Copper(II) arylhydrazone complexes as catalysts for C[sbnd]H activation in the Henry reaction in water

Article abstract of DOI:10.1016/j.molcata.2016.05.030

Three new water-soluble copper(II) complexes [Cu(HL)(H₂O){(CH₃)₂NCHO}] (1), [Cu(H₂L)₂(im)₄]·CH₃OH (2) and [Cu(HL)(CH₃OH)]₂(μ₂-py) (3) were synthe

Full text of DOI:10.1016/j.molcata.2016.05.030

Accepted Manuscript
Title: Copper(II) arylhydrazone complexes as catalysts for
C<ce:glyph name="sbnd"/>H activation in the Henry reaction
in water
Author: Zhen Ma Atash V. Gurbanov Abel M. Maharramov
Firudin I. Guseinov Maximilian N. Kopylovich Fedor I.
Zubkov Kamran T. Mahmudov Armando J.L. Pombeiro
PII:
S1381-1169(16)30212-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.05.030
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31-5-2016
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Copper(II) arylhydrazone complexes as catalysts for
C−H activation in the Henry reaction in water
Zhen Ma,a,b Atash V. Gurbanov,b,c Abel M. Maharramov,c Firudin I. Guseinov,d,e
Maximilian N. Kopylovichb, Fedor I. Zubkovf, Kamran T. Mahmudov,b,c,
*
Armando J. L. Pombeiro b,*
a School of Chemistry and Chemical Engineering, Guangxi University, Guangxi 530004, PR China
b Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049–
001 Lisbon, Portugal
c Department of Chemistry, Baku State University, Z. Xalilov Str. 23, Az 1148 Baku, Azerbaijan
d Department of Chemistry, M. V. Lomonosov Moscow State University, 1 Leninskie Gory, 119992
Moscow, Russian Federation
e National University of Science and Technology «MISIS», Moscow Leninsky prosp. 4, 119049 Moscow,
Russian Federation
f Department of Organic Chemistry, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St.,
Moscow, 117198 Russian Federation
*Corresponding authors. Phone: +351 218419237, Fax: (+1)-21-846-4455,
E-mail addresses: kamran_chem@mail.ru (K.T. Mahmudov), pombeiro@tecnico.ulisboa.pt (A.J.L.
Pombeiro).
Dedicated to Prof. Georgiy B. Shul'pin on the occasion of his 70th birthday.
1

Graphical abstract
Highlights
► Stereoselective C−H functionalization in water
► Water-soluble mono- and dinuclear copper(II) complexes
► Sulfo-functionalized arylhydrazone of acetoacetanilide ligand
► Copper(II) complexes effectively catalyze the Henry reaction
Abstract
Three new water-soluble copper(II) complexes [Cu(HL)(H2O){(CH3)2NCHO}] (1),
[Cu(H2L)2(im)4]·CH3OH (2) and [Cu(HL)(CH3OH)]2(μ2-py) (3) were synthesized from copper(II)
nitrate and sodium (Z)-2-(2-(1,3-dioxo-1-(phenylamino)butan-2-ylidene)hydrazinyl)benzene-
sulfonate (NaH2L), in the absence (for 1) and presence of imidazole (im) (for 2) or pyrazine (py)
(for 3), and fully characterized. The complexes 1−3 have been tested as stereoselective C−H
activating catalysts for the model nitroaldol (Henry) condensation of nitroethane with various
aldehydes in water. 1 was the most active catalyst affording 64−87% yields with syn/anti
diasteroselectivities up to 77:23.
Keywords: Arylhydrazone of acetoacetanilide, Copper(II) complexes, Henry reaction in aqueous
medium, C−H activation.
1. Introduction
The C−H activation of alkanes in water with Pt complexes (the so-called Shilov reaction) remains a
conceptual breakthrough which demonstrates the possibility to transform essentially inert and
hydrophobic substrates into their water-soluble oxidation products of a much higher added value
and reactivity [1]. In spite of the initial expectations, elaboration of new effective catalysts for such
transformations is still far from perfection, and many efforts continue to be poured into the field [2].
2

