Recyclable chiral Cu(II) macrocyclic salen complex catalyzed enantioselective aza-Henry reaction of isatin derived N-Boc ketimines and its application for the synthesis of β-diamine

Article abstract of DOI:10.1016/j.molcata.2016.05.021

Recyclable chiral Cu(II) macrocyclic salen complex Cu(II)-7 generated in situ efficiently catalyzed asymmetric aza-Henry reaction of various isatin derived N-Boc ketimines with nitromethane as nucleophile at RT to give a high yield (88%) of β-nitro amines with excellent chiral induction (ee, up to 99%) with the added advantage of six times catalyst recyclability. This catalytic system also worked well with nitroethane and nitropentane to furnish the corresponding products in moderate yields with high enantioselectivities for major diastereomers. This protocol is also used for the synthesis of enantiomerically pure (S)-β-diamines via asymmetric aza-Henry reaction of N-Boc ketimine (1b) in two steps in good yield with high enantioselectivity.

Full text of DOI:10.1016/j.molcata.2016.05.021

Accepted Manuscript
Title: Recyclable chiral Cu(II) macrocyclic salen complex
catalyzed enantioselective aza-Henry reaction of isatin derived
N-Boc ketimines and its application for the synthesis of
β-diamine
Author: Tusharkumar Menapara Manoj K. Choudhary
Rajkumar Tak Rukhsana I. Kureshy Noor-ul H. Khan Sayed
H.R. Abdi
PII:
S1381-1169(16)30201-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.05.021
MOLCAA 9896
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
21-3-2016
6-5-2016
20-5-2016
Please cite this article as: Tusharkumar Menapara, Manoj K.Choudhary, Rajkumar
Tak, Rukhsana I.Kureshy, Noor-ul H.Khan, Sayed H.R.Abdi, Recyclable chiral Cu(II)
macrocyclic salen complex catalyzed enantioselective aza-Henry reaction of isatin
derived N-Boc ketimines and its application for the synthesis of ␤-diamine, Journal
of Molecular Catalysis A: Chemical http://dx.doi.org/10.1016/j.molcata.2016.05.021
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Recyclable chiral Cu(II) macrocyclic salen complex catalyzed enantioselective
aza-Henry reaction of isatin derived N-Boc ketimines and its application for
the synthesis of β-diamine
Tusharkumar Menapara,a,b Manoj K. Choudhary,a,b Rajkumar Tak,a,b Rukhsana I. Kureshy,*a,b
Noor-ul H. Khan,a,b Sayed H. R. Abdi,a,b
a Inorganic Materials and Catalysis Division, Central Salt and Marine Chemicals Research Institute
(CSMCRI), Bhavnagar- 364 002, Gujarat, India. Fax: +91-0278-2566970; E-mail: rukhsana93@yahoo.co.in.
bAcademy of Scientific and Innovative Research (AcSIR), Central Salt and Marine Chemicals Research Institute
(CSMCRI), Council of Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagar- 364 002, Gujarat,
India.

GRAPHICAL ABSTRACT
O
O
O
O
t-Bu
t-Bu
t-Bu
O
N
N
N
OH
OH
OH
OH
R CH NO
2
+
N
2
2
t-Bu
O
O
O
Cu(OTf)2
Research Highlights


Chiral Cu(II) macrocyclic salen catalyst with trigol linker was used for the asymmetric
aza Henry reaction of various isatin derived N-Boc ketimines.
Various nitroalkanes were utilized for asymmetric aza Henry reaction with high yield
(upto 88%) with ee upto 99% at RT.


This protocol is used for the synthesis of (S)‐β‐diamine, precursor for pharmaceutically active
molecules in two steps
The catalyst worked well up to 6 cycles with retention of catalyst performance.
Abstract
Recyclable chiral Cu(II) macrocyclic salen complex Cu(II)-7 generated in situ efficiently
catalyzed asymmetric aza-Henry reaction of various isatin derived N-Boc ketimines with
nitromethane as nucleophile at RT to give a high yield (88%) of β-nitro amines with excellent
chiral induction (ee, up to 99%) with the added advantage of six times catalyst recyclability. This

