New piperidine scaffolds via nucleophilic reactivity of (-)-phenyloxazolopiperidine

Article abstract of DOI:10.1021/jo0499524

The present work illustrates the power of compound 2 as a chiral, nonracemic, and stable 2-piperideine (enamine) equivalent in the rapid and efficient construction of 3-substituted piperidines (carbon-carbon and carbon-sulfur bonds) such as 3-spiropiperidines. This methodology offers a new route to such systems that could compete with previously reported strategies.

Full text of DOI:10.1021/jo0499524

New P ip er id in e Sca ffold s via Nu cleop h ilic Rea ctivity of
(-)-P h en yloxa zolop ip er id in e
Erwan Poupon,† David Franc¸ois,‡ Nicole Kunesch,‡ and Henri-Philippe Husson*,‡
Laboratoire de Pharmacognosie Associe´ au CNRS, UMR 8076 (BioCIS),
Centre d’EÄ tudes Pharmaceutiques, Universite´ Paris-Sud 11, 5, Rue J ean-Baptiste Cle´ment,
92296 Chaˆtenay-Malabry CEDEX, France, and Laboratoire de Chimie The´rapeutique et Laboratoire de
Pharmacognosie, Faculte´ des Sciences Pharmaceutiques et Biologiques, UMR 8638 Associe´e au CNRS et a`
l’Universite´ Rene´-Descartes (Paris 5), 4, Avenue de l’Observatoire, 75256 Paris CEDEX 06, France
henri-philippe.husson@univ-paris5.fr
Received J anuary 7, 2004
The present work illustrates the power of compound 2 as a chiral, nonracemic, and stable
2-piperideine (enamine) equivalent in the rapid and efficient construction of 3-substituted piperidines
(carbon-carbon and carbon-sulfur bonds) such as 3-spiropiperidines. This methodology offers a
new route to such systems that could compete with previously reported strategies.
In tr od u ction
Functionalized piperidine structures embody some of
the key features found in numerous natural products,
biologically active compounds, and drugs. Synthesis of
such compounds often requires the use of stereoselective
methods involving carbon-carbon bond-forming reac-
tions, and in this regard, enamines have proved to be
useful intermediates.1 Recently, we have reported the
easy preparation of 2 from building block 1 via a mild
reductive decyanation (Scheme 1).2 Compound 2 is an
equivalent of 2-piperideine, which itself has proved to be
unstable and exist in the monomeric form in equilibrium
with the trimeric one.3 Moreover, 1-alkyl 2-piperideine
leads to dimerization products.4
Hence, problems associated with 2-piperideine chem-
istry do not arise so much in the production of tetrahy-
dropyridines, but rather in their exploitation for synthe-
ses. Thus, compound 2 overcomes the problems mentioned
above. We have therefore examined the reactivity of this
compound and showed its usefulness both in methodology
developments2 and in total synthesis.5 As depicted in
F IGURE 1. Synthetic potentialities of building block 2.
Figure 1, our preliminary studies suggest that its re-
markable reactivity can be explained by the equilibrium
between the bicyclic system 2 and its opened enamine-
iminium ion tautomeric form. Thus, the latter offers dual
properties, which should permit access to substituted
piperidines at the C-2 or C-3 positions by means of
electrophilic or nucleophilic attacks, respectively. More-
over, one can expect that the presence of the chiral
appendage would discriminate between the two faces of
the iminium or enamine during the course of such
reactions. Finally, elimination of the chiral appendage
would allow further substitutions on the nitrogen atom.
* To whom correspondence should be addressed. Phone: +33-1 53
73 97 54. Fax: +33-1 43 29 14 03.
† Universite´ Paris-Sud 11.
‡ Universite´ Rene´-Descartes (Paris 5).
(1) For some elegant examples of natural product synthesis featuring
tetrahydropyridines as nucleophilic key intermediates, see: Nicolaou,
K. C.; Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S. Angew. Chem.,
Int. Ed. 2002, 41, 1941-1945; J akubowicz, K.; Ben Abdelgelil, K.;
Herdemann, M.; Martin, M.-T.; Gateau-Olesker, A.; Al Mourabit, A.;
Marazano, C.; Das, B. C. J . Org. Chem. 1999, 64, 7381-7387. Wanner,
M. J .; Koomen, G.-J . J . Org. Chem. 1995, 60, 5634-5637.
(2) For preliminary results, see: Franc¸ois, D.; Poupon, E.; Lalle-
mand, M.-C.; Kunesch, N.; Husson, H.-P. J . Org. Chem. 2000, 65,
3209-3212.
As part of our continuing work on endocyclic enamine
reactivity study, we have elected to turn our attention
to the nucleophilic properties of 2 and, in the present
paper, report how various chiral nonracemic structures
can be easily obtained in one or two steps from this new
starting material by exploitation of its enamine reactiv-
ity.6 In particular, we investigated the condensation of
Michael acceptor, namely, methyl vinyl ketone (MVK),
together with mono- and dialdehydes with 2.
(3) (a) Scho¨pf, C.; Arm, H.; Braun, F. Chem. Ber. 1952, 85, 937-
948. (b) De Kimpe, N.; Stevens, C. J . Org. Chem. 1993, 58, 2904-
2906.
(4) (a) Martinez, S. J .; J oule, J . A. Tetrahedron 1978, 34, 3027-
3036. (b) Beeken, P.; Fowler, F. W. J . Org. Chem. 1980, 45, 1336-
1338.
