Synthesis of Phenanthrenes through Visible-Light Photoredox Catalyzed Intramolecular Cyclization of α-Bromochalcones

Article abstract of DOI:10.1002/ejoc.201800011

A mild and efficient photocatalytic protocol for the synthesis of the phenanthrene scaffold has been devised. The reaction involves intramolecular cyclization of α-keto vinyl radicals generated from α-bromochalcones under visible light photoredox catalyze

Full text of DOI:10.1002/ejoc.201800011

A Journal of
Accepted Article
Title: Synthesis of Phenanthrenes via Visible Light Photoredox
Catalyzed Intramolecular Cyclization of α-Bromochalcones
Authors: Namrata Rastogi, Savita Nagode, and Ruchir Kant
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10.1002/ejoc.201800011
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Phenanthrenes via Visible Light Photoredox
Catalyzed Intramolecular Cyclization of α-Bromochalcones
Savita B. Nagode,a,b Ruchir Kant,c and Namrata Rastogia,b*
aMedicinal & Process Chemistry Division and cMolecular & Structural Biology Division, CSIR-Central Drug Research
Institute, B.S. 10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India
bAcademy of Scientific and Innovative Research, New Delhi 110001, India
Corresponding Author’s Email: namrata.rastogi@cdri.res.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A mild and efficient photocatalytic protocol for
the synthesis of phenanthrene scaffold has been devised. The
reaction involves intramolecular cyclization of α-keto
radicals generated from α-bromochalcones under visible
light photoredox catalyzed conditions. The high product
yields, wide substrate scope and complete regioselectivity
are noticeable attributes of the reaction.
Keywords: Phenanthrene; visible light; photoredox; α-keto
radical; intramolecular
Introduction
Recently, emergence of photoredox catalysis as a
greener alternative to the traditional radical reactions
has led to the development of several useful protocols
for C-C as well as C-heteroatom bond formation.10
Although visible light photoredox catalyzed
intramolecular radical cyclizations have been
reported frequently for the synthesis of various fused
polycyclic scaffolds,11 the examples of phenantherene
synthesis under photoredox catalysis are limited.
Deronzier and co-workers first reported visible light
catalyzed Pschorr reaction with Ru(bpy)3Cl2 as
photocatalyst for the synthesis of phenanthrenes.12
Zhou and co-workers reported eosin Y catalyzed
[4+2] benzannulation of biaryldiazonium salts with
alkynes for the synthesis of phenanthrene scaffold.13a
Later, same strategy was practiced by Cho et al for
preparing polyheteroaromatic compounds.13b Recently,
Barriault and co-workers used gold complex for the
generation of vinyl radicals via photoexcitation of
C(sp2)-Br bond followed by intramolecular
cyclization leading to the synthesis of polycyclic
molecules including phenanthrene.14
Recently, Reiser and co-workers reported using α-
bromo chalcones as the source of α-keto radicals
which were subsequently trapped by heteroarenes and
alkenes yielding polycyclic molecular scaffolds under
photoredox catalyzed conditions.15a,b Later the same
group reported VLPC intramolecular cyclization of α-
keto radicals into indolines,15c indenones and
dihydroindeno[1,2-c]chromenes.15d
Herein we report the synthesis of phenanthren-9-yl
ketones via intramolecular cylization of α-keto
radicals generated from α-bromochalcones under
VLPC conditions (Scheme 1).
The phenanthrene motif occurs widely in nature and
exhibits several medicinal properties such as
analgesic, antimicrobial, anticancer, antifertility, anti-
inflammatory, antiallergic, antispasmolytic, antiviral
etc.1 Also, there are numerous drugs and synthetic
molecules of therapeutic potential bearing
phenanthrene scaffold (Figure 1).2
Figure 1. Phenanthrene Scaffold in natural/synthetic
medicinal compounds
Further, due to their unique photophysical properties
several phenanthrene based molecules and polymers
found use in the material science.3
The common methods for the synthesis of
phenanthrene scaffold include intramolecular4 or
intermolecular5 cyclization of biphenyl derivatives
with alkynes, intramolecular radical cyclizations of
stilbene derivatives6a including classical Pshorr
cyclization of stilbenes,6b,c photocyclization of
stilbenes,7 palladium-catalyzed annulation reactions
of dibromoarenes8 and transition metal catalyzed
[5+5] cycloaddition between α,β-unsaturated Fisher
carbene complex and o-alkynylbenzoyl system.9
1
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10.1002/ejoc.201800011
European Journal of Organic Chemistry
was intriguing (entry 4).17 Further, an excellent yield
of product was obtained with the stronger reducing
photocatalyst fac-[Ir(ppy)3] (IrIV/IrIII* = -1.73V vs
SCE) which was selected for further optimization of
reaction conditions (entry 5). The amount of fac-
[Ir(ppy)3] optimal for the reaction was found to be 1
mol% since a sharp decline in product yield occurred
with 0.5 mol% of it (entry 6) whereas slightly lower
yield i.e 70% was noted with 1.5 mol% of the
photocatalyst (entry 7). The reaction when carried out
in other solvents such as DMSO and MeCN proved to
be much less productive in terms of yields (entries 8-
9). Further, changing the base to potassium phosphate
drastically improved product yield which was only
moderate with other bases used i.e. NaHCO3 and
Na2HPO4 (entries 10-12). Also, optimization of the
amount of base revealed that 2 equivalent of base is
optimum considering the reaction yield and economy
(entries 10, 13-14). The reaction failed to furnish any
product in the absence of photocatalyst or visible
light, substantiating the importance of both for a
successful reaction (entries 15-16). However,
interestingly the product could be isolated in modest
yield without using base in the reaction (entry 17).
