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Selective Piperidine Synthesis Exploiting Iodine-Catalyzed Csp3-H
Amination under Visible Light
Hongwei Zhang1 and Kilian Muñiz*1,2
1

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, 16 Avgda. Països
Catalans, 43007 Tarragona, Spain.
2
ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
ABSTRACT: A route to selective piperidine formation through intramolecular catalytic Csp3-H amination is described. This hydrocarbon amination reaction employs a homogeneous iodine catalyst derived from halogen coordination between molecular iodine
and a terminal oxidant. It relies on visible light initiation and proceeds within two catalytic cycles that comprise a radical C-H functionalization and an iodine-catalyzed C-N bond formation. Under these conditions, the commonly observed preference for pyrrolidine synthesis based on halogenated nitrogen intermediates within the Hofmann-Löffler domain is effectively altered in favor of a
free radical promoted piperidine formation. The protocol is demonstrated for a total of 30 applications.
KEYWORDS: amination, C-H functionalization, halogen bonding, iodine, light initiation.

Intramolecular amination of remote aliphatic C-H bonds is
of particular conceptual interest as it streamlines existing protocols for the preparation of saturated N-heterocycles.1 These
compounds are usually accessible by classic radical chemistry,2 in which modified Hofmann-Löffler reactions have
demonstrated a unique potential.3 We recently initiated exploration into iodine-catalyzed Hofmann-Löffler reactions4 that
provide the expected access to pyrrolidines from positionselective C-H functionalization based on intramolecular 1,5-H
abstraction3,5 through a nitrogen centered radical pathway
(Figure 1, top).
In contrast, the related C-H amination strategy toward the
piperidine core is significantly more challenging as the required 1,6-H abstraction from nitrogen-centered radicals is
kinetically disfavored.6 Consequently, a C-H amination strategy owards piperidines has remained elusive.7 Piperidines represent important structural subunits in molecules of pharmaceutical, biological and medicinal interest, and exercise important pharmacophoric properties.8 In fact, a recent analysis
on the occurrence of nitrogen heterocycles in FDA approved
pharmaceuticals identified the piperidine core as the most frequent member.9 As a result, piperidine synthesis within intramolecular amination of remote C-H bonds would constitute an
important synthetic advance. We here report on conditions for
such a selective synthesis for the first time (Figure 2, bottom).
To override the given “innate” preference for pyrrolidine
formation, we decided to pursue conditions that would preferentially generate free radicals outside the amidyl radical manifold involved in the Hofmann-Löffler pathway.3 Within such a
scenario, free radical hydrogen atom abstraction should address the weakest C-H bond and could be predicted by the
introduction of carefully pre-organized substitution.10,11

I2 (catalyst)
PhI(O2CAr)2

Ts
N

Ar

[ref. 4]
H H
Ar
H H

pyrrolidine
amidyl radical (from tosylamide)
(Hofmann-Löffler product)
NHTs
free radical (from oxidant)
I2 (catalyst)
oxidant
[this work]

Ar

N
Ts

piperidine

Figure 1. Position-selective intramolecular C-H amination for
pyrrolidine and piperidine synthesis.

We previously reported that iodinated reagents such as NIS
1b effectively provide intermediates for exclusive HofmannLöffler reactions.12 As a consequence of this observation and
in order to prevent potential background reactions, we turned
to less reactive bromine-based reagents. Catalytic amounts of
molecular iodine13 were pursued to generate low amounts of
free radicals as the reaction carriers and thus to minimize potential side reactions. These halide reagent combinations provide the desired gateway to the elusive piperidine formation.
Table 1 provides insight in the optimization of catalytic reaction conditions that allow for selective piperidine synthesis
within C-H amination.

Table 1. Iodine-catalyzed piperidine formation: optimization.

NHTs

O

entry

O
IN

O
1a

N
Ts

visible light
(CH2Cl)2, RT

2a

BrN

catalyst
oxidant 1

O
1b

catalyst

O

3a
O
BrN

ClN
O

O
1c

oxidant (equiv)

1d
time [h]

yield [%]a

1

I2 (5 mol%)

1a (1.2 )

4

47

2

I2 (5 mol%)

1a (1.6 )

4

62

3

I2 (5 mol%)

1a (2.0 )

2

80

4

I2 (5 mol%)

1b (2.0 )

12

34

5

I2 (5 mol%)

1c (2.0 )

12

n.d.b

6

I2 (5 mol%)

1d (2.0 )

12

72

7

-

1a (2.0 )

12

0

8c

I2 (5 mol%)

1a (2.0 )

12

0

9

KI (10 mol%)

1a (2.0 )

12

50

10

TBAI (10 mol%)

1a (2.0 )

12

30

11d

I2 (5 mol%)

1a (2.0 )

12

73

12e

I2 (5 mol%)

1a (2.0 )

12

67

13f

I2 (5 mol%)

1a (2.0 )

12

0

a

Isolated yield after purification. bn.d. = not determined (observation of trace amounts of 3a in the crude NMR). cReaction in the
dark lab. dReaction in CH2Cl2. eReaction in MeCN. fReaction in
THF.

