Enantioselective copper(II)-catalyzed Henry reaction utilizing chiral aziridinyl alcohols

Article abstract of DOI:10.1002/aoc.3232

A family of enantiopure β-aminoalcohols based on aziridine backbones were synthesized, and examined as chiral ligands for the copper(II)-catalyzed asymmetric Henry reaction of aromatic aldehydes with nitromethane, giving β-nitroalcohols in excellent yield

Full text of DOI:10.1002/aoc.3232

Full Paper
Received: 11 August 2014
Revised: 1 September 2014
Accepted: 16 September 2014
Published online in Wiley Online Library: 27 October 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3232
Enantioselective copper(II)-catalyzed Henry
reaction utilizing chiral aziridinyl alcohols
Xiaojuan Wanga, Wenxian Zhaoa,b*, Gaowei Lia, Jin Wangb, Guanjun Liub,
Lantao Liua*, Ruijuan Zhaob and Mincan Wangb
A family of enantiopure β-aminoalcohols based on aziridine backbones were synthesized, and examined as chiral ligands for the
copper(II)-catalyzed asymmetric Henry reaction of aromatic aldehydes with nitromethane, giving β-nitroalcohols in excellent
yields (up to 93%) and moderate to good enantioselectivities (up to 82%). Moreover, possible transition states of the reaction
are proposed. 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: aziridinyl alcohols; copper; asymmetric synthesis; Henry reaction
In recent years, our group has paid continuing attention to the
synthesis and application of chiral small-ring nitrogen heterocycle
Introduction
Among the carbon–carbon bond-forming reactions, the catalytic
asymmetric Henry (nitroaldol) reaction is one of the atom-
economical and powerful methods in organic synthesis. The
resulting optically active β-nitroalcohols are versatile building blocks
for further transformations, for example chiral β-aminoalcohols, 1,2-
diamines, α-hydroxy acids or other valuable precursors of biologically
active compounds. It is thus of great importance to explore new chi-
ral catalysts for this reaction.[1]
ligands containing a β-aminoalcohol scaffold in catalytic asymmet-
ric addition reactions.[10] These aziridinyl alcohols (1–6; Scheme 1)
have been extensively used for various asymmetric addition reac-
tions including addition of alkyl/aryl zinc to aldehydes, ketone re-
duction and conjugate addition.[10,11] Based on the above idea,
we considered that nitrogen heterocyclic aminoalcohol ligands,
such as aziridinyl alcohols having a rigid three-membered ring,
and suitable stereochemistry would lead to ligands having affinities
for copper and might be good chiral ligands for copper-catalyzed
asymmetric reactions. To develop a novel ligand framework, and
study the behavior of different β-aminoalcohols in asymmetric re-
actions, herein we report the design and synthesis of a series of
new aziridinyl alcohol ligands and their application in copper(II)-
catalyzed asymmetric Henry reaction.
Since the pioneering work of Shibasaki and co-workers in 1992,[2]
much effort has been devoted towards more selective catalytic sys-
tems including chiral metal catalysts and organocatalysts for asym-
metric Henry reactions, and significant progress has been made
over the last two decades.[3] However, the design of efficient and se-
lective novel chiral ligands and catalytic systems for metal-catalyzed
asymmetric reactions remains an intriguing but challenging research
topic in the chemical community. Recently, the catalyst-controlled
enantioselective Henry reaction in good yields and stereoselectivities
has been the focus of extensive investigation.[4] A number of cata-
lysts containing rare earth, copper, zinc, cobalt, etc.,[5] as the metal
species have been described for transition metal catalysis to give ex-
cellent yields and enantioselectivity. Among them, copper(II) com-
plexes with chiral ligands (e.g. Cinchona alkaloids,[6] Schiff bases[7]
and aminoalcohols[8]) catalyzing the Henry reaction have received
much attention and have been successfully applied to provide
β-nitroalcohols with excellent enantioselectivities. However, these
catalytic systems show some limitations, such as moisture or air sen-
sitivity, need for high catalyst loading, low enantionselectivity or dif-
ficult catalyst preparation. Therefore, the development of simple and
readily available chiral copper(II) complexes would certainly expand
the scope of the asymmetric Henry reaction. In addition, we noticed
that chiral copper–aminoalcohol complexes exhibit high efficiencies
in the copper(II)-catalyzed Henry reaction. This asymmetric Henry re-
action can proceed at room temperature with tolerance to air and
moisture, has broad functional group compatibility and high effi-
ciency and enantioselectivity, which make this catalytic system useful
for the synthesis of many valuable compounds.[9]
Results and Discussion
Synthesis of Aziridinyl Alcohol Ligands
A four-step synthesis of a series of new chiral aziridinyl alcohols is
presented in Scheme 2. The synthesis of each ligand is achieved
*
Correspondence to: Wenxian Zhao, School of Chemistry and Chemical
Engineering, Shangqiu Normal University, Shangqiu, Henan 476000, PR China.
The College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, Henan 450052, PR China. E-mail: zhaowenxian@sqnc.edu.cn
Lantao Liu, School of Chemistry and Chemical Engineering, Shangqiu Normal
University, Shangqiu, Henan 476000, PR China. E-mail: liult05@iccas.ac.cn
a School of Chemistry and Chemical Engineering, Shangqiu Normal University,
Shangqiu, Henan, 476000, PR China
b College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, Henan, 450052, PR China
Appl. Organometal. Chem. 2014, 28, 892–899
Copyright © 2014 John Wiley & Sons, Ltd.

Henry reaction catalyzed by Cu complexes of aziridinyl alcohols
Scheme 1. Examples of aziridinyl alcohols bearing various substituents.
from commercially available L-serine as the starting material. The
reaction of L-serine with excess methanol in the presence of SOCl2
at ꢀ15°C gives methyl-L-serine ester hydrochloride 7. Aromatic
aldehydes are first condensed with 7 in methanol in the presence
of Et3N, and then reduced using NaBH4 to afford the
N-arylmethyl-L-serine ester 8. Cyclization of 8 is performed in
THF using triethylamine and p-toluenesulfonyl chloride at reflux
temperature for 48 h to yield N-arylmethylaziridine-2-carboxylic
esters 9. Treatment of 9 with excess of PhMgBr affords the li-
gands 10a (92%), 10b (90%) and 10c (90%).
