Synthesis and stereochemistry of cis-2,6-diphenyl-1-alkylpiperidines

Article abstract of DOI:10.1016/j.tetlet.2015.09.085

Facile and efficient synthesis of N-alkyl-2,6-diphenylpiperidines (NADPPs) was achieved by reductive amination cyclization (RAC) reaction on 1,5-diketones using alkylammonium formate. The reaction is a useful extension of classical Leuckart reductive amin

Full text of DOI:10.1016/j.tetlet.2015.09.085

Tetrahedron Letters 56 (2015) 6190–6193
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Synthesis and stereochemistry of cis-2,6-diphenyl-1-alkylpiperidines
y
⇑
H. Surya Prakash Rao , Elamvazhuthi Poonguzhali
Department of Chemistry, Pondicherry University, Puducherry 605014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2015
Revised 18 September 2015
Accepted 19 September 2015
Available online 21 September 2015
Facile and efficient synthesis of N-alkyl-2,6-diphenylpiperidines (NADPPs) was achieved by reductive
amination cyclization (RAC) reaction on 1,5-diketones using alkylammonium formate. The reaction is a
useful extension of classical Leuckart reductive amination. The RAC reaction is convenient and product
isolation is simple when conducted under microwave (MW) irradiation in polyethylene glycol-200
(PEG-200) medium. The N(1) alkyl groups in NADPPs prefer equatorial position in both solid and liquid
states possibly due to favorable CH–p-interactions to evade unfavorable 1,3-diaxial interactions. Incisive
Keywords:
analysis of 1H NMR spectra of NADPPs showed that anisotropic effects of C(2) and C(6) phenyl rings are
maximum on C(3)H of the alkyl chain.
2,6-Diphenyl-1-alkylpiperidines
Alkylammonium formate
Leuckart reaction
Microwave
Ó 2015 Elsevier Ltd. All rights reserved.
PEG-200
Introduction
in their pharmacopore.13 Generally 1-alkyl cis-2,6-diphenylpiperdi-
nes 1, for example, cis-2,6-diphenyl-N-methylpiperidine 1a are
Studies on the chemistry of piperidine and its derivatives have
continuously attracted attention of organic chemists from the days
of early developments of the field of Organic Chemistry.1 Their
importance is primarily due to profound biological activity and wide
representation in nature as structural motifs on natural products.2 In
contrast to their counterpart cyclohexanes, piperidines exhibit
unique and dynamic stereochemistry.3 In continuation of our
interest in synthesis and stereochemistry of piperidines,4 particu-
larly after total synthesis of anatalline a tobacco natural product,5
we became interested in the synthesis, characterization, and
stereochemistry of 1-alkyl-2,6-diphenylpiperidines (NADPPs) 1. A
few examples of piperidine natural products with substitution on
C(2) and C(6) position are dihydropinidine 2,6 isosolenopsine A 3,7
synthesized by initial N-alkylation of 2,6-diphenylpyridine with
alkyl p-toluenesulfonates, reduction of the resulting quaternary
ammonium salt with NaBH4, and finally by catalytic hydrogenation
over Pd/C.14 Reductive amination of 1,5-diphenylpentane-1,5-dione
6 with an alkyl amine to produce 1-alkyl cis-2,6-diphenylpiperdines
1 is an alternate method but the hydrogenation run on 5% Ru/C
catalyst provides two products namely cis-2,6-diphenyl-1-methyl-
piperidine and trans-2,6-diphenyl-1-methylpyridine.15 We have
now discovered new and environmentally benign reductive
amination cyclization (RAC) of 1,5-diphenylpentane-1,5-dione 6
with different alkylammonium formates for the synthesis of a series
of 1-alkyl cis-2,6-diphenylpiperdines 1 (Scheme 1) which we
present herein. This is the first Letter of reductive amination of
diketones with alkylammonium formates and is a useful extension
to classical Leuckart reaction.16 To carry out RAC reaction we have
employed food-compatible and non-toxic polyethyleneglycol-200
(PEG-200) and microwave (MW) irradiation. Furthermore, we
evaluated stereochemistry of the N(1)-alkyl group and anisotropic
effect of the C(2) and C(6)-phenyl rings on it.
and deoxoprosopinine
4
(Fig. 1).8 Many piperidine alkaloids
are active against central nervous system (CNS). Indeed, some 2,
6-disubsttuted piperidines, for example, isosolenopsine A isolated
from fire ant venom have shown to possess necrotic activity.9 In
addition, some 2,6-disubstituted piperidine alkaloids have been
used as tranquilizers and for inducing hypotensive activity.10
N-Methylanabasine 5 is a CNS active tobacco alkaloid that has sub-
stitution on N(1) and C(2) positions of the central piperidine core.11
In addition to being medicinally important natural products, many
non-natural piperidines found applications as drugs,12 for example,
few oral anesthetics and narcotic analgesics have the piperidine ring
Results and discussion
Synthesis of NADPPs 1 started with 1,5-diphenylpentane-1,5-
dione 6 that is readily available from microwave irradiation of an
intimate mixture of corresponding Mannich salt, acetophenone,
and five-fold excess of PEG-200.17 The reaction of 1,5-diphenylpen-
tane-1,5-dione 6 to produce 1-methyl-2,6-diphenylpiperidine 1a
was selected as a test case to arrive at optimal reaction condition
⇑
Corresponding author.
y
Present address: National Institute of Technology Puducherry, Karaikal 609605,
India.
http://dx.doi.org/10.1016/j.tetlet.2015.09.085
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

