“This is the peer reviewed version of the following article: N-Iodosuccinimide promoted Hofmann-Löffler Reactions of Sulfonimides under Visible Light, which has been published in final form at DOI: 10.1021/acs.orglett.5b03476. This article
may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving “.

N-Iodosuccinimide promoted Hofmann-Löffler Reactions of
Sulfonimides under Visible Light
Calvin Q. O’Broin,† Patricia Fernández,† Claudio Martínez,† Kilian Muñiz*†‡
†

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
‡
Catalan Institution for Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain.
Supporting Information Placeholder
O
NI
R'O2S
N
H

O

R R

NIS (2 equiv)
Ar
CH2Cl2, 5 h, rt
visible light or violet LED

R
R
Ar
N
SO2R'
17 examples
53-99%

ABSTRACT: Conditions for an attractive and productive protocol for the position-selective intramolecular C-H amination of aliphatic groups (Hofmann-Löffler reaction) are reported employing sulfonimides as nitrogen sources. N-Iodosuccinimide is the only
required promoter for this transformation, which is conveniently initiated by visible light. The overall transformation provides pyrrolidines under mild and selective conditions as demonstrated for 17 different substrates.

The intramolecular C-H amination of aliphatic groups has recently attracted significant interest from the synthetic community.
Major work has focused on the identification of suitable transition metal catalysts to provide the aforementioned transformation.1
Directed evolution of metalloproteins has recently emerged as a complimentary approach.2 An alternative consists of the use of
small organocatalysts3 as non-metallic promoters, which, due to their capability to avoid metal contamination, is of major importance to fields such as biological and medicinal synthesis.
From a historical perspective, the halide-mediated C-N bond formation at non-activated hydrocarbons was discovered over a century ago and is well established as the Hofmann-Löffler reaction.4 The general conditions call for preformation of a halogenated
amine, which upon irradiation in the presence of strong acid promotes C-H halogenation, which is usually followed by basemediated pyrrolidine formation. A useful modification providing significantly milder reaction conditions was introduced by Suarez,5 who reported that Hofmann-Löffler-type cyclization reactions can be conducted in the presence of a mixture of molecular iodine and a hypervalent iodine reagent of the general structure ArI(O2CR)2.6 This protocol was employed by Fan, who demonstrated
its compatibility with sulfonamides as nitrogen sources.7
We have recently demonstrated that this reaction can be conducted with catalytic amounts of iodine and the use of a single equivalent of hypervalent iodine(III) as the terminal oxidant.8 This accomplishment has demonstrated that iodine catalysis is indeed feasible within the borders of the Hofmann-Löffler reaction, provided that the iodine concentration is maintained at a sufficient level to
perpetuate the two intertwined catalytic cycles. However, the permanent requirement of using a hypervalent iodine reagent as a
terminal oxidant9 has triggered interest in whether the reaction could also be conducted with just a single amount of halide reagent
as a stoichiometric promoter. Such a reaction would serve as an important addition to the existing protocols for Hofmann-Löffler
reactions.

1

Scheme 1. Chloride-mediated intramolecular C-H functionalization.

Cl

Ts
N

Ph

H

MeCN
visible light, rt

1

Ts
N

Cl
Ph
2 (76%)

Our investigation on a halide-mediated Hofmann-Löffler transformation commenced from the corresponding N-chlorinated compound 1. In agreement with a recent literature report,10 we observed the expected chemoselective chlorination of the benzylic position, which proceeded readily even in the absence of the photocatalyst that was previously deemed indispensable (Scheme 1). Still,
the requirement of an individual treatment of 2 with base rendered the reaction less attractive from a synthetic point of view. In
addition, attempts to develop an in situ formation of 1 using N-chloro succinimide as chlorinating agent resulted in no conversion.11
In order to arrive at a direct pyrrolidine formation, we turned to the use of N-Br derivatives (Table 1).
Table 1. NBS/NBP-promoted Hofmann-Löffler reaction.
O
NBr
3
R'O2S
N
H

O
NBr

O

4

O

reagent
(x equiv)

R R
Ph

R
R

(CH2Cl)2, 24 h, rt

5a (R = Me, R' = Tol)
5b (R = Ph, R' = Me)
entry

substrate

6a
6b

Ph
N
SO2R'

reagent

x

conversion
[%]
-

1

KBr/NaClO2

0.1/2

5b

KBr/NaClO2

0.1/2

-

3

5a

3

1

40

4

5a

3

2

52

5a

5a

3

2

56

6

5a

4

2

55

7a

5a

4

2

55

8

5b

4

2

47

9

5a

4

3

66

10
a

5a

2

5b

4

3

81

Under irradiation (400 nm monochromatic wavelength).

