Substrate or Solvent-Controlled PdII-Catalyzed Regioselective Arylation of Quinolin-4(1H)-ones Using Diaryliodonium Salts: Facile Access to Benzoxocine and Aaptamine Analogues

Article abstract of DOI:10.1002/ejoc.202000013

Regioselective C3, C5, and C8 arylation of quinolin-4(1H)-ones have been accomplished either by substrate-control or by tuning the reaction solvent. A variety of aryl(mesityl)iodonium triflates could smoothly deliver arylated products in good to excellent yields. Additionally, it offers great flexibility by arylating medicinally potent quinolone related heterocycles such as acridin-9(10H)-one, and phenanthridin-6(5H)-one under standard reaction conditions. This strategy was further extended with diphenyleneiodonium triflate to access oxacine fused quinolines. The post-modifications of synthesized products enhance the further utility of this protocol in organic synthesis. To the best of our knowledge, this is the first report on C5 arylation of quinolin-4(1H)-ones using iodine(III) reagents.

Full text of DOI:10.1002/ejoc.202000013

DOI: 10.1002/ejoc.202000013
Communication
Topic: Arylation | Very Important Paper |
Substrate or Solvent-Controlled PdII-Catalyzed Regioselective
Arylation of Quinolin-4(1H)-ones Using Diaryliodonium Salts:
Facile Access to Benzoxocine and Aaptamine Analogues
Manish K. Mehra,[a] Shivani Sharma,[a] Krishnan Rangan,[b] and Dalip Kumar*[a]
Abstract: Regioselective C3, C5, and C8 arylation of quinolin- dard reaction conditions. This strategy was further extended
4(1H)-ones have been accomplished either by substrate-control with diphenyleneiodonium triflate to access oxacine fused
or by tuning the reaction solvent. A variety of aryl(mesityl)iodo- quinolines. The post-modifications of synthesized products en-
nium triflates could smoothly deliver arylated products in good hance the further utility of this protocol in organic synthesis. To
to excellent yields. Additionally, it offers great flexibility by aryl- the best of our knowledge, this is the first report on C5 aryl-
ating medicinally potent quinolone related heterocycles such ation of quinolin-4(1H)-ones using iodine(III) reagents.
as acridin-9(10H)-one, and phenanthridin-6(5H)-one under stan-
construction of quinoline analogues of medicinal intermediates,
alkaloids and natural products such as antimalarial agent (1),
distomadines A (2) and B (3), the families of aaptamines (4),
PDE4 inhibitor (5) isocryptolepine (6) and eight-membered cy-
clic ether ring analogue, heliannuol H (7) (Figure 1).[5] Therefore,
many research groups have been inspired to functionalize the
quinolone scaffold to identify bioactive compounds with im-
proved biological profiles and fascinating material-related prop-
erties. In literature, transition-metal-catalyzed C3 arylation of
preactivated quinolin-4(1H)-ones has been reported using halo-
arenes or aryl boronic acids as arylating agents (Scheme 1a).[6]
However, regioselective C5 arylation of quinolin-4(1H)-ones is
yet to be explored.
Over the past decade, the emergence of powerful transition-
metal-catalyzed C–H activation-based strategies offers new
tools in the toolkit of organic and medicinal chemists.[1] Transi-
tion-metal-catalyzed multisite-selective C–H functionalization is
an intrinsic and chronic challenge in organic chemistry.[2] In this
ambiance, the installation of a suitable “directing group (DG)
auxiliary” on the substrate can direct functionalization at the
suitable site via metallacycle intermediates and this coordina-
tion might address the issues of selectivity.[3] However, the prac-
ticality of directing group strategy is conciliated by the addi-
tional synthetic steps involving the incorporation and removal
of a directing group. Therefore, the utilization of intrinsic direct-
ing group became highly desirable in C–H functionalization.
