Sulfur-Promoted Aminative Aromatization of 1,2,3,4-Tetrahydrophenazines with Amines: Flexible Access to 1-Aminophenazines

Article abstract of DOI:10.1002/adsc.201800260

Elemental sulfur was found to be an excellent reagent for promoting the aminative aromatization of 1,2,3,4-tetrahydrophenazines with amines to provide a wide range of functionalized 1-aminophenazines. (Figure presented.).

Full text of DOI:10.1002/adsc.201800260

Title: Sulfur-Promoted Aminative Aromatization of 1,2,3,4-
Tetrahydrophenazines with Amines: Flexible Access to 1-
Aminophenazines
Authors: Thanh Binh Nguyen and pascal retailleau
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10.1002/adsc.201800260
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Sulfur-Promoted Aminative Aromatization of 1,2,3,4-
Tetrahydrophenazines with Amines: Flexible Access to 1-
Aminophenazines
Thanh Binh Nguyen,a* and Pascal Retailleaua
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1,
avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
thanh-binh.nguyen@cnrs.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
without any transition metal catalyst/ligand (Scheme
Abstract. Elemental sulfur was found to be an excellent
reagent for promoting the aminative aromatization of 1).
1,2,3,4-tetrahydrophenazines with amines to provide a wide
range of functionalized 1-aminophenazines.
Keywords: elemental sulfur; C-H amination;
aromatization; C-H functionalization; phenazine
Scheme 1. Aminative Aromatization of 5 with Amine
The formation of CArom-N bonds occupies a
significant place in chemistry for the synthesis of
secondary and tertiary aromatic amines, which are
important structural scaffolds in numerous functional
molecules and biologically active compounds.
Traditionally, these aromatic amines are conveniently
synthesized via Pd- or Cu-catalyzed cross-couplings
of amines and aryl halides.[1] These strategies require
however the use of expensive catalysts/ligands,
drastic conditions, and pre-functionalized aromatics.
In this context, simple and inexpensive methods for
the direct amination of readily available C-H bonds
with amine nucleophiles are very desirable but far
from being general.
Functionalized phenazines are important structural
motif in naturally occurring compounds[2] as well as
artificial bioactive molecules.[3] Moreover, as redox-
active scaffold, phenazine core is a potential
candidate for the development of organic batteries.[4]
Although many synthetic methods have been reported,
the syntheses of such molecules required generally
multistep sequences and employed starting materials
with preinstalled functional groups necessary for the
reactions.[2] In this regard, development of strategy
involving simple starting materials/reagents with
many transformations in a single pot provides several
will provide excellent solutions for saving time,
energy, resources and avoiding purification between
reaction steps.
In connection with our research program aimed at
exploiting the diverse reactivities of sulfur,[5] we
reported the oxidative coupling promoted by this
element between o-phenylenediamine 1a with
cyclohexanone 2a to provide tetrahydrophenazine
5aa.[6] The screening of sulfur activators showed that
most of nitrogen-containing basic additives that were
known to be capable of activating elemental sulfur
(N-methylmorpholine, N-methylpiperidine, DMF)
were found to be unsuitable to accelerate the expected
oxidative coupling due to the degradation of
cyclohexanone promoted by these basic amines.
When aniline was used as an additive, because of its
lower basicity, the observed activating effect was
negligible. To our surprise, we obtained the
unexpected 1-anilinophenazine 4aaa as
a red
crystalline compound in low yield (Scheme 2).
