Synthesis of stereodefined piperidines from aziridines and their transformation into conformationally constrained amino acids, amino alcohols and 2,7-diazabicyclo[3.3.1]nonanes

Article abstract of DOI:10.1021/jo101646u

2-(2-Cyano-2-phenylethyl)aziridines were converted into novel cis- and trans-2-chloromethyl-4-phenylpiperidine-4-carbonitriles via alkylation with 1-bromo-2-chloroethane followed by microwave-assisted 6-exo-tet cyclization and regiospecific ring opening.

Full text of DOI:10.1021/jo101646u

pubs.acs.org/joc
Synthesis of Stereodefined Piperidines from Aziridines and Their
Transformation into Conformationally Constrained Amino Acids,
Amino Alcohols and 2,7-Diazabicyclo[3.3.1]nonanes
†
Karel Vervisch, Matthias D’hooghe, Karl W. Tornroos, and Norbert De Kimpe*
†
‡
,†
€
†Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering,
Ghent University, Coupure Links 653, B-9000 Ghent, Belgium, and ‡Department of Chemistry,
ꢀ
University of Bergen, Allegt 41, 5007 Bergen, Norway
norbert.dekimpe@UGent.be
Received August 20, 2010
2-(2-Cyano-2-phenylethyl)aziridines were converted into novel cis- and trans-2-chloromethyl-
4-phenylpiperidine-4-carbonitriles via alkylation with 1-bromo-2-chloroethane followed by micro-
wave-assisted 6-exo-tet cyclization and regiospecific ring opening. The latter piperidines were used
as eligible substrates for the synthesis of stereodefined 2-chloromethyl-, 2-hydroxymethyl-, and
2-carboxymethyl-4-phenylpiperidine-4-carboxylic acids, 2-hydroxymethyl-4-phenylpiperidine-
4-carbonitriles, 3-hydroxy-5-phenylazepane-5-carbonitriles, and 5-phenyl-2,7-diazabicyclo[3.3.1]nonanes.
Introduction
for piperidine synthesis has attracted the attention of the
organic chemistry community for many years.2 In particular,
4-arylpiperidines represent an interesting class of biologically
relevant compounds, about which numerous examples can be
foundinthe patentliterature.3 4-Arylpiperidinesareknownto
be useful as for example tachykinin antagonists for the
treatment of pain and inflammation,4 and as R-1a adrenergic
receptor antagonists for the treatment of prostate disorders.5
The piperidine ring comprises an important structural unit
in natural products and biologically active agents, and
several thousands of piperidine compounds have been eval-
uated in clinical and preclinical studies.1 For these reasons,
the search for general, efficient, and stereoselective methods
(1) Watson, P. S.; Jiang, B.; Scott, B. Org. Biomol. Chem. 2000, 2,
3679.
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(3) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601.
(4) Macleod, A. M.; Stevenson, G. I. WO/94/13639, 1994. CAN
121:205217.
(5) Bock, M. G.; Patane, M. A.; Ponticello, R. A. WO/97/17967, 1997.
CAN 127:65787.
€
(2) (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (b) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953.
(c) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem Commun. 1998,
633. (d) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000,
2862.
7734 J. Org. Chem. 2010, 75, 7734–7744
Published on Web 10/26/2010
DOI: 10.1021/jo101646u
r
2010 American Chemical Society

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Moreover, a number of drugs each accommodates a 4-aryl-
piperidine unit in its structure, such as the analgesic meperi-
dine 1 and the antipsychotic haloperidol 2.6
been reported so far.11 Nevertheless, their synthetic useful-
ness has been demonstrated recently through the development
of a versatile aziridine-to-cyclopropane ring transforma-
tion.12 In continuation of our interest in 2-(cyanoalkyl)-
aziridines12,13 as substrates in organic chemistry, a new pro-
tocol for the conversion of 2-(2-cyanoethyl)aziridines into
functionalized piperidines was developed.
1-Arylmethyl-2-(bromomethyl)aziridines, 4, prepared from
the corresponding benzaldehydes in a three-step procedure,14
are known to be excellent substrates for the synthesis of a
variety of 2-substituted 1-(arylmethyl)aziridines.12,15 Thus,
2-(bromomethyl)aziridines 4 were treated with 1.1 equiv of
R-lithiated phenylacetonitrile in THF, affording 2-(2-cyano-2-
phenylethyl)aziridines, 5, as mixtures of diastereomers in good
yields.12b With the intention to introduce a 2-chloroethyl group
in the R-position with respect to the nitrile moiety in aziridines
5, the coupling between 1-bromo-2-chloroethane and aminoni-
triles 5 was accomplished using 1.2 equiv of lithium diisopro-
pylamide (LDA) in THF, furnishing novel 4-chloro-2-
[1-(arylmethyl)aziridin-2-ylmethyl]-2-phenylbutyronitriles
6 and 7 as a mixture of diastereomers (∼1/1) after one hour at
0 °C (Scheme 1). Interestingly, diastereomers 6 could be
easily isolated from the mixtures by crystallization from
ethanol (15-40% yield), and diastereomers 7 were obtained
in pure form through column chromatography on silica gel
(hexane/EtOAc, 3:1, 15-35% yield), allowing their full spec-
troscopic characterization.
From a synthetic point of view, aziridines have proven to
be excellent precursors for the preparation of functionalized
piperidines. Indeed, intramolecular ring opening of aziridines
by a remote amino moiety7 and ring opening using Grignard
reagents followed by elaboration of the tethered side chain8 are
known strategies for the synthesis of piperidines starting
from aziridines. Alternatively, [3þ3]-cycloadditions of Pd-
trimethylenemethane complexes with enantiomerically pure
aziridines,9 and aza-[2,3]-Wittig rearrangements of vinylaziri-
dines10 have also been used successfully in that respect.
In this paper, an efficient and direct method toward the
novel 2-chloromethyl-4-phenylpiperidine-4-carbonitrile scaf-
fold is presented starting from 2-(2-cyano-2-phenylethyl)-
aziridines. Piperidine-4-carbonitriles were employed success-
fully as substrates for the synthesis of a wide variety of
stereodefined piperidines ranging from γ-amino acids and
adipic acid derivatives to bicyclic piperidines with biological
interest.
The incorporation of a leaving group in the ε-position with
regard to the aziridine nitrogen atom renders aziridines 6 and
7 excellent substrates for a 6-exo-tet ring closure toward
intermediate bicyclic aziridinium salts, suitable for further
elaboration. It should be noted thatthe R-alkylation of nitriles
using 2-chloro-1-haloethanes has scarcely been reported in
the literature.16
Results and Discussion
(12) (a) D’hooghe, M.; Vervisch, K.; De Kimpe, N. J. Org. Chem. 2007,
€
72, 7329. (b) Vervisch, K.; D’hooghe, M.; Tornroos, K. W.; De Kimpe, N.
Org. Biomol. Chem. 2009, 7, 3271.
The chemistry of 2-(2-cyanoethyl)aziridines remains an
underexplored field of research, as only a few examples have
(13) (a) D’hooghe, M.; Mangelinckx, S.; Persyn, E.; Van Brabandt, W.;
De Kimpe, N. J. Org. Chem. 2006, 71, 4232. (b) D’hooghe, M.; Vervisch, K.;
Van Nieuwenhove, A.; De Kimpe, N. Tetrahedron Lett. 2007, 48, 1771.
(14) (a) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc., Chem.
Commun. 1994, 1221. (b) De Kimpe, N.; De Smaele, D.; Szakonyi, Z. J. Org.
Chem. 1997, 62, 2448. (c) D’hooghe, M.; Waterinckx, A.; De Kimpe, N.
J. Org. Chem. 2005, 70, 227. (d) D’hooghe, M.; Rottiers, M.; Jolie, R.;
De Kimpe, N. Synlett 2005, 931.
(6) (a) Vila, X.; Zard, S. Z. Heterocycles 2006, 70, 45. (b) Targum, S.;
Zborowski, J.; Henry, M.; Schmitz, P.; Sebree, T.; Wallin, B. Eur. Neuro-
psychopharmacol. 1995, 5, 4. (c) Janssen, P. A. J.; Niemegeers, C. J. E.;
Schellekens, K. H. L. Arzneim.-Forsch. 1959, 9, 765.
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7, 706.
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(b) Mumford, P. M.; Tarver, G. J.; Shipman, M. J. Org. Chem. 2009, 74,
3573.
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(b) Hedley, S. J.; Moran, W. J.; Prenzl, A. H. G. P.; Price, D. A.; Harrity,
J. P. A. Synlett 2001, 1596.
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Tetrahedron 1971, 27, 3527. (b) Nayak, S. K.; Lambertus, T.; Zwanenburg,
B. Tetrahedron Lett. 1999, 40, 981.
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hedron 2005, 61, 8746. (b) D’hooghe, M.; Kerkaert, I.; Rottiers, M.;
De Kimpe, N. Tetrahedron 2004, 60, 3637. (c) D’hooghe, M.; Waterinckx,
A.; Vanlangendonck, T.; De Kimpe, N. Tetrahedron 2006, 62, 2295.
(d) D’hooghe, M.; De Kimpe, N. Arkivoc 2008, No. ix, 6.
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Synth. Commun. 2007, 37, 3793. (b) Burk, R. M.; Overman, L. E. Hetero-
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Interestingly, when heated under reflux in THF, no cycli-
zation of aziridines 6 and 7 toward piperidines took place.
Clearly, a more polar solvent had to be used to allow intra-
molecular substitution and to stabilize the intermediate bicyclic
aziridinium ions. In accordance with the previously reported
ring-opening reactions of nonactivated aziridines with ben-
zyl bromide,12,15d,17 acetonitrile was used as a solvent, and
the premised 6-exo-tet ring-expansion reaction of aziridines
6 and 7 proceeded nicely under microwave irradiation at 136 °C
for 30 min or, alternatively, in DMSO for 3 h under reflux
applying conventional heating, affording 2-chloromethyl-4-
phenylpiperidine-4-carbonitriles 9 and 11 in excellent yields
and purity (Scheme 2). The proposed mechanism involves an
intramolecular substitution reaction, furnishing bicyclic
aziridinium intermediates 8 and 10, followed by regiospecific
ring opening by chloride at the less hindered aziridine
carbon atom toward 2-chloromethyl-4-phenylpiperidine-4-
carbonitriles 9 and 11.
