Asymmetric Henry reactions of aldehydes with various nitroalkanes catalyzed by copper(II) complexes of novel chiral N-monoalkyl cyclohexane-1,2-diamines

Article abstract of DOI:10.1002/aoc.3107

A number of novel chiral diamines 3, (1R,2R)-N-monoalkylcyclohexane-1,2- diamines, were designed and synthesized from trans-cyclohexane-1,2-diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β-nitroa

Full text of DOI:10.1002/aoc.3107

Full Paper
Received: 13 September 2013
Revised: 23 October 2013
Accepted: 6 November 2013
Published online in Wiley Online Library: 30 January 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3107
Asymmetric Henry reactions of aldehydes with
various nitroalkanes catalyzed by copper(II)
complexes of novel chiral N-monoalkyl
cyclohexane-1,2-diamines
Fei Liua, Shaohua Goua,b* and Lei Lia
A number of novel chiral diamines 3, (1R,2R)-N-monoalkylcyclohexane-1,2-diamines, were designed and synthesized from
trans-cyclohexane-1,2-diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane
to provide β-nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)-N1-(4-
methylpentan-2-yl)cyclohexane-1,2-diamine (3g), the reaction was optimized in terms of the metal ion, temperature, solvent and base.
Further experiments indicated that the complex, 3g–Cu(OAc)2, was an efficient catalyst in the asymmetric Henry reaction between differ-
ent aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantio-
meric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and
nitroalkane, which gave the corresponding anti-selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up
to gram quantities, the β-nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mech-
anism was tentatively explained on the basis of a previously proposed transition-state model. Copyright © 2014 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: asymmetric catalysis; Henry reaction; copper; N-monoalkyl (1R,2R)-diaminocyclohexane; β-nitroalcohol
more secondary diamine–copper complexes with bulky aromatic
Introduction
substituents[16–23] (e.g. 2a,[16] Fig. 2) in macrocyclic units[24–28]
(e.g. 2b,[28] Fig. 2) or with a nitrogen-containing heterocyclic ring[29,30]
The Henry reaction is one of the most important methods for the
formation of C―C bond in organic chemistry[1] and the resulting
products, chiral β-nitroalcohols, are important intermediates and
can be further transformed into other useful derivatives such as
carboxylic acids and amino alcohols in the synthesis of relevant
biologically active compounds.[2–4] The first asymmetric version of
the Henry reaction was reported by Shibasaki in 1992.[5] Since then,
interest in this area has been expanded upon considerably and
various catalyst systems for this reaction have been developed (e.
g. rare earth metal BINOL complexes,[6] Cu-bis(oxazoline) (BOX)
complexes,[7–9] dinuclear Zn complexes[4] and Zn salts-chiral amino
alcohol).[10]
(e.g. 2c,[30] Fig. 2) were synthesized and applied in Cu-catalyzed asym-
metric Henry reactions, which afforded various β-nitroalcohols in ex-
cellent yield and enantioselectivities under the optimized reaction
conditions. Other more specific diamines, such as secondary
amine–tertiary amines[31,32] (e.g. 2d,[31] Fig. 2) and tertiary amine–
In recent years, metal–salen complexes, especially the C2-sym-
metric metallosalen compounds (see Fig. 1, ligand 1), have been
proved to be useful catalysts for a wide range of organic
reactions.[11–14] Copper(II) complexes of chiral secondary diamines
derived from (1R,2R)-1,2-diaminocyclohexane (DACH) (see Fig. 1,
ligand 2) were first successfully applied for the asymmetric Henry
reaction with enantioselectivity up to 94% by Skarżewski and
his co-workers.[15] Asymmetric induction of asymmetric Henry
reaction is imparted from copper(II) complexes and it begins with
the statement of the impact of the Jahn-Teller effect on Cu(II)
coordination.[8] The carbonyl oxygen atom is coordinated at one
of the equatorial positions and the oxygen atom of nitromethane
approaches the metal center from the axial side. This positioning
of the reactants seems the most favorable orientation, taking into
account steric and electronic considerations.[15] Subsequently,
Figure 1. Chiral diamine or diimine ligands derived from (1R,2R)-
diaminocyclohexane: C2-symmetric salen ligand (1), secondary diamine
ligand (2), N-monoalkyl diamine ligand (3). R1 is an alkyl group.
*
Correspondence to: Shaohua Gou, School of Chemistry and Chemical
Engineering, Southeast University, Nanjing 211189, People’s Republic of China.
Email: sgou@seu.edu.cn
a Pharmaceutical Research Center and School of Chemistry and Chemical
Engineering, Southeast University, Nanjing211189, People’s Republic of China
b Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, Southeast
University, Nanjing211189, People’s Republic of China
Appl. Organometal. Chem. 2014, 28, 186–193
Copyright © 2014 John Wiley & Sons, Ltd.

Henry reactions catalyzed by copper complexes of N-monoalkyl diamine
Results and Discussion
Synthesis of Chiral Ligands
The synthetic process for novel chiral ligands 3
(N-monoalkyl diamines) was described by our group
previously[40] (as shown in Scheme 1). The N-monoalkyl
diamines were developed by protecting one of amino
groups with (Boc)2O first, followed by Schiff base
condensation with aldehyde or ketone and in situ
reduction using NaBH4. In this way, a number of such
compounds (3a–3o) were obtained in their hydrochlo-
ride salts in a yield of 42–84%.
The Asymmetric Henry Reaction
Ligand 3 was first examined in the Henry reaction be-
tween benzaldehyde and nitromethane. An optimized
method reported in the literature[16] was adopted and
developed to screen the ligands that can form effi-
cient catalysts with Cu(II) ions in the Henry reaction.
The Henry reactions were performed on a 0.5 mmol
scale, using 12 mol% of respective diamine, 10 mol%
Figure 2. Chiral diamine ligands used in asymmetric Henry reaction.
tertiary amines[33–35] (e.g. 2e,[34] Fig. 2), were prepared and applied
to asymmetric Henry reactions, and Henry adducts were produced
in high yield with excellent enantiomeric excess. Despite significant
progress in this field, there are still some shortcomings for this kind
of reaction, such as rather complicated ligand structures (some ligands
are difficult to synthesize or the yield is low) in addition to substrate
specificity limitations.
