Studies toward the construction of substituted piperidine-2-ones and pyridine-2-ones from Baylis-Hillman adducts: discovery of a facile synthesis of 5-methyl-4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates

Article abstract of DOI:10.1016/j.tet.2006.06.099

Studies toward the construction of functionalized piperidone derivatives from derivatives of Baylis-Hillman adducts are described. Interestingly the 6-oxo-4-aryl-piperidine-3-carboxylates generated during the study serve as precursor for the facile synthe

Full text of DOI:10.1016/j.tet.2006.06.099

Tetrahedron 62 (2006) 8731–8739
Studies toward the construction of substituted piperidine-2-ones
and pyridine-2-ones from Baylis–Hillman adducts: discovery of
a facile synthesis of 5-methyl-4-oxo-6-aryl-3-aza-
bicyclo[3.1.0]hexane-1-carboxylates*
V. Singh,a G. P. Yadav,b P. R. Maulikb,y and S. Batraa,
*
aMedicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
bMolecular and Structural Biology Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
Received 2 May 2006; revised 13 June 2006; accepted 29 June 2006
Available online 24 July 2006
Abstract—Studies toward the construction of functionalized piperidone derivatives from derivatives of Baylis–Hillman adducts are de-
scribed. Interestingly the 6-oxo-4-aryl-piperidine-3-carboxylates generated during the study serve as precursor for the facile synthesis of
4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
synthetic molecules, and organic chemicals. The syntheses
of piperidones and piperidines have been exhaustively re-
viewed recently by Sabol and co-workers.3 We envisaged
the synthesis of piperidine-2-ones from the nucleophilic ad-
dition products afforded by reactions between acetates of the
Baylis–Hillman adducts and ethyl cyanoacetate by reduction
of the cyano group and subsequent intramolecular cycliza-
tion between the amino group and the ester moiety. On the
other hand, the conversion of the cyano group to an amide
in the same substrate should lead to 3-methylene-piperi-
dine-2,6-diones (Fig. 1). The substituted piperidine-2,6-di-
ones are structural component of several natural products
and biologically active molecules.4
The multifunctional nature of the backbone of Baylis–Hill-
man adducts provides an excellent opportunity to generate
a variety of heterocycles employing simple synthetic mani-
pulations. Notably, the last decade has witnessed an extra-
ordinary growth in the number of reports describing different
approaches to achieve the syntheses of an array of cyclic
compounds using Baylis–Hillman chemistry.1 Recently,
we too have reported the synthesis of a variety of heterocy-
cles in solution and on solid phase utilizing Baylis–Hillman
chemistry.2 In our continuing efforts aimed at this objective,
we describe herein the results of our studies toward the
synthesis of substituted piperidine-2-ones and pyridine-2-
ones from the nucleophilic substitution reaction products
afforded by the reaction between the acetyl derivatives of
Baylis–Hillman adducts and ethyl cyanoacetate. We have
discovered that the substituted piperidine-2-one generated
during the endeavor may serve as precursor for the efficient
synthesis of 5-methyl-4-oxo-6-aryl-3-aza-bicyclo[3.1.0]-
hexane-1-carboxylates.
The piperidine ring system is a structural component of
numerous naturally occurring alkaloids, biologically active
Figure 1. Strategy for the synthesis of substituted piperidine-2-ones and
piperidine-2,6-diones.
*
CDRI communication no. 6975.
Keywords: Baylis–Hillman; Piperidine-2-one; DBU; 4-Oxo-3-aza-bicy-
clo[3.1.0]hexane; 3-Methylene-piperidine-2,6-dione.
2. Results and discussion
* Corresponding author. Tel.: +91 522 2262411–18x4368; fax: +91 522
2623405/938; e-mail: batra_san@yahoo.co.uk
For queries related to X-ray write to maulik_prakas@yahoo.com
The preparation of the starting materials in our synthetic
sequence (Scheme 1, acetates 3a–g) was accomplished by
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.099

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V. Singh et al. / Tetrahedron 62 (2006) 8731–8739
Scheme 1. Reagents and conditions: (i) CH2]CHCO2Me, DABCO, rt, 2–5 days; (ii) AcCl, pyridine, CH2Cl2, rt, 4–6 h; (iii) CNCH2CO2Et, DABCO,
THF:H2O, rt, 2 h; (iv) Raney-Ni, H2, 40 psi, rt, 3 h; (v) DDQ, dioxane, reflux, 24 h; (vi) POCl3, neat, reflux, 24 h; (vii) PCl5, POCl3, reflux, 2 h; (viii)
DBU, CH3CN, reflux, 14 h; (ix) FeCl3$6H2O, propionic acid, reflux, 2 h; (x) TFA:H2SO4, neat, rt, 3 h; (xi) NaH, toluene, rt, 30 min.
acetylating the Baylis–Hillman adducts 2a–g, which in turn
were obtained from substituted benzaldehydes (1a–g) fol-
lowing the literature procedure.5 The nucleophilic substitu-
tion of the acetates 3a–g with ethyl cyanoacetate in the
presence of DABCO in a THF:water system following a stan-
dard procedure yielded the substituted 1,5-dipentanoate
derivatives 4a–g as diastereoisomeric mixture in excellent
yields.2a As would be expected, the reduction of these com-
pounds in the presence of Raney-nickel under hydrogenation
conditions yielded 5-methyl-6-oxo-4-aryl-piperidine-3-carb-
oxylic acid ethyl esters 5a–g in 54–67% yields. These com-
pounds were obtained as mixtures of diastereoisomers. In
principle, oxidation of these piperidinones with a suitable
reagent should furnish pyridine-2-one derivatives 6. Accord-
ingly, the aromatization of these compounds was investi-
gated in the presence of DDQ.6 However, in our hands, the
desired oxidation did not take place and only the starting
material was recovered.
yielded a less polar product 8, the structure of which was
established on the basis of spectroscopic analysis. The gen-
eral nature of halogenation was confirmed by the synthesis
of compounds 8a–g. In principle, the tertiary nature of the
chloro-group in compound 8 should make it an appropriate
substrate for dehydrohalogenation followed by oxidation.
In order to achieve the envisaged product, several reactions
were attempted. It was gratifying to note that compounds
8a–g undergo reaction in the presence of DBU to furnish
products in good yields. On the basis of spectroscopic
evidence the structure of these compounds was identi-
fied as 5-methyl-4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-
1-carboxylates 9a–g. The structure of these products was
ascertained unambiguously via X-ray analysis of a represen-
tative compound 9e (Fig. 2).8 The formation of these prod-
ucts could be explained on the basis of the fact that the
hydrogen atom on the carbon bearing the alkoxycarbonyl
group being more acidic participates in the elimination of
the chloride ion.
At this point, we envisaged that if compound 5 was con-
verted to its chloro-derivative 7 with POCl3 it would easily
afford the desired pyridinone through oxidation.7 Unfortu-
nately, chlorination in the presence of POCl3 under several
conditions failed to afford the chloro-derivative 7. Subse-
quently, the chlorination of compound 5 was attempted
with a mixture of PCl5 and POCl3. Interestingly, this reaction
In a different strategy it was envisaged that the conversion of
the cyano group to an amide would lead to an intermediate,
which should undergo intramolecular cyclization resulting
in 3-methylene-piperidine-2,6-dione. Recently Wang et al.
have described an interesting FeCl3-mediated highly effi-
cient synthesis of 1,2-dihydro-2-oxo-3-pyridine-carboxylate
Figure 2. ORTEP diagram showing the crystal structure of 9e with atomic numbering scheme for non-H atoms only at 30% probability level.

V. Singh et al. / Tetrahedron 62 (2006) 8731–8739
8733
starting from enones and ethyl cyanoacetate.9 Following
their strategy, treatment of compounds 4b,e,g with 3 equiv
of FeCl3$6H2O in propionic acid at reflux for 2 h afforded
12.8 mmol) at room temperature and the reaction was al-
lowed to continue for 20 min. Thereafter, ethyl cyanoacetate
(1.1 mL, 10.3 mmol) was added to the reaction mixture and
the reaction was allowed to proceed at room temperature for
2 h. Then THF was removed from the reaction mixture via
rotary evaporation and the residue was diluted with water
(100 mL) and extracted with EtOAc (3ꢀ40 mL). The
organic layers were pooled, washed with brine (50 mL),
dried (Na2SO4), and evaporated in vacuo to yield a residue,
which was purified by silica gel chromatography employing
hexane:EtOAc (80:20, v/v) to afford 2.0 g (82%) of product
4a as colorless oil.
3-methylene-4-substituted
phenyl-piperidine-2,6-diones
10b,e,g in 60–65% yields. However, in contrast to their re-
sults, we observed that the carboxylate group was lost during
the reaction and dehydrogenation did not occurred. In order
to investigate the scope of our substrates for the generation
of the carboxylate group containing piperidine-2,6-dione
derivative, 4a,e,f were hydrolyzed in the presence of
TFA:H2SO4 mixture to afford the products 11a,e,f in good
yields. Subsequent treatment of the amides 11a,e,f with
NaH at room temperature furnished the desired 5-methyl-
ene-2,6-dioxo-4-phenyl-piperidine-3-carboxylic acid ethyl
esters 12a,e,f in good yields. Interestingly, the formation
of compounds 12a,e,f was highly stereoselective in favor
of the trans-isomer. The stereochemistry was assigned on
the basis of selective 1D NOESYexperiment with compound
12a. During the progress of this work, Kim et al. reported the
synthesis of 3,5-dimethylene-4-phenyl-piperidine-2,6-dione
and mono-alkylidene glutarimide by hydrolysis of the cyano
group with sulfuric acid in methanol followed by cyclization
in the presence of sodium bicarbonate.10 However, in our
hand, the sodium bicarbonate-mediated cyclization of sub-
strates 11a,e,f led to a complex mixture of product from
which the corresponding 3-methylene-piperidine-2,6-diones
12a,e,f were isolated in only low yields.