Scheme 2. Formation of 1-anilinophenazine 4aaa
This communication describes an unexpected
oxidative amination of 1,2,3,4-tetrahydrophenazine 5
with amine 3 to provide phenazine 4 in the presence
of elemental sulfur under mild thermal conditions
As the ratio 4aaa:5aa increased with prolonged
heating, 4aaa was obviously generated by an
1
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10.1002/adsc.201800260
Advanced Synthesis & Catalysis
aromatizing anilination of 5aa. This interesting initial toluidines 3b-d, meta- and para-isomers 3b-c reacted
observation prompted us to initiate an in-depth smoothly, leading to the expected phenazines 4aab
investigation for this original aromatizing amination and 4aac in 76-78% yields. On the contrary, o-
reaction promoted by sulfur. In the first instance, to toluidine 3d as well as other o-methylated anilines
avoid complication with side reactions involving 3e,f or 1-naphthylamine 3g exhibited lower reactivity.
cyclohexanone 2a, we replaced it by cyclohexane-1,2- Their reactions resulted in the expected product 3aae-
dione 7a,[7] which we found to react rapidly and 3aag in lower yields. Among our very first examples,
quantitatively with o-phenylenediamine 1a to provide 1-(p-isopropylanilino)phenazine 4aah was obtained
5aa. As expected, the yield of 4aaa was improved in high yield and its structure determined by X-ray
(entry 1). The conversion into 4aaa was further crystallography confirmed unambiguously the 1-
improved by lower the reaction temperature to 80 °C anilinophenazine scaffold of the family.[8] The
(entry 2). The influence of different sulfur activating reactions with all three anisidines 3i-k proceeded
additive was further inspected (entries 3-8). Among without any difficulty even with o-isomer 3k. On the
them, N-methylpiperidine (NMP), which was the contrary, o-halo anilines 3l,m displayed reduced
strongest base among the tested additives, appeared to reactivity even with small halogen atoms such as
be unsuitable to provide 4aaa (entry 3). Indeed, 4aaa fluorine or chlorine (phenazines 4aal and 4aam).
was formed in trace quantity along with significant Apart from this steric hindrance of the o-haloanilines,
amount of phenazine 6aa and extensive degradation. the reaction conditions tolerated all four halogens,
Other less basic additives such as N- including bromine 4aap and iodine derivatives 4aaq-
methylmorpholine (NMM), 3-picoline (entries 4-5) or 4aar. Anilines bearing strong electron withdrawing
weakly basic one such as DMF, 1,4-dioxane (entries groups such as CF3, ester, amide or nitro 3s-3v were
6-7) led to better yields of 4aaa. The best result was shown to be less reactive although these functional
obtained when DMSO was used as an additive (entry groups remained intact under the present reaction
8). The amount of DMSO used was found to be conditions.
S
N
important to the reaction yields, which culminated
NH2
O
H2N
6 (equiv)
+
+
R
with 3 equiv (entry 8 vs entries 9-10). Finally, we
found that while increasing the reaction temperature
led to degradation and lower the yield of 4aaa (entry
11), performing the reaction at lower temperature
resulted in incomplete conversion (entry 12).
N
DMSO
(1.5 equiv)
80 °C, 16 h
NH2
HO
HN
R
1a
7a
3
4
0.5 mmol, 1 equiv
2 equiv
2 equiv
N
N
4aab, 4-Me, 78%
4aac, 3-Me, 76%
4aad, 2-Me, 31%
4aae, 2,5-Me2, 33%
4aaf, 2,3-Me2, 38%
N
N
2
5
HN
HN
3
Table 1. Optimization of the Reaction Conditions
Me
4
4aag, 31%
N
N
HN
Me
X-ray structure of 4aah
4aah, 77%
Me
Entrya)
additive
n
t (°C)
yield of 4aaa (%)b)
N
N
4aap, R = 4-Br, 69%
4aaq, R = 4-I, 63%
4aar, R = 3-I, 55%
4aas, R = 3-CF3, 56%
4aat, R = 3-CO2Me, 63%
4aau, R = 3-CONH2, 63%
4aav, R = 3-NO2, 27%
4aai, R = 4-MeO, 60%
4aaj, R = 3-MeO, 66%
4aak,R = 2-MeO, 63%
4aal, R = 2-F, 42%
4aal, R = 2-Cl, 32%
4aan, R = 3-Cl, 48%
4aao, R = 4-Cl, 63%
1
2
3
4
5
6
7
8
9
-
-
-
-
100
80
80
80
80
80
80
80
80
80
100
60
25
30
2
HN
3
R
4
NMPc)
NMMe)
3-picoline
DMF
2
2
2
2
2
3
1
6
3
3
-
d)
31
50
55
35
78
62
71
48
44
N
N
N
N
N
N
Me
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
4aax, 0%
4aay, 54%
Reaction conditions: 1a (0.5 mmol), 2b (1 mmol), 3a (1 mmol), S
(3 mmol, 96 mg), DMSO (0.1 mL), 80 °C, 16 h.
