Synthesis of novel 3,4,6-trisubstituted quinolines enabled by a Gould-Jacobs cyclization

Article abstract of DOI:10.1016/j.tetlet.2017.01.042

A Gould-Jacobs cyclization enabled the synthesis of several novel, so far undescribed 3,4,6-trisubstituted quinoline derivatives. They all bear substituents which are well-suited for further transformations, e.g. carboxylic acid or ester functions, haloge

Full text of DOI:10.1016/j.tetlet.2017.01.042

Accepted Manuscript
Synthesis of novel 3,4,6-trisubstituted quinolines enabled by a Gould-Jacobs
cyclization
Stephan Trah, Clemens Lamberth
PII:
S0040-4039(17)30064-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.042
TETL 48545
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 December 2016
8 January 2017
13 January 2017
Please cite this article as: Trah, S., Lamberth, C., Synthesis of novel 3,4,6-trisubstituted quinolines enabled by a
Gould-Jacobs cyclization, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.042
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2
Synthesis of novel 3,4,6-trisubstituted quinolines enabled by a Gould-Jacobs
cyclization
Stephan Trah and Clemens Lamberth
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstr. 101, CH-4332 Stein, Switzerland
ABSTRACT
A Gould-Jacobs cyclization enabled the synthesis of several novel, so far undescribed 3,4,6-trisubstituted quinoline derivatives. They all bear
substituents which are well-suited for further transformations, e.g. carboxylic acid or ester functions, halogens, terminal alkynes and hydroxyl
groups. The synthesis of a highly active 3,4-disubstituted quinolin-6-yloxyacetamide fungicide gives proof of the manifold manipulations which are
possible with these interesting heterobicyclic building blocks.
Keywords:
Quinoline
Heterocycle
Fungicide
Gould-Jacobs reaction
Cyclization
Quinoline and its derivatives not only represent one of the longest known and most published heterobicyclic systems,1,2 many
compounds bearing this scaffold have been reported to have pronounced biological activities, e.g. against cancer,3,4 tuberculosis,5
malaria6 and inflammation.7 Recently, we have reported on quinolin-6-yloxyacetamides as a new class of experimental fungicides
with excellent activity against a broad range of phytopathogens from the group of Ascomycetes and Oomycetes, such as
Phytophthora infestans, the causal agent of potato and tomato late blight, Mycosphaerella graminicola, the causal agent of wheat
leaf blotch and Uncinula necator, the causal agent of grape powdery mildew.8 Their fungicidal activity is due to their ability to
inhibit the fungal tubulin polymerization, leading to microtubule destabilization. Typical examples of these quinolin-6-
yloxyacetamides bear either one additional substituent in quinoline position 3, such as 1, or two different substituents in positions 3
and 8, such as 2.8 The recent finding, that one of the ring carbons in 1 and 2 could be replaced by a nitrogen atom under preservation
of the fungicidal activity9 demonstrated potential scope in different, so far unexplored ring positions of the quinoline scaffold and
prompted us to check novel substitution patterns. Based on our structure-activity relationship knowledge, 3,4-disubstituted quinolin-
6-yloxyacetamides, such as 3, seemed to be attractive target compounds, but were not accessible through the synthesis methodology
used to obtain 1 and 2 (Figure 1).
1
2
3
 Corresponding author. Tel.: +41-62-866-0224; fax: +41-62-866-0860; e-mail: clemens.lamberth@syngenta.com