Alternatively, trans-piperidines 11 were isolated more easily
performing the 6-exo-tet ring-expansion reaction on the diaste-
reomeric mixture of aziridines 6 and 7, as trans-piperidines 11
could be crystallized from the reaction mixture using ethanol as
a solvent [40-43% of piperidines 11 starting from 2-(2-cyano-
2-phenylethyl)aziridines, 5]. The relative stereochemistry of
trans-2-chloromethyl-4-phenylpiperidine-4-carbonitriles, 11,
was unambiguously assigned by X-ray crystallographic
analysis of piperidine 11b (see Supporting Information).
2-Chloromethyl-4-phenylpiperidine-4-carbonitriles 9 and
11 exhibit a number of interesting structural characteristics,
making them suitable substrates for further elaboration. For
example, the presence of a cyano substituent at the 4-position
of the piperidine backbone provides an entry into conforma-
tionally restricted amino acid derivatives. Additionally, the
2-chloromethyl moiety is susceptible to nucleophilic substi-
tution reactions, both intra- and intermolecularly.
blocks for the corresponding β- and γ-peptides make these
compounds of high relevance in synthetic and medicinal
chemistry.18 Besides their use in peptidomimetics, some
β-amino acids exhibit strong antibacterial activity (e.g.,
cispentacin),18b while γ-amino acids are used for the treat-
ment of epilepsy, Parkinson disease, and schizophrenia (e.g.,
GABA analogues).19 In continuation of our interest in β-amino
acid chemistry,20 intensive efforts were devoted to the develop-
ment of new entries toward different constrained amino acids
bearing a piperidine moiety in their structure, starting from the
corresponding nitriles. Due to the synthetic utility of nitriles as
precursors of carboxylic acids, esters, and amides, the search for
novel types of functionalized aminonitriles has become an
important challenge in organic synthesis.21
In the first part of this work, cis-piperidine 9c was hydro-
lyzed, utilizing a HCl (3 M)/HOAc (6 M) mixture in water
under microwave irradiation for 1 h at 150 °C, resulting in
the formation of an inseparable mixture of 2-(chloromethyl)-
and 2-(hydroxymethyl)piperidines 12 and 13 (ratio 2:3). Sub-
sequently, this mixture was treated with 2 equiv of LiOH in
water for 30 min under reflux, followed by purification on
Dowex (Hþ, 50 ꢀ 8-100), furnishing ammonium cis-1-
(4-chlorobenzyl)-2-hydroxymethyl-4-phenylpiperidine-4-carbox-
ylate, 14, as the sole reaction product in 80% yield (Scheme 3).
Furthermore, trans-piperidine 11c was subjected to reac-
tion conditions similar to those of cis-isomer 9c, i.e. hydrolysis
(19) (a) Felluga, F.; Gombac, V.; Pitacco, G.; Valentin, E. Tetrahedron:
Asymmetry 2005, 16, 1341. (b) Goka, V. N.; Stenbol, T. B.; Krogsgaard-
Larsen, P.; Schlewer, G. Eur. J. Med. Chem. 2004, 39, 889. (c) Krogsgaard-
Larsen, P.; Scheel-Kruger, J.; Kofold, H. GABA-Neurotransmitters: Phar-
macochemical, Biochemical and Pharmacological Aspects; Munksgaard:
Copenhagen, 1979; p 552.
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(20) (a) Leemans, E.; D’hooghe, M; Dejaegher, Y.; Tornroos, K.;
De Kimpe, N. Eur. J. Org. Chem. 2010, 352. (b) Mangelinckx, S.; D’hooghe,
M.; Peeters, S.; De Kimpe, N. Synthesis 2009, 1105. (c) Mangelinckx, S.;
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_
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Zukauskaite, A.; Buinauskaite, V.; Sacus, A.; De Kimpe, N. Tetrahedron
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Lett. 2008, 49, 6896. (d) Kiss, L.; Mangelinckx, S.; Fulop, F.; De Kimpe, N.
€
Org. Lett. 2007, 9, 4399. (e) Giubellina, N.; Mangelinckx, S.; Tornroos,
β- and γ-Amino acids are known to possess unique phar-
macological properties, and their applications as building
K. W.; De Kimpe, N. J. Org. Chem. 2006, 71, 5881. (f) Mangelinckx, S.;
De Kimpe, N. Synlett 2005, 1521. (g) Colpaert, F; Mangelinckx, S.;
De Kimpe, N Org. Lett. 2010, 12, 1904.
(21) (a) Groger, H. Chem. Rev. 2003, 103, 2795. (b) Enders, D.; Shilvock,
J. P. Chem. Soc. Rev. 2000, 29, 359. (b) Blanco-Ania, D.; Valderas-Cortina,
C.; Hermkens, P. H. H.; Sliedregt, L. A. J. M.; Scheeren, H. W.; Rutjes, F. P.
J. T. Molecules 2010, 15, 2269. (c) Vink, M. K. S.; Schortinghuis, C. A.;
Luten, J.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes,
F. P. J. T. J. Org. Chem. 2002, 67, 7869. (d) Vink, M. K. S.; Wijtmans, R.;
Reisinger, C.; Van den Berg, R. J. F.; Schortinghuis, C. A.; Schwab, H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Biotechnol. J. 2006,
1, 569–573.
(17) (a) D’hooghe, M.; Van Brabandt, W.; De Kimpe, N. J. Org. Chem.
2004, 69, 2703. (b) D’hooghe, M.; Van Speybroeck, V.; Waroquier, M.;
De Kimpe, N. Chem. Commun. 2006, 1554. (c) D’hooghe, M.; De Kimpe, N.
Synlett 2006, 2089.
(18) (a) Juaristi., E.; Soloshonok, V. In Enantioselective Synthesis of
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β-Amino Acids; Wiley: NJ, 2005; Vol. 2, p 634. (b) Fulop, F.; Martinek,
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T. A.; Toth, G. K. Chem. Soc. Rev. 2006, 35, 323. (c) Fulop, F. Chem. Rev.
2001, 101, 2181.
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using a HCl (3 M)/HOAc (6 M) mixture in water under
microwave irradiation for 1 h 40 min at 150 °C, furnishing
trans-1-(4-chlorobenzyl)-2-chloromethyl-4-phenylpiperidine-
4-carboxylic acid 15 in 85% yield. Remarkably, no forma-
tion of the corresponding 2-(hydroxymethyl)piperidine was
observed in the latter case, pointing to a considerable steric
hindrance with regard to attack of the chlorinated carbon
atom in piperidine 11c and 15. Stereodefined 4-phenylpiper-
idine-4-carboxylic acids 14 and 15 represent a new class of
constrained γ-amino acids with biological relevance.
In light of the known biological importance of 3-amino-
adipic acids,22 efforts were made for the preparation of novel
conformational constrained analogues bearing a piperidine
framework. Thus, cis-2-chloromethyl-4-phenylpiperidine-
4-carbonitrile 9c was treated with 2 equiv of potassium cyanide
in DMSO, furnishing the corresponding cis-2-cyanomethyl-
4-phenylpiperidine-4-carbonitrile 16 after 1 h at 120 °C in
92% yield. From a mechanistic viewpoint, piperidine 9c
probably undergoes an intramolecular substitution reaction
toward bicyclic aziridinium intermediate 8c, followed by
regiospecific ring opening of this aziridinium salt by cyanide
at the least hindered position, although direct SN2-substitu-
tion at the chlorinated atom cannot be excluded. Upon 3D-
analysis of intermediate 8c, the occurrence of a favor-
able π-π-stacking23 between both aromatic rings can be
observed, which results in steric hindrance at the substituted
aziridinium carbon atom. This effect might (partially) ex-
plain the exclusive attack that occurred at the unhindered
position, resulting in the selective formation of piperidine 16.
Next, both cyano groups in compound 16 were transformed
to the corresponding carboxylic acids by acid hydrolysis.
Thus, treatment of dicyanopiperidine 16 with a HCl (3 M)/
HOAc (6 M) mixture in water gave rise to cis-2-carboxy-
methyl-1-(4-chlorobenzyl)-4-phenylpiperidine-4-carboxylic
acid 17 in 95% yield as a new constrained analogue of
3-aminoadipic acid after reflux for 3 days (Scheme 4).
Analogously, trans-1-(4-chlorobenzyl)-2-chloromethyl-
4-phenylpiperidine-4-carbonitrile 11c was treated with 2 equiv
of potassium cyanide in DMSO, resulting in a mixture of
azepane-3,5-dicarbonitrile 18 and 2-(cyanomethyl)piperidine-
4-carbonitrile 19 (ratio 3:10) after 1 h at 120 °C. Probably,
due to the absence of π-π-stacking interaction, competition
between attack at the unsubstituted and the substituted
positions in aziridinium intermediate 10c occurred, resulting
in a mixture of azepane 18 and piperidine 19. Interestingly,
azepane 18 could be easily transformed into the thermody-
namically more stable piperidine 19 by heating the mixture of
azepane 18 and piperidine 19 in DMSO at 120 °C for 4 h,
affording 2-(cyanomethyl)piperidine 19 as the sole reaction
product. Eventually, a nitrile to acid functional group trans-
formation was performed in acidic medium (HCl (3 M)/
HOAc (6 M) in H2O under reflux for 6 days), furnishing
trans-2-carboxymethyl-1-(4-chlorobenzyl)-4-phenylpiperidine-
4-carboxylic acid 20 in 95% yield (Scheme 4). In summary,
the above-described methodology allows the stereoselective
preparation of both diastereomers of 2-carboxymethyl-4-
phenylpiperidine-4-carboxylic acids 17 and 20 as biologically
relevant targets, underlining to the synthetic utility of this
approach.
