Sustainable synthesis of N-heterocycles in water using alcohols following the double dehydrogenation strategy

Article abstract of DOI:10.1016/j.jcat.2019.03.028

The present study describes the first example of synthesis of pharmaceutically relevant N-heterocycles like substituted quinolines, acridines and 1,8-naphthyridines in water under air using alcohols in presence of a new water soluble Ir-complex. The viability and efficiency of this approach was demonstrated by the efficient synthesis of biologically active natural product (±)-galipinine and gram scale synthesis of various N-heteroaromatics. Several kinetic experiments and DFT calculations were carried out to support the plausible reaction mechanism which disclosed that this system followed a concerted outer sphere mechanism for the dehydrogenation of alcohols.

Full text of DOI:10.1016/j.jcat.2019.03.028

Journal of Catalysis 373 (2019± 93–102
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Sustainable synthesis of N-heterocycles in water using alcohols
following the double dehydrogenation strategy
⇑
Milan Maji, Kaushik Chakrabarti, Dibyajyoti Panja, Sabuj Kundu
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh (U.P.), India
a r t i c l e i n f o
a b s t r a c t
Article history:
The present study describes the first example of synthesis of pharmaceutically relevant N-heterocycles
like substituted quinolines, acridines and 1,8-naphthyridines in water under air using alcohols in pres-
ence of a new water soluble Ir-complex. The viability and efficiency of this approach was demonstrated
by the efficient synthesis of biologically active natural product (± ±-galipinine and gram scale synthesis of
various N-heteroaromatics. Several kinetic experiments and DFT calculations were carried out to support
the plausible reaction mechanism which disclosed that this system followed a concerted outer sphere
mechanism for the dehydrogenation of alcohols.
Received 19 December 2018
Revised 15 March 2019
Accepted 18 March 2019
Keywords:
N-heterocycles
Double dehydrogenative strategy
Aerobic condition
Catalysis in water
Ó 2019 Elsevier Inc. All rights reserved.
1
,8-naphthyridines
1
. Introduction
As fossil feedstocks as well as the crude oil reserve are decreas-
condensation strategy were also well known in literature for the
sustainable CAC bond formation [25–32]. The catalytic synthesis
of quinolines and naphthyridines via cyclization of 2-
aminobenzyl alcohol with either ketones or alcohols was achieved
using Ru, Ir, Pd and other metals [23,33–36]. Notably, most of these
methodologies inevitably required organic solvents. Although,
organic solvents have many advantages, they are toxic, flammable
and relatively expensive [37]. On the other hand, water as a solvent
has many potential benefits over organic solvents as it is environ-
mentally friendly, safe, cheap, and easy to separate from organic
products.
In the last few decades, there has been a growing interest in uti-
lization of water as a solvent [38]. For that purpose numerous
water soluble metal complexes were synthesized and their cat-
alytic activity explored [39–43]. Lately, based on the alcohol dehy-
drogenation strategy, CAC and CAN bond formation reactions in
water were reported by Williams, Fujita, Yamaguchi, Li, and others
[44–55]. For the synthesis of nitrogen containing heteroaromatics,
the coupling reaction of 2-aminoaryl alcohol with sustainable and
readily available alcohols following the double dehydrogenation
strategy is challenging in aqueous medium and to the best of our
knowledge has not yet been reported.
ing rapidly, the search for alternative pathways for the production
of fine chemicals and fuels has become inevitably significant [1].
Alcohols are inexpensive precursors and easily accessible by con-
version of biomass or fermentation process [2,3]. Hence, develop-
ment of efficient and sustainable methodologies for the
transformation of alcohols to fine chemicals is highly desirable.
Among various nitrogen containing heteroaromatics, quinoli-
nes, acridines and naphthyridines have substantial importance,
owing to their higher abundance in various natural products and
pharmacologically important drugs [4–6]. Commonly quinoline
and naphthyridine scaffolds were synthesized following the
Friedländer synthesis, but owing to its high susceptibility towards
self-condensation, later on several metal/base catalyzed oxidative
cyclization reactions were developed using 2-aminobenzyl alcohol
[
7–10]. However, most of these procedures required either large
excess of ketones/alcohols or sacrificial hydrogen acceptors
11–14]. In recent years, transition metal catalyzed acceptorless
[
dehydrogenative condensation approach has received much atten-
tion for environmentally benign CAN bond formation reactions
[
15–20]. Following this protocol, Milstein, Beller, Kempe and
others reported formation of various N-heterocyclic compounds
21–24]. Similar transformations using the dehydrogenative aldol
For the designing of an efficient catalytic system, metal-ligand
cooperativity emerged as a powerful tool which received much
attention in last few decades [56–58]. In this regard, 2-
hydroxypyridine containing ligands represent an important class
of cooperative ligands. Various transition metal complexes bearing
[
⇑
Corresponding author.
E-mail address: sabuj@iitk.ac.in (S. Kundu±.
2
-hydroxypyridine fragment containing ligands were synthesized
https://doi.org/10.1016/j.jcat.2019.03.028
021-9517/Ó 2019 Elsevier Inc. All rights reserved.
0

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M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
and successfully explored in several transformations such as trans-
fer hydrogenation, CO hydrogenation, dehydrogenation of alco-
2
hols, dehydrogenation and hydrogenation of heterocycles, water
oxidation, etc. [41,59–63].
