An efficient synthetic approach towards a single diastereomer of (2R,3R)-N 2,N 3-bis((S)-1-phenylethyl)butane-2,3-diamine via metalation and demetalation

Article abstract of DOI:10.1007/s11243-019-00351-1

Abstract: A facile synthetic approach has been adopted towards the synthesis of (2R,3R)-N²,N³-bis((S)-1-phenylethyl)butane-2,3-diamine via demetalation of its dichloro Zn(II) complex, which itself was separated from a mixture of dias

Full text of DOI:10.1007/s11243-019-00351-1

Transition Metal Chemistry
https://doi.org/10.1007/s11243-019-00351-1
An efcient synthetic approach towards a single diastereomer
2
3
oꢀ (2R,3R)‑N ,N ‑bis((S)‑1‑phenylethyl)butane‑2,3‑diamine
via metalation and demetalation
1
2
1
Juhyun Cho · Saira Nayab · Jong Hwa Jeong
Received: 17 July 2019 / Accepted: 14 August 2019
©
Springer Nature Switzerland AG 2019
Abstract
2
3
A facile synthetic approach has been adopted towards the synthesis of (2R,3R)-N ,N -bis((S)-1-phenylethyl)butane-2,3-di-
amine via demetalation of its dichloro Zn(II) complex, which itself was separated from a mixture of diastereomeric Zn(II)
complexes by fractional crystallization. The synthesized chiral 1,2-diamine ligand was evaluated as a chiral auxiliary for the
Cu(II)-catalysed asymmetric Henry reaction of 3-phenylpropanal and nitromethane, yielding (S)-1-nitro-4-phenylbutan-2-ol
in excellent yields (up to 99%) and enantioselectivities (up to 97%).
Graphic abstract
2
3
A facile synthetic approach towards (2R,3R)-N ,N -bis((S)-1-phenylethyl)butane-2,3-diamine (2b) via fractional crystal-
lization and demetalation of its Zn(II) complex has been adopted. 2b served as a highly enantioselective pro-ligand with
Cu(OAc) for asymmetric Henry reaction of 3-phenylpropanal and nitromethane in the presence of base with 97%>ee and
2
9
9% yield.
Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11243-019-00351-1) contains
supplementary material, which is available to authorized users.
Chiral 1,2-diamines have emerged as powerful tools for
the synthesis of catalysts and bioactive compounds [1–7].
Diamines, especially C -symmetric diamines, have been
2
utilized as chiral auxiliaries for a wide array of asymmetric
Extended author information available on the last page of the article
Vol.:(0
1
123456789)
3

Transition Metal Chemistry
chemical transformations [8–10]. For example, they have
been used to develop a variety of innovative chiral catalysts
for reactions such as oxidations, reductions, and hydrogena-
tions. Additionally, they have also been used in a variety
of carbon–carbon bond-forming reactions such as allylic
alkylation, metathesis, Michael addition, aldol, cycloaddi-
tion, and ring-opening reactions [11–22]. The prevalence of
the diamine motif in catalysts and bioactive compounds has
led to the advancement of synthetic methodology for chiral
diamines [23–29]. However, when using these methods, sev-
eral limitations arise: limited scope, necessity for resolution,
proper temperature control, and low yields [30]. Due to these
limitations, it is a challenge to develop facile and eꢀcient
synthetic routes towards diverse chiral diamines that are
enantiomerically pure; such an approach would greatly facil-
itate the development of new diamine-based catalysts and
drugs. In previous years, we explored the generation of an
enantiopure ligand by demetalation of its enantiopure metal
complex. This was achieved in an economic manner by frac-
tional crystallization from a mixture of two diastereomeric
Zn(II) complexes [31]. Herein, we describe the synthetic
chemical shifts were recorded in ppm units (δ) relative
to residual protium in the deuterated solvents (CDCl ,
3
δ=7.26). Coupling constants were reported in Hertz (Hz).
Data were recorded as m=multiplet, br=broad, s=singlet,
d=doublet, t=triplet, and q=quartet. For the homonuclear
decoupling NMR spectroscopy, Bruker Avance digital 600-
NMR spectrometer was used. Infrared spectra (IR) (neat)
were recorded on Bruker FT-IR Alpha, and the data were
−1
reported in cm . Elemental analyses were determined using
the EA 1108-Elemental Analyzer at the Chemical Analy-
sis Laboratory of the Centre for Scientiꢂc Instruments of
Kyungpook National University. Enantiomeric excesses (ee)
were determined by HPLC with chiral OD-H and AD-H col-
umns using HPLC-grade IPA and n-Hex as eluting solvents.
