Enantioselective copper-aminopyridine-catalyzed aza-Henry reaction with chelating N-(2-pyridyl)sulfonyl imines

Article abstract of DOI:10.1002/chir.22009

This article describes a copper-catalyzed aza-Henry reaction. Copper complexes of camphor-derived aminopyridines catalyze the addition of nitromethane to N-(2-pyridyl)sulfonyl aldimines to give the corresponding β-nitrosulfonamides with good yields and va

Full text of DOI:10.1002/chir.22009

CHIRALITY (2012)
Enantioselective Copper-Aminopyridine-catalyzed aza-Henry Reaction
with Chelating N-(2-Pyridyl)Sulfonyl Imines
*
*
GONZALO BLAY, ANA ESCAMILLA, VÍCTOR HERNÁNDEZ-OLMOS, JOSÉ R. PEDRO, AND AMPARO SANZ-MARCO
Departament de Química Orgànica, Facultat de Química, Universitat de València, Burjassot, Spain
ABSTRACT
This article describes a copper-catalyzed aza-Henry reaction. Copper complexes of
camphor-derived aminopyridines catalyze the addition of nitromethane to N-(2-pyridyl)sulfonyl
aldimines to give the corresponding b-nitrosulfonamides with good yields and variable
enantiomeric excesses (up to 83%). An example of transformation of these compounds into
N-(2-pyridyl)sulfonyl-a-amino acids and deprotection of the sulfonamide with Mg–MeOH is
provided. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: nitro-Mannich reaction; chiral amines; nitro compounds; nucleophilic addition;
asymmetric catalysis; copper; chiral ligands
Silica Gel 60 F-254 thin layer plates. Flash column chromatography was per-
INTRODUCTION
formed on Merck silica gel 60, 0.040–0.063mm (Merck KGaA, Darmstadt,
Germany). Specific optical rotations were recorded on a Perkin-Elmer 241
polarimeter using sodium light (D line 589 nm). NMR spectra were
recorded on Bruker Avance spectrometers in deuterated solvents as stated,
using residual non-deuterated solvent as internal standard. The carbon type
was determined by distortionless enhancement by polarization transfer
(DEPT) experiments. Mass spectra (EI) were recorded on a Fisons Instru-
ments VG Autospec GC 8000 series at 70eV. Electrospray ionization mass
spectra (ESI) were recorded on a Waters Q-TOF premier mass spectrome-
ter with an electrospray source. The drying gas as well as the nebulizing gas
was nitrogen. Chiral high performance liquid chromatography (HPLC)
analyses were performed in a Hitachi Elite Lachrom instrument equipped
with a Hitachi UV diode-array L-4500 detector using chiral stationary col-
umns from Daicel and are included in the Supporting information. Retention
times (tr) are given in minutes. 2-Pyridylsulfonamide and 2-methoxyphenyl-
sulfonamide were prepared from the corresponding sulfonyl chlorides
according to known procedures.50–52 Pyridine-2-sulfonyl chloride was
prepared by oxidation of 2-pyridine-2-thiol (Alfa Aesar, Karlsruhe, Germany)
with sodium hypochlorite in sulfuric acid.50–52 2-Methoxybenzenesulfonyl
chloride was prepared from 2-methoxybenzenethiol (Sigma-Aldrich, St
Louis, MO, USA) following the same procedure in concentrated hydrochlo-
ric acid instead of sulfuric acid. Ligands 1–5 were prepared according to
our reported procedure.48
The nucleophilic addition of nitroalkanes to the CN of
imines, known as the aza-Henry (or nitro-Mannich) reaction,
is a useful carbon–carbon bond-forming reaction of prime
importance.1–3 The resulting b-nitroamines can be readily trans-
formed into valuable structural motifs such as 1,2-diamines by
reduction4–6 or into a-amino carbonyl compounds by oxidation
(Nef reaction).7–9 Most significantly, up to two new stereogenic
centers can be formed, both attached to two different
nitrogen functional groups. As a result, much attention has
been paid to the catalytic asymmetric version of this reaction
over the past several years by either using metal-based
procedures10–15,6,17–19 or organocatalysis.20–39 One of the
difficulties that arises when carrying out nucleophilic addition
reactions to imines is their lower electrophilicity compared with
the carbonyl group. However, this reactivity can be enhanced
by attaching strong electron-withdrawing groups to the
azomethinic nitrogen atom.40,41 In the reported aza-Henry
reactions, N-carbamoyl imines have been the most commonly
used electrophiles.11,12,17,19,20,22–31 However,
a
common
drawback associated with the use of this type of imines is that
precautions have to be taken during preparation, handling,
and storage because of their substantial hydrolytic lability.
N-phosphinoyl imines have been seldom used10,21,32 because
of their poor stability and relatively low reactivity, although
the phosphinoyl moiety can be easily removed by
acidic hydrolysis. Similarly, there are few reports on the
enantioselective aza-Henry reaction of N-sulfonyl protected
imines,13,6,16 which are usually bench-stable solids and can
be easily prepared. A possible explanation for this is the
difficult deprotection of the N-tosyl amines resulting from
the nucleophilic addition to the CN bond.
Synthesis of Starting Materials
Synthesis of N-sulfonyl imines 6–9.
N-Sulfonyl imines 6–9
were prepared according to procedures in the literature:52 A mixture of
the corresponding sulfonamides (11.4 mmol), aldehyde (11.4 mmol), acti-
vated 5 Å molecular sieves (Sigma-Aldrich, St Louis, MO, USA) (1.70 g),
and AmberlystW (Sigma-Aldrich, St Louis, MO, USA) (225 mg) in toluene
(35 mL) contained in a round bottom flask provided with a Dean–Stark
system was refluxed under nitrogen for 48–60 h. The reaction mixture
was cooled to room temperature (rt) and filtered through a sintered-glass
Our group has developed new iminopyridine and aminopyri-
dine ligands (Fig. 1), which in the presence of copper(II) salts
catalyzed the Henry reaction with carbonyl compounds very effi-
ciently and with very high enantioselectivity.42–49 In this article,
we describe the application of these catalysts in the enantioselec-
tive aza-Henry reaction with N-(2-pyridyl)sulfonyl aldimines.
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: Ministerio de Ciencia e Innovación and FEDER; Con-
tract grant number: CTQ2009-13083.
Contract grant sponsor: Generalitat Valenciana; Contract grant number:
ACOMP/2011/267.
*Correspondence to: José R. Pedro, Departament de Química Orgànica, Facultat
de Química, Universitat de València, C/ Dr. Moliner 50, E-46100-Burjassot, Spain.
E-mail: jose.r.pedro@uv.es; Gonzalo Blay, Departament de Química Orgànica,
Facultat de Química, Universitat de València, C/ Dr. Moliner 50, E-46100-
Burjassot, Spain. E-mail: gonzalo.blay@uv.es
Received for publication 08 September 2011; Accepted 29 December 2011
DOI: 10.1002/chir.22009
Published online in Wiley Online Library
(wileyonlinelibrary.com).
EXPERIMENTAL
Materials and Methods
Commercial reagents were used as purchased. Reactions were
monitored by thin layer chromatography (TLC) analysis using Merck
© 2012 Wiley Periodicals, Inc.

BLAY ET AL.
(E)-N-(2-chlorobenzylidene)pyridine-2-sulfonamide
(9d).
Obtained in 81% yield: mp 152–155 ꢀC; 1H NMR (300 MHz, CDCl3) d
9.71 (1H, s), 8.76 (1H, dq, J = 4.5, 0.9 Hz), 8.25 (1H, d, J = 8.1 Hz), 8.18
(1H, dd, J = 8.1, 1.8 Hz), 7.99 (1H, td, J = 7.8, 1.8 Hz), 7.56 (2H, m), 7.49
(1H, m), 7.34 (1H, t, J = 7.5 Hz); 13C NMR (75.5 MHz, CDCl3) d 170.7
(CH), 155.5 (C), 150.5 (CH), 139.4 (C), 138.1 (CH), 136.1 (CH), 130.6
(CH), 130.4 (CH), 129.7 (C), 127.38 (CH), 127.35 (CH), 123.5 (CH); MS
(EI) m/z (%): 281 [(M+ + H), 0.7], 79 (100); HRMS: 281.0141 (M+ + H),
C12H10ClN2O2S required 281.0152.
(E)-N-(4-methoxybenzylidene)pyridine-2-sulfonamide (9e)55
.
