Terminal methyl as a one-carbon synthon: Synthesis of quinoxaline derivatives: Via radical-type transformation

Article abstract of DOI:10.1039/c9nj04910j

An iron-promoted method for the construction of pyrrolo[1,2-a]quinoxaline derivatives has been developed. Ferric chloride served as a promoter and as a Lewis acid in the reaction. Solvents provided the corresponding carbon sources simultaneously. The majority of solvents with terminal methyl groups, including ethers, amines and dimethyl sulfoxide, were reactive in the synthesis of quinoxaline derivatives at a certain yield via C-H(sp³) amination/C-O or C-N (C-S) cleavage. This method was applicable to a wide range of pyrrolo[1,2-a]quinoxaline and indolo[1,2-a]quinazoline substrates.

Full text of DOI:10.1039/c9nj04910j

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DOI: 10.1039/C9NJ04910J
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Terminal Methyl as a One-Carbon Synthon: Synthesis of
Quinoxaline Derivatives via Radical-type Transformation†
Xinfeng Wang, a Huanhuan Liu,a Caixia Xie,a Feiyu Zhou,a and Chen Ma*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An iron-promoted method for the construction of pyrrolo[1,2-a]quinoxaline derivatives has been developed. Ferric
chloride served as promoter and Lewis acid in the reaction. Solvents provided corresponding carbon sources
simultaneously. A majority of solvents with terminal methyl group, including ethers, amines and dimethyl sulfoxide, were
reactive for the synthesis of quinoxaline derivatives at the certain yields via C−H(sp3) amination/C−O or C−N (C−S) cleavage.
The method was applicable to a wide range of pyrrolo[1,2-a]quinoxaline and indolo[1,2-a]quinazoline substrates.
Afterwards, numerous protocols for the construction of
pyrrolo[1,2-a]quinoxalines have sprung up. Among these
methodologies, the cyclization synthesis of substituted N-
Introduction
As a common polar solvent, N, N-dimethylformamide (DMF) is
also considered to be versatile organic synthon for
phenyl pyrroles has always been the most active part.
Generally, a nitro or amino group at the 2-position in phenyl
rings is more beneficial to the success of cyclization and
aromatization. In 2012, Thiery and Pereira groups explored a
synthetic method of quinoxaline derivatives in the condition of
iron and HCl which adopted alcohols as raw materials through
oxidation cyclization of nitrobenzene (Scheme 2, reaction
2a).18 But the low yield of reaction was accompanied by the
excessive use of iron and HCl. In 2015, Jayaprakash and co-
workers reported an iodine-promoted synthetic pathway
employing benzylamine and 2-(1H-pyrrol-1-yl)aniline as
a
formylation1, amination2 and cyanation3 of many complex
organic compounds. It’s not until Lou and Xu4a first reported
an iron-catalyzed benzylic vinylation in 2012 that the
utilization of DMF as methylenation agent have been gradually
developed. Recently, the N-methyl moiety of DMF served not
only for methylene insertion4 but also for the transformation
of
−
CH3,5
−CH− −
6 and C=O7 as one-carbon synthon (Scheme 1).
Pyrrolo[1,2-a]quinoxaline derivatives, an important class of
N-heterocyclic compounds, have rather widespread
application in organic functional materials, pharmaceuticals
and biological studies. In many cases, the functionalized
pyrrolo[1,2-a]quinoxaline derivatives were proved to possess a
wide range of biological and pharmaceutical properties, for
example anti-ulcer,8 antimalarial,9 anti-HIV,10 antitumor11 and
other activities. In addition, it has been used as 5-HT3 receptor
agonists,12 human protein kinase CK2 inhibitors,13 PARP-1
inhibitors,14 non-peptide glucagon receptor antagonists,15 and
so on. Furthermore, it can also be disposed as fluorescent
probes for amyloid fibril.16
Nowadays multifarious synthesis ways have been reported
to construct this structural skeleton. It was for the first time in
1966 that a method for the preparation of pyrrolo[1,2-
a]quinoxaline through the reactions between 2-(1H-pyrrol-1-
yl)aniline and formic acid under reflux conditions was reported
by Cheesman and Tuck groups (Scheme 2, reaction 1).17
a.Key Laboratory of Special Functional Aggregated Materials, Ministry of
Education, School of Chemistry and Chemical Engineering, Shandong University,
Jinan 250100, P. R. China.
b.State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing 100050, P. R. China.
