BF3·Et2O and trifluoroacetic acid/triethyl amine-mediated synthesis of functionalized piperidines

Article abstract of DOI:10.1016/j.tetlet.2011.10.072

A two-step short and efficient strategy for the synthesis of substituted piperidones and piperidines in high diastereoselectivity (only trans-configuration), by employing cascade type reaction using BF ₃·Et₂O or by carrying out one p

Full text of DOI:10.1016/j.tetlet.2011.10.072

Tetrahedron Letters 53 (2012) 30–35
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
BF3ÁEt2O and trifluoroacetic acid/triethyl amine-mediated synthesis
of functionalized piperidines
⇑
Amar R. Mohite, Prakash R. Sultane, Ramakrishna G. Bhat
Department of Chemistry, Indian Institute of Science Education and Research, Pune, Sai Trinity Building, Garware Circle, Sutarwadi, Pune, Maharashtra 411021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step short and efficient strategy for the synthesis of substituted piperidones and piperidines in
Received 22 August 2011
Revised 12 October 2011
Accepted 13 October 2011
Available online 18 October 2011
high diastereoselectivity (only trans-configuration), by employing cascade type reaction using BF3ÁEt2O
t
or by carrying out one pot deprotection of Boc group followed by intramolecular aza-Michael addition
of a,b-unsaturated beta keto esters has been developed. Using a similar strategy a short access to hydroxy
pipecolic acid is also described. Very simple and rapid experimental procedures involving mild conditions
and only one or two chromatographic purifications are the main features of the process.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Nitrogen heterocycles
Knoevenagel condensation
Michael addition
Cyclization
Piperidines
Functionalized piperidines and their derivatives are important
pharmacophores which are present in many pharmaceuticals and
many molecules in clinical and preclinical trials.1 Piperidine rings
are widespread in the core of the structure of many naturally
occurring alkaloids and drugs, and also their functionalized deriv-
atives are important pharmacophores. Great diversity of natural
products possesses piperidine core. Substituted piperidines partic-
ularly 2- and/or 2,6-substituted piperidines are synthetically
important2,3 and they exhibit a wide spectrum of biological activ-
ities.2e Piperidines also exist with great regularity in many natural
products hence, a huge amount of effort has been directed at their
construction by synthetic chemists.4
waste generation, and saving time. In this regard, we have success-
fully developed a simple strategy for the synthesis of functional-
ized piperidines in diastereopure forms in a cascade pathway or
one pot method by employing Knoevenagel reaction followed by
intramolecular aza-Michael reaction by exploring the use of either
BF3ÁEt2O or trifluoroacetic acid (TFA) followed by triethyl amine
(TEA). We wish to report the use of name reactions and old re-
agents for the construction of functionalized heterocycles like
piperidines in a short path with excellent diastereoselectively.
A straightforward strategy for the diastereoselective synthesis
of substituted piperidones (oxopiperidines) is reported herein. As
an initial study for this method of functionalized piperidones we
opted for a simple starting material, N-tBoc protected beta alanine
1. Then Masamune-Claisen beta keto ester 2 was assembled in one
pot through the reaction of N-tBoc beta-alanine with Meldrum’s
Few synthetic methods have been applied5 mostly from substi-
tuted pyridines,6a amino alcohols,6b–f imines,6g–k aldol reaction,6l
reductive amination reaction,6m–p ring expansion and heterocyclic
rearrangements,6q–u aza-conjugate additions,7 various metal and
acid-catalyzed cyclizations,8 Mannich type reactions,9 olefin
metathesis,10 and multicomponent reactions.11 It is still challeng-
ing and demanding for organic chemists to design and develop
more a simple, convenient and efficient method toward functional-
ized piperidines with structural diversity and diastereo- as well as
enantioselectivity.
O
O
O
aza-Michael
Addition
Knoevenagel
condensation
CO2R
Ar
OR
N
Cyclization
. H
PHN
Ar
TFA
3
4
The ‘one-pot’ and/or ‘cascade’ synthesis is an effective method
both for carrying out several and a variety of transformations
and making new bonds in a single reaction vessel, and simulta-
neously minimizing tedious purifications, minimizing chemical
O
O
O
OR
OH
P= tBoc
NHP
NHP
2
1
⇑
Corresponding author. Fax: +91 20 25898022.
E-mail address: rgb@iiserpune.ac.in (R.G. Bhat).