4.2.1. 2-Cyano-4-methylene-3-phenyl-pentanedioic acid-
1-ethyl ester-5-methyl ester (4a). nmax (neat) 1747
1
(CO2Me and CO2Et), 2255 (CN) cmꢁ1; H NMR (CDCl3,
200 MHz) d¼1.15 (t, 3H, J¼7.1 Hz, CH3CH2), 1.33 (t,
3H, J¼7.1 Hz, CH3CH2), 3.71 (s, 3H, CO2CH3), 3.76 (s,
3H, CO2CH3), 4.10–4.30 (m, 6H, 2ꢀCH2CH3 and
2ꢀCHAr), 4.45 (d, 1H, J¼8.2 Hz, CHCN), 4.64 (d, 1H,
J¼8.2 Hz, CHCN), 5.75 (d, 1H, J¼1.2 Hz, ]CH), 5.99
(d, 1H, J¼0.9 Hz, ]CH), 6.49 (s, 1H, ]CH), 6.51 (s, 1H,
]CH), 7.29–7.37 (m, 10H, 2ꢀ5ArH); 13C NMR (CDCl3,
50 MHz) d¼14.2, 14.3, 42.3, 42.6, 47.0, 47.6, 52.6, 52.7,
61.8, 63.3, 113.5, 116.0, 127.7, 128.5, 128.6, 128.9, 129.2,
136.9, 137.4, 139.0, 139.3, 163.4, 165.2, 166.4, 166.5;
mass (FAB+) m/z 288 (M++1); Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 67.08;
H, 5.76; N, 4.98.
3. Conclusions
4.2.2. 3-(2-Chloro-phenyl)-2-cyano-4-methylene-pentane-
dioic acid-1-ethyl ester-5-methyl ester (4b). Yield 84%
(2.3 g from 2.3 g) as a colorless oil; nmax (neat) 1746
In summary, we have demonstrated a convenient and general
process for the synthesis of 5-methyl-4-oxo-6-aryl-3-aza-bi-
cyclo[3.1.0]hexane-1-carboxylates via products afforded by
the nucleophilic addition reaction of ethyl cyanoacetate with
acetyl derivatives of the Baylis–Hillman adducts. Addi-
tionally these products have been readily hydrolyzed and
subsequently cyclized to yield new substituted piperidine-
2,6-diones in good yields.
1
(CO2Me and CO2Et), 2253 (CN) cmꢁ1; H NMR (CDCl3,
200 MHz) d¼1.13 (t, 3H, J¼7.1 Hz, CH3CH2), 1.24 (t, 3H,
J¼7.1 Hz, CH3CH2), 3.69 (s, 3H, CO2CH3), 3.80 (s, 3H,
CO2CH3), 4.13–4.25 (m, 4H, 2ꢀCH2CH3), 4.33 (d, 1H,
J¼7.2 Hz, CHAr), 4.61 (d, 1H, J¼7.2 Hz, CHAr), 5.08–
5.02 (m, 2H, 2ꢀCHCN), 5.61 (d, 1H, J¼0.9 Hz, ]CH),
6.15 (s, 1H, ]CH), 5.50 (s, 1H, ]CH), 6.60 (s, 1H,
]CH), 7.28–7.63 (m, 8H, 2ꢀ4ArH); mass (ES+) m/z 322.0
(M++1); Anal. Calcd for C16H16ClNO4: C, 59.73; H, 5.01;
N, 4.35. Found: C, 59.79; H, 4.87; N, 4.51.
4. Experimental
4.1. General
4.2.3. 2-Cyano-3-(2-fluoro-phenyl)-4-methylene-pentane-
dioic acid-1-ethyl ester-5-methyl ester (4c). Yield 92%
(1.1 g from 1.0 g) as a pale yellow oil; nmax (neat) 1744
Melting points were uncorrected and determined in capillary
tubes on a hot stage apparatus containing silicon oil. IR spec-
tra were recorded using a Perkin–Elmer RX I FTIR spectro-
1
(CO2Me and CO2Et), 2259 (CN) cmꢁ1; H NMR (CDCl3,
1
photometer. H and 13C NMR spectra were recorded on
200 MHz) d¼1.13–1.33 (m, 6H, 2ꢀCH3CH2), 3.71 (s, 3H,
CO2CH3), 3.78 (s, 3H, CO2CH3), 4.13–4.23 (m, 5H,
2ꢀCH2CH3 and CHAr), 4.39 (d, 1H, J¼7.3 Hz, CHAr),
4.93 (d, 2H, J¼7.1 Hz, 2ꢀCHCN), 5.75 (s, 1H, ]CH),
6.00 (s, 1H, ]CH), 6.50 (s, 1H, ]CH), 6.58 (s, 1H,
]CH), 7.11–7.30 (m, 6H, 2ꢀ3ArH), 7.53–7.56 (m, 2H,
2ꢀ1ArH); mass (ES+) m/z 306.1 (M++1); Anal. Calcd for
C16H16FNO4: C, 62.94; H, 5.28; N, 4.59. Found: C, 63.01;
H, 5.22; N, 4.58.
either 300 or 200 MHz FT spectrometer, using TMS as an in-
ternal standard (chemical shifts in d values, J in hertz). The
FABMS were recorded on a JEOL/SX-102 spectrometer
and ESMS were recorded in a Micromass LCMS system.
Elemental analyses as performed on a Carlo Erba 1108
microanalyzer or Elementar’s Vario EL III microanalyzer.
All compounds were obtained in the powder form unless
otherwise stated.
4.2. General procedure for the synthesis of compounds
4a–c, as exemplified for compound 4a
4.2.4. 3-(4-Bromo-phenyl)-2-cyano-4-methylene-pentane-
dioic acid-1-ethyl ester-5-methyl ester (4d). Yield 82%
(2.2 g from 2.3 g) as a colorless oil; nmax (neat) 1748
1
To a stirred solution of compound 3a (2.0 g, 8.5 mmol) in
THF:H2O (20 mL, 50:50, v/v) was added DABCO (1.5 g,
(CO2Me and CO2Et), 2254 (CN) cmꢁ1; H NMR (CDCl3,
200 MHz) d¼1.18 (t, 3H, J¼7.1 Hz, CH3CH2), 1.32 (t, 3H,

8734
V. Singh et al. / Tetrahedron 62 (2006) 8731–8739
J¼7.1 Hz, CH3CH2), 3.71 (s, 3H, CO2CH3), 3.75 (s, 3H,
CO2CH3), 4.13–4.41 (m, 6H, 2ꢀCH2CH3 and 2ꢀCHAr),
4.55–4.58 (m, 2H, 2ꢀCHCN), 5.75 (s, 1H, ]CH), 6.00 (s,
1H, ]CH), 6.50 (s, 1H, ]CH), 6.52 (s, 1H, ]CH), 7.15–
7.27 (m, 4H, 2ꢀ2ArH), 7.43–7.51 (m, 4H, 2ꢀ2ArH); mass
(FAB+) m/z 366 (M++1); Anal. Calcd for C16H16BrNO4: C,
52.48; H, 4.40; N, 3.82. Found: C, 52.63; H, 4.54; N, 3.77.
the hydrogenation assembly (Parr) at room temperature.
After completion, the catalyst was filtered over a bed of
Celite and the filtrate was evaporated in vacuo to yield the
crude product. Purification via silica gel column chromato-
graphy (hexane:EtOAc, 40:60, v/v) gave 0.65 g (60%) of
product 5a as a white solid.
4.3.1. 5-Methyl-6-oxo-4-phenyl-piperidine-3-carboxylic
acid ethyl ester (5a). Mp 102–104 ꢂC; nmax (KBr) 1661
4.2.5. 3-(4-Chloro-phenyl)-2-cyano-4-methylene-pentane-
dioic acid-1-ethyl ester-5-methyl ester (4e). Yield 76%
(1.8 g from 2.0 g) as a colorless oil; nmax (neat) 1747
(CONH), 1730 (CO2Et), 3402 (NH) cmꢁ1
;
1H NMR
(CDCl3, 200 MHz) d¼0.86 (t, 3H, J¼7.1 Hz, CH3CH2),
1.00–1.18 (m, 9H, CH3CH2 and 2ꢀCH3CH), 2.43–2.61
(m, 1H, CHCH3), 2.71–2.78 (m, 1H, CHCH3), 2.81–3.00
(m, 1H, CHCH2), 3.07–3.22 (m, 1H, CHCH2), 3.31–3.64
(m, 6H, 2ꢀCH2NH and 2ꢀCHAr), 3.83 (q, 2H, J¼7.1 Hz,
CH2CH3), 4.08 (q, 2H, J¼7.1 Hz, CH2CH3), 6.27 (s, 2H,
2ꢀNH), 7.17–7.36 (m, 10H, 2ꢀ5ArH); 13C NMR (CDCl3,
50 MHz) d¼13.6, 14.0, 14.4, 15.2, 38.9, 42.2, 42.5, 43.9,
44.0, 45.7, 47.4, 50.2, 61.0, 61.5, 127.04, 127.7, 128.3,
128.6, 129.0, 140.4, 140.9, 172.2, 172.7, 175.2, 176.4;
mass (ES+) m/z 262.1 (M++1); Anal. Calcd for
C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 69.08;
H, 7.55; N, 5.57.
