Designing Homogeneous Bromine Redox Catalysis for Selective Aliphatic C?H Bond Functionalization

Article abstract of DOI:10.1002/anie.201800375

The potential of homogeneous oxidation catalysis employing bromine has remained largely unexplored. We herein show that the combination of a tetraalkylammonium bromide and meta-chloroperbenzoic acid offers a unique catalyst system for the convenient and s

Full text of DOI:10.1002/anie.201800375

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Accepted Article
Title: Designing Homogeneous Bromine Redox Catalysis for Selective
Aliphatic C-H Bond Functionalization
Authors: Kilian Muniz, Peter Becker, Thomas Duhamel, and Claudio
Martinez
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800375
Angew. Chem. 10.1002/ange.201800375
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10.1002/anie.201800375
Angewandte Chemie International Edition
COMMUNICATION
Designing Homogeneous Bromine Redox Catalysis for Selective
Aliphatic C-H Bond Functionalization
Peter Becker,[a,+] Thomas Duhamel,[a,b,+] Claudio Martínez,[a] Kilian Muñiz*[a,c]
Dedication ((optional))
Abstract: The potential of homogeneous oxidation catalysis
employing bromine has remained largely unexplored. We herein
show that the combination of tetraalkylammonium bromide and 3-
chloroperbenzoic acid offers a unique catalyst system for the
convenient and selective oxidation of saturated Csp3-H bonds upon
photochemical initiation with visible light. It enables remote
intramolecular, position-selective C-H amination as demonstrated for
This work thus demonstrates the applicability of bromine
catalysis in homogeneous oxidation chemistry without the loss of
catalytic activity throughout the catalysis. Pyrrolidines and
related saturated nitrogen-containing heterocycles are
ubiquitous alkaloid scaffolds with outstanding biological and
pharmaceutical activity,[5] for which the direct amination of an
aliphatic C-H bond has been identified as
a logical and
20 different examples. For the first time,
a
N-halogenated
economic strategy.[6,7] Our recent development of related iodine
catalyzed Hofmann-Löffler reactions (Figure 1)[8] has triggered
our interest to develop related Br-based protocols. In contrast to
the existing paradigm,[2a] such an approach should be feasible
taking into account historic parent transformations utilizing
stoichiometric amounts of hypobromite as oxidizing reagent.[9,10]
Therefore, it would be particularly interesting as a proof of
principle for bromine oxidation catalysis outside the few existing
examples of alkene functionalization.[2-4,11]
intermediate could be isolated as the active catalyst state in a
catalytic Hofmann-Löffler reaction. In addition, a novel expeditious
one-pot synthesis of N-sulfonyloxaziridines from N-sulfonamides
was developed and exemplified for 15 transformations. These
pioneering examples provide a change in paradigm for molecular
catalysis with bromine.
The growing demand for environmentally benign oxidation
conditions has placed catalysis with redox-active halide reagents
into the focus of method development. While homogeneous
catalysis based on the iodine(I) platform is continuously
maturing into a viable synthetic tool,[1] related bromine catalysis
has virtually remained in its infancy. We became interested in
devising the as yet unprecedented bromine catalysis for aliphatic
hydrocarbon functionalization reactions. In a seminal study,
Sharpless had developed conditions for bromine-catalyzed
aziridination of alkenes with chloramine-T under homogeneous
conditions.[2] Later, a bromine catalyzed intramolecular alkene
diamination was reported.[3] In amination chemistry, these
reactions represent the presently small number of homogeneous
bromine-catalyzed alkene oxidations,[4] and the possibility of
employing bromine as redox active homogeneous oxidation
catalyst has been considered strongly limited. The usually low
turn-over rates of homogeneous bromine catalysts have been
suggested to be consequential of rapid catalyst deactivation
(disproportionation and/or over-oxidation to a sink of unreactive
BrV species).[2a] Here, we present the synthesis of pyrrolidines
through a remote hydrocarbon activation of benzylic C-H bonds
mediated by a homogeneous bromine catalyst. The carefully
elaborated conditions enable a uniform approach that is further
applicable to a novel oxaziridine formation from sulfonamides.