Scheme 1. Retrosynthetic analysis of substituted piperidones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.072

A. R. Mohite et al. / Tetrahedron Letters 53 (2012) 30–35
31
1. DMAP, DCC,
O
dry DCM,
O
O
O
O
O
O
0 °C to r.t., 4 h
R
O
N
O
O
N
OH
O
H
H
2. dry Methanol
or Benzyl alcohol
reflux, 4-5 h
O
1
2
2a = R = Me
2b = R = Bn
.
BF3 Et2O
CH2Cl2, r.t.,1.5-2 h
ArCHO, Piperidine
Acetic Acid
O
O
O
O
O
R
R
O
O
1. TFA, dry DCM
0 °C to r.t., 1.5 h
O
O
N
H
Benzene, Dean-Stark
N
H
Ar
H
Ar
3
2. TEA, dry THF
r.t. 2-15 min
Free amine
O
R
1.5 equiv. TFA
dry DCM
O
N
H
Ar
(±)
TFA
4
Scheme 2. Two step synthesis of functionalized piperidines from beta keto ester 2.
Table 1
Synthesis of 2, 3-disubstituted piperidines (oxopiperidines) mediated by TFA/TEA and BF3ÁEt2O
Entry
Unsaturated Beta keto ester (3a–j) (cis:trans) (yield)a
Oxopiperidines (4a–j)b
TFA/TEA (one pot method) (yield)c
BF3ÁEt2O (Cascade method) (yield)c
O
O
H
O
O
O
O
N
H
O
O
1
(4a) 85%
(4a) 64%
N
H
.TFA +
3a (44:56) (78%)
4a
O
O
O
O
O
O
O
N
O
Ph
O
Ph
H
H
N
H
2
3
(4b) 84%
(4c) 81%
(4b) 84%
(4c) 66%
.TFA
+
3b
(27:73) (88%)
4b
O
O
O
O
O
N
H
O
O
H
N
H
+
.TFA
3c (38:62) (75%)
4c
O
O
H
O
O
O
O
O
O
N
H
O
O
4
5
6
(4d) 82%
(4e) 88%
(4f) 85%
(4d) 64%
(4e) 62%
(4f) 85%
N
H
TFA
+
.
3d (36:64) (82%)
Br
O
4d
Br
O
O
O
O
OH
O
N
H
H
N
+
H
.TFA
4e
3e
(37:63) (78%)
O
O
OH
O
O
N
H
O
O
Ph
Ph
H
N
H
+
.TFA
3f (22:78) (77%)
4f
(continued on next page)

32
A. R. Mohite et al. / Tetrahedron Letters 53 (2012) 30–35
Table 1 (continued)
Entry
Unsaturated Beta keto ester (3a–j) (cis:trans) (yield)a
Oxopiperidines (4a–j)b
TFA/TEA (one pot method) (yield)c
BF3ÁEt2O (Cascade method) (yield)c
O
O
O
O
O
O
O
O
N
H
O
O
H
7
(4g) 84%
(4h) 86%
—
N
H
TFA
+
.
O
O
O
3g (55:45) (77%)
4g
O
O
O
O
O
N
H
O
O
8
—
H
N
+
H
.
O
TFA
O
O
3h (58:42) (79%)
4h
O
O
O
O
O
O
O
N
H
9
(4i) 80%
(4j) 72%
—
—
H
N
H
.TFA
+
Br
Br
3i (54:46) (76%)
4i
O
O
O
O
O
O
O
N
H
O
O
10
H
N
H
4j
+
O
3j
(63%)
a
b
c
Isolated yield of cis and trans mixture.
Product was obtained as single diastereomer in all the cases.
Isolated yield.
Figure 1. Stacked spectra show the gradual conversion of keto to enol form.
acid and further the intermediate formed in situ was refluxed in
beta keto esters 3, which in turn act as Michael acceptors. The pres-
ence of suitably located amino group and Michael acceptor in the
compound could be exploited in making piperidones 4, by cascade
methanol.12 Compound 2 was subjected to Knoevenagel condensa-
tion with various types of aldehydes to furnish
a,b-unsaturated

A. R. Mohite et al. / Tetrahedron Letters 53 (2012) 30–35
33
O
O
O
O
S
S
HS SH
.
