“This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright ©
American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work
see https://pubs.acs.org/doi/abs/10.1021/acscatal.8b00286“.

Engineering Molecular Iodine Catalysis for AlkylNitrogen Bond Formation
Thomas Duhamel,†,§ Christopher J. Stein, ‡ Claudio Martínez,† Markus Reiher‡* and Kilian
Muñiz†,∫*
†
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona,
Spain.
§
Facultad de Química, Universidad de Oviedo, C/Julián Claveria, 33006 Oviedo, Spain.
‡
Laboratorium für Physikalische Chemie, ETH Zürich, Vladimir-Prelog-Weg 2, 8093 Zürich,
Switzerland.
∫
ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
KEYWORDS: C-H Amination, Catalysis, Hofmann-Löffler reaction, Iodine, Oxidation.
ABSTRACT
An advanced protocol for the intramoleclar C-H amination of alkyl groups via amidyl radicals
(Hofmann-Löffler reaction) under homogeneous iodine catalysis is reported. This protocol
employs common mCPBA as terminal oxidant. It proceeds under mild conditions, with complete
chemoselectivity, is compatible with radical intermediates and allows for the selective
intramolecular amination reaction of secondary and tertiary hydrocarbon bonds and is not
restricted to benzylic C-H amination. The involvement of an iodine(III) catalyst state in the C-N
bond formation derives from selective oxidation at the stage of the corresponding alkyl iodide
with mCPBA. Its formation is corroborated by quantum-chemical calculations. This new
catalysis thus proceeds within a defined iodine(I/III) catalysis manifold.
Key Words
Amination, C-H Functionalisation, Hofmann-Löffler Reaction, Iodine, Oxidation, Radicals

1

Introduction
Homogeneous oxidation catalysis based on molecular iodine1 has emerged as a viable answer to
the quest for alternative concepts complimenting conventional transition metal based
transformations. Within this context, seminal iodine-catalyzed a-oxygenation reactions of
ketones were developed by Ishihara.2 We have recently presented selective Csp3-H amination
reactions that constitute the first Hofmann-Löffler reactions employing only a catalytic amount
of iodine (Scheme 1).3 Despite the common feature of deriving from iodine catalysis, the two
protocols display significantly different behavior depending on the respective re-oxidant. The
initial protocol made use of a stoichiometric amount of a non-commercial iodine(III) reagent as
terminal oxidant (eq. 1). This variant optimizes earlier stoichiometric protocols4,5 and
demonstrates a remarkably robust main group catalysis based on a defined iodine(I/III)
manifold.6 The broad scope of this catalytic transformation includes aliphatic primary, secondary
and tertiary C-H bonds alike. The hypervalent iodine(III) reagent as terminal oxidant (i) provides
an alkyliodine(III) intermediate for the observed general aliphatic C-N bond formation and (ii)
leads

to

the

generation

of

electrophilic

iodine

species

I-O2CR,

as

demonstrated

independently.3a,7,8 Despite the clean reaction conditions, the requirement for a preformed
iodine(III) reagent may be considered less optimum from economic and practical perspectives. In
search for a more economic re-oxidant, a terminal oxidation based on an organic photoredox
catalyst was developed (eq. 2).3b This reaction proceeds under significantly more benign
conditions, however, due to its iodine(-I/I) manifold, it is limited to the C-H amination at
benzylic positions.
Iodine(I/III) catalysis: requirement for a preformed iodine(III) oxidant3a
I2 (2.5 - 5 mol%)
H
R´´
(ArCO2)2IPh (1 equiv)
NHSO2R
R´
R´
R´´
N
DCE, RT, 12h,
SO2R
unfunctionalized
[visible light]
C-H amination products
remote C-H bond

(1)

Iodine(-I/I) catalysis: limitation to benzylic C-H positions3b
H
H

NHSO2R
Ar

unfunctionalized
remote benzylic C-H bond

I2 (5 mol%),
TPT (1 mol%)
HFIP/DCE, RT, 18h,
[blue LED]

