[Co(TPP)]-Catalyzed Formation of Substituted Piperidines

Article abstract of DOI:10.1002/chem.201900587

Radical cyclization via cobalt(III)-carbene radical intermediates is a powerful method for the synthesis of (hetero)cyclic structures. Building on the recently reported synthesis of five-membered N-heterocyclic pyrrolidines catalyzed by Co^II porphyrins, the [Co(TPP)]-catalyzed formation of useful six-membered N-heterocyclic piperidines directly from linear aldehydes is presented herein. The piperidines were obtained in overall high yields, with linear alkenes being formed as side products in small amounts. A DFT study was performed to gain a deeper mechanistic understanding of the cobalt(II)-porphyrin-catalyzed formation of pyrrolidines, piperidines, and linear alkenes. The calculations showed that the alkenes are unlikely to be formed through an expected 1,2-hydrogen-atom transfer to the carbene carbon. Instead, the calculations were consistent with a pathway involving benzyl-radical formation followed by radical-rebound ring closure to form the piperidines. Competitive 1,5-hydrogen-atom transfer from the β-position to the benzyl radical explained the formation of linear alkenes as side products.

Full text of DOI:10.1002/chem.201900587

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Accepted Article
Title: [Co(TPP)]-catalyzed formation of substituted piperidines
Authors: Marianne Lankelma, Astrid M. Olivares, and Bas de Bruin
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To be cited as: Chem. Eur. J. 10.1002/chem.201900587
Link to VoR: http://dx.doi.org/10.1002/chem.201900587
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[Co(TPP)]-catalyzed formation of substituted piperidines
Marianne Lankelma†,[a] Astrid M. Olivares†,[b] and Bas de Bruin*[a]
Dedicated to Professor Pablo Espinet on the occasion of his 70th birthday
Abstract: Radical cyclization via cobalt(III)–carbene radical
intermediates is a powerful method for the synthesis of (hetero)cyclic
structures. Building on the recently reported synthesis of five-
membered N-heterocyclic pyrrolidines catalyzed by Co(II) porphyrins,
we herein report the [Co(TPP)]-catalyzed formation of desirable
six-membered N-heterocyclic piperidines, directly from linear
aldehydes. Piperidines were obtained in overall high yields, with linear
alkenes being formed as side products in small amounts. A DFT study
was performed to gain a deeper mechanistic understanding of the
cobalt(II)-porphyrin-catalyzed formation of pyrrolidines, piperidines
and linear alkenes. The calculations show that the alkenes are
unlikely to be formed through an expected 1,2-hydrogen atom transfer
to the carbene carbon. Instead, the calculations are consistent with a
pathway involving benzyl radical formation followed by radical
rebound ring-closure to form the piperidines. Competitive 1,5-
hydrogen atom transfer from the β-position to the benzyl radical
explains the formation of linear alkenes as side products.
form a Co(III)–carbene radical, which can engage in controlled
radical addition or hydrogen atom transfer (HAT). This type of
reactivity belongs to a more general class of catalytic reactions
involving single-electron elementary steps, called metalloradical
catalysis.[ 5 ] Cobalt(III)–carbene radical chemistry has been
successfully applied in the synthesis of carbo- and heterocyclic
structures, including cyclopropanes,[ 6 ] chromenes,[ 7 ] furans,[8 ]
9
]
10
]
11
]
indenes,[
indolines,[
ketenes,[
butadienes
&
and
dihydronaphthalenes,[
dibenzocyclooctenes[
12
]
13
]
phenylindolizines.[14] Recently, the group of Zhang reported the
synthesis of chiral pyrrolidines and related five-membered ring
compounds, starting from N-tosylhydrazones and catalyzed by
cobalt(II) complexes of D2-symmetric chiral amidoporphyrins
(Scheme 1A).[15] Related reactions leading to five-membered N-
heterocycles via carbene insertion into activated CH bonds,
mediated by Grubbs-type catalysts, were recently disclosed by
the group of Fernández.[16]
Considerable efforts have been directed towards the synthesis of
nitrogen-based heterocycles because of their importance in
medicinal chemistry.[1] The most prevalent N-heterocycles in U.S.
