A mild and efficient procedure for ring-opening reactions of piperidine and pyrrolidine derivatives by single electron transfer photooxidation

Article abstract of DOI:10.1016/S0040-4020(00)00048-X

Various N-arylamino-1-pyrrolidines and N-arylamino-1-piperidines are selectively converted into the corresponding acyclic aminoaldehydes or amino- dialkylacetals under mild photooxidation conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00048-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2975±2984
A Mild and Ef®cient Procedure for Ring-Opening Reactions of
Piperidine and Pyrrolidine Derivatives by Single Electron
Transfer Photooxidation
*
Guillaume Cocquet, Clotilde Ferroud and Alain Guy
 Â
Laboratoire de Chimie Organique associe au CNRS, Conservatoire National des Arts et Metiers, 292, rue Saint Martin,
F-75141 Paris Cedex 03, France
Received 13 September 1999; accepted 13 January 2000
AbstractÐVarious N-arylamino-1-pyrrolidines and N-arylamino-1-piperidines are selectively converted into the corresponding acyclic
aminoaldehydes or amino-dialkylacetals under mild photooxidation conditions. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
have described a one-step ring-opening reaction of N-aryl-
1,2,3,4-tetrahydroisoquinoline and 2,3,4,5-tetrahydro-1H-2-
benzazepine derivatives when heated (1008C) in presence of
DMSO and O2 or NBS. Weinreb and others10±12 have
developed a process involving a cuprous ion-promoted
oxidation of o-aminobenzamides into a-methoxybenzamides
via N-acyliminium ion intermediates. It has been shown that
treatment of various o-aminobenzamides with sodium
nitrite and dry HCl in methanol containing 5% cuprous
chloride leads to oxidation products in good yields. In the
case of pyrrolidine-derived systems, ring-opening of
a-methoxybenzamide tends to occur only if extended
reaction times are used. However, mixtures of oxidation
products have been obtained and further studies are needed
in order to fully understand the mechanistic origin of the
selectivity observed.
During the course of our work on the reactivity of hetero-
cyclic nitrogen compounds to photooxidation by single
electron transfer, we have already reported the high regio-
and stereoselectivity observed during such oxidations.1±4
For example, we recently described the photooxidation of
N-arylamino-1-pyrrolidines and N-arylamino-1-piperidines.5
We then decided to investigate the ring-opening reactions of
some piperidine and pyrrolidine systems in order to demon-
strate the selectivity in such an approach to acyclic func-
tionalised nitrogen compounds.
Thus, we required a procedure for mild and ef®cient nitro-
gen ring-opening reactions. In the case of unsymmetrical
compounds 1 (R1±H), the regioselectivity should be
controlled, thereby leading either to ketonic compound 2
or aldehydic product 3 (Scheme 1).
We believe that photooxidation of cyclic amines by single
electron transfer followed by ring-opening has potential as a
convenient method for the synthesis. We therefore set out to
®nd reaction conditions for the process which satisfy the
following criteria:
The classical approach involves the oxidation of a lactam
intermediate which is then followed by hydrolysis on
heating.6 This sequence (oxidation, ring-opening) leads
regioselectively to cleavage on the less substituted side
but requires drastic conditions. Stanforth and co-workers7±9
² the oxidative cleavage must be mild and regioselective;
² the choice of the R substituent should provide access to
Scheme 1.
Keywords: photochemistry; oxidation; nitrogen heterocycles; azo compounds; cleavage reactions.
* Corresponding author. Tel.: 133-0-1-40-27-24-02; fax: 133-0-1-42-71-05-34; e-mail: ferroud@cnam.fr
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00048-X

2976
G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
Scheme 2.
the open forms 2 or 3, without any equilibration between
open and cyclised forms;
Symmetrical piperidine or pyrrolidine ring-opening
photochemical reactions
² the strategy would use an N-substituent, which is easily
removed under mild conditions (protecting group) and in
high yields.
As can be seen from Scheme 3, ring-opening of piperidine
compounds 8±11 was effected in high yields (75±97%) in
presence of water as nucleophile. In all these ring-opening
reactions, only aldehyde products (8a±11a) were observed
1
by H NMR spectroscopy and none of the corresponding
hemiaminal could be detected. Overall, the procedure for
such a transformation involves mild and selective oxidative
conditions compatible with the reactivity of the resulting
aldehyde group.
Results and Discussion
We decided to investigate further the oxidation of N-aryl-
amino-1-piperidines and N-arylamino-1-pyrrolidines. The
substrates 4 used in our previous study5 were irradiated by
visible light ꢀl . 630 nm†; with a catalytic amount of
methylene blue (MB) and trimethylsilylcyanide (TMSCN)
as a source of cyanide ion, and were converted into a-hydra-
zinonitrile derivatives 5 (Scheme 2). Application of this
amine oxidation procedure in the presence of alcohol or
water as nucleophile (ROH instead of cyanide ions), yields
Using alcoholic solvent as nucleophile allows us to obtain
the corresponding acetals 10b, 10c, 11b and 12b. However,
the purity of those products was substantially reduced, and
after puri®cation by column chromatography, overall
product yields were disappointingly low.
In the case of the pyrrolidine system 12, the ring was easily
opened in a mixture of acetonitrile and water (9:1). We
observed the formation of the intermediate aldehyde 12c
a-hydrazinoalkoxy derivatives
ultimately, after ring-opening the corresponding acetals or
aldehydes 7 are obtained in good yields.
6 (not isolated), and
Scheme 3. (i) Synthesis of products 8±12 are detailed in the Experimental; (ii) the structures of the products were fully determined by spectroscopic analyses;
(iii) besides the desired product, a by-product was also formed (25%) and separated by column chromatography; (iv) yield after puri®cation by ¯ash
chromatography on aluminium oxide; (v) these products were pure enough for further reactions.

G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
2977
Scheme 4.
(isolated and characterised), which spontaneously cyclised
to give the corresponding tetrahydropyridazine 12a (yield:
49% after puri®cation by ¯ash chromatography). A possible
mechanism which involves the formation of the azoalde-
hyde 12c from compound 12 followed by cyclisation of a
hydrazone intermediate 12d is shown in Scheme 4.
with unsymmetrical systems we decided to examine photo-
oxidation in a series of 2-alkyl-N-aminopiperidine deriva-
tives. Synthesis of these unsymmetrical compounds are
described in Scheme 6. The photocyanation5 of N-amino-
piperidine 11 gives the a-hydrazinonitrile (^)-14 in an
excellent yield of 96%. Thus treatment of 14 with an excess
of Grignard reagent in re¯uxing tetrahydrofuran under
argon atmosphere affords good yields of alkylated
piperidines (^)-15, (^)-16. With the same methodology
irradiation of 4-methyl-N-phenylamino-1-piperidine 9 in
presence of trimethylsilylcyanide as nucleophile source
leads stereospeci®cally to the corresponding trans-(^)-2-
cyano-4-methyl-N-phenylamino-1-piperidine 17 with 83%
yield (d.e..99%).5 Further alkylation of this compound by
propylmagnesium bromide gives only one dialkylated
product (^)-18 (d.e..99% determined by HPLC) bearing
a cis relationship between the methyl and propyl chains
(78% yield).
These one-pot ring-opening reactions proceed by three steps
as shown in Scheme 5:
² Preliminary step: as previously described,5 the oxidation
occurs on the carbon atom a to the nitrogen ring atom to
give an hydrazinium alkylidene cation. The nucleophilic
attack of ROH leads to the oxidised hemiaminal 6.