catalytic system also worked well with nitroethane and nitropentane to furnish the corresponding
products in moderate yields with high enantioselectivities for major diastereomers. This protocol
is also used for the synthesis of enantiomerically pure (S)-β-diamines via asymmetric aza-Henry
reaction of N-Boc ketimine (1b) in two steps in good yield with high enantioselectivity.
Keywords: β-diamines; Cu(II) macrocyclic complexes; isatin derived N-Boc ketimines;
nitroalkanes
Introduction
Transition metal catalyzed catalytic asymmetric aza-Henry reaction of ketimines is
an attractive and powerful method in the asymmetric synthesis of -nitro amines, amino
β
nitriles, amino acids and diamines. These aza-Henry products are versatile chiral building
blocks for commercially important bioactive natural products [1]. Despite the apparent
simplicity of nucleophilic addition reaction to imines (derived from ketones) as
substrates, it is still a challenge to control the regio- and enantioselectivity of such
reactions which directly generate the optically active quaternary carbon centers. In this
direction, the first example of catalytic enantioselective aza-Henry reaction of ketimines
was reported by Feng et al. [2] using chiral
source of metal to yield products in high enantioselectivity but in moderate yields. Blay
and Pedro et al. [3] in 2014 reported aza-Henry reaction of isatin -Boc ketimines using
N,N’-dioxide as a ligand and CuOTf as a
N
Cu(II)-BOX as a chiral catalyst and achieved excellent yields and enantioselectivities. At
the same time Arie and coworkers [4] have made use of (S,S)-diphenyldiamine-derived
ligands-bis(imidazolidine)-pyridine (PyBidine) with various metal ions to catalyse aza-

Henry reaction of isatin N-Boc ketimines, out of which the catalyst derived from NiCl2 in
the presence of a base additives gave the corresponding product in quantitative yield
(~99%) and enantioinduction (ee, ~95%). Besides metal based catalytic system, Wang et
al. [5] reported the first organocatalytic protocol using thiourea containing motif as
catalyst for the addition of nitroalkanes to highly reactive trifluoromethyl ketimines. In
2012, Alemán et al. [6] have used a bifunctional catalyst for enantioselective aza-Henry
reaction of cyclic α-carbonyl ketimines with nitromethane and achieved good yield (37-
99%) and enantioselectivity (60-90%). Later in 2013, Dixon et al. [7] reported
bifunctional thiourea catalysts containing an iminophosphorane basic moiety, which
catalyzed the addition of nitromethane to N-phosphinoyl ketimines with good yields and
enantioselectivities. However, none of these catalytic systems are recyclable. Recently,
our group reported chiral Cu(II)-complexes derived from aminoalcohol was used as
catalysts for the nitroaldol of trifluoromethyl ketone and aldehydes with nitromethane [8].
However, this method could not be extended to the less reactive substrates such as
ketimines. These precedents indicate that the catalytic enantioselective aza-Henry
reaction of isatin N-Boc ketimines has left enough room for further work on development
of efficient recyclable catalytic protocols for this important reaction. Earlier our group has
reported Cu(II)-macrocylic salen complexes with trigol and piperazine linkers for Henry
reaction of aromatic/aliphatic aldehydes [9] and also visualized the potential use of these
ligands in combination with different metals as enantioselective catalyst in various
organic transformations [10]. The present paper reports for the use of chiral Cu(II)-
complexes of monomeric salen 1-4, dimeric salen 5, dimeric macrocyclic salen 6,7 and
monomeric macrocyclic salen
8 ligands (Scheme 1) as catalysts for asymmetric aza-

Henry reaction of isatin
valuable -nitro amines. High yields (up to 88% with respect to the substrate) of
nitroamines with excellent enantioselectivity (ee, 99%) was achieved in the products
from respective substrates screened in the present study in 30 h by using catalyst formed
out of chiral macrocyclic salen ligand with Cu(OTf)2 in the presence of 4Å MS. Chiral
N-Boc ketimines with nitroalkanes as nucleophile to synthesize
β
β-
∼
7
macrocyclic salen catalyst Cu(II)-7 mediated aza-Henry process is recyclable (up to 6
cycles with no significant loss in its performance).
Experimental Section
Methods and Materials
All starting materials viz., copper acetate monohydrate, copper triflet, copper chloride,
copper bromide, copper iodide, nitromethane, nitroethane, 2-nitropropane nitropentane,
(
1R,2R)-(-)-1,2-diaminocyclohexane, (1S,2S)-(+)-1,2-diaminocyclohexane, 1
R,2R-(-)-1,2-
diphenyl-1,2-diaminoethane, ( )-(+)-1,1’-binaphthyl-2,2’-diamine were purchased from
R
Aldrich Chemicals and used as received. Synthesis of chiral monomeric /dimeric salen
and monomeric/dimeric macrocyclic salen ligands 1-8 [10d,11] and their precursors was
carried out by the reported procedure [10a,12].
N-Boc ketimines 1a-1j were synthesized
by the reported procedures [4,13]. All the solvents were dried by standard procedures,
distilled and stored under nitrogen. NMR spectra were obtained with 500 MHz/200 MHz
and are reference internally with TMS. High-resolution mass spectra were obtained with a
LC-MS (Q-TOFF) LC (Waters), MS (Micromass) instruments. For the product
purification column chromatography was performed using silica gel 60-200 mesh

