Regioselective direct arylation of fused 3-nitropyridines and other nitro-substituted heteroarenes: The multipurpose nature of the nitro group as a directing group

Article abstract of DOI:10.1002/cctc.201402715

We report Pd-and Ni-catalysed, guided and regioselective C-H arylations of a series of fused 3-nitropyridines. The method described here is a facile tool for the chemical functionalisation of drug-like fused pyridines. The scope and limitations of the rea

Full text of DOI:10.1002/cctc.201402715

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DOI: 10.1002/cctc.201402715
Regioselective Direct Arylation of Fused 3-Nitropyridines
and Other Nitro-Substituted Heteroarenes: The
Multipurpose Nature of the Nitro Group as a Directing
Group
Viktor O. Iaroshenko,*[a, b, c] Ashot Gevorgyan,[a] Satenik Mkrtchyan,[a] Tatevik Grigoryan,[a]
Ester Movsisyan,[a] Alexander Villinger,[a] and Peter Langer*[a, d]
We report Pd- and Ni-catalysed, guided and regioselective CÀH
arylations of a series of fused 3-nitropyridines. The method de-
scribed here is a facile tool for the chemical functionalisation
of drug-like fused pyridines. The scope and limitations of the
reaction, the chemical potential of the nitro group and a puta-
tive reaction mechanism are discussed.
Introduction
The formation of a single CÀC bond by catalytic coupling reac-
tions is a research area that has grown enormously in recent
decades and contributes significantly to the production of
both intermediates and fine chemicals.[1] As a result of their
simplicity and efficiency, coupling strategies are uniquely ame-
nable to modifications at the molecular level. However, during
the last decade, direct transition-metal-catalysed CÀH activa-
tion reactions by their virtue became one of the most prospec-
tive methodologies in modern organic chemistry.[2] Impressive
amounts of applications in a relatively short period of time
shows strong support for the importance and prospective of
this method.[3] CÀH activation became an important tool for
the construction and side- and/or chemoselective functionali-
sation of many biologically active molecules and drug-like scaf-
folds.[3] CÀH activation was also combined with many other
classical chemical transformations, such as simultaneous addi-
tions to double and triple bounds,[4] additions to hetero-
atoms[5] and domino consecutive reactions.[6] Directing groups
play an important role in the selective functionalisation of CÀH
bonds. Functionalised fragments contain potential donor
atoms, such as N, O, P, S or others: that is, atoms able to be co-
ordinated, even weakly, to the transition metal because of
their strong Lewis base properties.[7] Nevertheless, sometimes
these efficient moieties cannot be removed easily or they are
not prone to undergo further functionalisation. Moreover, the
need for greener reactants and reaction conditions to provide
a high level of atom economy and minimise waste does not fit
with the presence of non-convertible functional groups. As
a result, extensive research into multi-functional directing
groups is underway. That is, directing groups that can perform
extra tasks, in addition to their directing purpose, are of con-
siderable interest.[8] A clear example is the use of oxidising di-
recting groups that contain a covalent bond responsible for
the oxidation of the metal, which avoids the use of external
oxidants that usually generate waste byproducts.[9] Another
way to plan the multi-task character of the directing groups is
the use of “removable” functional groups.[8] In this respect, cut-
ting-edge innovations are the use of 2-pyridyl sulfoxide (A),[10a]
2-pyridyl ether (B),[10b,c] thioether (C),[10d] pyridyldiisopropylsilyl
(D),[10e–g] nitrile (E),[10h] triazene (F),[10i] silanol (G)[10j] and carboxy-
lates (H)[10k] as multi-functional and/or traceless directing
groups (Scheme 1).
