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Multiple Halogenation of Aliphatic C-H Bonds within the HofmannLöffler Manifold
Estefanía Del Castillo,[a,+] Mario D. Martínez,[a,+] Alexandra E. Bosnidou,[a] Thomas Duhamel,[a,b] Calvin
Q. O´Broin,[a] Hongwei Zhang,[a] Eduardo C. Escudero-Adán,[a] Marta Martínez-Belmonte,[a] Kilian
Muñiz*[a,c]
Abstract:
An
innovative
approach
to
position-selective
polyhalogenation of aliphatic hydrocarbon bonds is presented. The
reaction proceeds within the Hofmann-Löffler manifold with amidyl
radicals as the sole mediators to induce selective 1,5- and 1,6hydrogen atom transfer followed by halogenation. Multiple
halogenation events of up to four innate C-H bond functionalizations
have been accomplished. The broad applicability of this new entry into
polyhalogenation and the resulting synthetic possibilities are
demonstrated for a total of 27 different examples including mixed
halogenations.

Polyhalogenated aliphatic compounds represent fascinating
molecules with important properties that have triggered significant
interest from various fields of the chemical sciences. Nature has
made use of this particular motif to a large extent with the family
of polyhalogenated natural products, which have emerged as an
important class of natural marine toxins.[1] As a result, recent
synthetic efforts have elaborated on the polyhalogenation theme.
Apart from conventional functional group transformation,
commonly employed elegant approaches to this class of
compounds rely on allylic and olefinic halogenation strategies.[2,3]
An attractive alternative would consist of direct halogenation of
ubiquitous aliphatic C-H bonds. While attempts toward such
challenging
endeavors
have
been
undertaken
for
monohalogenation,[4] the synthetic concept of predictable multiple
C-H halogenation has remained notably unaddressed so far. A
possible synthetic realization may derive from the application of
suitable functional groups to direct the C-H halogenation event.
Within this aim, radical processes appear particularly promising.[5]
Amidyl radicals[6] are known to promote such C-H halogenation
as the key step in photochemically initiated Hofmann-Löffler
reactions.[7] Recent improvements by several groups have
provided mild reaction conditions based on the stoichiometric use
of electrophilic halide sources.[7,8] Our recent efforts to develop
new protocols for the Hofmann-Löffler reaction have identified
manifolds that are catalytic in halogen.[9] Their most important

[a]

[b]

[c]
[+]

E. Del Castillo, Dr. M. D. Martínez, A. E. Bosnidou, T. Duhamel, C.
Q. O’Broin, Dr. H. Zhang, Dr. E. C. Escudero-Adán, Dr. M. MartínezBelmonte, 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.
Supporting information for this article is given via a link at the end of
the document.

feature is the accelerated final C-N bond formation in order to
regenerate the halide catalyst. To accomplish with the aim of
multiple halogenation, the NH group must remain intact in order
to re-engage in the C-H halogenation. Unlike monofunctionalization, the anticipated multiple C-H functionalization
needs to address several challenges (Figure 1). At the outset, the
required N-halogenation of the substrate proceeds with an
external halogenating agent [N]X. The photochemically generated
amidyl radical provides the required selectivity through
intramolecular selection of accessible C-H bonds guided by 1,5[8]
or 1,6-hydrogen atom transfer[10] (HAT). In Hofmann-Löffler
reactions, the initial C-H halogenation is usually followed by
nucleophilic amination to the heterocyclic product, which is
commonly a pyrrolidine. Provided that another N-H halogenation
will kinetically outperform the nucleophilic amination, multiple
aliphatic C-H bond decoration including the depicted vicinal (from
sequential 1,5- and 1,6-HAT) and geminal (from two-fold 1,5- or
1,6-HAT) dihalogenation become available. Additional structural
motifs arise from branched or cyclic hydrocarbon substrates. As
to an additional challenge, a potential background reaction arising
from competing amidyl radicals from the halogenating agent itself
must be avoided, since the resulting non-guided C-H
functionalization process will result in unselective halogenation.