One of the approaches is related to the preparation of suitable metal-organic catalytic species,
which, on one hand, can provide (stereo)specific interaction with a hydrophobic substrate and a
catalytic centre (e.g. a transition metal ion), while, on the other hand, facilitate interaction with
reaction media, where water is the preferable case due to a number of reasons [1c,3].
Arylhydrazones of active methylene compounds (AHAMC) modified with −SO3H and/or –
COOH substituents can be used as ligands for a number of copper(II) catalyzed C−H
functionalizations in water [4]. Imidazole (im) and pyrazine (py) are also known to play an
important role in the design of many C−H activating homogeneous catalysts, regulating their
solubility, buffer capacity, stability and eventually the overall activity [4b,5]. Hence, the preparation
of new heteroligand water-soluble copper homogeneous catalysts with the abovementioned ligands
is of interest for the area of C−H (stereo)specific functionalization in aqueous media. The well
studied and widely applied Henry coupling can be used as a model reaction to test the activity and
stereoselectivity of the catalysts towards aliphatic nitroalkanes.
The Henry (nitroaldol) reaction concerns the interaction between the carbonyl carbon atom
of an aldehyde and the α-carbon atom of an aliphatic nitro compound to give a new C−C bond.
Using this simple transformation, one can construct a variety of biologically active
polyfunctionalized compounds with several stereogenic centres from relatively cheap and available
starting materials [6]. This reaction can be catalyzed by a base, transition d [7−11] or f [12] metal
complexes as well as some organocatalysts [13]. Amongst these protocols, Cu-catalyzed Henry
couplings have recently received much attention [7], but most of them are performed in harmful
organic solvents. In order to avoid the organic solvents, one can prepare water-soluble copper
complexes, e.g. by suitable functionalization of ligands, and study their catalytic performance
towards the Henry reaction in water medium.
Thus, in this work we combine the abovementioned approaches towards the following aims:
i) to synthesize a new water-soluble AHAMC ligand bearing a −SO3H group, namely (Z)-2-(2-(1,3-
dioxo-1-(phenylamino)butan-2-ylidene)hydrazinyl)benzenesulfonate (NaH2L); ii) to prepare new
aquasoluble CuII-AHAMC complexes, bearing imidazole and pyrazine ligands; iii) to test the
obtained complexes as catalysts or catalyst precursors for the Henry reaction in water medium, as
well as in other solvents or under solvent-free conditions, for comparative purposes.
3

2. Experimental
2.1. Materials and instrumentation
All the chemicals were obtained from commercial sources (Aldrich) and used as received. The
infrared spectra (4000–400 cm−1) were recorded on a BIO-RAD FTS 3000MX instrument in KBr
pellets. Carbon, hydrogen, and nitrogen elemental analyses were done using a "2400 CHN
Elemental Analyzer" by Perkin Elmer. The 1H and 13C NMR spectra were recorded at room
temperature on a Bruker Avance II + 300 (UltraShieldTM Magnet) spectrometer operating at
300.130 and 75.468 MHz for proton and carbon-13, respectively. The chemical shifts are reported
in ppm using tetramethylsilane as the internal reference. Electrospray mass spectra (ESI-MS) were
run with an ion-trap instrument (Varian 500-MS LC Ion Trap Mass Spectrometer) equipped with an
electrospray ion source. For electrospray ionization, the drying gas and flow rate were optimized
according to the particular sample with 35 p.s.i. nebulizer pressure. Scanning was performed from
m/z 0 to 1200 in methanol solution. The compounds were observed in the negative or positive mode
(capillary voltage = 80–105 V).
2.2. Synthesis of NaH2L
NaH2L was synthesized similarly to a well-established procedure [4], by azocoupling of 2-
sulfobenzenediazonium chloride with acetoacetanilide in the presence of sodium hydroxide.
Diazotization: A 10 mmol (1.73 g) portion of 2-aminobenzenesulfonic acid was dissolved in 50 mL
of water upon addition of 0.6 g of solid NaOH. The solution was cooled in an ice bath to 0 °C and
10 mmol (0.69 g) of NaNO2 were added with subsequent addition of 2 mL 33 % HCl in portions of
0.4 mL for 1 h, under vigorous stirring. During the reaction, the temperature of the mixture must not
exceed +5 °C. The obtained diazonium salt was used for the next stage (see below).
Azacoupling: 10 mmol (0.40 g) of NaOH were added to a mixture of 10 mmol (1.77 g) of
acetoacetanilide with 30 mL of water-ethanol (1/30, v/v). The solution was cooled in an ice bath,
and a suspension of the diazonium salt (prepared according to the procedure described above) was
added in two equal portions under rigorous stirring for 1 h. The formed yellow precipitate of NaH2L
was filtered off, recrystallized from methanol and dried in air.
NaH2L: Yield 77 % (based on acetoacetanilide), yellow powder, soluble in water, DMSO,
methanol, ethanol and dimethylformamide and insoluble in non-polar solvents. Anal. Calcd. for
C16H14N3NaO5S (Mr = 383.35): C, 50.13; H, 3.68; N, 10.96. Found: C, 50.03; H, 3.72; N, 10.88 %.
IR (KBr): 3532 (br.) ν(H2O), 3098 and 2925 ν(NH), 1669 ν(C=O), 1601 ν(C=O∙∙∙H), 1563 ν(C=N)
cm−1. MS (ESI) (negative ion mode): m/z: 360.3 [Mr–Na]–. 1H NMR (DMSO-d6): δ 2.55 (3H,
4