We initially investigated the application of our earlier KBr/NaClO2 protocol from intramolecular diamination of alkenes.12 For
the two selected starting materials 5a and 5b, no conversion could be obtained under these conditions (entries 1,2). In contrast, use
of conventional brominating reagents such as N-bromo succinimide (3) and N-bromo phthalimide (4) led to a clean pyrrolidine
formation. Initially, substrate 5a could be cyclized to 6a in 40% yield using a single equivalent of 3 (entry 3). Increasing the amount
of 3 to 2 equivalents gave a slightly increased yield (52%, entry 4). Changing visible light for monochromatic light of 400 nm had
little effect (entry 5). With 4 as bromine source, a comparable result was obtained (entry 7). Changing to mesylated substrate 5b, a
less efficient transformation was observed (47%, entry 8). A further increase of 4 to 3 equivalents only had a minor beneficial effect
for formation of 5a (66% yield, entry 9), while for 5b a significantly improved yield of 6b was obtained (entry 10). It is noteworthy
that the reaction proceeds with complete chemoselectivity and that even in the presence of an excess of reagents 3 and 4, there are
no products other than 6a,b formed. These are the first successful examples of a Hofmann-Löffler variant starting from in situ generated N-brominated tosylamides.
In another series of experiments (Table 2), the dibrominated hydantoin 7 was employed as the halide promoter in order to attempt
to lower the amount of halide promoter. While the initial work with the mesylated derivative 5b gave a very good yield of 74%
(entry 1), the tosylated derivative 5c resulted in low conversion (entry 2). Unexpectedly, the applicability of these conditions for a
general process with other substrates 5a,d-i was hampered by the occurrence of unexpected dibrominated imine products 8a,d-i,
which in all cases but one (6h/8h) constituted the main reaction product (entries 3-9). For all these transformations, the two products constituted the only oxidation products detected in the crude reaction mixture, the remaining material being unreacted starting
material. Employing higher amounts of reagent 7 only increased the relative formation of products 8.

2

Table 2. Oxidation of alkylsulfonamides 5 with reagent 7.
O
BrN

R'O2S
N
H

NBr

O
7
(1.5 equiv)

R R
Ar
5a-i

entry

R
R

CH2Cl2, 24 h, rt
visible light exposure

Ar + 8c-i
N
SO2R'
6a-i

products (yields)
Ph
Ph

1

Ph

6b (74%)

Ph

6c (29%, 99%a)

N
Ms
Ph
Ph

2

N
Ts

Br
Ph

3

Br

+

Ph

N
Ts
6a (39%)

N
8a (47%)
Br

Ph

4

N
Ns
6d (35%)

+

Br

Ph
N
8d (59%)
Br
Br

+

N
Ts
5
6
7
8

X = F:
X = Cl:
X = Me:
X = OMe:

X
6e (32%)
6f (26%)
6g (24%)
6h (48%)

N
X
8e (54%)
8f (62%)
8g (50%)
8h (40%)
Br

9

a

Ph
N
Ts
6i (16%)

+

Br

Ph
N
8i (76%)

Based on recovered starting material.

Control experiments suggest that formation of dibrominated imines 8 occurs after the pyrrolidine cyclization. For isolated products 6e and 6i, treatment with dibromo hydantoin 7 led to formation of compounds 8e and 8i, respectively, upon complete consumption of starting materials. Pyrrolidines 6 and dibromo imines 8 could be separated by column chromatography and isolated in
pure form. The formation of the latter is unexpected, but has some relation to an overoxidation reaction in the corresponding Hofmann-Löffler reactions under the Suárez conditions.13 In any case, compounds 8a,d-i may be interesting synthons for future organic
transformations.

3

Scheme 2. NIS-promoted Hofmann-Löffler reaction: scope.
O
NI
O
R'O2S
N
H

R

NIS (9) (2 equiv)

R R
R''

5a-c,e-q

Ph

Ph
Ph
Ph

Ph
N
Ts

N
Ts

N
Ms

6a (95%)

R''
N
SO2R'
6a-c,e-q

CH2Cl2, 5 h, rt
visible light exposure

Ph
Ph

N
Ts

R

6c (53%)

6b (80%)

6e (99%)

F

Ph
N
Ts

N
Ts

6f (65%)

Cl

N
Ts

6g (99%)

N
Ts

N
Ts
Ph

6j (95%)

N
Ts

Ph
+

Ph
N
Ts

6n/6n' (1/1, 99%)

Me

N
Ts

Ph
N
Ts

6k (99%)

N
Ts
6o (99%)

OMe 6i (99%)

6h (95%)

Ph
Ph

6l (99%)

N
Ts
6p (99%)

NMs
N
Ts

Ph

6m (99%)

N
Ts

Ph

6q (25%)

