A mild and convenient one-pot synthesis of 4-aryl-n-oh-hantzsch esters

Article abstract of DOI:10.3987/COM-13-12668

A general methodology to prepare a series of 4-Aryl-N-OH Hantzsch esters was developed. The key factor is to control the first-step of Michael addition at 0 °C. The method was practical to produce symmetrical and unsymmetric N-OH-Hantzsch esters in moderate yield. This class of compounds might have use in medicinal and material science.

Full text of DOI:10.3987/COM-13-12668

HETEROCYCLES, Vol. 87, No. 4, 2013
853
HETEROCYCLES, Vol. 87, No. 4, 2013, pp. 853 - 859. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 11th January, 2013, Accepted, 5th February, 2013, Published online, 22nd February, 2013
DOI: 10.3987/COM-13-12668
A
MILD
AND
CONVENIENT
ONE-POT
SYNTHESIS
OF
4-ARYL-N-OH-HANTZSCH ESTERS
Chun-Bao Miao,a* Chun-Ping Dong,a Yan-Hong Wang,a Hai-Tao Yang,a Qi
Meng,a Shu-Jiang Tu,b and Xiao-Qiang Suna*
a
School of Petrochemical Engineering, Changzhou University, Changzhou
213164, P. R. China. b School of Chemistry and Chemical Engineering, Jiangsu
Normal University, Xuzhou 221116, P. R. China
E-mail: estally898@yahoo.com.cn
Abstract –A general methodology to prepare a series of 4-Aryl-N-OH Hantzsch
esters was developed. The key factor is to control the first-step of Michael
addition at 0 C. The method was practical to produce symmetrical and
unsymmetric N-OH-Hantzsch esters in moderate yield. This class of compounds
might have use in medicinal and material science.
1,4-Dihydropyridines (1,4-DHPs) are an important class of biologically active heterocycles, as a
well-known class of calcium channel antagonist and potent calcium channel agonist,1,2 and as such
commercialized in for instance nifedipine, amlodipine or nimodipine. Besides their overwhelming
utilization in the cardiovascular pharmacology as Ca2+ channel blockers (CCBs),3 they have also been
investigated for other pharmacological activities such as antitumor,4 antiviral,5 anticancer,6 HIV-I protease
inhibition,7 anticonvulsant.8 A large amount of information is available on their medicinal chemistry
properties.9 Among the numerous methods developed for the synthesis of 1,4-dihydropyridines,10 the
traditional Hantzsch reaction is one of the most efficient methods.11 However, this methodology is not
applicable for the synthesis of chiral, unsymmetrical 1,4-DHPs. In many cases, chiral and/or
unsymmetrical DHPs exhibited better or in the case of enantiomers an opposite pharmacological
properties.12 The details of slight stereoelectronic requirements for interactions at various receptors are
still being investigated. The knowledge of stereochemical/conformational requirements for any biological
activity requires the investigation of other related analogues of the DHP ring.

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HETEROCYCLES, Vol. 87, No. 4, 2013
To have a better insight into the molecular interaction at the receptor level, an expansion investigation on
the structure-activity relationship was needed. The design, synthesis, and evaluation of novel 1,4-DHPs
with a varied pattern of substitution assumes a lot of significance. Most modification on 1,4-DHPs is
focused on the five carbon atoms. As a result, our recent interest in the 1,4-dihydropyridines chemistry
has been concentrated on the introduction a hetero atom on the nitrogen atom, which has rarely been
investigated. Tu had synthesyzed a series of symmetrical acridinediones with N-OH-1,4-DHPs nucleus
whose nitrogen atom was introdued a amino or hydroxyl group.13 Sharma also reported a similar route to
construct N-OH-1,4-DHPs from barbituric acid.14 In continuation of our interest in heterocyclic
chemistry.15 Herein, we reported a convenient and efficient method for the synthesis of various
symmetrical or unsymmetrical Hantzsch esters whose nitrogen atoms were introduced a hydroxyl group.
The preparation of N-OH-Hantzsch esters has only been reported in one patent.16 However, we could not
reduplicate the one-pot synthesis of symmetrical product and obtained complex mixture directly using
aldehydes and β-keto esters in the first-step reaction using zinc(II) chloride (ZnCl2) at 60 °C. What’s
more, the unsymmetrical Michael addition could not be well realized by using other reported catalysts
such as potassium fluoride (KF) or cesium fluoride (CsF).
Two strategies were applied in the synthesis of N-OH-Hantzsch esters. Firstly, the classical Hantzsch
esters synthetic method was tried through the three component reaction of m-nitrobenzaldhyde, methyl
acetoacetate and hydroxylamine hydrochloride in the presence of sodium acetate (NaOAc) (Scheme 1).
No any of the anticipated products were obtained. Then the second route was employed through the
reaction of condensation product 1j, methyl acetoacetate and hydroxylamine hydrochloride in the
presence of NaOAc at room temperature. To our disappointment, the undesired product 3 (mixture of two
isomers, 6:1) was generated in nearly quantitive yield. It revealed that reaction speed of addition between
1j and hydroxylamine is by far faster than that of Michael addition between 1j and methyl acetoacetate.
Therefore, the key factor to produce N-OH-Hantzsch esters is the first-step of Michael addition. Then the
two step strategy through Michael addition-condensation to generate the N-OH-Hantzsch esters was
employed. Although secondary amine-catalyzed the consendation of two molecular acetoacetate and one
molecular aldehyde is the classical method to generate the arylbisacetoacetate 4,17 it has few
shortcomings such as long reaction time and only generation of the symmetric condensation product.
O
O
HN
OH
O
O
NaOAc
EtOH, rt

