Synthesis of trans-4-aryl-3-(3-chloropropyl)azetidin-2-ones and their transformation into trans- and cis-2-arylpiperidine-3-carboxylates

Article abstract of DOI:10.1016/j.tet.2008.03.006

Treatment of arylmethylideneamines with 5-chloropentanoyl chloride in benzene in the presence of 2,6-lutidine afforded novel trans-4-aryl-3-(3-chloropropyl)azetidin-2-ones in good yields. The latter 3-(3-chloropropyl)-β-lactams were transformed selectively into trans-methyl 1-alkyl-2-arylpiperidine-3-carboxylates in high yields and purity upon subsequent treatment with hydrogen chloride in methanol and triethylamine in dichloromethane. These trans-1-alkyl-2-arylpiperidine-3-carboxylates were easily converted into either their cis-isomers upon treatment with hydrazine monohydrate in methanol, or into the corresponding piperidine-1,3-dicarboxylates by reaction with alkyl chloroformates in benzene. Finally, 3-(3-chloropropyl)-1-(4-methoxybenzyl)-4-phenylazetidin-2-one was transformed into the corresponding trans-1-tert-butoxycarbonyl-3-(4-methoxybenzylcarbamoyl)piperidine via a three-step sequence in a good overall yield.

Full text of DOI:10.1016/j.tet.2008.03.006

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4575e4584
www.elsevier.com/locate/tet
Synthesis of trans-4-aryl-3-(3-chloropropyl)azetidin-2-ones and their
transformation into trans- and cis-2-arylpiperidine-3-carboxylates
*
Matthias D’hooghe, Yves Dejaegher, Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Received 7 February 2008; received in revised form 29 February 2008; accepted 3 March 2008
Available online 7 March 2008
Abstract
Treatment of arylmethylideneamines with 5-chloropentanoyl chloride in benzene in the presence of 2,6-lutidine afforded novel trans-4-aryl-
3-(3-chloropropyl)azetidin-2-ones in good yields. The latter 3-(3-chloropropyl)-b-lactams were transformed selectively into trans-methyl 1-al-
kyl-2-arylpiperidine-3-carboxylates in high yields and purity upon subsequent treatment with hydrogen chloride in methanol and triethylamine
in dichloromethane. These trans-1-alkyl-2-arylpiperidine-3-carboxylates were easily converted into either their cis-isomers upon treatment with
hydrazine monohydrate in methanol, or into the corresponding piperidine-1,3-dicarboxylates by reaction with alkyl chloroformates in benzene.
Finally, 3-(3-chloropropyl)-1-(4-methoxybenzyl)-4-phenylazetidin-2-one was transformed into the corresponding trans-1-tert-butoxycarbonyl-3-
(4-methoxybenzylcarbamoyl)piperidine via a three-step sequence in a good overall yield.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
elaboration of this piperidine-3-carboxylate furnished cis-
3-(2-methoxybenzylamino)-2-phenylpiperidine (compound
Since the introduction of the term ‘b-lactam synthon
method’ in 1997,1 azetidin-2-ones have acquired a prominent
place in organic chemistry as synthons for further elaboration.
Consequently, the constrained azetidin-2-one ring has been
employed successfully in a large variety of different synthetic
methodologies towards all kinds of nitrogen-containing target
compounds.2 Whereas several efforts have been devoted to the
application of 1-(u-haloalkyl)-b-lactams3 and 4-(u-halo-
alkyl)-b-lactams4 in organic synthesis, the use of 3-(u-halo-
alkyl)azetidin-2-ones has been evaluated only sporadically
up to now, and no convenient and general procedure for their
preparation is available. In a report, the alkylation of 1-(tert-
butyldimethylsilyl)-4-phenylazetidin-2-one with 1-bromo-3-
chloropropane has been described, affording the corresponding
trans-1-(tert-butyldimethylsilyl)-3-(3-chloropropyl)-2-phenyl-
b-lactam in 77% yield.5 The latter trans-3-(3-chloropropyl)-
2-phenylazetidin-2-one was transformed into cis-methyl
2-phenylpiperidine-3-carboxylate upon subsequent treatment
with H2SO4 in methanol and NaI/NaHCO3 in DMF.5 Further
CP-99,994) as a potent substance P antagonist.6 Analogously,
the alkylation of a 1-silylated 4-carboxyazetidin-2-one with
1-iodo-3-chloropropane has been described. The resulting
3-(3-chloropropyl)-b-lactam served as a substrate for the
synthesis of different 3-(3-guanidinopropyl)azetidin-2-ones
as triptase inhibitors.7 However, the b-lactams used for
the above mentioned alkylation reactions are not readily avail-
able, hence there is an actual need for a more practical and
general method for the preparation of 3-(3-halopropyl)-b-
lactams.
In the present report, a convenient procedure for the synthe-
sis of 4-aryl-3-(3-chloropropyl)-b-lactams is described based
on the Staudinger reaction between arylmethylideneamines
and 5-chloropentanoyl chloride in the presence of a base.
The 3-(3-chloropropyl)azetidin-2-ones thus obtained were fur-
ther converted into novel trans- and cis-methyl 2-arylpiperi-
dine-3-carboxylates in high yields and purity. The final goal
of this work comprised the transformation of the latter piper-
idine-3-carboxylates into the corresponding 3-carbamoylpi-
peridines as precursors for the synthesis of biologically
relevant 3-aminopiperidines (CP-99,994 analogues)6 via a
Hofmann rearrangement protocol. The need for new
* Corresponding author. Tel.: þ32 92645951; fax: þ32 92646243.
E-mail address: norbert.dekimpe@UGent.be (N. De Kimpe).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.006

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M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
stereoselective routes to substituted piperidines has been
underlined very recently in a review of synthetic approaches
towards biologically relevant trans-3,4-disubstituted piperi-
dines.8 Furthermore, 2-arylpiperidine-3-carboxylic acid deriv-
atives are of significant interest due to their potential use in the
treatment of Alzheimer’s disease,9 while 2,4-diarylpiperidine-
3-carboxylic acid derivatives have been reported as potential
farnesyltransferase inhibitors.10
3 as compared to arylmethylideneamines 1. Nucleophilic addi-
tion of alkylideneamines 3 across the acid chloride carbonyl
group and subsequent a-deprotonation with respect to the in
situ formed iminium moiety can account for the formation
of the observed 5-chloropentanamides 4 (Scheme 2).
O
1.5 equiv
O
N
N
Cl
Cl
Cl
R1
R1
H
3 equiv 2,6-lutidine
C6H6, Δ, 72-144 h
R2
R2
2. Results and discussion
4a (R1 = R2 = Me, 63%)
3
O
N
4b (R1, R2 = -(CH2)5-, 88%)
The synthesis of 4-aryl-3-(3-chloropropyl)-b-lactams 2 was
performed by means of a Staudinger reaction between the ap-
propriate imines and ketenes. Thus, treatment of arylmethyli-
deneamines 1 with 1.5 equiv of 5-chloropentanoyl chloride in
benzene in the presence of 3 equiv of 2,6-lutidine afforded the
corresponding novel 3-(3-chloropropyl)azetidin-2-ones 2aeg
in good yields after reflux for 72e144 h (Scheme 1, Table
1). The stereochemical outcome of the Staudinger reaction to-
wards azetidin-2-ones 2 was shown to be trans based on the
Cl
R1
R2
H
B
H
Scheme 2.
In the next phase, the aptitude of 4-aryl-3-(3-chloropropyl)-
b-lactams 2 as substrates for ring expansion towards piperi-
dine derivatives was investigated, as the combination of the
constrained four-membered b-lactam ring and the electrophilic
centre (halogenated carbon atom) at a remote position results
in a potential useful substrate for various transformations.
In order to transform b-lactams 2 into piperidine deriva-
tives, hydrochloric acid was bubbled through an ice-cooled
methanolic solution of 3-(3-chloropropyl)azetidin-2-ones 2
for 1 h, followed by a resting period of 24 h at room temper-
ature and a reflux period of 4 h in dichloromethane in the pres-
ence of 4 equiv of triethylamine. In this way, novel methyl
1-alkyl-2-arylpiperidine-3-carboxylates 5aed were obtained
in high yields (82e93%) and purity (Scheme 3). The relative
stereochemistry of the latter piperidines 5 could be assigned as
trans based on a coupling constant of 9.9 Hz (1H NMR,
CDCl3) between the protons at C2 and C3.13 This reaction pro-
ceeds through initial nucleophilic ring opening of the proton-
ated b-lactam by methanol,14 followed by intramolecular
nucleophilic displacement of chloride by the in situ formed
free amine upon addition of base (Scheme 3). Apparently,
isomerization takes place during the reaction, as normally
cis-2,3-disubstituted piperidines would be expected. The ring
opening of azetidin-2-ones by methanol comprises a valuable
approach towards b-amino esters with plentiful applications.15
It should be noted that the application of literature-based reac-
tion conditions for the contemplated ring transformation of b-
lactams 2 into piperidines 5 proved to be less or not successful
at all. For example, the use of sulfuric acid in methanol5 re-
sulted in the desired piperidine-3-carboxylates 5 as major con-
stituents besides several unidentified side-products, whereas
the use of sodium cyanide in methanol16 led only to the com-
plete recovery of the starting material.