We then finally turned to N-iodo succinimide (NIS, 9) as the halogen promoter. This reagent enabled completely selective transformations of all investigated tosylamides 5 into the corresponding pyrrolidines 6 (Scheme 2). The reactions proceed readily in the
presence of visible light and at room temperature. Isolated yields are in the range of 53-99%, with several of the reactions yielding
quantitative product formation. In the latter cases, products are obtained in analytically pure form directly after work-up. Examples
include tolerance of common substituents as in 6e-h and 6j. The reaction works equally well for non-substituted chain (6k), for
cyclization at the dibenzylic position as in product 6l and for aminal synthesis (6m). In agreement with a radical process, acyclic
stereocontrol was not successful resulting in the formation of a 1:1-mixture of diastereoisomers for 6n/6n’. In contrast, annelation
led to quantitative yields of single diastereomeric products 6o and 6p, respectively. In contrast to benzylic C-H amination, related
aliphatic positions led to conversion at a reduced rate and resulted in lower yields as demonstrated for the homobenzylic amination
in 6q (25%, 99% based on recovered starting material). Given the commercial availability of NIS and its rather economic price, this
reagent appears as an optimum promoter for the iodine-mediated Hofmann-Löffler reaction under neutral conditions and with visible light as the only initiator being required. It is noteworthy that for the reactions with quantitative product formation, aqueous
work-up led to complete removal of succinimide and thus provided products 6 in pure form without any requirement for further
purification. All reactions are characterized by complete chemoselectivity leading to pyrrolidine formation without any overoxidation/iodination being observed in any case.
The corresponding 1,3-diiodo 2,2-dimethyl-hydantoin 10 was also successful in the transformation of 5e and 5p into 6e and 6p,
respectively. However, as it represents a significantly more expensive approach it was not investigated further in detail.

4

In cases with less effective cyclization under visible light conditions, exposure of the reaction mixture to LED irradiation results
in significantly better reaction yields. This was demonstrated for the two cyclization reactions of products 6d,r (Scheme 3). In line
with the previous determination of an optimum irradiation at 410 nm wave-length, conducting the reaction in the presence of violet
LED offered the best reaction conditions.

Scheme 3. LED-initiated Hofmann-Löffler reaction.

H

Ns
N

Ph
5d

H

Ns
N

NIS (9) (1.5 equiv)

Ts
N

Ph
CH2Cl2, 5 h, rt
LED exposure

6d:
79% (LED 400 nm)
58% (LED 475 nm)
49% (LED 510 nm)
Ts
N

NIS (9) (1.5 equiv)
OMe
5r

OMe
CH2Cl2, 5 h, rt
LED exposure

6r:
60% (LED 400 nm)
43% (LED 475 nm)
40% (LED 510 nm)

The mechanism is depicted in Figure 1 with 5a as the representative substrate and is reminiscent of our earlier catalytic transformation.8 It relies on the formation of the key intermediate A that is generated from the starting material 5a by iodination with NIS
under concomitant release of succinimide.
Ts
NH
Ph

I

N
Ts

Ph
HI

6a

Ts
N

NIS

H
Ph

5a

Ts
NH

Ts
N

Ts
N
I
Ph

O
A
N-H

Ph
C

D

Ph
initiation:

B

h!, - I

O

Figure 1. Mechanistic scenario for NIS-promoted Hofmann-Löffler reaction.
Visible light-induced homolytic cleavage initiates a radical chain reaction comprising nitrogen and carbon centered radical stages
B and C that ultimately generates the benzylic iodine D. Nucleophilic substitution generates the final pyrrolidine product 6a. Since
the radical chain reaction is identical to the one involved in the related catalytic variant, it requires the same optimum wavelength of
410 nm or violet LED. No conversion is observed in the absence of light (dark laboratory).11
Finally, the prospects of the present reaction may go beyond the common C-H amination. For compound 11, conditions could be
developed that allow promoting an allylic amination reaction14 to proceed without consumption of the free double bond (Scheme 4).
Mechanistically, this transformation should generate an allylic radical comparable to the benzylic one from intermediate A followed
by amination of the subsequent allylic iodide. Interestingly, blue LEDs provided the best irradiation conditions for the present transformation.

5

Scheme 4. NIS-promoted allylic amination.

Ts

9 (4 equiv)

N
H
11

CH2Cl2, 18 h, rt
475 nm (blue LED)

N
Ts
12 (50%)

In summary, we have developed convenient synthetic conditions for an iodine-mediated Hofmann-Löffler reaction. The scope
compares well with alternative protocols. The employed iodine reagent NIS is significantly more economic than related reagent
combinations that include the requirement for hypervalent iodine reagents.

ASSOCIATED CONTENT
Supporting Information
Full experimental details and characterization data for new compounds (pdf format). This material is available free of charge via the Internet at http://pubs.acs.org

AUTHOR INFORMATION
Corresponding Author
* Email address: kmuniz@iciq.es.

Author Contributions
The manuscript was jointly written by all authors. All authors have given approval to the final version of the manuscript.

Notes
The authors declare no competing financial interest.

ACKNOWLEDGMENT
Financial support for this project was provided from the Spanish Ministry for Economy and Competitiveness (CTQ2011-25027 and
CTQ2013-50105-EXP grants to K. M., and Severo Ochoa Excellence Accreditation 2014-2018 to ICIQ, SEV-2013-0319), the ICIQ Summer Fellow Programme (grants to C.Q. O’B. and P. F.) and Cellex-ICIQ Program (fellowship to C. M.).

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6

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O
NI
R'O2S
N
H

O

R R

NIS (2 equiv)
Ar
CH2Cl2, 5 h, rt
visible light or violet LED

R
R
Ar
N
SO2R'
17 examples
53-99%

7