Stereoselective conversion of 2H-1,4-oxazin-2-ones into 2,5,5-substituted piperidine-2-carboxamides and 2-methanamines and related octahydro-2H-pyrido[1,2-a]pyrazines, potential substance P antagonists

Article abstract of DOI:10.1016/S0040-4020(01)00888-2

4-(Hetero)aryl-2-oxa-5-azabicyclo[2.2.2]octan-3-ones and 3,6-diones, formed via cycloaddition of 2H-1,4-oxazin-2-ones and ethene followed by functional group transformation, undergo lactone cleavage by reaction with amines to yield substituted 2-(hetero)aryl-5-hydroxy-2-piperidinecarboxamides. Subsequent reduction affords the corresponding 2-piperidinemethanamines. Both amide and amine compounds are of interest as potential Substance P antagonists. A detailed NMR study, supported by conformational calculations, of an octahydro-2H-pyrido[1,2-a]pyrazine analogue revealed the existence of a temperature and solvent dependent equilibrium mixture of transoid and cisoid invertomers.

Full text of DOI:10.1016/S0040-4020(01)00888-2

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 8971±8981
Stereoselective conversion of 2H-1,4-oxazin-2-ones into 2,5,5-
substituted piperidine-2-carboxamides and 2-methanamines
and related octahydro-2H-pyrido[1,2-a]pyrazines,
potential substance P antagonists
Joeri Rogiers, Xiujuan Wu, Suzanne Toppet, Frans Compernolle and Georges J. Hoornaertp
Laboratorium voor Organische Synthese, Department of Organic Chemistry, K.U. Leuven, Celestijnenlaan 200F,
3001 Leuven #Heverlee), Belgium
Received 6 June 2001; revised 18 August 2001; accepted 4 September 2001
AbstractÐ4-*Hetero)aryl-2-oxa-5-azabicyclo[2.2.2]octan-3-ones and 3,6-diones, formed via cycloaddition of 2H-1,4-oxazin-2-ones and
ethene followed by functional group transformation, undergo lactone cleavage by reaction with amines to yield substituted 2-*hetero)aryl-5-
hydroxy-2-piperidinecarboxamides. Subsequent reduction affords the corresponding 2-piperidinemethanamines. Both amide and amine
compounds are of interest as potential Substance P antagonists. A detailed NMR study, supported by conformational calculations, of an
octahydro-2H-pyrido[1,2-a]pyrazine analogue revealed the existence of a temperature and solvent dependent equilibrium mixture of
transoid and cisoid invertomers. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
migraine, rheumatoid arthritis, emesis and asthma. One of
the most potent non-peptide SP antagonists discovered
to date is the 2-phenylpiperidine derivative CP 99,9941 *I)
*Fig. 1). Some time ago, Merck researchers have claimed SP
antagonist activity for the b-hydroxypiperidine derivative
Substance P *SP), a neurotransmitter peptide of the
tachykinin family, is implicated in pain control and in the
pathogenesis of a variety of in¯ammatory diseases, e.g.
Figure 1.
Keywords: bicyclic heterocyclic compounds; piperidines; Diels±Alder reactions; conformation.
Corresponding author. Tel.: 132-16-32-74-09; fax: 132-16-32-79-90; e-mail: georges.hoornaert@chem.kuleuven.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00888-2

8972
J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
Scheme 1.
II.2 Another class of selective SP antagonists identi®ed by
Lilly encompass a tryptophan derived structural unit as in
LY 303,870 *III).3 We recently described an ef®cient and
general approach leading to 2,5,5-substituted analogues of
2-piperidinemethanol and 2-piperidinecarboxylic acid.4 In
the present paper we report a short and stereoselective
route for the synthesis of 2-*hetero)aryl-2-piperidinecarbox-
amides of type 2 and 3 and the 2-*hetero)aryl-2-piperidine-
methanamines 4 *Scheme 1). This involves cycloaddition of
the readily accessible 3-*hetero)aryl-2H-1,4-oxazin-2-ones
with ethene followed by lactone cleavage. Compounds of
type 4 can be elaborated further into conformationally
constrained bicyclic analogues.
*20±40 bar) to produce bicyclic adducts 6. When exposed to
air moisture, the latter compounds are hydrolysed to give the
corresponding bridged lactam compounds.
The cycloaddition of the 3-indolyl-oxazinone 5c with
ethene gave not only the expected product 6c but mainly
the 5,6-dihydro-2-oxa-2H-pyran-6-carbonitrile 8 *Scheme
3). A similar ring transformation also has been observed
in the reaction of ole®ns with 3-amino-5-chloro-2H-1,4-
oxazin-2-ones.7 A plausible mechanism involves conver-
sion of the original adduct 6c into intermediate 7 *Scheme
3). This may proceed through initial C±N bond cleavage
assisted by the strongly electron donating 3-indolyl moiety
at the bridgehead position, followed by expulsion of
chloride. Further loss of a proton in position 4 provides
1
compound 8. The H NMR *CDCl3) spectrum of 2-carbo-
2. Results and discussion
nitrile 8 shows a dd-absorption at 7.13 ppm for H-4 *3Jˆ6.3,
2
3.2Hz) and two dd-absorptions at 2.90 ppm * Jˆ18.3 Hz,
The starting 3,5-dichloro-oxazin-2-one 1 was prepared in a
`one pot' synthesis from the corresponding a-hydroxy-
nitrile.5 A *hetero)aryl group in position 3 was introduced
by reaction of 1 with the corresponding *hetero)aromatic
system in the presence of *Lewis) acids *Scheme 2).6 The
3-*hetero)aryl substituted oxazinones 5 were made to react
with ethene at 1108C in toluene in a high pressure vessel
2
3
3Jˆ3.2Hz) and 2.97 ppm * Jˆ18.3 Hz, Jˆ6.3 Hz) for the
protons in position 3.
To prevent this rearrangement, the indole ring of compound
5c was N-acetylated using acetic anhydride and a catalytic
amount of 4-dimethylaminopyridine *DMAP) to produce 5d
Scheme 2. *i) 5a, 5e: 4 equiv. AlCl3, benzene, rt, 12h; 5b: EtOAc/HCl, 3 equiv. N-methyl pyrrole, rt, 4 h; 5c: EtOAc/HCl, 3 equiv. indole, rt, 12h;
*ii) *CH3CO)2O, DMAP, rt, 6 h; *iii) 20±40 bar ethene, toluene, 1108C, 2±4 h.
Scheme 3.

J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
8973
Scheme 4. *i) MeOH, CHCl3, rt; *ii) 2a: 2-MeOC6H4CH2NH2, MeOH, rt; *iii) 10b: silica gel; 10d: wet EtOAc; *iv) 2b,c: THF, 3 equiv. 2-MeOC6H4CH2NH2,
re¯ux; *v) THF, re¯ux, 4 equiv. BH3´SMe2; *vi) Pd/C, toluene, H2, DABCO, rt.
in 95% yield *Scheme 2). Subsequent Diels±Alder reaction
with ethene gave adduct 6d, which was used directly in the
subsequent hydrolysis step leading to the corresponding
dione *see below). It has been shown previously that
cycloadducts of 2H-1,4-oxazin-2-ones and alkene
compounds undergo lactone cleavage by reaction with
alcohols.8 Thus, when the ethene adduct 6a was treated
with MeOH in CHCl3 *1:1) for one day, compound 9a
was isolated in 65% yield calculated on 5a *Scheme 4).
The conversion of the imidoyl chloride function of 6a into
a lactam may proceed via formation of an imino ether
followed by a nucleophilic attack of MeOH on the methyl
group of the protonated imino ether *HCl-salt). Treatment of
the ester 9a with 2-methoxybenzylamine in methanol at
room temperature afforded the amide 2a in 95% yield.
from 5b). Subsequent lactone cleavage using 3 equiv. of
2-methoxybenzylamine in THF at re¯ux temperature gave
the 2-heteroaryl-2-piperidinecarboxamides 2b and 2c in
yields of 70 and 56%, respectively. Apparently, aminolysis
of 6d also led to deprotection of the N-acetylindole moiety
to give 2c. Compounds 4a±c were prepared by reducing
both amide functions of the 6-oxo-2-piperidinecarboxa-
mides 2a±c. The best yields for diamines 4 were obtained
when using 4 equiv. of BH3´SMe2 *2M) in THF.
Compounds 11b,d were obtained by selective hydrogena-
tion of the imidoyl chloride function of 6b and 6d. To
prevent amide formation by hydrolysis at the air, hydro-
genation of the adducts was carried out in situ. Thus, follow-
ing removal of ethene and addition of palladium on carbon
catalyst and 1,4-diazabicyclo[2.2.2]octane *DABCO), the
reaction mixture was stirred during 2±4 h under hydrogen
*3 bar) to afford 11b *44% from 5b) and 11d *48% from 5d).
The reduction of 6e was carried out using NaBH3CN to
produce 11e as described in a previous paper.4 Aminolysis
of lactone compounds 11 using 2-methoxybenzylamine was
In an alternative sequence the imidoyl chlorides 6b,d were
®rst converted into diones 10b,d, generated by treating 6b,d
with wet EtOAc for one day *yield for 10d: 90% over two
steps from 5d) or by ¯ash chromatography *silica gel; 5%
EtOAc/95% CH2Cl2; yield for 10b: 79% over two steps
Figure 2.