1
coupling constants between the protons at C3 and C4 in H
NMR (2.0 Hz, CDCl3).11 When triethylamine was used as
a base instead of 2,6-lutidine, complex reaction mixtures
were obtained in which the desired b-lactams 2 were present
in very low yields (<10%). The required imines 1 were easily
prepared via condensation of the corresponding benzaldehydes
with different primary amines under reflux for 1 h in dichloro-
methane in the presence of MgSO4 (yields 90e99%).12
R2
R1
H
1.5 equiv
N
O
Cl
Cl
Cl
N
3 equiv 2,6-lutidine
C6H6, Δ, 72-144 h
R2
O
R1
1
2a-g (55-87%)
Scheme 1.
In order to evaluate the synthesis of the analogous 4-alkyl-
3-(3-chloropropyl)-b-lactams, aliphatic alkylideneamines 3
were used for the Staudinger reaction with 5-chloropentanoyl
chloride, applying the same reaction conditions as described
above. Surprisingly, 5-chloropentanamides 4aeb were ob-
tained instead as the sole reaction products in 63e88% yield
(Scheme 2). Obviously, the presence of electron-donating al-
kyl groups has a distinct effect on the reactivity of the imines
Table 1
Synthesis of trans-4-aryl-3-(3-chloropropyl)-b-lactams 2aeg
Entry
R1
R2
Compound
Yield (%)
In order to expand the scope, the preparation of 1-(alkoxy-
carbonyl)piperidines 6 as the activated counterparts of 1-alkyl-
piperidines 5 was evaluated by means of two different
approaches. The direct conversion of 1-alkylpiperidines 5
into 1-(alkoxycarbonyl)piperidines 6 could be realized upon
treatment of piperidine-3-carboxylates 5a and 5b with a large
excess (10 equiv) of methyl or ethyl chloroformate in benzene,
1
2
3
4
5
6
7
i-Pr
H
2a
2b
2c
2d
2e
2f
75
60
55
70
62
87
66
Et
Bn
H
H
4-MeOC6H4CH2
H
c-Hex
i-Pr
i-Pr
H
Me
OMe
2g

M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
4577
R2
O
Cl
1) HCl / MeOH, 0 °C, 1 h
then r.t., 24 h
OMe
N
N
2) 4 equiv Et3N, CH2Cl2, Δ, 4 h
R1
O
R1
R2
2
5a (R1 = iPr, R2 = H, 79%)
5b (R1 = Bn, R2 = H, 93%)
5c (R1 = iPr, R2 = Me, 89%)
5d (R1 = iPr, R2 = OMe, 82%)
R2
Cl
NHR1
Cl
MeOH
MeOOC
N
O
R1
H
R2
Scheme 3.
affording piperidine-1,3-dicarboxylates 6a and 6b after reflux
for 10 h (Scheme 4, Table 2). On the other hand, N-Boc pro-
tected piperidine 6c was prepared starting from b-lactam 2c
through a sequence of transformations, involving acid-medi-
ated b-lactam ring opening by methanol, N-debenzylation by
means of hydrogenolysis, base-mediated cyclization towards
the free piperidine and finally N-Boc protection utilizing
1 equiv of Boc2O in acetonitrile for 2 h at room temperature
(Scheme 4, Table 2).
Table 2
Synthesis of piperidine-1,3-dicarboxylates 6aec
Entry
Substrate
Compound
Yield (%)
1
2
3
5a (R1¼i-Pr)
5b (R1¼Bn)
2c
6a (R¼Me)
6b (R¼Et)
6c (R¼t-Bu)
56
50
64
disubstituted piperidines 7aed were formed in good yields
through isomerization of the starting trans-derivatives 5aed
(Scheme 5). The relative stereochemistry of piperidines 7
could be assigned as cis based on coupling constants of
5.0e5.3 Hz (1H NMR, CDCl3) between the protons at C2
and C3.13 According to the literature, cis-piperidines 7 adopt
a chair conformation with an axial orientation for the alkoxy-
carbonyl group and an equatorial orientation for the aryl
group.19 The isomerization of trans-piperidines 5 to cis-piper-
idines 7 can be rationalized considering the basic properties of
hydrazine,20 as the hydroxide present in an aqueous solution of
hydrazine can be responsible for the deprotonation of piper-
idines 5 in a-position with respect to the ester moiety. Proton-
ation of the enolate thus formed should take place from the
Due to the biological relevance of 3-carbamoylpiperi-
dines,10 several attempts were performed in order to convert
the ester moiety of piperidine-3-carboxylates 5 into an
N-unsubstituted amide by means of reaction with dimethylalu-
minium amides.17 Furthermore, the latter 3-carbamoylpiperi-
dines could then serve as precursors for the synthesis of the
corresponding biologically relevant 3-aminopiperidines (CP-
99,994 analogues)6 via a Hofmann rearrangement protocol.
Treatment of 1-isopropylpiperidine 5a (or the corresponding
hydrochloride salt) with 2 equiv of dimethylaluminium amide,
derived from ammonia and trimethylaluminium, in dichloro-
methane at 40 ꢀC for 16 h only resulted in the recovery of
the starting material. When the dimethylaluminium reagent
derived from 4-methoxybenzylamine was used, again no con-
version was observed. Also treatment of piperidine-1,3-dicar-
boxylates 6 with 3e10 equiv of chloromethylaluminium
amide in toluene at 50 ꢀC for 12 h resulted in either recovery
of the starting material or in complex reaction mixtures.
According to another strategy,18 piperidine-3-carboxylates
5 were treated with 10 equiv of hydrazine monohydrate in re-
fluxing methanol for 4 h. Although complete conversion of the
starting compounds had taken place, this approach did not
afford the anticipated hydrazides. Surprisingly, only cis-2,3-
O
O
OMe
OMe
.
10 equiv NH2NH2 H2O
N
N
MeOH, Δ, 4 h
R1
R1
R2
R2
5a-d
7a (R1 = iPr, R2 = H, 67%)
7b (R1 = Bn, R2 = H, 70%)
7c (R1 = iPr, R2 = Me, 56%)
7d (R1 = iPr, R2 = OMe, 78%)
Scheme 5.
Cl
O
O
1) HCl, MeOH
2) H2 (5 bar), Pd/C
MeOH
OMe
OMe
10 equiv ClCOOR
N
N
C6H6, Δ, 15 h
3) NaOHaq
N
R1
4) 1 equiv Boc2O
O
RO
O
CH3CN, r.t., 2 h
5a-b
6a-c (50-64%)
2c
Scheme 4.

4578
M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
less hindered face, i.e., the opposite face with regard to the
aryl group, affording cis-piperidines 7.
2-arylpiperidine-3-carboxylates were converted into their cis-iso-
mers upon treatment with hydrazine monohydrate in methanol
and into the corresponding trans-piperidine-1,3-dicarboxylates
by reaction with alkyl chloroformates in benzene. Finally, 3-
(3-chloropropyl)-1-(4-methoxybenzyl)-4-phenylazetidin-2-one
was transformed into the corresponding 1-tert-butoxycarbonyl-
3-(4-methoxybenzylcarbamoyl)piperidine via subsequent N-
debenzylation, N-Boc protection, nucleophilic ring opening
by 4-methoxybenzylamine, N-deprotection, base-mediated
cyclization and N-Boc protection in a good overall yield.
As the ring opening of 3,3-disubstituted b-lactams by lith-
ium amides has been reported before,21 the direct conversion
of 3-(3-chloropropyl)-b-lactams 2 into the corresponding 3-
carbamoylpiperidines was evaluated upon treatment with
2 equiv of LiNH2 in THF and reflux for 20 h. Again, the sub-
strate was recovered completely. Apparently, in this case the
b-lactam ring had to be activated by the introduction of an
electron-withdrawing group at nitrogen in order to facilitate
ring opening by amines.
Thus, 1-(4-methoxybenzyl)azetidin-2-one 2d was con-
verted into b-lactam 8 bearing a free NH moiety through de-
benzylation by means of 3.4 equiv of potassium
peroxodisulfate in a 1/1 mixture of water/acetonitrile and re-
fluxed for 1 h in the presence of 6.8 equiv of KH2PO4 (Scheme
6). Subsequently, treatment of b-lactam 8 with 2 equiv of di-
tert-butyl dicarbonate (Boc2O) in the presence of 1 equiv of
Et3N and a catalytic amount of DMAP afforded the corre-
sponding N-Boc protected b-lactam 9 in 75% yield after 4 h
at room temperature (Scheme 6). The latter activated azeti-
din-2-one 9 was then successfully subjected to several subse-
quent transformations, i.e., the nucleophilic ring opening of
the b-lactam moiety by 4-methoxybenzylamine, N-deprotec-
tion by means of 20 equiv of trifluoroacetic acid, base-medi-
ated cyclization towards the corresponding piperidine and
finally N-Boc protection by means of Boc2O, furnishing
trans-1-tert-butoxycarbonyl-3-(4-methoxybenzylcarbamoyl)-
piperidine 10 in good overall yield (Scheme 6). Attempted
N-debenzylation of amide 10 using either ceric ammonium
nitrate or potassium peroxodisulfate resulted in recovery of
the starting material or in complex reaction mixtures.