Herein, we report the synthesis and catalytic activity of a new
phosphine-free water soluble Ir-complex bearing 2-(2-benzimida
zolyl±-6-hydroxypyridine ligand. Remarkably, a variety of quinoli-
nes, acridines and naphthyridines were synthesized in water under
air utilizing this Ir-complex (Scheme 1±. To the best of our knowl-
edge, this is the first report for oxidative cyclization of 2-aminoaryl
alcohols or 2-nitroaryl alcohols with alcohols in water.
2
. Results and discussion
Inspired by the high catalytic activities of bidentate N-
containing Ir-complexes [40,41,64], several substituted 2-(2-
benzimidazolyl± pyridine ligand containing Ir(III± complexes were
synthesized in good yields and complex 1 was characterized by
X-ray diffraction (Fig. 1±. The catalytic activity of the newly synthe-
sized complexes was investigated for the dehydrogenative cou-
pling between 2-aminobenzyl alcohol and 1-phenylethanol in
water (Table 1±.
Fig. 1. Solid state structures of complex 1 (30% thermal ellipsoids±.
Preliminary results showed that the reaction was facilitated in
air compared to argon (Table 1, entry 2± [65]. Several Ir-catalysts
were screened and among them cat. 1 displayed superior activity
withdrawing as well as electron donating group substituted
2-aminobenzyl alcohols afforded the corresponding products in
good to excellent yields (3a-3g±. Notably, naphthyl substituted
2-aminobenzyl alcohol also delivered good yield (3h±.
(Table 1±. Notably, cat. 1 and cat. 6 containing the easily deproto-
nated hydroxyl-pyridine group, showed significantly higher reac-
tivity compared to their AOMe (cat. 2 and 7± and AMe (cat. 3
and 8± analogue respectively. Optimization of catalyst amount,
base and amino alcohol/alcohol ratio suggested that 1.5 mol% of
In the acceptorless dehydrogenative coupling reaction using
alcohols, the liberated hydrogen could be used in transfer hydro-
genation of nitro functionality in situ without using any external
reducing agents [66,67]. As 2-aminoaryl alcohols can be easily
accessed from 2-nitroaryl alcohols, we were interested to explore
this strategy for the synthesis of quinolines directly from 2-
nitroaryl alcohols. Using this protocol various substituted aryl alco-
hols, heteronuclei containing alcohols and aliphatic alcohols fur-
nished the desired products in good to excellent yields ((Table 4;
4a-4g; 74–94%±.
catalyst
1 was sufficient to achieve the 97% yield of 2-
phenylquinoline (2a± within 24 h in presence of 1.5 equiv. of
KOH (Table 1, entries 3–19±. In contrast, using acetophenone, this
catalytic system delivered quantitative yield of 2a within 6 h
(Table 1, entry 22± [13]. This result demonstrated that, compared
to ketones, the dehydrogenative coupling of 2-aminobenzyl alco-
hol was more challenging with easily accessible alcohols.
Using the optimized reaction conditions, this protocol was
applied for the coupling of various secondary alcohols with 2-
aminobenzyl alcohol and the results are summarized in Table 2.
Different substituted secondary alcohols bearing both electron
donating and withdrawing groups in para and meta position
afforded good to excellent yields (78–98%± of quinoline derivatives
Acridine derivatives are highly important N-heterocyclic moiety
which has potential applications as antiparasitic drugs [5,68].
Owing to the widespread applicability of the acridine derivatives,
we were fascinated to synthesize them by using the dehydrogena-
tive condensation strategy. Several fused quinolines and acridines
were smoothly synthesized from 2-aminobenzyl alcohols and cyc-
lic alcohols employing the standard reaction conditions (Table 5;
5a-5h±. Interestingly, with decreasing ring size of the cyclic alco-
hols, the yield of fused quinoline derivatives increases (5a-5c± [5].
1,8-Naphthyridine derivatives have significant importance in
medicinal chemistry and materials science. Inspired by their mul-
tidirectional biological properties we next explored viable synthe-
sis of 1,8-naphthyridines in water. Notably, this protocol efficiently
delivered a variety of 1,8-naphthyridine derivatives (Table 6, 6a–
6g±. Notably, 1-(2-pyridinyl± ethanol with strong chelation site
(2a-2g±. Substitution in the ortho position of secondary alcohol
delivered poor yield and considerable amount of dehalogenated
quinoline was observed as by-product (2h±. Moreover, 1-(2-
naphthalenyl±ethanol and heteroatom substituted alcohols were
converted successfully (77–92%± under the reaction conditions
(2i-2k±. Acyclic aliphatic alcohols also reacted well and delivered
the desired products (2l-2n±. The scope of the reaction was further
explored towards the coupling of substituted 2-aminobenzyl
alcohols with various alcohols (Table 3±. Reaction of electron
Scheme 1. Synthesis of N-heteroaromatics following the double dehydrogenation strategy.