The reaction was developed with 2a as substrate and departed from the observation that a combination of visible light
exposure, 5 mol% molecular iodine and N-bromo succinimide
(NBS) 1a provided a selective transformation to the desired
piperidine 3a (entry 1). Subsequent rise of the amount of oxidant to 2 equivalents provided 3a in 80% yield (entries 2,3)
without detection of the corresponding pyrrolidine. This observation proofs that the current conditions are capable of
overriding conventional Hofmann-Löffler chemistry. Related
iodo and chloro derivatives NIS 1b and NCS 1c provided significantly decreased reactivity (entries 4,5) accompanied by
formation of the undesired pyrrolidine, while N-bromo
phthalimide 1d gave a comparable yield of 72% (entry 6).
Control experiments verify that no formation of 3a is obtained
without the iodine catalyst or in the absence of light (entries
7,8). Alternative iodine catalyst sources andreactions in alternative solvents gave lower yields (entries 9-13).
Under the optimized conditions, the scope of the reaction
was explored (Scheme 1). For tosylamide 2a, the reaction was
extended to a 1g-scale. Several additional sulfonimides 2b-e
including mesyl, nosyl, trimethylsilylethylsulfonyl (SES) and
2-bromophenyl sulfonyl also provide the corresponding piperidination products 3b-e. Use of different substituents in the
chain is demonstrated for 3f,g and the reaction could be extended to the synthesis of the unsubstituted 2-phenyl piperidine 3h.

Scheme 1. Piperidine Formation from C-H Amination: Scope
(0.2 mmol scale). Yields refer to isolated material after purification. All reactions proceed with >90% selectivity in favor of
piperidine formation (>95% yield based on recovered starting
material). a1.6 equiv. of NBS. b20 mol% I2, white LED.

Common organic substituents are well tolerated on the arene
group as demonstrated for derivatives 3i-3v. These examples
include 2-, 3- and 4-disubstitution patterns as well as higher
substitution and as for 3q,r also include carbonyl derivatives,
which are non-compatible with the corresponding light induced iodine-catalyzed Hofmann-Löffler reaction.4 The reaction also proceeds for heteroaromatic (3w,x) and dibenzylic
derivatives (3y), and yields diastereomerically pure piperidine
3z from cyclic stereocontrol, while acyclic stereocontrol is not
possible under the reaction conditions (3aa and 3ab). The C-H
amination scope also includes related heterocycles such as the
pharmaceutically relevant piperazine core 3ac. For compounds 3c, 3m and 3z their constitution was unambiguously
established by single crystal X- ray analyses.14
It is noteworthy that potentially competing pyrrolidine formation was not observed in any of these cases. While the reactions were usually conducted with tosylamides as the representative sulfonamide groups, the use of SES and Ns enables a
convenient approach to the corresponding free piperidines.14
The reaction conditions could also be extended to the selective
formation of a seven-membered derivative 5, using an increased catalyst loading. It demonstrates the inherent potential
of the current methodology for the synthesis of more advanced
nitrogen heterocycles such as azepanes as well.
This novel C-H amination reaction is rationalized by the following merger of two catalytic cycles (Figure 2).

er BDE than the competing ones, which provides the required
selectivity within this free radical reaction step.16 Control experiments with deuterated staring materials 2h-d1 and 2h-d2
provide intra- and intermolecular kinetic istope effects of 2.6
and 2.7, respectively (Scheme 2, eq. 1,2).14

Ph

TsHN
2h-d1

2

O

TsHN

TsHN

I2 (5 mol%)
Ph NBS 1a (2 equiv)

2h-d2
+
H H

Ph

2h

- Br

NBS (1a)

O
I

Br

N
O
NHTs

C

O
I

I

Br
B

NBS (1a)

IBr

iodine-catalyzed
C-N bond formation

N

I
NHTs

O

D

I2

HI
HBr

IBr

Ph

(1)

2a

H

+

N
Ts

I2 (5 mol%)
NBS 1a (2 equiv)

N
Ph
Ts
3h/3h-d1

2i,j,l,m

X

ρ = - 2.9

I2 (5 mol%)
IBr 6 (2 equiv)
Ph

TsHN
2a

Ar, DCE, light,
RT, 20 h
I2 (5 mol%)

Ph

NBS 1a (2 equiv)
Ar, DCE, light,
RT, 20 h

Ph (2)

(3)
N
Ts

Ar, DCE, light,
RT, 20 h

TsHN

HN
SO2Ar

D

+

+

H

N
Ts
3a + 3i,j,l,m
no reaction

X
(4)

Ph
NSO2Ar

(5)

3e (6 %)

hν

N
O

I

N
Ph
Ts
3h/3h-d1

Scheme 2. Control Experiments.