1
(CO2Me and CO2Et), 2255 (CN) cmꢁ1; H NMR (CDCl3,
200 MHz) d¼1.18 (t, 3H, J¼7.1 Hz, CH3CH2), 1.33 (t, 3H,
J¼7.1 Hz, CH3CH2), 3.71 (s, 3H, CO2CH3), 3.75 (s, 3H,
CO2CH3), 4.09–4.30 (m, 5H, 2ꢀCH2CH3 and CHAr), 4.39
(d, 1H, J¼7.3 Hz, CHAr), 4.56–4.63 (m, 2H, 2ꢀCHCN),
5.76 (d, 1H, J¼1.1 Hz, ]CH), 6.00 (s, 1H, ]CH), 6.50 (s,
1H, ]CH), 6.52 (s, 1H, ]CH), 7.25–7.32 (m, 8H,
2ꢀ4ArH); mass (ES+) m/z 344 (M++Na); Anal. Calcd for
C16H16ClNO4: C, 59.73; H, 5.01; N, 4.35. Found: C, 59.89;
H, 4.78; N, 4.31.
4.2.6. 2-Cyano-3-(4-fluoro-phenyl)-4-methylene-pentane-
dioic acid-1-ethyl ester-5-methyl ester (4f). Yield 72%
(1.3 g from 1.5 g) as a colorless oil; nmax (neat) 1746
4.3.2. 4-(2-Chloro-phenyl)-5-methyl-6-oxo-piperidine-3-
carboxylic acid ethyl ester (5b). Yield 67% (0.98 g from
1.6 g) as a pale yellow oil; nmax (neat) 1667 (CONH), 1731
1
(CO2Me and CO2Et), 2254 (CN) cmꢁ1; H NMR (CDCl3,
200 MHz) d¼1.16 (t, 3H, J¼7.1 Hz, CH3CH2), 1.33 (t, 3H,
J¼7.1 Hz, CH3CH2), 3.71 (s, 3H, CO2CH3), 3.76 (s, 3H,
CO2CH3), 4.12–4.22 (m, 4H, 2ꢀCH2CH3), 4.28 (d, 1H,
J¼7.1 Hz, CHAr), 4.39 (d, 1H, J¼7.3 Hz, CHAr), 4.58–
4.60 (m, 2H, 2ꢀCHCN), 5.75 (s, 1H, ]CH), 6.00 (s, 1H,
]CH), 6.49 (s, 1H, ]CH), 6.51 (s, 1H, ]CH), 7.00–7.09
(m, 4H, 2ꢀ2ArH), 7.23–7.39 (m, 4H, 2ꢀ2ArH); 13C NMR
(CDCl3, 50 MHz) d¼14.2, 14.3, 42.3, 42.6, 46.3, 47.1, 52.7,
52.8, 63.4, 116.0, 116.4, 127.7, 128.7, 130.2, 130.4, 130.6,
130.8, 132.6, 133.1, 138.8, 139.2, 165.0, 165.3, 166.3,
166.4; mass (ES+) m/z 306.2 (M++1); Anal. Calcd for
C16H16FNO4: C, 62.94; H, 5.28; N, 4.59. Found: C, 63.11;
H, 5.41; N, 4.67.
1
(CO2Et), 3222 (NH) cmꢁ1; H NMR (CDCl3, 200 MHz)
d¼0.93 (t, 3H, J¼7.1 Hz, CH3CH2), 1.01–1.18 (m, 9H,
CH3CH2 and 2ꢀCH3CH), 2.80–2.98 (m, 1H, CHCH3),
3.17–3.20 (m, 2H, CHCH3 and CHCH2), 3.59–3.60 (m,
1H, CHCH2), 3.63–3.66 (m, 4H, 2ꢀCH2NH), 3.87–3.92
(m, 2H, 2ꢀCHAr), 4.09–4.24 (m, 4H, 2ꢀCH2CH3), 6.19
(s, 2H, 2ꢀNH), 7.14–7.21 (m, 6H, 2ꢀ3ArH), 7.32–7.42
(m, 2H, 2ꢀ1ArH); 13C NMR (CDCl3, 50 MHz) d¼13.7,
14.0, 14.3, 14.6, 37.2, 37.6, 41.5, 41.8, 42.6, 42.8, 43.4,
43.5, 61.2, 61.6, 127.1, 127.7, 128.6, 129.0, 130.2, 130.4,
134.7, 135.0, 137.4, 138.8, 171.7, 172.3, 174.9, 176.0;
mass (FAB+) m/z 296 (M++1); Anal. Calcd for
C15H18ClNO3: C, 60.91; H, 6.13; N, 4.74. Found: 60.82;
H, 5.94; N, 4.89.
4.2.7. 2-Cyano-4-methylene-3-p-tolyl-pentanedioic acid-
1-ethyl ester-5-methyl ester (4g). Yield 78% (1.89 g from
2.0 g) as a colorless oil; nmax (neat) 1742 (CO2Me and
4.3.3. 4-(2-Fluoro-phenyl)-5-methyl-6-oxo-piperidine-3-
carboxylic acid ethyl ester (5c). Yield 57% (0.47 g from
0.9 g) as a colorless oil; nmax (neat) 1652 (CONH), 1723
CO2Et), 2256 (CN) cmꢁ1 1H NMR (CDCl3, 200 MHz)
;
d¼1.16 (t, 3H, J¼7.2 Hz, CH3CH2), 1.29 (t, 3H,
J¼7.2 Hz, CH3CH2), 2.31 (s, 3H, ArCH3), 2.32 (s, 3H,
ArCH3), 3.71 (s, 3H, CO2CH3), 3.75 (s, 3H, CO2CH3),
4.11–4.22 (m, 5H, 2ꢀCH2CH3 and CHAr), 4.40 (d, 1H,
J¼7.6 Hz, CHAr), 4.57–4.61 (m, 2H, 2ꢀCHCN), 5.75 (d,
1H, J¼1.0 Hz, ]CH), 5.97 (s, 1H, ]CH), 6.47 (s, 1H,
]CH), 6.49 (s, 1H, ]CH), 7.09–7.23 (m, 8H, 2ꢀ4ArH);
13C NMR (CDCl3, 50 MHz) d¼14.2, 14.5, 21.5, 42.4,
42.7, 46.7, 47.4, 52.6, 52.7, 61.9, 63.3, 116.1, 127.4,
128.3, 128.8, 129.9, 133.7, 134.3, 138.3, 139.1, 139.4,
165.3, 166.5, 166.6; mass (ES+) m/z 302.1 (M++1); Anal.
Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found:
C, 67.49; H, 6.51; N, 4.67.
1
(CO2Et), 3436 (NH) cmꢁ1; H NMR (CDCl3, 200 MHz)
d¼0.90 (t, 3H, J¼7.1 Hz, CH3CH2), 1.02–1.29 (m, 9H,
CH3CH2 and 2ꢀCH3CH), 2.62–2.93 (m, 2H, 2ꢀCHCH3),
3.24–3.26 (m, 2H, 2ꢀCHCH2), 3.58–3.61 (m, 4H,
2ꢀCH2NH), 3.87–3.91 (m, 2H, 2ꢀCHAr), 4.06–4.13 (m,
4H, 2ꢀCH2CH3), 6.37 (s, 2H, 2ꢀNH), 7.00–7.22 (m, 8H,
2ꢀ4ArH); 13C NMR (CDCl3, 50 MHz) d¼13.6, 14.0,
14.3, 15.2, 37.9, 38.5, 41.2, 42.8, 43.1, 43.9, 44.7, 45.8,
61.3, 61.5, 115.9, 116.4, 124.5, 124.7, 127.2, 127.5, 127.8,
128.0, 128.9, 129.2, 129.5, 130.1, 172.0, 172.4, 174.8,
176.0; mass (FAB+) m/z 280 (M++1); Anal. Calcd for
C15H18FNO3: C, 64.50; H, 6.50; N, 5.01. Found: C, 64.55;
H, 6.41; N, 5.09.
