δ-Cyano substituted: Para -quinone methides enable access to unsymmetric tri- And tetraarylmethanes containing all-carbon quaternary stereocenters

Article abstract of DOI:10.1039/d0ob00551g

para-Quinone methides bearing an electron-withdrawing cyano group at the exocyclic methylene δ-position were identified as valuable 1,6-conjugate addition building blocks for acyclic all-carbon quaternary stereocenter construction. A wide variety of electron-rich arenes as nucleophiles were tolerated, effectively furnishing diverse unsymmetrical triarylmethanes bearing all-carbon quaternary stereocenters. The robust transformable abilities of the cyano group provide a platform to access other valuable functional group-containing unsymmetrical tri- and tetraarylmethanes that are otherwise difficult to be prepared. Computational studies supported the hypothesis that the cyano group at the δ-position tunes the molecular electron-density distribution, and the stability of para-quinone methides is enhanced by lowering their polymerizability.

Full text of DOI:10.1039/d0ob00551g

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δ-Cyano substituted para-quinone methides
enable access to unsymmetric tri- and
tetraarylmethanes containing all-carbon
quaternary stereocenters†
Cite this: DOI: 10.1039/d0ob00551g
Yue Qi,‡a Fang Zhang,‡c Lin Wang,a Aili Feng,b Rongxiu Zhu, b Shutao Sun,*b
b
Wei Li*a and Lei Liu
*
para-Quinone methides bearing an electron-withdrawing cyano group at the exocyclic methylene
δ-position were identified as valuable 1,6-conjugate addition building blocks for acyclic all-carbon qua-
ternary stereocenter construction. A wide variety of electron-rich arenes as nucleophiles were tolerated,
effectively furnishing diverse unsymmetrical triarylmethanes bearing all-carbon quaternary stereocenters.
The robust transformable abilities of the cyano group provide a platform to access other valuable func-
tional group-containing unsymmetrical tri- and tetraarylmethanes that are otherwise difficult to be pre-
pared. Computational studies supported the hypothesis that the cyano group at the δ-position tunes the
molecular electron-density distribution, and the stability of para-quinone methides is enhanced by lower-
ing their polymerizability.
Received 14th March 2020,
Accepted 17th April 2020
DOI: 10.1039/d0ob00551g
rsc.li/obc
However, p-QMs bearing an electron-withdrawing group (EWG)
at the δ-position might not be accessible through such a proto-
Introduction
Because of the intrinsic electrophilic property, para-quinone col. Our group adopted an oxidative C–H cleavage strategy to
methides (p-QMs) have emerged as attractive and widely used
building blocks in a variety of valuable organic transform-
ations, particularly 1,6-conjugate addition reactions.1–3
However, owing to their general instability towards polymeriz-
ability,4 current studies suffered from significant structural
limitations of p-QMs (Fig. 1A).2,3 First, the existing methods
typically focused on p-QMs bearing a mono-aryl group at the
δ-position for tertiary stereocenter formation. Second, two
t
bulky α-substituents (e.g., Bu) were prerequisite. The state of
the art of structural limitations of p-QMs seriously hampers
the advance of the promising strategy in all-carbon quaternary
stereocenter construction. Accordingly, Sun developed an
elegant protocol to in situ generate δ-electron-donating group
(EDG) substituted p-QM intermediates through Brønsted acid
catalyzed dehydration of p-hydroxybenzyl alcohols (Fig. 1B).5
aDepartment of Pharmaceutical Analysis, School of Pharmacy, Shandong University
of Traditional Chinese Medicine, Jinan 250355, China. E-mail: liwei6911@163.com
bSchool of Chemistry and Chemical Engineering, Shandong University, Jinan 250100,
China. E-mail: leiliu@sdu.edu.cn
cDepartment of pharmacy, Jinan Central Hospital Affiliated to Shandong First
Medical University, Jinan 250013, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob00551g
Fig. 1 Overview of the scope of p-QMs in 1,6-conjugate addition
‡These authors contributed equally to this work.
reactions.
