Synthesis of conformationally locked analogs of quinolin-6-yloxyacetamide fungicides

Article abstract of DOI:10.1016/j.tetlet.2016.10.104

Three different synthesis pathways delivered novel tricyclic compounds which are conformationally locked analogs of quinolin-6-yloxyacetamide fungicides by cyclization of their acetal or O,S-acetal function to quinoline positions 5 or 7. Examples of the f

Full text of DOI:10.1016/j.tetlet.2016.10.104

Accepted Manuscript
Synthesis of conformationally locked analogs of quinolin-6-yloxyacetamide
fungicides
Fiona Murphy Kessabi, Renaud Beaudegnies, Laura Quaranta, Clemens
Lamberth
PII:
S0040-4039(16)31437-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.104
TETL 48274
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
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6 September 2016
26 October 2016
27 October 2016
Please cite this article as: Murphy Kessabi, F., Beaudegnies, R., Quaranta, L., Lamberth, C., Synthesis of
conformationally locked analogs of quinolin-6-yloxyacetamide fungicides, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.10.104
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Tetrahedron Letters
Synthesis of conformationally locked analogs of quinolin-6-yloxyacetamide
fungicides
Fiona Murphy Kessabi, Renaud Beaudegnies, Laura Quaranta and Clemens Lamberth
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstr. 101, CH-4332 Stein, Switzerland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Three different synthesis pathways delivered novel tricyclic compounds which are
conformationally locked analogs of quinolin-6-yloxyacetamide fungicides by cyclization of their
acetal or O,S-acetal function to quinoline positions 5 or 7. Examples of the fused ring systems of
[1,3]oxathiano[6,5-g]quinoline and [1,3]oxathiocino[6,7-f]quinoline, which have been unknown
to the chemical literature before, are herein reported for the first time.
Available online
Keywords:
quinoline
2009 Elsevier Ltd. All rights reserved.
heterocycle
fungicide
Claisen rearrangement
cyclization
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 late blight, Mycosphaerella
graminicola, the causal agent of wheat leaf blotch and Uncinula
necator, the causal agent of grape powdery mildew.1 Their
fungicidal activity is due to their ability to inhibit the fungal
tubulin polymerization, leading to microtubule destabilization.
Typical examples of this compound class are compounds, in
which either a O,S-acetal as in 1 or an acetal as in 2 serves as
two-atom spacer between the position 6 of a quinoline ring
system and a carboxamide function. The recent finding, that the
O,S-acetal of 1 could be reverted (oxygen and sulfur atoms
changing place) or replaced by a dithioacetal via a Newman-
Kwart-type synthesis approach under preservation of the
fungicidal activity demonstrated potential scope in this linker
area of the molecule.2 Therefore we planned to introduce some
new structural elements into this part of the scaffold. An idea
which immediately came to our mind was to freeze the flexible
conformation of the acetal linker by annulation to the quinoline
ring system. As demonstrated by target compounds 3 and 4, both
quinoline positions 7 ( 3) and 5 ( 4) offer the possibility to
tight the O,S-acetal or the acetal back to the benzene ring of the
quinoline bicycle. The concept of reducing the conformational
flexibility of a biologically active compound by freezing a certain
conformation through a ring closure reaction, leading to so-called
conformationally locked analogs with often increased binding
affinity to the target, is well-known in the pharmaceutical and
synthesis of conformationally locked analogs of quinolin-6-
yloxyacetamide fungicides and describe the very first examples
of the so far unknown tricyclic ring systems of
[1,3]oxathiano[6,5-g]quinoline
f]quinoline.
and
[1,3]oxathiocino[6,7-
Figure 1. Conformationally locked analogs 3 and 4 of
quinolin-6-yloxyacetamide fungicides 1 and 2.
The synthesis of the [1,3]oxathiano[6,5-g]quinoline derivative
3 started from commercially available 2-hydroxy-5-nitrobenzyl
bromide (5), which was converted with thiourea into the benzyl
imidothiocarbamate 6.7 Under basic conditions the
thiopseudourea function of 6 could be cleaved to obtain the
benzylmercaptan 7.8 Both phenol and thiol functions of 7 were
then cylized with ethyl glyoxylate to the 1,3-benzoxathian
agrochemical lead optimization.3-6 In this paper we report the
———
 Corresponding author. Tel.: +41-62-866-0224; fax: +41-62-866-0860; e-mail: clemens.lamberth@syngenta.com