CH3), 7.14−7.80 (9H, Ar−H), 11.11 (s, 1H, NH), 14.37 (s, 1H, NH). 13C{1H} (DMSO-d6): δ 26.6
(CH3), 116.0, 120.7, 124.3, 124.8, 128.0, 129.5 (Ar−H), 131.3 (Ar−SO3Na), 135.5 (C=N), 138.0
(C−NH), 139.0 (Ar−NH−N), 161.2 and 199.4(C=O).
2.3. Synthesis of [Cu(HL)(H2O){(CH3)2NCHO}] (1)
0.1 mmol (38 mg) of NaH2Lwere dissolved in 5 mL of methanol, then 0.1 mL DMF, 2 drops of
Et3N and 0.1 mmol (23 mg) of Cu(NO3)2∙2.5H2O were added. The mixture was stirred for 5 min
and left for slow evaporation. The greenish crystals of the product started to form after ca. 1 d at
room temperature; they were filtered off and dried in air.
1: Yield, 45 % (based on Cu). Calcd. for C19H22CuN4O7S (Mr = 514.01): C 44.40, H 4.31, N 10.90;
found C 44.13, H 4.22, N 10.83. MS (ESI, positive ion mode), m/z: 423.8 [Mr−H2O−DMF+H]+. IR
(KBr): 3616 and 3530 (s, br) ν(OH), 1694 (s) ν(C=O), 1561 (s) ν(C=N) cm–1.
2.4. Synthesis of [Cu(H2L)2(im)4]·CH3OH (2)
0.2 mmol (74 mg) of NaH2Lwere dissolved in 7 mL of methanol, then 0.1 mmol (23 mg) of
Cu(NO3)2∙2.5H2O and 0.4 mmol (27 mg) of imidazole (im) were added, and the system was stirred
for 5 min. After ca. 2 d at room temperature, greenish crystals precipitated, which were then filtered
off and dried in air.
2: Yield, 40 % (based on Cu). Calcd. for C45H48CuN14O11S2 (Mr = 1088.63): C 49.65, H 4.44, N
18.01; found C 49.54, H 4.32, N 17.94. MS (ESI, positive and negative ion modes), m/z: 423.8
[Mr−H2O−DMF+H]+, 168.7 [Cu(im)4]2+ and 360.3 [H2L]−. IR (KBr): 3173 (s, br) ν(OH), 2951 and
2846 ν(NH), 1681 and 1601 (s) ν(C=O), 1521 (s) ν(C=N) cm–1.
2.5. Synthesis of [Cu(HL)(CH3OH)]2(μ2-py) (3)
0.1 mmol (38 mg) of NaH2Lwere dissolved in 6 mL of methanol, then 0.1 mmol (23 mg) of
Cu(NO3)2∙2.5H2O and 0.1 mmol (8 mg) of pyrazine (py) were added, and the system was stirred for
5 min. After ca. 2 d at room temperature, greenish crystals precipitated, which were then filtered off
and dried in air.
3: Yield, 49 % (based on Cu). Calcd. for C38H38Cu2N8O12S2 (Mr = 989.98): C 46.10, H 3.87, N
11.32; found C 45.98, H 3.78, N 11.34. MS (ESI, positive ion mode), m/z: 926.8
[Mr−2CH3OH+H]+. IR (KBr): 3436 (s, br) ν(OH), 3103 and 3058 ν(NH), 1685 and 1593 (s)
ν(C=O), 1549 (s) ν(C=N) cm–1.
5