Synthetic procedures
2
3
Synthesis oꢀ N ,N ‑bis(1‑phenylethyl)butane‑2,3‑diamine
(2)
The analogous method as reported in the literature was
applied for synthesis of 2 [33]. The grafting of methyl
group at ethylene backbone resulted in 2 as a mixture of
SRRS, SSSS diastereomers in ratio of 1:0.7. The separa-
tion of resultant diastereomers via column chromatography
was not possible even after several trials. Thus, the crude
ligand was subjected in next reaction without separation of
diastereomers.
2
3
procedure to aꢁord (2R,3R)-N ,N -bis((S)-1-phenylethyl)
butane-2,3-diamine through the metalation and demetala-
tion of Zn(II) complexes. A preliminary catalytic study of
this ligand in Cu-catalysed asymmetric Henry reactions is
also presented.
Experimental section
Synthesis oꢀ 3b
General consideration and materials
EtOH (10 mL) solution of crude ligand 2 (4.00 g,
The alkylation of diimine using MeLi was carried out using
the standard Schlenk techniques and glove box under argon.
THF was dried over Na/benzophenone ketyl, while CH Cl
13.49 mmol) was treated with EtOH (10 mL) solution of
ZnCl (1.83 g, 13.49 mmol) at ambient temperature for
2
overnight. The precipitated solid was ꢂltered and subse-
2
2
was dried over CaH and deoxygenated by distillation under
quently washed with cold EtOH (10.00 mL× 2) and Et O
2
2
argon prior to use. Degas water was prepared by freeze and
(5.00 mL×2) to get a mixture of two diastereomeric Zn(II)
complexes as a ꢂnal product (5.19 g, 89%). Fractional crys-
tallization was carried out for the separation of two diastere-
omeric complexes using EtOH. The pure 3b was separated
from 3a as a ꢂne crystalline product [(3b: 4.50 g, 77%)].
The solubility of 3a in various organic solvents makes it
impractical to precipitate and separate it from mother liq-
uor in appreciable and quantitative amount. Characterization
data for 3b: Anal. Calcd. for C H Cl N Zn: C, 55.51; H,
thaw process. Ethanol (EtOH), methanol (MeOH), n-hexane
(
n-Hex), ethyl acetate (EA), isopropanol (IPA), and diethyl
ether (Et O) were purchased from high-grade commercial
2
supplier and used as received. Starting materials, MeLi
(
(
1.5 M in diethyl ether), (S)-methyl benzyl amine, Glyoxal
40% aqueous solution), ZnCl , Cu(OAc) , NaCN, and
2
2
i
N,N-diisopropylethylamine ( Pr NEt) were purchased from
2
Aldrich. NMR solvents were purchased from Aldrich and
stored over 3-Å molecular sieves. The synthesis of 1 was
carried out according to reported method [32].
2
0
28
2
2
1
6.52; N, 6.47. Found: C, 55.54; H, 6.55; N, 6.49. H NMR
(500 MHz, CDCl ) δ 7.42–7.32 (m, 4H, ArH), 7.35–7.32
3
(
m, 2H, ArH), 7.23–7.21 (m, 4H, ArH), 4.16 (sext, 2H,
Instrumentation
J = 6.7, 12.13 Hz, Ph(CH) (NH) ), 2.83–2.80 (m, 2H,
2 2
CH (CH) ), 1.58 (br s, 2H, (NH) ), 1.69 (d, 6H, J=6.7 Hz,
3
2
2
1
13
13
H (operating at 500 MHz) and C (operating at 125 MHz)
PhCH(CH ) ), 1.26 (d, 6H, J=6.7 Hz, NHCH(CH ) .
C
3
2
3 2
NMR spectra were recorded on a Bruker Avance Digi-
tal 500-NMR spectrometer (Bruker, Billerica, MA), and
NMR (125 MHz, CDCl ) δ 140.2 (2C), 129.4 (4C), 128.2
3
(4C), 125.7 (2C), 55.1 (2C), 54.6 (2C), 24.9 (2C), 15.0
1
3

Transition Metal Chemistry
−
1
3
(
2C). IR (solid neat; cm ): ν(N–H) 3458 w; ν(C–H) 3242
w; ν(C–H) 3060 w; ν(C=C), 1651 s; ν (C–H sp ) 1449 m;
bend
bend
3
2
2
w; ν(C=C), 1648 s; ν (C–H sp ) 1435 m; ν (C–H sp )
ν
(C–H sp ) 910 m.
bend
bend
9
35 m.