M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
95
Table 1
Optimization for the synthesis of 2-phenylquinoline from 2-aminobenzyl alcohol.
a
Entry
Ir-complex (x mol%±
Base (y equiv.±
Amino alcohol/alcohol
Yield (%±b
1c
2
3
4
5
6
7
8
9
Cat. 1 (2.0±
Cat. 1 (2.0±
Cat. 1 (2.0±
Cat. 1 (2.0±
Cat. 1 (2.0±
Cat. 2 (2.0±
Cat. 3 (2.0±
Cat. 4 (2.0±
Cat. 5 (2.0±
Cat. 6 (2.0±
Cat. 7 (2.0±
Cat. 8 (2.0±
Cat. 1 (2.0±
Cat. 1 (2.0±
Cat. 1 (2.0±
Cat. 1 (1.5)
Cat. 1 (1.5±
Cat. 1 (1.5±
Cat. 1 (1.5±
–
KOH (0.75±
KOH (0.75±
KOH (1.0±
KOH (1.5±
KOH (1.5±
KOH (1.5±
KOH (1.5±
KOH (1.5±
KOH (1.5±
KOH (1.5±
KOH (1.5±
KOH (1.5±
NaOH (1.5±
1:1.2
1:1.2
1:1.2
1:1.2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
68
79
84
90
98
49
31
27
43
73
21
37
87
65
69
97
<10
31
53
–
10
11
12
13
14
15
16
17
18
19
20
21
22
K
Cs
2
CO
CO
3
(1.5±
3
(1.5±
2
KOH (1.5)
KOH (0.25±
KOH (0.5±
KOH (0.75±
KOH (1.5±
KOH (1.5±
KOH (1.5±
[Cp*IrCl
2
]
2
(1.5±
19
>99
d
Cat. 1 (1.0±
a
b
c
Reaction conditions: 2-aminobenzyl alcohol (0.25 mmol±, Ir-complex (x mol%±, KOH (y equiv.±, water (1.5 mL± at 120 °C for 24 h under air.
Yield determined by GC analysis using n-dodecane as an internal standard.
Under argon atmosphere.
d
Reaction with 2-aminobenzyl alcohol (0.25 mmol± and acetophenone (0.375 mmol± for 6 h.
and also heteroatom containing 1-(3,4-methylenedioxyphenyl±
ethanol were efficiently converted to the expected products (6d-
alyst could be utilized for the synthesis of 2-phenylquinoline up to
the fourth run although yields reduced significantly after the sec-
ond run (Table S2±. To demonstrate the synthetic applicability of
this methodology, biologically active natural product (± ±-
galipinine was synthesized [69,70]. Following the optimized condi-
tions, 2l was smoothly prepared from 2-aminobenzyl alcohol.
Applying the same catalytic system, hydrogenation of 2l in water
followed by methylation using HCHO yielded (± ±-galipinine (2lb±
in excellent yield (Scheme 2±.
6
e±. Additionally, aliphatic cyclic and acyclic alcohols like
cyclopentanol and 1-phenyl-1-propanol were found to be efficient
coupling partners for the synthesis of 1,8-naphthyridine deriva-
tives (Table 6, entries 6f-6g±.
3
. Practical applicability of the methodology
This protocol was extended towards the gram scale synthesis of
a variety of quinolines, acridines and naphthyridines in water
under air (Table 7±. The green chemistry metrics [71] for the syn-
thesis of 2-(2-(benzo[d][1,3]dioxol-5-yl±ethyl±quinoline (2l± was
Next, we checked the reusability of this catalytic system for the
synthesis of 2-phenylquinoline in water by simple phase separa-
tion technique. The recovered aqueous solution containing the cat-

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6
M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
Table 2
a
Synthesis of quinolines from 2-aminobenzyl alcohol and various alcohols.
a
Reaction Conditions: 2-aminoaryl alcohol (0.5 mmol±, alcohol (0.75 mmol±, KOH (0.75 mmol±, water (3.0 mL±, isolated yields.
Cat. 1 (2.0 mol%± for 36 h.
b
Table 3
a
Synthesis of quinolines from various 2-aminobenzyl alcohols in water.
a
Reaction Conditions: 2-aminoaryl alcohol (0.5 mmol±, alcohol (0.75 mmol±, KOH (0.75 mmol±, water (3.0 mL±, isolated yields.
b
2.0 mol% of Cat. 1 was used.

M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
97
Table 4
a
Synthesis of quinolines from 2-nitrobenzyl alcohols.
a
Reaction Conditions: 2-nitrobenzyl alcohol (0.5 mmol±, alcohol (1.5 mmol±, KOH (0.75 mmol±, water (3.0 mL±, isolated
yields.
Table 5
a
Dehydrogenative synthesis of fused quinoline derivatives.
a
Reaction Conditions: 2-aminoaryl/2-nitrobenzyl alcohol (0.5 mmol±, alcohol (0.75 mmol±, KOH (0.75 mmol±, water
(3.0 mL±, isolated yields.
Table 6
a
Dehydrogenative synthesis of 1,8-naphthyridine derivatives.
a
Reaction Conditions: 2-aminoaryl alcohol (0.5 mmol±, alcohol (0.75 mmol±, KOH (0.75 mmol±, water (3.0 mL±, isolated yields.

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M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
Scheme 2. Synthesis of bio-active natural product: (± ±-galipinine.
of technical and environmental benefits and also indicates that this
methodology is highly sustainable.