3. Experimental part
3.1. General
1H NMR spectra were recorded at 270 MHz (JEOL JNM-
EX 270) with CDCl3 as solvent and tetramethylsilane as inter-
nal standard. 13C NMR spectra were recorded at 68 MHz
(JEOL JNM-EX 270) with CDCl3 as solvent. Mass spectra
were obtained with a mass spectrometer (VARIAN MAT
112, 70 eV) using a GCeMS coupling (RSL 200, 20 m glass
capillary column, i.d. 0.53 mm, He carrier gas). IR spectra
were measured with a PerkinElmer 1310 spectrophotometer
or a Spectrum One FT-IR. Elemental analyses were performed
with a PerkinElmer Series II CHNS/O Analyzer 2400. Di-
chloromethane was dried over calcium hydride, while diethyl
ether and THF were dried by distillation over sodium benzo-
phenone ketyl. Other solvents were used as received from
the supplier.
3.2. Synthesis of trans-4-aryl-3-(3-chloropropyl)-b-lactams 2
In summary, novel trans-4-aryl-3-(3-chloropropyl)azetidin-
2-ones have been prepared upon treatment of arylmethylidene-
amines with 5-chloropentanoyl chloride in benzene in the
presence of 2,6-lutidine. These 3-(3-chloropropyl)azetidin-2-
ones were transformed selectively into trans-methyl 1-alkyl-
2-arylpiperidine-3-carboxylates in high yields and purity upon
subsequent treatment with hydrogen chloride in methanol and
triethylamine in dichloromethane. Furthermore, trans-1-alkyl-
General procedure: To a refluxing solution of imine 1
(10 mmol) and 2,6-lutidine (30 mmol) in benzene (50 mL)
was added dropwise a solution of 5-chloropentanoyl chloride
(15 mmol) in benzene (50 mL). The resulting solution was
kept at reflux temperature for 72 h (or 144 h for b-lactams
2c and 2d). Subsequently, the precipitated 2,6-lutidine hydro-
chloride was filtered off and the filtrate was washed with
hydrochloric acid (2ꢁ35 mL, 1 M). Drying (magnesium
Cl
Cl
3.4 equiv K2S2O8
6.8 equiv KH2PO4
OMe
N
N
H2O / CH3CN, Δ, 1 h
O
O
H
2d
8 (70%)
2 equiv Boc2O
1 equiv Et3N, DMAP
CH2Cl2, r.t., 4 h
O
1) 2 equiv 4-MeOC6H4NH2
CH2Cl2, Δ, 16 h
Cl
N
H
2) 20 equiv TFA, CH2Cl2, r.t., 1 h
N
Boc
OMe
N
3) NaOHaq
4) 1.5 equiv Boc2O, 1 equiv Et3N
DMAP, CH2Cl2, r.t., 4 h
O
Boc
10 (75%)
9 (75%)
Scheme 6.

M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
4579
sulfate) and evaporation of the solvent afforded 4-aryl-3-(3-
chloropropyl)-b-lactam 2, which was further purified by means
of column chromatography on silica gel (hexane/EtOAc 3/2).
(CH2)2CH2Cl), 2.98e3.02 (1H, m, CHCH2), 3.50 (2H, t,
J¼5.0 Hz, CH2Cl), 3.68 (1H, d, J¼14.9 Hz, (HCH)N), 3.79
(3H, s, OCH3), 4.02 (1H, br s, NCH), 4.77 (1H, d, J¼
14.9 Hz, (HCH)N), 6.82 (2H, d, J¼7.3 Hz, CHar), 7.04 (2H,
d, J¼7.3 Hz, CHar), 7.21e7.41 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 25.9 and 30.1 ((CH2)2CH2Cl), 43.8
(CH2N), 44.5 (CH2Cl), 55.3 (OCH3), 59.7 (CHCH2), 60.3
(NCH), 114.1, 126.5, 127.6, 128.5, 129.1 and 129.8 (CHarom),
137.7 (Cq), 159.1 (Cq), 169.6 (C]O). IR (NaCl):
n¼1748 cmꢂ1 (C]O). MS (70 eV): m/z (%): 343/5 (8, Mþ),
342/4 (30), 255 (10), 179/81 (100), 162 (36), 142 (18), 121
(63), 117 (53), 91 (13). Anal. Calcd for C20H22ClNO2: C
69.86, H 6.45, N 4.07. Found: C 69.72, H 6.57, N 3.88.
3.2.1. trans-3-(3-Chloropropyl)-1-isopropyl-4-phenyl-
azetidin-2-one 2a
Light-yellow oil. Yield 75%. Rf 0.53 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3): d 1.01 and 1.26 (2ꢁ3H, 2ꢁd,
J¼6.6 Hz, CH(CH3)2), 1.83e2.00 (4H, m, (CH2)2CH2Cl),
2.89e2.93 (1H, m, CHCH2), 3.52 (2H, t, J¼5.0 Hz, CH2Cl),
3.76 (1H, septet, J¼6.6 Hz, CHMe2), 4.22 (1H, d, J¼2.0 Hz,
NCH), 7.35e7.39 (5H, m, C6H5). 13C NMR (68 MHz,
CDCl3): d 20.4 and 21.2 (CH(CH3)2), 26.0 and 30.1
((CH2)2CH2Cl), 44.6 (CH2Cl), 44.9 (CHMe2), 58.8 (CHCH2),
60.1 (NCH), 126.5, 128.4 and 128.9 (CHarom), 139.4 (Cq),
169.8 (C]O). IR (NaCl): n¼1745 cmꢂ1 (C]O). MS
(70 eV): m/z (%): 265/7 (0.66, Mþ), 230 (0.70, MþꢂCl),
180/2 (6), 117/9 (16), 88 (12), 86 (62), 84 (100), 73 (6), 57 (5),
55 (8), 51 (9), 49 (34), 47 (29). Anal. Calcd for C15H20ClNO:
C 67.79, H 7.58, N 5.27. Found: C 67.62, H 7.79, N 5.13.
3.2.5. trans-3-(3-Chloropropyl)-1-cyclohexyl-4-phenyl-
azetidin-2-one 2e
Light-yellow oil. Yield 62%. Rf 0.53 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3): d 0.97e1.99 (14H, m,
(CH2)2CH2Cl and (CH2)5), 2.89e2.94 (1H, m, CHCH2),
3.35e3.53 (1H, m, NCH), 3.51 (2H, t, J¼5.0 Hz, CH2Cl),
4.24 (1H, d, J¼2.0 Hz, NCH), 7.28e7.39 (5H, m, C6H5).
13C NMR (68 MHz, CDCl3): d 25.0, 25.15, 25.16, 30.7 and
31.4 (CH2)5), 26.0 and 30.0 ((CH2)2CH2Cl), 44.6 (CH2Cl),
52.6 (NCH), 58.8 (CHCH2), 60.3 (NCH), 126.5, 128.4 and
128.9 (CHarom), 139.4 (Cq), 170.1 (C]O). IR (NaCl): n¼
1744 cmꢂ1 (C]O). MS (70 eV): m/z (%): 305/7 (2, Mþ),
180/2 (100), 122 (9), 117 (69), 115 (9), 91 (9), 73 (15).
Anal. Calcd for C18H24ClNO: C 70.69, H 7.91, N 4.58. Found:
C 70.77, H 8.17, N 4.74.
3.2.2. trans-3-(3-Chloropropyl)-1-ethyl-4-phenylazetidin-
2-one 2b
Light-yellow oil. Yield 60%. Rf 0.28 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3): d 1.05 (3H, t, J¼7.3 Hz,
CH2CH3), 1.78e1.99 (4H, m, (CH2)2CH2Cl), 2.85e3.01
(2H, m, CHCH2 and (HCH)CH3), 3.40e3.65 (3H, m, CH2Cl
and (HCH)CH3), 4.13 (1H, d, J¼2.0 Hz, NCH), 7.28e7.42 (5H,
m, C6H5). 13C NMR (68 MHz, CDCl3): d 12.6 (CH2CH3), 25.6
and 29.8 ((CH2)2CH2Cl), 35.0 (CH2CH3), 44.3 (CH2Cl), 59.2
(CHCH2), 60.4 (NCH), 126.0, 128.2 and 128.7 (CHarom),
137.8 (Cq), 169.5 (C]O). IR (NaCl): n¼1745 cmꢂ1 (C]O).
MS (70 eV): m/z (%): no Mþ, 144 (10), 119 (9), 106 (33), 105
(38), 101 (12), 91 (11), 86 (42), 84 (55), 77 (41), 55 (22), 51
(51), 49 (100). Anal. Calcd for C14H18ClNO: C 66.79, H 7.21,
N 5.56. Found: C 66.66, H 7.41, N 5.40.