General procedure for Henry reaction
2
3
Synthesis oꢀ (2R,3R)‑N ,N ‑bis(S‑1‑phenylethyl)
butane‑2,3‑diamine, (2b)
A 20-mL flask was charged with Cu(OAc) (0.0908 g,
2
2
3
0
.50 mmol) and (2R,3R)-N ,N -bis((S)-1-phenylethyl)
CH Cl (20 mL) solution of 3b (4.00 g, 9.24 mmol) was
butane-2,3-diamine (0.148 g, 0.50 mmol) in IPA (10.00 mL)
and stirred at room temperature for 1 h to get in situ-gen-
erated diacetato Cu(II) complexes, and the resultant solu-
tion was applied to Henry reaction. Then, nitromethane
(CH NO ) (1.00 mL, 20.00 mmol) was added and stirred for
2
2
treated with aqueous solution (10 mL) of NaCN (3.17 g,
6
4.68 mmol) and stirred for 2 h at ambient temperature. The
clear organic layer was separated, dried over MgSO and
4
,
concentrated to yield 2a as light yellow oil (2.45 g, 90%).
3
2
Anal. Calcd. for C H N : C, 81.03; H, 9.52; N, 9.45.
10 min followed by the addition of benzaldehyde (0.50 mL,
2
0
28
2
1
Found: C, 81.08; H, 9.51; N, 9.49%. H NMR (500 MHz,
5.00 mmol) or 3-phenylpropanal (0.65 mL, 5.00 mmol).
i
CDCl ) δ 7.26–7.22 (m, 8H, ArH), 7.17–7.13 (m, 2H, ArH),
Finally, Pr NEt (0.62 g, 0.50 mmol) was added in the pre-
3
2
3
.75 (q, 2H, J=6.5, 18.34 Hz, Ph(CH) ), 2.01–1.98 (m, 2H,
vious mixture which acts as an eꢁective co-catalyst and
stirred for prescribed time at room temperature [34, 35].
The reaction progress was monitored by thin-layer chroma-
tography (TLC). Upon completion, the reaction mixture was
evaporated and the crude product was puriꢂed by column
chromatography using AcOEt/n-Hex eluent.
2
NH(CH) ), 1.50 (br s, 2H, (NH) ), 1.24 (d, 6H, J=6.5 Hz,
2
2
1
3
PhCH(CH ) ), 0.82 (d, 6H, J=6.5 Hz, NHCH(CH ) ).
C
3
2
3 2
NMR (125 MHz, CDCl ) δ 145.9, 128.3, 126.8, 126.7, 55.1,
3
−
1
5
5.0, 25.5, 16.5. IR (oily liquid neat; cm ): ν(N–H) 3300
Single diastereomer (2b) obtained from demetalation of pure
Zn(II) complex (3b)
SCAZnCl2.002.esp
MIX(R,S)CA-Lignad.001.esp
Pure Zn(II) complex, 3b, separated by fractional crystallization
MIX(R,S)CA-Zncl2.004.esp
Solvent
Mixture of two diastereomeric Zn(II) complexes, 3a & 3b
Impurity
Mixture of two diastereomeric ligands, 2a and 2b
Impurity
4.2
4.1
4.0
3.9
3.8
3.7
3.6
3.5
3.4
3.3
Chemical Shift (ppm)
1
Fig. 1 Comparative view of H NMR clearly demonstrating the methine protons region for various steps of separating process to obtain single
diastereomer (2b) of 2
1
3

Transition Metal Chemistry
Isolation and characterization
oꢀ (S)‑1‑phenyl‑2‑nitroethanol
rate=1.5 mL/min; λ=254 nm); R enantiomer t =12.2 min,
R
S enantiomer t =15.3 min.
R
The crude products were puriꢂed by column chromatogra-
X‑ray crystallography
phy (30% EtOAc/hexane) to give yellow oil as (S)-1-phenyl-
1
2
-nitroethanol [36]. H NMR (500 Hz, CDCl ): δ 7.30 (5H,
The single X-ray crystals were obtained from slow evap-
oration of EtOH. An X-ray quality single crystal of
3b was mounted in a thin-walled glass capillary on an
Enraf-Noius CAD-4 diꢁractometer with Mo Kα radiation
(λ=0.71073 Å). Unit cell parameters were determined by
least-squares analysis of 25 reꢃections (10°<θ<13°). Inten-
sity data were collected with θ range of 1.56°–25.47° in ω/2θ
scan mode. Three standard reꢃections were monitored every
3
m, Ph), 5.38 (1H, dd, CH), 4.51(1H, dd, CH ), 4.41 (1H, dd,
2
1
3
CH ), 2.89 (1H, br s, OH). C NMR (125 MHz, CDCl ): δ
2
3
2
0
1
38.2, 129.0, 128.9, 126.0, 81.2, 71.0. [ꢀ] =+14.8 (c 2.4,
D
CHCl ) [37]. Enantiomeric excess (ee) was determined using
3
HPLC on Chiracel OD-H column as reported earlier [38]
(
n-Hex: IPA=95:5; ꢃow rate=1.5 mL/min; λ=215 nm); R
enantiomer t =17.4 min, S enantiomer t =20.6 min.
