Chelation-assisted de-aryloxylative amination of 2-aryloxy quinolines: A new synthetic route to a key fragment of a bioactive PRMT5 inhibitor

Article abstract of DOI:10.1039/c8ob00911b

A highly regioselective de-aryloxylative amination of O- or N-chelating group-functionalized 2-aryloxy quinolines has been accomplished by means of a copper catalyst. The chelating functional groups of the substrate play a crucial role in directing the C-

Full text of DOI:10.1039/c8ob00911b

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Chelation-assisted de-aryloxylative amination of
2-aryloxy quinolines: a new synthetic route to a
key fragment of a bioactive PRMT5 inhibitor†
Cite this: DOI: 10.1039/c8ob00911b
Received 18th April 2018,
Accepted 2nd May 2018
Aniket Gupta, Jogendra Kumar and Sukalyan Bhadra
*
DOI: 10.1039/c8ob00911b
rsc.li/obc
A
highly regioselective de-aryloxylative amination of O- or the electrophilic coupling partner primarily due to the environ-
N-chelating group-functionalized 2-aryloxy quinolines has been mentally benign character, natural abundance, and easy acces-
accomplished by means of a copper catalyst. The chelating func- sibility of phenols and their derivatives.7 Typically, the C(aryl)–
tional groups of the substrate play a crucial role in directing the O bonds of unactivated aryl ethers are regioselectively functio-
C-2-selective amination process, which proceeds through a novel nalized by various Ni catalysts,7a–h and a few Rh, Pd or Cu cata-
aromatic nucleophilic substitution of the aryloxy group. The meth- lysts,8 with noteworthy exceptions of using harsh acidic9 or
odology provides expedient access to an important class of func- basic10 conditions and recently developed Nicewicz’s mild and
tionalized 2-aminoquinolines (up to 88% isolated yield) and was efficient organic photoredox catalysis.11 However, none of
successfully applied for the synthesis of a key fragment of an these approaches address the underlying challenges to functio-
important bioactive PRMT5 inhibitor.
nalize the C(aryl)–O bond of 2-alkoxy/aryloxyquinolines.6b In
this paper, we describe a new approach for the de-aryloxylative
amination of unactivated 2-aryloxy quinolines that proceeds
C-2-aminated quinolines, particularly embracing 8-hydroxy- or
8-amino-substituents, are ubiquitous in a broad range of phar-
maceutically active compounds and functional materials
(Fig. 1).1 In addition, these molecules have been used both as
efficient ligands in metal-catalyzed transformations and
organocatalysts.2 Thus, the development of catalytic methods
leading to these molecules are of fundamental importance.
Traditionally, these molecules are synthesised via metal-cata-
lyzed cross-coupling reactions or nucleophilic substitution
reactions between 2-haloquinolines and an amine.1,3,4 These
rather employ harsh reaction conditions and activated quino-
line substrates, making them unsuitable for the late-stage
functionalization of complex molecules. Modern amination
techniques involving inert C–H or C–O bond activation are
also restricted to a limited number of N-heteroarene sub-
strates.5,6 Thus, a powerful, efficient and convenient C-2 amin-
ation technique allowing for the straightforward synthesis of
via
reaction.
We postulated that if the hydroxy- or amine-function of a
a unique chelation-assisted nucleophilic substitution
quinoline nucleus exists in an appropriate arrangement with
the N-heteroatom and the 2-alkoxy/aryloxy substituent, it
would immediately bind to a metal catalyst forming a metalla-
2-amino-8-hydroxyquinoline-
and
2,8-diaminoquinoline-
derivatives has appeared as a longstanding problem for syn-
thetic organic chemists and needs an urgent solution.
In recent years, the use of aryl ethers has emerged as an
attractive replacement to the frequently used aryl halides as
Inorganic Materials and Catalysis Division, Academy of Scientific and Innovative
Research, CSIR-Central Salt and Marine Chemicals Research Institute, G.B. Marg,
Bhavnagar 364002, Gujarat, India. E-mail: sbhadra@csmcri.res.in
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob00911b
Fig. 1 Selected examples illustrating the significance of 2-amino-8-
hydroxyquinolines and 2,8-diaminoquinolines.
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Table 1 Identification of the appropriate aryl ether for the C-2-selec-
tive aminationa
Scheme 1 Chelation-assisted
C-2-selective
ipso-amination
of
N-heteroaryl ethers.
Entry
1
Substrate
MX2
8 (%)
8a (0)
cycle intermediate, which concurrently facilitates C(aryl)–O
bond cleavage and the nucleophilic attack by an amine at the
relatively electrophilic C-2-position (Scheme 1). This C-2 amin-
ation strategy would also avoid the stoichiometric use of waste-
intensive halide precursors.7e Herein, we report the chelation-
assisted C-2-selective ipso-amination of hydroxy or amine-func-
tionalized 2-aryloxy quinoline derivatives by means of a copper
catalyst.