10
11
12
a)
Reaction conditions: 1a (0.5 mmol, 54 mg), 7a (1 mmol,
112 mg), 3a (1 mmol, 93 mg), S (3 mmol, 96 mg), additive
(0.1 mL), t °C, 16 h. b) Isolated yield. c) N-Methylpiperidine.
d) Not isolated. e) N-Methylmorpholine.
Scheme 3. Scope of anilines 3
It should be noted that although the reaction
generate hydrogen sulfide as a by-product that was
known as a strong reducing agent for nitro group, the
nitro-substituted phenazine 4aav was obtained
without formation of the products in which the nitro
group was reduced. The reaction was found to be
sensitive to the steric hindrance on the nitrogen atom
of aniline. Only trace of the expected phenazine 4aax
With the optimized reaction conditions in hand, a
preliminary study was performed to determine the
substrate scope of this reaction. We first explored the
behavior of anilines with o-phenylenediamine 1a and
cyclohexane-1,2-dione 7a (Scheme 3). Among the
2
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10.1002/adsc.201800260
Advanced Synthesis & Catalysis
observed when N-methylaniline was used 3x. On the
Subsequently, we investigated the formation of
other hand, phenazine 4aay derived from indoline phenazines 4 bearing different functional groups on
could be obtained in moderate yield, undoubtedly due the ring
A
(Table 2). For this purpose,
to the more accessible nitrogen of indoline 3y.To tetrahydrophenazines 5 could be formed by in situ
further evaluate the scope of this reaction, a variety of condensation between o-phenylenediamine 1a with
analogues of o-phenylenediamine were employed cyclohexane-1,2-dione 2b (entry 1) or could be used
(Scheme 4). o-Phenylenediamines 4-substituted by a directly
(entries
2-6).
When
1-
methyl, an ethyl ester, a carboxylic acid, a methyltetrahydrophenazine was used (entry 2) instead
trifluoromethyl or a benzoyl group gave nearly of a mixture of o-phenylenediamine 1a and dione 2b
equimolar mixtures of both regioisomers 4baa, 4daa, (entry 1), the yield was significantly improved.
4eaa, 4faa or 4gaa, respectively. The reactivity of
these o-phenylenediamines as well as of 4,5- Table 2. Scope of Tetrahydrophenazines 5
dimethyl-o-phenylenediamine was found to be similar
to unsubstituted o-phenylenediamine. It should be
emphasized that the reaction was compatible with free
carboxylic acid group (4eaa). The regioisomers of
phenazine products bearing an electron-withdrawing
group such as ester (4daa), free carboxylic acid
Entrya)
(1a + 2) or
quinoxaline 5
product
yield
(%)
(4eaa), trifluoromethyl (4faa) or benzoyl (4gaa)
could be separated by column chromatography. The
structure of the less polar regioisomer 4faa-F1 was
determined by X-ray crystallography.[8]
S
N
NH2
NH2
O
H2N
6 (equiv)
4
R
R
+
+
N
DMSO
(1.5 equiv)
80 °C, 16 h
5
HO
7a
2 equiv
NHPh
1
3a
4
0.5 mmol, 1 equiv
2 equiv
N
Me
Me
N
N
N
Me
RO2C
N
N
NHPh
4baa, 77%
NHPh
4caa, 75%
NHPh
R = Et, 4daa, 66%
R = H, 4eaa, 65%
N
N
N
7
8
Bz
F3C
N
NHPh
4gaa, 71%
X-ray structure
of 4faa-F1
NHPh
4faa, 71%
N
N
7
8
MeO
Cl
N
N
10
NHPh
NHPh
X-ray structure
of 4haa
+
4haa, 26% at 70 °C
4iaa, 30%
Reaction conditions: 1a (0.5 mmol), 2b (1 mmol), 3a (1 mmol), S
(3 mmol, 96 mg), DMSO (0.1 mL), 80 °C, 16 h
a)
Reaction conditions: 1a (0.5 mmol), 2b (1 mmol), 3a (1
mmol), S (3 mmol, 96 mg), DMSO (0.1 mL), 80 °C, 16 h
for entry 1; 5ab-5ac (0.5 mmol) for entries 2-6.