4
. Mechanistic insights
To understand the mechanism of this dehydrogenative coupling
reaction, several kinetic experiments and theoretical calculations
were carried out. The progress of the catalytic cyclization of 2-
aminobenzyl alcohol and 1-phenylethanol was monitored by GC-
analysis. From the plot it is evident that several intermediates were
involved in the course of the reaction (Fig. 2±. Also it is noteworthy
that the concentration of in situ generated 2-aminobenzaldehyde
is much smaller than acetophenone, thus retarding the self-
condensation of 2-aminobenzaldehyde. Synthesis of 2a from 2-
aminobenzyl alcohol and acetophenone in presence of cat. 1
required only 4 h, while in absence of cat. 1, from 2-amino ben-
zaldehyde and acetophenone it took only 30 min (Scheme 3A–B±.
Additionally, formation of quinoline was not detected from both
coupling of alcohol-alcohol or alcohol-ketone in the absence of
cat. 1 (Scheme 3C–D±. These results suggested that cat. 1 facilitated
the dehydrogenation of the alcohols, and 2-amino benzaldehyde
and acetophenone were intermediates in this process.
Fig. 2. Time course of the reaction for the synthesis of 2-phenylquinoline.
estimated on a preparative scale with an E factor of 2.1, 87% atom
economy, 94% atom efficiency, 100% carbon efficiency, and 55%
reaction mass efficiency (Table 8±, which provides a clear overview
As Ir-H species is considered as one of the intermediates in this
catalytic cycle [48], we independently synthesized the correspond-
ing Ir-H species by treating cat. 1 with 10 equiv. of KO Bu in PrOH
t
i
Table 7
Gram scale synthesis of N-heterocycles.

M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
99
Table 8
Evaluation of green metrics for the current methodology.
Scheme 3. (I± Control experiments (II± Synthesis and reactivity of Ir-hydride.
at 82 °C for 1 h (Scheme 3E±. A sharp singlet at d = ꢀ11.97 ppm in
the precatalyst 1 would be converted to species I1 having pyrido-
nate ligand fragment [41,72]. Now, I1 could follow two pathways
for the alcohol dehydrogenation (i± outer sphere pathway or (ii±
inner sphere pathway (I2± [73]. In the concerted outer sphere path-
1
H NMR spectra confirmed the formation of Ir-H species [40]. This
complex under the standard reaction conditions yielded 81% of 2a
(Scheme 3F±, which suggested that the proposed Ir-H complex was
the active intermediate in this reaction.
way, 2-aminobenzyl alcohol was dehydrogenated through an eight
ǂ
To understand the reaction mechanism more clearly, DFT calcu-
lations for the dehydrogenation of 2-aminobenzyl alcohol were
performed (Fig. 3±. In the DFT study we focused on two major
steps: (a± dehydrogenation of 2-aminobenzyl alcohol and (b±
ligand assisted hydrogen liberation. Initially, in presence of base
membered transition state TS1out
(D
G = 18.5 kcal/mol± where the
hydroxyl hydrogen of the 2-aminobenzyl alcohol was transferred
to the pyridonate oxygen and CAH was transferred to the Ir center,
resulting in the formation of Ir-H intermediate I3 [74,75]. However,
for the dehydrogenation of alcohol the stepwise outer-sphere

1
00
M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
Fig. 3. DFT study: free energy profile for dehydrogenation of 2-aminobenzyl alcohol (Hybrid functional, M062X was used with the LANL2DZ basis set for Ir and 6-31G** basis
set for nonmetal elements±. Cp* rings in the pictorial representations were omitted for clarity.
pathway could not be ruled out [76]. Afterwards, hydrogen mole-
cule was eliminated from the metal hydride and ligand pendent
hydroxyl proton with an activation barrier of 30.3 kcal/mol, gener-
ating the active species (I1± [41]. On the other hand, in the inner
sphere route, first the metal-alkoxy complex (I2± was generated
from I1. Afterward, this alkoxy-complex underwent b-hydride
elimination through a four-membered transition-state (TS1in± with
an activation barrier of 48.6 kcal/mol and formed Ir-H species I3
and substituted secondary alcohols in water under air. Interest-
ingly, combination of transfer hydrogenation and acceptorless
dehydrogenative coupling was demonstrated in a single process
for synthesis of quinolines starting from 2-nitrobenzyl alcohols.
This sustainable protocol was successfully applied for the synthesis
of biologically active natural product (± ±-galipinine and gram scale
synthesis of important N-heterocycles. The green chemistry met-
rics were evaluated for the synthesis of 2-(2-(benzo[d]
[1,3]dioxol-5-yl±ethyl±quinoline, which showed the technical ben-
efits and sustainability of the present methodology. The proposed
reaction mechanism was supported by several control experi-
ments, kinetic studies and DFT calculations. To the best of our
knowledge, this is the first example for the synthesis of quinolines,
acridines and 1,8-naphthyridines in water using 2-aminobenzyl
alcohol and substituted secondary alcohols.
[
74]. Finally, hydrogen elimination from I3 regenerated the active
species I1. Catalyst 2–4 may follow inner sphere pathway for the
dehydrogenation of alcohol, as there is no hydroxyl group present
in the ligand. The activation energy for the dehydrogenation of 2-
aminobenzyl alcohol via the concerted pathway was much lower
ǂ
(
D
G = 21.7 kcal/mol± compared to the inner sphere route
ǂ
(D
G = 48.6 kcal/mol±. This clearly indicates that the outer sphere
pathway is more favoured over the inner sphere route (Fig. 2 and
SI, Fig. S3±.
