Transition-Metal-Free Deconstructive Lactamization of Piperidines

Article abstract of DOI:10.1002/anie.201903880

One of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp³)–C(sp³) bonds, which requires using transition or precious metal catalysts. We present here an alternative: the deconstructive lactamization of piperidines without using transition metal catalysts. To this end, we use 3-alkoxyamino-2-piperidones, which were prepared from piperidines through a dual C(sp³)–H oxidation, as transitory intermediates. Experimental and theoretical studies confirm that this unprecedented lactamization occurs in a tandem manner involving an oxidative deamination of 3-alkoxyamino-2-piperidones to 3-keto-2-piperidones, followed by a regioselective Baeyer–Villiger oxidation to give N-carboxyanhydride intermediates, which finally undergo a spontaneous and concerted decarboxylative intramolecular translactamization.

Full text of DOI:10.1002/anie.201903880

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Accepted Article
Title: Transition-Metal Free Deconstructive Lactamization of
Piperidines
Authors: Fernando Sartillo-Piscil, Julio Romero-Ibañez, Silvano
Cruz.Gregorio, Jacinto Sandoval-Lira, Julio M Hernández-
Pérez, and Leticia Quintero
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903880
Angew. Chem. 10.1002/ange.201903880
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10.1002/anie.201903880
Angewandte Chemie International Edition
COMMUNICATION
Transition-Metal Free Deconstructive Lactamization of
Piperidines
Julio Romero-Ibañez, Silvano Cruz-Gregorio, Jacinto Sandoval-Lira, Julio M. Hernández-Pérez, Leticia
Quintero, and Fernando Sartillo-Piscil*
Dedication ((optional))
C(sp3)−C(sp3) single bond to pyrrolidinone´s C(sp2)−N “single”
Abstract: One of the major synthetic challenges in organic synthesis
is the activation or deconstructive functionalization of unreactive
C(sp3)−C(sp3) bonds. This requires using transition or precious metal
catalysts. However, we present here a deconstructive lactamization
of piperidines without using transition metal catalysts. To this end,
we use 3-alkoxyamino-2-piperidones, which were prepared from
bond. This can be attained either by a two-step or one pot
protocol, but under transition-metal free conditions and using
only cheap and environmentally-friendly reagents. We designed
the title chemical transformation inspired by the seminal work of
the Sarpong group,[12] in which they developed a silver-mediated
deconstructive functionalization of piperidines into pyrrolidines in
two sequential steps, and one pot protocol (Scheme 1)
piperidines through
a
dual C(sp3)−H oxidation, as transitory
substrates. Experimental and theoretical studies confirm that this
unprecedent lactamization occurs in a tandem manner involving an
oxidative deamination of 3-alkoxyamino-2-piperidones to 3-keto-2-
piperidones, followed by a regioselective Baeyer-Villiger oxidation to
N-carboxyanhydride intermediates, which finally undergo
a
spontaneous and concerted decarboxylative intramolecular
translactamization.
Transition metal catalysts have played a major role on the
exponential advance of the “state-of-the-art” of organic
synthesis.[1] Transition-metal catalyzed C−C bond coupling
reactions,[2] Csp3−H bond activation-functionalization of
saturated compounds,[3] and Csp3−Csp3 bond cleavage-
functionalization[4] are representative chemical transformations
that have revolutionized the industrial and academic research.
However, the economic and ecological cost of employing these
reactive catalysts is high and is attracting the attention of
chemists who believe that organic synthesis should be
performed, not only with high efficiency and yields, but also with
an economic and ecological approach.[5] Fortunately,
a
considerable number of remarkable transition-metal-free
synthetic protocols are reported daily.[6-10]
In recent years, our research group has developed efficient,
accessible, economic and environmentally friendly protocols for
the functionalization of simple N-heterocycle substrates into
relevant bioactive precursors.[11] The success of this new form of
direct functionalization of pre-existing N-heterocycles lies on the
highly selective C−H oxidation at the alpha position mediated by
cheap and environmentally friendly reagents such as NaClO2,
NaOCl and TEMPO, in which, under modulated conditions, the
C−H oxidation at the beta position can be achieved, even under
catalytic conditions.[11a]
Scheme 1. Silver-mediated deconstructive dehomologation of piperidines
developed by Sarpong (eq 1),[12] and the transition-metal free deconstructive
lactamization of piperidines proposed here (eq 2).