H
I
R´´
R´
NHSO2R
R´
R´´
unfunctionalized
[visible light]
or [blue LED]
N
SO2R
C-H amination products
remote C-H bond
Iodine catalysis with a photoredox-
based terminal aerobic oxidation
Iodine catalysis with an iodine(III)
reagent as terminal oxidant
oxidant
(ArCO2)2IPh
oxidant
TPT (1 mol%), air
iodine catalyst
I-OH
iodine catalyst
ArCO2-I
Common N-iodinated intermediate
H
SO2R
N
I
elusive catalyst state
(information by
R´
R´´
computational chemistry)
Figure 1. Catalytic Hofmann-Löffler reactions based on molecular iodine as
catalyst source. Ar = 3-Cl-C6H4.
We started our investigation applying conditions similar to the
iodine-catalyzed Hofmann-Löffler reaction.[8a] When 1a was
converted in the presence of elemental bromine (10 mol%) as
the
catalyst
and
bis(3-chlorobenzoyloxy)iodobenzene
PhI(O2CAr)2 (1.1 equiv.) as the oxidant, 22% of the desired
pyrrolidine product 2a was obtained (Table 1, entry 1). A change
of the hypervalent iodine(III)-oxidant did not significantly improve
the yield of 2a (entry 2). We then turned to a bromide salt, which
can be administered as an ammonium derivative resulting in
better solubility in organic solvents. The combination of
tetrabutylammonium bromide with di(acetoxy)iodobenzene
(PIDA) and bis(trifluoroacetoxy)iodobenzene (PIFA) increased
the yield to 32 and 40%, respectively (entries 3,4), while the best
result was obtained with PhI(O2CAr)2 (entry 5). Moreover, based
on the particular effect of the 3-chlorobenzoate anion, more
conventional mCPBA (2 equiv.) was identified as an even better
oxidant in combination with 20 mol% of Bu4NBr (entry 6). The
reaction reached full conversion and the cyclized compound 2a
[a]
[b]
Dr. P. Becker, T. Duhamel, Prof. Dr. K. Muñiz
Institute of Chemical Research of Catalonia (ICIQ),
The Barcelona Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
T. Duhamel
Facultad de Química, Universidad de Oviedo
C/Julián Clavería, 33006 Oviedo (Spain)
Prof. Dr. K. Muñiz
ICREA, Pg. Lluís Companys 23, 08010 Barcelona (Spain)
These authors contributed equally.
[c]
[+]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201800375
Angewandte Chemie International Edition
COMMUNICATION
was isolated in 95% yield. The environmentally benign and
economic conditions for mCPBA as the oxidant deserve to be
highlighted. The use of lower concentrations of either Bu4NBr or
mCPBA resulted in decreased yields (entries 7-11). However,
the reactions still produced reasonable amounts of product
indicating significant robustness of the homogeneous bromine
catalysis.
92%, 2j and 2k). Backbone modification is well tolerated (94%,
2l). Acyclic stereocontrol cannot be realized as demonstrated for
compounds 2m/2m’, which produce
a
1:1-mixture of
diastereomers due to the radical reaction mechanism. However,
cyclization within ring annulation provides single diastereomers
2n (79%) and 2o (54%). The amination reaction in α-position to
a heteroatom also proceeds in good yields (54 and 98%, 2o and
2p). In addition, bromine catalysis tolerates benzylic tosylamides,
which provide the isoindolines 2q-2t without imine formation,
which is the dominating pathway in iodine catalysis.[8a]
Heteroaromatic substituents do not undergo potentially
competing bromination under these conditions (2r-t), and even
the notoriously oxidation-labile furane core in 2t is tolerated
entirely. These results demonstrate the first examples of a
Hofmann-Löffler-type reaction under expedious homogeneous
bromine catalysis. They significantly advance the harsh reaction
requirements of the traditional process, which is stoichiometric in
bromine promoter, requires a strong acidic reaction medium and
a basic work-up.[9]
Table 1. C-H Amination under Homogeneous Bromine Catalysis:
Optimization.