4.3. General procedure for the synthesis of compounds
5a–g, as exemplified for compound 5a
4.3.4. 4-(4-Bromo-phenyl)-5-methyl-6-oxo-piperidine-3-
carboxylic acid ethyl ester (5d). Yield 58% (0.7 g from
1.3 g) as a white solid, mp 126–128 ꢂC; nmax (KBr) 1667
A mixture of compound 4a (1.2 g, 4.18 mmol) and Raney-Ni
(0.3 g, wet) in MeOH (20 mL) was hydrogenated at 40 psi in
(CONH), 1724 (CO2Et), 3313 (NH) cmꢁ1 1H NMR
;

V. Singh et al. / Tetrahedron 62 (2006) 8731–8739
8735
(CDCl3, 200 MHz) d¼0.93 (t, 3H, J¼7.1 Hz, CH3CH2),
1.00 (d, 3H, J¼7.3 Hz, CH3CH), 1.08 (d, 3H, J¼6.9 Hz,
CH3CH), 1.17 (t, 3H, J¼7.1 Hz, CH3CH2), 2.38–2.60 (m,
1H, CHCH3), 2.68–2.82 (m, 1H, CHCH3), 2.75–3.10 (m,
2H, 2ꢀCHCH2), 3.45–3.68 (m, 6H, 2ꢀCH2NH and
2ꢀCHAr), 3.85 (q, 2H, J¼7.1 Hz, CH2CH3), 4.10 (q, 2H,
J¼7.2 Hz, CH2CH3), 6.21 (s, 2H, 2ꢀNH), 7.07–7.10 (m,
4H, 2ꢀ2ArH), 7.44–7.54 (m, 4H, 2ꢀ2ArH); 13C NMR
(CDCl3, 50 MHz) d¼13.6, 14.2, 14.4, 15.2, 38.8, 42.2,
42.4, 44.0, 44.1, 45.3, 47.2, 49.7, 61.2, 61.7, 121.4, 121.5,
130.0, 130.3, 132.2, 139.6, 140.0, 171.9, 172.4, 174.7,
176.0; mass (FAB+) m/z 340 (M++1); Anal. Calcd for
C15H18BrNO3: C, 52.96; H, 5.33; N, 4.12. Found: C,
52.58; H, 5.49; N, 3.97.
2ꢀNH), 7.04–7.14 (m, 8H, 2ꢀ4ArH); 13C NMR (CDCl3,
50 MHz) d¼13.6, 14.1, 14.4, 15.2, 21.4, 38.9, 41.6, 42.4,
44.0, 44.1, 45.4, 47.5, 49.9, 61.0, 61.5, 128.1, 128.5,
129.6, 137.0, 137.2, 137.3, 137.9, 171.8, 172.2, 172.8,
175.3, 176.5; mass (FAB+) m/z 276 (M++1); Anal. Calcd
for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C,
69.98; H, 7.54; N, 4.89.
4.4. General procedure for the synthesis of compounds
8a–g, as exemplified for compound 8a
A mixture of compound 5a (0.51 g, 1.95 mmol) and PCl5
(1.62 g, 7.8 mmol) in POCl3 (4 mL) was refluxed for 3 h.
Thereafter, the reaction mixture was poured into ice water,
neutralized with NaHCO3, and extracted with EtOAc
(2ꢀ25 mL). The combined organic layer was washed with
brine (50 mL), dried (Na2SO4), and the solvent was in vacuo.
The crude product obtained was purified by silica gel col-
umn chromatography (hexane:EtOAc, 50:50, v/v) to give
0.39 g (68%) of chloro-derivative 8a as a white solid.
4.3.5. 4-(4-Chloro-phenyl)-5-methyl-6-oxo-piperidine-3-
carboxylic acid ethyl ester (5e). Yield 62% (0.45 g from
0.79 g) as a white solid, mp 118–120 ꢂC; nmax (KBr) 1665
(CONH), 1733 (CO2Et), 3303 (NH) cmꢁ1
;
1H NMR
(CDCl3, 200 MHz) d¼0.92 (t, 3H, J¼7.1 Hz, CH3CH2),
1.00 (d, 3H, J¼7.2 Hz, CH3CH), 1.08 (d, 3H, J¼7.0 Hz,
CH3CH), 1.17 (t, 3H, J¼7.1 Hz, CH3CH2), 2.40–2.58 (m,
1H, CHCH3), 2.66–2.78 (m, 1H, CHCH3), 2.93–3.10 (m,
2H, 2ꢀCHCH2), 3.57–3.69 (m, 6H, 2ꢀCH2NH and
2ꢀCHAr), 3.85 (q, 2H, J¼7.1 Hz, CH2CH3), 4.09 (q, 2H,
J¼7.1 Hz, CH2CH3), 6.23 (s, 2H, 2ꢀNH), 7.09–7.15 (m,
4H, 2ꢀ2ArH), 7.29–7.33 (m, 4H, 2ꢀ2ArH); 13C NMR
(CDCl3, 50 MHz) d¼13.5, 14.1, 14.4, 15.2, 38.9, 42.3,
42.5, 44.0, 44.2, 45.2, 47.3, 49.7, 61.2, 61.6, 129.1, 129.2,
129.6, 130.0, 133.3, 133.5, 139.1, 139.5, 171.9, 172.5,
174.7, 176.2; mass (FAB+) m/z 296 (M++1); Anal. Calcd
for C15H18ClNO3: C, 60.91; H, 6.13; N, 4.74. Found: C,
61.15; H, 5.85; N, 4.88.
4.4.1. 5-Chloro-5-methyl-6-oxo-4-phenyl-piperidine-3-
carboxylic acid ethyl ester (8a). Mp 142–144 ꢂC; nmax
1
(KBr) 1678 (CONH), 1736 (CO2Et), 3200 (NH) cmꢁ1; H
NMR (CDCl3, 300 MHz) d¼0.90 (t, 3H, J¼7.1 Hz,
CH3CH2), 1.03 (t, 3H, J¼7.1 Hz, CH3CH2), 1.56 (s, 3H,
CH3), 1.61 (s, 3H, CH3), 3.32–3.38 (m, 2H, 2ꢀCHAr),
3.62–3.72 (m, 4H, 2ꢀCH2NH), 3.78–4.05 (m, 6H,
2ꢀCHCH2 and 2ꢀCH2CH3), 6.36 (br s, 1H, NH), 6.74 (br
s, 1H, NH), 7.24–7.40 (m, 10H, 2ꢀ5ArH);13C NMR
(CDCl3, 50 MHz) d¼14.1, 14.2, 26.0, 26.2, 42.4, 43.1,
43.9, 44.5, 52.9, 54.8, 61.4, 61.7, 67.8, 68.1, 128.2, 128.3,
128.4, 128.7, 130.0, 136.1, 138.0, 170.7, 171.3, 171.6,
172.0; mass (FAB+) m/z 296 (M++1); Anal. Calcd for
C15H18ClNO3: C, 60.91; H, 6.13; N, 4.74. Found: C,
61.19; H, 5.87; N, 4.78.
4.3.6. 4-(4-Fluoro-phenyl)-5-methyl-6-oxo-piperidine-3-
carboxylic acid ethyl ester (5f). Yield 54% (0.26 g from
0.53 g) as a yellow solid, mp 125–127 ꢂC; nmax (KBr)
1
1663 (CONH), 1729 (CO2Et), 3407 (NH) cmꢁ1; H NMR
4.4.2. 5-Chloro-4-(2-chloro-phenyl)-5-methyl-6-oxo-
piperidine-3-carboxylic acid ethyl ester (8b). Yield 65%
(0.59 g from 0.81 g) as a white crystalline solid, mp 142–
144 ꢂC; nmax (KBr) 1685 (CONH), 1735 (CO2Et), 3250
(CDCl3, 200 MHz) d¼0.90 (t, 3H, J¼7.1 Hz, CH3CH2),
1.02–1.29 (m, 9H, CH3CH2 and 2ꢀCH3CH), 2.38–2.76
(m, 2H, 2ꢀCHCH3), 2.80–3.18 (m, 2H, CHCH2), 3.53–
3.63 (m, 6H, 2ꢀCH2NH and 2ꢀCHAr), 3.85 (q, 2H,
J¼7.0 Hz, CH2CH3), 4.11 (q, 2H, J¼7.1 Hz, CH2CH3),
6.15 (s, 2H, 2ꢀNH), 6.96–7.06 (m, 4H, 2ꢀ2ArH), 7.11–
7.20 (m, 4H, 2ꢀ2ArH); 13C NMR (CDCl3, 50 MHz)
d¼13.6, 14.1, 14.4, 15.1, 39.0, 42.5, 44.0, 44.2, 45.0, 47.5,
49.6, 61.1, 61.6, 115.6, 116.0, 129.7, 129.8. 130.0, 130.2,
136.2, 136.7, 159.8, 164.6, 172.0, 172.6, 174.8, 176.2;
mass (FAB+) m/z 280 (M++1); Anal. Calcd for
C15H18FNO3: C, 64.50; H, 6.50; N, 5.01. Found: C, 64.80;
H, 6.36; N, 4.88.
1
(NH) cmꢁ1; H NMR (CDCl3, 300 MHz) d¼0.93 (t, 3H,
J¼6.0 Hz, CH3CH2), 1.17 (t, 3H, J¼6.0 Hz, CH3CH2),
1.58 (s, 3H, CH3), 1.60 (s, 3H, CH3), 3.26–3.40 (m, 2H,
2ꢀCHAr), 3.50–3.61 (m, 4H, 2ꢀCH2N), 3.86–4.03 (m,
6H, 2ꢀCH2CH3 and 2ꢀCHCO2Et), 6.18 (s, 1H, NH), 6.47
(s, 1H, NH), 7.20–7.30 (m, 6H, 2ꢀ3ArH), 7.42–7.46 (m,
2H, 2ꢀ1ArH); 13C NMR (CDCl3, 50 MHz) d¼14.2, 14.3,
25.9, 26.0, 41.5, 42.0, 45.6, 45.9, 49.2, 50.1, 61.5, 61.9,
67.0, 68.0, 126.8, 127.4, 127.6, 129.3, 129.4, 129.9, 130.6,
131.5, 135.7, 137.8, 171.2, 171.4, 171.7, 171.9; mass
(ES+) m/z 330.0 (M++1), 332.1 (M++3); Anal. Calcd for
C15H17Cl2NO3: C, 54.56; H, 5.19; N, 4.24. Found: C,
54.33; H, 5.11; N, 4.52.
