An Iodine-Catalyzed Hofmann-L?ffler Reaction

Article abstract of DOI:10.1002/anie.201501122

Iodine reagents have been identified as economically and ecologically benign alternatives to transition metals, although their application as molecular catalysts in challenging C-H oxidation reactions has remained elusive. An attractive iodine oxidation catalysis is now shown to promote the convenient conversion of carbon-hydrogen bonds into carbon-nitrogen bonds with unprecedented complete selectivity. The reaction proceeds by two interlocked catalytic cycles comprising a radical chain reaction, which is initiated by visible light as energy source. This unorthodox synthetic strategy for the direct oxidative amination of alkyl groups has no biosynthetic precedence and provides an efficient and straightforward access to a general class of saturated nitrogenated heterocycles.

Full text of DOI:10.1002/anie.201501122

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501122
German Edition: DOI: 10.1002/ange.201501122
Synthetic Methods
An Iodine-Catalyzed Hofmann–Lçffler Reaction**
Claudio Martínez and Kilian MuÇiz*
Dedicated to Professor Antonio Echavarren on the occasion of his 60th birthday
Abstract: Iodine reagents have been identified as economically
and ecologically benign alternatives to transition metals,
although their application as molecular catalysts in challenging
À
C H oxidation reactions has remained elusive. An attractive
iodine oxidation catalysis is now shown to promote the
convenient conversion of carbon–hydrogen bonds into
carbon–nitrogen bonds with unprecedented complete selectiv-
Scheme 1. Hofmann–Lçffler reactions: classical reaction conditions
ity. The reaction proceeds by two interlocked catalytic cycles
comprising a radical chain reaction, which is initiated by visible
light as energy source. This unorthodox synthetic strategy for
the direct oxidative amination of alkyl groups has no
biosynthetic precedence and provides an efficient and straight-
forward access to a general class of saturated nitrogenated
heterocycles.
(top) and Suµrez modification (bottom).
Although a significantly more desirable process from
a synthetic standpoint, a variant catalytic in iodine has not yet
been realized. Such a conceptually novel reaction is of
fundamental interest, since it would amount to a catalytic
À
remote C H amination of nonfunctionalized hydrocarbons
N
itrogen–halogen bonds have a long history in the synthesis
based on an iodine derivative as a benign non-metallic
catalyst. Molecular catalysis based on iodine[4] has recently
been considered an attractive, mechanistically distinct alter-
native to the far more common transition-metal catalysis,
of pyrrolidines and related heterocyclic structures through the
amination reaction of a distant carbon–hydrogen bond.[1] For
such approaches with preformed chlorinated and brominated
amines, the transformation is known as the Hofmann–Lçffler
reaction (Scheme 1, top). Despite the great attractiveness of
such an approach for the synthesis of aminated five-mem-
bered-ring compounds, the required rather harsh conditions
have prevented wider application.[1a,b] Modifications of the
common protocol include the in situ formation of the
corresponding N-iodinated amides through the combined
use of molecular iodine and a large excess of commonly
available iodine(III) reagents[2,3] with the requirement of an
external light source (Scheme 1, bottom). These reactions
usually start from compounds having electron-acceptor-sub-
stituted nitrogen groups and were employed largely in steroid
and carbohydrate chemistry.[3]
À
although truly efficient protocols for C N bond formation
remain to be developed.[5]
The required principle for such a reaction was explored
for the representative compound 1a (Table 1). Overstoichio-
metric oxidation conditions[3] could be employed; however,
changing to catalytic amounts of iodine shut down the
reaction (entries 1 and 2). This problem could be overcome
by changing the carboxylate component of the hypervalent
iodine reagent from acetate to pivalate. With this oxidant it
was possible to reduce the iodine amount to a catalytic
20 mol%, while the results remained similar to those
obtained in the stoichiometric reaction (entry 3 vs. 4). Still,
a significant excess of iodine(III) reagent was required
(entry 5). Further modification of the iodine(III) reagent to
PhI(mCBA)2 (mCBA = 3-chlorobenzoate) provided quanti-
tative yields of 2a, even when a single equivalent of this
oxidant was used (entries 6 and 7). The amount of the iodine
catalyst could be successively lowered to 2.5 mol%, without
loss in yield, and still 95% yield was obtained at a catalyst
loading of 1 mol%. Reasonable conversion was still achieved
at 0.5 mol%, while the amination no longer proceeds upon
further decrease of iodine to 0.1 mol% (entries 8–12). The
optimized conditions call for only a single equivalent of
terminal oxidant, which demonstrates the effectiveness of the
new reaction. Usually, iodine-catalyzed reactions require an
excess of terminal oxidants.[4,6] Moreover, it is noteworthy
that the catalytic use of iodine provides a significantly cleaner
reaction outcome in the oxidation of 1a than a comparable
protocol using the overstoichiometric reagent combination I2/
3PhI(OAc)2,[3f] which forms product mixtures.[7]
[*] Dr. C. Martínez, Prof. Dr. K. MuÇiz
Institute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
Prof. Dr. K. MuÇiz
Catalan Institution for Research and Advanced Studies (ICREA)
Pg. Lluís Companys 23, 08010 Barcelona (Spain)
[**] We thank Prof. Dr. J. M. Gonzµlez and Prof. Dr. P. Melchiorre for
helpful discussions and A. Bahamonde for support in the quantum
yield determination. Financial support of this project was provided
by the Cellex-ICIQ Programme (postdoctoral contract to C. M.) and
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).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501122.
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À
Table 1: Development of the iodine-catalyzed visible-light-induced C H
amination reaction.
Entry
I2 (x mol%)
X
y
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13[b]
14[c]
15[d]
16[e]
100
20
100
20
20
20
20
5
2.5
1
0.5
0.1
5
O2CMe
O2CMe
O2CtBu
O2CtBu
O2CtBu
mCBA
mCBA
mCBA
mCBA
mCBA
mCBA
mCBA
mCBA
mCBA
mCBA
mCBA
3
3
3
3
1
3
1
1
1
1
1
1
1
1
1
1
67
<10
89
78
<10
98
98
98
98
95
76
–
–
85
98
98
0.5
5
2.5
[a] Yields refer to isolated material of 2a after purification. [b] Reaction in
the dark laboratory (red light). [c] Reaction with irradiation at
l=400 nm. [d] Reaction on 13 mmol scale. [e] Reaction in the presence
of 10 equivalents of mCBAH.
The reaction progresses simply upon exposure to daylight.
In contrast to initial reports on stoichiometric reagent
combinations,[3] an external light bulb is not required, which
greatly facilitates the experimental setup. In the absence of
light irradiation, amination does not occur (entry 13). The
optimum wavelength within the visible-light spectrum was
deduced to be 400 nm from a series of individual experiments
at different wavelengths.[7] An experiment using a diode for
defined irradiation at 400 nm indeed led to slightly increased
yield (85 vs. 76%, entries 11 and 14).[7] To maintain opera-
tional simplicity, reactions were usually conducted by expo-
sure to daylight in the absence of a photoreactor. The
versatility of these conditions was demonstrated for a reaction
scale up to 13 mmol, which provided quantitative formation
of 2a (entry 15).
The initial reaction between molecular iodine and the
hypervalent iodine(III) reagent PhI(mCBA)2 should lead to
formation of I(mCBA) (Figure 1A),[8] which is the active
catalyst. With every turnover, the reaction from Table 1
generates two equivalents of carboxylic acid. However, the
presence of the free acid does not influence the overall
performance of the reaction. A control experiment conducted
with excess free carboxylic acid did not show any change in
reaction outcome (Table 1, entry 16). In fact, the catalyst
I(mCBA) might be stabilized by formation of an adduct with
the carboxylic acid. To confirm this hypothesis, we prepared
and structurally characterized the related tetrabutylammo-
nium derivative Bu4N[I(mCBA)2] (3).[9] The core anion
[I(mCBA)2]À displays the expected linear coordination geom-
etry at the central iodine atom (Figure 1B). A cyclization
Figure 1. Mechanistic context of the iodine-catalyzed visible-light-
À
induced C H amination reaction: A) catalyst formation, B) control
experiments, C) catalytic cycle, and D) in situ NMR monitoring for the
reaction progress in the presence (white background) and absence
(gray background) of a monochromatic light source. n.r.=no reaction.
reaction of 1a with this compound led to a reaction outcome
comparable to that of catalytic cycloaminations. This suggests
that the active catalyst I(mCBA) is stabilized by the free acid
as H[I(O2CAr)2] and regenerated upon dissociation. As
deduced from independent control experiments, hypoiodite
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catalysis is entirely ineffective for the present transformation,
as are related iodine species generated in the presence of
alternative oxidants.[7] Stoichiometric amounts of molecular
which the light source was periodically switched off. Reaction
monitoring revealed an expected 1–2% increase in yield due
to the continuing radical chain progress, before further
product formation ceased. At this point, renewed exposure
to light led to re-initiation of the reaction (Figure 1D).
The present iodine-catalyzed heterocycle synthesis is of
broad scope and can be conducted within the discussed
scenario with hypervalent iodine as the terminal oxidant.
Scheme 2 displays several examples of this new catalytic
platform, which is operationally simple and proceeds under
mild conditions. In addition to the tosylated substrate
(product 2a), more labile sulfonyl groups such as nosyl
(product 2b) and SES (product 2c) are tolerated. The alkyl
chain substitution can be varied (products 2d–f) as can the
substitution of its arene group, demonstrating tolerance
À
iodine as the sole promoter also fail to induce the C H
amination reaction.
The mechanistic rationale for the present iodine catalysis
is given in Figure 1C. Once the I(mCBA) catalyst is
À
generated, this compound promotes the N I bond formation
to generate the crucial intermediate A from 1a. Apparently,
the iodinated sulfonamide moiety in A represents the
chromophore for the photochemically induced homolysis of
À
the N I bond. The resulting nitrogen-centered radical B
engages in 1,5-hydrogen atom abstraction from the benzylic
position to generate the carbon-centered radical C. This
intermediate abstracts an iodine atom from another molecule
of A in a radical chain reaction[10] to arrive at the iodinated
intermediate D. Direct nucleophilic amination yielding 2a at
this stage appears possible; however, a significantly enhanced
reactivity arises from oxidation to the alkyl iodine(III)
intermediate E.[11,12] This catalyst state benefits from the
increased leaving-group ability due to the character of
iodine(III) as a nucleofuge.[16] The latter assumption is
corroborated by a Hammett correlation study with deriva-
tives of 1a.[7] No electronic effect was observed for the
manipulation at the benzylic position during formation of 2a,
which suggests this step to be comparably fast. An additional
advantage of the alkyl iodine(III) intermediate E lies in the
subsequent regeneration of the active catalyst I(mCBA)
directly from E. Hence, the amination proceeds within an
iodine(I/III) manifold,[17] which ensures that the reaction
cycle comprising the iodine catalyst proceeds at a sufficient
rate.
À
The nature of the C H functionalization reaction as
a visible-light-induced radical chain process is corroborated
by an experimentally determined quantum yield of 44.[7] The
radical chain pathway contains the rate-limiting step of the
reaction, which through the corresponding intramolecular
isotope-labeling experiment[18] was demonstrated to be the
hydrogen abstraction in the reaction step from B to C with
a primary kinetic isotope effect of 4.0.[7]
At suitable catalyst loading, the rate of the iodine-based
catalytic cycle provides a sufficient amount of the crucial
intermediate A to keep the radical chain reaction operative.
To this end, the limiting catalyst loading is around 0.5 mol%.
Below this value the concentration of the iodine catalyst is too
low to maintain the concentration of A sufficiently high. This
overall mechanistic context thus distinguishes the present
iodine catalysis from recent elegant developments using
À
hypoiodite catalysis for selective a-C H oxygenation in
carbonyl compounds.[19] These reactions proceed through
a single catalytic cycle and solely depend on regeneration of
the involved electrophilic iodine.[19b] In contrast, the present
scenario of two intertwined synergistic cycles demands an
efficient kinetic competence of the iodine catalyst to coop-
erate with the radical chain mechanism progressing in
parallel, as the two cycles cannot operate independently.[20]
Upon eventual chain termination, the present reaction is re-
initiated by visible-light-induced photochemical homolysis of
A. This context was modeled by an NMR experiment, in
À
Scheme 2. Substrate scope of the iodine-catalyzed C H bond amina-
tion under visible-light irradiation. Conditions: I2 (2.5 mol%), PhI-
(mCBA)2 (1.0 equiv), (CH2Cl)2, RT, visible light, 12 h. The newly formed
C N bonds are marked in blue. Yields refer to yields of isolated
product after chromatographic purification. All reactions proceeded
with >95% selectivity (>95% yield based on recovered starting
material).