8974
J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
Scheme 5. *i) Ethanolamine, MeOH, rt; *ii) *1) BH3´SMe2, THF *2) BnBr, K2CO3, MeOH; *iii) MsCl, TEA, CH2Cl2; *iv) *1) HCOONH4, Pd/C, MeOH;
*2) 3,5-bis*tri¯uoromethyl)benzoylchloride, Et3N, CH2Cl2.
effected under the same conditions as for the preparation of
diamides 2; however a longer reaction time was required to
produce 2-piperidinecarboxamides 3 *3 days). According to
a model study, this is due to a higher relief of steric strain
when opening the lactone bridge of lactam 10, i.e. a more
severe repulsion is experienced between the bridgehead
*hetero)aryl substituent and the planar lactam NH group
as compared to the non-planar NH of bridged amine 11.
The axial orientation of the 2-*hetero)aryl groups also
accords with that reported for model II. Apparently, the
preferred conformers depicted for 3 and 4 *Fig. 2) are
stabilised by the favourable disposition of the equatorial
5-Me or 5-Ph and axial 5-OH substituents. The latter may
form an internal H-bridge with the piperidine-N-atom as
observed earlier with 5-hydroxy-2-piperidinemethanols4
and other 3-piperidinols *see also below).9 All of these
structural features can enhance the binding af®nity to the
SP receptor as has been shown in preliminary in vitro
experiments carried out for the 2-piperidinemethanol ana-
logues of 3 and 4, in which the *2-methoxybenzyl)amino
group was replaced with the corresponding [3,5-bis*tri-
¯uoromethyl)benzyl]oxy moiety.
Consequent to the generation of compounds 2 and 3 via
lactone opening of 10 and 11, a cis-relationship is estab-
lished between their 5-OH and 2-CONH substituents. The
conformational characteristics of compounds 2±4 were
deduced from NMR spectroscopic data exempli®ed for 3b
and 4a in Fig. 2. In the 1H coupled 13C spectra, the coupling
between the 5-methyl group and the protons in 4- or 6-
For biological screening it is also of interest to evaluate
conformationally constrained analogues, e.g. bicyclic struc-
tures incorporating the required pharmacophoric groups. A
bicyclic analogue of 4 was constructed starting from the
ester 9a. This was converted ®rst into N2-*hydroxyethyl)-
2-piperidinecarboxamide 12 by treatment with ethanol-
amine *90% yield) *Scheme 5). Subsequent reduction of
both amide functions and selective N-benzylation using
1 equiv. of benzyl bromide at room temperature afforded
compound 13 in 89% yield. Treatment of 13 with methane-
sulfonyl chloride resulted in the formation of bicyclic
compound 14, which was debenzylated and N-benzoylated
to yield target compound 15.
3
position could not be resolved. These small J coupling
values indicate an equatorial orientation of the 5-methyl
group. The NOESY spectrum of 3b revealed the spatial
vicinity of H-3 and the N-methyl of the pyrrolyl group
with H-4ax and H-6ax, respectively. These data indicate a
preferred conformational structure with an equatorial 5-CH3
*or 5-Ph for 3e) group and axial orientations of 5-OH and
the 2-*hetero)aryl group. When comparing the structural and
conformational features of compounds 3 and 4 with those of
the bioactive models I and II, a very similar spatial orien-
tation is apparent for the pharmacophoric unit, i.e. the N2-*2-
methoxybenzyl)-1-hetero*aryl)-1,2-ethanediamine moiety.
Scheme 6.

J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
8975
4
Table 1. Selected 1H NMR data of compound 14: d values in ppm relative to TMS *2J, J in Hz)
CDCl3, 508C; trans A
CD2Cl2, 2808C; cis C 75%
CD3OD, 408C; trans A
CD3OD, 2858C; cis B 90%
H1, d
H1, d
H3ax, t
H3eq
H4ax
H4eq
H6, d
H6, d
H8ax
H8eq
H9ax
H9eq
CH3
2.60
2.88
1.75*11)
2.2, t
2.73, d *9.5)
3.68, t
2.6, *9.9)d
3.29*11.6)
2.35*11.6)
1.57, t
1.70, d*13.5)
0.84, t
2.48
2.27*11.6)
2.23
2.66*10.8)
3.45
3.05*12)
2.79
2.69*13.3, 2)
1.43
1.58*13.7, 2)
2.36
1.70*14)
1.0
3.37 A23.58; 3.16
2.44
1.68
2.1, t
2.9
4.22, t
2.8, d
2.74, d
2.5, d
1.45, t
1.60, d
2.9
2.28*11.2)
2.55
2.55
3.40
3.08*12)
3.04*12.6)
2.56*12.6, 2.3)
1.36
1.49*13.5, 2.3)
2.13
1.83*14)
1.06
3.33, 3.45
AB *13.5)
1.18, d*12.4)
0.9, d
3.53; 3.1
AB *14.4)
1.78, d
0.81
PhCH2N
AB *12.4)
At this point it was important to examine in further detail the
conformational restrictions imposed on the pharmacophoric
moiety by its incorporation into the octahydro-2H-
pyrido[1,2-a]pyrazine bicyclic system with angular 9a-
phenyl group. Compounds 14 and 15 can exist as transoid
or cisoid invertomers,10 corresponding to a unique trans-
fused structure A and the two cis-fused conformers B and
C, respectively *Scheme 6). As illustrated by the bold
substructures, each of these structures displays a different
orientation for the nitrogen lone pair and/or other parts of
the pharmacophoric group. Similar inversion of the bridge-
head nitrogen was shown to have a marked effect on bio-
logical pro®le for the analogous quinolizidine marine
alkaloids halichlorine and pinnaic acid.11 Extensive NMR
and IR analysis of compound 14, supported by conforma-
tional calculations, revealed the existence of an equilibrium
mixture of transoid *A) and cisoid *B, C) forms showing a
composition that is strongly dependent on temperature and
solvent. At higher temperatures structure A is the predomi-
nant form stabilised by internal H-bonding. However, at low
temperatures this stabilising effect is superseded by inter-
molecular H-bonding, which favours either B or C via inter-
action with, respectively, OH groups of the solvent
*CD3OD) or the equatorial 7-OH group *CD2Cl2).
H-6 and H-8. Moreover, an equatorial orientation for the
7-Me group was demonstrated by cross-peaks with each
of the vicinal protons H-6 and H-8 in the 1H NOESY spec-
trum *308C in CD2Cl2). These data suggest one predominant
chair form for the piperidine ring, corresponding to either
structure A or B, or to an equilibrium mixture A, B. Other
1H NOESY cross-peaks, involving the ortho-protons of the
9a-phenyl group, were due to 1,3-diaxial and vicinal inter-
actions with the cis-disposed protons H-4ax, H-6ax and
H-1eq, H-9eq, respectively. In particular the NOE's with
H-4ax and H-6ax strongly support structure A as the
major form. Since no NOE was observed with H-8ax, the
Ph ring apparently is oriented mainly in a plane between
H-4ax and H-6ax. The co-existence, besides H-bonded
structure A, of a component B or C that lacks an internal
1
H-bond was indicated by a H NOESY cross-peak relating
the 7-OH and 7-Me protons. According to the H coupling
1
data already mentioned, this component is presumed to be
B. Table 1 also displays selected 1H NMR data for the two
cisoid conformers B and C whose structures were assigned
1
on basis of the 13C NMR data and H±13C coupling values
discussed below. At 2858C in CD3OD, form B was shown
to be the main component *ca. 90%), whereas a 1:3 mixture
of components B and C was apparent from the spectra
determined at 2808C in CD2Cl2. From Table 1 it appears
that the 1H chemical shift values determined for each single
component B and C differ markedly from those assigned to
form A as the main constituent, proving that the high-
temperature values are not due to an average spectrum of
B and C. This conclusion was con®rmed by 13C characteri-
sation of each component A, B and C.
In the IR *KBr) spectrum of compound 14, a major contri-
bution of transoid structure A was indicated by a prominent
Bohlmann band observed at 2804 cm21 12,13
The spectrum
.
further displayed an OH absorption at 3410 cm21 corre-
sponding to intra- and/or intermolecular H-bonding. Upon
dissolution of 14 in CCl4, IR bands due to both free
*3610 cm21
,
sharp) and intramolecular H-bonded
*3520 cm21, broad) OH groups were detected; the intensity
ratio of these bands remained unchanged on further dilution
to a concentration below 0.01 M. These IR results are
consistent with the co-existence of form A exhibiting a
permanent internal H-bond as the main component, together
with component B and/or C characterised by intermolecular
H-bonding or free OH groups.