4.3.7. 5-Methyl-6-oxo-4-p-tolyl-piperidine-3-carboxylic
acid ethyl ester (5g). Yield 56% (0.56 g from 1.1 g) as
a white solid, mp 105–107 ꢂC; nmax (KBr) 1663 (CONH),
1726 (CO2Et), 3233 (NH) cmꢁ1
;
1H NMR (CDCl3,
4.4.3. 5-Chloro-4-(2-fluoro-phenyl)-5-methyl-6-oxo-
piperidine-3-carboxylic acid ethyl ester (8c). Yield 63%
(1.39 g from 2.0 g) as a white solid, mp 144–146 ꢂC; nmax
200 MHz) d¼0.89 (t, 3H, J¼7.2 Hz, CH3CH2), 1.01 (d,
3H, J¼7.2 Hz, CH3CH), 1.08 (d, 3H, J¼7.2 Hz, CH3CH),
1.17 (t, 3H, J¼7.1 Hz, CH3CH2), 2.32 (s, 6H, 2ꢀArCH3),
2.46–2.58 (m, 1H, CHCH3), 2.68–2.76 (m, 1H, CHCH3),
2.89–3.11 (m, 2H, 2ꢀCHCH2), 3.55–3.63 (m, 6H,
2ꢀCH2NH and 2ꢀCHAr), 3.84 (q, 2H, J¼7.1 Hz,
CH2CH3), 4.09 (q, 2H, J¼7.1 Hz, CH2CH3), 6.10 (s, 2H,
1
(KBr) 1679 (CONH), 1735 (CO2Et), 3401 (NH) cmꢁ1; H
NMR (CDCl3, 200 MHz) d¼0.93 (t, 3H, J¼7.1 Hz,
CH3CH2), 1.06 (t, 3H, J¼7.1 Hz, CH3CH2), 1.62 (s, 3H,
CH3), 1.65 (s, 3H, CH3), 3.28–3.41 (m, 2H, 2ꢀCHAr),
3.55–3.63 (m, 4H, 2ꢀCH2N), 3.88–4.07 (m, 6H,

8736
V. Singh et al. / Tetrahedron 62 (2006) 8731–8739
2ꢀCH2CH3 and 2ꢀCHCO2Et), 6.52 (s, 1H, NH), 6.83 (s,
1H, NH), 7.03–7.18 (m, 6H, 2ꢀ3ArH), 7.27–7.31 (m, 2H,
2ꢀ1ArH); mass (ES+) m/z 314.0 (M++1); Anal. Calcd for
C15H17ClFNO3: C, 57.42; H, 5.46; N, 4.46. Found: C,
57.60; H, 5.64; N, 4.31.
2ꢀ2ArH), 7.24–7.27 (m, 4H, 2ꢀ2ArH); 13C NMR
(CDCl3, 50 MHz) d¼14.1, 14.2, 21.6, 26.0, 26.2, 42.4,
43.0, 43.9, 44.5, 52.5, 54.4, 61.4, 61.6, 68.0, 68.2, 129.0,
129.4, 129.8, 130.4, 133.0, 135.0, 137.9, 138.1, 170.8,
171.3, 171.9, 172.0; mass (ES+) m/z 310 (M++1), 332.0
(M++Na); Anal. Calcd for C16H20ClNO3: C, 62.03; H,
6.51; N, 4.52. Found: C, 61.86; H, 6.42; N, 4.60.
4.4.4. 4-(4-Bromo-phenyl)-5-chloro-5-methyl-6-oxo-
piperidine-3-carboxylic acid ethyl ester (8d). Yield 60%
(0.13 g from 0.2 g) as a white solid, mp 148–150 ꢂC; nmax
4.5. General procedure for the synthesis of compounds
9a–g, as exemplified for compound 9a
(KBr) 1697 (CONH), 1726 (CO2Et), 3439 (NH) cmꢁ1
;
1H NMR (CDCl3, 200 MHz) d¼0.93–1.09 (m, 6H,
2ꢀCH3CH2), 1.55 (s, 3H, CH3), 1.59 (s, 3H, CH3), 3.28–
3.47 (m, 2H, 2ꢀCHAr), 3.58–3.83 (m, 4H, 2ꢀCHCO2Et
and 2ꢀCHHN), 3.89–4.06 (m, 6H, 2ꢀCH2CH3 and
2ꢀCHHN), 6.32 (s, 1H, NH), 6.67 (s, 1H, NH), 7.13–7.23
(m, 4H, 2ꢀ2ArH), 7.45–7.49 (m, 4H, 2ꢀ2ArH); mass
(ES+) m/z 374 (M++1); Anal. Calcd for C15H17BrClNO3:
C, 48.09; H, 4.57; N, 3.74. Found: C, 47.85; H, 4.83; N, 3.78.
To the solution of compound 8a (0.5 g, 1.69 mmol) in anhy-
drous acetonitrile was added DBU (0.52 mL, 3.39 mmol)
and the reaction mixture was heated at reflux for 14 h. There-
after, the solvent was evaporated in vacuo to yield a residue,
which via silica gel column chromatography (hexane:
EtOAc, 40:60 v/v) afforded 0.28 g (64%) of compound 9a
as a white solid.
4.4.5. 5-Chloro-4-(4-chloro-phenyl)-5-methyl-6-oxo-
piperidine-3-carboxylic acid ethyl ester (8e). Yield 54%
(1.2 g from 2.0 g) as a white solid, mp 158–160 ꢂC; nmax
4.5.1. 5-Methyl-4-oxo-6-phenyl-3-aza-bicyclo[3.1.0]hex-
ane-1-carboxylic acid ethyl ester (9a). Mp 115–117 ꢂC;
nmax (KBr) 1678 (CONH), 1718 (CO2Et), 3413 (NH) cmꢁ1
;
(KBr) 1690 (CONH), 1728 (CO2Et), 3312 (NH) cmꢁ1; H
1H NMR (CDCl3, 200 MHz) d¼1.02 (t, 3H, J¼7.2 Hz,
CH3CH2), 1.52 (s, 3H, CH3), 2.66 (s, 1H, CHAr), 3.66 (d,
1H, J¼10.4 Hz, CHHN), 3.90 (d, 1H, J¼10.6 Hz, CHHNH),
4.05 (q, 2H, J¼7.2 Hz, CH2CH3), 5.98 (s, 1H, NH), 7.15–
7.28 (m, 3H, ArH), 7.32–7.40 (m, 2H, ArH); 13C NMR
(CDCl3, 75 MHz) d¼9.1, 14.1, 35.0, 35.4, 37.9, 45.1, 61.3,
128.2, 128.4, 129.6, 136.0, 170.1, 178; mass (ES+) m/z
260.2 (M++1); Anal. Calcd for C15H17NO3: C, 69.48; H,
6.61; N, 5.40. Found: C, 69.42; H, 6.55; N, 5.31.
1
NMR (CDCl3, 200 MHz) d¼0.96 (t, 3H, J¼7.2 Hz,
CH3CH2), 1.05 (t, 3H, J¼7.2 Hz, CH3CH2), 1.55 (s, 3H,
CH3), 1.59 (s, 3H, CH3), 3.28–3.37 (m, 2H, 2ꢀCHAr),
3.58–3.88 (m, 4H, 2ꢀCHCO2Et and 2ꢀCHHN), 3.90–4.06
(m, 6H, 2ꢀCH2CH3 and 2ꢀCHHN), 6.45 (s, 1H, NH),
6.81 (s, 1H, NH), 7.19–7.34 (m, 8H, 2ꢀ4ArH); 13C NMR
(CDCl3, 50 MHz) d¼14.2, 14.3, 25.9, 26.1, 42.4, 43.2,
43.8, 44.3, 52.3, 54.2, 61.6, 61.8, 67.5, 67.8, 128.6, 128.9,
131.3, 131.8, 134.3, 134.5, 134.6, 136.2, 170.3, 170.9,
171.5, 171.8; mass (FAB+) m/z 330 (M++1); Anal. Calcd
for C15H17Cl2NO3: C, 54.56; H, 5.19; N, 4.24. Found: C,
54.77; H, 5.02; N, 4.31.