purchased from s.d. Fine-Chem Limited Mumbai (India). Enantiomeric excess (ee) of the
products were determined by HPLC (Shimadzu SCL-10AVP) using Daicel Chiralpak IA,
AD-H, AS-H and Chiralcel OD-H column with 2-propanol/hexane as eluent. Optical
rotations were measured with a Digipol 781 Automatic Polarimeter Rudolph Instruments.
Typical experimental procedure for asymmetric aza-Henry reaction
Chiral monomeric/dimeric/dimeric macrocyclic ligands 1-8 (10 mol%), Cu(OTf)2 (10/15
mol%) and anhydrous THF (1 mL) were taken in a screw-capped vial and the resulting
mass was stirred with the help of a stirring magnetic bar. A clear blue solution formed
after 30 minutes to which 4Ǻ molecular sieve (50 mg), desired substrates 1a- 1j (0.2
mmol, 1 equivalent) were added followed by addition of nitroalkanes like nitromethane
(5.0 mmol, 10 equiv). Resulting solution stirred for 30 h in N2 atmosphere. After running
the reaction the volatile components were removed under reduced pressure and the crude
product was purified by flash column chromatography.
Recycling of the catalyst Cu(II)-7
At the end of the catalytic run (checked on TLC) the solvent was reduced to
approximately 1/4 and in situ formed complex Cu(II)-7 was precipitated out by the
addition of excess of n-hexane:ethyl acetate (95:05). The precipitated catalyst was washed

thoroughly with hexane, dried in vacuum, stored under dry and inert atmosphere, and
reused for the subsequent catalytic run without further purification.
Results and discussion
At the very beginning, the role of the steric property of diamine collar of chiral
monomeric salen ligands 1-4 (10 mol%) (Scheme 1) in combination with Cu(OTf)2 (10
mol%) was examined for their catalytic performance in the aza-Henry reaction of isatin
derived
in THF. Data in the Fig. 1 revealed that the in-situ generated complexes with salen
ligands and having cyclohexanediamine collar (1 ,2 /1 ,2 ) worked better in terms
of reactivity (yield of the product was up to 76%) and enantioselectivity (up to 82%) of
-nitro amine as compared to other salen complexes Cu(II)-3 and Cu(II)-4 derived from
ligands and respectively with bulkier group. As monomeric salen ligands and with
cyclohexanediamine collar (optimized diamine collar) gave better performance, this collar
was retained to form dimeric ligands with variable linkers. Accordingly, dimeric salen
and macrocylic dimeric salen and were synthesized and used (10 mol%) to catalyze
aza-Henry reaction in the presence of Cu(OTf)2 (20 mol%) with the substrate 1a with
nitromethane. Among the dimeric salen, the ligand with trigol linker was found to be
N-Boc ketamine 1a as a model substrate (0.2 mmol) with nitromethane (5 mmol)
1
2
R R S S

3
4
1
2
5
6
7
7
most promising under the studied reaction parameters. The improved performance of the
catalyst Cu(II)-7 is possibly due to the flexibility of trigol linker where two catalytically
active units in the dimeric macrocyclic ligand may have chance to influence each other.
We compared the catalytic activity of the monomeric Cu(II)-8 [9c] and dimeric Cu(II)-7

