Copper-Catalyzed N?F Bond Activation for Uniform Intramolecular C?H Amination Yielding Pyrrolidines and Piperidines

Article abstract of DOI:10.1002/anie.201902716

The dual function of the N?F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C?H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio- and chemoselectivity control, which

Full text of DOI:10.1002/anie.201902716

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Accepted Article
Title: Copper-Catalyzed N-F Bond Activation for Uniform Intramolecular
C-H Amination to Pyrrolidines and Piperidines
Authors: Pedro J. Pérez, Feliu Maseras, Kilian Muñiz, Tomas
Belderrain, Daniel Bafaluy, Jose Maria Muñoz-Molina, Ignacio
Funes-Ardoiz, Sebastian Herold, Adiran J de Aguirre, and
Hongwei Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902716
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10.1002/anie.201902716
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Copper-Catalyzed N-F Bond Activation for Uniform
Intramolecular C-H Amination to Pyrrolidines and Piperidines
Daniel Bafaluy,‡,[a] José María Muñoz-Molina, ‡,[b] Ignacio Funes-Ardoiz,[a] Sebastian Herold,[a] Adiran de
Aguirre,[a] Hongwei Zhang,[a] Feliu Maseras,*[a,c] Tomás R. Belderrain,*[b] Pedro J. Pérez*[b] and Kilian
Muñiz*[a,d]
Dedication ((optional))
10
a]
Abstract: The dual function of the N-F bond as an effective oxidant
and subsequent nitrogen source in intramolecular aliphatic C-H
functionalization reactions is explored. Copper catalysis is
demonstrated to exercise full regio- and chemoselectivity control,
which opens new synthetic venues to nitrogenated heterocycles with
predictable ring size. For the first time, a uniform catalysis manifold
has been identified for the construction of both pyrrolidine and
piperidine cores. The individual steps of this new copper oxidation
catalysis are elucidated by control experiments and computational
studies, clarifying the singularity of the N-F function and
characterizing the catalytic cycle to be based on a copper(I/II)
manifold.
synthetic utility of the N-F bond by Zhu[
and Nagib,[10b] who
explored the use of preformed N-F bonds to initiate position-
selective C-H functionalization reactions from amidyl radical
intermediates (Scheme 1). Notably, the alternative formation of
heterocycles through pathways involving N-F and subsequent C-
H bond activation, has not been explored thus far. We have
previously developed copper-based catalytic systems toward C-
halide (Cl, Br) bond activation via radical pathways, in the so-
called atom transfer radical (ATR) reactions,[11 including the
]
successful cyclization to cycloalkanes. We herein report on a
well-defined copper catalyst enabling uniquely uniform
conditions for both pyrrolidine and piperidine formation and
provide experimental and computational studies that support an
unprecedented copper(I/II) redox cycle.
The chemistry of N-halogenated amines is a particularly
]
1
attractive
tool[
for
streamlining
the
oxidative
halofunctionalization of hydrocarbons. In the context of an
intramolecular reaction, the subsequent cyclization may be
2
]
pursued,[
which under conditions of catalysis results in a
sustainable one-pot formation of aminated aliphatic
3 4 5
,
heterocycles.[ , ] In these reactions, N-halogenated amides give
6
rise to the corresponding amidyl radicals,[ which initiate the
hydrocarbon functionalization within 1,n hydrogen atom transfer
(HAT) reactions. Contrarily to its heavier halogen counterparts,
the related fluorine-containing substrates have N-F bonds with
profoundly lower tendency toward homolytic bond cleavage.
Copper catalysts have shown useful synthetic propensity in
]
Scheme 1. C-H functionalization by copper-catalyzed N-F bond
activation.
