Advanced Synthesis & Catalysis
10.1002/adsc.201800749
biphasic system broke into
a
multitude of small
(otherwise,
the
product
decomposes).
Flash
hydrophobic drops. The reaction mixture was left under
these conditions for 16 h more and then was extracted with
chromatography on silica gel (0.063-0.200 mm) eluting
with methylene chloride / methanol (gradient eluent from
95:5 to 90:10 v/v) under a positive nitrogen atmosphere
delivered pure N-hydroxylamidines 7.
2 2
CH Cl (2x10 mL) and the combined organic extracts were
dried over sodium sulphate, filtered and the filtrate
concentrate to give the crude -nitronitriles 6 as a mixture
of diastereomers (yellow oil). Flash chromatography of the
crude residue (gradient eluent from 95/5 to 85/15 v/v of n-
hexanes/ethyl acetate) delivered the reaction products in
two bands: a less polar band corresponding to the 6-
anti,syn diastereomer and a more polar band formed by the
(
±) Ethyl (3R,4R,5S)-4-phenyl-1-hydroxyl-2-imino-5-
methylpyrrolidine-3-carboxylate (7a-cis,cis). Following
1
the general procedure: 142.1 mg; 69%; foam; H NMR
(
3
400 MHz, CDCl ): 7.36-7.29 (m, 3H), 7.14 (brd, J = 6.9
Hz, 2H), 5.75 (brs, 2H), 4.33-4.26 (m, 1H), 4.20 (q, J = 7.1
Hz, 2H), 4.08 (app. triplet, J = 7.8 Hz, 1H), 4.03 (brd, J =
mixture
of
6-syn,syn/syn,anti
isomers.
Diastereoconvergent crystallization of the more polar band
6
.0 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.00 ppm (d, J = 6.8
delivered the 6-syn,syn isomer pure.
13
Hz, 3H); C NMR (100 MHz, CDCl
3
): 168.5, 142.6,
1
36.9, 129.1 (2C), 128.6, (2C), 128.1, 66.1, 62.8, 49.6,
(
±) Ethyl (2S,3S,4R)-2-cyano-4-nitro-3-phenylpenta-
44.2, 14.8, 14.4 ppm; IR (CHCl
3
): 3494, 3371, 3033,
-
1
+
noate (6a-syn,syn). Following the general procedure: 251
2966, 1732, 1685, 1262, 1189, 1094 cm ; HRMS (ESI ):
mg, 65%; crystalline solid, m.p. 74
-
75 ºC
): 7.20-7.18
m, 2H), 6.95-6.88 (m, 3H), 4.90 (dq, J = 9.7, 6.7 Hz, 1H),
m/z calcd for C14
285.1220.
18 2 3
H N O Na [M+Na]: 285.1215; found:
1
(
(
3
6
6 6
EtOAc/Hexanes); H NMR (400 MHz, C D
.64-3.56 (m, 3H), 3.26 (d, J = 6.2 Hz, 1H), 0.92 (d, J =
(
±) Ethyl (3R,4R,5R)-4-phenyl-1-hydroxyl-2-imino-5-
methylpyrrolidine-3-carboxylate (7a-cis,trans).
Following the general procedure: 148.2 mg; 78%; foam;
1
13
.6 Hz, 3H), 0.59 ppm (t, J = 7.1 Hz, 3H); C NMR (100
): 164.6, 134.6, 129.8, 129.7 (2C), 129.3 (2C),
15.1, 85.4, 63.4, 49.5, 40.6, 17.8, 14.1 ppm; IR (CHCl ):
3030, 2988, 2251, 1747, 1560, 1261 cm ; HRMS (ESI):
Na [M+Na]: 299.1008; found:
99.1009; elemental analysis calcd (%) for C14 : C
0.86, H 5.84, N 10.14; found: C 60.86, H 5.75, N 9.