R
R
1
h during data collection. The data were corrected for Lor-
Isolation and characterization
oꢀ (S)‑1‑nitro‑4‑phenylbutan‑2‑ol
entz–polarization eꢁects and decay. Empirical absorption
corrections with ψ-scans were applied to the data. Structures
were solved by direct methods and reꢂned by full-matrix
least-squares reꢂnement using the SHELXL-97 [42] and
SHELXL program packages [43].
The crude products were puriꢂed by column chromatogra-
phy (10% EtOAc/hexane) to give a colourless needle-like
1
solid as (S)-1-nitro-4-phenylbutan-2-ol [39, 40]. H NMR
(
500 Hz, CDCl ): δ 7.30 (5H, m, Ar–H), 5.38 (1H, dd, –CH),
3
4
–
1
.51(1H, dd, CH ), 4.41 (1H, dd, –CH ), 2.89 (1H, br, s,
Results and discussion
2
2
13
OH). C NMR (125 Hz, CDCl ): δ 140.64, 128.69, 128.45,
3
2
5
26.37, 80.58, 67.80, 35.15, 31.35. [ꢀ] = − 13.26 (c 2.2,
Synthesis and physical properties
D
CH Cl ) [41]. Enantiomeric excess (ee) was determined
2
2
using HPLC on AD-H column [37] (n-Hex: IPA=95:5; ꢃow
The synthesis of compounds 1 and 2 was carried out as
reported previously [32, 33, 44]. Compound 2 was obtained
O
(
E)
(E)
O
2
H N
N
N
(
S)
(S)
(S)
1
Ph
HO
O
Ph
Ph
CH
2
Cl
2
/MgSO
4
/ RT
MeLi
THF/ -78 o
C
(
S)
(
S)
NH
HN
(R)
(
S)
(S)
2
a
(
R)
Ph
Ph
Ph
Ph
NH
HN
n
(S)
(S)
(
R)
2b
Column Seperatio
Ph
Ph
(
R)
NH
HN
(
S)
2b
(S)
ZnCl
2
aq. NaCN
CH Cl /RT
EtOH/RT
2
2
(
R)
(
S)
(R)
(
R)
(
R)
(
S)
(S)
N
H
N
H
N
H
N
H
(S)
N
H
N
H
Fractional Crystallization
(S)
(
S)
(S)
(S)
Zn
Zn
Ph
Ph
Ph
Zn
Ph
Ph
Ph
Cl
Cl
Cl
Cl
Cl
Cl
3a
3b
3b
Scheme 1 Synthetic route of C -symmetric diamine with diastereomeric conꢂgurations (SRRS) and its dichloro Zn(II) complex
2
1
3

Transition Metal Chemistry
as a mixture of two diastereomers in the ratio of 1:0.7, as
Table 1 Crystal data and structure reꢂnement for 3b·H O
2
1
indicated by the H NMR integration of two quartets for the
Empirical formula
Formula weight
Wavelength (Å)
Temperature (K)
Crystal system
Space group
Unit cell dimensions
a (Å)
C H Cl N Zn·H O
20 28 2 2 2
Ph–CH-Me groups (Fig. 1). Puriꢂcation using column chro-
225.36
0.71073
293 (2)
matography was unsuccessful. The mixture of diastereomers
(
2a and 2b) was ligated with ZnCl in a ratio of 1:1, con-
2
trolling the amount of EtOH, aꢁording two diastereomeric
Zn(II) complexes (3a and 3b) in a ratio of 1:0.7 (Scheme 1).
Opposite stereochemical outcomes have been achieved by
incorporating methyl substituents onto the ethylene back-
bone; however, no diastereoselectivity for the (SSSS) con-
ꢂguration was observed [1]. These interesting stereochemi-
cal properties could be due to better accommodation of any
steric clashes between methyl substituents on the ethylene
backbone and the pendent moieties of the amine groups.