2.6. Crystal structure determination
X-ray diffraction intensities of 1−3 were collected using a Bruker SMART APEX-II CCD area
detector equipped with graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) at 298(2) K.
Absorption correction was applied by SADABS [14a,b]. The structure was solved by direct
methods and refined on F2 by full-matrix least-squares using Bruker's SHELXTL-97 [14c]. All non-
hydrogen atoms were refined anisotropically. The details of the crystallographic data, selected bond
distances and angles for 1−3 are summarized in Tables S1 and S2 (Electronic supplementary
information). Crystallographic data for the structural analysis has been deposited to the Cambridge
Crystallographic Data Center (CCDC 1476160 for 1, 1476161 for 2 and 1476163 for 3). Copy of
this information can be obtained free of charge from The Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: (+44) 1223-336033; E-mail: deposit@ccdc.cam.ac.uk or
www.ccdc.cam.ac.uk/data_request/cif).
2.7. Catalytic activity studies
The catalyst (1.0−5.0 mol%), 2 mL solvent (MeCN, MeOH or H2O), aldehyde (1 mmol) and
nitroethane (4 mmol) were added, in this order, to a 10 mL flask and the resulting mixture was
stirred for a specified period of time at room temperature. After evaporation of the solvent, the
residue was dissolved in CDCl3 and analyzed by 1H NMR to evaluate the yield of the β-nitroalkanol
product as reported previously [15]. The adequacy of the procedure was verified by blank 1H NMR
analyses with 1,2-dimethoxyethane as an internal reference. The internal standard method [8e,15]
confirmed that no side products were formed. The ratio between the syn and anti isomers was also
determined by 1H NMR spectroscopy, since the values of vicinal coupling constants for the β-
nitroalkanol products between the α-N–C–H and the α-O–C–H protons are different (J = 7–9 and
3.2–4 Hz for the syn and anti isomers, respectively) [15].
3. Results and discussion
3.1. Synthesis and characterization of NaH2L and 1−3
The highly water soluble sodium salt NaH2L was synthesized via C−N coupling reaction between
2-sulfobenzenediazonium chloride and acetoacetanilide in a sodium hydroxide water-ethanol
solution, and characterized by IR, ESI-MS, NMR spectroscopies and elemental analysis. The
hydrazone =N−NH− signal is observed at δ 14.37 in the 1H-NMR spectrum. The IR spectrum
shows ν(OH), ν(NH)hydrazone and ν(NH)amide vibrations at 3532, 3098 and 2925 cm–1, respectively,
6