Scheme 4. Scope of o-phenylenediamines 1
Other tetrahydrophenazines 5ac-5af bearing a
substituent of different steric and electronic natures
(methyl, t-butyl, phenyl, and ethyl ester) reacted
smoothly at 80 °C, leading to the corresponding
phenazines (4aca-4afa) in moderate to good yields
(entries 2-6). The reaction was found to be highly
regioselective as only one regioisomer could be
isolated with 2-substituted tetrahydrophenazines (5ac-
5af) (entries 3-6). As noted previously, the formation
of C-N bond between aniline and phenazine moieties
depends on the steric hindrance of both of them.
4-Chloro-o-phenylenediamine 1h was found to be
sensitive to the reaction conditions and its reaction
was performed at lower temperature (70 °C) to yield
the phenazine product 4haa. Surprisingly, only 8-
chloro regioisomer was detected in the crude reaction
mixture and was isolated. [8] The low yield and the
obtention of a unique regioisomer could be explained
by the instability of 7-chloro regioisomer, which was
supposed to be initially formed in the reaction mixture
but further decomposed. Such instability would be a
direct result of an intramolecular hydrogen bond
between the aniline group and N-10 atom, which is at
the para position to C-7 atom.
As traces of phenazine 6aa was detected in the
reaction
mixtures,
it
was
possible
that
anilinophenazine 4aaa could be formed by an
oxidative anilination of phenazine 6aa in the presence
of sulfur. As the control experiment shown in Scheme
Readily oxidizable 4-methoxy-o-phenylenediamine
was also competent substrate, providing the product
4iaa as a 2:1 mixture of the two possible regioisomers.
3
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10.1002/adsc.201800260
Advanced Synthesis & Catalysis
5 did not lead to any trace of anilinophenazine 4aaa, is highly advantageous as some nitro derivatives are
this possibility was ruled out.
less expensive and more readily available than their
aniline analogs. Although sulfur could act as a
catalyst in this reaction, its catalytic activity is far
from efficient to be used in catalytic amount.
Scheme 5. Control experiment
In the present stage, our observations are consistent
with the reaction pathway presented in Scheme 6. As
previously described, the first step would be the
formation tetrahydrophenazine 5. The next step could
be a dearomatizing tautomerization of 5 into A. As a
Michael acceptor, A would subject to a nucleophilic
attack by aniline 3, leading to adduct B. Subsequent
sequential aromatization of B and C would provide 1-
anilinophenazine 4. The determining step is obviously
the Michael addition of 3 to A, which depends on
steric hindrance of both aniline and A.[8]
Scheme 8. Reactions with 2a and ArNH2/ArNO2
In conclusion, we have described a conceptually
simple but highly unusual strategy that allows a rapid
assembly of a new class of functionalized 1-
anilinophenazines. This reaction was achieved
through the formation of three C-N bonds and the
sequential double aromatization in a single operation.
The method represents
a
rare example of
multicomponent process for one-step construction of
complex structures starting from very simple starting
materials
such
as
cyclohexane-1,2-
diones/cyclohexanones, o-phenylenediamines and
anilines/nitrobenzenes. Once again, the method
highlights the usefulness of elemental sulfur as an
excellent synthetic tool for organic chemistry. Further
developments of such strategy with sulfur are ongoing
in our laboratory and the results will be reported in
due course.