Cu(OAc)2.H2O, 10 equiv. nitromethane and 7.7 mol% i-Pr2NEt in
i-PrOH at ꢀ20°C for 24 h (ꢀ30°C, 70 h).[16] The results showed that
under these conditions the desired product (6a) was obtained in
good yield with enantiomeric excess in most cases, as summa-
rized in Table 1. The ligands with N-alkyl groups usually gave
products with up to 89% ee (the (S)-enantiomer is the major
product). Among them, those with relatively long alkyl chains,
such as 3f, 3g, 3k, 3m and 3o, afforded reasonable results
Before long, Zhu et al. reported that a diimine (1a, Fig. 3) catalyst
in the asymmetric Michael reaction of 4-hydroxycoumarins and
2-cyclohexen-1-one was formed in situ with a primary amine–imine
(4, Fig. 3) system.[36] Their results hint that this may occur in an
analogous addition reaction. In other words, C2-symmetric salen
diimine or secondary diamine systems are not essential for the
catalyst, and primary amine–imine or primary amine–secondary
amine may be catalytically efficient in the similar asymmetric
reaction. The surmise leads us to design a very simple and novel
chiral diamine ligand for the analogous addition reaction. To our
delight, it is reported that some primary amine–imine[37] (Fig. 4,
5a), primary amine–tertiary amines[38,39] (Fig. 4, 5b and 5c) were
recently applied to the catalytic asymmetric Henry reaction of
benzaldehyde and nitromethane to provide β-nitroalcohol at low
enantiomeric excess values (Fig. 4; ee 29%, 19%, 36%). This
confirmed that such simple ligands have certain catalytic activities
in the asymmetric Henry reaction. Therefore, we believe that some
simple ligands that are easy to synthesize could be gained with a
rational design for the asymmetric Henry reaction.
Figure 3. Reported chiral ligand derived from the in situ preparation of
primary amine–imine.
In our recent study, we have designed and developed a series
of N-monoalkyl derivatives of DACH (see Fig. 1, ligand 3), which
can be expected as chiral ligands for asymmetric catalysis in ad-
dition to the preparation of Pt(II) complexes for antitumor agent
screening.[40] Thus this kind of simple and novel ligand (primary
amine–secondary amines) with copper(II) ions has been investi-
gated herein as catalysts in the asymmetric Henry reaction. Here,
we report that a series of Cu(II) complexes based on the novel
ligands show excellent catalytic activity in terms of activity and
selectivity. By using ligand 3, we would like to prove that those
ligands, including only one simple alkyl group, can also play a
similar role to aromatic groups in the asymmetric Henry reaction
with copper(II) ions in an excellent catalytic effect.
Figure 4. Chiral diamine ligands: primary amine–imine and primary
amine–tertiary amine (ee: the asymmetric Henry reaction of benzalde-
hyde with nitromethane catalyzed by copper(II) complexes).
Appl. Organometal. Chem. 2014, 28, 186–193
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

F. Liu et al.
91% ee (entry 21). An increase of the Et3N
loading from 7.7 to 15.4 mol% gave a minute
reduction in enantioselectivity (90%, entry
22). This indicates that our catalytic system
can tolerate a broad range of quantities of
base additive, and the uncoordinated base-
promoted background reaction is negligible.
Based on yield and the enantioselectivity of
Scheme 1. Synthesis of chiral ligand 3.2HCl: (i) aldehyde or ketone, MeOH; (ii) NaBH4; (iii) HCl/EtOAc, 0°C.
products, the optimization of reaction conditions was obtained as
follows: reactions were performed on a 0.5mmol scale, with
12 mol% ligand, 10 mol% Cu(OAc)2.H2O, 10 equiv. CH3NO2 and
7.7 mol% Et3N in i-PrOH at ꢀ40°C for 24 h (entry 18).
(≥88% ee; Table 1, entries 6, 7, 11, 13 and 15), while those such as
(the
3c and 3h gave poor results with only 45% and ꢀ6% ee
(R)-enantiomer is the major product), respectively (Table 1, en-
tries 3 and 8; 3h gave a reverse enantioselectivity). The best
results were obtained by using ligands 3g, 3k and 3o with 89%
ee (Table 1, entries 7, 11 and 15). Based upon the yield, 3g was
the best ligand for the Henry reaction (up to 99%).
On the basis of the optimized reaction parameters, the
scope of various aldehydes was explored (Table 3: aromatic
aldehydes, entries 1–13; aliphatic aldehydes, entries 14–16).
A variety of aromatic aldehydes provided the corresponding
β-nitroalcohols with moderate to high yields (up to 99%)
and enantioselectivities ranging from 77% to 93% (6o gave
a reverse enantioselectivity, ꢀ77%; the (R)-enantiomer is the
It is notable that ligands with a methyl group next to the
CH―N bond usually gave a good enantiomeric excess (Table 1,
entries 1, 4, 7, 11, 13 and 15, at least 82% ee) and the results
improved along with the increase of carbon atom numbers in
the alkyl carbon chain. However, ligand 3h with three methyl
groups did not afford good results, which appeared to show that
bulky substituted groups on the nitrogen atom are not necessary.
By using the best ligand, 3g, reaction conditions such as the
metal, temperature, solvent and base were examined in the
Henry reaction of benzaldehyde and nitromethane (Table 2).
When the reaction was carried out without a catalyst, no reaction
took place (entry 1). When reactions were performed in the ab-
sence of base (i-Pr2NEt, entry 2) or chiral ligand 3g (entry 3),
nitroalcohols were produced with 96% and 60% yield, respec-
tively, but, unfortunately, as a racemic compound or with the de-
sired product in very low enantiomeric excess (6%). Very low
enantioselective reaction proceeded in the presence of 12 mol%
3g and 7.7 mol% i-Pr2NEt to give 6a in very low yield (6%) and
2% ee (entry 4). Benzaldehyde could react smoothly with nitro-
methane in the presence of 12 mol% 3g, 10 mol% Cu(OAc)2.