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address such a limitation (Fig. 1C).6 However, diverse carbon catalyst (entry 1, Table 1). Brønsted acid additives such as
nucleophiles are not compatible with the strongly oxidative AcOH and diphenyl phosphate proved to be futile (entries 2
conditions, thus limiting the scope of nucleophilic com- and 3, Table 1). An extensive investigation of Lewis acid addi-
ponents. Using pre-prepared, isolable, and storable tives revealed that when 10 mol% of Bi(OTf)3 was used, the
δ,δ-disubstituted p-QMs as substrates can avoid the aforemen- arylation of 1a proceeded efficiently at rt in 0.25 h, providing
tioned incompatibility, and the nucleophilic component scope the expected unsymmetrical triarylmethane 3a in 93% yield
would be extremely expanded. We envisioned that installing (entries 4–8, Table 1).
an electron-withdrawing group at the exocyclic methylene
With the optimized conditions in hand, the scope of the
δ-position would tune the molecular electron-density distri- quinone part of p-QMs was investigated (Scheme 1). p-QMs
bution, and the stability of the resulting p-QMs might be bearing two small substituents at the α-positions were well tol-
enhanced by lowering their polymerizability.7 In light of the erated, as demonstrated by the formation of triarylmethane 3b
significance in modern pharmacology and robust transform- in 90% yield. α-Mono-substituted p-QMs 1c–1e bearing diverse
able properties, a cyano group was placed at the δ-position for electron-donating and electron-withdrawing moieties were also
study (Fig. 1D).8
suitable substrates, and the respective products 3c–3e were iso-
Triarylmethanes are privileged structure motifs in medic- lated in 88%–92% yields.
inal chemistry, materials science, and organic synthesis.9
The scope of δ-aryl substituents was next explored
Construction of unsymmetrical triarylmethanes containing ter- (Scheme 2). In general, p-QMs 4a–4k bearing a wide range of
tiary stereocenters has been extensively studied.10 However, electronically varied aryl moieties with different substitution
efficient preparation of unsymmetrical triarylmethanes patterns at the δ-position were well compatible with the mild
bearing all-carbon quaternary stereocenters has remained conditions, furnishing the respective triarylmethanes 5a–5k in
underdeveloped.11 Herein, we reported 1,6-conjugate addition 86–94% yields. Polyarene naphthalene substituted 4l and 4m
of a variety of electron-rich arenes to pre-synthesized δ-CN- also proved to be suitable coupling partners.
δ-aryl substituted p-QMs for preparation of diverse unsymme-
The scope of nucleophilic arene components was then eval-
trical triarylmethanes bearing all-carbon quaternary stereocen- uated (Scheme 3). A broad range of electron-rich heteroarenes
ters (Fig. 1D). Further manipulation of the nitrile group pro- proved to be well compatible with the mild conditions
vides access to a range of untouched, highly functionalized (Scheme 3A). Substituted furans were suitable coupling part-
molecules of great interest. For example, unsymmetrical tetra- ners, as demonstrated by the generation of unsymmetrical tri-
arylmethanes, which are extraordinarily difficult to synthesize arylmethanes 7a and 7b with high efficiency. Thiophenes (6c
by the existing methods, can be readily prepared.11a,b
and 6d) together with pyrroles (7e and 7f) and indole 7g were
also competent nucleophiles for the process. Phenols and ani-
lines participated in the 1,6-conjugate addition reactions
smoothly, affording the corresponding products 7h–7m in
85–95% yields (Scheme 3B). Anisole derivatives (6n and 6o)
were also found to be well tolerated, though a slightly higher
temperature was required (Scheme 3C). Electron-deficient
arenes proved to be futile nucleophilic components for the
method. While the scope of carbon nucleophiles was not
Results and discussion
Initially, 1,6-conjugate addition of furan 2a to δ-CN-δ-aryl di-
substituted p-QM 1a was selected as the model for optimiz-
ation (Table 1). No reaction was observed in the absence of any
Table 1 Reaction condition optimizationa
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
AcOH
Diphenyl phosphate
Mg(OTf)2
Cu(OTf)2
Sc(OTf)3
AgOTf
24
24
24
24
24
24
24
0.25
<5
<5
<5
<5
10
27
62
93
Bi(OTf)3
a Reaction conditions: a mixture of 1a (0.1 mmol), 2a (0.12 mmol), and
catalyst (10 mol%) in CH2Cl2 (2 mL) at rt. b Yield of the isolated
product. Tf = trifluoromethanesulfonyl.
Scheme 1 Scope of substituent patterns on the quinone moiety.
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Scheme 2 Scope of δ-aryl moieties.
thoroughly examined, these results provide a proof-of-concept
for the generality and modularity of δ-CN-δ-aryl disubstituted
p-QMs as valuable 1,6-conjugate addition building blocks for
constructing unsymmetric triarylmethanes containing all-
carbon quaternary stereocenters.