Conflicts of interest
5
. Conclusions
There are no conflicts to declare.
In conclusion, a new class of water soluble Ir-complexes was
synthesized and characterized. Among them 2-hydroxypyridine
based cat. 1 presented excellent catalytic activity and offered a
greener methodology for the synthesis of quinoline, 1,8-
naphthyridine and acridine derivatives from 2-aminoaryl alcohols
Acknowledgements
We are grateful to the Science and Engineering Research Board
(SERB±, India and Council of Scientific & Industrial Research, India

M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
[27] Y. Obora, Recent advances in
101
(
CSIR± for financial support. M.M. thanks CSIR India, K.C. thanks
a
-alkylation reactions using alcohols with
hydrogen borrowing methodologies, ACS Catal. 4 (2014± 3972–3981.
28] K. Chakrabarti, M. Maji, D. Panja, B. Paul, S. Shee, G.K. Das, S. Kundu, Utilization
of MeOH as a C1 building block in tandem three-component coupling reaction,
Org. Lett. 19 (2017± 4750–4753.
UGC India, D.P. thanks IITK for the fellowship.
[
Appendix A. Supplementary material
[29] K. Chakrabarti, B. Paul, M. Maji, B.C. Roy, S. Shee, S. Kundu, Bifunctional Ru(ii±
complex catalysed carbon–carbon bond formation: an eco-friendly hydrogen
borrowing strategy, Org. Biomol. Chem. 14 (2016± 10988–10997.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jcat.2019.03.028.
[
[
[
30] N. Deibl, K. Ament, R. Kempe, A sustainable multicomponent pyrimidine
synthesis, J. Am. Chem. Soc. 137 (2015± 12804–12807.
31] S. Musa, L. Ackermann, D. Gelman, Dehydrogenative cross-coupling of primary
and secondary alcohols, Adv. Synth. Catal. 355 (2013± 3077–3080.
32] M.V. Jiménez, J. Fernández-Tornos, F.J. Modrego, J.J. Pérez-Torrente, L.A. Oro,
Oxidation and b-alkylation of alcohols catalysed by iridium(i± complexes with
functionalised N-heterocyclic carbene ligands, Chem. Eur. J. 21 (2015± 17877–
References
[
1] G.A. Olah, Beyond oil and gas: the methanol economy, Angew. Chem., Int. Ed.
4 (2005± 2636–2639.
1
7889.
33] D. Srimani, Y. Ben-David, D. Milstein, Direct synthesis of pyridines and
quinolines by coupling of -amino-alcohols with secondary alcohols liberating
H2 catalyzed by ruthenium pincer complexes, Chem. Commun. 49 (2013±
632–6634.
4
[
[
2] T.P. Vispute, H. Zhang, A. Sanna, R. Xiao, G.W. Huber, Renewable chemical
commodity feedstocks from integrated catalytic processing of pyrolysis oils,
Science 330 (2010± 1222–1227.
c
6
[
[
[
3] S. Michlik, R. Kempe, A sustainable catalytic pyrrole synthesis, Nat. Chem. 5
[
[
[
34] C.S. Cho, B.T. Kim, T.-J. Kim, S.C. Shim, Ruthenium-catalysed oxidative
cyclisation of 2-aminobenzyl alcohol with ketones: modified Friedlaender
quinoline synthesis, Chem. Commun. 2576–2577 (2001±.
35] K. Taguchi, S. Sakaguchi, Y. Ishii, Synthesis of quinolines from amino alcohol
and ketones catalyzed by [IrCl(cod±]2 or IrCl3 under solvent-free conditions,
Tetrahedron Lett. 46 (2005± 4539–4542.
36] B.W.J. Chen, L.L. Chng, J. Yang, Y. Wei, J. Yang, J.Y. Ying, Palladium-Based
Nanocatalyst for One-Pot Synthesis of Polysubstituted Quinolines,
ChemCatChem 5 (2013± 277–283.
(
2013± 140.
4] J.P. Michael, Quinoline, quinazoline and acridone alkaloids, Nat. Prod. Rep. 19
2002± 742–760.
(
5] G.C. Muscia, G.Y. Buldain, S.E. Asís, Design, synthesis and evaluation of acridine
and fused-quinoline derivatives as potential anti-tuberculosis agents, Eur. J.
Med. Chem. 73 (2014± 243–249.
[
6] W.W.P., R.M. Sheets, Advances in Heterocyclic Chemistry, Academic Press, New
York, 1983.
[
7] J. Marco-Contelles, E. Pérez-Mayoral, A. Samadi, M.d.C. Carreiras, E. Soriano,
Recent advances in the Friedländer reaction, Chem. Rev. 109 (2009± 2652–
[
[
[
[
37] T. Welton, Solvents and sustainable chemistry, Proc. Roy. Soc. A: Math. Phys.
Eng. Sci. 471 (2015±.
38] B. Li, P.H. Dixneuf, sp2 C-H bond activation in water and catalytic cross-
coupling reactions, Chem. Soc. Rev. 42 (2013± 5744–5767.
39] P.H. Dixneuf, V. Cadierno, Metal-Catalyzed Reactions in Water, 1st ed., Wiley-
VCH, 2013.