² Second and third steps: the proposed reaction sequence
involves an initial cleavage of the nitrogen carbon bond
of the hemiaminal leading to the arylhydrazine 13 which
is subsequently photooxidised in situ. However, the
sequence of those two steps is not determined.
Finally, the 2-methyl-N-arylamino-1-piperidine (^)-19 is
produced by consecutive reductive amination steps of the
two carbonyl groups of 5-oxohexanal with 4-nitrophenyl-
hydrazine by using sodium cyanoborohydride in methanol.
It should be noted that such nitrogen±carbon bond cleavage
leading to ring-opening of piperidine derivatives does not
work under the conditions used in this methodology when
tertiary amines are involved. Thus, irradiation by visible
light of N-cyclohexylpiperidine in a mixture of CH3CN/
H2O (9:1) in presence of catalytic amount of methylene
blue and with oxygen bubbling affords the unchanged
starting material.
As can be seen from Scheme 7, the ring-opening of cyclic
compounds 15, 16, 18, 19 by irradiation in visible light leads
with satisfactory to good yields (46±98%) to the selective
bond cleavage between the nitrogen atom and the less
substituted carbon atom. No ketonic product has been
detected. The reaction proceeds smoothly and regiospeci®-
cally, and the resulting acyclic compounds conserve the
high diastereomerical purity of the starting substrates (e.g.
the photochemical ring-opening reaction of compound 18
affords the acyclic azoaldehyde (^)-18a, conserving the
Regioselectivity of piperidine ring-opening
photochemical reactions with unsymmetrical systems
Since the scope of this new methodology would be greatly
expanded if the procedure showed good regioselectivity
Scheme 5.

2978
G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
Scheme 6.
Scheme 7. (i) The structures of the products were fully determined by complete spectroscopic analyses and they were pure enough for further reactions.
relative stereochemistry of the initial ring substituents).
Further example illustrating such relative stereocontrol
will be reported in due course.
recorded on a Bruker AM400 spectrometer or a Bruker
AC300P spectrometer. Chemical shift data are reported in
parts per million down®eld from TMS, and coupling
constants (J) are reported in hertz (Hz). GC±MS spectra
(EI and CI) were performed on a HP G1019A (70 ev, m/z)
spectrometer. Elemental analyses were performed by the
In summary, our results illustrate a new application of
photosensitization of N-arylamino-1-piperidine and N-aryl-
amino-1-pyrrolidines. We have developed experimental
conditions for converting the prepared cyclic hydrazium
alkylidene cation intermediates into linear aldehydes with
excellent yields and a total regioselectivity. The reactions
described herein allow a practical method for the prepa-
ration of azoaldehydes. These compounds would give
aminoaldehydes which are versatile tools in organic
chemistry.13±16
Â
SIAR (Service Regional de Microanalyse de l'Universite
Paris VI). HRMS spectra were performed by the Laboratory
Â
Â
of the ENS (Ecole Normale Superieure de Paris). Flash
column and thin-layer chromatography were done by
using Aluminium oxide 90 (Merck, act. II-III) or Silica
gel 60 (230±400 Mesh).
For a better homogeneity of the attribution of the NMR
signals, the structures have the following numbering
systems which are different from the IUPAC one:
Experimental
All materials were obtained from commercial suppliers and
used without further puri®cation. Tetrahydrofuran (THF)
was distilled from benzophenone/sodium prior to use. IR
spectra (cm21 with polystyrene calibration, in CHCl3 unless
otherwise noted) were recorded on a Perkin±Elmer 457
spectrophotometer or on Philips PU9716 spectrophoto-
1
meter. H NMR (400 or 300 MHz, in CDCl3, reference:
TMS, dHˆ0.0 ppm) and 13C NMR (100.6 or 75.4 MHz, in
CDCl3, reference: CDCl3, dCˆ77.0 ppm) spectra were

G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
2979
1600 cm21; H NMR (300 MHz, CDCl3): d 8.09 (2H, d,
J3ˆ8.5 Hz, H-30), 6.84 (2H, d, J3ˆ8.5 Hz, H-20), 5.17
(1H, s, N±H), 2.69 (4H, s, H-2), 1.73 (4H, tt, J3ˆ5.7,
5.7 Hz, H-3), 1.46 (2H, s, H-4); 13C NMR (75.4 MHz,
CDCl3): d 152.8 (C-10), 139.1 (C-40), 126.3 (C-30), 111.1
(C-20), 57.2 (C-2), 25.8 (C-3), 23.3 (C-4); MS (EI) m/z (rel.
intensity): 222 (13), 221 (M1z, 100), 220 (16), 138 (9), 122
(19), 99 (8), 91 (10), 90 (10), 84 (16), 83 (10), 65 (9), 64
(10), 55 (18); Anal. Calcd for C11H15N3O2: C 59.71; H 6.83;
N 18.99. Found: C 59.68; H 6.89; N 19.09.
1
N-Phenylamino-1-piperidine (8). To a 2788C solution of
1.144 g (10.5 mmol) of N-phenyl hydroxylamine, 1.46 mL
(10.5 mmol) of triethylamine and 80 mL of CH2Cl2 was
added dropwise a solution of 2.00 mL (10.5 mmol) of
diphenylphosphinyl chloride in 20 mL of CH2Cl2. The
white suspension which was quickly formed was stirred at
2308C for 30 min. The mixture was then cooled to 2788C
and a solution of 1.56 mL (15.75 mmol) of piperidine,
1.46 mL (10.5 mmol) of triethylamine and 40 mL of
CH2Cl2 was added dropwise over 10 min. The resulting
solution was allowed to warm to rt overnight. After removal
of the solvent in vacuo, the residue was puri®ed by ¯ash
chromatography (Al2O3, 20% CH2Cl2/cyclohexane) to give
540 mg (3.07 mmol, 29%) of N-phenylamino-1-piperidine
(8) as an orange oil: spectral data are in agreement with
Katritzky's results.17
4-[(Piperidin-1-yl)amino]ethylbenzoate (11). To a 08C
solution of 3.0 g (19.7 mmol) of 4-hydrazinobenzoic acid
in 100 mL of ethanol was added dropwise 2.7 g
(22.3 mmol) of thionyl chloride. The resulting solution
was allowed to warm to room temperature and was stirred
for 15 min. The mixture was then re¯uxed for 15 h. After
cooling at room temperature, 90 mL of Et2O was added and
the resulting solution was ®ltered. The solid was washed
with Et2O (2£30 mL) and dried in vacuo to give 3.48 g
(16.1 mmol, 82%) of (4-hydrazino)ethylbenzoate hydro-
chloride as a glossy solid, which was identical in all respects
to the literature data.18 This product was stirred for 15 min at
room temperature in a mixture of 50 mL of an aqueous