[a] Dr. V. O. Iaroshenko, A. Gevorgyan, S. Mkrtchyan, T. Grigoryan,
E. Movsisyan, Dr. A. Villinger, Prof. Dr. P. Langer
Institut fꢀr Chemie, Universitꢁt Rostock
Albert-Einstein-Str. 3a, 18059 Rostock (Germany)
Fax: (+49)381-4986412
E-mail: iva108@gmail.com
peter.langer@uni-rostock.de
In this context, the nitro group is almost the paradigm of
what a multi-purpose directing group could be. It can behave
as a classical directing group[11] that selects the position in
which the metal has to be incorporated and, typically, forms
part of the target molecule by further functionalisation after
the CÀH activation step. This two-step approach undoubtedly
has an enormous synthetic utility.[12,13]
[b] Dr. V. O. Iaroshenko
National Taras Shevchenko University
62 Volodymyrska st., Kyiv-33, 01033 (Ukraine)
[c] Dr. V. O. Iaroshenko
Department of Chemistry (MC 111)
University Illinois at Chicago
845 W Taylor St., RM 4500, Chicago, IL, 60607 (USA)
[d] Prof. Dr. P. Langer
The use of the nitro group as a regio-directing substituent
in CÀH activation has scarcely been reported to date
(Scheme 2).[14] Examples include the Pd-catalysed ortho-aryla-
tion of nitrobenzene derivatives[14a] (A) and the CÀH activation
of the 4- and 5-positions of 3-nitropyridine (B).[14b] In spite of
Leibniz-Institut fꢀr Katalyse e. V.
Universitꢁt Rostock
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402715.
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Results and Discussion
Based on our experience and fol-
lowing general movements in
the field, to achieve the desired
selective arylation, a number of
crucial challenges had to be
overcome: 1) the first challenge
is the optimisation of reaction
conditions so that only stoichio-
metric amounts of fused nitro-
pyridines need to be used;
2) the second challenge is the in-
vestigation of regioselectivity in
two potential active positions in
the pyridine ring (a and g);
3) among these, in most cases
we have several functional
groups that can in principle
Scheme 1. Removable directing groups in directed CÀH activation reactions. Hal=Halogen; pin=Pinacol.
Scheme 2. Reported use of the nitro group as a regio-directing substituent
in CÀH activation; A) see Ref. [14a], B) see Ref. [14b], C) see Ref. [14c],
D) present study.
this, the authors did not demonstrate the vast chemical poten-
tial of the nitro group. In contrast, very recently we communi-
cated the selective and guided functionalisation of 4-nitropyra-
zoles by Pd- and Ni-catalysed CÀH arylation followed by a dem-
onstration of the multi-purpose character of the nitro group as
a directing group (Scheme 2C).[14c]
Scheme 3. Synthesis of fused pyridines i) DMF, TMSCl, Ar, 1008C, 2–12 h.
Cy=Cyclohexyl.
direct CÀH arylation, hence we have several potentially active
CÀH bonds in most of the targets, which should be investigat-
ed; and 4) it is important to demonstrate the utility of the
nitro group in follow-up chemistry and for downstream pro-
cesses.
In our present study, we continue to investigate the direct-
ing ability of the nitro group with the example of several fused
3-nitropyridines 3a–m, which represent an important class of
purine-like compounds (Scheme 3).[15] The starting fused pyri-
dines were prepared by the reaction of several electron-exces-
sive aminoheterocycles 1 with the enolate of nitromalonalde-
hyde 2 in DMF in the presence of trimethylsilyl chloride
(TMSCl) as a water scavenger (Scheme 3).[16a]
With the set of fused pyridines in hand, we focused on the
optimisation of the reaction conditions. On the basis of our
previous results, we considered Pd catalysts with CuI as an ad-
ditive as the starting point in this study.[14c,17] Gratifyingly, pilot
experiments indicated that the Pd/CuI system is efficient to ac-
tivate the g-CÀH bond of the pyridine ring (Table 1, entries 2–
8, 14, 17). The best catalyst for 3a is [PdCl2(PPh3)2], with which
we obtained the desired product in 77% yield (entry 17). We
found that the addition of phosphine ligands as well as biden-
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responding g-CÀH arylation
products in good yields. Notably,
[NiCl2(PPh3)2] was also active
with the range of aryl bromides.