3.2.6. trans-3-(3-Chloropropyl)-1-isopropyl-4-(4-methyl-
phenyl)azetidin-2-one 2f
Light-yellow oil. Yield 87%. Rf 0.45 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3): d 1.01 and 1.25 (2ꢁ3H, 2ꢁd,
J¼6.6 Hz, CH(CH3)2), 1.81e1.99 (4H, m, (CH2)2CH2Cl),
2.36 (3H, s, CH3), 2.88e2.93 (1H, m, CHCH2), 3.51 (2H, t,
J¼5.0 Hz, CH2Cl), 3.76 (1H, septet, J¼6.6 Hz, CHMe2),
4.21 (1H, d, J¼2.0 Hz, NCH), 7.18 and 7.25 (2ꢁ2H, 2ꢁd,
J¼8.3 Hz, C6H4). 13C NMR (68 MHz, CDCl3): d 20.4 and
21.17 (CH(CH3)2), 21.24 (CH3), 25.9 and 30.1
((CH2)2CH2Cl), 44.6 (CH2Cl), 44.8 (CHMe2), 58.7
(CHCH2), 60.1 (NCH), 126.5 and 129.6 (CHarom), 136.2 and
138.3 (2ꢁCq), 170.0 (C]O). IR (NaCl): n¼1744 cmꢂ1
(C]O). MS (70 eV): m/z (%): 279/81 (3, Mþ), 193/5 (100),
146 (15), 130 (96), 91 (14). Anal. Calcd for C16H22ClNO: C
68.68, H 7.93, N 5.01. Found: C 68.53, H 7.82, N 4.87.
3.2.3. trans-1-Benzyl-3-(3-chloropropyl)-4-phenylazetidin-
2-one 2c
Light-yellow oil. Yield 55%. Rf 0.44 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3):
d 1.75e1.98 (4H, m,
(CH2)2CH2Cl), 2.93e3.04 (1H, m, CHCH2), 3.48 (2H, t,
J¼5.0 Hz, CH2Cl), 3.64 (1H, d, J¼14.9 Hz, (HCH)N), 4.02
(1H, d, J¼2.0 Hz, NCH), 4.81 (1H, d, J¼14.9 Hz, (HCH)N),
7.10e7.40 (10H, m, C6H5). 13C NMR (68 MHz, CDCl3):
d 25.9 and 30.0 ((CH2)2CH2Cl), 44.3 (CH2N), 44.5 (CH2Cl),
59.8 (CHCH2), 60.5 (NCH), 126.5, 127.7, 128.4, 128.5,
128.8 and 129.1 (CHarom), 135.6 and 137.5 (2ꢁCq), 169.7
(C]O). IR (NaCl): n¼1750 cmꢂ1 (C]O). MS (70 eV): m/z
(%): 313/5 (0.3, Mþ), 180/2 (100), 118 (10), 117 (69), 115
(10), 91 (27). Anal. Calcd for C19H20ClNO: C 72.72, H 6.42,
N 4.46. Found: C 72.86, H 6.65, N 4.38.
3.2.7. trans-3-(3-Chloropropyl)-1-isopropyl-4-(4-methoxy-
phenyl)azetidin-2-one 2g
Light-yellow oil. Yield 66%. Rf 0.33 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3): d 1.00 and 1.24 (2ꢁ3H, 2ꢁd,
J¼6.6 Hz, CH(CH3)2), 1.82e2.00 (4H, m, (CH2)2CH2Cl),
2.86e2.91 (1H, m, CHCH2), 3.52 (2H, t, J¼5.3 Hz, CH2Cl),
3.75 (1H, septet, J¼6.6 Hz, CHMe2), 3.82 (3H, s, OCH3),
4.18 (1H, d, J¼2.0 Hz, NCH), 6.90 and 7.28 (2ꢁ2H, 2ꢁd,
J¼8.6 Hz, C6H4). 13C NMR (68 MHz, CDCl3): d 20.4 and
21.3 (CH(CH3)2), 25.9 and 30.1 ((CH2)2CH2Cl), 44.6
3.2.4. trans-3-(3-Chloropropyl)-1-(4-methoxybenzyl)-4-
phenylazetidin-2-one 2d
Light-yellow oil. Yield 70%. Rf 0.38 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3):
d 1.82e1.97 (4H, m,

4580
M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
(CH2Cl), 44.7 (CHMe2), 55.3 (OCH3), 58.7 (CHCH2), 59.7
(NCH), 114.3 and 127.7 (CHarom), 131.2 (Cq), 159.7 (Cq),
169.9 (C]O). IR (NaCl): n¼1742 cmꢂ1 (C]O). MS
(70 eV): m/z (%): 295/7 (11, Mþ), 218 (18), 210/2 (69), 176
(12), 162 (42), 147 (100), 134 (9), 117 (12), 115 (9), 91
(13). Anal. Calcd for C16H22ClNO2: C 64.97, H 7.50, N
4.74. Found: C 65.06, H 7.68, N 4.89.
Afterwards, methanol was removed in vacuo, followed by
the addition of dichloromethane (25 mL) and triethylamine
(20 mmol, 4 equiv). The resulting mixture was heated under
reflux for 4 h, after which the solvent was removed in vacuo.
Addition of diethyl ether, filtration of triethylamine hydrochlo-
ride, drying of the filtrate (MgSO4), filtration of the drying
agent and removal of the solvent in vacuo afforded the crude
methyl 1-alkyl-2-arylpiperidine-3-carboxylate 5, which was
purified by means of column chromatography on silica gel
(CH2Cl2/MeOH 95/5).
3.3. Synthesis of N-isopropyl-5-chloropentanamides 4
5-Chloropentanamides 4 were obtained upon reaction of al-
kylideneamines 3 with 5-chloropentanoyl chloride applying
the same reaction conditions as described for the synthesis
of 3-(3-chloropropyl)-b-lactams 2.
3.4.1. trans-Methyl 1-isopropyl-2-phenylpiperidine-3-
carboxylate 5a
Light-yellow oil. Yield 79%. Rf 0.20 (CH2Cl2/MeOH 95/5).
1H NMR (270 MHz, CDCl3): d 0.94 and 0.97 (2ꢁ3H, 2ꢁd,
J¼6.3 Hz, CH(CH3)2), 1.13e1.72 (4H, m, (CH2)2CH2N),
2.53 (1H, septet, J¼6.3 Hz, CH(CH3)2), 2.66e2.72 (1H, m,
CHCOOMe), 3.20e3.40 (2H, m, CH2N), 3.73 (3H, s,
OCH3), 3.85 (1H, d, J¼9.9 Hz, NCH), 7.25e7.38 (5H, m,
C6H5). 13C NMR (68 MHz, CDCl3): d 21.3 and 23.9
(CH(CH3)2), 27.2 and 30.2 ((CH2)2CH2N), 44.3 (CH2N),
45.6 (CHMe2), 51.8 (OCH3), 52.3 (CHCOOMe), 62.2
(NCH), 127.5, 127.7 and 128.7 (CHarom), 141.1 (Cq), 175.1
(C]O). IR (NaCl): n¼1738 cmꢂ1 (C]O). MS (70 eV): m/z
(%): 261 (12, Mþ), 246 (92), 218 (12), 214 (10), 184 (13),
148 (100), 146 (11), 132 (30), 121 (11), 107 (24), 106 (11),
105 (13), 91 (23), 86 (15), 84 (22), 55 (10). Anal. Calcd for
C16H23NO2: C 73.53, H 8.87, N 5.36. Found: C 73.67, H
9.03, N 5.10.
3.3.1. N-isopropyl-N-(2-Methylprop-1-enyl)-5-chloro-
pentanamide 4a
Light-yellow oil. Yield 63%. Rf 0.52 (hexane/EtOAc 3/2). 1H
NMR (270 MHz, CDCl3): d 1.04 (6H, d, J¼6.6 Hz, CH(CH3)2),
1.59 and 1.80 (6H, 2ꢁd, J¼1.3 Hz, C(CH3)2), 1.70e1.84 (4H,
m, (CH2)2CH2Cl), 2.19 (2H, t, J¼6.9 Hz, CH2CO), 3.53 (2H, t,
J¼6.3 Hz, CH2Cl), 4.82 (1H, septet, J¼6.6 Hz, CHMe2), 5.71
(1H, septet, J¼1.3 Hz, C]CH). 13C NMR (68 MHz, CDCl3):
d 17.9 and 22.0 (C(CH3)2), 19.8 (CH(CH3)2), 22.5 and 32.2
((CH2)2CH2Cl), 33.3 (CH2CO), 44.8 (CH2Cl), 45.6 (CHMe2),
119.28 (C]CH), 138.3 (C]CH), 172.1 (C]O). IR (NaCl):
n¼1736, 1647 cmꢂ1. MS (70 eV): m/z (%): 231/3 (19, Mþ),
216/8 (64, MþꢂCH3), 174/6 (10), 113 (57), 98 (100), 91
(15), 70 (10), 55 (37). Anal. Calcd for C12H22ClNO: C 62.19,
H 9.57, N 6.04. Found: C 62.42, H 9.76, N 5.91.