H. Surya Prakash Rao, E. Poonguzhali / Tetrahedron Letters 56 (2015) 6190–6193
6191
OH
OH
N
Me
Me
N
H
C11H23
N
H
N
CnH2n
N
H
Me
n-C12H25
H3C
N
1
2
3
4
5
Figure 1. Structures of 1-alkyl-2,6-diphenylpiperidine 1, dihydropinidine 2, isosolenopsine A 3, deoxoprosopinine 4, and N-methylanabasine 5.
RNH3+HCOO-
O
O
PEG-200
MW, 100 oC
2 min, 74-90%
N
R
6
1a-i
1a
1b
: R = CH3 (83%);
: R = CH2CH3 (81%);
1c: R = CH2CH2CH3 (79%);
1d
1e
: R = CH2CH2CH2CH3 (90%);
: R = CH2CH2CH2CH2CH3 (75%);
1f: R = CH2CH2CH2CH2CH2CH3 (74%);
1g
1h
: R = CH2CH2CH2CH2CH2CH2CH3 (81%);
: R = CH(CH3)2 (76%);
1i: R = CH2CH(CH3)2 (83%).
Scheme 1. Synthesis of 1-alkyl-2,6-diphenylpiperidines 1a–i by reductive amination cyclization reaction on 1,5-diketone 6.
for RAC. Instead of using methylamine and subsequent reduction
with a reducing agent we selected to employ methylammonium
formate for RAC reaction to be carried out under MW irradiation.
We reasoned that the methylammonium formate will decompose
under MW irradiation to provide methylamine and formic acid.18
Released amine will then be utilized for imine formation and
formic acid will provide necessary acidic conditions for this transfor-
mation. Subsequently, formic acid will be utilized for reduction of
the imine intermediate by transfer hydrogenation. Resulting amine
will undergo cyclization to generate cyclic imine and formic acid
once again will be involved in the reduction of the intermediate to
generate NADPP 1a.19 We employed PEG-200 as the medium to
absorb and transfer MW energy to the reactants and facilitate to
cross energy barriers encountered during the multi-step transfor-
mation.20 PEG-200 is a mixture of oligomeric ethylene glycols with
average molecular weight of 200.21 The mixture is dominated by
tetraethylene glycol. PEG-200 has several desirable characteristics
like being liquid at room temperature, good solvent for organic com-
pounds, water solubility, capacity to respond to microwaves of
2.45 GHz frequency, non-toxic and safe because of its high boiling
point (above 230 °C).22 The reaction of the diketone 6 and methy-
lammonium formate conducted in mono-mode microwave oven at
100 °C provided RAC product 1-methyl-cis-2,6-diphenylpipeeridi-
ene 1a in 90% yield as a single diastereomer. There was no contam-
ination with corresponding comparatively less stable trans-isomer,
possibly because of the thermodynamic control in the rate deter-
mining step.23 The MW reaction conducted at higher temperature
(125 °C) leads to charring consequently lower yield (41%). At lower
temperature (60 °C) the reaction was sluggish (10 min). Reaction
under direct heating took 6 h for completion and yield was lower