Ar
H
N
SO2R

(2)

C-H amination products

2

Scheme 1. Iodine-catalyzed Hofmann-Löffler reactions using hypervalent iodine as terminal
oxidant (1) or photoredox catalysis for terminal oxidation (2). Ar = 3-Cl-C6H4.
Despite its undisputable progress,1 iodine redox catalysis still requires the development of
defined general and benign re-oxidation conditions for a broader application in organic synthesis.
Some interesting contributions have arisen in the recent past, which include the combination of
molecular iodine with cleaner oxidants such as peracids or peroxides.1,2 We here report on a
modified protocol of increased economic nature for catalytic Hofmann-Löffler reactions of
general substrate scope. It relies on a suitable engineering of the iodine catalyst, which is
generated from molecular iodine as a single iodine component in combination with a commercial
terminal oxidant.
2. Results and Discussion
2.1. Reaction Development
In previous investigation, we had disclosed that several attempts to implement common
hypoiodite catalysis2 for catalytic Hofmann-Löffler reactions were unsuccessful. In order to
render the reaction more economic and replace the required preformed hypervalent iodine as
terminal oxidant, we were intrigued to test whether common organic peroxides or peracids could
promote the desired Hofmann-Löffler reaction (Table 1).9 While tert-butyl hydroperoxide
(TBHP) was completely ineffective (entry 1), peracetic acid showed some low conversion
(entries 2,3). In contrast, mCPBA in acetonitrile/acetic acid directly provided a 52% of yield
(entry 4). Using a limiting amount of this oxidant in acetonitrile, 44% product was observed
(entry 5). Screening of alternative solvents in the presence of a three-fold excess of mCPBA
revealed that acetonitrile represented the best solvent (entries 6-11). Finally, addition of tertbutanol as co-solvent provided quantitative conversion and 98% isolated yield of 2a (entry 12),
which was maintained at 2.2 equivalents of terminal oxidant (entry 13). Under these conditions,
reduced iodine loadings of even 2.5 mol% provide lower, albeit synthetically useful yields
(entries 13-15).

3

Table 1. Iodine-catalyzed Hofmann-Löffler reactions: Optimization of reaction conditions for
mCPBA as terminal oxidant.
NHTs

Ph

conditions

Ph
N
Ts

12 h, 25 ºC

1a

2a

No

Conditions

Conversiona

1

I2 (15%), TBHP (3.0 eq), CH3CN/tBuOH (1/1)

s.m

2

I2 (15%), CH3CO3H (3 eq), DCE

12%

3

I2 (15%), CH3CO3H (3 eq), CH3CN

s.m

4

I2 (15%), mCPBA (3 eq), CH3CN/AcOH (1/1)

52%

5

I2 (15%), mCPBA (1 eq), CH3CN

44%

6

I2 (15%), mCPBA (3 eq), PhCN

38%

7

I2 (15%), mCPBA (3 eq), AcOH

32%

8

I2 (15%), mCPBA (3 eq), TFE

37%

9

I2 (15%), mCPBA (3 eq), MeOH

26%

10

I2 (15%), mCPBA (3 eq), EtOAc

56%

11

I2 (15%), mCPBA (3 eq), CH3CN

60%

12

I2 (15%), mCPBA (3 eq), CH3CN/tBuOH (1/1)

98% b

13

I2 (15%), mCPBA (2.2 eq), CH3CN/tBuOH (1/1)

98% b

14

I2 (5%), mCPBA (2.2 eq), CH3CN/tBuOH (1/1)

70% b

15

I2 (2.5%), mCPBA (2.2 eq), CH3CN/tBuOH (1/1)

56% b

a

Estimated conversion from integration of the 1H NMR spectrum of the crude reaction product.

b

Isolated yield after purification.