+ NH2OH HCl
+
O
O
O
O
O
O2N
NO2
3
1j
2a
Scheme 1

HETEROCYCLES, Vol. 87, No. 4, 2013
855
The Michael reaction is generally regarded as one of the most efficient carbon-carbon bond forming
reactions, which can be catalyzed by various bases.18 Therefore, the influence of different bases and
solvents on the Michael addition of 1a with 2a was studied (Table 1). At first, the reaction of 1a with 2a
was performed with various bases (0.1 equiv) in EtOH at 0 C. The results showed that cyclic product 5a
was the main competitive byproduct and the inorganic bases such as sodium carbonate (Na2CO3),
potassium carbonate (K2CO3) and sodium hydroxide (NaOH) was the relatively efficient base. Using
NaOH as the base, intermediate 1,5-diketone compound 4a could be obtained in the highest yield of 84%.
While using other solvents such as THF, DMF, aceetonitrile (MeCN), acetone or dichloromethane
(CH2Cl2), the yield or the selectivity was not good as EtOH. Herein, sodium hrdroxide/EtOH system was
the optimal system to realize the Michael addition. In similar condition, prolonging the time or raising
temperature was both favorable to the generation of byproduct 5a. Reducing the amount of NaOH to 5
mol % still resulted in similar yield in a little longer time.
Table 1. Screening of the reaction condition.a
O
O
O
O
O
O
O
O
O
base
solvent, 0 oC
O
O
O
O
+
+
O
O
1a
2a
O O
4a
HO
5a
yield
of 4a
(%)b
yield
of 5a
(%)b
yield
of 4a
(%)b
time
(h)
time
(h)
yield of
entry
solvent
base
KF
entry
solvent
base
5a (%)b
1
2
3
4
5
6
7
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
24
24
4
20
29
78
60
84
82
67
2
4
8
9
EtOH
EtOH
THF
piperidine
(Et)3N
5
17
27
25
82
20
2
NaOAc
Na2CO3
K2CO3
NaOH
NaOHc
DBU
24
24
3.5
9
10
11
NaOH
19
9
4
15
6
DMF
NaOH
1
12
13
MeCN
NaOH
NaOH
3.5
3.5
73
77
10
11
acetone
2
8
14
CH2Cl2
NaOH
24
37
3
3.5
9
a
o
1 mmol of 1a, 1.2 mmol of 2a, and 10 mol % of base was stirred in 10 mL solvent at 0 C. b All the yields were
determined by HPLC analysis. c 5 mol % of NaOH was used.
Next, the one-pot reaction was tried by adding solution of 5 equiv of hydroxylamine in EtOH to the
first-step reaction mixture at 0 °C, the desired N-OH-Hantzsch ester 6a was obtained as a yellow solid in
55% yield after stirring for 1 h (Scheme 2). Increasing the temperature leads to more byproducts. Under
these optimized conditions, the reaction scope was evaluated by using various condensation products 1

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HETEROCYCLES, Vol. 87, No. 4, 2013
and β-keto esters 2. Symmetrical and unsymmetric N-OH-Hantzsch esters 6 could be obtained in
moderate to good yields of 40-60% at 0 °C. The slight electronic effects were observed. 1 with strong
electron-withdrawing groups or strong electron-rich groups resulted in little lower yields.
Given the easy access to N-OH-Hantzsch esters, the present method should be applied in the synthesis of
libraries with high functional group diversity, which may find application in the field of DHP chemistry,
diversity-oriented synthesis and drug discovery. In this study, all the products were characterized by their
NMR, IR and MS spectra. The N-OH proton was appeared in the range of 10-11 ppm in DMSO-d6.
Sometimes, the signal of OH was very weak probably due to a fast exchange with water present in
DMSO-d6. The structure of the product 6m was further established by the X-ray diffraction analysis.19
R1
R1
O
O
O
O
o
O
1)
2)
10 mol % NaOH, EtOH, 0 C
O
OR2
+
OR2
O
o
5 equiv NH2OH in EtOH, 0 C
N
O
OH
1
2
6
6m
X-Ray crystal structure of
OMe
OMe
OMe
Cl
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
OH
N
OH
N
OH
N
OH
N
OH
N
OH
N
OH
6d, yield = 43%
6e
6a, yield = 55%
6b, yield = 58%
, yield = 45%
6g
6c, yield = 60%
6f, yield = 41%
, yield = 57%
Cl
Cl
NO2
NO2
NO2
NO2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
OH
N
OH
N
OH
N
OH
N
OH
N
OH
6k, yield = 42%
6l
6m
6h, yield = 50%
, yield = 40%
, yield = 45%
6i, yield = 45%
6j, yield = 44%
Scheme 2
In conclusion, we have developed a useful protocol for the synthesis of a series of N-OH-1,4-Hantzsch
esters whose nitrogen atom was introduced a hydroxyl group. The key factor is to controll the Michael
addition reaction to prevent the further cyclization. Particularly, the method shows several attractive
characteristics, namely, one-pot, convenient, simple work-up procedure. N-OH-1,4-DHPs represent an
interesting family of compounds for the development of effective drugs. The terminal hydroxyl group
makes 1,4-DHP be further transformed or introduced to other molecule easily for further studies of the
potential use in medicinal fields.

