Dehydrogenative Synthesis of Quinolines, 2-Aminoquinolines, and Quinazolines Using Singlet Diradical Ni(II)-Catalysts

Article abstract of DOI:10.1021/acs.joc.8b03070

Simple, straightforward, and atom economic methods for the synthesis of quinolines, 2-aminoquinolines, and quinazolines via biomimetic dehydrogenative condensation/coupling reactions, catalyzed by well-defined inexpensive and easy to prepare singlet diradical Ni(II)-catalysts featuring two antiferromagnetically coupled singlet diradical diamine type ligands are described. Various polysubstituted quinolines, 2-aminoquinolines, and quinazolines were synthesized in moderate to good yields from different low-cost and readily accessible starting materials. Several control experiments were carried out to get insight into the reaction mechanism which shows that the nickel and the coordinated diamine ligands participate in a synergistic way during the dehydrogenation of alcohols.

Full text of DOI:10.1021/acs.joc.8b03070

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Article
Dehydrogenative Synthesis of Quinolines, 2-Aminoquinolines
and Quinazolines using Singlet Di-radical Ni(II)-Catalysts
Gargi Chakraborty, Rina Sikari, Siuli Das, Rakesh Mondal,
Suman Sinha, Seemika Banerjee, and Nanda D. Paul
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03070 • Publication Date (Web): 28 Jan 2019
Downloaded from http://pubs.acs.org on January 28, 2019
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Dehydrogenative Synthesis of Quinolines, 2-Aminoquinolines and
Quinazolines using Singlet Di-radical Ni(II)-Catalysts
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Gargi Chakraborty,† Rina Sikari,† Siuli Das, Rakesh Mondal, Suman Sinha, Seemika Banerjee
and Nanda D. Paul*
Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur,
Botanic Garden, Howrah 711103, India
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Abstract. Simple, straightforward and atom economic methods for the synthesis of quinolines,
2-aminoquinolines and quinazolines via bio-mimetic dehydrogenative condensation/coupling
reactions, catalyzed by well defined inexpensive and easy to prepare singlet di-radical Ni(II)-
catalysts featuring two antiferromagnetically coupled singlet di-radical diamine type ligands are
described. Various polysubstituted quinolines, 2-aminoquinolines and quinazolines were
synthesized in moderate to good yields from different low-cost and readily accessible starting
materials. Several control experiments were carried out to get insight into the reaction
mechanism which shows that the nickel and the coordinated diamine ligands participate in a
synergistic way during the dehydrogenation of alcohols.
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Introduction. Nitrogen-heterocycles are ubiquitous in nature and constitute the backbone of
numerous natural products, pharmaceutically important molecules and organic functional
materials.1 Among various nitrogen-heterocycles known, Quinolines, 2-Aminoquinolines and
Quinazolines are important structural motifs found in a myriad of pharmacologically active and
biologically relevant compounds.2 They exhibit wide range of pharmacological and biological
activities such as antibacterial,3 antiinflammatory,4 anticonvulsant,5 antimalarial,6 antiasthmatic,7
anti-Alzheimer,8 and anticancer9 activities.
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Over the decades significant advances have been made for the synthesis of these
heterocycles via the classical metal-free methods as well as several metal-catalyzed multi-
component coupling reactions were developed.10,11 In-spite of notable progress, the developed
protocols are mostly associated with multi step reaction sequences, generation of copious waste
and almost always require pre-functionalized starting materials. Therefore, development of new
alternative efficient and environmentally benign atom economic synthetic methods involving
cheap and easily available starting materials for the construction of these nitrogen-heterocycles
are desirable.
In this regard, the dehydrogenative functionalization of alcohols offers an
environmentally benign and atom economic synthetic method for the benign construction of
complex organic molecules, including N-heterocycles, from sustainable and abundant
alcohols.12-26 Presently, the chemistry of dehydrogenative functionalization of alcohols is
undergoing a renaissance and a significant progress has been made on developing new catalysts
and catalytic methodologies to achieve efficient dehydrogenative functionalization of alcohols to
various value added products.12-26 In the last one decade, several research groups made notable
contribution for the synthesis of various useful organic materials including N-heterocycles such
as pyrroles,13 pyridines,14 pyrimidines,15 quinolines,16 quinazolinones,17 quinazolines,18 etc. via
this dehydrogenative coupling approach. Other than organo-heterocycles, some reports have
come up in recent times for the dehydrogenative synthesis of other useful organic materials such
as amines,19 imines,20 amides,21 and esters.22
Despite of the significant advances on dehydrogenative functionalization of alcohols to
various value added complex organic molecules including N-heterocycles, the catalysts mostly
used during dehydrogenation reactions are of precious metals such as Ru, Rh, and Ir.12-22
Therefore, in terms of sustainability, these expensive noble metals ought to be replaced by
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inexpensive and environmentally benign earth-abundant first-row base metals such as Mn, Fe,
Co, and Ni.23-26
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Recently, we reported [NiII(MeTAA)] (tetramethyltetraaza[14]annulene (MeTAA))
catalyzed synthesis of quinazoline,26a quinazolin-4(3H)-one,26b and quinoline,26c through
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dehydrogenative
condensation/coupling
reactions.
The
[NiII(MeTAA)]
catalyzed
dehydrogenation of alcohols proceeds via the formation of transient nickel hydride intermediate
involving exclusively metal centered redox events which are usually energetically uphill and
hence almost always require high temperature.26 In this regard, the bio-inspired catalysis utilizing
transition metal complexes featuring redox noninnocent scaffolds offer an attractive alternative
where the high energetic metal centered redox events may be avoided during catalysis via the
synergistic participation of both metal and coordinated ligand centered redox or in some cases
via exclusive ligand centered redox events.27,28 The synergistic participation of copper and the
coordinated phenoxyl radical in dehydrogenation of alcohols catalyzed by metallozyme
Galactose Oxidase (GO) under biological conditions is noteworthy to mention.28b
Herein we report a new bio-mimetic method for the construction of various
polysubstituted quinolines, 2-aminoquinolines and quinazolines through dehydrogenative
condensation/coupling of 2-aminobenzylalcohols with ketones (for quinolines); 2-
phenylacetonitrile (for 2-aminoquinolines) and nitriles (for quinazolines) respectively, catalyzed
by well defined singlet di-radical Ni(II)-complexes featuring two simple diamine type of ligands
where all or part of the redox events are expected to take place at the ligands.29 We envisaged
that a Ni(II)-ion coordinated to a one electron oxidized semiquinone radical ligand can possibly
mimic the activity of the metalloenzyme GO during the dehydrogenation of alcohols. The nickel
bound ligand centered radical would trap the -CH atom of any alcohol (similar to that of
phenoxyl radical in GO) affording nickel bound ketyl radical intermediate which then upon
intermolecular electron transfer can produce the desired aldehydes. In the subsequent steps, base
promoted intermolecular/intramolecular condensation of 2-aminobenzaldehyde with the other
coupling partners would afford the desired nitrogen heterocycles; quinolines, 2-aminoquinolines
and quinazolines respectively. Various polysubstituted quinolines, 2-aminoquinolines and
quinazolines were synthesized in moderate to good yields from readily accessible starting
materials under relatively mild reaction conditions (<100 °C).
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Result and Discussion. Three tetracoordinated singlet di-radical Ni(II)-complexes bearing two
antiferromagnetically coupled one-electron oxidized redox noninnocent ligands (L1-3) with the
valence configuration of [NiII{(L1-3)}2] were used in this study to synthesize quinoline, 2-
aminoquinoline and quinazolines (Scheme 1).29 In catalyst 1, two one electron oxidized o-
phenylenediamine (L1) ligands are coordinated to the nickel center in a square planer
geometry,29a whereas in catalyst 2, the coordinated ligands are two one electron oxidized N-
phenyl-o-phenylenediamine (L2).29b In catalyst 3, two one electron oxidized tridentate N-(2-
aminophenyl)benzene-1,2-diamine (L3) ligands are coordinated to the nickel center in a bidentate
fashion with one pendant amine arm from each of the ligands.29c All these complexes were
prepared following the available literature methodes.29
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Scheme 1. Ni(II)-complexes used as catalysts.