(5) Poupon, E.; Kunesch, N.; Husson, H.-P. Ang. Chem., Int. Ed.
2000, 39, 1493-1495.
(6) General and versatile asymmetric methods for synthesizing
3-substituted piperidines are by far less numerous compared to
methodologies for access to 2-subsituted systems.
10.1021/jo0499524 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/01/2004
3836
J . Org. Chem. 2004, 69, 3836-3841

New Piperidine Scaffolds
SCHEME 1. Dia ster eoselective Mon oa lk yla tion a
However, it gave similar results both in terms of yield
and stereoselectivity (Scheme 1). Furthermore, the struc-
tural assignment of 3 was made on the basis of NMR
analysis.
The stereochemical outcome thus observed can be
accounted for by both stereoelectronic and steric effects.10
As depicted in Scheme 1, stereoelectronic effects imply a
preferred alkylation on the same face as the nitrogen lone
electronic pair; conjointly, the presence of the phenyle-
thanol moiety imposes a transition state with a highly
hindered face. Finally, formation of the oxazolidine is
stereoelectronically controlled according to a model often
discussed in the chemistry of iminiums (i.e., equatorial
position of the oxygen atom, cis position for H-2 and
H-7).10 It is interesting to note that the Mannich deriva-
tives between the potential iminium salt and the methyl
ketone were not formed.
Access to 3-Sp ir op ip er id in es. It is worth noting that
3-spiropiperidines have attracted some attention because
of their unique structure found only in a few natural
products11 (e.g., nitramine, serratezomine A, gymnodi-
mine) and also due to their particular biological profile.
Recently, studies of different spiropiperidine systems
have resulted in a novel 3-spiropiperidine series of potent
growth hormone secretagogues.12 Conformationally re-
stricted GABA and Gabapentin analogues, in which the
3-spiropiperidine pattern is found, have also been pre-
pared as well as GABA-uptake inhibitors.13 Furthermore,
this spirocyclic skeleton is found not only in some
applications in the pharmaceutical field but also in
agrochemistry, as exemplified by the discovery of insect
repellent molecules.14
a
Reagents and conditions: MVK (1 equiv), MeOH, reflux, 4 h
or room temperature, 5 days (60-63%).
Resu lts a n d Discu ssion
The preparation of enantiopure compound 2 was
achieved via a high-yielding reductive decyanation with
Raney nickel starting from 1.7 This reaction can be
carried out on a multigram scale with a satisfying 90%
yield and without any racemization of the oxazolidine
ring.8 The most interesting advantage of this new process
is the ease of the protocol, which makes this reaction
more feasible in comparison with the existing methods
such as Na in liquid ammonia. With this compound in
hand, we herein report new expedient entries into the
rich chemistry of tetrahydropyridine systems.
Mon oa lk yla tion w ith Mich a el Accep tor . MVK is
a Michael acceptor that has been widely used in enamine
alkylation.9 This reaction appeared to be a simple test
to determine the diastereoselectivity control imposed by
the chiral appendage borne at the nitrogen atom, keeping
in mind that the synthetic applications of alkylated
intermediates could be of great interest, for example, in
natural product synthesis. Reaction of 2 with 1 equiv of
MVK in a boiling protic solvent such as MeOH provided
Michael adduct (2R,3R)-3 in acceptable yield (63%) with
a satisfactory level of diastereomeric induction (de ) 92%,
inseparable compounds). At room temperature, the same
reaction was slower, occurring over a period of a few days.
To successfully achieve our goal and in order to
continue our investigations into the chemistry of 3-spiropi-
peridines, upon which we had embarked a few years
ago,15 compound 2 was reacted with an excess of MVK
to give rise to the formation of the Michael-type bis-
adduct 4. Subsequent acidic treatment of 4 with concen-
trated hydrochloric ethanol gave a 1:1 mixture of two
isomeric spirocyclic compounds 5 and 6, which were
easily and totally separable by flash chromatography.
This sequence formally proceeds by an initial attack of a
thermodynamic enol of a side chain at C-3 on the
carbonyl function of the other side chain tethered to C-3.
As shown in Scheme 2, the crotonization followed the two
(10) For a leading reference, see: Stevens, R. V. Acc. Chem. Res.
1984, 17, 7, 289-296.
(11) Nitramine: see ref 15 and references therein. Serratezomine
A: Morita, H.; Arisaka, M.; Yoshida, N.; Kobayashi, J . J . Org. Chem.
2000, 65, 6241-6245. Gymnodimine: Seki, T.; Satake, M.; Mackenzie,
L.; Kaspar, H. F.; Yasumoto, T. Tetrahedron Lett. 1995, 36, 7093-
7096. For the construction of the spirocyclic moiety: Yang, J .; Cohn,
S. T.; Romo, D. Org. Lett. 2000, 2, 763-766. For racemic synthesis of
the key pharmacophoric spirocyclic imine, see: Trzoss, M.; Brimble,
M. A. Synlett 2003, 2042-2046.
(7) For
a
comprehensive review on the CN(R,S) strategy see:
(12) Yang, L.; Morriello, G.; Prendergast, K.; Cheng, K.; J acks, T.;
Chan, W. W.-S.; Schleim, K. D.; Smith, R. G.; Patchett, A. Bioorg. Med.
Chem. Lett. 1998, 8, 107-112.
