Thiourea catalyzed 1,6-conjugate addition of indoles to para-quinone methides

Article abstract of DOI:10.1016/j.tetlet.2021.153315

An efficient thiourea catalyzed 1,6-conjugate addition of indoles to para-quinone methides (p-QMs) was developed. p-QMs was activated by a weak hydrogen-bond effect. The reaction is featured mild reaction conditions and wide substrate scope. A series of C-3 bisaryl methine substituted indoles are prepared in high yield.

Full text of DOI:10.1016/j.tetlet.2021.153315

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thiourea catalyzed 1,6-conjugate addition of indoles to para-quinone
methides
Guangmiao Wu a, Tao Li a, Fuhai Liu a, Yulong Zhao a, Shiqiang Ma a, Shouchu Tang b, Xingang Xie a,
,
⇑
Xuegong She a
a State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
b School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient thiourea catalyzed 1,6-conjugate addition of indoles to para-quinone methides (p-QMs) was
developed. p-QMs was activated by a weak hydrogen-bond effect. The reaction is featured mild reaction
conditions and wide substrate scope. A series of C-3 bisaryl methine substituted indoles are prepared in
high yield.
Received 4 May 2021
Revised 26 July 2021
Accepted 3 August 2021
Available online xxxx
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
para-Quinone methides
1,6-Conjugate addition
Thiourea
Indole
Introduction
chemistry has been initially explored by several groups (Scheme 2).
Anand group developed a series of 1,6-additions to p-QMs using a
Indoles are ubiquitous structure motifs found in bioactive natu-
ral products and pharmaceuticals (Fig. 1) [1]. And nowadays there
are a lot of convenient measures to prepare indole derivatives
among which modification of an existed indole core is the most
direct and rapid way to obtain new functionalized indole ana-
logues [2]. The C3 position of indoles is innately electron-rich
and favored to be modified by an electrophile. Many methods to
modify indoles are based on this rule [3].
And recently para-quinone methides (p-QMs) with steric hin-
dered substitutes located on the two ortho position of the ketone
groups have attracted a lot of research interest and they are
regarded as good 1,6-conjugate addition acceptors due to their
unique electrophilic reactivity. A lot of carbon or heteroatom
nucleophiles are tested on this 1,6-conjugate addition platform
to prepare divergent diaryl methine substituted compounds and
greatly improve the chemical space (Scheme 1) [4].
Lewis acid/metal catalyst [6]. Then Anand’s group reported an
atom-economic preparation of unsymmetrical diarylindolyl-
methanes through palladium-catalyzed domino electrophilic
cyclization/1,6-conjugate addition approach (Scheme 2, a) [7].
Yao and Lin reported a strong Lewis acid BF3ꢀEt2O catalyzed 1,6-
addition arylation of p-QMs to prepare unsymmetrical triaryl-
methane (Scheme 2, b) [8]. Among the explored substrates scope,
only indole was tested to give the corresponding product. Recently
Zhang, Mei and Shi’s group reported an elegant chiral phosphoric
acid (CPA)-catalyzed asymmetric conjugate addition of indoles to
p-QMs and the corresponding C3-diaryl methine substituted
indoles were obtained in modest to high yields and up to 96:4 er
(Scheme 2, c) [9]. However, the reaction scope was limited to
ortho-hydroxyphenyl substituted p-QMs. And a mechanism study
indicated that ortho-hydroxyphenyl substituted p-QMs’ transform-
ing into ortho-quinone methides (o-QMs) was an essential step for
the subsequent CPA catalyzed double activation of the generated o-
QMs and indoles via two hydrogen bonds interfered effect. The fail-
ure of ortho-OMe phenyl and phenyl substituted p-QMs further
valid the possible 1,4-conjugate reaction mechanism. And, Partha-
sarathy group reported the synthesis of diaryl indole via the addi-
tion reaction of indoles to p-QMs by heating (Scheme 2, d) [10].
More recently, Anand group has uncovered the application of the
bis(amino)cyclopropenium ion in 1,6-conjugate addition reactions
Due to our longstanding interest in total synthesis of indole
alkaloids, our group also devoted to method developments for
preparation of substituted indoles [5]. And we became interested
in the combined chemical reactivity of electron-rich indoles and
electron-poor p-QMs. Before we commenced our research, this
⇑
Corresponding author.
E-mail address: xiexg@lzu.edu.cn (X. Xie).
https://doi.org/10.1016/j.tetlet.2021.153315
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: G. Wu, T. Li, F. Liu et al., Thiourea catalyzed 1,6-conjugate addition of indoles to para-quinone methides, Tetrahedron Letters,
https://doi.org/10.1016/j.tetlet.2021.153315