O
radical C-Habstraction

A

Ar, DCE, light,
RT, 20 h
kH/kD = 2.6

TsHN

7 (Ar = 2-Br-C6H4)
NHTs

N
Ts

kH/kD = 2.7

Br
NHTs

HN

Ar, DCE, light,
RT, 20 h

D

+

D D

H

O

I2 (5 mol%)
NBS 1a (2 equiv)

D

N
Ts
3

Figure 2. Position-selective intramolecular C-H amination.
It initiates from visible light-assisted homolytic cleavage of
the N-Br bond in NBS.15 The N-centered succinimidoyl radical then abstracts a hydrogen atom at the benzylic position of
the substrate 2. The respective benzylic C-H bonds are of low-

These results suggest the intramolecular radical C-H abstraction to be the slow step of the reaction, which is further
corroborated for a Hammett correlation with a r-value of -2.9
(eq. 3). The intermediary benzylic radical A abstracts an iodine atom from a halogen-bonded17 I2-NBS adduct B to generate IBr 6 and the intermediary benzyl iodide D and regenerates
the succinimide radical.18 The formation of the latter closes the
catalytic cycle of radical C-H functionalization. The benzylic
iodide undergoes nucleophilic substitution to the pyrrolidine
product 3.19 The liberated HI regenerates the molecular iodine
catalyst upon reaction with IBr 6. This compound could potentially engage in radical halide formation itself, but is unproductive under the current conditions as demonstrated by a
control experiment (Scheme 2, eq. 4). Molecular iodine recoordinates NBS 1a within a halogen bonding mode,17 which
closes the second catalytic cycle of iodine catalysis. Closely
related species such as I2-N-chloropthalimide had been invoked previously by Ishihara in iodolactonization reactions.20,21 The postulation of a free radical mechanism outside
the classical N-centered radical from N-halogenation as in the
Hofmann-Löffler scenario is in agreement with the observation that molecular iodine does not convert tosylamides into
their N-iodinated derivatives.4 However, upon polarization by
halogen bonding with the N-bromo succinimide 1a the radical
pathway to C-H functionalization is switched on. The postulated pathways do not involve direct benzylic bromination
with NBS 1a. This is in agreement with the observation that
benzyl bromide derivative 7 does not cyclize to piperidine 3e
under the reaction conditions (Scheme 2, eq. 5) and thus con-

stitutes a dead-end. Obviously, successful nucleophilic piperidine formation requires the more reactive benzyl iodide intermediate D.14
In summary, we have identified mild and uniform conditions for a selective iodine-catalyzed C-H amination of 2-aryl
substituted piperidines. This reaction overrides the common
preference for pyrrolidine formation within the HofmannLöffler manifold and significantly enlarges both the scope of
light-induced iodine-catalysis and position-selective C-H amination reactions. In addition, it diversifies the chemical space
of piperidines.

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AUTHOR INFORMATION
Corresponding Author

* kmuniz@iciq.es
Notes
The authors declare no competing financial interest.

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ASSOCIATED CONTENT
Supporting Information. Experimental details, control
experiments and compound characterization (PDF), and
details on the X-ray analyses (CIF). The Supporting Information is available free of charge on the ACS Publications
website.

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ACKNOWLEDGMENT
Financial support for this project was provided from the
Spanish Ministry for Economy and Competitiveness and
FEDER (CTQ2014-56474R grant to K. M., and Severo
Ochoa Excellence Accreditation 2014-2018 to ICIQ, SEV2013-0319), and the ICIQ-COFUND Program (fellowship
to H. Z.). The authors are grateful to the CERCA Programme of the Government of Catalonia and to COST Action CA15106 “C-H Activation in Organic Synthesis”
(CHAOS).

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ABBREVIATIONS
NBS, N-bromo succinimide; DCE, dichloroethane.

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REFERENCES
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I2, (5 mol %)
NBS (2 equiv)
TsHN

Ar
R R

visible light
(CH2Cl)2, RT, 4 h

- selective piperidine formation

R
R
N
Ts

Ar

27 examples,
42-81% yield

- benign light induced reaction
- radical C-H functionalization
- iodine-catalyzed C-N bond formation

5