4.5.2. 6-(2-Chloro-phenyl)-5-methyl-4-oxo-3-aza-bicy-
clo[3.1.0]hexane-1-carboxylic acid ethyl ester (9b). Yield
61% (0.27 g from 0.5 g) as a yellow oil; nmax (neat) 1679
(CONH), 1732 (CO2Et), 3406 (NH) cmꢁ1
;
1H NMR
4.4.6. 5-Chloro-4-(4-fluoro-phenyl)-5-methyl-6-oxo-
piperidine-3-carboxylic acid ethyl ester (8f). Yield 72%
(0.97 g from 1.2 g) as a white solid, mp 110–112 ꢂC; nmax
(CDCl3, 200 MHz) d¼0.99 (t, 3H, J¼7.2 Hz, CH3CH2),
1.60 (s, 3H, CH3), 2.49 (s, 1H, CHAr), 3.75 (d, 1H,
J¼10.5 Hz, CHHNH), 3.93–4.07 (m, 3H, CHHNH and
CH2CH3), 6.11 (s, 1H, NH), 7.21–7.32 (m, 3H, ArH),
7.34–7.40 (m, 1H, ArH); 13C NMR (CDCl3, 75 MHz)
d¼9.3, 14.2, 34.5, 35.6, 37.9, 45.2, 52.2, 61.3, 127.2,
128.6, 130.2, 134.6, 137.4, 171.2, 175.4; mass (ES+) m/z
294.1 (M++1); Anal. Calcd for C15H16ClNO3: C, 61.31; H,
5.49; N, 4.77. Found: C, 61.59; H, 5.70; N, 4.68.
1
(KBr) 1696 (CONH), 1728 (CO2Et), 3412 (NH) cmꢁ1; H
NMR (CDCl3, 200 MHz) d¼0.94 (t, 3H, J¼7.2 Hz,
CH3CH2), 1.04 (t, 3H, J¼7.2 Hz, CH3CH2), 1.56 (s, 3H,
CH3), 1.59 (s, 3H, CH3), 3.29–3.44 (m, 2H, 2ꢀCHAr),
3.57–3.67 (m, 4H, 2ꢀCH2N), 3.83–4.01 (m, 6H,
2ꢀCH2CH3 and 2ꢀCHCO2Et), 6.36 (s, 1H, NH), 6.72 (s,
1H, NH), 6.99–7.07 (m, 4H, 2ꢀ2ArH), 7.31–7.34 (m, 4H,
2ꢀ2ArH), 13C NMR (CDCl3, 50 MHz) d¼14.1, 14.2, 25.9,
26.0, 42.5, 43.2, 43.8, 44.4, 52.2, 54.1, 61.5, 61.8, 67.7,
68.1, 115.1, 115.4, 115.5, 115.8, 131.6, 132.0, 133.4,
170.5, 171.0, 171.7, 171.9; mass (ES+) m/z 314.0 (M++1);
Anal. Calcd for C15H17ClFNO3: C, 57.42; H, 5.46; N,
4.46. Found: C, 57.71; H, 5.40; N, 4.44.
4.5.3. 6-(2-Fluoro-phenyl)-5-methyl-4-oxo-3-aza-bicy-
clo[3.1.0]hexane-1-carboxylic acid ethyl ester (9c). Yield
65% (0.16 g from 0.28 g) as a white solid, mp 142–
144 ꢂC; nmax (KBr) 1657 (CONH), 1729 (CO2Et), 3280
1
(NH) cmꢁ1; H NMR (CDCl3, 200 MHz) d¼1.04 (t, 3H,
J¼7.2 Hz, CH3CH2), 1.52 (s, 3H, CH3), 2.48 (s, 1H,
CHAr), 3.65 (d, 1H, J¼10.8 Hz, CHHN), 3.97–4.09 (m,
3H, CH2CH3 and CHHN), 5.95 (s, 1H, NH), 6.98–7.15 (m,
2H, ArH), 7.23–7.27 (m, 2H, ArH); 13C NMR (CDCl3,
50 MHz) d¼9.2, 14.2, 34.4, 35.4, 38.0, 45.3, 61.3, 115.4,
115.8, 121.0, 121.3, 124.2, 129.4, 129.6, 131.8, 169.1,
178.5; mass (FAB+) m/z 278 (M++1); Anal. Calcd for
C15H16FNO3: C, 64.57; H, 5.82; N, 5.05. Found: C, 64.77;
H, 5.70; N, 4.86.
4.4.7. 5-Chloro-5-methyl-6-oxo-4-p-tolyl-piperidine-3-
carboxylic acid ethyl ester (8g). Yield 67% (0.45 g from
0.6 g) as a white solid, mp 134–136 ꢂC; nmax (KBr) 1679
(CONH), 1724 (CO2Et), 3365 (NH) cmꢁ1
;
1H NMR
(CDCl3, 300 MHz) d¼0.94 (t, 3H, J¼7.5 Hz, CH3CH2),
1.07 (t, 3H, J¼7.5 Hz, CH3CH2), 1.56 (s, 3H, CH3), 1.61
(s, 3H, CH3), 2.34 (s, 6H, 2ꢀArCH3), 3.23–3.40 (m, 2H,
2ꢀCHAr), 3.78–3.80 (m, 3H, 2ꢀCHCO2Et and CHHN),
3.84–4.06 (m, 7H, 2ꢀCH2CH3, CHHN and 2ꢀCHHN),
6.18 (s, 1H, NH), 6.56 (s, 1H, NH), 7.12–7.14 (m, 4H,
4.5.4. 6-(4-Bromo-phenyl)-5-methyl-4-oxo-3-aza-bicy-
clo[3.1.0]hexane-1-carboxylic acid ethyl ester (9d). Yield

V. Singh et al. / Tetrahedron 62 (2006) 8731–8739
8737
58% (0.05 g from 0.1 g) as a white solid, mp 136–138 ꢂC;
nmax (KBr) 1704 (CONH), 1728 (CO2Et), 3268 (NH) cmꢁ1
mixture to room temperature, it was poured into 1 N HCl
(20 mL) and extracted with EtOAc (3ꢀ30 mL). The organic
layers were pooled and washed with NaHCO3 (50 mL),
dried over Na2SO4, and evaporated to yield a residue, which
was purified via silica gel column chromatography. Elution
with hexane:EtOAc (60:40, v/v) yielded 0.13 g (60%) of
product 10g as a brown solid.
;
1H NMR (CDCl3, 300 MHz) d¼1.08 (t, 3H, J¼7.5 Hz,
CH3CH2), 1.51 (s, 3H, CH3), 2.59 (s, 1H, CHAr), 3.66 (d,
1H, J¼12.0 Hz, CHHN), 3.93 (d, 1H, J¼12.0 Hz, CHHN),
4.08 (q, 2H, J¼7.5 Hz, CH2CH3), 5.72 (s, 1H, NH), 7.07
(d, 2H, J¼8.5 Hz, ArH), 7.45 (d, 2H, J¼8.5 Hz, ArH); 13C
NMR (CDCl3, 75 MHz) d¼8.8, 13.9, 32.2, 37.4, 38.5,
44.8, 61.1, 121.4, 131.4, 131.5, 132.0, 168.8, 177.7; mass
(ES+) m/z 338.1 (M++1), 340.1 (M++3); Anal. Calcd for
C15H16BrNO3: C, 53.27; H, 4.77; N, 4.14. Found: C,
53.55; H, 4.91; N, 3.86.
4.6.1. 4-(2-Chloro-phenyl)-3-methylene-piperidine-2,6-
dione (10b). Yield 58% (0.26 g from 0.62 g) as a white solid,
108–110 ꢂC; nmax (KBr) 1701 (CONH), 3408 (NH) cmꢁ1
;
1H NMR (CDCl3, 200 MHz) d¼2.94–3.05 (m, 2H,
CH2CH), 4.54–4.59 (m, 1H, CHAr), 5.33 (s, 1H, ]CH),
6.52 (d, 1H, J¼0.9 Hz, ]CH), 7.15–7.32 (m, 3H, ArH),
7.43–7.48 (m, 1H, ArH), 8.24 (s, 1H, NH);13C NMR
(CDCl3, 50 MHz) d¼37.7, 39.1, 127.2, 127.9, 128.5,
129.4, 130.6, 137.1, 137.7, 166.2, 171.8; mass (FAB+) m/z
236 (M++1); Anal. Calcd for C12H10ClNO2: C, 61.16; H,
4.28; N, 5.94. Found: C, 60.80; H, 4.49; N, 6.01.
4.5.5. 6-(4-Chloro-phenyl)-5-methyl-4-oxo-3-aza-bicy-
clo[3.1.0]hexane-1-carboxylic acid ethyl ester (9e). Yield
60% (0.16 g from 0.3 g) as a white crystalline solid, mp
125–127 ꢂC; nmax (KBr) 1705 (CONH), 1732 (CO2Et),
1
3312 (NH) cmꢁ1; H NMR (CDCl3, 200 MHz) d¼1.07 (t,
3H, J¼7.1 Hz, CH3CH2), 1.50 (s, 3H, CH3), 2.60 (s, 1H,
CHAr), 3.65 (d, 1H, J¼10.0 Hz, CHHN), 3.98 (d, 1H,
J¼10.5 Hz, CHHN), 4.00 (q, 2H, J¼7.1 Hz, CH2CH3),
5.69 (s, 1H, NH), 7.10 (d, 2H, J¼8.3 Hz, ArH), 7.29 (d,
2H, J¼8.2 Hz, ArH); 13C NMR (CDCl3, 50 MHz) d¼9.2,
14.3, 35.7, 37.9, 38.8, 45.4, 61.4, 128.9, 131.6, 131.8,
133.6, 169.3, 178.3; mass (FAB+) m/z 294 (M++1); Anal.
Calcd for C15H16ClNO3: C, 61.33; H, 5.49; N, 4.77. Found:
C, 61.68; H, 5.41; N, 4.49.