]
activating N-F bonds.[7 However, while Cu(I) catalysis tends to
8
promote single electron transfers,[ ] fluorinated bonds are usually
9
activated via concerted pathways.[ ] Recently, powerful copper-
N-alkyl-N-fluorosulfonamide 1a (Table 1) was prepared
using N-fluorobis(benzenesulfonyl)imide (NFSI) as the most
convenient F-transfer reagent and was employed as the initial
substrate.[12] The structure of 1a was unambiguously assigned
by X-ray analysis.[ 13 ] The N-F bond length of 1.434(9) Å
compares well with that found in other common electrophilic
fluorinating agents[ 14 ] and indicates that it should exercise
efficient oxidative behavior. Exploratory results from Table 1
confirm this hypothesis for several copper catalysts varying from
simple salts to more elaborated complexes of formula
TpxCu(NCMe) (Tpx = hydrotrispyrazolylborate ligand).[15] A blank
experiment established that essentially none of the cyclization
product is generated in the absence of the copper complex
(entry 1). Pyrrolidine 2a was obtained with several cationic or
neutral, in situ generated or previously isolated copper catalysts,
in the +1 or +2 oxidation state (entries 2-6). The best results
were obtained with the Cu(I) complexes Tp*Cu(NCMe) and
TpiPr2Cu(NCMe) (Tp* = hydrotris(3,5-dimethyl-1-pyrazolyl)borate;
TpiPr2 = hydrotris(3,5-diisopropyl-1-pyrazolyl)borate), that yielded
quantitative conversions into the targeted product (entries 7-8). It
is possible to lower the catalyst loading even to 0.1 mol%
[a]
[b]
D. Bafaluy, Dr. I. Funes-Ardoiz, Dr. S. Herold, A. J. de Aguirre, Dr.
H. Zhang, Prof. Dr. F. Maseras, Prof. Dr. K. Muniz
Institute of Chemical Research of Catalonia, ICIQ, The Barcelona
Institute of Science and Technology, Av. Països Catalans, 16,
43007 Tarragona, Spain
E-mails: fmaseras@iciq.es , kmuniz@iciq.es
Dr. J. M. Muñoz-Molina, Prof. Dr. T. R. Berderrain, Prof. Dr. P. J.
Pérez
Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC,
CIQSO-Centro de Investigación en Química Sostenible and
Departamento de Química, Universidad de Huelva, 21007 Huelva,
Spain
E-mails: perez@dqcm.uhu.es, trodri@dqcm.uhu.es
Prof. Dr. F. Maseras, Departament de Química, Universitat
Autònoma de Barcelona, 08193 Bellaterra, Spain
Prof. Dr. K. Muniz, ICREA, 08010 Barcelona, Spain
D. B. and J.M.M.-M. contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
[c]
[d]
‡
based redox catalysis has been explored for the activation and
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10.1002/anie.201902716
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COMMUNICATION
without an important loss of performance (entry 9, no further
reaction after 24 h). The reaction proceeds less efficiently at 25
C (entry 10), and within shorter reaction time (8 h, entry 11).
The use of other metal-based catalysts containing Ag, Au, Ni, Fe
or Ru centers were unsuccessful.[16]
The successful identification of suitable reaction conditions
for formation of pyrrolidine 2a represents a notable new entry
into heterocycle formation comprising cyclization of N-fluorinated
amine precursors 1a-q (Scheme 2). After the above screening,
TpiPr2Cu(NCMe) was chosen as the catalyst for exploration of
the substrate scope, since this complex is more stable than the
Tp* analog toward oxidation with adventitious air. A total of 17
pyrrolidines were obtained. The scope includes alternative
substitution pattern at nitrogen (2b,c) and different electronic
substitution at the arene core (2d-i), which even tolerates
potential steric impediment through 2-substitution as
demonstrated with 2h (99%). Backbone modification has been
studied (2j,l, 47-87%), and even for a non-substituted alkyl chain
Table 1. Copper-Catalyzed Intramolecular N-F activation and C-H
Amination: Catalyst Screening and Optimization.[a]
Scheme 2. Scope of the Cu-catalyzed pyrrolidine synthesis. Yields of
purified product (average of two experiments).
in the 1k precursor, formation of 2k is straightforward (71%). As
expected for a radical reaction, acyclic diasterocontrol is not
possible leading to diastereomeric products 2m (d.r. = 1:1) and
2n (d.r. = 1:1.2). The reaction can be extended to the -
amination of an ether to provide heterocycle 2o. In addition,
dioxoisothiazole derivative 2p is also compatible with the
present cyclization conditions. Substitution at the carbon next to
the aryl ring is also tolerated providing tert-alkyl amine 2q in
good yield. It is worth mentioning that the robustness of the
protocol is underlined by a 1 gram-reaction (2.95 mmol) of the
parent 1a substrate, which provides 2a in 79% isolated yield.