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Figure 1. Fungicidally active quinolin-6-yloxyacetamides with different quinoline substitution pattern.
The quinoline core of all so far prepared 3- and 3,8-substituted quinolin-6-yloxyacetamides8,10 has been built via a Skraup-type
condensation of an appropriate aniline with 2,2,3-tribromopropanal,11 however, this reaction is not applicable to the synthesis of
their 3,4-disubstituted equivalents as the pyridine moiety is formed by the tribrominated aldehyde which only delivers a bromo
substituent in position 3 of the newly formed quinoline. Besides the mentioned Skraup/Doebner-Miller reaction,12 there are also
several other methods known for the construction of the quinoline scaffold, such as the synthesis approaches named after
Friedländer,13 Niementowski,14 Combes,15 Povarov,16 Pfitzinger,17 Conrad-Limpach18 and Gould-Jacobs.19 Especially the latter
reaction seemed attractive for our purpose as this transformation of an aniline with an alkoxymethylenemalonic ester usually
delivers a quinolin-4-ol which offers many options for the introduction of an additional substituent in position 3 and for the
derivatization of the hydroxyl function in position 4. The Gould-Jacobs quinoline cyclization is a versatile tool which has been
recently applied to the synthesis of complex active ingredients, such as bosutinib,20 ivacaftor21 and ethyl nalidixate.22 In this paper
we describe how a Goud-Jacobs reaction enabled the synthesis of a whole series of novel 3,4,6-trisubstituted quinolines.
We identified ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (6) as suitable building block for the further derivatization into
the desired trisubstituted quinolines. The synthesis of 6 has been described starting from diethyl ethoxymethylenemalonate (4) by
conversion with p-anisidine to the intermediate imine 5 and subsequent Gould-Jacobs cyclization to the quinoline derivative 6.23-26
Saponification of the ester 6 delivered the carboxylic acid 7 which gave by decarboxylation 4-hydroxy-6-methoxyquinoline (8).26
The regioselective introduction of a bromine atom into position 327,28 of 8 did not only deliver the novel 3,4,6-trisubstituted
quinoline 9, but was even more the entry to several further analogs with the same substitution pattern, as all three substituents of 9,
the halogen atom in position 3, the hydroxyl function in position 4 and the methoxy group in position 6 can be easily transformed
into other rests. The replacement of the hydroxyl group by a chlorine atom, for example, led to 10, which was converted with boron
tribromide to the dihalogenated quinolinol 11. On the other side it was also possible to reach further 3,4,6-trisubstituted quinolines
from the intermediate 6 by keeping the ester function in the molecule. Also here the hydroxyl function in position 4 could be
replaced by a chloro substituent ( 12), which in turn was exchanged by a thiomethyl group ( 13), before it finally made place
for a methylamine function ( 14). Ester saponification of 14 delivered the novel heterocyclic -amino acid derivative 15 (Scheme
1).
(Ph)2O,
3 h
250 oC
POCl3
2 h,
reflux
4-MeOPhNH2,
120 oC
41 %
100 %
98 %
4
6
12
NaSMe,
DMF,
1 h, rt
5
2 N NaOH,
1.5 h, 90 oC
95 %
99 %
(Ph)2O,
2 h
250 oC
NBS, AcOH,
3 h, rt
100 %
89 %
9
8
13
7
MeNH2,
EtOH,
POCl3,
2 h,
90 %
95 %
16 h, rt
reflux
2 N NaOH,
1.5 h, reflux
BBr3, CH2Cl2,
18 h, rt
82 %
84 %
11
10
15
14

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Scheme 1. Synthesis of diverse 3,4,6-trisubstituted quinolines.
The regioselective bromination of 7 with N-bromosucccinimide in warm glacial acetic acid which afforded 9, could be extended
to the use of N-iodosuccinimide, leading to 16. The following two manipulations, the exchange of the hydroxyl function by a chloro
substituent and the ether cleavage of the methoxy group, shifted the hydroxyl function from position 4 ( 16) to position 6 ( 18).
This phenolic function was then alkylated with methyl 2-chloro-2-(methylsulfanyl)acetate to deliver the mixed O,S acetal 19. Ester
saponification and conversion of the resulting carboxylic acid 20 with tert-butyl amine under peptide coupling conditions delivered
the amide 21, which displays potent fungicidal activity against species of three major fungal classes, e.g. Colletotrichum orbiculare,
the causal agent of antracnosis on several crop species, from the Ascomyctoa; Plasmopara viticola, the causal agent of grape downy
mildew, from the Oomycota and Puccinia recondita, the causal agent of brown rust on cereals, from the Basidiomycota. However,
from our structure-activity relationship experience with related 3-substituted quinolin-6-yloxyacetamides we assumed that an
ethylene group in place of the iodo substituent in position 3 would deliver the even better efficacy. Therefore we converted 21 in a
transition metal-catalyzed Sonogashira coupling with trimethylsilylacetylene to the silylated alkyne derivative 22, which upon
deprotection delivered the desired 3-ethynyl-4-chloro-substituted quinolinyl-6-oxyacetamide 3 (Scheme 2). This compound fully
controlled the economically important phytopathogens Botryotinia fuckeliana, the causal agent of gray mold on several crop
species, Monographella nivalis, the causal agent of cereal foot rot and the above mentioned M. graminicola at the low concentration
of 2 ppm.
NIS, AcOH,
3h, rt
POCl3,
1 h, reflux
BBr3, CH2Cl2,
22 h, rt
92 %
91 %
74 %
8
18
16
17
ClCH(SMe)CO2Me,
K2CO3, DMF,
16 h, rt
77 %
HOAt, EDCI,
tBuNH2,NEt3,
DMF, 16 h, rt
2 N NaOH,
EtOH, 2 h, rt
97 %
74 %
21
20
19
PdCl2(PPh3)2,
CuI, iPr2NH,
THF, 1 h, rt
83 %
1 N KOH, MeOH,
45 min, rt
86 %
22
3