The absolute configuration of chiral ligand 10a was further deter-
mined using X-ray diffraction and is shown in Fig. 1. The aziridine
ring has a completely planar ring structure, and thereby free of
ring-flip conformation. The crystal structure of compound 10a re-
veals that the torsion angle N(1)–C(10)–C(11)–C(18) is 65.7°, angle
N(1)–C(10)–C(11)–C(12) is ꢀ131.4° and the dihedral angle between
the two phenyl rings is 89.2°, suggesting that two phenyl substitu-
ents on the α-carbon occupy an axial position and an equatorial po-
sition with regard to the five-membered ring, where this
arrangement minimizes the steric interaction between the phenyl
groups and the aziridine ring moiety. In addition, the distribution
of C(8)–N(1) and C(10)–C(11) in the aziridine ring plane is on both
sides from the steric stabilization.
Figure 1. ORTEP diagram of the molecular structure of 10a.
low yields (Table 1, entries 1 and 2). Using a protic solvent such as
EtOH, the reaction gives the desired product 11a with moderate
45% ee (Table 1, entry 3). When THF or ether is used as solvent,
the reaction proceeds in good yields (71–85%) and preferable
enantioselectivities (up to 72% ee) (Table 1, entries 4 and 5). As
can be seen, aprotic solvents are superior to protic solvents.
The effect of various additives on the reactivity and enan-
tioselectivity was then investigated (Table 1, entries 6–8) under the
same reaction conditions. Pyridine can increase the turnover fre-
quency, but the enantioselectivity is sharply decreased (Table 1, entry
6). Isopropanol has no significant influence on the reaction results
(Table 1, entry 7), whereas 5 Å molecular sieves lead to a good effi-
cient catalytic system with 90% yield with 82% ee (Table 1, entry
8). So, the use of additive has an important effect on both the reac-
tivity and enantioselectivity of this transformation. Next, the catalytic
activities of ligands 10b and 10c were investigated under the opti-
mal conditions. These ligands show good reaction activities, but
lower enantioselectivity (Table 1, entries 9 and 10). Additionally, the
N-benzyl moiety aziridino alcohol 2, the N-ferrocenylmethyl moiety
aziridino alcohol 3 and the N-(S)-phenylethyl moiety aziridino alcohol
5 were also screened in this model reaction and the results are listed
in Table 1 (entries 11–13). On the basis of these experimental data,
we propose that steric hindrance effects in N-substituted ligands
make little decisive contribution to the stereoselective induction in
the asymmetric Henry reaction. Therefore, ligand 10a is considered
to be the best ligand.
Since 10a gives the highest enantioselectivity in the Henry reac-
tion, it is identified as more effective among the chiral ligand series
(Table 1, entries 8–13) and was selected for optimizing further the
reaction conditions. The type of metal salt, the ligand/metal ratio,
the amount of chiral ligand and the reaction temperature were
screened for the enantioselective Henry reaction using ligand 10a
(Table 2). The effect of metal salts was investigated for the model
reaction at room temperature. Copper salts (Cu(OTf)2, Cu(OAc)
2ꢁH2O, CuBr2) are found to be more effective than zinc salts for
the reaction (Table 2, entries 3–5 versus 1 and 2); other copper(I)
salts such as CuCl afford nitroaldol adduct in moderate yield but
with poor enantioselectivity (Table 2, entry 6).
Screening of Ligands
With the aziridinyl alcohol ligands 10a–c and previously reported
chiral ligands 2,11c 310b,10d and 510b,10d in hand, we evaluated their
abilities to promote the copper(II)-catalyzed enantioselective Henry
reaction. The reaction between benzaldehyde and nitromethane in
the presence of chiral aziridinyl alcohol (5mol%) and copper ace-
tate monohydrate (Cu(OAc)2ꢁH2O; 7.5mol%) in various solvents at
room temperature was used as a model reaction. The results are
summarized in Table 1.
Initially, the dependence of reactivity and enantioselectivity of
the Henry reaction on various solvents was investigated. When tol-
uene or dichloromethane is used as solvent, the reaction results in
The effect of the ligand/metal ratio was tested at room tempera-
ture (Table 2, entries 7–9). When the amount of ligand 10a is kept
constant at 5 mol%, a gradual increase in the amount of Cu(OAc)
2ꢁH2O from 5 to 7.5 to 10 to 15 mol% gives comparable
enantioselectivity (Table 2, entries 3, 7–9). Next, the effect of the
amount of chiral ligand 10a was examined in the presence of Cu
(OAc)2ꢁH2O as metal source, by keeping the ligand/metal ratio at
1:1.5, and decreasing the amount of ligand 10a to 3 mol%. This re-
sults in lower ee value (67%) (Table 2, entry 10). Changing the
amount of ligand 10a from 7 to 10mol% leads to low
Scheme 2. Representative synthetic route to chiral aziridinyl alcohols.
Appl. Organometal. Chem. 2014, 28, 892–899
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

X. Wang et al.
Table 1. Optimization of chiral ligand, additive and solvent for the
enantioselectivities (Table 2, entries 11 and 12). The reaction tem-
perature also has an important effect on the ee value of
nitroalcohols. When the reaction temperature is reduced from
room temperature to ꢀ20°C, the corresponding product is ob-
tained in 72–73% yield and 40–42% ee (Table 2, entries 13–15).
Overall, the optimized reaction conditions are the following: li-
gand 10a, Cu(OAc)2ꢁH2O (1:1.5) complex catalyst, 5 Å molecular
sieves as additives, Et2O used as solvent, at room temperature.