After the extensive optimization, we proceeded to
examine the scope of α-bromochalcones 1 in the
reaction (Table 2).
Scheme 1. Synthesis of phenanthrene scaffold under
VLPC conditions
We first investigated the proposed reaction with
bromochalcone 1a (Ered = -0.82 V vs. SCE; please see
the supporting information) with photocatalyst
[Ru(bpy)3Cl2] (ERuIII/RuII* = -0.81 V vs. SCE)16b and
base potassium carbonate in DMF under blue light
irradiation anticipating an oxidative quenching
mechanism (Table 1).
Table 1. Optimization of reaction conditions.a
Entry
Photocatalyst (mol%), Base (equiv), Solvent
Yield
(%)b
21
Table 2. Scope of α-bromochalcones 1a
1
2
[Ru(bpy)3Cl2] (1), K2CO3 (2), DMF
[Ir{dF(CF3)ppy}2(dtb-bpy)]PF6 (1),
K2CO3 (2), DMF
36
3
4c
5
6
7
Rose Bengal (1), K2CO3 (2), DMF
Eosin Y (1), K2CO3 (2), DMF
0
0
75
44
70
fac-[Ir(ppy)3] (1), K2CO3 (2), DMF
fac-[Ir(ppy)3] (0.5), K2CO3 (2), DMF
fac-[Ir(ppy)3] (1.5), K2CO3 (2), DMF
fac-[Ir(ppy)3] (1), K2CO3 (2), DMSO
fac-[Ir(ppy)3] (1), K2CO3 (2), MeCN
fac-[Ir(ppy)3] (1), K3PO4 (2), DMF
fac-[Ir(ppy)3] (1), NaHCO3 (2), DMF
fac-[Ir(ppy)3] (1), Na2HPO4 (2), DMF
fac-[Ir(ppy)3] (1), K3PO4 (1.5), DMF
fac-[Ir(ppy)3] (1), K3PO4 (2.5), DMF
no photocatalyst, K3PO4 (2), DMF
fac-[Ir(ppy)3] (1), K3PO4 (2), DMF, no light
fac-[Ir(ppy)3] (1), no base, DMF
8
9
47
24
86 (81)d
60
10
11
12
13
14
15
16
60
82
87
NR
NR
52
17
a)
Reaction Conditions: 1a (0.3 mmol) with specified amounts of
photocatalyst and base was irradiated in solvent (2.0 mL) with a 450 nm
b)
c)
d)
blue LED for 3 h.
parentheses.
NMR yields. Green LED.
Isolated yield in
The reaction resulted into the formation of desired
product 2a in 3 hours, albeit in low yield (entry 1).
Similarly, the photocatalyst [Ir{dF(CF3)ppy}2(dtb-
bpy)]PF6 (IrIV/IrIII* = -0.89 V vs SCE)16a also afforded
the desired product but only with
a
slight
a) Reaction Conditions: 1 (0.3 mmol), K3PO4 (0.6 mmol, 2.0 equiv) and
fac-[Ir(ppy)3] (0.003 mmol, 1.0 mol%) were irradiated in anhydrous DMF
(2.0 mL) with a 450 nm blue LED for 3 h. b) Please see reference 18
improvement in the yield (entry 2). As anticipated, no
reaction was noticed when organic dye Rose Bengal
(RB•+/RB*
=
-0.68V vs SCE) was used as
The α-bromochalcones with various R1 groups
including aryl, heteroaryl as well as aliphatic moieties
photocatalyst (entry 3), however failure of Eosin Y
(EY•+/EY* = -1.11V vs SCE) to provide any product
2
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10.1002/ejoc.201800011
European Journal of Organic Chemistry
were utilized successfully in the reaction. Moreover,
the substituents in the β-biaryl part (R2) were varied
to include the neutral, electron releasing as well as
electron withdrawing groups. The reaction worked
smoothly under optimized conditions to afford the
products in high yields in most of the cases. The
reaction provided phenanthrene-aryl ketones where
the aryl part could be benzene (2a-m), naphthalene
(2n), anthracene (2o) as well as phenanthrene ring
(2p-q). Also, the phenanthrenyl-heteroaryl ketones
(2r-t) were isolated in excellent yields under the
optimized reaction conditions. The reaction also
successfully afforded the phenanthrene-alkyl ketones
(2u-v) in high yields. Finally, changing the ring “Aˮ
from aryl to heteroaryl also worked well yielding
allyltributyltin to furnish product 3a (please see the
supporting information). The oxidation of radical
intermediate II effected by the strong oxidant [fac-
Ir(IV)(ppy)3]+ completes the catalytic cycle and
produces cyclohexadienyl cation III. Finally, cation
III undergoes deprotonation in the presence of base
to provide the corresponding phenanthrene product 2.