while ν(C=O), ν(C=O∙∙∙H) and ν(C=N) are observed at 1669, 1601 and 1563 cm–1, correspondingly,
supporting the existence of the H-bonded hydrazone structure in the solid state.
Treatment of Cu(NO3)2∙2.5H2O with NaH2L in methanol in the absence or presence of
imidazole or pyrazine led to the CuII complexes [Cu(HL)(H2O){(CH3)2NCHO}] (1),
[Cu(H2L)2(im)4]·CH3OH (2) and [Cu(HL)(CH3OH)]2(μ2-py) (3), respectively (Scheme 1). All
complexes are characterized by elemental analysis, ESI-MS, IR spectroscopy and single crystal X-
ray diffraction (see below). In the IR spectra of 1−3, the ν(C=O) and ν(C=N) signals appear at 1694
and 1561, 1681 and 1521, 1685 and 1549 cm–1, respectively, values that are significantly shifted in
relation to the corresponding signals of NaH2L (see above). Mass spectrometry of a methanol
solution of 1−3 shows relevant peaks at m/z = 423.8 [Mr−H2O−DMF+H]+ (for 1), 168.7 [Cu(im)4]2+
and 360.3 [H2L]− (for 2), and 926.8 [Mr−2CH3OH+H]+ (for 3). Elemental analyses and X-ray
crystallography are also in agreement with the proposed formulations.
The structure of complex 1 shows the Cu atom in a square pyramidal environment formed,
in the basal plane, by two O and one N atoms from HL2- [O2, O6 and N1] and the formamide O7
atom; the apical position is taken by O1 of a water molecule (Scheme 1, Fig.). In compound 2, the
Cu atom is within a distorted octahedral coordination environment, where the positions are
occupied by four im ligands (4 equatorial N atoms) and two H2L ligands (the 2 apical O atoms,
Scheme 1, Fig.). The copper cations adopt a square pyramid geometry in the dinuclear compound 3
(Fig.). All compounds present intra- and intermolecular hydrogen bond interactions that lead to
intricate supramolecular frameworks (Fig. S1).
3.2. Catalytic activity of 1−3 in the Henry reaction
A series of reactions of nitroethane and benzaldehyde (representative model substrates) in various
solvents (MeCN, MeOH and H2O) were studied in order to evaluate the catalytic efficacy of 1−3 in
different solvents (Scheme 2, Table 1). For comparative purposes, blank reactions in the absence of
1−3 were also performed in such solvents or in added solvent-free conditions and in the presence of
Cu(NO3)2·2.5H2O, and in all the blank experiments no β-nitroalkanol was detected (entries 1−7,
Table 1).
When catalyst 1 was tested in water, the obtained yield (Table 1, entry 10) was better than in
acetonitrile or methanol media (entries 8 and 9, respectively), and much higher than those achieved
in the presence of 2 and 3 (entries 11−16). The higher catalytic activity of 1 is possibly stipulated by
7

the two adjacent labile sites, coordinated water and DMF molecules, which can be easily replaced
along the reaction. Thus, 1 and water were chosen as catalyst and green solvent, respectively, for
the following studies.
On the next step, for the reaction with catalyst 1 in water media, we optimized the reaction
temperature within the interval of 10−75 oC (Table 2, entries 4, 14−17). To this end, 20 oC was
found to be a suitable compromise for the following studies, since the yield increase until 75 oC
(from 79 to 84 %) is not marked, whereas the diasteroselectivity decreases. The increase of reaction
time from 0.5 h to 24 h (entries 1−6) led to higher conversions, but 5 h is the best compromise since
extending the reaction beyond this period does not result in a significance yield increase (e.g., from
79 to 80 % for 5 h to 24 h). The same can be concluded about the catalyst loading of 3 mol%
(entries 8−12). Possibly due to the poor solubility of 1 in the reaction mixture (nitroethane +
benzaldehyde), a lower yield (51 %) was achieved under added solvent-free conditions (entry 13).
Under the established optimal conditions, the scope of the system (with catalyst 1) was also
investigated for a variety of aldehydes, in water at room temperature (Table 3). The electronic
properties of the substituent in the aromatic aldehydes have a pronounced effect on the yield and
diastereoselectivity. In general, the aromatic aldehydes with an electron-withdrawing group (nitro
or chloro) in para position provide the nitroaldol products in higher yields (85 or 82 %,
respectively) and stereoselectivities (Table 3, entries 5 and 6). This is consistent with the higher
electrophilicity of the aldehyde CHO carbon and eventually can also be related to a possible
strengthening of the - stacking interactions in reaction intermediates (see below), which can
increase if an electron-withdrawing group is introduced into an aryl ring [16]. When aliphatic
aldehydes, such as propionaldehyde, butyraldehyde and pentanal, are applied as substrates, also
high yields and diastereoselectivities are achieved (Table 3, entries 10−12).
The nitroaldol yields obtained in this work, diastereoselectivities, used solvents and reaction
times and temperatures were compared with those reported for other copper complexes with: i)
Schiff base ligands derived from Cinchona alkaloids [17a]; ii) N'1,N'2-bis((Z)-pyridin-2-
ylmethylene)oxalohydrazide [17b]; iii) (S)-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-
6-(trifluoromethyl)phenol [17c] (Table 4). Our catalytic system, besides its simplicity, has also the
advantage of operating in water and at the convenient room temperature, leading usually to
comparable yields and stereoselectivities.
A proposed mechanism for the nitroaldol reaction of nitroethane with benzaldehyde in the
presence of 1 (Scheme 3) could involve the substitution of solvent (DMF or water) for aldehyde to
form an intermediate I (observed at the positive ion mode in methanol) with an increased
electrophilicity of the carbonyl group. In fact, the liberated DMF molecule was detected by ESI-MS
8

