Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones

Article abstract of DOI:10.1002/chem.201905262

Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp³)-H oxidation of piperidines to α,β-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.

Full text of DOI:10.1002/chem.201905262

A Journal of
Accepted Article
Title: Transition-Metal-Free Multiple Functionalization of Piperidines to
4-Substituted and 3,4-Disubstituted 2-Piperidinones
Authors: Fernando Sartillo-Piscil, Delfino Chamorro-Arenas, Alejandro
A Nolasco-Hernández, Lilia Fuentes, and Leticia Quintero
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201905262
Link to VoR: http://dx.doi.org/10.1002/chem.201905262
Supported by

10.1002/chem.201905262
Chemistry - A European Journal
COMMUNICATION
Transition-Metal-Free Multiple Functionalization of Piperidines to
4-Substituted and 3,4-Disubstituted 2-Piperidinones
Delfino Chamorro-Arenas, Alejandro A. Nolasco-Hernández, Lilia Fuentes, Leticia Quintero, and
Fernando Sartillo-Piscil*
Abstract: Remote and multiple functionalization of piperidines
without the use of transition metal catalysts and elaborate directing
groups is one of the major challenges in organic synthesis. We
report herein an unprecedented two-step protocol that enables the
multiple functionalization of piperidines to either 4-substituted or
trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality
of TEMPO reactivity, which under oxidative and thermal conditions
fluctuates between cation and persistent radical form, a novel
multiple C(sp3)−H oxidation of piperidines to ,-unsaturated 2-
piperidones was developed. Second, the intrinsic low reactivity of the
unsaturated piperidones toward conjugated Grignard addition was
overcome by using TMSCl as Lewis acid. Subsequently, conjugated
Grignard addition/electrophilic trapping protocol provided substituted
2-piperidone intermediates, from which some of them were
transformed into pharmaceutical alkaloids.
development of a general synthetic methodology that directly
transforms piperidines (E) into ,-unsaturated piperidones (G)
(Scheme 1, eq. 2) rather than to employ dehydrogenation of
amides[5] or the conventional ring-closing metathesis of allyl
amides.[6] Thus, the success of this novel approach would
provide, not only a new way for remote mono and double
functionalization of piperidines, but also the shortest route to
pharmaceutical alkaloids such as Vesamicol,[7] Paroxetine,[8]
Femoxetine,[9] and Roche-1[10] under an economical and
ecofriendly fashion (Scheme 1, eq. 3).
The selective C−H functionalization of sp3 carbon atoms can
be defined as the chemical transformation that converts a
specific unreactive carbon atom into a functionalized carbon
group. Accordingly, we could be able to visualize an unreactive
methyl or methylene group as a potential functional group in a
similar manner to the well-established functional group
interchange (FGI) strategy of the conventional retrosynthetic
analysis.[1] However, this chemical operation is way more
complicated to achieve than the classical FGI, particularly at the
remote position from
a nitrogen atom of saturated N-
heterocycles.[2] Nevertheless, the Sanford group reported a
remote palladium-catalyzed C−H arylation of alicyclic amines (A)
to various N-heterocycle precursors of pharmaceutical alkaloids
(B) via palladabicycle intermediate C, which is formed, in the
first instance, by the interaction of palladium catalyst with a
directing group derived from amide p-CF3C6F4 aniline (Scheme 1,
eq. 1).[3] Although this seminal report probably provides the most
direct access to various monosubstituted piperidine alkaloid
precursors (B), the 3,4-disubstituted analogues (D), cannot be
prepared following this approach. Therefore, we report the
development of a transition-metal-free protocol for accessing to
type D compounds in only two steps from simple piperidines (E),
without the necessity of using neither transition-metal catalysts
nor directing groups.[4] Consequently, we envisioned a carbon-
based nucleophilic addition/electrophilic trapping reaction to 3,4-
dipolar synthon (F), from which the unsaturated piperidine (G)
would be the synthetic equivalent. Our prime objective was the
Scheme 1. Palladium catalyzed -C−H arylation of piperidines (R = p-CF3C6F4;
eq. 1). Proposed retrosynthetic analysis for the transition-metal free mono and
dual C−H alkyl-and arylation of piperidines (eq. 2). Pharmaceutical mono and
trans-3,4-disubstituted piperidine alkaloids (Ar = p-OMeC5H4, eq. 3).