In addition to cyanide, acetate was used as an oxygen
nucleophile for the synthesis of versatile β-amino alcohols
using the same approach as described above. β-Amino
alcohols comprise an important class of compounds, as this
moiety is found in a wide variety of biologically active
alkaloids and peptides.24 Furthermore, β-amino alcohols
find applications as building blocks in the synthesis of
various natural products and pharmaceuticals,25 and they
(24) (a) Olofsson, B.; Somfai, P. J. Org. Chem. 2002, 67, 8574.
(b) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120,
431. (c) Castejon, P.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron
1996, 52, 7063.
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Chem. 2001, 25, 221. (b) Rodriguez, J. R.; Navarro, A. Tetrahedron Lett.
2004, 45, 7495.
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Bioorg. Med. Chem. 2009, 17, 2038. (b) Bautista, A. D.; Appelbaum, J. S.;
Craig, C. J.; Michel, J.; Schepartz, A. J. Am. Chem. Soc. 2010, 132, 2904.
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Van Speybroeck, V. J. Org. Chem. 2010, 75, 885.
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SCHEME 4
are useful as chiral auxiliaries for asymmetric synthesis and
catalysis.26
gel, providing a pure sample suitable for full spectroscopic
characterization.
cis-2-Chloromethyl-4-phenylpiperidine-4-carbonitriles 9a,c
were treated with 2 equiv of sodium acetate in ethanol,
affording cis-6-acetoxy-4-phenylazepane-4-carbonitriles 21
and cis-2-acetoxymethyl-4-phenylpiperidine-4-carbonitriles
22 in a ratio of 1:2 after 2 h under reflux (Scheme 5). Again,
the reaction proceeded via intermediate bicyclic aziridinium
salts 8a,c, followed by preferential ring opening of the latter
salts by acetate at the least hindered position. In this case,
prolonged heating did not afford a single thermodynamic
product, in contrast with the synthesis of aminonitriles 19
(Scheme 4). Furthermore, changing the solvent from ethanol
to DMSO did not alter the isomeric ratio of the obtained
products 21 and 22. Unfortunately, piperidines 22 and
azepanes 21 appeared to be inseparable by column chroma-
tography on silica gel.
Analogously, trans-piperidine 11c was subjected to a
nucleophilic substitution reaction using sodium acetate in
ethanol. In this case, the reaction proceeded more sluggishly,
and only after 13 h of reflux was the substrate consumed
completely, affording a mixture of trans-6-acetoxy-4-phenyl-
azepane-4-carbonitrile 25 and trans-2-acetoxymethyl-
4-phenylpiperidine-4-carbonitrile 26 (25/26, 3:1). Due to
the long reaction time, partial formation (26%) of hydro-
lyzed products 27 and 28 was observed as well under the
given reaction conditions, making a full characterization of
acetates 25 and 26 impossible. In an attempt to shorten the
reaction time, experiments were conducted using microwave
irradiation, resulting in a reduction of the conversion time
from 13 h to 20 min at 110 °C using 2 equiv of NaOAc in
EtOH. Also in this case, the reaction mixture contained a
mixture of both the acetates 25 and 26 as major components
(74%) and alcohols 27 and 28 as minor impurities (26%).
Again, functional group transformation of the acetate to
corresponding alcohol was performed using 2 equiv of LiOH
in MeOH for 1 h at reflux temperature, furnishing trans-
6-hydroxy-4-phenylazepane-4-carbonitrile 27 and trans-
2-hydroxymethyl-4-phenylpiperidine-4-carbonitrile 28 in 79%
yieldina ratio of 3:1 (27/28). Carbonitrile27 was separated via
column chromatography on silica gel, affording an analyt-
ically pure sample.
Finally, acetates 21b and 22b were hydrolyzed using 2
equiv of lithium hydroxide in methanol under reflux for 2 h,
furnishing a mixture of cis-6-hydroxy-4-phenylazepane-4-
carbonitrile 23 and cis-2-hydroxymethyl-4-phenylpiperi-
dine-4-carbonitrile 24 in 83% yield (Scheme 5). Piperidine
24 was separated through column chromatography on silica
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1996, 96, 835. (c) Chakraborti, A. K.; Kondaskar, A. Tetrahedron Lett. 2003,
44, 8315.
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It should be remarked that, starting from cis-piperidines
9a,c, the preferential formation of piperidines 22 was ob-
served, whereas azepane 25 was the major reaction product if
trans-piperidine 11c was used as a substrate. This observa-
tion can partially be explained by considering π-π-stacking
in intermediates 8a,c, making an attack at the substituted
aziridinium carbon atom more difficult due to steric hin-
drance. In addition, the polarizability of the nucleophiles
might play an important role with regard to the regioselec-
tivity, with cyanide being a strong and acetate a moderate
nucleophile.
It should be noted that the ring enlargement of 2-(halo-
methyl)piperidines to 3-substituted azepanes via intermedi-
ate aziridinium salts has only been described sporadically in
the literature.27
Finally, attempts were made to induce dehydrochlorina-
tion of 2-chloromethyl-4-phenylpiperidine-4-carbonitriles 9
and 11, followed by migration of the double bond toward the
thermodynamically more stable endocyclic position in order
to form tetrahydropyridine-4-carbonitriles. Many bases (KOtBu,
NaH, LDA) and solvents (THF, tBuOH, DMSO) were used, but
complex reaction mixtures were obtained in all cases.
Next to intermolecular nucleophilic substitutions with
cyanide and acetate, an intramolecular reaction of cis-
2-(chloromethyl)piperidines 9 was examined, taking ad-
vantage of the presence of a nitrile group at the 4-position
as a masked aminomethyl moiety. Gratifyingly, treatment
of piperidines 9 with 2 equiv of LiAlH4 in THF afforded
5-phenyl-2,7-diazabicyclo[3.3.1]nonanes 29 as single reac-
tion products (Scheme 6, yields after purification). This
conversion proceeded via the formation of an aminomethyl
substituent through cyanide reduction, which subsequently
induced an intramolecular 6-exo-tet ring closure toward
5-phenyl-2,7-diazabicyclo[3.3.1]nonanes 29 by attack of the
free amino moiety onto the chlorinated carbon atom. At first
sight, it cannot be excluded that this ring-closing reaction
proceeds via an intermediate bicyclic aziridinium salt 8 as
described above, which might give rise to 6-phenyl-3,8-
diazabicyclo[4.2.1]nonanes upon ring opening as an alter-
native for 5-phenyl-2,7-diazabicyclo[3.3.1]nonanes 29. In
order to confirm the presence of a bicyclo[3.3.1]nonane
instead of a bicyclo[4.2.1]nonane skeleton in the obtained
(27) (a) Chong, H.-S.; Garmestani, K.; Bryant, H. L., Jr.; Brechbiel,
M. W. J. Chem. Soc., Perkin Trans. 1 2002, 2080. (b) Chong, H.-S.;
Garmestani, K.; Bryant, H. L., Jr.; Brechbiel, M. W. J. Org. Chem. 2001,
66, 7745. (c) Berkes, D.; Decroix, B. B. Soc. Chim. Fr. 1994, 131, 986.
(d) Morie, T.; Kato, S.; Harada, H.; Fujiwara, I.; Watanabe, K.; Matsumoto,
J. J. Chem. Soc., Perkin Trans. 1 1994, 2565.
J. Org. Chem. Vol. 75, No. 22, 2010 7739

Vervisch et al.
JOCArticle
SCHEME 6
reaction products, the free amino group at the 7-position
was protected with a tert-butoxycarbonyl group using 1.1
equiv of di-tert-butyl dicarbonate, 1.1 equiv of pyridine, and
DMAP (10 mol %) as the catalyst in CH2Cl2 for 3 h at room
temperature (Scheme 6). This protection step resulted in
substantial shifts of the signals of two CH2N carbon atoms
in the Boc-protected amine 30 (46.39 ppm f 42.84 ppm and
58.68 ppm f 53.19 ppm, 13C NMR, CDCl3), whereas a less
pronounced shift was observed for the CHN signal (52.09
ppm f 50.82 ppm). These observations point into the direc-
tion of a bicyclo[3.3.1]nonane backbone. In order to resolve
all doubts, X-ray analysis of compound 29c unambiguously
assigned the 5-phenyl-2,7-diazabicyclo[3.3.1]nonane system
present in compounds 29 obtained through reduction of
piperidines 9 by LiAlH4 (see Supporting Information).
In this way, a convenient entry toward the 2,7-diazabicyclo-
[3.3.1]nonane28 skeleton is presented through a straightfor-
ward approach. These compounds 29 can be regarded as
novel aza-analogues of 5-phenylmorphans 32, which act as
opioid agonists or antagonists.29
In analogy, trans-piperidines 11a,b were treated with 2
equiv of LiAlH4 in THF under refux for 2 h, resulting in the
formation of trans-4-aminomethyl-2-methyl-4-phenylpiper-
idines 31 in 60-65% yield (Scheme 6). The dechlorination of
2-(chloromethyl)piperidines 11 can take place via initial
formation of an intermediate aziridinium salt 10 or via direct
dechlorination, following either an ionic or a radical path-
way.30 4-(Aminomethyl)piperidines have been patented as
potent tachykinin antagonists for the treatment of pain and
inflammation,4 and can be used for the treatment of epilepsy,
anxiety and inflammatory diseases.31
In conclusion, a short and convenient approach toward
novel cis- and trans-2-chloromethyl-4-phenylpiperidine-4-
carbonitriles is reported starting from 2-(2-cyano-2-phenylethyl)-
aziridines. Furthermore, the high synthetic flexibility of these
piperidine building blocks was demonstrated by the synthesis of a
variety of stereodefined conformationally constrained amino
acids, β-amino alcohols, and unprecedented 2,7-diazabicyclo-
[3.3.1]nonanes.