On the other hand, site-selectivity plays a potent role in syn-
thetic organic chemistry. Controlling site selectivity is the main
concern in C–H functionalization as various C–H bonds exist in
the substrate could exhibit similar bond dissociation energy
and chemical reactivity. Thus, the coordination ability of the
intrinsic directing group controls the efficacy and outcome of
the reaction. Drawing attention from substrate-controlled strat-
egies,[4] where the controlling element for site-selectivity is in-
herent to the substrate, we proposed an analogous strategy for
direct C–H functionalization via designing the substrates resid-
ing different intrinsic directing groups.
Quinolones are prominent structural motifs found in numer-
ous bioactive molecules, pharmaceuticals and materials. In par-
ticular, arylquinolones are potential precursors for the divergent
[a] Department of Chemistry, BITS Pilani,
Pilani Campus, Pilani 333031, Rajasthan, India
Figure 1. Natural products containing quinoline skeleton and Heliannuol.
E-mail: dalipk@pilani.bits-pilani.ac.in
https://www.bits-pilani.ac.in/pilani/dalipk/profile
[b] Department of Chemistry, BITS Pilani,
Thus far, only few reports involve the use of keto as a direct-
ing group as its weak coordinating ability restricts the substrate
scope. A number of reports have disclosed keto group directed
C–H arylation using in situ generated strongly coordinating im-
Hyderabad Campus, Secunderabad 500078, Telangana, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000013.
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in good yields (72–73 %). Fortunately, sterically hindered
bis(mesityl)iodonium triflate (7r) worked smoothly to afford 8ar
in 70 % yield. The structure of 8ac was affirmed by single-crys-
tal X-ray analysis. The methoxy group crystallographically found
to occupy two different orientations as labeled as C16 towards
C12 of the phenyl ring (52 % occupancy) and C16A towards
C15 of the phenyl rings (48 % occupancy) (see the SI for details).
Scheme 1. Pd-catalyzed C3/C5 and C8 arylations of quinolones.
ine or oxime directing groups in order to overcome the issue
of weak co-ordination associated with keto group. Previously,
Yu and co-workers have described a Pd-catalyzed aldehyde or
keto-directed ortho-C(sp2)–H and benzylic C(sp3)–H arylation of
aromatic aldehydes and aliphatic ketones with aryl iodides by
employing amino acids as a transient DGs.[7] Likewise, Hu et
al.[8] have illustrated Pd-catalyzed synthesis of 2-benzyl-benz-
aldehyde derivatives from 2-methylbenzaldehyde and iodo-
benzene through the implement of acetohydrazide as a tran-
sient DG. Very recently, ortho-C–H arylation of ketones has been
achieved by Jin's group via Pd-catalyzed in situ procreated ket-
imine/carboxylate as directing groups by utilizing transient DG
glycine.[9] In recent years, diaryliodonium salts have emerged
as versatile and environmental friendly arylating agents due to
their high reactivity, mild and non-toxic nature.[10] In continua-
tion of our interest to demonstrate the usefulness of diaryl-
iodonium salts, we report herein Pd-catalyzed site-selective
C5/C8 and C3 arylation of quinolones (Scheme 1b).
In efforts to achieve a concise and regioselective keto-
directed C5 arylation, our investigation commenced with the
model reaction of quinolin-4(1H)-one (6a) and diphenyl-
iodonium triflate (7a) using 5 mol-% Pd(OAc)2 as a catalyst in
AcOH (1 mL) at 100 °C for 6 h. To our delight, 5-phenylquinolin-
4(1H)-one (8aa) was obtained in 96 % yield (refer SI for details).
The reaction was then screened meticulously by varying differ-
ent parameters such as solvent, catalyst, temperature and coun-
terions (more detailed scrutinize are shown in Table S1, SI).