Na2CO3 solution (10%) and 50 mL of CH2Cl2. The organic
layer was separated and the aqueous solution was extracted
with CH2Cl2 (2£50 mL). The combined organic layers were
washed with an aqueous solution of Na2CO3 (10%), dried
over MgSO4 and concentrated under reduced pressure. The
residue was dissolved in 100 mL of methanol and 1 mL
(17.5 mmol) of acetic acid, and the solution was cooled to
2158C. A solution of 1.89 g (18.9 mmol) of glutaric dialde-
hyde in 50 mL of methanol was added dropwise, followed
by the addition of 1.02 g (16.2 mmol) of NaBH3CN. The
resulting solution was allowed to warm to room temperature
and was stirred for 20 h and monitored by TLC. The mixture
was cooled to 08C and quenched with 0.5 M HCl solution
(30 mL). The volatiles were removed under reduced
pressure and aqueous Na2CO3 (50 mL, 10%) was added,
followed by 60 mL of CH2Cl2. The organic solution was
separated and the aqueous solution was extracted with
CH2Cl2 (2£60 mL). The combined organic layers were
washed with aqueous Na2CO3 (30 mL, 10%), dried over
MgSO4 and concentrated under reduced pressure. The
residue was puri®ed by ¯ash chromatography (Al2O3, 40%
CH2Cl2/cyclohexane) to give 2.20 g (8.9 mmol, 55%) of
4-[(piperidin-1-yl)amino]ethylbenzoate (11) as a white
crystalline solid: mp 125±1268C; IR (KBr) 3040, 1700,
4-Methyl-N-phenylamino-1-piperidine (9). This com-
pound was prepared from 1.144 g (10.5 mmol) of N-phenyl-
hydroxylamine
and
1.86 mL
(15.75 mmol)
4-methylpiperidine by the procedure used to synthesise
of
product 8. The desired piperidine 9 was obtained as a yellow
oil (618 mg, 3.25 mmol, 31%): IR (neat) 2940, 1610 cm21
;
1H NMR (300 MHz, CDCl3): d 7.19 (2H, dd, J3ˆ8.4,
7.4 Hz, H-30), 6.88 (2H, d, J3ˆ8.4 Hz, H-20), 6.76 (1H, tt,
J3ˆ7.4, 1.1 Hz, H-40), 4.30 (H, s, N±H), 3.14 (2H, d,
J2ˆ11.0 Hz, H-2eq), 2.18 (2H, dd, J2ˆ10.8 Hz,
J3ˆ10.8 Hz, H-2ax), 1.67 (2H, d, J2ˆ9.2 Hz, H-3eq), 1.45±
1.30 (3H, m, H-4ax, H-3ax), 0.95 (3H, d, J3ˆ5.9 Hz, 4-CH3);
13C NMR (75.4 MHz, CDCl3): d 147.8 (C-10), 129.1 (C-30),
119.1 (C-40), 113.6 (C-20), 56.6 (C-2), 34.3 (C-3), 30.2
(C-4), 21.5 (4-CH3); MS (EI) m/z (rel. intensity): 191 (14),
190 (M1z, 100), 133 (14), 98 (16), 93 (38), 92 (36), 77 (22),
65 (17). HR-MS (EI):calcd for C11H14N2O: (M1z) m/z
190.1470, obsd 190.1463.
N-(4-Nitrophenyl)amino-1-piperidine (10). To a 2158C
solution of 3.25 g (21.2 mmol) of 4-nitrophenylhydrazine
and 1.00 mL of acetic acid (17.5 mmol) in 100 mL of
methanol was added dropwise a solution of 2.30 g
(23.0 mmol) of glutaric dialdehyde in 50 mL of methanol,
followed by the addition of 1.34 g (21.2 mmol) of
NaBH3CN. The resulting solution was allowed to warm to
room temperature and was stirred for 20 h and monitored by
TLC. The mixture was cooled to 08C and quenched with
0.5 M HCl solution (30 mL). The volatiles were removed
under reduced pressure and aqueous Na2CO3 (50 mL, 10%)
was added, followed by 60 mL of CH2Cl2. The organic
solution was separated and the aqueous solution was
extracted with CH2Cl2 (2£60 mL). The combined organic
layers were washed with aqueous Na2CO3 (30 mL, 10%),
dried over MgSO4 and concentrated under reduced pressure.
The residue was puri®ed by ¯ash chromatography (Al2O3,
30% cyclohexane/CH2Cl2) to give as a yellow crystalline
solid, the N-(4-nitrophenyl)amino-1-piperidine (10) (2.00 g,
9.0 mmol, 43%): mp 121±1228C; IR (KBr) 3280, 2940,
1
1600, 1280 cm21; H NMR (400 MHz, CDCl3): d 7.87
(2H, d, J3ˆ8.8 Hz, H-30), 6.84 (2H, d, J3ˆ8.7 Hz, H-20),
4.77 (1H, s, N±H), 4.30 (2H, q, J3ˆ7.1 Hz, O±CH2),
2.70±2.60 (4H, m, H-2), 1.70 (4H, tt, J3ˆ5.6, 5.6 Hz,
H-3), 1.48±1.39 (2H, m, H-4), 1.37 (3H, t, J3ˆ7.1 Hz,
CH3); 13C NMR (100.6 MHz, CDCl3): d 166.8 (CvO),
151.5 (C-10), 131.3 (C-30), 120.3 (C-40), 111.8 (C-20),
60.2 (O±CH2), 57.3 (C-2), 25.9 (C-3), 23.5 (C-4), 14.5
(CH3); MS (EI) m/z (rel. intensity): 248 (M1z, 100), 203
(16), 149 (21), 119 (16), 108 (16), 92 (14), 84 (27), 65
(15); Anal. Calcd for C11H15N3O2: C 67.71; H 8.12; N
11.28. Found: C 67.89; H 8.16; N 11.32.
N-(4-Nitrophenyl)amino-1-pyrrolidine (12). To a 08C
suspension of LiAlH4 (1.14 g, 29.9 mmol) in 75 mL of dry

2980
G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
THF was added dropwise a solution of 2.34 g (10.0 mmol)
of 1-[(4-nitrophenyl)amino]-1H-pyrrole-2,5-dione (synthe-
sised as previously described19) in 25 mL of dry THF. The
red mixture was stirred at room temperature for 3 h,
monitored by TLC and then was cooled to 08C. 125 mL of
water, 1.21 mL of aqueous NaOH (15%) and 7.8 mL of
water were successively added and the resulting mixture
was stirred at room temperature for 1 h, and then ®ltered,
dried over MgSO4 and concentrated under reduced pressure
to give as an orange solid the N-(4-nitrophenyl)amino-1-
pyrrolidine (12) (1.00 g, 4.83 mmol, 49%). It was identical
in all respects to the literature compound:20 Anal. Calcd for
C10H13N3O2: C 57.96; H 6.32; N 20.28. Found: C 57.97; H
6.29; N 20.35.
67.1 (C-5), 50.8 (C-2), 34.6 (C-3), 26.4 (C-4), 19.9 (3-CH3);
MS (EI) m/z (rel. intensity): 204 (M1z, 9), 120 (6), 105 (35),
78 (8), 77 (100), 55 (5), 51(8); HR-MS (EI): calcd for
C12H16N2O: (M1z) m/z 204.1263, obsd 204.1263.
5-[(4-Nitrophenyl)azo]pentanal (10a). According to the
typical procedure, 10a (237 mg, 1.01 mmol, 97%) was
prepared by irradiation of the N-(4-nitrophenyl)amino-1-
piperidine (10) (230 mg, 1.04 mmol) in a solution of aceto-
nitrile (18 mL) and water (2 mL) for 3.5 h and was obtained
as a yellow oil: IR (neat) 2940, 1750, 1600 cm21; 1H NMR
(300 MHz, CDCl3): d 9.81 (1H, t, J3ˆ1.5 Hz, H-1), 8.33
(2H, d, J3ˆ9.0 Hz, H-30), 7.77 (2H, d, J3ˆ9.0 Hz, H-20),
4.16 (2H, t, J3ˆ7.0 Hz, H-5), 2.55 (2H, td, J3ˆ7.3 Hz,
1.5, H-2), 2.02 (2H, tt, J3ˆ7.3, 7.3 Hz, H-3), 1.81 (2H, tt,
J3ˆ7.7, 7.7 Hz, H-4); 13C NMR (75.4 MHz, CDCl3): d
201.9 (C-1), 155.1 (C-10), 148.6 (C-40), 124.7 (C-30),
122.8 (C-20), 69.8 (C-5), 43.5 (C-2), 27.2 (C-3), 19.9
(C-4); MS (CI/NH3) m/z (rel. intensity): 253 (M1118,
20), 237 (37), 236 (M111, 100), 220 (10); HR-MS (CI/
CH4): calcd for C11H14N3O3: (M111) m/z 236.1035, obsd
236.1032.