FDA-approved drugs are piperidines (Figure 1).[ 2 ] Common
synthetic routes to the piperidine motif include hydroamination
and ring-closing metathesis.[3] An attractive alternative strategy
for the formation of piperidines could be ring-closing C–C bond
formation catalyzed by complexes based on earth-abundant
transition metals.[4]
Scheme 1. (A) Formation of chiral pyrrolidines and other five-membered hetero-
or carbocycles from N-tosylhydrazones, catalyzed by cobalt(II) complexes of D2-
symmetric chiral amidoporphyrins. (B) [Co(TPP)]-catalyzed one-pot synthesis
of six-membered piperidine rings directly from linear aldehydes (this work).
Figure 1. A few examples of piperidine-based drugs and natural products.
As part of our ongoing exploration of the reactivity of cobalt(III)–
carbene radicals, and in view of the importance of six-membered
N-heterocycles in medicinal chemistry, we sought to explore the
feasibility of this approach for the development of a novel method
to synthesize substituted piperidines (Scheme 1B, compounds 2).
Furthermore, instead of starting from N-tosylhydrazones, we
opted for in situ formation of N-tosylhydrazones from aldehydes,
followed by in situ deprotonation of the hydrazones to form the
necessary diazo compounds. This one-pot approach reduces the
number of synthetic steps and thereby provides accelerated
access to the desired products. The potential of in situ
N-tosylhydrazone formation in other reactions was briefly
illustrated in 2014 by the group of Che[17] and more recently by
Chattopadhyay and co-workers.[14]
In recent years, our group and others have demonstrated that low-
spin d7 cobalt(II) porphyrin complexes are excellent catalysts for
C–C bond formation through radical-type carbene-transfer. In
these reactions, the cobalt(II) porphyrin reacts with a carbene
precursor (usually a diazo compound or N-tosylhydrazone) to
[a]
Marianne Lankelma,† Prof. dr. B. de Bruin
Van ’t Hoff Institute for Molecular Sciences (HIMS)
Homogeneous, Supramolecular & Bio-Inspired Catalysis
University of Amsterdam, Science Park 904
1098 XH, Amsterdam, The Netherlands
E-mail: b.debruin@uva.nl
[b]
Astrid M. Olivares†
Department of Chemistry, University of Rochester
404 Hutchison Hall, Rochester, NY 14627-0216 (USA)
Initial screening proved this approach to be successful,
yielding the targeted piperidines 2 in overall high yields. Linear
alkenes 3 were obtained as side products, in most instances in
small amounts (Scheme 1B). In this paper we describe the details
of the catalytic reactions, including optimization studies, substrate
† These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under: DOI
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screening and mechanistic investigations aimed at understanding
the formation of both ring products and linear alkenes.
Elevated temperatures (entries 6 and 7) promoted alkene
formation, possibly due to an increased entropy contribution to
Gǂ. Exclusion of light (entry 8) did not affect the yield or product
ratio. The use of solvents with reduced ability to π-stack (vs.
benzene) (entries 9–11) did not improve the yield or product ratio
either, and in the case of toluene the product ratio was even
negatively affected. Notably, use of the isolated N-tosylhydrazone
provided effectively the same results as in situ generation from 1a,
with the latter approach giving faster access to the same products
in the same yield and product ratio.
Next we investigated the scope of the reaction (Table 2),
applying the reaction conditions of entry 1 of Table 1. The reaction
proved to be compatible with a wide variety of substituents (13
examples, Table 2). We observed the relative amount of alkene
to be dependent on the substitution of the substrate.
The reaction parameters involved in the conversion of 1a to 2a
and 3a were screened in an effort to optimize product ratio and
yield (Table 1; R = Ph). Without [Co(TPP)] (entry 0), only the diazo
compound was formed. The use of 5 mol% [Co(TPP)], 1.2
equivalents of p-TsNHNH2, 2 equivalents of Cs2CO3, benzene (1
or 2 mL) and 60 ºC (entries 1 and 2) resulted in a quantitative
combined yield and a 2a/3a ratio of ca. 1 : 0.10. Increasing the
catalyst loading (entry 3) did not have a beneficial influence.
Addition of more than 1.2 equivalents of p-TsNHNH2 (entry 4) or
>2 equivalents Cs2CO3 (entry 5) was disadvantageous for both
yield and product ratio.
Table 1. Screening of conditions to optimize the yield and product ratio of the
conversion of 1a to 2a and 3a.
