Transition-Metal-Free Synthesis of Polyfunctional Triarylmethanes and 1,1-Diarylalkanes by Sequential Cross-Coupling of Benzal Diacetates with Organozinc Reagents

Article abstract of DOI:10.1002/anie.202101682

A variety of functionalized triarylmethane and 1,1-diarylalkane derivatives were prepared via a transition-metal-free, one-pot and two-step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross-coupling is enabled by changing the solvent from THF to toluene, and a two-step S_N1-type mechanism was proposed and evidenced by experimental studies. The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules, such as an anti-tuberculosis agent, an anti-breast cancer agent, a precursor of a sphingosine-1-phosphate (S1P) receptor modulator, and a FLAP inhibitor.

Full text of DOI:10.1002/anie.202101682

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10409–10414
International Edition: doi.org/10.1002/anie.202101682
German Edition: doi.org/10.1002/ange.202101682
Synthetic Methods Very Important Paper
Transition-Metal-Free Synthesis of Polyfunctional Triarylmethanes and
1,1-Diarylalkanes by Sequential Cross-Coupling of Benzal Diacetates
with Organozinc Reagents
Baosheng Wei, Qianyi Ren, Thomas Bein, and Paul Knochel*
Abstract: A variety of functionalized triarylmethane and 1,1-
diarylalkane derivatives were prepared via a transition-metal-
free, one-pot and two-step procedure, involving the reaction of
various benzal diacetates with organozinc reagents. A sequen-
tial cross-coupling is enabled by changing the solvent from
THF to toluene, and a two-step SN1-type mechanism was
proposed and evidenced by experimental studies. The synthetic
utility of the method is further demonstrated by the synthesis of
several biologically relevant molecules, such as an anti-tuber-
culosis agent, an anti-breast cancer agent, a precursor of
a sphingosine-1-phosphate (S1P) receptor modulator, and
a FLAP inhibitor.
Introduction
Triarylmethane and 1,1-diarylalkane scaffolds are impor-
tant core structures in many pharmaceuticals and biologically
active molecules,[1] and are potentially valuable building
blocks for the construction of covalent organic and metal–
organic frameworks (COFs and MOFs) that can play a role in
hydrogen storage, photocatalysis, photoelectrochemistry, and
Scheme 1. Typical methods for the synthesis of triarylmethanes and
1,1-diarylalkanes.
solar cells.[2] Thus, their preparation has attracted much
attention over the past decade.[3] Typically, triarylmethanes
may be prepared by Friedel–Crafts-type reactions (Sche-
me 1a),[4,5] or by various transition-metal-catalyzed cross-
coupling reactions (Scheme 1b).[6–8] These methods were also
used for the preparation of related 1,1-diarylalkanes (Sche-
me 1c).[9,10] Recently, some other methods have also been
developed for the synthesis of triarylmethanes and 1,1-
diarylalkanes.[11,12] Despite the popularity of these methods,
transition-metal-involved cross-couplings often leads to non-
productive synthesis.[6,7,10] Thus, the selective and modular
synthesis of polyfunctional triarylmethanes and 1,1-diaryl-
alkanes from readily accessible starting materials[13] under
transition-metal-free conditions is still an important synthetic
goal, and a general method that can deliver both triaryl-
there are some important drawbacks. For example, Friedel– methanes and 1,1-diarylalkanes would be highly desirable.[14]
Crafts-type reactions are typically limited to electron-rich and
unhindered (hetero)arenes and often result in poor regiose-
lectivity.[4,9] Cross-coupling methods usually require the
troublesome prefunctionalization of coupling partners, and
b-hydride elimination of alkyl or benzylic reagents in
Zinc organometallics are very useful organometallic
À
intermediates for forming new carbon carbon bonds, and
allow the synthesis of a variety of polyfunctional organic
molecules.[15] Usually, transition-metal catalysts are required
for achieving good yields and selectivities.[15c,d] Only a few
reactions of organozinc reagents with electrophiles proceed in
the absence of catalysts.[16] We envisioned that benzal gem-
diacetates of type 1, which can be easily prepared from the
corresponding aldehydes,[17] may be an ideal class of electro-
philes for reaction with organozinc reagents allowing a mod-
ular synthesis of triarylmethanes and 1,1-diarylalkanes
(Scheme 1d). Herein, we wish to report a convenient tran-
sition-metal-free, one-pot and two-step synthesis of triaryl-
methanes and 1,1-diarylalkanes starting from 1. Thus, the
treatment of 1 with excess arylzinc halides of type 2
(Ar2ZnX)[18] either in THF or toluene at 808C smoothly
provides the symmetrical triarylmethanes of type 3. However,
[*] Dr. B. Wei, Q. Ren, Prof. Dr. T. Bein, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101682.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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the treatment of 1 with 2 (1.0 equiv) in THF at 25–608C
selectively provides the diarylmethyl acetate (4), which reacts
in situ with aryl- or alkylzinc halides (Ar3ZnX or alkylZnX)
in toluene at 808C, producing either triarylmethanes of type 5
or 1,1-diarylalkanes of type 6.