4

2.2. Scope of the iodine/mCPBA catalyzed Hofmann-Löffler reaction
Under the optimized conditions, a number of pyrrolidines were prepared from the corresponding
linear sulfonamides 1a-aa (Scheme 2). In agreement with earlier protocols,3a cyclization onto
benzylic positions is straightforward and includes variation at the nitrogen substitution (2b),
along the aliphatic chain (2c,k), at the arene (2d-2i, including an acetylenic group) and at the
benzylic position (2l,m). The accurate screening of re-oxidants has identified mCPBA to provide
suitable conditions for the important substrate class of C-H amination even at non-benzylic
aliphatic positions (2n-r), including the new compounds 2o and 2p/2p’. Here, the synthesis of
the a-tertiary amine derivative 2r stands out, as it represents an uncommon synthetic access to
this important class of compounds in natural alkaloids.10 The reaction proceeds at alpha-position
to heteroatoms (2s) and with excellent diastereoselectivity for cyclic stereocontrol (2t-u), while
acyclic stereocontrol is not possible due to the involved radical pathway (2v/v’). Transannular CH amination11 is also possible (2w).

5

R''

I2 (15 mol%)
mCPBA (2.2 equiv.)

R'

RO2SHN

R''
R'
N
SO2R

visible light,
CH3CN/tBuOH, 25 ºC, 12 h

H
1a-z

2a-z

Ph
N
SO2R

Ph

2a (R = Tol): 95%
2b (R = 4-NO2-Ph): 63%a

N
Ts

N
Ts

N
Ts

2l: 36%a

2k: 54%

X
2d (X = F): 83%
2e (X = Cl): 82%
2f (X = Br): 73%
2g (X = Me): 96%
2h (X = OMe): 99%
2i (X = CCPh): 58%

2c: 99%

Ph

Ph

N
Ts

N
Ts

Ph
Ph

2m: 84%a

Ph

N
Ts

Ph

N
Ts

N
Ts

2n: 58%

2o: 54%

N
Ts

N
Ts

2r:

Ph

2p/2p´: 1:1 d.r., 69%

N
Ts

N
Ts

2q: 65%

Ph

+

61%a,b

OMe
TsHN
NHTs

2s: 60%

Ph

Ph
N
Ts
2t: 100:0 d.r.,
96%
O2
S

N
Ts
2u: 100:0 d.r.,
85%
O2S N

N

Ph
N
Ts

2v/2v´: 1:1 d.r., 94%

+

2x (R = Me): 63%
2y(R = Et): 85%
NHTs

Ph +

R
Ph

2w: 70%

N
Ts

N
Ts

Ph

Ph
N
Ts
2z/2z': 1:1 d.r., 67%

I2 (15 mol%)
mCPBA (3 equiv)

NTs

CH3CN/tBuOH (1/1)
3a

4a (40%)c

6

Scheme 2. Iodine-catalyzed Hofmann-Löffler reaction with mCPBA: Scope.
a Reaction in 1,2-dichloroethane. b with 3 equivalents of mCPBA. c >55% recovered starting
material.
New substrates were investigated for the amination of 1x and 1y, which cyclized under the
present conditions, while they are entirely unreactive under the previous ones.3 Compound 1z
demonstrates that in the case of competitive secondary hydrocarbon bonds, the common 1,5HAT12,13 is preferred for the weaker benzylic C-H bond, thus providing 2z/2z’ as the exclusive
amination products. The reaction was further expanded to an interesting example of sixmembered ring formation. For the case of compound 3a, clean formation of the corresponding
tetrahydroisoquinoline 4a was observed (40%, together with amost fully recovered remaining
starting material). This example represents a rare case of a 1,6-HAT reaction,14-16 which in the
present case is the result of an impossible 1,5-HAT. However, the potentially competing aelimination to an aldimine6f was not observed at all for this case. Noteworthily, previous iodine
catalyses do not promote this particular reaction. In order to further demonstrate the difference
between the individual protocols, we explored the performance of the benzyl methylether
derivative 3b (Scheme 3). While the iodine/iodine(III) system3a provides the expected C-H
amination product 4c, the present iodine/mCPBA variant promotes overoxidation to the lactam
4b. Finally, the inherent reaction differences between the protocols of the reoxidants iodine(III)
and mCPBA may open new synthetic possibilities. For the case of a substrate with a tertiary
alcohol, clean Hofmann-Löffler cyclization is obtained for the substrates 5a,b in the presence of
the iodine/mCPBA system, yielding the pyrrolidine products 6a,b in good isolated yields. In
contrast, the iodine/iodine(III) system leads to concomitant opening of the tertiary alcohol to
form w-iodo ketones. Such a scission reaction had previously been reported by Barluenga and
González for the use of a cationic iodonium reagent.17 Since the active iodine species is also an
electrophilic iodine(I) in the present case, ketone formation represents the expected outcome.
However, the incorporation of the iodine into the carbon framework of the product prevents the
progress of the catalytic Hofmann-Löffler cyclization, and, consequently, yields could not
exceed the range of 10%. When conducting the reaction in the presence of equimolar reagent
amounts, synthetically relevant yields of 7a,b could be obtained.