In view of easy synthesis and selectively transfer of a less
hindered aryl ring,[11] the reaction of mesityl(aryl)iodonium salt
having electronically neutral phenyl (7a′) was performed with
quinolin-4(1H)-one 6a to afford the corresponding 5-phenyl-
quinolin-4(1H)-one (8aa) in 95 % yield (Scheme 2). In addition,
diaryliodonium salts bearing electronically donating [methyl
(7b, 7i, 7o, 7r), methoxy (7c, 7j)], halo [fluoro (7d, 7p), chloro
(7e, 7q), bromo (7f, 7m)] as well as electron-deficient substitu-
tions [COMe (7g), NO2 (7h, 7n), CF3 (7k), CO2Me (7l)] either at
m- or p-position of aryl rings were effectively transferred in the
reaction and provided the corresponding 5-arylquinolin-
4(1H)ones in excellent yields as depicted in Scheme 2. Interest-
ingly, more challenging ortho-substituted groups such as 2-Br
Scheme 2. Synthesis of 5-arylquinolin-4(1H)-ones. Reaction conditions: 6a
(0.69 mmol), 7 (0.69 mmol), Pd(OAc)2 (0.03 mmol), AcOH (2.0 mL), 6 h.
[a] Used diphenyliodonium salt (7a).
Notably, the reaction of mesityl(quinolin-3-yl)iodonium tri-
flate (7s) with quinolin-4(1H)-one 6a proceeded efficiently to
give 8as in 71 % yield. Furthermore, pharmaceutically active
phenanthridin-6(5H)-one (6d) and acridin-9(10H)-one (6e) were
also worked well with diphenyliodonium triflate (7a) under
these conditions to furnish 8da and 8ea in 85 % and 78 %
yields, respectively (Scheme 3).
Scheme 3. Substrate scope for arylation. Reaction conditions: 6b–f
(0.69 mmol), 7a (0.69 mmol), Pd(OAc)2 (0.03 mmol), AcOH (2.0 mL), 6 h.
[a] 2.0 equiv. of 7a was used.
Current strategies, however, are typically limited to single
(7m) and 2-NO2 (7n) were well tolerated under the optimized site-selective functionalization, ascribable to the challenges as-
conditions to deliver the corresponding products 8am and 8an sociated with achieving a high yielding reaction even at just
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one position. Toward the goal of multisite selectivity, important tion.[16] However, only limited approaches are available for the
seminal advances have been made with heteroaromatic sub- construction of medium-sized heterocycles.[17] In an effort to
strates.[12] In analogy to 5-arylquinolin-4(1H)-ones, C3 and C8 demonstrate atom-economical uses of cyclic diaryliodonium
substituted quinolin-4(1H)-ones are also found to exhibit excel- salts,[18] we extended this strategy to access oxocino-fused
lent medicinal properties.[13] Taking this into consideration, we quinoline derivative via sequential C–C and C–O bond forma-
also explored C3 and C8 arylations of quinolin-4(1H)-ones via tion. Reaction of quinolin-4(1H)-one (6a) with diphenyleneiodo-
substrate modification or switching the reaction solvent.
For C8 arylation, readily available 1-hydroxy-2-methylquin-
olin-4(1H)-one[14] (6g) and 1-hydroxy-2-phenylquinolin-4(1H)-
one (6g′) bearing N-hydroxy as a directing group were
smoothly coupled with 7a to produce the corresponding 8-
phenylquinolin-4(1H)-ones 8ga (70 %) and 8g′a (74 %) in high
yields (Scheme 4).
nium triflate 9a under standard conditions afforded oxo-
cino[2,3,4-de]quinoline (10a) in 70 % yield along with minor
amount (20 % yield) of 5-(2′-iodo-[1,1′-biphenyl]-2-yl)quinolin-
4(1H)-one (11a) (Scheme 6). Formation of 11a suggested that
initially, Pd-catalyzed C–C bond formation led to 11a followed
by intramolecular nucleophilic substitution provided oxo-
cino[2,3,4-de]quinoline (10a). Disappearance of C5–H proton
(≈ 8.1 ppm) varified the C5-arylation and further shifting a dou-
blet of C3–H proton from 5.91 ppm to 6.97 ppm in proton NMR
of 10a clarify the presence of quinoline scaffold. Also, the 13C
NMR of 10a is devoid of any keto (>C=O) carbon (present in
precursor 6a) and observed chemical shifts for C2 (≈ 151 ppm)
and C4 (≈ 159.2 ppm) carbons imply the presence of quinoline
nucleus and ether linkage (C–O–C) at C4. Further, chemical
shifts of remaining carbon atoms are in agreement with oxo-
cino-quinoline system. The mass spectrum of 10a showed a
molecular ion peak at 296.1074 in agreement with the calcu-
lated mass at 296.1070 (see the SI for spectrum). Hence, these
structural analyses confirm the formation of oxocino-fused
quinoline 10a.