Initially the reactions of 2-aminobenzylalcohol (4a) with acetophenone (5a), 2-
phenylacetonitrile (6a) and benzonitrile (7a) respectively, were studied separately under different
reaction conditions to get the optimal reaction parameters for the synthesis of quinolines, 2-
aminoquinolines and quinazolines catalyzed by 3. Since the catalysts used in this study are all air
stable, we opted to carry out the catalytic reactions under aerial conditions. Optimization of the
reaction conditions revealed that these reactions proceed efficiently in toluene or xylene in
presence of an inorganic base like KOtBu or NaOtBu. Poor yields were obtained in polar solvents
such as MeOH, acetonitrile, etc; no desired product was obtained in absence of base. Highest
yield of quinoline (8aa) (85%) was obtained when the reaction was carried out in toluene at 80
°C for 10h (Table 1, entry 1). However, 2-aminoquinoline (9aa) and quinazoline (10aa) required
slightly higher temperature and prolong reaction time. At 95 °C in toluene 65% of 2-
aminoquinoline (9aa) was obtained in 30h whereas 82% of quinazoline (10aa) was isolated at 90
°C in toluene (Table 1, entry 7, 13). A catalyst loading of 4.0 mol% has been found to be
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sufficient to bring about the highest yields of 8aa in presence of 0.5 equiv. of KOtBu. Slightly
higher base loading (0.75 equiv.) is required to obtain the highest yields of 9aa, and 10aa
respectively. Increasing the temperature or base loading did not lead to any noticeable increase in
yields, however, decreasing the temperature or base loading below 0.5 equiv. significantly
diminish the yields.
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In presence of only base, quinoline (8aa), 2-aminoquinoline (9aa) and quinazoline (10aa)
were not obtained. Catalysts 1 and 2 were found to be comparably less effective than catalyst 3
(Table 1, entries 15, 16). In presence of other nickel(II) salts such as Ni(ClO4)2.6H2O and
NiCl2.6H2O, desired products were obtained in trace amounts (Table 1, entries 22, 23).
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Table 1. Optimization of the Reaction Conditions.a-c
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Entry
Ni-catalyst
(mol%)
Solvent
Base
Temperature
(°C)
Yield (%)
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8aa
85
74
72
70
trace
NR
85
9aa
45
48
41
40
trace
NR
49
10aa
78
70
69
67
trace
NR
82
1
2
3
4
5
6
7
8
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
3 (4.0 mol%)
1 (4.0 mol%)
2 (4.0 mol%)
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
acetonitr
ethanol
THF
KOtBu
NaOtBu
KOH
NaOH
K3PO4
NEt3
80
80
80
80
80
80
90
80
80
80
80
80
95
120
100
120
100
100
80
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
-
85
44
77
9
trace
NR
NR
NR
83
80
56
43
NR
NR
trace
-
trace
trace
trace
trace
65
60
25
30
NR
NR
-
NR
-
trace
trace
trace
trace
82
80
40
47
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DMF
toluene
xylene
toluene
xylene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NR
NR
-
3 (4.0 mol%)
-
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
95
90
100
100
-
-
-
-
NR
trace
trace
Ni(ClO4)2.6H2O (10 mol%)
NiCl2.6H2O (10 mol%)
trace
trace
trace
trace
aStoichiometry : Path A : 2-aminobenzylalcohol (4a) (1.0 mmol), acetophenone (5a) (1.0 mmol), base
(0.50 mmol, 0.5equiv.), time 10h; Path B: 2-aminobenzylalcohol (4a) (1.0 mmol), 2-phenylacetonitrile
(6a) (1.0 mmol), base (0.75 mmol, 0.75 equiv.), time 30h; Path C: 2-aminobenzylalcohol (4a) (1.0
mmol), benzonitrile (7a) (1.0 mmol), base (0.75 mmol, 0.75 equiv.), time 30h; bsolvent : 5.0 mL;
cIsolated yields after column chromatography.
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With the optimal conditions in hand we explored the scope and the versatility of the
present nickel-catalyzed dehydrogenative coupling reactions. Initially we studied the reaction of
2-aminobenzylalcohol and ketones catalyzed by 3 (Table 2). A wide variety of ketones bearing
various functionalities such as aryl, alkyl, naphthyl, and heterocycles were found to be
compatible under our optimal reaction conditions. Reactions proceeded efficiently with
acetophenones having both electron withdrawing and donating functionalities. For example, 2-
aminobenzylalcohol (4a) when reacted with 2′-methylacetophenone (5b) and 4′-
methylacetophenone (5c) respectively, under our optimal conditions produced 8ab and 8ac in
80% and 89% yields respectively (Table 2, entry 2, 3). The presence of amino group was also
tolerated under our optimal reaction conditions yielding the desired quinoline, 8af in 79% yield
(Table 2, entry 6).
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Reactions also proceeded with acetophenones containing electron withdrawing
functionalities. 2′-haloacetophenones (5g, 5i) produced the corresponding quinolines 8ag and 8ai
in 65 and 77% yields respectively. 2-aminobenzylalcohol (4a) when reacted with the
corresponding 4′-haloacetophenones (5h, 5j, 5l) under our optimal reaction conditions produced
the corresponding quinolines 8ah, 8aj and 8al in 69, 74 and 57% yields respectively (Table 2,
entries 8, 10, 12). 3′-bromoacetophenone (5k) was also tolerated under our optimal reaction
conditions to afford the desired quinoline, 8ak in 64% isolated yield. However, the desired
quinolines were obtained in moderate yields (Table 2, entries 13-15) in presence of strong
electron withdrawing groups like -CF3, -NO2 etc. Reactions also proceeded with ketones bearing
heterocycle functionalities as the coupling partners. 1-(pyridin-3-yl)ethanone (5r), 1-(thiophen-2-
yl)ethanone (5p) when reacted separately under the optimal reaction conditions with 2-
aminobenzylalcohol (4a) produced 8ar and 8ap in 89 and 84% yields respectively (Table 2,
entries 16-18). Reactions also proceeded with non-methyl and aliphatic ketones. Using non-
methyl ketones, quinolines, 8as and 8at were isolated in 88 and 90% yields respectively (Table
2, entries 19, 20). Using aliphatic ketone, cyclopropylethanone (5u) the corresponding quinoline,
8au was obtained in 70% isolated yield (Table 2, entry 21).
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Table 2. Synthesis of Polysubstituted Quinolines via Dehydrogenative Coupling of Various
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Ketones with 2-Aminobenzylalcohol Catalyzed by 3.a-e
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Next, we explored the substrate scope of the dehydrogenative coupling of 2-
aminobenzylalcohol (4a) and 2-phenylacetonitrile, catalyzed by 3 (Table 3) to synthesize various
polysubstituted 2-aminoquinolines. As was observed during quinoline synthesis, 2-
phenylacetonitrile containing electron withdrawing and donating functionalities were found to be
suitable producing the desired 2-aminoquinolines in 65-73% yields. For example, 2-p-
tolylacetonitrile (6b) and 2-(4-methoxyphenyl)acetonitrile (6c) afforded the corresponding 2-
aminoquinolines 9ab and 9ac in 70 and 67% yields respectively (Table 3, entry 2, 3). Reactions
proceeded also with 2-phenylacetonitriles containing electron withdrawing halogens (Table 3,
entries 4-5).
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Table 3. Synthesis of Polysubstituted 2-Aminoquinolines via Dehydrogenative Coupling of
Various 2-phenylacetonitriles with 2-Aminobenzylalcohol Catalyzed by 3.a-e
To explore the substrate scope and versatility of the dehydrogenative synthesis of
quinazolines catalyzed by 3, 2-aminobenzylalcohol (4a) was reacted with various substituted
benzonitriles under the optimal reaction conditions (Table 4). To our delight, the
dehydrogenative coupling reactions proceeded smoothly with benzonitriles having both electron
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withdrawing and donating groups. The corresponding quinazolines were isolated in moderate to
good yields. Quinazolines were isolated in slightly higher yields with substrates containing
electron withdrawing functionalities compared to the substrates bearing electron donating
groups. For example, benzonitriles bearing methyl groups at the meta- or para- positions
produced the corresponding quinazolines, 10ab and 10ac in 67 and 66% (Table 4, entries 2, 3)
yields respectively.