3.4.2. trans-Methyl 1-benzyl-2-phenylpiperidine-3-
carboxylate 5b
3.3.2. N-Cyclohexylidenemethyl-N-isopropyl-5-chloro-
pentanamide 4b
Light-yellow oil. Yield 93%. Rf 0.83 (CH2Cl2/MeOH 95/5).
1H NMR (270 MHz, CDCl3): d 1.22e1.35 and 1.49e1.65 (4H,
2ꢁm, (CH2)2CH2N), 2.65e2.73 (1H, m, CHCOOMe), 3.32e
3.37 (2H, m, CH2N), 3.42 and 3.63 (2ꢁ1H, 2ꢁd, J¼13.0 Hz,
N(HCH)C6H5), 3.72 (3H, s, OCH3), 3.74 (1H, d, J¼8.0 Hz,
NCH), 7.16e7.40 (10H, m, 2ꢁC6H5). 13C NMR (68 MHz,
CDCl3): d 27.2 and 30.3 ((CH2)2CH2N), 44.2 (CH2N), 50.7
(NCH2C6H5), 51.7 (OCH3), 52.4 (CHCOOMe), 63.9 (NCH),
127.6, 127.8, 128.2, and 128.8 (CHarom), 139.7 and 140.5
(2ꢁCq), 175.0 (C]O). IR (NaCl): n¼1736 cmꢂ1 (C]O). MS
(70 eV): m/z (%): 309 (16, Mþ), 262 (11), 247 (100), 239
(19), 235 (11), 232 (12), 218 (40), 214 (12), 194 (21), 184
(19), 174 (13), 146 (11), 138 (16), 132 (20), 115 (13), 111
(15), 106 (15), 104 (15), 97 (38), 91 (64), 82 (18), 79 (14), 77
(13), 65 (16), 57 (78), 55 (18). Anal. Calcd for C20H23NO2: C
77.64, H 7.49, N 4.53. Found: C 77.79, H 7.72, N 4.61.
Light-yellow oil. Yield 88%. Rf 0.49 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3): d 1.05 (6H, d, J¼6.9 Hz,
CH(CH3)2), 1.70e2.24 (16H, m, (CH2)5, (CH2)2CH2Cl and
CH2CO), 3.53 (2H, t, J¼6.3 Hz, CH2Cl), 4.82 (1H, septet,
J¼6.9 Hz, CHMe2), 5.67 (1H, s, C]CH). 13C NMR
(68 MHz, CDCl3): d 19.9 (CH(CH3)2), 22.6, 26.4, 26.6, 28.0,
28.2, 32.3, 33.3 and 33.4 ((CH2)5, (CH2)2CH2Cl and CH2CO),
44.8 (CH2Cl), 45.3 (CHMe2), 116.0 (C]CH), 145.1
(C]CH), 172.1 (C]O). IR (NaCl): n¼1735, 1646 cmꢂ1
.
MS (70 eV): m/z (%): no Mþ, 270/2 (27), 236 (9, MþꢂCl),
227/9 (33), 179 (13), 152 (37), 151 (39), 137 (67), 119 (10),
118 (9), 111 (12), 110 (72), 95 (11), 93 (17), 91 (24), 82
(14), 67 (14), 55 (63). Anal. Calcd for C15H26ClNO: C
66.28, H 9.64, N 5.15. Found: C 66.37, H 9.80, N 5.02.
3.4. Synthesis of trans-methyl 1-alkyl-2-arylpiperidine-3-
carboxylates 5aed
3.4.3. trans-Methyl 1-isopropyl-2-(4-methylphenyl)-
piperidine-3-carboxylate 5c
General procedure: Gaseous hydrochloric acid, generated
by adding sulfuric acid dropwise to a mixture of sodium chlo-
ride and hydrochloric acid (CAUTION), was bubbled through
Light-yellow oil. Yield 89%. Rf 0.53 (CH2Cl2/MeOH 95/5).
1H NMR (270 MHz, CDCl3): d 0.91 and 0.94 (2ꢁ3H, 2ꢁd,
J¼6.3 Hz, CH(CH3)2), 1.21e1.69 (4H, m, (CH2)2CH2N),
2.34 (3H, s, CCH3), 2.50 (1H, septet, J¼6.3 Hz, CH(CH3)2),
2.60e2.66 (1H, m, CHCOOMe), 3.33e3.40 (2H, m, CH2N),
a
solution of 3-(3-chloropropyl)-b-lactam
2 (5 mmol)
in methanol (15 mL) at 0 ꢀC for 1 h, followed by a resting
period of 24 h at room temperature in a closed vessel.

M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
4581
3.73 (3H, s, OCH3), 3.78 (1H, d, J¼9.9 Hz, NCH), 7.12 and
7.15 (2ꢁ2H, 2ꢁd, J¼8.0 Hz, C6H4). 13C NMR (68 MHz,
CDCl3): d 21.4 (CCH3), 21.7 and 24.3 (CH(CH3)2), 27.5 and
30.6 ((CH2)2CH2N), 44.5 (CH2N), 45.6 (CHMe2), 51.8
(OCH3), 53.0 (CHCOOMe), 62.1 (NCH), 127.6 and 129.6
(CHarom), 137.3 and 138.5 (2ꢁCq), 175.4 (C]O). IR
(NaCl): n¼1736 cmꢂ1 (C]O). MS (70 eV): m/z (%): 275
(7, Mþ), 260 (37), 162 (34), 119 (14), 115 (13), 103 (15),
91 (10), 86 (66), 84 (100), 83 (13), 73 (18), 59 (75), 56
(18), 55 (21), 51 (16), 49 (47). Anal. Calcd for C17H25NO2:
C 74.14, H 9.15, N 5.09. Found: C 73.98, H 9.37, N 4.91.
(%): no Mþ, 205 (100), 164 (39), 121 (26), 91 (9). Anal. Calcd
for C15H19NO4: C 64.97, H 6.91, N 5.05. Found: C 65.12, H
7.15, N 4.92.
3.5.1.2. trans-Methyl 1-ethoxycarbonyl-2-phenylpiperidine-3-
carboxylate 6b. Colourless crystals. Mp 97.5e98.1 ꢀC. Yield
50%. Recrystallized from methanol. 1H NMR (270 MHz,
CDCl3): d 1.21e1.78 (4H, m, (CH2)2CH2N), 1.76 (3H, t,
J¼6.0 Hz, OCH2CH3), 3.44 (2H, t, J¼6.3 Hz, CH2N), 3.45e
3.58 (1H, m, CHCOOMe), 3.65 (3H, s, OCH3), 4.12 (2H, m,
OCH2CH3), 5.16 (1H, d, J¼11.0 Hz, NCH), 7.21e7.42 (5H,
m, C6H5). 13C NMR (68 MHz, CDCl3): d 14.5 (OCH2CH3),
27.7 and 30.1 ((CH2)2CH2N), 44.0 (CH2N), 46.5
(CHCOOMe), 49.3 (OCH2CH3), 51.8 (OCH3), 62.9 (NCH),
127.9, 128.6 and 128.9 (CHarom), 138.0 (Cq), 156.2 (C]O),
174.0 (C]O). IR (NaCl): n¼1732, 1682 cmꢂ1 (2ꢁC]O).
MS (70 eV): m/z (%): no Mþ, 219 (12), 194 (13), 132 (14),
131 (24), 121 (14), 119 (21), 115 (24), 114 (12), 106 (16),
91 (29), 88 (13), 87 (21), 86 (67), 84 (100), 83 (10), 82
(10), 74 (9), 73 (9), 59 (15), 55 (36), 51 (10), 49 (29). Anal.
Calcd for C16H21NO4: C 65.96, H 7.27, N 4.81. Found: C
65.78, H 7.40, N 4.95.
3.4.4. trans-Methyl 1-isopropyl-2-(4-methoxyphenyl)-
piperidine-3-carboxylate 5d
Light-yellow oil. Yield 82%. Rf 0.36 (CH2Cl2/MeOH 95/5).
1H NMR (270 MHz, CDCl3): d 0.88 and 0.92 (2ꢁ3H, 2ꢁd,
J¼6.3 Hz, CH(CH3)2), 1.22e1.64 (4H, m, (CH2)2CH2N),
2.50 (1H, septet, J¼6.3 Hz, CH(CH3)2), 2.45e2.60 (1H, m,
CHCOOMe), 3.35e3.42 (2H, m, CH2N), 3.72 (3H, s,
OCH3), 3.75 (1H, d, J¼9.9 Hz, NCH), 3.79 (3H, s, OCH3),
6.87 and 7.13 (2ꢁ2H, 2ꢁd, J¼8.6 Hz, C6H4). 13C NMR
(68 MHz, CDCl3): d 21.6 and 24.2 (CH(CH3)2), 27.2 and
30.4 ((CH2)2CH2N), 44.3 (CH2N), 45.2 (CHMe2), 51.5
(OCH3), 53.1 (CHCOOMe), 55.2 (OCH3), 61.6 (NCH),
123.9 and 128.3 (CHarom), 133.8 (Cq), 158.9 (Cq), 175.2
(C]O). IR (NaCl): n¼1732 cmꢂ1 (C]O). MS (70 eV): m/z
(%): 291 (7, Mþ), 276 (20), 211 (10), 204 (29), 178 (100),
176 (17), 162 (25), 151 (14), 136 (33), 134 (17), 124 (13),
121 (21), 84 (17). Anal. Calcd for C17H25NO3: C 70.07, H
8.65, N 4.81. Found: C 70.21, H 8.82, N 4.95.