(13) (a) GABA analogues: Bendl, M.; Eder, M.; Langhammer, I.;
Urban, E. Heterocycles 2000, 53, 115-126. (b) Gabapentin analogues:
Receveur, J .-M.; Bryans, J . S.; Field, M. J .; Singh, L.; Horwell, D. C.
Bioorg. Med. Chem. Lett. 1999, 9, 2329-2334. (c) GABA-uptake
inhibitors: Fleischhacker, W.; Lauritz, S.; Urban, E.; Baurmann, P.;
Bittiger, H. Eur. J . Med. Chem. 1995, 30, 707-713.
(14) (a) Smolanoff, J . U.S. Patent 4 374 991, 1983. (b) Smolanoff, J .
U.S. Patent 4 400 512, 1983.
(15) Franc¸ois, D.; Lallemand, M.-C.; Selkti, M.; Tomas, A.; Kunesch,
N.; Husson, H.-P. Ang. Chem., Int. Ed. 1998, 37, 104-105.
Husson, H.-P.; Royer, J . Chem. Soc. Rev. 1999, 28, 383-394.
(8) See Supporting Information for an improved synthesis of building
block 2.
(9) See inter alia: (a) Asymmetric Michael addition reactions
involving chiral imines, reviews: Christoffers, J .; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688-1690. Christoffers, J . Chem. Eur. J .
2003, 9, 4862-4867. D’Angelo, J .; Desmae¨le, D.; Dumas, F.; Guinguant,
A. Tetrahedron: Asymmetry 1992, 3, 459-505. (b) Michael additions
involving piperideines: Stevens, R. V.; Hrib, N. J . Chem. Soc., Chem.
Commun. 1983, 1422-1424. (c) Mitch, C. H. Tetrahedron Lett. 1988,
29, 6831-6834. (d) Va´zquez, E.; Galindo, A.; Gnecco, D.; Berne`s, B.
Tetrahedron: Asymmetry 2001, 12, 2099-2102.
J . Org. Chem, Vol. 69, No. 11, 2004 3837

Poupon et al.
SCHEME 3. Syn th esis of Sp ir op ip er id in e 7 a n d
P la u sible Mech a n ism a
F IGURE 2. Selected NMR data for compounds 5 and 6.
SCHEME 2. Tw o-Step Access to Sp ir op ip er id in es
via a Dou ble Alk yla tion /Cr oton iza tion Sequ en cea
a
Reagents and conditions: glutaraldehyde (4 equiv), MeOH,
reflux, 18 h (50%).
SCHEME 4. Rea ction s w ith F or m a ld eh yd ea
a
Reagents and conditions: (a) MVK (10 equiv), MeOH, rt, 2
days (60%); (b) MeOH, HCl, reflux, 0.5 h (60%, 5/6 ) 1).
possible pathways 1 and 2, and respectively led to two
quaternary alcohols, which in situ underwent a dehydra-
tion to yield the corresponding R,â-unsaturated deriva-
tives 5 and 6.
a
Reagents and conditions: (a) (HCHO)n (5 equiv), MeOH, rt, 2
days (82%); (b) (HCHO)n (1 equiv), MeOH, molecular sieves 4 Å,
rt, 6 days (20%).
Despite similar analytical data, the structure elucida-
tion of these two compounds was achieved unambigu-
ously by extensive two-dimensional NMR studies (see
selected NMR data in Figure 2). For instance, NOE
correlations between axial H-2 and axial H-13 or equato-
rial H-9 in compounds 5 and 6, respectively, were
observed. These two 3-spiropiperidine systems represent
a strong example of the degree of complexity and diver-
sity reachable from 2 through the use of two easy and
well-known reactions. Moreover, 5 and 6 are also ideal
templates because of their high level of rigidity (bicyclic
spiro core) and their diverse chemical potential (ketone,
double bond, potential iminium). It is noteworthy that
reductive opening of the oxazolidine ring and/or concomi-
tant debenzylation of 5 and 6 would lead to enantiomeric
compounds. They can be subjected to a variety of organic
transformations and will be the basis for the generation
of a library of small molecules. As described for compound
3, no Mannich reaction onto the potential iminium was
observed.
glutaraldehyde followed by dehydration of the formed
alcohol. A methanol molecule then acted as a nucleophile
in a stereocontrolled 1,4-addition, thereby creating a new
stereogenic center. A second enamine reaction on the
remaining aldehyde function gave rise, after residual
iminium trapping, to compound 7 with acceptable yield.
Stereochemistry was unambiguously established by two-
dimensional NMR and by the observation of NOE cor-
relation between methoxy protons and axial H-2. Trap-
ping of the intermediate with other nucleophiles can be
envisaged. The result of this reaction is to be compared
to previous work from our laboratory.15
Rea ction s w ith Ca r bon yls. These first examples
constitute a new and straightforward route for the
construction of 3-spiropiperidines. To extend the scope
of this reaction, we tested the behavior of 2 toward
formaldehyde used either in excess or default. In the first
case, a double addition was observed and diol 8 was
obtained with good yield (Scheme 4). Among the few
aldehydes tested only formaldehyde gave double addi-
tion.17 When used in default, in dehydrating conditions,
the only isolated compound was the unsymmetrical dimer
9, obtained as a pure diastereomer in low yield. Once
again, trapping of the putative R,â-unsaturated iminium
10 by a nucleophile, in this case a second molecule of the
Another example of efficient access to a 3-spiropiperi-
dine was demonstrated when 2 was treated with glut-
araldehyde in boiling methanol (Scheme 3). Spirocom-
pound 7 was obtained as a single diastereomer. The first
step consisted of the reaction of the enamine 2 with
3838 J . Org. Chem., Vol. 69, No. 11, 2004

New Piperidine Scaffolds
SCHEME 5. Rea ction w ith Ma lon ic-Typ e Nu cleop h ile: En a m in e vs Im in iu m a
a
Reagents and conditions: methylacetoacetate (4 equiv), MeOH/H2O (7:3), reflux, 2 days (60%).
enamine form of 2, can explain the stereocontrolled
formation of 9.