7

NTs
O
4b: 99%

NHTs

I2 (15 mol%)
mCPBA (2.2 equiv)
CH3CN/tBuOH (1/1)

I2 (5 mol%)
PhI(O2CAr)2 (1 equiv)

OMe

NTs

(CH2Cl)2

OMe

3b

4c: 89%

I2 (15 mol%)
mCPBA (3 equiv)
CH3CN/tBuOH (1/1)

N
Ts

HO

TsHN
HO

5a (n = 1)
5b (n = 3)

6a: 60%
6b: 50%

n

n

I2 (1 equiv)
PhI(O2CAr)2 (2 equiv)
(CH2Cl)2

N
Ts

I
n

7a (n = 10): 63%
7b (n = 13): 79%

O

Scheme 3. Iodine-catalyzed Hofmann-Löffler reactions with mCPBA: Influence of the
terminal oxidant. Ar = 3-Cl-C6H4.
2.3 Mechanistic Discussion
Several control experiments were conducted to gain insight into the mechanism of the present
transformation (Scheme 4). At the outset, it is noteworthy that mCPBA as the optimum oxidant
generates the 3-chlorobenzoate anion, which had been identified as a component in the best
hypervalent iodine reagent in our earlier reaction.3a This could suggest that these two iodine
catalyses actually proceed through the formation of identical iodine(I) states such as I-O2CAr.7
However, control experiments with the isolated compound 8 showed a completely different
picture. First, a reaction employing 8 as catalyst source led to no reaction either with mCPBA
alone or in the presence of additional free 3-chlorobenzoic acid. Next, it was observed that
tetrabutylammonium iodide could also not serve as catalyst source upon oxidation with mCPBA.

8

NHTs
conditions
Ph
1a

visible light
CH3CN/tBuOH, 12h, 25 ºC

Ph
N
Ts
2a

conditions
[(ArCO2)2I]NBu4 8 (30 mol%), mCPBA (1.5 eq)

No reaction

[(ArCO2)2I]NBu4 8 (30 mol%), mCPBA (1.5 eq) ArCO2H (2 eq) No reaction
INBu4 (30 mol%), mCPBA (1.5 eq)

No reaction

IOtBu (1.2 equiv), c-C6H12

51%

IOtBu (30 mol%), c-C6H12, mCPBA (1.5 equiv)

83%

I2 (15 mol%), mCPBA (2.2 eq), dark laboratory

No reaction

Scheme 4. Control Experiments. Ar = 3-Cl-C6H4.
These observations make an iodine(I) catalyst state IO2CAr less probable. In view of the positive
influence of the tBuOH co-solvent, the participation of tert-butyl hypoiodite IOtBu becomes an
intriguing alternative. We investigated the participation of this reagent using its in situ formation
following Wirth’s protocol.18 Indeed, a stoichiometric amount of this oxidant promotes a 51%
isolated yield for the standard transformation of 1a into 2a. When IOtBu is employed as the
catalyst source in the presence of mCPBA as terminal oxidant under standard conditions, the
reaction outcome closely resembles the yield from the corresponding reaction with in situ
catalyst formation.