In the 13C NMR spectrum determined at 258C in CDCl3,
severe broadening was observed for several carbon signals,
e.g. C-1, C-6, and C-9. In support of the supposed equi-
librium mixture of A and B, a nearly exclusive equatorial
orientation was inferred for the 7-Me group on basis of the
low J value measured for coupling of the 7-Me carbon
P
1
with H-6, H-8 in the H-coupled spectrum *CDCl3, 508C;
peak width at half-height: 7.5 Hz). In contrast to the results
obtained at higher temperature, B and C were the only
components detected at low temperature. At 2858C in
CD2Cl2, two series of carbon signals were discerned corre-
sponding to a 3:1 mixture of C and B *Table 2). Structure C
was assigned to the major component, based on the large
In the 1H NMR spectra determined at 258C in CD2Cl2 or at
508C in CDCl3 *Table 1), characteristic ax, eq-coupling
patterns were observed for protons H-6, H-8, and H-9, e.g.
4
a long-range coupling J6eq,8eqˆ2.3 Hz, which allowed a
clear differentiation between axial and equatorial protons

8976
J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
Table 2. Selected 13C NMR data of compound 14: d values in ppm relative to TMS
CDCl3, 508C; trans A
CD2Cl2, 2858C; cis B and C
B, 2 5% C, 75%
67.0 67.1
CD3OD, 408C; trans A
CD3OD, 2808C; cis B, 90%
C-1
C-3
C-4
C-6
C-7
C-8
C-9
C-9a
CH3
PhCH2N
C-ipsoBn
C-ipsoPh
65.7
53.8
50.3
60.3
68.268.0
34.3
30.0 *br)
59.8
27.2
63.8
53.7
50.7
58.5
69.5
35.5
28.1
61.1
28.3
64.0
139.5
146.6
68.0
55.9
50.1
*54.3)
48.7
57.3
54.3
49.7
60.259.9
66.8
69.6
34.1
19.0
33.7
32.4
35.1
20.4
61.2
29.6
63.7
138.5
145.4
59.0
29.3
58.9
25.3
62.7
138.6
143.8
62.0
138.0
144.0
61.5
137.4
142.0
P
J value measured for the axial 7-Me carbon atom *peak
width at half-height: 16 Hz). An equatorial orientation of the
7-Me group was indicated for the minor component by a low
1.1 kcal mol21). As the MM1 calculations did not take
into account any H-bonding, we applied standard density
functional theory *DFT) to calculate the stabilising effect
provided by the supposed internal H-bridge *for compu-
tational details Section 4). Two MM1 optimised rotamers
of the N±Me transoid structure A with OH bond pointing
either to the angular N-5 atom or in between 7-Me and C-8,
were submitted to DFT geometry optimisation. This indi-
cated a stabilisation of ca. 3.4 kcal mol21 for the internal
H-bridge, whereas the initial energy difference for the two
P
J value *10 Hz). De®nite assignment of structure B to this
component ®nally rested on the large up®eld shift observed
for C-9, i.e. d 19.0 versus 32.4 for C and d 30.0 for a
mixture enriched in A. This up®eld shift can be attributed
to a double g-gauche effect exerted by C-4 and N-2, since
both atoms exhibit a syn-orientation relative to C-9 in struc-
ture B, opposite to the anti-orientation for A and C. The 13C
spectra also reveal a characteristic difference in chemical
shift values for an axial and equatorial 7-Me group *d 25.3
and 29.3).
rotamers calculated by MM1 was only ca. 0.1 kcal mol21
.
During the DFT optimisation process the OH±N bond
Ê
distance decreased from 2.51 A *original MM1 value) to
Ê
2.27 A *DFT), with a C7±O±H bond angle of 105.58.
To examine whether intermolecular H-bonding with a
hydroxylic solvent affects the position of the equilibrium
between B and C,1H and 13C NMR spectra also were deter-
mined in CD3OD at low-temperature *2858C) *Tables 1 and
2). Interestingly, under these conditions the equilibrium was
shifted nearly exclusively *ca. 90%) towards form B, again
characterised by the up®eld value d 20.4 for C-9. Overall,
the low-temperature results in two different solvents
indicate a slow conformational equilibrium between the
two cisoid conformers B and C *Scheme 6). At higher
temperature *408C) in CD3OD, A is again found to be the
predominant form *Table 2).
Owing to the rigid character of the bicyclic system, this
effect was found to be lower than that determined for a
monocyclic analogue of A, 3-methyl-3-piperidinol *stabili-
sing effect ca. 5.3 kcal mol21; OH±N bond distance 2.02 A;
Ê
C3±O±H bond angle 1048). Hence, the energy gained from
the internal H-bridge *ca.3.4 kcal mol21) is able to over-
come the increased non-bonded interactions of the axial
Ph group in form A relative to those in B or C *ca.
2±3 kcal mol21). These comparable energy values may
further explain why form A occurs along with the non
H-bonded form B at room temperature.
Apparently, intra- and intermolecular H-bonding governs
the equilibrium between the various forms. At low tempera-
ture, structures B and C may be stabilised by intermolecular
association involving H-bonding to the N lone pairs. In
methanol, form B appears to be favoured by interaction
with OH groups of the solvent, whereas in CD2Cl2 structure
C is stabilised via H-bonding with the equatorial OH group.
Due to the entropy effect intermolecular associations are
disrupted at higher temperature and the equilibrium shifts
to transoid form A, stabilised by an internal H-bridge. To
verify the latter assumption, conformational calculations
were carried out on the N±Me analogue of 14 representing
a simpli®ed, more rigid bicyclic system. Molecular
mechanics and semi-empirical calculations using Hyper-
cheme *version 4.5; MM1 force-®eld and semi-empirical
AM1 method) disfavoured transoid structure A relative to B
and C by ca. 2±3 kcal mol21, due to the additional 1,3-
diaxial repulsions experienced by the 9a-phenyl group.
Cisoid conformer B was slightly favoured over C *0.3±
3. Conclusion
Nucleophilic opening of the lactone bridged compounds 10
or 11 *obtained from the reaction of 3-*hetero)aryl-5-chloro-
2H-1,4-oxazinones 5 and ethene followed by hydrolysis or
reduction of the imidoyl chloride function) with amines
offers an interesting route for the preparation of stereoselec-
tively substituted 2-*hetero)aryl-5-hydroxy-2-piperidine-
carboxamides of type 2 and 3. Subsequent reduction of
compounds 2 afforded the corresponding 2-piperidine-
methanamines 4. Further conversions of 9a gave the more
conformationally constrained bicyclic analogues 14 and 15.
From a detailed NMR study supported by conformational
calculations, the latter were shown to exist as a temperature
and solvent dependent equilibrium mixture of transoid and
cisoid invertomers A±C, controlled by intra- and inter-
molecular H-bonding. These speci®cally substituted piperi-
dines are of interest as potential SP antagonists.

J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
8977
4. Experimental
4.1. General methods
4.3. Generation of compounds 8±11
In a stainless steel tube a solution of 5 mmol 2H-1,4-oxazin-
2-one 5a±e in 30 mL dry toluene was heated at 1108C for 2
or 4 h under ethene pressure *40 or 20 atm. respectively).
After removal of ethene and evaporation of the solvent, the
crude product from 5c was found to be 8 instead of 6c. It was
puri®ed by column chromatography *silica gel; CH2Cl2).
For the other reactions the crude product 6 was converted
into compounds 9±11. Compound 9a was obtained after
treatment of 6a with MeOH, as described previously.4 The
crude product 6b was hydrolysed during ¯ash chroma-
tography *silica gel; 5% CH2Cl2/95% EtOAc) to provide
the pure lactam 10b. Crude product 6d was ®rst hydrolysed
by treatment with wet EtOAc for one day. After removal of
the solvent and crystallisation from a dichloromethane±
hexane mixture white crystals of 10d were obtained. The
compounds 11b±e were obtained from in situ hydrogena-
tion of the adducts 6b±e. After removal of ethene, 30%
*w/w) Pd/C *10%) and 60% *w/w) DABCO was added
and the reaction mixture was stirred for 2±4 h *MS control)
under hydrogen pressure *3 atm.). The mixture was ®ltered
over celite and the ®ltrate was concentrated in vacuo and
puri®ed with column chromatography *11b: silica gel; 5%
EtOAc/95% CH2Cl2, 11d: silica gel; 5% MeOH±95%
CH2Cl2) and crystallisation from a dichloromethane±
hexane mixture.
Melting points were taken using a Reichert±Jung Thermo-
var apparatus and an Electrothermal IA 9000 digital
melting point apparatus and are uncorrected. Infrared
spectra were recorded on a Perkin±Elmer 297 grating IR
spectrophotometer and a Perkin±Elmer 1720 Fourier
1
transform spectrometer. H and 13C NMR spectra were
recorded on Bruker Avance 300, WM 250, and AMX
400 instruments. The 1H and 13C chemical shifts are
reported in ppm relative to tetramethylsilane or the
deuterated solvent as an internal reference. One- and
two-dimensional NMR techniques were used to assign
1
the H and 13C chemical shifts. At room temperature and
at higher temperatures, assignment of the various protons
was carried out by careful spin±spin coupling analysis.
