Aerobic oxidative C-H/C-H coupling of azaaromatics with indoles and pyrroles in the presence of TiO2 as a photocatalyst

Article abstract of DOI:10.1039/c5gc00753d

In this paper we wish to report a highly selective and benign method for the double C-H/C-H coupling of azaaromatics with indoles or pyrrole in the presence of air oxygen/TiO₂, as an effective photocatalytic oxidative system. It has been shown that this versatile approach can be applied for direct C-H functionalisation of a variety of azaaromatic systems, such as mono-, di- and triazines, substituted and unsubstituted azines and their benzo-annelated analogues.

Full text of DOI:10.1039/c5gc00753d

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Table of contents
The pyrrolyl and indolyl derivatives of azaaromatics have been
prepared by method of aerobic photo-induced oxidative C–H/C–H
coupling in the presence of nanosized TiO2.

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Aerobic oxidative C–H/C–H coupling of azaaromatics with indoles
and pyrroles in the presence of TiO2 as a photocatalyst
I. A. Utepova,a,b M. A. Trestsova,a O. N. Chupakhin,a,b* V. N. Charushina,b and A. A. Rempela,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
In this paper we wish to report a highly selective and benign method for the double C–H/C–H coupling of azaaromatics
with indoles or pyrrole in the presence of air oxygen/TiO2, as an effective рhotocatalytic oxidative system. It has been
shown that this versatile approach can be applied for direct C-H functionalisation of a variety of azaaromatic systems, such
as mono-, di,- and triazines, substituted and unsubstituted azines and their benzo-annelated analogues.
www.rsc.org/
N
Introduction
O
Br
Organic compounds, bearing pyrrole or indole moieties in their
structures, appear to be very attractive for biological
screening, since the data of biological tests indicate that
derivatives of this family quite often become lead molecules.1
Also azinyl fragments are dominating in the structures of
biologically active compounds.2 This is also true for pyrrolyl
and indolyl substituted azaaromatic compounds bearing the С-
С bond, linking two aromatic fragments; these structures are
well presented in both natural and pharmaceutical products.3
Several examples are given in Figure 1. Indeed, Nicergoline4
acts as α-adrenoceptor blocking agent; it also possesses a
pronounced spasmolytic activity in relation to cerebral
vascular and peripheral vessels. Hyrtinadine A is an alkaloid,
having 2,5-bis(indolyl) substituted pyrimidine structure,5 which
exhibits cytotoxic activity in vitro against murine leukemia
L1210 cells and human epidermoid carcinoma KB cells.
Another bis-indolyl alkaloid Dragmacidin E is a potent inhibitor
of serine-threonine protein phosphatases (PP).6 Variolin B has
been shown to exhibit cytotoxic activity against a variety of
human cancer cell lines.7
H
CH3
O
OH
HO
O
N
H
CH3
N
N
N
N
H
N
H
H3C
Nicergoline [ref. 4]
α1-adrenoceptor antagonist
Hyrtinadine A [ref. 5]
cytotoxic activity
H
N
NH2
Br
H2
N
N
N
HO
N
N
N
HN
O
NH
N
N
H
N
NH2
OH
Dragmacidin E [ref. 6]
serine-threonine (PP) inhibitor
Variolin B [ref. 7]
antitumor activity
Fig. 1 Natural compounds bearing indole and azine moieties.
proved to be a well known and widely used synthetic
methodology, enabling to obtain the above mentioned
heterocyclic ensembles, bearing bi(hetero)aryl moieties.
During the last decade a new synthetic methodology for
the direct metal-catalysed functionalisation of the C(sp2)-H
bond in (hetero)aromatics, including the formation of new C-X
(X= C, N, O, P, S) chemical bonds, has been advanced.9 This C-H
A great deal of efforts are currently undertaken in order to
develop novel and advanced synthetic approaches for
preparation of indolyl and pyrrolyl substituted azaaromatics,
by using both metal-catalysed cross-coupling reactions and
metal free C-H functionalisations, as well as multi-component
reactions and other synthetic methodologies.
functionalisation
methodology
provides
a
better
correspondence to the atom economy principle,10 and it is
certainly a more attractive from the ecological point of view,
than other synthetic procedures, exploiting displacement of
halogen atoms.
