Tracing of ethyl 2-acetyl-3-(arylamino)butanoate intermediates (β-amino ketones) and their structural confinement

Article abstract of DOI:10.1007/s11164-012-0489-x

Tracing of ethyl 2-acetyl-3-(phenylamino)butanoate intermediates (β-amino ketones) was performed during the course of N-arylpiperidone synthesis by reaction of aromatic amines, acetaldehyde, and ethyl acetoacetate. The structural confinement and stereoche

Full text of DOI:10.1007/s11164-012-0489-x

Res Chem Intermed (2012) 38:1629–1635
DOI 10.1007/s11164-012-0489-x
Tracing of ethyl 2-acetyl-3-(arylamino)butanoate
intermediates (b-amino ketones) and their structural
confinement
•
K. Rajesh B. Palakshi Reddy G. L. Balaji
•
•
•
S. Sarveswari V. Vijayakumar
Received: 24 August 2011 / Accepted: 12 January 2012 / Published online: 26 January 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Tracing of ethyl 2-acetyl-3-(phenylamino)butanoate intermediates
(b-amino ketones) was performed during the course of N-arylpiperidone synthesis
by reaction of aromatic amines, acetaldehyde, and ethyl acetoacetate. The structural
confinement and stereochemistry of these molecules were explained by use of 2D
NMR spectroscopy and X-ray crystallography.
Keywords Mannich condensation ꢀ b-Amino ketones ꢀ
Ethyl 2-acetyl-3-(phenylamino)butanoates ꢀ Intermediates ꢀ Piperidin-4-one
Introduction
The stereochemistry and synthesis of 2,6-disubstituted piperidin-4-ones have been
of interest since their discovery [1, 2], owing to their biological importance [3, 4].
Prostakov and Gaivoronskaya [5] have reviewed the importance of piperidin-4-ones
as intermediates in the synthesis of a variety of physiologically active compounds.
Although the synthesis of 2,6-diaryl-substituted piperidin-4-ones has been reported
in the literature, we found no report on N-arylpiperidin-4-one synthesis by reaction
of aromatic amines, acetaldehyde, and ethyl acetoacetate, which is of interest. Most
literature methods for piperidin-4-one synthesis do not discuss intermediate
formation; the obvious importance of this prompted us to study the formation of
intermediates via which differently substituted 4-piperidones can be synthesized.
Electronic supplementary material The online version of this article
(doi:10.1007/s11164-012-0489-x) contains supplementary material, which is available to authorized
users.
K. Rajesh ꢀ B. Palakshi Reddy ꢀ G. L. Balaji ꢀ S. Sarveswari ꢀ V. Vijayakumar (&)
Synthetic Organic Chemistry Research Laboratory, Organic Chemistry Division,
School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: kvpsvijayakumar@gmail.com
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K. Rajesh et al.
Results and discussion
The three-component reaction of aromatic amines, acetaldehyde, and ethyl
acetoacetate does not favor the usual double Mannich condensation for formation
of 2,6-disubstituted piperidin-4-ones. It should be noted that the reaction stops at an
intermediate stage when conducted at low temperatures (0 °C) using aniline or halo-
substituted anilines and ethyl acetoacetate under nitrogen atmosphere, resulting in
the formation of ethyl 2-acetyl-3-(phenylamino)butanoates (2a–e) (Scheme 1) as
crystalline solids [6–8] in high yields (Table 1).
The reaction was expected to proceed via a two-step process. In step 1,
nucleophilic addition of an aromatic amine to a carbonyl group followed by
dehydration takes place to for the aldimines, whereas in step 2 electrophilic addition
of aldimines to the a-methylene carbonyl results in a b-amino carbonyl compound
(Mannich base). A plausible mechanism is depicted in Fig. 1, which shows the
sequential formation of ethyl 2-acetyl-3-(arylamino)butanoate intermediates.
To exclude the possibity of an aldol-type pathway, further reaction between
b-amino ketones and the corresponding aldehyde was also attempted, but no
reaction was detected (Scheme 2).