H

H

H

R'

H

[N]R
H

H

H

hυ
(R = X)

H

H

[N]

from
1,6-HAT

X

H

repeated guided C-Hfunctionalization:
selective

H

H

R'

H

[N]H
X

cyclization

from
1,5-HAT

H

X

H

[N]H
H

R'
H

H

R'

R-X

non-guided C-Hfunctionalization:
unselective

H

guided C-Hfunctionalization:
selective

R=X

hυ
R-H

H

[N]
H

R=H

[N]X

H

R'

H

vicinal dihalogenation

[N]

R'

H

[N]H
H

X X H
from
1,5-HAT

geminal dihalogenation

Figure 1. Strategy for multiple carbon-halogen bond formation via consecutive
Hofmann-Löffler reaction. [N]X = halogenating agent. Representative
hydrogens depicted for each methylene group.

As a result, multiple C-H halogenation appears challenging at the
outset, since only pertinent kinetic dominance of the guided
pathway from Figure 1 will ensure the required selectivity. Based
on these considerations we screened possible conditions for
multiple halogenation reactions and chose the 2-adamantane
derivatives 1a-e as substrates targeting tertiary C-H bonds
(Scheme 1). Halogenated hydantoins 2a-c were chosen as
halogenating agents.[11,12] Under photochemical initiation, in situ
formed N-halogenated derivatives engaged cleanly in the
expected C-H halogenation reactions for X = I, Br.

mesylamides generated the expected brominated products,
which were isolated as dibromide 3e and tribromide 3f. The
former is generated through the common 1,5-HAT, while the latter
is formed via sequential 1,5- and 1,6-HAT. Potentially competing
non-guided bromination of the remaining tertiary C-H bonds via
free radical halogenation directly through reagents 2a,b was
never observed indicating the exclusive involvement of innate
Hofmann-Löffler pathways.[14] These reactions provide the
selectivity proof of principle for the kinetic dominance of innate
amidyl-radical guided multiple C-H halogenation.
In a related manner, recently introduced N-alkyl sulfamate
groups[10] could be employed for this purpose (Scheme 1). While
halogenation with N-alkyl sulfamates have been reported,[10] their
use in polyhalogenation is again entirely without precedence.
These groups promote the expected preferential 1,6-HAT with
visible light as the only initiator and, consequently, substrate 1e
provided the selectively diiodinated and dibrominated products 3g
and 3h. Applying sequential halogenation reactions with (i) 2c and
(ii) 2a or 2b allowed for the introduction of two different halide
groups as demonstrated for 3i and 3j. To the best of our
knowledge, these are the first examples of defined mixed
dihalogenation from Hofmann-Löffler reaction conditions.

Scheme 1. Multiple directed halogenation at the adamantine core: reaction
scope. [a] With 2a as reagent. [b] i) 2c, CH2Cl2, ii) C6H6, black LEDs, iii) 2a-b,
CH2Cl2, visible light. Yields refer to the overall 3-step-process.

The reaction outcome depends on the length of the alkyl chain
spacer. For ethylenylamides clean diiodination products 3a,b
were observed.[13] The position-selective C-H halogenation draws
its origin from innate 1,5-HAT via N-centered radicals of the
Hofmann-Löffler pathway. In contrast, the homologous
propylenylamides provide a sufficiently fast cyclization after the
initial iodination leading to selective formation of the pyrrolidine
products 3c,d. Such a cyclization should be disfavored for the less
reactive bromination products. Indeed, the corresponding

Scheme 2. Additional halogenation at the adamantane core.
the overall 2-step-process from 1a.