Classical palladium-catalysed cross-coupling reactions of
halogenated heteroaromatics with organometallic derivatives8
a.Ural Federal University, 19 Mira Street, 620002 Ekaterinburg Russia
b.Institute of Organic Synthesis of the Russian Academy of Sciences, 22 S.
Kovalevskoy Street, 620219 Ekaterinburg, Russia
Cross-coupling reactions of π-deficient (hetero)aromatic
compounds with nucleophilic heteroarenes, such as indoles or
pyrroles, which are non-catalysed by transition metals, have
received much less attention. At the same time, a remarkable
progress in studying of these reactions, classified as
c. Institute of Solid State Chemistry of the Russian Academy of Sciences, 91
Pervomaiskaya Street, 620990 Ekaterinburg, Russia, Е-mail: rempel@ihim.uran.ru
*
E-mail: chupakhin@ios.uran.ru; Fax: (+7343) 3693058; Tel: (+7343) 3741189
Electronic Supplementary Information (ESI) available: details of any supplementary
information available should be included here. See DOI: 10.1039/x0xx00000x
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nucleophilic aromatic substitution of hydrogen11 SNHAr (briefly providing an opportunity to develop environmentally friendly
SNH), has been achieved during the last decade due to their processes.
H
practical advantages.11,12 In these SN reactions the formation
In the course of our studies on using various oxidants and
H
of new bonds C(sp2)-X (X= C, Hal, N, O, P, S, Si) requires neither improvement of methods for the oxidative version of the SN
a preliminary functionalisation of the parent (hetero)aromatic reactions we have paid our attention that, when irradiated
compounds, nor use of transition metals (usually Pd), as with UV light, the system O2/TiO2 produces an electron/hole
catalysts. The latter is very important for the synthesis of drugs pair (e-/h+), and oxygen dissolved in a solution can be
and/or organic dyes for solar cells, in which even traces of scavenged with the exited electrons, thus affording the
•
‾
19
transition metals are not permitted. This is why the direct superoxide radicals O2 (Scheme 2), as very active oxidative
metal-free C-H functionalisation of aromatics is considered to species.
be so aspirational approach for both academic and industrial
chemists, thus enabling them to avoid impurities of metals in
the target products.
H
As far as the SN reactions are concerned, these usually
proceed according to the “Addition-Elimination” sequence of
steps with the formal departure of the hydride ion H¯ (Scheme
Scheme 2 Formation superoxide radicals O2•‾.
1). The first step involves a reversible addition of nucleophile
to electron-deficient arene
Since spontaneous elimination of H¯ from the intermediate σH-
adduct is unlikely, an oxidising agent is needed for
rearomatisation of
1 2.
to give the so-called σH-adduct
It is worth mentioning that materials on the basis of TiO2
and its doped forms have found quite wide application in
organic synthesis.20 A number of examples concerning use of
TiO2 for oxidation of alcohols,21 transformation of amines into
imines,21 oxidative cyclisation of diamino compounds,23
oxidation of tetrahydropyrimidin-2-ones,24 and also to initiate
the addition of alkynes to aldehydes,25 have recently been
described.
2
2
, in order to take away a couple of
electrons, while hydrogen is departed as proton H+ (Scheme 1,
H
Path A).11,13 In a vast majority of cases, the SN reactions
proceed under rather mild conditions, and can be realised as
one-pot procedure (Path B), without isolation of the
intermediate σH-adducts
2, and this synthetic procedure
H
As far as application of TiO2 in photo-induced oxidative SN
appears to be a convenient one for oxidative metal free cross-
couplings.
reactions is concerned, no data on this subject have so far
been reported in the literature. In this paper we wish to
describe the first examples of using the system air oxygen/TiO2
for the SNH reactions of azaaromatic compounds with aromatic
nucleophiles, as illustrated by the synthesis of indolyl-azinyl
and pyrrolyl-azinyl heterocyclic ensembles.