1
One-bond H±13C correlated spectroscopy *HMQC) was
used to assign carbon atoms and their corresponding pair
of diastereotopic protons. The chemical shift values for the
main component of compound 14 present in CD2Cl2 *C)
and CD3OD *B) at 2808 also were determined by using
HMQC. Mass spectra were run using a Hewlett Packard
MS-Engine 5989A apparatus for EI and CI spectra, and a
Kratos MS50TC instrument for exact mass measurements
performed in the EI mode at a resolution of 10,000. For
the chromatography, analytical TLC plates *Alugram Sil
G/UV254) and 70±230 mesh silica gel 60 *E.M. Merck)
were used. Microanalyses were performed by Janssen
Pharmaceutica. The preparations and spectroscopic data
of compounds 5a±c,e16, 6a17, 9a4 and 11e4 have been
described in previous papers.
4.3.1. 5-11H-Indol-3-yl)-2-methyl-6-oxo-3,6-dihydro-2H-
pyran-2-carbonitrile 18). Yield from 5c: 806 mg, 64%;
Yellow crystals; mp 1458C *CH2Cl2/n-C6H14); IR *KBr)
cm21: 2365 *CN), 3250 *NH);1H NMR *CDCl3): 1.94 *s,
3H, CH3), 2.90 *dd, 1H, 2Jˆ18.3 Hz, 3J*H3eq±H4)ˆ3.2Hz,
2
3
H3eq), 2.97 *dd, 1H, Jˆ18.3 Hz, J*H3ax±H4)ˆ6.3 Hz,
H3ax), 7.00 *td, 1H, indH-5), 7.08 *td, 1H, indH-6), 7.13
*dd, 1H, 3J*H4±H3ax)ˆ6.3 Hz, 3J*H4±H3eq)ˆ3.2Hz,
H4), 7.18 *s, 1H, indH-2), 7.33 *d, 1H, indH-7), 7.82 *d,
1H, indH-4); 13C NMR *CDCl3): 26.6 *CH3), 33.0 *C-3),
73.5 *C-2), 109.5 *indC-3), 110.4 *indC-7), 119.4 *CN),
119.5 *indC-4), 120.5 *indC-5), 122.1 *indC-6), 124.8
*indC-3a), 126.9 *C-5), 129.0 *indC-2), 131.4 *C-4), 136.8
*indC-7a), 161.5 *C-6); m/z CI *%): 253 *MH1, 100), 226
*MH12HCN, 28).
4.2. Computational details
Conformational calculations were carried out using
Hypercheme *version 4.5; MM1 force-®eld and semi-
empirical AM1 method). For the DFT calculations, the
B3LYP functional was applied in combination with the
È
14
split-valence *SV) basis sets from Schafer, extended
with a polarisation function. These DFT calculations were
performed with the Turbomole code.15
4.3.2. 1-Methyl-4-11-methyl-1H-pyrrol-2-yl)-2-oxa-5-aza-
bicyclo[2.2.2]octane-3,6-dione 110b). Yield: 880 mg, 79%
over two steps from 5b; white crystals; mp 2118C *CH2Cl2/
4.2.1. 3-11-Acetyl-1H-indol-3-yl)-5-chloro-6-methyl-2H-
1,4-oxazin-2-one 15d). To a solution of 3.9 g *15 mmol)
5-chloro-6-methyl-3-*indol-3-yl)-2H-1,4-oxazin-2-one
*5c) in 120 mL acetic acid anhydride was added a small
amount of DMAP and the reaction mixture was stirred for
6 h at room temperature. After evaporation the residue
was puri®ed by ¯ash chromatography *silica gel;
CH2Cl2). Yield: 4.3 g, 95%; yellow crystals; mp 2338C;
IR *KBr) cm21: 1600 *CvN), 1710 *OCO), 1743
*NCO);1H NMR *DMSO-d6): 2.39 *s, 3H, CH3), 2.77 *s,
3H, COCH3), 7.44 and 8.45 *2£m, 2£2H, indH-4,5,6,7),
8.77 *s, 1H, indH-2); 13C NMR *DMSO-d6): 16.8 *CH3),
23.9 *COCH3), 114.0 *indC-3), 115.9 *indC-7), 122.3
*indC-4), 124.0 *C-5), 124.6 *indC-5), 126.0 *indC-6),
127.2 *indC-3a), 132.1 *indC-2), 135.2 *indC-7a), 143.1
*C-6), 146.6 *C-3), 152.7 *C-2), 169.8 *NCO); m/z CI *%):
303 *MH1, 100); exact mass for C15H11ClN2O3: 302.0458;
found: 302.0463.
1
n-C6H14); IR *KBr) cm21: 1695 *OCO), 1747 *NCO); H
2
NMR *CDCl3): 1.50 *s, 3H, CH3), 2.05 *ddd, 1H, Jˆ
3
14.5 Hz, Jˆ10.5, 4.2 Hz, H7), 2.24 *m, 1H, H7), 2.41 *m,
2H, H8), 3.52 *s, 3H, NCH3), 5.98 *dd, 1H, pyrH-4), 6.18
*dd, 1H, pyrH-3), 6.86 *t, 1H, pyrH-5), 9.35 *s broad, 1H,
NH); 13C NMR *CDCl3): 18.4 *CH3), 29.1 *C-7), 29.3 *C-8),
35.2*NCH 3), 57.4 *C-4), 82.3 *C-1), 106.0 *pyrC-4), 109.5
*pyrC-3), 125.1 *pyrC-2), 125.6 *pyrC-5), 169.5 *C-3),
169.9 *C-6); m/z CI *%): 235 *MH1,100), 207
*MH12CO, 13); exact mass for C12H14N2O3: 234.1004;
found: 234.1008; CHN analysis *%): calcd: C 61.53, H
6.02, N 11.96, found: C 61.61, H 5.83, N 11.86.
4.3.3. 4-11-Acetyl-1H-indol-3-yl)-1-methyl-2-oxa-5-aza-
bicyclo[2.2.2]octane-3,6-dione 110d). Yield: 1.36 g, 90%
over two steps from 5d; white crystals; mp 2238C

8978
J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
*CH2Cl2/n-C6H14); IR *KBr) cm21: 1700 *OCO), 1752
*C-4), 40.4 *NHCH2), 55.2*OCH ), 66.9, 69.8 *C-2and
3
1
*NCO); H NMR *CDCl3): 1.52*s, 3H, CH ), 2.30 *ddd,
C-5), 110.4 *ArC-3), 120.6 *ArC-5), 125.1±129.6 *PhC
and ArC), 141.0 *PhC-1), 157.5 *ArC-2), 171.0 *CONH),
177.0 *C-6); m/z CI *%): 369 *MH1, 100), 204 *MH12
[HCONHCH2Ar], 13); CHN analysis *%): calcd: C 68.46,
H 6.57, N 7.60, found: C 68.59, H 6.66, N 7.66.
3
1H, 2Jˆ14.5 Hz, 3Jˆ10.5, 4.2Hz, H7), 2.51 *m, 3H,
H7,8), 2.67 *s, 3H, COCH3), 7.37 *s, 1H, indH-2), 7.42±
7.75 *m, 4H, indH-4,5,6,7); 13C NMR *CDCl3): 19.7 *CH3),
24.1 *COCH3), 29.7 *C-7), 30.1 *C-8), 57.1 *C-4), 81.8
*C-1), 109.4 *indC-3), 116.7 *indC-7), 117.7 *indC-4),
119.1 *indC-6), 125.3 *indC-5), 127.1 *indC-2),129.9
*indC-3a), 138.8 *indC-7a), 164.3 *COCH3), 169.2*C-3),
172.2 *C-6); m/z CI *%): 313 *MH1,83), 269 *MH12[N-
acetyl-indole], 100); exact mass for C17H16N2O4: 312.1110;
found: 312.1124
4.5. General procedure for the conversions of
compounds 10 and 11 into target compounds 2 and 3
4 mmol 2-oxa-5-azabicyclo[2.2.2]octane-3 one or 3,6-dione
*10 or 11) was dissolved in 20 mL THF and 3 equiv. 2-
methoxybenzylamine were added. The reaction mixture
was re¯uxed until all starting material had disappeared
*24 h). After evaporation of the solvent the residue was
diluted with 15 mL CH2Cl2 and extracted with 3£10 mL
2N HCl solution. The organic layer was dried over
MgSO4, evaporated under reduced pressure and puri®ed
by column chromatography *silica gel; 5% MeOH±95%
CH2Cl2) or crystallisation *dichloromethane/n-hexane).
4.3.4. 1-Methyl-4-11-methyl-1H-pyrrol-2-yl)-2-oxa-5-aza-
bicyclo[2.2.2]octan-3-one 111b). Yield: 44% over two
steps from 5b; white crystals; mp 1368C *CH2Cl2/n-C6H14);
IR *KBr) cm21: 1747 *OCO); H NMR *CDCl3): 1.19 *s
1
broad, 1H, NH), 1.42*s, 3H, CH ), 1.99 *m, 2H, H7), 2.36
3
*m, 2H, H8), 3.14 *s, 2H, H6), 3.70 *s, 3H, NCH3), 6.03 *dd,
1H, pyrH-4), 6.10 *dd, 1H, pyrH-3), 6.63 *t, 1H, pyrH-5);
13C NMR *CDCl3): 23.0 *CH3), 35.9 *NCH3), 51.1 *C-6),
54.9 *C-4), 80.3 *C-1), 106.2*pyrC-4), 108.0 *pyrC-3),
125.0 *pyrC-5), 129.0 *pyrC-2), 172.8 *C-3); m/z *%): 220
*M1., 6), 176 *M1.2CO2, 100); exact mass for C12H16N2O2:
220.1212; found: 220.1212.; CHN analysis *%): calcd: C
65.43, H 7.32, N 12.72, found: C 65.40, H 7.49, N 12.62.