In order to examine the substrate scope of this transforma-
tion by ligand 10a with the optimum reaction system men-
tioned above, the reactions were carried out using various
substrates. The results are summarized in Table 3. A wide range of ar-
omatic aldehydes participate well in this reaction affording the corre-
sponding Henry products 11a–k in good to high yields (76–93%)
and moderate to good enantioselectivities (71–82% ee). A strong ste-
ric hindrance effect is identified by comparing the stereoselective
outcomes of the same substituent group at different substituted po-
sitions on benzaldehyde. p-Methoxybenzaldehyde renders better
stereocontrol than the o-substituted form (Table 3, entries 2 and 3).
The benzaldehydes bearing methyl (Table 3, entries 4 and 5) and
chloro (Table 3, entries 6 and 7) substituents also demonstrate the
same effect. Notably, a sterically hindered 2-naphthaldehyde also
gives the (R)-2-nitroarylethanol in higher ee compared with
1-naphthaldehyde (Table 3, entries 8 and 9). It is found that the aro-
matic aldehydes with p-substituents show better enantioselectivity
than those with o-substituents. Other aromatic aldehydes,
p-nitrobenzaldehyde and 3,4-methylenedioxybenzaldehyde, are also
suitable substrates, and the reaction affords the desired Henry prod-
ucts 11j and 11k in high yields (79–86%) and enantioselectivities
(76–81% ee) (Table 3, entries 10 and 11).
enantioselective Henry reactiona
Entry Ligand Additiveb
Solvent
Yield (%)c ee (%)d Config.e
1
10a
10a
10a
10a
10a
10a
10a
10a
10b
10c
2
None
Toluene
CH2Cl2
EtOH
THF
65
68
64
71
85
95
87
90
74
77
61
65
56
56
59
45
65
72
7.5
72
82
38
62
62
64
65
R
R
R
R
R
R
R
R
R
R
R
R
R
2
None
3
None
4
None
5
None
Et2O
6
Pyridine
i-PrOH
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
5 Å MS
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
7
8
9
10
11
12
13
3
5
aAll reactions were carried out with 0.5 mmol benzaldehyde and 20
equiv. CH3NO2 in the presence of 5 mol% ligand and 7.5 mol% Cu
(OAc)2ꢁH2O, at room temperature.
bThe amount of additive is 50 mg. MS, molecular sieves.
cIsolated yields.
dDetermined by chiral HPLC of the product.
eAbsolute configuration was assigned by known elution order from
chiral column according to the literature.
Table 2. Effects of ligand loading, metal salts and reaction temperature on the asymmetric Henry reaction of benzaldehyde and nitromethane using the
chiral ligand 10aa
Entry
Ligand 10a (x mol%)
Metal salt
Et2Zn
Metal salt (y mol%)
Temp. (°C)
Yield (%)b
ee (%)c
Config.d
1
5
5
5
5
5
5
5
5
5
3
7
10
5
5
5
7.5
7.5
7.5
7.5
7.5
7.5
5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
81
63
85
78
71
78
75
79
72
67
72
73
76
73
72
47
61
72
70
67
13
68
70
61
62
56
52
50
42
40
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
2
Zn(OTf)2
3
Cu(OAc)2ꢁH2O
Cu(OTf)2
4
5
CuBr2
6
CuCl
7
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
Cu(OAc)2ꢁH2O
8
10
9
15
10
11
12
13
14
15
4.5
10.5
15
7.5
7.5
7.5
ꢀ10
ꢀ20
aAll reactions were carried out with 0.5 mmol benzaldehyde and 20 equiv. CH3NO2 in ethyl ether in the presence of ligand 10a and metal salt.
bIsolated yields.
cDetermined by chiral HPLC of the product.
dAbsolute configuration was assigned by known elution order from chiral column according to the literature.
wileyonlinelibrary.com/journal/aoc
Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 892–899

Henry reaction catalyzed by Cu complexes of aziridinyl alcohols
Table 3. Scope of aldehydes in the catalytic enantioselective Henry
with good substrate generality, moderate to good yields and high
enantioselectivities. In addition, the steric hindrance effect is signif-
icant in this reaction. Possible transition states of the reaction were
also proposed. Further application of chiral ligand 10a for other
asymmetric reactions is under investigation in our laboratory.
reactiona
Entry
R
Product Yield (%)b ee (%)c Config.d
Experimental
1
Ph
11a
11b
11c
11d
11e
11f
90
93
84
81
85
76
79
83
78
86
79
82
69
79
77
82
71
76
74
78
81
76
R
R
R
R
R
R
R
R
R
R
R
2
o-MeOC6H4
p-MeOC6H4
o-MeC6H4
General Methods
3
Melting points were determined using YRT-3 melting point appara-
tus and are uncorrected. Optical rotations were measured with a
PerkinElmer model 341 polarimeter at 20°C in CH2Cl2. The en-
antiomeric purity was determined by HPLC using a chiral col-
umn with hexane–propan-2-ol (ratio as indicated) as the
eluent. The chromatographic system consisted of a Varian
Prostar model 210 intelligent HPLC pump and a Sovent delivery
module model 320 intelligent UV–visible detector (254 nm).
The injection loop had a 20 μl capacity. The column used was
a Chiralpak OD (250 × 4.6 mm) from Daicel Chemical Ind. Ltd
(Japan). The column was operated at ambient temperature.
TLC was performed on dry silica gel plates developed with
hexane–ethyl acetate. NMR spectra (1H and 13C) were obtained
with a Bruker DPX 400 (400 MHz) spectrometer using solutions
in CDCl3 (referenced internally to Me4Si). J values are given in
Hz. FT-IR spectra were obtained with a PerkinElmer FT-IR 1750
spectrophotometer. Mass spectra were obtained using a Bruker
esquire-3000 instrument with an electrospray ionization source
(ESI-MS). All the ESI-MS spectra were obtained using MeOH as
the solvent.
4
5
p-MeC6H4
6
o-ClC6H4
7
p-ClC6H4
11g
11h
11i
8
1-Naphthyl
2-Naphthyl
p-NO2C6H4
3,4-OCH2OC6H3
9
10
11
11j
11k
aAll reactions were carried out with 0.5 mmol aromatic aldehyde and
20 equiv. CH3NO2 in ethyl ether in the presence of 5 mol% 10a
and 7.5 mol% Cu(OAc)2ꢁH2O, at room temperature.
bIsolated yields.
cDetermined by HPLC using a Chiralpak OD-H column. The product
chromatograms were compared against known racemic mixtures.
dAbsolute configuration was assigned by known elution order from
chiral column according to the literature.