MHz, C
6
D
6
1
3
H NMR (400 MHz, CDCl
3
): 7.36-7.29 (m, 3H), 7.26-
-
1
7
3
=
=
.24 (m, 2H), 5.75 (brs, 2H), 4.21 (brq, J = 6.9 Hz, 2H),
.99-3.96 (m, 1H), 3.81 (brd, J = 7.8 Hz, 1H), 3.40 (appt, J
m/z calcd for C14
H
16
N
2
O
4
2
6
16 2 4
H N O
7.4 Hz, 1H), 1.47 (brd, J = 5.9 Hz, 3H), 1.25 ppm (brt, J
13
7.0 Hz, 3H); C NMR (100 MHz, CDCl ): 168.6,
3
1
43.0, 139.6, 129.3 (2C), 128.0 (3C), 69.2, 62.6, 52.2, 48.7,
): 3494, 3371, 3033, 2986,
(
±) Ethyl (2S,3S,4S)-2-cyano-4-nitro-3-phenylpenta-
17.8, 14.3 ppm; IR (CHCl
3
-
1
+
noate (6a-anti,syn). Following the general procedure: 116
2938, 1732, 1685, 1273, 1184, 1096 cm ; HRMS (ESI ):
m/z calcd for C14
285.1213.
mg, 30%; crystalline solid, m.p. 107
(
(
-
108 ºC
18 2 3
H N O Na [M+Na]: 285.1215; found:
1
EtOAc/Hexanes); H NMR (400 MHz, C D ): 7.04-7.01
6 6
m, 2H), 6.92-6.91 (m, 3H), 4.85 (dq, J = 11.3, 6.6 Hz, 1H),
3
3
.66 (dd, J = 11.2, 4.8 Hz, 1H), 3.50 (q, J = 7.1 Hz, 2H),
.30 (brd, J = 4.7 Hz, 1H), 0.72 (d, J = 6.6 Hz, 3H), 0.55
General procedure for the auto-oxidation of N-
hydroxylamidine 7 (Method A). In a 25 mL round-
bottomed flask were placed N-hydroxylamidine 7 (1.0
equiv.) dissolved in acetonitrile (10 mL) and the solution
was stirred under continuous irradiation with blue LED for
1
3
ppm (t, J = 7.1 Hz, 3H); C NMR (100 MHz, C
6
D
6
):
1
4
1
64.3, 134.2, 129.7 (4C), 129.6, 115.1, 85.1, 63.1, 49.6,
1.8, 18.7, 14.0 ppm; IR (CHCl ): 3029, 2987, 2251,
3
1
+)
748, 1557, 1259 cm- ; HRMS (ESI : m/z calcd for
Na [M+Na]: 299.1008; found: 299.1002;
: C 60.86, H
.84, N 10.14; found: C 60.80, H 5.87, N 9.89.
2
4 h at room temperature. The reaction mixture was
C
14
H
16
N
2
O
4
concentrated at reduced pressure and the oxidation product
was purified by flash chromatography on silica gel (0.063-
1 2 4
elemental analysis calcd (%) for C 4H16N O
5
0
.200 mm) using methylene chloride / methanol as eluent
v
(
v
gradient eluent from 90:10 to 80:20 / ).
Scaling of the multicomponent reaction. In a 250 mL
round-bottomed flask equipped with a stirring bar was
placed distilled water (130 mL). While stirring at 200 r.p.m.
and room temperature, benzaldehyde (4a) (2.04 mL, 20
mmol), ethyl-2-cyanoacetate (3) (2.50 mL, 20 mmol),
nitroethane (5a) (2.80 mL, 40 mmol), thiourea 12 (500 mg,
General procedure for the oxidation of N-
hydroxylamidine 7 with meta-chloroperbenzoic acid
(
Method B). To a cooled (ice-water bath, 0 ºC) solution of
N-hydroxylamidine 7 (1.0 equiv.) in methylene chloride
10.0 mL/ mmol) was added m-chloroperbenzoic acid
(
1
mol, 5 mol%) and N,N-dimethylcyclohexylamine
portion-wise (1.1 equiv.) and the resulting reaction mixture
was allowed to stir at this temperature for a few minutes.