Results and discussion
H
As mentioned above, the SN reactions can be carried out as
two-steps processes with isolation of the intermediates
(Scheme 1, Path A). On the other hand, taking into account
that adducts are able to undergo dissociation into starting
2
2
Scheme 1 The C-H functionalisation through nucleophilic substitution of
hydrogen proceeding according the two-step “Addition-Oxidation” mechanism.
materials, a more economical one-pot “through-out” three-
component process, involving starting reagents and oxidant,
appears to be a more attractive procedure (Scheme 1, Path
The oxidation step is a less studied one. Since not only
B).11,13 The target products of these one-pot SN reactions are
H
intermediates
oxidative processes, the right choice of an appropriate oxidant
is of crucial value for C-H functionalisation reactions.11e,12b,14
2, but also nucleophilic species are vulnerable to
usually stable compounds, bearing two aromatic fragments,
linked to each other due to C-H functionalisation of two C-H
bonds of different nature.
A
variety of one- and two-electron oxidants, of both organic
origin and inorganic nature,11-13 have been used as
aromatisation agents. For instance, Hartwig and co-workers
have recently exploited AgF2,14d,15 which proved to be a very
We have established that azaaromatic compounds and
their activated forms (N-H and N-alkyl quaternary salts, аs well
as azinones) are able to undergo the double С-H/С-H coupling
reaction with indoles (5a-d) and pyrrole (5e) under aerobic
conditions in the presence of nanosized particles of TiO2
(commercial accessible, Hombifine N, 100% anatase). All
reactions have been carried out in a quartz flask under
irradiation with a Xe lamp (5000 K, 35 W). It has previously
been shown that the catalysts Degussa P-25 and rutile TiO2
exhibit a remarkably lower activity in oxidative reactions
H
efficient oxidising agent for the SN fluorination of azines.
Besides transition metals,16 hypervalent iodine compounds
have been used in the oxidative C-H/C-H coupling reactions of
(hetero)arenes.16f, 17
The data concerning use of heterogeneous catalysts are
scarcely available in the literature.18 Air oxygen is of special
value as oxidant, since it affords water, as by-product, thus
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relative to anatase TiO2.21b,24 In order to enhance the activity this SNH reaction does not occur, even on reflux in n-butanol or
of TiO2 and to avoid the coagulation of nano-sized particles, a acetonitrile.
mixture of starting materials has been previously treated in
The optimal conditions, found for the reaction of acridine
ultrasonic bath for 5 minutes. The catalyst used can be with indole, have been applied for the С-С coupling of other
separated easily by filtration or centrifugation, washed and azines with indoles and pyrrole. Highly electrophilic azines,
used repeatedly. It has been shown that it does not loose its such as acridine (4a) (Table 2, entry 1), and 5-phenyl-1,2,5-
catalytic activity for at least 5 catalytic cycles.
oxadiazolo[3,4-b]pyrazine (4c) (Table 2, entry 3), have been
The SNH reactions of azaaromatics considered above are of found to react smoothly with indoles (5a-c) and pyrrole (5e) in
general character, and can be applied to a variety of mono-, di- acetic acid at room temperature to give compounds 6a-c,e and
and triazines, including their benzo analogues and substituted 8a-c,e in yields ranged from 49% to 99%. In case of 3,6-
derivatives. The data obtained and references to the diphenyl-1,2,4-triazine (Table 2, entry 2) the reactions of 4b
previously described compounds are summarised in Tables 1- with indoles (5a-c) and pyrrole (5e) have been carried out
3. It is worth noting that interaction of azaaromatics with C- under acidic conditions at 120 °C to afford derivatives 7a-c,e in
nucleophiles of aromatic nature, such as indoles and pyrroles 56-92% yields. Also less electrophilic pyridine, quinoline and
(
5), takes place regioselectively; no by-products due to self- isoquinoline do not undergo these double C-H/C-H coupling
coupling of starting materials, or other substitution reactions reactions of aromatics.