Compounds 3a and 3b were separated using fractional crys-
tallization in EtOH. Compounds 3a and 3b, in the SSSS and
SRRS conꢂgurations, respectively, have diꢁerent physical
properties. Compound 3b is sparingly soluble in EtOH and
was easily crystallized from the more soluble diastereomer
Orthorhombic
P2 2 2
1
1
7.4872 (7)
19.8981 (15)
7.4690 (6)
1112.74 (16), 2
1.345
1.355
472
b (Å)
c (Å)
Volume (Å ), Z
3
3
Density (calcd.) (Mg/m )
Absorption coeꢀcient (mm−1)
F (000)
Crystal size (mm)
θ range for data collection
Index ranges
0.45×0.25×0.25
2.05–25.47
−9≤h≤9; −24≤k≤24;
−
9≤l≤9
3
a. Unfortunately, extensive crystallization trials using a
Reꢃections collected
2504
variety of solvents did not aꢁord compound 3a.
Independent reꢃections
Reꢃections observed (>2σ)
Data completeness
2061 [R(int)=0.0178]
1679
0.998
1
The H NMR spectrum of the isolated single diastere-
omeric Zn(II) complex 3b showed a diagnostic sextet for the
methine protons of the Ph–CH-Me group (Fig. 1). Complex
Max. and min. transmission
Reꢂnement method
Data/restraints/parameters
Goodness-of-ꢂt (GOF) on F
Final R indices [I>2σ(I)]
R indices (all data)
0.7282 and 0.5808
3
b was subjected to demetalation yielding compound 2b as
Full-matrix least-squares on F2
a ꢂnal ligand. The isolated ligand 2b and the Zn(II) complex
b were characterized by various spectroscopic techniques,
2061/1/124
1.044
3
2
including elemental analysis. The IR spectra of complex
showed that the peak corresponding to aromatic C=C stretch
and aromatic C–H bands shifts from the lower wavenum-
ber to the higher wavenumber in comparison with its cor-
responding ligand. Elemental analysis of the synthesized
ligand and its corresponding Zn(II) complex was consistent
with the proposed structures in Scheme 1 and conꢂrmed the
purity of the isolated compounds. These compounds were
stable in the air with long shelf life.
R =0.0265 wR =0.0655
1
2
R =0.043 wR =0.0691
1
2
Absolute structure parameter
Largest diꢁ. peak and hole (e/Å )
−0.005 (18)
0.203 and −0.240
3
Table 2 Selected bond lengths and angles for 3b·H O
2
Bond lengths
Zn1–N1#
Zn1–Cl1
N1–C2
Bond angles
1
N1–Zn1–N1#1
2.081 (2)
2.2150
1.484 (3)
1.502 (3)
1.515 (3)
1.532 (5)
86.57 (11)
112.14 (6)
111.84 (6)
112.14 (6)
111.84 (6)
118.09 (5)
#
1
#1
N1–Zn1–Cl1
X‑ray diꢀraction studies
#
1
#1
N1 –Zn1–Cl1
#
1
N1–C10
C2–C3
C10–C10
N1 –Zn1–Cl1
The absolute stereochemistry and conꢂguration of com-
pound 2b were conꢂrmed by X-ray crystallographic studies
of complex 3b. The complex crystallized in an orthorhombic
system with the P2 2 2 space group (Table 1). As expected,
N1–Zn1–Cl1
#
1
#1
Cl1 –Zn1–Cl1
1
1
Symmetry transformations used to generate equivalent atoms: #1
x+1,−y, z
a distorted tetrahedral geometry was observed around the
Zn(II) centre. Both the bond lengths and the angles agree
well with those of complexes bearing an identical ligand
−
(
Table 2) [45–47]. The plane angle between Cl–Zn–Cl
to be (S,S) in complex 3b. These results were contradictory
to those of our previous studies, in which the N atoms were
found to be in the (R,R) conꢂguration [44]. The hydrogen
atoms on the chiral carbons and nitrogens were in a head-to-
tail conformation (Fig. 2). Furthermore, the resultant ꢂve-
membered chelated ring (Zn–N–C–C–N) was solely in a δ
conformation.
and N–Zn–N was found to be 82.38(7)°. Complexation of
Zn with ligand 2b resulted in a ꢂve-membered heterocy-
clic ring, restricting the freedom of the ligand’s N atoms
(
increasing the N-inversion barrier) and inducing chirality,
provided the nitrogen substituents were inequivalent [48,
9]. The resulting conꢂgurations of the N atoms were found
4
1
3

Transition Metal Chemistry
Fig. 2 ORTEP diagram of the molecular structure of complex 3b. Thermal ellipsoids are drawn at the 30% probability level
Table 3 Four-coordinate geometry indices (τ ) for 3b and representa-
square planar geometry. The degree of distortion based on
bond angles around Zn(II) centre using these structural
4
tive examples from the literature
indexes has been observed. τ value of 3b was observed to
Complexes
Geometry
τ4
References
4
be 0.920, which is closer to 1 rather than zero. Thus, the
geometry of 3b can be best described as distorted tetrahe-
dron geometry.