H2O, 10 equiv. CH3NO2 and 7.7 mol% base at ꢀ20°C for 24 h in
99% yield and 89% ee (entry 6). Then various copper salts were
evaluated in combination with 3g and i-Pr2NEt. As a conse-
quence, several divalent copper salts were effective for the asym-
metric Henry reaction, and Cu(OAc)2 gave the best value of 89%
ee (entry 6). Other metal (acetate) complexes were also tested as
catalysts for the reaction. The application of ligand 3g in combi-
nation with Co(OAc)2 did not affect the yield but led to significant
loss in enantioselectivity (entry 10), while with Zn(OAc)2 and 3g
as the catalyst only 12% yield and 3% ee of 6a were obtained
(entry 11). Reducing the temperature to ꢀ40°C increased the
value to 90% ee (entry 13). A further decrease to ꢀ60°C did not
have a significant effect on enantiomeric excess, but led to very
low yield (entry 14). Thus ꢀ40° was found to be the optimum
temperature. The reaction was further subjected to solvent
variation (entries 13, 15–17). It was demonstrated that the solvent
affected to a limited extent the yield and enantioselectivity. With
i-PrOH as the solvent (entry 13), the nitroalcohol was isolated in
90% ee. A series of bases were also tested for the Henry reaction
of benzaldehyde with nitromethane (entries 18–20). Et3N turned
out to be the best choice, with 91% ee and 99% yield (entry 18),
while i-Pr2NEt induced almost the same result (entry 13). The
amount of base (Et3N) additive had little influence on the
enantioselectivity but was responsible for the yield (entries 18,
21,22). While the base loading decreased to 2.6 mol%, the
reaction could go to completion within 72 h in 72% yield with
Table 1. Screening N-monoalkyl diamine ligands in the Henry reac-
tion of benzaldehyde and nitromethane
Ligand
3a-o
Cu(OAc)2 H2O
i-PrOH
i-Pr2NEt
Ph
(S)
PhCHO
+
CH3NO2
OH
NO2
6a
H
N R1
NH2
3
Entrya Ligand
R1
Yield (%)b
ee (%)c
1
3a
3b
3c
3d
3e
3f
i-Pr
96
89
90
90
99
99
99
90
90
99
95
95
99
90
96
85d
73
45
82
74
88
89
ꢀ6
75
72
89
79
88
82
89
2
n-Bu
i-Bu
s-Bu
3
4
5
n-Pentyl
6
1-Ethylpropyl
1,3-Dimethylbutyl
Neopentyl
Cyclopentyl
n-Hexyl
7
8e
3g
3h
3i
9
10
11
12
13
14
15
3j
3k
3l
2-Hexyl
Cyclohexyl
2-Heptyl
3m
3n
3o
3-Octyl
2-Undecyl
aReactions were performed on a 0.5 mmol scale, with 12 mol% of
respective N-monoalkyl diamine 3a–o, 10 mol% of Cu(OAc)2.
H2O, 10 equiv. CH3NO2 and 7.7 mol% of i-Pr2NEt in i-PrOH at
ꢀ20°C for 24 h.
bYield of isolated product.
cEnantiomeric excess was determined by HPLC using Chiralpak
IC column (see Supporting Information).
dThe (S)-enantiomer was the major product.
eThe (R)-enantiomer was the major product.
wileyonlinelibrary.com/journal/aoc
Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 186–193

Henry reactions catalyzed by copper complexes of N-monoalkyl diamine
Table 2. Optimization of reaction conditions for the Henry reaction of benzaldehyde and nitromethane with ligand 3g
Entrya
Ligand
MXn
Base
Solvent
T (°C)
Yield (%)b
ee (%)c
1
—
—
—
—
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
EtOH
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
—
96
60
4
—
0
2
—
i-Pr2NEt
—
3
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
—
6
4
—
i-Pr2NEt
—
2
5d
6e
7
Cu(OAc)2.H2O
Cu(OAc)2.H2O
CuCl2
84
99
99
15
86
99
12
99
99
10
99
99
67
99
43
95
71
83
89
89
85
60
74
3
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
Et3N
8
Cu(NO3)2.3H2O
CuBr
9
10
11
12
13
14f
15
16
17
18
19
20
21g
22h
Co(OAc)2.4H2O
Zn(OAc)2.2H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
3
81
90
92
88
82
86
91
88
66
91
90
ꢀ40
ꢀ60
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
CH2Cl2
THF
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
Pyridine
Cs2CO3
Et3N
Et3N
aGeneral procedure: reactions were performed on a 0.5 mmol scale (0.3 ml corresponding solvent), with 12 mol% 3g (1 ml corresponding solvent),
10 mol% MXn, 10 equiv. CH3NO2 and 7.7 mol% base (0.2 ml corresponding solvent ) at corresponding temperature for 24 h.
bYield of isolated product.
cEnantiomeric excess was determined by HPLC using Chiralpak IC chiral column.
dReaction was performed for 72 h.
eSee Table 1, entry 7.
fReaction was performed for 72 h.
gThe amount of Et3N was 2.6 mol% (1.7 mg, 0.2 ml) and the reaction was performed for 72 h.
hThe amount of Et3N was 15.4 mol% (10.0 mg, 0.2 ml).
major product, entry 13). It is noted that the electronic char-
acter of the substituent on the aromatic ring and its steric
hindrance have a slight influence on the enantioselectivity
of the resulting products. In general, no matter whether the
aromatic aldehydes were electron rich (entries 1–4), electron poor
(entries 5–8), sterically hindered (entries 9–11) or heterocyclic (entry
12), all of them smoothly underwent the Henry reaction with high
yields (up to 99%) and good enantioselectivities (up to 93%). The
highest value of 93% ee accompanied by 97% yield was found for
2-methoxybenzaldehyde (entry 1). However, for aliphatic alde-
hydes, the corresponding β-nitroalcohols were obtained with
relatively low yields (38–53%) and enantioselectivities (75–86%). It
was noted that the reaction activity of the aliphatic aldehyde was
relatively low (low yields), but the enantioselectivity of products
was not affected (moderate to good selectivity). These results dem-
onstrated that 3g can be effectively applied in the Henry reaction
with various aromatic aldehydes.