Finally, to illustrate the primacy of the enamine
reactivity in mild conditions versus iminium electrophilic
reactivity, compound 11, a stable bis-vinylogous amide,
was synthesized as a 93:7 mixture of E/Z isomers by
treatment of 2 with an excess of methylacetoacetate in a
mixture of water and methanol at reflux. A likely
mechanism involves an initial attack of the enamine on
the ketone followed by dehydration of the quaternary
alcohol and isomerization of the iminium into the enam-
F IGURE 3. Retrosynthetic plans concerning sulfur substitu-
tions.
ine. No reaction on the iminium could be detected, which
could have led to a pelletierine-type compound after
decarboxylation (Scheme 5).
Ca r bon -Su lfu r Bon d F or m a tion a n d Access to a
New Aza bicyclic System . We then studied the pos-
sibility of creating a carbon-heteroatom bond from 2. We
chose to use sulfur-containing electrophiles for at least
two reasons. First, 3-thiopiperidines have been seldom
described in the literature,18 and second, on the basis of
the experience gained from MVK studies, a double
addition could conceivably provide access to a precursor
of a ketone function as represented in Figure 3. Such
target compounds could presumably give us a synthetic
pathway to 4-substituted piperidines after deprotonation
and alkylation.
F IGURE 4. Selected NMR data for compounds 12.
SCHEME 6. Ca r bon -Su lfu r Bon d F or m a tion a
We decided to use S-methylmethanethiosulfonate as
an electrophilic thiolating agent. When used in default
(0.5 equiv) at room temperature in methanol, monosub-
stituted compound 12 was formed in 70% yield (Scheme
6). If used in excess, a 1:1 mixture of compound 12 and
disubstituted 13 was obtained. Changes in experimental
conditions never made the sole obtention of 13 possible,
even when a large excess of reagent was engaged.
a
Reagents and conditions: MeSO2SMe (0.5 equiv), MeOH, rt,
3 days (70%, based on MeSO2SMe); (b) MeSO2SMe (10 equiv),
MeOH, rt, 5 days (12, 30%; 13, 30% based on 1).
Fortunately, both compounds were completely separable
by flash chromatography. Concerning diastereoselectivity
during the formation of 12, it appeared to be better than
the one observed with the MVK system (de 95%). Ster-
eochemistry at the C-2 and C-3 positions on the piperi-
dine ring was deduced from NMR studies (Figure 4). For
example, a trans diaxial coupling constant of 13 Hz was
measured between H-3 and axial H-4.
(16) For recent examples of spirocyclic compounds constructed by
the means of an enamine/Michael and aldol sequence, see: Christoffers,
J .; Kreidler, B.; Oertling, H.; Unger, S.; Frey, W. Synlett 2003, 493-
496. Christoffers, J .; Kreidler, B.; Unger, S.; Frey, W. Eur. J . Org.
Chem. 2003, 2845-2853.
(17) See ref 5 for examples.
We then investigated further transformations of com-
pound 13 into 3-oxopiperidine. By means of oxidative
conditions, we attempted to convert this dithioketal into
the corresponding ketone using bis-trifluoroacetoxyiodo-
benzene (BTIB) as described by Stork and Coll.19 This
method led not to the desired target molecule but rather
(18) For examples, see the following. (a) For the preparation of
racemic 3-thiopiperidines: Ibarra, C. A.; Cuervo, R.; Ferna´ndez-
Monreal, M. C.; Garc´ıa, M.; Ruiz, M. P.; Elliel, E. L. J . Chem. Soc.,
Perkin Trans 1 1991, 1473-1477. (b) For enantioselective strategy
starting from a lactam derived from (R)-(-)-phenylglycinol, see: Forns,
P.; Montserrat Ferna´ndez, M.; Diez, A.; Rubiralta, M.; Cherrier, M.-
P.; Bonin, M.; Quirion, J .-C. Synthesis 1999, 258-263.
J . Org. Chem, Vol. 69, No. 11, 2004 3839

Poupon et al.
Noteworthy were these molecules that can be rapidly
assembled using short sequences (maximum of two) of
simple transformations usually carried out in protic
solvents at room temperature (Figure 6). This work is
intended to show how diversity-oriented chemistry, using
simple starting materials, can lead to enantiopure drug-
like and/or natural product-like compounds.22
F IGURE 5. Selected NMR data for compounds 14.