Scheme 1. Reactions of DMF as methylenating agent
† Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the Reaction ConditionsaView Article Online
DOI: 10.1039/C9NJ04910J
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entry
1
[Fe]
FeCl3
[O]
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
TBPB
K2S2O8
Na2S2O8
(NH4)2S2O8
TBPB
--
T (°C )
110
120
130
120
120
120
120
120
120
120
120
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120
120
120
yield (%)b
62
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FeCl3
75
3
FeCl3
74
Scheme 2. Synthesis of Pyrrolo[1,2-a]quinoxaline
4
FeBr3
62
5
Fe2(SO4)3
Fe(NO3)3•9H2O
FePO4
FeCl3
37
6
trace
39
reaction substrates (Scheme 2, reaction 2b).19 Nonetheless,
there is still no solution to the excessive use of toxic additive.
In the subsequent reports on the cyclochemistry of aniline, it
was found that acids20 and alcohols21 could also be utilized as
substrates to participate in the reaction for efficient synthesis
of pyrrolo[1,2-a]quinoxaline under certain conditions. There
are still many ineluctable imperfections in these methods yet,
for instance, tedious procedure, complicated operation, toxic
reagent, low productive, poor applicability and the like.
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9
FeCl3
88
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FeCl3
11
FeCl3
10
FeCl3
8
--
n.d.
9
In 2017,
a method of metal-free catalytic oxidation
FeCl3
cyclization of 2-(1H-pyrrol-1-yl)aniline with dimethyl sulfoxide
was developed for synthesizing various substituted
pyrrolo[1,2-a]quinoxalines by our group (Scheme 3, reaction
FeCl3
O2
38
FeCl3
N2
8
1).22 Nevertheless
， methyl mercaptan was generated as
a1a (0.3 mmol), DMF (2 mL), iron (0.3 mmol), oxidant (0.9 mmol),
under air (unless otherwise noted), 120 °C (5~9 h). bIsolated yields.
environmentally unfriendly byproducts in the reaction which S-
methyl group of DMSO was used as the carbon source. It is not
difficult to find that all of the aforementioned methodologies
were merely appropriate for such single substances as alcohols,
amines or acids. Hence, we disclosed a novel and efficient
approach to preparing pyrrolo[1,2-a]quinoxalines and
indolo[1,2-a]quinoxalines via an iron-promoted sp3 C−H
activation and oxidative cyclization process (Scheme 3,
reaction 2). Except that the solvents can be used as carbon
sources, readily available Fe (III) which was a Lewis acid in
place of Bronsted acid also acted as reaction facilitation. In
comparison to the past limitations of single carbon sources,
not only S-methyl group of DMSO but N-methyl group of
amines and o-Methyl group of ethers can also be used as the
carbon source in this reaction.