(60%) for formation of 1a.24 The reaction conducted in higher boiling
PEG-400 provided the product 1a in lower yield (45%) possibly
because of viscous nature of the solvent. The MW mediated RAC
reaction took place in ethanol or in ethylene glycol but required
sealed 30 bar resistant glass vials. Reaction under solvent-less con-
ditions but under microwave irradiation provided the product in
low yield (15%) with considerable charring. Workup of the reaction
conducted in PEG-200 was very facile as simple dilution with water
separated the product which was extracted with ethyl acetate.
Alternatively, in one run, we could isolate the product by washing
the reaction mixture with ten-fold excess of tert-butyl methyl ether
Me
Ph
Ph
N
N
Me
Ph
Ph
1cA
1cB
1cC
Figure 2. Single crystal XRD structure of N-propyl-2,6-diphenylpiperidine 1cA and
solution phase equilibrium between two conformations of 1c with the propyl group
axially oriented 1cB and equatorially oriented 1cC.
as the product 1a but not PEG-200 dissolved in the solvent. Recov-
ered PEG-200 could be used for second run. Structure of 1a was
assigned on the basis of spectral (IR, 1H, 13C, DEPT-135 NMR) and
analytical data. The 13C NMR spectrum of 1a displayed 8 signals
which confirmed C2 symmetric nature of the compound. The C(2)
H and C(6)H appeared as double doublet with J = 9.0, 3.0 Hz which
indicated their axial disposition. Consequently sterically bulky C(2)
and C(6) phenyl groups occupy equatorial positions and they have
cis stereochemistry.
Subsequent to achieving facile synthesis of 2,6-diphenyl-1-
methylpiperidine 1a, we extended the study for the synthesis
of homologous series of hitherto unknown N-alkyl cis-2,6-diphen-
ylpiperidines 1b–g (Scheme 1). In each case the RAC reaction
provided diastereoselective cis-isomer. Spectral data of 1b–g com-
pared well with the parent 1a. Further, the structure of N-propyl-
cis-2,6-diphenylpiperidine 1c was confirmed by single crystal
XRD analysis (structure 1cA in Fig. 2).25 The solid state structure
displayed a flattened chair for the piperidine ring with equatorial
orientation for the two phenyl rings and for the N-propyl group.
Two phenyl rings were orthogonal to the mean plane of the
piperidine ring.
The solution phase stereochemistry of N-alkyl 2,6-diphenyl-1-
methylpiperidines 1 is interesting as the N(1) alkyl groups could
occupy axial orientation to avoid steric interactions with C(2)
and C(6) phenyl rings 1cB (Fig. 2) or occupy equatorial orientation
p interactions with electron rich aromatic
rings 1cC and also avoid unfavorable 1,3-diaxial interactions with
to have favorable CH–
C(3)Hax and C(5)Hax. The conformational isomers 1cB and 1cC