In Sarpong´s work, the C−H oxidation of a deactivated
piperidine A allowed the initial C−N bond cleavage to amino
aldehyde B, which after oxidation and decarboxylative
halogenation
provided
the
respective
deconstructive
halogenation product C. Finally, after treatment C with a base,
the dehomolgated pyrrolidine D was obtained (eq 1, Scheme 1).
In our approach, on the other hand, deconstructive
functionalization of the sp3 C−C bond at the alpha and beta
positions of the respective piperidine was envisioned by applying
the selective and dual C−H oxidation of tertiary piperidines 1 to
3-alkoxyaminolactams 2 mediated by NaClO2, NaOCl and
TEMPO.[11b,11c] Thereafter, precursor 2 would be transformed
into keto lactam 3 via an oxidative deamination mediated by a
suitable oxidizing reagent that would catalyze a regioselective
Baeyer-Villiger (SBV)[13] oxidation to N-carboxyanhydride
intermediate 4. Finally, the respective 2-pyrrolidinone 5 would be
obtained after a hydrolysis and an intramolecular amidation (eq
2, Scheme 1). The two major challenges of this synthesis
In this work, we are pleased to introduce a simple protocol
that permits the transformation of piperidines to 2-pyrrolidinones
via
a
deconstructive functionalization of
a
piperidine´s
[*]
J. Romero-Ibañez, Dr. S. Cruz-Gregorio, Dr. J. Sandoval-Lira, Dr. J.
M. Hernández-Pérez, Dr. L. Quintero, Prof. Dr. F. Sartillo-Piscil
Centro de Investigación de la Facultad de Ciencias Químicas
Benemérita Universidad Autónoma de Puebla (BUAP)
14 Sur Esq. San Claudio, Col. San Manuel, 72570, Puebla, México
fernando.sartillo@correo.buap.mx
Supporting information for experimental and spectroscopic data for
all products. Also theoretical details.((Please delete this text if not
appropriate))
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10.1002/anie.201903880
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proposal would be the regioselective Baeyer-Villiger oxidation,[14]
as well as the development of an efficient “one-pot” or sequential
transformation of N-carboxyanhydride into the desired
pyrrolidinones.
acceptable yields of lactams 5 and 9. The regioselectivity in the
Baeyer-Villiger reaction was tested with piperidines substituted
at the C-4 position (12, 14, 16, 18, 20, 22, 24, and 28, Table 2).
Following the plan depicted in Scheme 1 (eq 2), piperidine 1
was transformed into piperidone 2 with NaClO2, NaOCl and
TEMPO, and after adding 3 equivalents of m-CPBA to a solution
of 2 in CH2Cl2, lactam 5 was unexpectedly obtained in 72% yield
in 15 min. Remarkably, not only the BV reaction was highly
selective, but also all the subsequent transformations, which
were planned to occur in four separated steps, occurred in an
unprecedent tandem fashion (Scheme 2). We postulate that this
novel domino reaction begins with an oxidative deamination of 2
with m-CPBA to ketoamide 3 (via N-oxide intermediate 6),
followed by a regioselective BV reaction[13] of 3 to 4 (through a
Criegee intermediate 7), and finally, a concerted decarboxylative
Table 1. Screening conditions for the direct translactamization 3-alkoxyamine
lactam 8 to lactam 9.[a]
[O]
Solvent
Time
Isolated yield[b]
Entry
intramolecular translactamization of N-carboxyanhydride
(Scheme 2).
4
m-CPBA (3)
m-CPBA (3)
m-CPBA (2.5)
CH2Cl2
Et2O
10 min
10 min
10 min
9 (71%)[c]
9 (88%)[c]
9 (45%)
1
2
3
Et2O
9 (12%) + 10
m-CPBA (1.5)
Et2O
20 min
4
(13%)
H2O2 (15)
Oxone (3)
Et2O
Et2O
2 h
2 h
dnr[d]
dnr[d]
5
6
7
9 (67%)[c]
Scheme 2. Tandem translactamization of alkoxyamino lactam 2 to lactam 5,
and proposed intermediates.