3.5.2. Synthesis of 2-phenylpiperidine-1,3-dicarboxylate 6c
trans-1-Benzyl-3-(3-chloropropyl)-4-phenylazetidin-2-one
2c (2.00 g, 6.4 mmol) was hydrolyzed by means of gaseous
hydrochloric acid in methanol according to the procedure de-
scribed for the synthesis of 2-arylpiperidine-3-carboxylates 5.
After evaporation of methanol and residual hydrochloric acid,
ethyl acetate (30 mL) was added from which the obtained am-
monium salt precipitated. After filtration and additional drying
under reduced pressure, the intermediate hydrochloride salt
was used in a catalytic hydrogenolysis protocol. Thus, 10
weight% of palladium on carbon (10%) was added to a 10%
solution of the substrate in absolute methanol, and the resulting
mixture was stirred for 15 h in a Parr apparatus under pressure
(5 bar of hydrogen gas). After filtration over CeliteÒ and evap-
oration of the solvent, sodium hydroxide (30 mL, 1 M) was
added. The aqueous phase was extracted with dichloromethane
(3ꢁ30 mL), and the combined organic layers were dried (mag-
nesium sulfate). The residue obtained after filtration and evap-
oration of the solvent was dissolved in acetonitrile (20 mL).
Addition of di-tert-butyl dicarbonate (1.39 g, 6.4 mmol), stir-
ring of the reaction mixture for 2 h at room temperature and
removal of the solvent in vacuo furnished 2-phenylpiperidine-
1,3-dicarboxylate 6c, which was purified by means of column
chromatography on silica gel (hexane/EtOAc 3/2) and recrys-
tallization from ethanol.
3.5. Synthesis of piperidine-1,3-dicarboxylates 6aec
Two different approaches were used for the synthesis of
piperidine-1,3-dicarboxylates 6.
3.5.1. Synthesis of piperidine-1,3-dicarboxylates 6aeb
General procedure: To a refluxing solution of 2-phenyl-3-
piperidinecarboxylate 5 (3.2 mmol) in benzene (10 mL) was
added slowly a solution of alkyl chloroformate (32.4 mmol)
in benzene (5 mL). This mixture was refluxed overnight (15 h)
and the solvent was evaporated in vacuo, affording the corre-
sponding 2-phenylpiperidine-l,3-dicarboxylate 6. Piperidine 6
was purified by means of column chromatography on silica gel
(hexane/EtOAc 3/2) or by recrystallization from methanol.
3.5.1.1. trans-Methyl 1-methoxycarbonyl-2-phenylpiperidine-3-
carboxylate 6a. Light-yellow oil. Yield 56%. Rf 0.58 (hexane/
1
EtOAc 3/2). H NMR (270 MHz, CDCl3): d 1.51e1.62 and
1.64e1.79 (4H, 2ꢁm, (CH2)2CH2N), 3.45 (2H, t, J¼6.3 Hz,
CH2N), 3.50e3.59 (1H, m, CHCOOMe), 3.73 (6H, s,
2ꢁOCH3), 5.32 (1H, d, J¼11.0 Hz, NCH), 7.30e7.39 (5H,
m, C6H5). 13C NMR (68 MHz, CDCl3): d 27.8 and 30.2
((CH2)2CH2N), 44.1 (CH2N), 48.1 (CHCOOMe), 51.7 and
52.1 (2ꢁOCH3), 61.8 (NCH), 128.0, 128.6 and 128.7
(CHarom), 138.0 (Cq), 157.3 (C]O), 174.2 (C]O). IR
(NaCl): n¼1735, 1694 cmꢂ1 (2ꢁC]O). MS (70 eV): m/z
3.5.2.1. trans-Methyl 1-tert-butoxycarbonyl-2-phenylpiperidine-
3-carboxylate 6c. Colourless crystals. Mp 111.4e111.7 ꢀC.
Yield 64%. Column chromatography, Rf 0.65 (hexane/EtOAc
1
3/2) and recrystallization from ethanol. H NMR (270 MHz,
CDCl3): d 1.24e1.43 and 1.61e1.91 (4H, 2ꢁm, (CH2)2CH2N),
1.43 (9H, s, C(CH3)3), 2.82e2.84 (1H, m, CHCOOMe), 3.52
(2H, m, CH2N), 3.55 (3H, s, OCH3), 4.93e4.95 (1H, m,
NCH), 7.20e7.35 (5H, m, C6H5). 13C NMR (68 MHz, CDCl3):

4582
M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
d 27.6 and 30.3 ((CH2)2CH2N), 28.3 (C(CH3)3), 44.3 (CH2N),
50.6 (CHCOOMe), 51.8 (OCH3), 55.1 (NCH), 79.6 (C(CH3)3),
126.0, 127.5 and 128.6 (CHarom), 140.8 (Cq), 155.4 (C]O),
174.6 (C]O). IR (NaCl): n¼1737, 1690 cmꢂ1 (2ꢁC]O).
MS (70 eV): m/z (%): no Mþ, 304 (28, MþꢂOMe), 276 (12),
256 (44), 239 (100), 121 (98). Anal. Calcd for C16H21NO4: C
67.69, H 7.89, N 4.39. Found: C 67.53, H 8.13, N 4.17.
(43), 222 (34), 218 (100), 194 (43), 149 (15), 105 (13), 91
(47), 57 (9). Anal. Calcd for C20H23NO2: C 77.64, H 7.49,
N 4.53. Found: C 77.83, H 7.67, N 4.36.
3.6.3. cis-Methyl 1-isopropyl-2-(4-methylphenyl)-
piperidine-3-carboxylate 7c
Light-yellow oil. Yield 56%. Rf 0.18 (CH2Cl2/MeOH 95/5).
1H NMR (270 MHz, CDCl3): d 0.82 and 0.97 (2ꢁ3H, 2ꢁd,
J¼6.6 Hz, CH(CH3)2), 1.56e1.70 and 1.97e2.17 (4H, 2ꢁm,
(CH2)2CH2N), 2.31 (3H, s, CCH3), 2.41e2.50 (1H, m,
(HCH)N), 2.84e3.02 (3H, m, CH(CH3)2, (HCH)N,
CHCOOMe), 3.67 (3H, s, OCH3), 3.97 (1H, d, J¼5.3 Hz,
NCH), 7.07 and 7.20 (2ꢁ2H, 2ꢁd, J¼8.0 Hz, C6H4). 13C
NMR (68 MHz, CDCl3): d 15.6 and 21.1 (CH(CH3)2), 20.9
(CCH3), 22.8 and 24.2 ((CH2)2CH2N), 42.6 (CH2N), 46.6
(CHCOOMe), 49.8 (CHMe2), 50.9 (OCH3), 64.0 (NCH),
128.6 and 128.7 (CHarom), 136.5 and 138.3 (2ꢁCq), 173.9
(C]O). IR (NaCl): n¼1739 cmꢂ1 (C]O). MS (70 eV): m/z
(%): 275 (23, Mþ), 260 (100), 232 (14), 228 (15), 188 (11),
184 (15), 160 (11), 146 (14). Anal. Calcd for C17H25NO2: C
74.14, H 9.15, N 5.09. Found: C 74.36, H 9.30, N 4.87.
3.6. Synthesis of cis-methyl 1-alkyl-2-arylpiperidine-3-
carboxylates 7aed
The synthesis of cis-methyl 1-isopropyl-2-phenylpiperi-
dine-3-carboxylate 7a is described as a representative example.
To a stirred solution of trans-methyl 1-isopropyl-2-phenyl-
piperidine-3-carboxylate 5a (1.00 g, 3.8 mmol) in methanol
(5 mL) at room temperature, hydrazine monohydrate (1.92 g,
38.4 mmol) was added and the resulting mixture was kept at
reflux temperature for 4 h. Subsequently, methanol was evap-
orated in vacuo and the residue was dissolved in dichlorome-
thane (15 mL) and dried (magnesium sulfate). After filtration
and evaporation of the solvent, the crude cis-methyl 1-iso-
propyl-2-phenylpiperidine-3-carboxylate 7a was obtained,
which was purified by column chromatography on silica gel
(CH2Cl2/MeOH 95/5).