Experimental Section
General. 1H NMR spectra were recorded at 300 MHz (JEOL
ECLIPSEþ) with tetramethylsilane as internal standard. 13C
NMR spectra were recorded at 75 MHz (JEOL ECLIPSEþ).
Mass spectra were recorded on an Agilent 1100 series mass
spectrometer using either a direct inlet system (electron spray,
4000 V) or LC-MS coupling (UV detector). IR spectra were
recorded on a Perkin-Elemer Spectrum BX FT-IR spectrom-
eter. All compounds were analysed in neat form with an
attenuated total reflectance (ATR) accessory. Melting points
€
were measured using a Buchi B-540 apparatus and are uncor-
rected. Dichloromethane was distilled over calcium hydride,
while diethyl ether and THF were distilled from sodium and
sodium benzophenone ketyl before use. Microwave reactions
were performed in a CEM Discover Microwave Reactor
(200 Wmax) in an 80-mL sealed vessel using a fiber-optic
temperature sensor.
Synthesis of 4-Chloro-2-[1-(arylmethyl)aziridin-2-ylmethyl]-
2-phenylbutyronitriles, 6 and 7. As a representative example,
the synthesis of 4-chloro-2-[1-benzylaziridin-2-ylmethyl]-5-phenyl-
butyronitriles 6a and 7a is described here. To an ice-cooled
solution of diisopropylamine (60 mmol, 1.2 equiv) in dry THF
(75 mL) was added n-BuLi (1.2 equiv, 2.5 M) via a syringe under
nitrogen atmosphere, and the resulting solution was stirred for
15 min at 0 °C. Subsequently, a solution of 1-benzyl-2-(2-cyano-
2-phenylethyl)aziridine 5a (50 mmol)12b in THF (20 mL) was
added via a syringe at 0 °C, and the resulting solution was stirred
for 1 h at 0 °C. Finally, 1-bromo-2-chloroethane (55 mmol, 1.1
equiv) was added via a syringe at 0 °C, and the reaction mixture
was stirred for 1 h at 0 °C under nitrogen atmosphere. The
reaction mixture was poured into a saturated NH4Cl solution
(28) Leeson, P. D.; Williams, B. J.; Rowley, M.; Moore, K. W.; Baker, R.;
Kemp, J. A.; Priestley, T.; Foster, A. C.; Donald, A. E. Biorg. Med. Chem.
Lett. 1993, 3, 71.
(29) (a) Hashimoto, A.; Jacobson, A. E.; Rothman, R. B.; Dersch, C. G.;
Flippen-Anderson, J. L.; Rice, K. C. Bioorg. Med. Chem. 2002, 10, 3319.
(b) Kim, I. J.; Dersch, C. G.; Rothman, R. B.; Jacobson, A. E.; Rice, K. C.
Bioorg. Med. Chem. 2004, 12, 4543. (c) Li, W.; Wang, X.-H.; Lau, C-W;
Tang, Y.; Xie, Q.; Qui, Z.-B. Acta Pharm. Sin. 2006, 27, 1247.
(30) (a) Welder, C. O.; Ashby, E. C. J. Org. Chem. 1997, 62, 4829.
(b) D’hooghe, M.; Dekeukeleire, S.; De Kimpe, N. Org. Biomol. Chem.
2008, 6, 1190.
(31) Bryans, J. S.; Horwell, D. C.; Kneen, C. O.; Wustrow, D. WO 99/
31057, 1999. CAN 131:44829.
7740 J. Org. Chem. Vol. 75, No. 22, 2010

Vervisch et al.
JOCArticle
(75 mL) and was extracted with Et2O (3 ꢀ 75 mL). Drying
(MgSO4), filtration of the drying agent and evaporation of
the solvent in vacuo afforded 4-chloro-2-[1-benzylaziridine-2-
ylmethyl]-2-phenylbutyronitriles 6a and 7a as a mixture of iso-
mers (∼1:1). Isolation of the mixture of (2R,20R)- and (2S,20S)-
isomers 6a was realized by means of a selective crystallization
from ethanol, whereas the (2R,20S)- and (2S,20R)-isomers 7a
were obtained by column chromatography on silica gel (hexane/
EtOAc, 3:1).
(2R,20R)- and (2S,20S)-2-[1-Benzylaziridin-2-ylmethyl]-4-chloro-
2-phenylbutyronitrile, 6a: (38%) white crystals. Mp = 79.7 °C.
Rf = 0.21 (hexane/EtOAc, 3:1). 1H NMR (CDCl3) δ 1.39-1.47
(2H, m); 1.75 (1H, d, J = 2.8 Hz); 2.03 and 2.26 (2H, 2 ꢀ dd, J =
14.0, 5.8, 5.2 Hz); 2.38 (1H, ddd, J = 13.7, 11.3, 5.1 Hz); 2.52
(1H, ddd, J = 13.7, 11.1, 5.4 Hz); 2.92 and 3.23 (2H, 2 ꢀ d, J =
12.9 Hz); 3.19 (1H, ddd, J = 11.0, 10.9, 4.8 Hz); 3.56 (1H, ddd,
J = 11.1, 11.0, 5.3 Hz); 7.13-7.52 (10H, m). 13C NMR (CDCl3)
δ 33.8 (CH2); 35.2 (CH); 39.4 (CH2); 43.2 (CH2); 44.2 (CH2);
46.1 (C); 64.3 (CH2); 121.4 (C); 126.1 (CH); 127.3 (CH); 128.3
(CH); 128.5 (CH); 128.6 (CH); 129.4 (CH); 136.4 (C); 138.7 (C).
IR (cm-1): νCN = 2236. MS (70 eV): m/z (%): 325/7 (Mþ þ 1,
100). Anal. Calcd for C20H21ClN2: C 73.95; H 6.52; N 8.62.
Found: C 74.23; H 6.87; N 8.49.
trans-1-Benzyl-2-chloromethyl-4-phenylpiperidine-4-carbo-
nitriles, 11a: (99%) white crystals. Mp = 115.1 °C. Rf = 0.21
(hexane/EtOAc, 3:1). 1H NMR (CDCl3) δ 1.98-2.02 (2H, m);
2.14-2.28 (2H, m); 2.57 (1H, ddd, J = 12.5, 8.4, 6.2 Hz);
2.95-3.05 (2H, m); 3.18 (1H, d, J = 13.2 Hz); 3.63 and 3.96
(2H, 2 ꢀ dd, J = 12.1, 5.0, 1.7 Hz); 4.21 (1H, d, J = 13.2 Hz);
7.23-7.51 (10H, m). 13C NMR (CDCl3) δ 35.9 (CH2); 40.9
(CH2); 43.3 (C); 46.6 (CH2); 49.3 (CH2); 57.3 (CH2); 59.1 (CH);
122.2 (C); 125.7 (CH); 127.4 (CH); 128.4 (CH); 128.6 (CH);
129.2 (CH); 138.4 (C); 139.9 (C). IR (cm-1): νCN = 2233. MS
(70 eV): m/z (%): 325/7 (Mþ þ 1, 100). Anal. Calcd for C20H21-
ClN2: C 73.95; H 6.52; N 8.62. Found: C 74.11; H 6.68; N 8.66.
Synthesis of Ammonium cis-1-(4-Chlorobenzyl)-2-hydroxy-
methyl-4-phenylpiperidine-4-carboxylate, 14. To a solution of cis-
1-(4-chlorobenzyl)-2-chloromethyl-4-phenylpiperidine-4-carbo-
nitrile (1.4 mmol) 9c in water (5 mL) was added 3 M hydrochloric
acid (1.62 mL) and 6 M acetic acid (3.42 mL). The mixture was
placed in an 80-mL sealed glass vessel, provided with an appro-
priatestirringbar andsubjected tomicrowaveconditions (150 °C,
1 h). Afterward, the solvent was evaporated under high vacuum,
and the residue was redissolved in water (10 mL). Subsequently,
LiOH (2.4 mmol, 2 equiv) was added to this solution, after which
the resulting mixture was heated under reflux for 30 min. Isolation
of ammonium cis-1-(4-chlorobenzyl)-2-hydroxymethyl-4-phenyl-
piperidine-4-carboxylate 14 was realized by means of ion-exchange
chromatography on Dowex Hþ (50 ꢀ 8-100).
(2S, 20R)- and (2R, 20S)-2-[1-Benzylaziridin-2-ylmethyl]-
4-chloro-2-phenylbutyronitrile 7a: (15%) yellow oil. Rf = 0.13
(hexane/EtOAc, 3:1). 1H NMR (CDCl3) δ 1.32 (1H, d, J = 6.1
Hz); 1.40 (1H, d, J = 3.9 Hz); 1.63-1.70 (1H, m); 2.02 and 2.10
(2H, 2 ꢀ dd, J = 14.3, 7.2, 5.5 Hz); 2.34 (1H, ddd, J = 13.8, 11.3,
5.1 Hz); 2.48 (1H, ddd, J = 13.8, 11.0, 5.5 Hz); 3.14 (1H, ddd,
J = 11.0, 11.0, 5.0 Hz); 3.46 (1H, ddd, J = 11.0, 11.0, 5.6 Hz);
Ammonium cis-1-(4-Chlorobenzyl)-2-hydroxymethyl-4-phenyl-
piperidine-4-carboxylate, 14: (80%) white crystals. Mp = 228.3
°C. 1H NMR (CD3OD) δ 2.14 (1H, ddd, J = 14.9, 11.6, 3.6 Hz);
2.26 (1H, dd, J = 14.9, 11.0 Hz); 2.45 (1H, dt, J = 12.2, 2.4 Hz);
2.58 (1H, d (broad), J = 14.9 Hz); 2.74 (1H, d (broad), J = 14.9
Hz); 2.83-2.86 (1H, m); 2.95 (1H, dt, J = 12.2, 3.6 Hz); 3.57
(1H, d, J = 13.2 Hz); 3.78 and 3.93 (2H, 2 ꢀ dd, J = 12.1, 5.0,
3.9 Hz); 4.36 (1H, d, J = 13.2 Hz); 7.16-7.50 (9H, m). 13C NMR
(CD3OD) δ 30.6 (CH2); 34.3 (CH2); 41.1 (C); 48.5 (CH2); 55.6
(CH2); 60.8 (CH); 61.3 (CH2); 126.0 (CH); 127.0 (CH); 128.2
(CH); 128.4 (CH); 131.8 (CH); 126.8 (C); 134.2 (C); 141.5 (C);
180.5 (C). IR (cm-1): νOH = 3365, νCO = 1579. MS (70 eV): m/z
(%): 360/2 (Mþ þ 1, 100). Anal. Calcd for C20H25ClN2O3: C
63.74; H 6.69; N 7.43. Found: C 63.86; H 6.81; N 7.23.