4.6.2. 4-(4-Chloro-phenyl)-3-methylene-piperidine-2,6-
dione (10e). Yield 65% (0.23 g from 0.49 g) as a white solid,
182–184 ꢂC; nmax (KBr) 1699 (CONH), 3404 (NH) cmꢁ1
;
1H NMR (CDCl3, 200 MHz) d¼2.96–2.99 (m, 2H,
CH2CH), 4.02–4.12 (m, 1H, CHAr), 5.39 (s, 1H, ]CH),
6.50 (s, 1H, ]CH), 7.15 (d, 2H, J¼8.5 Hz, ArH), 7.36 (d,
2H, J¼8.5 Hz, ArH), 8.19 (br s, 1H, NH);13C NMR
(CDCl3, 50 MHz) d¼43.3, 46.5, 131.2, 134.2, 134.4,
138.1, 143.3, 144.5, 171.1, 177.0; mass (FAB+) m/z 236
(M++1); Anal. Calcd for C12H10ClNO2: C, 61.16; H, 4.28;
N, 5.94. Found: C, 61.22; H, 4.03; N, 5.78.
4.5.6. 6-(4-Fluoro-phenyl)-5-methyl-4-oxo-3-aza-bicy-
clo[3.1.0]hexane-1-carboxylic acid ethyl ester (9f). Yield
63% (0.14 g from 0.25 g) as a yellow oil; nmax (neat) 1701
(CONH), 1738 (CO2Et), 3400 (NH) cmꢁ1
;
1H NMR
(CDCl3, 200 MHz) d¼1.06 (t, 3H, J¼7.2 Hz, CH3CH2),
1.50 (s, 3H, CH3), 2.61 (s, 1H, CHAr), 3.65 (d, 1H,
J¼11.2 Hz, CHHNH), 3.92 (d, 1H, J¼11.0 Hz, CHHNH),
3.98–4.13 (m, 2H, CH2CH3), 5.89 (s, 1H, NH), 6.98–7.22
(m, 4H, ArH); 13C NMR (CDCl3, 50 MHz) d¼9.2, 14.3,
35.7, 38.2, 38.8, 45.6, 61.4, 115.4, 115.8, 128.2, 129.2,
131.7, 131.9, 169.4, 178.9; mass (ES+) m/z 278.1 (M++1);
Anal. Calcd for C15H16FNO3: C, 64.97; H, 5.82; N, 5.05.
Found: C, 64.90; H, 5.69; N, 4.98.
4.6.3. 3-Methylene-4-p-tolyl-piperidine-2,6-dione (10g).
Mp 152–154 ꢂC; nmax (KBr) 1697 (CONH), 3427
1
(NH) cmꢁ1; H NMR (CDCl3, 200 MHz) d¼2.35 (s, 3H,
ArCH3), 2.89–3.02 (m, 2H, CH2CH), 3.99–4.15 (m, 1H,
CHAr), 5.39 (s, 1H, ]CH), 6.47 (s, 1H, ]CH), 7.09 (d,
2H, J¼8.0 Hz, ArH), 7.19 (d, 2H, J¼8.0 Hz, ArH), 8.18
(s, 1H, NH); mass (FAB+) m/z 216 (M++1); Anal. Calcd
for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C,
72.67; H, 5.85; N, 6.82.
4.5.7. 5-Methyl-4-oxo-6-p-tolyl-3-aza-bicyclo[3.1.0] hex-
ane-1-carboxylic acid ethyl ester (9g). Yield 65% (0.23 g
from 0.4 g) as a white solid, mp 156–158 ꢂC; nmax (KBr)
4.7. General procedure for the synthesis of compounds
11a,e,f, as exemplified for compound 11a
1
1696 (CONH), 1735 (CO2Et), 3426 (NH) cmꢁ1; H NMR
To a flask charged with compound 4a (0.9 g, 3.14 mmol)
was added 6 mL mixture of TFA and H2SO4 (1: 1) at room
temperature and the reaction was continued for 4 h. There-
after, the reaction mixture was poured into ice cold water
(50 mL) and neutralized with NaHCO3 and extracted with
EtOAc (2ꢀ30 mL). Combined organic layer was dried
over Na2SO4 and evaporated in vacuo to afford a residue,
which was purified via column chromatography over silica
gel using hexane:EtOAc (30:70, v/v) to furnish 0.76 g
(80%) of amide 11a as a white solid.
(CDCl3, 200 MHz) d¼1.05 (t, 3H, J¼7.1 Hz, CH3CH2),
1.50 (s, 3H, CH3), 2.33 (s, 3H, ArCH3), 2.62 (s, 1H,
CHAr), 3.65 (d, 1H, J¼10.5 Hz, CHHN), 3.89 (d, 1H,
J¼10.4 Hz, CHHN), 4.08 (q, 2H, J¼7.1 Hz, CH2CH3),
5.80 (s, 1H, NH), 7.04 (d, 2H, J¼8.1 Hz, ArH), 7.12 (d,
2H, J¼8.2 Hz, ArH); 13C NMR (CDCl3, 50 MHz) d¼9.3,
14.3, 21.6, 35.6, 38.0, 39.5, 42.6, 61.8, 128.5, 129.4,
136.7, 139.6, 168.0, 171.2; mass (ES+) m/z 274.1 (M++1);
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.10; H, 6.75; N, 4.88.
4.7.1. 2-Carbamoyl-4-methylene-3-phenyl-pentanedioic
acid-1-ethyl ester-5-methyl ester (11a). Mp 120–122 ꢂC;
nmax (KBr) 1666 (CONH2), 1724 (CO2Me and CO2Et),
4.6. General procedure for the synthesis of compounds
10b,e,g, as exemplified for compound 10g
1
3396 (NH2) cmꢁ1; H NMR (CDCl3, 200 MHz) d¼1.01 (t,
Compound 4g (0.3 g, 1.0 mmol) and FeCl3$6H2O (0.80 g,
3.0 mmol) were dissolved in propionic acid (6 mL) and the
mixture was heated at reflux for 2 h. After cooling the
3H, J¼7.1 Hz, CH3CH2), 1.26 (t, 3H, J¼7.1 Hz,
CH3CH2), 3.69 (s, 6H, 2ꢀCO2CH3), 3.97 (q, 2H,
J¼7.1 Hz, CH2CH3), 4.10–4.21 (m, 4H, CH2CH3 and

8738
V. Singh et al. / Tetrahedron 62 (2006) 8731–8739
2ꢀCHAr), 4.53 (d, 1H, J¼12.4 Hz, CHCON), 4.62 (d, 1H,
J¼12.4 Hz, CHCON), 5.36 (s, 1H, 1H of NH2), 5.53 (s,
1H, 1H of NH2), 5.80 (s, 1H, ]CH), 5.94 (s, 1H, ]CH),
5.98 (s, 1H, 1H of NH2), 6.28 (s, 1H, 1H of NH2), 6.32 (s,
1H, ]CH), 6.33 (s, 1H, ]CH), 7.14–7.20 (m, 6H,
2ꢀ3ArH), 7.38–7.42 (m, 4H, 2ꢀ2ArH); 13C NMR
(CDCl3, 50 MHz) d¼19.0, 19.3, 50.7, 50.8, 57.1, 61.5,
61.7, 66.4, 66.5, 125.9, 129.6, 130.5, 135.6, 135.9, 136.3,
143.6, 144.0, 145.3, 146.5, 171.4, 173.5, 173.8; mass
(FAB+) m/z 306 (M++1); Anal. Calcd for C16H19NO5: C,
62.94; H, 6.27; N, 4.59. Found: C, 63.05; H, 6.13; N, 4.83.
hexane:EtOAc (40:60 v/v) over silica gel to yield 0.32 g
(72%) of compound 12a as a white solid.
4.8.1. 5-Methylene-2,6-dioxo-4-phenyl-piperidine-3-car-
boxylic acid ethyl ester (12a). Mp 114–116 ꢂC; nmax
1
(KBr) 1705 (CONH), 1748 (CO2Et), 3418 (NH) cmꢁ1; H
NMR (CDCl3, 300 MHz) d¼1.13 (t, 3H, J¼7.5 Hz,
CH3CH2), 3.40 (d, 1H, J¼9.0 Hz, CHAr), 4.14 (q, 2H,
J¼7.5 Hz, CH2CH), 4.43 (d, 1H, J¼9.0 Hz, CHCO2Et),
5.45 (s, 1H, ]CH), 6.57 (s, 1H, ]CH), 7.21–7.33 (m, 3H,
ArH), 7.35–7.41 (m, 2H, ArH), 8.15 (s, 1H, NH); 13C
NMR (CDCl3, 50 MHz) d¼14.3, 46.2, 55.3, 62.5, 128.3,
128.6, 129.6, 137.2, 137.4, 165.1, 167.5, 168.3; mass
(ES+) m/z 274.1 (M++1); Anal. Calcd for C15H15NO4: C,
65.52; H, 5.53; N, 5.13. Found: C, 65.59; H, 5.71; N, 4.93.
4.7.2. 2-Carbamoyl-3-(4-chloro-phenyl)-4-methylene-
pentanedioic acid-1-ethyl ester-5-methyl ester (11e).