a
Square planar (D )
Square planar
Tetrahedral
Tetrahedral
Tetrahedral
Tetrahedral
0.00
[50]
[51, 52]
[52]
This work
[50]
4h
b
[
(L-a)ZnCl2]
0.866
0.885
0.920
1.00
c
[
(L-c)ZnCl2]
3
b
Asymmetric Henry reaction
a
Tetrahedral (Td)
a
b
c
One of the challenging tasks in the advancement of catalytic
asymmetric Henry reaction is the development of new chi-
ral ligands with improved catalyst eꢀciency and enantiose-
See Ref. [50]
See Refs. [51, 52]
See Ref. [52]
lectivity. Copper with a variety of C -symmetric diamines
2
displayed promising results in an asymmetric Henry reac-
tion yielding enantio-enriched β-nitroalcohols with excel-
lent yields and moderate to high enantioselectivities [44,
49, 53, 54]. The catalytic eꢀcacy of in situ-generated cop-
per acetate complex in asymmetric Henry reaction between
The geometric parameters for the 4‐coordinated com-
plexes, τ , as improved simple metrics for quantitatively
4
evaluating the geometry are presented in Table 3 [50]. τ
4
values for perfect tetrahedron are 1.00 and zero for perfect
Scheme 2 Schematic repre-
sentation of asymmetric Henry
reaction catalysed by in situ-
generated [2b-Cu(OAc) ]
2
1
3

Transition Metal Chemistry
Table 4 Asymmetry Henry reaction catalysed by 2b and Cu(OAc)2
in situ-generated chiral Cu(II) complexes bearing l-proline
as the ligand [58]. Moreover, compared to well-known core-
chiral bispidine-based copper complexes (with 88% yield;
ee 97% in 48 h) [59], our system has shown improved activ-
ity and selectivity. However, although the Henry reaction
between benzaldehyde and nitromethane showed activities
of up to 99%, the enantiomeric excess was found to be only
44%. It was revealed that the diastereomeric conforma-
tion of the chiral centres (SRRS) in the ligand framework
inꢃuences the stereochemical outcome of the asymmetric
Henry reaction between 3-phenylpropanal and nitromethane.
Detailed study towards asymmetric Henry reaction using a
variety of aldehydes and nitromethanes to yield a library
of β-nitroalcohols is underway in our laboratory. Further,
Runa Substrate
Time (h) Yield (%)b ee(%)c Conꢂg.d
1
2
Benzaldehyde
3-Phenylpropanal 24
24
99
99
44
97
(S)
(S)
a
Reactions were carried out 5.0 mmol scale aldehyde, 10 mol% of
i
Cu(OAc) , 10 mol% of chiral ligand 2b, 10 mol% of Pr NEt, 2 equiv.
2
2
of CH NO in IPA (10 mL) at 25 °C
3
2
b
c
1
Yields of isolated alcohols were determined by H NMR
ee was determined by Chiralcel HPLC analysis using chiral OD-H
and chiral AD-H columns
d
The absolute conꢂguration of the major product was assigned by
comparison with the literature values [39]
benzaldehyde or 3-phenylpropanal and nitromethane with
the adopted strategy towards the synthesis of C -symmetric
2
i
1
0 mol % Pr NEt as co-initiator in IPA at ambient tempera-
chiral diamine that possesses diastereomeric conꢂgurations
(SRRS) is facile and paves the way towards the synthesis of
variety of analogous.
2
ture was examined (Scheme 2). The preliminary results for
asymmetric Henry reaction are summarized in Table 4. The
Cu(OAc) –2b complex exhibited excellent activity (99%
2
in 24 h) and enantioselectivity (up to 97%) for the reac-
tion between nitromethane and 3-phenylpropanal, yielding
Conclusions
(
S)-1-nitro-4-phenylbutan-2-ol. The reaction catalysed by
in situ-generated Cu(II) species resulted in the correspond-
ing β-nitroalcohols with an (S)-conformation, at the stereo-
genic centre, that might be due to the favourable orientation
of the phenyl group of aldehydes and pendant moieties of the
ligand architecture [54–56]. Moreover, the possible transi-
tion states of the reaction and their resultant stereochemical
outcomes in asymmetric Henry reaction with 2b as a ligand
In summary, an eꢀcient approach has been adopted towards
the synthesis of C -symmetric chiral diamine using demeta-
2
lation of its dichloro Zn(II) complex, which itself was sepa-
rated by fractional crystallization from a mixture of diastere-
omeric Zn(II) complexes. A Cu(II) acetate complex of the
synthesized chiral diamine, generated in situ, was explored
for its catalytic eꢀciency in an asymmetric Henry reaction.