have been observed. Although some compounds have
In the series of C-H/C-H transformations of azaaromatics by
previously been described, we have suggested an action of indoles, there are some features for the SNH reactions
environmentally benign approach, which takes place without in the series of 1,3-diazines, such as pyrimidine (4e) or
oxidant (halogenes, hypohalides, permanganate, sulphur, quinazoline (4d), which can be realised either through a step-
chloranil, DDQ, N-bromosuccinimide, etc.) or additional wise mechanism with isolation of the intermediates
2 (Scheme
reagents (acetyl or benzoyl chloride).11e,13
1, path A), or directly (Scheme 1, path B). It is known that
A number of experiments have been performed for diazines, being protonated in acidic media,29 are capable of
optimisation of the reaction conditions: varying ratio of reacting with nucleophilic reagents to give fairly stable adducts
reagents and catalyst, reaction time, solvent and temperature. 2a-c (Scheme 3). Oxidation of the latter is usually carried out
Acridine having the only electrophilic C-9 center, has been with K3Fe(CN)6 in aqueous solution of KOH.29a,30 We have
chosen as the model azine substrate (Table 1).
succeeded to isolate compounds 2a-c, and have shown that
the oxidative system O2/TiO2 can be used successfully for their
aromatisation according to Scheme 2. It is worth mentioning
that oxidation of 2a-c takes place smoothly and quantitatively
in aqueous alcohol in the presence of equivalent amounts of
NaOH.
Table 1 Optimisation of the C–H/C–H coupling of acridine (4a) with indole (5a)a
Entry
TiO2,
Solvent
Temp., Time,
Yield,
(%)
-
(mass.%)
[°C]
120
90
160
25
25
25
25
120
25
[h]
5
5
5
5
5
5
5
5
4
3
5
5
5
1
2
3
10
10
10
10
-
5
15
10
10
n-BuOH
CH3CN
DMFA
-
10
60
16
53
60
60
47
34
41
26
32
4
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CF3COOH
CH3COOH
5b
7
6
7
8
9
10
11
10
10
25
25
25
25
10 (rutile)
12 10 (Degussa P25) CH3COOH
a
Reaction conditions: acridine 4a, indole 5a, TiO2 catalysts, an appropriate
solvent were irradiated with Xe lamp (5000 K, 35 W) under air oxygen, bubbling
through the reaction mixture. b The reaction was carried out without irradiation.
Scheme 3 SNH Reaction of 1,3-diazines with indole.
H
The SN reactions of quinazoline (4d) and pyrimidine (4e
H
)
It has been established that the best yield (60%) of the SN
with indole (5a) or pyrrole (5e) have also been performed
without isolation of intermediates (Scheme 3). In this case
the reactions have been carried out in mixture of
trifluoroacetic acid and benzene (1:2) for 5 hours (for 9a 10a
product derived from the reaction of acridine (4a) with indole
2
(
5a) is reached under the following conditions: acetic acid as
a
solvent, ambient temperature, and irradiation in the presence
of anatase TiO2 on bubbling air for 5 hours (Table 1, entry 4).
,
)
or in a mixture of HCl and methanol (1:2) for 5 hours (for 9e).
After evaporation of acid and treatment with aqueous NaOH
(2 equiv.) and catalytic amounts of TiO2, an air flow was
bubbled through the reaction mixture on irradiation to give
compounds 9a,e, 10a in 68-70% yields (Table 2, entries 4, 5).