Ring-opening reactions by SET photooxidation of
symmetrical compounds
The ring-opening reactions were realised according to a
general procedure. The preparation of 8a outlined below
represents a typical experiment.
5-(Phenylazo)pentanal (8a). A solution of N-phenylamino-
1-piperidine (8) (200 mg, 1.14 mmol) in acetonitrile
(18 mL) and water (2 mL) to which was added a catalytic
amount of MB (4 mg, 0.01 mmol) was irradiated under
oxygen bubbling for 4 h with a 1800 W Xenon lamp through
a UV cut-off glass ®lter (l.630 nm) at 208C. After
reaction, monitored by TLC, the resulting reaction mixture
was concentrated under reduced pressure to give a blue oil.
The crude product was dissolved in 50 mL of water,
followed by 50 mL of CH2Cl2. The organic layer was
separated and the aqueous solution was extracted with
CH2Cl2 (2£50 mL). The combined organic layers were
washed with aqueous Na2CO3 (30 mL, 10%), dried over
MgSO4 and concentrated under reduced pressure to give
as a yellow oil the 5-(phenylazo)pentanal (8a) (162 mg,
1-(5,5-Dimethoxypentyl)-2-(4-nitrophenyl)diazene (10b).
According to the typical procedure, 10b (99 mg,
0.35 mmol, 52%) was prepared by irradiation of the
N-(4-nitrophenyl)amino-1-piperidine (10) (150 mg, 0.68
mmol) in a solution of acetonitrile (18 mL) and dry metha-
nol (2 mL) for 7 h followed by ¯ash chromatography
(Al2O3, 30% cyclohexane/(CH2Cl2): and was obtained as a
1
yellow oil: IR (neat) 2920, 1600, 1530 cm21; H NMR
(300 MHz, CDCl3): d 8.33 (2H, d, J3ˆ9.0 Hz, H-30), 7.77
(2H, d, J3ˆ9.0 Hz, H-20), 4.40 (1H, t, J3ˆ5.7 Hz, H-5), 4.14
(2H, t, J3ˆ7.0 Hz, H-1), 3.33 (6H, s, O±CH3), 1.99 (2H, tt,
J3ˆ7.4 Hz, H-3), 1.75±1.66 (2H, m, H-2), 1.58±1.46 (2H,
13
m, H-4); C NMR (75.4 MHz, CDCl3): d 155.2 (C-10),
148.6 (C-40), 124.7 (C-30), 122.9 (C-20), 104.3 (C-5), 70.2
(C-1), 52.8 (O±CH3), 32.3 (C-4), 27.6 (C-3), 22.6 (C-2); MS
(CI) m/z (rel. intensity): 292 (M1118, 4), 282 (M111, 19),
251 (20), 250 (100); HR-MS (CI/CH4): calcd for
C13H20N3O4: (M111) m/z 282.1454, obsd 282.1459.
0.85 mmol, 75%): IR (neat) 2940, 1740, 1720, 1600 cm21
;
1H NMR (300 MHz, CDCl3): d 9.79 (1H, t, J3ˆ1.8 Hz,
H-1), 7.69±7.63 (2H, m, H-30), 7.51±7.39 (3H, m, H-20,
H-40), 4.07 (2H, t, J3ˆ7.0 Hz, H-5), 2.53 (2H, dt, J3ˆ7.4,
1.8 Hz, H-2), 2.04±1.74 (4H, m, H-3, H-4); 13C NMR
(75.4 MHz, CDCl3): d 202.2 (C-1), 152.0 (C-40), 130.5
(C-10), 129.0 (C-30), 122.2 (C-20), 68.9 (C-5), 43.6 (C-2),
27.3 (C-3), 20.0 (C-4); MS (EI) m/z (rel. intensity): 190
(M1z, 9), 106 (3), 105 (38), 94 (3), 91 (2), 85 (2), 78 (9),
77 (100), 65 (2), 51 (9); HR-MS (EI): calcd for C11H14N2O:
(M1z) m/z 190.1106, obsd 190.1104.
1-(5,5-Diethoxypentyl)-2-(4-nitrophenyl)diazene (10c).
According to the typical procedure, 10c (101 mg,
0.33 mmol, 48%) was prepared by irradiation of the
N-(4-nitrophenyl)amino-1-piperidine (10) (150 mg, 0.68
mmol) in a solution of acetonitrile (18 mL) and anhydrous
ethanol (2 mL) for 8 h followed by ¯ash chromatography
(Al2O3, 30% cyclohexane/CH2Cl2) and was obtained as a
1
yellow oil: IR (neat) 2920, 1600, 1530 cm21; H NMR
3-Methyl-5-(phenylazo)pentanal (9a). According to the
typical procedure, 9a (180 mg, 0.88 mmol, 84%) was
prepared by irradiation of the 4-methyl-N-phenylamino-1-
piperidine (9) (200 mg, 1.05 mmol) in a solution of aceto-
nitrile (18 mL) and water (2 mL) for 4 h and was obtained as
(300 MHz, CDCl3): d 8.33 (2H, d, J3ˆ9.2 Hz, H-30), 7.77
(2H, d, J3ˆ9.2 Hz, H-20), 4.51 (1H, t, J3ˆ5.6 Hz, H-5), 4.15
(2H, t, J3ˆ7.0 Hz, H-1), 3.65 (2H, dq, J2ˆ9.2 Hz,
J3ˆ7.0 Hz, O±CHa), 3.50 (2H, dq, J2ˆ9.2 Hz, J3ˆ7.0 Hz,
O±CHb), 1.98 (2H, tt, tt, J3ˆ7.3 Hz, H-3), 1.76±1.67 (2H,
m, H-2); 1.59±1.47 (2H, m, H-4); 1.20 (6H, dd, J3ˆ7.0 Hz,
CH3), 13C NMR (75.4 MHz, CDCl3): d 155.2 (C-10), 148.6
(C-40), 124.7 (C-30), 122.9 (C-20), 102.7 (C-5), 70.2 (C-1),
61.1 (O±CH2), 33.4 (C-4), 27.7 (C-3), 22.7 (C-2), 15.4
(CH3); MS (CI) m/z (rel. intensity): 310 (M111, 8), 265
(22), 264 (100), 239 (13), 222 (8); HR-MS (CI/NH3):
calcd for C15H24N3O4: (M111) m/z 310.1767, obsd
310.1764.
