A mild and efficient synthesis of substituted quinolines via a cross-dehydrogenative coupling of (Bio)available alcohols and aminoarenes

Article abstract of DOI:10.1002/adsc.201400815

A ruthenium-catalysed dehydrogenative cross-coupling of primary alcohols and imines in the presence of TFA provided a library of differently substituted quinolines. Imines can be prepared in situ from various anilines and several benzyl alcohols using a ruthenium-catalysed hydrogen-transfer procedure. Without changing the catalyst, quinolines can be obtained in moderate to good yields by adding various primary alcohols in the presence of TFA (30 mol%) via a "telescopic" protocol. The use of alcohols, the absence of strong oxidants and the diversity of potential starting materials make this modern version of the Skraup reaction superior to most of the conventional quinoline syntheses.

Full text of DOI:10.1002/adsc.201400815

UPDATES
DOI: 10.1002/adsc.201400815
A Mild and Efficient Synthesis of Substituted Quinolines via
a Cross-Dehydrogenative Coupling of (Bio)available Alcohols
and Aminoarenes
a
a
a
b
Manuel G. Mura, Suvi Rajamꢀki, Lidia De Luca, Elena Cini,
a,
and Andrea Porcheddu *
Dipartimento di Chimica e Farmacia, Universitꢁ degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
Fax : (+39)-079-229-559; phone: (+39)-079-229-528; e-mail: anpo@uniss.it
a
b
Dipartimento di Biotecnologie, Chimica e Farmacia, Universitꢁ di Siena, Via A. Moro 2, 53100 Siena, Italy
Received: August 17, 2014; Revised: November 13, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400815.
Abstract: A ruthenium-catalysed dehydrogenative
cross-coupling of primary alcohols and imines in
the presence of TFA provided a library of different-
ly substituted quinolines. Imines can be prepared in
situ from various anilines and several benzyl alco-
hols using a ruthenium-catalysed hydrogen-transfer
procedure. Without changing the catalyst, quino-
lines can be obtained in moderate to good yields by
adding various primary alcohols in the presence of
TFA (30 mol%) via a “telescopic” protocol. The
use of alcohols, the absence of strong oxidants and
the diversity of potential starting materials make
this modern version of the Skraup reaction superior
to most of the conventional quinoline syntheses.
a growing number of elegant syntheses for substituted
quinolines, the use of harsh reaction conditions and
some limits based on the nature of the reagents in-
volved still make the development of more effective
[8]
approaches an important topic in organic chemistry.
The acid-catalysed reaction between imines and eno-
lisable aldehydes, a more recent evolution of the orig-
[
9]
inal Skraup synthesis, represents an interesting and
versatile approach to the preparation of diversely
[
10]
functionalised quinolines. Although this procedure
provides a straightforward and practical access to qui-
nolines, often, the starting materials can be very ex-
pensive or difficult to prepare, leaving considerable
room for improvement.
We recently reported on the cross-dehydrogenative
coupling (CDC) of two different primary alcohols in
the presence of methylamine to obtain a,b-unsaturat-
ed aldehydes using a Ru-based catalyst (Scheme 1,
Keywords: alcohols; cross-coupling reactions; mi-
crowave irradiation; quinolines; transfer hydroge-
nation
[
11]
pathway 1).
We hypothesised that this protocol
could also be extended to the preparation of substi-
tuted quinolines by using a hydrogen-transfer (HT)
[
12]
methodology
with simple and stable alcohols in-
[13]
The quinoline nucleus is a recurrent motif in several stead of aldehydes as starting materials. Switching
natural compounds and is present in many synthetic from methylamine to arylamines, should allow us to
entities with a broad range of pharmacological and generate the quinoline skeleton via the subsequent
[
1]
[2]
[3]
[
4]
biological activities.
Quinoline derivatives are acid-mediated cyclocondesation (Scheme 1, pathway
among the oldest substances isolated from natural re- 2).
sources and used in medicinal chemistry as anti-ma-
The use of alcohols as in-situ sources of aldehydes
larial, anti-bacterial, anti-inflammatory, anti-asthmatic should further improve the classical quinoline synthe-
[
5]
and anti-hypertensive agents. In recent times, sever- sis not only from the atom-economic point of view
al members of the quinoline family have displayed in- but also from the environmental and general econom-
[
14]
teresting electronic and photonic properties and ic points of view.
found attractive applications as valuable synthons in At the onset of our investigation, we focused our
[
6]
the preparation of nano- and mesostructures. Due efforts on the synthesis of arylimines using a hydro-
to these positive traits, considerable attention has gen-transfer synthetic protocol and chose aniline 1a
been paid to developing new methodologies for the and benzyl alcohol 2a as our model substrates for es-
[
7]
preparation of quinoline-based structures. Despite tablishing the optimal reaction conditions for Schiff
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Manuel G. Mura et al.