Without irradiation the reaction of acridine (4a) with indole
H
5a) affords the target SN product in only 16% yield. Also
(
acidic catalysis is of great importance. Indeed, without an acid
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Table 2 The C–H/C–H coupling of azaaromatics with indoles and pyrrolea
Solvent,
temperature
Entry
5a
5c
5e
5d
5b
AcOH, RT
(for 6a-c,e)
AcOH, 120 °C
(for 6d)
1
(4a)b
60% (6а)
85% (6c)
80% (6b)
49% (6e)
48%26
38% (6d)
64%26
68%26
N
Ph
N
Ph
N
NH
2
3
AcOH, 120 °C
56% (7e)
(4b)
(4c)
73%27
92% (7а)
70% (7b)
75% (7c)
Br
80%27
43%27
33%27
35% (7d)
AcOH, RT
98% (8e)
>99% (8b)
>99% (8c)
>99% (8а)
70% (9а)
70% (10а)
89% (8d)
1) CF3COOH -
C6H6 (1:2) (for
9a) or HCl -
MeOH (1:2)
(for 9e)
4
5
(4d)
(4e)
2) NaOH (2
equiv.), RT
68% (9e)
CF3COOH -
C6H6 (1:2),
NaOH (2
equiv.), RT
NH
6
n-BuOH, RT
N+
Cl-
H
(4f)
70% (11e)
63% (11c)
46% (11d)
70% (11а)
55% (11b)
7
8
n-BuOH, RT
n-BuOH, RT
(4g)
(4h)
86% (12e)
>99% (12а)
50%13
73% (12d)
52% (13d)
38%13
90% (12c)
74% (13c)
85% (12b)
N
N+
I-
CH3
N
CH3
75% (13а)
46% (13e)
60%13
78% (13b)
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AcOH, 120 °C
AcOH, 120 °C
>99% (14а)
92% (14c)
87% (14d)
99% (14e)
65% (15e)
(4i)
85%28b
86%28b
>99% (14b)
86%28b
10
48% (15d)
(4j)
62% (15а)
62% (15c)
60% (15b)
a Reaction conditions: azaaromatics 4a-j, indoles 5a-c (or pyrrole 5d), TiO2 (10 mass.%, anatase), an appropriate solvent were irradiated with Xe lamp (5000 K, 35 W)
under air oxygen, bubbling through the reaction mixture for 5 h. Yields of isolated, analytically pure products.
The C-C coupling of activated N-alkyl quaternary and N-H
protonated salts of azaaromatics 4f-h (Table 2) with indoles SN products 14a-c,e and 15a-c,e in yields of 92-99% and 60-
5a-d) and pyrrole (5e) have been found to proceed smoothly 62%, respectively.
even at room temperature under neutral conditions. In order As can be expected, electron-withdrawing substituents (Ac,
(5a-c) and pyrrole (5e) in refluxing acetic acid, thus giving the
H
(
to find optimal conditions the reaction of 10-methylacridinium CF3) in the pyrrole ring have a negative effect on nucleophilic
iodide (4g) with indole has been carried out in two-phase properties of pyrroles and indoles. Indeed, all attempts to
systems (Table 3), however yields proved to be rather poor carry out the C-H/C-H couplings of azaheterocycles with 2-
(below 5%).
acetyl- and 2-(trifluoromethyl) substituted pyrroles, as well as
with 3-acetyl and 2-(trifluoromethyl) substituted indoles have
failed. Positive results have been obtained only in the case of
using 5-bromoindole (5d) as a nucleophilic reagent. The yields
Table 3 Optimisation of the C–H/C–H coupling of 10-methylacridinium iodide (4g) with
indole (5a)a
Entry
TiO2,
(mass.%)
Solvent
Temp.,
[°C]
60
60
RT
RT
RT
RT
RT
Time,
[h]
5
5
5
5
5
5
5
Yields,
(%)
5
Trace
71
>99
33
80
of compounds 6d-8d and 11d-15d are 35-89%. Also, it is worth
noting that a more drastic reaction conditions (reflux in acetic
1
2
10
10
10
10
-
5
15
10
Benzene/Water
DMFA/Water
CH3CN
acid) were needed to obtain compound 6d (Table 2).
A plausible mechanism for participation of the oxidative
H
system hv/O2/TiO2 in the SN reactions of azaaromatics
3
4b
5
n-BuOH
n-BuOH
n-BuOH
n-BuOH
4 is
given in Scheme 4.
6
7
8
At the first step a reversible addition of nucleophilic
reagents 5a-e at a carbon atom of heteroarenes takes place.
The second step involves elimination of hydrogen from the C-H
bond of the intermediate σΗ-adducts 17, as two electrons and
99
74
n-BuOH
RT
3
a Reaction conditions: 10-methylacridinium iodide (4g), indole (5a), anatase TiO2,
an appropriate solvent were irradiated with Xe lamp (5000 K, 35W) air oxygen,
H+. The considered oxidative system (Schemes 2, 4) facilitates
b
bubbling through the reaction mixture. The reaction was carried out without
H
aromatization of dihydroazines 17 into SN products 6-10
,
14,
irradiation.