part or to the organozinc reagent. However, by using
electron-poor arylzinc reagents such as p-fluorophenylzinc
halide (2d), the substitution reaction with p-methylbenzal
diacetate (1a) proceeded quite sluggishly in THF at 808C
providing 3i in 54% yield after 12 h, but much faster and
high-yielding in toluene at 808C (76% yield, 1 h). A similar
behavior was noticed in the reaction of p-methoxy (1b) and p-
fluoro (1c) benzal diacetates with 2d, and yields of 65% (3j:
808C, 12 h) and 42% (3k: 808C, 12 h) were obtained in THF,
whereas in toluene a clean reaction produced the triaryl-
methanes 3j and 3k in 84% and 72% yield (808C, 1 h),
respectively. A scale-up of these reactions was possible and 3j
was obtained in 82% yield at a 10 mmol scale. The preparation
of triarylmethanes bearing electron-withdrawing substituents
was difficult by Friedel–Crafts reactions, however, using
arylzinc halides bearing electron-poor substituents such as 4-
CF3C6H4ZnX (2e) allowed the preparation of the correspond-
ing triarylmethane 3l in 80% yield. Also, the presence of an
ethynyl substituent in the benzal diacetate was well tolerated
and a cross-coupling with PhZnX provided the desired product
3m in 98% yield. Finally, the reaction of 2,2’-bis-zincated
biphenyl with various benzal diacetates led to 9-aryl-fluorene
derivatives such as 3n and 3o in 72–85% yield (Scheme 2).
A one-pot selective double arylation of benzal diacetates
of type 1 can be readily achieved (Scheme 3). First, the
treatment of 1 with Ar2ZnX (2, 1.0 equiv) in THF at 258C
selectively generated the mono-substituted product of type 4,
and heating the reaction mixture at 608C was necessary in
some cases to achieve a full conversion in this step. Then, after
addition of a second arylzinc reagent (Ar3ZnX) and subse-
quent removal of THF in vacuum, toluene was added and the
reaction mixture was heated typically at 808C for 1 h, leading
to various unsymmetrical triarylmethanes 5a–5l in 51–90%
isolated yield. Heteroarylzinc reagents such as thienyl-,
benzothienyl-, or benzofuranylzinc halides can be used in
the first or second arylation providing triarylmethanes 5m–5r
in 52–75% yield. A range of functional groups were well-
tolerated in the benzal diacetates of type 1 (CN, CF3, Br, Cl,
CO2Me, OMe) as well as in (hetero)arylzinc reagents (F,
OMe, OCF3, SMe, acetal, SiMe3, OTBS, NMe2, CO2Et).
These reactions were scalable as exemplified in the case of 5b
obtained in 83% yield at a 10 mmol scale. Polycyclic arylzinc
halides were also suited affording 5h and 5r. The aldehyde
group in product 5k was introduced by using 4-dimethoxy-
methylphenylzinc halide (2 f)[17] in the reaction performing
the deprotection during work-up. Notably, several compouds
obtained by this method were otherwise unavailable using
previously reported methods,[4,8] which shows the versatility
and synthetic utility of this reaction.
