A Modular Synthesis of 4-Aminoquinolines and [1,3] N-to-C Rearrangement to Quinolin-4-ylmethanesulfonamides

Article abstract of DOI:10.1021/acs.orglett.7b01701

A copper-catalyzed regiocontrolled three-component reaction afforded diversified 4-aminoquinolines using nitriles, diaryliodoniums, and ynamides. The C7-substituted regioisomers were formed regioselectively when meta-substituted phenyliodonium salts were used. [1,3] N-to-C rearrangement of the products to quinolin-4-ylmethanesulfonamides and simultaneous deprotection of benzyl and sulfonamide group were newly developed. Finally, antimalarial CK-2-68 was successfully prepared.

Full text of DOI:10.1021/acs.orglett.7b01701

Letter
pubs.acs.org/OrgLett
A Modular Synthesis of 4‑Aminoquinolines and [1,3] N‑to‑C
Rearrangement to Quinolin-4-ylmethanesulfonamides
Kyung Hwan Oh, Jin Gyeong Kim, and Jin Kyoon Park*
Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 609-735, Korea
S
* Supporting Information
ABSTRACT: A copper-catalyzed regiocontrolled three-component
reaction afforded diversified 4-aminoquinolines using nitriles, diary-
liodoniums, and ynamides. The C7-substituted regioisomers were
formed regioselectively when meta-substituted phenyliodonium salts
were used. [1,3] N-to-C rearrangement of the products to quinolin-4-
ylmethanesulfonamides and simultaneous deprotection of benzyl and
sulfonamide group were newly developed. Finally, antimalarial CK-2-
68 was successfully prepared.
alaria remains a serious parasitic infection with high
mortality rates.1 4-Aminoquinolines are known as potent
for the systematic synthesis of heterocycles.11 In this regard, we
were interested in ynamides12 and investigated the three-
component annulation of a nitrile (A), diaryliodonium salt
(B),13 and ynamide (C).14 To date, two-component cycliza-
tions have been reported to provide quinazolines (2A+B);15
2,4-diaminopyridines (A+2C),16 4-aminopyrimidines (2A
+C),17a,b 3-aminoisoquinolines (A+C),17b and 2-aminopyri-
dines (A+C);17c and 1-amino-dihydronaphthalenes (B+C).18
Therefore, three-component annulation may lead to the
mixture of N-heterocycles due to their possible combinations.
In the case of simple alkynes, however, quinolines have been
successfully prepared by the Chen group.19a Recognizing the
amphoteric property of ynamide as electrophile and nucleo-
phile12 and Chen’s previous work,19a,i we hypothesized that if
copper-catalyzed arylation of a nitrile with a diaryliodonium
salt15,19 is fast enough, nucleophilic addition with an ynamide
and subsequent cyclization could proceed smoothly to afford a
4-aminoquinoline.20 Furthermore, regioselective formation of
C-7 substituted products would be expected from the proper
substituent interaction using m-substituted phenyliodonium
salts.21 Herein, we introduce a modular [2 + 2 + 2]
cycloaddition allowing systematic functionalization of 4-amino-
quinolines and [1,3] N-to-C rearrangement to provide
quinolin-4-ylmethanesulfonamides by base treatment (Scheme
1). In comparison, in the metal-free approaches developed by
M
antimalarial drugs;2 however, some drugs such as chloroquine
and amodiaquine have posed resistance and toxicity problems.3
Although promising structural analogues such as isoquine have
received much attention,4 the limited number of systematic
synthetic approaches5 to diversify 4-aminoquinolines may have
hindered the advent of new drugs.6 Additionally, as shown in
Figure 1, the group at the C7 position has important effects on
Figure 1. Important 4-aminoquinolines and quinolin-4-ylmethane-
sulfonamide.
the association strength of hematin and pKa of the quinoline
nitrogen for antiplasmodial activities.7 Other biological
activities, such as ATM (ataxia telangiectasia mutated) and
HER (human epidermal growth factor receptor) inhibition,
have been found for functionalized 4-aminoquinoline structures
as well.8 On the other hand, sulfonamide derivatives exhibit a
broad range of biological activities and are used as antibacterial
drugs, antiviral agents, and antifungal agents since sulfa drugs
have been developed as synthetic antibiotics.9 Especially,
quinolin-4-ylmethanesulfonamides are also known to exhibit
the stress tolerance in plants to abiotic stress.10
the Movassaghi20a and Brase groups,20b two components
̈
condensed to give 4-aminoquinolines in moderate yields with
no singly meta-substituted amides.