In continuing efforts for developing novel synthetic
methodologies directed to the selective functionalization of
unreactive C(sp3)−C(sp3)[11] and C(sp3)−H[12] bonds of N-
heterocycle compounds, in which the main premise is to replace
the use of precious and transition metal catalysts by cheap and
environmentally friendly reagents, the title work was developed.
[*]
Delfino Chamorro-Arenas, Alejandro A. Nolasco-Hernández, Dr.
Lilia Fuentes, Dr. L. Quintero, and Prof. Dr. F. Sartillo-Piscil
Centro de Investigación de la Facultad de Ciencias Químicas
Benemérita
Universidad
Autónoma
de
Puebla
(BUAP)
From
those
efforts
we
learned
that
the
14 Sur Esq. San Claudio, Col. San Manuel, 72570, Puebla, México
fernando.sartillo@correo.buap.mx
TEMPO•→TEMPO+→TEMPOH→TEMPO• chemical redox cycle
mediates the dual C−H oxidation of tertiary piperidines (H) to 3-
alkoxyamino-2-piperidones (I)12c (Scheme 2). According to the
Supporting information for experimental and spectroscopic data for
new compounds. ((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/chem.201905262
Chemistry - A European Journal
COMMUNICATION
reaction mechanism, piperidine H is oxidized to enamine
intermediate K via iminium intermediate J. The reaction of
enamine K and oxammonium cation affords another iminium
intermediate L, which is oxidized into alkoxyamino lactam I with
chlorite anion (Scheme 2). Consequently, we realized that the
triple C−H oxidation of piperidines (H) to ,-unsaturated
piperidones (N) can be obtained if we are able to incorporate a
homolytic C−O bond cleavage step (i.e., thermally) from I to
radical M,13 from which the ,-unsaturated 2-piperidone N
would be formed after hydrogen atom transfer from M to TEMPO
(Scheme 2)
best chemical yield was obtained when 1.0 equivalent of
TEMPO was employed (entry 9).
Table 1.a Screening conditions for the triple C−H oxidation of piperidine 1 to
,-unsaturated piperidone 2
TEMPO, buffer
Solvent (mL)
Time (h)
Entry
(equiv.)
Yield[b]
TEMPO (1.5)
NaH2PO4 (10)
THF/t-BuOH/H2O
1
2
3
4
5
6
7
8
9
20
24
14
14
14
14
14
14
14
35%
33%
35%
46%
48%
54%
21%
32%
64%
(3/7/7)
TEMPO (1.5)
NaH2PO4 (10)
THF/t-BuOH/H2O
(3/7/7)
TEMPO (1.5)
NaH2PO4 (10)
t-BuOH/H2O
(4/4)
TEMPO (1.5)
NaH2PO4 (4)
t-BuOH/H2O
(4/4)
TEMPO (1.5)
NaH2PO4 (2.5)
t-BuOH/H2O
(2/1)
TEMPO (1.5)
NaH2PO4 (2.5)
t-BuOH
(2)
TEMPO (0.3)
NaH2PO4 (2.5)
t-BuOH
(2)
TEMPO (0.7)
NaH2PO4 (2.5)
t-BuOH
(2)
TEMPO (1.0)
NaH2PO4 (2.5)
t-BuOH
(2)
Scheme 2. Designing triple C−H oxidation of piperidines (H) to ,-
unsaturated piperidones (N) inspired by the reaction mechanism of the dual
C−H oxidation of piperidines (H) to 3-alkoxyamino-2-piperidones (I).
aReactions performed at 0.3 mmol of benzyl piperidine (1). bChemical yields of
2 are reported after chromatography on silica gel.