Obtained in 77% yield: mp 110–112 ꢀC; 1H NMR (300MHz, CDCl3) d 9.15
(1H, s), 8.70 (1H, dq, J= 4.8, 0.9 Hz), 8.22 (1H, dt, J = 8.1, 0.9Hz), 7.95 (1H,
td, J= 7.8, 1.8Hz), 7.93 (1H, d, J = 8.7Hz), 7.51 (1H, ddd, J = 7.8, 4.8,
1.2 Hz), 6.79 (2H, d, J= 8.7 Hz), 3.88 (3H, s); 13C NMR (75.5 MHz, CDCl3)
d 173.2 (CH), 165.7 (C), 156.2 (C), 150.3 (CH), 138.0 (CH), 134.2 (CH),
127.0 (CH), 125.1 (C), 123.1 (CH), 114.7 (CH), 55.7 (CH3).
Fig. 1. Iminopyridine and aminopyridine ligands used in this study.
funnel, washing the solid with dichloromethane (40 mL). The filtrates
were evaporated under reduced pressure to give a solid that was washed
with 1:1 diethyl ether/hexane (3 Â 7 mL) to give the imine.
(E)-N-benzylidene-4-methylbenzenesulfonamide (6)53.
Obtained
(E)-N-(4-methylbenzylidene)pyridine-2-sulfonamide (9f)56
.
in 93% yield: mp 109–111 ꢀC; 1H NMR (300MHz, CDCl3) d 9.03 (1H, s),
7.97–7.88 (4H, m), 7.62 (1H, tt, J= 6.6, 1.2 Hz), 7.49 (2H, t, J=7.8Hz), 7.35
(2H, d, J= 8.1 Hz), 2.44 (3H, s).
Obtained in 83% yield: mp 144–145 ꢀC; 1H NMR (300 MHz, CDCl3) d 9.20
(1H, s), 8.71 (1H, dq, J = 4.8, 0.9 Hz), 8.23 (1H, dt, J = 7.8, 0.9 Hz), 7.96 (1H,
td, J = 7.8, 1.8Hz), 7.85 (1H, d, J= 8.4 Hz), 7.52 (1H, ddd, J= 7.8, 4.8,
0.9 Hz), 7.29 (2H, d, J = 8.4 Hz), 2.43 (3H, s); 13C NMR (75.5MHz, CDCl3)
d 174.1 (CH), 155.9 (C), 150.4 (CH), 147.0 (C), 138.1 (CH), 131.8 (CH),
130.0 (CH), 129.7 (C), 127.2 (CH), 123.3 (CH), 22.0 (CH3).
(E)-N-benzylidenethiophene-2-sulfonamide (7)52
.
Obtained in
93% yield: mp 108–109 ꢀC; 1H NMR (300 MHz, CDCl3) d 9.01 (1H, s),
7.97–7.94 (2H, m), 7.80 (1H, dd, J = 3.6, 1.2 Hz), 7.71 (1H, dd, J = 5.1,
1.2 Hz), 7.64 (1H, tt, J = 6.9, 1.2 Hz), 7.51 (2H, t, J = 7.2 Hz), 7.15 (1H, dd,
J = 5.1, 3.9 Hz).
(E)-N-(4-chlorobenzylidene)pyridine-2-sulfonamide (9g)56
.
Obtained in 83% yield: mp 163–165 ꢀC; 1H NMR (300 MHz, CDCl3) d
9.22 (1H, s), 8.73 (1H, dq, J = 4.8, 0.6 Hz), 8.25 (1H, dt, J = 7.8, 0.6 Hz),
7.99 (1H, td, J = 7.8, 1.8 Hz), 7.92 (1H, d, J = 8.7 Hz), 7.55 (1H, ddd,
J = 7.8, 4.8, 1.2 Hz), 7.49 (2H, d, J = 8.7 Hz); 13C NMR (75.5 MHz, CDCl3)
d 172.9 (CH), 155.5 (C), 150.4 (CH), 142.0 (C), 138.2 (CH), 132.7 (CH),
130.6 (C), 129.7 (CH), 127.4 (CH), 123.4 (CH).
(E)-N-benzylidene-2-methoxybenzenesulfonamide
(8)54
.
Obtained in 63% yield: mp 115–116 ꢀC; 1H NMR (300 MHz, CDCl3) d
9.14 (1H, s), 8.12 (1H, dd, J = 8.1, 1.7 Hz), 7.97–7.94 (2H, m), 7.66–7.55
(2H, m), 7.50 (2H, t, J = 7.2 Hz), 7.13 (1H, td, J = 7.8, 0.6 Hz), 6.97
(1H, d, J = 8.4 Hz), 3.82 (3H, s); 13C NMR (75.5 MHz, CDCl3) d 173.0
(CH), 157.1 (C), 135.6 (CH), 134.9 (CH), 132.5 (C), 131.3 (CH), 130.7
(CH), 129.2 (CH), 125.3 (C), 120.7 (CH), 112.3 (CH), 56.2 (CH3).
(E)-N-(4-nitrobenzylidene)pyridine-2-sulfonamide
(9h)57
.
1
Obtained in 82% yield: mp 192–194 ꢀC; H NMR (300 MHz, DMSO-d6) d
10.17 (1H, s), 8.72 (1H, dq, J = 4.8, 0.9 Hz), 8.42 (2H, d, J = 8.7 Hz), 8.17
(2H, d, J = 8.7 Hz), 8.07 (1H, td, J = 7.8, 1.8 Hz), 7.93 (1H, dt, J = 7.8,
0.9 Hz), 7.64 (1H, ddd, J = 7.8, 4.8, 1.2 Hz); 13C NMR (75.5 MHz, DMSO-
d6) d 192.3 (CH), 159.7 (C), 150.6 (C), 149.6 (CH), 140.0 (C), 138.5
(CH), 130.6 (CH), 126.6 (CH), 124.2 (CH), 120.4 (CH).
(E)-N-benzylidenepyridine-2-sulfonamide (9a)50
.
Obtained in
87% yield: mp 142–144 ꢀC; 1H NMR (300 MHz, DMSO-d6) d 9.31 (1H,
s), 8.77 (1H, dq, J = 4.5, 1.2 Hz), 8.23–8.15 (2H, m), 8.10–8.08 (2H, m),
7.78–7.72 (2H, m), 7.59 (2H, t, J = 7.8 Hz); 13C NMR (75.5 MHz, DMSO-
d6) d 174.9 (CH), 154.9 (C), 150.5 (CH), 139.1 (CH), 135.6 (CH), 132.0
(C), 131.5 (CH), 129.3 (CH), 128.0 (CH), 122.8 (CH); MS (EI) m/z (%):
247 [(M+ + H), 2.8], 181 (14), 79 (100); HRMS: 247.0547 (M+ + H),
(E)-N-(3-methoxybenzylidene)pyridine-2-sulfonamide
(9i)58
.
Obtained in 75% yield: mp 95–97 ꢀC; 1H NMR (300 MHz,
C
12H11N2O2S required 247.0541.
CDCl3) d 9.19 (1H, s), 8.71 (1H, dq, J = 4.6, 0.9 Hz), 8.22 (1H, dt, J = 7.8,
0.9 Hz), 7.96 (1H, dt, J = 6.0, 1.8 H, m), 7.52 (1H, ddd, J = 0.9, 4.6,
8.1 Hz), 7.50–7.45 (2H, m), 7.39 (1H, t, J = 8.1 Hz), 7.16 (1H, ddd, J = 1.3,
2.6, 8.1 Hz), 3.81 (3H, s); 13C NMR (75.5 MHz, CDCl3) d 174.3 (d),
160.1 (s), 155.8 (s), 150.4 (d), 133.6 (s), 130.1 (d), 127.3 (d), 125.8 (d),
123.4 (d), 122.8 (d), 113.4 (d), 55.5 (q).
(E)-N-(2-methoxybenzylidene)pyridine-2-sulfonamide (9b)55
.
1
Obtained in 83% yield: mp 116–118 ꢀC; H NMR (300 MHz, CDCl3) d 9.74
(1H, s), 8.73 (1H, dq, J = 4.5, 0.9Hz), 8.23 (1H, dt, J = 7.8, 0.9 Hz), 8.07 (1H,
dd, J= 7.8, 1.8Hz), 7.95 (1H, td, J = 7.8, 1.8 Hz), 7.59 (1H, td, J= 7.8, 1.8Hz),
7.51 (1H, ddd, J= 7.8, 4.8 1.2 Hz), 6.98 (2H, m), 3.93 (3H, s); 13C NMR
(75.5MHz, CDCl3) d 170.2 (CH), 162.1 (C), 156.1 (C), 150.3 (CH), 138.0
(CH), 137.5 (CH), 129.5 (CH), 127.1 (CH), 123.2 (CH), 120.84 (CH),
120.82 (C), 111.5 (CH), 55.7 (CH3); MS (EI) m/z (%): 277 [(M+ + H), 20],
181 (12), 79 (100); HRMS: 277.0645 (M+ + H), C13H13N2O3S required
277.0647.