In all cases the g-arylated adduct
was the only observed regioiso-
mer. At the same time, the use
of iodoarenes resulted in the for-
mation of a great amount of bi-
phenyls by homocoupling in-
duced by CuI; this demanded
a large excess of iodoarene, and
the overall yields were visibly
lower than that with aryl bro-
mides. Together with this, aryl
chlorides, in general, were not
active enough, although in the
case of electron-deficient 2-
chloropyrimidine we obtained
the corresponding heteroaryla-
tion product 4n in a moderate
yield of 48%. If 5-bromothio-
phene-2-carboxylic acid was
used as the coupling partner,
the CÀH arylation reaction was
followed by decarboxylation to
form the arylation product 4o in
a low yield of 28%.
Table 1. Optimisation of reaction conditions for the synthesis of 4a.
Entry
Catalyst
Ligand
Additive
1
Additive
2
Base
Solvent
T
[8C]
Yield
[%]
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[PdCl2(PPh3)2]
[NiCl2(PPh3)2]
RuCl3·H2O
[Ru(p-cymene)Cl2]2
–
–
CuI
CuI
CuI
CuI
CuI
CuI
CuI
PivOH
PivOH
PivOH
PivOH
–
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K3PO4
KOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
toluene
TFA[a]
DMF
DMF
DMA
DMA
DMA
DMA
DMA
130
130
130
130
130
130
130
130
130
130
130
130
130
160
100
100
130
130
160
160
160
160
160
–
48
52
43
12
15
40
8
–
27
–
–
–
50
–
–
77
43
–
–
–
–
–
Cy3P·HBF4
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Ph3CCO2H
PivOH
–
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
–
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
9
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ag2CO3
CuI+Ag2CO3
AuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
Cy3P·HBF4
–
–
–
– or CuI
– or CuI
– or CuI
– or CuI
[b]
[Rh(cod)Cl]2
[Rh(OAc)2]2
IrCl3·H2O
Cy3P·HBF4
As a wide range of haloarenes
was established, we examined
the scope of fused nitropyri-
dines. Gratifyingly, a wide range
[a] TFA=Trifluoroacetic acid. [b] cod=Cyclooctadiene.
tate ligands such as 1,10-phenanthroline has no real impact on
overall yield of the reaction (entries 2 and 3). Notably, the salts
of coinage metals such as CuI and Ag2CO3 in stoichiometric
amounts were necessary to achieve at least some conversion
of fused pyridines, otherwise we obtained traces of 4’’. Inter-
estingly, the use of Lewis acids such as CuI or Ag2CO3 blocks
this pathway of the reaction. However, the mixture of CuI and
Ag2CO3 produced an intensive reduction of Ag and oxidation
of Cu without any conversion of reactants (entry 11). The best
base for the reaction was the K2CO3/pivalic acid (PivOH)
system, and any change in the system decreased the yield. The
use of different solvents and temperatures showed that the re-
action occurs only in DMF, dimethylacetamide (DMA) and N-
methyl-2-pyrrolidone (NMP) without any notable differences in
yields. Finally, the use of other catalysts to obtain another re-
gioisomer and/or the same product with better yields was inef-
fective (entries 19–23). Among these, perhaps unsurprisingly,
[NiCl2(PPh3)2] was active, although the conversion of reactants
was not very high (entry 18).
of substituents and substitution patterns are tolerated with no
changes in the reaction conditions. That is, 1,3-dimethyl-6-ni-
tropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3b), 6-nitro-1H-
imidazo[4,5-b]pyridine-2(3H)-thione derivatives 3c–e and 6-ni-
trothiazolo[4,5-b]pyridine derivatives 3 f react uneventfully
with the appropriate aryl bromides to lead to the correspond-
ing g-CÀH arylation products in good yields (Scheme 5, 5–7).
Notably, in these cases the g-arylated adduct was again the
only observed regioisomer. Additionally the reactions can be
catalysed by [NiCl2(PPh3)2], however, with a lower efficiency.
Of the target fused nitropyridines, pyrrolo[2,3-b]pyridine de-
rivative 3h stands out because it has two potentially active CÀ
H bonds and directing groups.[18] Because the chemistry of in-
doles is somewhat similar to that of pyrrolo[2,3-b]pyridine de-
rivatives, unsurprisingly, we obtained simultaneous CÀH aryla-
tion at both rings.[19] As a result we isolated two isomers,
namely, the C2 and C4 arylation products (Scheme 6, 8a–h).
