Catalyst-Enabled Chemodivergent Construction of Alkynyl- And Vinyl-Substituted Diarylmethanes from p-Quinone Methides and Alkynes

Article abstract of DOI:10.1021/acs.orglett.9b02810

Here, a catalyst-controlled chemodivergent 1,6-addition of p-quinone methides with alkynes was developed, affording diverse alkynyl- and vinyl-substituted diarymethanes. In this transformation, copper catalyzed the direct 1,6-addition of p-QMs with alkynes, while iron promoted the three components reaction of p-QMs, alkynes, and halogens from iron salts or added HX acid. The salient features of this transformation include completely controllable chemoselectivity, mild conditions, inexpensive catalysts, and good substrates scopes.

Full text of DOI:10.1021/acs.orglett.9b02810

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalyst-Enabled Chemodivergent Construction of Alkynyl- and
Vinyl-Substituted Diarylmethanes from p‑Quinone Methides and
Alkynes
Zhenli Liu, Haofeng Xu, Tengfei Yao, Junliang Zhang,* and Lu Liu*,†,‡
†
†
†
,†
†School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, P.R.
China
‡
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University,
Shanghai 200062, P.R. China
*
S Supporting Information
ABSTRACT: Here, a catalyst-controlled chemodivergent 1,6-
addition of p-quinone methides with alkynes was developed,
affording diverse alkynyl- and vinyl-substituted diarymethanes.
In this transformation, copper catalyzed the direct 1,6-addition
of p-QMs with alkynes, while iron promoted the three
components reaction of p-QMs, alkynes, and halogens from
iron salts or added HX acid. The salient features of this
transformation include completely controllable chemoselec-
tivity, mild conditions, inexpensive catalysts, and good
substrates scopes.
5e
5f
5g
5h
he development of efficient methodologies to selectively
Enders, Deng, Lin and Yao, Zhao, and others have
T
construct diverse compound libraries is highly important
in modern organic synthesis. In this context, divergent
explored a lot of 1,6-conjugate addition reactions of p-QMs with
1
3
C(sp ) nucleophiles, such as malonates, aldehydes, oxindoles,
5
6a
6b
6c
6d
synthesis of diverse products from the same starting materials
by tuning the reaction conditions such as temperature, pressure,
solvent, catalyst, and so on attracts more and more attention but
and glycine Schiff base. Liao, Sun, Anand, Fan, our
6e,f
6g
6h
group, Wu, Lin, and Yao have reported a few examples of
,6-conjugate addition reactions with C(sp ) nucleophiles
2
1
2
poses considerable challenges. Diaryl or polyarylmethane
compounds are important structural units in many natural
products and bioactive molecules (Figure 1). For example,
6
including aromatic rings and alkenes. However, to the best of
our knowledge, there is only one example for the 1,6-addition of
p-QMs with C(sp) nucleophiles. Very recently, Anand reported
a N-heterocyclic carbene (NHC)-catalyzed 1,6-conjugate
addition of p-QMs with TMSCN for access to α,α′-diarylated
7
nitriles. However, alkynes, which are known as versatile
building blocks and important intermediates for compounds
of value in biochemistry and material science, have not yet been
explored for the nucleophilic addition to p-QMs. Although there
are few reactions of p-QMs with alkynes, alkynyl normally serve
as electrophiles. Lin and co-workers discovered a cascade three-
component iodoazidation of p-quinone methides to construct
Figure 1. Bioactive molecules containing diarymethanes.
9a
spiro[4.5]deca-6,9-dien-8-ones (Scheme 1a). The same group
reported a silver-catalyzed cascade 1,6-addition/5-exo-dig
cyclization reaction between p-quinone methides and propargyl
DAMNIs and DABOs were expected to suppress HIV-1 and
3
antagonists of the thyroid hormone receptor. Thus, the
development of efficient and diverse methods to access diaryl
and polyarylmethane compounds is highly desirable.