(E)-N-(3-methylbenzylidene)pyridine-2-sulfonamide (9j)50
.
Obtained in 80% yield: mp 141–143 ꢀC; 1H NMR (300 MHz, CDCl3) d
9.22 (1H, s), 8.73 (1H, dq, J = 4.6, 0.9 Hz), 8.26 (1H, dt, J = 7.8, 0.9 Hz),
7.97 (1H, dt, J = 6.0, 1.8 H, m), 7.82 (1H, br s), 7.76 (1H, br d, J = 7.5 Hz),
7.53 (1H, ddd, J = 0.9, 4.6, 7.8 Hz), 7.46 (1H, br d, J = 7.8 Hz), 7.39 (1H, t,
J = 7.5 Hz), 2.40 (3H, s); 13C NMR (75.5 MHz, CDCl3) d 174.6 (d), 155.9
(s), 150.4 (d), 139.2 (s), 138.1 (d), 136.3 (d), 132.3 (s), 131.6 (d), 129.5
(d), 129.1 (d), 127.2 (d), 123.3 (d), 21.1 (q).
(E)-N-(2-methylbenzylidene)pyridine-2-sulfonamide (9c).
1
Obtained in 75% yield: mp 109–111 ꢀC; H NMR (300 MHz, CDCl3) d 9.55
(1H, s), 8.72 (1H, d, J = 4.5 Hz), 8.24 (1H, d, J= 7.8Hz), 8.05 (1H, dd,
J= 8.4, 1.5 Hz), 7.97 (1H, td, J = 7.8, 1.5 Hz), 7.55–7.47 (2H, m), 7.30–7.25
(2H, m), 2.64 (3H, s); 13C NMR (75.5 MHz, CDCl3) d 172.7 (CH), 162.1
(C), 155.9 (C), 150.3 (CH), 142.8 (C), 138.1 (CH), 135.1 (CH), 131.6 (CH),
130.7 (CH), 130.3 (C), 127.2 (CH), 126.6 (CH), 123.3 (CH), 19.6 (CH3);
MS (EI) m/z (%): 261 [(M+ + H), 0.5], 118 (59), 79 (100); HRMS: 261.0686
(M+ + H), C13H13N2O2S required 261.0698.
(E)-N-(3-chlorobenzylidene)pyridine-2-sulfonamide (9k)57
.
Obtained in 75% yield: mp 133–135 ꢀC; 1H NMR (300 MHz, CDCl3) d
9.22 (1H, s), 8.73 (1H, dq, J = 4.5, 0.9 Hz), 8.26 (1H, dt, J = 7.8, 0.9 Hz),
8.02–7.97 (2H, m), 7.83 (1H, dt, J = 7.5, 1.2 Hz), 7.61 (1H, dq, J = 7.8,
0.9 Hz), 7.55 (1H, ddd, J = 7.8, 4.8, 1.2 Hz), 7.46 (1H, t, J = 7.8 Hz); 13C
Chirality DOI 10.1002/chir

ASYMMETRIC AZA-HENRY REACTION
TABLE 1. Addition of nitromethane to N-sulfonyl imines
according to Scheme 1. Effect of the N-sulfonyl groupa
NMR (75.5 MHz, CDCl3) d 172.9 (CH), 155.5 (C), 150.5 (CH), 138.2
(2xCH), 135.5 (C), 135.1 (CH), 134.4 (C), 130.5 (CH), 130.4 (CH), 123.5
(CH); MS (EI) m/z (%): 281 [(M+ + H), 10], 215 (12), 154 (13), 111 (26),
79 (100); HRMS: 281.0139 (M+ + H), C12H10ClN2O2S required 281.0152.
t
Yield
(%)
ee
Entry
R
Imine (h) Product
(%)b
(E)-N-(3-nitrobenzylidene)pyridine-2-sulfonamide
(9l).
1
2
3
4
p-Ts
6
7
24
22
16
5
10
11
99
80
75
80
18
11
23
59
Obtained in 52% yield: mp 114–116 ꢀC; 1H NMR (300 MHz, DMSO-d6) d
9.49 (1H, s), 8.87 (1H, t, J = 1.9 Hz), 8.79 (1H, dq, J = 4.5, 0.8 Hz), 8.55–8.46
(2H, m), 8.25 (dt, J = 6.6, 0.9 Hz), 8.20 (dt, J = 7.8, 1.5Hz), 7.89 (1H, t,
J= 7.8Hz), 7.79 (ddd, J = 8.7, 3.0, 1.5 Hz); 13C NMR (300MHz, DMSO-d6) d
173.0 (d), 155.7 (s), 150.6 (d), 148.2 (s), 139.2 (d), 136.7 (d), 134.9 (s),
136.7 (d), 134.9 (s), 130.9 (d), 129.2 (d), 128.3 (d), 125.6 (d), 123.1 (d);
HRMS (ESI): 314.0228 (M+ + Na), C12H9N3NaO4S required 314.02115.
2-Thiophenyl
2-Methoxyphenyl
2-Pyridyl
8
12
9a
13a
aLigand 2 (20 mol%), Cu(OTf)2 (20 mol%), DIPEA (30 mol%), 4 Å MS (100 mg/
mmol imine), THF (1.64 mL), nitromethane (0.76 mL), 0 ꢀC.
bDetermined by HPLC using chiral stationary phases.
(E)-N-(thiophen-3-ylmethylene)thiophene-2-sulfonamide (9m).
Obtained in 64% yield: mp 161–163 ꢀC; 1H NMR (300 MHz, CDCl3) d 9.21 (1H,
s), 8.71 (1H, dq, J= 4.5, 0.9 Hz), 8.24–8.21 (2H, m), 7.96 (1H, td, J= 7.8, 1.5 Hz),
7.61 (1H, dd, J= 5.9, 0.9 Hz), 7.52 (1H, ddd, J=7.8, 4.8, 1.2Hz), 7.39 (1H, ddd,
J=5.1, 2.7, 0.6Hz); 13C NMR (75.5 MHz, CDCl3) d 167.0 (CH), 155.9 (C),
150.4 (CH), 139.3 (CH), 138.1 (CH), 137.0 (C), 127.9 (CH), 127.2 (CH),
126.6 (CH), 123.3 (CH); HRMS (ESI): 274.9925 (M+ +Na), C10H8N2NaO2S2
required 274.9925.
mp 116–118 ꢀC; [a]D25 À0.69 (c 0.51, CH2Cl2, ee 8%); 1H NMR (300 MHz,
DMSO-d6) d 8.98 (1H, br s), 7.74 (1H, dd, J = 4.8, 1.2 Hz), 7.29–7.20 (6H,
m), 6.92 (1H, dd, J = 4.8, 3.6 Hz), 5.08 (1H, m), 4.86 (1H, dd, J = 13.2,
5.1 Hz), 4.68 (1H, dd, J = 13.2, 9.9 Hz); 13C NMR (75.5 MHz, DMSO-d6) d
141.6 (C), 136.0 (C), 132.6 (CH), 131.8 (CH), 128.4 (CH), 128.1 (CH),
127.2 (CH), 126.8 (CH), 78.9 (CH2), 55.8 (CH); MS (EI) m/z (%): 312
(M+, 0.1), 251 (17), 146 (100), 104 (22); HRMS: 312.0238, C12H12N2O4S
required 312.0238.
(E)-N-(furan-3-ylmethylene)pyridine-2-sulfonamide
(9n).
Obtained in 70% yield: mp 146–147 ꢀC; 1H NMR (300 MHz, CDCl3)
d 9.20 (1H, s), 8.71 (1H, dq, J = 4.5, 0.9 Hz), 8.21 (1H, dt, J = 7.8, 0.9 Hz),
8.16 (1H, t, J = 0.9 Hz), 7.96 (1H, td, J = 7.8, 1.5 Hz), 7.54–750 (2H, m),
6.85 (1H, d, J = 1.8 Hz); 13C NMR (75.5 MHz, CDCl3) d 165.9 (CH),
155.8 (C), 152.9 (CH), 150.4 (CH), 145.5 (CH), 138.1 (CH), 127.2 (CH),
123.4 (C), 123.3 (CH), 108.0 (CH); HRMS (ESI): 259.0151 (M+ + Na),
(À)-2-methoxy-N-(2-nitro-1-phenylethyl)
benzenesulfonamide
(12). Obtained according to the conditions in Table 1. Enantiomeric
excess (23%) was determined by HPLC (Chiralpak AD-H), hexane–i-PrOH
80:20, 1 mL/min, major enantiomer tr = 19.8, minor enantiomer tr = 16.5.