4.5.1. 5a-Hydroxy-N2-12-methoxybenzyl)-5b-methyl-2b-
11-methyl-1H-pyrrol-2-yl)-6-oxo-2a-piperidinecarboxa-
mide 12b). Yield from 10b: 70%; white crystals; mp 1478C
*CH2Cl2/n-C6H14); IR *KBr) cm21: 1660, 1662*NCO), 3380
*OH, NH);1H NMR *CDCl3): 1.33 *s, 3H, CH3), 2.06 and
2.38 *2£m, 2£2H, H3 and H4), 1.63 *s broad, 1H, OH), 3.25
2
4.3.5. 4-11-Acetyl-1H-indol-3-yl)-1-methyl-2-oxa-5-aza-
bicyclo[2.2.2]octan-3-one 111d). Yield: 48% over two
steps from 5d; white crystals; mp 1538C *CH2Cl2/n-C6H14);
IR *KBr) cm21: 1698 *OCO), 1747 *NCO); 1H NMR
*CDCl3): 1.44 *s, 3H, CH3), 1.57 *s broad, 1H, NH), 2.02
*m, 2H, H7), 2.37 *m, 2H, H8), 2.57 *s, 3H, COCH3), 3.11
*s, 2H, H6), 7.25 *s, 1H, indH-2), 7.32±7.52 *m, 4H, indH-
4,5,6,7); 13C NMR *CDCl3): 21.2 *CH3), 24.3 *COCH3),
30.2*C-7), 30.3 *C-8), 50.8 *C-6), 55.4 *C-4), 73.4 *C-1),
115.1 *indC-3), 115.7 *indC-7), 117.3 *indC-4), 118.2
*indC-6), 123.2 *indC-2), 124.8 *indC-5), 130.2 *indC-3a),
140.0 *indC-7a), 164.4 *COCH3), 171.9 *C-3); m/z CI *%):
299 *MH1, 65), 255 *MH12CO2, 100); exact mass for
C17H18N2O3: 298.1317; found: 298.1315
*s, 3H, NCH3), 3.69 *s, 3H, OCH3), 4.34 *dd, 1H, Jˆ
3
2
14.3 Hz, Jˆ6.0 Hz, NHCH2), 4.40 *dd, 1H, Jˆ14.3 Hz,
3Jˆ6.0 Hz, NHCH2), 6.06 *dd, 1H, pyrH-4), 6.21 *dd, 1H,
pyrH-3), 6.27 *t broad, 1H, CH2NHCO), 6.43 *s broad, 1H,
NHCO), 6.52*t, 1H, pyrH-5), 6.80 *d, 1H, ArH-3), 6.87 *t,
1H, ArH-5), 7.17 *dd, 1H, ArH-6), 7.24 *td, 1H, ArH-4); 13C
NMR *CDCl3): 28.0 *CH3), 29.7 *C-3), 32.2 *C-4), 34.9
*NCH3), 40.8 *NHCH2), 55.1 *OCH3), 62.4 *C-5), 69.6
*C-2), 107.1 *pyrH-4), 108.9 *pyrH-3), 110.1 *ArC-3),
120.6 *ArC-5), 125.5 *ArC-1), 125.5 *pyrH-5), 129.2
*ArC-6), 129.9 *ArC-4), 130.3 *pyrH-2), 157.4 *ArC-2),
1
171.2*CONH), 176.7 *C-6); m/z CI *%): 372*MH
,
100), 291 *MH12[N-Me-pyrrole], 77), 207 *MH12
[o-MeOC6H4CH2NH2], 31); exact mass for C20H25N3O4:
371.1845; found: 371.1847; CHN analysis *%): calcd: C
64.67, H 6.78, N 11.31, found: C 64.31, H 6.84, N 11.21.
4.4. Conversion of compound 9a into 2a
4.4.1. 5a-Hydroxy-N2-12-methoxybenzyl)-5b-methyl-6-
oxo-2b-phenyl-2a-piperidinecarboxamide 12a) from 9a.
To a stirred solution of 565 mg methyl 2-piperidinecarb-
oxylate 9a4 *2.15 mmol) in 28 mL absolute methanol was
added 588 mg *2equiv.) 2-methoxybenzylamine. The
resulting solution was stirred at room temperature for one
day. After evaporation of the solvent, the crude product was
puri®ed by column chromatography *silica gel; 5% MeOH±
95% CH2Cl2) and crystallisation *CH2Cl2/Et2O). Yield:
751 mg, 95%; white crystals; mp 1478C *CH2Cl2/n-Et2O);
4.5.2. 5a-Hydroxy-2b-11H-indol-3-yl)-N2-12-methoxy-
benzyl)-5b-methyl-6-oxo-2a-piperidinecarboxamide 12c).
Yield from 10d: 56%; white crystals; mp 1278C; IR *KBr)
cm21: 1665 *NCO), 3374 *OH, NH);1H NMR *CDCl3): 1.49
*s, 3H, CH3), 1.90 *ddd, 1H, 2Jˆ13.8 Hz, 3J*H4eq±H3eq)ˆ
6.5 Hz, 3J*H4eq±H3ax)ˆ3.0 Hz, H4eq), 2.00 *ddd, 1H,
2Jˆ13.8 Hz, 3J*H4ax±H3ax)ˆ11.4 Hz, 3J*H4ax±H3eq)ˆ
3.0 Hz, H4ax), 2.42 *ddd, 1H, 2Jˆ13.8 Hz, 3J*H3ax±H4ax)ˆ
2Jˆ13.8 Hz, 3J*H3eq±H4eq)ˆ6.5 Hz, 3J*H3eq±H4ax)ˆ
3.0 Hz, H3eq), 3.59 *s, 3H, OCH3), 4.38 *d, 1H, NHCH2),
4.45 *d, 1H, NHCH2), 6.77 *d, 1H, indH-7), 6.80 *d, 1H,
ArH-3), 6.97 *t, 1H, ArH-5), 7.13 *d, 1H, ArH-6), 7.15 *m,
2H, ArH-4 and indH-5), 7.20 *s, 2H, indH-2), 7.41 *m, 2H,
indH-4,6), 8.72*s broad, 1H, indH-1); 13C NMR *CDCl3):
28.4 *CH3), 31.8 *C-3), 35.5 *C-4), 41.9 *NHCH2), 56.8
*OCH3), 66.1 *C-5), 72.2 *C-2), 112.5 *ArC-3), 114.0
*indC-7), 117.7 *indC-3), 121.3 *ArC-5), 122.4 *indC-4),
124.1 *indC-5), 125.4 *indC-6), 126.7 *ArC-6), 126.7
3
11.4 Hz, J*H3ax±H4eq)ˆ3.0 Hz, H3ax), 2.73 *ddd, 1H,
1
IR *KBr) cm21: 1656 *NCO), 3401, 3191 *OH, NH); H
NMR *CDCl3): 1.35 *s, 3H, CH3), 1.80 *m, 1H, H4eq),
1.94±2.05 *m, 2H, H3ax and H4ax), 2.82 *m, 1H, H3eq),
3.29 *s, 1H, OH), 3.71 *s, 3H, OCH3), 4.42*d, 2Jˆ14.0 Hz,
2
3
3Jˆ6.2Hz, 1H, NHC H2), 4.46 *d, Jˆ14.0 Hz, Jˆ6.2Hz,
1H, NHCH2), 6.80 *d, 1H, ArH-3), 6.85 *t, 1H, ArH-5), 6.94
*t, 1H, 3Jˆ5.1 Hz, CH2NHCO), 7.16 *d, 1H, ArH-6), 7.21 *t,
1H, ArH-4), 7.29 *s broad, 1H, NHCO), 7.30±7.39 *m, 5H,
PhH); 13C NMR *CDCl3): 27.4 *CH3), 31.2*C-3), 3.22

J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
8979
*ArC-1), 128.0 *indC-3a), 130.9 *indC-2), 131.2 *ArC-4),
139.8 *indC-7a) 159.9 *ArC-2) 175.5 *CONH), 178.9
*C-6); m/z CI *%): 408 *MH1, 100), 291 *MH12indole,
37), 271 *MH12[o-MeOC6H4CH2NH2], 18); exact mass
for C20H29N2O3: 407.1845; found: 407.1845.
4Jˆ1.0 Hz, ArH-3,5), 6.98 *t broad, 1H, 3Jˆ5.4 Hz,
3
4
CONHCH2), 7.04 *1H, dd, Jˆ7.3 Hz, Jˆ1.4 Hz, ArH-6),
7.17±7.62*m, 11H, ArH-4, PhH); 13C NMR *CDCl3): 27.8
*C-3), 33.4 *C-4), 39.4 *CH2Ar), 52.6 *C-6), 55.2 *OCH3),
63.4, 70.4 *C-2 and C-5), 110.2 *ArC-3), 120.5±129.3,
138.9, *ArC, PhC), 145.7 *PhC-1), 157.4 *ArC-2), 173.9
*CONH); m/z CI *%): 417 *MH1, 100), 399 *MH12H2O,
45).
