodium hydrate to give 1-substituted aryl-4-carboxyl-5-amino-1,2,3-triazole
2 in excellent yields. Treatment with compounds 2 using thionyl chloride
results in 1-substituted aryl-4-carboxyl chloride-5-amino-1,2,3-triazole 3.
Reaction of compounds 3 with (S)-(þ)-1-phenylethylamine leads to (S)-(þ)
1-substituted aryl-4-(1-phenyl) ethylformamido-5-amino-1,2,3-triazole. After
usual workup and purification by silica-gel column chromatography,
compounds 4 were obtained as colorless solids in moderate to good yield.
In addition, by using (S)-(þ)-1-phenylethylamine as a chiral scaffold
reacting with 1-substituted aryl-4-ethoxycarbonyl-5-amino-1,2,3-triazole,
we tried to synthesize the novel chiral ligand 4. No reaction took place
between (S)-(þ)-1-phenylethylamine and 1-substituted aryl-4-ethoxycarbo-
nyl-5-amino-1,2,3-triazoles. For the synthesis route of compounds 4, see
Scheme 1. Structures of compounds 4 were confirmed by spectral data and
microanalysis. These chiral ligands were used by the silver(I) to promote
enantioselective allylation reaction of aldehydes with allyltributyltin.

Enantioselective Allylation of Aldehydes
1065
Scheme 1. The synthesis of compounds 4. For a: X ¼ H; b: 30-F; c: 40-Cl; d: 40-CH3;
e: 40-OCH3; f: 40-OC2H5; g; 30-CF3; h; 30-Br.
The ee value of the products was determined by HPLC analysis using a
chiral stationary-phase column (Chiralcel OD and OJ), and the absolute con-
figuration of the major enantiomer was assigned according to the sign of the
specific rotation. Silver(I) triflate is a good catalyst for allylation of
aldehydes. By means of the novel chiral ligand 4, the ee value can reach
42% in THF at 2208C. In addition, if the reaction was carried out below
2308C, the reaction proceeded very slowly. By means of these optimized
reaction conditions, various aldehydes were used as substrates for this
addition reaction, and the corresponding sec-alcohol could be obtained in
39–65% yield and 13.5–42% ee with S-configuration. These results are
summarized in Table 1. The chiral compounds 4 are quite stable chiral
ligands. For chiral ligands 4, as is expected, the nitrogen atoms can coordi-
nate to the silver(I) metal center to some extent, giving a chiral
environment, although the achieved ee value is low. This result strongly
suggests that the coordination between the nitrogen atom and silver(I)
metal plays an important role in this reaction. Thus, we believe that chiral
ligand 4 is a useful chiral ligand; namely, the nitrogen atoms can coordinate
to the silver(I) metal, affording a chiral silver(I) Lewis acid. To verify this
speculation, we attempted to obtain a single crystal of the catalyst to
confirm its structure. But despite extensive efforts, we could not obtain a
single crystal of chiral silver(I) complex that could be subjected to X-ray
crystal analysis.

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M. Chen et al.
Table 1.
Temp.
(8C)
Time
(h)
Yield
(%)
Entry
Ligand
Solvent
Ee%
Config.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
THF
THF
THF
THF
THF
THF
THF
THF
220
220
220
220
220
220
220
220
48
48
48
48
48
48
48
48
49
55
43
65
56
43
60
39
16.5
23.4
19
S
S
S
S
S
S
S
S
42
34
15
29
4g
4h
13.5
In conclusion, the chiral amine 4 was found to be a new class of relatively
effective chiral ligands for the silver(I) to promote enantioselective allylation
reaction of aldehydes with allyltributyltin, although they are not as effective as
BINAP–silver(I) complex.[5] This aritlce, for the first time, discloses that
chiral amine obtaining v-triazole can catalyze the enantioselective allylation
reaction using silver(I) salt. These results open a new way to design and
synthesize new chiral ligands for asymmetric reactions. Efforts are under
way to elucidate the mechanistic details of this addition reaction and to
disclose the exact structure of the active species. Moreover, we are planning
to synthesize similar amines, obtaining v-triazole, to find more effective and
stereoselective chiral ligands and to utilize these novel chiral ligands with
regard to other catalytic asymmetric reactions.