We found that both positions are approximately equally active,
that is, the addition of one equivalent of aryl bromide led to
a mixture of products without the full conversion of reactant
3h. A reduction of the amount of bromide as well as changing
the reaction conditions does not change the regioselectivity of
the reaction, or even in some cases, vice versa, the conversion
of reactant decreased significantly. Good yields for both re-
gioisomers can be achieved using similar conditions to those
With the optimised conditions in hand, we examined the
scope of the reaction with respect to the aryl halide coupling
partner (Scheme 4).
We demonstrated that aryl bromides substituted with Me, F,
NO2, CF3, CN, Ac, formyl and OMe as well as heterocyclic bro-
mides are compatible with the procedure and lead to the cor-
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Next, we turned our attention to the possibility to introduce
aryl groups at the a-position of fused nitropyridines (see also
the scheme of Table 1, 4’). Unfortunately, all our attempts to ar-
ylate the a-position of fused nitropyridines failed. Although
a number of procedures were tested, in most cases we ob-
tained complex mixtures and/or the poor conversion of reac-
tants.
Thereby, to further extend the substrate scope, we synthes-
ised nitro-substituted heteroarenes 11 and 12, which already
bear an aryl substituent at the a-position following a methodol-
ogy we developed previously (Scheme 8).[16b]
Although the chosen systems 11 and 12 have an OH group
that can potentially lead to a CÀO cross-coupling reaction: the
reactions under standard conditions for CÀH activation gave
an unexpected result. In spite of a mixture of products, we
could isolate two pure compounds, which were surprisingly
13b and 14b (Scheme 8). Further optimisation of the reaction
conditions has shown that the reaction constitutes a two-step
process. The first step is a type of intramolecular nucleophilic
substitution reaction, which is followed by Pd-catalysed CÀH
activation. We found that the first step can occur in the ab-
sence of catalyst. Furthermore, we excluded reaction compo-
nents successively to find that CuI and PivOH do not play deci-
sive roles in this transformation and just base can initiate the
cyclisation. Encouraged by these results, we substituted the
nitro group successfully in a wide range of substrates; the only
systems that were unreactive and/or unstable under basic con-
ditions were pyrazoles 12b and
c and isoxazole 12d
(Scheme 8). With a number of fused furo[3,2-b]pyridine deriva-
tives 13 in hand, we examined CÀH arylation at the pyridine
ring. Interestingly, CÀH arylation can occur effectively under
the standard conditions that were found to be optimal for
fused nitropyridines. Fused furo[3,2-b]pyridine derivatives 13
react unprecedentedly with appropriate aryl bromides to lead
to the corresponding g-CÀH arylation products in good yields
(Scheme 8, 14a–d). We demonstrated that the reaction can be
performed either in one-pot or consecutively. Not surprisingly,
the consecutive manner led to higher yields.
Scheme 4. Scope of the reaction with respect to aryl bromides. * The yields
of the CÀH arylation catalysed by Ni are given in brackets in red.
used for other fused nitropyridines. Additionally, to avoid
double arylation and/or a disastrous mixture of products, no
more than two equivalents of aryl bromide should be used
(see also Supporting Information Section B).
Eventually, to demonstrate the synthetic potential of this
methodology fully, we explored the chemical versatility of the
directing group briefly. The simple reduction of the nitro
group was tested first (Scheme 9). Thus, the reduction of the
CÀH arylation products of fused nitropyridines 4–8 in metha-
nol under typical conditions (Pd/C as the catalyst, normal pres-
sure of H2) resulted in the formation of amines 15a–c in good
yields (Scheme 9). Moreover, if the reduction was performed in
the presence of an excess of formalin, the N,N-dimethylamine
16a was obtained. Remarkably, if the amount of formalin was
reduced to 1.5 equivalents, the reduction was followed by iso-
quinoline ring formation to give 17a. In addition to this aston-
ishing finding, 17a can be prepared by the simple reduction
of 4i (Scheme 4) in a high yield. To summarise this with the
substitution of nitro group described above, we have an easily
modifiable directing group for the CÀH functionalisation of
heteroarenes.