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Quinazolines were also isolated in good yields when benzonitriles having electron
withdrawing functionalities were used as the substrates. Benzonitriles having halogens (Cl, Br) at
different positions of the phenyl ring were also found to be compatible producing the desired
quinazolines 10ah-10am in 72-84% yields respectively (Table 4, entries 8-13). Benzonitriles
containing multiple electron withdrawing functionalities were also tolerated under our optimal
reaction conditions. The reaction of 2-aminobenzylalcohol (4a) with 3, 5-difluorobenzonitrile
(7n) under the optimal reaction conditions produced 2-(3,5-difluorophenyl)quinazoline (10an) in
88% yield (Table 4, entry 14). Benzonitriles containing -CF3 groups were also found to be
suitable; afforded the desired quinazoline, 10ao in 85% yields (Table 4, entry 15). Quinazolines
were also obtained in moderate to good yields starting from nitriles bearing heterocyclic
functionalities (Table 4, entries 17-19). Reaction also proceeded with long chain alkyl nitrile,
albeit required slightly prolonged reaction time and the corresponding quinazoline was isolated
in moderate yield (Table 4, entry 20).
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Table 4. Synthesis of Polysubstituted Quinazolines via Dehydrogenative Coupling of Various
Nitriles with 2-Aminobenzylalcohol Catalyzed by 3.a-e
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To explore the versatility and expand the substrate scope of the present nickel catalyzed
dehydrogenative coupling reactions, several substituted 2-aminobenzylalcohols were reacted
separately with acetophenone (5a), 2-phenylacetonitrile (6a) and benzonitrile (7a) under our
optimal conditions (Table 5-7). To our delight, quinolines (8ba-8fa), 2-aminoquinolines (9ba-
9fa) and quinazolines (10ba-10fa) were obtained in 66-87% (quinolines); 59-65% (2-
aminoquinolines); and 78-84% (quinazolines) yields respectively starting from 2-
aminobenzylalcohols containing electron donating or electron withdrawing functionalities.
Reactions also proceeded with 2-aminobenzylalcohols containing both electron donating and
electron withdrawing groups.
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Table 5. Synthesis of Polysubstituted Quinolines via Dehydrogenative Coupling of
Acetophenone with Various 2-Aminobenzylalcohol Catalyzed by 3.a-e
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Table 6. Synthesis of Polysubstituted 2-Aminoquinolines via Dehydrogenative Coupling of 2-
phenylacetonitrile with Various 2-Aminobenzylalcohol Catalyzed by 3.a-e
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Table 7. Synthesis of Polysubstituted Quinazolines via Dehydrogenative Coupling of
Benzonitrile with Various 2-Aminobenzylalcohol Catalyzed by 3.a-e
To gain insight into the reaction mechanism, several control experiments were performed
under the optimal conditions. Initial mechanistic investigations were focused on to explore the
plausible pathways of alcohol dehydrogenation reaction catalyzed by 3.
Since the catalysts used in this study are all singlet di-radical Ni(II)-complexes containing
two antiferromagnetically coupled ligand centered radicals, the dehydrogenation of alcohols as
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well as the dehydrogenative coupling reactions mentioned above were carried out in presence of
a radical scavenger 2,2-diphenyl-1-picrylhydrazyl (DPPH) to check the involvement of organic
radical during catalytic turnover. In presence of one equivalent DPPH, only 5% of the aldehyde
was obtained as the dehydrogenation product of the alcohol and no products were obtained in all
the above mentioned dehydrogenative coupling reactions.
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The color of the catalysts 2 and 3 immediately changes upon addition of KtBuO. Since,
other than acting as base, alkali metal tertiary butoxides, are known to be capable of acting as a
reducing agent,30 the observed color change may be because of simple deprotonation of any of
the -NH group of the coordinated ligand or it may be because of the reduction of the coordinated
ligands. Therefore, to check whether the origin of the color changes observed upon addition of
KtBuO is because of reduction of the catalyst, the reaction mixtures containing KtBuO and
catalyst 2 or 3 were studied by EPR. Both the reaction mixtures showed very weak EPR signals
representing at most a tiny amount of the bulk of the nickel complex when treated with KtBuO
(see SI). Hence, the color change seems to be because of deprotonation of any of the -NH arms
of the coordinated ligand and possibly the deprotonated complex [3]- acts as the active catalyst.
Notably, when the dehydrogenation of benzylalcohol was carried out in a stoichiometric manner
using the preformed [3]- as the catalyst, in absence of any added base, 92% of the
dehydrogenated product was isolated indicating the active role of the deprotonated complex [3]-
during catalysis.
Next, intermolecular transfer hydrogenation experiments were performed in presence of
easily reducible substrates to test the possibility of H2 evolution during dehydrogenation of
alcohols. Notably, no transfer hydrogenation was observed during the dehydrogenation of 1-
phenylethanol (11a) in presence of 4-methoxybenzaldehyde (11b) under closed conditions in
presence of argon. Moreover, the dehydrogenated product, acetophenone (5a) was obtained in
trace amount (See SI). On the other hand, when the same transfer hydrogenation reaction was
carried out under aerial conditions, the yield of the dehydrogenated product, acetophenone (5a)
increases to 85%. In presence of air, no transfer hydrogenation was observed, rather H2O2 was
detected as the hydrogenated product of molecular oxygen (Figure S1).
Attempts were made to quantify the liberated H2O2 under aerial conditions. Under
optimized catalytic conditions in presence of 0.5 equiv. of KOtBu, 0.68 equiv. of H2O2 was
detected with respect to the alcohol. In presence of 1.0 equiv. of KOtBu the amount of H2O2
becomes almost half (0.48 equiv.) with respect to 1-phenyl ethanol, indicating the incorporation
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of only one hydrogen atom of the 1-phenylethanol to H2O2. On the other hand, the stoichiometric
reaction, using [3]- as the catalyst, in absence of any added base afforded 0.82 equiv. of H2O2,
indicating that almost two hydrogen atoms of the alcohol (-OH and C-H) are incorporated in
H2O2. Overall, in presence of excess base (deprotonating agent), H2O2 was found to form in 0.48
equiv. whereas in absence of base using [3]-, almost one equivalent H2O2 was obtained which
indeed indicates that the deprotonated complex [3]- can also act as an deprotonating agent.
Therefore, under the optimal catalytic conditions, it is believed that both the added base as well
as the active catalyst [3]- act as the deprotonating agent.
To further confirm the role of [3]- during the deprotonation of alcohols, a stoichiometric
reaction was carried out between [3]- and D2-1-phenylethanol under inert conditions. IR
spectroscopic analysis of the reaction mixture shows an absorption band at 2163 cm-1 indicating
N-D stretching. The stoichiometric dehydrogenation of D1-1-phenylethanol also showed N-D
stretching at 2162 cm-1 which indeed confirmed that the C-D bond in 1-phenyl ethanol is cleaved
and the deuterium is transferred to the coordinated ligand forming N-D bond. Since, the catalyst
3 used herein is a singlet di-radical species containing two antiferromagnetically coupled ligand
centered radicals, the transfer of hydrogen atom from the alcohol to the coordinated ligand may
indeed take place either via the1e- hydrogen atom transfer process (HAT) forming ketyl radical
intermediate28a or via 2e- hydride transfer pathway forming a transient nickel-hydride
intermediate followed by hydrogen atom walking mechanism.28f
To probe the 1e- hydrogen atom transfer process (HAT) vs. 2e- hydride transfer pathway
the radical clock substrate cyclobutanol was subjected to dehydrogenation under our optimal
reaction conditions using 3 as the catalyst. Formation of multiple ring opening products points to
the possibility of HAT process rather than hydride transfer as also evident from the fact that in
presence of radical scavenger like DPPH, the yield of the product decreases significantly.