Compounds 2, 3 and 4 were synthesized according to similar lit-
erature procedures.[13]
Typical Procedure for Preparation of Compounds 8a–c
Compound 7 (4.5 g, 29.3mmol) was dissolved in 30ml of anhy-
drous methanol and cooled to 0°C. Triethylamine (3.4 ml, 27 mmol)
was added, and the reaction was stirred for 10 min. Aromatic alde-
hyde (17mmol) was added, and the reaction mixture was stirred for
2 h, at which time sodium borohydride (1.6g, 43 mmol) was added
portionwise to the reaction mixture over a period of 0.5 h. The solu-
tion was carefully neutralized with 8% HCl to pH= 7–8, and ex-
tracted three times with 40 ml portions of diethyl ether. The
combined ether extract was washed with brine, dried over Na2SO4
and evaporated under reduced pressure. The resulting residue was
purified using preparative TLC with petroleum ether–EtOAc as de-
veloping solvent to give a pale yellow solid of 8a–c.
Figure 2. A plausible stereochemical model.
On the basis of the reported mechanistic studies of the asymmet-
ric Henry reaction catalyzed by Cu(II) complexes,[12] the results can
be rationalized in terms of the transition state mode as shown in
Fig. 2. The reaction may involve Cu(II)-mediated dual activation of
both the nitronate and aldehyde. In the transition state, the nucle-
ophilic carbon of the nitronate ion formed in situ by the deproton-
ation of nitromethane with an acetate ion attacks the aldehyde
from the Re face to afford the (R)-isomer as a major product. Si face
attack is not favorable due to steric interaction between the bulky R
group and the piperonylmethyl group.
N-Piperonylmethyl-L-serine methyl ester (8a)
8a
White solid; yield 93%; m.p. 98–99°C; [α]2D0 = ꢀ23.2 (c 1.05, in
CH2Cl2). 1H NMR (400MHz, CDCl3, δ, ppm): 6.83 (s, 1H, PhH at C2),
6.75 (s, 2H, PhH at C5, C6), 5.94 (s, 2H, –OCH2O– at C7), 3.79
(d, J = 12.9 Hz, 1H, PhCH2NH– at C8), 3.78–3.76 (m, 1H, OHCH2CH–
at C9), 3.74 (s, 3H, –COOCH3 at C11), 3.63 (d, J = 12.9 Hz, 1H,
PhCH2NH– at C8), 3.62–3.58 (m, 1H, OHCH2CH– at C9), 3.41 (dd,
J = 6.2, 4.6Hz, 1H, –NHCH at C10), 2.69–1.86 (br, 2H, –OH, –NH).
Conclusions
A novel class of β-aminoalcohol based on an aziridine backbone
has been synthesized through a five-step procedure with commer-
cially available starting materials. The ligand 10a was coordinated
to Cu(II) and then employed in the asymmetric Henry reaction be-
tween nitromethane and aromatic aldehydes under mild condition
Appl. Organometal. Chem. 2014, 28, 892–899
Copyright © 2014 John Wiley & Sons, Ltd.
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X. Wang et al.
13C NMR (CDCl3, 100 MHz, δ, ppm): 173.45 (C¼O at C12), 147.81 (C
(Ph) at C3), 146.82 (C(Ph) at C4), 133.20 (C(Ph) at C1), 121.45 (CH
(Ph) at C6), 108.74 (CH(Ph) at C2), 108.14 (CH(Ph) at C5), 100.98
(–OCH2O– at C7), 62.39 (–NHCHCH2OH at C10), 61.52 (–CH2OH
at C9), 51.86 (–COOCH3 at C11), 52.23 (PhCH2NH– at C8). Anal.
Calcd for C12H15NO5 (%):C, 56.91; H, 5.97; N, 5.53. Found (%): C,
56.99; H, 6.04; N, 5.45. FT-IR (KBr pellet, ν, cmꢀ1): 3302, 3108, 2948,
2905, 1731, 1498, 1444, 1368, 1226, 1139, 1091, 1038, 928, 806, 760.
Typical Procedure for Preparation of Compounds 9a–c
Compound 8 (about 3 g, 12 mmol) was dissolved in THF (15 ml) at
room temperature. Triethylamine (3 ml) was added, followed by
the addition of p-toluenesulfonyl chloride (2.3g, 12mmol), and
the mixture was stirred for 30 min at room temperature. The tem-
perature was then raised to 50°C and the reaction mixture heated
to refluxing. The reaction was monitored using TLC. After 24 h the
reaction was finished and quenched by cooling to room tempera-
ture. The solution was filtered and the solid washed with Et2O. After
removal of the solvent, the resulting residue was purified by col-
umn chromatography with hexane–EtOAc as developing solvent
to give compounds 9a–c.
N-Indanylmethyl-L-serine methyl ester (8b)
(2S)-Methyl 1-piperonylmethylaziridine-2-carboxylate (9a)
8b
Yellow solid; yield 72%; m.p. 59–60°C; [α]2D0 = ꢀ31.7 (c 1.05, in
CH2Cl2). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.18–7.16 (m, 2H,
PhH at C2, C6), 7.07 (d, J = 7.9 Hz, 1H, PhH at C5), 3.82 (d,
J = 4.8 Hz, 1H, PhCH2NH– at C10), 3.78 (dd, J = 10.8, 4.4 Hz, 1H,
OHCH2CH– at C11), 3.74 (s, 3H, –COOCH3 at C13), 3.61 (dd,
J = 10.8, 6.4 Hz, 1H, OHCH2CH– at C11), 3.67 (d, J = 4.8 Hz, 1H,
PhCH2NH– at C10), 3.44 (dd, J = 6.4, 4.4 Hz, 1H, –NHCH at C12),
2.91–2.85 (m, 4H, 2 × PhCH2– at C8 and C9), 2.46–2.02 (br, 2H,
–OH, –NH), 2.12–2.02 (m, 2H, –CH2CH2CH2– at C7). 13C NMR
(CDCl3, 100 MHz, δ, ppm): 173.47 (C¼O at C14), 144.62 (C(Ph)
at C3), 143.35 (C(Ph) at C4), 137.07 (C(Ph) at C1), 126.17 (CH(Ph)
at C5), 124.33 (CH(Ph) at C2), 124.31 (CH(Ph) at C6), 62.30
(–NHCHCH2OH at C12), 61.72 (–CH2OH at C11), 52.11 (–COOCH3
at C13), 52.04 (PhCH2NH– at C10), 32.72 (–CH2CH2Ph at C8), 32.50
(–CH2CH2Ph at C9), 25.48 (–CH2CH2CH2– at C7). Anal. Calcd for
C14H19NO3 (%): C, 67.45; H, 7.68; N, 5.62. Found (%): C, 67.47; H,
7.54; N, 5.66. FT-IR (KBr pellet, ν, cmꢀ1): 3265, 3090, 2921, 1740,
1648, 1481, 1438, 1346, 1307, 1208, 1128, 1060, 994, 919, 876,
825, 742.