Cu(OTf)2
2
Cu(OTf)2
PdCl2
NiBr2
Mg(OTf)2
CuBr2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
8a (85)
8a (21)
8a (0)
8a (0)
8a (25)
8a (68)
8a (84)b
8a (80)c
8a (41)d
8a-1 (0)
To probe the viability of this approach, we started investi-
gating the regiospecific C-2-amination of various 8-hydroxy-
quinoline derived ethers using Cu(OTf)2 as a Lewis acid cata-
lyst (Table 1 and Table S1, ESI†).12 Thus, the amination of
2-methoxy-8-hydroxyquinoline with piperidine was conducted
in the presence of 20 mol% Cu(OTf)2 in DMF at 120 °C.
However, this reaction did not proceed to give the desired ami-
nated product (Table 1, entry 1). Gratifyingly, when 2-phenoxy-
8-hydroxyquinoline 2 was subjected to the amination with
piperidine under identical reaction conditions, the desired C-2
aminated product was formed in high yield (85%) (entry 2).
Soon it turned out that the amination could also be oper-
ational at a lower catalyst loading (10 mol%) and at a tempera-
ture as low as 70 °C. Further alteration of the reaction para-
meters, such as temperature, solvent etc. did not lead to the
complete conversion of the substrate even after a prolonged
period. Other metal catalysts including PdCl2, NiBr2, Mg(OTf)2
and other copper salts remained ineffective for this transform-
ation (entry 2 and Table S1, ESI†). As expected, the C-2 selec-
tive amination was not functional for 2-phenoxy-8-methoxyqui-
noline (3), 2-phenoxyquinoline (4), and 2-phenoxy-6-hydroxy-
quinoline (5) indicating the anchoring effect of the free
hydroxy function of the substrate (entries 3–5). An attempted
3
4
5
6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
8a-2 (0)
8a-3 (0)
8a-4 (0)
a Reaction conditions: 1–6 (0.15 mmol), piperidine (0.75 mmol), MX2
(20 mol%), DMF (2.5 mL), 120 °C, 16 h; isolated yields of pure pro-
ducts. b 10 mol% Cu(OTf)2. c 70 °C. d r.t., 36 h.
C-4-selective dearyloxylative amination of 4-phenoxy 8-hydroxy- to proceed with primary amines, imidazole and aniline-deriva-
quinoline (6) also failed to proceed, demonstrating the obliga- tives under the optimized reaction conditions. Although
tory requirement of the 2-aryloxy substituent for this reaction primary amines remained ineffective to afford the corres-
(entry 6).
ponding secondary amines, we were delighted to find that an
With an effective reaction system in hand, we subsequently intended secondary amine 9 can be simply accessed via hydro-
studied the scope of the amination of 2-phenoxy-8-hydroxy- genolysis of the benzylated tertiary amine product 8h.
quinoline with regard to the amine nucleophiles. As can be seen
We further examined the scope of the amination with
in Scheme 2, a diverse range of secondary amines was success- respect to various 2-aryloxy-8-hydroxyquinolines (Scheme 3). It
fully introduced at the C-2 position of the hydroxyquinoline appeared that 20 mol% Cu(OTf)2 was necessary to improve the
nucleus via the new amination method (8a–8i). Both cyclic yield of the aminated products under otherwise identical reac-
amines with varied ring size and different substitution pat- tion conditions (Table S2, ESI†). 8-Hydroxyquinolines bearing
terns (8a–8e), as well as acyclic N,N-dialkyl amines (8f–8i) were either an electron-withdrawing or -donating aryloxy leaving
successfully coupled with 2-phenoxy-8-hydroxyquinoline fur- group were found to be consistently functional under the opti-
nishing the corresponding C-2 aminated products in a practi- mized reaction conditions (10–12). An additional N-chelating
cally useful yield. However, the C-2-selective amination failed group in the aryloxy leaving group can be used (13–15).
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Scheme 2 Scope of the C-2-selective amination with regard to
amines. Reaction conditions: 2 (0.15 mmol), amine (7a–7i) (0.75 mmol),
Cu(OTf)2 (10 mol%), DMF (2.5 mL), 16 h; isolated yields of pure products.
a 1.5 equiv. of Cs2CO3 were used as an additive. b 20 mol% Cu(OTf)2.
c H2-balloon. 10 wt% Pd–C (180 mg mmol−1), MeOH, r.t., 24 h. d 72 h.
Various functional groups in the quinoline nucleus were also
tolerant to the reaction conditions of the amination process to
furnish the corresponding C-2-aminated 8-quinolinol deriva-
tives regioselectively (Scheme 3B). Notably, competitive C–N
cross-couplings at the C–Br and C–Cl bonds were completely
suppressed (11, 8a-8 and 8a-9). These C–Br and C–Cl bonds
are expected to be replaced by a nucleophile under otherwise
developed metal-catalyzed cross-coupling and/or nucleophilic
substitution reaction conditions of the corresponding 2-halo-
quinoline. The C-2 amination was regiospecific in all cases; no
other nucleophilic addition/substitution product at the quino-
line ring was detected and the corresponding phenol was
obtained as the single by-product.13 Importantly, the reaction
system is robust and does not employ any anhydrous con-
ditions or an inert atmosphere.
