Nickel-Catalyzed Direct Synthesis of Quinoxalines from 2-Nitroanilines and Vicinal Diols: Identifying Nature of the Active Catalyst

Article abstract of DOI:10.1021/acs.joc.9b03104

The inexpensive and simple NiBr₂/1,10-phenanthroline system-catalyzed synthesis of a series of quinoxalines from both 2-nitroanilines and 1,2-diamines is demonstrated. The reusability test for this system was performed up to the seventh cycle, which afforded good yields of the desired product without losing its reactivity significantly. Notably, during the catalytic reaction, the formation of the heterogeneous Ni-particle was observed, which was characterized by PXRD, XPS, and TEM techniques.

Full text of DOI:10.1021/acs.joc.9b03104

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Note
Nickel Catalyzed Direct Synthesis of Quinoxalines from 2-
Nitroanilines and Vicinal Diols: Identifying Nature of the Active Catalyst
Sujan Shee, Dibyajyoti Panja, and Sabuj Kundu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03104 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 6, 2020
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Sujan Shee, Dibyajyoti Panja, and Sabuj Kundu*
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Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh (U.P.), India
ABSTRACT: Inexpensive and simple NiBr2/1,10-phenanthroline system catalyzed synthesis of a series of quinoxalines from both
2-nitroanilines and 1,2-diamines is demonstrated. The reusability test for this system was performed up to 7th cycle which afforded
good yields of the desired product without losing its reactivity significantly. Notably, during the catalytic reaction, formation of
heterogeneous Ni-particle was observed which was characterized by PXRD, XPS and TEM techniques.
N-Heterocycles are important bio-active and naturally
occurring molecules which have wide range of applications in
pharmaceutical, agricultural and material chemistry.1-4
Multistep synthetic processes, inadequate starting materials and
generation of stoichiometric wastages are the major
disadvantages for the synthesis of these N-heterocyclic
molecules following the classical metal free cyclization or
metal catalyzed multicomponent coupling reactions.5-7 In
contrast, hydrogen borrowing methodology or dehydrogenative
coupling process are the most elegant sustainable methods for
the production of such heterocycles via construction of C-C or
C-N bonds.8,9 Generally, these atom-economical processes
circumvent multistep synthetic routes and use of excess
reagents. Additionally, water or hydrogen are produced as by-
product which makes these protocols environmentally benign
and sustainable. Inspired by the pioneering work carried out by
Williams,8,10-13 Beller,14-16 Milstein,17-19 Kempe,20-22 several
borrowing hydrogen and dehydrogenative coupling
methodologies were developed utilizing alcohols for the
catalyzed synthesis of various N-heterocycles such as
tetrahydroquinoxalines, tetrahydro-β-carbolines, piperidines,
quinoxalines, etc. However, for this system, additional two
equivalents of 4-methyl cinnamic acid was required for the
synthesis of quinoxalines.44
Scheme 1. Nickel Catalyzed Synthesis of Quinoxalines
synthesis of various organic molecules.23-26
.
Recently, nickel catalyzed hydrogen borrowing and
dehydrogenative coupling strategies have become attractive for
sustainable and environmentally benign processes.24,45 Utilizing
these protocols, nickel catalyzed synthesis of pyrroles,
pyridines, quinazolin-4(3H)-ones, quinolines, C/N-alkylated
products, etc. are well-documented in literature.46-51 Although,
most of the cases, homogeneous Ni complexes were utilized as
the pre-catalysts; however, fate of the active catalysts or the
materials formed after the catalytic cycle is unknown. To design
an efficient catalytic system and to understand the reaction
mechanism, identifying the nature of active catalyst
(homogeneous, heterogeneous, etc.) during and after the
reaction is essential.52-56
Quinoxaline derivatives are important structural motifs
present in natural products, pharmacological and biologically
active molecules.27-29 Quinoxalines are widely used in
therapeutic drugs, agrochemical, material chemistry and
industries.30,31 Traditional methods for the synthesis of
quinoxalines mostly suffered from limited functional group
tolerance, generation of salt wastes and in few cases, the
requirement of excessive additives. The coupling between 1,2-
diketones and 1,2-diamines for the synthesis of quinoxalines is
well represented in literature.32,33 However, utilization of bio-
derived readily available alcohols as a coupling partner is one
of the attractive routes. For this purpose, various transition
metal based homogeneous and heterogeneous catalysts have
been explored. Among them, precious 4d and 5d metal based
catalysts are mostly common.34-38 First row transition metal
catalyzed few reports are known for the synthesis of
quinoxaline derivatives.39-42 During the preparation of this
manuscript, NiBr2/phen catalyzed synthesis of benzimidazoles
and quinoxalines was revealed.43 However, substrate scope for
the synthesis of quinoxalines was limited to only two
derivatives. Remarkably, Tang et al. recently reported a
Ni(OTf)2 and 1,2-bis(dicyclohexylphosphino)ethane (dcype)
Herein, we reveal a simple nickel based catalytic system
which produced a variety of substituted quinoxalines from
dehydrogenative coupling of vicinal diols with 1,2-diamines
and 2-nitroaniline derivatives (Scheme 1).
To optimize the reaction parameters for synthesis of quinox-
aline derivatives, initially, 1,2-diaminobenzene and 1,2-pro-
panediol were selected as model substrates. For this purpose,
several bidentate and tridentate nitrogen based ligands (5
mol%) in combination with anhydrous NiBr2 (5 mol%) were
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refluxed at 150 °C (oil bath temperature), GC yield; bL2 (7.5
screened in presence of 0.5 equiv. Cs2CO3 in toluene at oil bath
temperature 150 °C (Table 1). Among all the ligands,
c
d
mol%); CsOH.H2O (0.75 equiv.); 1,2-propanediol (0.75 mmol),
1
2
3
4
CsOH.H2O (0.75 equiv.); eheated at 140 °C; fabsence of ligand L2.
Table 1. Ligand Screening for the Synthesis of
Quinoxalinesa
NiBr2/phen and 0.75 equiv. CsOH.H2O in toluene at 150 °C was
the optimal reaction conditions for this dehydrogenative
coupling reaction.
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9
With this optimized reaction conditions, next, we explored the
scope of the coupling reactions for the synthesis of various
substituted quinoxaline derivatives. Reaction of 1,2-
diaminobenzene with various unsymmetrical vicinal diols
furnished up to 93% isolated yields of the expected
quinoxalines (Table 3, a1 and a3-a6). However, for 1,2-
hexanediol and 3,3-dimethylbutane-1,2-diol slightly higher
amount of catalyst and 1,2-diol were required to achieve
satisfactory yields of the corresponding quinoxalines (Table 3,
a4 and a5). On the other hand, substituted 1,2-diamines with
various 1,2-diols also showed moderate to excellent yields.
Notably, 1-phenylethanediol and 1,2-diphenylethane-1,2-diol
with various 1,2-diamines furnished excellent yields of the
desired quinoxalines; probably dehydrogenation of these two
diols was relatively more easier than the aliphatic vicinal diols.
Both unsymmetrical 1,2-diamines and 1,2-diols produced two
regio-isomers with isomeric ratio of 3:2, analyzed by 1H NMR
spectroscopy (Table 3, a20 and a21). Unfortunately, 2,3-
diaminopyridine did not lead to the formation of the desired
product (Table 3, a22).