Although it seems reasonable that the third C−H oxidation
step occurs through a radical process, as depicted in Scheme 2
(I→M→N), a base mediated-anionic elimination process is a
possibility that needed to be reviewed.[14] Accordingly, a radical
clock experiment was designed. Piperidine 3[11] was subjected to
multiple C−H oxidation protocol, and a diastereomeric mixture of
hexahydrofuro[3,2-c]pyridinones 4 was obtained in moderate
yield (37%) with a 1.8:1 diastereomeric ratio (Scheme 3). It is
worth to mention that the radical clock experiment is efficient
(5[11] →O→P→4: 73% yield); but the dual C−H oxidation step
Benzyl amine 1 was selected as suitable substrate for
initial experiments. Piperidine 1 was placed into a sealed tube
and treated under dual C−H oxidation of piperidines
conditions,12c e.g. NaClO2 (3 equiv.), NaOCl (1.5 equiv.),
NaH2PO4 (10 equiv.) and TEMPO (1.5 equiv.) in
a t-
BuOH/H2O/THF (7:7:3) solvent mixture. Gratefully, we found that
when the reaction mixture was stirred for 1 h at room
temperature and then heated to 140 °C for 20 h, the expected
,-unsaturated piperidone 2 was obtained in a modest 35%
yield (Table 1, entry 1). Longer reaction time did not improve the
chemical yield (entry 2). Modifying the solvent mixture gave
diverse results but not significantly important (entry 3), except
when THF was excluded from the solvent system and the
equivalents of buffer (NaH2PO4) were considerably reduced
(entries 4 and 5). The decrease of the buffer salt allowed us to
conduct the reaction only in t-BuOH, and the chemical yield was
considerably improved (entry 6). Since TEMPOH is the final
byproduct for the triple C−H oxidation, the possibility to perform
this reaction catalytically or pseudo-catalytically was explored.
Reducing the amount of TEMPO from 1.5 to 0.3 equiv, afforded
the expected product, albeit in low yield (entry 7). Exciting result
was obtained when 0.7 equivalents of TEMPO were employed;
indeed, the chemical yield of the triple C−H oxidation was similar
as when 1.5 equivalents were employed (entry 8). Moreover, the
occurs in a moderate chemical yield (3→5; 50%).[15]
We then faced, without the use of transition metal catalysts,
the intrinsic low reactivity of the ,-unsaturated lactams toward
the conjugated additions of Grignard reagents.[16] Furthermore,
we were able to achieve the PhMgBr conjugate addition of 2 to 6
in excellent chemical yield by simply adding equimolar amounts
of TMSCl as carbonyl activating agent (Scheme 4, entry 1). The
same quantitative yield was obtained for 7 with p-F-PhMgBr
(entry 2). High chemical yields of 8 and 9 were obtained with
other p-substituted phenyl Grignard reagents (entries 3 and 4).
Lower but still good yields were obtained for 4-buthyl and 4-ethyl
substituted piperidones 10 and 11, respectively (entries 5 and 6).
This article is protected by copyright. All rights reserved.

10.1002/chem.201905262
Chemistry - A European Journal
COMMUNICATION
it with the transition-metal-free triple C−H oxidation (TCHO)
protocol, and selected piperidines were multi-functionalized at
remote sites to nitrogen. Thus, starting from simple piperidines,
the rapid access to either 4-substituted or trans-3,4-disubstituted
piperidones, from which some of them were transformed into
pharmaceutic synthetic alkaloids, was achieved (Schemes 4-8).
Applying both tandem protocols to piperidine 1, paroxetine
precursor 2018 was obtained after reducing the carbonyl group of
14 with LiAlH4 (Scheme 4).
Scheme 3. Radical clock experiment.
Table 2.a Developing transition-metal free tandem conjugated Grignard
reagent addition/electrophilic trapping protocol.