In addition, the effect of substituents on the aromatic ring was also investigated.
As shown in Table 1, electron-donating groups (halogens) gave better results, and
electron-withdrawing groups do not favor formation of the desired intermediate. It is
easy to understand that the nucleophilicity of anilino groups was enhanced when
electron-donating groups (halogens) were present; this would accelerate the
intramolecular substitution to produce the ethyl 2-acetyl-3-(arylamino)butanoates
1
in good yield (Table 1). The structures of the compounds were confirmed by H,
13C, and 2D NMR spectroscopy, mass spectrometry, and single-crystal X-ray
diffraction studies. From the structures of the products we can see that two stereo
centers were generated in one step, which theoretically means that four stereo-
isomers would be produced. However, under the reaction conditions used, only one
enantiomer with the 2S,3S configuration was isolated. This might be because of the
formation of a carbanion by loss of pro-S hydrogen in the active methylene group of
ethyl acetoacetate, which in turn undergoes Si face addition on possible formation
of the E aldimine leading to the formation ethyl 2S-acetyl-3S-(arylamino)butanoate.
Although the driving force behind the stereoselectivity is unclear, this work assumes
importance because different substituted piperidones can be constructed from these
intermediates as a base, and they can also act as synthons for construction of a
variety of molecules.
H3C
O
R1
R1
H
N
H
1
2'
NH2
O
O
O
CH3
1'
3
2
0°C
stirring
3'
CH3CHO
H
OC2H5
4
O
6'
R2
4'
R2
5'
1a-e
2a-e
Scheme 1 Synthesis of ethyl 2-acetyl-3-(arylamino)butanoates 2a–e
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Structural confinement
1631
Table 1 Ethyl 2-acetyl-3-(arylamino)butanoate derivatives
Entry
1
Aryl amines
C6H5NH2
Intermediate
Yield (%)
91
H3C
NH
O
O
H3C
C
EtO
2
3
2F-C6H4NH2
88
89
H3C
NH
O
F
H3C
C
O
EtO
4F-C6H4NH2
H3C
F
NH
O
H3C
C
C
C
O
EtO
H3C
4
5
4Cl-C6H4NH2
90
88
Cl
NH
O
O
H3C
EtO
H3C
4Br-C6H4NH2
Br
NH
O
O
H3C
EtO
Experimental
General
Solvents and reagents were commercially sourced and used without further
purification. Melting points were taken on Elchem Microprocessor-based DT
apparatus in open capillary tubes and are corrected relative to benzoic acid. IR
spectra were obtained on an Avatar-330 FTIR spectrophotometer (Thermo Nicolet)
using KBr pellets, and only noteworthy absorption levels (reciprocal centimeters)
are listed. The NMR spectra were recorded on a Bruker Avance-200 and 300 MHz
spectrometer at room temperature using TMS as internal standard (chemical shifts,
d, in ppm). Mass spectra were obtained by use of ESI and GC–MS (Agilent GCMS-
5973 Inert MSD series) mass spectrometers. Thin-layer chromatography (TLC) was
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K. Rajesh et al.
Step 1:
Ph
H
N
Ph
H
H
H
CH3
Ph
H
H
+H+
OH
CH3
H
OH
H
-H+
N
HO
N
O
CH3
H
N
CH3
Ph
H
H
Ph
H
H
OH2
+H+
-H2O
N
CH3
CH3
Step 2:
O
OH
OH
COOEt
+H+
-H+
COOEt
COOEt
H3C
H3C
H3C
H
H
H
H
H
OH
H3C
O
H
Ph
H
H
H
EtOOC
N
+
CH3
N
COOEt
CH3
Ph
H
H
CH3
H
H3C
O
H
H
N
-H+
O
CH3
1
3
2
H
4
O
Fig. 1 Plausible mechanism for the formation of ethyl 2-acetyl-3-(arylamino)butanoate intermediates
performed on preparative plates of silica gel (s.d. fine). Visualization was by use of
an iodine chamber. Column chromatography was performed on silica gel
(60–120 mesh).