Once we understood the plausible mechanistic pathway for the dehydrogenation of
alcohols catalyzed by 3, our next control experiments were focused on to explore the plausible
mechanistic pathways for the dehydrogenative coupling reactions. The dehydrogenative coupling
of alcohols with carbonyl species having active methylene group is known to proceed through
the base mediated formation of α, β-unsaturated ketones followed by intramolecular
cyclodehydration to produce quinolines.26c The dehydrogenative coupling of nitriles with
alcohols is reported to proceed through the formation of amidine intermediate which upon
subsequent dehydrogenation followed by intramolecular condensation affords quinazolines.18a
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However, in our recent report we shown that in presence of KOtBu, nitriles can be converted to
the corresponding amides which upon base promoted intermolecular condensation followed by
cyclization can also produce quinazolines.26a
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Control experiments showed that under our optimal reaction conditions, in presence of
0.75 equiv. of KOtBu, 46% 2-phenylacetamide (6a') was isolated from 2-phenylacetonitrile (6a)
(Scheme 2, equation (i)). On the other hand, 59% of benzamide (7a') was isolated from
benzonitrile (7a) under our optimal reaction conditions. Therefore, the dehydrogenative coupling
of 2-aminobenzylalcohol with 2-phenylacetonitriles or benzonitriles can either proceed via
amidine intermediate or the direct condensation of in-situ formed 2-aminobenzaldehyde
(dehydrogenated product of 2-aminbenzylalcohol) and amide (formed from nitriles) can also lead
to the formation of 2-aminoquinolines and quinazolines. It is worthy to mention here that the
direct condensation of preformed 2-aminobenzaldehyde with 2-phenylacetamide (6a') and
benzamide (7a') respectively produce the corresponding 2-aminoquinoline (9aa) and 2-
phenylquinazoline (10aa) in 12% and 15% isolated yields respectively (Scheme 2, equation
(ii)).26a
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However, the direct reactions of 2-aminobenzaldehyde with benzonitrile and 2-
phenylacetonitrile respectively, in absence of base (KOtBu), afforded 2-aminoquinolines (9aa) or
2-phenyl quinazoline (10aa) in trace amounts (Scheme 2, equation (vi)). Similarly, 2-
aminoquinoline (9aa) and 2-phenyl quinazoline (10aa) were also obtained in trace amounts from
the reactions of the Na-salt of 2-aminobenzylalcohol with 2-phenylacetonitrile and benzonitrile
respectively in absence of KOtBu under the optimal reaction conditions (Scheme 2, equation
(iv)). However, the same reactions of the Na-salt of 2-aminobenzylalcohol with 2-
phenylacetonitrile or benzonitrile in presence of 0.75 equiv. of KOtBu, under the optimal
reaction conditions, afforded 61% of 9aa and 79% of 10aa (Scheme 2, equation (viii)).
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Scheme 2. Mechanistic investigation during dehydrogenative coupling of 2-aminobenzylalcohol
and benzonitrile catalyzed by 3.
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Scheme 3. Proposed mechanism.
In accordance with available literature and above experimental results a possible
mechanism for the present dehydrogenative coupling of 2-aminobenzylalcohols with carbonyls,
2-phenylacetonitriels and nitriles, catalyzed by the singlet di-radical Ni(II)-catalyst 3 is shown in
Scheme 3. The reaction proceeds via the initial base promoted deprotonation of one of the
coordinated ligand in 3 to form the deprotonated complex [3]- which then acts as the active
catalyst. The catalytic reaction begins with the deprotonation of the alcohol followed by the
formation of nickel-alkoxy intermediate 3A. As evident from the control reactions, other than
base the deprotonated complex [3]- can also abstract the OH proton of the alcohols. In the next
step hydrogen atom abstraction from the nickel-alkoxy intermediate produces an O-coordinated
ketyl radical intermediate (3B) which upon rapid one-electron oxidation produce the desired 2-
aminobenzaldehydes.
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2-aminobenzaldehyde, thus formed, undergoes base promoted cross-aldol condensation
with ketones (preformed or formed in-situ from 2-phenylacetonitrile) to form the α, ß-
unsaturated ketones. Intramolecular cyclodehydration of these α, ß-unsaturated ketones then
produce the desired quinolines and 2-aminoquinolines. Base mediated condensation 2-
aminobenzyldehyde with benzamide (formed in-situ from benzonitrile) afforded the
quinazolines. Formation of quinazoline via amidine intermediate as reported by others seems less
likely, however, cannot be ignored.
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Conclusion. In summary the present work provides a simple, straightforward and atom
economic alternative approach to access quinolines, 2-aminoquinolines and quinazolines via bio-
mimetic dehydrogenative coupling of various cheap and easily accessible starting precursors,
catalyzed by well defined cheap and earth abundant singlet di-radical Ni(II)-catalysts featuring
two antiferromagnetically coupled singlet di-radical diamine type ligands. A wide variety of
quinolines, 2-aminoquinolines and quinazolines were synthesized in moderate to good yields
under aerial conditions. Mechanistic studies showed that during dehydrogenation of alcohols,
both nickel and the coordinated redox active ligand act in a synergistic manner.
Experimental Section.
General Information. Unless otherwise mentioned, all the reagents and starting materials were
commercially available and used without further purification. Solvents were dried prior to use
following the available standard procedures. Bruker DPX-300 (300 MHz) and Bruker DPX-400
(400 MHz) spectrometers were used for NMR experiments using SiMe4 (tetramethylsilane) as
the internal standard. GF254 silica gel plates (0.25 mm thickness) were used for TLC and Merck
60 silica gel of 60-120 mesh was used for column chromatography. Micromass Q-TOF mass
spectrometer (serial no. YA 263) was used to collect the ESI mass spectra.
Synthesis of Catalysts. The catalysts 1-3 were prepared following the available literature
methodes.29
General Procedure for Synthesis of Quinolines via Dehydrogenative Coupling of 2-
Aminobenzylalcohol with Ketones. Under air, in an oven dried 50 mL bound-bottom flask, a
mixture of 2-aminobenzylalcohol (1.0 mmol), KOtBu (0.50 mmol) and catalyst 3 were taken. A
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magnetic stir bar was then inserted to the round-bottom flask and using a syringe, acetophenone
(1.0 mmol) dissolved in 5.0 mL dry toluene was added to the reaction vessel. The round-bottom
flask containing the reaction mixture was then placed in an oil bath and heated at 80°C. The
reaction was monitored through TLC. Once the reaction was complete after 10h, the reaction
mixture was cooled to room temperature and the solvent was evaporated to dryness using rotary
vacuum evaporator. The residue was purified by flash column chromatography using petroleum
ether/ethyl acetate (20:1) as eluent.
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General Procedure for Synthesis of 2-Aminoquinolines via Dehydrogenative Coupling of 2-
Aminobenzylalcohol with 2-Phenylaetonitriles. Under air, a mixture of 2-aminobenzylalcohol
(1.0 mmol), KOtBu (0.75 mmol) and catalyst 3 were taken in an oven-dried 50 mL round-bottom
flask containing a magnetic stir bar. Using a syringe, 2-phenylacetonitrile (1.0 mmol) dissolved
in 5.0 mL dry toluene was added to the reaction vessel. The round-bottom flask containing the
reaction mixture was then placed in an oil bath and heated at 95oC. The reaction was monitored
through TLC. After 30h, the reaction mixture was cooled to room temperature and the solvent
was evaporated to dryness using rotary vacuum evaporator. The residue was purified by flash
column chromatography (silica gel) using petroleum ether/ ethyl acetate (3:1) as eluent.
General Procedure for Synthesis of Quinazolin by Dehydrogenative Coupling of 2-
Aminobenzylalcohol with Nitriles. Under air, a mixture of 2-aminobenzylalcohol (1.0 mmol),
KOtBu (0.75 mmol) and catalyst 3 were taken in an oven-dried 50 mL round-bottom flask
containing a magnetic stir bar. Using a syringe, nitriles (1.0 mmol) dissolved in 5.0 mL dry
toluene were added to the reaction vessel. The round-bottom flask containing the reaction
mixture was then placed in an oil bath and heated at 90oC. The reaction was monitored through
TLC. After 30h, the reaction mixture was cooled to room temperature and the solvent was
evaporated to dryness using rotary vacuum evaporator. The residue was purified by flash column
chromatography (silica gel) using petroleum ether/ ethyl acetate (19:1) as eluent.
Characterization Data of the Isolated Compounds.
2-Phenylquinoline (8aa).10d, 26c Eluent: petroleum ether/ethyl acetate (20: 1). White solid (85%,
174 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) = 8.25- 8.16 (m, 4H), 7.90-7.83 (m, 2H), 7.76-
7.70 (m, 1H), 7.56-7.47 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) = 157.5, 148.4,
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139.8, 136.9, 129.9, 129.7, 129.6, 128.9, 127.7, 127.6, 127.3, 126.4, 119.1. HRMS (ESI, positive
ions): m/z calcd for C15H12N+ [M + H+] 206.0964, found 206.0977.