2
Tetrahedron Letters
derivative 8. 2-Substituted 1,3-benzoxathians have found
application as isovanillyl sweeteners,9-11 but also as antioxidants12
and insecticides.13 However, so far a 1,3-benzoxathian derivative
with a carboxyl function in position 2, such as 8, has never been
described. Ester saponification of 8 and subsequent amidation
with tert-butylamine delivered amide 10. The reduction of the
nitro function under Bechamp conditions afforded the 6-amino-
1,3-benzoxathian 11. This intermediate could be directly
converted by a special Skraup-type cyclization with 2,2,3-
tribromopropanal, which we have worked out recently,14 into the
desired [1,3]oxathiano[6,5-g]quinoline 3, a conformationally
locked analog of lead structure 1, in which the methylsulfanyl
function has been cyclized to position 7 of the quinoline.
Scheme 1. Synthesis of the [1,3]oxathiano[6,5-g]quinoline
derivative 3.
Scheme 2. Synthesis of the [1,4]dioxano[2,3-f]quinoline
derivative 4.
The synthesis of target compound 4, in which the acetal bridge
has been tied back to position 5 of the quinoline, followed a
completely different strategy. Here, we started from 3-bromo-
quinolin-6-ol (12), which can be prepared in only two steps by
Another
5,6-annulated
O,S-acetal
mimic,
the
dihydro[1,3]oxathiocino[6,7-f]quinoline derivative 22, was
prepared in a completely different manner. O-allylation of 3-
bromo-8-methylquinolin-6-ol 1614 and subsequent regioselective
thermal Claisen rearrangement of the allyl ether delivered the
tetrasubstituted quinoline 18. Radical addition of thioacetic acid
to the alkene function17,18 transformed the allyl group of 18 into
the S-3-(5-quinolinyl)propyl thioacetate 19. After cleavage of the
thioester under basic conditions, the aromatic hydroxyl group and
the aliphatic mercaptan function can be cyclized with methyl
dichloroacetate to the desired dihydro[1,3]oxathiocino[6,7-
f]quinoline 20. So far compounds with this unique tricyclic
scaffold have not been described in the literature. Saponification
of the methyl ester in 20 to the free acid 21 and subsequent
amidation delivered the conformationally locked analog 22 of the
O,S-acetal derivative 3.
Skraup
cyclization
from
4-nitroaniline
and
2,2,3-
tribromopropanal.14 The introduction of a second phenol function
was achieved by oxidation with 2-iodoxybenzoic acid (IBX).14
Both hydroxyl groups of the resulting 13 were then ring-closed
with methyl 2,3-dibromopropanoate to the [1,4]dioxano[2,3-
f]quinoline 14. Compounds with this tricyclic ring system are
found in experimental compounds of several different medicinal
chemistry indications. The most prominent examples of a drug
candidate with such a scaffold are the dual SSRI/5-HT1A
antagonists WAY-25375215 and WAY-262398.16 Ester
saponification of delivered the carboxylic acid 15, which was
transformed into the tert-butyl amide 4, a conformationally
locked analog of the quinolin-6-yloxyacetamide 2.
Scheme 3. Synthesis of the dihydro[1,3]oxathiocino[6,7-
f]quinoline derivative 22.
In conclusion, we have developed three different methods for
the synthesis of conformationally locked analogs of quinolin-6-
yloxyacetamide fungicides, which have their acetal or O,S-acetal
function tied back to the neighboring positions of quinoline ring.

Acknowledgements
Supplementary data (experimental details and spectroscopic
data for compounds 3 - 22) associated with this article can be
found in the online version.
The authors gratefully acknowledge the excellent synthetic
contributions of Thomas Grether and Thomas Steffen.
Supplementary data
10. Bassoli, A.; Merlini, L.; Morini, G.; Vedani, A. J. Chem. Soc.
Perkin Trans. 2 1998, 1449-1454.
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Perkin Trans 1 1993, 1359-1366.
References and notes
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2009/127514 ; Chem. Abstr. 2009, 151, 493948.
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Patent Application EP 525877; Chem. Abstr. 1993, 119, 95537.
14. Lamberth, C. ; Murphy Kessabi, F.; Beaudegnies, R.; Quaranta,
L.; Trah, S.; Berthon, G.; Cederbaum, F.; Vettiger, T.; Prasanna,
CS Synlett 2014, 25, 858-862.
15. Nikitenko, A.; Evrard, D.; Sabb, A. L.; Vogel, R. L.; Stack, G.;
Young, M.; Lin, M.; Harrison, B. L.; Potoski, J. R. Org. Process
Res. Dev. 2008, 12, 76-80.
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Synthesis of conformationally locked analogs
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Fiona Murphy Kessabi, Renaud Beaudegnies, Laura Quaranta, Clemens Lamberth

4
Tetrahedron
Highlights

Three different methods for the synthesis of conformationally locked quinoil-6-yloxyacetamide fungicides
are described



The O,S-acetal of the lead compounds has been tied back to the adjacent quinoline positions 5 or 7
First examples with a [1,3]oxathiano[6,5-g]quinoline scaffold are described
First examples with a [1,3]oxathiocino[6,7-f]quinoline scaffold are described