UPDATES
crotononitrile (1.5 mmol) under solvent-free micro-
wave dielectric heating at 1308C for 1 h resulted in
[
16]
quantitative conversion of 1a and 2a into imine 3a
(
Table 1, entry 9). Crotononitrile plays a crucial role
as a hydrogen acceptor in this reaction promoting the
formal oxidation of the benzyl alcohol and preventing
the hydrogenation of the imine group (Table 1,
[
17]
entry 11).
Despite screening of a wide variety of organic sol-
vents (toluene, 2-methyl-2-butanol and 1,4-dioxane),
the reaction proceeded more efficiently when no sol-
vent was present. After halving the reaction time or
Scheme 1. CDC strategies for the synthesis of a,b-unsaturat- lowering the temperature, the imine conversions
ed aldehydes and quinolines.
dropped significantly, even after prolonged reaction
times (Table 1, entries 12–14).
Now having an efficient procedure for preparing
base formation (Table 1). We evaluated the per- imines in hand, we extended the application of our
formance of several Ru-based catalysts that are catalytic system to the reaction between imine 3a and
[
18]
known to be particularly active in hydrogen-transfer heptanol 4a for the synthesis of quinolines.
We
[15]
reactions. RuH CO(PPh ) gave us the best results were pleased to find that the reaction of imine 3a
2
3 3
(
Table 1, compare entries 1–4 with entry 5) and addi- (3.0 mmol) with heptanol 4a (1.0 mmol) in the pres-
tion of a catalytic amount of Xantphos as a ligand led ence of catalytic amounts of RuH CO(PPh )
2
3
to a noticeable improvement of the catalytic efficien- (4 mol%), Xantphos (4 mol%), a suitable acid cata-
cy (Table 1, compare entries 5 and 6). Using a slight lyst and crotononitrile (3.0 mmol) afforded the corre-
excess of benzyl alcohol further improved the Schiff sponding quinoline 5a in good yields (Table 2).
base formation (Table 1, entries 7–10).
Among the screened acids, CF COOH (TFA) pro-
3
The treatment of 1a (1.0 mmol) with 1.2 equivalents vided the best results in terms of promoting the cycli-
of 2a in the presence of catalytic amounts of sation reaction (Table 2, compare entries 1–7 with
RuH CO(PPh ) (4 mol%), Xantphos (4 mol%) and entry 9). We observed no product formation in the ab-
2
3
Table 1. Ruthenium-catalysed imine synthesis under HT conditions.
[a]
[a]
[b]
Entry
1a (mmol)
2a (mmol)
Catalyst
Ligand
3a [%]
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
1.5
1.2
1.0
1.2
1.2
1.2
1.2
Ru (CO)
–
–
–
–
–
58
43
57
48
63
97
98
98
99
97[
3
12
RuH (PPh )
3 3
2
[Ru(p-cymene)Cl2]2
RuHCl(CO)(PPh3)3
RuH (CO)(PPh )
2
3
3
3
3
3
RuH (CO)(PPh )
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
2
3
RuH (CO)(PPh )
2
3
RuH (CO)(PPh )
2
3
RuH (CO)(PPh )
2
3 3
10
11
12
13
14
RuH (CO)(PPh )
2 3 3
c]
RuH (CO)(PPh )
36[
2
3
3
3
3
3
d]
RuH (CO)(PPh )
83[
2
3
e]
RuH (CO)(PPh )
90
77
2
3
[
f]
RuH (CO)(PPh )
2
3
[
[
[
[
[
[
a]
4
mol%.
b]
1
Conversion of 1a and 2a into imine 3a is determined by H NMR spectroscopic analysis.
Reaction performed without crotononitrile.
Reaction performed at 1308C (MWI) for 30 min.
Reaction performed at 1208C (MWI) for 1 h.
Reaction performed at 1108C (MWI) for 3 h.
c]
d]
e]
f]
2
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

UPDATES
A Mild and Efficient Synthesis of Substituted Quinolines
Table 2. Ruthenium-catalysed quinoline synthesis under HT conditions and in the presence of an acid catalyst.
[a]
Entry
3a (mmol)
4a (mmol)
Acid catalyst
5a Yield [%]
[
b]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.5
1.0
1.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
HCl (0.5 mmol)[
HCl (0.5 mmol)
10
12
51
53
20
20
20
58
60
51
–
65
69
49
51
55
c]
[
d]
TsOH (0.5 mmol)
MsOH (0.5 mmol)
SiO -OSO H (100 mg)
SiO -OSO H (250 mg)
SiO -OSO H (500 mg)
TFA (0.5 mmol)
TFA (0.3 mmol)
TFA (0.15 mmol)
–
[e]
2
3
2
3
2
3
[f]
0
1
2
3
4
5
6
TFA (0.3 mmol)
TFA (0.3 mmol)
TFA (0.3 mmol)[
g]
TFA (0.3 mmol)[
TFA (0.3 mmol)
h]
[
[
[
[
[
[
[
[
a]
Isolated yields.
b]
4
4
M in dioxane.
M in CPME.
c]
d]
e]
f]
TsOH=para-toluenesulfonic acid.
MsOH=methanesulfonic acid.
TFA=trifluoroacetic acid.