The ice bath was retired and the reaction mixture was
stirred for 2h. The reaction mixture was concentrated at
reduced pressure and the oxidation product was purified by
flash chromatography on silica gel (0.063-0.200 mm) using
(
13)(0.3 mL, 2 mmol, 10 mol%) were sequentially added,
in this order, to generate a biphasic system. The stirring
was increased to 1200 r.p.m. to transform the biphasic
system into an aqueous emulsion. The reaction mixture
was left under these conditions for 16 h more and then was
2 2
extracted with CH Cl (2x150 mL) and the combined
methylene chloride / methanol as eluent (gradient eluent
organic extracts were dried over sodium sulfate, filtered
v
from 90:10 to 80:20 /
v
).
and the filtrate concentrate to give the crude -nitronitrile
6
1
a (5.5 g, ≥ 95% yield) as a diastereomeric mixture (dr:
(
±) Ethyl (3S,4R,5S)-1,3-dihydroxy-2-imino-5-methyl-4-
phenylpyr-rolidine-3-carboxylate (3-OH-7a-cis,cis).
Following the general procedure: method A: 74.9 mg,
:0.4:1). Flash chromatography of the crude residue
(
gradient eluent from 95/5 to 85/15 v/v of n-hexanes/ethyl
acetate) delivered the reaction products in two bands: less
polar band: 6a-anti,syn diastereomer (2.3 g, 41%); more
polar band: mixture of 6a-syn,syn/syn,anti isomers (3.2 g,
1
8
2%, mixture of diastereomers (dr: 7:1; calculated by H
NMR analysis of the mixture); amorphous solid; method
1
B: 41.5 mg; 98% (dr: ≥20:1). H NMR (400 MHz, MeOD):
5
8%; dr: 1:0.4). Quantitative diastereoconvergent
7.34-7.32 (m, 3H), 7.18-7.15 (m, 2H), 4.47 (app. quintet,
crystallization of the more polar band delivered the 6a-
syn,syn isomer pure (3.2 g, 58%).
J = 7.0 Hz, 1H), 4.06-3.90 (m, 2H), 3.78 (d, J = 7.2 Hz,
1
H), 1.23 (d, J = 6.9 Hz, 3H), 1.00 ppm (t, J = 7.1 Hz, 3H);
C NMR (100 MHz, MeOD): 171.0, 152.8, 136.2, 131.9
2C), 130.2 (2C), 130.0, 84.2, 65.5, 64.0, 57.6, 14.8, 14.7
13
General procedure for the synthesis of N-
hydroxylamidines 7. To a solution of -nitronitrile 6 (1
equiv.) in ethanol (15 mL) was added Pd/C (10%) (0.4
mg/mg substrate) and the heterogeneous mixture was
stirred at room temperature under a hydrogen atmosphere
(
ppm; IR (nujol): 3420, 3295, 3247, 1733, 1677, 1586,
-1
+
1
254, 1202, 1070 cm ; HRMS (ESI ): m/z calcd for
Na [M+Na]: 301.1164; found: 301.1161;
elemental analysis calcd (%) for C14 : C 60.42, H
.52, N 10.07; found: C 60.84, H 6.66, N 9.96.
14 18 2 4
C H N O
18 2 4
H N O
(
5 bar) for 16 h. The reaction mixture was filtered on a
6
2
plug of celite under an atmosphere of N . The celite was
exhaustively washed with ethanol and the combined
filtrates were concentrated at reduced pressure in the rotary
evaporator, keeping the bath temperature below 30 ºC
(
4
±) Ethyl (3S,4R,5R)-1,3-dihydroxy-2-imino-5-methyl-
-phenylpyrrolidine-3-carboxylate (3-OH-7a-cis,trans).
7
This article is protected by copyright. All rights reserved.