O
O
O
BF3 Et2O
Raney/Ni
dry DCM, 8 h
Ethanol, reflux
N
H
N
N
H
5
6
4aA
Scheme 3. Synthesis of N-ethyl 2,3-disubstituted piperidine.
deprotection of tert-butoxy carbonyl (tBoc) group and intramolec-
ular aza-Michael addition takes place in a ‘cascade’ pathway when
treated with BF3ÁEt2O in 1.5–2 h. The same transformation takes
place in ‘one pot’ under TFA/TEA conditions to give 2,3-disubsti-
tuted piperidones. Good to excellent yields were obtained by both
the methods. The trans-disubstituted piperdones were stable for a
short period of time to enable purification. Therefore we treated
the trans-2,3-disubstituted piperidone with trifluoroacetic acid to
make the corresponding salts, which were found to be crystalline
and stable. It was evident from the coupling constant
(J = ꢀ12 Hz) that the substituents R and CO2Me were in trans
arrangement in all the compounds. It was observed from the 1H
NMR spectra that most of the disubstituted piperidone derivatives
were slowly converting into enolic form from the initial keto form.
We also observed that the compounds were rapidly converting
from keto to enolic form in chloroform-d3, whereas keto form
was relatively stable in DMSO-d6 and gradually converted into
the respective enolic form (Fig. 1). The molecular structure of 4c
by X-ray analysis confirmed that it existed in enolic form and thus
the arrangement of the substituents was not confirmed. Hence, we
planned for masking the keto group by protecting it with 1,2-eth-
anedithiol to establish the stereo-chemical arrangement of substit-
uents (Scheme 3). The compound (4aA, free amine) was protected
with 1,2-ethanedithiol to obtain 1,4-dithiane derived disubstituted
piperidine derivative, 5. The coupling constants from 1H NMR spec-
tra confirmed that substituents were in trans configuration. Molec-
Figure 2. Molecular structure of 5.
approach or in one pot by subjecting them to BF3ÁEt2O or TFA fol-
lowed by TEA, respectively (Scheme 1). We surmise that BF3ÁEt2O
not only deprotects the tert-butoxycarbonyl (tBoc) group but also
facilitates the intramolecular aza-Michael addition resulting in
the formation of 2,3-disubstituted piperidones in good to excellent
yields. To the best of our knowledge we utilized for the first time
BF3ÁEt2O as Lewis acid for the intramolecular aza-Michael addition
for synthesizing piperidine derivatives in a cascade pathway. It was
found that optimum condition for the cyclization was 0 °C with
TFA/TEA in CH2Cl2 and when treated with BF3ÁEt2O in THF
cyclization was facile at room temperature. Very pure products
were formed when TFA/TEA condition was used for cyclization
(Scheme 2).
ular structure of
5 elucidated by X-ray analysis confirms
unequivocally that the substituents -phenyl and -COOMe were in
trans arrangement (see Fig. 2).17 Hence identical configuration
was assumed for the rest of the disubstituted piperidones. Then
we turned our attention toward the synthesis of piperidine deriv-
ative from the dithiane protected intermediate 5. It was synthe-
sized by treating 2,3-disubstituted piperidone (4aA, free amine)
with 1,2-ethanedithiol and BF3ÁEt2O. Treatment of 5 with Raney-
Ni in ethanol resulted in the formation of an unexpected product
N-ethyl 2, 3-disubstituted piperidine 6. When we gleaned through
the literature we learnt that a slight excess of Raney Nickel in alco-
hol leads to the corresponding N-alkylation.18
We found in the literature that Haddad et al. and Davis et al.
employed enantiopure 2-phenyl piperidinol 8 as a key intermedi-
ate for the synthesis of enantiopure 4-hydroxy pipecolic acid
employing RuCl3.19,20
Encouraged by this we then focused our attention toward the
synthesis of 2-phenyl piperidine 4-ol by employing our methodol-
ogy. We subjected compound 4aA for the beta keto decarboxyl-
ation using NaOH/MeOH but we could not isolate the pure
A series of a,b-unsaturated beta keto esters were synthesized in
good yields and all the compounds were obtained as a mixture of
(E)-trans and (Z)-cis isomers (Table 1). Initially E and Z isomers
(3a–e) were isolated and in certain cases it was difficult to separate
E- and Z-isomers ( 3d, 3i). Interestingly both the isomers when
treated separately under intramolecular aza-Michael conditions
resulted in only trans-2, 3-disubstituted oxopiperidines in good
yields. Even a little amount of cis product was not traced. Hence,
we decided not to isolate the isomers and treated the mixture of
E
and
Z
isomers with TFA/TEA or BF3ÁEt2O to synthesize
piperidones.