Scheme 6. Proposed mechanism
The versatility of our approach was further
demonstrated with aliphatic amines 8a-8c (Scheme
7). To our delight, the expected products 9aaa-9aac
were obtained under the standard reaction conditions,
with better yields for less hindered primary amines.
Acknowledgements
We thank Dr. A. Marinetti (Institut de Chimie des Substances
Naturelles) for her support.
References
[1] For reviews, see: a) C. Sambiagio, S. P. Marsden, A. J.
Blacker, P. C. McGowan, Chem. Soc. Rev. 2014, 43,
3525; b) A. R. Muci and S. L. Buchwald, Top. Curr.
Chem. 2002, 219, 131; c) J. F. Hartwig, Acc. Chem. Res.
2008, 41, 1534.
Scheme 7. Reactions with selected aliphatic amines 8
To complete our investigation, we applied
cyclohexanone as an inexpensive precursor for the
ring A of phenazine 4 (Scheme 8, eq. 1). Its reaction
with o-phenylenediamine 1a and m-toluidine 3c at
100 °C provided the expected phenazine 4aac in 42%
yield. Moreover, because hydrogen sulfide is a by-
product of the reaction, it is desirable to limit its
formation. By using nitrobenzene 10a as a less
expensive surrogate of aniline 1a, we could obtain the
phenazine product 4aaa while lowering the formation
of H2S from 5 equiv to only 2 equiv as 3 equiv was
used for reduction of the nitro group (eq. 2).
Additionally, from practical standpoint, this approach
[2] For an excellent review on recent developments in the
isolation, biological function, biosynthesis and
synthesis of natural products bearing a phenazine motif,
see: N. Guttenberger, W. Blankenfeldt R. Breinbauer,
Bioorg. Med. Chem. 2017, 25, 6149.
[3] a) V. Udumula, J. L. Endres, C. N. Harper, L. Jaramillo,
H. A. Zhong, K. W. Bayles, M. Conda-Sheridan, Eur. J.
Med. Chem. 2017, 125, 710; b) A. T. Garrison, Y.
Abouelhassan, V. M. Norwood IV, D. Kallifidas, F. Bai,
4
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10.1002/adsc.201800260
Advanced Synthesis & Catalysis
M. T. Nguyen, Rolfe, M. G. M. Burch, S. Jin, H.
Luesch, R. W. Huigens, J. Med. Chem. 2016, 59, 3808.
[4] M. Lee, J. Hong, B. Lee, K. Ku, S. Lee, C. B. Park, K.
Kang, Green Chem. 2017, 19, 2980.
[5] a) T. B. Nguyen, Adv. Synth. Catal. 2017, 359, 1106; b)
T. B. Nguyen, Asian J. Org. Chem. 2017, 6, 477.
[6] T. B. Nguyen, P. Retailleau, Adv. Synth. Catal. 2017,
359, 3843.
[7] Although cyclohexane-1,2-dione 7a is frequently
described as 1,2-dione form, its 1H NMR spectrum
shows that one of its ketone group is under enol form in
CDCl3.
[8] The crystallographic coordinates have been deposited
with the Cambridge Crystallographic Data Centre;
deposition no. CCDC 1544067 (4aah), CCDC
1584933 (4faa-F1), and CCDC 1811702 (4haa).
[9] For an example of heteroaromatization promoted by
sulfur in DMSO, see: F. Shibahara, R. Sugiura, E.
Yamaguchi, A. Kitagawa, T. Murai, J. Org. Chem.
2009, 74, 3566.
[10]Trace amount of 4aaa was formed when S was used in
10 mol %.
5
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10.1002/adsc.201800260
Advanced Synthesis & Catalysis
UPDATE
Sulfur-Promoted Aminative Aromatization of
1,2,3,4-Tetrahydrophenazines with Amines:
Flexible Access to 1-Aminophenazines
Adv. Synth. Catal. Year, Volume, Page – Page
Thanh Binh Nguyen,* and Pascal Retailleau
6
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