Results and discussion
Initially, the reaction of 2-(1H-pyrrol-1-yl)aniline 1a (0.3 mmol)
with the participation of FeCl3 (0.3 mmol) and TBHP (0.9 mmol)
stirred in 2 mL solvent (DMF) at 110 °C under air atmosphere
for 5h was chosen as the model reaction to examine the
diversity of reaction parameters and the desired product 2a
was gained in 62% yield (Table 1, entry 1). To our delight, a
satisfactory yield of 75% was obtained at 120 °C (Table 1, entry
2). There was no significant change in the yield when the
reaction was conducted at a relatively high temperature of
130 °C (Table 1, entry 3). The variable amount of neither Fe (III)
nor oxidant increased the yield. Examinations of diverse iron
salts, including FeBr3, Fe2 (SO4)3, Fe (NO3)3•9H2O and FePO4, did
not produce ideal results (Table 1, entries 4−7). Subsequently,
when other oxidants such as DTBP, TBPB, K2S2O8, Na2S2O8 and
(NH4)2S2O8 were examined, TBPB gave the best yield (88%) of
all (Table 1, entries 8−12). When the reaction was carried out
in the absence of iron, no target product was detected (Table 1,
entry 13) and the yield of heterocyclic product was as low as 9%
without TBPB (Table 1, entry 14), suggesting that ferric iron and
TBPB was essential for the process. The yield of 2a decreased
precipitously to 38% when oxygen was employed as the
Scheme 3. Synthesis of Heterocyclic Compounds Employing Solvent
as a One-Carbon Synthon
2 | J. Name., 2012, 00, 1-3
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Table 2. Substrate Scope of Carbon Sourcesa
bond, we explored the reaction under standard VcieownAdrtiitcileoOnnlbinye
using 1, 4-dioxane S11 as carbon source. DBOyI:c1o0m.10p3a9r/iCso9NnJt0o49S1100J
S11 gave a slightly higher yield (Table 2, entries 10).
Correspondingly, a series of chain ethers also achieved a good
yield (Table 2, entries 11−13). Moreover, DMSO S15 also gave
,
the expected cyclization products 2a in 58% yields. In summary,
N-methyl was much more reactive than o-Methyl and S-methyl
by contrast, and the reactions using heterocyclic amines and
ethers as carbon sources were also feasible, albeit in
somewhat low yields.
Having established the optimal carbon source S1, the
substrate scope of the 2-(1H-pyrrol-1-yl) anilines with
disparate substituents on the aromatic ring was surveyed. A
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majority of different substituted
achieve medium yield. Compared with
1
was able to participate to
containing an
1
electron-withdrawing group, that bearing an electron-donating
Table 3. Substrate Scope of 2-(1H-Pyrrol-1-yl) anilinea,b
a1a (0.3 mmol), carbon source (2 mL), FeCl3 (0.3 mmol), TBPB (0.9
mmol), under air (unless otherwise noted), 120 °C (5~10 h).
bIsolated yields.
oxidant (Table 1, entry 15), which demonstrated that TBPB was
not just an oxidant. As expected, the further experiment
proved that oxidant was indispensable for this transformation
(Table 1, entry 16). Thus, the optimal conditions were
determined as described in entry 11.
With the optimal reaction conditions established, we
investigated the substrate scope of carbon sources for the
route to pyrrolo[1,2-a]quinoxalines. The prospective product
2a was obtained in excellent yield when DMA was employed
as carbon source, while the secondary amine S3 exhibited a
lower reactivity than the tertiary S2 (Table 2, entries 1−2). We
therewith utilized the other two alternative amides of N,N-
dimethyl benzamide S4 and NMP S5 to test this notable
transformation founding that S5 reacted well with a yield of 62%
and when S4 was substituted for S5, only a trace amount of 2a
was detected (Table 2, entries 3−4). Moreover
，the reactions
of aliphatic amines and aromatic amine S8 also would
generate 2a in moderate yield, with the exception of 1-
methylpyrrole S7 (Table 2, entries 5−9). The reason we
suspected that S4 and S7 have no yield was probably
associated with the difference in the stability of the iminium
intermediate in the reaction. Obviously, the yield of 4-
methylmorpholine S10 was superior to that of 1-
methylpiperidine S6. Herein, considering the effect of ether
a1 (0.3 mmol), DMF (2 mL), FeCl3 (0.3 mmol), TBPB (0.9 mmol),
under air (unless otherwise noted), 120 °C (5~12 h). bIsolated yields.