Scheme 4. Synthesis of Paroxetine from piperidine 1.
We gratefully found that, not only the chemical yields were
not significantly affected when the conjugated addition was
quenched by carbon-based electrophiles, but also the
stereoselectivity of the 3,4-disubtituted 2-piperidones were
obtained with complete trans relative stereochemistry (entries 7-
14). Thus, trans-4-aryl-3-carbinol piperidinones 12 and 14 were
obtained in good yields (entries 7 and 9, respectively). High and
good yields for trans-4-aryl-3-allyl piperidones 13, 15 and 16
(entries 8, 10 and 11). Also, propargyl bromide, iodomethane
and ethyl bromoacetate served as good electrophiles to provide
trans-disubstituted piperidones (17, 18 and 19, respectively) in
good and acceptable yields (entries 12, 13 and 14).
Scheme 5. Synthesis of Roche-1 intermediate, 4-aryl-2-piperidones (23 and
25) and trans-3,4-disubstitute-2-piperidone 24 from piperidine 21.
Piperidine 21 was subjected to TCHO and unsaturated
piperidone 22 was obtained in good yield; the latter was
exposed to CGAET using p-Cl-C6H4MgBr and formaldehyde as
electrophile, and trans-3,4-disubstituted piperidone 24 was
obtained in high yield, which was transformed into Roche-1
intermediate in two sequential steps (carbonyl reduction and SN2
displacement of mesylate by the respective phenolate ion, see
Scheme 5). Unsaturated piperidone 22 was also transformed
into 4-aryl-2-piperidones 23 and 25 in high yields when was
treated with p-F-C6H4MgBr and p-Cl-C6H4MgBr, respectively,
and quenched both with H+ (Scheme 5). A challenge substrate
was the 1,2-aminoalcohol 26, which was selected to synthesize
vesamicol. Fortunately, the application of TCHO to 26 afforded
Having standardized this unprecedent transition-metal-free
conjugated Grignard addition/electrophilic trapping (CGAET)
protocol[17] applied to ,-unsaturated piperidone 2, we coupled
This article is protected by copyright. All rights reserved.

10.1002/chem.201905262
Chemistry - A European Journal
COMMUNICATION
the desired unsaturated piperidone 27 in good yield, which was
straightforwardly transformed to vesamicol by applying the
conjugated PhMgBr addition followed by carbonyl reduction of
28 with LiAlH4 (Scheme 6).
the Grignard conjugated addition did not provide the expected
results: starting material remains unchanged (Scheme 8).
Scheme 8. Triple C-H oxidation of 4-substituted.
We have developed, under transition-metal free conditions
and using environmentally friendly reagents, an unprecedent
synthetic strategy that permits multiple and remote
functionalization of piperidines to either 4-substituted or trans-
Scheme 6. Synthesis of Vesamicol from aminoalcohol 26.
N-methyl piperidine 29 was the most complicated
substrate: under standard reaction conditions, N-formyl
piperidine 31 was obtained as the major product; however, when
buffer is changed to AcOH, the expected unsaturated lactam 30
is obtained in moderate chemical yield (see SI for details). It is
important to note that this unexpected result might signify an
eco-friendly alternative to the recently reported copper-catalyzed
formylation of N-methyl amines to N-formamides.[19] Thus, trans-
3,4-disubstituted piperidone 33 was obtained from 30 when
PhMgBr and formaldehyde were used as nucleophile and
electrophile, respectively; then carbonyl reductions of 33 with
LiAlH4 followed by reported procedure gave Femoxetine
(Scheme 7).[20] Further Grignard conjugated additions to 30
afforded 4-phenyl and 4-aryl-2-piperidones 32 and 34 in good
and high yield, respectively (Scheme 7).
3,4-disubstituted 2-piperidones through
a
triple C(sp3)−H
oxidation and tandem Grignard
a
conjugated
addition/electrophilic trapping reaction. The synthesis scope and
synthetic applications of this novel methodology offers, not only
a promising alternative for development of a wide range of
pharmaceutic 4-substituted and 3,4-disubstituted piperidine
alkaloids, but also
a new way to visualize a synthetic
disconnection at long sites to the piperidine nitrogen atom.