9a
1
Yellow oil; yield 65%; [α]2D0 = ꢀ50.4 (c 1.05, in CH2Cl2). H NMR
(CDCl3, 400 MHz, δ, ppm): 6.86 (s, 1H, PhH at C2), 6.75 (s, 2H, PhH
at C5, C6), 5.93 (s, 2H, –OCH2O– at C7), 3.71 (s, 3H, –COOCH3 at
C11), 3.53–3.43 (m, 2H, PhCH2N– at C8), 2.24 (dd, J = 3.1, 0.7 Hz,
1H, –NCH2CH– at C9), 2.20 (dd, J = 6.5, 3.1Hz, 1H, –NCH– at C10),
1.74 (dd, J= 6.5, 0.7Hz, 1H, –NCH2CH– at C9). 13C NMR (CDCl3,
100 MHz, δ, ppm): 171.05 (C¼O at C12), 147.61 (C(Ph) at C3),
146.79 (C(Ph) at C4), 131.37 (C(Ph) at C1), 121.30 (CH(Ph) at
C6), 108.67 (CH(Ph) at C5), 108.02 (CH(Ph) at C2), 100.87 (–OCH2O–
at C7), 63.59 (PhCH2N– at C8), 52.14 (–COOCH3 at C11), 37.09
(–NCHCH2– at C10), 34.36 (–NCH2CH– at C9). HRMS m/z (ESI)
calcd for C12H13NO4 [M + Na+] 258.0845, found 258.0732. Anal.
Calcd for C12H13NO4 (%): C, 61.27; H, 5.57; N, 5.95. Found (%): C,
61.38; H, 5.64; N, 6.03. FT-IR (KBr pellet, ν, cmꢀ1): 2960, 2899, 1739,
1495, 1444, 1244, 1192, 1036, 925, 811.
N-Dihydrobenzofurylmethyl-L-serine methyl ester (8c)
(2S)-Methyl 1-indanylmethylaziridine-2-carboxylate (9b)
8c
9b
Yellow solid; yield 76%; m.p. 58–59°C; [α]2D0 = ꢀ17.6 (c 1.00, in
CH2Cl2). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.17 (s, 1H, PhH at C2),
7.03 (d, J = 8.1Hz, 1H, PhH at C5), 6.73 (d, J = 8.1Hz, 1H, PhH at
C6), 4.56 (t, J = 8.7 Hz, 2H, –CH2O– at C7), 3.78 (d, J = 12.4 Hz, 1H,
PhCH2NH– at C9), 3.77–3.76 (m, 1H, OHCH2CH– at C10), 3.75 (s,
3H, –COOCH3 at C12), 3.64 (d, J = 12.4 Hz, 1H, PhCH2NH– at C9),
3.62–3.58 (m, 1H, OHCH2CH– at C10), 3.43 (dd, J = 6.3, 4.6 Hz, 1H,
–NHCH– at C11), 3.19 (t, J= 8.7 Hz, 2H, –CH2CH2Ph at C8), 2.79–
1.74 (br, 2H, –OH, –NH). 13C NMR (CDCl3, 100MHz, δ, ppm): 173.52
(C¼O at C13), 159.47 (C(Ph) at C4), 131.33 (C(Ph) at C1), 128.18 (C
(Ph) at C3), 127.33 (CH(Ph) at C6), 125.08 (CH(Ph) at C2), 109.07
(CH(Ph) at C5), 71.31 (–OCH2CH2– at C7), 62.40 (–NHCHCH2OH at
C11), 61.66 (–CH2OH at C10), 51.83 (–COOCH3 at C12), 52.18
(PhCH2NH– at C9), 29.69 (–OCH2CH2– at C8). Anal. Calcd for
C13H17NO4 (%): C, 62.14; H, 6.82; N, 5.57. Found (%): C, 62.11; H,
6.93; N, 5.64. FT-IR (KBr pellet, ν, cmꢀ1): 3346, 3157, 2931, 1732,
1648, 1492, 1440, 1362, 1228, 1139, 1042, 970, 939, 840.