[a]2D5 À2.5 (c 0.90, CH2Cl2, ee 23%); 1H NMR (300 MHz, CDCl3) d 7.87
(1H, dd, J = 7.8, 1.8 Hz), 7.46 (1H, td, J = 8.4, 1.8 Hz), 7.18 (3H, m), 7.02
(3H, m), 6.73 (1H, d, J = 8.4 Hz), 5.98 (1H, t, J = 8.4 Hz), 4.88 (2H, m),
4.63 (1H, m); 13C NMR (75.5 MHz, CDCl3) d 155.8 (C), 135.4 (C), 134.9
(CH), 130.1 (CH), 128.91 (CH), 128.86 (CH), 126.6 (C),126.5 (CH),
120.4 (CH), 111.7 (C), 78.7 (CH2), 55.9 (CH3), 55.6 (CH); HRMS (ESI):
359.0676 (M+ + Na), C15H16N2NaO5S required 359.0678.
C10H8N2NaO3S required 259.0153.
Asymmetric Reaction
General procedure.
A solution of amino pyridine 2 (9.7 mg,
0.04 mmol) in dry diethyl ether (Sigma-Aldrich, St. Louis, MO, USA)
(1.2 mL) was added to a suspension of previously dried Cu(OTf)2 (Alfa
Aesar, Karlsruhe, Germany) (14.4 mg, 0.04 mmol) and activated 4 Å MS
(Sigma-Aldrich, St. Louis, MO, USA) (10mg) in nitromethane (Sigma-
Aldrich, St. Louis, MO, USA) (0.6 mL) contained in a Schlenk tube under
nitrogen. The mixture was stirred for 1 h at rt until the formation of a deep
blue solution. The imine 9 (0.2 mmol) dissolved in dry diethyl ether:
nitromethane (0.24mL:0.16 mL) was added via syringe, and the reaction
flask was introduced in a bath at the reaction temperature. After 10min,
N,N-diisopropylethylamine (DIPEA) (Sigma-Aldrich, St. Louis, MO, USA)
(10 mL, 0.06 mmol) dissolved in diethyl ether (0.2mL) was added, and the
reaction mixture was stirred for the indicated time. The mixture was filtered
through a short pad of silica gel eluting with hexane/EtOAc (6:4). The
filtrate was concentrated under reduced pressure and chromatographed
eluting with hexane/EtOAc mixtures to give the corresponding products.
(À)-N-(2-nitro-1-phenylethyl)pyridine-2-sulfonamide (13a).
Enantiomeric excess (83%) was determined by HPLC (Chiralpak AD-H),
hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (R) tr = 23.8, minor
enantiomer (S) tr = 29.7.
mp 114–116 ꢀC; [a]D25 À17.1 (c 0.52, CH2Cl2, ee 83%); 1H NMR
(300 MHz, DMSO-d6) d 8.96 (1H, d, J = 9.0 Hz), 8.49 (1H, dq, J = 4.5,
0.9 Hz), 7.86 (1H, td, J = 7.8, 1.8 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.48 (1H,
ddd, J = 7.5, 4.5, 0.9 Hz), 7.24–7.14 (5H, s), 5.16 (1H, m), 4.85 (1H, dd,
J = 13.2, 5.4 Hz), 4.78 (1H, dd, J = 13.2, 9.6 Hz); 13C NMR (75.5 MHz,
DMSO-d6) d 157.3 (C), 149.6 (CH), 138.1 (CH), 136.4 (C), 128.2 (CH),
127.9 (CH), 126.9 (CH), 126.6 (CH), 121.2 (CH), 78.7 (CH2), 55.7 (CH);
MS (EI) m/z (%): 261 [(M+-NO2), 0.1], 149 (30), 102 (58), 94 (89), 91
(57), 78 (91), 77 (73), 51 (100); HRMS: 261.0695, C13H13N2O2S required
261.0700.
(À)-(R)-4-methyl-N-(2-nitro-1-phenylethyl)benzenesulfonamide
(À)-N-(1-(2-methoxyphenyl)-2-nitroethyl)pyridine-2-sulfonamide
(10).
Obtained according to the conditions in Table 1. Enantiomeric
(13b).
Enantiomeric excess (78%) was determined by HPLC
excess (17%) was determined by HPLC (Chiralcel OD-H), hexane–i-
PrOH 90:10, 1 mL/min, major enantiomer (R) tr = 51.8, minor enantiomer
(S) tr = 45.0.
(Chiralpak AD-H), hexane–i-PrOH 80:20, 1 mL/min, major enantiomer
(R) tr = 38.0, minor enantiomer (S) tr = 44.2.
mp 134–135 ꢀC; [a]D25 À23.6 (c 0.48, CH2Cl2, ee 78%); 1H NMR
(300 MHz, CDCl3) d 8.39 (1H, dq, J = 4.5, 0.9 Hz), 7.81 (1H, dt, J = 7.8,
0.9 Hz), 7.72 (1H, td, J = 7.5, 1.5 Hz), 7.29 (1H, ddd, J = 7.5, 4.8, 1.2 Hz),
7.15 (1H, td, J = 8.4, 1.8 Hz), 6.93 (1H, dd, J = 7.2, 1.5 Hz), 6.71 (2H, m),
6.36 (1H,d, J = 9.9 Hz), 5.28 (1H, m), 4.93 (1H, dd, J = 12.9, 7.5 Hz), 4.72
(1H, dd, J = 12.9, 6.6 Hz), 3.84 (3H, s); 13C NMR (75.5 MHz, CDCl3) d
157.1 (C), 156.5 (C), 149.7 (CH), 137.6 (CH), 130.2 (CH), 129.7 (CH),
126.5 (CH), 122.3 (C), 121.8 (CH), 120.8 (CH), 110.7 (CH), 77.6 (CH2),
55.4 (CH), 55.1 (CH3); HRMS (ESI): 360.0631 (M+ + Na), C14H15N3NaO5S
required 360.0630.
mp 155–157 ꢀC; [a]D25 À14.5 (c 0.11, CH2Cl2, ee 18%), Lit.6 [a]2D5 73.5 (c
0.11, CH2Cl2, for the S-enantiomer, ee 91%), 1H NMR (300 MHz, CDCl3) d
7.64 (2H, d, J = 8.4 Hz), 7.26–7.20 (5H, m), 7.12–7.08 (2H, m), 5.69 (1H, d,
J = 7.8 Hz), 5.00 (1H, q, J = 6.9 Hz), 4.84 (1H, dd, J = 12.9, 6.6 Hz), 4.66 (1H,
dd, J = 12.9, 6.3 Hz), 2.40 (3H, s).
(À)-N-(2-nitro-1-phenylethyl)thiophene-2-sulfonamide (11).
Obtained according to the conditions in Table 1. Enantiomeric excess (8%)
was determined by HPLC (Chiralcel OD-H), hexane–i-PrOH 85:15, 1 mL/
min, major enantiomer tr = 44.5, minor enantiomer tr = 32.0.
Chirality DOI 10.1002/chir

BLAY ET AL.
(À)-N-(2-nitro-1-o-tolylethyl)pyridine-2-sulfonamide (13c).
(1H, ddd, J = 7.8, 4.8, 0.9 Hz), 7.27–7.21 (4H, m), 5.16–5.08 (1H, m), 4.86
(1H, dd, J = 13.2, 5.4 Hz), 4.77 (1H, dd, J = 13.2, 9.6 Hz); 13C NMR
(75.5 MHz, DMSO-d6) d 157.2 (C), 149.7 (CH), 138.2 (CH), 135.5 (C),
132.6 (C), 129.0 (CH), 128.2 (CH), 126.6 (CH), 121.4 (CH), 78.3 (CH2),
55.0 (CH); HRMS (ESI): 342.0319 (M+ + Na), C13H12ClN3NaO4S required
342.0315.
Enantiomeric excess (58%) was determined by HPLC (Chiralpak AD-H),
hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (R) tr = 21.1, minor
enantiomer (S) tr = 24.8.
mp 109–101 ꢀC; [a]D25 À3.3 (c 0.49, CH2Cl2, ee 58%); 1H NMR (300 MHz,
CDCl3) d 8.48 (1H, dq, J = 5.4, 0.9 Hz), 7.82–7.71 (2H, m), 7.40–7.36 (1H,
m), 7.17–7.13 (1H, m), 7.10–6.96 (3H, m), 6.65 (1H, d, J = 6.9 Hz), 5.54
(1H, q, J = 6.9 Hz), 4.89 (1H, dd, J = 13.5, 7.8 Hz), 4.68 (1H, dd, J = 13.5,
6.6 Hz), 2.27 (3H, s); 13C NMR (75.5 MHz, CDCl3) d 157.0 (C), 149.8
(CH), 138.0 (CH), 135.6 (C), 133.4 (C), 130.8 (CH), 128.7 (CH), 126.8
(CH), 126.7 (CH), 126.1 (CH), 121.9 (CH), 78.3 (CH2), 51.8 (CH), 19.0
(CH3); HRMS (ESI): 344.0683 (M+ + Na), C14H15N3NaO4S required
344.0681.