This journal is © The Royal Society of Chemistry 20xx
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Table 4. Substrate Scope of 2-(1H-Indol-1-yl) anilinea,b
4a). Whereas, the yield got a visible improvement when there
View Article Online
was a methyl group in indolyl ring (TableDO4,I: 410b.1).03It9/sCe9eNmJ0s4t9h10aJt
methyl group at the 3-position of indolyl should play a vital
role in the reaction due to the influence of competitive
reaction between the 2-position and 3-position of indolyl and
the electron-donating effect of alkyl group. Distinct substituted
2-(3-methyl-1H-indol-1-yl) aniline exhibited favorable yield
displaying the advantage of strong electron-donating group to
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yield (Table 4, 4c−4j). Remarkably, 2-(3-methyl-1H-indol-1-yl)
aniline having disubstituted chlorine was tolerated to give the
desired product in 33% yield (Table 4, 4k). Yet the effect of
benzene ring on electronic density causes sluggish reactivity
for the indole derivatives.
Meanwhile, several control experiments in regard to
mechanistic investigations were carried out. In the presence of
4 equiv of 1,1-diphenylethylene as a radical scavenger, the
extreme reduction of reaction yield occurred (Scheme 4a) and
a3 (0.3 mmol), DMF (2 mL), FeCl3 (0.3 mmol), TBPB (0.9 mmol),
under air (unless otherwise noted), 120 °C (24~72 h). bIsolated
yields.
Scheme 4. Control Experiments for Mechanistic Studies
group was easier to have a more optimistic yield (Table 3,
2b−2f). Interestingly, strong electron-donating and electron-
withdrawing groups with steric hindrance had no significant
impact on either the required reaction time or product yield
(Table 3, 2g
the 5-position on the ring have a better function on the reaction
than groups located at the 4-position (Table 3, 2j 2l). desired
products in 71% yield (Table 3, 2m). Furthermore,
disubstituted substrates also smoothly furnished
corresponding products, conforming to the above-mentioned
law of electronic effect (Table 3, 2n 2p). In the development
−2i). Further results indicated that substituents at
−
−
of heterocyclic substrates, it was found that imidazolyl in place
of pyrrolyl yielded only 2s of 13% while the replacement of
pyridine ring was efficiently engaged in the reaction (Table 3,
2q−2u).
In light of these decent results, we decided to expand the
range of pyrrolo[1,2-a]quinoxaline derivatives to investigate
the versatility of the present method by substitution of the
pyrrole ring with the indole ring. It turned out that 2-(1H-Indol-
1-yl) aniline may took a longer reaction time affected by the
possibility of steric hindrance and the yield of indolo[1,2-
a]quinoxaline 4a dropped sharply, with only 28% yield (Table 4,
Scheme 5. Plausible Reaction Mechanism
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the analogous result of TEMPO involvement was received
(Scheme 4b), suggesting that a radical mechanism may be
existed involved in this reaction. Additionally, the relevant free
radical addition product of TEMPO was detected by HRMS
implying that the corresponding radical was generated from
DMF via C−H cleavage. Futher isotope experiments also proved
that the one-carbon synthon was indeed from DMF (Scheme
4c). In the preliminary conditional screening, we were aware of
that FeCl3 and TBPB account for the crucial factor of reaction
and not a single one can be omitted (Table 1, entries 15,16).
TBPB was a radical initiator involved in the reaction as well as
an oxidant (Table 1, entries 17,18).
View Article Online
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On the basis of results described above and previous reports,
a plausible mechanism is proposed by our group in Scheme 5.
3
4
The initial reaction gives acylaminomethyl radical
A through
abstraction of hydrogen radical from sp3 C−H bond of DMF S1
by the tert-butoxy radical. In the presence of Fe (III), the
radical
Subsequently, nucleophilic addition of 1a to
intermediate by removal of one molecular HCl. Imine
be formed C−N cleavage together with an elimination of N-
methylformamide from . Ultimately, the target product 2a is
A .
followed by the oxidation to acyliminium salt B 23
B
provides an
could
C
D
(a) S. J. Lou, D. Q. Xu, D. F. Shen, Y. F. Wang, Y. K. Liu, Z. Y. Xu,
Chem. Commun. 2012, 48, 11993. (b) Y. F. Li, F. F. Guo, Z. G.