Excellent catalytic activity (up to 99% in 24 h) and enanti-
oselectivity (up to 97%) for the reaction between nitrometh-
ane and 3-phenylpropanal, yielding (S)-1-nitro-4-phenylbu-
tan-2-ol, were observed. The chiral diamine obtained in this
study has considerable potential to be exploited in various
with Cu(OAc) are proposed [55, 57] (Scheme 3).
2
Our current catalytic system showed superior activity (up
to 99%) as well enantioselectivity (up to 97%) compared
to well-known Cu(II) complexes for 3-phenylpropanal
and nitromethane. For instance, the activity and selectiv-
ity of our current system are superior to recently reported
Scheme 3 Proposed model representing the transition states for the catalytic asymmetric Henry reaction with Cu(OAC) -2b system
2
1
3

Transition Metal Chemistry
metal-catalysed transformations. Further work is ongoing to
modify the ligand architecture and to identify the scope of
the synthesized ligand with a variety of substrates/aldehydes
in asymmetric Henry reaction.
22. Kim KH, Lee SS, Lee D-W, Ko DH, Ha DC (2005) Tetrahedron
Lett 46:5991
2
2
3. Kim H, Yen C, Preston P, Chin J (2006) Org Lett 8:5239
4. Lemaire M, Mangeney P (eds) (2005) Chiral diazaligands for
asymmetric synthesis. Topics in organometallic chemistry.
Springer, Berlin, p 15
2
5. Saibabu Kotti SRS, Timmons C, Li G (2006) Chem Biol Drug
Des 67:101
Supplementary Data
2
2
2
2
3
3
6. Roskamp EJ, Pedersen SF (1987) J Am Chem Soc 109:3152
7. Kise N, Ueda N (2001) Tetrahedron Lett 42:2365
8. Zhong Y, Izumi K, Xu M, Lin G (2004) Org Lett 6:4747
9. Hilgraf R, Pfaltz A (2005) Adv Synth Catal 347:61
0. Arai S, Takita S, Nishida A (2005) Eur J Org Chem 2005:5262
1. Remarchuk T, Corey EJ (2018) Tetrahedron Lett 59:2256
CCDC 1910912 contains the supplementary crystallographic
data for 3b. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/ retrieving.html, or from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033;
32. Roland S, Mangeney P (2000) Eur J Org Chem 2000:611
3
3
3. Martelli G, Morri S, Savoia D (2000) Tetrahedron 56:8367
4. Qin B, Xiao X, Liu X, Huang J, Wen Y, Feng X (2007) J Org
Chem 72:9323
1
or e-mail: deposit@ccdc.cam.ac.uk. Additionally, H NMR,
1
3
C NMR and FT-IR spectra of ligand (2b), dichloro Zn(II)
3
3
5. Blay G, Climent E, Fernandez I, Hernandez-Olmos V, Pedro JR
(2007) Tetrahedron Asymmetry 18:1063
complex (3b), and resultant β-nitroalcohols are also pre-
6. Song SE, Nguyen QT, Yu JJ, Lee H-I, Jeong JH (2014) Polyhe-
dron 67:264
sented in supplementary material.
3
3
7. Nguyen QT, Jeong JH (2008) Polyhedron 27:3227
8. Zheng B, Wang M, Li Z, Bian Q, Mao J, Li S, Liu S, Wang M,
Zhong J, Guo H (2011) Tetrahedron Asymmetry 22:1156
9. Guo ZL, Zhong S, Li YB, Lu G (2011) Tetrahedron Asymmetry
Acknowledgements This research was supported by Basic Science
Research Program through the National Research Foundation of Korea
(
NRF-2017R1D1A3B03030670).
3
2
2:238
Compliance with ethical standards
40. Lai G, Guo F, Zheng Y, Fang Y, Song H, Xu K, Wang S, Zha Z,
Wang Z (2011) Chem Eur J 17:1114
4
4
4
4
4
4
4
4
1. Ginotra SK, Singh VK (2007) Org Biomol Chem 7:3932
2. Sheldrick GM (2008) Acta Crystallogr Sect A64:112
3. Sheldrick GM (2015) Acta Crystallogr Sect C71:3
4. Nayab S, Jeong JH (2016) Inorg Chem Commun 65:35
5. Nayab S, Lee H, Jeong JH (2012) Polyhedron 31:682
6. Nayab S, Jeong JH (2013) Polyhedron 59:138
Conꢀlict oꢀ interest The authors declare that they have no conꢃict to
interest.