To extend our methodology, a number of variously nitro-
substituted heteroarenes were investigated. Among others, 3-
nitro-2H-chromen-2-one (9a), 3-nitro-4H-chromen-4-one (9b),
4-oxo-4H-chromene-3-carbonitrile (9c), 5-nitropyrimidine deriv-
atives 9d–f, 4-nitroisoxazole (9g) and methyl 4-nitrofuran-2-
carboxylate (9h; Scheme 7) in addition to fused pyridines 3i
and j and quinolines 3k–m (Scheme 3) were unreactive and/or
unstable in our typical reaction protocol.
Gratifyingly, in contrast to these unsuccessful trials, 1-
methyl-4-nitro-1H-pyrrole-2-carbonitrile (9i) and 2-nitrothio-
phene (9j) react readily with aryl bromides under standard
conditions to lead to mono-arylated products 10a–c in good
yields (Scheme 7). In all cases, the product of the arylation of
the b-CÀH bond to the nitro group was the only observed re-
gioisomer. Further optimisation of reaction conditions and ex-
ploration of new methods for CÀH arylation of nitro-substitut-
ed heteroarenes is underway in our laboratory.
The structure of the synthesised compounds was established
mainly by 1D and 2D NMR spectroscopy (10b). The structures
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of 4a, h, l, 5d, 8h, 13b, d and 15c were confirmed
independently by single-crystal X-ray analyses (Figur-
es S1–S8).[20]
To shed light on the directing ability of the nitro
group and to obtain additional insights into the reac-
tion mechanism, we designed substrates 18a–e,[21]
which were subjected to our standard Pd- and Ni-cat-
alysed reaction conditions (Scheme 10). First the nitro
group was changed into a polar substituent, namely,
CN[21a] in 18a and CO2Et[21b] in 18b (Scheme 10).
However, to our astonishment, all attempts to per-
form the CÀH arylation under standard conditions,
elaborated for previous reactions, experienced a fail-
ure; substrates 18a and 18b were recovered com-
pletely. The same reactivity was observed for sub-
strate 18c.[21c] Additionally, the introduction of non-
coordinating, bulky p-tolyl 18d[16a] and CC-Ar 18e[16a]
substituents did not trigger the CÀH activation. Com-
pound 18d was recovered fully, however, an inten-
sive degradation was observed for 18e, which might
be because of the reactivity of the triple bond under
transition-metal-catalysed conditions (Scheme 10).
However, in previous reports on imidazo[4,5-b]pyri-
dines and related fused pyridines, we[17] and others[22]
demonstrated that the pyridine ring remains intact
under typical CÀH activation protocols if the nitro
group is replaced by H or the electron-withdrawing
CF3 group. In addition, the Pd-catalysed non-directed
CÀH arylation of unprotected simple pyridines leads
to a mixture of isomers (C3/C4/C2) with predominant
C(3)ÀH selectivity.[23] Notably, the reaction demands
an excess of starting pyridine (solvent), which indi-
cates the importance of directing groups.[14b,23]
Scheme 5. Scope of the reaction with respect to nitro-substituted pyrido[2,3-d]pyrimi-
dine 3b, 1H-imidazo[4,5-b]pyridine-2(3H)-thiones 3d and e and thiazolo[4,5-b]pyridine
3 f. * The yields of the CÀH arylation catalysed by Ni are given in brackets in red.
Finally, the regioselectivity might be explained by
the assumption that the free electron pair of the N
atom of pyridine shields the 2-position (structure A in
Scheme 11).[14b] Thus, intermediate B should be more
favourable. However, pyridines have a tendency to
adopt a non-productive N-bound coordination mode
with metal centres (structure C or D in Scheme 11,
similar considerations are appropriate for Ni as
well).[24] In this respect, the protection of the N atom
by conversion to N-oxides and N-iminopyridinium
ylides has allowed the development of several C2-se-
lective arylation reactions of pyridines.[25]
On this basis, we envisioned that high levels of re-
activity with our catalytic system could be a result of
the strong coordination of the N atom of the pyri-
dine ring to CuI that would prevent the N-bound co-
ordination mode of the pyridine substrates with Pd
or Ni (C, D). Recently, in this context, two research
groups found independently that the coordination of
a strong and bulky Al-based Lewis acid with the pyr-
idyl N atom not only activated the pyridyl rings but
also favoured C(4)ÀH cleavage.[26] Hence, under these
circumstances, it is possible that C4-selective CÀH
cleavage could take place if the appropriate orienta-
Scheme 6. Scope of the reaction with respect to nitro-substituted pyrrolo[2,3-b]pyridine
3h.