G. Wu, T. Li, F. Liu et al.
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Fig. 1. Important indole compounds and bioactive indole compounds containing C-3 diaryl-methine substituent.
eas C2, C3 and squaric acids C4, C5) were also tested in place of C1
and they were all less effective and gave the desired 3aa in a lower
yield and racemic form (Table 1). The less effectiveness in enan-
tioselective induction might attribute to the poor basic character
of tertiary amine group which couldn’t form a tight interfered com-
plex with indoles. And the optimal reaction conditions at this time
turned out to be performing the reaction in CH2Cl2 or THF at ambi-
ent temperature using 10 mol% C1 as catalyst.
Scheme 1. p-QMs and their resonance structures.
With the optimal reaction conditions in hand, the scope of p-
QMs was firstly explored. As shown in Table 2, a variety of p-
QMs bearing a single electron-donating or electron-withdrawing
substituent at the aryl ring were readily converted to the corre-
sponding 1,6-adducts in modest to high yields indicating that the
electronic properties of p-QMs did not have a significant impact
on the reaction outcome (Table 2, 3aa–3na). p-QM 1e with 3,4-
dimethoxyl phenyl substitute gave the corresponding 1,6-adduct
3ea in a little lower yield compared with its analogues with a sin-
gle methoxyl substitutes 1a and 1f (Table 2, 3ea vs 3aa, 3fa). And
the ortho-OMe phenyl substituted p-QM 1f gave the corresponding
1,6-adduct 3fa in 91% yield which were slightly lower than 1a
(with a p-OMe substitute) and 1 g (with a m-OMe substitute)
revealed the 1,6-conjugate addition reaction was somewhat sensi-
tive to the steric factors. And more importantly, heteroaryl substi-
tuted p-QMs were also compatible with the reaction conditions,
leading to the corresponding indole derivatives 3oa-3ra in high
yields which excellently demonstrate the mildness of the reaction
conditions and wide potential applicability.
Then the scope of indoles were accessed which results were
summarized in Table 3. Indoles 2a-2g with an electron-donating
methyl group located at the N1, C2, C4, C5, C6 or C7 positions
(Table 3, 3aa–3ag) and 2h with stronger donating methoxyl group
at the C4 (Table 3, 3ah) all proceeded well under the optimal con-
ditions affording the corresponding 1,6-adducts in high yields.
Indole 2i with an electron-withdrawing methoxyl carbonyl substi-
tute at the C4 position didn’t react at all which indicated that the
of p-QMs with various nucleophiles (Scheme 2, e) [11]. Although
the above demonstrated works are elegant and effective to afford
the substituted indoles in chiral or racemic form, they are limited
in the specific substituted pattern in the substrates or harsh reac-
tion condition. Herein we reported a thiourea catalyzed 1,6-conju-
gate addition of indoles to p-QMs in which p-QMs was activated by
a weak hydrogen-bond effect. The mild reaction conditions toler-
ated a wide substrate scope and a series of C-3 bisaryl methine
substituted indoles are prepared in high yields.
Results and discussion
Initially, p-QM 1a and indole 2a were chose as model substrates
to test the feasibility and screening the optimal reaction conditions
of this 1,6-conjugate addition reaction which results are depicted
in Table 1. MeCN soon proved to be a suitable solvent and the
desired 1,6-conjugative addition product 3aa was obtained in
73% isolated yield (Table 1, entry 1). No desired reaction occurred
in more polar DMF or DMSO (Table 1, entries 2–3). An alternative
1,6-conjugate reaction product 4a was obtained in 42% yield when
MeOH was used as solvent (Table 1, entry 4). Ethyl acetate and
toluene were both less effective than MeCN (Table 1, entries 5–
6). And finally CH2Cl2 and THF proved to be more suitable solvents
than MeCN and in both cases the corresponding 1,6-adduct 3aa
was obtained in 97% high yield (Table 1, entries 7–13). Four com-
mon chiral H-bond donor catalysts (commercially available thiour-
2