3. EXPERIMENTAL
Melting points were determined on X4 micromelting-point apparatus (China)
1
and are uncorrected. H NMR spectra were recorded on a Bruker 400A
instrument (CDCl3, DMSO-d6) with TMS as internal reference. IR spectra
were recorded (KBr) using a Bruker IFS 120 HP spectrophotometer. Mass
spectra were recorded on a HP6890/5973GC/MS. Optical rotations were
determined in a solution of CHCl3 at 258C using a Perkin-Elmer 241 MC
polarimeter; [a]D values are given in units of 1021 deg cm2 g21. The
organic solvents used were dried by standard methods when necessary. All
solid compounds reported gave satisfactory CHN microanalyses with a
Vario EL Elemental Analyzer. Commercially obtained reagents were
used without further purification. All reactions were monitored by TLC.

Enantioselective Allylation of Aldehydes
1067
Flash-column chromatography was carried out using flash chromatography
on silica gel. All allylation experiments were performed under nitrogen
using standard Schlenk techniques. The enantiomeric excesses of sec-
alcohols were determined by HPLC analysis using a chiral stationary-phase
column (Daicel Co. Chiralcel OD and OJ; eluent, 99:1 hexane–2-propanol
mixture).
Preparation of Chiral (S)-(1) 1-Substituted Aryl-4-(1-phenyl)
Ethylformamido-5-amino-1,2,3-triazole 4
1-Substituted aryl-4-ethoxycarbonyl-5-amino-1,2,3-triazoles 1 were prepared
according to the literature procedure.[6]
1-Substituted aryl-4-ethoxycarbonyl-5-amino-1,2,3-triazole 1 (2 mmol)
in ethanol (95%) (25 mL) was added to sodium hydrate at room temperature,
after which the mixture was refluxed for 2 h and then cooled to room tempera-
ture. A watery solution of acetic acid was added slowly, after adjustment to
PH , 6 with a watery solution of acetic acid, and a solid material slowly
precipitated. It was collected by filtration and washed with water, giving
1-substituted aryl-4-carboxyl-5-amino-1,2,3-triazole 2. Excess thionyl
chloride was added to a stirred solution of compounds 2 (1 mmol) in
anhydrous acetonitrile (10 mL) at room temperature. After the mixture was
stirred for 4 h at room temperature, the solvent and excess thionyl chloride
were removed under reduced pressure to give 1-substituted aryl-4-carboxyl
chloride-5-amino-1,2,3-triazole 3. Anhydrous acetonitrile solution (10 mL)
of (S)-(þ)-1-phenylethylamine (1 mmol) was added to the residue at room
temperature, the mixture was stirred for 24 h, the solvent was evaporated
under reduced pressure, the residue was purified by flash chromatography
on silica gel (hexane/EtOAc) and finally (S)-(þ)-1-substituted aryl-4-
(1-phenyl) ethylformamido-5-amino-1,2,3-triazole was produced. The
structure model of compounds 4 is shown in Scheme 2.
Data
4a: (S)-(þ)-1-phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-triazole:
1
mp 135–1368C, H NMR (CDCl3) d: 1.56 (d, J ¼ 4 Hz, 3H, CH3), 3.65
(q, J ¼ 6.4 Hz, 1H, CH–N), 5.17 (2H, s, NH2); 7.29 (5H, s), 7.49(5H, s);
13C NMR (CDCl3), d 23.6 (CH3), 47.7 (CH–N), 126.5 (CH), 127.1 (CH),
128.3 (CH), 128.4 (CH), 128.8 (CH), 129 (C), 142.4 (C), 145 (C–NH2),
147 (C–CO), 167.9 (CO). IR (KBr) n: 3450, 3413, 3336, 1665 (C55O),
1625(C55N), 1010 (–N–N55N) cm21; MS-EI m/z (%): 307 (52.5), 203
(40.3) 132 (36.6) 120 (32.3) 105 (100) 91 (12.3), 77 (64.6), 65 (10). Anal.
calcd. for C17H17N5O:C, 66.45; H, 5.54; N, 22.80; found C, 66.34; H, 5.49;
N, 22.73.

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M. Chen et al.
Scheme 2. Structure model of compounds 4d.
4b: (S)-(þ)-1-(30-F)phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-triazole:
1
mp 135–1368C, H NMR (CDCl3) d: 1.57 (d, J ¼ 4 Hz, 3H, CH3), 3.67
(q, J ¼ 6.4 Hz, 1H, CH–N), 5.17 (2H, s, NH2); 7.18–7.28 (9H, m), 13C NMR
(CDCl3), d 23.6 (CH3), 47.7 (CH–N), 118 (CH), 124 (CH), 126.5 (CH), 127.1
(CH), 128.3 (CH), 130 (CH), 130 (CH), 131 (C), 142.4 (C), 145 (C–NH2),
147 (C–CO), 162 (C–F), 167.9 (CO). IR (KBr) n: 3404, 3336, 3298, 1657
(C55O), 1622(C55N), 1023 (–N–N55N) cm21; MS-EI m/z (%): 325 (58.5)
310 (6.3) 221 (44.6) 120 (19.3) 105 (100), 91 (22.3), 77 (24.6). Anal. calcd.
for C17H16FN5O:C, 62.77; H, 4.96; N, 21.53; found C, 62.65; H, 4.90; N, 21.45.