The E and Z mixture on treatment with BF3ÁEt2O or TFA/TEA re-
sulted in the formation trans-2,3-disubstituted piperidones in good
yields (Table 1).13–16 It is interesting and appealing to note that
O
OH
O
O
LiAl(OiPr)3H
Pd/C
O
Ph
dry THF,
N
dry MeOH,
40°C, 24 h
N
H
N
H
Ph
H
-78 °C, 5 h
4bA
8
7
Scheme 4. Synthesis of 2-phenyl piperidinol.

34
A. R. Mohite et al. / Tetrahedron Letters 53 (2012) 30–35
Schamp, N. Tetrahedron 1989, 45, 3907; (k) Kimpe De, N.; Boelens, M.; Piqueur,
J.; Baele, J. Tetrahedron Lett. 1994, 35, 1925; (l) Kazmaier, U.; Grandel, R. Eur. J.
Org. Chem. 1998, 1833; (m) Ryckman, D. M.; Stevens, R. V. J. Org. Chem. 1987, 52,
4274; (n) Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2005, 70, 7342; (o) Kokatla, H.
P.; Lahiri, R.; Kancharla, P. K.; Doddi, V. R.; Vankar, Y. D. J. Org. Chem. 2010, 75,
4608; (p) Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X.; Hu, Y. Org. Biomol. Chem.
2010, 8, 1899; (q) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009,
11, 1935; (r) Van Brabandt, W.; Van Landeghem, R.; Kimpe De, N. Org. Lett.
2006, 8, 1105; (s) Kimpe De, N.; Boelens, M.; Contreras, J. Tetrahedron Lett.
1996, 37, 3171; (t) D’hooghe, M.; Dejaegher, Y.; Kimpe De, N. Tetrahedron 2008,
64, 4575; (u) Leemans, E.; D’hooghe, M.; Dejaegher, Y.; Törnroos, K. W.; Kimpe
De, N. J. Org. Chem. 2008, 73, 1422.
product; 2-phenyl piperidone 7. Hence we synthesized compound
7 via beta keto decarboxylation,21by subjecting 4bA (free amine) to
hydrogenolysis with Pd/C, H2. 2-Phenyl piperidone, 7 was then re-
duced by lithium trialkoxy aluminum hydride to give 2-phenyl
piperidinol, 8 (Scheme 4) in good yield. This method proves to be
very efficient and accessible for the synthesis of racemic 4-hydroxy
pipecolic acid.
In summary, we have developed an efficient two step diastereo-
convergent strategy that provides a straightforward access to a
number of diastereopure substituted piperidines, using simple
experimental protocols. A short access to hydroxy pipecolic acid
is also described. Structural variation can be set up in the substitu-
ent appended at C-2 including heterocyclic, aromatic groups. Dia-
stereopurity was confirmed by NMR and strongly supported by
X-ray analysis. Application of this method for the synthesis of a
variety of enantiopure derivatives is under progress.
7. (a) Schneider, C.; Börner, C.; Schuffenhauer, A. Eur. J. Org. Chem. 1999, 3353; (b)
Dörrenbächer, S.; Kazmaier, U.; Ruf, S. Synlett 2006, 547; (c) Abrunhosa-
Thomas, I.; Roy, O.; Barra, M.; Besset, T.; Chalard, P.; Troin, Y. Synlett 2007,
1613; (d) Wynne, E. L.; Clarkson, G. J.; Shipman, M. Tetrahedron Lett. 2008, 49,
250.
8. (a) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J. Am. Chem. Soc. 2000, 122,
12007; (b) Singh, O. V.; Han, H. Org. Lett. 2004, 6, 3067; (c) Dobbs, A. P.; Guesné,
S. J. J. Synlett 2005, 2101; (d) Kobayashi, T.; Nakashima, M.; Hakogi, T.; Tanaka,
K.; Katsumura, S. Org. Lett. 2006, 8, 3809; (e) Hande, S. M.; Kawai, N.; Uenishi, J.
J. Org. Chem. 2009, 74, 244; (f) Gnamm, C.; Brödner, K.; Krauter, C. M.;
Helmchen, G. Chem. Eur. J. 2009, 10514; (g) Lebold, T. P.; Leduc, A. B.; Kerr, M. A.