Synthesis of trans-1-(4-Chlorobenzyl)-2-chloromethyl-4-phe-
nylpiperidine-4-carboxylic Acid, 15. To a solution of trans-1-(4-
chlorobenzyl)-2-chloromethyl-4-phenylpiperidine-4-carbonitrile
(1.4 mmol) 11c in water (5 mL) was added 3 M hydrochloric acid
(1.62 mL) and 6 M acetic acid (3.42 mL). The mixture was placed
in an 80-mL sealed glass vessel, provided with an appropriate
stirring bar and subjected to microwave conditions (150 °C, 1 h
40 min). Afterward, the solvent was evaporated under high
vacuum, affording trans-1-(4-chlorobenzyl)-2-chloromethyl-
4-phenylpiperidine-4-carboxylic acid 15 in good yield and high
purity (>95% based on NMR analysis).
3.19 and 3.64 (2H, 2 ꢀ d, J = 12.7 Hz); 7.23-7.47 (1H, m). 13
C
NMR (CDCl3) δ 33.3 (CH2); 35.4 (CH); 39.4 (CH2); 42.4 (CH2);
44.7 (CH2); 46.1 (C); 64.6 (CH2); 121.1 (C); 125.8 (CH); 127.5
(CH); 128.5 (CH); 128.6 (CH); 128.6 (CH); 129.3 (CH); 137.1
(C); 138.5 (C). IR (cm-1): νCN = 2237. MS (70 eV): m/z (%):
325/7 (Mþ þ 1, 100). Anal. Calcd for C20H21ClN2: C 73.95; H
6.52; N 8.62. Found: C 74.20; H 6.72; N 8.51.
Synthesis of cis-1-Arylmethyl-2-chloromethyl-4-phenylpiperi-
dine-4-carbonitriles, 9. As a representative example, the synthesis
of cis-1-benzyl-2-chloromethyl-4-phenylpiperidine-4-carbonitrile
9a is described here. A solution of 2-[1-benzylaziridin-2-ylmethyl]-
4-chloro-2-phenylbutyronitrile 6a (20 mmol) in acetonitrile (20
mL) was placed in an 80-mL sealed glass vessel, provided with an
appropriate stirring bar and subjected to microwave conditions
(136 °C, 30 min). Afterward, evaporation of the solvent afforded
cis-1-benzyl-2-chloromethyl-4-phenylpiperidine-4-carbonitrile 9a
in quantitative yield.
cis-1-Benzyl-2-chloromethyl-4-phenylpiperidine-4-carbonitrile, 9a:
(99%) yellow oil. Rf = 0.15 (hexane/EtOAc, 3:1). H NMR
1
(CDCl3) δ 2.11-2.35 (3H, m); 2.56-2.66 (2H, m); 2.98 (1H,
ddd, J = 12.8, 9.5, 3.2 Hz); 3.16 (1H, m); 3.66 and 3.87 (2H,
2 ꢀ d, J = 13.5 Hz); 3.87 and 4.19 (2H, 2 ꢀ dd, J = 11.3, 9.1, 4.7
Hz); 7.23-7.52 (10H, m). 13C NMR (CDCl3) δ 35.0 (CH2); 36.1
(CH2); 38.5 (C); 42.3 (CH2); 44.2 (CH2); 58.4 (CH2); 58.5 (CH);
124.0 (C); 126.2 (CH); 127.5 (CH); 128.3 (CH); 128.6 (CH);
129.3 (CH); 138.6 (C); 139.4 (C). IR (cm-1): νCN = 2231. MS
(70 eV): m/z (%): 325/7 (Mþ þ 1, 100). Anal. Calcd for C20H21-
ClN2: C 73.95; H 6.52; N 8.62. Found: C 74.31; H 6.74; N 8.49.
Synthesis of trans-1-Arylmethyl-2-chloromethyl-4-phenylpi-
peridine-4-carbonitriles, 11. As a representative example, the
synthesis of trans-1-benzyl-2-chloromethyl-4-phenylpiperidine-
4-carbonitrile 11a is described here. A solution of 2-[1-benzylazi-
ridin-2-ylmethyl]-4-chloro-2-phenylbutyronitrile 7a (17.5 mmol)
in acetonitrile (20 mL) was placed in an 80-mL sealed glass
vessel, provided with an appropriate stirring bar and subjected
to microwave conditions (136 °C, 30 min). Afterward, evapora-
tion of the solvent afforded trans-1-benzyl-2-chloromethyl-
4-phenylpiperidine-4-carbonitrile 11a in a quantitative yield.
trans-1-(4-Chlorobenzyl)-2-chloromethyl-4-phenylpiperidine-
4-carboxylic acid, 15: (85%) white crystals. Mp = 216.6 °C. 1H
NMR (CD3OD) δ 1.92-2.03 (1H, m); 2.20 (1H, dd, J = 14.5,
12.4 Hz); 2.73 (1H, d (broad), J = 14.3 Hz); 2.89 (1H, dd, J =
14.5, 2.5 Hz,); 3.10 (1H, dt, J = 13.3, 2.5 Hz); 3.34 (1H, ddd, J =
13.3, 4.0, 2.6 Hz); 3.81-3.86 (1H, m); 4.05 (1H, dd, J = 13.4, 2.5
Hz); 4.13 (1H, d, J = 13.2 Hz); 4.38-4.42 (1H, m); 4.70 (1H, d,
J = 13.2 Hz); 7.18-7.48 (9H, m). 13C NMR (CD3OD) δ 30.0
(CH2); 35.2 (CH2); 42.8 (CH2); 48.2 (C); 49.8 (CH2); 55.2 (CH2);
62.3 (CH); 125.1 (CH); 127.7 (CH); 128.7 (CH); 129.3 (CH);
133.2 (CH); 127.4 (C); 136.3 (C); 141.0 (C); 174.4 (C). IR (cm-1):
ν
OH = 3362, νCO = 1715. MS (70 eV): m/z (%): 378/80/82 (Mþ
þ 1, 100). Anal. Calcd for C20H21Cl2NO2: C 63.50; H 5.60; N
3.70. Found: C 63.77; H 5.95; N 3.51.
Synthesis of cis-1-(4-Chlorobenzyl)-2-cyanomethyl-4-phenyl-
piperidine-4-carbonitrile, 16. To a solution of cis-1-(4-chlorobenzyl)-
2-chloromethyl-4-phenylpiperidine-4-carbonitrile (1.0 mmol) 9c in
J. Org. Chem. Vol. 75, No. 22, 2010 7741

Vervisch et al.
JOCArticle
DMSO (10 mL) was added potassium cyanide (2 mmol, 2 equiv),
and the resulting solution was heated for 1 h at 120 °C. The reaction
mixture was poured into water (10 mL) and extracted with Et2O
(3 ꢀ 10 mL). Drying (MgSO4), filtration of the drying agent, and
evaporation of the solvent in vacuo afforded cis-1-(4-chlorobenzyl)-
2-cyanomethyl-4-phenylpiperidine-4-carbonitrile 16, which was
isolated in pure form by means of column chromatography on silica
gel (hexane/EtOAc, 3:1).
cis-1-(4-Chlorobenzyl)-2-cyanomethyl-4-phenylpiperidine-4-
carbonitrile, 16: (92%) white crystals. Mp = 135.3 °C. Rf =
0.16 (hexane/EtOAc, 3:1). 1H NMR (CDCl3) δ 2.08-2.25
(2H, m); 2.35 and 2.45 (2H, 2 ꢀ dd, J = 14.4, 5.0, 3.6 Hz);
2.55-2.62 (1H, m); 2.80 (1H, dd, J = 17.1, 5.5 Hz); 2.82-2.90
(1H, m); 3.09 (1H, dd, J = 17.1, 8.3 Hz); 3.29-3.37 (1H, m); 3.55
and 3.72 (2H, 2 ꢀ d, J = 13.2 Hz); 7.22-7.48 (9H, m). 13C NMR
(CDCl3) δ 16.9 (CH2); 34.9 (CH2); 38.2 (CH2); 38.4 (C); 43.5
(CH2); 54.1 (CH); 57.6 (CH2); 118.6 (C); 123.9 (C); 126.1 (CH);
128.6 (CH); 128.8 (CH); 129.4 (CH); 130.0 (CH); 132.2 (C);
136.6 (C); 138.9 (C). IR (cm-1): νCN = 2249. MS (70 eV): m/z
(%): 350/2 (Mþ þ 1, 100). Anal. Calcd for C21H20ClN3: C 72.09;
H 5.76; N 12.01. Found: C 72.19; H 5.84; N 11.93.
Synthesis of cis-2-Carboxymethyl-1-(4-chlorobenzyl)-4-phe-
nylpiperidine-4-carboxylic Acid, 17. To a solution of cis-1-(4-
chlorobenzyl)-2-cyanomethyl-4-phenylpiperidine-4-carboni-
trile 16 (0.43 mmol) in water (5 mL) was added 3 M hydrochloric
acid (1.62 mL) and 6 M acetic acid (3.42 mL) at room tempera-
ture, and the resulting solution was heated under reflux for 3
days. Isolation of cis-2-carboxymethyl-1-(4-chlorobenzyl)-4-
phenylpiperidine-4-carboxylic acid 17 was performed by crys-
tallization from the resulting solution upon standing at room
temperature for 2 days.