3.6.4. cis-Methyl 1-isopropyl-2-(4-methoxyphenyl)-
piperidine-3-carboxylate 7d
Light-yellow oil. Yield 78%. Rf 0.28 (CH2Cl2/MeOH 95/
1
3.6.1. cis-Methyl 1-isopropyl-2-phenylpiperidine-3-
carboxylate 7a
5). H NMR (270 MHz, CDCl3): d 0.82 and 0.96 (2ꢁ3H,
2ꢁd, J¼6.3 Hz, CH(CH3)2), 1.54e1.75 and 1.95e2.16 (4H,
2ꢁm, (CH2)2CH2N), 2.41e2.50 (1H, m, (HCH)N), 2.83e
3.01 (3H, m, CH(CH3)2, (HCH)N, CHCOOMe), 3.37 (3H,
s, OCH3), 3.78 (3H, s, OCH3), 3.98 (1H, d, J¼5.0 Hz,
NCH), 6.80 and 7.24 (2ꢁ2H, 2ꢁd, J¼8.6 Hz, C6H4). 13C
NMR (68 MHz, CDCl3): d 15.7 and 20.8 (CH(CH3)2), 22.8
and 24.0 ((CH2)2CH2N), 42.5 (CH2N), 46.7 (CHCOOMe),
49.8 (CHMe2), 50.9 (OCH3), 55.1 (OCH3), 63.5 (NCH),
113.3 and 129.8 (CHarom), 133.3 (Cq), 158.5 (Cq), 173.8
(C]O). IR (NaCl): n¼1736 cmꢂ1 (C]O). MS (70 eV): m/z
(%): 291 (38, Mþ), 276 (100), 248 (25), 244 (31), 204 (29),
190 (11), 184 (14), 176 (37), 162 (35), 148 (10), 134 (16),
121 (25), 115 (9), 91 (11). Anal. Calcd for C17H25NO3: C
70.07, H 8.65, N 4.81. Found: C 70.29, H 8.91, N 4.66.
Light-yellow oil. Yield 67%. Rf 0.26 (CH2Cl2/MeOH 95/5).
1H NMR (270 MHz, CDCl3): d 0.81 and 0.97 (2ꢁ3H, 2ꢁd,
J¼6.6 Hz, CH(CH3)2), 1.57e1.73 and 1.97e2.19 (4H, 2ꢁm,
(CH2)2CH2N), 2.39e2.48 (1H, m, (HCH)N), 2.85e3.03 (3H,
m, CH(CH3)2, (HCH)N, CHCOOMe), 3.32 (3H, s, OCH3),
3.97 (1H, d, J¼5.0 Hz, NCH), 7.19e7.34 (5H, m, C6H5).
13C NMR (68 MHz, CDCl3): d 15.2 and 20.9 (CH(CH3)2),
22.6 and 24.4 ((CH2)2CH2N), 42.6 (CH2N), 46.6
(CHCOOMe), 49.7 (CHMe2), 50.8 (OCH3), 64.5 (NCH),
127.0, 128.0 and 128.6 (CHarom), 141.5 (Cq), 173.7 (C]O).
IR (NaCl): n¼1740 cmꢂ1 (C]O). MS (70 eV): m/z (%): 261
(15, Mþ), 246 (100), 218 (12), 214 (8), 184 (15), 174 (11),
132 (17), 106 (11), 91 (12), 86 (13), 84 (19), 49 (13). Anal.
Calcd for C16H23NO2: C 73.53, H 8.87, N 5.36. Found: C
73.75, H 9.08, N 5.22.
3.6.5. trans-3-(3-Chloropropyl)-4-phenylazetidin-2-one 8
A solution of potassium hydrogenphosphate (13.16 g,
75.6 mmol) and potassium peroxodisulfate (40.84 g,
151.1 mmol) in water (240 mL) was added in four portions
to a solution of trans-3-(3-chloropropyl)-1-(4-methoxyben-
zyl)-4-phenylazetidin-2-one 2d (7.63 g, 22.2 mmol) in water/
acetonitrile (1/2, 715 mL). The solution was kept at reflux
for 1 h, and was subsequently concentrated at reduced pressure
and extracted with ethyl acetate (3ꢁ150 mL). The organic
layers were washed with saturated sodium bicarbonate
(500 mL) and brine (500 mL), and the aqueous layers were
extracted with ethyl acetate (200 mL). Drying of the combined
organic layers (magnesium sulfate), filtration and evaporation
of the solvent yielded crude trans-3-(3-chloropropyl)-4-phe-
nylazetidin-2-one 8, which was purified by column chroma-
tography on silica gel (hexane/EtOAc 3/2).
3.6.2. cis-Methyl 1-benzyl-2-phenylpiperidine-3-carb-
oxylate 7b
Light-yellow oil. Yield 70%. Rf 0.80 (CH2Cl2/MeOH 95/5).
1H NMR (270 MHz, CDCl3): d 1.50e1.77 and 2.01e2.17
(4H, 2ꢁm, (CH2)2CH2N), 2.17e2.20 (1H, m, (HCH)N),
2.91e2.97 (1H, m, CHCOOMe), 2.95e3.02 (1H, m,
(HCH)N), 3.10 and 3.72 (2ꢁ1H, 2ꢁd, J¼13.9 Hz,
N(HCH)C6H5), 3.34 (3H, s, OCH3), 3.74 (1H, d, J¼5.0 Hz,
NCH), 7.18e7.39 (10H, m, 2ꢁC6H5). 13C NMR (68 MHz,
CDCl3): d 22.1 and 25.1 ((CH2)2CH2N), 46.5 (CHCOOMe),
50.5 (CH2N), 50.8 (OCH3), 59.3 (NCH2C6H5), 66.8 (NCH),
126.6, 127.2, 128.0, 128.36 and 128.43 (CHarom), 139.1 and
140.6 (2ꢁCq), 173.4 (C]O). IR (NaCl): n¼1738 cmꢂ1
(C]O). MS (70 eV): m/z (%): 309 (32, Mþ), 308 (28), 232

M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
4583
Light-yellow oil. Yield 70%. Rf 0.28 (hexane/EtOAc 3/2).
1H NMR (270 MHz, CDCl3):
1.86e2.05 (4H, m,
the solvent was removed in vacuo and the residue was dis-
solved in dichloromethane (60 mL), to which trifluoroacetic
acid (31.60 g, 277.1 mmol) was added. This solution was
stirred at room temperature for 1 h and was subsequently
cooled to 0 ꢀC, followed by the addition of a sodium hydr-
oxide solution (2 M) until pH 10. The organic layer was re-
moved and the remaining aqueous layer was extracted with
dichloromethane (2ꢁ30 mL). The combined organic layers
were dried (magnesium sulfate), and after filtration and evap-
oration the crude reaction product was obtained. The latter
was dissolved in dichloromethane (50 mL), to which di-tert-
butyl dicarbonate (5.47 g, 25.0 mmol), triethylamine (1.69 g,
16.7 mmol) and one crystal of DMAP were added subse-
quently. The resulting solution was stirred for 4 h at room tem-
perature, and workup proceeded as described before for the
synthesis of b-lactam 9, affording piperidine 10 in 75% yield
after purification by column chromatography on silica gel
(hexane/EtOAc 3/2).
d
(CH2)2CH2Cl), 2.98e3.04 (1H, m, CHCH2), 3.55 (2H, t,
J¼6.0 Hz, CH2Cl), 4.40 (1H, d, J¼2.3 Hz, NCH), 6.63 (1H,
br s, NH), 7.27e7.41 (5H, m, C6H5). 13C NMR (68 MHz,
CDCl3): d 26.0 and 30.0 ((CH2)2CH2Cl), 44.6 (CH2Cl), 57.5
(CHCH2), 60.8 (NCH), 125.6, 128.2 and 128.9 (CHarom),
139.8 (Cq), 171.1 (C]O). IR (NaCl): n¼1751 cmꢂ1 (C]O).
MS (70 eV): m/z (%): 223/5 (9, Mþ), 182 (27), 180 (83),
160 (13), 132 (13), 129 (10), 117 (100), 116 (12), 115 (34),
106 (63), 105 (18), 104 (30), 91 (27), 77 (21), 55 (24), 51
(11). Anal. Calcd for C12H14ClNO: C 64.43, H 6.31, N 6.26.
Found: C 64.30, H 6.54, N 6.38.
3.6.6. trans-1-tert-Butoxycarbonyl-3-(3-chloropropyl)-4-
phenylazetidin-2-one 9
To a solution of trans-3-(3-chloropropyl)-4-phenylazeti-
din-2-one
8 (4.96 g, 22.2 mmol) in dichloromethane
(200 mL) was added di-tert-butyl dicarbonate (9.69 g,
44.4 mmol), triethylamine (2.25 g, 22.2 mmol) and 4-(N,N-
dimethylamino)pyridine (1 mmol). The resulting reaction
mixture was then stirred for 4 h at room temperature. After-
wards, diethyl ether (150 mL) was added and the resulting
solution was successively washed with brine (150 mL), sat-
urated ammonium chloride (75 mL) and again brine
(150 mL). The organic layer was dried (magnesium sulfate),
the drying agent removed by filtration and the solvent was
removed in vacuo. Further purification was performed by
means of column chromatography on silica gel (hexane/
EtOAc 3/2).