Subsequently, in view of the less explored nitroalkane substrate
scope, nitroethane and 1-nitropropane were tested in the
diastereoselective Henry reaction (Table 4). The reaction of aro-
matic aldehydes gave the respective β-nitroalcohols with good to
high yields (up to 99%), good enantioselectivities (up to 90%) and
moderate diastereoselectivities (dr, anti:syn, up to 83:17, favoring
the anti product; Table 4, entries 1–11). For the aliphatic aldehyde,
the reaction activity is relatively low and the major products are the
syn isomers (Table 4, entries 12 and 13).
Upon scaling up to gram quantities (benzaldehyde, 10 mmol,
1.06 g), the desired product 6a was obtained in high yield (96%)
Appl. Organometal. Chem. 2014, 28, 186–193
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

F. Liu et al.
Table 3. Henry reactions of different aromatic aldehydes (R4CHO)
and nitromethane catalyzed by 3g–Cu(OAc)2
Table 4. Henry reactions of different aldehydes (R4CHO) and
nitroalkanes (R5CH2NO2) catalyzed by 3g–Cu(OAc)2
Ligand 3g
Cu(OAc)2 H2O
i-PrOH
HO
NO2
R5
Et3N
R4CHO R5CH NO
+
2
2
R4
7
Entrya
R4
6
Yield (%)b
ee (%)c
Entrya
R5
R6
7
Yield (%)bdr (anti:syn)c ee (%)d
1
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-MeC6H4
2-NO2C6H4
4-FC6H4
6b
6c
6d
6e
6f
97
91
98
90
90
97
99
92
90
93
96
99
89
53
29
38
93d
92
1
Ph
Ph
Me
Et
7a
7b
7c
7d
7e
7f
99
88
86
97
87
86
84
85
83
86
91
34
30
78:22
74:26
76:24
78:22
71:29
66:34
83:17
78:22
77:23
79:21
72:28
22:78
37:63
87/85
89/87
86/72
85/66
–/49
2
2
3
92
3
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-MeOC6H4
3-MeOC6H4
4-ClC6H4
Me
Me
Me
Et
4
91
4
5
80
5
6
6h
6i
87
6
78/58
84/90
87/88
85/80
86/83
85/88
51/85
12/56
7
3-ClC6H4
4-ClC6H4
4-PhC6H4
1-Naphthyl
2-Naphthyl
2-Furyl
91
7
Me
Me
Me
Et
7g
7h
7i
8
6j
90
8
9
6k
6l
92
9
10
11
12
13
14
15
16
91
10
11
12
13
4-ClC6H4
7j
6m
6n
6o
6p
6q
6r
91
4-CH3C6H4
i-Pr
Et
7k
7l
87
ꢀ77e
Me
Me
PhCH=CH-
i-Pr
Cyclohexyl
7m
86
aReactions were performed on a 0.5 mmol scale (0.3 ml i-PrOH),
with 12 mol% 3g (1 ml i-PrOH), 10 mol% Cu(OAc)2.H2O,
10 equiv. CH3NO2 and 7.7 mol% Et3N (3.9 mg, 0.2 ml i-PrOH) in
i-PrOH at ꢀ40°C for 24 h.
n-Bu
82
Cyclohexyl
75
aReactions were performed on a 0.5 mmol scale (0.3 ml i-PrOH),
with 12 mol% 3g (1 ml i-PrOH), 10 mol% Cu(OAc)2.H2O,
10 equiv. CH3NO2, 7.7 mol% Et3N (3.9 mg, 0.2 ml i-PrOH) in i-
PrOH at ꢀ40°C for 24 h.
bYield of isolated product.
cDiastereomeric ratios were determined by HPLC using Chiracel
chiral column (see Supporting Information).
dDiastereomeric ratios and enantiomeric excess were determined
by HPLC using Chiracel chiral column.
bYield of isolated product.
cEnantiomeric excess was determined by HPLC using chiral
column (see Supporting Information).
dThe (S)-enantiomer was the major product.
eThe (R)-enantiomer was the major product.
copper(II) complexes as catalysts in the asymmetric Henry reaction
of various aldehydes and nitromethane. The results showed that
most catalysts consisting of 3g–Cu(OAc)2 have brought about
good yields and enantiomeric excess for the desired product. Fur-
ther investigation on the copper(II) complex, 3g–Cu(OAc)2, indi-
cated that it is an efficient catalyst in the asymmetric Henry
reaction between various aldehydes and nitromethane. The
resulting β-hydroxy nitroalkanes have been obtained with high
chemical yields (up to 99%) and high enantiomeric excess (up to
93%). The optimized catalyst promoted the diastereoselective
Henry reaction of various aldehyde substrates and nitroalkane,
and gave the corresponding anti-selective adduct with up to a
99% yield and 83:17 anti/syn selectivity. Our results show that
3g–Cu(OAc)2 can be applied in the asymmetric Henry reaction to
obtain large amounts of β-nitroalcohol with high enantioselectivity.
with excellent selectivity (93% ee) using 12mol% 3g (20 ml i-PrOH),
10 mol% Cu(OAc)2.H2O at ꢀ40°C (Scheme 2). Therefore 3g–Cu
(OAc)2 could be used as a suitable catalyst to prepare large
amounts of β-nitroalcohol with high enantiomeric excess value.
Based on the generally accepted model proposed by Evans,[8]
Kureshy[28] and Kodama,[39] a general mechanism for the asymmet-
ric Henry reaction is herein proposed (Fig. 5). The copper(II) ion with
an octahedral geometry has four strong coordination sites at the
equatorial positions and two weak coordination sites at the apical
positions due to the Jahn–Teller effect. Two nitrogen atoms of
ligand 3g occupy two neighboring coordination sites. Both the al-
dehyde and nitromethane are efficiently activated by coordination
to the equatorial and the apical position of the metal atom, respec-
tively. To reduce spatial hindrance, the Re face of the carbonyl
group of benzaldehyde is much more accessible to a nucleophilic
group (nitromethane) than the Si face (A). Furthermore, the
attacking group will strongly increase repulsion between phenyl
subunits as in transition state B.
Conclusion
Scheme 2. Scale-up experiments. Reaction conditions: reactions were
performed at a 10 mmol scale (6 ml i-PrOH), 12 mol% 3g (20 ml i-PrOH),
10 mol% Cu(OAc)2.H2O, 10 equiv. CH3NO2, 7.7mol% Et3N (78mg, 4ml i-PrOH)
at ꢀ40°C for 24 h.