40] L. Wang, N. Onishi, K. Murata, T. Hirose, J.T. Muckerman, E. Fujita, Y. Himeda,
2
671.
[
8] H. Vander Mierde, P. Van Der Voort, D. De Vos, F. Verpoort, A ruthenium-
catalyzed approach to the Friedländer quinoline synthesis, Eur. J. Org. Chem.
(
2008, 2008,± 1625–1631.
[
9] W.Y.X. Yu, W. Hu, D. Wang, Iridium-catalyzed synthesis of quinolines from 2-
aminobenzyl alcohols with secondary alcohols, Russ. J. Gen. Chem. 86 (2016±
Efficient hydrogen storage and production using
imidazoline-based, proton-responsive ligand, ChemSusChem 10 (2017±
071–1075.
a catalyst with an
3
76–379.
[
10] H.V. Mierde, P.V.D. Voort, F. Verpoort, Base-mediated synthesis of quinolines:
an unexpected cyclization reaction between 2-aminobenzylalcohol and
ketones, Tetrahedron Lett. 49 (2008± 6893–6895.
1
[
41] R. Kawahara, K.-I. Fujita, R. Yamaguchi, Dehydrogenative oxidation of alcohols
in aqueous media using water-soluble and reusable Cp*Ir catalysts bearing a
functional bipyridine ligand, J. Am. Chem. Soc. 134 (2012± 3643–3646.
42] T. Kitanosono, K. Masuda, P. Xu, S. Kobayashi, Catalytic organic reactions in
water toward sustainable society, Chem. Rev. 118 (2018± 679–746.
43] Z. Yang, Z. Zhu, R. Luo, X. Qiu, J.-T. Liu, J.-K. Yang, W. Tang, Iridium-catalyzed
highly efficient chemoselective reduction of aldehydes in water using formic
acid as the hydrogen source, Green Chem. 19 (2017± 3296–3301.
[
[
[
11] R. Martínez, D.J. Ramón, M. Yus, Transition-metal-free indirect Friedländer
synthesis of quinolines from alcohols, J. Org. Chem. 73 (2008± 9778–9780.
12] Y. Zhu, C. Cai, An N-heterocyclic carbene-catalyzed approach to the indirect
Friedländer quinoline synthesis, RSC Adv. 4 (2014± 52911–52914.
13] N. Anand, S. Koley, B.J. Ramulu, M.S. Singh, Metal-free aerobic one-pot
synthesis of substituted/annulated quinolines from alcohols via indirect
Friedländer annulation, Org. Biomol. Chem. 13 (2015± 9570–9574.
[
[
[
44] P. Qu, C. Sun, J. Ma, F. Li, The N-alkylation of sulfonamides with alcohols in
[
14] H.V. Mierde, P.V.D. Voort, F. Verpoort, Fast and convenient base-mediated
synthesis of 3-substituted quinolines, Tetrahedron Lett. 50 (2009± 201–203.
15] P. Daw, S. Chakraborty, J.A. Garg, Y. Ben-David, D. Milstein, Direct synthesis of
pyrroles by dehydrogenative coupling of diols and amines catalyzed by cobalt
pincer complexes, Angew. Chem., Int. Ed. 55 (2016± 14373–14377.
0
water catalyzed by the water-soluble iridium complex {Cp*Ir[6,6 -(OH±2bpy]
(
H2O±}[OTf]2, Adv. Synth. Catal. 356 (2014± 447–459.
[
[
45] R. Kawahara, K.-I. Fujita, R. Yamaguchi, N-alkylation of amines with alcohols
catalyzed by a water-soluble Cp*iridium complex: an efficient method for the
synthesis of amines in aqueous media, Adv. Synth. Catal. 353 (2011± 1161–
[
16] S.P. Midya, V.G. Landge, M.K. Sahoo, J. Rana, E. Balaraman, Cobalt-catalyzed
acceptorless dehydrogenative coupling of aminoalcohols with alcohols: direct
access to pyrrole, pyridine and pyrazine derivatives, Chem. Commun. 54
1168.
[
[
[
46] R. Kawahara, K.-I. Fujita, R. Yamaguchi, Multialkylation of aqueous ammonia
with alcohols catalyzed by water-soluble Cp*Irꢀammine complexes, J. Am.
Chem. Soc. 132 (2010± 15108–15111.
(
2018± 90–93.
[
17] W. Zhao, P. Liu, F. Li, Quinazolinones from o-aminobenzonitriles by one-pot
sequential selective hydration/condensation/acceptorless dehydrogenation
catalyzed by an iridium complex, ChemCatChem 8 (2016± 1523–1530.
18] R.H. Crabtree, Homogeneous transition metal catalysis of acceptorless
dehydrogenative alcohol oxidation: applications in hydrogen storage and to
heterocycle synthesis, Chem. Rev. 117 (2017± 9228–9246.
47] H. Hikawa, Y. Ino, H. Suzuki, Y. Yokoyama, Pd-catalyzed benzylic C-H
amidation with benzyl alcohols in water:
a strategy to construct
quinazolinones, J. Org. Chem. 77 (2012± 7046–7051.