(À)-N-(2-nitro-1-(4-nitrophenyl)ethyl)pyridine-2-sulfonamide
(13h).
Enantiomeric excess (58%) was determined by HPLC (Chiralpak
AD-H), hexane–i-PrOH 70:30, 1 mL/min, major enantiomer (R) tr = 30.9,
minor enantiomer (S) tr = 45.5.
mp 192–194 ꢀC; [a]D25 À27.2 (c 0.14, CH2Cl2, ee 58%); 1H NMR
(300 MHz, DMSO-d6) d 9.17 (1H, d, J = 9.3 Hz), 8.48 (1H, dq, J = 4.8,
0.9 Hz), 8.06 (2H, d, J = 9.0 Hz), 7.89 (1H, td, J = 7.8, 1.8 Hz), 7.73 (1H, dt,
J = 7.8, 0.9 Hz), 7.55 (2H, d, J = 9.0 Hz), 7.49 (1H, ddd, J = 7.8, 4.8, 1.2 Hz),
5.29 (1H, m), 4.94 (1H, dd, J = 13.5, 5.1 Hz), 4.82 (1H, dd, J = 13.5,
9.6 Hz); 13C NMR (75.5 MHz, DMSO-d6) d 157.0 (C), 149.7 (CH), 147.0
(C), 144.0 (C), 138.3 (CH), 128.6 (CH), 126.8 (CH), 123.2 (CH), 121.3
(CH), 77.9 (CH2), 54.9 (CH); HRMS (ESI): 353.0556 (M+ + Na),
(À)-N-(1-(2-chlorophenyl)-2-nitroethyl)pyridine-2-sulfonamide
(13d).
Enantiomeric excess (54%) was determined by HPLC (Chiralpak
AD-H), hexane–i-PrOH 70:30, 1 mL/min, major enantiomer (R) tr =13.7,
minor enantiomer (S) tr =33.1.
mp 127–128 ꢀC; [a]D25 À13.5 (c 0.27, CH2Cl2, ee 54%); 1H NMR
(300 MHz, DMSO-d6) d 9.17 (1H, d, J = 9.3 Hz), 8.45 (1H, dq, J = 4.8,
0.9 Hz), 7.87 (1H, td, J = 7.8, 1.8 Hz), 7.72 (1H, dt, J = 7.8, 0.9 Hz), 7.46
(1H, ddd, J = 7.8, 4.8, 1.2 Hz), 7.46–7.42 (1H, m), 7.32–7.29 (1H, m),
7.20–7.13 (2H, m), 5.63 (1H, dt, J = 9.9, 4.2 Hz), 4.82 (1H, dd, J = 13.2,
4.2 Hz), 4.65 (1H, dd, J = 13.2, 9.9 Hz); 13C NMR (75.5 MHz, DMSO-d6) d
156.8 (C), 149.6 (CH), 138.1 (CH), 133.8 (C), 131.3 (C), 129.7 (CH),
129.1 (CH), 128.6 (CH), 127.2 (CH), 126.7 (CH), 121.1 (CH), 77.7
(CH2), 52.3 (CH); HRMS (ESI): 342.0323 (M+ + Na), C13H12ClN3NaO4S
required 342.0315.
C13H12N4NaO6S required 353.0556.
(À)-N-(1-(3-methoxyphenyl)-2-nitroethyl)pyridine-2-sulfonamide
(13i).
Enantiomeric excess (69%) was determined by HPLC (Chiralpak
IC), hexane–i-PrOH 70:30, 1 mL/min, major enantiomer (R) tr = 38.8, minor
enantiomer (S) tr = 53.3.
mp 123–124 ꢀC; [a]D25 À32.7 (c 0.52, CH2Cl2, ee 69%); 1H NMR
(300 MHz, CDCl3) d 8.52 (1H, dq, J = 4.5, 0.9 Hz), 7.84–7.80 (1H, m),
7.77 (1H, td, J = 7.2, 1.8 Hz), 7.40 (1H, ddd, J = 7.2, 4.8, 1.5 Hz), 7.10 (1H,
t, J = 7.8 Hz), 6.84 (1H, d, J = 7.8 Hz), 6.76–6.68 (3H, m), 5.30–5.22 (1H,
m), 4.92 (1H, dd, J = 13.5, 7.5 Hz), 4.73 (1H, dd, J = 13.5, 6 Hz), 3.69 (3H,
s); 13C NMR (75.5 MHz, CDCl3) d 159.8 (C), 157.2 (C), 149.8 (CH),
138.0 (CH), 136.6 (C), 130.0 (CH), 126.8 (CH), 122.2 (CH), 118.9 (CH),
114.6 (CH), 112.2 (CH), 78.6 (CH2), 55.8 (CH), 55.2 (CH3); HRMS
(ESI): 338.0805 (M+ + H), C14H16N3O5S required 338.0810.
(À)-N-(1-(4-methoxyphenyl)-2-nitroethyl)pyridine-2-sulfonamide
(13e).
Enantiomeric excess (66%) was determined by HPLC (Chiralpak
AD-H), hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (R) tr =31.1,
minor enantiomer (S) tr =36.4.
mp 110–112 ꢀC; [a]D25 À43.4 (c 0.47, CH2Cl2, ee 66%); 1H NMR
(300 MHz, DMSO-d6) d 8.82 (1H, d, J = 9.0 Hz), 8.51 (1H, dq, J = 4.5,
0.9 Hz), 7.87 (1H, td, J = 7.8, 1.8 Hz), 7.68 (1H, dt, J = 7.8, 0.9 Hz), 7.49
(1H, ddd, J = 7.5, 4.5, 0.9 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.70 (2H, d,
J = 8.7 Hz), 5.06 (1H, q, J = 8.1 Hz), 4.86–4.77 (2H, m), 3.67 (3H, s); 13C
NMR (75.5 MHz, DMSO-d6) d 158.8 (C), 157.4 (C), 149.6 (CH), 138.1
(CH), 128.3 (C), 128.2 (CH), 126.5 (CH), 121.3 (CH), 113.6 (CH), 78.8
(CH2), 55.2 (CH), 55.0 (CH3); HRMS (ESI): 360.0640 (M+ + Na),
(À)-N-(2-nitro-1-m-tolylethyl)pyridine-2-sulfonamide (13j).
Enantiomeric excess (70%) was determined by HPLC (Chiralcel OD-H),
hexane–i-PrOH 85:15, 1 mL/min, major enantiomer (R) tr = 29.3, minor
enantiomer (S) tr = 27.3.
mp 140–141 ꢀC; [a]D25 À51.9 (c 0.47, CH2Cl2) (ee 70%); 1H NMR
(300 MHz, DMSO-d6) d 8.89 (1H, d, J = 8.1 Hz), 8.51 (1H, d, J = 3.9 Hz),
7.85 (1H, td, J = 7.5, 1.5 Hz), 7.68 (1H, d, J = 7.8 Hz), 7.47 (1H, ddd,
J = 7.5, 4.5, 0.9 Hz), 7.06–6.94 (4H, m), 5.06 (1H, br s), 4.87–4.74 (2H,
m), 2.15 (3H, s); 13C NMR (75.5 MHz, DMSO) d 157.9 (C), 150.0 (CH),
138.5 (CH), 137.9(C), 136.7 (C), 129.0 (CH), 128.7 (CH), 128.1 (CH),
127.1 (CH), 124.5 (CH), 121.8 (CH), 79.2 (CH2), 56.2 (CH), 21.3 (CH3);
HRMS (ESI): 344.0676 (M+ + Na), C14H15N3NaO4S required 344.0681.
C
14H15N3NaO5S required 360.0630.
(À)-N-(2-nitro-1-p-tolylethyl)pyridine-2-sulfonamide (13f).
Enantiomeric excess (60%) was determined by HPLC (Chiralpak AD-H),
hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (R) tr = 23.2, minor
enantiomer (S) tr = 27.6.
mp 144–145 ꢀC; [a]D25 À29.8 (c 0.58, CH2Cl2, ee 60%); 1H NMR
(300 MHz, CDCl3) d 8.55 (1H, dq, J = 4.8, 0.9 Hz), 7.87 (1H, dt, J = 7.5,
0.9 Hz), 7.80 (1H, td, J = 7.8, 1.5 Hz), 7.43 (1H, ddd, J = 7.2, 4.8, 1.5 Hz),
7.07–7.00 (4H, m) 6.25 (1H, d, J = 7.5 Hz), 5.22 (1H, q, J = 6.6 Hz), 4.92
(1H, dd, J = 13.2, 6.6 Hz), 4.77 (1H, dd, J = 13.2, 6.3 Hz), 2.27 (3H, s); 13C
NMR (75.5 MHz, DMSO-d6) d 157.4 (C), 149.6 (CH), 138.1 (CH), 137.2
(C), 133.5 (C), 128.7 (CH), 126.8 (CH), 126.5 (CH), 121.2 (CH), 78.7
(CH2), 55.4 (CH), 20.5 (CH3); HRMS (ESI): 344.0675 (M+ + Na),
(À)-N-(1-(3-chlorophenyl)-2-nitroethyl)pyridine-2-sulfonamide
(13k).