4c:
(S)-(þ)-1-(40-Cl)phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-
1
triazole: mp 130–1318C, H NMR (CDCl3) d: 1.56 (d, J ¼ 4 Hz, 3H, CH3),
3.77 (m, 1H, CH–N), 5.14 (2H, s, NH2); 7.21–7.53 (9H, m), 13C NMR
(CDCl3), d 23.6 (CH3), 47.7 (CH–N), 126.5 (CH), 127.1 (CH), 127 (C-
triazole), 128.3 (CH), 129 (CH), 130 (CH), 134 (C–F), 142.4 (C), 145 (C–
NH2), 147 (C–CO), 167.9 (CO). IR (KBr) n: 3448, 3410, 3335, 1660
(C55O), 1627 (C55N), 1023 (–N–N55N) cm21; MS-EI m/z (%): 341(27)
312 (2.4), 237 (22) 138 (14.6) 120 (12), 105 (100), 91 (7), 77 (27.6). Anal.
calcd. for C17H16ClN5O:C, 59.74; H, 4.72; N, 20.49; found C, 59.63; H,
4.66; N, 20.40.
4d:
(S)-(þ)-1-(40-CH3)phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-
1
triazole: mp 112–1138C, H NMR (CDCl3) d: 1.56 (d, J ¼ 4 Hz, 3H, CH3),
2.44 (s, 3H, Ph–CH3), 2.56 (m, 1H, CH–N), 5.26 (s, 2H, NH2); 7.26–7.37
(9H, m), 13C NMR (CDCl3), d 20.9 (CH3), 23.6 (CH3), 47.7 (CH–N), 126
(C-triazole), 126.5 (CH), 127.1 (CH), 128 (CH), 128.3 (CH), 129 (CH), 138
(ArC–CH3), 142.4 (C), 145 (C–NH2), 147 (C–CO), 167.9 (CO). IR (KBr) n:

Enantioselective Allylation of Aldehydes
1069
3459, 3423, 3355, 1653 (C55O), 1624(C55N), 1026 (–N–N55N) cm21; MS-EI
m/z (%): 321 (81.3) 250 (16.3) 217 (39.4) 146 (61.2) 105(100), 91 (62.3), 77
(31), 65 (20.5). Anal. calcd. for C18H19N5O:C,67.27; H, 5.96; N, 21.80;
found C, 67.16; H, 5.90; N, 21.7.
4e: (S)-(þ)-1-(40-OCH3)phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-
1
triazole: mp 112–1138C, H NMR (CDCl3) d: 1.56 (d, J ¼ 4 Hz, 3H, CH3),
3.71 (m, 1H, CH–N), 3.98 (s, 3H, Ph–OCH3), 5.22 (s, 2H, NH2); 7.10–
7.48 (9H, m), 13C NMR (CDCl3), (20.9(CH3), 23.6 (CH3), 47.7 (CH–N),
56 (OCH3), 114 (CH), 121 (C-triazole), 126.5 (CH), 127.1 (CH), 128.3
(CH), 130 (CH), 142.4 (C), 145 (C–NH2), 147 (C–CO), 162 (ArC–OCH3),
167.9 (CO). IR (KBr) n: 3449, 3412, 3353, 1661 (C55O), 1626 (C55N),
1023 (–N–N55N) cm21; MS-EI m/z (%): 337 (75.3) 266 (16.3) 233 (9.4)
162 (71.2) 134 (55.3), 105 (100), 92 (32.3), 77 (51), 65 (15.3). Anal. calcd.
for C18H19N5O2: C, 64.09; H, 5.68; N, 20.77; found C, 63.97; H, 5.60; N,
20.69.