6192
H. Surya Prakash Rao, E. Poonguzhali / Tetrahedron Letters 56 (2015) 6190–6193
CH3CH2CH2NH3+HCOO-
PEG-200, MW (100 oC),
2 min, 47%
LAH, THF
N
O
N
OO
OMe
rt, 2 h, 36%
Me
Me
7
8
9
Scheme 2. Two-step synthesis of 2-phenyl-1-propylpiperidine 9.
are inter-convertible through Walden inversion at nitrogen. We
have taken cis-2,6-diphenyl-N-propylpiperidine 1c as a representa-
tive example to evaluate solution phase stereochemistry of
NADPPs 1a–g, particularly since the solid state structure of 1c is
available. The 1H NMR spectrum of the CDCl3 solution of 1c exhib-
ited triplet for methyl in the propyl group at d 0.31 ppm. When this
value is compared with the chemical shift of d 0.96 ppm for the
methyl group in N-propylpiperidine,26 it is up-field shifted by d
0.65 ppm. This observation indicates that the propyl group prefers
equatorial orientation so that the terminal methyl group gets into
the shielding zone of the C(2) and C(6) phenyl rings. To evaluate
chemical shift value of terminal methyl of the N-propyl group that
is flanked by one phenyl ring, we have synthesized 2-phenyl-1-
Acknowledgments
H.S.P.R. thanks University Grants Commission (UGC), Council
for Scientific Industrial Research (CSIR) and Department of Science
and Technology (DST), Government of India for financial assistance
in the form of UGC MRP, UGC DSA, DST FIST grants. E.P. thanks CSIR
for fellowship. We thank Central Instrumentation Facility (CIF) at
Pondicherry University and Department of Organic Chemistry,
Indian Institute of Science for spectra. We thank Mr. A. Veera
Bhadra Rao for help in preparation of the manuscript.
Supplementary data
propylpiperidine 9 from methyl 5-oxo-5-phenylpentanoate27
7
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
085.
by following two-step protocol (Scheme 2). The MW mediated
RAC reaction on 7 with propylammonium formate provided lactam
8. Reduction of the lactam 8 with lithium aluminum hydride fur-
nished piperidine 9 in moderate yield. The terminal methyl group
in 9 appeared at d 0.70 ppm in its 1H NMR spectrum indicating that
it is under anisotropic shielding influence of the C(2) phenyl ring.
Careful study of 1H NMR spectra of NADPPs 1d–g indicated that
C(3) methylene of the N-alkyl group gets maximum shielding influ-
ence of C(2) and C(6) phenyl rings.28
Since the straight-chain alkyl groups in 1a–g displayed resi-
dency at equatorial position in preference to axial position, in con-
tinuation, we evaluated the stereochemistry of branched alkyl
chains. For this purpose we synthesized NADPPs with N(1) iso-
propyl 1h and N(1) isobutyl 1i groups. The MW mediated RAC
reaction with isopropylammonium formate or isobutylammonium
formate and the 1,5-diketone 6 provided corresponding piperidine
derivatives 1h–i in good yield (Scheme 1). In each case spectral and
analytical data confirmed the assigned structure and they com-
pared well with the parent 1a. The chemical shift value of terminal
methyl of N-isopropyl (d 0.60 ppm) in 1h compared well with that
of the N-ethyl (d 0.59 ppm) group in 1b. Similarly the chemical
shift value of terminal methyl of N-isobutyl (d 0.35 ppm) in 1i com-
pared well with that of methyl in N-propyl (d 0.31 ppm) in 1c.
Anticipated up-field shift of methyl groups in 1h–i indicated
preference of the N(1) alkyl groups to occupy equatorial position.
Overall, the 1H NMR spectral data indicated that similar to that
of its solid state structure, the piperidine ring 1 adopts chair
conformation and the N(1) alkyl groups occupy equatorial position.
Preference for equatorial position for the alkyl groups could be
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Conclusion
In summary, we have demonstrated facile synthesis of N-alkyl-
2,6-diphenylpiperidines by RAC reaction on 1,5-diketones using
alkylammonium formates. The RAC reaction works well when con-
ducted in PEG-200 medium under the influence of MWs. Incisive
analysis of 1H NMR spectra showed that N(1) alkyl groups occupy
equatorial position. The anisotropic effect of C(2) and C(6) phenyl
rings are maximum on C(3)H of the alkyl chain.

H. Surya Prakash Rao, E. Poonguzhali / Tetrahedron Letters 56 (2015) 6190–6193
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19. General experimental procedure for the synthesis of 1-alkyl-cis-2,6-
diphenylpiperidines: To a 30 mL glass vial charged with 1,5-diphenylpentane-
1,5-dione (1 mmol) and alkyl ammonium formate (10 mmol) PEG-200 (2 mL),
was added. Intimately mixed content was irradiated with microwaves using
Anton parr-300 mono-mode microwave oven at 100 °C for 2 min. After
completion of the reaction (TLC) 1 N sodium hydroxide (2 mL) and crushed
ice (20 mL) was added to the cooled the reaction mixture (pH = 10). The
product was extracted with dichloromethane (25 mL ꢀ 2). The organic layer
was washed with water (2 ꢀ 25 mL) followed by brine solution (20 mL) and
dried over anhydrous sodium sulfate. Removal of solvent under reduced
pressure provided crude piperidine. The crude product was purified by