We began the screening using CuCl and PhI(Mes)OTf in
EtOAc at 75 °C for 3 h with molecular sieves (MS) 4 Å to
prevent hydrolysis of the intermediate nitrillium salt (Table 1).
Ynamides and diaryliodonium salts were prepared according to
known methods.14c,22 During the optimization, no 3-amino-
isoquinoline side product was detected. In the absence of CuCl,
A regioselective multicomponent reaction strategy would
provide atom economy, efficiency, diversity, and step economy
Received: June 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nucleophilicity (entries 12−13). A Boc-protected ynamine gave
almost no desired product (entry 14).
With the optimum ynamide and conditions in hand, we
focused on the reaction regioselectivity and substrate
compatibility of the diaryliodonium salts (Scheme 2). o- and
Scheme 1. Regiocontrolled Modular Syntheses of 4-
Aminoquinolines and [1,3] N-to-C Rearrangement to
Quinolin-4-ylmethanesulfonamides
a
Scheme 2. Substrate Scope of Ar(Mes)IOTf
a
Table 1. Optimization of Reaction Conditions
b
entry
Cu
R1-N-R2
1:2:3
yield (%)
c
1
−
CuCl
Me-N-Ms
Me-N-Ms
Me-N-Ms
Me-N-Ms
Me-N-Ms
Me-N-Ms
Me-N-Ms
Me-N-Ms
Ph-N-Ms
1.5:1.0:1.5
1.5:1.0:1.5
1.2:1.3:1.0
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
1.0:1.2:1.3
NR
a
c
Standard reaction conditions: nitrile/iodonium salt/ynamide =
2
31
51 (39 )
c
1.0:1.2:1.3, nitrile (0.2 mmol), CuTC (10 mol %), MS 4 Å, EtOAc
3
CuCl
b
c
d
e
(0.15 M), 75 °C, 40 min. Yield at 1 mmol scale Reaction time was 7
4
CuCl
62 (52, 12 )
d
h. Yield of combined regioisomers and regioisomeric ratio
5
CuI
35
55
51
69
75
77
95
42
36
<5
determined by GC in the parentheses.
6
Cu(OAc)2
f
7
CuPF6
p-Me-substituted iodonium salts gave the desired products in
good yields (4b−c). m-Me substituted iodonium salt afforded a
single regioisomeric product (4d). However, two-electron-
releasing methoxy and amino groups strongly activate the
benzene ring toward electrophilic attack at the o-position,
giving an inseparable mixture of 4e (78:22). In particular, when
electron-withdrawing m-F- and m-Cl-substituted iodonium salts
were used, the single C7-substituted isomers (4f−g) were
obtained. This indicates that not only the steric but also the
electronic properties seem to be of influence on the
regioselectivity.21 The structure was confirmed by X-ray
analysis of 4g.24 And all p-halogen- and ester-substituted
iodonium salts provided the desired products (4h−k).25
Next, we screened the scope of ynamides and nitriles
(Scheme 3). Regardless of their electronic and steric properties,
most of the substrates afforded desired products with good to
excellent yields.25 Thiophene-substituted ynamide and alkyl
nitriles gave slightly lower yields (4u and 4af). 4m, 4o, and 4q
were isolated with almost equal amounts of atrop-diastereo-
meric mixtures, while a single product 4l was produced. A tosyl
substrate gave a lower yield (4a vs 4ah).