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Scheme 2. Synthesis of the 3,4-disubstututed quinolin-6-yloxyacetamide fungicide 3.
In conclusion, we have worked out a synthesis pathway to a whole range of so far unknown quinoline derivatives. All 3,4,6-
trisubstituted quinoline described in this article, except 6 and 7, are new and did not appear in the chemical literature so far. All of
these 15 novel heterobiyclic compounds bear functional groups which are well-suited for further transformations, e.g. carboxylic
acid or ester functions, halogen substituents, terminal alkynes and hydroxyl groups either introduced by the Gould-Jacobs ring
closure reaction or formed by the cleavable of ethers. One of these many possible manipulations led to the synthesis of 3,4-
disubstituted quinolin-6-yloxyacetamide fungicides such as 3, which could not be prepared via the Skraup-type approach used to
obtain its analogs 1 and 2 without any substituent in position 4.
Acknowledgements
The authors gratefully acknowledge the excellent synthetic contributions of Antonietta Crisante, Thomas Fischer and Nadja
Kirchmair.
Supplementary data
Supplementary data (experimental details and spectroscopic data for compounds 3, 5 - 22) associated with this article can be found
in the online version.
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Synthesis of novel 3,4,6-trisubstituted quinolines
enabled by a Gould-Jacobs cyclization
Stephan Trah, Clemens Lamberth
Gould-Jacobs product

8
Highlights




15 previously unpublished 3,4,6-trisubstituted quinoline derivatives are described
They all could be prepared from one Gould-Jacobs cyclization product
They all bear substituents which are well-suited for further transformations
The synthesis of 3,4-disubstituted quinolin-6-yloxyacetamide fungicides is described

9
1
2
3
Figure 1. Fungicidally active quinolin-6-yloxyacetamides with different quinoline substitution pattern.
(Ph)2O,
3 h
POCl3
2 h,
reflux
4-MeOPhNH2,
120 o
250 o
C
C
41 %
100 %
98 %
4
6
12
NaSMe,
DMF,
1 h, rt
5
2 N NaOH,
1.5 h, 90 o
95 %
99 %
C
(Ph)2O,
NBS, AcOH,
3 h, rt
2 h
250 o
C
100 %
89 %
9
8
13
7
MeNH2,
EtOH,
POCl3,
2 h,
90 %
95 %
16 h, rt
reflux
2 N NaOH,
1.5 h, reflux
BBr3, CH2Cl2,
18 h, rt
82 %
84 %
11
10
15
14
Scheme 1. Synthesis of diverse 3,4,6-trisubstituted quinolines.

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Scheme 2. Synthesis of the 3,4-disubstituted quinolin-6-yloxyacetamide fungicide 3.
NIS, AcOH,
3h, rt
POCl3,
1 h, reflux
BBr3, CH2Cl2,
22 h, rt
92 %
91 %
74 %
8
18
16
17
ClCH(SMe)CO2Me,
K2CO3, DMF,
16 h, rt
77 %
HOAt, EDCI,
tBuNH2,NEt3,
DMF, 16 h, rt
2 N NaOH,
EtOH, 2 h, rt
97 %
74 %
21
20
19
PdCl2(PPh3)2,
CuI, iPr2NH,
THF, 1 h, rt
83 %
1 N KOH, MeOH,
45 min, rt
86 %
22
3