2-o-Tolylquinoline (8ab).26c Eluent: petroleum ether/ethyl acetate (20:1). White solid (80%,
175 mg). 1H NMR (400 MHz, CDCl3):  (ppm) = 8.18 - 8.13 (t, J = 9.5 Hz, 2H), 7.80 (d, J = 8.0
Hz, 1H), 7.72 - 7.68 (m, 1H), 7.53 - 7.48 (m, 3H), 7.31-7.29 (m, 3H), 2.40 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3):  (ppm) = 160.3, 147.9, 140.7, 136.1, 136.0, 130.9, 129.8, 129.7,
129.6, 128.6, 127.6, 126.8, 126.5, 126.1, 122.4, 20.4.
2-p-Tolylquinoline (8ac).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid (89% 195
mg). 1H NMR (300 MHz, CDCl3):  (ppm) = 8.21 – 8.16 (t, J = 9.0 Hz, 2H), 8.08 (d, J = 6.6 Hz,
2H), 7.88 -7.80 (m,2H), 7.75 – 7.70 (t, J = 7.0 Hz, 1H), 7.54 – 7.49 (t, J = 7.6 Hz, 1H), 7.34 (d, J
=8.1 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) =157.5, 148.4, 139.7,
137.1, 139.8, 129.7, 129.5, 127.6, 127.4, 126.2, 119.0, 21.6.
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2-(2-Methoxyphenyl)quinoline (8ad).26c Eluent: petroleum ether/ethyl acetate (20 : 1). Yellow
liquid (75%, 176 mg). 1H NMR (400 MHz, CDCl3):  (ppm) = 8.07 (d, J = 8.0 Hz, 1H), 8.00 (d,
J = 8.0 Hz, 1H), 7.77-7.74 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.69-7.56 (m, 1H), 7.40-7.37 (t, J =
8.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.03-6.99 (t, J = 8.0 Hz, 1H), 6.90- 6.88 (d, J = 8.0 Hz, 1H),
13
3.71 (s, 3H). C{1H} NMR (100 MHz, CDCl3):  (ppm) = 157.2, 157.2, 148.3, 135.1, 131.5,
130.4, 129.7, 129.6, 129.3, 127.4, 127.1, 126.2, 123.5, 121.3, 111.5, 55.6.
2-(4-Methoxyphenyl)quinoline (8ae).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White
solid (90%, 212 mg). 1H NMR (300 MHz, CDCl3):  (ppm) = 8.20 - 8.13 (m, 4H), 7.85-7.79 (t, J
= 7.5 Hz, 2H), 7.74-7.68 (t, J = 9.3 Hz, 1H), 7.52-7.48 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 9.4 Hz,
2H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) = 161.0, 157.2, 148.6, 136.9,
132.4, 129.9, 129.7, 129.1, 127.6, 127.1, 126.0, 118.7, 114.4, 55.6. HRMS (ESI, positive ions):
m/z calcd for C16H14NO+ [M + H+] 236.10699, found 236.1060.
4-(Quinolin-2-yl)benzenamine (8af).26c Eluent: petroleum ether/ethyl acetate (20 : 1). Yellow
solid (79%, 174 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) = 8.10 (d, J = 8.0 Hz, 2H), 8.01 (d, J
= 8.0 Hz, 2H), 7.78- 7.74 (m, 2H), 7.69- 7.65 (m, 1H), 7.47-7.43 (m, 1H), 6.78 (d, J = 8.0 Hz,
13
2H), 3.85 ( br. s, 2H). C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 157.3, 148.2, 148.1, 136.4,
130.7, 129.4, 129.0, 128.7, 127.4, 126.7, 125.5, 118.3, 115.0.
2-(2-Fluorophenyl)quinoline (8ag).26c Eluent: petroleum ether/ethyl acetate (20 : 1). Yellow
liquid (65% , 145 mg). 1H NMR (300 MHz, CDCl3): δ (ppm) =8.19-8.14 (m, 2H), 8.11-8.07 (m,
1H), 7.88-7.78 (m, 2H), 7.74-7.70 (m, 1H), 7.55-7.51 (m, 1H), 7.44-7.38 (m, 1H), 7.32-7.28 (m,
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1H), 7.21-7.16 (m, 1H). C{1H} NMR (100 MHz, CDCl3): δ (ppm) =160.8 (d, J = 248.1 Hz),
148.3, 136.2, 131.5, 130.9, 130.8, 129.7(d, J = 3.9 Hz), 127.5, 127.2, 126.7, 124.7, 124.7, 122.5,
122.4, 116.3(d, J = 22.0 Hz). HRMS (ESI, positive ions): m/z calcd for C15H11FN+ [M + H+]
224.087, found 224.0886.
2-(4-Fluorophenyl)quinoline (8ah).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White
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solid (69%, 154 mg ). H NMR (300 MHz, CDCl3): δ (ppm) = 8.23-8.15 (m, 4H), 7.83 (d, J =
12.2 Hz, 2H), 7.76-7.71(t, J=7.5 Hz, 1H), 7.56-7.51 (t, J=7.5 Hz, 1H), 7.26-7.19 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 161.8, 156.4, 148.4, 137.0, 135.9, 129.9, 129.8,
129.5 (d, J = 13.9 Hz), 127.6, 127.2, 126.5, 118.8, 115.9 (d, J = 24.3 Hz) .
2-(2-Chlorophenyl)quinoline (8ai).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
(77% , 185 mg). 1H NMR (300 MHz, CDCl3): δ (ppm) = 8.23-8.18 (t, J = 8.7 Hz, 2H), 7.85 (d, J
= 8.0 Hz, 1H), 7.75-7.70 (m, 3H), 7.59–7.50 (m, 2H), 7.43-7.36 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) = 157.4, 148.1, 139.7, 135.7, 132.4, 131.8, 130.1, 129.9, 129.7, 129.7,
127.6, 127.2, 127.2, 126.8, 122.8.
2-(4-Chlorophenyl)quinoline (8aj).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
1
(74%, 177 mg). H NMR (300 MHz, CDCl3): δ (ppm) = 8.19-8.08 (m, 4H), 7.80-7.70 (m, 3H),
7.54-7.46 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ (ppm) = 155.9, 148.1, 137.9, 137.1,
135.7, 129.9, 129.6, 129.1, 128.9, 127.5, 127.3, 126.6, 118.6. HRMS (ESI, positive ions): m/z
calcd for C15H11ClN+ [M + H+] 240.0575, found 240.0552.
2-(3-Bromophenyl)quinoline (8ak).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White
1
solid (64%, 181 mg). H NMR (300 MHz, CDCl3): δ (ppm) = 8.26 (s, 1H), 8.12-8.06 (m, 2H),
7.96 (d, J = 9.0 Hz, 1H), 7.72-7.61 (m, 3H), 7.49-7.41 (m, 2H), 7.30-7.25 (t, J = 6.0 Hz,1H).
13C{1H} NMR (125 MHz, CDCl3): δ (ppm) = 155.5, 148.2, 141.6, 136.9, 132.2, 130.6, 130.3,
129.9, 129.7, 127.5, 127.3,126.6, 126.0, 123.1, 118.6. HRMS (ESI, positive ions): m/z calcd for
C15H11BrN+ [M + H+] 284.0069, found 284.0059.
2-(4-Bromophenyl)quinoline (8al).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
(57% , 162 mg). 1H NMR (300 MHz, CDCl3): δ (ppm) = 8.17 (d, J= 8.7 Hz, 2H), 8.04 (d, J= 8.1
Hz, 2H), 7.79-7.75 (m, 2H), 7.72 (d, J= 7.5 Hz, 1H), 7.64-7.49 (m, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ (ppm) = 156.0, 148.3, 138.6, 137.0, 132.0, 131.9, 129.9, 129.8, 129.8, 129.2,
127.6, 127.3, 126.6, 124.0, 118.5.
2-(4-(Trifluoromethyl)phenyl)quinoline (8am).26c Eluent: petroleum ether/ethyl acetate (20: 1).