Synthesis of trans-1-(4-Chlorobenzyl)-2-cyanomethyl-4-phe-
nylpiperidine-4-carbonitrile, 19. To a solution of trans-1-(4-
chlorobenzyl)-2-chloromethyl-4-phenylpiperidine-4-carboni-
trile (1.0 mmol) 11c in DMSO (10 mL) was added potassium
cyanide (2 mmol, 2 equiv), and the resulting solution was
heated for 5 h at 120 °C. The reaction mixture was poured
into water (10 mL) and extracted with Et2O (3 ꢀ 10 mL).
Drying (MgSO4), filtration of the drying agent, and evapora-
tion of the solvent in vacuo afforded trans-1-(4-chlorobenzyl)-
2-cyanomethyl-4-phenylpiperidine-4-carbonitrile 19, which
was isolated in pure form by means of column chromatogra-
phy on silica gel (hexane/EtOAc, 3:1).
trans-1-(4-Chlorobenzyl)-2-cyanomethyl-4-phenylpiperidine-
4-carbonitrile, 19: (88%) white crystals. Mp = 129.9 °C. Rf =
0.16 (hexane/EtOAc, 3:1). 1H NMR (CDCl3) δ 2.03-2.08 (2H, m);
2.11-2.25 (2H, m); 2.50-2.59 (2H, m); 2.94-3.08 (3H, m); 3.18
and 4.12 (2H, 2 ꢀ d, J = 12.9 Hz); 7.26-7.52 (9H, m). 13C NMR
(CDCl3) δ 23.3 (CH2); 35.6 (CH2); 42.7 (CH2); 43.2 (C); 49.3
(CH2); 55.0 (CH); 57.1 (CH2); 116.7 (C); 121.7 (C); 125.6 (CH);
128.6 (CH); 128.8 (CH); 129.3 (CH); 130.3 (CH); 133.4 (C);
136.4 (C); 139.1 (C). IR (cm-1): νCN = 2248. MS (70 eV): m/z
(%): 350/2 (Mþ þ 1, 100). Anal. Calcd for C21H20ClN3: C 72.09;
H 5.76; N 12.01. Found: C 72.21; H 5.93; N 11.92.
Synthesis of trans-2-Carboxymethyl-1-(4-chlorobenzyl)-4-
phenylpiperidine-4-carboxylic Acid, 20. To a solution of trans-
1-(4-chlorobenzyl)-2-cyanomethyl-4-phenylpiperidine-4-carbo-
nitrile 19 (0,65 mmol) in water (5 mL) was added 3 M hydro-
chloric acid (1.62 mL) and 6 M acetic acid (3.42 mL) at room
temperature, and the resulting solution was heated under reflux
for 6 days. Isolation of trans-2-carboxymethyl-1-(4-chlorobenzyl)-
4-phenylpiperidine-4-carboxylic acid 20 was performed by crys-
tallization from the resulting solution upon standing at room
temperature for 2 days.
trans-2-Carboxymethyl-1-(4-chlorobenzyl)-4-phenylpiperidine-
4-carboxylic acid, 20: (95%) white crystals. Mp = 243.3 °C.
1H NMR ((CD3)2SO) δ 1.88-2.02 (2H, m); 2.57 (1H, d, J =
13.0 Hz); 2.74-2.82 (2H, m); 2.92 (1H, t, J = 13.0 Hz); 3.12-
3.25 (2H, m); 3.56-3.64 (1H, m); 4.11 and 4.53 (2H, 2 ꢀ d, J =
13.0 Hz); 7.24-7.53 (9H, m). 13C NMR ((CD3)2SO) δ 30.0
(CH2N)) δ 36.9 (CH2); 37.3 (CH2); 48.3 (C); 49.3 (CH2); 54.4
(CH2); 58.8 (CH); 125.7 (CH); 128.2 (CH); 129.4 (CH); 129.5
(CH); 133.7 (CH); 135.0 (C); 141.9 (C); 171.8 (C); 174.6 (C). IR
(cm-1): νOH = 3240, νCO = 1742, 1692. MS (70 eV): m/z (%):
388/90 (Mþ þ 1, 100). Anal. Calcd for C21H22ClNO4: C 65.03; H
5.72; N 3.61. Found: C 65.41; H 5.94; N 3.39.
Synthesis of cis-6-Acetoxy-1-arylmethyl-4-phenylazepane-
4-carbonitriles, 21, and cis-2-Acetoxymethyl-1-arylmethyl-4-phe-
nylpiperidine-4-carbonitriles, 22. As a representative example,
the synthesis of cis-6-acetoxy-1-(4-chlorobenzyl)-4-phenylaze-
pane-4-carbonitrile 21b and cis-2-acetoxymethyl-1-(4-chloro-
benzyl)-4-phenylpiperidine-4-carbonitrile 22b is presented here.
To a solution of cis-1-(4-chlorobenzyl)-2-chloromethyl-4-phe-
nylpiperidine-4-carbonitrile 9c (0.95 mmol) in ethanol (10 mL)
was added sodium acetate (1.9 mmol, 2 equiv), and the resulting
solution was heated under reflux for 2 h. The reaction mixture
was poured into water (10 mL) and extracted with Et2O (3 ꢀ
10 mL). Drying (MgSO4), filtration of the drying agent, and
evaporation of the solvent in vacuo afforded cis-6-acetoxy-1-
(4-chlorobenzyl)-4-phenylazepane-4-carbonitrile 21b and cis-2-
acetoxymethyl-1-(4-chlorobenzyl)-4-phenylpiperidine-4-carbo-
nitrile 22b. Isolation of pure samples of azepane 21b and
piperidine 22b from the mixture by means of column chroma-
tography on silica gel (hexane/EtOAc, 9:1) was not possible, and
spectral data were derived from the mixture of 21b and 22b.
cis-6-Acetoxy-1-(4-chlorobenzyl)-4-phenylazepane-4-carboni-
trile, 21b. Spectral data were derived from a mixture of diastereo-
mers. Yellow oil. Rf = 0.16 (hexane/EtOAc, 9:1). 1H NMR
(CDCl3) δ 2.03 (3H, s); 2.17-2.28 (2H, m); 2.49-2.56 (2H, m);
cis-2-Carboxymethyl-1-(4-chlorobenzyl)-4-phenylpiperidine-
4-carboxylic acid, 17: (95%) white crystals. Mp = 169.5 °C. 1H
NMR (CD3OD) δ 2.26-2.37 (1H, m); 2.39 (1H, dd, J = 15.4,
11.6 Hz); 2.78-2.90 (2H, m); 3.04 (1H, dd, J = 17.3, 7.4 Hz);
3.14 (1H, d, J = 15.4 Hz); 3.24-3.31 (2H, m); 3.56-3.63 (1H, m);
3.98 and 4.72 (2H, 2 ꢀ d, J = 13.2 Hz); 7.32-7.58 (9H, m). 13
C
NMR (CD3OD) δ 29.1 (CH2); 34.7 (CH2); 35.0 (CH2); 46.8 (C);
48.4 (CH2); 55.8 (CH2); 58.0 (CH); 127.1 (CH); 127.7 (CH);
127.7 (CH); 129.1 (CH); 132.9 (CH); 136.0 (C); 136.8 (C); 171.8
(C); 175.1 (C). IR (cm-1): νOH = 3010 νCO = 1724. MS (70 eV):
m/z (%): 388/90 (Mþ þ 1, 100). Anal. Calcd for C21H22ClNO4:
C 65.03; H 5.72; N 3.61. Found: C 65.46; H 5.92; N 3.48.
Synthesis of trans-1-(4-Chlorobenzyl)-5-phenylazepane-3,5-
dicarbonitrile, 18. To a solution of trans-1-(4-chlorobenzyl)-2-
chloromethyl-4-phenylpiperidine-4-carbonitrile 11c (0.5 mmol)
in DMSO (10 mL) was added potassium cyanide (1 mmol, 2
equiv), and the resulting solution was heated at 120 °C for 1 h.
The reaction mixture was poured into water (10 mL) and
extracted with Et2O (3 ꢀ 10 mL). Drying (MgSO4), filtration
of the drying agent, and evaporation of the solvent in vacuo
afforded a mixture of trans-1-(4-chlorobenzyl)-5-phenylaze-
pane-3,5-dicarbonitrile 18 and trans-1-(4-chlorobenzyl)-2-cya-
nomethyl-4-phenylpiperidine-4-carbonitrile 19 in a 3:10 ratio
(18/19). trans-1-(4-Chlorobenzyl)-5-phenylazepane-3,5-dicar-
bonitrile 18 was isolated in pure form by means of column
chromatography on silica gel (hexane/EtOAc, 3:1).
trans-1-(4-Chlorobenzyl)-5-phenylazepane-3,5-dicarbonitrile,
18: (21%) yellow oil. Rf = 0.22 (hexane/EtOAc, 3:1). 1H NMR
(CDCl3) δ 2.18-2.25 (2H, m); 2.45-2.51 (2H, m); 2.87-3.01
(2H, m); 3.03-3.24 (3H, m); 3.71 and 3.81 (2H, 2 ꢀ d, J = 13.2
Hz); 7.26-7.50 (9H, m). 13C NMR (CDCl3) δ 29.9 (CH); 40.7
(CH2); 42.2 (CH2); 44.9 (C); 51.8 (CH2); 55.0 (CH2); 62.0 (CH2);
120.5 (C); 121.0 (C); 125.1 (CH); 128.5 (CH); 128.9 (CH); 129.4
(CH); 130.2 (CH); 133.4 (C); 136.8 (C); 141.2 (C). IR (cm-1):
ν
Calcd for C21H20ClN3: C 72.09; H 5.76; N 12.01. Found: C
71.90; H 5.86; N 12.17.