[a]

Yields refer to

Attempts to generate such compounds through alternative
halogen exchange reactions did not materialize. For example,
treatment of crude 3a with hydantoins 2b,c lead to exclusive
formation of the chlorinated and brominated pyrrolidines 4a,b
(Scheme 2). A control experiment with the N-methylated

derivative of 3a provided halogen exchange as well, indicating
that the potential involvement of a sulfonamide amidyl radical is
not the case.[15] Instead, iodine oxidation[16] to iodine(III) A should
be involved in these transformations. This would generate an
iodine leaving group for pyrrolidine formation to B, as previously
demonstrated[9a] and corroborated with a control experiment with
PhICl2.[15] Oxidation of the remaining iodine with liberated IX[17]
would initiate iodide extrusion to cationic C and subsequent
nucleophilic halogenation[16a,b,18] thus provides the halogenated
pyrrolidines 4a,b within a unique oxidatively induced
transformation of a diiodide.
Interestingly, the corresponding unsaturated substrate 1f
undergoes unprecedented diiodination with 2a to the
corresponding product 3k. Mechanistically, an unprecedented
sequence of two Hofmann-Löffler reactions may be involved.
After the initial iodination, non-bonded interactions should initiate
the known double bond isomerization[19] under the present
reaction conditions followed by a second Hofmann-Löffler
iodination.[15] Alternative allylic functionalization events appear
less plausible due to the lack of stabilization of the putative allylic
radical since the rigid adamantyl core would induce orthogonality
between the radical and the alkene p-system. With an excess of
hydantoin, double bond oxidation takes place leading to the
formation of the triiodinated aziridine 3l. The selective aziridine
formation over the azetidine is believed to originate from steric
preferences. In fact, chlorination of 1f leads to clean fourmembered ring formation.
Given the observed higher stability in the cases of the brominated
adamantyl derivatives and the general interest in brominated
organic compounds as important synthons,[20] polybromination
was investigated further for additional alicyclic substrates
(Scheme 3). For indane-derived substrates 5a-c, the 2ethylenylamides induce selective 1,5-HAT at the benzylic
positions demonstrating that dual halogenation is also possible
involving methylene groups. Concomitant cyclization takes place
to provide the annelated pyrrolidines 6a-c as single
diastereoisomers. The same occurs for the related
tetrahydronaphthalene substrates, which display additional
selective C-H bromination from 1,5- and 1,6-HAT, products 6e,f,
which are again formed in a completely diastereoselective
manner. In case of a higher excess of hydantoin 2b, dibrominated
ketone 6d is obtained as a single diastereomer, in which the
carbonyl is formed from hydrolysis of the geminal dibromination
product.[8d,21] Use of a longer propyl spacer provided the
tribrominated products 6g,h without cyclization. Control
experiments indicate again that free non-guided radical
bromination[22c-e] is not competitive with the Hofmann-Löffler
reactions in the cases for 6a-h.[15] While all products 6a-h form in
high yields, their tendency for decomposition reduced the isolated
yields.
In view of the interesting formation of 6d, we next sought to
stabilize the geminal dibromination motif and to this end decided
to choose a more flexible cycloheptane ring system (Scheme 4).
For mesylated and tosylated derivatives 7a,b the expected
selective tribromination at the homobenzylic position was
obtained. This outcome corresponds to three independent 1,5HAT processes and exemplifies the potential of sequential
Hofmann-Löffler reactions. For the first time, this process has thus
been employed for the formation of a geminal dihalogenation
motif.[23] In contrast, lesser stabilized triflamide and

trifluoroacetamide amidyl radicals[6b] do not promote halogenation
via the amidyl pathway and due to free radical benzylic
bromination only low yields are obtained for products 8c,d. The
outcome for 8a,b suggests that loss of rigidity in the substrate
favors multiple halogenation.

Scheme 3. Multiple halogenation of cyclic apliphatic C-H bonds. [a] With 5 equiv.
2b.

Scheme 4. Selectivity in multiple C-H amination. Hofmann-Löffler vs. free
radical pathways.