Enantiomeric excess (60%) was determined by HPLC (Chiralcel
OD-H), hexane–i-PrOH 75:25, 1mL/min, major enantiomer (R) tr =17.4,
minor enantiomer (S) tr =15.4.
mp 147–148 ꢀC; [a]D25 À29.2 (c 0.53, CH2Cl2, ee 60%); 1H NMR
(300 MHz, MeOD) d 8.96 (1H, d, J = 9.0 Hz), 8.49 (1H, dq, J = 4.5,
0.9 Hz), 7.86 (1H, td, J = 7.8, 1.8 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.48 (1H,
ddd, J = 7.5, 4.5, 0.9 Hz), 7.24–7.14 (5H, s), 5.16 (1H, m), 4.85 (1H, dd,
J = 13.2, 5.4 Hz), 4.78 (1H, dd, J = 13.2, 9.6 Hz); 13C NMR (75.5 MHz,
MeOD) d 157.3 (C), 149.6 (CH), 138.1 (CH), 136.4 (C), 128.2 (CH),
127.9 (CH), 126.9 (CH), 126.6 (CH), 121.2 (CH), 78.7 (CH2), 55.7 (CH);
HRMS (ESI): 364.0139 (M+ + Na), C13H12ClN3NaO4S required 364.0135.
C14H15N3NaO4S required 344.0681.
(À)-N-(1-(4-chlorophenyl)-2-nitroethyl)pyridine-2-sulfonamide
(13g).
Enantiomeric excess (66%) was determined by HPLC (Chiralpak
AD-H), hexane–i-PrOH 80:20, 1 mL/min, major enantiomer (R) tr = 26.8,
minor enantiomer (S) tr = 37.7.
(À)-N-(2-nitro-1-(3-nitrophenyl)ethyl)pyridine-2-sulfonamide
mp 163–165 ꢀC; [a]D25 À35.9 (c 0.48, CH2Cl2, ee 66%); 1H NMR
(300 MHz, DMSO-d6) d 9.00 (1H, d, J = 9.3 Hz), 8.50 (1H, dq, J = 4.8,
0.9 Hz), 7.89 (1H, td, J = 7.8, 1.5 Hz), 7.71 (1H, dt, J = 7.8, 0.9 Hz), 7.51
Chirality DOI 10.1002/chir
(13l).
Enantiomeric excess (66%) was determined by HPLC (Chiralcel
AD-H), hexane–i-PrOH 70:30, 1 mL/min, major enantiomer (R) tr = 18.6,
minor enantiomer (S) tr = 16.7.

ASYMMETRIC AZA-HENRY REACTION
mp 166–168 ꢀC; [a]D25 À47.2 (c 0.4, CH2Cl2, ee 66%); 1H NMR (300 MHz,
DMSO-d6) d 9.2 (1H, br s), 8.44 (1H, ddd, J = 4.5, 1.5, 0.9 Hz), 8.13 (1H, t,
J = 2.1 Hz), 8.02 (1H, ddd, J = 8.4, 2.4, 1.2 Hz), 7.85 (1H, td, J = 7.8, 1.8 Hz),
7.74–7.69 (2H, m), 7.50 (1H, t, J = 7.8 Hz), 7 (1H, ddd, J = 7.8, 4.8, 1.2 Hz),
5.31 (1H, br s), 4.95 (1H, dd, J = 13.8, 5.1 Hz), 4.84 (1H, dd, J = 13.8,
9.6 Hz); 13C NMR (75.5 MHz, DMSO-d6) d 157.5 (C), 150.2 (CH), 147.9
(C), 139.1 (C), 138.8(CH), 134.6 (CH), 130.4 (CH), 127.2 (CH), 123.4
(CH), 122.6 (CH), 121.9 (CH), 78.5 (CH2), 55.4 (CH); HRMS (ESI):
375.0370 (M+ + Na), C13H12N4NaO6S required 375.0375.
Synthesis of (+)-(S)-methyl 2-phenyl-2-(pyridine-2-sulfonamido)
acetate (14) from (S)-(+)-phenylglycine methyl ester hydrochlo-
ride. A solution of pyridine-2-sulfonyl chloride (195 mg, 1.1 mmol)
in CH2Cl2 (10 mL) was added to a solution of (S)-(+)-phenylglycine
methyl ester hydrochloride (15, 208 mg, 1 mmol) and Et3N (277 mL,
2 mmol) in CH2Cl2 (40 mL) cooled to 0 ꢀC. The resulting mixture was
allowed to reach rt and was stirred for 2 h. The reaction mixture was
washed with saturated aqueous NaHCO3 (2 Â 25 mL) water (25 mL).
The organic layer was dried over anhydrous MgSO4 and evaporated
under reduced pressure. Column chromatography eluting with hexane/
EtOAc (6:4) gave 281 mg (92%) of (S)-14. Enantiomeric excess (99%)
was determined by HPLC (Chiralcel OD-H), hexane:i-PrOH 80:20,
1 mL/min, major enantiomer (S) tr = 12.3, minor enantiomer (R) tr = 13.9.
[a]2D5 +113.7 (c 0.59, CHCl3, ee 99%).
(À)-N-(2-nitro-1-(thiophen-3-yl)ethyl)pyridine-2-sulfonamide
(13m).
Enantiomeric excess (77%) was determined by HPLC (Chiralpak
AD-H), hexane–i-PrOH 75:25, 1 mL/min, major enantiomer (R) tr = 18.5,
minor enantiomer (S) tr = 20.5.
mp 135–136 ꢀC; [a]D25 À32.8 (c 0.24, CH2Cl2, ee 77%); 1H NMR
(300 MHz, DMSO-d6) d 8.84 (1H, d, J = 9.3 Hz), 8.53 (1H, dq, J = 4.5,
0.9 Hz), 7.91 (1H, td, J = 7.8, 1.5 Hz), 7.74 (1H, d, J = 7.8 Hz), 7.52 (1H,
ddd, J = 7.5, 4.5, 0.9 Hz), 7.33–7.28 (2H, m), 6.94 (1H, dd, J = 5.1, 1.5 Hz),
5.27–5.19 (1H, m), 4.87 (1H, dd, J = 13.2, 5.4 Hz), 4.78 (1H, dd, J = 13.2,
9.3 Hz); 13C NMR (75.5 MHz, DMSO-d6) d 157.3 (C), 149.6 (CH), 138.2
(CH), 137.2 (C), 126.6 (CH), 126.5 (CH), 126.2 (CH), 123.4 (CH), 121.2
(CH), 78.5 (CH2), 51.5 (CH); HRMS (ESI): 336.0095 (M+ + Na),
(À)-(R)-methyl 2-amino-2-phenylacetate (16).
To a solution of
(R)-14 (30.0 mg, 0.098 mmol, ee 83%) in MeOH (2.5 mL) and THF
(0.65 mL) under nitrogen at 0 ꢀC was added Mg powder (23.6 mg,
0.98 mmol), and the resulting suspension was stirred at rt for 4 h. Then,
diethyl ether (3.8 mL) and a saturated aqueous NH4Cl (3.8 mL) were
added, and the resulting solution was stirred for additional 2 h at rt. The
reaction mixture was diluted with water (15 mL) and extracted with
diethyl ether (3 Â 15 mL). The combined organic layers were dried over
anhydrous MgSO4 and concentrated under reduced pressure. Chroma-
tography on a short pad of silica gel gave 14.5 mg (87%) of compound 16.
[a]2D5 À90.0 (c 0.05, MeOH, ee 83%), Lit59 [a]2D5 +130 (c 0.02, MeOH, for
the S-enantiomer); 1H NMR (300 MHz, CDCl3) d 7.37–7.30 (5H, m), 4.64
(1H, s), 3.70 (3H, m), 2.56 (2H, br s).
C11H11N3NaO4S2 required 336.0089.
(À)-N-(1-(furan-3-yl)-2-nitroethyl)pyridine-2-sulfonamide
(13n).