References
7. Kwon KS, Nayab S, Lee H, Jeong JH (2014) Polyhedron 77:32
8. Raꢂi E, Dassonneville B, Heumann A (2007) Chem Commun
1
.
Lucet D, Le Gall T, Mioskowski C (1998) Angew Chem Int Ed
Engl 37:2580
2
007:583
4
5
5
9. Cho J, Lee GH, Nayab S, Jeong JH (2015) Polyhedron 99:198
0. Yang L, Powell DR, Houser RP (2007) Dalton Trans 2007:955
1. Roy AS, Saha P, Mitra P, Maity SS, Ghosh S, Ghosh P (2011)
Dalton Trans 40:7375
2
3
4
.
.
.
Bennani YL, Hanessian S (1997) Chem Rev 97:3161
Witiak D, Wei Y (1991) J Org Chem 56:5408
Jones DS, Srinivasan A, Kasina S, Fritzberg A, Wilkening DW
(
1989) J Org Chem 54:1940
5
5
5
5
5
5
5
5
2. Park S, Lee JK, Lee H, Nayab S, Shin JW (2019) Appl Organo-
metal Chem 33:4797
5
6
7
8
9
.
.
.
.
.
Pasini A, Zunino F (1987) Angew Chem Int Ed Engl 26:615
Sherman SE, Lippard SJ (1987) Chem Rev 87:1153
3. Selvakumar S, Sivasankaran D, Singh VK (2009) Org Biomol
Chem 7:3156
Michalson ET, Szmuszkovicz J (1989) Prog Drug Res 33:135
Alakonda L, Periasamy M (2009) J Organomet Chem 694:3859
Cho J, Nayab S, Jeong JH (2016) Polyhedron 113:81
4. Kowalczyk R, Sidorowicz Ł, Skarzewski J (2008) Tetrahedron
Asymmetry 119:2310
1
0. Huang X, Rickman BH, Borhan B, Berova N, Nakanishi K (1998)
J Am Chem Soc 120:6185
5. Evans DA, Seidel D, Rueping M, Lam HW, Shaw JT, Downey
CW (2003) J Am Chem Soc 115:12692
1
1
1
1
1
1. Kim H, So SM, Chin J, Kim BM (2008) Aldrichimi Acta 41:77
2. Jäkel C, Paciello R (2006) Chem Rev 106:2912
3. McGarrigle EM, Gilheany DG (2005) Chem Rev 105:1563
4. Jacobsen EN (2000) Acc Chem Res 33:421
6. Christensen C, Juhl K, Hazell RG, Jorgensen KA (2002) J Org
Chem 67:4875
7. Dixit A, Kumar P, Yadav GD, Singh S (2018) Inorg Chim Acta
4
79:240
5. Trost BM, Machacek MR, Aponick A (2006) Acc Chem Res
8. Xu D, Sun Q, Quan Z, Sun W, Wang X (2017) Tetrahedron Asym-
metry 28:954
3
9:747
1
6. Funk TW, Berlin JM, Grubbs RH (2006) J Am Chem Soc
9. Scharnagel D, Miller A, Prause F, Eck M, Goller J, Milius W,
Breuning M (2015) Chem Eur J 21:12488
1
28:1840
1
1
1
7. Evans DA, Mito S, Seidel D (2007) J Am Chem Soc 129:11583
8. Luo S, Li J, Zhang L, Xu H, Cheng JP (2008) Chem Eur J 14:1273
9. Berthiol F, Matsubara R, Kawai N, Kobayashi S (2007) Angew
Chem Int Ed 46:7803
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional aꢀliations.
2
2
0. Denmark SE, Stavenger RA (2000) Acc Chem Res 33:432
1. Lou Y, Remarchuk TP, Corey EJ (2005) J Am Chem Soc
1
27:14223
1
3

Transition Metal Chemistry
Aꢀliations
1
2
1
Juhyun Cho · Saira Nayab · Jong Hwa Jeong
2
*
*
Saira Nayab
Department of Chemistry, Shaheed Benazir Bhutto
University, Sheringal, Dir (Upper), Khyber Pakhtunkhwa,
Pakistan
drnayab@sbbu.edu.pk; sairanayab07@yahoo.com
Jong Hwa Jeong
jeongjh@knu.ac.kr
1
Department of Chemistry and Green-Nano Materials
Research Center, Kyungpook National University, 1370
Sankyuk-dong, Taegu 702-701, Republic of Korea
1
3