Exp er im en ta l Section 23
4-[(3R,8aR)-8-(3-Oxo-bu tyl)-3-ph en yl-h exah ydr o-oxazolo-
[3,2-a ]p yr id in -8-yl]-bu ta n -2-on e 4. A solution of phenylox-
azolopiperidine 28 (500 mg, 2.46 mmol) and MVK (1.724 g, 2
mL, 24.6 mmol, 10 equiv) in MeOH (20 mL) was stirred at
room temperature for 6 days. The mixture was concentrated
under reduced pressure and the crude mixture submitted to
purification by flash chromatography on silica gel (cyclohexane/
ether 6:4) to afford 3 as a colorless oil: C21H29NO3, Rf ) 0.2
(cyclohexane/ether 6:4); [R]28 ) -71 (c 1, CHCl3); IR (film,
D
CHCl3) 1720 cm-1; H NMR (300 MHz, CDCl3) δ 1.01 (td, J
1
2
3J ) 14 Hz, 3J ) 5 Hz, 1 H), 1.34 (br d, 3J ) 13 Hz, 1 H),
2
3
1.45-1.65 (m, 4 H), 1.91 (td, J 3J ) 10 Hz, J ) 3 Hz), 1.98
(t, 3J ) 8.5 Hz), 2.11 (s, 3 H), 2.14 (s, 3 H), 2.25-2.50 (m, 3
H), 2.62 (dd, 3J ) 13 Hz, 3J ) 6 Hz, 1 H), 2.75 (m, 1 H), 3.35-
3.45 (m, 2 H), 3.48 (s, 1 H), 4.04 (t, 2J 3J ) 7 Hz, 1 H), 7.1-7.3
(m, 5 H); 13C NMR (75 MHz, CDCl3) δ 21.1, 21.2, 29.9, 30.6,
32.8, 37.8, 38.3, 47.9, 66.7, 73.0, 101.1, 127.6, 128.4, 138.8,
209.0, 209.4; MS (CI, NH3), m/z (M + H)+ 344; HRMS (CI,
CH4) m/z (M + 1)+ calcd for C21H30NO3 344.2225, found
344.2227.
F IGURE 6. Diverse structures from 2. (a) Ref 2, (b) this work.
SCHEME 7. Oxid a tive Rea r r a n gem en t of 13 in to
La cta m 14a
(1R,6R)-8-Acetyl-9-m eth yl-(3R-p h en yl-5H-oxa zolo[3,2-
a ])-2-a za -sp ir o[5.5]u n d ec-8-en e 5 a n d (1R,6S)-8-Acetyl-
9-m eth yl-(3R-p h en yl-5H-oxa zolo[3,2-a ])-2-a za -sp ir o[5.5]-
u n d ec-8-en e 6. Diketone 4 (172 mg, 0.98 mmol) was diluted
in concentrated hydrochloric EtOH (5 mL) and refluxed for
30 min. The reaction mixture was then brought to pH 9 by
addition of an aqueous solution of NaHCO3 and extracted (4
times) with CH2Cl2 (20 mL). The combined organic phases
were dried (Na2SO4) and concentrated under reduced pressure.
The oily residue was purified by flash chromatography on silica
gel (CH2Cl2/MeOH 98:2) to give in the order of elution 5 (48
mg, 30%) and 6 (49 mg, 30%) as colorless oils. Sp ir op ip er i-
a
Reagents and conditions: (CF3CO2)2IPh (2 equiv), CH3CN/H2O
(9:1), rt, 2 h (60%).
to the rearranged original lactam 14, obtained as a single
diastereomer in a very clean reaction (Scheme 7).20
Compound 14, sharing the same mass with the initial
target, constituted a chiral, nonracemic, unprecedented
bicyclic morpholinone-based scaffold that was fully and
unambiguously ascertained by two-dimensional NMR
(see Figure 5). An 8 Hz coupling constant between H-3
and axial H-4 was observed, indicating a cis equatorial/
axial relationship consistent with an axial position of the
oxygen at the C-3 position.
Recently, mild conditions of conversion of dithioketals
into the corresponding ketone function using Dess-
Martin periodinane have been reported.21 Starting from
13, similar conditions were disappointing, resulting in
the formation of a complex mixture of compounds.
d in e 5: C21H27NO2, Rf ) 0.6 (cyclohexane/ether 6:4); [R]20
)
D
-33 (c 1, CHCl3); IR (CHCl3, film) 1685, 1604 cm-1; H NMR
(300 MHz, CDCl3) δ 0.95 (td, 2J 3J ) 13.5 Hz, 3J ) 5.5 Hz),
1.25-1.35 (m, 1 H), 1.38-1.50 (m, 1 H), 1.58-1.72 (m, 1 H),
1
1.72-1.85 (m, 2 H), 1.86 (s, 3 H), 2.0 (td, J 3J ) 12 Hz, J )
2
3
3 Hz, 1 H), 2.08-2.20 (m, 2 H), 2.31 (s, 3 H), 2.43, 2.54 (2 d
2
2
3
(AB), J ) 17.5 Hz), 2.83 (dd, J ) 12 Hz, J ) 4.5 Hz), 3.4-
3.6 (m, 3 H), 4.16 (t, J 3J ) 7 Hz), 7.2-7.4 (m, 5H); 13C NMR
2
(75 MHz, CDCl3) δ 20.9, 21.2, 26.9, 29.5, 29.7, 30.0, 30.8, 48.0,
67.2, 73.4, 101.0, 127.6, 128.4, 132.3, 138.1, 138.7, 205.1; MS
(CI, NH3), m/z (M + 1)+ 326; HRMS (CI, CH4) m/z (M + 1)+
calcd for C21H28NO2 326.2120, found 326.2120. Sp ir op ip er i-
d in e 6: C21H27NO2, Rf ) 0.5 (cyclohexane/ether 6:4); [R]20
)
D
Con clu sion
-20 (c 1, CHCl3); IR (CHCl3, film) 1683, 1604 cm-1; H NMR
1
(300 MHz, CDCl3) δ 0.92 (td, 2J 3J ) 13.5 Hz, 3J ) 4 Hz), 1.35-
In conclusion, the present work illustrates the power
of compound 2 as a chiral and stable enamine equivalent
in the rapid and efficient construction of 3-subsituted
piperidines.