1
a yellow oil: IR (neat) 2940, 1740, 1720, 1600 cm21; H
NMR (300 MHz, CDCl3): d 9.77 (1H, dd, J3ˆ2.2, 1.9 Hz,
H-1), 7.69±7.63 (2H, m, H-30), 7.56±7.39 (3H, m, H-20,
H-40), 4.10 (2H, dd, J3ˆ7.0, 7.0 Hz, H-5), 2.55 (1H, ddd,
J2ˆ16.2 Hz, J3ˆ7.0, 1.9 HZ, H-2a), 2.34 (1H, ddd,
J2ˆ16.2 Hz, J3ˆ7.7, 1.9 Hz, H-2b), 2.32±2.20 (1H, m,
H-3), 1.98 (1H, m, H-4a), 1.87 (1H, m, H-4b), 1.07 (3H, d,
J3ˆ6.6 Hz, 3-CH3); 13C NMR (75.4 MHz, CDCl3): d 202.4
(C-1), 152.0 (C-40), 130.5 (C-10), 128.8 (C-30), 122.1 (C-20),

G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
2981
4-[(5-Oxopentyl)diazenyl]ethylbenzoate (11a). According
to the typical procedure, 11a (184 mg, 0.74 mmol, 83%)
was prepared by irradiation of the 4-[(piperidin-1-
yl)amino]-ethylbenzoate (11) (234 mg, 0.90 mmol) in a
solution of acetonitrile (18 mL) and water (2 mL) for 4 h
and was obtained as a brown oil: IR (neat) 3300, 3000, 1700,
1580, 1260 cm21; 1H NMR (400 MHz, CDCl3): d 9.80 (1H,
t, J3ˆ1.5 Hz, H-1), 8.13 (2H, d, J3ˆ8.6 Hz, H-30), 7.68 (2H,
d, J3ˆ8.5 Hz, H-20), 4.39 (2H, q, J3ˆ7.1 Hz, O±CH2), 4.11
(2H, t, J3ˆ7.0 Hz, H-5), 2.56 (2H, td, J3ˆ7.3, 1.5 Hz, H-2),
2.00 (2H, tt, J3ˆ7.3, 7.3 Hz, H-3), 1.80 (2H, tt, J3ˆ7.6,
7.6 Hz, H-4), 1.42 (3H, t, J3ˆ7.2, CH3); 13C NMR
(100.6 MHz, CDCl3): d 201.9 (C-1), 165.9 (CvO), 154.4
(C-10), 130.5 (C-30), 122.8 (C-40), 121.9 (C-20), 69.4 (C-5),
61.2 (O±CH2), 43.6 (C-2), 27.3 (C-3), 20.0 (C-4), 14.3
(CH3); MS (CI) m/z (rel. intensity): 280 (M1118, 25),
263 (M111, 100); HR-MS (CI/CH4): calcd for
C14H19N2O3: (M111) m/z 263.1396, obsd 263.1399.
(2H, t, J3ˆ7.0 Hz, H-4), 2.68 (2H, td, J3ˆ7.3, 1.1 Hz,
H-2), 2.31 (2H, tt, J3ˆ7.0, 7.0 Hz, H-3); 13C NMR
(75.4 MHz, CDCl3): d 201.2 (C-1), 154.9 (C-10), 148.7
(C-40), 124.7 (C-30), 122.9 (C-20), 68.9 (C-4), 41.5 (C-2),
20.3 (C-3); MS (CI) m/z (rel. intensity): 239 (M1118, 23),
223 (30), 222 (M111, 100), 206 (12).
1-(5,5-Dimethoxybutyl)-2-(4-nitrophenyl)diazene (12b).
According to the typical procedure, 12b (104 mg,
0.39 mmol, 46%) was prepared by irradiation of the
N-(4-nitrophenyl)amino-1-piperidine (12) (175 mg, 0.85
mmol) in a solution of acetonitrile (18 mL) and anhydrous
methanol (2 mL) for 5 h followed by ¯ash chromatography
(Al2O3, 30% cyclohexane/CH2Cl2) and was obtained as a
yellow oil: IR (neat) 2940, 1600 1520 cm21 1H NMR
;
(300 MHz, CDCl3): d 8.33 (2H, d, J3ˆ9.0 Hz, H-30), 7.77
(2H, d, J3ˆ9.0 Hz, H-20), 4.46 (1H, t, J3ˆ5.7 Hz, H-4), 4.16
(2H, t, J3ˆ7.3 Hz, H-1), 3.34 (6H, s, O±CH3), 2.03 (2H, tt,
J3ˆ7.3, 7.3 Hz, H-2), 1.82±1.72 (2H, m, H-3); 13C NMR
(75.4 MHz, CDCl3): d 155.1 (C-10), 148.6 (C-40), 124.7
(C-30), 122.9 (C-20), 104.1 (C-4), 69.8 (C-1), 52.8
(O±CH3), 30.3 (C-3), 22.9 (C-2); MS (EI) m/z (rel. inten-
sity): 235 (M1z232, 33), 150 (26), 122 (94), 117 (19), 85
(100), 71 (59), 58 (19); HR-MS (CI/CH4): calcd for
C12H18N3O4: (M111) m/z 268.1297, obsd 268.1295.
4-[(5,5-Dimethoxypentyl)diazenyl]ethylbenzoate (11b).
According to the typical procedure, 11b (112 mg,
0.36 mmol, 45%) was prepared by irradiation of the
4-[(piperidin-1-yl)amino]-ethylbenzoate (11) (200 mg,
0.81 mmol) in a solution of acetonitrile (18 mL) and anhy-
drous methanol (2 mL) for 4 h followed by ¯ash chroma-
tography (Al2O3, 30% cyclohexane/CH2Cl2) and was
obtained as a brown oil: IR (neat) 3300, 3000, 1700,
Synthesis of unsymmetrical compounds
1600 cm21 1H NMR (400 MHz, CDCl3): 8.13 (2H, d,
;
J3ˆ8.6 Hz, H-30), 7.68 (2H, d, J3ˆ8.5 Hz, H-20), 4.43±
4.35 (3H, m, H-5, O±CH2), 4.11 (2H, t, J3ˆ7.1 Hz, H-1),
3.31 (6H, s, O±CH3), 1.99 (2H, tt, J3ˆ7.4 Hz, H-3), 1.75±
1.66 (2H, m, H-2), 1.58±1.46 (2H, m, H-4), 1.41 (3H, t,
J3ˆ7.1 Hz, CH3); 13C NMR (100.6 MHz, CDCl3): d 166.0
(CvO), 154.5 (C-10), 130.4 (C-30), 122.8 (C-40), 121.9
(C-20), 104.3 (C-5), 69.8 (C-1), 61.2 (O±CH2), 52.8
(O±CH3), 32.3 (C-4), 27.6 (C-3), 22.6 (C-2), 14.3 (CH3);
MS (CI) m/z (rel. intensity): 326 (M1118, 7), 309 (M111,
22); 277 (100); HR-MS (CI/CH4): calcd for C16H24N2O4:
(M1z) m/z 308.1736, obsd 308.1731.
The cyanations were realised according to a general pro-
cedure. The preparation of 14 outlined below represents a
typical experiment.
4-[20-Cyanopiperidin-1-yl)amino]ethylbenzoate (14). A
solution of 4-[(piperidin-1-yl)amino]-ethylbenzoate (11)
(200 mg, 0.81 mmol) in acetonitrile (20 mL) to which was
added a catalytic amount of MB (4 mg, 0.01 mmol) and
300 mL of TMSCN (2.24 mmol) was irradiated under
oxygen bubbling for 5 h with a 1800 W Xenon lamp through
a UV cut-off glass ®lter (l.630 nm) at about 208C. After
reaction, monitored by TLC, the resulting reaction mixture
was concentrated under reduced pressure to give a blue oil.
The crude product was dissolved in 50 mL of aqueous
Na2CO3 (10%), followed by 50 mL of CH2Cl2. The organic
layer was separated and the aqueous solution was extracted
with CH2Cl2 (2£50 mL). The combined organic layers were
washed with an aqueous solution of Na2CO3 (30 mL, 10%),
dried over MgSO4 and concentrated under reduced pressure
to give as a brown oil the 4-[(20-cyanopiperidin-1-yl)-
amino]ethylbenzoate (14) (211 mg, 0.77 mmol, 96%): IR
2-(4-Nitrophenyl)-2,3,4,5-tetrahydropyridazin-3-ol (12a).