Entry
[Co(TPP)] p-TsNHNH2 Cs2CO3 Solvent
Volume Temperature Time
Yield (%)
Piperidine :
alkene ratio
N/A
(mmol)
0
(mmol)
0.12
0.12
0.12
0.12
0.15
0.12
0.12
0.12
0.12
0.12
0.12
0.12
(mmol)
0.20
0.20
0.20
0.20
0.20
0.22
0.20
0.20
0.20
0.20
0.20
0.20
(mL)
(ºC)
60
60
60
60
60
60
80
105
60
60
60
60
(h)
24
24
24
24
24
24
24
24
24
24
24
24
0 a, b
1 a
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Toluene
2
2
1
2
2
2
2
2
1
2
2
2
0
0.005
0.005
0.015
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
Quant.
Quant.
Quant.
78
92
Quant.
96%
Quant.
85%
Quant.
85%
1 : 0.10
1 : 0.08
1 : 0.14
1 : 0.40
1 : 0.42
1 : 0.28
1 : 0.59
1 : 0.07
1 : 0.11
1 : 0.51
1 : 0.16
2 a
3 a
4 a
5 a
6 a
7 a
8 a, c
9 a
Benzene
o-dichlorobenzene
Toluene
10 a
11 a
Cyclohexane
a 0.1 mmol substrate, 24h. b Only the corresponding diazo compound
formed. c Excluded from light.
Table 2. Investigation of the substrate scope of [Co(TPP)]-catalyzed piperidine
formation.
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In most instances, piperidine and alkene formed in a ratio varying
between 1 : 0.07 and 1 : 0.28, but there seems to be a delicate
balance between the product ratio and the stability of the
proposed benzylic radical intermediate (vide infra). Steric bulk
and/or considerable stability of this intermediate appears to
induce substantial alkene formation (entries c and d), whereas
absence of radical-stabilizing substituents seems to favour ring
closure. Density functional theory (DFT) calculations support
these observations (Scheme S4 and S16).
porphyrin without phenyl substituents on the meso-positions was
used, abbreviated as [Co(por)].
A first important observation is that alkene formation via the
expected 1,2-HAT from the β-position to the carbene-radical
carbon of the proposed intermediate C has a high computed free
energy barrier of +20 kcal mol-1 (Scheme 3). This barrier is too
high to compete with radical rebound ring-closure to form 2a
(barrier: +7 kcal mol-1; Scheme 4).
Notably, in reactions leading to formation of five-membered
N-heterocyclic pyrrolidines, no linear alkenes were formed as side
products.[15] We wondered if this is due to a beneficial effect of the
D2-symmetric Co(II) amidoporphyrins used by Zhang and co-
workers, or rather due to five-membered ring formation being
substantially more favorable than linear alkene formation. We
therefore investigated formation of pyrrolidine 4 using [Co(TPP)]
and the above described in situ approach (Scheme 2A).
Interestingly, as in the report of Zhang and co-workers, this led to
clean pyrrolidine formation without detectable amounts of linear
alkene.
Scheme 3. Linear alkene formation from cobalt(III)–carbene radical
intermediate C via 1,2-HAT from the β- to the α-position has a rather high energy
barrier. The ellipse represents the porphyrin ligand.
However, we found an alternative pathway for linear alkene
formation, involving 1,5-HAT from the β-position to the benzylic
radical carbon of D over TS5, which has a similar barrier as radical
rebound ring-closure over TS4. As such, the DFT calculations
point in the direction of the two competitive pathways depicted in
Scheme 4.
Scheme 2. (A) [Co(TPP)]-catalyzed formation of pyrrolidine 4 via in situ
generation of the N-tosylhydrazone. (B) Formation of piperidine 2a and alkene
3a catalyzed by [Co(3,5-di(tBu)ChenPhyrin)].
Furthermore, when using Zhang’s D2-symmetric chiral catalyst
[Co(3,5-di(tBu)ChenPhyrin)]
to synthesize six-membered
N-heterocyclic piperidine 2a (Scheme 2B), we observed a higher
amount of linear alkene than with [Co(TPP)]. With this catalyst,
piperidine 2a and alkene 3a were formed in an almost equimolar
ratio (1 : 0.70), which might be attributed to the formation of
hydrogen bonds between the substrate and amide substituents of
the porphyrin.[18] The products were obtained in poor combined
yield (67%) compared to [Co(TPP)], and asymmetric induction
proved inefficient (ee of 2a: 25%). Optimization of asymmetric
induction with other chiral catalysts is beyond the scope of this
paper, but would be of interest for subsequent studies.