General procedure for preparation of ethyl 2-acetyl-3-anilinobutanoate
derivatives (2a–e)
A mixture of aniline or substituted aniline (1 mol) and acetaldehyde (2 mol) was
placed in a round-bottomed flask containing ethanol (20 mL) and stirred at 0 °C for
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Structural confinement
1633
O
N
COOEt
R
O
O
CH3
H
N
+
R-CHO
H3C
H3C
O
Ar
(R = -H, -CH3, -C6H5)
Scheme 2 Reaction of b-amino ketones with aldehydes (aldol-type pathway)
30 min. Ethyl acetoacetate (1 mol) in 10 mL ethanol was then added dropwise with
stirring. The reaction mixture was then stirred for a further 5 h under a nitrogen
atmosphere at 0 °C. Progress of the reaction was monitored by TLC. A paste-like
solid was formed, which was repeatedly washed with diethyl ether. The resulting
compound was recrystallized from diethyl ether, affording the products 2a–e in the
pure form.
Ethyl 2-acetyl-3-anilinobutanoate (2a)
White crystalline solid; m.p: 90 °C (diethyl ether). IR spectrum, m, cm-1: 3327
(NH), 2972, 1728 (CO), 1701 (COOEt), 1602, 1293; 1H NMR spectrum (300 MHz,
CDCl3), d, ppm (J, Hz): 1.25–1.28 (m, 6H, –CH3CH, –CH2CH3); 2.24 (s, 3H,
–CH3CO); 3.64 (d, 1H, J = 6.9, –COCHCO); 3.84 (bs, 1H, –NH); 4.15–4.25 (m,
3H, –OCH2CH3, –NHCH); 6.65–6.70 (m, 3H, H-40, 20, 60); 7.17 (t, 2H, J = 7.95,
H-30, 50); 13C NMR spectrum (75 MHz, CDCl3), d, ppm (J, Hz): 14.08 (–CH2CH3);
18.59 (–CHCH3); 29.45 (–CH3CO); 48.87 (–NHCH); 61.51 (–CH2CH3); 63.97
(–COCH); 114.01 (C-20, 60); 118.28 (C-40), 129.40 (C-30, 50); 146.44 (C-10); 168.36
(–COOCH3); 202.99 (–CH3CO); GC–MS (m/z): 249 [M?]; Anal Calcd for
C14H19NO3: C 67.45, H 7.68, N 5.62; Found: C 67.72, H 7.75, N 5.59.
Ethyl 2-acetyl-3-(2-fluorophenylamino)butanoate (2b)
White crystalline solid; m.p: 86 °C (diethyl ether). IR spectrum, m, cm-1: 3358
(–NH), 2980, 1736 (–CO), 1700 (–COOEt); 1H NMR spectrum (300 MHz, CDCl3),
d, ppm (J, Hz): 1.25–1.29 (m, 6H, –CH3CH, –CH2CH3); 2.26 (s, 3H, –CH3CO); 3.67
(d, 1H, J = 6.5, –COCHCO); 4.11 (bs, 1H, –NH); 4.16–4.25 (m, 3H, –OCH2CH3,
–NHCH); 6.53–6.68 (q, 1H, H-40); 6.78 (t, 1H, J = 9, H-30); 6.93–7.02 (m, 2H, H-50,
60); 13C NMR spectrum (75 MHz, CDCl3), d, ppm (J, Hz): 14.05 (–CH2CH3); 18.69
(–CHCH3); 29.82 (–CH3CO); 48.66 (–NHCH); 61.60 (–CH2CH3); 63.77 (–COCH);
113.37 (C-60); 114.85 (C-30, JC2 –F = 18.75), 117.66 (C-40, J3C–F = 6.75); 124.67 (C-50,
J4C–F = 3); 134.91 (C-10, JC2 –F = 11.25); 152.04 (C-20, J1C–F = 237); 168.20
(–COOCH3); 202.90 (–CH3CO); ESI (m/z): 268.1 [M?1]; Anal Calcd for
C14H18FNO3: C 62.91, H 6.79, N 5.24; Found: C 62.85, H 6.86, N 5.22.