White solid (55%, 150 mg). 1H NMR (300 MHz, CDCl3): δ (ppm) = 8.28-8.23 (m, 2H), 8.20 (d,
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J = 8.3 Hz, 2H), 7.86-7.82 (m, 2H), 7.79-7.73 (m, 3H), 7.59-7.53 (t, J= 7.8 Hz, 1H). 13C {1H}
NMR (75 MHz, CDCl3): δ (ppm) = 155.7, 148.4, 143.1, 137.3, 131.4, 130.1, 129.9, 127.9, 127.6,
127.5, 126.9, 126.1, 125.9-125.8 (q, JC-F = 4.0 Hz), 118.8. HRMS (ESI, positive ions): m/z calcd
for C16H11F3N+ [M + H+] 274.0838, found 274.0847.
2-(3-Nitrophenyl)quinoline (8an).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
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(52%, 130 mg). H NMR (400 MHz, CDCl3): δ (ppm) = 8.99 (s, 1H), 8.50 (d, J= 8.0 Hz, 1H),
8.25 (d, J= 8.0 Hz, 2H), 8.13 (d, J= 8.0 Hz, 1H), 7.88 (d, J= 8.0 Hz,1H), 7.81 (d, J= 8.0 Hz, 1H),
7.74-7.70 (t, J= 8.0 Hz, 1H), 7.67-7.63 (t, J= 8.0 Hz, 1H), 7.54-7.51 (t, J= 8.0 Hz,1H). C{1H}
13
NMR (75 MHz, CDCl3): δ (ppm) = 154.3, 148.3, 141.2, 137.5, 133.9, 130.2, 129.9, 129.8, 127.6,
127.4, 127.1, 123.9, 123.2, 122.4, 118.4.
2-(4-Nitrophenyl)quinoline (8ao).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
(49%,123 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) = 8.07-8.03 (t, J= 7.8 Hz, 2H), 7.95 (d, J=
8.8 Hz, 2H), 7.73-7.69 (m, 2H), 7.63-7.59 (m, 1H), 7.39-7.37 (t, J= 8.0 Hz, 1H), 6.73 (d, J= 8.0
Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) = 157.2, 148.3, 147.8, 136.5, 129.9, 129.5,
129.3, 128.8, 127.4, 126.8, 125.6, 118.5, 115.3.
2-(Thiophen-2-yl)quinoline (8ap).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
(84%, 177 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) = 8.07 (d, J= 8.0 Hz, 1H), 8.00 (d, J= 8.0
Hz, 1H), 7.69-7.62(m, 4H), 7.43-7.39 (m, 2H), 7.09 -7.08(m, 1H). HRMS (ESI, positive ions):
m/z calcd for C13H10SN+ [M + H+] 212.0528, found 212.0527.
2-(Thiophen-3-yl)quinoline (8aq).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
(81% , 171 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) = 8.10(d, J= 8.0 Hz, 1H), 8.04 (d, J= 8.4
Hz, 1H), 7.98-7.97 (m, 1H), 7.85-7.84 (dd, J= 1.12, 4.40 Hz, 1H), 7.71-7.65 (m, 3H), 7.45- 7.42
(m, 1H), 7.39-7.37 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 153.2, 148.2, 142.6,
136.7, 129.7, 129.4, 127.5, 127.1, 126.8, 126.4, 126.1, 124.7, 119.1.
2-(Pyridin-3-yl)quinoline (8ar).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
1
(89%, 184 mg). H NMR (400 MHz, CDCl3): δ (ppm) = 9.34 (d, J=1.8 Hz, 1H), 8.68-8.66 (dd,
J= 1.6, 4.6 Hz, 1H), 8.45- 8.42 (m, 1H), 8.16- 8.13 (dd, J= 2.72, 8.40 Hz, 2H), 7.78-7.72 (m,
2H), 7.73-7.68 (m, 1H), 7.52-7.48(m, 1H), 7.40-7.37 (m,1H) .
3-Methyl-2-phenylquinoline (8as).26c Eluent: petroleum ether/ethyl acetate (20 : 1). Yellow oil
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(88% , 193 mg). H NMR (400 MHz, CDCl3): δ (ppm) = 8.03 (d, J= 8.0 Hz, 1H), 7.88 (s, 1H),
7.65 (d, J=7.6 Hz, 1H), 7.56-7.52 (t, J= 6.9 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.41-7.32 (m, 4H),
2.34 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 160.5, 146.6, 140.9, 136.8, 129.3,
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129.2, 128.9, 128.8, 128.3, 128.2, 127.6, 126.7, 126.4, 20.6. HRMS (ESI, positive ions): m/z
calcd for C16H14N+ [M + H+] 220.1121 found 220.1128.
5,6-Dihydrobenzo[c]acridine (8at).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White
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solid (90% , 208 mg). H NMR (400 MHz, CDCl3): δ (ppm) = 9.35 (d, J= 7.96, 1H), 9.15 (s,
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1H), 8.59 (s, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.60 (d, J= 6.0 Hz, 1H),7.41
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(s, 2H), 7.25 (d, J= 3.2 Hz, 1H), 3.12 (s, 2H), 2.92 (s, 2H). C{1H} NMR (100 MHz, CDCl3): δ
(ppm) = 150.0, 143.1, 141.6, 138.3, 134.3, 133.5,132.1, 129.8, 129.3, 128.8, 128.4, 127.7, 127.4,
125.6, 122.1, 27.8, 27.7. HRMS (ESI, positive ions): m/z calcd for C17H14N+ [M + H+]
232.11208 found 232.1127.
2-Cyclopropylquinoline (8au).26c Eluent: petroleum ether/ethyl acetate (20 : 1). White solid
1
(70% , 118 mg). H NMR (300 MHz, CDCl3): δ (ppm) = 8.01-7.92 (m, 2H), 7.71-7.61 (m, 2H),
7.43-7.38 (t, J= 7.3 Hz, 1H), 7.12 (d, J= 8.0 Hz, 1H), 2.25-2.19 (m, 1H), 1.18-1.08 (m, 4H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) = 163.4, 147.9, 135.8, 129.3, 128.6, 127.5, 126.7,
125.2, 119.4, 18.1, 10.4.
3-(Phenyl)quinoline-2-amine (9aa). Eluent: petroleum ether/ethyl acetate (3:1). White solid
(65%, 143 mg). M.p: 108-110oC; 1H NMR (CDCl3, 300 MHz): δ (ppm) = 7.78 (s, 1H), 7.70-7.62
(m, 2H), 7.58-7.46 (m, 5H), 7.44-7.41 (m, 1H), 7.29-7.24 (t, J = 7.7 Hz, 1H), 5.06 (s,
2H).13C{1H} NMR (100 MHz, CDCl3):  (ppm) = 154.2, 145.6, 136.4, 136.3, 128.7, 128.1,
127.8, 127.2, 126.5, 124.1, 124.1, 123.0, 121.8. HRMS (ESI, positive ions): m/z calcd for
+
C15H13N2 [M + H+] 221.1073, found 221.1076.
3-(p-Tolyl)quinoline-2-amine (9ab). Eluent: petroleum ether/ethyl acetate (3:1). White solid
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(70%, 164 mg). M.p : 123-125oC ; H NMR (CDCl3, 300 MHz): δ (ppm) = 7.67 (s, 1H), 7.61-
7.53 (m, 2H), 7.49-7.43 (m, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.22-7.14 (m, 3H), 5.06 (s, 2H), 2.34
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) = 154.4, 145.8, 137.1, 136.1, 133.4, 128.8,
128.5, 127.7, 126.4, 124.3, 124.0, 123.1, 121.7, 20.2. HRMS (ESI, positive ions): m/z calcd for
+
C16H15N2 [M + H+] 235.1229, found 235.1219
3-(4-Methoxyphenyl)quinoline-2-amine (9ac). Eluent: petroleum ether/ethyl acetate (3:1).
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White solid (67%,167 mg). M.p:136-138oC; H NMR (CDCl3, 300 MHz): δ (ppm) = 7.67 (s,
1H), 7.62-7.53 (m, 2H), 7.49-7.44 (t, J = 6.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.20-7.15(m,
1H), 6.94 (d, J = 9.0 Hz, 2H), 4.99 (s, 2H), 3.78 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): 
(ppm) = 158.7, 154.4, 136.5, 129.1, 128.8, 128.1, 126.4, 123.9, 123.6, 122.9, 122.0, 113.6,
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113.0, 54.4. HRMS (ESI, positive ions): m/z calcd for C16H15N2O+ [M + H+] 251.1179, found
251.1158.