1
Yellow oil; yield 42%; [α]2D0 = ꢀ27.8 (c 1.05, in CH2Cl2). H NMR
(CDCl3, 400 MHz, δ, ppm): 7.21 (s, 1H, PhH at C2), 7.17 (d,
J = 7.5 Hz, 1H, PhH at C6), 7.07 (d, J = 7.5 Hz, 1H, PhH at C5), 3.71 (s,
3H, –COOCH3 at C13), 3.54 (d, J = 13.2 Hz, 1H, –NCH2Ph at C10),
3.47 (d, J = 13.2 Hz, 1H, –NCH2Ph at C10), 2.89 (t, J = 7.4Hz, 4H,
2 × PhCH2– at C8 and C9), 2.23 (dd, J = 3.1, 0.7Hz, 1H, –NCH2CH–
at C11), 2.21 (dd, J = 6.4, 3.1 Hz, 1H, –NCHCH2– at C12), 2.07 (dq,
J = 14.8, 7.4 Hz, 2H, –CH2CH2CH2– at C7), 1.74 (dd, J = 6.4, 0.7Hz,
1H, –NCH2CH– at C11). 13C NMR (CDCl3, 100 MHz, δ, ppm):
171.24 (C¼O at C14), 144.51 (C(Ph) at C3), 143.41 (C(Ph) at C4),
135.33 (C(Ph) at C1), 126.07 (CH(Ph) at C5), 124.30 (CH(Ph)
at C2), 124.20 (CH(Ph) at C6), 63.97 (PhCH2N– at C10), 52.16
(–COOCH3 at C13), 37.26 (–NCHCH2– at C12), 34.41 (–NCH2CH–
at C11), 32.72 (–CH2CH2Ph at C8), 32.51 (–CH2CH2Ph at C9),
25.44 (–CH2CH2CH2– at C7). Anal. Calcd for C14H17NO2 (%): C,
72.70; H, 7.41; N, 6.06. Found (%): C, 72.78; H, 7.44; N, 6.09.
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Appl. Organometal. Chem. 2014, 28, 892–899

Henry reaction catalyzed by Cu complexes of aziridinyl alcohols
FT-IR (KBr pellet, ν, cmꢀ1): 2947, 2843, 1741, 1442, 1395, 1290,
1188, 1087, 1031, 818.
J = 6.3Hz, 1H, –NCH2CH at C9). 13C NMR (CDCl3, 100 MHz, δ, ppm):
147.52 (C(Ph) at C3), 147.46 (C(Ph) at C4), 146.75 (C(Ph) at C11),
144.88 (C(Ph) at C11’), 132.22 (C(Ph) at C1), 128.04× 2 (CH(Ph) at
C14, C14’), 127.93 × 2 (CH(Ph) at C13, 13’), 127.05 (CH(Ph) at C15),
126.68 (CH(Ph) at C15’), 126.35× 2 (CH(Ph) at C12, C12’), 126.22 × 2
(CH(Ph) at C16, C16’), 121.45 (CH(Ph) at C6), 108.84 (CH(Ph) at C5),
107.96 (CH(Ph) at C2), 100.89 (–OCH2O– at C7), 74.06 (–C–OH
at C17), 62.89 (–NCH2Ph at C8), 45.92 (–NCHCH2– at C10), 30.58
(–NCH2CH– at C9). HRMS m/z (ESI) calcd for C23H21NO3 [M + H+]
360.1555, found 360.1591. Anal. Calcd for C23H21NO3 (%): C,
76.86; H, 5.89; N, 3.90. Found (%): C, 76.18; H, 5.84; N, 3.89. FT-IR
(KBr pellet, ν, cmꢀ1): 3350, 3024, 2980, 2888, 1491, 1444, 1368,
1242, 1193, 1037, 989, 931, 778, 760, 696.
(2S)-Methyl 1-dihydrobenzofurylmethylaziridine-2-carboxylate (9c)
9c
1
Yellow oil; yield 42%; [α]2D0 = ꢀ9.4 (c 1.05, in CH2Cl2). H NMR
(400 MHz, CDCl3, δ, ppm): 7.20 (s, 1H, PhH at C2), 7.02 (d,
J =8.0 Hz, 1H, PhH at C6), 6.72 (d, J = 8.0Hz, 1H, PhH at C5), 4.55 (t,
J =8.7 Hz, 2H, –CH2O– at C7), 3.71 (s, 3H, –COOCH3 at C12),
3.50–3.40 (m, 2H, PhCH2N– at C9), 3.19 (t, J = 8.7 Hz, 2H, PhCH2CH2–
at C8), 2.29–2.11 (m, 2H, –NCH2CH at C10, –NCHCH2– at C11),
1.74 (d, J = 6.1 Hz, 1H, –NCH2CH– at C10). 13C NMR (CDCl3,
100 MHz, δ, ppm): 171.28 (C¼O at C13), 159.54 (C(Ph) at C4),
129.62 (C(Ph) at C1), 128.13 (C(Ph) at C3), 127.28 (CH(Ph) at C6),
125.14 (CH(Ph) at C2), 108.96 (CH(Ph) at C5), 71.30 (–OCH2CH2–
at C7), 63.71 (PhCH2N– at C9), 52.22 (–COOCH3 at C12),
37.16 (–NCHCH2– at C11), 34.41 (–NCH2CH– at C10), 29.67
(–OCH2CH2– at C8). Anal. Calcd for C13H15NO3 (%): C, 66.94;
H, 6.48; N, 6.00. Found (%): C, 67.18; H, 6.49; N, 6.09. FT-IR (KBr pellet,
ν, cmꢀ1): 2954, 2846, 1738, 1610, 1490, 1444, 1395, 1357, 1291,
1228, 1093, 1031, 980, 941, 814.
