N-iodosuccinimide-promoted hofmann-l?ffler reactions of sulfonimides under visible light

Article abstract of DOI:10.1021/acs.orglett.5b03476

Conditions for an attractive and productive protocol for the position-selective intramolecular C-H amination of aliphatic groups (Hofmann-L?ffler reaction) are reported employing sulfonimides as nitrogen sources. N-Iodosuccinimide is the only required pro

Full text of DOI:10.1021/acs.orglett.5b03476

Letter
pubs.acs.org/OrgLett
̈
N‑Iodosuccinimide-Promoted Hofmann−Loffler Reactions of
Sulfonimides under Visible Light
Calvin Q. O’Broin,† Patricia Fernandez,† Claudio Martínez,† and Kilian Muniz*,†,‡
†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
́
̃
S
* Supporting Information
ABSTRACT: Conditions for an attractive and productive protocol
for the position-selective intramolecular C−H amination of aliphatic
groups (Hofmann−Loffler 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.
he intramolecular C−H amination of aliphatic groups has
a stoichiometric promoter. Such a reaction would serve as an
Trecently attracted significant interest from the synthetic important addition to the existing protocols for Hofmann−
Loffler reactions.
̈
community. Major work has focused on the identification of
suitable transition-metal catalysts to provide the aforemen-
tioned transformation.1 Directed evolution of metalloproteins
has recently emerged as a complementary approach.2 An
alternative consists of the use of small organocatalysts3 as
nonmetallic promoters, which, due to their capability to avoid
metal contamination, is of major importance to fields such as
biological and medicinal synthesis.
Our investigation on a halide-mediated Hofmann−Loffler
̈
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
From a historical perspective, the halide-mediated C−N
bond formation at nonactivated hydrocarbons was discovered
over a century ago and is well established as the Hofmann−
Scheme 1. Chloride-Mediated Intramolecular C−H
Functionalization
Loffler 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 base-mediated pyrrolidine formation. A useful
modification providing significantly milder reaction conditions
was introduced by Suar
́
ez,5 who reported that Hofmann−
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-chlorosuccinimide
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).
Loffler-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 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 and 2). In contrast, use of conventional brominating reagents
such as N-bromosuccinimide (3) and N-bromophthalimide (4)
led to a clean pyrrolidine formation. Initially, substrate 5a could
be cyclized to 6a in 40% yield using a single equivalent of 3
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−
Loffler reaction, provided that the iodine concentration is
̈
maintained at a sufficient level to perpetuate the two
intertwined catalytic cycles. However, the permanent require-
ment 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
Received: December 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03476
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Organic Letters
Table 1. NBS/NBP-Promoted Hofmann−Loffler Reaction
Letter
Table 2. Oxidation of Alkylsulfonamides 5 with Reagent 7
̈
entry
substrate
reagent
x
conv (%)
1
2
3
4
5a
5b
5a
5a
5a
5a
5a
5b
5a
5b
KBr/NaClO2
0.1/2
KBr/NaClO2
0.1/2
3
3
3
4
4
4
4
4
1
2
2
2
2
2
3
3
40
52
56
55
55
47
66
81
a
5
6
a
7
8
9
10
a
Under irradiation (400 nm monochromatic wavelength).
(entry 3). Increasing the amount of 3 to 2 equiv 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 equiv 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−Loffler 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.
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
a
Based on recovered starting material.
reactions under the Suar
́
ez conditions.13 In any case,
compounds 8a,d−i may be interesting synthons for future
organic transformations.
We then finally turned to N-iodosuccinimide (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 workup. Examples include tolerance of
common substituents as in 6e−h and 6j. The reaction works
equally well for nonsubstituted 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
overoxidation reaction in the corresponding Hofmann−Loffler
̈
B
DOI: 10.1021/acs.orglett.5b03476
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. NIS-Promoted Hofmann−Loffler Reaction:
Scheme 3. LED-Initiated Hofmann−Loffler Reaction
̈
̈
Scope
Figure 1. Mechanistic scenario for NIS-promoted Hofmann−Loffler
̈
reaction.
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 economical price, this reagent appears as an optimum
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
promoter for the iodine-mediated Hofmann−Loffler 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 workup 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-dimethylhydantoin 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.
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 wavelength, conducting the
reaction in the presence of violet LED offered the best reaction
conditions.
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.
Scheme 4. NIS-Promoted Allylic Amination
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.
In summary, we have developed convenient synthetic
conditions for an iodine-mediated Hofmann−Loffler reaction.
The scope compares well with alternative protocols. The
̈
employed iodine reagent NIS is significantly more economic
C
DOI: 10.1021/acs.orglett.5b03476
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Organic Letters
Letter
Chemistry. Modern Developments in Organic Synthesis. In Topics in
Current Chemistry; Wirth, T., Ed.; Springer: Berlin, 2003; Vol. 224.
(c) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(d) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523.
(e) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(7) Fan, R.; Pu, D.; Wen, F.; Wu, J. J. Org. Chem. 2007, 72, 8994.
than related reagent combinations that include the requirement
for hypervalent iodine reagents.
ASSOCIATED CONTENT
* Supporting Information
■
S
(8) Martínez, C.; Muniz, K. Angew. Chem., Int. Ed. 2015, 54, 8287.
̃
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03476.
(9) In addition, recent progress has identified hypervalent iodine
catalysis for C−H amination: Zhu, C.; Liang, Y.; Hong, X.; Sun, H.;
Sun, W.-Y.; Houk, K. N.; Shi, Z. J. Am. Chem. Soc. 2015, 137, 7564.
(10) Qin, Q.; Yu, S. Org. Lett. 2015, 17, 1894.
Full experimental details and characterization data for
new compounds (PDF)
(11) See the Supporting Information for details.
(12) Chavez, P.; Kirsch, J.; Hovelmann, C. H.; Streuff, J.; M.
̈
Martínez-Belmonte, M.; Escudero-Adan
Chem. Sci. 2012, 3, 2375.
(13) Paz, N. R.; Rodríguez-Sosa, D.; Valdes
Melian, D.; Copano, M. B.; Gonzalez, C. C.; Herrera, A. J. Org. Lett.
2015, 17, 2370.
(14) For alternative metal-free allylic amination: (a) Souto, J. A.;
́
, E. C.; Martin, E.; Muniz, K.
̃
AUTHOR INFORMATION
Corresponding Author
■
́
, H.; Marticorena, R.;
́
́
*E-mail: kmuniz@iciq.es.
Notes
The authors declare no competing financial interest.
Zian, D.; Muniz, K. J. Am. Chem. Soc. 2012, 134, 7242. (b) Sun, J.;
̃
Wang, Y.; Pan, Y. J. Org. Chem. 2015, 80, 8945. (c) Wei, Y.; Liang, F.
S.; Zhang, X. T. Org. Lett. 2013, 15, 5186. (d) Zhang, X.; Wang, M.; Li,
P.; Wang, L. Chem. Commun. 2014, 50, 8006.
ACKNOWLEDGMENTS
■
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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