in the aza-Henry reaction of 1a with nitromethane under identical reaction condition i.e.
monomeric ligand (20 mol%) with Cu(OTf)2 (20 mol%) and dimeric ligand (10
mol%) with Cu(OTf)2 (20 mol%) to give -nitro amine with 72% yield; ee 82% and 88%
8
7
β
yield; 99% ee respectively in 30 h. The increase in the performance of dimeric Cu(II)-7
over monomeric complex suggest that the two catalytic units are not working in isolation.
The exact reasons behind this behavior are not known at this point of time.
Encouraged by the preliminary result with the identified catalyst Cu(II)-7 and to
ascertain an effective in situ metal complex formation during the catalytic reaction, we
carried out systematic screening of various copper salts (both monovalent and divalent)
with the chiral ligand
7 (most active and enantioselective). The rationale behind this is
based on the perception that copper salts with different counter ions are well known to
form structurally different complexes with a given ligand, hence strongly affect the
catalytic performance [9c]. Among all the copper salts screened, Cu(OTf)2 with the chiral
dimeric macrocyclic salen ligand
enantioselective addition of nitromethane to 1a giving good yield and selectivity of the
product -nitro amine (Table 1) even in the absence of any base additive as reported
elsewhere [2,3].
It is well known in the literature that metal to ligand ratio play an extremely
important role in cases where the active catalyst is generated in situ [9a-d,10c]. Therefore,
we have used fixed amount of the ligand (10 mol%) with varying amounts of Cu(OTf)2
(5-25 mol%) (Fig. 2) to catalyze aza-Henry reaction of 1a with nitromethane at RT. It is
understood from the Figure 2 that the ligand (10 mol%), with Cu(OTf)2 (15 mol%) is
optimum to catalyze the aza-Henry reaction to give the product in 88%yield and excellent
7 generated most active catalyst to promote the

7
7

enantioselectivity (ee; 99%) indicating that a slight higher concentration of ligand is
essential in order to ensure the absence of free metal ion in the solution that may cause
formation of racemic product [9c].
Further, solvent is known to influence the activity and enantioselectivity of a
catalytic protocol. Hence, it was pertinent for us to screen different solvents for aza-Henry
reaction of 1a in the presence of nitromethane as nucleophile using Cu(II)-7 under the
above optimized reaction condition (Fig. 2). Accordingly, solvents like acetone,
acetonitrile, CHCl3, CH2Cl2, EtOAc, THF and 1,4-dioxane were screened, but as shown
in the Figure 3, none of these could match the performance of THF (ee 99%, Yield 88%).
Temperature also plays significant effect on the enantioselectivity of the product.
Accordingly, lowering the temperature from RT to 0 °C for aza Henry reaction 1a
catalyzed by Cu(II)-7 with nitromethane as nucleophile has shown a decrease in the yield
of product
hand by increasing the temperature from RT to 40 ºC the yield of the corresponding
nitro amine was little more but with lower enantioselectivity. Hence, RT was taken as
-nitro amine without any increase in enantioselectivity (Fig. 4). On the other

-
optimized temperature for this reaction giving good yield (88%) of corresponding
amine with 99% enantio-induction.
-nitro
With these optimized reaction conditions in hand, a series of isatin derived
Boc ketimines having different substituents at the aromatic ring and -protecting groups
1a-j were tested with nitromethane to widen substrates scope in aza-Henry reaction
(Scheme 2). Good to high yield (80-88%) of -nitro amines 1’a-1’j with high enantio-
N-
N
β
induction (up to ee, 99%) was achieved at RT in THF. However, no clear trend was
observed for the electronic effect of the substituents on the yield as well as in selectivity

except N-protecting benzyl group 1’c where the yield was moderate. These results of the
aza-Henry reaction using the active complex Cu(II)-7 are superior in term of yield and
enantioselectivity of
require i-Pr2NH as additive [3].
To further investigate this reaction protocol, several less explored nitroalkanes
viz., nitroethane, 2-nitropropane and nitropentane were then screened for aza-Henry
reaction of various isatin derived -Boc ketimines having different substituents (R, R1=
H, Cl, Br) at the aromatic ring (Table 2) in the presence of the complex Cu(II)-7
β-nitro amines than the earlier reported copper (II) system which
N
.
Moderate yields (up to 67%) with high enantioselectivities (up to 98%) and
diastereoselectivities (up to 98:02, favoring the major product) were achieved in the case
of nitroethane and 1-nitropentane (entries 1-4). This catalytic system also worked very
well when 2-nitropropane was used as nucleophile giving high enantioselectivity (94%)
with moderate yield of β-nitro amines (entry 5).
Catalyst recyclability experiments were conducted with a 10 mmol sample of 1a
as a model substrate using catalyst Cu(II)-7 with nitromethane in THF at RT. After the
catalytic run, the solvent was reduced to approximately 1/4 and complex Cu(II)-7 was
precipitated out by the addition of excess of n-hexane:ethyl acetate (95:05). The
precipitated catalyst was washed thoroughly with hexane, dried in vacuum, stored under
dry and inert atmosphere, and reused for the subsequent catalytic run without further
purification. The recovered catalyst worked well for the enantioselective aza-Henry
reaction in the same manner as that of the fresh catalyst. The recycling data, as given in
Figure 5, suggests that the recovered catalysts Cu(II)-7 is stable and worked well for six
cycles without significant loss in performance. The stability of the complex Cu(II)-7