4.5.3. 5a-Hydroxy-N2-12-methoxybenzyl)-5b-methyl-2b-
11-methyl-1H-pyrrol-2-yl)-2a-piperidinecarboxamide
13b). Yield from 11b: 58%; white crystals; mp 1488C; IR
*KBr) cm21: 1649 *NCO), 3407 *OH, NH);1H NMR
4.6. General procedure for the BH3´SMe2 reduction of
amides 2 to yield amines 4
2
*CDCl3): 1.05 *s, 3H, CH3), 1.69 *dq, 1H, Jˆ3J*H4eq±
4
H3ax)ˆ3J*H4eq±H3eq)ˆ6.3 Hz, J*H4eq±H6eq)ˆ2.7 Hz,
H4eq), 1.94 *m, 1H, H4ax), 2.07 *m, 2H, H3ax and
Four equivalents BH3´SMe2 *2M in THF) were added drop-
wise to a solution of 2 *0.6 mmol) in 15 mL dry THF at
re¯ux temperature. The reaction mixture was re¯uxed for
one night; after removal of solvent in vacuo the residue was
treated with 15 mL saturated HCl±MeOH solution and
re¯uxed for 30 min. The solvent was evaporated, 15 mL
MeOH was added and subsequently removed under reduced
pressure. The residue was further treated with 15 mL water
and slightly neutralised with K2CO3. The aqueous suspen-
sion was extracted with three portions of 15 mL dichloro-
methane. The combined extracts were dried *MgSO4) and
evaporated to give the crude product 4. Further puri®cation
was carried out by chromatography *silica gel; 5% MeOH/
95% CH2Cl2!20% MeOH/80% CH2Cl2).
2
H3eq), 2.33 *d, 1H, Jˆ14.0 Hz, H6ax), 2.45 *s broad, 2H,
2
NH and OH), 2.60 *dd, 1H, Jˆ14.0 Hz, 4J*H6eq±H4eq)ˆ
2.7 Hz, H6eq), 3.44 *s, 3H, NCH3), 3.68 *s, 3H, OCH3), 4.28
*dd, 1H, 2Jˆ14.0 Hz, 3Jˆ5.6 Hz, NHCH2Ar), 4.39 *dd, 1H,
2Jˆ14.0 Hz, 3Jˆ5.6 Hz, NHCH2Ar), 6.06 *dd, 1H, pyrH-4),
6.08 *t, 1H, 3Jˆ5.6 Hz, CONHCH2Ar), 6.20 *dd, 1H, pyrH-
3), 6.55 *t, 1H, pyrH-5), 6.77 *d, 1H, ArH-3), 6.85 *t, 1H,
ArH-5), 7.15 *dd, 1H, ArH-6), 7.21 *td, 1H, ArH-4); 13C
NMR *CDCl3): 27.5 *CH3), 29.8 *C-3), 34.4 *C-4), 35.5
*NCH3), 39.8 *NHCH2), 52.0 *C-6), 55.0 *OCH3), 60.6,
65.9 *C-2and C-5), 106.2*pyrC-4), 109.9 *pyrC-3), 110.9
*ArC-3), 120.5 *ArC-5), 124.7 *pyrC-5), 128.9 *pyrC-2),
126.1 *ArC-1), 128.7 *ArC-6), 129.4 *ArC-4), 157.4 *ArC-
2), 174.5 *CONH); m/z CI *%): 358 *MH1, 82), 340
*MH12H2O, 18), 277 *MH12[N-Me-pyrrole], 100), 193
*MH12[o-MeOC6H4CH2NH2], 66); exact mass for
C20H27N3O3: 357.2052; found: 357.2048.
4.6.1. 2a-{[12-Methoxybenzyl)amino]methyl}-5b-methyl-
2b-phenyl-5a-piperidinol 14a). Yield from 2a: 80%; oil;
IR *NaCl) cm21: 3349 *OH, NH); 1H NMR *CDCl3): 1.01 *s,
3H, CH3), 1.24 *td, 1H, 2Jˆ3J*H4ax±H3ax)ˆ14.0 Hz,
3J*H4ax±H3eq)ˆ4.0 Hz, H4ax), 1.50 *m, 1H, H4eq), 1.93
*td, 1H, 2Jˆ3J*H3ax±H4ax)ˆ14.0 Hz, 3J*H3ax±H4eq)ˆ
4.0 Hz, H3ax), 2.18 *dt, 1H, 2Jˆ14.0 Hz, 3J*H3eq±
H4ax)ˆ4.0 Hz, 3J*H3eq±H4eq)ˆ4.0 Hz, H3eq), 2.54 *s,
4.5.4. 5a-Hydroxy-2b-11H-indol-3-yl)-N2-12-methoxy-
benzyl)-5b-methyl-2a-piperidinecarboxamide 13c). Yield
from 11d: 55%; white crystals; mp 1198C; IR *KBr) cm21
:
1655 *NCO), 3295, 3405 *OH, NH); 1H NMR *CDCl3): 1.05
*s, 3H, CH3), 1.69 and 2.32 *2£m, 2£2H, H3 and H4), 2.55
*d, 1H, 2Jˆ13.6 Hz, H6ax), 2.63 *d, 1H, 2Jˆ13.6 Hz, H6eq),
4.35 *dd, 1H,2Jˆ14.5 Hz, 3Jˆ6.0 Hz, NHCH2Ar), 4.39 *dd,
1H,2Jˆ14.5 Hz, 3Jˆ6.0 Hz, NHCH2Ar), 6.77 *m, 2H, ArH-
3,4), 7.00 *s, 1H, indH-2), 7.01±7.26 *m, 4H, ArH-5,6 and
indH-5,6), 7.33 *d, 1H, indH-7), 7.38 *t, 3Jˆ6.0 Hz,
CONHCH2), 7.77 *d, 1H, indH-4), 8.97 *s broad, 1H,
indH-1); 13C NMR *CDCl3): 26.6 *CH3), 29.5 *C-3), 34.5
*C-4), 39.6 *NHCH2), 52.8 *C-6), 55.0 *OCH3), 61.7, 66.7
*C-2and C-5), 110.1 *indC-7), 111.6 *ArC-3), 113.8 *indC-
3), 119.6 *indC-6), 120.5 *indC-5), 120.6 *ArC-5), 121.9
*indC-4), 124.6 *ArC-6), 125.5 *ArC-1), 126.1 *indC-3a),
128.6 *indC-2), 129.4 *ArC-4), 136.9 *indC-7a) 157.4
*ArC-2) 174.7 *CONH); m/z CI *%): 394 *MH1, 100), 376
*MH12H2O, 23), 277 *MH12indole, 46), 299 *MH12[o-
MeOC6H4CH2NH2], 90); exact mass for C23H27N3O3:
393.2052; found: 393.2043.
2
2H, H6), 2.56 *d, 1H, Jˆ11.4 Hz, C2CH2NH), 2.60 *d,
2
1H, Jˆ11.4 Hz, C2CH2NH), 3.59 *s, 3H, OCH3), 3.62*d,
1H, 2Jˆ13.8 Hz, CH2Ar), 3.66 *d, 1H, 2Jˆ13.8 Hz, CH2Ar),
3
3
6.74 *d, 1H, Jˆ8.0 Hz, ArH-3), 6.85 *td, 1H, Jˆ8.0 Hz,
4Jˆ1.0 Hz, ArH-5), 7.08 *dd, 1H, Jˆ8.0 Hz, Jˆ1.0 Hz,
ArH-6), 7.18 *td, 1H, 3Jˆ8.0 Hz, 4Jˆ1.0 Hz, ArH-4), 7.26±
7.36 *m, 5H, PhH); 13C NMR *CDCl3): 26.2 *CH3), 29.0
*C-3), 33.8 *C-4), 49.9 *NHCH2Ar), 52.9 *C-6), 54.9
*OCH3), 62.3 *C2CH2NH), 58.8, 67.0 *C-2and C-5),
110.4 *ArC-3), 120.2 *ArC-5), 126.3, 128.4 *ArC), 127.9,
128.3, 129.5 *PhC), 141.6 *PhC-1), 157.5 *ArC-2); m/z CI
*%): 341 *MH1, 100), 323 *MH12H2O, 23), 190 *MH12
[o-MeOC6H4CH2NHMe], 29); exact mass for C12H16N1O1
*M12CH2NHCH2Ar): 190.1232 found: 190.1238; CHN
analysis *%): calcd: C 74.08, H 8.29, N 8.23, found: C
73.81, H 8.06, N 7.90.
3
4
4.6.2.
2a-{[12-Methoxybenzyl)amino]methyl}-2b-11-
4.5.5.
5a-Hydroxy-N2-12-methoxybenzyl)-2b,5b-di-
phenyl-2a-piperidinecarboxamide 13e). Yield from 11e:
methyl-1H-pyrrol-2-yl)-5b-methyl-5a-piperidinol 14b).