CN = 2238. MS (70 eV): m/z (%): 350/2 (Mþ þ 1, 100). Anal.
7742 J. Org. Chem. Vol. 75, No. 22, 2010

Vervisch et al.
JOCArticle
2.81-3.14 (4H, m); 3.62 and 3.70 (2H, 2 ꢀ d, J = 13.8 Hz);
5.13-5.22 (1H, m); 7.21-7.54 (9H, m). 13C NMR (CDCl3) δ
21.3 (CH3); 40.6 (CH2); 42.3 (C); 43.4 (CH2); 53.1 (CH2); 57.5
(CH2); 62.3 (CH2); 70.4 (CH); 122.9 (C); 125.4 (CH); 128.0
(CH); 128.3 (CH); 130.3 (CH); 132.9 (C); 137.6 (C); 141.9 (C);
170.5 (C). IR (cm-1): νCO = 1736 νCN = 2232. MS (70 eV): m/z
(%): 383/5 (Mþ þ 1, 100).
chlorobenzyl)-6-hydroxy-4-phenylazepane-4-carbonitrile 27, was
isolated in pure form by means of column chromatography on
silica gel (hexane/EtOAc 1/1).
Alternative procedure: To a solution of trans-1-(4-chloro-
benzyl)-2-chloromethyl-4-phenylpiperidine-4-carbonitrile 11c
(0.95 mmol) in ethanol (10 mL), sodium acetate (1.9 mmol, 2
equiv) was added, and the resulting solution was placed in an
80-mL sealed glass vessel, provided with an appropriate stirring
bar, and subjected to microwave conditions (110 °C, 20 min).
Afterward, the reaction mixture was poured into water (10 mL)
and extracted with Et2O (3 ꢀ 10 mL). Drying (MgSO4), filtra-
tion of the drying agent, and evaporation of the solvent in vacuo
afforded trans-6-acetoxy-1-(4-chlorobenzyl)-4-phenylazepane-
4-carbonitrile 25 and trans-2-acetoxymethyl-1-(4-chlorobenzyl)-
4-phenylpiperidin-4-carbonitrile 26 in a ratio of 71-79:21-29
( 25/26). Subsequently, acetates 25 and 26 were redissolved in
MeOH, after which lithium hydroxide (1.3 mmol, 2 equiv) was
added, and the resulting solution was heated under reflux for
1 h. Afterward, the reaction mixture was poured into water
(10 mL) and extracted with Et2O (3 ꢀ 10 mL). Drying (MgSO4),
filtration of the drying agent, and evaporation of the solvent in
vacuo afforded a mixture of trans-1-(4-chlorobenzyl)-6-hydroxy-
4-phenylazepane-4-carbonitrile, 27, and trans-1-(4-chlorobenzyl)-
2-hydroxymethyl-4-phenylpiperidin-4-carbonitrile, 28, in a ra-
tio of 71-79:21-29 ( 27/28). The major constituent, trans-1-(4-
chlorobenzyl)-6-hydroxy-4-phenylazepane-4-carbonitrile, 27, was
isolated in pure form by means of column chromatography on
silica gel (hexane/EtOAc 1/1).
trans-1-(4-Chlorobenzyl)-6-hydroxy-4-phenylazepane-4-car-
bonitrile, 27: (55%) yellow oil. Rf = 0.29 (hexane/EtOAc, 3:1).
1H NMR (CDCl3) δ 2.02-2.07 (2H, m); 2.15-2.40 (2H, m); 2.41
(1H, dd, J = 14.3, 5.0, 1.1 Hz); 2.83-2.91 (3H, m); 3.01 (1H, dd,
J = 13.2, 3.3 Hz); 3.65 (1H, d, J = 13.5 Hz); 3.71 (1H, d, J =
13.5 Hz); 4.06-4.17 (1H, m); 7.24-7.51 (9H, m). 13C NMR
(CDCl3) δ 40.7 (CH2); 43.6 (C); 47.7 (CH2); 52.8 (CH2); 59.8
(CH2); 62.6 (CH2); 68.3 (CH); 122.6 (C); 125.2 (CH); 127.9
(CH); 128.7 (CH); 129.2 (CH); 130.4 (CH); 133.1 (C); 137.5 (C);
142.6 (C). IR (cm-1): νOH = 3422 νCN = 2236. MS (70 eV): m/z
(%): 341/3 (Mþ þ 1, 100). Anal. Calcd for C20H21ClN2O: C
70.48; H 6.21; N 8.22. Found: C 70.74; H 6.49; N 8.08.
cis-2-Acetoxymethyl-1-(4-chlorobenzyl)-4-phenylpiperidine-4-
carbonitrile, 22b. Spectral data were derived from a mixture
of diastereomers. Yellow oil. Rf = 0.16 (hexane/EtOAc, 9:1).
1H NMR (CDCl3) δ 2.06 (3H, s); 2.08-2.28 (2H, m); 2.36 (2H,
d, J = 5.0 Hz); 2.49-2.56 (1H, m); 2.81-3.04 (1H, m); 3.07-
3.14 (1H, m); 3.59 and 3.82 (2H, 2 ꢀ d, J = 13.8 Hz); 4.50 and
4.57 (2H, 2 ꢀ dd, J = 11.9, 6.1, 5.8 Hz); 7.21-7.54 (9H, m). 13C
NMR (CDCl3) δ 21.5 (CH3); 35.0 (CH2); 37.0 (CH2); 38.6 (C);
44.6 (CH2N); 56.0 (CH); 57.7 (CH2); 62.6 (CH2); 123.9 (C);
126.2 (CH); 128.6 (CH); 129.2 (CH); 129.8 (CH); 130.0 (CH);
132.8 (C); 137.6 (C); 139.3 (C); 170.8 (C). IR (cm-1): νCO = 1736
ν
CN = 2232. MS (70 eV): m/z (%): 383/5 (Mþ þ 1, 100).
Synthesis of cis-1-(4-Chlorobenzyl)-2-hydroxymethyl-4-phe-
nylpiperidine-4-carbonitrile, 24. To a solution of cis-2-acetoxy-
methyl-1-(4-chlorobenzyl)-4-phenylpiperidine-4-carbonitrile 22b
and cis-6-acetoxy-1-(4-chlorobenzyl)-4-phenylazepane-4-car-
bonitriles 21b (0.6 mmol) in methanol (10 mL) was added
lithium hydroxide (1.3 mmol, 2 equiv), and the resulting solution
was heated under reflux for 2 h. The reaction mixture was
poured into water (10 mL) and extracted with Et2O (3 ꢀ 10 mL).
Drying (MgSO4), filtration of the drying agent, and evaporation
of the solvent in vacuo afforded a mixture of cis-1-(4-chloro-
benzyl)-6-hydroxy-4-phenylazepane-4-carbonitrile 23 and cis-
1-(4-chlorobenzyl)-2-hydroxymethyl-4-phenylpiperidin-4-car-
bonitrile 24 in a ratio of 33-36/64-67 (23/24). The major
isomer cis-1-(4-chlorobenzyl)-2-hydroxymethyl-4-phenylpiper-
idin-4-carbonitrile 24 was isolated and purified by means of
column chromatography on silica gel (hexane/EtOAc 1/1).
cis-1-(4-Chlorobenzyl)-2-hydroxymethyl-4-phenylpiperidine-
4-carbonitrile, 24: (55%) yellow oil. Rf = 0.34 (hexane/EtOAc
1/1). 1H NMR (CDCl3) δ 2.10 (1H, ddd, J = 13.8, 7.2, 2.8 Hz);
2.29-2.40 (3H, m); 2.50 (1H, ddd, J = 13.4, 7.2, 3.2 Hz); 2.91
(1H, pent., J = 5.6 Hz); 3.03 (1H, ddd, J = 13.4, 8.7, 2.8 Hz);
3.51 and 3.89 (2H, 2 ꢀ d, J = 13.5 Hz); 3.88 and 4.00 (2H, 2 ꢀ
dd, J = 11.6, 6.1, 5.5 Hz); 7.22-7.50 (9H, m). 13C NMR
(CDCl3) δ 33.0 (CH2); 35.1 (CH2); 38.4 (C); 44.4 (CH2); 57.4
(CH); 58.1 (CH2); 60.9 (CH2); 124.3 (C); 126.4 (CH); 128.4
(CH); 128.8 (CH); 129.3 (CH); 130.0 (CH); 133.2 (C); 137.2 (C);
138.9 (C). IR (cm-1): νOH = 3435 νCN = 2232. MS (70 eV): m/z
(%): 341/3 (Mþ þ 1, 100). Anal. Calcd for C20H21ClN2O: C
70.48; H 6.21; N 8.22. Found: C 70.69; H 6.44; N 8.05.
Synthesis of trans-1-(4-Chlorobenzyl)-6-hydroxy-4-phenylaze-
pane-4-carbonitrile, 27. To a solution of trans-1-(4-chlorobenzyl)-
2-chloromethyl-4-phenylpiperidine-4-carbonitrile 11c (0.95 mmol)
in ethanol (10 mL) was added sodium acetate (1.9 mmol, 2 equiv),
and the resulting solution was heated under reflux for 13 h. The
reaction mixture was poured into water (10 mL) and extracted with
Et2O (3 ꢀ 10 mL). Drying (MgSO4), filtration of the drying agent
and evaporation of the solvent afforded trans-6-acetoxy-1-(4-
chlorobenzyl)-4-phenylazepane-4-carbonitrile 25 and trans-2-acet-
oxymethyl-1-(4-chlorobenzyl)-4-phenylpiperidin-4-carbonitrile 26
in a ratio of 71-79/21-29 (25/26). Subsequently, acetates 25 and
26 were redissolved in MeOH, after which lithium hydroxide (1.3
mmol, 2 equiv) was added and the resulting solution was heated
under reflux for 1 h. Afterward, the reaction mixture was poured
into water (10 mL) and extracted with Et2O (3 ꢀ 10 mL). Drying
(MgSO4), filtration of the drying agent and evaporation of the
solvent in vacuo afforded a mixture of trans-1-(4-chlorobenzyl)-6-
hydroxy-4-phenylazepane-4-carbonitrile 27 and trans-1-(4-chloro-
benzyl)-2-hydroxymethyl-4-phenylpiperidin-4-carbonitrile 28 in a
71-79/21-29 (27/28) ratio. The major constituent, trans-1-(4-
trans-1-(4-Chlorobenzyl)-2-hydroxymethyl-4-phenylpiperidine-
4-carbonitrile, 28. Spectral data were derived from a mixture
of nitriles 27 and 28. Yellow oil. Rf = 0.16 (hexane/EtOAc, 9:1).