during the catalytic run was confirmed by the IR spectra (Figure 6) and elemental analysis
(data is given in supporting information) which matched well with virgin catalyst Cu(II)-
7
suggesting that no major structural changes had taken place during the course of post
catalytic workup procedure.
A 10 mmol scale of aza-Henry reaction of 1b with nitromethane gave the corresponding
β-nitro amine in excellent ee (96%) and high yield (80%) with Cu(II)-7 under the optimized
reaction condition. The aza-Henry product gave (S)-β-diamine, precursor for pharmaceutically
active molecules in two steps in overall 64% yield with 95% ee (Scheme 3).
Conclusions
This work has uncovered chiral Cu(II) dimeric macrocyclic salen complex with flexible
trigol linker as efficient, recyclable and scalable catalysts for asymmetric aza-Henry
reaction of various isatin derived
RT to give a high yield (88%) of
N
-Boc ketimines with nitromethane as nucleophile at
β
-nitro amines with excellent chiral induction (ee, up to
99%) with the added advantage of very good catalyst recyclability. This catalytic system
also worked well with other nitroalkanes to furnish the corresponding products in
moderate yields and high enantioselectivities and diastereoselectivity for major product.
This protocol is also used for the synthesis of enantiomerically pure (
S)-β-diamines via
asymmetric aza-Henry reaction of
high enantioselectivity.
N-Boc ketimine 1b in two steps in good yield with

Acknowledgements
(CSMCRI Communication No.005 /2016). Tusharkumar Menapara and RIK are thankful
to DST, CSIR and CSIR-Indus Magic Project CSC-0123 for financial assistance.
Tusharkumar Menapara is thankful to AcSIR for Ph. D. Registration. Authors are also
thankful to Analytical Science and centralized instrument facilities for providing
instruments facilities.
Appendix A. Supplementary data
1
All the Characterization data of aza Henry products like H NMR, 13C NMR, optical
rotation and HPLC profile were provided in this section.
References
1. (a) B. Westermann, Angew. Chem., Int. Ed. 42 (2003) 151-153;
(b) T. Vilaivan, W. Bhanthumnavin,; Y. Sritana-Anant, Curr.Org. Chem. 9 (2005) 1315-
1392;
(c) G. K. Friestad, A. K. Mathies, Tetrahedron 63 (2007) 2541-2569;
(d) A. Ting, S. E. Schaus, Eur. J. Org. Chem. 35 (2007) 5797-5815.
2. C. Tan, X. Liu, L. Wang, J. Wang and X. Feng, Org. Lett., 10 (2008) 5305-5308.
3. M. Holmquist, G. Blay, J. R. Pedro Chem. Commun. 50 (2014) 9309-9312.
4. T. Arai, E. Matsumura, and H. Masu, Org. Lett. 16 (2014) 2768-2771.
5. H. Xie, Y. Zhang, S. Zhang, X. Chen and W. Wang, Angew. Chem., Int. Ed. 50 (2011)
11773-11776.