Reaction performed at 1208C (MWI) for 3 h.
Reaction performed at 1308C (MWI) for 1 h.
g]
h]
sence of an acid catalyst even with prolonged reaction prepare quinoline 5a via a telescopic reaction that, in
times (Table 2, entry 11). Further optimisation studies our case, consisted of a one-pot, two-step protocol
showed that decreasing the amount of TFA to (Scheme 2).
0.3 equivalents did not adversely affect the reaction
In a typical optimised experiment, benzyl alcohol
outcome (Table 2, compare entries 8 and 9).
2a (1.8 mmol) and aniline 1a (1.5 mmol) were reacted
Competition experiments varying the molar alcohol in the presence of RuH CO(PPh ) (4 mol%), Xant-
2
3 3
4a to imine 3a ratio under the optimised conditions
afforded quinoline 5a in different yields (Table 2 en-
tries 12–14). The best results were achieved with
a 1.5:1 molar ratio (Table 2, entry 13). A decrease of
the reaction temperature below 1308C resulted in
a significantly lower quinoline yield (Table 2, en-
tries 15). The yields of quinoline 5a also dropped
markedly in response to shortened reaction times
(
Table 2, entries 16).
With the feasibility of both pathways established,
we attempted the direct one-pot conversion of all sub-
strates into quinoline 5a under transfer hydrogenation
conditions. Unfortunately, any attempt to perform
both transformations in a one-pot fashion resulted in
a complex reaction mixture in which the main prod-
Scheme 2. Synthesis of quinoline 5a via a telescopic reaction
ucts were N-alkylated anilines and cinnamaldehyde (one-pot, two-steps) under HT conditions and in the pres-
derivatives. In view of these results, we decided to ence of an acid catalyst.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Manuel G. Mura et al.
UPDATES
phos (4 mol%) and crotononitrile (2 mmol) under
MWI at 1308C for 1 h. Heptanol 4a (1 mmol), was
subsequently added to the crude reaction mixture fol-
lowed by fresh crotononitrile (2.2 mmol) and a catalyt-
ic amount of TFA (0.3 mmol). The resulting reaction
[
19]
mixture was heated (MWI) at 1308C for a further
h, affording the expected quinoline 5a in 71% isolat-
ed yield.
We then used these optimised conditions to explore
3
the scope and limitations of this procedure combining
a broad range of anilines with benzyl and aliphatic al-
cohols. To our delight, we obtained a series of differ-
ently substituted quinolines in moderate to good
yields, as shown in Scheme 3.
In general, both electron-donating and electron-
withdrawing aromatic alcohols were amenable to this
protocol. Alcohols bearing electron-poor groups on
their aromatic systems showed better activity than
those bearing electron-rich substituents, indicating
that the reaction is sensitive to electronic effects
(
Scheme 3, compare quinolines 5b–d and 5e–f). With
benzyl alcohols incorporating a bulky substituent at
the ortho-position of the aromatic ring, the yields of
quinolines dropped drastically (Scheme 3, compare
products 5g and 5h in Scheme 3). The reaction readily
tolerates a wide range of functional groups such as
halogen, carboxymethyl, alkoxy and hydroxy substitu-
ents on the aromatic alcohol moiety (Scheme 3, qui-
nolines 5c–f).
Encouraged by these results, the protocol was then
extended to a variety of arylamines as shown in
Scheme 3. Aniline derivatives with various functional-
ities worked satisfactorily although anilines containing
electron-withdrawing groups on their aromatic ring
were found to be less reactive providing slightly lower
yields of quinoline products (Scheme 3, compare, for
example, products 5l and 5p).
The 4-nitroaniline and 4-cyanoaniline precursors in
combination with benzyl alcohol, not only failed to
yield the intended quinoline 5s and 5t, but also
showed poor Schiff base conversion. When 3-meth-
ACHTUNGTRENNUNGo xyaniline was used, the reaction yielded a 85/15 mix-
[20]
[21]
ture of two regioisomers 5m and 5n, which were
extremely difficult to purify.
Regarding the nature of the quinoline substituent
in position 3, long-chain primary alcohols, such as un-
decanol, could be transformed into the desired prod-
ucts 5v in 74% isolated yield. Primary alcohols with
various chain-end functionalities worked satisfactorily
in the reaction (Scheme 3, quinolines 5w–z). The
functional groups on their backbone turned out to be
compatible with the reaction conditions. Subsequent
manipulation to increase the molecular diversity on
the quinoline core further is possible.
Scheme 3. Reaction scope for alcohols and arylamines. Reac-
tion conditions: i) 1a (1.5 mmol), 2a (1.8 mmol),
RuH CO(PPh ) (4 mol%), Xantphos (4 mol%), crotononi-
trile (2 mmol), MWI, 1308C, 1 h; ii), 4a (1.0 mmol), crotono-
nitrile (2.2 mmol), TFA (0.3 mmol), MWI, 1308C, 3 h.