We aimed to demonstrate through this series of
examples that readily available stable tetrahydropyridine
surrogate 2 can lead to diverse and complex frameworks.
2
1.45 (m, 1 H), 1.65 (m, 3 H), 1.88 (s, 3 H), 2.05 (ddd, J ) 14
3
3
Hz, J ) 11.5 Hz, J ) 3 Hz, 1 H), 2.1-2.2 (m, 2 H), 2.23 (s, 3
2
3
3
H), 2.63 (ddd, J ) 16 Hz, J ) 2.5 Hz, J ) 2 Hz), 2.85 (ddd,
2J ) 11.5 Hz, J ) 4 Hz, J ) 2.5 Hz), 3.53 (m, 1 H), 3.65 (br
s, 1 H), 4.14 (t, 2J 3J ) 11.5 Hz, 1 H), 7.2-7.5 (m, 5 H); 13C
NMR (75 MHz, CDCl3) δ 21.1, 21.2, 21.3, 29.5, 30.1, 30.6, 36.2,
48.0, 67.1, 73.3, 99.9, 127.6, 128.4, 130.8, 139.0, 140.7, 203.7;
3
3
(19) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
Conditions as used in ref 18b.
(20) Mechanistic considerations for the ready formation of this 4-oxo-
1-azabicyclo[3.3.1]nonane derivative are discussed in Supporting
Information.
(21) Langille, N. F.; Dakin, L. A.; Panek, J . S. Org. Lett. 2003, 5,
575-578.
(22) Recent reviews in the field of piperidines and piperidones: (a)
Weintraub, P. M.; Sabol, J . S.; Kane, J . M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953-2989. (b) Buffat, M. G. P. Tetrahedron
2004, 60, 1701-1729.
(23) See ref 2 for general methods. All compounds were fully
characterized by IR, MS, HRMS, 1H NMR, 13C NMR, COSY, HETCOR
and, when needed, NOESY experiments.
3840 J . Org. Chem., Vol. 69, No. 11, 2004

New Piperidine Scaffolds
MS (CI, NH3), m/z (M + 1)+ 326; HRMS (CI, CH4) m/z (M +
128.6, 137.5, 139.5, 155.5, 168.9 ppm; MS (CI, NH3), m/z (M
+ 1)+ 302; HRMS (CI, CH4) m/z (M + 1)+ calcd for C18H24NO3
302.1756, found 302.1760.
1)+ calcd for C21H28NO2 326.2120, found 326.2135.
(1R,6S,7R,11S)-11-Meth oxy-(3R-p h en yl-5H-oxa zolo[3,2-
a ])-2-a za -sp ir o[5.5]u n d eca n -7-ol 7. A solution of 2 (100 mg,
0.49 mmol) and glutaraldehyde (192 mg, 1.96 mmol, 0.8 mL
of a 25% aqueous solution) in MeOH (10 mL) was refluxed for
18 h. The cooled mixture was diluted with a saturated solution
of NaHCO3 (30 mL) and extracted with CH2Cl2 (4 × 20 mL).
The dried (Na2SO4), combined organic layers were concen-
trated under reduced pressure and purified by flash chroma-
tography on silica gel (cyclohexane/ether 7:3) to afford spiropi-
peridine 7 as a colorless oil (77 mg, 50%): C19H27NO3, Rf )
(3R,8S,8a R)-8-Meth ylsu lfa n yl-3-p h en yl-h exa h yd r o-ox-
a zolo[3,2-a ]p yr id in e 12. A mixture of phenyloxazolopiperi-
dine 2 (50 mg, 0.24 mmol) and methylmethanethiosulfonate
(15 mg, 0.12 mmol, 0.5 equiv) in MeOH (5 mL) was stirred at
room temperature for 3 days. After concentration under
reduced pressure, the crude oily residue was submitted to
purification by flash chromatography on silica gel (cyclohexane/
ether 96:4) to afford thiopiperidine 12 as a colorless oil (15
mg, 50% based on thiosulfonate, recovered 2 ) 20 mg):
C
14H19NOS, Rf ) 0.4 (cyclohexane/ether 96:4); [R]25 ) -20 (c
0.3 (cyclohexane/ether 1:1); [R]20 ) -3 (c 1, CHCl3); 1H NMR
D
D
1, CHCl3); IR (film, CHCl3) 2886 cm-1
;
1H NMR (300 MHz,
(300 MHz, CDCl3) δ 1.2-2.2 (m, 11 H), 2.86 (br d, 3J ) 5.5
3
3
CDCl3) δ 1.35-1.60 (m, 1 H), 1.7-1.9 (m, 2 H), 1.9-2.2 (m, 2
Hz, 1 H), 3.11 (dd, J ) 12.5 Hz, J ) 3.5 Hz), 3.34 (s, 3 H),
3
3
H), 2.41 (s, 3 H), 2.85 (ddd, 3J ) 4 Hz, J ) 9 Hz, J ) 13 Hz),
3.49 (t, J 3J ) 8.5 Hz), 3.78 (t, J 3J ) 8.5 Hz), 4.1-4.2 (m, 1
H), 4.24 (s, 1 H), 4.27 (t, 2J 3J ) 8.5 Hz, 1 H), 7.2-7.4 ppm (m,
5 H); 13C NMR (75 MHz, CDCl3) δ 20.5, 20.6, 22.4, 24.5, 28.6,
44.8, 47.9, 57.5, 68.1, 71.8, 72.8, 79.8, 96.3, 127.6, 128.5, 128.7,
137.3 ppm; MS (CI, NH3), m/z (M + 1)+ 318; HRMS (CI, CH4)
m/z (M + 1)+ calcd for C19H28NO3 318.2069, found 318.2072.