A number of chiral N-monoalkyl cyclohexane-1,2-diamines (ligand
3) have been designed and applied to form the corresponding
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 186–193

Henry reactions catalyzed by copper complexes of N-monoalkyl diamine
(1R,2R)-N1-n-Butylcyclohexane-1,2-diamine dihydrochloride (3b.2HCl)
White powder; yield 6.81 g, 70%;½αꢁ2D5 = ꢀ43.0 (c 0.44, H2O); IR (KBr)
υ = 3416, 2942, 2870, 1607, 1519, 1458, 1027 cmꢀ1 1H NMR
;
(300 MHz, D2O, 25°C) δ = 0.93 (t, 3H, J = 7.4Hz, CH2CH3), 1.38–1.40
(m, 4H, NHCH2CH2CH2CH3), 1.51–2.32 (m, 8H, CH2 of DACH),
3.04–3.27 (m, 2H, NHCH2), 3.40–3.50 (m, 2H, NHCH and NH2CH);
13C NMR (75 MHz, D2O, 25°C) δ = 15.0 (CH3), 21.4 (CH3CH2), 24.6
(C4), 24.7 (C5), 28.3 (C6), 29.9 (C3), 31.6 (CH3CH2CH2), 47.5 (NHCH2),
53.5 (C2), 60.6 (C1); HRMS (ESI) calcd for C10H23N2 [M+H]+
171.1861, found 171.1852. Anal. Calcd (%) for C10H24Cl2N2: C,
49.38; H, 9.95; N, 11.52. Found: C, 49.30; H, 9.92; N, 11.46.
Figure 5. Proposed transition state for the catalytic asymmetric Henry
reaction with 3g as the ligand.
(1R,2R)-N1-Isobutylcyclohexane-1,2-diamine dihydrochloride (3c.2HCl)
Experimental
White powder; yield 7.10 g, 73%;½αꢁ2D5 = ꢀ33.0 (c 0.52, H2O); IR (KBr)
υ = 3430, 2945, 2871, 1615, 1519, 1470, 1456, 1027 cmꢀ1; 1H NMR
(300 MHz, D2O, 25°C) δ = 1.00 (d, 6H, J = 6.7Hz, CH(CH3)2), 1.32–1.84
(m, 6H, CH2 of DACH), 2.02–2.11 (m, 1H, CH(CH3)2), 2.16–2.33 (m,
2H, CH2 of DACH), 2.93–3.11 (m, 2H, NHCH2CH), 3.35–3.55 (m, 2H,
NHCH and NH2CH); 13C NMR (75 MHz, D2O, 25°C) δ = 21.7 (CHCH3),
22.0 (CHCH3), 25.1 (C4), 25.2 (C5), 28.5 (C6), 28.7 (CH), 32.2 (C3), 53.9
(C2), 55.0 (NHCH2), 61.8 (C1); HRMS (ESI) calcd for C10H23N2
[M+ H]+ 171.1861, found 171.1850. Anal. Calcd (%) for C10H24Cl2N2:
C, 49.38; H, 9.95; N, 11.52. Found: C, 49.32; H, 9.97; N, 11.43.
General
All chemicals and solvents were of analytical reagent grade and
used without further purification. (Boc)2O and (1R,2R)-DACH were
obtained from a local chemical company. IR spectra were mea-
sured on KBr pellets on a Nicolet IR200 FT-IR spectrometer in
the range 4000–400 cmꢀ1, and 1H NMR and 13C NMR spectra
were recorded with a Bruker 300 MHz or 500 MHz spectrometer.
Elemental analyses for C, H and N were done on a Vario MICRO
CHNOS Elementar elemental analyzer. Mass spectra were mea-
sured on an Agilent accurate mass 6224 TOF LC-MS system.
(1R,2R)-N1-sec-Butylcyclohexane-1,2-diamine dihydrochloride (3d.2HCl)
White powder; yield 7.39 g, 76%;½αꢁ2D5 = ꢀ39.6 (c 0.44, H2O); IR (KBr)
Synthesis of Ligand 3
υ = 2938, 2866, 1596, 1553, 1502, 1450, 1031 cmꢀ1 1H NMR
;
(300 MHz, D2O, 25°C) δ = 0.94–1.01 (m, 3H, CH3CH2), 1.30–1.32 (m,
3H, CH3CH), 1.35–1.41 (m, 2H, CH3CH2), 1.44–2.29 (m, 8H, CH2 of
DACH), 3.39–3.43 (m, 1H, CH3CH), 3.44–3.51 (m, 2H, NHCH and
NH2CH); 13C NMR (75 MHz, D2O, 25°C) δ = 11.8 (CH2CH3), 16.5
(CHCH3), 25.1 (C4), 25.4 (C5), 28.8 (C6), 29.4 (CHCH2), 32.2 (C3),
54.4 (CHCH3), 56.6 (C1), 58.2 (C2); HRMS (ESI) calcd for C10H23N2
[M+H]+ 171.1861, found 171.1852. Anal. Calcd (%) for C10H24Cl2N2:
C, 49.38; H, 9.95; N, 11.52. Found: C, 49.44; H, 10.04; N, 11.55.
The corresponding aldehyde or ketone (80 mmol) was added to the
stirring solution of mono-Boc protected (1R,2R)-DACH (40 mmol) in
MeOH (150 ml). After the mixture was kept for 2 h at room temper-
ature, it was cooled in an ice-water bath, followed by adding NaBH4
(120mmol) slowly, and kept stirred overnight at 50°C. Water (10 ml)
was then added to the above mixture and white solids were
obtained by concentrating the solution. After addition of 50ml
water, the aqueous phase was extracted with EtOAc (50 ml× 3).
The combined organic extracts were washed with saturated NaCl
solution and dried with anhydrous Na2SO4. By concentrating the
solution in vacuo, the intermediate N1-monoalkyl, N2-Boc-(1R,2R)-
diaminocyclohexane was obtained. The intermediate was then
dissolved in absolute ether (75 ml) and a solution of HCl–EtOAc
(1mol lꢀ1, 50 ml) was added slowly with stirring. The mixture was
kept stirred for 12 h at room temperature. The white solid was
filtered off, washed with absolute ether and dried in vacuo. The
product was obtained as dihydrochloride salt (3.2HCl) (see
Supporting Information, 1H and 13C NMR spectra of ligand 3). Since
a new stereogenic center was generated when a branched alkyl
group was linked to one of the nitrogen atoms of (1R,2R)-
cylcohexyldiamine, such as ligands 3d, 3g, 3k, 3m, 3n and 3o,
the ligands used were a mixture of diastereomers.