Org. Lett. 2009, 11, 3770; (h) Chen, M. Z.; Micalizio, G. C. Org. Lett. 2009, 11,
4982; (i) Guérinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond, S.;
Cossy, J. Org. Lett. 2010, 12, 1808.
Acknowledgments
A.R.M. and authors thank the IISER-Pune and the CSIR, New Del-
hi, India for the generous financial support.
9. (a) Carbonnel, S.; Fayet, C.; Gelas, J.; Troin, Y. Tetrahedron Lett. 2000, 41, 8293;
Rougnon-Glasson, S.; Tratrat, C.; Canet, J.-L.; Chalard, P.; Troin, Y. Tetrahedron:
Asymmetry 2004, 15, 1561; (b) Bariau, A.; Jatoi, W. B.; Calinaud, P.; Troin, Y.;
Canet, J.-L. Eur. J. Org. Chem. 2006, 3421.
Supplementary data
10. (a) Wallace, D. J.; Goodman, J. M.; Kennedy, D. J.; Davies, A. J.; Cowden, C. J.;
Ashwood, M. S.; Cottrell, I. F.; Dolling, U.; Reider, P. J. Org. Lett. 2001, 3, 671; (b)
Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002,
124, 6991; (c) Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2007, 46, 4534; (d) González-Gómez, J. C.; Foubelo, F.; Yus, M. Synlett 2008,
2777.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.072.
References and notes
11. (a) Noller, C. R.; Baliah, V. J. Am. Chem. Soc. 1948, 70, 3853; (b) Baliah, V.;
Jeyaraman, R.; Chandrasekaran, L. Chem. Rev. 1983, 83, 379; (c) Srinivasan, M.;
Perumal, S.; Selvaraj, S. Chem. Pharm. Bull. 2006, 54, 795; (d) Aridoss, G.;
Amirthaganesan, S.; Kumar, N. A.; Kim, J. T.; Lim, K. T.; Kabilan, S.; Jeong, Y. T.
Bioorg. Med. Chem. Lett. 2008, 18, 6542; (e) Clarke, P. A.; Zaytzev, A. V.;
Whitwood, A. C. Tetrahedron Lett. 2007, 48, 5209; (f) Khan, A. T.; Parvin, T.;
Choudhury, L. H. J.Org. Chem. 2008, 73, 8398.
12. Kral, D.; Friedrich, M.; Grošelj, U.; Kiraly-Potpara, S.; Meden, A.; Wagger, J.;
Dahmann, G.; Stanovnik, B.; Svete, J. Tetrahedron 2009, 65, 7151.
13. General Experimental procedure for one-pot aza-Michael reaction of piperidones
1. Watson, P. S.; Jiang, B. Org. Lett. 2000, 2, 3679.
2. (a) Braekman, J. C.; Daloze, D. In Studies in Natural Products Chemistry,
‘Stereoselective Synthesis’, Part D; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
The Netherlands, 1990; Vol. 6, pp 421–466; (b) Davis, F. A.; Zhang, Y.;
Anilkumar, G. J. Org.Chem. 2003, 68, 8061; (c) Davis, F. A.; Zhang, J.; Li, Y.; Xu,
H.; DeBrosse, C. J. Org. Chem. 2005, 70, 5413; (d) Davis, F. A.; Santhanaraman, M.
J. Org. Chem. 2006, 71, 4222; (e) Davis, F. A.; Xu, H.; Zhang, J. J. Org. Chem. 2007,
72, 2046; (f) Leclercq, S.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. Prog. Chem.
Org. Nat. Prod. 2000, 79, 115.
using TFA/TEA: To
a well stirred mixture of Knoevenagel product (3a–j)
3. (a) Shu, C.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 2878; (b) Atobe, M.;
Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2005, 46, 2669; (c) Lemire, A.;
Charette, A. B. Org. Lett. 2005, 7, 2747; (d) Pissarnitski, D. A.; Asberom, T.; Bara,
T. A.; Buevich, A. V.; Clader, J. W.; Greenlee, W. J.; Guzik, H. S.; Josien, H. B.; Li,
W.; McEwan, M.; McKittrick, B. A.; Nechuta, T. L.; Parker, E. M.; Sinning, L.;
Smith, E. M.; Song, L.; Vaccaro, H. A.; Voigt, J. H.; Zhang, L.; Zhang, Q.; Zhao, Z.
