Br?nsted acid catalyzed radical addition to quinone methides

Article abstract of DOI:10.1039/d1cc01335a

A fundamental quest for alkyl radical generation under mild conditions through photoinduced Br?nsted acid catalysis is addressed. The optimized protocol does not require any organic dyes or transition metal photocatalyst. Under blue light irradiation with diphenyl phosphate as a catalyst and dihydropyridine derivatives as a radical source, functionalized arylmethane derivatives are obtained in high yield.

Full text of DOI:10.1039/d1cc01335a

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Brønsted acid catalyzed radical addition
to quinone methides†
Cite this: DOI: 10.1039/d1cc01335a
ab
Shiv Shankar Patel,a Dileep Kumara and Chandra Bhushan Tripathi
*
Received 11th March 2021,
Accepted 16th April 2021
DOI: 10.1039/d1cc01335a
rsc.li/chemcomm
A fundamental quest for alkyl radical generation under mild con- arylmethane derivatives is reported. The optimized reaction con-
ditions through photoinduced Brønsted acid catalysis is addressed. ditions do not involve an external photocatalyst and the catalyst
The optimized protocol does not require any organic dyes or utilized is inexpensive and readily available. Moreover, this
transition metal photocatalyst. Under blue light irradiation with method offers a viable route for the synthesis of arylalkylmethyl-
diphenyl phosphate as a catalyst and dihydropyridine derivatives phosphonates, which are prevalent in several biologically active
as a radical source, functionalized arylmethane derivatives are compounds (Scheme 1B).8 Due to their significance various
obtained in high yield.
methods for synthesizing diarylmethyl phosphonates are reported
whereas routes for synthesizing arylalkylmethylphosphonates are
Development of novel radical reactions underpins the notion underexplored.9 In addition, prior to this work the chemistry of
behind the advancements in photocatalysis.1 Lately the empha- phosphorylated quinomethanes is unfledged in the domain of
sis in this field has been upon finding simple yet effective radical reactions.10 At the outset of our investigation, we envisaged
catalytic systems and in this context the discovery of sustain-
a mechanistic cycle involving a donor–acceptor complex
able organocatalytic photochemical reactions has been at the (Scheme 1C). We reasoned that in the presence of DPP as a
fore front.2 Amid several principles and concepts in photoca- catalyst, preorganization of substrates takes place and donor–
talysis, our lab got interested in hydrogen atom transfer (HAT) acceptor complex I is obtained. The subsequent electron transfer
reactions3 which encompass mechanistic possibilities such as under blue light irradiation provides II, which upon radical
sequential electron transfer/proton transfer and concerted pro- addition and protonation delivers 3 in high yield. We also realized
ton coupled electron transfer reactions (PCET).4,5,6
that the substituents at the 2,6-position in quinomethane will
In photochemical reactions the carbon centered radicals are impart stability to the radical intermediate and thus they will be
of great significance and amongst several radical precursors the critical for successful fruition of this reaction.
dihydropyridine derivatives have a special place. Their wide
With this premise, the optimization of the reaction condi-
range of applications and ease of synthesis makes them tions for photochemical radical addition arylation of phos-
attractive.7 In general, the photochemical reactions of dihydro- phorylated quinomethanes was initiated. Substrates 1a and
pyridine derivatives are carried out with a transition metal 2a were chosen as model substrates (Table 1). In blue light
based catalyst or an organic dye. For these catalysts a cost irradiation (455 nm) and CHCl3 as the reaction medium,
comparison in Indian rupee (INR) is provided in Scheme 1A. 10 mol% of diphenyl phosphate efficiently catalyzed the radical
Thus, we envisioned the possibility to develop a transition addition to phosphorylated quinomethane 1a and furnished 3a
metal/organic dye free protocol for radical addition with a in 90% yield (entry 1). Both the blue light and catalyst were
readily available catalyst.
essential for the reaction and in their absence no product was
In this communication, a diphenyl phosphate (DPP) catalyzed obtained (entries 2 and 3). Lowering the catalyst loading to
photochemical radical addition protocol to access functionalized 5 mol% proved detrimental to the reaction yield and 3a was
obtained in 50% yield (entry 4). The use of dibenzyl phosphate
a Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow-226031, India. E-mail: chandra.tripathi@cdri.res.in
b Chemical Sciences Division, Academy of Scientific and Innovative Research
(AcSIR), Ghaziabad-201002, India
as a catalyst was also effective (entry 5). However, given the easy
availability of diphenyl phosphate, it was used for further
studies. The effect of commonly used excited state photooxi-
dants was also probed. The reaction in the presence of 5 mol%
of these well-established photocatalysts proceeded smoothly
and 3a was obtained in good yield (entries 6–10). The reaction
† Electronic supplementary information (ESI) available: Detailed Experimental
procedures with experimental data and spectroscopic data for all the relevant
compounds. See DOI: 10.1039/d1cc01335a
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was also conducted under a green LED (entry 11). Although the
reaction proceeded smoothly, 3a was obtained in only 52%
yield. In addition, readily available acids such as H2SO4, TfOH,
TsOH, H3PO4 and benzoic acid were also screened and the
product 3a was obtained is moderate to good yield (see the ESI†
for details).
The optimum reaction conditions were applied to probe the