2
3 3
We were pleasantly surprised by the high number
of unknown compounds (78%) prepared using this
procedure suggesting that our methodology may pro-
4
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

UPDATES
A Mild and Efficient Synthesis of Substituted Quinolines
and in the presence of a ruthenium catalyst to pro-
duce quinolines in moderate to good yields. In this
methodology, alcohols, which are attractive, readily
available and easily handled starting materials, play
a key role as aldehyde precursors. The simple experi-
mental procedure combined with the wide availability
of cheap building blocks, makes this method reasona-
bly general, efficient, rapid, and environmentally
benign. The application of microwave irradiation
heating dramatically reduced reaction times, promot-
ing the synthesis of highly functionalised quinolines.
Experimental Section
3-Pentyl-2-phenylquinoline (5a); Typical Procedure
The procedure for the synthesis of quinoline 5a is illustra-
tive: to a 10-mL MW tube were added aniline 1a (140 mg,
1
.5 mmol), benzyl alcohol 2a (195 mg, 1.8 mmol), crotononi-
trile (134 mg, 2.0 mmol), RuH CO(PPh ) (37 mg, 4 mol%)
2
3
and Xantphos (23 mg, 4 mol%). The reaction mixture was
irradiated in a sealed tube at 1308C for 1 h to allow com-
plete conversion into the Schiff base 3a (monitored by
Scheme 4. A plausible mechanistic pathway.
1
H NMR). Heptanol (116 mg, 1.0 mmol) and crotononitrile
(
148 mg, 2.2 mmol) were then added to the resulting solu-
vide a direct route to quinoline structures otherwise
inaccessible using a conventional approach.
The reaction seems to proceed via a sequence in-
volving an initial hydrogen transfer from the benzyl
alcohol 2a to the ruthenium catalyst, generating the
tion and the reaction was subjected to microwave irradiation
for 3 h at 1308C in a monomodal microwave oven. The
crude reaction mixture was then concentrated to afford the
crude product as a slightly orange-coloued oil, which was
further purified by flash column chromatography (hexane/
ethyl acetate 9/1). The expected quinoline 5a was then ob-
corresponding aromatic aldehyde along with [Ru]H2
(
Scheme 4). Crotononitrile acts as a sacrificial hydro- tained as white solid; yield: 196 mg (71%); m.p. 42–448C
[10f]
gen acceptor oxidising [Ru]H back to the starting (lit.,
43–448C); R
=0.59 (hexane/AcOEt: 8/2); IR (film):
2
f
À1
active catalytic species. The aliphatic alcohol 4a un- n=3059, 2955, 2927, 2858, 1636, 1487, 1418, 1007 cm ;
1
H NMR (400 MHz; CDCl ): d=8.12 (d, J=8 Hz, 1H), 8.03
dergoes a ruthenium-assisted oxidative dehydrogena-
tion reaction in a similar fashion, giving the desired
aliphatic aldehyde. The nucleophilic attack of enol 6a
on protonated imine 7a gives intermediate 8a, which
in the subsequent heteroannulation reaction forms
the 1,2-dihydroquinoline 9a.
The aromatisation process is accompanied by the
generation of one equivalent of hydrogen, which is
primarily trapped by crotonitrile with the concomitant
formation of quinoline 5a. In the absence of crotoni-
trile, the imine intermediate 3a also works as a hydro-
gen acceptor leading to very low reaction yields.
In order to validate the proposed reaction mecha-
nism, the model reaction was reinvestigated using
benzaldehyde (first step) and heptanal (second step)
3
(
s, 1H), 7.80 (d, J=8 Hz, 1H), 7.66 (t, J=7 Hz, 1H), 7.53 (t,
J=8 Hz, 3H), 7.50–7.41 (m, 3H), 2.76 (t, J=8H, 2H), 1.54
quint. J=7 Hz, 2H), 1.25–1.20 (m, 4H), 0.81(t, J=6 Hz,
(
3
1
1
13
H); C NMR (100 MHz; CDCl ): d=160.8, 146.4, 141.0,
3
35.7, 134.1, 129.3, 128.8, 128.7 (2C), 128.2 (2C), 128.0,
27.6, 126.9, 126.3,32.8, 31.5, 30.2, 22.3, 13.9. These assign-
[10f]
ments matched those previously published.
Acknowledgements
Financial support from Regione Autonoma della Sardegna
Project RAS: F71J11001240002) and Fondazione Banco di
Sardegna (Project: Prot. U875.2014/AI.758.MGB, Prat.2014.
(
instead of the corresponding alcohols. Under the 0803) is gratefully acknowledged.
same experimental conditions, we did indeed obtain
the quinoline 5a, albeit at a lower yield (47%). We
hypothesise that the use of alcohols as in-situ sources
References
of aldehydes may avoid or at least limit several side
[
22]
reactions that are typical of aldehydes.
[
1] K. C. Majumdar, S. K. Chattopadhyay, Quinolines and
Isoquinolines, in: Heterocycles in Natural Product Syn-
thesis, (Ed.: A. G. Montalban), Wiley-VCH, Weinheim,
2011.