The synthetic utilities of the method were next studied
(Scheme 4). The phenolic hydroxyl group in 5g was removed
through triflation followed by Pd-catalyzed hydrogenation,
affording 8 in 87% yield over two steps (Scheme 4A). The
nitrile moiety can be converted into a range of valuable func-
tional groups. For examples, 3a underwent basic hydrolysis,
giving triarylacetamide 9 in 92% yield (Scheme 4B). Moreover,
the nitrile moiety in 3a was reduced by DIBAl-H providing
triarylated acetaldehyde 10 in 83% yield (Scheme 4C). Finally,
the cyano group can be transformed into heteroaromatics,
leading to tetraarylmethanes 11 and 12 that are otherwise
difficult to be prepared (Schemes 4D and E).
Scheme 3 Scope of nucleophilic arene components. a Reaction for 2 h.
b Reaction for 12 h. c Reaction for 4 h. d Reaction for 1 h. e Reaction in
ClCH2CH2Cl at 70 °C for 2 h.
δ-Aryl mono-substituted p-QM 1f without any substituent
on the quinone moiety is an unstable species and cannot be The obtained molecular electrostatic potential diagrams
isolated (Fig. 2A). Instead, installing a cyano group into the suggested obvious differences in the electron densities around
δ-position of 1f provides disubstituted p-QM 1a, which has the p-QM substructures of 1f and 1a (Fig. 2B). The NBO ana-
proved to be a stable, isolable, and storable species. To lyses further certify the variance of atomic charges on p-QM
examine the electronic structures and their effects on the stabi- motifs (Fig. 2C). Given that the instability of 1f mainly origi-
lity of the respective p-QMs 1f and 1a, we performed electro- nated from self-polymerization, several variances of partial
static potential analyses (Fig. 2B) using the Multiwfn program atomic charges in 1a by introducing an electron-withdrawing
and natural bond orbital (NBO) analyses (Fig. 2C) using the cyano group into the δ-position of 1f merit further comment.
NBO 3.1 version of Gaussian 09 at the B3LYP/6-311+g** level. First, the anionic property of the nucleophilic carbonyl oxygen
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somewhat enhanced, the increased steric hindrance at the
δ-position might counteract the influence on electrophilicity.
The calculated data support our initial hypothesis that instal-
ling an electron-withdrawing cyano group at the exocyclic
methylene δ-position would tune the molecular electron-
density distribution, and the thermal stability of the resulting
p-QMs would be enhanced by lowering their polymerizability.
Conclusions
In summary, placing an electron-withdrawing cyano group into
the exocyclic methylene δ-position of p-QMs proved to be ben-
eficial for enhancing their stability, and thus the scope of
these valuable building blocks for 1,6-conjugate addition reac-
tions was significantly expanded. By employing pre-syn-
thesized δ-CN-δ-aryl substituted p-QMs as substrates, a broad
range of electron-rich arenes participated in the arylation
process, providing a wide array of unsymmetrical triarylmeth-
anes bearing all-carbon quaternary stereocenters with high
efficiency. The robust transformable properties of the nitrile
moiety enable facile access to other valuable functional group-
containing unsymmetrical tri- and tetraarylmethanes that are
otherwise difficult to be prepared. Computational studies sup-
ported the hypothesis that installing an electron-withdrawing
cyano group at the exocyclic methylene δ-position would tune
the molecular electron-density distribution, and the thermal
stability of the resulting p-QMs would be enhanced by lowering
their polymerizability. Ongoing studies focus on exploring the
reactivities of pre-synthesized p-QMs bearing other valuable
EWGs at the δ-position and the corresponding asymmetric
variants.
Scheme 4 Synthetic utilities.
Experimental
General procedure for 1,6-conjugate arylation of
pre-synthesized δ-CN-δ-aryl substituted p-QMs with
electron-rich arenes (Schemes 1–3)
To a solution of 1 or 4 (0.1 mmol, 1.0 equiv.) in CH2Cl2
(3.0 mL) were successively added Bi(OTf)3 (0.01 mmol, 0.1
equiv.) and arene 2 or 6 (0.12 mmol, 1.2 equiv.) at rt. The
mixture was stirred at the same temperature for 20 min. Then
the mixture was concentrated and purified by flash column
chromatography (petroleum ether/ethyl acetate) to give the
desired triarylmethane 3, 5, or 7 in good yields.
Fig. 2 (A) Two representative p-QMs for comparison. (B) Molecular
electrostatic potential diagrams of p-QMs 1f and 1a. (C) Calculated NBO
charges (in e) for p-QMs 1f and 1a.
Conflicts of interest
There are no conflicts to declare.
in 1a significantly diminished. Second, the cationic properties
of two electrophilic β-carbons in 1a also diminished, though
no change was observed on the carbonyl carbon. Third, while
the cationic property of the electrophilic δ-carbon in 1a was
Acknowledgements
We gratefully acknowledge the National Science Foundation of
China (21722204, 21971148).
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