(2S)-1-Indanylmethylaziridin-2-yl(diphenyl)methanol (10b)
10b
White solid; yield 90%; m.p. 105.5–106.3°C; [α]2D0 = ꢀ12.4 (c 1.05,
1
in CH2Cl2). H NMR (400MHz, CDCl3, δ, ppm): 7.48–7.40 (m, 2H,
PhH at C16, C16’), 7.38–7.29 (m, 4H, PhH at C15, C15’ and C17,
C17’), 7.29–7.17 (m, 4H, PhH at C14, C14’ and C18, C18’), 7.13 (d,
J = 7.6Hz, 1H, PhH at C5), 7.09 (s, 1H, PhH at C2), 7.01 (d, J = 7.6 Hz,
1H, PhH at C6), 3.90 (s, 1H, –OH of tertiary alcohol), 3.62 (d,
J = 13.0 Hz, 1H, –NCH2Ph at C10), 3.45 (d, J= 13.0 Hz, 1H, –NCH2Ph
at C10), 2.88 (dt, J= 17.9, 7.4 Hz, 4H, 2 × PhCH2 at C8 and C9), 2.55
(dd, J= 6.3, 3.5Hz, 1H, –NCH– at C12), 2.19–2.04 (m, 2H,
–CH2CH2CH2– at C7), 2.03 (d, J= 6.3 Hz, 1H, –NCH2CH– at C11),
1.57 (d, J= 6.3Hz, 1H, –NCH2CH– at C11). 13C NMR (CDCl3,
100 MHz, δ, ppm): 147.66 (C(Ph) at C3), 145.07 (C(Ph) at C13),
144.45 (C(Ph) at C13’), 143.33 (C(Ph) at C4), 136.13 (C(Ph) at C1),
128.05 × 2 (CH(Ph) at C16, C16’), 127.96× 2 (CH(Ph) at C15, C15’),
127.03 (CH(Ph) at C17), 126.70 (CH(Ph) at C17’), 126.38 × 2 (CH(Ph)
at C14, C14’), 126.37 × 2 (CH(Ph) at C18, C18’), 126.26 (CH(Ph)
at C5), 124.41 (CH(Ph) at C2), 124.19 (CH(Ph) at C6), 74.10 (–C–OH
at C19), 63.16 (–CH2NPh at C10), 45.95 (–NCHCH2– at C12), 32.80
(–CH2CH2Ph at C8), 32.60 (–CH2CH2Ph at C9), 30.61(–NCH2CH– at
C11), 25.54 (–CH2CH2CH2– at C7). HRMS m/z (ESI) calcd for
C25H25NO [M + H+] 356.1970, found 356.2012. Anal. Calcd for
C25H25NO (%): C, 84.47; H, 7.09; N, 3.94. Found (%): C, 84.48; H,
7.14; N, 3.99. FT-IR (KBr pellet, ν, cmꢀ1): 3347, 3045, 2915, 1442,
1333, 1176, 1057, 984, 912, 861, 811, 755, 696.
Representative Procedure for Synthesis of Ligands 10a–c
To the Grignard reagent solution prepared from 2.2ml (20 mmol) of
bromobenzene in 2 ml of THF and 500 mg (20 mmol) of magne-
sium in 20 ml of THF was gradually added compound 9
(2.0 mmol) dissolved in 5 ml of THF at ꢀ5°C over a period of
30 min. The mixture was then allowed to reach room tempera-
ture. After stirring for 24 h, the reaction was quenched with
saturated aqueous NH4Cl (10 ml) at 0°C. The product was sepa-
rated and the aqueous phase extracted with ethyl acetate
(3 × 10 ml). The combined organic phases were washed with
brine (15 ml), dried over Na2SO4 and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography on silica with petroleum ether–EtOAc as eluent,
obtaining white solid ligands 10a–c.
(2S)-1-Piperonylmethylaziridin-2-yl(diphenyl)methanol (10a)
(2S)-1-Dihydrobenzofurylmethylaziridin-2-yl(diphenyl)methanol (10c)
10a
White solid; yield 92%; m.p. 91.4–92.2°C; [α]2D0 = ꢀ2.0 (c 1.05, in
1
CH2Cl2). H NMR (400 MHz, CDCl3, δ, ppm): 7.41–7.39 (m, 2H, PhH
at C14, C14’), 7.31–7.28 (m, 4H, PhH at C13, C13’ and C15, C15’),
7.25–7.15 (m, 4H, PhH at C12, C12’ and C16, C16), 6.69 (s, 1H, PhH
at C2), 6.66 (d, J = 8.0 Hz, 1H, PhH at C5), 6.62 (d, J = 8.0 Hz, 1H,
PhH at C6), 5.92 (s, 2H, –OCH2O– at C7), 3.77 (s, 1H, –OH of tertiary
alcohol), 3.52 (d, J = 12.9 Hz, 1H, PhCH2N– at C8), 3.43 (d,
J = 12.9 Hz, 1H, PhCH2N– at C8), 2.50 (dd, J = 6.3, 3.5 Hz, 1H,
–NCH2CH– at C9), 2.02 (d, J =3.5 Hz, 1H, –NCHCH2 at C10), 1.54 (d,
10c
White solid; yield 90%; m.p. 145.1–145.4°C; [α]2D0 = ꢀ1.5 (c
1.05, in CH2Cl2). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.45–7.37
(m, 2H, PhH at C15, C15’), 7.31–7.28 (m, 4H, PhH at C14,
C14’ and C16, C16’), 7.26–7.13 (m, 4H, PhH at C13, C13’ and
Appl. Organometal. Chem. 2014, 28, 892–899
Copyright © 2014 John Wiley & Sons, Ltd.
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X. Wang et al.
C17, C17’), 7.00 (s, 1H, PhH at C2), 6.92 (d, J = 8.1 Hz, 1H, PhH
at C6), 6.65 (d, J = 8.1 Hz, 1H, PhH at C5), 4.54 (t, J = 8.7 Hz, 2H,
–CH2O– at C7), 3.84 (s, 1H, –OH of tertiary alcohol), 3.54 (d,
J = 12.8 Hz, 1H, PhCH2N– at C9), 3.47 (d, J = 12.8 Hz, 1H,
PhCH2N– at C9), 3.10 (t, J = 8.6 Hz, 2H, PhCH2– at C8), 2.50
(dd, J = 6.3, 3.5 Hz, 1H, –NCH– at C11), 1.99 (d, J = 3.5 Hz, 1H,
–NCH2CH– at C10), 1.55 (d, J = 6.3 Hz, 1H, –NCH2CH– at C10).
13C NMR (CDCl3, 100 MHz, δ, ppm): 159.42 (C(Ph) at C4),
147.62 (C(Ph) at C12), 145.02 (C(Ph) at C12’), 130.43 (C(Ph) at
C3), 128.16 (C(Ph) at C1), 128.04 × 2 (CH(Ph) at C15, C15’),
127.92 (CH(Ph) at C2), 127.10 (CH(Ph) at C16), 127.03 (CH(Ph)
at C16’), 126.66 (CH(Ph) at C6), 126.36 (CH(Ph) at C17),
126.30 × 2 (CH(Ph) at C13, C13’), 125.04 (CH(Ph) at C17’),
108.88 (CH(Ph) at C5), 74.06 (–C–OH at C18), 71.28 (–OCH2CH2– at
C7), 62.86 (–CH2NPh at C9), 45.93 (–NCHCH2– at C11), 30.52
(–NCH2CH– at C10), 29.70 (–OCH2CH2– at C8). HRMS m/z
(ESI) calcd for C24H23NO2 [M + H+] 358.1762, found 358.1800.