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K. Rajesh et al.
Ethyl 2-acetyl-3-(4-fluorophenylamino)butanoate (2c)
White crystalline solid; m.p: 74 °C (diethyl ether). IR spectrum, m, cm-1: 3316
(–NH), 2979, 1733 (–CO), 1703 (–COOEt), 1508; H NMR spectrum (200 MHz,
1
CDCl3), d, ppm (J, Hz): 1.24–1.31 (m, 6H, –CH3CH, –CH2CH3); 2.27 (s, 3H,
–CH3CO); 3.67 (d, 1H, J = 6, –COCHCO); 4.06 (bs, 1H, –NH); 4.15–4.27 (m, 3H,
–OCH2CH3, –NHCH); 6.61–6.68 (m, 2H, H-20, 60); 6.93–7.02 (m, 2H, H-30, 50);
ESI(m/z): 268.1 [M?1]. Anal Calcd for C14H18FNO3: C 62.91, H 6.79, N 5.24;
Found: C 63.24, H 6.86, N 5.19.
Ethyl 2-acetyl-3-(4-chlorophenylamino)butanoate (2d)
White crystalline solid; m.p: 84 °C (diethyl ether). IR spectrum, m, cm-1: 3338
(–NH), 2982, 1726 (–CO), 1703 (–COOEt), 1598, 1294; 1H NMR spectrum
(200 MHz, CDCl3), d, ppm (J, Hz): 1.22–1.29 (m, 6H, –CH3CH, –CH2CH3); 2.25
(s, 3H, –CH3CO); 3.62 (d, 1H, J = 6, –COCHCO); 3.96 (bs, 1H, –NH); 4.14–4.24
(m, 3H, –OCH2CH3, –NHCH); 6.56 (d, 2H, J = 8, H-20, 60); 7.12 (d, 2H, J = 10,
H-30, 50); 13C NMR spectrum (75 MHz, CDCl3), d, ppm (J, Hz): 14.03 (–CH2CH3);
18.46 (–CHCH3); 29.74 (–CH3CO); 49.07 (–NHCH); 61.58 (–CH2CH3); 63.48
(–COCH); 114.99 (C-20, 60); 122.71 (C-40), 129.17 (C-30, 50); 145.04 (C-10); 168.19
(–COOCH3); 202.94 (–CH3CO); ESI (m/z): 284.1 [M?1]. Anal Calcd for
C14H18ClNO3: C 59.26, H 6.39, N 4.94; Found: C 59.43, H 6.41, N 4.91.
Ethyl 2-acetyl-3-(4-bromophenylamino)butanoate (2e)
White crystalline solid; m.p: 76 °C (diethyl ether). IR spectrum, m, cm-1: 3337
(–NH), 2981, 1725 (–CO), 1701 (–COOEt), 1595, 1294; 1H NMR spectrum
(200 MHz, CDCl3), d, ppm (J, Hz): 1.24–1.28 (m, 6H, –CH3CH, –CH2CH3); 2.26
(s, 3H, –CH3CO); 3.62 (d, 1H, J = 6, –COCHCO); 3.82 (bs, 1H, –NH); 4.17–4.26
(m, 3H, –OCH2CH3, –NHCH); 6.62 (d, 2H, J = 8, H-20, 60); 7.19 (d, 2H, J = 8,
H-30, 50); ESI (m/z): 328.0 [M?1]. Anal Calcd for C14H18BrNO3: C 51.23, H 5.53,
N 4.27; Found: C 51.12, H 5.56, N 4.33.
Conclusion
We have described the synthesis of novel ethyl 2-acetyl-3-(arylamino)butanoates as
intermediates in piperidin-4-one synthesis. The stereochemistry, and the configu-
ration at the stereo centers, is also described. A plausible mechanism is given to
explain formation of product. This method results in clean conversion and high
selectivity, and workup is easy, making this procedure practical and economically
attractive.
Acknowledgment This work was supported by Department of Science and Technology Government of
India (grant no. SR/FTP/CS-108/2006). The authors are thankful to the VIT University management for
their generous support and facilities.
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