Bioorg. Med. Chem. Lett. 2007, 17, 57; (e) Krishnan, S.; Bagdanoff, J. T.; Ebner, D.
C.; Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130,
13745; (f) Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2008,
6, 3464; (g) Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117, 5399; (h)
Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith, D.; Hartley, R. C. Eur. J. Org.
Chem. 2006, 4998; (i) Liang, N.; Datta, A. J. Org. Chem. 2005, 70, 10182; (j)
Pandey, G.; Bharadwaj, K. C.; Khan, M. I.; Shashidhara, K. S.; Puranik, V. G. Org.
Biomol. Chem. 2008, 6, 2587; (k) Takahata, H.; Yotsui, Y.; Momose, T.
Tetrahedron 1998, 54, 13505; Kumar, R. S. C.; Sreedhar, E.; Reddy, G. V.; Babu,
K. S.; Rao, J. M. Tetrahedron: Asymmetry 2009, 20, 1160; (l) Arseniyadis, S.;
Sartoretti, J. Tetrahedron Lett. 1985, 26, 729.
(2 mmol) in anhydrous dichloromethane (DCM) (5 mL) at 0 °C, was added
drop-wise trifluoro acetic acid (TFA) (40 mmol) maintaining temperature of
the reaction mixture at 0 °C. The reaction mixture was allowed to stir for 1.5 h.
Excess of TFA was evaporated on rotary evaporator to furnish pale yellow
residue. Then the residue was dissolved in anhydrous THF (70 mL) under inert
atmosphere. To this solution triethyl amine (TEA) (10 mmol) was added drop-
wise at room temperature (time required for completion of reaction 2–15 min).
Reaction mixture was concentrated to dryness under reduced pressure to get
light yellow residue. The residue was dissolved in ethyl acetate (25 mL),
washed with distilled water (2 Â 20 mL), brine (2 Â 20 mL), dried over
anhydrous sodium sulfate and concentrated to dryness under reduced
pressure to give light yellow residue as a single diastereomer as confirmed
by 1H NMR. The free amine was further treated with trifluoro acetic acid to
afford stable 2,3-disubstituted piperidone. TFA salt.
14. Trans-methyl 4-oxo-2-phenylpiperidine-3-carboxylate (4a): Starting with
3a(0.67 g, 2 mmol), TFA (3 mL, 40 mmol), Et3N(1.4 mL, 10 mmol) 4a (0.56 g,
85%) was isolated as a white solid; IR (KBr) cmÀ1: 3440, 2965, 1710, 1580,
1444, 1160, 1141, 826, 735; mixture of keto: enol (1: 0.21); dH (400 MHz,
DMSO-d6) 12.11 (br s, 1H, enol), 7.54-7.43 (m, 10H, keto and enol), 5.49 (s, 1H,
enol), 5.00 (d, J = 12 Hz, 1H, keto), 4.49 (d, J = 12 Hz, 1H, keto), 4.63 (m, 2H,
keto), 3.54 (s, 3H, enol), 3.49 (s, 3H, keto), 3.24-3.20 (m, 1H, enol), 3.06-2.91 (m,
2H, keto and enol), 2.74-2.70 (m, 2H, enol), 2.62-2.58 (m, 1H, keto);
dc(100 MHz, DMSO-d6) 199.4, 169.5, 169.1, 166.5, 135.3, 134.3, 129.8, 129.4,
129.3, 129.1, 128.8, 128.1, 95.2, 59.9, 52.8, 52.1, 42.4, 37.2, 35.0, 25.5; HRMS
(ESI-TOF)- m/z Calcd For C13H15NO3 [M+Na]+ 256.0950, obsd 256.0949.
15. General Experimental procedure for domino strategy to synthesise Piperidone using
BF3ÁEt2O: To a well stirred solution of Knoevenagel compound (3a–f) (1 mmol)
in anhydrous dichloromethane (DCM) (15 mL) activated molecular sieves 4 Å
(0.2 g) was added. To this mixture BF3ÁEt2O (5 mmol) was added drop-wise at
room temperature and stirred for 1–2 h. After completion of the reaction DCM
was evaporated, and the residue was dissolved in ethyl acetate (30 mL), and it
was washed with water (3 Â 25 mL), brine solution (2 Â 20 mL), the collective
organic layer was dried over anhydrous sodium sulphate. The solution was
rotary evaporated to afford crude material which was purified by flash
chromatography by using neutral alumina pet. ether:EtOAc (50:50 to 0:100) to
afford 2,3-disubstituted piperidone (free amine). The free amine was further
treated with trifluoro acetic acid to afford stable 2,3-disubstituted
piperidone.TFA salt.
