Direct diversification of unmasked quinazolin-4(3: H)-ones through orthogonal reactivity modulation

Article abstract of DOI:10.1039/c7cc05794f

Here we report a set of direct functionalization methods of unmasked 2-phenylquinazolin-4(3H)-ones, a privileged alkaloid core, without the installation/removal event of protecting groups or exogenous coordinating moieties. Divergent pathways were modulated with transition-metal catalysts by suppressing competitive reactivities, leading to N-arylation, annulative π-extension, or C-H fluorination.

Full text of DOI:10.1039/c7cc05794f

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Direct diversification of unmasked quinazolin-4(3H)-ones through
orthogonal reactivity modulation
Jae Bin Lee,a Mi Eun Kang,a Joohee Kim,b Chang Young Lee,a Jung-Min Kee,c Kyungjae Myung,d
Jang-Ung Park*b and Sung You Hong*ad
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here we report a set of direct functionalization methods of unmasked 2-phenylquinazolin-4(3H)-ones via orthogonal
unmasked 2-phenylquinazolin-4(3H)-ones, a privileged alkaloid reaction manifolds. This catalyst-controlled reactivity
core, without the installation/removal event of protecting groups modulation strategy enables efficient and site-selective
or exogenous coordinating moieties. Divergent pathways were derivatizations of the alkaloid core scaffold without employing
modulated with transition-metal catalysts by suppressing exogenous coordinating moieties or protecting groups.
competitive reactivities, leading to N-arylation, annulative π-
extension, or C–H fluorination.
Access to a high-level molecular complexity and diversity
typically requires multi-step transformation processes
involving functional group interconversion and protecting
group chemistry.1 In sharp contrast, direct (late-stage)
diversification of a parent molecule can provide atom- and
step-economic routes to afford various synthetic analogues.2–5
To realize such strategies, a set of reliable and orthogonal
reaction manifolds is essential. We envisioned that the
combination of carefully selected transition-metal catalysts
and intrinsic directing groups (DGs) would create opportunities
to modulate intrinsic reactivities of
a substrate, while
alleviating the need for laborious synthetic manipulation steps.
Quinazolin-4(3H)-one is a privileged alkaloid scaffold in the
context of the pharmacological potential for anticancer agents
or kinase inhibitors.6–9 Recently, palladium-catalyzed O-
alkenylation and C–H arylation of quinazolinones have been
reported.10,11 The molecular structure possesses nucleophilic
nitrogen, which can easily afford N-functionalized derivatives
(Scheme 1, pathway (i)).12 In addition, this substrate scaffold is
endowed with intrinsic DGs that can promote tandem C–H
arylation and C–H amidation (Scheme 1, pathway (ii)) or C–H
fluorination (Scheme 1, pathway (iii)).5,11,13,14 Herein, we report
the development of straightforward diversification methods of
Scheme 1 Divergent pathways of a 2-phenylquinazolin-4(3H)-one
.
Diversification of unmasked and readily available 1a
commenced with N-arylation using hypervalent
diphenyliodonium triflate, which features bench stability and
unique reactivity patterns.15,16 We envisaged that the N-
arylation could be achieved via the formation of a reactive
aryl-copper(III) intermediate, as depicted in Table 1.17–19 To our
delight, the addition of 10 mol% copper iodide enabled direct
access to the N-arylated product 2a in 74% yield under aerobic
conditions (Table 1, entry 1). As
a control, metal-free
conditions provided only a trace amount of 2a (Table 1, entry
2). The addition of simple 2,2’-bipyridyl ligand L1 slightly
increased the yield (Table 1, entry 3), and ligand screening
(Table 1, entries 4–9) revealed that quinoline-based L7
performed the best, giving a yield of 93%.