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aReaction conditions: 1,2-diaminobenzene (0.5 mmol), 1,2-pro-
panediol (1.0 mmol), toluene (2 mL), refluxed at 150 °C (oil bath
temperature), GC yield (n-dodecane was used as internal standard).
1,10-phenanthroline (L2) displayed the best result, yielding
69% of a1. After getting the optimized ligand system, other
common nickel precursors such as NiCl2, Ni(OAc)2.4H2O,
Ni(COD)2, NiBr2(DME) and NiCl2(DME) were screened which
showed moderate yields, indicating NiBr2/phen was the best
catalytic system for this coupling reaction (Table 2, entries 1-
6). Increasing the amount of ligand did not alter the product
formation significantly; 74% a1 was formed in presence of 7.5
mol% of L2 under the reaction conditions (Table 2, entry 7).
Afterward, various bases and their amount and other reaction
parameters were tested in presence of NiBr2/phen system (Table
2, entries 8-14). Finally, it was observed that 1:2 ratio of 1,2-
diaminobenzene and 1,2-propanediol in presence of 5 mol%
Table 3. Ni-Catalyzed Synthesis of Quinoxalines: Scope of
1,2-Diaminesa
Table 2. Optimization of the Reaction Parametersa
Entry [Ni] (5 mol%)
Base (0.5 equiv.) Yield (%)
1
NiCl2
Cs2CO3
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27
69
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60
65
74
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99
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2
Ni(OAc)2.4H2O
NiBr2
Cs2CO3
3
Cs2CO3
4
Ni(COD)2
NiCl2(DME)
NiBr2(DME)
NiBr2
Cs2CO3
5
Cs2CO3
6
7b
Cs2CO3
Cs2CO3
KOtBu
aReaction conditions: 1,2-diamine (0.5 mmol), 1,2-diol (1.0 mmol),
toluene (2 mL), refluxed at 150 °C (oil bath temperature), GC
yields (isolated yields in parenthesis), preparative scale reactions in
third bracket. bNiBr2/ L2 (7.5 mol%), 1,2-diol (1.5 mmol).
8
NiBr2
9
NiBr2
KOH
10
11c
12d
13e
14f
15
NiBr2
CsOH.H2O
CsOH.H2O
CsOH.H2O
CsOH.H2O
CsOH.H2O
CsOH.H2O
Afterward, we explored the scope of this catalytic system for
synthesis of quinoxalines from various 2-nitroanilines and
vicinal diols. In this scenario, 2-nitroanilines and 1,2-diols acted
as hydrogen acceptor and hydrogen donor respectively. This
environmental friendly protocol did not require any additional
reducing agents for reduction of the nitro group. For this
transformation, few other transition metal catalyzed protocols
are known in literature.34,40,57 To establish this methodology, we
optimized the reaction parameters by selecting 2-nitroaniline
NiBr2
NiBr2
NiBr2
NiBr2
-
aReaction conditions: 1,2-diaminobenzene (0.5 mmol), 1,2-
propanediol (1.0 mmol), NiBr2/L2 (5 mol%), toluene (2 mL),
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and 2,3-butanediol as coupling partners (SI, Table S2). It was
observed that 2-nitroaniline and 2,3-butanediol in 1:3 ratio in
Scheme 2. Control Experiments
1
presence of 3 mol% NiBr2/L2 with 0.4 equiv. CsOH.H2O
delivered the best result which produced 98% yield of a2 (GC
yield). Next, we examined the scope of this methodology with
various 2-nitroaniline derivatives and 1,2-diols (Table 4).
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Table 4 Ni-Catalyzed Synthesis of Quinoxalines: Scope of 2-
Nitroanilinesa
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After getting exciting catalytic activity of this nickel system,
next we carried out few control experiments for the mechanistic
insight. During the coupling of 1,2-diaminobenzene with 1,2-
propanediol, the initial concentration of 1,2-diaminobenzene
was high and it can also act as a bidentate ligand. Hence,
formation of (1,2-diaminobenzene)NiBr2 during the reaction
was quite possible which can behave as the pre-catalyst instead
of the in-situ generated (phen)NiBr2 (complex A). To resolve
this issue, we separately prepared (1,2-diaminobenzene)NiBr2
and complex A and tested their catalytic activity for 1,2-
diaminobenzene and 1,2-propanediol coupling reaction under
the optimized conditions (Scheme 2a and 2b).60,61 Interestingly,
for synthesis of a1 from 1,2-diaminobenzene, complex A
provided excellent yield (91% GC yield) while (1,2-
diaminobenzene)NiBr2 produced only 23% yield which was
very similar to the result obtained with only NiBr2 in absence of
ligand L2 (Table 2, entry 14). This observation confirmed that
complex A was generated in-situ at the beginning of the
reaction which performed as the pre-catalyst during the course
of this reaction. The reaction of 2-nitroaniline under standard
conditions provided slighly lower yield of a2 in presence of
externally added radical scavengers; indicating this Ni system
probably did not follow the radical pathway (SI S5).
aReaction conditions: 2-nitroarylamine (0.5 mmol), 1,2-diol (1.5
mmol), toluene (2 mL), reflux at 150 °C (oil bath temperature), GC
yields (isolated yields in parenthesis), preparative scale reactions in
third bracket.
2-Nitroanilines with different symmetrical and also with
unsymmetrical vicinal diols furnished good to excellent isolated
yields of the quinoxaline products (Table 4, a1-a7), while 1,2-
hexanediol and 3,3-dimethylbutane-1,2-diol afforded moderate
yields (Table 4, a4 and a5). Different substituted 2-nitroanilines
also provided moderate to excellent yields with various vicinal
diols. Utilizing this methodology, two regio-isomers 6-chloro-
2-phenylquinoxaline and 7-chloro-2-phenylquinoxaline were
produced in 1:1 ratio with overall 73% isolated yields by the
coupling reaction of 4-chloro-2-nitroaniline and 1-
phenylethane-1,2-diol (Table 4, a30). Similarly, the reactions of
6-methoxy-2-phenylquinoxaline and 6-bromo-8-methyl-2-
phenylquinoxaline with 1-phenylethane-1,2-diol exhibited a
mixture of two regio-isomers in good yields (Table 4, a31 and
a32).
Additionally, using complex A (5 mol%), LiBEt3H (15 mol%)
and 5 mol% CsOH.H2O under the standard conditions furnished
64% yield of a1 from 1,2-diaminobenzene (conv. 90%,
hydrogenated product of a1 26%), indicating dehydrogenation
of diol was occurred via formation of Ni-H species (Scheme
2c). However, all our attempts toward isolation and
characterization of the Ni-H species were unsuccessful.
To test the practical applicability of this methodology, we
carried out preparative scale reaction for the synthesis of several
quinoxaline derivatives from both 1,2-diamine and 2-
nitroaniline derivatives which resulted moderate to good
isolated yields of the corresponding products (Table 3 and 4).
Synthesis of important drug molecules from the readily
available starting materials is highly desirable. Gratifyingly,
gram scale synthesis of EGFR tyrosine kinase inhibitor (a27),
tyrphostin AG 1296 (a15) and anti-HIV derivative(a8) were
performed which furnished up to 73% isolated yields (Table 3
and 4).58,59
Figure 1. a) Reusability test of Ni-catalyzed synthesis of a1; b)
Time dependent product distribution study.
Interestingly, this catalytic system did not lose its catalytic
activity significantly even after 7th catalytic cycle for synthesis
of a1 from 1,2-diaminobenzene. This demonstrated the
reusability and practical applicability of this protocol (Figure
1a).