H2O2/Oxone (15/3)
CH2Cl2
12 h
[a] Reactions performed at 0.03 mmol of 3-alkoxyamine piperidone. [b] Yields
are reported after chromatography. [c] Traces of hydroxylactam
detected. [d] dnr = did not react.
I were
Screening optimal reaction conditions were conducted with
3-alkoxyamino piperidone 8 (Table 1). Compound 8 was treated
under the same reactions conditions as for 2, and the expected
2-pyrrolidinone 9 was obtained with practically the same
chemical yield (entry 1). Switching the solvent from CH2Cl2 to
Et2O improved the chemical yield to 88% (entry 2). Reducing the
equivalents of m-CPBA, from 3.0 to 2.5, affected the chemical
yield (entry 3). Poor yield of 9 was obtained when 1.5
equivalents were employed (entry 4). While lactam 8 was
Good yields of pyrrolidinones were obtained not only for
piperidines bearing 4-isobutyl (13, 56%), 4-ethyl (15, 65%), and
4-methyl (17, 63%) groups, but also for both 4-aryl substituted
(19, 50%; and 21, 51%). Both, ester and ether groups at the
same position of the piperidine ring (22 and 24) gave acceptable
yields of pyrrolidinones 23 and 25, 46% and 42%, respectively.
A similar result was obtained for the reaction from piperidine 26
to its respective pyrrolidinone 27 (42%). Unfortunately, albeit the
dual C−H oxidation of 4-hydroxy-pirrolidine 28 proceeded in
good yield (68%), translactamization of the respective 3-
alkoxyamine piperidone (not shown in Table 2) did not occurred
(Table 2).
The potential use of this novel synthetic methodology was
demonstrated in the synthesis of (S)-4-hydroxy-2-pyrrolidinone
(S)-30,[16] which is a key precursor of various bioactive products
such as the oral antibiotic CS-834[17] and a nootropic agent
oxiracetam (31).[18] In addition, the formal synthesis of (+)-
harmicine (32)[19] was achieved by a simple application of
TMFDL to indole piperidine 33 (Scheme 3). Proline derivative 34
was transformed into (R)-3-hydroxy-piperidine 35 in two
sequential steps: first, a reduction of the ester group with LiAlH4;
and second, a ring expansion mediated by trifluoroacetic
anhydride and quenched with NaOH.[20] As observed from the
unreactive with H2O2 (entry 5) and Oxone (entry 6),[15]
a
moderate yield of lactam 9 was obtained when both oxidizing
reagents were used as a mixture (entry 7). Further combinations
of these oxidizing reagents produced worse yields. Because of
an interrupted oxidative deamination, traces of hydroxylactam I
were obtained in some cases (entries 1, 2, 4).
With the optimized reaction conditions for translactamization
of 3-alkoxyamino lactams in hand, we proceed to establish the
scope of the transition-metal free deconstructive lactamization
(TMFDL) of piperidines, including, as a first step, the dual and
tandem oxidation of piperidines to 3-alkoxyamine pyrrolidinones
(Table 2). High chemical yields were obtained for the
lactamization of piperidines 1 and 11 to lactams 5 and 9,
respectively. We thought that m-CPBA could be compatible with
the oxidizing reagents employed for the dual oxidation, then a
“one-pot” protocol was applied to piperidines 1 and 11 providing
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Table 2. Developing transition-metal free deconstructive lactamization (TMFDL) of piperidines.