Scheme 3 Scope of the C-2-selective amination with regard to
2-aryloxy 8-hydroxyquinolines. Reaction conditions: Substrate (10–20)
(0.15 mmol), piperidine (0.75 mmol), Cu(OTf)2 (20 mol%), DMF (2.5 mL),
120 °C, 16 h; isolated yields. a 10 mol% Cu(OTf)2. b 36 h.
In order to establish the general synthetic applicability of
this new approach, we further expanded the substrate scope of
our de-aryloxylative amination to 8-aminoquinoline and 1,10-
phenanthroline derived ethers (Scheme 4). In all cases, the
desired C-2 aminated products (21a–25a) were formed in mod-
erate to good yields. However, when 2-phenoxy 8-mercapto-
quinoline was subjected to amination with piperidine, it led to
a complicated reaction mixture and could not produce the
desired aminated compound 26a under the optimized reaction
conditions.
Scheme 4 C-2-selective amination of 2-phenoxy 8-amino/8-mercapto-
quinolines. Reaction conditions: Substrate (21–26) (0.15 mmol), piper-
idine (0.75 mmol), Cu(OTf)2 (20 mol%), DMF (2.5 mL), 120 °C, 24 h; iso-
lated yields. a 36 h. b THF, 70 °C, 16 h. Ts = p-toluenesulfonyl; Ms =
To shed light on the reaction mechanism, a series of experi-
ments were conducted (see the ESI†). The presence of a radical Methanesulfonyl.
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scavenger 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) (1.5 yield via a base-mediated O-alkylation process within a single
equiv.) could not alter the rate of the reaction, thus precluding reaction step (Scheme 5). Compound 27, thus obtained, can be
the involvement of the radical steps. A reaction pathway con- successively converted into the desired PRMT5 inhibitor by
sisting of dephenoxylation of 2 and a subsequent C–H amin- means of a known literature procedure.1f
ation of the resulting compound was excluded as 8-hydroxyqui-
noline could not be converted into 8a under the optimized
conditions.14,15
Conclusions
When 1 equiv. of 2 was heated with 1 equiv. of Cu(OTf)2 in
In conclusion, we have developed a regiospecific C-2 selective
DMF at 120 °C for 5 h prior to the addition of 5 equiv. of piper-
amination of 2-aryloxy quinolines via chelation assistance.
idine, 8a was produced in the expected yield; however, when 2
This dearyloxylative transformation represents a rare example
was added to a preheated equimolar mixture of Cu(OTf)2 and
of an aromatic nucleophilic substitution reaction giving expe-
piperidine in DMF at 120 °C, 8a was not formed (see the ESI†).
Furthermore, substrates 3, 4, and 5 that cannot form a cupra-
cycle intermediate via chelation assistance do not undergo the
title reaction. These findings indicate that the copper complex,
dient access to 2-aminoquinolines starting from the corres-
ponding aryl ethers. The synthetic utility of the amination
process has been demonstrated by achieving the key fragment
of a bioactive PRMT5 inhibitor. To the best of our knowledge,
which is formed by the reaction between the substrate and the
this is the first instance, in which the chelating interaction
Cu catalyst, facilitates the amine to attack at the relatively elec-
between the substrate and the catalyst in promoting a C(aryl)–O
trophilic C-2 position of the quinoline nucleus, and rule out
bond functionalization has been accomplished. Thus, this
method opens up new avenues in the field of “substrate
directed organic synthesis”.17
the involvement of
a
copper-mediated amine-transfer
process.15 Furthermore, the initially formed substrate–copper
complex may favourably be stabilized via an ortho-cupration of
the phenoxy leaving group.16 The ortho-cupration event is also
supported by the fact that 2-methoxy 8-hydroxyquinoline 1 and
4-phenoxy 8-hydroxyquinoline 6 could not be aminated at the
C-2 and C-4 positions, respectively, under the optimized con-
ditions. All these findings are in accord with the feasibility of
an SNAr pathway. An excess of piperidine possibly acts as a
bifunctional mediator to accelerate the rate of the title reaction
(see Table S1, ESI†).6a
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Finally, to demonstrate the synthetic utility of this dearylox-
ylative amination approach in the synthesis of complex struc-
tures, the synthesis of a key fragment of a bioactive PRMT5
inhibitor 27 has been exemplified using one of our C-2 ami-
nated products 8c as the precursor. This PRMT5 inhibitor is
capable of preventing the activity of PRMT5 and thereby helps
to prevent the associated diseases, such as proliferative dis-
orders, metabolic disorders, and blood disorders. We were
delighted to find that 8c was readily converted into 27 in high
This work has been supported by the DST-INSPIRE Faculty
Award, Govt. of India to SB (Grant no. DST/INSPIRE/04/2015/
002248). AG and JK acknowledge DST-INSPIRE and UGC,
respectively, for their fellowships. We are grateful to the
“Analytical and Environmental Science Division and
Centralized Instrument Facility” of CSIR-CSMCRI for providing
instrument facilities. CSIR-CSMCRI communication no. 156/
2017.
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