In literature, several reports are known for the
dehydrogenative coupling reactions of alcohols using
phosphine free NiX2/L (L = nitrogen containing ligands e.g.
phen, TMEDA, etc.) system where Ni-H species was proposed
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as the active species.62-67 However, nature of the active catalyst
and subsequently coupling with carbonyl group generated from
1,2-diol, cannot be ruled out (SI, Fig. S3, path b).
1
was not clear; with many systems catalytic cycle with
homogeneous Ni-complexes were proposed. To check the
homogeneity of this Ni system, mercury poisoning experiment
was carried out by using 100 equiv. of Hg0 for the coupling of
1,2-diaminobenzene and 1,2-propanediol, which resulted 71%
of a1 product. This study indicated that this catalytic system
was not fully homogeneous and some heterogeneous Ni parti-
cles may formed during the reaction. Notably, with our system
after the catalytic reaction (24 h), we observed a yellow color
solution along with a small quantity of insoluble black particles
in the bottom of the reaction tube which was insoluble in the
common organic solvents. In order to identify the insoluble
particles, we performed the characterization of this materials
using PXRD (powder X-ray diffraction), XPS (X-ray
photoelectron spectroscopy) and TEM (transmission electron
microscope) techniques. The powder XRD pattern of the
material revealed the presence of Ni(0) and Ni(II) nanoparticles
with 2θ values at 43.44° and 49.30° for Ni(0) and 42.60° and
63.06° for Ni(II) (Figure 2a).68 TEM analysis further confirmed
that the material was crystalline in form and the presence of
metallic Ni with well-resolved lattice spacing of 0.203 nm for
(111) plane of cubic Ni- phase (Figure 2b & 2c).69 XPS analysis
also revealed that the presence of metallic Ni in the material. In
the Ni2p spectra with the peaks at 854.24 and 871.8 eV
suggested the presence of metallic Ni and peaks at 855.86 and
873.6 eV represented NiO (Figure 2d).70 After the 1st catalytic
cycle, we filtered out the solution under inert atmosphere and
separately carried out the same reaction using both the
homogeneous solution and heterogeneous materials.
Considerable amount of a1 was formed in both the reactions.
This clearly suggested that both heterogeneous and
homogeneous Ni-materials were catalytically active and
participated in this reaction (SI S6). Notably, non-noble metal
based nanoparticles are highly valued for chemical synthesis
due to their recyclability.71-73 Quantification of the amount of
Ni present in both homogeneous and heterogeneous phases are
currently underway in our laboratory.
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In summary, various substituted quinoxaline derivatives were
synthesized by applying both hydrogen borrowing and dehy-
drogenative coupling strategies. Additionally, several biologi-
cally active quinoxalines were also effectively synthesized in
gram scale. Importantly, utilization of both inexpensive metal
precursor (NiBr2) and ligand (1,10-phenanthroline) made this
protocol attractive. Remarkably, this catalytic system did not
lose its reactivity considerably even after 7th cycle. Notably, for-
mation of some heterogeneous Ni-particles was observed after
the reaction. Both the heterogeneous and homogeneous Ni-ma-
terials formed during the reaction was found to be catalytically
active. The heterogeneous Ni-nanoparticles was characterized
by PXRD, XPS and TEM analysis.
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General Information: All the experiments were carried out
under argon atmosphere either inside the argon filled glove box
or using standard Schlenk line technique unless otherwise
stated. Glasswares were oven dried prior to use. Solvents were
distilled under argon atmosphere according to literature
procedures and deoxygenated prior to use. All the commercial
reagents, ligands L1, L2 and metal precursors were purchased
from Sigma-Aldrich, Alfa-Aesar, Spectrochem, Avra and SD-
fine chemical, India. Ligands L3, L6-L9 were synthesized
according to the literature procedures.40,74-77 All the 1H and 13
C
spectra were recorded with CDCl3 and DMSO-D6 in JEOL
Spectrometer. All the GC analysis were performed using
Perkein Elmer Clarus 600 and Agilent 7890
B Gas
Chromatograph, whereas GC-MS were measured using Agilent
7890 A Gas Chromatograph equipped with Agilent 5890 triple-
quadrupole mass system. ESI-MS were recorded on a Waters
Micromass Quattro Micro triple-quadrupole mass spectrometer.
Chemical states of the heterogeneous material were determined
by X-ray photoelectron spectroscopy (XPS) using a PHI 5000
(Versa Probe II, FEI Inc). The morphologies of the material
were observed using high resolution transmission electron
microscope (HRTEM, FEI Titan G2 60-300 KV). X-ray
diffraction (XRD) patterns were obtained by Bruker D8
advance powder X-ray diffractometer using Cu-Kα as X-ray
source (1.54 Å). The elemental composition was determined by
energy dispersive X-ray spectroscopy (EDX linked to FESEM,
Oxford Instrument).
Procedure for Synthesis of 2-(3,5-diphenyl-1H-pyrazol-1-
yl)-6-methylpyridine (L4): 2-Hydrazinyl-6-methylpyridine
was synthesized following the literature procedure.78 A mixture
of 2-hydrazinyl-6-methylpyridine (200 mg, 1.62 mmol) and
1,3-diphenyl-1,3-propanedione (437 mg, 1.95 mmol) were
stirred in presence of 1.5 mL glacial acetic acid in 15 mL dry
methanol for 16 h. After that the reaction mixture was refluxed
for 12 h. The solvent was removed under reduced pressure and
the remaining solid was dissolved in dichloromethane. The or-
ganic layer was washed with saturated sodium bicarbonate so-
lution, brine solution and finally dried over anhydrous Na2SO4.
The organic part was removed under reduced pressure. Final
product was purified by column chromatography with silica gel
using 30% ethyl acetate in hexane. Crystalline white solid was
obtained. Yield: 464 mg (92%). 1H NMR (500 MHz, CDCl3): δ
= 7.94 (d, JH,H = 7.15 Hz, 2H), 7.42 (t, JH,H = 7.35 Hz, 2H), 7.35-
7.28 (m, 7H), 7.07 (d, JH,H = 7.55 Hz, 1H), 6.82 (s, 1H), 2.39 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 158.1, 152.7, 151.9,
Figure 2. a) PXRD pattern of the materials; b) and c) HRTEM
images of the materials; d) XP spectra of Ni2p electrons.
Next, we focused on the mechanism for the synthesis of
quinoxalines from 2-nitroanilines and 1,2-diols. From the time
dependent product distribution study, a steady formation of 1,2-
diamine (maximum 9%) was observed (Figure 1b). This
signified the reaction might preferentially proceed via the 1,2-
diamine intermediate (SI, Fig. S3, path a). However, imination
of amine with ketone followed by the reduction of nitro group
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2-Ethylquinoxaline (a3).37 Produced following the general
145.3, 138.5, 133.1, 131.3, 129.0, 128.8, 128.3, 128.2, 126.2,
1
2
3
4
5
6
7
8
116.1, 106.3, 29.9, 24.2. HRMS (ESI-TOF): calcd. for C21H18N3
procedure as mentioned above by reacting 1,2-diaminoben-
zene/2-nitroaniline (54.0 mg/69.0 mg, 0.5 mmol, 1 equiv.) and
1,2-butanediol (89.5 μL, 1 mmol, 2 equiv. for diamine; 134.3
μL, 1.5 mmol, 3 equiv. for 2-nitroaniline). The title product was
purified by column chromatography with silica gel using 20%
EtOAc in hexane as yellow liquid (73 mg; 93% from 1,2-dia-
[M+H]+: 312.1501; found: 312.1499.