Related substrates other than benzylic positions are unreactive
under the present conditions.[16]
Entry
Catalyst
---
% Yield 2a [b]
0
1
2
CuCl2/TPMA[c]
CuI/TPMA[c]
83
90
As to another relevant aspect of our system, the more
challenging piperidine formation within six-membered cyclization
was also possible under the general conditions (Scheme 3). The
exciting synthetic possibilities include the successful examples
4a-j with and without backbone substitution and in a comparable
3
TpBr3Cu(NCMe)
Tp*,BrCu(NCMe)
TpiPr2CuCl
60
4
74
5
85
6
scope
to
pyrrolidines
and
also
the
important
Tp*Cu(NCMe)
TpiPr2Cu(NCMe)
TpiPr2Cu(NCMe)
TpiPr2Cu(NCMe)
TpiPr2Cu(NCMe)
TpiPr2Cu(NCMe)
99
tetrahydrosioquinoline core 4k and the 1,3-oxazinane 4l. This
transformation has been a long-standing quest in radical-
mediated C-H amination. It is well established that 1,5-HAT
7
99
8
17
]
outperforms the required 1,6-HAT[
and that, therefore,
9[d]
10[e]
11[f]
12[g]
93
piperidines are notoriously difficult to generate under amidyl-
radical promoted conditions. For example, related iodinated
precursors only generate pyrrolidines due to a dominance of the
1,5-HAT.[4a] Although uniform reaction conditions to be
applicable to both pyrrolidine and piperidine formation are in
high demand, there has been no general solution to this problem,
traces
62
99
[a]See SI for full details. 0.1 mmol of 1a employed, 1% catalyst loading.
[b]
18
]
except recent exploration of electrochemistry.[
Yields were determined by 1H NMR analysis versus diphenylmethane as
[c]
internal standard.
TPMA = tris(2-pyridylmethyl)amine. [d]0.1 mol% of
We have also investigated the intramolecular competition
between five- and six-membered ring formation (Scheme 4). For
substrate 1r with two different benzylic reaction sites, only
catalyst employed. [e]Temperature
[g]Acetonitrile as solvent at 80 °C
= h of reaction time.
25 °C. [f]8
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TSOx.Add.(S) c1-c2
18.5
pyrrolidine formation to 2s was observed. Even for substrate 1s
with a statistically increased possibility for piperidine formation,
again only the five-membered ring product 2r was obtained.
A number of experiments have been carried out with the aim of
collecting mechanistic information. Experimentation under the
conditions from Table 1 reveals that the presence of water or air
Ts
Ph
N
F
3
MECP c1-c2(S-T)
12.1
c1F
[Cu]
8.9
9.5
MeCN
MECP c1F-c2F(S-T)
11.3
Ts
Ph
Ph
F
N
3
[Cu](NCMe)
0.0
c1
3.6
[CuIII
]
c2S
Ts
Ph
Ts
N
F
3 N
3
c2S
F
-12.8
c2F
-13.4
c1F
[CuII]
c2F
[CuI]
Ts
Ph
Ts
N
3
F
Ph
F
N
c1 [CuI]
3
c2
-23.0
[CuII]
c2
Scheme 5. Free energy profile of the N-F activation step of reaction with 1k as
the substrate. Energies in kcal/mol. ([Cu] = Tp*Cu).
Scheme 3. Scope of the Cu-catalyzed piperidine synthesis. Yields of
purified product (average of two experiments).