In summary, we have demonstrated that a set of ali-
phatic and aromatic alcohols can be oxidatively cy-
clised with an array of anilines under acidic conditions
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Manuel G. Mura et al.
UPDATES
[
[
2] G. Jones, in: Chemistry of Heterocyclic Compounds:
Quinolines, Part I, Vol. 32, (Ed.: G. Jones), John Wiley
J. D. Carrol, P. Davis, T. R. Verhoeven, P. J. Reider, M.
Labelle, J. Y. Gauthier, Y. B. Xiang, R. J. Zamboni, J.
Org. Chem. 1996, 61, 3398–3405; q) M. P. Maguire,
K. R. Sheets, K. McVety, A. P. Spada, A. Zilberstein, J.
Med. Chem. 1994, 37, 2129–2137.
&
Sons, Hoboken, 2008.
3] a) B. D. Bax, P. F. Chan, D. S. Eggleston, A. Fosberry,
D. R. Gentry, F. Gorrec, I. Giordano, M. M. Hann, A.
Hennessy, M. Hibbs, J. Huang, E. Jones, J. Jones, K. K.
Brown, C. J. Lewis, E. W. May, M. R. Saunders, O.
Singh, C. E. Spitzfaden, C. Shen, A. Shillings, A. J.
Theobald, A. Wohlkonig, N. D. Pearson, M. N. Gwynn,
Nature 2010, 466, 935–940; b) M. Rouffet, C. A. F.
de Oliveira, Y. Udi, A. Agrawal, I. Sagi, J. A. McCam-
mon, S. M. Cohen, J. Am. Chem. Soc. 2010, 132, 8232–
[6] a) V. Bhalla, V. Vij, M. Kumar, P. R. Sharma, T. Kaur,
Org. Lett. 2012, 14, 1012–1015; b) M. Velusamy, C.-H.
Chen, Y. S. Wen, J. T. Lin, C.-C. Lin, C.-H. Lai, P.-T.
Chou, Organometallics 2010, 29, 3912–3921; c) H. Li, F.
Jꢀkle, Macromolecules 2009, 42, 3448–3453; d) S. Tao,
L. Li, J. Yu, Y. Jiang, Y. Zhou, C.-S. Lee, S.-T. Lee, X.
Zhang, O. Kwon, Chem. Mater. 2009, 21, 1284–1287.
[7] a) Y. Wang, C. Chen, J. Peng, M. Li, Angew. Chem. Int.
Ed. 2013, 52, 5323–5327; b) R. I. Khusnutdinov, A. R.
Bayguzina, R. I. Aminov, Russ. Chem. Bull. Int. Ed.
2013, 62, 133–137; c) Y. Zhang, M. Wang, P. Li, L.
Wang, Org. Lett. 2012, 14, 2206–2209; d) J. L. Wu, X. L.
Cui, L. M. Chen, G. J. Jiang, Y. J. Wu, J. Am. Chem.
Soc. 2009, 131, 13888–13889; e) J. Marco-Contelles, E.
Perez-Mayoral, A. Samadi, M. do Carmo Carreiras, E.
Soriano, Chem. Rev. 2009, 109, 2652–2671; f) Z. Zhang,
J. Tan, Z. Wang, Org. Lett. 2008, 10, 173–175; g) S.
Madapa, Z. Tusi, S. Batra, Curr. Org. Chem. 2008, 12,
1116–1183; h) R. Zong, H. Zhou, R. P. Thummel, J.
Org. Chem. 2008, 73, 4334–4337; i) B. K. Chan, M. A.
Ciufolini, J. Org. Chem. 2007, 72, 8489–8495; j) Z.
Liang, J. Wu, Adv. Synth. Catal. 2007, 349, 1047–1051;
k) R. P. Korivi, C. Cheng, J. Org. Chem. 2006, 71, 7079–
7082; l) Y. Wu, L. Liu, H. Li, D. Wang, Y. Chen, J. Org.
Chem. 2006, 71, 6592–6595; m) S. E. Denmark, S. Ven-
katraman, J. Org. Chem. 2006, 71, 1668–1676; n) B. R.
McNaughton, B. L. Miller, Org. Lett. 2003, 5, 4257–
4259; o) D. A. Powell, R. A. Batey, Org. Lett. 2002, 4,
2913–2916; p) T. Takahashi, Y. Li, P. Stepnicka, M. Ki-
tamura, Y. Liu, K. Nakajima, M. Kotora, J. Am. Chem.
Soc. 2002, 124, 576–582; q) C. S. Cho, B. T. Kim, T. J.
Kim, S. C. Shim, Chem. Commun. 2001, 2576–2577;
r) M. Tokunaga, M. Eckert, Y. Wakatsuki, Angew.
Chem. 1999, 111, 3416–3419; Angew. Chem. Int. Ed.
1999, 38, 3222–3225; s) E. C. Riesgo, X. Jin, R. P.
Thummel, J. Org. Chem. 1996, 61, 3017–3022; t) I. S.