Enantiomeric excess (60%) was determined by HPLC (Chiralpak
AY-H), hexane–i-PrOH 70:30, 1 mL/min, major enantiomer (R) tr = 32.8,
minor enantiomer (S) tr =27.9.
mp 152–154 ꢀC; [a]D25 À15.0 (c 0.25, CH2Cl2, ee 60%); 1H NMR
(300 MHz, DMSO-d6) d 8.72 (1H, d, J = 9.0 Hz), 8.60 (1H, dq, J = 4.8,
0.9 Hz), 7.98 (1H, td, J = 7.8, 1.8 Hz), 7.82 (1H, dt, J = 7.8, 0.9 Hz), 7.57
(1H, ddd, J = 7.5, 4.5, 0.9 Hz), 7.43–7.42 (2H, m), 6.32 (1H, s), 5.16–5.08
(1H, m), 4.83 (1H, dd, J = 12.9, 5.7 Hz), 4.76 (1H, dd, J = 12.9, 8.7 Hz);
13C NMR (75.5 MHz, DMSO-d6) d 157.4 (C), 149.7 (CH), 143.4 (CH),
140.4 (C), 138.3 (CH), 126.8 (CH), 121.4 (C), 121.3 (CH), 108.9 (CH),
78.4 (CH2), 48.0 (CH); HRMS (ESI): 320.0316 (M+ + Na), C11H11N3NaO5S
required 320.0317.
RESULTS AND DISCUSSION
In the onset of our research, we tested the effect of different
N-sulfonyl groups. Thus, N-tosyl- (6), N-(2-thiophenyl)sulfo-
nyl- (7), N-(2-methoxyphenyl) sulfonyl- (8), and N-(2-pyri-
dyl)sulfonyl- (9) imines derived from benzaldehyde were pre-
pared, and their reaction with nitromethane in the presence of
aminopyridine 2 (the best ligand for the enantioselective
Henry reaction44) and Cu(II) was studied (Scheme 1).
Initially, the reaction was carried out under conditions
similar to those described by Feng,6 using ligand 2, Cu
(OTf)2, catalytic DIPEA in THF-nitromethane, and 4 Å molec-
ular sieves. The results are gathered in Table 1.
Determination of the Absolute Stereochemistry of 13a
Synthesis of (À)-(R)-methyl 2-phenyl-2-(pyridine-2-sulfonamido)
acetate (14) by ozonolysis of compound 13a.
To a solution of
13a (50.0 mg, 0.16 mmol) in MeOH (3 mL) under nitrogen was added a
30% solution of NaOMe in MeOH (46.3 mL, 0.24 mmol), and the resulting
solution was stirred at rt for 10 min. This methanolic solution was cooled
to À78 ꢀC, and a stream of O3 was passed through during 60 min. The
reaction was purged with N2 to remove the excess of O3. The resulting
solution was allowed to reach rt, BF3ÁEt2O (0.4 mL) was added, and the
mixture was heated at reflux temperature for 3.5 h. After cooling to rt,
saturated aqueous NaHCO3 (10 mL) was added, the organic solvent was
removed under reduced pressure, and the resulting aqueous solution
was extracted with dichloromethane (3 Â 15 mL), washed with brine
(10 mL), dried over anhydrous MgSO4, and concentrated under reduced
pressure. The mixture was purified by column chromatography eluting
with hexane/EtOAc (7:3) to give 35.7 mg (71%) of (R)-14. Enantiomeric
excess (83%) was determined by HPLC (Chiralcel OD-H), hexane : i-
PrOH 80:20, 1 mL/min, major enantiomer (R) tr = 13.4, minor enantiomer
(S) tr = 12.4.
The best results were obtained with the N-(2-methoxyphe-
nyl) sulfonyl imine 8 and especially with the N-(2-pyridyl)
1
[a]2D5 À50.2 (c 0.53, CHCl3, ee 83%). H NMR (300 MHz, CDCl3) d 8.59
(1H, dq, J = 4.5, 0.9Hz), 7.82–7.74 (2H, m), 7.43–7.39 (1H, m), 7.29–7.23
(5H, m), 6.13 (1H, d, J= 8.1 Hz), 5.40 (1H, d, J = 8.1Hz), 3.67 (3H, s); 13C
NMR (75.5MHz, CDCl3) d 170.5, (C), 157.8 (C), 149.7 (CH), 137.8 (CH),
135.4 (C), 128.7 (CH), 128.5 (CH), 127.2 (CH), 126.5 (CH), 121.7 (CH),
60.1 (CH), 53.0 (CH3); HRMS (ESI): 329.0576 (M+ + Na), C14H14N2NaO4S
required 329.0572.
Scheme 1. Copper-catalyzed addition of nitromethane to different
N-sulfonyl imines.
Chirality DOI 10.1002/chir

BLAY ET AL.
TABLE 2. Addition of nitromethane to N-sulfonyl imine 9a
TABLE 3. Addition of nitromethane to N-sulfonyl imine 9a
according to Scheme 1. Effect of ligand, amount of base
according to Scheme 1. Effect of base and MSa
and solventa
T
t
Yield
(%)
ee
Entry
L
Solvent
Base
Yield (%)
ee (%)b
Entryb
Base
MS
(ꢀC) (h)
(%)c
1
2
3
4
5
6
7
8
2
1
3
4
5
2
2
2
2
2
2
2
2
2
2
2
2
THF
THF
THF
THF
THF
THF
THF
THF
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (20 mol%)
DIPEA (10 mol%)
DIPEA (50 mol%)
DIPEA (100 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
DIPEA (30 mol%)
80
65
70
70
50
54
–
59
6
13
6
0
55
–
1d
2d
3d
4
5
6
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
Na2CO3
0BProton
SpongeW
Bu3N
4 Å MS
3 Å MS
5 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
0
0
0
0
0
0
0
5
5
5
4
4
3
24
85
80
85
90
90
65
50
74
56
49
82
79
63
72
7
85
85
60
65
85
95
90
90
90
85
50
39
3
26
57
38
55
64
64
74
9
THF
8
9
10
11
4 Å MS
4 Å MS
4 Å MS
4 Å MS
0
À15
À25
À40
22
3
3
70
85
80
80
44
83
78
79
10
11
12
13
14
15
16
17
EtOH
CH2Cl2
Toluene
CH3NO2
Dioxane
t-BuOMe
i-Pr2O
Et2O
DIPEA
DIPEA
DIPEA
3
a2 (20 mol%), Cu(OTf)2 (20 mol%), base (30 mol%), MS (50 mg/mmol imine),
Et2O.
bExperiments in entries 1–5 were not checked before the annotated times.
cDetermined by HPLC using chiral stationary phases.
d100 mg MS/mmol imine was used.
aLigand (20 mol%), Cu(OTf)2 (20 mol%), base, 4 Å MS (100 mg/mmol imine),
0 ꢀC.
bDetermined by HPLC using chiral stationary phases.
with different bases and with different kinds and amounts of
molecular sieves (Table 3). Changing 4 Å MS to 3 or 5 Å MS
led to a decrease in the enantiomeric excess of the product
(entries 1–3). The amount of 4 Å MS was also adjusted, so
when the reaction was carried out with 50 mg MS per mmol
of imine, an appreciable increase in enantioselectivity was
observed with respect to the reaction in the presence of
100 mg MS per mmol of imine (entry 1 versus entry 4).
Although the use of MS as an additive in several enantioselec-
tive reactions involving nitrocompounds6,12,13,22 has been
shown to have a beneficial effect on the yield and stereoselec-
tivity, the mechanism of this effect is not clear. It has been
suggested that, further to act as scavenger for water and
proton contaminants that may have a deleterious effect,12,60
MS could facilitate the enolization of nitromethane.61,62 It
may also be possible that a heterogeneous catalyst is formed
from the copper complex and molecular sieves, which may
help to improve the stability of the catalyst and its stereodiffer-
entiation ability.63,64 Other bases were tested, but none of them
performed better than DIPEA. Finally, we tested the reaction at
lower temperatures. A slight increase in the enantioselectivity
was observed when the temperature was decreased from 0 to
À15ꢀC (entry 9); however, further decrease of the temperature
(entries 10–11) did not bring about any noticeable improve-
ment of the reaction.
sulfonyl imine 9a. It is remarkable that both compounds
8 and 9a have a potential coordinating group at the sulfone
substituent, which may indicate that the reaction proceed
through a chelated transition state.1 As a matter of fact, the
chelating character of the pyridine nitrogen has been shown
to play an essential role in other metal-catalyzed enantioselec-
tive reactions with N-(2-pyridyl)sulfonyl imines.50–52
Further optimization was carried out with N-(2-pyridyl)sul-
fonyl imine 9a. First, we tested the iminopyridine ligand 1
under the same conditions that allowed obtaining compound
13a with 65% yield but only 6% ee (Table 2, entry 2). Then,
we focused our study on aminopyridine ligands 3–5 (entries
3–5), but none of them improved the results obtained with
ligand 2. The optimal amount of base was found to be
30 mol%. Higher base loads had a deleterious effect on the
enantioselectivity (entries 8–9), whereas when using a too
low amount of base (10 mol%), the reaction did not take place
(entry 7). The effect of the different solvents was also tested.