Procedure for Synthesis of 2-(3,5-di-tert-butyl-1H-
pyrazol-1-yl)-6-methylpyridine (L5):
A mixture of 2-
hydrazinyl-6-methylpyridine (200 mg, 1.62 mmol) and 2,2,6,6-
tetramethylheptane-3,5-dione (359 mg, 1.95 mmol) were stirred
in presence of 3 mL glacial acetic acid in 15 mL dry methanol
for 16 h. After that the reaction mixture was refluxed for 12 h.
The solvent was removed under reduced pressure and the re-
maining solid was dissolved in dichloromethane. The organic
layer was washed with saturated sodium bicarbonate solution,
brine solution and finally dried over anhydrous Na2SO4. The or-
ganic part was removed under reduced pressure. Final product
was purified by column chromatography with silica gel using
30% ethyl acetate in hexane. Crystalline white solid was ob-
tained. Yield: 378 mg (86%). 1H NMR (500 MHz, CDCl3): δ =
7.67 (t, JH,H = 7.70 Hz, 1H), 7.30 (d, JH,H = 7.85 Hz, 1H), 7.14
(d, JH,H = 7.55 Hz, 1H), 6.04 (s, 1H), 2.55 (s, 3H), 1.31 (s, 9H),
1.26 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3): δ = 161.4,
157.3, 154.5, 153.5, 138.6, 122.5, 118.9, 101.9, 32.5, 32.2, 30.9,
30.7, 24.1. HRMS (ESI-TOF): calcd. for C17H26N3 [M+H]+:
272.2127; found: 272.2126.
1
minobenzene and 72 mg; 92% from 2-nitroaniline). H NMR
(400 MHz, CDCl3): δ = 8.74 (s, 1H), 8.06-8.00 (m, 2H), 7.73-
7.66 (m, 2H), 3.04 (q, JH,H = 7.52 Hz, 2H), 1.41 (t, JH,H = 7.80
Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ = 158.7, 145.8,
142.4, 141.4, 130.1, 129.4, 129.1, 129.1, 29.8, 13.6. GC-MS
(M+): 158.1.
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2-Butylquinoxaline (a4).37 Produced following the general
procedure as mentioned above by reacting 1,2-diaminoben-
zene/2-nitroaniline (54.0 mg/69.0 mg, 0.5 mmol, 1 equiv.) and
1,2-hexanediol (124.2 μL, 1 mmol, 2 equiv. for diamine; 186.3
μL, 1.5 mmol, 3 equiv. for 2-nitroaniline). The title product was
purified by column chromatography with silica gel using 20%
EtOAc in hexane as yellow dense liquid (37 mg; 40% from 1,2-
1
diaminobenzene and 46.5 mg; 50% from 2-nitroaniline). H
NMR (400 MHz, CDCl3): δ = 8.72 (s, 1H), 8.06-8.01 (m, 2H),
7.74-7.66 (m, 2H), 3.00 (t, JH,H = 7.80 Hz, 2H), 1.85-1.78 (m,
2H), 1.49-1.40 (m, 2H), 0.96 (t, JH,H = 7.32 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 157.9, 146.0, 142.4, 141.4, 130.1,
129.4, 129.1, 129.1, 36.4, 31.8, 22.8, 14.1. GC-MS (M+): 186.1.
General Procedure for Synthesis of Quinoxalines from
1,2-Diamines and 2-Nitroanilines: 1,2-Diamine/2-nitroaniline
(0.5 mmol), vicinal diol (1.0 mmol; 1.5 mmol for 2-nitroan-
iline), anhydrous NiBr2/L2 (5 mol%; 3 mol% for 2-nitroan-
iline), CsOH.H2O (0.375 mmol; 0.2 mmol for 2-nitroaniline)
and 2 mL toluene were taken in a pressure tube and sealed it
under argon atmosphere. Then, the tube was placed in a pre-
heated oil bath (150 °C) and refluxed for 24 h. The reaction
mixture was cooled and 8 mL water was added to the mixture.
After that, the organic part was extracted with ethyl acetate (3x8
mL). The combined organic part was dried over anhydrous
Na2SO4 and solvent was evaporated under reduced pressure.
The final product was purified by silica gel column chromatog-
raphy using ethyl acetate/hexane as eluent.
2-tert-Butylquinoxaline (a5).37 Produced following the gen-
eral procedure as mentioned above by reacting 1,2-diaminoben-
zene/2-nitroaniline (54.0 mg/69.0 mg, 0.5 mmol, 1 equiv.) and
3,3-dimethylbutane-1,2-diol (118.1 mg, 1 mmol, 2 equiv. for
diamine; 177.1 mg, 1.5 mmol, 3 equiv. for 2-nitroaniline). The
title product was purified by column chromatography with sil-
ica gel using 20% EtOAc in hexane as yellow dense liquid (28
mg; 30% from 1,2-diaminobenzene and 48 mg; 52% from 2-
1
nitroaniline). H NMR (400 MHz, CDCl3): δ = 8.97 (s, 1H),
8.05-8.02 (m, 2H), 7.73-7.65 (m, 2H), 1.49 (s, 9H). 13C{1H}
NMR (125 MHz, CDCl3): δ = 163.9, 143.6, 141.8, 140.9, 129.8,
129.5, 129.1, 37.4, 29.9. GC-MS (M+): 186.1.
2-Methylquinoxaline (a1).37 Produced following the general
procedure as mentioned above by reacting 1,2-diaminoben-
zene/2-nitroaniline (54.0 mg/69.0 mg, 0.5 mmol, 1 equiv.) and
1,2-propanediol (73.4 μL, 1 mmol, 2 equiv. for diamine; 110.1
μL, 1.5 mmol, 3 equiv. for 2-nitroaniline). The title product was
purified by column chromatography with silica gel using 20%
EtOAc in hexane as yellow liquid (67 mg; 93% from 1,2-dia-
2-Phenylquinoxaline (a6).37 Produced following the general
procedure as mentioned above by reacting 1,2-diaminoben-
zene/2-nitroaniline (54.0 mg/69.0 mg, 0.5 mmol, 1 equiv.) and
1-phenylethane-1,2-diol (138.0 mg, 1 mmol, 2 equiv. for dia-
mine; 207.0 mg, 1.5 mmol, 3 equiv. for 2-nitroaniline). The title
product was purified by column chromatography with silica gel
using 10% EtOAc in hexane as yellow dense liquid (88 mg;
86% from 1,2-diaminobenzene and 75 mg; 73% from 2-nitroan-
iline). 1H NMR (400 MHz, CDCl3): δ = 9.31 (s, 1H), 8.19-8.09
(m, 4H), 7.78-7.70 (m, 2H), 7.57-7.50 (m, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 152.0, 143.5, 142.5, 141.7, 136.9,
130.5, 130.4, 129.8, 129.7, 129.3, 127.7. GC-MS (M+): 206.0.
1,2,3,4-Tetrahydrophenazine (a7).34 Produced following the
general procedure as mentioned above by reacting 1,2-diamino-
benzene/2-nitroaniline (54.0 mg/69.0 mg, 0.5 mmol, 1 equiv.)
and cyclohexane-1,2-diol (116.0 mg, 1 mmol, 2 equiv. for dia-
mine; 174.0 mg, 1.5 mmol, 3 equiv. for 2-nitroaniline). The title
product was purified by column chromatography with silica gel
using 10% EtOAc in hexane as pale yellow solid (47.0 mg; 51%
from 1,2-diaminobenzene and 64 mg; 70% from 2-nitroaniline).