Cho, L. Gong, J. M. Muchowski, J. Org. Chem. 1991,
56, 7288–7291; u) G. Jones, in: Comprehensive Hetero-
cyclic Chemistry, Vol. 2, Part 2A, (Eds.: A. R. Katritz-
ky, A. R. Katritzky, C. W. Rees), Pergamon, New York,
1984, pp. 395–482.
8
233; c) S. Andrews, S. J. Burgess, D. Skaalrud, J. X.
Kelly, D. H. Peyton, J. Med. Chem. 2010, 53, 916–919.
4] a) J. P. Michael, Nat. Prod. Rep. 1997, 14, 605; b) J. P.
Michael, Nat. Prod. Rep. 2001, 18, 543–559; c) S. Fu-
nayama, K. Murata, T. Noshita, Heterocycles 2001, 54,
[
1
139–1148; d) M. Balasubramanian, J. G. Keay, in:
Comprehensive Heterocyclic Chemistry II, (Eds.: A. R.
Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon
Press, Oxford, New York, 1996, Vol. 5, p 245; e) A.
Marella, O. P. Tanwar, R. Saha, M. R. Ali, S. Srivastava,
M. Akhter, M. Shaquiquzzaman, M. M. Alam, Saudi
Pharm. J. 2013, 21, 1–12.
[
5] a) B. Hu, M. Collini, R. Unwalla, J. Med. Chem. 2006,
4
9, 6151–6154; b) A. Nayyar, A. Malde, R. Jain, E.
Coutinho, Bioorg. Med. Chem. 2006, 14, 847–856;
c) A. G. Tempone, A. C. M. P. daSilva, C. A. Brandt,
F. S. Martinez, S. E. T. Borborema, M. A. B. da Silveira,
H. F. de Andrade, Antimicrob. Agents Chemother. 2005,
4
9, 1076–1080; d) S. J. Benkovic, S. J. Baker, M. R. K.
Alley, Y.-H. Woo, Y.-K Zhang, T. Akama, W. Mao, J.
Baboval, P. T. R. Rajagopalan, M. Wall, L. S. Kahng, A.
Tavassoli, L. Shapiro, J. Med. Chem. 2005, 48, 7468–
7
476; e) A. Tsotinis, M. Vlachou, S. Zouroudis, A.
Jeney, F. Timar, D. E. Thurston, C. Roussakis, Lett.
Drug Des. Discovery 2005, 2, 189–192; f) C. Benard, F.
Zouhiri, M. Normand-Bayle, M. Danet, D. Desmaele,
H. Leh, J. F. Mouscadet, G. Mbemba, C. M. Thomas, S.
Bonnenfant, S. Le, M. Bret, J. d’Angelo, Bioorg. Med.
Chem. Lett. 2004, 14, 2473–2476; g) X. Franck, A. Four-
net, E. Prina, R. Mahieux, R. Hocquemiller, B. Figa-
dere, Bioorg. Med. Chem. Lett. 2004, 14, 3635–3638;
h) S. Vangapamdu, M. Jain, R. Jain, S. Kaur, P. P. Singh,
Bioorg. Med. Chem. 2004, 12, 2501–2508; i) J. Charris,
P. Martinez, J. Dominguez, S. Lopez, J. Angel, G. Espi-
noza, Heterocycl. Commun. 2003, 9, 251–255; j) N. P.
Sahu, C. Pal, N. B. Mandal, S. Banerjee, M. Raha, A. P.
Kundu, A. Basu, M. Ghosh, K. Roy, S. Bandyopadhyay,
Bioorg. Med. Chem. 2002, 10, 1687–1693; k) Y.-L.
Chen, K.-C. Fang, Y.-J. Sheu, S.-L. Hsu, C.-C. Tzeng, J.
Med. Chem. 2001, 44, 2374–2377; l) G. Roma, M. D.
Braccio, G. Grossi, F. Mattioli, M. Ghia, Eur. J. Med.
Chem. 2000, 35, 1021–1035; m) P. A. Winstanley, Para-
sitol. Today 2000, 16, 146–153; n) D. Dubeꢃ, M. Blouin,
C. Brideau, C.-C. Chan, S. Desmarais, D. Ethier, J.-P.
Falgueyret, R. W. Friesen, M. Girard, Y. Girard, J.
Guay, D. Riendeau, P. Tagari, R. N. Young, Bioorg.
Med. Chem. Lett. 1998, 8, 1255–1260; o) O. Bilker, V.
Lindo, M. Panico, A. E. Etiene, T. Paxton, A. Dell, M.
Rogers, R. E. Sinden, H. R. Morris, Nature 1998, 392,
[8] a) For recent reports on quinoline synthesis, see: S. M.
Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal,
H. D. Patel, RSC Adv. 2014, 4, 24463–24476, and refer-
ences cited therein; b) for some relevant syntheses of
quinolines see: http://www.organic-chemistry.org/syn-
thesis/heterocycles/quinolines.shtm.
[9] In the archetypal Skraup reaction, quinolines were pre-
pared by mixing together and heating at over 1008C an
arylamine, glycerol, concentrated sulphuric acid and an
oxidising agent such as nitrobenzene. The reaction may
sometimes proceed with destructive results; a) Z. H.