4. (a) Laschat, S.; Dickner, T. Synthesis 2000, 1781; (b) Weintraub, P. M.; Sabol, J.
S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953; (c) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701.
5. For reviews on piperidine syntheses, see: (a) Meyers, A. I.; Brengel, G. P. Chem.
Commun. 1997, 1; (b) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633; (c) Laschat, S.; Dickner, T. Synthesis 2000, 13, 1781; (d) Mitchinson,
A.; Nadin, A.; J. Chem. Soc., Perkin Trans. 1 2000, 2862.; (e) Groaning, M. D.;
Meyers, A. I. Tetrahedron 2000, 56, 9843; (f) Felpin, F.-X.; Lebreton, J. Eur. J. Org.
Chem. 2003, 3693; (g) Pearson, M. S. M.; Mathé-Allainmat, M.; Fargeas, V.;
Lebreton, J. Eur. J. Org. Chem. 2005, 2159.; (h) Escolano, C.; Amat, M.; Bosch, J.
Chem. Eur. J. 2006, 12, 8198; (i) Källström, S.; Leino, R. Bioorg. Med. Chem. 2008,
16, 601; (j) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558.
6. (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679; (b) Agami, C.;
Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2000, 65, 4435; (c) Agami, C.;
Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2002, 67, 2424; (d) Amat, M.; Llor,
N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919; (e) Enders, D.;
Thiebes, C. Pure Appl. Chem. 2001, 73, 573; (f) Poerwono, H.; Higashiyama, K.;
Yamauchi, T.; Kubo, H.; Ohmiya, S.; Takahashi, H. Tetrahedron 1998, 54, 13955;
(g) Kang, K.-T.; Kim, E. H.; Kim, W. J.; Song, N. S.; Shin, J. K.; Cho, B. Y. Synlett
1998, 921; (h) Keck, G. E.; Palani, A. Tetrahedron Lett. 1993, 34, 3223; (i)
Verniest, G.; Surmont, R.; Hende Van, E.; Deweweire, A.; Deroose, F.; Thuring, J.
W.; Kimpe De, N. J. Org. Chem. 2008, 73, 5458; (j) Sulmon, P.; Kimpe De, N.;

A. R. Mohite et al. / Tetrahedron Letters 53 (2012) 30–35
35
16. Methyl
2-(4-(tert-butyl)phenyl)-4-hydroxy-1,2,5,6-tetrahydropyridine-3-
17. CCDC numbers of 5 and 4c: CCDC 836665 & 836666. These numbers contain all
crystallographic details of this publication and are available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html.
18. (a) Ainswort, C. J. Am. Chem. Soc. 1956, 78, 1635; (b) Ruano, J. L. G.; Parra, A.;
Alemán, J.; Yusteb, F.; Mastranzob, V. M. Chem. Commun. 2009, 404.
19. Haddad, M.; Larchevêque, M. Tetrahedron: Asymmetry 1999, 10, 4231.
20. Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000, 14, 2106.
21. García, O.; Arrayás, M. R. G.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456.
carboxylate (4e): Starting with 3e (0.39 g, 1 mmol), BF3ÁEt2O (0.63 mL,
5 mmol), molecular Sieves 4 Å (0.2 g), 4e (0.24 g, 62%) was isolated as a
white solid; enol form; dH (400 MHz, DMSO-d6) 12.1 (bs, 1H), 7.43 (d, J = 8 Hz,
2H), 7.33 (d, J = 8.4 Hz, 2H), 5.42 (s, 1H), 3.52 (s, 3H), 3.18-3.13 (m, 1H), 2.92-
2.85 (m, 1H), 2.74-2.2.60 (m, 2H), 1.25 (s, 9H); dc (100 MHz, DMSO-d6) 169.8,
169.6, 152.3, 132.8, 129.5, 128.3, 126.4, 126.1, 95.8, 52.9, 52.7, 35.4, 34.9, 31.5,
31.48, 25.9; HRMS (ESI -TOF)-m/z Calcd. For C17H23NO3 [M + H]+ 290.1756,
observed. 290.1753.