15 in case of neutral azines or 11-13 for cationic quaternary
The activation of azaaromatics by means of their
transformations into quaternary or NH-protonated salts 4f-h
(Table 2, entries 6-8) makes it possible to carry out their
reactions with indoles (5a-c) and pyrrole (5e) under rather mild
conditions, namely in n-butanol at room temperature. Yields of
compounds 11a-c,e, derived from acridinium hydrochloride
salts.
(
4f) proved to be in the range 55-70%. It can likely be
explained by deprotonation of NH-azinium salts into
nonactivated azines. Indeed, higher yields (85-99%) can be
achieved by reacting of N-methylacridinium iodide (4g) with
nucleophilic agents
5 (Table 2, entry 7). N-Alkylazinium salts
are more stable, and have no tendency to loose their N-alkyl
substituents in the reactions with nucleophilic reagents.13 N-
Methylquinoxalinium iodide (4h) proved to be less active
toward nucleophiles
5 relative to the acridinium ion (4g), thus
Scheme 4 A plausible mechanism for the SNH transformations.
giving compounds 13a-c,e in 74-78% yields (Table 2, entry 8),
while quaternary salts of unsubstituted pyridine, quinoline and
isoquinoline are unreactive under these conditions.
Although the paper is dedicated to the synthesis of indoles
and pyrroles derivatives, which are supposed to be interesting
H
Azinones are rarely used as electrophilic agents in the SN
reactions.28 We were able to show that quinoxalin-2-one (4i
for medicinal chemistry, we have done
a number of
)
experiments, thus demonstrating that other aromatic C-
nucleophiles, such as anilines and phenols, can be involved in
(Table 2, entry 9) and 3-(pyridine-2-yl)-1,2,4-triazin-5(2H)-one
4j) (Table 2, entry 10) exhibit a high reactivity toward indoles
(
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the conversions described above. Indeed, quinazoline easily earlier in the literature13,26-28 (Tables 2, 4). Use of the O2/TiO2
adds diethylaniline at room temperature in mixture system for the synthesis of indolyl substituted acridines 6a-c
trifluoroacetic acid-benzene (1:2) to give the corresponding σH- enables the temperature of the process to be decreased from
a
26
)
13
)
adduct (Table 2, entry 4) which is oxidised into 4-(4'-N,N- 70 °C (for 6a-c
and 130 °C (for 21
to room temperature,
diethylaminophenyl)-quinazoline (19) in 56% yield. Heating of while the reaction time for obtaining 12a proved to be
quinoxalin-2-one (4i) with N,N-diethylaniline in acetic acid considerably reduced from 3 days13 to 5 hours. Also the TiO2-
affords compound 22 in 95% yield. 9-(4'-Diethylaminophenyl)- catalysed aerobic oxidative reactions of 3,6-diphenyl-1,2,4-
H
10-methylacridinium iodide (20) and 9-(4'-aminophenyl)-10- triazine afford the SN products 7a-c,e, unlike the literature
methylacridinium iodide (21) have been obtained at room data,27 without additional activation by benzoyl or acetyl
temperature in n-BuOH in 75% and 96% yields, chlorides.
correspondingly (Table 4).
Table 4 C–H/C–H coupling of azaaromatics with anilinesa
Experimental
All reagents were purchased by Sigma Aldrich and used
without any further purification. 1H NMR spectra (400 MHz)
and 13C NMR spectra (100 MHz) were measured on a Bruker-
400 AVANCE II spectrometer and recorded in ppm relative to
an internal tetramethylsilane standard using DMSO-d6 as the
solvent. The mass spectra were measured on Bruker Daltonics
micrOTOF-Q II mass spectrometer equipped with an
orthogonal electrospray ionization (ESI) source, a six-port
divert valve and syringe pump kd Scientific with flow rate 180
μl/hour. The elemental analysis was carried out on an
95% (22)d
automated Perkin Elmer PE 2400 series II CHNS/O analyzer.