Skraup, Monatsh. Chem. 1880, 1, 316; b) Z. H. Skraup,
Ber. Dtsch. Chem. Ges. 1880, 13, 2086; c) A. Moore,
Skraup Doebner–von Miller Reaction, in: Name Reac-
tions in Heterocyclic Chemistry, (Ed.: J. J. Li), Wiley &
Sons, Hoboken, 2005, pp 488–494.
2
89–292; p) R. D. Larsen, E. G. Corley, A. O. King,
6
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

UPDATES
A Mild and Efficient Synthesis of Substituted Quinolines
[
10] a) R. Yan, X. Liu, C. Pan, X. Zhou, X. Li, X. Kang, G.
Huang, Org. Lett. 2013, 15, 4876–4879; b) X. Zhang, B.
Liu, X. Shu, Y. Gao, H. Lv, J. Zhu, J. Org. Chem. 2012,
[13] Some of our recent published article on this topic, see:
a) M. Taddei, M. G. Mura, S. Rajamꢀki, L. De Luca, A.
Porcheddu, Adv. Synth. Catal. 2013, 355, 3002–3013;
b) P. Linciano, M. Pizzetti, A. Porcheddu, M. Taddei,
Synlett 2013, 2249–2254; c) M. Pizzetti, L. De Luca, E.
Petricci, A. Porcheddu, M. Taddei, Adv. Synth. Catal.
2012, 354, 2453–2464; d) A. Porcheddu, M. G. Mura, L.
De Luca, M. Pizzetti, M. Taddei, Org. Lett. 2012, 14,
6112–6115; e) M. G. Mura, L. De Luca, G. Giacomelli,
Adv. Synth. Catal. 2012, 354, 3180–3186; f) L. De Luca,
A. Porcheddu, Eur. J. Org. Chem. 2011, 5791–5795;
g) M. Lubinu, L. De Luca, G. Giacomelli, A. Porched-
du, Chem. Eur. J. 2011, 17, 82–85.
7
7, 501–510; c) H. Huang, H. Jiang, K. Chen, H. Liu, J.
Org. Chem. 2009, 74, 5476–5480; d) Y. Wang, C. Peng,
L. Liu, J. Zhao, L, Su, Q. Zhu, Tetrahedron Lett. 2009,
5
0, 2261–2265; e) X. Geng, S. Li, X. Bian, Z. Xie, C.
Wang, Arkivoc 2008, 14, 50–57; f) S.-Y. Tanaka, M.
Yasuda, A. Baba, J. Org. Chem. 2006, 71, 800–803;
g) X.-F. Lin, S.-L. Cui, Y.-G. Wang, Tetrahedron Lett.
2
006, 47, 3127–3130; h) B. R. McNaughton, B. L.
Miller, Org. Lett. 2003, 5, 4257–4259.
[11] M. G. Mura, L. De Luca, M. Taddei, J. M. J. Williams,
A. Porcheddu, Org. Lett. 2014, 16, 2586–2589.
[14] a) J. Bartoszewicz, Dissertation, Stockholm University,
2012; b) H. Vander Mierde, Dissertation, Gent Univer-
sity, 2009; c) R. B. Dripps, Dissertation, George Mason
University, 2007.
[
12] a) J. M. J. Williams, OH activation for nucleophilic sub-
stitution, in: Sustainable Catalysis, (Eds.: P. J. Dunn,
K. K. Hii, M. J. Krische, M. T. Williams), Wiley, Hobo-
ken, New Jersey, 2013, pp 121–137; b) A. J. A. Watson,
A. C. Maxwell, J. M. J. Williams, Org. Biomol. Chem.
[15] a) G. Guillena, D. J. Ramꢄn, M. Yus, Angew. Chem.
2007, 119, 2410–2416; Angew. Chem. Int. Ed. 2007, 46,
2358–2364; b) M. H. S. A. Hamid, P. A. Slatford, J. M. J.
Williams, Adv. Synth. Catal. 2007, 349, 1555–1575;
c) T. D. Nixon, M. K. Whittlesey, J. M. J. Williams,
Dalton Trans. 2009, 753–762; d) G. Guillena, D. J.
Ramꢄn, M. Yus, Chem. Rev. 2010, 110, 1611–1641; e) F.
Alonso, P. Riente, M. Yus, Acc. Chem. Res. 2011, 44,
379–391; f) C. Gunanathan, D. Milstein, Acc. Chem.
Res. 2011, 44, 588–602; g) C. Gunanathan, D. Milstein,
Science 2013, 341, 1229712.
2
012, 10, 240–243; c) S. Bahn, S. Imm, L. Neubert, M.
Zhang, H. Neumann, M. Beller, ChemCatChem 2011,
, 1853–1864; d) Y. Matsubara, S. Hirakawa, Y. Yama-
guchi, Z.-I. Yoshida, Angew. Chem. 2011, 123, 7812–
815; Angew. Chem. Int. Ed. 2011, 50, 7670–7673; e) N.