Results and Discussion
In preliminary experiments, we have treated the benzal
diacetate 1a (1.0 equiv) with PhZnX (2a, 1.0 equiv, X =
Cl·MgCl2) at 258C in THF for 12 h and have observed the
exclusive formation of the mono-substituted product 4a in
86% isolated yield. Alternatively, heating the reaction
mixture at 608C also led to a full conversion after 3 h.[17] On
the other hand, using an excess of 2a (3.0 equiv) and heating
the reaction mixture at 808C for 6 h produced the double-
substituted product 3a in 81% isolated yield. Notably, a scale-
up of this reaction (15 mmol) provided the similar yield of 3a
(Scheme 2).
Also, the p-methoxybenzal diacetate (1b) reacted well
with 4-MeOC6H4ZnX (2b) providing the triarylmethane 3b
in 85% yield. Similarly, various benzal diacetates (1c–1e)
reacted with 2b providing the triarylmethanes 3c–3e in 93–
95% yield. The more sterically hindered organozinc reagent
2-MeOC6H4ZnX (2c) also gave the triarylmethane 3 f in 63%
yield. Products of type 3 bearing heterocyclic rings, such as 3g
and 3h, were readily prepared by this method showing that
the heterocyclic moiety can be attached either to the benzal
The above-mentioned method can be extended to the
synthesis of nonsymmetrical 1,1-diarylalkanes of type 6 by
adding a second alkyl- or alkenylzinc reagent to the in situ
formed diarylmethyl acetate 4, followed by heating the
reaction mixture in toluene typically at 808C for 1 h
(Scheme 4A). Thus, various 1,1-diarylalkane derivatives 6a–
6l were obtained in 59–92% yield. A scale-up of these
reactions was also feasible as shown for the formation of 6 f in
60% yield at a 10 mmol scale. Also, many functional groups
were well-tolerated in the benzal diacetates of type 1 (CN,
Scheme 2. Synthesis of symmetrical triarylmethanes from benzal diace-
tates (1) and (hetero)arylzinc reagents (2). [a] The reaction was
performed at room temperature and was completed within 3 h.
[b] Toluene, 808C, 1 h. [c] Toluene, 1208C, 1 h. [d] The 2,2’-bis-zincated
biphenyl was prepared by adding ZnCl2 into the corresponding bis-
magnesiated or cyclometalated lanthanum reagents.[19]
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Scheme 3. One-pot synthesis of unsymmetrical triarylmethane deriva-
tives. [a] In the first step, the reaction mixture was heated in THF at
608C for 3–12 h. [b] The aldehyde moiety was generated after work-up
from a protecting dimethyl acetal.
Scheme 4. One-pot synthesis of 1,1-diarylalkane derivatives of type 6
and 8. [a] In the first step, the reaction mixture was heated in THF at
608C for 3–12 h. [b] The second step required heating in toluene at
1208C for 3 h.
CO2Me, OMe, F, Br) as well as in (hetero)arylzinc reagents (F,
SMe, OMe, CF3, OCF3, CO2Et) and in alkylzinc reagents (Cl,
acetal, CO2Et, CN, cyclohexyl). Besides, E-2-trimethylsilylal-
kenylzinc halide was used in this reaction providing 6m in
43% yield with full configurational retention of the double
bond (E/Z > 99:1). Furthermore, symmetrical 1,1-diarylal-
kanes of type 8 were also obtained starting from the
corresponding alkyl or alkenyl gem-diacetates of type 7
(Scheme 4B). In comparison, the solvent effect of these
reactions was unconspicuous and the scope of arylzinc
reagents was narrow. Only electron-rich arylzinc reagents
with NMe2 or OR substituents gave good results. All efforts to
prepare nonsymmetrical 1,1-diarylalkanes starting from di-
acetates of type 7 failed. As shown in Scheme 4B, 1,1-diaryl-
alkanes 8a–8d were obtained in 54–75% yield. Diacetates
with an adjacent E-alkenyl moiety reacted with full config-
urational retention (E/Z > 99:1), providing 8c’ and 8d’ in
80% and 52% yield, respectively. Besides, a cholesteryl gem-
diacetate gave the expected product 8e in 72% yield, showing
that the reaction may be useful in late-stage functionalization
of steroids and other complex substrates.