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Experimental Section
The dry solvents were purchased. Other solvents were purified by
distillation. All reactions were performed under an inert atmos-
1
phere. For H, 19F and 13C NMR spectra the deuterated solvents in-
dicated were used. MS data were obtained by electron ionisation
(EI, 70 eV), chemical ionisation (CI, isobutane) or ESI (mass analyser
type was ESI-TOF/MS). For preparative-scale chromatography silica
gel 60 (0.063–0.200 mm, 70–230 mesh) was used. The solvents for
column chromatography were distilled before use.
General procedure for the synthesis of compounds 4a–o
and 5–7
The corresponding fused 3-nitropyridine 3a–f (1 equiv.), CuI
(1.2 equiv.), K2CO3 (1.3 equiv.), (CH3)3CCO2H (0.3 equiv.) and
[PdCl2(PPh3)2] (or [NiCl2(PPh3)2]; 0.05 equiv.) were weighed in air
and placed successively in a Schlenk flask equipped with a magnet-
ic stir bar, which was capped with a rubber septum. The reaction
vessel was evacuated and back-filled with Ar (three times). Dry
DMF (8 mL for 0.3 g of fused 3-nitropyridine) and aryl bromide
(4 equiv.) were added with a syringe, and the reaction mixture was
heated to 1308C for 16 h. The reaction mixture was cooled to RT
and concentrated under vacuum. The residue was purified by
column chromatography typically using a heptane/ethyl acetate
mixture to provide the desired arylated product.
Scheme 7. Scope of the reaction with respect to nitro-substituted heteroar-
enes.
General procedure for the synthesis of compounds 8a–h
and 10a–c
tion between the nitro group of the pyridine and Pd (Ni) is as-
sembled (E).
The corresponding nitro-substituted heteroarene 3h, 9i or
j
(1 equiv.), CuI (1.2 equiv.), K2CO3 (1.3 equiv.), (CH3)3CCO2H
(0.3 equiv.) and [PdCl2(PPh3)2] (0.05 equiv.) were weighed in air and
placed successively into a Schlenk flask equipped with a magnetic
stir bar, which was capped with a rubber septum. The reaction
vessel was evacuated and back-filled with Ar (three times). Dry
DMF (8 mL for 0.3 g of nitro-substituted heteroarene) and aryl bro-
mide (2 equiv.) were added with a syringe, and the reaction was
heated to 1308C for 16 h. Upon completion, the reaction was
cooled to RT and concentrated under vacuum. The residue was pu-
rified by column chromatography typically using a heptane/ethyl
acetate mixture to provide the desired arylated product.
Conclusions
We have studied in detail the transition-metal-catalysed aryla-
tion of fused nitropyridines by Pd and Ni using CuI as an addi-
tive. Pd was superior in terms of yields compared to Ni. Fur-
thermore, we succeeded to activate the CÀH bond using stoi-
chiometric amounts of fused nitropyridines. The scope of the
reaction with respect to the aryl halide coupling partner as
well as for fused nitropyridines was examined. In all cases
except pyrrolo[2,3-b]pyridine derivative 3h, the reactions pro-
ceeded with exclusive g regioselectivity. For the pyrrolo[2,3-
b]pyridine derivative, we have shown that the C2 and C4 posi-
tions are almost equally active. Additionally, various nitro-sub-
stituted heteroarenes were investigated. During an investiga-
tion of the extension of substrate scope, a domino nitro group
substitution–CÀH arylation reaction was found. Within the
course of this study the multi-purpose character of the nitro
group was demonstrated. A mechanistic explanation of the re-
sults was proposed. The developed method shows a number
of advantages, which include high experimental simplicity, cat-
alyst efficiency, functional group compatibility and the low
cost of the catalytic system. The products are purine-like com-
pounds, which are of considerable pharmacological relevance.