9

ArCO2H

Ts
NH
O

I

Ph
N
Ts
2a

ArCO3H

Ph

Ts
NH

I

E

Ph

Ph

D

I-OH

Ts
N

HOtBu

H2O

I

Ts
NH

C
Ts
N

I

I-OtBu
Ph
NHTs

HOtBu

A

B

Ph

Initiation:
initiation:18a
I2 + HOtBu

Ph

1a

hυ, - I
kinetic isotope effect:
1.4 [mCPBA] vs 4.0 [PhI(O2CAr)2]3a
quantum yield:
3.0 [mCPBA] vs 49 [PhI(O2CAr)2]3a

Figure 1. Catalytic cycle for the iodine-catalyzed Hofmann-Löffler reaction with mCPBA as
terminal oxidant. Values for control experiments are given with the corresponding oxidant in
brackets. Ar = 3-Cl-C6H4.
With these observations in hand, it is plausible to conclude that the reaction proceeds through an
iodine catalysis that involves IOtBu as a competent catalyst state (Figure 1). This compound is
formed at the outset from molecular iodine and tBuOH.18 Reaction with the substrate 1a provides
the crucial intermediate A. In the absence of tBuOH, intermediate A is directly formed from
IOH.3b Obviously, this latter pathway is slower than the one through tBuOI, and this context
explains the observed acceleration effect of tBuOH. Intermediate A then undergoes photolytic NI bond cleavage as investigated previously.3 This homolytic light-induced amidyl radical
formation19 is in agreement with the corresponding control experiment in the absence of light,
which does not show product formation (Scheme 4). It obviously overrides the potentially
competing unselective radical C-H iodination by the tBuOI reagent itself.18a The resulting
intermediate B promotes a 1,5-HAT to C,3,19,20 which engages in a radical chain reaction with A

10

to finally generated the aliphatic iodide D. Alternatively, radical recombination with iodine
would provide the same outcome in a direct transformation. In view of the demonstrated
successful reaction scope including aliphatic, non-benzylic C-H amination, it can be concluded
that the reaction should involve an alkyl-iodine(III) intermediate E prior to nucleophilic C-N
bond formation to product 2a. The enhanced leaving group capacity21 of alkyliodine(III) E over
the comparable iodine(I) state D enables amination reactions outside the activated benzylic or
neighboring heteroatom scaffold. This postulation of an alkyliodine(III) catalyst state E is in
agreement with literature precedence on the formation of iodosyl alkanes from alkyl iodides
upon oxidation with mCPBA.22,23 A somewhat slower leaving group capacity than for related
alkyl[(dicarboxy)iodine](III) intermediates3 is generally expected for iodosyl derivative E. This
assumption should affect the relative rate of C-N bond formation, and the subsequent
nucleophilic substitution should be slightly slower than in the case of comparable
di(acyloxy)iodosylalkanes,3 which display a comparably higher nucleophuge character.24 This
observation is corroborated by Hammett studies9 and by a pronounced observation of an
electronic influence of the nitrogen substituent on the reaction. For a competition experiment
between 1a and 1b, the less nucleophilic nosyl group displays a decreased reactivity and the two
products are formed in a 1.7:1 ratio in favor of 2a (Scheme 5).

NHTs

NHNs
+

I2 (15 mol%),
mCPBA (1 equiv)
CH3CN/tBuOH (1/1),
12h, 25 ºC

1a

1b

N
Ts

+

N
Ns

89%, 2a:2b = 1.7:1

Scheme 5. Competition experiment between 1a and 1b. Conversion based on the terminal
oxidant mCPBA as limiting agent.
In any case, the leaving group ability of the alkyliodine(III) intermediate is required to guarantee
a sufficient rate in the iodine-based catalytic cycle, in particular for those examples, that promote
amination of non-activated carbon atoms. In comparison to the previous catalytic HofmannLöffler reaction with iodine(III) PhI(O2CAr)2 as the terminal oxidant, the relative rates of the
individual steps of both catalytic cycles are different. First, the 1,5-HAT step now occurs at
comparably faster relative rate as suggested from the corresponding KIE of 1.49 measured for the

11

overall transformation from 1a to 2a. In addition, the observed quantum yield of only 39 suggests
that significant interruption of the radical chain reaction occurs. This may be the result of partial
radical recombination with an iodine radical at the intermediary state B, and due to the
comparably slow regeneration of the crucial intermediate A, even at a comparably higher iodine
catalyst loading.