Br catalyst source
TsHN
oxidant,
Ph
Ph
N
solvent, 12 h, RT
Ts
1a
2a
Conversion
[%][a]
Entry
Conditions
1
2
3
4
5
Br2 (10 mol%), PhI(O2CAr)2 (1.1 equiv.), DCE
Br2 (10 mol%), PIFA (1.1 equiv.), DCE
22
30
32
40
46
Bu4NBr (20 mol%)
mCPBA (2 equiv.)
R
O
O
R''
Bu4NBr (20 mol%), PIDA (1.1 equiv.), CH3CN
Bu4NBr (20 mol%), PIFA (1.1 equiv.), CH3CN
R
S
R'
O
N
H
Rʼ
N
MeCN, 12 h, RT
S
R''
O
2a-r
1a-r
Bu4NBr (20 mol%), PhI(O2CAr)2 (1.1 equiv.),
CH3CN
Ph
X
Ph
Ph
N
N
Ts
N
N
Ts
R
S
6
7
8
9
100 (95)[b]
O
Bu4NBr (20 mol%), mCPBA (2 equiv.),
CH3CN
2b (X = Me): 95%
2c (X = OMe): 94%
2d (X = F): 76%
2e (X = Cl): 68%
O
2a: 95%
2h: 82%
2f (R = Ns): 71%
2g (R = Ms): 98%
Bu4NBr (20 mol%), mCPBA (1.5 equiv.),
CH3CN
77
69
50
Ph
+
Ph
Ph
N
Bu4NBr (20 mol%), mCPBA (1.2 equiv.),
CH3CN
Ph
N
N
N
Ph
Ts
S
S
S
Ts
Ar
O
N
O
O
O
Ts
2m:2m' = 1:1 dr, 74%
Bu4NBr (10 mol%), mCPBA (2 equiv.),
2j (Ar = 2-Tol): 87%
2k (Ar = 3-Tol): 92%
2l: 94%
2i: 63%
CH3CN
Ts
Ts
10
11
Bu4NBr (5 mol%), mCPBA (2 equiv.), CH3CN
40
Ph
N
N
OMe
N
Bu4NBr (2.5 mol%), mCPBA (2 equiv.),
s.m.
O
Ts
CH3CN
2p: 98%
2o: 1:0 dr, 54%
2n 1:0 dr, 79%
[a]Estimated from integration in the 1H NMR
spectrum of the crude reaction mixture. [b]Isolated
yield of 2a after purification. Ar = 3-ClC6H4, PIDA
= PhI(OAc)2, PIFA = PhI(O2CCF3)2.
Ts
N
N
Ts
N
Ts
N
Ts
S
O
S
The reaction conditions show generality for the formation of
pyrrolidines (Scheme 1) and are applicable in the presence of
electron withdrawing and electron donating groups on the arene
affording the products 2b-e with complete selectivity and in good
yields (68-95%). Different sulfonyl protecting groups at the
nitrogen atom are well tolerated providing the respective
nosylated (2f) and mesylated (2g) products in high yields (71-
98%). Also, a cyclopropylsulfonylamide is readily tolerated
suggesting that potentially competing radical ring opening does
not compete (82%, 2h), while the 2-thiophenylsulfonylamide is
likewise stable (63%, 2i). More congested 2- and 3-tosylgroups
provide comparable yields to the standard 4-tosyl indicating that
increased sterics do not interfere during the cyclisation (87 and
2q: 77%
2s: 48%
2r: 59%
2t: 38 (99)%[a]
Scheme 1. C-H Amination under Homogeneous Bromine Catalysis: Scope.
[a]Addition of mCPBA in four portions. Yield in bracket based on isolated
starting material.
Mechanistically, the reaction could proceed through various
intermediary bromine(I) states, which derive from oxidation of
the bromine source and could be either conventional
hypobromite or 3-chlorobenzoyl hypobromite. Based on control
experiments, we propose 3-chlorobenzoyl hypobromite 4 as the
active catalyst (Scheme 2). This hypobromite 4 is directly formed
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10.1002/anie.201800375
Angewandte Chemie International Edition
COMMUNICATION
from Bu4NBr and mCPBA.[12] Independent synthesis of the
active catalyst 4 from the corresponding silver benzoate 3[13] was
successful, although 4 is of pronounced instability. Addition of 1
equivalent of standard substrate 1a to the solution of 4 provided
24% of product 2a. Successive investigation confirmed that
hypobromite 4 indeed initiates catalysis, and a 65% overall
formation of 2a was obtained in the presence of 2 equivalents of
mCPBA. The involvement of free hypobromite was excluded
Scheme 2. Potential catalysts, control experiments and isolation of N-
brominated intermediate.