6. A. Parra, R. Alfaro, L. Marzo, A. Moreno-Carrasco, J. L. García Ruano J. Alemán, Chem.
Commun. 48 (2012) 9759-9761.
7. M. G. Núñez, A. J. M. Farley and D. J. Dixon, J. Am. Chem. Soc. 135 (2013) 16348-16351.
8. A. Das, M. K. Choudhary, R. I. Kureshy, K. Jana, S. Verma, N. H. Khan, S. H. R. Abdi, H.
C. Bajaj, B. Ganguly, Tetrahedron 71 (2015) 5229-5237.
9. (a) A. Das, R. I. Kureshy, K. J. Prathap, M. K. Choudhary, G. V.S. Rao, N. H. Khan, S. H.R.
Abdi, H. C. Bajaj, Applied Catalysis A: General, 459 (2013) 97-105;
(b) R. I. Kureshy, B. Dangi, A. Das, N. H. Khan, S. H. R. Abdi, H. C. Bajaj, Applied
Catalysis. A: General 74 (2012) 439-440;
(c) R. I. Kureshy, A. Das, N. H. Khan, S. H. R. Abdi, H. C. Bajaj, ACS Catal. 1 (2011) 1529-
1535;
(d) R. I. Kureshy, N. H. Khan, S. H. R. Abdi, S. T. Patel, R. V. Jasra, Tet. Lett. 42 (2001) 29
15-2918;
(e) M. K. Choudhary, A. Das, R. I. Kureshy, M. Kumar, N. H. Khan, S. H. R. Abdi, H.C.
Bajaj, Catal. Sci. Technol. 4 (2014) 548-555;
(f) M. K. Choudhary, R. Tak, R. I. Kureshy, A. Ansari, N. H. Khan, S. H. R. Abdi, H. C.
Bajaj, Journal of Molecular Catalysis A-Chemical 409 (2015) 85-93.
10. (a) R. I. Kureshy, K. J. Prathap, M. Kumar, P. K. Bera, N. H. Khan, S. H. R. Abdi, H. C.
Bajaj, Tetrahedron 67 (2011) 8300-8307;
(b) A. Sadhukhan, N. H. Khan, T. Roy, R. I. Kureshy, S. H. R. Abdi, H. C. Bajaj, Chem.
Eur. J. 18 (2012) 5256-5260;
(c) R. I. Kureshy, T. Roy, N. H. Khan, S. H. R. Abdi, A. Sadhukhan, H. C. Bajaj, J. Catal. 28
6 (2012) 41-50;

(d) S. Saravanan, N. H. Khan, R. I. Kureshy, P. K. Bera, S. H. R. Abdi, P. Kumari, H. C.
Bajaj, ChemCatChem. 5 (2013) 1374-1385;
(e) A. Sadhukhan, M. Choudhary, N. H. Khan, R. I. Kureshy, S. H. R. Abdi, H. C. Bajaj, Che
mCatChem. 5 (2013) 1441-1448.
11. (a) E. N. Jacobsen, W. Zhang, A. R. Muci, J. R. Ecker, L. Deng, J. Am. Chem. Soc. 113
(1991) 7063–7064;
(b) M. Palucki, N.S. Finney, P.J. Pospisil, M.L. Güler, T. Ishida, E.N. Jacobsen, J. Am.
Chem. Soc. 120 (1998) 948–954.
12. (a) M. Kumar, R. I. Kureshy, D. Ghosh, N. H. Khan, S. H. R. Abdi and H. C. Bajaj,
ChemCatChem. 5 (2013) 2336-2342;
(b) N. H. Khan, A. Sadhukhan, N. C. Maity, R. I. Kureshy, S. H. R. Abdi, S.
Saravanan, H. C. Bajaj, Tetrahedron 67 (2011) 7073-7080.
13. M. G. Sankar, M. Garcia-Castro, Y. Wang, K. Kumar, Asian J. Org. Chem. 2 (2013)
646-649.

Boc
O
Boc
HN
N
8
Ligand 1- (10 mol%),
NO2
O
Cu(OTf)2 (10/20 mol%)
(S)
CH3NO2
N
Dry THF, N2-atm, RT
4Å MS
N
H
H
1'a
1a
100
82
76
82
80
60
40
20
99
85
74
75
88
84
72
84
88
71
81
72
71
%
0
1
2
3
4
Ee
Yield
5
6
7
8
Figure 1 Screening of the ligands

mol %
% Yield
% Ee
99
97
95
90
84
89
90
88
78
70
5
10
25
15
20
Figure 2 Variation of catalysis loading for the synthesis of β-nitro amine
.