According to the typical procedure, 12a (108 mg,
0.49 mmol, 49%) was prepared by irradiation of the
N-(4-nitrophenyl)amino-1-pyrrolidine
(12)
(207 mg,
1.00 mmol) in a solution of acetonitrile (18 mL) and water
(2 mL) for 3 h, followed by ¯ash chromatography (Al2O3,
1% methanol/CH2Cl2) and was obtained as a green
1
amorphous solid: IR (KBr) 3420, 1580, 1490 cm21; H
NMR (300 MHz, CDCl3): d 8.08 (2H, d, J3ˆ9.6 Hz,
H-30), 7.29 (2H, d, J3ˆ9.6 Hz, H-20), 7.09 (1H, m, H-2),
5.65 (1H, m, H-5), 3.42 (1H, s, O±H), 2.44 (1H, dddd,
J2ˆ20.2 Hz, J3ˆ14.0, 6.6, 1.5 Hz, H-3ax), 2.29±2.09 (2H,
m, H-3eq, H-4eq), 1.84 (1H, dddd, J2ˆ13.7 Hz, J3ˆ13.7, 5.9,
2.7 Hz, H-4ax); 13C NMR (75.4 MHz, CDCl3): d 150.7
(C-10), 142.0 (C-2), 140.3 (C-40), 125.6 (C-30), 112.8
(C-20), 73.7 (C-5), 23.8 (C-4), 17.4 (C-3); HR-MS (CI/
CH4): calcd for C10H11N3O3: (M1z) m/z 221.0800, obsd
221.0802. The by-product 4-[(4-nitrophenyl)azo]butanol
(12c) isolated as a yellow oil (15 mg, 0.07 mmol, 7%)
during the ¯ash chromatography was fully characterised:
(neat) 3250, 2920, 2220, 1675, 1590 cm21 1H NMR
;
(400 MHz, CDCl3): d 7.90 (2H, d, J3ˆ8.8 Hz, H-30), 6.85
(2H, d, J3ˆ8.8 Hz, H-20), 5.22 (1H, s, N±H), 4.31 (2H, q,
J3ˆ7.2 Hz, O±CH2), 4.10 (1H, m, H-2eq), 3.02 (1H, d,
J2ˆ10.8 Hz, H-6eq), 2.66 (1H, ddd, J2ˆ10.1 Hz, J3ˆ10.1,
2.7 Hz, H-6ax), 2.07±1.92 (2H, m, H-3), 1.60±1.82 (4H, m,
H-4, H-5), 1.36 (3H, q, J3ˆ7.1 Hz, CH3); 13C NMR
(100.6 MHz, CDCl3): d 166.5 (CvO), 150.1 (C-10), 131.4
(C-30), 121.8 (C-40), 116.5 (CN), 112.2 (C-20), 60.4
(O±CH2), 56.1 (C-2), 52.2 (C-6), 28.7 (C-3), 25.1 (C-5),
19.6 (C-4), 14.4 (CH3); Anal. Calcd for C15H19N3O2: C
65.93; H 6.96; N 15.38. Found: C 65.89; H 7.01; N 15.42;
HR-MS (EI): calcd for C15H19N3O2: (M111) m/z 274.1556,
obsd 274.1558.
IR (neat) 2940, 1750, 1600 cm21 1H NMR (300 MHz,
;
CDCl3): d 9.84 (1H, t, J3ˆ1.1 Hz, H-1), 8.34 (2H, d,
J3ˆ9.0 Hz, H-30), 7.78 (2H, d, J3ˆ9.0 Hz, H-20), 4.17

2982
G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
(2Rp, 4Rp)-4-Methyl-1-(phenylamino)piperidin-2-carbo-
nitrile (17). According to the typical procedure, 17
(187 mg, 0.87 mmol, 83%) was prepared by irradiation of
0.65 mmol, 84%) was prepared from 211 mg (0.77 mmol)
of 4-[(20-cyanopiperidin-1-yl)amino]-ethylbenzoate (14)
and isopropylmagnesium bromide (prepared by classical
procedure with 55 mg (2.31 mmol) of magnesium turnings
and 203 mL of propyl bromide (2.16 mmol)) and was
obtained as a yellow oil: IR (neat) 3040, 1700, 1600,
4-methyl-N-phenylamino-1-piperidine
(9)
(200 mg,
1.05 mmol) with TMSCN (300 mL, 2.24 mmol) in a
solution of acetonitrile (20 mL) for 6 h and was obtained
as an orange oil: IR (neat) 3260, 2930, 2220, 1610 cm21; 1H
NMR (300 MHz, CDCl3): d 7.21 (2H, dd, J3ˆ8.8, 7.4 Hz,
H-30), 6.90±6.80 (3H, m, H-20, H-40), 4.80 (1H, s, N±H),
4.17 (1H, m, H-2eq), 3.10 (1H, dddd, J2ˆ11.4 Hz, J3ˆ4.4,
2.4, 1.1 Hz, H-6eq), 2.63 (1H, ddd, J2ˆ11.4 Hz, J3ˆ11.4,
2.5 Hz, H-6ax), 1.96 (1H, ddd, J2ˆ12.9 Hz, J3ˆ5.5,
2.6 Hz, H-3eq), 1.84±1.58 (3H, m, H-3ax, H-5), 1.39 (1H,
m, H-4ax), 1.00 (3H, d, J3ˆ6.2 Hz, 4-CH3); 13C NMR
(75.4 MHz, CDCl3): d 146.2 (C-10), 129.2 (C-30), 120.3
(C-40), 116.8 (CN), 113.7 (C-20), 55.7 (C-2), 51.5 (C-6),
36.4 (C-3), 33.6 (C-5), 26.5 (C-4), 21.0 (4-CH3); MS (EI)
m/z (rel. intensity): 215 (M1z; 100), 188 (15), 133 (48), 120
(16), 119 (21), 107 (20), 106 (19), 93 (65), 92 (59), 77 (39),
65 (30); HR-MS (EI): calcd for C13H17N3: (M1z) m/z
215.1422, obsd 215.1417.
1
1280 cm21; H NMR (400 MHz, CDCl3): d 7.86 (2H, d,
J3ˆ8.9 Hz, H-30), 6.82 (2H, d, J3ˆ8.6 Hz, H-20), 4.49
(1H, s, N±H), 4.31 (2H, q, J3ˆ7.1 Hz, O±CH2), 3.17 (1H,
d, J2ˆ11.6 Hz, H-6eq), 2.27 (1H, m, H-2ax), 2.18 (1H, ddd,
J2ˆ11.2 Hz, J3ˆ11.2, 4.0 Hz, H-6ax), 2.09 (1H, d,
J2ˆ10.8 Hz, H-3eq or H-5eq), 1.77 (1H, d, J2ˆ12.4 Hz, H-
5eq or H-3eq), 1.70±1.50 (4H, m, H-3ax, H-5ax, H-4), 1.34
(3H, t, J3ˆ7.1, O±CH2±CH3), 1.30±1.16 (1H, m, 2-CH),
0.84 (3H, d, J3ˆ7.1 Hz, CH3), 0.80 (3H, d, J3ˆ6.8 Hz,
CH3 ); 13C NMR (100.6 MHz, CDCl3): d 166.7 (CvO),
0
152.2 (C-10), 131.3 (C-30), 119.7 (C-40), 111.3 (C-20),
70.4 (C-2), 60.1 (O±CH2), 58.1 (C-6), 27.8 (2-CH), 26.9
(C-3), 24.2, 24.1 (C-5, C-4), 19.6 (2-CH±CH3), 16.5
0
(2-CH±CH3 ), 14.5 (O±CH2±CH3); MS (EI) m/z (rel.
intensity): 290 (M1z; 19), 248 (17), 247 (100), 217 (24),
174 (11), 173 (26), 164 (13), 108 (10), 84 (10); HR-MS
(EI): calcd for C17H26N2O2: (M1z) m/z 290.1994, obsd
290.1994.