Yield from 2b: 69%; oil; IR *NaCl) cm21: 3389 *OH,
NH);1H NMR *CDCl3): 1.03 *s, 3H, CH3), 1.68 *m, 2H,
H4eq and H4ax), 2.06 *m, 2H, H3ax and H3eq), 2.42 *d,
1H, 2Jˆ12.6 Hz, H6ax), 2.62 *dd, 1H, 2Jˆ12.6 Hz,
54%; oil; IR *KBr) cm21: 1654 *NCO), 3406 *OH, NH);1H
2
NMR *CDCl3): 1.84 *m, 1H, H4eq), 2.08 *td, 1H, Jˆ
14.0 Hz, 3J*H4ax±H3ax)ˆ14.0 Hz, 3J*H4ax±H3eq)ˆ
4.0 Hz, H4ax), 2.45 *m, 1H, H3ax), 2.60 *dt, 1H, 2Jˆ
4J*H6eq±H4eq)ˆ2.4 Hz, H6eq), 2.74 *d, 1H, Jˆ12.0 Hz,
2
14.0 Hz, J*H3eq±H4ax)ˆ3J*H3eq±H4eq)ˆ4.0 Hz, H3eq),
3
2
C2CH2NH), 3.00 *d, 1H, Jˆ12.0 Hz, C2CH2NH), 3.56 *s,
2.80 *dd, 1H, 2Jˆ14.0 Hz, 4J*H6eq±H4eq)ˆ2.5 Hz, H6eq),
2
3H, NCH3), 3.73 *s, 3H, OCH3), 3.89 *d, 1H, Jˆ14.0 Hz,
2
NHCH2Ar), 4.07 *d, 1H, 2Jˆ14.0 Hz, NHCH2Ar), 6.02*dd,
2.92 *d, 1H, Jˆ14.0 Hz, H6ax), 3.74 *s, 3H, OMe), 4.32,
4.33 *2d, 2H, NHCH2Ar), 6.82*td, H2,
3Jˆ7.5 Hz,
1H, pyrH-4), 6.06 *dd, 1H, pyrH-3), 6.46 *t, 1H, pyrH-5),

8980
J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
6.80 *d, 1H, ArH-3), 6.91 *t, 1H, ArH-5), 7.27 *m, 2H, ArH-
4,6); 13C NMR *CDCl3): 27.0 *CH3), 29.8 *C-3), 34.4 *C-4),
36.3 *CH3N), 48.4 *NHCH2Ar), 52.6 *C2CH2NH), 55.4
*OCH3), 55.6 *C-6), 56.6 *C-2), 66.6 *C-5), 106.3 *pyrC-
4), 110.3 *pyrC-3), 111.2 *ArC-3), 120.7 *ArC-5), 125.1
*pyrC-5), 129.3 *pyrC-2), 129.8 *ArC-6), 129.9 *ArC-1),
131.1 *ArC-4), 157.6 *ArC-2); m/z CI *%): 344 *MH1,
91), 326 *MH12H2O, 30), 263 *MH12[N-Me-pyrrole],
100), 193 *MH12[o-MeOC6H4CH2NHMe], 74); exact
mass for C20H29N3O2: 343.2260; found: 343.2258.
1H, CONH); 13C NMR *DMSO-d6): 26.6 *CH3), 30.3,
33.1 *C-3 and C-4), 42.2 *NHCH2CH2OH), 59.5
*NHCH2CH2OH), 65.9 *C-2), 68.5 *C-5), 125.0 *PhCortho),
127.4 *PhCpara), 128.4 *PhCmeta), 142.8 *PhCipso), 171.6
*CONH),174.6 *C-6); m/z *%): 293 *1, MH1), 204 *100, M1.2
CONHCH2CH2OH), 186 *35, M1.2CONHCH2CH2OH±
H2O), 176 *34, M1.2CONHCH2CH2OH±CO); exact mass
for C15H20N2O4: 292.1423; found: 292.1417.
4.7.2.
2a-{[Benzyl1hydroxyethyl)amino)]methyl}-5b-
methyl-2b-phenyl-5a-piperidinol 113). To a stirred solu-
tion of amide 12 *1.27 g, 4.20 mmol) in dry THF *40 mL)
under argon atomsphere at re¯ux were added dropwise
5 equiv. BH3´SMe2 *10 M in THF). After 8 hours, the reac-
tion mixture was cooled to room temperature and 10 mL
HCl saturated methanol was added. After 1 h, the solvent
was evaporated; the residue was neutralized with 1N NaOH
and extracted with dichloromethane. The combined organic
layers were dried with MgSO4, ®ltered and evaporated
under vacuum. The white solid obtained *1.30 g) was
dissolved in 30 mL absolute methanol, 520 mg *1.0
equiv.) potassium carbonate and 0.45 mL *1.0 equiv.) ben-
zyl bromide were added. The resulting mixture was stirred
for 4 h. After work-up, the crude product was puri®ed by
chromatography *EtOAc/MeOH/Et3N 90:8:2) to give 1.32 g
white crystals Yield: 89%; mp 1508C; IR *KBr) cm21: 3267,
3339 *OH, NH);1H NMR *CDCl3): 1.01 *s, 3H, CH3), 1.36
4.6.3. 2b-11H-Indol-3-yl)-2a-{[12-methoxybenzyl)amino]-
methyl}-5b-methyl-5a-piperidinol 14c). Yield from 2c:
64%; yellow crystals; mp 1648C; IR *KBr) cm21: 2930,
3288 *NH, OH);1H NMR *CDCl3): 1.02*s, 3H, CH 3),
1.47 *td, 1H, 2Jˆ3J*H4ax±H3ax)ˆ14.0 Hz, 3J*H4ax±
H3eq)ˆ3.6 Hz, H4ax), 1.55 *m, 1H, H4eq), 1.98 *td, 1H,
2Jˆ3J*H3ax±H4ax)ˆ14.0 Hz,
3J*H3ax±H4eq)ˆ4.2Hz,
H3ax), 2.24 *dt, 1H, 2Jˆ14.0 Hz, 3J*H3eq±H4ax)ˆ
3J*H3eq±H4eq)ˆ3.6 Hz, H3eq), 2.56 *dd, 1H, 2Jˆ
4
2
12.0 Hz, J*H6eq±H4eq)ˆ2.0 Hz, H6eq), 2.71 *d, 1H, Jˆ
12.0 Hz, H6ax), 2.75 *s broad, 3H, OH and 2xNH), 2.79 *d,
1H, 2Jˆ10.7 Hz, C2CH2NH), 2.87 *d, 1H, 2Jˆ10.7 Hz,
C2CH2NH), 3.35 *s, 3H, OCH3), 3.64 *d, 1H,2Jˆ13.9 Hz,
NHCH2Ar), 3.72*d, 1H, 2Jˆ13.9 Hz, NHCH2Ar), 6.63 *d,
1H, ArH-3), 6.81 *t, 1H, ArH-5), 7.00±7.07 *m, 2H, ArH-6
and indH-6), 7.08 *s, 1H, indH-2), 7.13±7.18 *m, 2H, ArH-4
and indH-5), 7.37 *d, 1H, indH-7), 7.66 *d, 1H, indH-4),
8.50 *s broad, 1H, indH-1); 13C NMR *CDCl3): 26.3
*CH3), 29.9 *C-3), 34.0 *C-4), 49.7 *NHCH2Ar), 52.9
*C2CH2NH), 54.6 *OCH3), 56.9 *C-2), 60.6 *C-6), 67.0
*C-5), 110.0 *ArC-3), 111.3 *indC-7), 115.8 *indC-3),
119.4 *indC-6), 120.2 *ArC-5), 120.5 *indC-4), 121.7
*indC-5), 124.0 *indC-2), 125.9 *ArC-1), 127.6 *indC-3a),
128.0 *ArC-4), 129.6 *ArC-6), 137.1 *indC-7a) 157.4 *ArC-
2); m/z CI *%): 380 *MH1, 73), 362*MH 12H2O, 8), 263
*MH12indole, 100), 245 *MH12indole-H2O, 45); exact
mass for C23H29N3O2: 379.2260; found: 379.2259.
3
*ddd, 1H, 2Jˆ13.8 Hz, 3J*H4ax±H3ax)ˆ11.2Hz, J*H4eq±
H3eq)ˆ6.4 Hz, H4ax), 1.55 *dq, 1H, 2Jˆ13.8 Hz, 3J*H4eq±
H3eq)ˆ3J*H4eq±H3ax)ˆ4J*H4eq±H6eq)ˆ2.5 Hz, H4eq),
2.11 *m, 2H, H3), 2.35 *broad s, 1H, NH), 2.55 *m, 2H,
2
NCH2CH2OH), 2.59 *d, 1H, Jˆ13.0 Hz, H6ax), 2.62 *dd,
2
4
1H, Jˆ13.0 Hz, J*H6eq±H4eq)ˆ2.5 Hz, H6eq), 2.71 *d,
1H, 2Jˆ14.2Hz, C2CH N), 2.78 *d, 1H, 2Jˆ14.2Hz,
2
2
C2CH2N), 3.44 *d, 1H, Jˆ14.0 Hz, NCH2Ph), 3.50 *d,
2
1H, Jˆ14.0 Hz, NCH2Ph), 3.46±3.53 *m, 2H, CH2OH),
7.18±7.44 *m, 10H, 2xPh), 13C NMR *CDCl3): 27.3
*CH3), 28.2*C-3), 33.8 *C-4), 52.5 *C-6), 58.0
*NCH2CH2OH), 60.2*C-)2, 61.9 *NCH 2CH2OH), 62.4
*NCH2Ph), 67.0 *C-5), 69.6 *C2CH2N), 126.6, 126.9,
128.3, 128.6 *Ph±C), 139.4, 141.9 *Ph±Cipso); m/z *%):
355 *MH1, 2), 190 *M12CH2N *CH2Ph)CH2CH2OH,
100); exact mass for C22H31N2O2*MH1): 355.2385, found:
355.2381; CHN analysis *%): calcd: C 74.54, H 8.53, N
7.90; found: C 74.24, H 8.66, N 7.76.