3-(4-Fluorophenyl)quinoline-2-amine (9ad). Eluent: petroleum ether/ethyl acetate (3:1). White
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solid (70%, 166 mg). M.p: 176-178oC H NMR (CDCl3, 400 MHz): δ (ppm) = 7.77 (s, 1H), 7.70
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(d, J = 7.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.51-7.48 (m, 2H), 7.30-
7.26 (m, 1H), 7.19 (t, J = 8.4 Hz, 2H), 4.99 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3):  (ppm)
= 161.7 (d, J= 243.9 Hz), 154.1, 145.5, 138.3, 136.7, 132.2, 129.7 (d, J= 8.3 Hz), 129.1, 126.5,
124.1, 122.9 (d, J= 11.0 Hz), 122.1, 115.3 (d, J= 22.2 Hz). HRMS (ESI, positive ions): m/z calcd
+
for C15H12FN2 [M + H+] 239.0979, found 239.0958.
3-(4-Bromophenyl)quinoline-2-amine (9ae). Eluent: petroleum ether/ethyl acetate (3:1). White
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solid (73%, 218 mg). M.p: 167-169oC; H NMR (CDCl3, 400 MHz): δ (ppm) = 7.76 (s, 1H),
7.69 (d, J = 8.0 Hz, 1H), 7.65- 7.61 (m, 3H), 7.60-7.56 (m, 1H), 7.40-7.39 (m, 2H), 7.30-7.27
13
(m, 1H), 4.95 (s, 2H). C{1H} NMR (100 MHz, CDCl3):  (ppm) = 153.7, 146.2, 136.4, 135.4,
131.3, 129.6, 128.9, 126.5, 124.6, 123.0, 122.7, 121.9, 121.4. HRMS (ESI, positive ions): m/z
+
calcd for C15H12BrN2 [M + H+] 299.0178, found 299.0158.
2-Phenylquinazoline (10aa).18a,26a Eluent: petroleum ether/ethyl acetate (19:1). White solid
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(82% , 169 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.45 (s, 1H), 8.63-8.61 (m, 2H), 8.08
13
(d, J = 8 Hz, 1H), 7.91-7.87 (m, 2H), 7.61-7.50 (m, 4H). C{1H} NMR (100 MHz, CDCl3): 
(ppm) = 160.0, 159.4, 149.7, 137.0, 133.1, 129.6, 127.6, 127.5, 126.2, 126.1, 122.5.
2-m-Tolylquinazoline (10ab).26a Eluent: petroleum ether/ethyl acetate (19:1). White solid ( 67%,
1
148 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.37 (s, 1H), 8.34 (d, J = 10.4 Hz, 2H), 8.00
(d, J = 8.0 Hz, 1H), 7.83-7.79 (m, 2H), 7.53-7.49 (t, J = 7.4 Hz, 1H), 7.37- 7.33 (t, J = 7.5 Hz,
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1H ), 7.24 (d, J = 7.4 Hz, 1H), 2.40 (s, 3H). C{1H} NMR (100 MHz, CDCl3):  (ppm)= 161.2,
160.5, 150.8, 138.3, 137.9, 134.1, 131.5, 129.1, 128.6, 127.2, 127.1, 125.8, 123.6, 21.5.
2-p-Tolylquinazoline (10ac).26a Eluent: petroleum ether/ethyl acetate (19:1). White solid ( 66%,
1
145 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.34 (s, 1H), 8.43- 8.41 (m, 2H), 7.98 -7.96
(m, 1H), 7.80 - 7.76 (m, 2H), 7.50 - 7.46 (m, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.351 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3):  (ppm)= 160.1, 159.4, 149.7, 139.8, 134.3, 132.9, 128.4,
127.5, 126.1, 125.9, 122.4, 20.5.
2-(3-Methoxyphenyl)quinazoline (10ad).26a Eluent: petroleum ether/ethyl acetate (19:1). White
1
solid (65%, 154 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.34 (s, 1H), 8.14 -8.09 (m, 2H),
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7.98 (d, J = 8 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.50 -7.47 (m, 1H), 7.37 - 7.33 (t, J = 7.96 Hz, 1H),
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6.98 - 6.96 (m, 1H), 3.84 (d, J = 8.0 Hz, 3H). C{1H} NMR (100 MHz, CDCl3):  (ppm)=
160.8, 160.5, 160.0, 150.7, 139.5, 134.1, 129.7, 128.7, 127.3, 127.1, 123.7, 121.2, 117.3, 112.9,
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55.5.
2-(4-Methoxyphenyl)quinazoline (10ae).26a Eluent: petroleum ether/ethyl acetate (17:1). White
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solid (59%, 139 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.41 (s, 1H), 8.58 (d, J = 7.8 Hz,
2H), 8.04 (d, J = 7.58 Hz, 1H), 7.88 (d, J = 7.1 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 8.4
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Hz, 2H), 3.89 (s, 1H). C{1H} NMR (100 MHz, CDCl3):  (ppm)= 161.8, 160.9, 160.4, 150.8,
134.0, 130.7, 130.2, 128.4, 127.1, 126.8, 123.3, 113.9, 55.4.
2-(2, 4-dimethoxyphenyl)quinazoline (10af).26a Eluent: petroleum ether/ethyl acetate (9:1).
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White solid (60% 184 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.40 (s, 1H), 8.01 (d, J = 8.4
Hz, 1H), 7.85-7.76 (m, 3H), 7.55-7.51 (t, J = 7.7 Hz, 1H), 6.58-6.54 (m, 2H), 3.99 (d, J = 2.0 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3):  (ppm)= 162.2, 162.1, 160.0, 159.2, 150.7, 134.0,
133.2, 128.4, 127.2, 127.1, 122.9, 121.8, 105.0, 99.4, 56.1, 55.5.
2-(4-Tert-butylphenyl)quinazoline (10ag).26a Eluent: petroleum ether/ethyl acetate (19:1).
White solid (71%, 186 mg). 1H NMR (400 MHz, CDCl3):  (ppm) = 9.35 (s, 1H), 8.45 (d, J = 8
Hz, 2H), 7.98 (d, J = 8 Hz, 1H), 7.81-7.77 (t, J = 8 Hz, 2H), 7.50-7.46 (m, 3H), 1.30 (s, 9H).
2-(4-Fluorophenyl)quinazoline (10ah).11g,26a Eluent: petroleum ether/ethyl acetate (19:1).
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White solid (70%, 157 mg). H NMR (400 MHz, CDCl3): (ppm) = 9.43 (s,1H), 8.63-8.59 (m,
2H), 8.04 (d, J = 8 Hz, 1H), 7.89-7.85 (m, 2H), 7.59-7.56 (t, J = 8 Hz, 1H), 7.25-7.16 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3): (ppm)=164.7 (d, J = 248.7 Hz), 160.5, 160.1, 150.7, 134.2,
130.7, 130.6, 128.5, 127.3, 127.1, 123.5, 115.6 (d, J = 21.4 Hz).
2-(2-Chlorophenyl)quinazoline (10ai).26a Eluent: petroleum ether/ethyl acetate (19:1). White
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solid (72%, 173 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.45 (s, 1H), 8.06 (d, J = 8 Hz,
1H), 7.93-7.87 (m, 2H), 7.76-7.74 (m, 1H), 7.65-7.61 (t, J = 8 Hz, 1H), 7.48-7.45 (m, 1H), 7.35-
7.32 (m, 2H).
2-(3-Chlorophenyl)quinazoline (10aj).26a Eluent: petroleum ether/ethyl acetate (19:1). White
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solid (76%, 183 mg). H NMR (400 MHz, CDCl3):  (ppm) = 9.34 (s, 1H), 8.55 (d, J = 2 Hz,
1H), 8.44 - 8.41 (m, 1H), 7.99 (d, J = 4.0 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.56 - 7.53 (m, 1H), 7.40
- 7.35 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) = 160.6, 159.7, 150.6, 139.8, 134.8,
134.3, 130.5, 129.8, 128.6, 127.6, 127.1, 126.6, 123.7.
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2-(4-Chlorophenyl)quinazoline (10ak).18a,26a Eluent: petroleum ether/ethyl acetate (19:1).
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White solid ( 84%, 202 mg). H NMR (300 MHz, CDCl3):  (ppm) = 9.48-9.43 (m, 1H), 8.63-
6
8.55 (m, 2H), 8.12-8.05 (m, 1H), 7.97-7.90 (m, 2H), 7.68-7.61 (m, 1H), 7.59-7.48 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3):  (ppm) = 160.5, 160.0, 150.6, 136.8, 136.5, 134.2, 129.9,
128.8, 128.6, 127.5, 127.1, 123.6.
2-(3-Bromophenyl)quinazoline (10al).26a Eluent: petroleum ether/ethyl acetate (19:1). White
solid ( 69%, 197 mg). 1H NMR (400 MHz, CDCl3):  (ppm) = 9.33 (s, 1H), 8.67 (s, 1H), 8.45 (d,
J = 8 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 7.82-7.79 (m, 2H), 7.54-7.50 (m, 2H), 7.31-7.27 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3):  (ppm) = 160.5, 159.5, 150.6, 140.1, 134.3, 133.5, 131.6,
130.2, 128.7, 127.6, 127.1, 127.1, 123.7, 122.9.
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2-(4-Bromophenyl)quinazoline (10am).18a,26a Eluent: petroleum ether/ethyl acetate (19:1).
White solid ( 75%, 214 mg). 1H NMR (400 MHz, CDCl3):  (ppm) = 9.35 (s, 1H), 8.43-8.39 (m,
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2H), 7.98 (d, J = 8 Hz, 1H), 7.84-7.80 (m, 2H), 7.59-7.51 (m, 3H). C{1H} NMR (100 MHz,
CDCl3):  (ppm) = 160.5, 160.1, 150.7, 136.9, 134.3, 131.8, 130.2, 128.6, 127.5, 127.2, 125.4,
123.7.
2-(3,5-Difluorophenyl)quinazoline (10an).26a Eluent: petroleum ether/ethyl acetate (19:1).
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White solid ( 88%, 213 mg). H NMR (300 MHz, CDCl3):  (ppm) = 9.47 (d, J= 10.6 Hz, 1H),
8.21-8.07 (m, 3H), 7.99-7.93 (m, 2H), 7.72-7.66 (m, 1H), 7.00-7.94 (m, 1H). 13C{1H} NMR (100
MHz, CDCl3):  (ppm) = 164.5 (d, J = 13.0 Hz) , 162.08 (d, J = 11.9 Hz), 160.6, 158.7, 150.5,
141.6 (t, J = 10.0 Hz) , 134.5, 128.7, 127.9, 127.2, 123.9, 111.5-111.2 (m), 105.99-105.48 (m).
2-(4-(Trifluoromethyl)phenyl)quinazoline (10ao).18a,26a Eluent: petroleum ether/ethyl acetate
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(19:1). White solid ( 85%, 233 mg). H NMR (300 MHz, CDCl3):  (ppm) = 9.53 (d, J = 18.9
Hz, 1H), 8.84-8.75(dd, J = 7.9 Hz, 19.0 Hz, 2H), 8.21-8.11 (dd, J = 8.7 Hz, 19.0 Hz, 1H), 8.05-
7.96 (m, 2H), 7.88-7.82 (t, J = 12 Hz, 1H), 7.79-7.68 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3):  (ppm) = 160.7, 159.6, 150.7, 141.4, 134.4, 132.3, 131.9, 128.9, 128.8, 127.9, 127.2,
+
125.6-125.5 (q, JC-F = 4.0 Hz), 123.8. HRMS (ESI, positive ions): m/z calcd for C15H10F3N2 [M
+ H+] 275.0791, found 275.0795.
3-(Quinazolin-2-yl)benzonitrile (10ap).11g Eluent: petroleum ether/ethyl acetate (9:1). Yellow
solid ( 63%, 146 mg). 1H NMR (400 MHz, CDCl3):  (ppm) = 9.42 (s, 1H), 8.69-8.67 (m, 2H),
8.04 (d, J= 8.0 Hz, 1H), 7.91-7.87 (m, 2H), 7.75 (m, 2H), 7.64-7.60 (m, 1H) ). 13C{1H} NMR
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The Journal of Organic Chemistry
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(100 MHz, CDCl3):  (ppm) = 160.7, 159.1, 150.6, 142.1, 134.5, 132.4, 129.0, 128.8, 128.2,
127.2, 123.9, 118.9, 113.8.
2-(Thiophen-2-yl)quinazoline (10aq).11g,18a,26a Eluent: petroleum ether/ethyl acetate (17:1).
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White solid (65%, 138 mg). H NMR (CDCl3, 400 MHz): δ (ppm) = 9.27 (s, 1H), 8.07 (d, J =
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3.6 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.81-7.78 (m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 4.9
Hz, 1H), 7.11 (t, J = 4.0 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3):  (ppm) = 160.5, 157.8,
150.6, 143.8, 134.4, 129.9, 129.3, 128.4, 128.2, 127.3, 127.0, 123.3.
2-(Pyridin-3-yl)quinazoline (10ar).11g Eluent: petroleum ether/ethyl acetate (17:1). Yellow
solid (59%, 122 mg). 1H NMR (CDCl3, 400 MHz): δ (ppm) = 9.73 (s, 1H), 9.39 (s, 1H), 8.79 (d,
J = 8 Hz, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.86 (m, 2H), 7.58 (t, J = 7.28
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Hz, 1H), 7.39-7.36 (m, 1H). C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 160.7, 159.2, 151.1,
150.6, 150.2, 135.8, 134.5, 129.3, 128.7, 127.8, 127.2, 123.8, 123.5.
2-(Pyridin-4-yl)quinazoline (10as).11g,26a Eluent: petroleum ether/ethyl acetate (17:1). Yellow
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solid (61%, 126 mg). H NMR (CDCl3, 400 MHz): δ (ppm) = 9.43 (s, 1H), 8.74 (s, 2H), 8.40 (s,
2H), 8.06 (d, J = 8.0 Hz, 1H), 7.91- 7.87 (m, 2H), 7.64-7.60 (m, 1H).
26a
2-Butylquinazoline (10at).18a,
Eluent: petroleum ether/ethyl acetate (20:1). yellow oil
(25%, 47 mg ). 1H NMR (CDCl3, 300 MHz) δ (ppm) = 9.37 (s, 1H), 7.97-7.91 (m, 1H), 7.84-7.79
(m, 2H), 7.53-7.50 (m, 1H), 3.61-3.56 (m, 2H), 1.99-1.94 (m, 2H), 1.61-1.53 (t, J= 8.73 Hz, 2H)
0.83-0.79 (t, J = 7.47 Hz, 3H).
6-Methyl-2-phenylquinoline (8ba).26c Eluent: petroleum ether/ethyl acetate (19 : 1). White solid
(87%, 191 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.12 (d, J = 7.8 Hz, 2H), 8.07-8.02 (t, J =
8.8 Hz, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.52-7.47 (m, 4H), 7.44-7.42 (m,1H), 2.49 (s, 3H).
8-Methyl-2-phenylquinoline (8ca).26c Eluent: petroleum ether/ethyl acetate (19 : 1). Pale-yellow
oil (81%, 178 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) =8.12 (d, J = 7.20 Hz, 2H), 7.97 (d, J =
8.88 Hz, 1H), 7.71 (d, J =8.88 Hz, 1H), 7.48 (d, J = 7.76 Hz, 1H), 7.43-7.37 (m, 3H),7.33-7.29
(m, 1H), 7.27-7.29 (m, 1H), 2.78 (s, 3H).
8-Bromo-6-methyl-2-phenylquinoline (8da).26c Eluent: petroleum ether/ethyl acetate (19 : 1).
White solid (66%, 197 mg). 1H NMR(400 MHz, CDCl3): δ (ppm) = 8.16-8.14 (dd, J = 1.28, 8.84
Hz, 2H), 7.85 (d, J = 8.88 Hz, 1H), 7.73-7.68 (m, 2H), 7.41-7.37 (m, 2H), 7.35-7.30 (m, 2H),
2.32 (s, 3H).
7-Chloro-2-phenylquinoline (8ea).26c Eluent: petroleum ether/ethyl acetate (19 : 1). White solid
(80%, 192 mg).1H NMR (300 MHz, CDCl3): δ (ppm) = 8.19-8.14 (m, 3H), 8.09 (d, J = 8.73 Hz,
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