To further explore this context, acyclic substrates were
investigated. In contrast to cyclic aliphatic substrates, their acyclic
counterparts perform less efficiently for sulfonamides. An
exception was encountered for acyclic sulfonamide 9, which
under reported conditions[23] underwent dihalogenation followed
by amination at the more activated benzylic position to
diastereomerically pure piperidine 10 (Scheme 5). Importantly, Nmethyl sulfamates 11a-d could be applied for amidyl radicalpromoted sequential di- and tribromination within a HofmannLöffler pathway. These reactions again rely on their common 1,6HAT,[10] and provide selective dibromination for symmetric 11a
and for terpene derivative 11b. For the latter, the remote tertiary

C-H bond remains intact due to the absence of any free radical
pathway. The reaction is not restricted to tertiary C-H bonds, and
provides exclusive double bromination at the benzylic and tertiary
positions of 11c, respectively. Furthermore, in the presence of an
excess of hydantoin 2b, multiple bromination of 11d accesses
tribrominated 12d with a geminal dibromination motif.

[2]

[3]

[4]

[5]
[6]
[7]
[8]

Scheme 5. Multiple halogenation of acyclic apliphatic C-H bonds.
equiv. 2b.

[a]

With 4

In summary, we have pioneered conditions that allow for multiple
position-selective C-H halogenation reactions within the
Hofmann-Löffler manifold. These reactions provide access to
various new structures, which derive from unprecedented mixed
dihalogenation and polyhalogenation of up to four selective C-H
oxidation events and geminal dihalogenation. These results
render amidyl radicals important tools for sequential innate C-H
halogenation and overall streamline C-H halogenation strategy.

[9]

[10]

[11]

[12]

Acknowledgements
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 20142018 to ICIQ, SEV-2013-0319). H. Z. thanks ICIQ-COFUND
Program for a postdoctoral fellowship. The authors are grateful to
the CERCA Program of the Government of Catalonia and to
COST Action CA15106 “C–H Activation in Organic Synthesis
(CHAOS)”.
Keywords: Bromine • C-H Functionalization • Hofmann-Löffler
Reaction • Iodine • Polyhalogenation
[1]

a) W.-j. Chung, C. D. Vanderwal, Angew. Chem. 2016, 128, 4470;
Angew. Chem. Int. Ed. 2016, 55, 4396; b) W.-j. Chung, C. D. Vanderwal,
Acc. Chem. Res. 2014, 47, 718; c) C. Nilewski, E. N. Carreira, Eur. J.
Org. Chem. 2012, 1685; d) T. Umezawa, F. Matsuda, Tetrahedron Lett.
2014, 55, 3003.

[13]

[14]
[15]
[16]

[17]
[18]
[19]