G. Wu, T. Li, F. Liu et al.
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Scheme 2. Previous works.
3

G. Wu, T. Li, F. Liu et al.
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Table 1
Optimization of reaction conditions.
aStandard conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (0.75 mmol, 1.5 equiv.) and catalyst (10 mol%) were add into the solvents (1.5 mL), the mixture was stirred at room
b
temperature for 20–60 h. Isolated Yields.
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G. Wu, T. Li, F. Liu et al.
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Table 2
The scope of p-QMs.
electron effect of the indoles’ substitutes had a significant effect on
this reaction (Table 3, 3ai). To our delight, indoles with F, Cl or Br
substitutes at the C4 succeeded in the 1,6-addition reaction and
the corresponding adducts could be obtained in 87–92% yield
(Table 3, 3aj–3al). Several other nucleophiles, such as 7-azaindole,
benzimidazole, pyrrole, imidazole, 2-phenyl indole and carbazole
were also tried under the standard reaction conditions. They all
failed to give the desired adducts except for pyrrole which pro-
ceeded smoothly at the C-3 position to afford the corresponding
1,6- conjugate adduct 2am in 81% yield.
To demonstrate the practical value of this reaction, scale-up
experiments and derivative transformations were subsequently
carried out. As shown in Scheme 3, the gram-scale conjugate addi-
tion reaction of 1q and 2a underwent smoothly in the presence of
10 mol% C1 affording the desired 1,6-adduct 3qa in 90% high yield
(Scheme 3, a). A sequential removal of Ts protecting group of 3qa
gave 4qa in 94% isolated yield (Scheme 3, b). And a Suzuki coupling
reaction between 3ha and 4-methylthio-phenylboronic acid 5 gen-
erated more complex indole derivative 4ha in a modest yield
(Scheme 3, c).
On the basis of experimental results and relevant literature
reports [4e,12], a possible reaction mechanism was proposed
which was depicted in Scheme 4. Initially, thiourea catalyst C1
and p-QM 1b form a complex via the weak H-bond effect. The com-
plex undergoes resonance between neutral non-aromatic structure
A and zwitterionic structure A0 which display remarkable chemical
reactivity as a reactive acceptor for 1,6-addition reactions. Then
indole 2a attacks the C6 of the reactive complex affording B which
was deprotonated to give the more stable C. Finally protonation of
C affords the product 3ba and releases the thiourea catalyst C1.
In summary, an efficient preparation of 3-diaryl methine substi-
tuted indoles via a thiourea catalyzed 1,6-conjugate addition of
indoles to p-QMs was developed. p-QMs are activated by a weak
and mild hydrogen-bond effect. The reaction features with wide
substrates scope and mild reaction conditions. Further scale up
experiments and derivative transformations of the obtained 3-dia-
ryl methine substituted indoles increase the practical value of the
developed method.
Table 3
The scope of indoles.
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Scheme 3. Scale-up preparation and derivative transformation of the obtained products.
Scheme 4. Possible mechanism.
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G. Wu, T. Li, F. Liu et al.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We wish to thank the generous financial support by NSFC
(21472079, 21772074).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153315.
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