substrate scope of the reaction. In general, the reaction pro-
ceeded smoothly with a broad array of substrates and the
products were obtained in excellent yields (Table 2). Initially
the scope with respect to phosphorylated quinomethanes was
tested (Table 2A). The reaction remained unperturbed by the
different ester groups on phosphorylated quinomethanes and
products 3a–3j were obtained in excellent yield. The effect of
the t-Bu group on phosphorylated quinomethanes was also
tested and substrates containing different alkyl groups on the
quinone ring furnished 3k–3m in good yield. At this point, the
scope with respect to different radical precursors was also
studied (Table 2B). Several alkyl and benzyl radical precursors
were well suited and 3n–3v were obtained in good yields.
Notably heteroatom substituted radical sources furnished 3w
and 3x in good yield. Phosphine oxide substituted quino-
methane derivatives also emerged as excellent substrates and
3y–3za were obtained in good yields. Having explored the scope
with phosphorylated quinomethanes, the generality with
respect to other p-QM’s was also tested (Table 3).11 The aryl
and alkyl substituted p-QM’s furnished 5a–5f in good yield.
Scaling up the reaction at 1 mmol scale had no detrimental
effect and 3i was obtained in 82% yield (Scheme 2A). The utility
of the optimized protocol was further demonstrated through
synthetic applications. In the presence of AlCl3 both the t-Bu
groups from 3y were removed to provide 6 in 84% yield
(Scheme 2A). Subsequently the reaction protocol was applied
for the synthesis of an established bioactive compound. Grat-
ifyingly through this Brønsted acid catalyzed photoinduced
radical reaction the compound 7, a Lp(a) and cholesterol low-
ering agent8d was obtained in good yield (Scheme 2B).
Scheme 1 Photochemistry of quinomethanes.
Table 1 Reaction condition optimizationab
Control experiments were also carried out to understand the
reaction mechanism. In the presence of N-methylated radical
precursor 8, no reaction was observed (Scheme 2C) This experi-
ment clearly illustrates the pivotal role of N–H of the dihydro-
pyridine radical precursor. The role of additives was also
probed. With radical trapping agents such as BHT and TEMPO
no measurable reaction was observed (Scheme 2D). The corres-
ponding adducts of BHT and TEMPO with 1a and cyclohexyl
radical of 2a were characterized through HRMS analysis.12
Similarly, no measurable reaction was observed in the presence
of O2. These experiments illustrated the involvement of a
radical species (Scheme 2D). A light ON–OFF experiment was
also carried out and it was concluded that the reaction proceeds
only upon blue light irradiation.12 The reaction exhibited a
quantum yield of 0.0216 and thus the possibility of a radical
chain process was ruled out.12 The EDA complex formation
(Scheme 1C) was further supported through UV/Visible
studies.12 Through these studies generation of a donor–acceptor
complex between 1a and 2a with 1 : 1 stoichiometry was
Entry
Variation in standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
None
No DPP
No light
98 (90)c
o5
o5
50
90
86
68
86
52
76
5 mol% DPP instead of 10 mol%
Dibenzyl phosphate instead of DPP
Mes-Acr+ instead of DPP
Mes-Acr+ and KH2PO4 instead of DPP
Rose Bengal instead of DPP
Eosin Y disodium salt instead of DPP
Ir(ppy)3 instead of DPP
Green LED instead of Blue
9
10
11
52
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol,
1.5 equiv.) and Catalyst (0.01 mmol, 0.1 equiv.). b 1H-NMR yield.
c
Isolated yield.
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Table 2 Substrate scopeab
Table 3 Substrate Scope for p-QM’sab
R1
R2
Yield (%)
Ph
Ph
Ph
Ph
4-CF3C6H4
Me
c-Hex (5a)
i-Pr (5b)
Bn (5c)
4-ClC6H4CH2 (5d)
c-Hex (5e)
c-Hex (5f)
68
73
77
42
44
69
a
Reaction conditions:
4 (0.1 mmol, 1.0 equiv.), 2 (0.15 mmol,
b
1.5 equiv.) and Diphenyl phosphate (0.01 mmol, 0.1 equiv.). Isolated
yield.
Scheme 2 Synthetic utility and control experiments.
a
Reaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2 (0.15 mmol, 1.5 equiv.)
b
c
and DPP (0.01 mmol, 0.1 equiv.). Isolated yield. Reaction time: 30 h.
d
1
(0.1 mmol, 1.5 equiv.),
2 (0.1 mmol, 1.0 equiv.) and DPP
established. We were also intrigued by the possibility of direct
excitation of 4-substituted Hantzsch ester as an alternative pathway.
However, 4-alkyl dihydropyridines tend to undergo blue shift.7j In
(0.01 mmol, 0.1 equiv.).
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3a was obtained in 52% yield (Table 1, entry 11). This experiment
also disfavors the direct excitation pathway. Attempts were also
made to develop an asymmetric variant. However, our efforts in
this direction yielded a racemic product (Scheme 2E).
In summary, a photoinduced organocatalytic radical addi-
tion protocol is developed. This straight forward protocol
utilizes no expensive photocatalyst or external additives. The
significance of this protocol is demonstrated through broad
substrate scope and synthesis of biologically active compounds.
Given the wide implications of Brønsted acid catalysis we
believe that this simple yet efficient strategy will further expand
its horizons and pave the way for further development of
sustainable organocatalytic photochemical reactions.
We gratefully acknowledge Prof. Takashi Ooi (Nagoya
University, Aichi, Japan) for helpful discussions. Financial
support was provided by SERB, New Delhi through an Early
Career Research Award (Grant no. ECR/2018/001910). Analy-
tical support from SAIF division of CSIR-CDRI is gratefully
acknowledged. Shiv Shankar Patel and Dileep Kumar thank
UGC, New Delhi for the doctoral fellowship. CDRI Communica-
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Conflicts of interest
There are no conflicts to declare.
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Chem. Commun.
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