(1R,2R)-N1-n-Pentylcyclohexane-1,2-diamine dihydrochloride (3e.2HCl)
25
White powder; yield 8.44 g, 82%; ½αꢁD = ꢀ38.7 (c 0.54, H2O); IR
(KBr) υ = 3420, 2947, 1615, 1579, 1509, 1444, 1032 cmꢀ1
;
1H NMR (500 MHz, D2O, 25°C) δ = 0.88 (t, 3H, J = 6.9 Hz, CH3),
1.34–1.42 (m, 6H, CH2CH2CH2CH3), 1.48–2.30 (m, 8H, CH2 of
DACH), 2.99–3.27 (m, 2H, NHCH and NH2CH), 3.36–3.51 (m, 1H,
NHCH(CH3)2); 13C NMR (75 MHz, D2O, 25°C) δ = 15.8 (CH3), 24.1
(CH3CH2), 25.1 (C4), 25.2 (C5), 28.0 (C6), 28.8 (CH3CH2CH2), 30.5
(NHCH2CH2), 32.0 (C3), 48.1 (NHCH2), 54.0 (C2), 61.0 (C1); HRMS
(ESI) calcd for C11H25N2 [M+H]+ 185.2018, found 185.2012. Anal.
Calcd (%) for C11H26Cl2N2: C, 51.36; H, 10.19; N, 10.89. Found: C,
51.42; H, 10.21; N, 10.94.
(1R,2R)-N1-(Pentan-3-yl)cyclohexane-1,2-diamine dihydrochloride (3f.2HCl)
(1R,2R)-N1-Isopropylcyclohexane-1,2-diamine dihydrochloride (3a.2HCl)
25
White powder; yield 4.32 g, 42%; ½αꢁD = ꢀ55.2 (c 0.63, H2O); IR
25
1
(KBr) υ = 3421, 2944, 1604, 1575, 1519, 1456, 1025 cm-1; H NMR
White powder; yield 7.33 g, 80%; ½αꢁD = ꢀ45.2 (c 0.90, H2O); IR
(KBr) υ = 3431, 2975, 2812, 1585, 1450, 1032 cmꢀ1
;
1H NMR
(300 MHz, D2O, 25°C) δ = 0.93–1.01 (m, 6H, CH2CH3), 1.30–2.35
(m, 12H, CH3CH2 and CH2 of DACH), 3.34-3.65 (m, 3H, NHCH and
NH2CH); 13C NMR (75 MHz, D2O, 25°C) δ = 10.8 (CH3), 11.1 (CH3),
23.3 (C4), 25.0 (C5), 25.4 (CH3CH2), 25.6 (CH3CH2), 29.1 (C6), 32.1
(C3), 54.3 (C2), 58.8 (C1), 61.6 (CH3CH2CH); HRMS (ESI) calcd for
C11H25N2 [M+H]+ 185.2012, found 185.2011.Anal. Calcd (%) for
C11H26Cl2N2: C, 51.36; H, 10.19; N, 10.89. Found: C, 51.44; H,
10.25; N, 10.92.
(300 MHz, D2O, 25°C): δ = 1.33 (d, 6H, J = 6.5 Hz, CH(CH3)2), 1.38–
2.32 (m, 8H, CH2 of DACH), 3.38–3.48 (m, 2H, NHCH and NH2CH),
3.64–3.73 (m, 1H, NHCH(CH3)2); 13C NMR (75 MHz, D2O, 25°C)
δ = 19.5 (C4), 22.0 (C5), 25.0 (2C, CH3), 28.8 (C6), 32.0 (C3), 51.5
(CH), 54.4 (C1), 58.1 (C2); HRMS (ESI) calcd for C9H21N2 [M+H]+
157.1705, found 157.1693. Anal. Calcd (%) for C9H22Cl2N2: C,
47.16; H, 9.68; N, 12.22. Found: C, 47.22; H, 9.69; N, 12.23.
Appl. Organometal. Chem. 2014, 28, 186–193
Copyright © 2014 John Wiley & Sons, Ltd.
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F. Liu et al.
(1R,2R)-N1-(4-Methylpentan-2-yl)cyclohexane-1,2-diamine dihydrochloride
(3g.2HCl)
Calcd (%) for C12H28Cl2N2: C, 53.13; H, 10.40; N, 10.33. Found: C,
53.13; H, 10.36; N, 10.28.
White powder; yield 5.43 g, 50%;½αꢁ2D5 = ꢀ52.9 (c 0.52, H2O); IR (KBr)
(1R,2R)-N1-Cyclohexylcyclohexane-1,2-diamine dihydrochloride (3l.2HCl)
υ = 3421, 2956, 2869, 1576, 1519, 1451, 1023 cmꢀ1 1H NMR
;
25
White powder; yield 8.51 g, 79%; ½αꢁD = ꢀ39.5 (c 0.44, H2O); IR
(300 MHz, D2O, 25°C) δ = 0.89-0.97 (m, 6H, CH(CH3)2), 1.31 (d, 3H,
J = 6.5Hz, NHCHCH3), 1.35–2.35 (m, 11H, CH3CH and CH2 of DACH),
3.36–3.58 (m, 3H, NHCH and NH2CH); 13C NMR (75 MHz, D2O, 25°C)
δ = 17.0 (2C, CH(CH3)2), 23.0 (NHCHCH3), 25.1 (C4), 25.3 (C5), 26.7
(CH(CH3)2), 28.7 (C6), 32.1 (C3), 45.0 (NHCHCH3), 53.7 (CH3CHCH2),
54.4 (C1), 58.1 (C2); HRMS (ESI) calcd for C12H27N2 [M+H]+
199.2169, found 199.2162. Anal. Calcd (%) for C12H28Cl2N2: C,
53.13; H, 10.40; N, 10.33. Found: C, 53.11; H, 10.35; N, 10.26.