90%13
80% (20)c
56% (19)b
The course of the reactions was monitored by TCL on 0.25 mm
silica gel plates (Merck 60F 254). The ultrasonic treatment was
carried out on the digital ultrasonic cleaner Bandelin DT 31H
(100 W, 35 kHz).
75%13
Synthesis of pyrrolyl and indolyl derivatives of acridine
(6a-c,e) and 6-phenyl-[1,2,5]oxadiazolo[3,4-b]pyrazine (8a-e).
A quartz tube containing a solution of acridine 4a (1 mmol) or
6-phenyl-1,2,5-oxadiazolo[3,4-b]pyrazine 4c (1 mmol),
nucleophile (5a-e) (1 mmol) and TiO2 (10 mass.%, anatase) in
acetic acid (10 mL) was treated in ultrasonic bath for 5 min to
obtain a suspension. The resulting mixture was exposed to Xe
lamp (5000 K, 35 W) under air oxygen, bubbling through the
96% (21)c
90%13
a
Reaction conditions: azaaromatics 4, anilines 18a,b, TiO2 (10 mass.%, anatase) were
irradiated with Xe lamp (5000 K, 35 W) under air oxygen, bubbling through the reaction
b
mixture for 5 h. Appropriate solvents and temperature: CF3COOH - C6H6 (1:2), NaOH
(2 equiv.), RT; c n-BuOH, RT; d AcOH, 120 °C.
Phenol and 2,6-dimethylphenol (in their anionic forms) reaction mixture at room temperature for 5 h. The reaction
enter the reaction with N-methylacridinium iodide (4g) to give mixture was concentrated under a reduce pressure. The
the dihydroacridines 24a,b, which can be oxidised with O2/TiO2 residue was purified by column chromatography on silica gel
in eluting with mixture hexane/ethyl acetate (8/2).
system on irradiation in n-BuOH into biaryl derivatives 25a
,
b
overall yields 80% and 90%, correspondingly.
Synthesis of 9-(5-bromo-1H-indol-3-yl)acridine (6d) and
pyrrolyl, indolyl derivatives of 3,6-diphenyl-1,2,4-triazine (7a-
e). A quartz tube containing a solution of acridine 4a or 3,6-
diphenyl-1,2,4-triazine 4b (1 mmol), nucleophile (5a-e) (2
mmol) and TiO2 (10 mass.%, anatase) in acetic acid (10 mL)
was treated in ultrasonic bath for
5 min to obtain a
suspension. The resulting mixture was exposed to Xe lamp
(5000 K, 35 W) under air oxygen, bubbling through the
reaction mixture and was held at boiling for 5 h. The reaction
mixture was concentrated under a reduce pressure. The
residue was purified by column chromatography on silica gel
eluting with mixture hexane/ethyl acetate (8/2).
Scheme 5 C–H/C–H coupling of 4g with phenols 23a,b.
A common feature of the studied reactions is that yields of
vast majority of products derived from the C-H/C-H coupling of
azaaromatics with indoles and pyrrole by using the aerobic
oxidative procedure in the presence of TiO2 and irradiation
proved to be higher (from 5 to 50%), than those reported
Synthesis of 4-(1H-indol-3-yl)quinazoline (9a), 4-(1H-indol-
3-yl)pyrimidine (10a) and 4-(4'-N,N-diethylaminophenyl)-
quinazoline (19). To a round bottom flask were added a
solution of quinazoline 4d (1 mmol) or pyrimidine 4e (1 mmol),
indole 5a (1 mmol) or N,N-diethylaniline 18b (1,5 mmol) in
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mixture trifluoroacetic acid/benzene 1/2 (10 mL). The reaction hexane/ethyl acetate (8/2) (for 14a-e, 22) or mixture ethyl
mixture was stirred at room temperature for 5 h. The solvent acetate/methanol (10/1) (for 15a-e).