2
2
2.95 (br d, J ) 10 Hz, 1 H), 3.65-3.85 (m, 3 H), 4.2 (t, J 3J
) 7.5 Hz, 1 H), 7.2-7.4 ppm (m, 5 H); 13C NMR (75 MHz,
CDCl3) δ 14.8, 25.4, 29.8, 47.2, 66.7, 73.0, 99., 127.6, 127.8,
128.4, 138.7 ppm; MS (CI, NH3), m/z (M + 1)+ 250; HRMS
(CI, CH4) m/z (M + 1)+ calcd for C14H20NOS 250.1266, found
250.1265.
2
2
[(3R,8a R)-8-H yd r oxym et h yl-3-p h en yl-h exa h yd r o-ox-
a zolo[3,2-a ]p yr id in -8-yl]-m eth a n ol 8. A mixture of 2 (200
mg, 0.98 mmol) and paraformaldehyde (150 mg, 4.92 mmol, 5
equiv) in MeOH (10 mL) was stirred at room temperature for
2 d. After concentration under reduced pressure, the crude
material was purified by flash chromatography on silica gel
(CH2Cl2/MeOH 97:3) to furnish diol 8 as a colorless oil (213
(3R,8a R)-8,8-Bis-m eth ylsu lfa n yl-3-p h en yl-h exa h yd r o-
oxa zolo[3,2-a ]p yr id in e 13. A solution of phenyloxazolopip-
eridine 2 (100 mg, 0.49 mmol) and an excess of methyl-
methanethiosulfonate (621 mg, 0.51 mL, 4.90 mmol, 10 equiv)
in MeOH (10 mL) was stirred at room temperature for 3 days.
After concentration under reduced pressure, the crude oily
residue was submitted to purification by flash chromatography
on silica gel (cyclohexane/ether 96:4) to afford bis-thiopiperi-
dine 13 as a colorless oil (43 mg, 30%), which crystallizes
slowly, followed by monothiopiperidine 12 (36 mg, 30%). 13:
mg, 82%); C15H21NO3, Rf ) 0.3 (CH2Cl2/MeOH 9:1); [R]20
)
D
1
-37 (c 1, CHCl3); H NMR (CDCl3) δ 0.9-2.0 (m, 4 H), 2.05
3
2
3
(td, 2J 3J ) 13 Hz, J ) 4 Hz), 2.9 (dd, J ) 13 Hz, J ) 4 Hz),
3.3-4.0 (m, 6 H), 3.8 (s, 1 H), 4.2 (t, 2J 3J ) 9 Hz), 7.1-7.5
ppm (m, 5 H); 13C NMR (CDCl3) δ 21.5, 28.4, 42.4, 47.8, 63.6,
66.7, 67.9, 73.3, 99.2, 127.6, 128.0, 128.6, 137.9 ppm; MS (CI,
NH3), m/z (M + 1)+ 264; HRMS (CI, CH4) m/z (M + 1)+ calcd
for C15H22NO3 264.1600, found 264.1608.
C
15H21NOS2, Rf ) 0.5 (cyclohexane/ether 96:4); [R]25 ) -1.5
D
(c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.4-1.55 (m, 2 H),
3
1.95-2.2 (m, 3 H), 2.07 (s, 3 H), 2.28 (s, 3 H), 2.85 (br d, J )
3
2
3
6 Hz, 1 H), 3.51 (t, J ) 8 Hz), 3.62 (dd, J ) 8 Hz, J ) 7.5
Hz, 1 H), 4.1 (s, 1 H), 4.17 (t, J 3J ) 8 Hz, 1 H), 7.2-7.5 ppm
2
(3R,8R,8a R)-8-[(3R,8R,8a R)-8-(3-P h en yl-h exa h yd r o-ox-
a zolo[3,2-a ]p yr id in e)]-m et h yl-3-p h en yl-h exa h yd r o-ox-
a zolo[3,2-a ]p yr id in e 9. A mixture of 2 (200 mg, 0.98 mmol)
and paraformaldehyde (27 mg, 0.88 mmol, 0.9 equiv) in MeOH
was stirred at room temperature for 6 days in the presence of
1 g of molecular sieves (4 Å). After filtration and washing with
CH2Cl2, the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica
gel (cyclohexane/ether 9:1) to give 9 (39 mg, 20%, recovered 2
(m, 5 H); 13C NMR (75 MHz, CDCl3) δ 10.4, 22.0, 32.8, 47.3,
62.4, 66.0, 73.5, 102.7, 127.7, 128.5, 138.5 ppm; IR (film,
CHCl3) 2886 cm-1; MS (CI, NH3), m/z (M + 1)+ 296; HRMS
(CI, CH4) m/z (M + 1)+ calcd for C15H22NOS2 295.1065, found
295.1067.