1H NMR (400 MHz, CDCl3): δ = 7.95-7.91 (m, 2H), 7.64-7.60
(m, 2H), 3.15-3.11 (m, 4H), 2.02-1.99 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 154.3, 141.3, 129.1, 128.5, 33.4, 22.9.
GC-MS (M+): 184.1.
1
minobenzene and 67 mg; 93% from 2-nitroaniline). H NMR
(400 MHz, CDCl3): δ = 8.72 (s, 1H), 8.05 (d, JH,H = 7.96 Hz,
1H), 8.00 (d, JH,H = 7.96 Hz, 1H), 7.73-7.65 (m, 2H), 2.75 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 154.0, 146.2, 142.3,
141.2, 130.2, 129.4, 129.1, 128.8, 22.8. GC-MS (M+): 144.0.
2,3-Dimethylquinoxaline (a2).37 Produced following the gen-
eral procedure as mentioned above by reacting 1,2-diaminoben-
zene/2-nitroaniline (54.0 mg/69.0 mg, 0.5 mmol, 1 equiv.) and
2,3-butanediol (90.0 μL, 1 mmol, 2 equiv. for diamine; 135.0
μL, 1.5 mmol, 3 equiv. for 2-nitroaniline). The title product was
purified by column chromatography with silica gel using 20%
EtOAc in hexane as yellow solid (67 mg; 85% from 1,2-dia-
1
minobenzene and 74 mg; 94% from 2-nitroaniline). H NMR
(400 MHz, CDCl3): δ = 7.96 (dd, JH,H = 6.28, 3.48 Hz, 2H), 7.64
(dd, JH,H = 6.48, 3.60 Hz, 2H), 2.71 (s, 6H). 13C{1H} NMR (100
MHz, CDCl3): δ = 153.7, 141.3, 129.0, 128.5, 23.4. GC-MS
(M+): 158.0.
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2,3-Diphenylquinoxaline (a8).37 Produced following the gen- 2,3,6,7-Tetramethylquinoxaline (a13).34 Produced following
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5
6
7
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eral procedure as mentioned above by reacting 1,2-diaminoben-
zene (54.0 mg, 0.5 mmol, 1 equiv.) and 1,2-diphenylethane-1,2-
diol (214 mg, 1 mmol, 2 equiv.). The title product was purified
by column chromatography with silica gel using 10% EtOAc in
hexane as white solid (120 mg; 85%). For 3.0 mmol scale reac-
the general procedure as mentioned above by reacting 4,5-di-
methylbenzene-1,2-diamine/4,5-dimethyl-2-nitroaniline (68.5
mg/83.0 mg, 0.5 mmol, 1 equiv.) and 2,3-butanediol (89.5 μL,
1 mmol, 2 equiv.). The title product was purified by column
chromatography with silica gel using 20% EtOAc in hexane as
light yellow solid (81 mg; 87% from 4,5-dimethylbenzene-1,2-
diamine and 86 mg; 93% from 4,5-dimethyl-2-nitroaniline). gel
using 20% EtOAc in hexane as yellow solid (120 mg; 81%).
For 3.0 mmol scale reaction isolated yield was 73% (0.407 g).
1H NMR (400 MHz, CDCl3): δ = 7.68 (s, 2H), 2.65 (s, 6H), 2.41
(s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ = 152.5, 140.1,
139.2, 127.6, 23.2, 20.4. GC-MS (M+): 186.1.
2-tert-Butyl-6,7-dimethylquinoxaline (a14).81 Produced fol-
lowing the general procedure as mentioned above by reacting
4,5-dimethylbenzene-1,2-diamine/4,5-dimethyl-2-nitroaniline
(68.5 mg/83.0 mg, 0.5 mmol, 1 equiv.) and 3,3-dimethylbutane-
1,2-diol (118.1 mg, 1 mmol, 2 equiv. for diamine; 177.1 mg, 1.5
mmol, 3 equiv. for 2-nitroaniline). The title product was puri-
fied by column chromatography with silica gel using 20%
EtOAc in hexane as yellow solid (42 mg; 40% from 4,5-dime-
thylbenzene-1,2-diamine and 51 mg; 48% from 4,5-dimethyl-
2-nitroaniline). 1H NMR (400 MHz, CDCl3): δ = 8.85 (s, 1H),
7.78 (d, JH,H = 6.48 Hz, 2H),2.44 (s, 6H), 1.47 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 162.9, 142.5, 140.7, 140.2, 139.8,
139.3, 128.5, 128.1, 37.2, 30.0, 20.4. GC-MS (M+): 214.1.
1
tion isolated yield was 73% (0.617 g). H NMR (400 MHz,
CDCl3): δ = 8.19 (dd, JH,H = 6.48, 3.44 Hz, 2H), 7.77 (dd, JH,H
= 6.44, 3.36 Hz, 2H), 7.52-7.50 (m, 4H), 7.35-7.30 (m, 6H).
13C{1H} NMR (125 MHz, CDCl3): δ = 153.7, 141.4, 139.3,
130.1, 130.0, 129.4, 129.0, 128.5. GC-MS (M+): 282.0.
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6-Methyl-2,3-diphenylquinoxaline (a9).41 Produced following
the general procedure as mentioned above by reacting 4-
methylbenzene-1,2-diamine (61.0 mg, 0.5 mmol, 1 equiv.) and
1,2-diphenylethane-1,2-diol (214 mg, 1 mmol, 2 equiv.). The
title product was purified by column chromatography with sil-
ica gel using 20% EtOAc in hexane as yellow solid (120 mg;
81%). For 2.8 mmol scale reaction isolated yield was 67%
(0.554 g). 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, JH,H = 8.56
Hz, 1H), 7.94 (s, 1H), 7.60 (d, JH,H = 8.56 Hz, 1H), 7.51-7.49
(m, 4H), 7.34-7.29 (m, 6H), 2.60 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ = 153.5, 152.7, 141.4, 140.7, 139.9, 139.4,
132.5, 130.0, 128.9, 128.8, 128.4, 128.2, 22.1. GC-MS (M+):
296.1.
6-tert-Butyl-2,3-diphenylquinoxaline (a10).79 Produced fol-
lowing the general procedure as mentioned above by reacting
4-tert-butylbenzene-1,2-diamine (82.0 mg, 0.5 mmol, 1 equiv.)
and 1,2-diphenylethane-1,2-diol (107 mg, 1 mmol, 2 equiv.).
The title product was purified by column chromatography with
silica gel using 20% EtOAc in hexane as yellow solid (133 mg;
79%). 1H NMR (400 MHz, CDCl3): δ =8.13 (d, JH,H = 2.12 Hz,
1H), 8.11 (d, JH,H = 8.88 Hz, 1H),7.87 (dd, JH,H = 9.08 Hz, JH,H
= 2.36 Hz, 1H), 7.49 (m, 4H), 7.33 (m, 6H), 1.46 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ = 153.7, 153.6, 153.1,
141.3, 139.9, 139.4, 130.0, 130.0, 129.2, 128.9, 128.7, 128.5,
124.7, 35.6, 31.4. GC-MS (M+): 338.1.