(KBr) υ = 3429, 2939, 2860, 1519, 1452, 1030 cmꢀ1 1H NMR
;
(300 MHz, D2O, 25°C) δ =1.14–2.32 (m, 18H, CH2 of DACH and
cyclohexyl), 3.34–3.65 (m, 3H, NHCH and NH2CH); 13C NMR (75MHz,
D2O, 25°C) δ = 25.0 (C4), 26.4 (C5), 26.7 (2C, CHCH2CH2, N1-cyclohexyl),
27.0 (CHCH2CH2CH2, N1-cyclohexyl), 28.9 (C6), 30.1 (CHCH2,
N1-cyclohexyl), 32.1 (CHCH2, N1-cyclohexyl), 32.5 (C3), 54.3 (C2), 57.5
(CH, N1-cyclohexyl), 57.8 (C1); HRMS (ESI) calcd for C12H25N2 [M+H]+
197.2012, found 197.2004. Anal. Calcd (%) for C12H26Cl2N2: C, 53.53;
H, 9.73; N, 10.40. Found: C, 53.56; H, 9.77; N, 10.44.
(1R,2R)-N1-Neopentylcyclohexane-1,2-diamine dihydrochloride (3h.2HCl)
(1R,2R)-N1-(Heptan-2-yl)cyclohexane-1,2-diamine dihydrochloride (3m.2HCl)
25
White powder; yield 8.64 g, 84%; ½αꢁD = ꢀ30.6 (c 0.52, H2O); IR
(KBr) υ = 3434, 2945, 1611, 1518, 1453, 1029 cmꢀ1
;
1H NMR
25
White powder; yield 7.19 g, 63%; ½αꢁD = ꢀ46.4 (c 0.53, H2O); IR
(300 MHz, D2O, 25°C) δ = 1.05 (s, 9H, C(CH3)3), 1.31–2.36 (m, 8H,
CH2 of DACH), 2.92–3.16 (m, 2H, NHCH2), 3.37–3.59 (m, 2H, NHCH
and NH2CH); 13C NMR (75 MHz, D2O, 25°C) δ = 25.3 (C4), 25.4 (C5),
29.0 (C6), 31.9 (C3), 32.6 (3C, CH3), 53.6 (NHCH2CH), 54.9 (NHCH2),
59.2 (C2), 62.5 (C1); HRMS (ESI) calcd for C11H25N2 [M+H]+
185.2012, found 185.2010. Anal. Calcd (%) for C11H26Cl2N2: C,
51.36; H, 10.19; N, 10.89. Found: C, 51.42; H, 10.27; N, 10.89.
(KBr) υ = 3375, 2937, 2865, 1590, 1519, 1452, 1029 cmꢀ1 1H
;
NMR (500 MHz, D2O, 25°C) δ = 0.86 (s, 3H, CH2CH3), 1.31 (d, 3H,
J = 6.1 Hz, CHCH3), 1.35–2.31 (m, 16H, CH3CH2CH2CH2CH2 and
CH2 of DACH), 3.37–3.52 (m, 3H, NHCH2 and NH2CH); 13C NMR
(125 MHz, D2O, 25 °C) δ = 15.5 (CH3), 16.7 (NHCHCH3), 18.8
(CH3CH2), 23.9 (C4), 24.7 (C5), 26.6 (CH3CH2CH2CH2), 28.4 (C6),
31.5 (CH3CH2CH2), 32.8 (C3), 35.6 (CH3CHCH2), 54.0 (NHCHCH3),
55.0 (C2), 57.8 (C1); HRMS (ESI) calcd for C13H29N2 [M+H]+
213.2325, found 213.2336. Anal. Calcd (%) for C13H30Cl2N2: C,
54.73; H, 10.60; N, 9.82. Found: C, 53.76; H, 10.64; N, 9.84.
(1R,2R)-N1-Cyclopentylcyclohexane-1,2-diamine dihydrochloride (3i.2HCl)
25
White powder; yield 7.15 g, 70%; ½αꢁD = ꢀ37.0 (c 0.44, H2O); IR (KBr)
υ = 3430, 2940, 2869, 1613, 1506, 1452, 1030 cmꢀ1 1H NMR
;
(1R,2R)-N1-(Octan-3-yl)cyclohexane-1,2-diamine dihydrochloride (3n.2HCl)
(300 MHz, D2O, 25°C) δ = 1.11-2.59 (m, 16H, CH2 of DACH and
cyclopentyl), 3.40–3.47 (m, 3H, NHCH and NH2CH); 13C NMR
(75 MHz, D2O, 25°C) δ = 24.4 (CHCH2CH2, cyclopentyl), 24.5
(CHCH2CH2, cyclopentyl), 25.8 (C4), 25.9 (C5), 28.5 (C6), 30.8
(CHCH2CH2, cyclopentyl), 31.4 (CHCH2CH2, cyclopentyl), 32.2 (C3),
53.9 (NHCH, cyclopentyl), 59.4 (C2), 59.5 (C1); HRMS (ESI) calcd for
C11H23N2 [M+H]+ 183.1856, found 183.1846. Anal. Calcd (%) for
C11H24Cl2N2: C, 51.76; H, 9.48; N, 10.98. Found: C, 51.71; H, 9.41;
N, 10.91.
25
White powder; yield 5.63 g, 47%; ½αꢁD = ꢀ27.0 (c 0.60, H2O); IR
(KBr) υ = 3435, 2937, 2863, 1592, 1499, 1450, 1029 cmꢀ1 1H
;