a) A. J. Cresswell, S. T.-C. Eey, S. E. Denmark, Angew. Chem. 2015,
127, 15866; Angew. Chem. Int. Ed. 2015, 54, 15642; b) A. M. Arnold, A.
Ulmer, T. Gulder, Chem. Eur. J. 2016, 22, 8728; c) U. Henneke, Chem.
Asian J. 2012, 7, 456.
a) Y. Tan, S. Luo, D. Li, N. Zhang, S. Jia, Y. Liu, W. Qin, C. E. Song, H.
Yan, J. Am. Chem. Soc. 2017, 139, 6431; b) K. C. Nicolaou, N. L.
Simmons, Y. Ying, P. M. Heretsch, J. S. Chen, J. Am. Chem. Soc. 2011,
133, 8134; c) A. J. Cresswell, S. T.-C. Eey, S. E. Denmark, Nature Chem.
2015, 7, 146.
a) R. K. Quinn, Z. A. Konst, S. E. Michalak, Y. Schmidt, A. R. Szklarski,
A. R. Flores, S. Nam, D. A. Horne, C. D. Vanderwal, E. J. Alexanian, J.
Am. Chem. Soc. 2016, 138, 696; b) A. Artaryan, A. Mardyukov, K.
Kulbitski, I. Avigdori, G. A. Nisnevich, P. R. Schreiner, M. Gandelman, J.
Org. Chem. 2017, 82, 7093; c) S. H. Combe, A. Hosseini, L. Song, H.
Hausmann, P. R. Schreiner, Org. Lett. 2017, 19, 6156; d) J. Ozawa, M.
Kanai, Org. Lett. 2017, 19, 1430; e) R. Y. Zhu, T. G. Saint-Denis, Y. Shao,
J. He, J. D. Sieber, C. H. Senanayake, J.-Q. Yu, J. Am. Chem. Soc. 2017,
139, 5724; f) T. Liu, M. C. Myers, J.-Q. Yu, Angew. Chem. 2017, 129,
312; Angew. Chem. Int. Ed. 2017, 56, 306.
A. Studer, D. P. Curran, Angew. Chem. 2016, 128, 58; Angew. Chem.
Int. Ed. 2016, 55, 58.
M. D. Kärkäs, ACS Catal. 2017, 7, 4999; b) D. Sakic, H. Zipse, Adv.
Synth. Catal. 2016, 358, 3983.
a) M. E. Wolff, Chem. Rev. 1963, 63, 55; b) R. S. Neale, Synthesis 1971,
1.
Recent examples: a) J. Long, X. Cao, L. Zhu, R. Qiu, C.-T. Au, S.-F. Yin,
T. Iwasaki, N. Kambe, Org. Lett. 2017, 19, 2793; b) E. A. Wappes, K. M.
Nakafuku, D. A. Nagib, J. Am. Chem. Soc. 2017, 139, 10204; c) N. R:
Paz, D. Rodríguez-Sosa, H.Valdés, R. Marticorena, D. Melián, M. B.
Copano, C. C. González, A. Herrera, Org. Lett. 2015, 17, 2370; d) C. Q.
O’Broin, P. Fernández, C. Martínez, K. Muñiz, Org. Lett. 2016, 18, 436.
a) C. Martínez, K. Muñiz, Angew. Chem. 2015, 127, 8405; Angew. Chem.
Int. Ed. 2015, 54, 8287; b) P. Becker, T. Duhamel, C. J. Stein, M. Reiher,
K. Muñiz, Angew. Chem. 2017, 129, 8117; Angew. Chem. Int. Ed. 2017,
56, 8004; c) P. Becker, T. Duhamel, C. Martínez, K. Muñiz, Angew.
Chem. 2018, 130, 5262; Angew. Chem. Int. Ed. 2018, 57, 5166.
Recent examples: a) M. A. Short, J. M. Blackburn, J. L. Roizen, Angew.
Chem. 2018,130, 302; Angew. Chem. Int. Ed. 2018, 57, 296; b) S.
Sathyamoorthi, S. Banerjee, J. Du Bois, N. Z. Burns, R. N. Zare, Chem.
Sci. 2018, 9, 100.
S. H. Combe, A. Hosseini, L. Song, H. Hausmann, P. R. Schreiner, Org.
Lett. 2017, 19, 6156; b) A. Artaryan, A. Mardyukov, K. Kulbitski, G. A.;
Nisnevich, P. R. Schreiner, M. Gandelman, J. Org. Chem. 2017, 82,
7093.
For alternative approaches to amidyl-mediated C-H halogenation: a) E.
M. Dauncey, S. P. Morcillo, J. J. Douglas, N. S. Sheikh, D. Leonori,
Angew. Chem. Int. Ed. 2018, 57, 744; b) V. A. Schmidt, R. K. Quinn, A.
T. Brusoe, E. J. Alexanian, J. Am. Chem. Soc. 2014, 136, 14389; c) R.
K. Quinn, Z. A. Könst, S. E: Michalak, Y. Schmidt, A. R. Szklarski, A. R.;
Flores, S. Nam, D. A. Horne, C. D. Vanderwal, E. J. Alexanian, J. Am.
Chem. Soc. 2016, 138, 696.
X-ray crystallographic data for compounds 3a-c, 3f, 3g, 3k-m, 6b, 6f and
10 have been deposited with the Cambridge Crystallographic Data
Centre database (http://www.ccdc.cam.ac.uk/) under codes CCDC
1838889
 (3a), CCDC 1838890
(3b), CCDC 1838891
(3c), CCDC
1838892
(3f), CCDC 1838893
(3g), CCDC 1838894 (3l), CCDC
1838895
(3m), CCDC 1838896
(6b), CCDC 1838897
(6f), CCDC
1838898
(3k), CCDC 1838899
(10).
In contrast, 1-adamantyl derivatives generate product mixtures.[15]
Please see Supporting Information for further details.
a) J. Thiele, W. Peter, Chem. Ber. 1905, 38, 2842; b) J. Thiele, J.; W.
Peter, Liebigs Ann. Chem. 1909, 369, 149; c) F. M. Beringer, H. S.
Schultz, J. Am. Chem. Soc. 1955, 77, 5533.
A. G. Yurchenko, N. I. Kulik, V. P. Kuchar, V. M. Djakovkaja, V. F. Baklan,
Tetrahedron Lett. 1986, 27, 1399.
a) E. J. Corey, W. J. Wechter, J. Am. Chem. Soc. 1954, 76, 6040; b) K.
B. Wiberg, W. E. Pratt, M. G. Matturo, J. Org. Chem. 1982, 47, 2720.
Y. Ohga, K. Takeuchi, J. Phys. Org. Chem. 1993, 6, 293.