The alkylations were realised according to a general pro-
cedure. The preparation of 15 outlined below represents a
typical experiment.
(2Rp, 4Rp)-2-Propyl-4-methyl-N-phenylamino-1-piperidine
(18). According to the typical procedure, 18 (168 mg,
0.73 mmol, 78%) was prepared from 200 mg (0.93 mmol)
of (2Rp, 4Rp)-4-methyl-1-(phenylamino)piperidin-2-carbo-
nitrile (17) and propylmagnesium bromide (prepared by
classical procedure with 67 mg (2.79 mmol) of magnesium
turnings and 228 mL of propyl bromide (2.51 mmol) and
was obtained as a yellow oil: IR (neat) 3260, 2930, 1710,
4-[(20-Propylpiperidin-1-yl)amino]ethylbenzoate (15).
To a 08C solution of 211 mg (0.77 mmol) of 4-[(20-cyano-
piperidin-1-yl)amino]ethylbenzoate (14) in dry THF
(20 mL) was added dropwise a solution of propylmag-
nesium bromide (prepared by classical procedure with
55 mg (2.31 mmol) of magnesium turnings and 196 mL of
propyl bromide (2.16 mmol)) in 10 mL of dry THF. The
mixture was stirred for 2 h at room temperature and the
reaction was monitored by TLC. The resulting mixture
was cooled to 08C and 10 mL of aqueous NH4Cl were
added, followed by 10 mL of aqueous Na2CO3 (10%). The
organic solution was separated and the aqueous solution was
extracted with Et2O (2£30 mL). The combined organic
layers were washed with aqueous Na2CO3 (30 mL, 10%),
dried over MgSO4 and concentrated under reduced pressure.
The residue was puri®ed by ¯ash chromatography (Al2O3,
30% CH2Cl2/cyclohexane) to give as a yellow oil the 4-[(20-
propylpiperidin-1-yl)amino]ethylbenzoate (15) (166 mg,
1
1590 cm21; H NMR (300 MHz, CDCl3): d 7.17 (2H, dd,
J3ˆ8.4, 7.14 Hz, H-30), 6.88 (2H, d, J3ˆ8.5 Hz, H-20), 6.74
(1H, dd, J3ˆ7.5, 7.5 Hz, H-40), 4.62 (1H, s, N±H), 2.84 (1H,
ddd, J2ˆ11.7 Hz, J3ˆ8.0, 3.7 Hz, H-2ax), 2.72 (1H, m,
H-6aq), 2.61 (1H, ddd, J2ˆ11.1 Hz, J3ˆ7.1, 3.7 Hz, H-6ax),
1.87±1.17 (9H, m, H-4ax, H-3, H-5, 2-CH2±CH2), 0.95 (3H,
d, J3ˆ6.7 Hz, 4-CH3), 0.88 (3H, t, J3ˆ7.2 Hz, 2-(CH2)2±
13
CH3); C NMR (75.4 MHz, CDCl3): d 148.4 (C-10),
128.6 (C-30), 118.4 (C-40), 113.0 (C-20), 59.0 (C-2), 49.7
(C-6), 35.8 (C-3), 31.8 (C-4), 26.7 (2-CH2), 24.7 (C-5), 19.8
(4-CH3), 19.4 (2-CH2±CH2), 16.1 (2-(CH2)2±CH3); MS (EI)
m/z (rel. intensity): 232 (M1z; 33), 190 (13), 189 (100), 187
(21), 98 (12), 93 (9), 92 (29), 69 (10), 65 (9); HR-MS (EI):
calcd for C15H24N2: (M1z) m/z 232.1939, obsd 232.1949.
0.57 mmol, 74%): IR (neat) 3040, 1700, 1600, 1280 cm21
;
1H NMR (400 MHz, CDCl3): d 7.85 (2H, d, J3ˆ8.9 Hz,
H-30), 6.81 (2H, d, J3ˆ8.7 Hz, H-20), 4.61 (1H, s, N-H),
4.31 (2H, q, J3ˆ7.1 Hz, O±CH2), 3.10 (1H, d, J2ˆ10.6,
H-6eq), 2.28 (2H, m, H-6ax, H-2ax), 1.84±1.57 (6H, m,
H-3, H-4, H-5), 1.35 (3H, t, J3ˆ7.1 Hz, O±CH2±CH3),
1.43±1.10 (4H, m, 2-CH2±CH2), 0.81 (3H, t, J3ˆ7.1 Hz,
2-(CH2)2±CH3); 13C NMR (100.6 MHz, CDCl3): d 166.8
(CvO), 152.6 (C-10), 131.3 (C-30), 119.7 (C-40), 111.3
(C-20), 65.5 (C-2), 60.4 (O±CH2), 57.6 (C-6), 35.1 (C-3),
26.9 (2-CH2), 25.7 (C-5), 24.0 (C-4), 18.8 (2-CH2±CH2),
14.5 (2-(CH2)2±CH3), 14.5 (O±CH2±CH3); MS (EI) m/z
(rel. intensity): 290 (M1z; 34), 248 (16), 247 (100), 245
(11), 217 (22), 174 (11), 173 (25), 164 (13), 108 (10), 84
(11); HR-MS (EI): calcd for C17H26N2O2: (M1z) m/z
290.1994, obsd 290.1989.
2-Methyl-N-(4-nitrophenyl)amino-1-piperidine (19). To
a 2158C solution of 450 mg (2.94 mmol) of 4-nitrophenyl-
hydrazine and 0.25 mL of acetic acid (4.5 mmol) in 20 mL
of methanol was added dropwise a solution of 370 mg
(3.2 mmol) of 5-oxohexanal in 5 mL of methanol, followed
by the addition of 190 mg (3.0 mmol) of NaBH3CN. The
resulting solution was allowed to warm to rt and was stirred
for 20 h and monitored by TLC. The mixture was cooled to
08C and quenched with a solution 0.5 M HCl (10 mL). The
volatiles were removed under reduced pressure and aqueous
Na2CO3 (20 mL, 10%) was added, followed by 30 mL of
CH2Cl2. The organic layer was separated and the aqueous
solution was extracted with CH2Cl2 (2£30 mL). The
combined organic layers were washed with aqueous
Na2CO3 (10 mL, 10%), dried over MgSO4 and concentrated
4-[(20-Isopropylpiperidin-1-yl)amino]ethylbenzoate (16).
According to the typical procedure, 16 (189 mg,

G. Cocquet et al. / Tetrahedron 56 (2000) 2975±2984
2983
under reduced pressure. The residue was puri®ed by ¯ash
chromatography (Al2O3, 30% cyclohexane/CH2Cl2) to give
as a yellow crystalline solid the 2-methyl-N-(4-nitrophenyl)-
amino-1-piperidine 19 (420 mg, 1.8 mmol, 61%: mp 134±
(C-5), 61.2 (O±CH2), 43.6 (C-2), 31.9 (5-CH), 29.9 (C-4),
0
19.4 (CH3), 19.1 (CH3 ), 18.8 (C-3), 14.3 (O±CH2±CH3);
MS (CI) m/z (rel. intensity): 322 (M1118, 24), 305 (M111,
100); HR-MS (Cl/CH4): calcd for C17H25N2O3: (M111) m/z
305.1865, obsd 305.1863.