positional
isomers
naphtho[2,1-b]furan-4-
yl(phenyl)methanone 2w and naphtho[1,2-b]furan-4-
yl(phenyl)methanone 2x.18 This is specially
noteworthy that our strategy provides both the
positional isomers 2w and 2x by selecting the
appropriate substrate, whereas only 2x is accessible
through the cascade cyclization of α-keto radical with
furan as reported by Reiser and co-workers due to the
preferential addition of the α-keto radical on the C-2
position of furan ring.15a
It is also important to note that in case of substrates
1d, 1g, and 1w, the reaction exhibited complete
regioselectivity in favour of the products 2d, 2g and
2w over the other regioisomers 2d’, 2g’ and 2w’,
respectively.18 The structure of 2w was confirmed by
comparing with the reported structure15a whereas the
structures of 2d and 2g were assigned on the basis of
spectroscopic data and X-ray analysis of 2g (Figure
2).19
Scheme 2. Plausible mechanism
Conclusion
In conclusion, we established a simple methodology
for the synthesis of phenanthrene scaffold by
employing conveniently accessible starting materials.
The reactions take place at room temperature in short
reaction time with photocatalyst fac-[Ir(ppy)3] under
visible light photoredox catalyzed conditions. The
highlights of the methodology are wide substrate
scope, complete regioselectivity, and accessibility of
positional isomers in case of heteroaryl substrates.
Experimental Section
General procedure for the photoredox catalyzed
intramolecular cyclization
In an oven dried 5 mL snap vial equipped with a
magnetic stirring bar, the α-bromochalcone 1 (0.3
mmol), K3PO4 (0.13 g, 0.6 mmol, 2.0 equiv) and
photocatalyst fac-[Ir(ppy)3] (0.002 g, 0.003 mmol,
1.0 mol%) were dissolved in anhydrous DMF (2 mL).
The resulting reaction mixture was degassed by three
“pump-freeze-thaw” cycles via a syringe needle. The
vial was irradiated using 450 nm blue LEDs with a
cooling device maintaining the temperature around
Figure 2. ORTEP diagram drawn with 10% ellipsoid
probability for non-H atoms of the crystal structure of
compound 2g determined at 293 K
o
25 C. After 3 h of irradiation (TLC monitoring), the
reaction mixture was diluted with water (10 mL) and
extracted with ethyl acetate (3 x 10 mL). The
combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel
using hexane/ethyl acetate as eluent to afford the pure
product 2.
On the basis of our observations during photocatalyst
screening and from literature reports the reaction
possibly follows the oxidative quenching mechanism
(Scheme 2). Initially, the photocatalyst [fac-
Ir(III)(ppy)3] excited by blue light in the state [fac-
Ir(III)(ppy)3*] reduces the bromochalcone 1 by
single-electron transfer. The α-keto radical I thus
generated adds on to the aryl ring intramolecularly
leading to the generation of radical II. The generation
of radical species I was confirmed by trapping with
Acknowledgements
SBN thanks UGC, New Delhi for the Ph. D.
fellowship. We thank SAIF division of CSIR-CDRI
3
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10.1002/ejoc.201800011
European Journal of Organic Chemistry
Saifuddin, P. K. Agarwal, B. Kundu, J. Org.
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for the analytical support. We thank Dr. Tejender S.
Thakur of Molecular and Structural Biology Division,
CSIR-Central Drug Research Institute for supervising
the X-ray Data collection and structure determination
of 2g. We are also thankful to Ms. Shachi Mishra and
Dr. Atul Goel, of Medicinal and Process Chemistry
Division, CSIR-Central Drug Research Institute for
determining the redox potential value of 1a by cyclic
voltammetry. We gratefully acknowledge Department
of Science & Technology (DST), New Delhi for the
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European Journal of Organic Chemistry
FULL PAPER
Synthesis of Phenanthrenes via Visible Light
Photoredox Catalyzed Intramolecular
Cyclization of α-Bromochalcones
Adv. Synth. Catal. Year, Volume, Page – Page
Savita B. Nagode, Ruchir Kant, Namrata Rastogi*
6
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