9b
malonates (Scheme 1b). The Shi group disclosed base-
catalyzed [4 + 2] cycloaddition of o-hydroxyphenyl-substituted
Recently, p-quinone methides (p-QMs) have been proven to
be an important Michael acceptor to obtain diaryl and
polyarylmethane compounds via 1,6-conjugated addition and
related cycloaddition. In the past decade, a series of efficient
catalytic systems including metal catalysts and organocatalysts
have been established for the reactions of p-QMs with a wide
9c
p-quinone methides with ynones or benzyne (Scheme 1c).
6e,f
During the course of our ongoing studies on p-QMs and
alkyne chemistry, we wondered whether teminal alkynes could
10
Received: August 8, 2019
4
−8
5a−c
5d
range of nucleophiles.
Recently, Fan,
Jørgensen,
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02810
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Reactions of p-QMs with Alkynes
Table 1. Optimization of Reaction Conditions
serve as C(sp) nucleophiles via 1,6-addition of p-QMs (Scheme
1
d).
To validate this hypothesis, we initiated our investigation
a
Unless otherwise noted, all reactions were carried out with 2a (0.2
mmol), 1a (0.4 mmol), Cat (X mol %) in solvent (2 mL) at 50 °C for
b
c
d
using aryl acetylene 1a and p-QM 2a as the model substrates.
The selected results of conditional optimization are summarized
in Table 1. The desired product alkynyl-substituted diaryl-
methane 3aa was isolated in 69% yield at 50 °C with the catalysis
6−24 h. Isolated yield. 60 °C. 2 equiv of HBr was added at room
e
temperature for 24 h. FeBr (5 mol %) and HBr (2.0 equiv) were
3
added at room temperature for 3 h.
of 10 mol % of In(OTf) in toluene for 48 h (Table 1, entry 1).
3
Because of this promising result, we then investigated several
Lewis acids including Bi(OTf) and Cu(OTf) (Table 1, entries
proceeds smoothly, affording the corresponding product 3ak in
71% yield. In the case of alkynes, this conjugated 1,6-addition
tolerated various substituents on the phenyl ring close to alkynyl,
such as H (3ba), electron-donating methyl (3ca), ethoxyl (3da),
and electron-withdrawing halo (3ea−3ga) at the para position,
delivering the corresponding products in good yields (65−
78%). It was noteworthy that alkynes with heteroaryl and
ferrocenyl derived alkynes were also suitable substrates for this
transformation (3ha−3ia). In addition, the enyne substituted
diarylmethane 3ja can also be obtained via this approach.
However, aliphatic alkyne (1-octyne) was not suitable in this
transformation, affording messy products. We also synthesized
TMS-substituted p-QM 2l. Unfortunately, only 41% ketone
from hydrolysis of alkyne 1a was isolated after the reaction of 2l
and 1a under the standard conditions.
3
2
2
and 3 and Table S1), among which Cu(OTf) was found to be
2
the best catalyst, delivering 80% isolated yield at 60 °C. Cu(I)
can also catalyze this reaction, but the yield is lower than Cu(II)
(
Table 1, entry 4). Solvent screening showed that acetonitrile,
DMF, dioxane, and THF cannot improve the isolated yield
(
Table 1, entries 5−8). Unfortunately, no enantioselectivity was
obtained after several chiral ligands such as Box and PyBox were
tried (for more details, see Table S1, entries 14−17). To our
surprise, Fe(OTf) could not catalyze the reaction of p-QM 2a
3
with terminal alkyne 1a (Table 1, entry 9). When FeBr was
3
added in this reaction, a new product 4a via three-component
reaction involving alkyne, p-QMs, and bromine was obtained.
After further careful screening, the catalytic system involving 5
mol % of FeBr and 2 equiv of HBr showed the best catalytic
Having successfully achieved the Cu-catalyzed 1,6-addition of
p-QMs with alkynes, we then examined the substrate scope of
iron-promoted three-component bromoalkenylation. There are
3
activity, and 4a was obtained in 86% yield after 3 h at room
temperature (Table 1, entry 14). This result indicated that iron
was an efficient catalyst for this three-component reaction.