Having optimized the N-arylation process, our attention
shifted to the tandem synthesis of phenanthridine-fused
derivative 3a from 1a (Table 2). There are two challenges
associated with our direct oxidative annulation strategy,
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namely (i) a sequential combination of C–H arylation and C–H Supplementary Information, Scheme S1).24 In order to test our
amidation and (ii) competition with ortho di-arylation. Indeed, hypothesis and address the catalyst loading issue, we decided
a few synthetic methods for this useful scaffold are reported, to regenerate active Pd(II) species through terminal oxidation.
but only from prehalogenated substrates.20,21 To our delight, After screening a series of oxidants, addition of 1.0 equivalent
the initial ligand-free screening conditions afforded the desired of silver trifluoroacetate (AgTFA) was found to be optimal,
annulated product (Table 2, entry 1), albeit with a high catalyst improving both the yield (74%) and the catalyst loading (Table
loading. The formation of 3a was restricted when bulky 2, entry 8; Table S4). In addition, BrettPhos ligand led to the
[MesIPh]OTf was employed (Table 2, entry 2). Pd(OAc)2 was highest yield and reduced the amount of palladium catalyst
found to be the most effective catalyst (see the Supplementary (Table 2, entry 9; Table S5). Finally, our optimal conditions
Information, Table S1), and KOAc was the most suitable base (Table 2, entry 10; Table S6) provided the desired annulated
for this reaction (Table 2, entry 3; Table S2). Other solvents product in excellent yield (97%).
and reaction temperatures were also screened, and DMF and
130 °C were selected (Table 2, entries 4, 5; Table S3).
Table 2 Optimization of annulative π-extensiona
Increasing the amount of diphenyliodonium salt slightly
decreased the yield of product 3a (71%), owing to the
formation of the di-arylated product 3a’ (8%) (Table 2, entry 6).
Table 1 Optimization of N-arylationa
Entry
Deviation from the above
Yieldb
(%)
82
initial ligand-free screening conditions
None
1
2
3
4
5
6
7
8
9
[MesIPh]OTf instead of Ph2IOTf
NaOAc instead of KOAc
–
68
100 °C instead of 130 °C
27
DMSO instead of DMF
72
71 (8)c
Ph2IOTf (1.5 equiv)
Pd(OAc)2 (10 mol%)
37
Pd(OAc)2 (20 mol%), AgTFA (1.0 equiv), 15 h
Pd(OAc)2 (10 mol%), BrettPhos (40 mol%), Ph2IOTf
(1.2 equiv), AgTFA (1.0 equiv), 24 h
Optimal conditions: Pd(OAc)2 (20 mol%),
BrettPhos (30 mol%), Ph2IOTf (1.1 equiv), AgTFA
(1.0 equiv), KOAc (4.0 equiv), 24 h, O2
74
76d
10
97d
Entry
Catalyst
CuI
–
Ligand
–
Yieldb (%)
a Optimal conditions: 1a (0.09 mmol, 1.0 equiv), Ph2IOTf (0.1 mmol, 1.1 equiv),
Pd(OAc)2 (20 mol%), BrettPhos (30 mol%), AgTFA (0.09 mmol, 1.0 equiv), KOAc
(0.36 mmol, 4.0 equiv), DMF (2.0 mL), 130 °C, 24 h, O2. b Yield determined by GC
1
2
3
4
5
6
7
8
9
74
3
–
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L5
L6
L7
83
65
87
75
58
67
93
c
d
analysis using n-dodecane as an internal standard. Di-arylated product 3a’.
Isolated yield. Mes, 2,4,6-trimethylphenyl.
a
Optimal conditions: 1a (0.09 mmol, 1.0 equiv), Ph2IOTf (0.135
mmol, 1.5 equiv), CuI (10 mol%), L7 (40 mol%), Na2CO3 (0.18 mmol,
2.0 equiv), DMF (2.0 mL), 130
C, 24 h, air. b Yield determined by GC
°
analysis using n-dodecane as an internal standard. Tf,
trifluoromethanesulfonyl.
When the catalyst loading was reduced to 10 mol%, the
product was formed in a significantly diminished yield (37%)
(Table 2, entry 7). We speculated that this low catalytic
inefficiency is presumably linked to a Pd(II)/Pd(0) cycle of the Scheme 2 Proposed mechanism of annulative
π-extension.
C–H amidation (Scheme 2, cycle II) on the basis of previous
literature reports,22,23 where Pd(0) precipitation as Pd black
may consume active catalysts. Yet, a Pd(II)/Pd(IV) manifold
cannot be completely ruled out (see Section III.3 in the
With the optimal conditions in hand, the substrate scope of
the annulation was examined (Scheme 3). The reactions
proceeded smoothly under an oxygen atmosphere with a wide
range of quinazolin-4(3H)-ones. Both electron-donating and
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electron-withdrawing substituents such as methoxy (3b, 3c), undisputable significance in pharmaceuticals, since it confers
methyl (3d
95%). Fluoro groups generally led to moderate to excellent groups independently developed C–H fluorination methods
yields (3g
3j). Remarkably, both chloro and bromo groups involving high-valent transition-metal catalysis.26–28 After
remained intact to give the corresponding products (3k 3m) in screening of reaction conditions, fluorinated 4a was obtained
,
3e), and nitro (3f) groups were well-tolerated (88– the lipophilicity and metabolic stability.25 The Yu and Sanford
–
–
moderate to good yields (54–78%). These halides can be in 91% yield under aerobic conditions (Table 3, entry 1).