To further demonstrate the synthetic utility of this
reaction, we targeted the synthesis of several biologically
relevant compounds. However, anti-tuberculosis agent 5u[20a]
and anti-breast cancer agent 5v[20b] were obtained in low yield
by the above two-step procedure, because the formation of
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Scheme 5. Synthesis of various biologically relevant compounds.
quinonemethide precursors will easily lead to symmetrical
triarylmethanes in the above conditions.[21] Thus, as shown in
Scheme 5, 5u and 5v were prepared by a modified procedure,
which makes use of the reactivity difference of organozinc
reagents.[17] The dropwise addition of a mixture of 2b
(1.0 equiv) and 2g (3.0 equiv) to 1g over 12 h led to 5s in
67% yield. Similarly, the mixture of 2g (1.0 equiv) and 2h
(3.0 equiv) was added dropwise to 1b leading to 5t in 70%
yield. Follow-up desilylation and alkylation led to the desired
anti-tuberculosis agent 5u (94% yield) and anti-breast cancer
agent 5v (89% yield). Besides, a precursor (6n) of a sphingo-
sine-1-phosphate (S1P) receptor modulator[22a] was obtained
in 91% yield by sequential cross-coupling of 1m with 2i and
4-chlorobutylzinc halide under indicated conditions. Also, the
FLAP inhibitor 6q[22b] was prepared in 5 steps (1.23 g, 54%
overall yield starting from 1n). Specifically, the sequential
cross-coupling of 1n with 2a and neopentylzinc halide led to
6o in 83% yield. 6o was treated with magnesium in the
presence of LiCl to produce a magnesium reagent which was
treated with NCCO2Me providing 6p in 71% yield. Follow-up
desilylation and alkylation led to 6q in 92% yield.
(2a), and their final reaction mixture, indicating the absence
of transition-metal catalysis.[24]
To elucidate the mechanism of the reaction, we proposed
that the first step was a nucleophilic addition of the arylzinc
species to an in situ formed ketone oxonium. The second step
may proceed by virtue of the coordination of the zinc center
with the acetyl moiety, followed by a nucleophilic addition to
the generated benzhydryl cation to form the final product
(Scheme 6a). Toluene favors coordination of zinc reagents,
thus promoting the reaction. For experimental evidence, an
intramolecular diacetate 9 was treated with excess 2b in
toluene at 1208C for 3 h, only generating the mono-substi-
tuted product 10 in 74% isolated yield. The difficulty of
a second substitution on 10 may be explained by the extra
stabilization of the lactone 10. An allyl-substituted benzhy-
dryl acetate 4d was treated with excess 1-penten-5-ylzinc
halide providing 11 in 58% yield, which revealed the possible
formation of a benzhydryl carbocation in this reaction
(Scheme 6b).
To examine the salt effect on the reaction, control Conclusion
experiments[17] were done showing that the involved halide
ions, LiCl, and MgCl2 have no observable effect, and ZnCl2
may have a limited accelerating effect on the reaction.[23] To
examine whether any transition metal catalysts were present,
ICP-MS analysis was performed on solvents (THF and
toluene), a representative substrate (1a), organozinc reagent
We have developed a useful method for the preparation of
functionalized triarylmethane and 1,1-diarylalkane derivatives
from readily available diacetates and organozinc reagents. This
one-pot reaction is transition-metal-free, also featuring its
versatility, scaleability, wide scope, and synthetic utility in the
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efficient synthesis of biologically relevant molecules. The
solvent effect (toluene vs. THF) is remarkable. A two-step
SN1-type mechanism was proposed and partly evidenced by
experimental study. Further studies for applications in
material science are underway in our laboratories.
Acknowledgements
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We thank the Deutsche Forschungsgemeinschaft (DFG) and
the Cluster of Excellence e-conversion for financial support.
We also thank Albemarle (Frankfurt) and BASF (Ludwig-
shafen) for generous gifts of chemicals. Open access funding
enabled and organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
À
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Keywords: cross-coupling ·diacetates ·organozinc reagents ·
transition-metal-free ·triarylmethane and 1,1-diarylalkane
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Manuscript received: February 3, 2021
Accepted manuscript online: February 24, 2021
Liu, L. Yu, S. Zhu, Angew. Chem. Int. Ed. 2020, 59, 21530 – Version of record online: March 17, 2021
10414 www.angewandte.org ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew. Chem. Int. Ed. 2021, 60, 10409 –10414