The above observations show that six-membered ring
formation and linear alkene production are competitive, while
linear alkenes are not formed in the synthesis of five-membered
pyrrolidine rings, irrespective of the type of cobalt(II)-porphyrin
used. Such behaviour is not easy to understand in terms of a
mechanism involving linear alkene formation via a commonly
accepted 1,2-hydrogen shift (Scheme 3).[19]
Scheme 4. Proposed mechanisms for [Co(por)]-catalyzed competitive
formation of piperidines and alkenes. All Gibbs free energies (ΔGº333K, in kcal
mol-1) including those of TS1-TS5, are reported relative to the energy of
intermediate A. The ellipse represents the porphyrin ligand.
The catalytic cycle is preceded by the (presumably) uncatalyzed
formation of diazo compound 1a’’ from N-tosylhydrazone 1a’
which is in turn in situ generated from aldehyde 1a. Coordination
of diazo compound 1a’’ to the cobalt(II) porphyrin generates
intermediate B. Dinitrogen loss from diazo adduct B over TS1 to
Therefore, to gain
a
better understanding of the
mechanisms of cobalt(II)-porphyrin-catalyzed formation of
pyrrolidines, piperidines and alkenes, the reactions were
investigated using DFT. To reduce computation time, a simplified
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form cobalt(III)–carbene radical intermediate C is an exergonic,
low-barrier process (+13.4 kcal mol-1). Similar to previously
reported cobalt(III)–carbene radical species, intermediate C
carries most of its spin density localized at the carbene
carbon.[20,21] An intramolecular 1,6-HAT process then relocates
the radical character from the α-position to the ζ-position to yield
Coordination of ammonia resulted in a computed k1/k2 value of
10.4 (k1 for piperidine formation, k2 for alkene formation) at 60 ºC,
which is in accord with the experimentally observed 2a/3a ratio of
1 : 0.10.[26] The other axial ligand donors give rise to slightly
different k1/k2 values (pyridine: 14.4; methylimidazole: 5.9),
suggesting that changes in the composition of the reaction
mixture over time could indeed lead to a change in product ratio.
This was experimentally confirmed. Monitoring the reaction of 1a
by 1H-NMR over time indeed showed that the 2a/3a ratio
gradually shifts from 1 : 0.33 toward 1 : 0.10. We interpret this
behaviour as the result of a changing composition of the reaction
mixture over the course of the reaction, with (on average) different
axial ligands being coordinated to cobalt (vide supra).[23]
benzyl-radical intermediate
D
or its bent analogue D’.
Intramolecular ring-closure (effectively involving radical
combination of the α- and ζ-positions) over TS4 yields piperidine
2a, while a 1,5-β-HAT over TS5 leads to formation of alkene 3a.
The almost identical TS4 and TS5 barriers suggest that these two
pathways should be in close competition (see also Scheme S1,
S3 and S15). While these DFT results explain the formation of
both 2a and 3a, the computed barriers are too similar to explain
the experimentally observed 2a/3a ratio of 1 : 0.10. Therefore we
also explored alternative pathways involving six-coordinate
intermediates.
The absolute amounts of piperidine and alkene formed over
time clearly indicate that alkenes 3 are not converted to
piperidines 2 (Figure 2). More details on the monitoring
experiments can be found in the Supporting Information.
Insertion of the carbene carbon of intermediate C into the bond
between the metal and a pyrrolato nitrogen of the porphyrin can
cause the carbene to adopt a bridging position (Scheme 4,
C’).[21, 22 ] One could also envision a hexacoordinate species
bearing both a bridging carbene and a terminal carbene (Dbridged).
When the pathways toward products 2a and 3a are computed
starting from Dbridged and passing through TS4bridged and TS5bridged
the radical rebound and 1,5-β-HAT pathways remain too similar
(see Scheme S8 and S20). For that reason we also computed the
energy barriers (from D onwards) for six-coordinated cobalt
complexes formed upon coordination of a few different nitrogen-
donor ligands at the axial position trans to the substrate. Ammonia,
methylimidazole and pyridine were used as simplified
computational models to study the effects of different axial ligands
coordinated to cobalt under the applied reaction conditions.[23]
Indeed axial coordination to cobalt(III)–alkyl radical intermediate
D changes the selectivity in favour of ring closure, and the
different donors were found to have different degrees of influence
on the product ratio (Scheme 5 and S9–S12).[24, 25]
,
Figure 2. Monitoring piperidine and alkene formation over time.
To fully exclude the possibility that alkenes 3 could be converted
to piperidines 2, aldehyde 1a was subjected to the general
reaction conditions (Table 1, entry 1) in presence of an equimolar
amount of alkene 3h. From all alkenes formed from the substrates
1
enumerated in Table 2, 3h was selected based on its H-NMR
signature, which was most distinct from the 1H-NMR signatures of
2a and 3a. Based on 1H-NMR analysis, it was clear that no
piperidine 2h had formed from alkene 3h; only piperidine 2a and
alkenes 3a and 3h were detected in the crude reaction mixture.
Lastly, we also computed the reaction pathway leading to five-
membered pyrrolidines, in order to explain why alkene formation
is not in competition with this reaction. The results are detailed in
the Supporting Information (Scheme S5–7 and S17–19) and are
in excellent agreement with the experimental results. The DFT
calculations confirm that [Co(por)]-catalyzed ring-closure toward
pyrrolidines has a much lower transition state barrier than
pathways leading to alkene formation. Neither alkene formation
through 1,4-β-HAT nor through 1,2-β-HAT is competitive, with the
computed barriers being respectively 8 and 11 kcal mol-1 higher
in energy than the barrier for radical rebound ring-closure.
Scheme 5. The computed effect of coordination of NH3 (as a simplified model
for a variety of possible ligands)[23] on the energy barriers for [Co(por)]-catalyzed
piperidine and alkene formation. All Gibbs free energies (ΔGº333K, in kcal mol-1),
including those of TS4 and TS5, are reported relative to the energy of
intermediate D-NH3. The ellipse represents the porphyrin ligand.
In conclusion, we developed a new base-metal-catalyzed
synthetic route toward six-membered piperidine rings, which are
important substructures of various medicinal compounds. Overall,
the reaction is high-yielding and compatible with a wide range of
functional groups. In contrast to the cobalt(II)porphyrin-catalyzed
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synthesis of five-membered pyrrolidines, the cobalt(II)porphyrin-
catalyzed construction of piperidines is accompanied by formation
of (generally small amounts of) olefinic side products. The relative
amount of alkene was found to be dependent on the substitution
of the substrate. DFT calculations indicate a mechanism involving
1,6-HAT from the carbene radical carbon to the benzylic position
of intermediate C, to form benzyl radical intermediate D. The latter
can undergo radical rebound ring-closure to form piperidines.
Competitive 1,5-HAT from the β-position to the benzylic radical
carbon explains the formation of linear alkenes as side products.
DFT and 1H-NMR monitoring experiments suggest that axial
ligand coordination influences the product ratio.
Acknowledgements
The work described in this paper was financially supported by the
Netherlands Organization for Scientific Research (NWO TOP-
Grant 716.015.001), the University of Amsterdam (Research
Priority Area Sustainable Chemistry) and the National Science
Foundation (Graduate Research Fellowship Program, NSF-
NWO-GROW-project, no. DGE-1419118). We thank Prof. dr.
Joost N.H. Reek for a valuable suggestion, Ed Zuidinga for HRMS
measurements and Dylan E. Parsons (University of Rochester)
for helpful scientific discussions.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Homogeneous catalysis • Radicals • Nitrogen
heterocycles • C-H activation • C-C coupling
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[22] Involvement of a bis-carbene species was considered unlikely, based on
previously published calculations. See reference [21]
[23] Under catalytic conditions the reaction medium changes, and various
different donors could be coordinated to cobalt, not necessarily the same
in the beginning and end of the reaction: e.g. p-TsNHNH2, the oxygen
atoms of the base, the terminal nitrogen atom of the N-tosylhydrazone,
the internal nitrogen atom of the deprotonated N-tosylhydrazone and the
terminal nitrogen atom of the diazo compound could all act as axial
ligands.
[24] Only the relative energy barriers were significantly affected by these
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10.1002/chem.201900587
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Marianne Lankelma, Astrid M. Olivares,
and Bas de Bruin*
Page No. – Page No.
[Co(TPP)]-catalyzed formation of
substituted piperidines
Radical cyclization via cobalt(III)–carbene radical intermediates is a powerful method
for the synthesis of (hetero)cyclic structures. Building on the recently reported
synthesis of five-membered pyrrolidine rings catalyzed by Co(II) amidoporphyrins,
we herein report the [Co(TPP)]-catalyzed formation of six-membered piperidine rings,
which was found to be accompanied by formation of small amounts of linear alkenes.
A DFT study was performed to gain a deeper mechanistic understanding.
TOC Keyword: Nitrogen heterocycles
This article is protected by copyright. All rights reserved.