DFT calculations were carried out to further analyze the
reaction mechanism. All the structures were optimized using the
in toluene solution, energies being
refined with triple- basis set plus polarization and diffusion
22
]
B3LYP-D3 functional,[
induced lower yields. EPR studies with a mixture of the catalyst
TpiPr2Cu(NCMe) and substrate 1k showed the appearance of a
typical resonance for Cu(II) at 3260 Gauss, both at room
shells. All reported energies are free energies. A data set of all
19
]
23
]
temperature and 77 K[12
,
Mass spectrometric studies
species of composition
computed structures is available in the ioChem-BD repository.[
confirmed the presence of
a
Compound 1k was chosen as the model substrate together with
Tp*Cu(NCMe) as the catalyst because of the more limited
conformational flexibility and the similar experimental behavior
with the optimal catalyst TpiPr2Cu(NCMe) (Table 1, entries 7 and
8). The reaction starts with the coordination of 1k to the vacant
copper site generated from acetonitrile ligand release (Scheme
5). The substrate can be coordinated via the nitrogen (c1) or the
fluorine atom (c1F). Single electron transfers from the Cu(I)
center to the N-F σ* orbital, either from c1 (black path) or from
c1F (red path), results in the cleavage of the N-F bond together
with the formation of a new Cu-F bond in intermediate c2, which
contains a nitrogen centered radical coordinated to a Cu(II)
center. These reactions involve a change from singlet to triplet
spin state, and are thus characterized by minimum energy
crossing points (MECP) instead of transition states.[24] The two
processes from either c1 or c1F have similar low barriers of 12.1
kcal/mol and 11.3 kcal/mol, and they are likely to coexist. In
contrast, the oxidative addition pathway to yield the Cu(III)
intermediate c2S (blue path) is 6.4 kcal/mol higher in energy, and
thus discarded. This is an important observation taking into
account the commonly postulated copper(III) intermediates in
related reactions. Results are very similar for the related mesyl-
substituted systems, corroborating the experimentally observed
related outcome for 2a and 2c.[12]
[TpiPr2CuF(NCMe)]. Additional control experiments used partially
deuterated substrates.[12] Individual reaction rates for substrates
1k and 1k-d2 with fully deuterated benzylic position showed a
relative rate acceleration for compound 1k, which corresponds
to a kinetic isotope effect of 1.7 at 80 ºC. This KIE value is
consistent with C–H bond cleavage as the turnover-limiting
step.[20] The kinetic data on the transformation of 1k into 2k at
variable catalyst concentration are consistent with the reaction
being first order in catalyst. [12]
The observed superiority of the ancillary Tpx ligand was
further investigated for the formation of diastereomeric
Scheme 4. Intramolecular competition experiment for the Cu-catalysis in
favor of pyrrolidine synthesis.
pyrrolidines 2m.[12] While Tp*Cu(NCMe) catalyst gave a 1:1
mixture, bulkier Tpx ligands such as TpMS (hydrotris(3-(2,4,6-
21
]
trimethylphenyl)pyrazolyl)borate)[
or TpiPr2 provided just
slightly higher diastereoselectivities pointing toward a subtle
influence of the copper catalysts on the C-N bond formation step.
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10.1002/anie.201902716
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products is highly exergonic, by 56.5 kcal/mol. The computed
mechanism confirms the experimentally observed presence of
radical species in the process, reproduces the measured kinetic
isotope effect, and hints at the crucial role of the fluorine
substituent, as other halogens do not have the same ability to
form bonds with copper and abstract protons.
It is noteworthy pointing out that the existence of a putative
benzylic cation intermediate deriving from benzylic oxidation at
c4 could not be substantiated by theoretical calculations, as the
reductive pathway from c4 is energetically straightforward.
There is indeed an intramolecular electron-transfer between the
benzyl radical and the copper(II) centre, but it is coupled with the
formation of the C-N bond, without a detectable cationic state
being involved.