Then, we investigated deprotection conditions and found
unexpected simultaneous deprotection of benzyl and sulfona-
mide group with KOt-Bu under an Ar atmosphere, where base
may induce elimination to form imine.26 A 40% yield of fully
deprotected product 5a was improved to 88% when changing
Ms to the Ts group. The unknown product observed in the
case of the Ms substrate (4a) was identified as quinolin-4-
ylmethanesulfonamide 6a by X-ray analysis.24 Surprisingly, the
yield of 6a increased to 91% with LiHMDS in THF with no
formation of 5a. The reaction proceeded via deprotonation of
the Ms group and [1,3] N-to-C rearrangement through unusual
4-membered ring formation owing to the electron-deficient
quinoline ring.27 The reaction has a wide scope as shown in
8
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
9
10
11
12
Allyl-N-Ms
Bn-N-Ms
Bn-N-CO2Et
Oxazolidone
Ph-N-Boc
d
13
14
a
Reaction conditions: Cu (10 mol %), MS 4 Å, EtOAc (0.15 M), 75
b
c
d
e
°C, 3 h. NMR yield. Under 0.4 M. Ph2IOTf. Ph2IPF6.
f
[Cu(CH3CN)4]PF6 was used.
the desired reaction did not occur, as expected (entry 1). We
experimented with various ratios of the three starting materials
(1, 2, and 3) at a concentration of 0.4 M. Yields were not
satisfactory when 2 or 3 was used as the limiting reagent
(entries 2 and 3). However, the yield increased to 51% when
the concentration was decreased to 0.15 M (entry 3). The yield
increased further to 62% upon setting 1 as the limiting reagent.
The use of Ph2IOTf and Ph2IPF6, however, decreased the yield
to 52% and 12%, respectively (entry 4). Screening of the
copper catalysts revealed that CuTC (copper(I) thiophene-2-
carboxylate) provided the highest yield, 69% (entries 5−8).
Then, we tested the effect of the N-substituents of the
ynamides on the yield because their reactivities are known to be
related to the functional groups.23 To our delight, the yield
increased gradually to 95% upon changing the methyl group to
a phenyl, allyl, and benzyl (Bn) group (entries 9−11). Careful
monitoring of the reaction with the Bn-substituted ynamide
revealed that the reaction was complete to give 4a within 20
min. When a carbamate group was utilized, yields decreased
sharply. Substrates with ethyl carbamate and oxazolidone gave
42% and 36% yields, respectively, presumably owing to weak
B
DOI: 10.1021/acs.orglett.7b01701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of Ynamides and Nitriles
Scheme 5. Synthesis of CK-2-68
chlorophenyliodonium salt, nitrile 8, and ynamide 9 gave 10 in
44% yield with inseparable oxidized ynamide. Finally,
simultaneous deprotection to 11 with KOt-Bu, followed by
diazonium salt formation and hydration, afforded CK-2-68 in
68% and 71% yields, respectively.
In summary, we developed a Cu-catalyzed regiocontrolled [2
+ 2 + 2] three-component tandem reaction that provides highly
functionalized 4-aminoquinolines. m-Substituted aryliodonium
salts gave C7-substituted isomers regioselectively. To show the
utility of the transformation, we discovered [1,3] rearrangement
of the methanesulfonamide group to quinolin-4-ylmethane-
sulfonamides and simultaneous deprotection of the benzyl and
sulfonamide group and successfully prepared the active
antimalarial compound CK-2-68. We expect our synthetic
approach to provide a convenient tool for the syntheses of
valuable compounds toward useful applications.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01701.
a
b
c
Standard reaction conditions. Reaction time was 2 h. Atrop-
1
Experimental procedures, full characterization of prod-
ucts, and NMR spectra (PDF)
diastereomeric ratio determined by H NMR.
Scheme 4. Subsequent debenzylation to 7 was accomplished
with H2SO4 under O2 in 75% yield.
To demonstrate the utility of this synthetic method, we
prepared the active antimalarial compound CK-2-68,28 as
shown in Scheme 5. Three-component condensation of m-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pjkyoon@pusan.ac.kr.
ORCID
Jin Kyoon Park: 0000-0001-6768-2788
Notes
Scheme 4. Simultaneous Deprotection of Benzyl and
Sulfonamide Group and [1,3] Rearrangement
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported financially by the National Research
Foundation of Korea (NRF) funded by the Korean government
(NRF-2016R1D1A1B03933754) and the Nano Material
Development Program (NRF-2015M3A7B4070612) through
the NRF funded by the Ministry of Education, Science and
Technology (MEST). Lastly, J.K.P. thanks the Posco TJ Park
Foundation for their generous support and Professor Ok-Sang
Jung at PNU for helpful discussion for X-ray analysis.
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