[
48] R. Wang, H. Fan, W. Zhao, F. Li, Acceptorless dehydrogenative cyclization of o-
aminobenzyl alcohols with ketones to quinolines in water catalyzed by water-
0
soluble metal-ligand bifunctional catalyst [Cp*(6,6 -(OH±2bpy±(H2O±][OTf]2,
[
19] S. Elangovan, J.-B. Sortais, M. Beller, C. Darcel, Iron-catalyzed a-alkylation of
Org. Lett. 18 (2016± 3558–3561.
ketones with alcohols, Angew. Chem., Int. Ed. 54 (2015± 14483–14486.
20] M. Maji, K. Chakrabarti, B. Paul, B.C. Roy, S. Kundu, Ruthenium(II±-NNN-pincer-
complex-catalyzed reactions between various alcohols and amines for
sustainable CꢀN and CꢀC bond formation, Adv. Synth. Catal. 360 (2018±
[
[
[
49] A. Wetzel, S. Wöckel, M. Schelwies, M.K. Brinks, F. Rominger, P. Hofmann, M.
Limbach, Selective alkylation of amines with alcohols by Cp*–Iridium(III± half-
sandwich complexes, Org. Lett. 15 (2013± 266–269.
[
50] A. Fernandes, B. Royo, Water-soluble iridium N-heterocyclic carbene
7
22–729.
complexes for the alkylation of amines with alcohols, ChemCatChem
2017± 3912–3917.
9
[
21] D. Srimani, Y. Ben-David, D. Milstein, Direct synthesis of pyrroles by
dehydrogenative coupling of b-aminoalcohols with secondary alcohols
catalyzed by ruthenium pincer complexes, Angew. Chem., Int. Ed. 52 (2013±
(
51] C. Ge, X. Sang, W. Yao, L. Zhang, D. Wang, Unsymmetrical indazolyl-pyridinyl-
triazole ligand-promoted highly active iridium complexes supported on
hydrotalcite and its catalytic application in water, Green Chem. 20 (2018±
4
012–4015.
[
22] M. Zhang, H. Neumann, M. Beller, Selective ruthenium-catalyzed three-
component synthesis of pyrroles, Angew. Chem., Int. Ed. 52 (2013± 597–601.
23] S. Ruch, T. Irrgang, R. Kempe, New iridium catalysts for the selective alkylation
of amines by alcohols under mild conditions and for the synthesis of
quinolines by acceptor-less dehydrogenative condensation, Chem. Eur. J. 20
1805–1812.
[
52] Z. Xu, X. Yu, X. Sang, D. Wang, BINAP-copper supported by hydrotalcite as an
efficient catalyst for the borrowing hydrogen reaction and dehydrogenation
cyclization under water or solvent-free conditions, Green Chem. 20 (2018±
[
2571–2577.
(
2014± 13279–13285.
[
[
53] G. Xu, Q. Li, J. Feng, Q. Liu, Z. Zhang, X. Wang, X. Zhang, X. Mu, Direct
alkylation of ketones with alcohols in water, ChemSusChem 7 (2014± 105–109.
54] H. Hikawa, T. Koike, K. Izumi, S. Kikkawa, I. Azumaya, Borrowing hydrogen
a-
[
[
[
24] M. Mastalir, M. Glatz, E. Pittenauer, G. Allmaier, K. Kirchner, Sustainable
synthesis of quinolines and pyrimidines catalyzed by manganese PNP pincer
complexes, J. Am. Chem. Soc. 138 (2016± 15543–15546.
25] C.S. Cho, B.T. Kim, H.-S. Kim, T.-J. Kim, S.C. Shim, Ruthenium-catalyzed one-pot
b-alkylation of secondary alcohols with primary alcohols, Organometallics 22
methodology for N-benzylation using a
Adv. Synth. Catal. 358 (2016± 784–791.
p-benzylpalladium system in water,
[
55] L. Rakers, F. Schäfers, F. Glorius, In water and under mild conditions: a-
(
2003± 3608–3610.
alkylation of ketones with alcohols by phase-transfer-assisted borrowing
hydrogen catalysis, Chem. Eur. J. 24 (2018± 15529–15532.
26] S. Michlik, R. Kempe, Regioselectively functionalized pyridines from
sustainable resources, Angew. Chem., Int. Ed. 52 (2013± 6326–6329.

1
02
M. Maji et al. / Journal of Catalysis 373 (2019) 93–102
[
56] J. Frank, A.R. Katritzky, Tautomeric pyridines. Part XV. Pyridone–
hydroxypyridine equilibria in solvents of differing polarity, J. Chem. Soc.,
Perkin Trans. 2 (1976± 1428–1431.
[66] S. Shee, K. Ganguli, K. Jana, S. Kundu, Cobalt complex catalyzed atom-
economical synthesis of quinoxaline, quinoline and 2-alkylaminoquinoline
derivatives, Chem. Commun. 54 (2018± 6883–6886.
[
57] J.R. Khusnutdinova, D. Milstein, Metal-ligand cooperation, Angew. Chem., Int.
Ed. 54 (2015± 12236–12273.