Further synthetic application of this novel methodology will be
reported elsewhere.
Acknowledgements
Financial support was provided by the CONACyT (project
number: 255891) and the Marcos Moshinsky Foundation. D. C.
A. acknowledges CONACyT for graduate scholarship. Partial
support from BUAP-VIEP.
Keywords: Alkaloids, Piperidines, Transition-metal free, C−H
Oxidation, Tandem conjugated additions/electrophilic trapping
[1]
[2]
(a) E. J. Corey, X. M. Cheng, The Logic of Chemical Synthesis. John
Wiley and Sons, Inc.: New York, 1995.
Remote C-H functionalization: (a) D. Antermite, D. P. Affron, J. A. Bull,
Org. Lett. 2018, 20, 3948-3952. (b) M. Lee, M. S. Sanford, Org. Lett.
2017, 19, 572-575. Alpha functionalization of cyclic amines (c) E. A.
Mitchell, A. Peschiulli, N. Lefevre, L. Meerpoel, B. U. W. Maes, Chem.
Eur. J. 2012, 18, 10092-10142. (d) K. R. Campos, Chem. Soc. Rev.
2007, 36, 1069-1084. Beta functionalization of cyclic amines (e) B. F. V.
Steijvoort, N. Kaval, A. A. Kulago, B. U. W. Maes, ACS Catal. 2016, 6,
4486-4490. (f) A. Millet, P. Larini, E. Clot, O. Baudoin, Chem. Sci. 2013,
4, 2241-2247.
[3]
(a) J. J. Topeczewski, P. J. Cabrera, N. I. Saper, M. S. Sanford, Nature
2016, 531, 220-224. Also see (b) M. Lee, A. Adams, P. B. Cox, M. S.
Sanford, Synlett 2019, 30, 417-422. (c) P. J. Cabrera, M. Lee, M. S.
Sanford, J. Am. Chem. Soc. 2018, 140, 5599-5606.
Scheme 7. Synthesis of Femoxetine, 4-aryl-2-piperidones (32 and 34) and
trans-3,4-disubstitute-2-piperidone 33 from piperidine 29.
[4]
[5]
M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li, W. Su, Org. Chem. Front.
2014, 1, 843-895
(a) M. Chen, G. Dong, J. Am. Chem. Soc. 2017, 139, 7757-7760. (b) M.
Chen, A. J. Rago, G. Dong, Angew. Chem. Int. Ed. 2018, 57, 16205-
16209; Angew. Chem. 2018, 130, 16437-16441. (c) C. J. Teskey, P.
Finally, we briefly explored both protocols with 4-
substituted piperidines 35 and 36. Although the triple C−H
oxidation gave unsaturated piperidones 37 and 38 in good yields,
This article is protected by copyright. All rights reserved.

10.1002/chem.201905262
Chemistry - A European Journal
COMMUNICATION
Adler, C. R. Goncalves, N. Maulide, Angew. Chem. Int. Ed. 2019, 58,
447-451; Angew. Chem. 2019, 131, 456-460.
[6]
(a) H. M. A. Hassan, Chem. Commun. 2010, 46, 9100-9106. (b) G.
Vincent, Synthesis of Lactams by Metathesis Reactions. J. Prunet
(eds): Synthesis of Heterocycles by Metathesis Reactions. Topics in
Heterocyclic Chemistry, 2015, vol 47. Springer. (c) H. Y. Gondal, B. A.
Didier, Chemistry of Heterocyclic Compounds 2016, 52, 183-191.
C. Prior, I. G. Marshall, S. Parsons, Gen. Pharmacol. 1992, 23, 1011-
1022.
[7]
[8]
[9]
B. A. Davis, A. Nagarajan, L. R. Forrest, S. K. Singh, Sci. Rep. 2016, 6,
23789.