Protic solvents (EtOH) provided the expected product almost
in racemic form (entry 10). Toluene (entry 12) gave almost
the same results as THF, whereas dichloromethane gave
lower yield and ee (entry 11). Ether-type solvents gave the
best performance, the best result being obtained in diethyl
ether (entry 17).
Once the best reaction conditions have been established,
we studied the scope of the reaction with several N-(2-
pyridyl)sulfonyl aldimines (Scheme 2). The results are gath-
ered in Table 4.
Once the amount of the base (30 mol%) and the solvent
(diethyl ether) had been established, we studied the reaction
In general, the reactions with aromatic and heteroaro-
matic65 sulfonamides 9a–n were completed in less than 3 h,
providing the expected nitro sulfonamides 13a–n with fair
yields and moderate enantiomeric excesses. The highest ee
values were obtained with the imines derived from benzalde-
hyde (entry 1), 2-methoxybenzaldehyde (entry 2), and
thiophene-3-carbaldehyde (entry 10) with ee close to 80%.
However, with the rest of imines, the ee values were lower,
being around 60% in most cases.
1During the reviewing process, one of the referees suggested that the re-
action may not proceed through a chelated transition state, because imine
7, bearing a thiophene ring with a potentially coordinating sulfur atom,
gave poor results. Although the chelating character of N-(2-pyridyl)sulfo-
nyl imines has been demonstrated in other enantioselective reactions, it
cannot be excluded for the thiophene derivative. However, the size and
bite angle of the potential chelate formed with the thiophene derivative
may largely differ from those of the pyridine derivative, which may
explain the different enantioselectivities obtained in entries 2 and 4 of
Table 1.
Compounds 13 can be easily transformed into N-(2-pyri-
dyl)sulfonyl amino acid derivatives. Thus, upon ozonolysis
Chirality DOI 10.1002/chir

ASYMMETRIC AZA-HENRY REACTION
Scheme 2. Enantioselective addition of nitromethane to N-sulfonyl
imines 9.
TABLE 4. Addition of nitromethane to N-sulfonyl imines 9a
Entry
9
R
t (h)
13
Yield (%) ee (%)b
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
Ph
3
3
3.5
4
3
3
3
3
3
3
3
3
3
3
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
77
88
70
64
60
71
67
54
55
63
68
50
70
72
83
78
58
54
64
60
66
58
69
70
60
66
77
60
2-MeOC6H4
2-MeC6H4
2-ClC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
3-MeOC6H4
3-MeC6H4
3-ClC6H4
Scheme 3. Determination of the absolute stereochemistry of compound 13a.
9
10
11
12
13
14
9j
9k
9l
3-NO2C6H5
9m 3-Thiophenyl
9n 3-Furanyl
a2 (20 mol%), Cu(OTf)2 (20 mol%), DIPEA (30 mol%), 4 Å MS (50 mg/mmol
imine), Et2O, À15 ꢀC.
bDetermined by HPLC using chiral stationary phases.
of the nitronate of 13a followed by esterification with metha-
nol in the presence of BF3ÁEt2O, we could obtain directly the
N-sulfonyl amino ester 14 (Scheme 3).
Scheme 4. Deprotection of the amine.
The absolute stereochemistry of compound 14, and hence
that of compound 13a, was determined by comparison with
the same product prepared by sulfonylation of commercially
available (S)-(+)-methyl phenylglycinate (15) with 2-pyridyl-
sulfonyl chloride (Scheme 3). The product prepared in this
way showed opposite optical rotation sign to that prepared
from 13a. In this way, the aza-Henry product 13a was
assigned the R configuration at the stereogenic center. The
rest of compounds 13b–n were tentatively assigned as R on
the assumption of a uniform mechanistic pathway.2
One of the advantages of the N-(2-pyridyl)sulfonyl group
is that it can be removed under milder conditions than other
N-sulfonyl groups. Thus, compound 14 could be transformed
into methyl phenylglycinate upon treatment with magnesium
in MeOH–THF with good yield and without loss of optical
purity (Scheme 4).
the coordination of the N-(2-pyridyl)sulfonyl imine to the cop-
per atom of the 2-Cu(OTf)2 complex and the presence of a
deprotonated molecule of nitromethane (a nitronate). A com-
petitive equilibrium between DIPEA and the initial 2-Cu(OTf)
with an inactive 2-CuOTf(DIPEA) is established. The reac-
2
tion requires the presence in the solution of enough base to
deprotonate the nitromethane. If the base is in excess with re-
spect to the Lewis acid, the equilibrium is shifted toward the
inactive complex, hence trapping the chiral Lewis acid. The
remaining base induces a nonenantioselective pathway be-
tween the nitronate and the uncoordinated imine. If the Lewis
acid is in excess with respect to the base, then the low con-
centration of free amine brings about a slow reaction with
low conversion.
The results obtained with different amounts of base
(Table 2, entries 1, 6–9) can be rationalized (Scheme 5) in
terms very similar to those described by Jørgensen66,67 and
for us45 for the Cu(II)-catalyzed addition of nitromethane to
a-keto esters. The enantioselective catalytic pathway requires
With respect to the stereochemical mechanism, the results
indicate a preference for the nitronate to attack from the Si
face of the CN double bond. According to our previous
studies on the Henry reaction,42–49 we propose a plausible
stereochemical model that would account for the observed
stereochemistry (Fig. 2). This model is similar to that
proposed for the Henry reaction with aldehydes catalyzed
by 2-Cu(OAc)2,44 but with the imine coordinating the two
more acidic equatorial positions of the Cu(II) ion by the
azomethine and pyridine nitrogen atoms, for a maximum
electrophilic activation. The nitronate would occupy the less
Chirality DOI 10.1002/chir
2All compounds 13 showed identical optical rotation signs (À). Com-
pounds 13a–h and 13n also showed identical behavior during HPLC
analysis with the Chiralpak AD-H column. Compounds 13j and 13k
showed identical behavior with the Chiralcel OD-H column.

BLAY ET AL.
Scheme 5. Competitive catalytic and non-catalytic pathways.
2. For a recent review on this reaction, see: Ting A, Schaus SE. Organocata-
lytic asymmetric Mannich reactions. New methodology, catalyst design,
and synthetic applications. Eur J Org Chem 2007;5797–5815.
3. For a recent review on this reaction, see: Marqués-López E, Merino P,
Tejero P, Herrera RP. Catalytic enantioselective aza-Henry reactions.
Eur J Org Chem 2009;2401–2420.
4. Lucet D, Le Gall T, Mioskowski C. The chemistry of vicinal diamines.
Angew Chem Int Ed 1998;37:2580–2627.
5. Bernardi L, Bonini BF, Capitò E, Dessole G, Comes-Franchini M,
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7. For a review on the Nef reaction, see: Ballini R, Petrini M. Recent syn-
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Fig. 2. Proposed transition state model for the copper-catalyzed enantiose-
lective aza-Henry reaction of imines 9 with ligand 2.
8. For a review on the Nef reaction, see: Foresti E, Palmieri G, Petrini M,
Profeta R. Highly diastereoselective addition of nitromethane anion to chi-
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derivatives. Org Biomol Chem 2003;1:4275–4281.
hindered apical position from which it would be transferred to
the Si face of the imine.
9. For a review on the Nef reaction, see: Matt C, Wagner A, Moiskowski C.
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11. For representative work, see: Zinc catalyst Trost BM, Lupton DW.
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12. For representative work, see: Zinc catalyst Palomo C, Oiarbide M,
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CONCLUSIONS
In conclusion, we have described a new catalytic enantiose-
lective aza-Henry reaction. The reaction expands the applica-
tion of camphor-derived aminopyridine ligands in asymmetric
catalysis. This is the first example of aza-Henry reaction with
N-(2-pyridyl)sulfonyl imines, which have the advantage of an
easy removal of the N-protecting group under mild reductive
conditions.
ACKNOWLEDGMENTS
Financial support from the Ministerio de Ciencia e Innovación
and FEDER (CTQ2009-13083) and from Generalitat Valenciana
(ACOMP/2011/267) is acknowledged. V H-O thanks the
Universitat de València for a pre-doctoral grant (V Segles
program).
15. For representative work, see: Copper catalyst Anderson JC, Howell GP,
Lawrence RM, Wilson CS. An asymmetric nitro-Mannich reaction applica-
ble to alkyl, aryl, and heterocyclic imines. J Org Chem 2005;70:5665–5670.
16. For representative work, see: Copper catalyst Tan C, Liu X, Wang L,
Wang J, Feng X. Highly enantioselective aza-Henry reaction of ketoimines
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