Light-yellow oil. Yield 75%. Rf 0.28 (hexane/EtOAc 3/2). 1H
NMR (270 MHz, CDCl3): d 1.42 (9H, s, C(CH3)3), 1.64e2.05
(4H, m, (CH2)2CH2N), 2.40e2.44 (1H, m, CHCON), 3.55
(2H, t, J¼5.9 Hz, CH2N), 3.77 (3H, s, OCH3), 4.05 (1H,
dꢁd, J¼14.5, 4.6 Hz, N(HCH)Ar), 4.19 (1H, dꢁd, J¼14.5,
5.9 Hz, N(HCH)Ar), 4.88 (1H, d, J¼8.1 Hz, NCH), 5.30e
5.40 (1H, br s, NH), 6.95e7.30 (9H, m, CHarom). 13C NMR
(68 MHz, CDCl3): d 28.2 and 30.4 ((CH2)2CH2N), 28.4
(C(CH3)3), 42.7 (CH2NH), 44.6 (CH2N), 52.0 (CHCON), 55.3
(OCH3), 55.7 (NCH), 79.3 (C(CH3)3), 113.9, 125.8, 127.2,
128.6 and 128.8 (CHarom), 129.4 and 141.6 (2ꢁCq), 155.8
(Cq), 158.8 (C]O), 173.1 (C]O). IR (NaCl): n¼1682,
1647 cmꢂ1 (2ꢁC]O). MS (70 eV): m/z (%): no Mþ, 124
(100), 96 (9), 84 (11). Anal. Calcd for C25H32N2O4: C 70.73,
H 7.60, N 6.60. Found: C 70.58, H 7.84, N 6.77.
Light-yellow oil. Yield 75%. Rf 0.62 (hexane/EtOAc 3/
1
2). H NMR (270 MHz, CDCl3): d 1.36 (9H, s, C(CH3)3),
1.91e2.05 (4H, m, (CH2)2CH2Cl), 3.05e3.06 (1H, m,
CHCH2), 3.53 (2H, t, J¼5.9 Hz, CH2Cl), 4.60 (1H, d,
J¼3.0 Hz, NCH), 7.32e7.40 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 25.8 and 29.9 ((CH2)2CH2Cl), 27.8
(C(CH3)3), 44.3 (CH2Cl), 58.8 (CHCH2), 60.7 (NCH),
83.2 (C(CH3)3), 125.8, 128.5 and 128.9 (CHarom), 137.9
(Cq), 147.4 (C]O), 167.6 (C]O). IR (NaCl): n¼1805,
1721 cmꢂ1 (2ꢁC]O). MS (70 eV): m/z (%): no Mþ,
182 (39), 180 (100), 132 (39), 118 (12), 117 (76), 115
(14), 91 (13), 77 (9), 57 (30). Anal. Calcd for
C17H22ClNO3: C 63.06, H 6.85, N 4.33. Found: C 63.24,
H 7.07, N 4.49.
Acknowledgements
The authors are indebted to the ‘Fund for Scientific Re-
searchdFlanders (Belgium)’ (F.W.O.dVlaanderen) and to
Ghent University (GOA) for financial support.
References and notes
1. Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 377.
2. (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383; (b) Fisher, J. F.; Meroueh,
S. O.; Mobashery, S. Chem. Rev. 2005, 105, 395; (c) Alcaide, B.;
Almendros, P. Synlett 2002, 381; (d) Singh, G. S. Tetrahedron 2003, 59,
7631; (e) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc.
Chem. Res. 2004, 37, 592; (f) Alcaide, B.; Almendros, P.; Aragoncillo,
C. Chem. Rev. 2007, 107, 4437.
3.6.7. trans-tert-Butyl 3-{[(4-methoxybenzyl)amino]-
carbonyl}-2-phenylpiperidine-1-carboxylate 10
The conversion of trans-1-(tert-butoxycarbonyl)-3-(3-
chloropropyl)-4-phenylazetidin-2-one 9 into trans-tert-butyl
3-{[(4-methoxybenzyl)amino]carbonyl}-2-phenylpiperidine-
1-carboxylate 10 was performed in one pot through a sequence
of different reaction steps.
To a solution of trans-1-(tert-butoxycarbonyl)-3-(3-chloro-
propyl)-4-phenylazetidin-2-one 9 (5.40 g, 16.7 mmol) in di-
chloromethane (30 mL) was added 4-methoxybenzylamine
(4.57 g, 33.4 mmol), after which the resulting reaction mixture
was kept under gentle reflux overnight (16 h). Subsequently,
3. (a) Begley, M. J.; Crombie, L.; Haigh, D.; Jones, R. C. F.; Osborne, S.;
Webster, R. A. B. J. Chem. Soc., Perkin Trans. 1 1993, 2027; (b) Crombie,
L.; Jones, R. C. F.; Osborne, S.; Mat-Zin, A. R. J. Chem. Soc., Chem.
Commun. 1983, 959; (c) Van Brabandt, W.; Vanwalleghem, M.;
D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2006, 71, 7083.
4. (a) Leemans, E.; D’hooghe, M.; Dejaegher, Y.; Tornroos, K. W.; De Kimpe,
¨
N. J. Org. Chem. 2008, 73, 1422; (b) Van Brabandt, W.; Van Landeghem,
R.; De Kimpe, N. Org. Lett. 2006, 8, 1105; (c) Van Brabandt, W.;
Dejaegher, Y.; Van Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8,

4584
M. D’hooghe et al. / Tetrahedron 64 (2008) 4575e4584
1101; (d) Lee, E.; Kim, S. K.; Kim, J. Y.; Lim, J. Tetrahedron Lett. 2000,
41, 5915.
12. Van Driessche, B.; Van Brabandt, W.; D’hooghe, M.; Dejaegher, Y.;
De Kimpe, N. Tetrahedron 2006, 62, 6882.
13. Pedersen, C. M.; Bols, M. Tetrahedron 2005, 61, 115.
5. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Snider, R. M.
J. Med. Chem. 1992, 35, 4911.
14. Gyonfalvi, S.; Szakonyi, Z.; Fulop, F. Tetrahedron: Asymmetry 2003, 14,
3965.
¨ ¨
6. (a) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545; (b) Calvez, O.; Langlois, N. Tetrahedron Lett.
1999, 40, 7099; (c) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett.
1999, 40, 5071; (d) Rupniak, N. M. J. Neurotransmissions 1999, 15, 3.
7. Sutton, J. C.; Bolton, S. A.; Hartl, K. S.; Huang, M.-H.; Jacobs, G.; Meng,
W.; Ogletree, M. L.; Pi, Z.; Schumacher, W. A.; Seiler, S. M.; Slusarchyk,
W. A.; Treuner, U.; Zahler, R.; Zhao, G.; Bisacchi, G. S. Bioorg. Med.
Chem. Lett. 2002, 12, 3229.
15. For a few recent examples, see: (a) Alcaide, B.; Almendros, P.; Cabrero,
G.; Ruiz, M. P. J. Org. Chem. 2007, 72, 7980; (b) De Vitis, L.; Troisi, L.;
Granito, C.; Pindinelli, E.; Ronzini, L. Eur. J. Org. Chem. 2007, 356; (c)
Mishra, R. K.; Coates, C. M.; Revell, K. D.; Turos, E. Org. Lett. 2007, 9,
575.
16. Cavagna, F.; Linkies, A.; Pietsch, H.; Reuschling, D. Angew. Chem. 1980,
92, 126.
8. De Risi, C.; Fanton, G.; Pollini, G. P.; Trapella, C.; Valente, F.; Zanirato,
V. Tetrahedron: Asymmetry 2008, 19, 131.
17. (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18,
4171; (b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989.
9. Hannam, J. C.; Kulagowski, J. J.; Madin, A.; Ridgill, M. P.; Seward, E. M.
PCT Int. Appl. 2006, WO 2006043064 A1; Chem. Abstr. 2006, 144,
432693.
18. Jean, L.; Baglin, I.; Rouden, J.; Maddaluno, J.; Lasne, M.-C. Tetrahedron
Lett. 2001, 42, 5645.
10. Tanaka, R.; Rubio, A.; Harn, N. K.; Gernert, D.; Grese, T. A.; Eishima, J.;
Hara, M.; Yoda, N.; Ohashi, R.; Kuwabara, T.; Soga, S.; Akinaga, S.;
Nara, S.; Kanda, Y. Bioorg. Med. Chem. 2007, 15, 1363.
11. (a) Barrow, K. D.; Spotswood, T. M. Tetrahedron Lett. 1965, 6, 3325;
(b) Decazes, J.; Luche, J. L.; Kagan, H. B. Tetrahedron Lett. 1970,
11, 3365.
19. Lapuyade, G.; Schlewer, G.; Wermuth, C. G. Bull. Soc. Chim. Fr. 1986,
663.
20. Schmidt, E. W. Hydrazine and its Derivatives: Preparation, Properties,
Applications; Wiley-Interscience: New York, NY, 1984.
21. Allen, M. P.; Blake, J. F.; Bryce, D. K.; Haggan, M. E.; Liras, S.; McLean,
S.; Segelstein, B. E. Bioorg. Med. Chem. Lett. 2000, 10, 523.