NMR (300 MHz, D2O, 25°C) δ = 0.87 (s, 3H, CH2CH2CH3), 0.91–1.01
(m, 3H, CHCH2CH3), 1.33–2.34 (m, 18H, CH3CH2CH2CH2CH2,
CH3CH2CH and CH2 of DACH), 3.35–3.48 (m, 3H, NHCH2 and
NH2CH); 13C NMR (75 MHz, D2O, 25°C) δ = 10.9 (CH3CH2CH), 11.2
(CH3CH2CH2), 16.0 (CH3CH2CH2), 24.4 (CH3CH2CH2CH2), 25.1 (C4),
25.4 (C5), 26.5 (CH3CH2CH), 29.2 (C6), 32.0 (CH3CH2CH2), 32.2
(CH3CH2CH2CH2CH2), 33.4 (C3), 54.3 (C2), 54.9 (CH3CH2CH), 58.9
(C1); HRMS (ESI) calcd for C14H31N2 [M+H]+ 227.2482, found
227.2476.Anal. Calcd (%) for C14H32Cl2N2: C, 56.18; H, 10.78; N,
9.36. Found: C, 56.16; H, 10.72; N, 9.31.
(1R,2R)-N1-n-Hexylcyclohexane-1,2-diamine dihydrochloride (3j.2HCl)
White powder; yield 8.79 g, 81%;½αꢁ2D5 = ꢀ39.9 (c 0.52, H2O); IR (KBr)
υ = 3430, 2935, 2863, 1575, 1519, 1456, 1024 cmꢀ1 1H NMR
;
(1R,2R)-N1-(Undecan-2-yl)cyclohexane-1,2-diamine dihydrochloride (3o.2HCl)
White powder; yield 6.42 g, 47%; ½αꢁ2D5 = ꢀ31.6 (c 0.56, H2O); IR (KBr)
(300 MHz, D2O, 25°C) δ = 0.86 (t, 3H, J = 6.9 Hz, CH2CH3), 1.29–2.30
(m, 16H, CH3CH2CH2CH2CH2 and CH2 of DACH), 3.00–3.51 (m, 4H,
NHCH2 and NH2CH); 13C NMR (75 MHz, D2O, 25°C) δ = 16.1 (CH3),
24.4 (CH3CH2), 25.1 (C4), 25.2 (C5), 28.1 (NHCH2CH2CH2), 28.2 (C6),
28.8 (NHCH2CH2), 32.0 (CH3CH2CH2), 33.1 (C3), 48.1 (NHCH2), 54.0
(C2), 61.0 (C1); HRMS (ESI) calcd for C12H27N2 [M+H]+ 199.2169,
found 199.2160. Anal. Calcd (%) for C12H28Cl2N2: C, 53.13; H,
10.40; N, 10.33. Found: C, 53.11; H, 10.37; N, 10.30.
υ = 3403, 2927, 2855, 1576, 1532, 1455, 1027 cmꢀ1 1H NMR
;
(500 MHz, D2O, 25°C) δ = 0.84 (t, 3H, J = 6.2 Hz, CH2CH3), 1.26 (s, 3H,
CHCH3), 1.30–2.27 (m, 24H, CH3CH2CH2CH2CH2CH2CH2CH2CH2 and
CH2 of DACH), 3.38–3.51 (m, 3H, NHCH2 and NH2CH); 13C NMR
(75 MHz, D2O, 25 °C) δ = 16.4 (CH3CH2), 17.2 (CH3CH), 19.5 (CH3CH2),
25.2 (C4), 25.3 (C5), 28.3 (CH3CHCH2CH2), 28.9 (C6), 31.7
(CH3CH2CH2CH2), 31.8 (CH3CHCH2CH2CH2CH2), 31.9 (CH3CH2-
CH2CH2CH2), 32.1 (CH3CHCH2CH2CH2), 32.2 (CH3CH2CH2), 34.5
(C3), 36.2 (CH3CHCH2), 54.4 (NHCHCH3), 54.8 (C2), 58.3 (C1); HRMS
(ESI) calcd for C17H37N2 [M+H]+ 269.2951, found 269.2947. Anal.
Calcd (%) for C17H38Cl2N2: C, 59.81; H, 11.22; N, 8.21. Found: C,
59.82; H, 11.24; N, 8.19.
(1R,2R)-N1-(Hexan-2-yl)cyclohexane-1,2-diamine dihydrochloride (3k.2HCl)
25
White powder; yield 7.70 g, 71%; ½αꢁD = ꢀ53.9 (c 0.41, H2O); IR
(KBr) υ = 3411, 2941, 2867, 1579, 1521, 1454, 1027 cmꢀ1 1H
;
NMR (500 MHz, D2O, 25°C) δ = 0.89 (t, 3H, J = 7.1 Hz, CH2CH3),
1.32 (d, 3H, J = 6.5 Hz, CHCH3), 1.33–2.30 (m, 14H, CH3CH2CH2CH2
and CH2 of DACH), 3.44–3.54 (m, 3H, NHCH2 and NH2CH); 13C
NMR (75 MHz, D2O, 25°C) δ = 15.7 (CH2CH3), 17.1 (CHCH3), 24.4
(CH3CH2), 25.1 (C4), 25.4 (C5), 28.8 (CH3CH2CH2), 29.5 (C6), 32.2
(C3), 35.8 (CH3CHCH2), 54.4 (NHCHCH3), 55.4 (C2), 58.2 (C1); HRMS
(ESI) calcd for C12H27N2 [M+H]+ 199.2169, found 199.2161. Anal.
General Procedure for the Henry Reaction
A test tube with a stirring bar was charged with a ligand (0.06 mmol,
12 mol%, 3, free diamine (prepared from the corresponding
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 186–193

Henry reactions catalyzed by copper complexes of N-monoalkyl diamine
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was gently heated for 30 s and stirred for 1 h to ensure completion
of the complex formation. A solution of aldehyde (0.5 mmol,
1 equiv.) in i-PrOH (0.3 ml) was then added at 25°C. The whole mix-
ture was cooled to ꢀ40°C for 15 min and treated with nitromethane
(5.0 mmol, 10 equiv.) via a syringe. After 5 min, a solution of Et3N
(3.9 mg, 7.70 mol%) in i-PrOH (0.2 ml) was added via a syringe. The
mixture was stirred for 24 h at ꢀ40°C. Purification by flash chroma-
tography on silica gel (30 g, n-hexane–AcOEt; 4:1, v/v) afforded the
desired β-nitroalcohols.
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Acknowledgments
This work is supported by the National Natural Science Founda-
tion of China (Project No. 21271041) and the New Drug Creation
Project of the National Science and Technology Major Founda-
tion of China (Project 2013ZX09402102-001-006). Li would like
to thank the Scientific Research Innovation Project for College
Graduates of Jiangsu Province (Project CXZZ12_0118).
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Appl. Organometal. Chem. 2014, 28, 186–193
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