38.29
35.42

‡

0.00

1.37

E / kcal mol

1

24.23

-15.57
-20.25

‡
-34.09

-63.26

Figure 2. Electronic energy profile of the proposed catalytic cycle from Figure 1. All energies
are calculated either with the PBE functional and with (light green) and without (dark green) D3
dispersion correction, or with the PBE0 hybrid functional again with (gray) and without (black)
dispersion correction. Transition state energies, indicated by the double dagger, are connected to
the energies of the minimum structures by solid lines, whereas the dashed lines connect
minimum energies for which no transition state was calculated or already discussed previously.3b
All structures were optimized with PBE/def2-TZVPP and the green numbers indicate the exact
values for these relative energies.

12

In order to understand in more detail the mechanism and in particular the two crucial steps of
1,5-HAT and alkyliodine oxidation in particular, we carried out density functional theory
calculations for the catalytic cycle from Figure 1. We optimized the structures with the PBE
functional25 and the def2-TZVPP basis set26 in Turbomole27 and solvent effects were modeled
with the COSMO continuum model28 employing a dielectric constant of e = 24.95, which is the
average of the dielectric constants of MeCN and tBuOH. Transition state structures were
optimized with the QST3 transition state search29 as implemented in Gaussian 09.30 The effect of
exact exchange and dispersion interaction on the energies was investigated with the PBE0 hybrid
functional31 and the empirical D3 dispersion correction,32 respectively.
As in our previous work,3b we adopted a closed conformation for all structures but note that the
relative energy barriers to the open structure are on the order of 2 kcal mol-1. Figure 2 displays
the electronic energy profile of the proposed catalytic cycle. As expected, the photochemical
initiation step, corresponding to the homolytic N-I bond cleavage,3b leads to radical structure B
that is destabilized by about 35 kcal mol-1 compared to structure A. The intramolecular radical
transfer to form the more stable benzylic radical C is almost barrierless. Structure D is then
significantly stabilized by a recombination with an iodine radical in the next step. The crucial
iodine oxidation with mCPBA has a barrier (TS D-E) of 4.68 (11.63) kcal mol-1 as calculated
with the PBE (PBE0) functional. The corresponding transition state structure is displayed in
Figure 3. It is important to note, however, that both transition states have several vibrations with
very low wave numbers (four (twelve) vibrations with less than 50 cm-1 for TS B-C (TS D-E)).
Therefore, the concept of a transition state is not strictly valid but we can confirm that both
transformations correspond to very flat regions of the potential energy hyper-surface. Despite the
prominence of mCPBA in iodine(I/III) catalysis,33 a more detailed picture on the course of the
oxidation of organic iodine(I) compounds had not been generated previously. The detected low
barrier now provides the rationale for the success of this particular oxidant.
The direct reaction from D to 2a is endothermic, with energies ranging from 1.32 kcal mol-1
(PBE0) to 5.10 kcal mol-1 (PBE-D3), underlining the necessity of the iodine oxidation with
mCPBA. It is interesting that for the alternative peroxide TBHP as oxidant (Table 1, entry 1) the
corresponding transition state from D to E is significantly increased by almost 20 kcal/mol (see
the Supporting Information), indicating that iodine(I) to iodine(III) oxidation is a kinetically less
feasible process with this oxidant.9,34 These results again demonstrate that the involvement of an