6,7-Dimethoxy-2-phenylquinoxaline (a15).58 Produced fol-
lowing the general procedure as mentioned above by reacting
4,5-dimethoxybenzene-1,2-diamine (84.0 mg, 0.5 mmol, 1
equiv.) and 1-phenylethane-1,2-diol (138.0 mg, 1 mmol, 2
equiv.). The title product was purified by column chromatog-
raphy with silica gel using 20% EtOAc in hexane as yellow
solid (99 mg; 75%). gel using 20% EtOAc in hexane as yellow
solid (120 mg; 81%). For 3.0 mmol scale reaction isolated yield
1
was 60% (0.479 g). H NMR (400 MHz, CDCl3): δ = 9.10 (s,
1H), 8.11 (d, JH,H = 7.65 Hz, 1H), 7.54-7.51 (m, 2H), 7.48-7.45
(m, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 4.06 (s, 3H), 4.05 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ = 153.3, 152.8, 150.1,
140.8, 139.7, 138.9, 137.4, 129.8, 129.3, 128.7, 127.4, 126.3,
107.3, 106.8, 56.6, 56.6. GC-MS (M+): 266.1.
2,6,7-Trimethylquinoxaline (a11).34 Produced following the
general procedure as mentioned above by reacting 4,5-dime-
thylbenzene-1,2-diamine (68.5 mg, 0.5 mmol, 1 equiv.) and
1,2-propanediol (73.4 μL, 1 mmol, 2 equiv.). The title product
was purified by column chromatography with silica gel using
2,3,6-Trimethylquinoxaline (a16).82 Produced following the
general procedure as mentioned above by reacting 4-
methylbenzene-1,2-diamine (61.0 mg, 0.5 mmol, 1 equiv.) and
2,3-butanediol (90.0 μL, 1 mmol, 2 equiv.). The title product
was purified by column chromatography with silica gel using
20% EtOAc in hexane as light yellow solid (79 mg; 92%). gel
using 20% EtOAc in hexane as yellow solid (120 mg; 81%).
For 3.0 mmol scale reaction isolated yield was 76% (0.392 g).
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, JH,H = 8.52 Hz, 1H),
7.72 (s, 1H), 7.47 (d, JH,H = 8.44 Hz, 1H), 2.68 (s, 6H), 2.53 (s,
3H),. 13C{1H} NMR (100 MHz, CDCl3): δ = 153.5, 152.6,
141.3, 139.7, 139.3, 131.2, 128.0, 127.5, 23.3, 23.2, 21.9. GC-
MS (M+): 172.0.
1
20% EtOAc in hexane as pale yellow solid (63 mg; 74%). H
NMR (400 MHz, CDCl3): δ = 8.61 (s, 1H), 7.77 (s, 1H), 7.73
(s, 1H), 2.71 (s, 3H), 2.46 (s, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 152.9, 145.2, 141.2, 140.7, 140.1, 139.5, 128.4,
128.0, 22.7, 20.6, 20.4. GC-MS (M+): 172.1.
2-Ethyl-6,7-dimethylquinoxaline (a12).80 Produced following
the general procedure as mentioned above by reacting 4,5-di-
methylbenzene-1,2-diamine/4,5-dimethyl-2-nitroaniline (68.5
mg/83.0 mg, 0.5 mmol, 1 equiv.) and 1,2-butanediol (89.5 μL,
1 mmol, 2 equiv.). The title product was purified by column
chromatography with silica gel using 20% EtOAc in hexane as
yellow solid (55 mg; 60% from 4,5-dimethylbenzene-1,2-dia-
mine and 74 mg; 80% from 4,5-dimethyl-2-nitroaniline). gel us-
ing 20% EtOAc in hexane as yellow solid (120 mg; 81%). For
6-tert-Butyl-2,3-dimethylquinoxaline (a17).43 Produced fol-
lowing the general procedure as mentioned above by reacting
4-tert-butylbenzene-1,2-diamine (82.0 mg, 0.5 mmol, 1 equiv.)
and 2,3-butanediol (90.0 μL, 1 mmol, 2 equiv.). The title prod-
uct was purified by column chromatography with silica gel us-
1
3.0 mmol scale reaction isolated yield was 66% (0.378 g). H
NMR (400 MHz, CDCl3): δ = 8.61 (s, 1H), 7.76 (d, JH,H = 7.40
Hz, 2H), 2.98 (q, JH,H = 7.64 Hz, 2H), 2.43 (s, 6H), 1.38 (t, JH,H
= 7.56 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 157.6,
144.7, 141.2, 140.5, 140.3, 139.4, 128.3, 128.1, 29.7, 20.6, 20.4,
13.7. GC-MS (M+): 186.1.
1
ing 20% EtOAc in hexane as yellow solid (58 mg; 55%). H
NMR (400 MHz, CDCl3): δ = 7.91 (d, JH,H = 2.12 Hz, 1H), 7.89
(d, JH,H = 8.80 Hz, 1H), 7.73 (dd, JH,H = 8.76 Hz, JH,H = 2.04 Hz,
1H), 2.68 (s, 6H), 1.39 (s, 9H). 13C{1H} NMR (100 MHz,
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The Journal of Organic Chemistry
(s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ = 154.7, 153.9,
CDCl3): δ = 153.4, 152.9, 152.5, 141.1, 139.6, 127.9, 127.8,
123.8, 35.3, 31.4, 23.3, 23.2. GC-MS (M+): 214.1.
141.6, 139.7, 134.6, 129.9, 129.7, 127.5, 23.4, 23.3. GC-MS
1
(M+): 192.0.
7-Methyl-1,2,3,4-tetrahydrophenazine (a18).83 Produced fol-
lowing the general procedure as mentioned above by reacting
4-methylbenzene-1,2-diamine (61.0 mg, 0.5 mmol, 1 equiv.)
cyclohexane-1,2-diol (116.0 mg, 1 mmol, 2 equiv.). The title
product was purified by column chromatography with silica gel
using 15% EtOAc in hexane as pale yellow solid (55.5 mg;
56%). 1H NMR (400 MHz, CDCl3): δ = 7.80 (d, JH,H = 8.56 Hz,
1H), 7.68 (s, 1H), 7.44 (dd, JH,H = 8.56, 1.76 Hz, 1H), 3.19-3.00
(m, 4H), 2.50 (s, 3H), 1.99-1.95 (m, 4H). 13C{1H} NMR (100
MHz, CDCl3): δ = 154.0, 153.2, 141.4, 139.8, 129.3, 131.3,
127.9, 127.4, 33.3, 33.2, 23.0, 21.9. GC-MS (M+): 198.1.
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6-Methoxy-2,3-dimethylquinoxaline (a24).84 Produced fol-
lowing the general procedure as mentioned above by reacting
4-methoxy-2-nitroaniline (84.0 mg, 0.5 mmol, 1 equiv.) and
2,3-butanediol (135.0 μL, 1.5 mmol, 3 equiv.). The title product
was purified by column chromatography with silica gel using
1
20% EtOAc in hexane as light yellow solid (77 mg; 82%). H
NMR (500 MHz, CDCl3): δ = 7.84 (d, JH,H = 8.68 Hz, 1H), 7.30-
7.26 (m, 2H), 3.91 (s, 3H), 2.68 (m, 3H), 2.66 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 160.1, 153.5, 150.8, 142.6, 137.2,
129.4, 121.9, 106.3, 55.9, 23.3, 23.0. GC-MS (M+): 188.0.