With the optimized reaction conditions for the synthesis of
alkynyl-substituted diarylmethanes in hand (Table 1, entry 3),
we then investigated the substrate scope of various p-QMs 2 and
alkynes 1. As shown in Figure 2, diverse substituents on p-QMs 2
are tolerable in this reaction. The reaction of p-QMs 2 with an
electron-donating group and H affords the corresponding
products 3aa−3ag in 70−82% yield. The p-QMs involving
naphthyl and electron-withdrawing groups (F, CN) on phenyl
were suitable for this transformation (3ah−3ai). Gratifyingly,
the reaction of p-QMs with an alkyl group (2k) and alkyne 1a
two catalytic conditions: In conditions A, 40 mol % of FeBr was
3
added as the catalyst and bromine source. In conditions B, the
amount of FeBr decreased to 5 mol %, and 2 equiv of HBr was
3
added as bromine source. We first examined the substrate scope
of p-QMs. In conditions A, it was found that p-QMs bearing
1
electron-donating R groups at different positions of the phenyl
ring could generate products 4 in moderate yields (52%−85%)
and good to excellent Z/E selectivity (Figure 3, 4a−4i). If the
phenyl ring of p-QM was replaced by tert-butyl, the reaction
could afford the corresponding product 3ak in 67% yield and 5:1
stereoselectivity. Then a variety of alkynes were tested. 4-
B
DOI: 10.1021/acs.orglett.9b02810
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ethoxyphenylacetylene gave the corresponding products 4k in
good yield (72%) with excellent selectivity (>20:1). Further-
more, the alkynes involving heteroaryl and ferrocenyl were also
suitable for this transformation (4i−4m). However, the
electron-withdrawing group (−NO ) on alkynes lowered the
2
yield and selectivity (4n). Compared with conditions A, the
reaction temperature in conditions B was lowered to room
temperature, and the yield of 4 was higher with the decreasing
Z/E selectivities (4a−4n). Unfortunately, the reaction of the p-
QM with isopropyl instead of tert-butyl could not give the
corresponding product in conditions A. However, the product
4
o could be obtained in 77% yield with 1:1 Z/E selectivity under
conditions B. The p-QM with methyl on phenol was also
suitable for this transformation and gave the product 4p under
conditions A and B. Similarly, both aliphatic alkyne- and TMS-
substituted p-QM 2l were still not compatible in these two
conditions. In addition, the reaction of internal alkyne does not
work (for more details, see Table S6).
To further broaden the substrate scope of the reaction, we
wondered if other halogens (F, Cl, I) can also be involved in the
reaction. When HCl was used instead of HBr, the reaction also
worked smoothly to afford the corresponding chloro-substituted
olefin product 5a. However, the yield of chloro olefin is lower
than that yield of brominated olefin, which might be attributed
to the lower nucleophilicity of chloride than that of bromide. We
then examined the substrate scope of this chloroalkylation
reaction of alkynes. As shown in Figure 4, when the substituent
Figure 2. Copper-catalyzed 1,6-additions of p-QMs with terminal
alkynes. Unless otherwise noted, all reactions were carried out with 2
(
0.2 mmol), 1 (0.4 mmol), and Cu(OTf) (10 mol %) in toluene (2
2
mL) for 6−24 h.
Figure 4. FeBr -mediated haloalkenylation of p-QMs. Conditions A: 2
3
(
0.2 mmol), 1 (0.4 mmol), and 40 mol % of FeCl was added in toluene
3
(
2 mL) at 50 °C for 6−12 h. Conditions B: 2 (0.2 mmol), 1 (0.4 mmol),
HX (2 equiv), and 5 mol % of FeBr were added in toluene (2 mL) at
3
room temperature for 3−8 h. Total yield of two isolated isomers. Z/E
1
were determined by H NMR.