4.7. Conversion of compound 9a into a bicyclic analogue
of 4
4.7.1. 5a-Hydroxy-N2-1hydroxyethyl)-5b-methyl-6-oxo-
2b-phenyl-2a-piperidinecarboxamide 112). To a stirred
solution of methyl 6-oxo-5-hydroxy-5-methyl-2-phenyl-2-
piperidinecarboxylate 9a *1.40 mg, 5.32mmol) in abso-
lute methanol *28 mL) was added 5 equiv. *1.60 mL)
2-aminoethanol. After stirring at room temperature for
24 h, the solvent was evaporated, the residue dissolved in
water *20 mL) and extracted with dichloromethane
*3£25 mL). The combined organic layers were dried with
MgSO4, ®ltered and evaporated. The crude product was
puri®ed by crystallisation *CH2Cl2/Et2O) to give 1.38 g
amide 12. Yield: 90%; white crystals; mp 1428C; IR
*KBr) cm21: 1531, 1654 *NCO), 3327, 3476 *OH, NH);
1H NMR *DMSO-d6) *2 85C): 1.25 *s, 3H, CH3), 1.51
4.7.3.
2-Benzyl-7a-methyl-9aaphenyloctahydro-2H-
pyrido[1,2-a]pyrazin-7b-ol 114). To a stirred solution of
alcohol 13 *0.95 g, 2.68 mmol) and TEA in dry dichloro-
methane *30 mL) at 2158C was added methanesulfonyl
chloride *1.2equiv., 0.30 mL) via syringe. After reacting
for 30 min at this temperature, the reaction mixture was
treated with 20 mL saturated aqueous NaHCO3 solution
and 20 mL water. The aqueous layer was extracted with
3£30 mL CH2Cl2 and the organic layers were dried with
MgSO4. After puri®cation via chromatography 0.76 g color-
less oil 14 was obtained. Yield: 84%; oil; IR *KBr) cm21
:
2
3
*ddd, 1H, Jˆ13.5 Hz, Jˆ7.7, 2.8 Hz, Heq), 1.70 *ddd,
3413 *OH);1H NMR *558C, CDCl3): 1.06 *s, 3H, CH3), 1.36
*td, 1H, 2Jˆ3J*H8ax±H9ax)ˆ13.8 Hz, 3J*H8ax±H9eq)ˆ
4.2Hz, H8ax), 1.49 *dtd, 1H, 2Jˆ13.8 Hz, 3J*H8eq±
H9ax)ˆ3J*H8eq±H9eq)ˆ4.2Hz, 4J*H8eq±H6eq)ˆ2.3 Hz,
H8eq), 1.83 *dt, 1H, 2Jˆ13.8 Hz, 3J*H9eq±H8ax)ˆ
3J*H9eq±H8eq)ˆ4.2Hz, H9eq), 2.13 *td, 1H, 2Jˆ
2
3
1H, Jˆ13.5 Hz, Jˆ10.6, 2.8 Hz, Hax), 1.90 *ddd, 1H,
3
2
2Jˆ13.5 Hz, Jˆ10.6, 2.8 Hz, Hax), 2.60 *ddd, 1H, Jˆ
13.5 Hz, 3Jˆ7.7, 2.8 Hz, Heq), 3.20 *m, 2H,
CONHCH2CH2OH), 3.41 *m, 2H, CONHCH2CH2OH),
4.70 *s, 1H, CH2CH2OH), 5.15 *s, 1H, OH), 7.27±7.37
*m, 5H, Ph-H), 7.84 *t, 1H, CONHCH2CH2OH), 7.87 *s,

J. Rogiers et al. / Tetrahedron 57 #2001) 8971±8981
8981
3J*H9ax±H8ax)ˆ13.8 Hz, 3J*H9ax±H8eq)ˆ4.0 Hz, H9ax),
IUAP-4-11 funding by DWTC, and the Janssen Pharma-
ceutica company for ®nancial support. They are also
grateful to R. De Boer for mass spectral analysis and to
Dr A. Delabie for the DFT calculations. J. Rogiers, X. Wu
wish to thank the K. U. Leuven for the fellowships received.
2
2.28 *d, 1H, Jˆ11.2Hz, H1ax), 2.42*s broad, 1H, OH),
2.55 *m, 2H, 3-CH2), 2.56 *dd, 2Jˆ12.6 Hz,
2
4J*H6eq±H8eq)ˆ2.3 Hz, H6eq), 2.60 *d, 1H, Jˆ11.2Hz,
2
H1eq), 3.04 *d, Jˆ12.6 Hz, H6ax), 3.08 *m, 1H, H4eq),
3.33 *d, 1H, 2Jˆ13.4 Hz, CH2Ph), 3.45 *d, 1H, 2Jˆ
13.4 Hz, CH2Ph), 3.40 *m, 1H, H4ax), 7.07 *dd, 2H, Ph±
HorthoBn), 7.10 *m, 4H, Ph±H), 7.25 *t, 2H, Ph±H), 7.38 *d,
2H, Ph±Hortho9a-Ph); 13C NMR *CDCl3): 27.0 *CH3), 30.2
*C-9), 34.1 *C-8), 50.2*C-4), 53.8 *C-3), 59.6 *C-9a), 60.2
*C-6), 62.6 *CH2Ph), 65.8 *C-1), 68.1 *C-7), 125.9, 126.7,
127.8, 127.9, 128.5 *Ph±C), 138.4, 143.8 *Ph±Cipso); m/z
*%): 337 *MH1, 2); 318 *M12H2O, 100); 245 *M12
CH2Ph, 100); exact mass for C22H28N2O *M12H2O):
318.2096, found: 318.2099.
References
1. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.;
Snider, R. M. J. Med. Chem. 1992, 35, 4911±4913.
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4.7.4. 2-[Bis1tri¯uorobenzoyl)]-7a-methyl-9aa-phenyl-
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a
solution of 530 mg *1.58 mmol) benzyl protected bicyclic
piperazine 14 in absolute methanol *10 mL) was added
0.26 g 10% Pd/C and 1.00 g HCOONH4 *10 equiv.). The
resulting mixture was stirred and heated at re¯ux tempera-
ture for 30 min. After cooling, the mixture was ®ltered over
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and potassium carbonate *0.436 g, 2equiv.) in THF *50 mL)
was added 0.315 mL *1.1 equiv.) 3,5-bis*tri¯uoromethyl)-
benzoyl chloride at 2158C. After stirring at this temperature
for 2h, the reaction mixture was worked up and crystallised
from dichloromethane/hexane. A white pure crystalline
product was obtained in 78% yield *0.60 g). Yield: 78%;
10. *a) Prokai-Tatrai, K.; Zoltewics, J. A.; Kem, R. M.
Tetrahedron 1994, 33, 9909. *b) McIntosh, J. M.; Matassa,
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:
È
therein. *c) Gossinger, E. Monatsh. Chem. 1980, 111, 143.
1628 *NCO), 3402 *OH);1H NMR *CDCl3): 1.07 *s, 3H,
CH3), 1.29 *m, 1H), 1.52 *m, 1H), 1.92 *m, 2H), 2.00±
2.55 *br, 1H), 2.60 *d, 1H), 3.06 *d, 1H), 3.14 *m, 1H),
3.42 *m, 2H), 3.50±4.80 *br, 2H), 7.25 *m, 7H), 7.82 *s,
1H); 13C NMR *558C, CDCl3): 27.0 *CH3), 31.1 *C-9),
33.6 *C-8), 43.2*C-4), 49.1 *C-3), 60.5, 60.8 *C-1, C-6),
67.4, 68.7 *C-9a, C-7), 121.4, 123.2, 124.1, 126.8, 128.1,
128.6 *Ph±C, Ar±C), 131.4 *q, CF3), 137.2, 139.8 *C ipso),
167.3 *CO); m/z CI *%):486 *M1, 75); 485 *M12H, 100);
467 *M12F, 16); exact mass for C24H24N2O2F6: 486.1742;
found: 486.1742; CHN analysis *%): calcd: C 59.26, H 4.97,
N 5.76; found: C 59.08, H 4.76, N 5.72.
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È
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È
È
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Acknowledgements
The authors wish to thank the `F. W. O. Vlaanderen', the