Further exploration of this chemistry is in progress in our labo-
ratory.
General procedure for the synthesis of compounds 11 and
12a–d
The corresponding 3-nitrochromone (1 equiv.) and the nucleophile
(appropriate amino heterocyclic, 3-aminocrotononitrile, corre-
sponding substituted hydrazine, hydroxylamine hydrochloride;
1.2 equiv.) were dissolved in acetic acid (20 mL for 1 g of nucleo-
phile). The mixture was heated under reflux under an inert atmos-
phere for 8 h. Then the solution was evaporated under reduced
pressure. The residue was purified by column chromatography typ-
ically using a heptane/ethyl acetate mixture.
General procedure for synthesis of compounds 13a–f
The corresponding fused 3-nitropyridine 11 or 12a (1 equiv.) and
K2CO3 (1.3 equiv.) were weighed in air and placed successively into
a Schlenk flask equipped with a magnetic stir bar, which was
capped with a rubber septum. The reaction vessel was evacuated
and back-filled with Ar. Dry DMF (8 mL for 0.3 g of starting materi-
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The residue was purified by column chromatography
typically using a heptane/ethyl acetate mixture to pro-
vide the desired arylated product.
General procedure for the synthesis of compounds
14a–d
The corresponding fused furo[3,2-b]pyridine derivative
13 (1 equiv.), CuI (1.2 equiv.), K2CO3 (1.3 equiv.),
(CH3)3CCO2H (0.3 equiv.) and [PdCl2(PPh3)2] (0.05 equiv.)
were weighed in air and placed successively into
a Schlenk flask equipped with a magnetic stir bar, which
was capped with a rubber septum. The reaction vessel
was evacuated and back-filled with Ar (three times). Dry
DMF (8 mL for 0.3 g of fused furo[3,2-b]pyridine deriva-
tive) and aryl bromide (4 equiv.) were added with a sy-
ringe, and the reaction was heated to 1308C for 16 h.
Upon completion, the reaction was cooled to RT and
concentrated under vacuum. The residue was purified by
column chromatography typically using a heptane/ethyl
acetate mixture to provide the desired arylated product.
General procedure for the synthesis of compounds
15a–c and 17a
To a Schlenk flask equipped with a magnetic stir bar and
filled with the corresponding fused 3-nitropyridine 4b, l,
i or 5c (1 equiv.) was added 10% Pd/C (0.1 equiv.). The
flask was fitted with a rubber septum and then held
under vacuum for 3 min before it was filled with MeOH
(25 mL for 0.3 g of fused 3-nitropyridine) and H2. Holding
under vacuum was repeated one more time, and after
sequential filling with H2, the reaction mixture was
stirred for 5 h under a H2 atmosphere. The reaction mix-
ture was filtered through a Celite pad, and the filtrate
was evaporated to dryness or (if necessary) purified by
column chromatography typically using a heptane/ethyl
acetate mixture to provide the desired product.
Scheme 8. The domino nitro group substitution–CÀH arylation reaction; i) ArBr (4 equiv.),
[PdCl2(PPh3)2] (5 mol%), CuI (1.2 equiv.), PivOH (0.3 equiv.), K2CO3 (2.3 equiv.), DMF, under
Ar, 1308C, 16 h; ii) K2CO3 (1.3 equiv.), DMF, under Ar, 1308C, 16 h; iii) ArBr (4 equiv.),
[PdCl2(PPh3)2] (5 mol%), CuI (1.2 equiv.), PivOH (0.3 equiv.), K2CO3 (1.3 equiv.), DMF, under
Ar, 1308C, 16 h. * The yields of the one-pot CÀH arylation are given in brackets in red.
al) was added with a syringe, and the reaction mixture was heated
General procedure for the synthesis of compound 16a
to 1308C for 16 h. Upon completion, the reaction was cooled to RT
and concentrated under vacuum. The residue was purified by
column chromatography typically using a heptane/ethyl acetate
mixture to provide the desired product.