4f: (S)-(þ)-1-(40-OC2H5)phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-
1
triazole: mp 116–1188C, H NMR (CDCl3) d: 1.31 (t, J ¼ 6.0, 3H, OC2H5),
1.59 (d, J ¼ 4 Hz, 3H, CH3), 3.71 (m, 1H, CH–N), 4.07 (q, 2H,
OCH2CH3), 5.22 (s, 2H, NH2); 7. 01–7.54 (9H, m). 13C NMR (CDCl3),
(14.3(CH3), 23.6 (CH3), 47.7 (CH–N), 65.1 (CH2–O), 114 (CH), 120
(C-triazole), 126.5 (CH), 127.1 (CH), 128.3 (CH), 129 (CH), 142.4 (C), 145
(C–NH2), 159 (ArC–OCH3), 147 (C–CO), 167.9 (CO). IR (KBr) n: 3444,
3413, 3351, 1660 (C55O), 1625(C55N), 1020 (–N–N55N) cm21; MS-EI
m/z (%): 351 (83.3) 280 (16.3) 247 (15.4) 176 (51.2) 148 (58.5), 105 (100),
91 (12.3) 77 (24.4), 29 (10.5). Anal. calcd. for C19H21N5O2: C, 64.94; H,
6.02; N, 19.93; found C, 64.83; H, 5.96; N, 19.85.
4g: (S)-(þ)-1-(30-CF3)phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-
1
triazole: mp 126–1288C, H NMR (CDCl3) d: 1.65 (d, J ¼ 4 Hz, 3H, CH3),
3.68 (m, 1H, CH-N), 5.20 (2H, s, NH2); 7.23–7.53 (9H, m). 13C NMR
(CDCl3), (23.6(CH3), 47.7(CH–N), 119.3 (CF3), 125 (CH), 126.5(CH),
127.1 (CH), 128.3 (CH), 129 (C-triazole), 129 (CH), 131 (C–CF3), 132
(CH), 142.4 (C), 145 (C–NH2), 147 (C–CO), 167.9 (CO). IR (KBr) n:
3448, 3411, 3335, 1660 (C55O), 1627 (C55N), 1018 (–N–N55N) cm21
;
MS-EI m/z (%): 375 (38.3) 271 (40.3) 145 (21.4) 120 (19.2) (10.2) 105
(100), 91 (1.9) 77 (76.4). Anal. calcd. for C18H16F3N5O: C, 57.6; H, 4.30;
N, 18.67; found C, 57.49; H, 4.23; N, 18.59.
4h:
(S)-(þ)-1-(30-Br)phenyl-4-(1-phenyl)ethylformamido-5-amino-1,2,3-
1
triazole: mp 116–1178C, H NMR (CDCl3) d: 1.56 (d, J ¼ 4 Hz, 3H, CH3),
3.70 (m, 1H, CH–N), 5.19 (2H, s, NH2); 7.34–7.76 (9H, m), 13C NMR
(CDCl3), (23.6(CH3), 47.7 (CH–N), 123 (C–Br), 126.5 (CH), 127.1 (CH),
128 (CH), 128.3 (CH), 131 (C-triazole), 131 (CH), 132 (CH), 142.4 (C), 145

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M. Chen et al.
(C–NH2), 147 (C–CO), 167.9 (CO). IR (KBr) n: 3441, 3409, 3329, 1655
(C55O), 1627 (C55N), 1019 (–N–N55N) cm21; MS-EI m/z (%): 385 (24.3)
280 (22.3) 185 (11.4) 157 (10.2) 105(100), 91 (2.3) 77 (19.4). Anal. calcd. for
C17H16BrN5O: C, 52.86; H, 4.18; N, 18.13; found C, 52.74; H, 4.12; N, 18.05.
Typical Reaction Procedure
Benzaldehyde (53 mg, 0.5 mmol, 50 ml) at room temperature was added to a
solution of (S)-(þ)1-substituted aryl-4-(1-phenyl) ethylformamido-5-amino-
1,2,3-triazole 4. (0.1 mmol) and AgOTf (25.7 mg, 0.1 mmol) in THF (4 ml).
After stirring the reaction mixture for 2 h, allyltributyltin (199 mg,
0.6 mmol, 186 ml) was added into the reaction solution at 2208C and the
reaction mixture was stirred at 2208C for 24 h. The reaction was quenched
by a mixture of 10% aq. HCl (8 ml) and solid KF (1 g) at ambient temperature
for 1 h. The resulting precipitate was filtered off, and the filtrate was dried with
MgSO4 and then concentrated under reduced pressure. The residue was
purified by silica-gel column chromatography to give the homoallylic
alcohol as a colorless oil.
ACKNOWLEDGMENTS
This work was financially supported by the Social Development Foundation
of Jiangsu Province (No. BS 2003034), the University Natural Science
Foundation of Jiangsu Education Bureau (No. 04KJB150056), and the
National Natural Science Foundation of China (No. 30472066).
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