(2R,5R)-2-P h en yl-4-oxa -1-a za -b icyclo[3.3.1]n on a n -9-
on e 14. Bis-thiopiperidine 13 (54 mg, 0.13 mmol) was dis-
solved in a mixture of acetonitrile and water (9:1, 10 mL). Bis-
trifluoroacetoxyiodobenzene (146 mg, 0.27 mmol, 2 equiv) was
then added at once. After 2 h of stirring at room temperature,
the reaction mixture was diluted with an aqueous saturated
solution of NaHCO3 (30 mL) and extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to give an oily residue
that was purified by flash chromatography (CH2Cl2/MeOH 99:
1) to afford lactam 14 (29 mg, 60%) as a colorless oil:
) 11 mg): colorless oil; C27H34N2O2, Rf ) 0.3 (cyclohexane/ether
1
8:2); [R]18 ) -51 (c 0.5, CHCl3); H NMR (300 MHz, CDCl3)
D
2
3
δ 1.0-2.2 (m, 7 H), 2.85 (br d, J ) 10.5 Hz), 3.4 (d, J ) 10
Hz, 1H), 3.53 (t, J ) 7 Hz), 3.64 (td, J 3J ) 7 Hz, J ) 1.5
3
2
3
Hz, 1 H), 4.16 (t, 2J 3J ) 7 Hz, 1 H), 7.2-7.4 ppm (m, 5 H); 13
C
NMR (75 MHz, CDCl3) δ 24.9, 28.1, 33.0, 37.5, 47.7, 67.4, 72.8,
99.1, 127.7, 128.4, 138.4 ppm; MS (CI, NH3), m/z (M + 1)+ 419;
HRMS (CI, CH4) m/z (M + 1)+ calcd for C27H35N2O2 419.2699,
found 419.2695.
C
13H15NO2, Rf ) 0.3 (CH2Cl2/MeOH 99:1); IR (film, CHCl3)
1676 cm-1 1H NMR (300 MHz, CDCl3) δ 1.7-1.9 (m, 2 H),
2.2-2.35 (m, 2 H), 2.35-2.5 (m, 1 H), 2.9-3.1 (m, 1 H), 2.9-
;
3-[1-(2-H yd r oxy-1R-p h en yl-et h yl)-1,4,5,6-t et r a h yd r o-
p yr id in -3-yl]-bu t-2-en oic Acid Meth yl Ester 11. A solution
of 2 (1 g, 4.92 mmol) and methylacetoacetate (2.28 g, 2.12 mL,
19.70 mmol, 4 equiv) in a (7:3) MeOH/H2O mixture (25 mL)
was refluxed for 2 days. The cooled mixture was diluted with
water (100 mL) and extracted with CH2Cl2 (3 × 40 mL). The
combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. Purification of the oily residue by
flash chromatography (CH2Cl2/MeOH 99:1) afforded 11 as a
yellowish oil (892 mg, 60%). 11 (93:7 mixture of E/Z isomers):
3
3
3.1 (m, 1 H), 3.78 (t, J ) 7 Hz), 4.08 (t, J ) 7.5 Hz,), 4.35 (d,
3J ) 7 Hz), 7.2-7.7 (m, 5 H); 13C NMR (75 MHz, CDCl3) δ
20.3, 23.9, 53.8, 58.8, 63.9, 71.8, 127.2, 127.7, 127.8, 128.1,
128.6, 138.2, 173.5 ppm; MS (ESI), m/z (M + K)+ 256; HRMS
(ESI) m/z (M + K)+ calcd for C13H15NO2K 256.0740, found
256.0738.
Ackn owledgm en t. Jean-Christophe Jullian is grate-
fully acknowledged for NMR assistance.
C
18H23NO3, Rf ) 0.3 (CH2Cl2/MeOH 97:3); [R]20 ) -91 (c 1,
D
CHCl3); IR (film, CHCl3) 3384, 1553, 1162, 1136 cm-1; 1H NMR
(major diastereomer) (300 MHz, CDCl3) δ 1.80-1.90 (m, 2 H),
2.15-2.25 (m, 2 H), 2.37 (s, 3 H), 2.90-3.00 (m, 1 H), 3.00-
Su p p or tin g In for m a tion Ava ila ble: Improved procedure
1
for the preparation of 2, H and 13C NMR spectra for all new
compounds (4-9, 11-14), and mechanistic considerations for
the formation of 14. This material is available free of charge
via the Internet at http://pubs.acs.org.
3
3.10 (m, 1 H), 3.65 (s, 3 H), 4.00-4.20 (m, 2 H), 4.35 (dd, J )
3
5.5 Hz, J ) 5 Hz, 1 H), 5.41 (s, 1 H), 7.05 (s, 1 H), 7.15-7.45
ppm (m, 5 H); 13C NMR (75 MHz, CDCl3) δ 13.6, 21.6, 22.1,
43.8, 50.3, 62.0, 69.0, 103.0, 107.2, 126.9, 127.6, 127.8, 128.4,
J O0499524
J . Org. Chem, Vol. 69, No. 11, 2004 3841