À
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[12] Despite repeated attempts, we have so far been unable to access
and study intermediate D through an independent synthesis. To
probe the viability of an iodine(I/III) process, we have employed
an intermediate from our earlier iodine-mediated diamina-
tion.[13] Thus, at RT compound 4 undergoes formation of diamine
5[14] only when treated with a hypervalent iodine reagent.[7,15]
towards common functional groups (products 2g–l). Both the
acetylene in 2l and the free alkene group in 2m remain
untouched. The cyclization proceeds equally well without
substituents on the alkyl chain (product 2n). Stereochemical
information at an acyclic position leads to the formation of
two diastereoisomers 2o, 2o’ as a consequence of the radical
reaction pathway, while stereocontrolled cyclization in the
context of ring annelation furnishes single diastereoisomers
(products 2p, 2q). The reaction is also applicable to the
amination of tertiary benzylic positions (products 2r, 2s).
However, the involvement of a benzylic position is not
a requirement. For example, pyrrolidine 2t is obtained from
selective amination in homobenzylic position, and pro-
ducts 2u–x demonstrate the applicability of the present
iodine-catalyzed amination to the entire spectrum of non-
À
functionalized primary, secondary, and tertiary C H bonds.
À
Finally, the scope includes C H amination reactions a to
heteroatoms as demonstrated for the four examples 2y–ab
and for the diastereoselective formation of 2ac. To further
À
demonstrate its synthetic potential, the catalytic C H ami-
nation reaction was applied to the synthesis of more advanced
alkaloid building blocks. For example, the reaction provides
the tricyclic product 2ad in the context of a highly efficient
[21]
À
transannular C H amination reaction.
The tryptamine
derivative 1ae is transformed selectively into the cyclized
aminal product 2ae, which opens new possibilities for the
synthesis of cyclotryptamine alkaloids.[22]
We have presented a unique iodine-catalyzed oxidative
amination of saturated hydrocarbons that proceeds by means
of two intertwined catalytic cycles. In this context, this
reaction combines a radical chain reaction with an iodine
catalysis that proceeds within the iodine(I/III) manifold. The
reaction is operationally simple, proceeds under unprece-
dented mild conditions[23] with only a single equivalent of
oxidant, and is conveniently initiated by visible light. This
straightforward heterocycle synthesis through the intramo-
À
lecular C H amination of alkyl groups provides an attractive
iodine-catalyzed oxidation reaction that represents the first
example of a Hofmann–Lçffler-type amination reaction that
is truly catalytic in halogen promoter. The reaction is of
À
significant scope as it is applicable to the C H amination of
primary, secondary, and tertiary bonds. It compliments
conventional metal-catalyzed variants and demonstrates the
potential of iodine catalysis as a conceptual alternative.
[13] K. MuÇiz, C. H. Hçvelmann, E. Campos-Gómez, J. Barluenga,
J. M. Gonzµlez, J. Streuff, M. Nieger, Chem. Asian J. 2008, 3,
776 – 788.
À
Keywords: amination · C H functionalization ·
homogeneous catalysis · iodine · oxidation
[14] P. Chµvez, J. Kirsch, C. H. Hçvelmann, J. Streuff, E. C. Escudero,
M. Martínez, E. Martin, Chem. Sci. 2012, 3, 2375 – 2382.
[15] For related alkyl–nitrogen bond formation with iodine(III)
reagents: a) P. Mizar, A. Laverny, M. El-Sherbini, U. Farid, M.
Brown, F. Malmedy, T. Wirth, Chem. Eur. J. 2014, 20, 9910 –
9913; b) J. A. Souto, C. Martínez, I. Velilla, K. MuÇiz, Angew.
Chem. Int. Ed. 2013, 52, 1324 – 1328; Angew. Chem. 2013, 125,
1363 – 1367; c) U. Farid, T. Wirth, Angew. Chem. Int. Ed. 2012,
51, 3462 – 3465; Angew. Chem. 2012, 124, 3518 – 3522; d) J. A.
Souto, Y. Gonzµlez, A. Iglesias, D. Zian, A. Lishchynskyi, K.
MuÇiz, Chem. Asian J. 2012, 7, 1103 – 1111; e) C. Rçben, J. A.
Souto, Y. Gonzµlez, A. Lishchynskyi, K. MuÇiz, Angew. Chem.
Int. Ed. 2011, 50, 9478 – 9482; Angew. Chem. 2011, 123, 9650 –
9654.
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Angew. Chem. 2015, 127, 8405–8409
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Received: February 5, 2015
Revised: March 20, 2015
Published online: May 28, 2015
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