Under the catalytic conditions, the reaction between 4 and the
substrate 1 provides the N-brominated tosylamide 5, which
undergoes light-induced homolysis to the N-centered radical
based on Raman spectroscopy.[14] The involvement of
a
intermediate
A
(Figure 2). The selectivity of the C-H
functionalization event arises from the involvement of
a
stabilized anionic species [Br(O2CAr)2] appears less likely. Such
species had been previously isolated and documented to
constitute electrophilic bromine sources in stoichiometric alkene
oxidation reactions.[15] We have generated such compounds by
interaction between Bu4NBr and PIFA or PhI(O2CAr)2,
respectively, as they are presumably produced under the
conditions from Table 1, entries 4 and 5. However, isolated
anionic bromine(I) compounds do not show activity in the
cyclization of 1a, that would be comparable to the active catalyst
4.[14] This is an important mechanistic difference in behavior
when compared to the corresponding iodine-based catalysts.[8]
In contrast to previous mechanistic investigations of iodine
catalyzed Hofmann-Löffler reactions,[8] it was possible to obtain
the N-brominated intermediate 5a from a reaction between 1a,
an ammonium bromide and mCPBA and to unambiguously
identify it by NMR spectroscopy and by HRMS measurements
displaying correct isotope pattern. This synthesis resembles the
formation of 5a under the real catalytic conditions. N-Brominated
5a displays a remarkably high reactivity as evidenced from its
estimated half-life time of 30 min. The isolation of 5a constitutes
the first detection and structural characterization of an N-
halogenated intermediate in halogen-catalyzed Hofmann-Löffler
reactions. In comparison to free 1a, the UV spectrum of N-
brominated 5a exemplifies a bathochromic shift to around 300
nm, which is in agreement with a photochemical activation under
normal environmental daylight.[14] It also explains that reactions
with LED light sources experience a strong decrease in yield.[14]
The required energy for N-Br bond cleavage is significantly
different from related iodinated species.[8b] This observation
demonstrates that the development of light-initiated bromine
oxidation catalysis cannot be predicted readily from the
corresponding iodine catalysis.
kinetically preferred 1,5-H abstraction at this stage. A kinetic
isotope effect of 3 was determined for this pathway as the rate-
determining step. The intermediary alkyl bromide B forms
through either
a radical chain mechanism involving 5, 3-
chlorobenzoyl hypobromite or from radical recombination. Given
the occurrence of free 1a in the stoichiometric experiment with
5a from Figure 4, the former appears more reasonable.
Subsequent nucleophilic cyclization requires the activated
benzylic position or an α-alkoxylation to provide a sufficiently
fast reaction. This is the first case of direct pyrrolidine formation
from Br-based Hofmann-Löffler reactions as previous methods
always terminate at the C-Br stage requiring subsequent base
administration for C-N bond formation.[9,10,16] The liberated
hydrogen bromide regenerates the catalyst precursor R4NBr
from neutralization with R4NOH. These individual events provide
the molecular basis for selective catalysis within a defined
bromine(-I/I) catalysis manifold. Over-oxidation to an unreactive
bromine catalyst in an oxidation state higher than +I could never
be detected. For example, isolated 4 does not react with excess
mCPBA, and treatment of Bu4NBr with 1-5 equivalents of
mCPBA does not provide bromine over-oxidation, but
decomposition of the oxidant instead.[14]
NHTs
Y
Y
N
Ts
Br
2
NTs
Br
B
Y
HBr
A
Bromine(-I/I)
Catalysis
Manifold
h!