Yield 89% (0.63 g from 0.67 g) as a white solid, mp 102–
104 ꢂC; nmax (KBr) 1667 (CONH2), 1725 (CO2Me and
1
CO2Et), 3389 (NH2) cmꢁ1; H NMR (CDCl3, 200 MHz)
4.8.2. 4-(4-Chloro-phenyl)-5-methylene-2,6-dioxo-piperi-
dine-3-carboxylic acid ethyl ester (12e). Yield 74%
(0.15 g from 0.22 g) as a white solid, mp 108–110 ꢂC; nmax
d¼1.02 (t, 3H, J¼7.2 Hz, CH3CH2), 1.25 (t, 3H,
J¼7.2 Hz, CH3CH2), 3.69 (s, 6H, 2ꢀCO2CH3), 3.96 (q,
2H, J¼7.2 Hz, CH2CH3), 4.11–4.25 (m, 4H, CH2CH3 and
2ꢀCHAr), 4.54 (d, 1H, J¼12.4 Hz, CHCON), 4.63 (d, 1H,
J¼12.4 Hz, CHCON), 5.62 (s, 1H, 1H of NH2), 5.73 (s,
1H, 1H of NH2), 5.81 (s, 1H, ]CH), 5.85 (s, 1H, 1H of
NH2), 5.94 (s, 1H, ]CH), 5.98 (s, 1H, 1H of NH2), 6.32
(s, 1H, ]CH), 6.33 (s, 1H, ]CH), 7.23–7.31 (m, 8H,
2ꢀ4ArH); 13C NMR (CDCl3, 50 MHz) d¼19.0, 19.2,
50.8, 51.1, 57.3, 61.7, 61.8, 66.3, 66.5, 129.5, 130.5,
133.4, 135.2, 135.4, 137.7, 142.9, 143.4, 145.4, 146.5,
171.4, 173.6, 173.8; mass (ES+) m/z 340.0 (M++1); 342.0
(M++3); Anal. Calcd for C16H18ClNO5: C, 56.56; H, 5.34;
N, 4.12. Found: C, 56.79; H, 5.22; N, 3.95.
1
(KBr) 1695 (CONH), 1748 (CO2Et), 3418 (NH) cmꢁ1; H
NMR (CDCl3, 200 MHz) d¼1.14 (t, 3H, J¼7.1 Hz,
CH3CH2), 3.40 (d, 1H, J¼9.5 Hz, CHAr), 4.14 (q, 2H,
J¼7.1 Hz, CH2CH), 4.38 (d, 1H, J¼9.2 Hz, CHCO2Et),
5.40 (s, 1H, ]CH), 6.58 (s, 1H, ]CH), 7.16 (d, 2H,
J¼7.8 Hz, ArH), 7.36 (d, 2H, J¼8.0 Hz, ArH), 8.21 (s,
1H, NH); 13C NMR (CDCl3, 50 MHz) d¼14.3, 45.5, 51.1,
62.6, 129.3, 130.5, 134.5, 135.7, 137.1, 164.8, 167.2,
167.9; mass (FAB+) m/z 308 (M++1); Anal. Calcd for
C15H14ClNO4: C, 58.54; H, 4.59; N, 4.55. Found: C, 58.50;
H, 4.69; N, 4.58.
4.8.3. 4-(4-Fluoro-phenyl)-5-methylene-2,6-dioxo-piperi-
dine-3-carboxylic acid ethyl ester (12f). Yield 76% (0.25 g
from 0.36 g) as a white solid, mp 135–137 ꢂC; nmax (KBr)
4.7.3. 2-Carbamoyl-3-(4-fluoro-phenyl)-4-methylene-
pentanedioic acid-1-ethyl ester-5-methyl ester (11f).
Yield 78% (0.68 g from 0.83 g) as a white solid, mp 110–
112 ꢂC; nmax (KBr) 1664 (CONH2), 1726 (CO2Me and
1
1703 (CONH), 1740 (CO2Et), 3372 (NH) cmꢁ1; H NMR
(CDCl3, 300 MHz) d¼1.15 (t, 3H, J¼7.5 Hz, CH3CH2),
3.95 (d, 1H, J¼9.0 Hz, CHAr), 4.15 (q, 2H, J¼7.5 Hz,
CH2CH), 4.40 (d, 1H, J¼9.0 Hz, CHCO2Et), 5.41 (s, 1H,
]CH), 6.58 (s, 1H, ]CH), 7.06–7.12 (m, 2H, ArH),
7.19–7.24 (m, 2H, ArH), 8.12 (s, 1H, NH); 13C NMR
(CDCl3, 50 MHz) d¼14.3, 45.4, 55.4, 62.6, 116.3, 116.8,
129.6, 130.0, 130.2, 132.9, 137.4, 165.0, 167.3, 168.1;
mass (FAB+) m/z 292 (M++1); Anal. Calcd for
C15H14FNO4: C, 61.58; H, 4.85; N, 4.81. Found: C, 61.55;
H, 4.56; N, 4.77.
1
CO2Et), 3403 (NH2) cmꢁ1; H NMR (CDCl3, 300 MHz)
d¼1.02 (t, 3H, J¼7.5 Hz, CH3CH2), 1.27 (t, 3H,
J¼7.5 Hz, CH3CH2), 3.70 (s, 3H, CO2CH3), 3.71 (s, 3H,
CO2CH3), 3.94–4.01 (m, 3H, CH2CH3 and CHAr), 4.12–
4.25 (m, 3H, CH2CH3 and CHAr), 4.57 (d, 1H,
J¼12.0 Hz, CHCON), 4.66 (d, 1H, J¼12.0 Hz, CHCON),
5.28 (s, 1H, 1H of NH2), 5.43 (s, 1H, 1H of NH2), 5.81 (s,
1H, ]CH), 5.95 (s, 2H, ]CH and 1H of NH2), 6.28 (s,
1H, 1H of NH2), 6.34 (s, 2H, 2ꢀ]CH), 6.94–7.00 (m,
4H, 2ꢀ2ArH), 7.26–7.32 (m, 4H, 2ꢀ2ArH); 13C NMR
(CDCl3, 50 MHz) d¼14.1, 14.3, 46.1, 46.6, 52.3, 57.5,
61.7, 61.8, 115.1, 115.6, 124.5, 125.7, 130.3, 130.5, 130.6,
134.9, 135.2, 140.5, 141.7, 159.6, 164.4, 166.6, 166.7,
168.6, 169.2; mass (ES+) m/z 324.1 (M++1); Anal. Calcd
for C16H18FNO5: C, 59.44; H, 5.61; N, 4.33. Found: C,
59.63; H, 5.40; N, 4.47.
Acknowledgements
Two of the authors (V.S. and G.P.Y.) acknowledge the finan-
cial support from DSTand CSIR, respectively, in the form of
fellowship. This work was supported by the financial grant
from DST, New Delhi.
4.8. General procedure for the synthesis of compounds
12a,e,f, as exemplified for compound 12a
References and notes
To the stirred solution of compound 11a (0.5 g, 1.64 mmol)
in anhydrous toluene was added NaH (0.098 g in 60% oil,
2.46 mmol) at ambient temperature. After 30 min reaction
mixture was quenched carefully with water and extracted
with ethyl acetate (2ꢀ25 mL). The organic layer was dried
(Na2SO4) and evaporated in vacuo to obtain a residue that
was subjected to column chromatography using
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8739
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Kundu, B.; Joshi, B. S.; Roy, R.; Bhaduri, A. P. Synthesis
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4. (a) Kumar, S.; Raje, N.; Hideshima, T.; Ishitsuka, K.; Podar, K.;
Le Gouille, S.; Chauhan, D.; Richardson, P.; Munshi, N. C.;
Anderson, K. Br. J. Haematol. 2006, 132, 698; (b) Gaul, C.;
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8. Crystal data of compound 9e: C15H16NO3Cl, M¼293.75,
orthorhombic,
P212121,
a¼6.323(1),
b¼9.076(2),
3
ꢁ3
˚
˚
c¼26.253(2) A, V¼1506.5(4) A , Z¼4, Dc¼1.295 g cm
,
m(Mo Ka)¼0.026 mmꢁ1, F(000)¼616.0, colorless block,
dimension 0.3ꢀ0.25ꢀ0.2 mm, 2196 reflections measured
(Rint¼0.0234), 1978 unique, wR2¼0.098, conventional
R¼0.0401 on F values of 1485 reflections with I>2s(I), (D/
s)max¼000), S¼1.02 for all data and 184 parameters. Unit
cell determination and intensity data collection (2q¼50ꢂ) was
performed on a Bruker P4 diffractometer at 293(2) K.
Structure solutions by direct methods and refinements by
full-matrix least-squares methods on F2. Programs: XSCANS
(Siemens Analytical X-ray Instrument Inc.: Madison, WI,
USA, 1996) for data collection and data processing;
SHELXTL-NT (Bruker AXS Inc.: Madison, Wisconsin,
USA, 1997) for structure determination, refinements, and mo-
lecular graphics. Further details of the crystal structure investi-
gation can be obtained from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK
(CCDC deposition no. of 9e: 609070).
9. Wang, S.; Tan, T.; Li, J.; Hu, H. Synlett 2005, 2658.
10. Lee, M. J.; Kim, S. C.; Kim, J. N. Bull. Korean Chem. Soc.
2006, 27, 140.