was further removed under vacuum. A quartz tube containing
Synthesis of 9-(4'-hydroxyphenyl)-10-methylacridinium
a solution of residue in ethanol, aqueous NaOH (2 equiv.) and chloride (25a) and 9-(4'-hydroxy-3',5'-dimethylphenyl)-10-
TiO2 (10 mass.%, anatase) was treated in ultrasonic bath for 5 methylacridinium chloride (25b). To a round bottom flask
min to obtain a suspension. The resulting mixture was exposed were added a solution of phenol 23a (1 mmol) or 2,6-
to Xe lamp (5000 K, 35 W) under air oxygen, bubbling through dimethylphenol 23b (1 mmol) in dry ethanol and NaOH. The
the reaction mixture at room temperature for 5 h. The reaction mixture was refluxed for 2 h. The hot solution of N-
reaction mixture was then transferred to separatory funnel. methylacridinium iodide 4g was added in solution of phenol
The aqueous layer was extracted with CHCl3 (3 x 10 mL). The and refluxing was continued for 4 h. The reaction mixture was
organic extracts were combined and dried over Na2SO4, further concentrated under a reduce pressure. A quartz tube
filtered and concentrated under a reduce pressure. The containing solution of residue and TiO2 (10 mass.%, anatase) in
residue was purified by column chromatography on silica gel n-BuOH and HCl (2 equiv.) was treated in ultrasonic bath for 5
eluting with a mixture ethyl acetate/methanol (10/1).
min to obtain a suspension. The resulting mixture was exposed
Synthesis of 4-(1H-pyrrol-3-yl)quinazoline (9e). To a round to Xe lamp (5000 K, 35 W) under air oxygen, bubbling through
bottom flask were added a solution of quinazoline 4d (1 the reaction mixture at room temperature for 4 h. The
mmol), pyrrole 5e (1 mmol) in mixture HCl/MeOH 1/2 (2 mL). reaction mixture was filtered. The solvent from filtrate was
The reaction mixture was stirred at room temperature for 10 removed under vacuum. Then dry diethyl ether was added to
h. The solvent was further removed under vacuum. A quartz resulting mixture and the form suspension was filtered. The
tube containing a solution of residue in ethanol, aqueous residue
was
recrystallized
from
mixture
ethyl
NaOH (2 equiv.) and TiO2 (10 mass.%, anatase) was treated in acetate/methanol (1/1).
ultrasonic bath for 5 min to obtain a suspension. The resulting
mixture was exposed to Xe lamp (5000 K, 35 W) under air
Conclusions
oxygen, bubbling through the reaction mixture at room
temperature for h. The reaction mixture was then
5
In conclusion, the aerobic photo-induced reactions of azines
with indoles or pyrrole, proceeding in the presence of
nanosized TiO2, proved to be an easy, atom-economical, highly
selective and environmentally benign method for the oxidative
transferred to separatory funnel. The aqueous layer was
extracted with CHCl3 (3 x 10 mL). The organic extracts were
combined and dried over Na2SO4, filtered and concentrated
under a reduce pressure. The residue was purified by column
chromatography on silica gel eluting with a mixture ethyl
acetate/methanol (10/1).
H
C-H/C-H coupling of two aromatic fragments. These SN
reactions have been shown to occur under ambient conditions,
thus providing a convenient way to produce a variety of
heterocyclic compounds of high value to pharmaceutical
chemistry.
Synthesis of derivatives of acridinium chloride (11a-e), 10-
methylacridinium iodide (12a-e, 20, 21) and 1-
methylquinoxalin-1-ium iodide (13a-e).
A quartz tube
containing a solution of 10-hydroacridinium chloride 4f, 10-
methylacridinium iodide 4g or 1-methylquinoxalinum iodide
4h (1 mmol), nucleophile 5a-e (2 mmol) or 18a,b (2 mmol) in
n-BuOH (10 mL) and TiO2 (10 mass.%, anatase) was treated in
ultrasonic bath for 5 min to obtain a suspension. The resulting
mixture was exposed to Xe lamp (5000 K, 35 W) under air
oxygen, bubbling through the reaction mixture at room
temperature for 5 h. The reaction mixture was concentrated
under a reduce pressure. Then dry diethyl ether was added to
a solution and the form suspension was filtered. The residue
was recrystallized from benzene or acetonitrile.
Acknowledgements
The research was financially supported by the Russian Science
Foundation (Project No. 14-13-01177).
Notes and references
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