(day light)
R4NOH
H2O
NTsBr
O
O
R4NBr
Y
OAg
5
OBr
Br2
ArCO2H
NHTs
CD2Cl2,
- AgBr
ArCO2Br
Cl
Cl
ArCO3H
4 (52%)
4
3
Y
1
Br-O2CAr (4)
NHTs
Ph
N
Ph
Figure 2. Mechanistic proposal: exploiting Br catalyst stability for a Br(-I/I)
catalysis manifold. Y = aryl, alkoxy; Ar = 3-Cl-C6H4.
CD2Cl2, CH3CN,
12 h, RT
Ts
2a (24%)
1a
2a (65%)
with mCPBA (2 equiv)
Me2(C18H37)2NBr (1 equiv)
In contrast to the successful formation of pyrrolidines, the
corresponding 1,3- or 1,4-C-H abstractions to aziridines or
azetidines, respectively, do not constitute viable reaction
pathways. For these derivatives, however, exposure to the
Br/mCPBA system afforded an unexpected result. When
Ts
N
ArCO3H (1 equiv)
NHTs
Ph
Ph
Br
CD3CN, 1 h, RT
1a
5a
(day light)
1a (66%) + 2a (34%)
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10.1002/anie.201800375
Angewandte Chemie International Edition
COMMUNICATION
Scheme 3. Oxaziridine synthesis from linear N-sulfonamides: scope.
exploring the reaction with 3-phenylpropanyl-1-amine 6a as
substrate, a single product was obtained in 86% yield, which
was identified as the N-sulfonyloxaziridine 7a (Scheme 3). This
overall sequence thus represents a new one-pot approach to the
important class of N-sulfonyloxaziridines, which depict unique
oxidants within the synthetic arsenal of modern organic
chemistry.[17] Moreover, this synthesis represents a rare case in
halogen catalysis, in which oxidants are generated within a
catalytic oxidative transformation.[18] The reaction was
rationalized to consist of two individual consecutive oxidation
events. In the absence of available hydrogen atoms for a
kinetically competent C-H abstraction the initially formed N-
bromo species 5 undergoes an α-elimination to the aldimine C.
The oxaziridine formation is then accomplished by oxidation of
the intermediary aldimine with the terminal oxidant mCPBA.[19]
Importantly, attempts to conduct the same transformation with
catalytic amounts of iodine or Bu4NI did not succeed
demonstrating a superior performance of bromine over iodine.
The involvement of the N-Br intermediate 5 and the absence
of the alternative benzylic bromination product is important as it
confirms that the reactions from Figure 2 do proceed through a
Hofmann-Löffler pathway and do not derive from the potential
direct benzylic C-H bromination under conventional radical
conditions. The oxaziridine formation from linear sulfonamides 6
is a general reaction as displayed in Scheme 3 with 15
examples. Standard N-tosyl phenylpropylamide gives the
corresponding oxaziridine 7b in 60% yield as a single oxidation
product. Variation of the arene substituent provides the products
7c-d (59-70%), while the sulfonyl variation includes mesyl (7e,
44%), nosyl (7f, 65%) and 2-thiophenylsulfonyl (7g, 64%). A
phenyl ether derivative 7h could also be accessed conveniently
(68%).
With respect to the variation of the N-tosyl phenylethylamide
motif 6a, its 2-brominated arene derivative 7i was accessed in
55% yield and structurally characterized by solid state X-ray
analysis.[20] Variation of the sulfonyl group includes the
benzylsulfonyl derivative (7j, 72%) and the cyclopropylsulfonyl
derivative (7k, 44%). Although potentially labile under reaction
conditions involving free radicals, the two transformations
proceed with chemoselectivity in favor of the oxaziridine
formation. The reaction scope further includes
a
2-
naphthylsulfonyl (7l, 71%), a 4-fluorobenzenesulfonyl (7m, 60%)
and an aliphatic neopentyl substitution (7n, 85%). Usually,
oxaziridines were never formed under any conditions for the
examples of pyrrolidine formation from Scheme 1. A single
exception was encountered for the nitrile-substituted derivative
6o.[21] This outcome is due to the increased acidity of the α-
hydrogens, which prevents radical hydrogen atom transfer and
thus leads to imine and ultimately oxaziridine formation.