utilized as synthetic handles for further modifications. Di- Control experiments involving the alteration of the
substituted substrates
(3n–3p) containing both electron- electrophilic fluorinating reagent, temperature, and solvent
donating and electron-withdrawing groups showed similar or invariably led to reduced yields (Table 3, entries 2–8).
better reactivities.
Table 3 Optimization of C–H fluorinationa
Entry
Deviation from the above
optimal conditions
Yieldb (%)
1
2
3
4
5
6
7
8
None
91
13
1
F2 instead of F1
F3 instead of F1
F4 instead of F1
–
1.5 equiv of F1 instead of 3.0 equiv
MeCN instead of DMF
100 °C instead of 150 °C
24 h at 130 °C instead of 12 h at 150 °C
63
39
58
38
Scheme 3 Substrate scope of annulative π-extension and isolated yields of 3.
a Optimal conditions: 1a (0.09 mmol, 1.0 equiv), NFSI F1 (0.27 mmol, 3.0 equiv),
b
Pd(OAc)2 (10 mol%), DMF (2.0 mL), 150 °C, 12 h, air. Yield determined by GC
analysis using n-dodecane as an internal standard. NFSI, N-
fluorobenzenesulfonimide.
To highlight the synthetic utility, we applied our annulation
product to a chemically-modified graphene-FET device for the
nanoelectronic detection of metal ions as illustrated in Fig. 1a.
A phenanthridine-fused 3a was noncovalently incorporated
Scheme 4 Aryl transfer reactions with substituted iodonium salts.
into the graphene-FET through the
π-π interaction. A
microfluidic channel was integrated onto the chemically-
modified graphene-FET (Fig. 1b). As shown in Fig. 1c, the
addition of a Hg2+ solution (100 ppm) into the microfluidic
channel changed the current (ΔID). A positive shift of ~0.2 V in
the Dirac voltage was observed upon binding of Hg2+. In
contrast, the 3a-modified graphene-FET sensor showed a
negative shift in the Dirac voltage for Na+, K+, and Cu2+ ions (Fig.
S1). The phenomenon is presumably associated with the
metal-dependent coordination of heterocyclic 3a, affecting the
current in the conductive channel.29,30 To investigate the
reversibility of the sensors further, imidazole aqueous solution
was consecutively injected to wash out the immobilized Hg2+.31
As a result, the current level of the device was recovered to
the original state (Fig. 1d).
The regioselectivity of aryl transfer reactions was also
evaluated with substituted iodonium salts bearing fluoro,
methyl, or tert-butyl groups (Scheme 4). Notably, these
iodonium salts invariably afforded the corresponding products
as
a single isolated regioisomer (3q–3s). The exclusive
regioselectivity clearly indicates the tandem sequence of
intermolecular C–C bond formation, and subsequent
intramolecular C–N bond formation (see also the
aforementioned Scheme 2).
As the next diversification pathway, we set out to
investigate C–H fluorination. Efficient incorporation of fluorine
functionalities into bioactive molecular scaffolds has
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In conclusion, we have demonstrated the facile
diversification of unmasked 2-phenylquinazolin-4(3H)-ones, a
privileged alkaloid scaffold endowed with intrinsic
coordinating moieties. Transition-metal catalyst-controlled
reactivity modulation enabled access to the derivatives of the
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and C–H fluorination in straightforward manner. The
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a
reactions were performed with no special equipment to
exclude air or moisture. Finally, the synthetic value of a
phenanthridine-fused quinazolinone derivative was featured
by the construction of a chemically-modified graphene-based
nanoelectronic device, which allowed real-time electronic
recognition of Hg2+ ions in aqueous solution.
This work was supported by the National Research
Foundation of Korea (NRF-2016R1A2B4015497) and the IT
R&D program of MOTIE/KEIT (10046306). We are grateful to
Prof. R. Tenne for his helpful comments.
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