B97XD/6-311+G(d,p) level of theory[26] revealed the existence
of two stable Criegee intermediate conformers (CI1 and CI2)
prone to form N-carboxyanhydride intermediates. Because of
the presence of an intramolecular hydrogen bond (with an
energy E(2) = 2.24 kcal/mol), Criegee intermediate CI1 (in which
C2−C3 bond and O−O bond are anti-periplanar oriented), is 4.36
kcal/mol more stable than CI2. From the optimization and the
characterization of the TS1 and TS2 transition state structures
above, the regioselective BV reaction did not occur in the
presence of a free hydroxyl group; thus, we decided to employ
the Mitsunobu reaction[21] after the dual oxidation. This allowed
to attain, not only the desired stereochemistry (3S), but also the
protection of the hydroxyl group. Thus, chiral pirrolidinone (S)-36
was prepared from (R)-35 in three sequential steps. Removal of
the protecting groups of (S)-36 provided the target product (S)-
30 (Scheme 3). On the other hand, the indole derivative 33 was
subjected to TMDFL, and pyrrolidinone 37 was obtained with a
moderate yield. After removal of the Boc protecting group with
TBAF, and following reported procedures,[22,23] the (+)-harmicine
32 can be obtained (Scheme 3).
In order to prove the formation of the putative N-
carboxyanhydride intermediate and its concerted conversion to
the lactam product, the reaction of keto lactam 10[11b] with m-
CPBA was conducted into the NMR tube. The NMR tube was
charged with equimolar amounts of m-CPBA and 10 in CDCl3.
The N-carboxyanhydride F, lactam 9, and the remaining starting
material 10 with a 8:7:5 ratio, respectively, were observed after 3
min of stirring at 20 °C. The ratio in favor to product 9 changed
to 1:8:2 in 20 min (see SI). The complete conversion of 10 to 9
was rapidly achieved by adding 0.5 equivalents of m-CPBA.
Since intermediate F cannot be isolated, its molecular structure
was confirmed by computational modeling of the 1H NMR at
B3LYP/6-31++G(2d,p)//B3LYP/6-31G(d) level of theory with the
SMD model to describe the solvent effect [CDCl3 (ε = 4.7)].[24]
According to the prevailing mechanism of the BV, the Criegee
intermediate (CI) favors the group migration of those who can
stabilize better the partial positive charge.[25] Therefore, the
migratory atom should be the C-4 atom, and not the C-2 atom
from the carbonyl group (Scheme 4). Computational analysis at
Scheme 3. Synthetic applications of the transition-metal free deconstructive
lactamization (TMFDL) of piperidines.
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Scheme 4. Regioselective BV and decarboxylative translactamization mechanism.
for CI1 to F and for CI2 to E reactions, respectively, we found
that the former transformation occurs at much lower energetic
cost (G(TS1) = 20.22 kcal/mol) than the later (G(TS2) =
28.35 kcal/mol). Additionally, the transformation of intermediate
F, which was detected by 1H NMR, into lactam 9, was also
computed. It was found that the activation energy for F to 9 is
lower (G(TS3) = 19.71 kcal/mol) than the activation energy for
CI1 to F reaction (20.22 kcal/mol), confirming that it also occurs
in a concerted process (Scheme 4).
We have developed, under transition-metal free conditions
and using environmentally friendly reagents, a new synthetic
protocol that permits the access to 2-pyrrolidinones from simple
tertiary piperidines via a selective oxidative ring contraction of N-
substituted piperidines, either in two step or “one pot” protocol.
The synthesis scope, synthetic applications and mechanistic
findings of this novel synthetic technology offers, not only a
promising alternative for development of a wide-range of
bioactive pyrrolidinones and derivative molecules, but also a
new synthetic disconnection complementary to the classical
lactamization protocols.
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Acknowledgements
Financial support was provided by the CONACyT (project
number: 255891) and the Marcos Moshinsky Foundation. J. R. I.
acknowledges CONACyT for graduate scholarship. Partial
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Keywords: Baeyer-Villiger • Decarboxylative translactamization
• Deconstructive functionalization • Piperidines • Pyrrolidinones •
Transition-metal free synthesis.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Transition-Metal Free Deconstructive
Lactamization of Piperidines:
Julio Romero-Ibañez, Silvano Cruz-
Gregorio, Jacinto Sandoval-Lira,
Julio M. Hernández-Pérez, Leticia
Quintero, and Fernando Sartillo-
Piscil*
An unprecedent transition-metal free
“one-pot” or two step protocol for the
lactamization of piperidines is reported.
This represent a new synthetic
Page No. – Page No.
Transition-Metal Free
Deconstructive Lactamization of
Piperidines
disconnection complementary to the
classical lactamization protocols.
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