HETEROCYCLES, Vol. 87, No. 4, 2013
857
EXPERIMENTAL
General Methods: Flash chromatographic purification of products was performed on silica gel (200-300
mesh). Thin-layer chromatography was visualized with a UV light (254 and 365 nm). IR spectra were
1
taken on a Bruker Vector-22 spectrometer in KBr pellets and reported in cm-1. H NMR spectra were
recorded at 500 MHz on a Bruker Avance-500 spectrometer in CDCl3 with chemical shifts (δ) given in
13
ppm relative to TMS as an internal standard. C NMR spectra were recorded on a Bruker Avance-500
(125 MHz) spectrometer with complete proton decoupling, chemical shifts are reported in ppm relative to
13
the solvent resonance as the internal standard (CDCl3, δ = 77.16 ppm). All intensities in the C NMR
spectral data are 1C except where indicated.
Three component reaction of 1j, methyl acetoacetate and hydroxylamine: To a 25 mL of one neck
flask was sequentially added 1j (125 mg, 0.5 mmol), methyl acetoacetate (58 mg, 0.5 mmol),
hydroxylamine hydrochloride (69 mg, 1.0 mmol), sodium acetate (82 mg, 0.1 mmol) and 10 mL of EtOH.
The mixture was stirred at room temperature until the disappearance of 1j. Most of the solvent was
removed and then 15 mL of water was added. After extraction with CH2Cl2 (10 mL  3) the combined
organic layers were dried over anhydrous MgSO4. Filtration and evaporation of the solvent followed by
column chromatography on silica gel using petroleum ether/EtOAc (3:1) gave the corresponding product
3 (diastereo mixture, 6:1, 138 mg, 98%). 1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.10 (d, J = 7.5
Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 6.9 Hz, 1H), 6.56 (s, 1H), 5.07 (t,
J = 6.4 Hz, 1H), 3.69 (s, 3H), 3.17 (d, J = 5.6 Hz, 1H), 1.58 (s, 3H); 1H NMR (300 MHz, CDCl3) 8.30 (s,
1H), 8.13 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 6.7 Hz, 1H,
13
NH), 5.17 (t, J = 6.0 Hz, 1H), 3.84 (s, 3H), 3.20 (d, J = 5.1 Hz, 1H), 2.87 (s, 1H, OH), 1.75 (s, 3H); C
NMR (125 MHz, DMSO-d6) δ 169.0, 147.9, 133.1, 130.1, 121.8, 120.7, 106.1, 65.9, 62.3, 52.1, 23.2;
IR(KBr) v/cm-1: 3228, 2950, 1696, 1662, 1587, 1429, 1378, 1357, 1298, 1243, 1206, 1193, 1155, 1042,
1028, 866, 831, 772, 764, 700; MS-ESI 305 [M+Na]+.
General procedure for the synthesis of N-OH-1,4-Hantzsch esters 6：Sodium hydroxide (200 mg, 5
mmol) was added to a solution of hydroxylamine hydrochloride (348 mg, 5 mmol) in dry EtOH (10 mL),
and the resulting mixture was stirred for 1 h and filtered. A mixture of 1 (1 mmol), acetoacetate 2 (1.2
mmol), and 10% NaOH (4 mg, 0.1 mmol) was stirred in 10 mL of EtOH in ice bath for 1-2 h. Upon
completion as shown by TLC, NH2OH solution in EtOH was added to the mixture and then the mixture
was allowed to stir at 0 °C for 6-8 h. After completion of the reaction detected by TLC, the mixture was
added 20 mL water, and then extracted with CH2Cl2 (15 mL  3). The organic layer was dried over
MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/petroleum ether) to provide N-OH-1,4-Hantzsch esters 6. All the characteristic data and spectra

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HETEROCYCLES, Vol. 87, No. 4, 2013
could be found in the supporting information.
ACKNOWLEDGEMENTS
The authors are grateful for financial support from the National Natural Science Foundation of China
(Nos. 21202011 and 20902039).
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