Metal-free annulation of arenes with 2-aminopyridine derivatives: The methyl group as a traceless non-chelating directing group

Article abstract of DOI:10.1002/anie.201403712

A novel annulation reaction between 2-aminopyridine derivatives and arenes under metal-free conditions is described. The presented intermolecular transformation provided straightforward access to the important pyrido[1,2-a]benzimidazole scaffold under mild reaction conditions. The unprecedented application of the methyl group of methylbenzenes as a traceless, non-chelating, and highly regioselective directing group is reported.

Full text of DOI:10.1002/anie.201403712

Angewandte
Chemie
DOI: 10.1002/anie.201403712
À
C H Amination
Metal-Free Annulation of Arenes with 2-Aminopyridine Derivatives:
The Methyl Group as a Traceless Non-Chelating Directing Group**
Srimanta Manna, Kiran Matcha, and Andrey P. Antonchick*
Abstract: A novel annulation reaction between 2-aminopyr-
idine derivatives and arenes under metal-free conditions is
described. The presented intermolecular transformation pro-
vided straightforward access to the important pyrido[1,2-
a]benzimidazole scaffold under mild reaction conditions.
The unprecedented application of the methyl group of
methylbenzenes as a traceless, non-chelating, and highly
regioselective directing group is reported.
using an expensive transition-metal complex and ligands
(Scheme 1).[3] In this context, the discovery of a direct
intermolecular annulation of 2-aminopyridine and non-pre-
functionalized arene would be
a significant advance
(Scheme 1). Moreover, a mild and efficient method under
metal-free conditions with a substrate scope beyond 2-
aminopyridines would be in great demand. Herein we
report a metal-free, selective annulation of 2-aminoazarenes
and arenes for the synthesis of the pyrido[1,2-a]benzimida-
zole scaffold. Furthermore, a novel application of the methyl
group of methylbenzenes as a traceless directing group in
a highly regioselective synthesis is reported.
Benzimidazoles are prevalent in many natural products and
pharmaceuticals.[1] For example, rifaximin is a semisynthetic
antibiotic obtained from the secondary metabolite rifamycin.
The introduction of 4-methylpyridine-2-amine to the aro-
matic part of the natural product to form the pyrido[1,2-
a]benzimidazole derivative led to improved pharmacological
properties for clinical application.[2] Owing to their interesting
biological properties, pyrido[1,2-a]benzimidazoles are of
synthetic importance.[3,4] Reported synthesis routes to pyrido-
[1,2-a]benzimidazoles rely on multistep protocols and often
require harsh reaction conditions.[3,4] The most common route
to pyrido[1,2-a]benzimidazoles is an intramolecular cycliza-
tion of N-aryl-2-aminopyridines (Scheme 1). The efficacy of
À
Among the C N bond-forming reactions, direct C–H
amination is an atom-economical and highly demanding
transformation in organic synthesis.[5] Recently, environmen-
tally benign hypervalent iodine reagents[6] proved to be
exceptional in driving C–H amination under mild condi-
tions.[7] Our group was actively involved in developing metal-
free direct C–H amination reactions using hypervalent iodine
compounds in selective syntheses.[8] We were curious to
investigate the anticipated intermolecular annulation via C–H
amination under metal-free conditions as well.
For the initial studies, we chose 2-aminopyridine (1a) and
para-xylene (2a) as substrates to explore the anticipated
annulation mediated by hypervalent iodine reagents
(Table 1). Initially, when 1a and 2a were reacted with two
Table 1: Optimization of reaction conditions.[a]
Scheme 1. Synthesis routes to pyrido[1,2-a]benzimidazole compounds.
intramolecular cyclization was initially investigated in the
presence of transition-metal catalysts.[3d] Very recently an
organocatalytic cyclization by in situ generated hypervalent
iodine reagent was also elegantly demonstrated.[3a] However,
the required N-aryl-2-aminopyridines were synthesized by
Buchwald–Hartwig coupling of 2-halopyridines with anilines
Entry
Solvent
IIII reagent
(equiv)
T [8C]
Yield
[%][b]
1
2
3
4
5
6
7
8
HFIP
HFIP
HFIP
DCM
HFIP:DCM (1:1)
CF3CH2OH
HFIP
HFIP
HFIP
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OCOCF3)2 (2)
PhI(OCOtBu)2 (2)
PhI(OAc)2 (2.5)
PhI(OAc)2 (3)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
reflux
RT
40
40
40
40
40
40
40
19
63
74
n.d.
31
n.d.
n.d.
33
68
44
[*] S. Manna, Dr. K. Matcha, Dr. A. P. Antonchick
Abteilung Chemische Biologie
Max-Planck-Institut fꢀr Molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
9
10
11[c]
12[d]
HFIP
HFIP
HFIP
40
40
40
55
75
S. Manna, Dr. A. P. Antonchick
Fakultꢁt Chemie und Chemische Biologie
Technische Universitꢁt Dortmund
[a] Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), IIII reagent
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
(equiv) in solvent (1.5 mL) at the given temperature for 12 h. [b] Yield
refers to isolated products after column chromatography. [c] 2a
(0.4 mmol) used. [d] 2a (2.0 mmol) used. HFIP=1,1,1,3,3,3-hexafluoro-
2-propanol.
[**] We thank Prof. Dr. Herbert Waldmann for his generous support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403712.
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equivalents of PhI(OAc)2 at reflux in HFIP, the desired
pyrido[1,2-a]benzimidazole derivative (3a) was isolated in
19% yield (Table 1, entry 1). To our delight, the reaction was
also very facile at room temperature giving 3a in 63% yield
(Table 1, entry 2). Changing the reaction temperature to 408C
was found to provide the product in 74% yield (Table 1,
entry 3). Among the solvents screened for the reaction, only
HFIP proved to be efficient (Table 1, entries 3–6). Our
investigations focused afterwards on varying the iodine
reagent. Highly reactive PhI(OCOCF3)2 did not provide the
desired product, and less reactive PhI(OCOtBu)2 was inferior
to PhI(OAc)2 (Table 1, entries 7 and 8). Increasing the
amount of PhI(OAc)2 led to a decrease in yield (Table 1,
entries 9 and 10). Finally, increasing the amount of arene did
not prove beneficial, while decreasing provided lower yields
(Table 1, entries 11 and 12).
With a set of optimized reaction conditions in hand, we
moved on to investigate the scope of this metal-free
annulation. A series of arenes were subjected to the
annulation conditions (Scheme 2). The reaction was found
to be very facile with both electron-rich and moderately
electron-deficient arenes (Scheme 2). Simple electron-rich
arenes, anisole and diphenyl ether, provided products in
excellent yields (Scheme 2, compounds 3b and 3c). To our
delight the reaction preceded selectively and formation of
regioisomers was not detected. Various disubstituted arenes
also provided the desired products with excellent to moderate
yields (Scheme 2, compounds 3d, 3 f–h, 3j). Among the
unsymmetrically disubstituted arenes, product 3g was isolated
as single regioisomer, whereas 3h was obtained as mixture of
two isomers. Application of 1-methylnaphthalene in the
metal-free annulation provided the desired product in good
yield with 5:1 ratio of regioisomers(Scheme 2, compound 3e,
major isomer is shown). Tetrahydronaphthalene gave a mix-
ture of regioisomers (Scheme 2, compound 3j). Furthermore,
toluene and iodobenzene also provided the desired products
in acceptable yields (Scheme 2, compounds 3i and 3k).
Next, we investigated the scope of various 2-aminopyr-
idines in the metal-free annulation (Scheme 2). Pleasingly we
found that the reaction tolerated various electronic influences
on the 2-aminopyridines well. Very good yields were con-
sistently observed with 2-aminopyridines having electron-
donating or electron-withdrawing groups at various positions
(Scheme 2, compounds 3i, 3l, and 3m). Furthermore, disub-
stituted 2-aminopyridines also provided moderate to good
yields (Scheme 2, products 3q and 3r). Trisubstituted 2-
aminopyridine provided the product in excellent yield, too
(Scheme 2, compound 3s). It is noteworthy that product 3t
could be directly obtained by selective oxidation of product
3p using an additional equivalent of PhI(OAc)2 in a one-pot
reaction.
Scheme 2. Scope of the metal-free annulation of arenes. Reaction
conditions: 1 (0.2 mmol), 2 (1.0 mmol), PhI(OAc)2 (0.4 mmol) in
HFIP at 408C for 12 h. [a] 2 (0.6 mmol) used. [b] After 12 h PhI(OAc)2
(0.2 mmol) was added and the reaction continued for 24 h.
[c] Obtained from product 3p by adding additional PhI(OAc)2
(0.2 mmol) and after a reaction time of 24 h.
demethylated product is unprecedented. Furthermore, the
reaction proceeds absolutely selectively and the formation of
isomers or other annulated products was not observed.
Product 5a reflect the introduction of toluene with non-
innate regioselectivity. In general, one methyl group of para-
xylene has the unprecedented function of a traceless, non-
chelating, directing group.[9,10]
We then investigated the generality of this unprecedented
annulation. 4-Iodotoluene reacted in analogy to para-xylene
and provided compound 5b in moderate yield (Scheme 3).
Furthermore, various 2-aminoquinolines also provided the
corresponding products in moderate yields and regioselectiv-
ity (Scheme 3, compounds 5c–f). In general, electronic effects
on the arene ring in 2-aminoquinoline have some influence on
the product yield. Substrates with electron-poor substituents
provided better yields than electron-rich 2-aminoquinolines
Having described the annulation between 2-aminopyri-
dines and arenes, we were interested in expanding the scope
to other derivatives. In this context, 2-aminoquinoline and
para-xylene were subjected to our optimized reaction con-
ditions (Scheme 3). Although anticipated cross-coupling
occurred, we isolated product 5a which lacks a methyl
group (Scheme 3). Unlike the reaction of 2-aminopyridine,
the analogous reaction of 2-aminoquinoline providing mono-
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nucleophilic attack of pyridine nitrogen on xylene produces
intermediate 9.[3a] Finally, rearomatization of 9 produces the
annulated product 3a (Scheme 4). In the control experiment
under optimized reaction conditions intermediate 7 provided
exclusively 3a in 95% yield (see the Supporting Information).
In contrast, a similar experiment with compound 10 provided
product 11 instead of 5a suggesting a different mechanism for
the annulation of 2-aminoquinoline (4a) with arenes
(Scheme 5). In a plausible mechanism for the formation of
5a, the reaction of xylene (2a) with PhI(OAc)2 generates
benzylic radical 12, which is subsequently converted to cation
Scheme 3. Scope of application of the methyl-directed reaction. Reac-
tion conditions: 5 (0.2 mmol), 2 (1.0 mmol), PhI(OAc)2 (0.6 mmol
total; added in 0.2 mmol portions every 6 h) in HFIP at 408C for 18 h.
[a] PhI(OAc)2 (0.8 mmol) used, reaction time 24 h.
Scheme 5. Reaction of compound 10 with PhI(OAc)2.
(Scheme 3, compounds 5c and 5d). Substituents on the
heteroaromatic ring had little influence and moderate yields
were consistently observed (Scheme 3, compounds 5e and
5 f).
A proposed mechanism for the PhI(OAc)2-mediated
annulation of 2-aminopyridine with arenes is described in
Scheme 4. Based on our previous experience,[8] we propose
initially a ligand exchange between 1a and PhI(OAc)2 which
provides intermediate 6. Then nucleophilic attack of arene 2a
on 6 provides N-arylated 2-aminopyridine 7. Subsequent
oxidation of 7 with a second equivalent of PhI(OAc)2 and
13. Nucleophilic attack of amine 4a onto cation 13 gives
benzylic amine 14 (Scheme 4).[7j] The difference in the
reaction mechanisms might be explained by the fact that the
reactivity of 2-aminoquinoline (4a) with PhI(OAc)2 is less
than that of 2-aminopyridine (1a). In a control experiment,
amine 14 in thepresence of PhI(OAc)2 was converted to the
desired product 5a with a yield of 80% (see the Supporting
Information). Nevertheless, when deuterated 2a was used in
the reaction with 4a, a relative small kinetic isotope effect
(KIE = 1.4) was observed. Therefore, the abstraction of
deuterium is not the rate-limiting step in the annulation
(see the Supporting Information for details). Intermediate 15
obtained from oxidation of amine 14 with PhI(OAc)2 is
engaged in an intramolecular cyclization via ipso substitution
to give 16.[3b] Attack of HFIP on 16 gives intermediate 17.
Subsequent reaction of 17 with PhI(OAc)2 provides 18.
À
Cleavage of the C N bond in intermediate 18 by HFIP
initiates annulation onto the quinoline moiety to produce
intermediate 20. Finally, rearomatization provides product
5a.[3b] It is notable that intramolecular demethylative cycliza-
tion during the cleavage of carbon–heteroatom bonds has
been reported[11] but to the best of our knowledge not in the
À
context of C C bond cleavage. Further studies of the
mechanism of demethylative annulation are in progress.
In conclusion, we have developed a novel annulation of
arenes with 2-aminopyridine derivatives mediated by a hyper-
valent iodine reagent under mild reaction conditions. This
intermolecular approach was applied to the efficient synthesis
of pyrido[1,2-a]benzimidazoles and quinolino[1,2-a]benzimi-
dazoles under metal-free conditions. For the first time, we
demonstrated the application of the methyl group in methyl
arenes as a directing, non-chelating, and traceless group in
a highly regioselective cross-annulation.
Received: March 25, 2014
Published online: && &&, &&&&
À
Keywords: annulation · benzimidazoles · C H amination ·
hypervalent iodine reagents · metal-free reactions
.
Scheme 4. Proposed mechanism for metal-free annulation.
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À
C H Amination
S. Manna, K. Matcha,
A. P. Antonchick*
&&&& — &&&&
Metal-Free Annulation of Arenes with 2-
Aminopyridine Derivatives: The Methyl
Group as a Traceless Non-Chelating
Directing Group
Disappearing Me: A novel selective
annulation between 2-aminopyridine
derivatives and arenes under metal-free
conditions provides the important
pyrido[1,2-a]benzimidazole scaffold
under mild reaction conditions. In this
intermolecular reaction the methyl group
of methylbenzenes serves as a traceless,
non-chelating, and highly regioselective
directing group.
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www.angewandte.org
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These are not the final page numbers!