on the phenyl ring of p-QMs was an electron-donating group, it
gave the corresponding chloroolefins 5a−5d in 50−67% yield. It
seemed that the position of the substituents had little influence
on the reaction, while the Z/E ratio of the corresponding
chloroolefin product had a huge impact. Methoxy at the para
position of the phenyl ring of p-QMs gave an excellent Z/E ratio
(5a, Z/E = 12:1), but when the phenyl ring of p-QM was
replaced by naphthyl, Z/E of 5d was reduced to 1:1. When the
Figure 3. FeBr -mediated bromoalkenylation of p-QMs. Conditions A:
3
2
(0.2 mmol), 1 (0.4 mmol), and 40 mol % of FeBr were added in
3
toluene (2 mL) at 50 °C for 6−12 h. Conditions B: 2 (0.2 mmol), 1 (0.4
mmol), HBr (2 equiv), and 5 mol % of FeBr was added in toluene (2
3
mL) at room temperature for 3−8 h. Total yield of two isolated isomers.
1
Z/E ratios were determined by H NMR.
C
DOI: 10.1021/acs.orglett.9b02810
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituent in phenyl ring of p-QMs was an electron-with-
drawing group, the yield of 5f decreased to 32%. When the tert-
butyl of p-QM was changed by isopropyl, the yield was 48% (Z/
E = 2:1). Ferrocenylethyne gave the corresponding product 5f in
Scheme 3. Proposed Mechanism
5
0% yield and 12:1 Z/E ratio. In addition, the moderate Z/E
ratios of 5b−5e could be improved by using 40 mol % of FeCl
3
(
conditions A) as promoter instead of HCl. Considering the
commonality of halogenated hydrogen, we envisioned whether
HF and HI could also react accordingly. As we hypothesized,
fluorinated product 5h was obtained in 41% yield (Z/E = 3.5:1)
when HF (2 equiv) was added to the reaction with iron catalyst
at room temperature for 48 h. Because the nucleophilicity of I is
the highest in halogen, the corresponding iodo product 5i was
obtained in a yield of 87% (Z/E = 1.5:1).
Furthermore, these two divergent reactions were easy to scale
up. A gram-scale reaction of 1.5 g of 1a and 0.8 g of 2a was
carried out under the standard conditions, furnishing 1.58 g of
3
aa in 75% isolated yield catalyzed by Cu(OTf) and 1.64 g of 4a
2
in 66% isolated yield promoted by FeBr , respectively (Scheme
3
2
). Moreover, to exhibit the synthetic application of these
11g
the copper alkynylide bond intermediate IF,
which then
Scheme 2. Gram Scale-up and Transformation of Products
attacked p-QMs 2 to generate intermediate IG. After
protonation and regeneration of the catalyst Cu(OTf) , product
2
3
was obtained. Two plausible pathways for the Fe-catalyzed
three-component reaction are depicted in Scheme 3B. If HBr
was absent in the reaction, FeBr -coordinated p-QMs 1 afforded
3
the intermediate IA, which was attacked by the π electron of
alkyne 2 to give the vinyl cation IB. Then intimate ion pair IB
underwent the intramolecular type addition of bromide anion to
generate intermediate IC, which posed a Z double bond. Finally,
the hydrolysis of IC gave the product 4 with Z as the major
isomer and released Fe(OH)Br to promote the next trans-
2
formation. Under conditions B, p-QMs 1 coordinated with Fe or
protonation to afford the intermediate ID, which was attacked
by the π electron of alkyne 2 to give the vinyl cation IE. Because a
−
lot of Br was generated in solution, intermediate IE underwent
the intermolecular addition of free bromide anion to afford the
product 4 as a Z/E mixture.
In summary, we have developed a novel catalyst-controlled
chemodivergent reaction of p-quinone methides and alkynes.
This protocol provides facile access to diverse substituted
alkynyl- and vinyl-substituted diarylmethanes, which widely
exist in many natural products and bioactive molecules. The
salient features of this transformation include broad scope of
substrates, inexpensive metal catalysts, controllable chemo-
selectivity, mild conditions, simple operation, easy gram-scale
use, and diverse convenient transformations of the products.
divergent reactions, several transformations of 3aa and 4a are
shown in Scheme 2. Compound 3aa can be oxidized by MnO at
2
room temperature, affording alkynyl p-QMs 6 in excellent yield.