1H NMR (CDCl3) δ 1.92-2.10 (2H, m); 2.36 (2H, d, J = 5.0
Hz); 2.55 (1H, dt, J = 11.7, 4.0 Hz); 2.78-3.01 (2H, m); 3.16
(1H, d, J = 13.8 Hz); 3.51 (1H, d (broad), J = 11.0 Hz); 3.98
(1H, dd, J = 11.0, 3.3 Hz); 4.17 (1H, d, J = 13.8 Hz); 7.23-7.49
(9H, m). 13C NMR (CDCl3) δ 35.7 (CH2); 39.8 (CH2); 43.0 (C);
49.6 (CH2); 57.0 (CH2); 60.0 (CH); 62.9 (CH2); 122.2 (C); 125.6
(CH); 128.4 (CH); 128.8 (CH); 129.2 (CH); 130.3 (CH); 133.1
(C); 137.0 (C); 139.9 (C). IR (cm-1): νOH = 3423 νCN = 2234.
MS (70 eV): m/z (%): 341/3 (Mþ þ 1, 100).
Synthesis of 2-Arylmethyl-5-phenyl-2,7-diazabicyclo[3.3.1]-
nonanes, 29. As a representative example, the synthesis of 2-(4-
methylbenzyl)-5-phenyl-2,7-diazabicyclo[3.3.1]nonane 29b is
described here. To a solution of cis-1-(4-methylbenzyl)-2-chlor-
omethyl-4-phenylpiperidine-4-carbonitrile 9b (0.6 mmol) in dry
THF (10 mL), LiAlH4 (1.2 mmol, 2 equiv) was added and the
resulting solution was heated under reflux for 2 h under nitrogen
atmosphere. The reaction mixture was poured into water (10
mL) and extracted with Et2O (3 ꢀ 10 mL). Drying (MgSO4),
filtration of the drying agent, and evaporation of the solvent in
vacuo afforded 2-(4-methylbenzyl)-5-phenyl-2,7-diazabicyclo-
[3.3.1]nonane 29b, which was purified through crystallization
from Et2O/hexane (1/1).
2-(4-Methylbenzyl)-5-phenyl-2,7-diazabicyclo[3.3.1]nonane, 29b:
(75%) white crystals. Mp = 110.3 °C. 1H NMR (CDCl3)
δ 1.92-2.03 (2H, m); 2.13-2.27 (2H, m); 2.34 (3H, s); 2.65
J. Org. Chem. Vol. 75, No. 22, 2010 7743

Vervisch et al.
JOCArticle
(1H, dd, J = 12.9, 1.9 Hz); 2.80-2.90 (3H, m); 3.27 (1H, dd, J =
12.7, 2.8 Hz); 3.39-3.49 (2H, m); 3.73 (1H, d, J = 13.2 Hz); 3.78
(1H, d, J = 13.2 Hz); 7.11-7.36 (9H, m). 13C NMR (CDCl3) δ
21.3 (CH3); 35.4 (C); 37.1 (CH2); 37.4 (CH2); 46.4 (CH2); 49.7
(CH2); 52.1 (CH); 58.7 (CH2); 60.0 (CH2); 125.1 (CH); 126.1
(CH); 128.4 (CH); 128.9 (CH); 129.1 (CH); 136.5 (C); 136.6 (C);
149.2 (C). IR (cm-1): νNH2 = 3336. MS (70 eV): m/z (%): 307
(Mþ þ 1, 100). Anal. Calcd for C21H26N2: C 82.31; H 8.55; N
9.14. Found: C 82.39; H 8.63; N 9.02.
Synthesis of tert-Butyl 2-(4-methylbenzyl)-5-phenyl-2,7-dia-
zabicyclo[3.3.1]nonane-7-carboxylate, 30. To a solution of 2-(4-
methylbenzyl)-5-phenyl-2,7-diazabicyclo[3.3.1]nonane 29b
(0.2 mmol) in dry CH2Cl2 (10 mL), Boc2O (0.22 mmol, 1.1 equiv),
pyridine (0.22 mmol, 1.1 equiv) and DMAP (0.022 mmol,
0.1 equiv) were added, and the resulting solution was stirred at
room temperature for 3 h. The reaction mixture was poured into
brine (10 mL) and extracted with CH2Cl2 (3 ꢀ 10 mL). Drying
(MgSO4), filtration of the drying agent,and evaporation of the
solvent invacuoaffordedtert-butyl 2-(4-methylbenzyl)-5-phenyl-
2,7-diazabicyclo[3.3.1]nonane-7-carboxylate,30, which was iso-
lated in pure form by means of column chromatography on
silica gel (hexane/EtOAc, 3:1).
tert-Butyl 2-(4-Methylbenzyl)-5-phenyl-2,7-diazabicyclo[3.3.1]-
nonane-7-carboxylate, 30: (90%) yellow oil. 1H NMR (CDCl3) δ
1.57 (9H, s); 1.82-2.03 (2H, m); 2.11-2.25 (2H, m); 2.33 (3H, s);
2.63-2.81 (3H, m); 2.96-3.07 (2H, m); 3.75 (2H, 2 ꢀ d, J = 14.3
Hz); 4.55 (2H, d, J = 13.2 Hz); 7.12-7.38 (9H, m). 13C NMR
(CDCl3) δ21.2(CH3);28.9(CH3); 35.5 (C); 37.0 (CH2);38.0(CH2);
42.8(CH2); 48.1 (CH2);50.8(CH);53.2(CH2);60.0(CH2); 79.8 (C);
125.2 (CH); 126.6 (CH); 128.6 (CH); 128.8 (CH); 129.2 (CH); 136.0
(C); 136.7 (C);147.4 (C); 154.3 (C). IR (cm-1): νCO = 1687. MS (70
eV): m/z (%): 407 (Mþ þ 1, 100). Anal. Calcd for C26H34N2O2: C
76.81; H 8.43; N 6.89. Found: C 77.06; H 8.71; N 6.98.
trans-2-chloromethyl-1-(4-methylbenzyl)-4-phenylpiperidine-
4-carbonitrile 11b (0.6 mmol) in dry THF (10 mL), LiAlH4
(1.2 mmol, 2 equiv) was added and the resulting solution was
heated under reflux for 2 h under nitrogen atmosphere. The
reaction mixture was poured into water (10 mL) and extracted
with Et2O (3 ꢀ 10 mL). Drying (MgSO4), filtration of the drying
agent and evaporation of the solvent afforded trans-4-amino-
methyl-2-methyl-1-(4-methylbenzyl)-4-phenylpiperidine, 31b,
which was isolated in pure form by means of column chroma-
tography on silica gel (CH2Cl2/MeOH 94/6).
trans-4-Aminomethyl-2-methyl-1-(4-methylbenzyl)-4-phenyl-
piperidine, 31b: (65%) yellow oil. Rf = 0.06 (CH2Cl2/MeOH,
94:6). 1H NMR (CDCl3) δ 1.23 (1H, d, J = 6.1 Hz); 1.67 (1H,
dd, J = 13.2, 11.6 Hz); 1.81 (1H, dt, J = 13.1, 3.8 Hz); 2.00
(1H, dd, J = 13.2, 2.8 Hz); 2.07 (1H, dt, J = 13.1, 2.5 Hz); 2.24
(1H, dt, J = 12.1, 2.5 Hz); 2.33 (3H, s); 2.54-2.60 (1H, m); 2.75
(1H, dt, J = 12.1, 3.8 Hz); 2.92 and 2.98 (2H, 2 ꢀ d, J = 12.9
Hz); 3.17 (2H, d, J = 13.2 Hz); 4.08 (2H, d, J = 13.2 Hz);
7.10-7.34 (9H, m). 13C NMR (CDCl3) δ 21.2 (CH3); 21.6
(CH3); 32.3 (CH2); 41.0 (C); 42.6 (CH2); 47.5 (CH2); 48.2
(CH2); 52.5 (CH); 57.8 (CH2); 125.9 (CH); 126.1 (CH); 128.4
(CH); 129.0 (CH); 129.2 (CH); 135.9 (C); 136.5 (C); 147.6 (C).
IR (cm-1): νNH2 = 3370. MS (70 eV): m/z (%): 309 (Mþ þ 1,
100). Anal. Calcd for C21H28N2: C 81.77; H 9.15; N 9.08. Found:
C 81.95; H 9.32; N 8.98.
Acknowledgment. We are indebted to the “Institute for the
Promotion of Innovation through Science and Technology -
Flanders” (IWT-Vlaanderen), to the “Fund for Scientific
Research - Flanders” (FWO-Vlaanderen), and to Ghent
University (GOA) for financial support.
Supporting Information Available: Spectroscopic data of
compounds 6b,c, 7b,c, 9b,c, 11b,c, 21a, 22a, 29a,c, and 31a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Synthesis of trans-4-Aminomethyl-1-arylmethyl-2-methyl-4-
phenylpiperidine, 31. As a representative example, the synthe-
sis of trans-4-aminomethyl-2-methyl-1-(4-methylbenzyl)-
4-phenylpiperidine 31b is described here. To a solution of
7744 J. Org. Chem. Vol. 75, No. 22, 2010