Scheme 4. Synthesis of 8-arylquinolin-4(1H)-ones. Reaction conditions: 6g
(0.69 mmol), 7a (0.69 mmol), Pd(OAc)2 (0.03 mmol), AcOH (2.0 mL), 6 h.
By switching the reaction solvent from acetic acid to 1,4-
dioxane, followed by the addition of silver carbonate intrigu-
ingly, led to an unexpected mixture of N-arylated quinolone
and C3 arylated quinolone. Further protection of quinolone
nitrogen atom gave C3 arylated quinolones (8ha, 8ia, 8ja and
8hn) in 82–92 % yields with complete regioselectivity
(Scheme 5). Notably, the reaction of 1-benzylquinolin-4(1H)-one
(6h) with 7a did not proceed when we used Pd(OAc)2 in acetic
acid (for more details see the SI).
Scheme 6. Synthesis of oxocino[2,3,4-de]quinolines. Reaction conditions: 6a
(0.69 mmol), 9a (0.69 mmol), Pd(OAc)2 (0.03 mmol), AcOH (2.0 mL), 12 h.
To gain more insight into the reaction mechanism, a series
of control experiments were performed. Firstly, the arylation of
quinolin-4(1H)-one (6a) in the absence of catalyst failed to give
the expected product (refer to the SI). The reaction of N-benzyl-
quinolin-4(1H)-one (6h) under the standard conditions did not
provide any trace of the requisite product. This observation
Scheme 5. Regioselective synthesis of 3-arylquinolin-4(1H)-ones. Reaction
conditions: 6h–j (0.69 mmol), 7 (0.69 mmol), Pd(OAc)2 (0.03 mmol), Ag2CO3
(0.69 mmol), 1,4-dioxane (2.5 mL),14 h.
To demonstrate the synthetic utility of this transformation, demonstrates the participation of enol-form via in situ keto-
naturally occurring bioactive oxocine, isocryptolepine and aapt- enol tautomerism and suggests the reaction path through in-
amine analogues were prepared. Oxocine, an eight-membered termediate complex B. Stoichiometric studies supported the
heterocyclic ring system with oxygen, is an important structural formation of brown colour solid, palladacycle B, which was con-
subunit present in numerous biologically active molecules such verted to 8aa upon treatment with 7a at 100 °C in AcOH.
as heliannuol H (Figure 1) and radulanins A, H, and L which are Formation of palladacycle B was confirmed by HRMS analysis
isolated from Haliclona fascigera and Radula variabilis, respec- (for detail see the SI). Second ortho-CH arylation of 5-phenyl-
tively.[15] Although many examples are available to construct quinolin-4(1H)-one (8aa) using 7a under optimized conditions
five- and six-membered heterocycles via intramolecular cycliza- didn't proceed to give the further arylated product.
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Scheme 7. Plausible mechanism for C5, C8 and C3 arylation of quinolones.