The alkynyl p-QMs 6 can be converted into spiro compound 11
in 80% yield via tandem 1,8-conjugated addition/6-endo trig
cyclization. Under acidic conditions, 3aa isomerized to vinyl p-
QMs 7 in moderate yield. Compound 4a could also deliver vinyl
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02810.
p-QMs 7 in 47% yield promoted by AlCl . Compound 4a could
3
be easily oxidized to quinone 8 by Ag O, and the protection of
2
Experimental procedures and characterization data
hydroxyl of 4a was achieved in excellent yield. Various coupling
reactions on alkenyls should be suitable for 4a. For example, 10
can be obtained in 64% yield via Sonogashira coupling reaction
of 4a and terminal alkynes. However, 3aa could not convert into
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
4
a under conditions A.
Based on the above results and previous studies, we
*
E-mail: lliu@chem.ecnu.edu.cn.
E-mail: jlzhang@chem.ecnu.edu.cn.
considered that the Cu(II)-catalyzed 1,6-addition reaction is
somehow similar to the known Cu(II)-catalyzed addition
*
11
ORCID
reaction of alkynes to unsaturated double bonds. As illustrated
in Scheme 3A, Cu(OTf) -activated terminal alkyne 1 resulted in
Junliang Zhang: 0000-0002-4636-2846
2
D
DOI: 10.1021/acs.orglett.9b02810
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
(
6) For selected examplexs of C(sp ) nucleophiles, see: (a) Lou, Y.;
Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem., Int. Ed.
015, 54, 12134−12138. (b) Wang, Z.; Wong, Y.-F.; Sun, J. Angew.
Lu Liu: 0000-0003-2151-891X
Notes
2
Chem., Int. Ed. 2015, 54, 13711−13714. (c) Ramanjaneyulu, B. T.;
Mahesh, S.; Anand, R. V. Org. Lett. 2015, 17, 3952−3955. (d) Goswami,
P.; Sharma, S.; Singh, G.; Anand, R. V. J. Org. Chem. 2018, 83, 4213−
4220. (e) Zhang, X.; Gan, K.; Liu, X.; Deng, Y.; Wang, F.; Yu, K.; Zhang,
J.; Fan, C. Org. Lett. 2017, 19, 3207−3210. (f) Li, S.-H.; Liu, Y.-Y.;
Huang, B.; Zhou, T.; Tao, H.-M.; Xiao, Y.-J.; Liu, L.; Zhang, J.-L. ACS
Catal. 2017, 7, 2805−2809. (g) Zhou, T.; Li, S.-H.; Huang, B.; Li, C.;
Zhao, Y.; Chen, J.-Q.; Chen, A.-L.; Xiao, Y.-J.; Liu, L.; Zhang, J.-L. Org.
Biomol. Chem. 2017, 15, 4941. (h) Kang, T.-C.; Wu, L.-P.; Yu, Q.-W.;
Wu, X.-Y. Chem. - Eur. J. 2017, 23, 6509−6513. (i) Yang, C.; Gao, S.;
Yao, H.-Q.; Lin, A.-J. J. Org. Chem. 2016, 81, 11956−11964.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21572065 and 21772042), the Science and
Technology Commission of Shanghai Municipality
(
18JC1412300), and the Program for Changjiang Scholars
and Innovative Research Team in University (IRT_16R25) for
financial support.
(
7) For the C(sp) nucleophile, see: Goswami, P.; Singh, G.; Anand, R.
V. Org. Lett. 2017, 19, 1982−1985.
8) For selected others examplexs of p-QMs, see: (a) Chen, M.; Sun,
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DOI: 10.1021/acs.orglett.9b02810
Org. Lett. XXXX, XXX, XXX−XXX