analysis in the positive ion mode (m/z =74, DMF+H+, Fig. S2). The - interactions between
aromatic moieties of the substrate and ligand, known [16,18−20] to occur in some catalytic
intermediates, can provide additional stabilization and orient the aldehyde in a specific way to
facilitate the following stereoselective transformation. Intermediates related to I are known [19,20]
and its formation is supported by ESI-MS data (Fig. S2). Displacement of the solvent ligand in I by
nitroethane forms a nitronate type intermediate II (also supported by ESI-MS analysis at the
positive ion mode in methanol, Fig. S3), which, in its turn, can be additionally stabilized by a
charge-assisted hydrogen bonding (CAHB, Scheme 3). The formation of such non-covalent
interactions is well documented [21−23] and was proposed to play crucial role in some catalytic
intermediates [24]. Within II, the nucleophilic attack of the nitronate ligand to the activated
aldehyde gives the nitroaldol product (see Fig. S4, ESI-MS data after 5 hours) which, upon
replacement by solvent, completes the catalytic cycle.
3. Conclusions
Three new water soluble copper(II) molecular catalysts bearing a sulfo-functionalized
arylhydrazone of acetoacetanilide have been synthesized, characterized and applied for an effective
activation of nitroethane towards its addition to various aldehydes (Henry or nitroaldol reaction) to
give the corresponding -nitroalkanols in aqueous media. Complex 1 was found to be the most
active one, providing β-nitroalcohols in good yields (up to 87 %) and diastereoselectivities (syn/anti
up to 77:23). Compared to other related catalytic systems, that studied in this work appears to be
among the best ones for the nitroalkane CH activation, having also the advantage of operating in
aqueous media at room temperature.
Acknowledgements
This work has been partially supported by The Science Foundation of China (21261002) as well as
by the Foundation for Science and Technology (FCT), Portugal (UID/QUI/00100/2013 and
"Investigador 2013" [IF/01270/2013/CP1163/CT0007] programs). The authors also
acknowledge the financial support by the Baku State University, Azerbaijan. A.V.G. and M.N.K.
express gratitude to Erasmus Mundus Action 2 EUROEAST Program and FCT for the post-doc
fellowship (EURO1400134) and working contract, respectively. The work was also carried out with
the financial support from the Ministry of Education and Science of the Russian Federation in the
framework of Increase Competitiveness Program of NUST «MISiS» (grant no. К1-2015-045).
9

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13

1
2
3
Figure. Crystal structures of 1−3 with partial atom numbering scheme. H-bond interactions are
shown as dashed blue lines.
14

1
2
3
Scheme 1. Schematic representation of 1−3.
15

Scheme 2. Nitroaldol reaction of aldehydes with nitroethane.
16

Scheme 3. Possible mechanistic pathway for the nitroaldol formation catalyzed by 1.
17

Table 1. Catalyst screening and solvent optimization for the Henry reaction of benzaldehyde with
nitroethane.a
Entry
Catalyst
Blank
Solvent
Yield, %c Selectivity,
syn/antid
1b
2
No solvent
MeCN
MeOH
H2O
−
−
−
−
3
−
−
4
−
−
5
MeCN
MeOH
H2O
−
−
Cu(NO3)2·2.5H2O
6
−
−
7
−
−
8
MeCN
MeOH
H2O
46
54
60
30
41
46
35
46
49
63:37
69:31
76:24
50:50
58:42
68:32
58:42
63:37
70:30
1
2
3
9
10
11
12
13
14
15
16
MeCN
MeOH
H2O
MeCN
MeOH
H2O
a Reaction conditions: catalyst precursor: Cu(NO3)2·2.5H2O, 1−3 (1.0 mol%), acetonitrile, methanol
or H2O (2 mL), nitroethane (4 mmol) and benzaldehyde (1 mmol), reaction time: 24 h, reaction
temperature: 20 oC. b Added solvent-free conditions, using the substrate nitroethane as solvent (2
mL), c Determined by 1H NMR, based on the starting benzaldehyde. d Calculated by 1H NMR.
18

Table 2. Optimization of the Henry reaction conditions catalyzed by 1.a
Amount of
Selectivity,
Entry
Time, h
Temp., ºC Yield, %b
catalyst, mol%
syn/antic
76:24
77:23
76:24
76:24
77:23
77:23
1
2
3
4
5
6
0.5
1
3.0
3.0
3.0
3.0
3.0
3.0
20
20
20
20
20
20
49
66
73
79
79
80
3
5
10
24
8
5
5
5
5
5
1.0
2.0
3.0
4.0
5.0
20
20
20
20
20
60
72
78
79
80
76:24
77:23
76:24
77:23
76:24
9
10
11
12
13d
5
3.0
20
51
71:29
14
15
16
17
5
5
5
5
3.0
3.0
3.0
3.0
10
35
55
75
35
82
83
84
75:25
75:25
71:29
66:34
a Reaction conditions: 1.0−5.0 mol% of catalyst 1, H2O (2 mL), nitroethane (4 mmol) and
benzaldehyde (1 mmol), 20 oC. b Determined by 1H NMR analysis (see Experimental section). c
Calculated by 1H NMR. d Solvent-free conditions, using nitroethane as solvent (2 mL).
19

Table 3. Henry reaction of nitroethane with various aldehydes catalyzed by 1.a
Entry Substrate
Yield, % b
Selectivity, syn/antic
1
4-(Dimethylamino)benzaldehyde
64
70
75
78
82
85
72
68
60
87
86
86
75:25
2
4-Methoxybenzaldehyde
4-Methylbenzaldehyde
Benzaldehyde
75:25
3
76:24
4
76:24
5
4-Chlorobenzaldehyde
4-Nitrobenzaldehyde
2-Nitrobenzaldehyde
2-Methylbenzaldehyde
2,4,6-trimethylbenzaldehyde
Propionaldehyde
77:23
6
77:23
7
70:30
8
68:32
9
61:39
10
11
12
77:23
Butyraldehyde
76:24
Pentanal
76:24
a Reaction conditions: 3.0 mol% of catalyst 1, H2O (2 mL), nitroethane (4 mmol) and aldehyde (1
mmol), reaction time: 5 h, 20 oC. b Determined by 1H NMR analysis (see Experimental part). c
Calculated by 1H NMR.
20

Table 4. Comparison of catalytic activity in the Henry reaction of benzaldehyde with nitroethane
catalyzed by homogeneous copper complexes.
syn/anti
Catalyst
Time, h
5
Temp. 0C
20
Solvent
Water
Yield, %
78
Ref.
selectivityc
76:24
this work
1
20
−20
THF
72
83
76:24
82:18
[17a]
Water+
MeOH
8
45
[17b]
[17c]
24
−15
THF
81
1:20
21