1358C; IR (KBr) 3240, 2960, 1630 cm21
;
1H NMR
(300 MHz, CDCl3): d 8.07 (2H, d, J3ˆ9.0 Hz, H-30), 6.83
(2H, d, J3ˆ9.0 Hz, H-20), 5.14 (1H, s, N±H), 3.07 (1H, m,
H-6eq), 2.45±2.26 (2H, m, H-2eq, H-6ax), 1.81±1.60 (4H, m,
H-3, H-5), 1.48±1.20 (2H, m, H-4), 1.05 (3H, d, J3ˆ6.2 Hz,
(3Sp, 5Rp)-3-Methyl-5-(phenylazo)octanal (18a). Accor-
ding to the typical procedure, 18a (180 mg, 0.88 mmol,
46%) was prepared by irradiation of the 2-propyl-4-meth-
yl-N-phenylamino-1-piperidine (18) (200 mg, 1.05 mmol)
in a solution of acetonitrile (18 mL) and water (2 mL) for
4 h and was obtained as a yellow oil: IR (neat) 2940, 1740,
1720, 1600 cm21; 1H NMR (300 MHz, CDCl3): d 9.77 (1H,
dd, J3ˆ2.2 Hz, 1.9, H-1), 7.69±7.63 (2H, m, H-30), 7.56±
7.39 (3H, m, H-20, H-40), 3.65 (1H, m, H-5), 2.50 (1H, m,
H-2), 2.20±1.45 (6H, m, H-2, H-3, H-4, 5-CH2), 1.40±1.00
(2H, m, 5-CH2±CH2) 1.00±0.64 (6H, m, 5-(CH2)2±CH3, 3-
CH3); 13C NMR (75.4 MHz, CDCl3): d 202.3 (C-1), 152.0
(C-40), 130.1 (C-10), 128.8 (C-30), 121.9 (C-20), 75.4 (C-5),
49.8 (C-2), 40.2 (C-3), 35.7 (5-CH2), 29.5 (C-4), 20.4 (3-
CH3), 19.1 (5-CH2±CH2), 13.8 (5-(CH2)2±CH3); MS
(EI) m/z (rel. intensity): 247 (17), 246 (M1z; 100), 203
(19), 161 (22), 108 (54) 93 (65), 92 (52), 77 (27), 69
(31), 65 (24); HR-MS (EI): calcd for C15H22N2O: (M1z)
m/z 246.1732, obsd 246.1726.
13
2-CH3); C NMR (75.4 MHz, CDCl3): d 154.0 (C-10),
138.4 (C-40), 126.2 (C-30), 110.5 (C-20), 61.3 (C-2), 57.4
(C-6), 33.9 (C-3), 25.9 (C-5), 23.8 (C-4), 19.6 (2-CH3); MS
(EI) m/z (rel. intensity): 235 (M1z; 46), 221 (14), 220 (100),
186 (12), 118 (12), 84 (31), 69 (11), 64 (12), 56 (14), 55
(19); HR-MS (EI): calcd for C12H17N3O2: (M1z) m/z
235.1321, obsd 235.1328.
Ring-opening reactions by SET photooxidation of
unsymmetrical compounds
The ring-opening reactions were realised according to the
general procedure previously described for the ring-opening
reactions of symmetrical compounds.
4-[(2-Propyl-5-oxopentyl)diazenyl]ethylbenzoate (15a).
According to the typical procedure, 15a (105 mg,
0.35 mmol, 78%) was prepared by irradiation of 4-[(20-
propylpiperidin-1-yl)amino]ethylbenzoate (15) (129 mg,
0.44 mmol) in a solution of acetonitrile (9 mL) and water
(1 mL) for 4 h and was obtained as a brown oil: IR (neat)
5-[(4-Nitrophenyl)azo]hexanal (19a). According to the
typical procedure, 19a (172 mg, 0.69 mmol, 81%) was
prepared by irradiation of the 2-methyl-N-(4-nitrophenyl)-
amino-1-piperidine (19) (200 mg, 0.85 mmol) in a solution
of acetonitrile (18 mL) and water (2 mL) for 6 h and was
1
3300, 3000, 1700, 1580, 1260 cm21; H NMR (400 MHz,
obtained as a yellow oil: IR (neat) 2940, 1750, 1600 cm21
;
CDCl3): d 9.73 (1H, t, J3ˆ1.6 Hz, H-1), 8.12 (2H, d,
J3ˆ8.7 Hz, H-30), 7.66 (2H, d, J3ˆ8.7 Hz, H-20), 4.39
(2H, q, J3ˆ7.1 Hz, O±CH2), 3.63 (1H, qt, J3ˆ4.3 Hz,
H-5), 2.44 (2H, t, J3ˆ7.2 Hz, H-2), 2.05±1.85 (2H, m,
H-3), 1.85±1.65 (2H, m, H-4), 1.65±1.48 (2H, m, 5-CH2),
1.41 (3H, t, J3ˆ7.1 Hz, O±CH2±CH3); 1.25 (2H, td,
J3ˆ7.5 Hz, 5-CH2±CH2), 0.89 (3H, t, J3ˆ7.3 Hz,
1H NMR (300 MHz, CDCl3); d 9.78 (1H, t, J3ˆ1.5 Hz,
H-1), 8.33 (2H, d, J3ˆ9.2 Hz, H-30), 7.77 (2H, d,
J3ˆ8.8 Hz, H-20), 3.86 (1H, qt, J3ˆ7.3, 6.7 Hz, H-5), 2.49
(2H, td, J3ˆ7.3 Hz, 1.5, H-2), 2.10±1.58 (4H, m, H-3, H-4),
1.38 (3H, d, J3ˆ6.6 Hz, 5-CH3), 13C NMR (75.4 MHz,
CDCl3): d 201.7 (C-1), 154.9 (C-10), 148.4 (C-40), 124.5
(C-30), 122.8 (C-20), 73.5 (C-5), 43.5 (C-2), 34.3 (C-3),
18.6 (5-CH3), 18.6 (C-4); MS (EI) m/z (rel. intensity): 249
(M1z; 1), 150 (25), 122 (60), 99 (41), 92 (13), 81 (100), 76
(28), 75 (23), 57 (21), 55 (100); HR-MS (CI/CH4): calcd for
C12H15N3O3: (M111) m/z 250.1192, obsd 250.1190.
5-(CH2)2±CH3); 13C NMR (100.6 MHz, CDCl3):
d
202.0)C-1), 165.9 (CvO), 154.4 (C-10), 130.5 (C-30),
122.8 (C-40), 121.9 (C-20), 77.9 (C-5), 61.2 (O±CH2),
43.6 (C-2), 35.7 (C-3), 32.9 (5-CH2), 19.3 (C-4), 18.7
(5-CH2±CH2), 14.3 (O±CH2±CH3), 13.9 (5-(CH2)2±CH3);
MS (CI) m/z (rel. intensity): 322 (M1118, 20), 305 (M111,
100); HR-MS (CI/CH4): calcd for C17H25N2O3: (M111) m/z
305.1865, obsd 305.1865.
References
4-[(2-Isopropyl-5-oxopentyl)diazenyl]ethylbenzoate (16a).
According to the typical procedure, 16a (164 mg,
0.54 mmol, 98%) was prepared by irradiation of 4-[(20-
isopropylpiperidin-1-yl)amino]ethylbenzoate (16) (160 mg,
0.55 mmol) in a solution of acetonitrile (18 mL) and water
(2 mL) for 4 h and was obtained as a brown oil: IR (neat)
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