Anal. Calcd for C24H23NO2 (%): C, 80.64; H, 6.49; N, 3.92. Found
(%): C, 80.58; H, 6.44; N, 3.99. FT-IR (KBr pellet, ν, cmꢀ1): 3364,
3025, 2972, 2902, 2846, 1484, 1446, 1334, 1231, 1098, 1046,
984, 938, 836, 794.
3% i-PrOH in hexane). Retention times: 11.8 min (major (R)-enantio-
mer) and 15.8min (minor (S)-enantiomer).
(R)-1-(4-Chlorophenyl)-2-nitroethanol 11g. 79% isolated yield, 76% ee
by HPLC analysis (Chiralpak OD-H column, 254nm, 0.8mlminꢀ1
,
5% i-PrOH in hexane). Retention times: 32.0 min (major (R)-enantio-
mer) and 48.0min (minor (S)-enantiomer).
(R)-1-(1-Naphthyl)-2-nitroethanol 11h. 83% isolated yield, 74% ee by
HPLC analysis (Chiralpak OD-H column, 254nm, 0.8 ml minꢀ1, 15%
i-PrOH in hexane). Retention times: 19.0 min (major (R)-enantiomer)
and 28.0min (minor (S)-enantiomer).
(R)-1-(2-Naphthyl)-2-nitroethanol 11i. 78% isolated yield, 76% ee by
HPLC analysis (Chiralpak OD-H column, 254nm, 0.8 ml minꢀ1, 20%
i-PrOH in hexane). Retention times: 32.0 min (major (R)-enantiomer)
and 48.0min (minor (S)-enantiomer).
(R)-1-(4-Nitrophenyl)-2-nitroethanol 11j. 86% isolated yield, 81% ee by
HPLC analysis (Chiralpak OD-H column, 254nm, 0.8 ml minꢀ1, 15%
i-PrOH in hexane). Retention times: 21.4 min (major (R)-enantiomer)
and 26.5min (minor (S)-enantiomer).
General Procedure for Enantioselective Henry Reaction
(R)-1-Piperonyl-2-nitroethanol 11k. 79% isolated yield, 76% ee by HPLC
analysis (Chiralpak OD-H column, 254 nm, 0.8ml minꢀ1, 10% i-PrOH
in hexane). Retention times: 38.2 min (major (R)-enantiomer) and
51.2 min (minor (S)-enantiomer).
To a 10 ml screw-capped vial were added ligand 10a (9.0 mg,
0.025 mmol), Cu(OAc)2ꢁH2O (7.5mg, 0.035 mmol), 5 Å molecular
sieves (50 mg) and dried ethyl ether (2.0 ml). The mixture was
stirred at room temperature for 12 h. Then the aldehyde (0.5mmol)
and nitromethane (0.54 ml, 10mmol) were added and the resulting
mixture was stirred at the same temperature for 24 h (monitored
using TLC). After completion, the solvent was removed and the
resulting residue was washed with brine, dried over anhydrous
Na2SO4 and evaporated under reduced pressure. Purification of
the residue using a preparative silica gel TLC plate (petroleum
ether–EtOAc) afforded the Henry product 11. Enantiomeric excess
was determined using HPLC with a Chiralpak OD-H chiral column
(flow rate: 0.8 ml minꢀ1, λ = 254 nm). In all cases, the product chro-
matograms were compared against a known racemic mixture.
Acknowledgements
We are grateful for the financial support from the National Natural
Science Foundation of China (nos. 20972091, 21172139, 21202095)
and the Education Department of Henan Province Science and Tech-
nology Research Projects (nos. 13A150835, 14A150055).
References
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(R)-2-Nitro-1-phenylethanol 11a. 90% isolated yield, 82% ee by HPLC
analysis (Chiralpak OD-H column, 254nm, 0.8 ml minꢀ1, 10% i-PrOH
in hexane). Retention times: 14.6 min (major (R)-enantiomer) and
18.0min (minor (S)-enantiomer).
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(R)-1-(2-Methoxyphenyl)-2-nitroethanol 11b. 93% isolated yield, 69% ee
by HPLC analysis (Chiralpak OD-H column, 254 nm, 0.8ml minꢀ1
,
10% i-PrOH in hexane). Retention times: 16.3 min (major (R)-enan-
tiomer) and 19.4 min (minor (S)-enantiomer).
(R)-1-(4-Methoxyphenyl)-2-nitroethanol 11c. 84% isolated yield, 79% ee
by HPLC analysis (Chiralpak OD-H column, 254 nm, 0.8ml minꢀ1
,
10% i-PrOH in hexane). Retention times: 30.9 min (major (R)-enan-
tiomer) and 39.3 min (minor (S)-enantiomer).
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(R)-1-(2-Methylphenyl)-2-nitroethanol 11d. 81% isolated yield, 77% ee
by HPLC analysis (Chiralpak OD-H column, 254 nm, 0.8ml minꢀ1
,
5% i-PrOH in hexane). Retention times: 25.8min (major (R)-enantio-
mer) and 42.4 min (minor (S)-enantiomer).
(R)-1-(4-Methylphenyl)-2-nitroethanol 11e. 85% isolated yield, 82% ee
by HPLC analysis (Chiralpak OD-H column, 254 nm, 0.8ml minꢀ1
,
10% i-PrOH in hexane). Retention times: 18.9 min (major (R)-enan-
tiomer) and 25.5 min (minor (S)-enantiomer).
(R)-1-(2-Chlorophenyl)-2-nitroethanol 11f. 76% isolated yield, 71% ee
by HPLC analysis (Chiralpak OD-H column, 254 nm, 0.8ml minꢀ1
,
wileyonlinelibrary.com/journal/aoc
Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 892–899

Henry reaction catalyzed by Cu complexes of aziridinyl alcohols
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