Zha and and Z. Y. Wang, Asian J. Org. Chem. 2013, 8, 534. (c)
C
J. M. Liu, H. Yi, X. Zhang, C. Liu, R. Liu, G. T. Zhang and A. W.
Lei, Chem. Commun. 2014, 50, 7636. (d) M. Itoh, K. Hirano, T.
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Y. H. Song, J. L. Xiao, Z. W. Liu, C. Wang, Z. T. Liu, J. G. Chen
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obtained through cyclization and oxidation under acidic
condition. During transformation, the acid-base reaction
between HCl and t-BuOFeCl2 produced by the reaction of FeCl2
and oxidant gave FeCl3 to complete cycle of iron complexes.24
Conclusions
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2014, 16, 66. (b) A. Borah, L. Goswami, K. Neog and P. Gogoi,
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In summary, we have developed an interesting reaction for
assembling pyrrolo[1,2-a]quinoxalines from 2-(1H-pyrrol-1-
yl)anilines and various carbon sources. The synthesis method is
applicable to multiple types of solvents with terminal methyl
groups. At the same time, there are a great many advantages
of available raw materials, simple operation, reaction
efficiency, universal solvent applicability and wide substrates
scope.
(a) M. N. Zhao, R. R. Hui, Z. H. Ren, Y. Y. Wang and Z. H.
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Conflicts of interest
There are no conflicts to declare.
(a) J. Guillon, P. Grellier, M. Labaied, P. Sonnet, J. Léger, R.
Déprez-Poulain, I. Forfar-Bares, P. Dallemagne, N. Lemaître,
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Chem. 2004, 47, 1997. (b) J. Guillon, S. Moreau, E. Mouray, V.
Sinou, I. Forfar, S. B. Fabre, V. Desplat, P. Millet, D. Parzy, C.
Jarry and P. Grellie, Bio. Med. Chem. 2008, 16, 9133. (c) J.
Guillon, E. Mouray, S. Moreau, C. Mulliꢁ, I. Forfar, V.
Desplat, S. Belisle-Fabre, N. Pinaud, F. Ravanello, A. Le-
Naour, J-M. Lꢁger, G. Gosmann, C. Jarry, G. Dꢁlꢁris, P.
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Acknowledgements
We are grateful to the National Science Foundation of China
(No. 21572117) and the Shandong Key Research Program (Nos.
2019JZZY021015, 2019GHY112053) for financial support of this
research. We also are grateful to the Analytical Center for
Structural Constituent and Physical Property of Core Facilities
Sharing Platform, Shandong University for their technology
and services support.
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New Journal of Chemistry
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DOI: 10.1039/C9NJ04910J
Synthesis of Quinoxaline Derivatives with Terminal Methyl
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as a One-Carbon Synthon via Radical-type Transformation
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Xinfeng Wang, Huanhuan Liu, Caixia Xie, Feiyu Zhou, and Chen Ma*
An iron-promoted method for the construction of pyrrolo[1,2-a]quinoxaline
derivatives has been developed. Ferric chloride served as promoter and Lewis acid in
the reaction. Solvents provided corresponding carbon sources simultaneously. Under
the optimal reaction conditions, a variety of solvents were utilized as carbon sources
for the synthesis of quinoxalines. A majority of solvents with terminal methyl group,
including ethers, amines and dimethyl sulfoxide, were reactive for the synthesis of
quinoxaline derivatives at the certain yields via radical-type transformation. The
method was applicable to a wide range of pyrrolo[1,2-a]quinoxaline and
indolo[1,2-a]quinazoline substrates.
Y2
Y2
R2
X
Y1
N
Y1
N
FeCl3, TBPB
120 °C
+
R
R
R1
X = O, N, S.
Y1 = C, N.
Y2 = C, N.
NH2
N
30 examples
up to 97% yield
13 carbon sources
Key words: Iron, Solvent, Terminal Methyl, Quinoxaline Derivatives.