[67] F. Xie, M. Zhang, M. Chen, W. Lv, H. Jiang, Convenient synthesis of quinolines
from a-2-nitroaryl alcohols and alcohols via a ruthenium-catalyzed hydrogen
[
58] R. Kawahara, K.-I. Fujita, R. Yamaguchi, Cooperative catalysis by iridium
complexes with a bipyridonate ligand: versatile dehydrogenative oxidation of
alcohols and reversible dehydrogenation-hydrogenation between 2-propanol
and acetone, Angew. Chem., Int. Ed. 51 (2012± 12790–12794.
transfer strategy, ChemCatChem 7 (2015± 349–353.
[68] G.C. Muscia, M. Bollini, J.P. Carnevale, A.M. Bruno, S.E. Asís, Microwave-
assisted Friedländer synthesis of quinolines derivatives as potential
antiparasitic agents, Tetrahedron Lett. 47 (2006± 8811–8815.
[
59] K.-I. Fujita, Y. Tanaka, M. Kobayashi, R. Yamaguchi, Homogeneous
perdehydrogenation and perhydrogenation of fused bicyclic N-heterocycles
catalyzed by iridium complexes bearing a functional bipyridonate ligand, J.
Am. Chem. Soc. 136 (2014± 4829–4832.
[69] P.J. Houghton, T.Z. Woldemariam, Y. Watanabe, M. Yates, Activity against
mycobacterium tuberculosis of alkaloid constituents of angostura bark,
Galipea officinalis, Planta Med. 65 (1999± 250–254.
[70] R. Adam, J.R. Cabrero-Antonino, A. Spannenberg, K. Junge, R. Jackstell, M.
Beller, A general and highly selective cobalt-catalyzed hydrogenation of N-
heteroarenes under mild reaction conditions, Angew. Chem., Int. Ed. 56 (2017±
3216–3220.
[71] N.S. Upadhyay, V.H. Thorat, R. Sato, P. Annamalai, S.-C. Chuang, C.-H. Cheng,
Synthesis of isoquinolones via Rh-catalyzed C-H activation of substituted
benzamides using air as the sole oxidant in water, Green Chem. 19 (2017±
3219–3224.
[
[
60] K.-I. Fujita, W. Ito, R. Yamaguchi, Dehydrogenative lactonization of diols in
aqueous media catalyzed by a water-soluble iridium complex bearing
functional bipyridine ligand, ChemCatChem 6 (2014± 109–112.
a
61] C.M. Moore, B. Bark, N.K. Szymczak, Simple ligand modifications with pendent
oh groups dramatically impact the activity and selectivity of ruthenium
catalysts for transfer hydrogenation: the importance of alkali metals, ACS
Catal. 6 (2016± 1981–1990.
[
62] J. DePasquale, I. Nieto, L.E. Reuther, C.J. Herbst-Gervasoni, J.J. Paul, V. Mochalin,
M. Zeller, C.M. Thomas, A.W. Addison, E.T. Papish, Iridium dihydroxybipyridine
complexes show that ligand deprotonation dramatically speeds rates of
catalytic water oxidation, Inorg. Chem. 52 (2013± 9175–9183.
[72] A.M. Royer, T.B. Rauchfuss, D.L. Gray, Organoiridium pyridonates and their role
in the dehydrogenation of alcohols, Organometallics 29 (2010± 6763–6768.
[73] G. Zeng, S. Sakaki, K.-I. Fujita, H. Sano, R. Yamaguchi, Efficient catalyst for
acceptorless alcohol dehydrogenation: interplay of theoretical and
experimental studies, ACS Catal. 4 (2014± 1010–1020.
[
63] N. Onishi, S. Xu, Y. Manaka, Y. Suna, W.-H. Wang, J.T. Muckerman, E. Fujita, Y.
Himeda, CO
2
Hydrogenation catalyzed by iridium complexes with a proton-
[74] H. Li, G. Lu, J. Jiang, F. Huang, Z.-X. Wang, Computational mechanistic study on
Cp*Ir complex-mediated acceptorless alcohol dehydrogenation: bifunctional
hydrogen transfer vs b-H elimination, Organometallics 30 (2011± 2349–2363.
[75] K.-I. Fujita, R. Tamura, Y. Tanaka, M. Yoshida, M. Onoda, R. Yamaguchi,
Dehydrogenative oxidation of alcohols in aqueous media catalyzed by a water-
responsive ligand, Inorg. Chem. 54 (2015± 5114–5123.
[
64] W.-H. Wang, M.Z. Ertem, S. Xu, N. Onishi, Y. Manaka, Y. Suna, H. Kambayashi, J.
T. Muckerman, E. Fujita, Y. Himeda, Highly robust hydrogen generation by
bioinspired Ir complexes for dehydrogenation of formic acid in water:
experimental and theoretical mechanistic investigations at different pH, ACS
Catal. 5 (2015± 5496–5504.
65] X. Wang, C. Wang, Y. Liu, J. Xiao, Acceptorless dehydrogenation and aerobic
oxidation of alcohols with a reusable binuclear rhodium(ii± catalyst in water,
Green Chem. 18 (2016± 4605–4610.
soluble dicationic iridium complex bearing
a functional N-heterocyclic
carbene ligand without using base, ACS Catal. 7 (2017± 7226–7230.
[76] P.A. Dub, J.C. Gordon, Metal-ligand bifunctional catalysis: the ‘‘Accepted”
mechanism, the issue of concertedness, and the function of the ligand in
catalytic cycles involving hydrogen atoms, ACS Catal. 7 (2017± 6635–6655.
[