99
100
80
60
40
20
0
90
89
88
66
62
51
48
Yield
Ee
36
36
32
30
18
13
Acetone CH3CN CHCl3
DCM
EtOAc
THF
1,4
Dioxane
Figure 3. Solvent variation in aza-Henry reaction of 1a in presence of nitromethane

99
99
99
78
88
100
90
80
60
40
20
0
72
%
40
60
27
10
0
Temp. (oC)
Yield
Ee
Figure 4. Temperature variation in aza-Henry reaction of 1a in presence of nitromethane

99
99
98
98
100
80
98
98
88
88
87
86
85
84
60
%
40
20
0
Yield
Ee
1
2
3
4
5
6
Figure 5. Recyclability study of the catalytic system using 1a as model substrate and
nitromethane in THF.

24
22
20
18
16
14
12
10
8
6
Fresh catalyst
catalyst (after 4 cycle)
Catalyst (after six cycle)
4
2
0
4000
3500
3000
2500
2000
1500
1000
500
Figure 6. IR spectra of fresh and recycled catalyst.

Scheme 1 Structure of the ligands 1-8
.

Boc
HN
NO2
O
(S)
N
H
1'a
Boc
HN
Boc
HN
bYield= 88%
cee=99%
NO2
O
NO2
O
(S)
(S)
N
N
Boc
HN
Br
1'b Me
H
1'j
NO2
O
Boc
HN
bYield= 80%
cee=96%
NO2
O
(S)
bYield= 82%
cee=93%
(S)
N
N
Cl
1'c
Ph
H
1'i
bYield= 71%
cee=98%
Boc
N
Boc
HN
bYield= 81%
c ee=99%
Ligand 7 (10 mol%),
NO2
O
R1
R3
R1
Cu(OTf)2 (15 mol%)
CH3NO2
O
(S)
N
R2
N
Dry THF, N2-atm,
4Å MS, RT, 30 h
R3
Boc
HN
R2
Boc
HN
NO2
O
Me
a1a-1j
Br
1'a-1'j
NO2
O
(S)
(S)
O
N
H
N
1'd
H
Boc
HN
1'h
Boc
HN
bYield= 80%
cee=99%
bYield= 85%
cee=92%
NO2
NO2
O
Me
O2N
(S)
(S)
O
N
N
H
H
1'e
1'g
Boc
HN
bYield= 81%
cee=99%
bYield= 83%
cee=98%
NO2
O
Cl
(S)
N
H
1'f
bYield= 80%
c ee=99%
aAll reactions were performed with 1a-1j (0.2 mmol), nitromethane (5.0 mmol), 50 mg of 4Ǻ
MS, ligand 7 (0.02 mmol),Cu(OTf)2 (0.03 mmol) in 1 mL dry THF.
bIsolated yields after 30 h by flash column chromatography.
cDetermined by HPLC (Chiralpak IA, AD-H and Chiralcel OD-H)
Scheme 2 Variation of Substrate in aza-Henry reaction.

Scheme 3 Synthesis of 1,2-diamine from 1’b

Table 1. Screening of counter ions for asymmetric aza-Henry reaction of 1a using the
with different copper salts.a
ligand
7
Entry Metal Source
Yieldb (%)
Eec(%)
76
1
Cu(OAc)2.H2O 76
2
3
CuBr
12
63
8
CuCl2. 2H2O
94
4
5
6
CuI
Cu(OTf)2.H2O
CuCl2
15
88
70
3
99
95
aAll reactions were performed with 1a (0.2 mmol), nitromethane (5.0 mmol), 50 mg of
4Ǻ MS, ligand
7 (0.02 mmol), CuX2/CuX (0.04 mmol) in 1 mL dry THF.
bIsolated yields after 30 h by flash column chromatography.
cDetermined by HPLC (chiralpak IA)

Table 2 Variation of substrates in asymmetric aza-Henry reaction.
Entry
R
R1
R2
time
yieldb
drc
eed
(major)
1
2
3
4
5
H
H
Cl
Cl
Cl
H
Br
H
H
H
-CH3
-CH3
-CH3
46
41
39
67
67
65
62
71
98:02
96:04
95:05
95:05
-
98
98
98
97
94
-CH3CH2CH2CH2 65
-(CH3)2 44
aAll reactions were performed with 2a-2e (0.2 mmol ), nitroalkane (5.0 mmol), 50 mg of
4Ǻ MS, ligand
7 (0.02 mmol), Cu(OTf)2 (0.03 mmol) in 1 mL dry THF.
bIsolated yields after 41-65 h by flash column chromatography.
c,dDetermined by HPLC (Chiralpak IA) ee determine with major diasteriomer.