To a Schlenk flask equipped with a magnetic stir bar and filled
with the fused 3-nitropyridine 4e (1 equiv.) was added 10% Pd/C
(0.1 equiv.). The flask was fitted with a rubber septum and held
under vacuum for 3 min before it was filled with MeOH (25 mL for
0.3 g of fused 3-nitropyridine), formaldehyde solution (6 equiv.,
37 wt% in H2O, contains 10–15% methanol as stabiliser), and H2.
Holding under vacuum was repeated one more time, and after se-
quential filling with H2, the reaction mixture was stirred for 5 h
under a H2 atmosphere. The reaction mixture was filtered through
a Celite pad, and the filtrate was evaporated to dryness. The resi-
due was purified by column chromatography typically using a hep-
tane/ethyl acetate mixture to provide the desired product.
General procedure for the synthesis of compounds 14a–c
The corresponding fused 3-nitropyridine 11 or 12a (1 equiv.), CuI
(1.2 equiv.), K2CO3 (2.3 equiv.) and (CH3)3CCO2H (0.3 equiv.) were
weighed in air and placed successively into a Schlenk flask
equipped with a magnetic stir bar, which was capped with
a rubber septum. The reaction vessel was evacuated and back-
filled with Ar (three times). Dry DMF (8 mL for 0.3 g of fused 3-ni-
tropyridine) was added with a syringe, and the reaction mixture
was heated to 1308C for 6 h. The reaction was cooled to RT, and
[PdCl2(PPh3)2] (0.05 equiv.) was weighed in air and placed into the
Schlenk flask. The aryl bromide (4 equiv.) was added with a syringe,
the reaction vessel was evacuated and back-filled with Ar, and the
reaction mixture was heated to 1308C for 10 h. Upon completion,
the reaction was cooled to RT and concentrated under vacuum.
General procedure for the synthesis of compound 17a
To a Schlenk flask equipped with a magnetic stir bar and filled
with the fused 3-nitropyridine 4a (1 equiv.) was added 10% Pd/C
(0.1 equiv.). The flask was fitted with a rubber septum and held
under vacuum for 3 min before it was filled with MeOH (25 mL for
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Scheme 11. Proposed mechanistic explanation of the regioselectivity.
Acknowledgements
Financial support by the DAAD (scholarships for A.G. and S.M.)
and by the State of Mecklenburg-Vorpommern is gratefully ac-
knowledged. We are grateful to Enamine Ltd Company (Ukraine)
for support.
Scheme 9. Reduction of the nitro group; i) MeOH, H2, Pd/C (10 mol%), 208C,
5 h. ii) MeOH, H2, Pd/C (10 mol%), CH2O in H2O (37%, 6 equiv.), 208C, 5 h. iii)
MeOH, H2, Pd/C (10 mol%), CH2O in H2O (37%, 1.5 equiv.), 208C, 5 h. * The
yield of the reduction of 4i is given in brackets in red.
Keywords: CÀH activation · fused-ring systems · nickel ·
nitrogen heterocycles · palladium
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Received: September 7, 2014
Revised: October 12, 2014
Published online on && &&, 0000
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 10
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These are not the final page numbers!

FULL PAPERS
V. O. Iaroshenko,* A. Gevorgyan,
S. Mkrtchyan, T. Grigoryan, E. Movsisyan,
A. Villinger, P. Langer*
So nitro: We report Pd- and Ni-cata-
lyzed, guided, and regioselective CÀH
arylations of a series of fused 3-nitropyr-
idines. The method described here is
a facile tool for the chemical functionali-
zation of drug-like fused pyridines. The
scope and limitations of the reaction,
the chemical potential of the nitro
group, and a putative reaction mecha-
nism are discussed.
&& – &&
Regioselective Direct Arylation of
Fused 3-Nitropyridines and Other
Nitro-Substituted Heteroarenes: The
Multipurpose Nature of the Nitro
Group as a Directing Group
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 10
&10
&
ÞÞ
These are not the final page numbers!