Monrad, R. Madsen, Org. Biomol. Chem. 2011, 9, 610–
3
7
6
15; f) G. Guillena, D. J. Ramꢄn, M. Yus, Chem. Rev.
2
010, 110, 1611–1641; g) F. Alonso, J. C. Foubelo, J. C.
Gonzꢅlez-Gꢄmez, R. Martꢆnez, D. J. Ramꢄn, P. Riente,
M. Yus, Mol. Diversity 2010, 14, 411–424; h) A. J. A.
Watson, J. M. J. Williams, Science 2010, 329, 635–636;
i) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010,
1
[16] Conversion to imine 3a was determined by H NMR
spectroscopic analysis.
[17] Any attempt in preparing Schiff bases by reacting aryl-
amines with aliphatic primary alcohols failed because
the resulting imines (ArNH=CHR) are better hydrogen
acceptors than crotononitrile. The search for molecular
structures able to intercept molecular hydrogen more
efficiently is the subject of our on-going research in this
field.
[18] This second step was driven by the need to find a versa-
tile catalytic system that would be able to promote the
dehydrogenative oxidation of primary alcohols, the
consequent intra-molecular annulation reaction and the
final aromatisation of the intermediate hydroquinoline
ring system.
1
10, 681–703; j) T. D. Nixon, M. K. Whittlesey, J. M. J.
Williams, Dalton Trans. 2009, 753–762; k) J. F. Bower,
I. S. Kim, R. L. Patman, M. J. Krische, Angew. Chem.
2
4
009, 121, 36–48; Angew. Chem. Int. Ed. 2009, 48, 34–
6; l) M. Hamid, P. A. Slatford, J. M. J. Williams, Adv.
Synth. Catal. 2007, 349, 1555–1575; m) G. Guillena,
D. J. Ramꢄn, M. Yus, Angew. Chem. 2007, 119, 2410–
2
416; Angew. Chem. Int. Ed. 2007, 46, 2358–2364;
n) C. S. Cho, J. U. Kim, Tetrahedron Lett. 2007, 48,
775–3778; o) C. S. Cho, S. G. Oh, J. Mol. Catal. A:
3
Chem. 2007, 276, 205–210; p) C. S. Cho, W. X. Ren, J.
Organomet. Chem. 2007, 692, 4182; q) C. S. Cho, W. X.
Ren, S. C. Shim, Tetrahedron Lett. 2006, 47, 6781–6785;
r) S. Anguille, J.-J. Brunet, N. C. Chu, O. Diallo, C.
Pages, S. Vincendeau, Organometallics 2006, 25, 2943–
[19] In comparison with the conventional heating proce-
dure, the microwave dielectric heating (MWI) allows
considerable acceleration of the reaction rate, reducing
the reaction time from 14 h down to 3 h without any
appreciable change in the quinoline yields.
2
948; s) K. Taguchi, S. Sakaguchi, Y. Ishii, Tetrahedron
Lett. 2005, 46, 4539–4542; t) N. Y. Lee, T.-J. Kim, S. C.
Shim, J. Heterocycl. Chem. 2004, 41, 423–429; u) K.
Motokura, T. Mizugaki, K. Ebitani, K. Kaneda, Tetra-
hedron Lett. 2004, 45, 6029–6032; v) C. S. Cho, D. T.
Kim, T.-J. Kim, S. C. Shim, Bull. Korean Chem. Soc.
[20] The ratio of the two regioisomers was determined by
1
H NMR analysis of the crude reaction mixture.
[21] In spite of the many efforts made, we have failed in at-
tempts to isolate a pure sample of the minor regioiso-
mer 5n.
[22] Although the hydrogen-transfer reaction proceeds via
a formal oxidation of the alcohol functional group, only
a very small amount of the alcohol is converted into an
aldehyde at any given time. The ruthenium-promoted
removal of hydrogen from the alcohol generates very
low amounts of aldehydes in-situ, which leads to the
formation of the target quinoline.
2
003, 24, 1026–1028; w) C. S. Cho, B. T. Kim, H.-J.
Choi, T.-J. Kim, S. C. Shim, Tetrahedron 2003, 59, 7997–
002; x) C. S. Cho, B. T. Kim, T.-J. Kim, S. C. Shim,
8
Chem. Commun. 2001, 2576–2577; y) Y. Hsiao, N. R.
Rivera, N. Yasuda, D. L. Hughes, P. J. Reider, Org.
Lett. 2001, 3, 1101–1103; z) C. S. Cho, B. H. Oh, J. S.
Kim, T.-J. Kim, S. C. Shim, Chem. Commun. 2000,
1
885–1886.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

UPDATES
8
A Mild and Efficient Synthesis of Substituted Quinolines
via a Cross-Dehydrogenative Coupling of (Bio)available
Alcohols and Aminoarenes
Adv. Synth. Catal. 2015, 357, 1 – 8
Manuel G. Mura, Suvi Rajamꢀki, Lidia De Luca,
Elena Cini, Andrea Porcheddu*
8
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!