On the basis of all collected data, the full catalytic cycle for
N-fluorinated substrates is depicted in Scheme 7. Within the
initial N-F cleavage phase, the reaction of the copper catalyst
starts with acetonitrile release and substrate N-coordination prior
to N-F cleavage via a single electron transfer (SET) from Cu to
the N-F bond. Radical transfer from nitrogen to the benzylic
carbon by a fluorine-assisted hydrogen atom transfer (HAT)
initiates the C-H functionalization phase. The generated Cu(II)
intermediate yields the product by a second N-H-F shuttled SET
from the benzylic radical to the copper center. In the final
cyclization phase, the C-N bond and the HF byproduct are
provided within tandem bond formation. Finally, combined
dissociation of both product and HF regenerate the active
copper(I) catalyst. At variance with Atom Transfer Radical
reactions, once the halide is extruded from the substrate, the
latter remains coordinated to the metal center instead of
becoming a free radical, thus propelling this alternative reaction
pathway.
Scheme 6. Free energy profile of the C-H activation and cyclization steps of
reaction with 1k as the substrate. Energies in kcal/mol. ([Cu] = Tp*Cu).
Intermediate c2 undergoes alkyl chain rotation to
intermediate c2’ resulting in fluoride interaction with one of the
benzylic C-H bonds (Scheme 6). At this stage, F-assisted
hydrogen atom transfer relocates the radical from the nitrogen
atom to the benzylic carbon center. According to the calculated
mechanism, TS c2’-c3 is rate-determining with a barrier of 15.6
Concerning some catalyst precursors containing Cu(II)
centers in Table 1, one could propose a Cu(II)/Cu(III) scheme
similar to the Cu(I)/Cu(II) mechanism we have outlined above.
However, calculations clearly discard this option, since Cu(II) is
unable to release one electron to the organic moiety at the initial
stage of the N-F cleavage.[16] At present, this suggests that
these precursors react either through the presence of small
amounts of Cu(I) or through some alternative mechanism
involving an active role for the chloride ligand. More detailed
investigation is required to clarify if an involvement of copper(II)
catalysts can pose productive pathways for N-F bond activation.
In conclusion, we have developed a catalytic system capable
of promoting both N-F and C-H activation processes leading to
the formation of heterocycles in moderate to high yields, which is
based on
a defined copper(I) precatalyst. The resulting
copper(I/II) catalysis manifold allows for a rare case of uniform
reaction conditions for the one-pot formation of piperidines and
pyrrolidines and therefore exemplifies an advanced use of the
always challenging class of fluorine derivatives toward practical
synthetic applications.
Scheme 7. Mechanistic proposal based on combined experimental and
computational data.
kcal/mol. The transition vector in TS c2’-c3 is localized mainly in
the F-H-C moiety, and we confirmed that its relaxation
irreversibly yields the protonated amide intermediate c3. Once
the radical is located in the carbon chain in c3, the system
undergoes a series of low-barrier rearrangements that end up in
the release of the pyrrolidine product and the HF by-product
from intermediate c5. The overall process from reactants to
Acknowledgements
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10.1002/anie.201902716
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We thank MINECO for Grants CTQ2017-82893-C2-1-R,
CTQ2017-87792-R, CTQ2017-88496-R, COST Action CA15106
“C–H Activation in Organic Synthesis (CHAOS)”and Red Intecat
(CTQ2016-81923-REDC).
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Keywords: amination catalysis • C-H bond activation • C-N
bond formation • copper catalysis • DFT calculation
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10.1002/anie.201902716
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Daniel Bafaluy, José María Muñoz-
Molina, Ignacio Funes-Ardoiz, Sebastian
Herold, Adiran de Aguirre, Hongwei
Zhang, Feliu Maseras,*] Tomás R.
Belderrain,* Pedro J. Pérez* and Kilian
Muñiz*
Copper-Catalyzed N-F Bond
Activation for Uniform Intramolecular
C-H Amination to Pyrrolidines and
Piperidines
Text for Table of Contents
A copper-based catalytic protocol involving C-F activation that serves for the synthesis of pyrrolidines and the more
challenging piperidines has been developed, which operates through a Cu(I)/Cu(II) cycle.
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