[20]
[21]
[22]

[23]
[24]

I. Saikia, A. J. Borah, P. Phukan, Chem. Rev. 2016, 11, 6837.
M. Katohgi, H. Togo, K. Yamaguchi, Y. Masataka, Tetrahedron 1999, 55,
14885.
a) C. Djerassi, Chem. Rev. 1948, 48, 271; b) P. S. Skell, J. C. Day, Acc.
Chem. Res. 1978, 11, 381; c) K. Shibatomi, Y. Zhang, H. Yamamoto,
Chem. Asian J. 2008, 3, 1581; d) M. Movassaghi, M. A. Schmidt, Angew.
Chem. 2007, 119, 3799; Angew. Chem. Int. Ed. 2007, 46, 3725; e) D.
Domínguez, R. J. Ardecky, M. P. Cava, J. Am. Chem. Soc. 1983, 105,
1608.
During review, a complimentary dihalogenation process was reported: E.
A. Wappes, A. Vanitcha, D. A. Nagib, Chem. Sci. 2018, 9, 4500.
H. Zhang, K. Muñiz, ACS Catal. 2017, 7, 4122.

Entry for the Table of Contents

COMMUNICATION
More than one at a time! Multiple
site-selective C-H halogenation events
can be accomplished as an innovative
variant of the classic Hofmann-Löffler
reaction using halogenated
hydantoins as oxidants and halide
source. The scope includes cyclic and
linear hydrocarbons, as well as vicinal
and geminal halogenation.

Estefanía Del Castillo, Mario D.
Martínez, Alexandra E. Bosnidou,
Thomas Duhamel, Calvin Q. O´Broin,
Hongwei Zhang, Eduardo C. EscuderoAdán, Marta Martínez-Belmonte, Kilian
Muñiz*

O

H

XN

[N]

NX

O
H
X = I, Br, Cl
via
[N]: Nitrogen group:       1,5/1,6-HAT

X2
X1

amidyl radical precursor

Scope for cyclic and linear C-H bonds
Site-selective multiple halogenation
Mixed halogenation

Page No. – Page No.
[N]

Multiple Halogenation of Aliphatic CH Bonds within the Hofmann-Löffler
Manifold