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7-Bromo-2,3,5-trimethylquinoxaline (a19).40 Produced fol-
lowing the general procedure as mentioned above by reacting
5-bromo-3-methylbenzene-1,2-diamine (100.0 mg, 0.5 mmol, 1
equiv.) and 2,3-butanediol (90.0 μL, 1 mmol, 2 equiv.). The title
product was purified by column chromatography with silica gel
using 20% EtOAc in hexane as yellow solid (61 mg; 49%). 1H
NMR (400 MHz, CDCl3): δ = 7.95 (s, 1H), 7.56 (s, 1H), 2.70
(s, 3H), 2.68 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ =
154.1, 152.8, 141.9, 139.3, 138.9, 132.2, 128.6, 122.3, 23.5,
23.3, 17.1. HRMS (ESI-TOF): calcd. for C11H12BrN2[M+H]+:
251.0184; found: 251.0182.
6-Methoxy-2,3-diphenylquinoxaline (a25).34 Produced fol-
lowing the general procedure as mentioned above by reacting
4-methoxy-2-nitroaniline (84.0 mg, 0.5 mmol, 1 equiv.) and
1,2-diphenylethane-1,2-diol (321.3 mg, 1.5 mmol, 3 equiv.).
The title product was purified by column chromatography with
silica gel using 10% EtOAc in hexane as pale yellow solid (134
mg; 86%). gel using 20% EtOAc in hexane as yellow solid (120
mg; 81%). For 3.0 mmol scale reaction isolated yield was 71%
(0.664 g). 1H NMR (400 MHz, CDCl3): δ = 8.05 (d, JH,H = 9.16
Hz, 1H), 7.51-7.47 (m, 4H), 7.46 (d, JH,H = 2.84 Hz, 1H), 7.42-
7.39 (m, 1H), 7.34-7.30 (m, 6H), 3.97 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 161.1, 153.5, 151.1, 143.0, 139.4,
139.4, 137.6, 130.3, 130.0, 128.9, 128.7, 128.4, 128.4, 123.6,
106.6, 56.0. GC-MS (M+): 312.1.
2-Butyl-6,7-dimethylquinoxaline (a26).80 Produced following
the general procedure as mentioned above by reacting 4,5-di-
methyl-2-nitroaniline (83.0 mg, 0.5 mmol, 1 equiv.) and 1,2-
hexanediol (186.3 μL, 1.5 mmol, 3 equiv.). The title product
was purified by column chromatography with silica gel using
20% EtOAc in hexane as yellow solid (50 mg; 47%). 1H NMR
(400 MHz, CDCl3): δ = 8.60 (s, 1H), 7.77 (d, JH,H = 6.52
Hz,2H), 2.94 (t, JH,H = 7.76 Hz, 2H), 2.45 (s, 6H), 1.82-1.74 (m,
2H), 1.46-1.37 (m, 2H), 0.94 (t, JH,H = 7.32 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 156.8, 145.0, 141.3, 140.5, 140.3,
139.4, 128.4, 128.1, 36.3, 31.9, 22.7, 20.5, 20.4, 14.1. GC-MS
(M+): 214.1.
6-tert-Butyl-2-methylquinoxaline (a20) and 7-tert-butyl-2-
methylquinoxaline (a20'). Produced following the general pro-
cedure as mentioned above by reacting 4-tert-butylbenzene-
1,2-diamine (82.0 mg, 0.5 mmol, 1 equiv.) and 1,2-propanediol
(73.4 μL, 1 mmol, 2 equiv.). The title product was purified by
column chromatography with silica gel using 15% EtOAc in
hexane as yellow solid; Two regio-isomers (3:2) were insepara-
1
ble in column chromatography (74 mg; 74%). H NMR (500
MHz, CDCl3): δ = 8.67-8.65 (s, 1H), 7.97-7.90 (m, 2H), 7.81-
7.75 (m, 1H), 2.73-2.72 (s, 3H), 1.40 (s, 9H). 13C{1H} NMR
(125 MHz, CDCl3): δ = 153.7, 153.2, 152.5, 151.2, 146.7,
146.0, 129.1, 128.6, 128.1, 128.0, 124.6, 124.1, 35.4, 35.3, 31.3,
22.7. GC-MS (M+): 200.0. HRMS (ESI-TOF): calcd. for
C13H17N2[M+H]+: 201.1392; found: 201.1388.
6-tert-Butyl-2-phenylquinoxaline (a21) and 7-tert-butyl-2-
phenylquinoxaline (a21'). Produced following the general pro-
cedure as mentioned above by reacting 4-tert-butylbenzene-
1,2-diamine (82.0 mg, 0.5 mmol, 1 equiv.) and , 1-phe-
nylethane-1,2-diol (138.0 mg, 1 mmol, 2 equiv.). The title prod-
uct was purified by column chromatography with silica gel us-
ing 15% EtOAc in hexane as yellow solid; Two regio-isomers
(3:2) were inseparable in column chromatography (85 mg;
65%). 1H NMR (400 MHz, CDCl3): δ = 9.28-9.25 (s, 1H), 8.18-
8.16 (m, 2H), 8.10-8.03 (m, 2H), 7.88-7.82 (m, 1H), 7.57-7.47
(m, 3H), 1.46-1.45 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ = 154.0, 152.3, 152.0, 151.5, 143.4, 142.9, 142.4, 141.7,
140.9, 140.2, 137.2, 130.2, 130.2, 129.5, 129.3, 129.1, 128.8,
128.7, 128.6, 128.5, 128.2, 127.7, 127.6, 125.0, 124.5, 35.5,
35.4, 31.3. GC-MS (M+): 262.1. HRMS (ESI-TOF): calcd. for
C18H19N2[M+H]+: 263.1548; found: 263.1544.
6,7-Dimethyl-2-phenylquinoxaline (a27).85 Produced follow-
ing the general procedure as mentioned above by reacting 4,5-
dimethyl-2-nitroaniline (83.0 mg, 0.5 mmol, 1 equiv.) and 1-
phenylethane-1,2-diol (207.0 mg, 1.5 mmol, 3 equiv.). The title
product was purified by column chromatography with silica gel
using 20% EtOAc in hexane as yellow solid (90 mg; 77%). gel
using 20% EtOAc in hexane as yellow solid (120 mg; 81%).
For 3.0 mmol scale reaction isolated yield was 62% (0.435 g).
1H NMR (400 MHz, CDCl3): δ = 9.19 (s, 1H), 8.15 (d, JH,H
=
7.00 Hz, 2H), 7.87 (s, 1H), 7.82 (s, 1H), 7.53 (m, 3H), 2.47 (s,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ = 151.1, 142.5, 141.4,
140.9, 140.7, 140.3, 137.3 130.0, 129.2, 128.8, 128.3, 127.5,
20.5. GC-MS (M+): 234.1.
7-Methoxy-1,2,3,4-tetrahydrophenazine (a28).34 Produced
following the general procedure as mentioned above by reacting
4-methoxy-2-nitroaniline (69.0 mg, 0.5 mmol, 1 equiv.) and cy-
clohexane-1,2-diol (174.0 mg, 1.5 mmol, 3 equiv.). The title
product was purified by column chromatography with silica gel
using 30% EtOAc in hexane as pale yellow solid (96 mg; 90%).