In summary, protocols for unprecedented bromine(-I/I)-
catalysis in C-H aminative functionalization and oxaziridine
formation have been designed. The reactions proceed within
defined homogeneous catalytic cycles and rely on an
engineered bromine(I) catalyst that is accessed from direct
oxidation with the terminal oxidant mCPBA. For the first time in
halide catalysis, the crucial N-halogenated intermediate as the
initiator of the radical C-H functionalization could be isolated and
characterized. These accomplishments will be an instrumental
guide for the development of general bromine catalysts and
complimentary radical C-H transformations.
Bu4NBr (20 mol%)
mCPBA (2 equiv.)
Acknowledgements
O
O
O
N
R
R
S
N
H
Rʼ
n
n
MeCN, 12 h, RT
S
Rʼ
Financial support was provided by the Spanish Ministry for
Economy and Competitiveness and FEDER (CTQ2017-88496R
grant to K. M., and Severo Ochoa Excellence Accreditation
2014-2018 to ICIQ, SEV-2013-0319). The authors are grateful to
the CERCA Program of the Government of Catalonia and to
O
O
6a-n (n = 0, 1, 2)
7a-n
BrO2CAr - HO2CAr
HO3CAr - HO2CAr
O
O
O O
R
S
R
S
N
Rʼ
N
Rʼ
- HBr
n
5
n
COST Action CA15106 “C
Synthesis (CHAOS)”.
–
H
Activation in Organic
Br
C
O
O
N
Ts
N
N
Ts
Keywords: Amination • Bromine • C-H Functionalization •
O
R
n
X
Catalysis • Hofmann-Löffler Reaction
7a: (n = 1) 86%
7b: (n = 2) 60%
7c: (X = OMe) 59%
7d: (X = Cl) 70%
7e (R = Ms): 44%
7f (R = Ns): 65%
Ts
Br
O
Ts
[1]
[2]
a) M. Uyanik, K. Ishihara, ChemCatChem 2012, 4, 177; b) P.
Finkbeiner, B. J. Nachtsheim, Synthesis 2013, 45, 979.
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Am. Chem, Soc. 1998, 128, 6844; b) S. Minakata, Acc. Chem. Res.
2009, 42, 1172.
N
O
N
O
N
S
O
S
O
7g: 64%
7h: 68%
7i: 55%
O
O
O
O
O
O
O
S
S
S
[3]
[4]
[5]
P. Chavez, J. Kirsch, C. H. Hövelmann, J. Streuff, M. Martínez-
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3, 2375.
N
O
N
N
O
O
7k: 44%
7l: 71%
7j: 72%
a) K. Muñiz, Pure Appl. Chem. 2013, 85, 755 (2013); b) For non-related
Bromine(III) chemistry: M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi,
W. Nakanishi, Science 2011, 332, 448.
O
S
O
CN
F
Ts
O
N
N
O
N
Ts
a) E. Fattorusso, O. Taglialatela-Scafati (Eds.) Modern Alkaloids. Wiley-
VCH, Weinheim, 2007; b) D. O'Hagan, Nat. Prod. Rep. 2000, 17, 435.
O
7m: 60%
7n: 85%
7o: 97%
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10.1002/anie.201800375
Angewandte Chemie International Edition
COMMUNICATION
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[8]
[9]
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[20] X-ray crystallographic data for compound 7i has been deposited with
the
Cambridge
Crystallographic
Data
Centre
database
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(http://www.ccdc.cam.ac.uk/) under code CCDC 1583024.
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[11] It is interesting to compare this context in main group catalysis with the
recent case of non-related C-H functionalization using conventional
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10.1002/anie.201800375
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Br enters catalysis! New
P. Becker, T. Duhamel, C. Martínez, K.
Muñiz*
homogeneous bromine catalysis by
combining an ammonium bromide
with mCPBA as oxidant enables the
first catalytic variant of the classic
bromine-mediated Hofmann-Löffler
reaction. The same conditions
transform sulfonamides into
oxaziridine derivatives within a single
operation.
Page No. – Page No.
Designing Homogeneous Bromine
Redox Catalysis for Selective
Aliphatic C-H Bond Functionalization
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