J. B. Lassen, E. Petersen, B. Kjellberg, S. O. Olsson, Eur. J. Pharmacol.
1975, 32, 108-115.
[10] (a) C. De Risi; G. Fanton, G. P. Pollini, C. Trapella, F. Valente, V.
Zanirato. Recent Advances in the Stereoselective Synthesis of trans-
3,4-disubstituted-Piperidines:
Aplications
to
(-)-Paroxetine.
Tetrahedron: Asymmetry 2008, 19, 131-155. (b) S. Brandau, A. Landa,
J. Franzén, M. Marigo, K. A. Jorgensen, Angew. Chem. 2006, 118,
4411-4415.
[11] (a) J. Romero-Ibañez, S. Cruz-Gregorio, J. Sandoval-Lira, J. M.
Hernández-Pérez, L. Quintero, F. Sartillo-Piscil, Angew. Chem. Int. Ed.
2019, 58, 8867-8871; Angew. Chem. 2019, 131, 8959-8963.
[12] (a) D. Chamorro-Arenas, U. Osorio-Nieto, L. Quintero, L. Hernández-
García, F. Sartillo-Piscil, J. Org. Chem. 2018, 83, 15333-15346. (b) J.
Romero-Ibañez, S. Cruz-Gregorio, L. Quintero, F. Sartillo-Piscil,
Synthesis 2018, 50, 2878-2886. (c) U. Osorio-Nieto, D. Chamorro-
Arenas, L. Quintero, H. Höpfl, F. Sartillo-Piscil, J. Org. Chem. 2016, 81,
8625-8632.
[13] T. Vogler, A. Studer, Synthesis 2008, 13, 1979-1993.
[14] Elimination step is mediated by t-BuO-K+. See: M.-M. Wang, G.-H. Sui,
X.-C. Cui, H. Wang, J.-P. Qu, Y.-B. Kang, J. Org. Chem. 2019, 84,
8267-8274.
[15] Chemical yields for each step were determined separately.
[16] K. M. Byrd, J. Org. Chem. 2015, 11, 530-562.
[17] Although the tandem conjugate addition/electrophilic trapping reaction
in ,-unsaturated esters and ketones has been well-stablished, there
is not report with unsaturated lactams under transition metal-free
condition. However, Baldía and coworkers have succeeded with
unsaturated amides derived from pseudoephedrine. See: (a) E. Reyes,
J. L. Vicario, L. Carrillo, D. Badía, A. Iza, U. Uria, Org. Lett. 2006, 8,
2535-2538. (b) E. Reyes, J. L. Vicario, L.; Carrillo, D. Badía, U. Uria, A.
Iza, J. Org. Chem. 2006, 72, 7763-7772.
[18] L. Czibula, A. Nemes, F. Sebôk, C. Szántay Jr., M. A. Mák, Eur. J. Org.
Chem. 2002, 3336-3339.
[19] S. Nakai, T. Yatabe, K. Suzuki, Y. Sasano, Y. Iwabuchi, J.-y.;
Hasegawa, N. Mizuno, K. Yamaguchi, Angew. Chem. Int. Ed. 2019, 58,
16651-16659; Angew. Chem. 2019, 131, 16804-16812.
[20] J. A. Christensen, M. Engelstoft, K. Schaumburg, H. Schou, F. Wâtjen,
Tetrahedron Lett. 1983, 24, 5151-5152.
This article is protected by copyright. All rights reserved.

10.1002/chem.201905262
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Delfino Chamorro-Arenas,
Alejandro A. Nolasco-
Hernández, Lilia Fuentes,
Leticia Quintero, and Fernando
Sartillo-Piscil*
Page No. – Page No.
Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-
Disubstituted 2-Piperidinones
We report herein unprecedent two-step protocols that enable the multiple functionalization of
piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidinones which some of
them were transformed into pharmaceutical alkaloids.
This article is protected by copyright. All rights reserved.