1H NMR (500 MHz, CDCl3): δ = 7.83 (d, JH,H = 9.10 Hz, 1H),
7.29 (dd, JH,H = 9.10, 2.70 Hz, 1H), 7.25 (s, 1H), 3.91 (s, 3H),
3.11-3.09 (m, 4H), 2.01-1.99 (m, 4H). 13C{1H} NMR (100
6-Chloro-2,3-dimethylquinoxaline (a23).40 Produced follow-
ing the general procedure as mentioned above by reacting 4-
chloro-2-nitroaniline (86.0 mg, 0.5 mmol, 1 equiv.) and 2,3-bu-
tanediol (135.0 μL, 1.5 mmol, 3 equiv.). The title product was
purified by column chromatography with silica gel using 20%
EtOAc in hexane as yellow solid (61 mg; 64%). 1H NMR (500
MHz, CDCl3): δ = 7.92 (d, JH,H = 2.25 Hz, 1H). 7.87 (d, JH,H
=
8.85 Hz, 1H), 7.56 (dd, JH,H = 8.85, 2.30, 1H), 2.69 (s, 3H), 2.68
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MHz, CDCl3): δ = 160.2, 154.1, 151.4, 142.8, 137.8, 129.5,
8.10 (m, 3H), 7.69-7.65 (m, 1H), 7.57-7.51 (m, 3H), 2.83-2.78
122.2, 106.1, 55.8, 33.3, 33.0, 23.1, 23.0. GC-MS (M+): 214.1.
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 152.3, 150.6,
143.6, 143.2, 142.4, 142.3, 140.4, 140.1, 139.8, 139.5, 136.8,
136.6, 133.7, 133.0, 130.6, 130.5, 129.9, 129.4, 129.3, 127.7,
127.6, 124.2, 123.4, 17.3, 17.1. GC-MS (M+): 298.0. HRMS
(ESI-TOF): calcd. for C15H12BrN2[M+H]+: 299.0184; found:
299.0181.
1
2
3
4
5
6
7
8
7-Bromo-5-methyl-2,3-diphenylquinoxaline (a29).57 Pro-
duced following the general procedure as mentioned above by
reacting 4-bromo-2-methyl-6-nitroaniline (115.5 mg, 0.5
mmol, 1 equiv.) and 1,2-diphenylethane-1,2-diol (321.3 mg, 1.5
mmol, 3 equiv.). The title product was purified by column chro-
matography with silica gel using 20% EtOAc in hexane as yel-
low solid (164 mg; 88%). gel using 20% EtOAc in hexane as
yellow solid (120 mg; 81%). For 3.0 mmol scale reaction iso-
Detail reaction optimization, preparative scale reaction, control ex-
periments, reaction kinetics and mechanism, characterization of the
material, 1H and 13C spectra of all compounds.
9
1
lated yield was 70% (0.785 g). H NMR (400 MHz, CDCl3): δ
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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43
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= 8.18 (s, 1H), 7.68 (s, 1H), 7.56-7.49 (m, 4H), 7.37-7.31 (m,
6H), 2.82 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 153.9,
152.3, 142.0, 139.8, 139.4, 139.2, 133.3, 130.3, 130.0, 129.4,
129.2, 129.1, 128.5, 128.4, 123.8, 17.1. GC-MS (M+): 374.0.
Two regio-isomers (a30 and a30') with 1:1 selectivity, were
separated by column chromatography. Produced following the
general procedure as mentioned above by reacting 4-chloro-2-
nitroaniline (86.0 mg, 0.5 mmol, 1 equiv.) and 1-phenylethane-
1,2-diol (207.0 mg, 1.5 mmol, 3 equiv.). The title product was
was purified by column chromatography with silica gel using
10% EtOAc in hexane as white solid (total yield 87.6 mg,
*Email: sabuj@iitk.ac.in
The authors declare no competing financial interest.
We are grateful to Science and Engineering Research Board
(SERB), India and Council of Scientific & Industrial Research
(CSIR), India for financial support. SS thanks CSIR for fellowship.
DP thanks IITK for fellowship.
1
73%).57 6-Chloro-2-phenylquinoxaline (a30). H NMR (500
MHz, CDCl3): δ = 9.31 (s, 1H), 8.18-8.16 (m, 2H), 8.10-8.06
(m, 2H), 7.72 (dd, JH,H = 8.90, 2.30 Hz, 1H), 7.57-7.52 (m, 3H).
13C{1H} NMR (125 MHz, CDCl3): 152.2, 144.4, 142.0, 141.1,
136.6, 135.5, 131.5, 131.1, 130.1, 129.4, 128.3, 127.7. GC-MS
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1555-1575.
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1
(M+): 240.0. 7-Chloro-2-phenylquinoxaline (a30'). H NMR
(400 MHz, CDCl3): δ = 9.29 (s, 1H), 8.18 (dd, JH,H = 8.32, 1.76
Hz, 2H), 8.14 (d, JH,H = 2.28 Hz, 1H), 8.04 (d, JH,H = 9.00 Hz,
1H), 7.67 (dd, JH,H = 9.04, 2.28 Hz, 1H), 7.58-7.52 (m, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ = 152.7, 143.6, 142.8,
140.3, 136.5, 136.3, 130.8, 130.7, 130.5, 129.4, 128.7, 127.8.
GC-MS (M+): 240.0.
Two regio-isomers (a31 and a31') with 3:2 selectivity, were
separated by column chromatography. Produced following the
general procedure as mentioned above by reacting 4-methoxy-
2-nitroaniline (84.0 mg, 0.5 mmol, 1 equiv.) and 1-phe-
nylethane-1,2-diol (207.0 mg, 1.5 mmol, 3 equiv.). The title
product was was purified by column chromatography with sil-
ica gel using 20% EtOAc in hexane as yellow solid (total yield
88 mg, 75%).34 7-Methoxy-2-phenylquinoxaline (a31). 1H
NMR (400 MHz, CDCl3): δ = 9.14 (s, 1H), 8.15 (d, JH,H = 9.96
Hz, 2H), 7.97 (d, JH,H = 9.12 Hz, 1H), 7.55-7.47 (m, 3H), 7.41-
7.35 (m, 2H), 3.96 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
161.2, 152.1, 144.1, 140.9, 137.7, 137.1, 130.2, 130.2, 129.3,
127.7, 123.1, 107.0, 56.0. GC-MS (M+): 236.0. 6-Methoxy-2-
1
phenylquinoxaline (a31'). H NMR (400 MHz, CDCl3): δ =
9.23 (s, 1H), 8.15 (d, JH,H = 7.36 Hz, 2H), 8.03 (d, JH,H = 9.12
Hz, 1H), 7.56-7.48 (m, 3H), 7.44-7.39 (m, 2H), 3.98 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ = 160.8, 149.8, 143.4,
143.3, 138.6, 137.2, 130.8, 129.9, 129.3, 127.4, 123.8, 106.7,
56.0. GC-MS (M+): 236.0.
6-Bromo-8-methyl-2-phenylquinoxaline (a32) and 7-bromo-
8-methyl-2-phenylquinoxaline (a32'). Produced following the
general procedure as mentioned above by reacting 4-bromo-2-
methyl-6-nitroaniline (115.5 mg, 0.5 mmol, 1 equiv.) and 1-
phenylethane-1,2-diol (207.0 mg, 1.5 mmol, 3 equiv.). The title
product was was purified by column chromatography with sil-
ica gel using 20% EtOAc in hexane as yellow solid; Two regio-
isomers (3:2) were inseparable in column chromatography (123
mg; 83%). 1H NMR (400 MHz, CDCl3): δ = 9.29 (s, 1H), 8.23-
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