13

iodine(III) intermediate is crucial in order to provide kinetically competent pyrrolidine
formation.
We further calculated the energy of a radical quenching reaction by a solvent molecule. For the
most stable radical structure C, H-atom abstraction from an acetonitrile molecule has an
enthalpic penalty of 12 kcal mol-1, whereas it is as high as 19 kcal mol-1 for H-atom abstraction
from tBuOH (both values are obtained from PBE/def2-TZVPP calculations). Even if present,
these reactions do not affect the overall yield because they lead to regeneration of the starting
material 1a. However, they contribute an explanation to the comparably low quantum yield of
the present radical chain.34
a

b

c

TS	D-E
Ar
O
O

H

I

Ar
O

O
O

Ar
O

O

H

I

OH

O
I

Ph

Ph

Ph

NHTs

NHTs

NHTs

Figure 3. Three structures obtained from displacements along the imaginary vibrational mode
corresponding to the transition state structure TS D-E. The transition state is shown in the middle
(b), whereas the structure on the left (a) is closer to the starting structures mCPBA and D and the

14

structure on the right (c) resembles the oxidized structure E. Hydrogen atoms were removed for
clarity.
The combined experimental and theoretical observations demonstrate that the development of
catalytic iodine catalyzes for Hofmann-Löffler reactions require an accurate engineering of a
number of different factors in order to arrive at suitably balanced rates for all involved individual
steps. It includes the identification of tBuOH as a suitable co-solvent for stabilization of the
electrophilic iodine catalyst in the form of tBuOI, mCPBA as a suitably rapid oxidant to generate
the crucial alkyliodine(III) intermediate and acetonitrile as non-chlorinated solvent. As a
consequence, the catalytic system based on mCPBA that is presented here is only the second
catalytic reaction that is general for C-H amination of aliphatic positions including non-benzylic
ones and it provides the advantage of employing only conventional bulk reagents and solvents.
3 Conclusion
We have identified suitable conditions for the selective intramolecular amination of aliphatic
positions, which include activated and non-activated aliphatic C-H bonds. The reaction proceeds
with high selectivity and synthetically useful yields. The robust homogeneous catalyst is
conveniently generated in situ from molecular iodine and tert-butanol and is continuously
regenerated from 3-chloro perbenzoic acid as terminal oxidant, which are all commodity
reagents. The reaction represents the currently most economic variant of an iodine-catalyzed
Hofmann-Löffler reaction. It proceeds through an iodine(I/III) catalytic manifold, which is active
in the presence of visible light irradiation. Although related to alternative catalysis with an
iodine(III) reagent as terminal oxidant, the present system shows significant changes in the rate
of the relative steps of the catalytic cycle and for some substrate classes can even provide
alternative reactivity. The present work thus demonstrates that careful engineering of molecular
iodine catalysis can provide an entry into versatile improvement of the economic conditions of
homogeneous catalysis.

15

ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications

website.

The

following

files

are

available

free

of

charge.

Details on experimental procedures for the catalytic reactions, spectroscopic data for the
products and xyz structure files for all molecules included in the calculations (PDF).
AUTHOR INFORMATION
Corresponding Author
* E-mail for K.M.: kmuniz@iciq.es
* E-mail for M.R.: markus.reiher@phys.chem.ethz.ch
ORCID
Thomas Duhamel: 0000-0003-3397-0639
Christopher J. Stein: 0000-0003-2050-4866
Markus Reiher: 0000-0002-9508-1565
Kilian Muñiz: 0000-0002-8109-1762
Author Contributions
TD and CM conducted the experimental research and CJS and MR designed and conducted the
theoretical investigation. The manuscript was written by KM after consultation with all authors.
All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Spanish Ministry for Economy and Competitiveness and FEDER (CTQ201456474R grant to K. M., Severo Ochoa Excellence Accreditation 2014-2018 to ICIQ, SEV-20130319), the region of Catalonia and the Schweizerischer Nationalfonds (No. 20020 169120 to
M.R.) for financial support.

16

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22

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55, 58.

23

Synopsis

Ar
O
NHSO2R'

R

I
[mCPBA]

O

O
H

I
Ph

R
N
SO2R'

NHTs
Oxidation to Iodine(III) Catalyst

24