To investigate the reversibility of the metalation step, a H/D
In conclusion, we have developed a substrate-controlled and
exchange experiment was performed. H/D exchange of 6a at catalyst-enabled efficient route for the multisite (C3, C5, and C8)
the position-5 (53 % D) imply reversible nature of C–H activa- arylation of quinolin-4(1H)-ones. This protocol employed readily
tion step (see the SI). Based on the experimental findings and accessible quinolin-4(1H)-ones and diaryliodonium triflates as
literature precedences,[19] we proposed plausible reaction path- electrophilic coupling partners, providing a straightforward and
ways for C5/C8 and C3 arylation of quinolones. In case of C5 high yielding (70–96 %) strategy to synthetically useful aryl-
and C8 arylation, initially, the oxygen atom of the keto or quinolin-4(1H)-one building blocks. Having great functional
hydroxy group might coordinated to the PdII metal. Next, the group compatibility with iodonium salts containing electron-
activation of C–H bond of C5 or C8 position believes to produce neutral, electron-withdrawing, and electron-donating moieties,
cyclopalladation species B or E with the removal of acetic acid. the protocol is widely applicable to other related substrates
Then the oxidative addition of diaryliodonium salt 7 would gen- such as acridin-9(10H)-one, and phenanthridin-6(5H)-one.
erate either PdIV intermediate C or F. Finally, reductive elimina- Identified reaction conditions successfully delivered aaptamine
tion of C or F would provide C5/C8 arylated product 8 and alkaloid analogues and dibenzo[5,6:7,8]-oxocino[2,3,4-de]quin-
emancipate the active PdII species to complete the catalytic cy- oline derivatives in good yields (65–70 %).
cle (as shown in Scheme 7).
For C3 arylation, initial electrophilic palladation of N-pro-
tected quinolin-4(1H)-one 6 likely to generate PdII adduct G.
Subsequently oxidative addition of mesityl(aryl)iodonium tri-
flate 7 to adduct G may afford PdIV species H which upon re-
ductive elimination believed to produce the desired C3 arylated
product 8 with the release of Pd species I. Finally, the catalytic
cycle completes with the regeneration of active Pd(OAc)2 by
the Ag2CO3 (Scheme 7).
To evince the synthetic potential of this approach, a gram-
scale reaction of 6a and 7n was carried out to afford the desired
product 8an in 68 % yield (Scheme 7). The atom-economy of
this arylated strategy was improved by recovering the released
iodoarene (by-product). While the gram-scale synthesis of 8an,
we recovered released iodomesitylene in 70 % yield. Recovered
iodomesitylene was further reused for the synthesis of
mesityl(p-tolyl)iodonium triflate (7b). Next, intermediate 8an
was effectively utilized to access various structural analogues
of marine alkaloid, aaptamines 12a and 12b (Scheme 8a).[20]
Similarly, 8aa was converted into potential antimalarial agent
12c.[21]
The post-modification of C3 arylated 8ha and 8hn effectively
utilized to achieve antimalarial and cytotoxic agents[22] iso-
cryptolepine alkaloid derivatives 12d and 12e as shown in
Scheme 8b. Moreover, 12e can be utilized to afford the iso-
cryptolepine alkaloid in a single step by using the literature
reported method.
Scheme 8. Post-modification strategies.
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Acknowledgments
Authors are highly thankful to CSIR, New Delhi for financial sup-
ports in form of research project [Ref. No. 02(0290)/17/EMR-II]
and Senior Research Fellowship (MKM). Also, we would like to
acknowledge DST, New Delhi and BITS Pilani for HRMS (DST-
FIST) and NMR facilities.
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Keywords: C–H functionalization · Quinolin-4(1H)-one ·
Diaryliodonium salts · Palladium catalyst · Regioselectivety
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Received: January 5, 2020
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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Topic: Arylation
M. K. Mehra, S. Sharma,
K. Rangan, D. Kumar* ....................... 1–6
Substrate or Solvent-Controlled PdII-
Catalyzed Regioselective Arylation
of Quinolin-4(1H)-ones Using Diaryl-
iodonium Salts: Facile Access to
Benzoxocine and Aaptamine Ana-
logues
Substrate or solvent controlled regio- These protocols are applicable to a
selective C3, C5, and C8 arylation wide range of quinolone related het-
of quinolin-4(1H)-ones with diaryl- erocycles and provide potential access
iodonium salts have been successfully to naturally occurring benzoxocine
achieved in high yields (up to 96 %). and aaptamine analogues
DOI: 10.1002/ejoc.202000013
Eur. J. Org. Chem. 0000, 0–0
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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim