Enantioselective synthesis of triarylmethanes by chiral imidodiphosphoric acids catalyzed friedel-crafts reactions

Article abstract of DOI:10.1021/ol403680c

The first enantioselective synthesis of pyrrolyl-substituted triarylmethanes has been accomplished using a novel imidodiphosphoric acid catalyst, which is derived from two (R)-BINOL frameworks with different 3,3′-substituents. This strategy was also expanded to the synthesis of bis(indolyl)-substituted triarylmethanes with high enantioselectivities, which could only be obtained with moderate ee values in previous reports. These two efficient Friedel-Crafts alkylation processes feature low catalyst loading, broad functional group compatibilities, and the potential to provide practical pathways for the synthesis of enantioenriched bioactive triarylmethanes.

Full text of DOI:10.1021/ol403680c

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of Triarylmethanes by Chiral
Imidodiphosphoric Acids Catalyzed Friedel−Crafts Reactions
Ming-Hua Zhuo, Yi-Jun Jiang,* Yan-Sen Fan, Yang Gao, Song Liu, and Suoqin Zhang*
College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
S
* Supporting Information
ABSTRACT: The first enantioselective synthesis of pyrrolyl-
substituted triarylmethanes has been accomplished using a novel
imidodiphosphoric acid catalyst, which is derived from two (R)-
BINOL frameworks with different 3,3′-substituents. This
strategy was also expanded to the synthesis of bis(indolyl)-
substituted triarylmethanes with high enantioselectivities, which
could only be obtained with moderate ee values in previous
reports. These two efficient Friedel−Crafts alkylation processes
feature low catalyst loading, broad functional group compatibilities, and the potential to provide practical pathways for the
synthesis of enantioenriched bioactive triarylmethanes.
riarylmethanes are attractive molecules which have been
widely used in medicinal and material sciences.1
Scheme 2. Chiral Imidodiphosphoric Acids Catalyzed Highly
Enantioselective Syntheses of Two Different Types of
Triarylmethanes 1 and 2
T
Heteroaryl-substituted triarylmethanes present privileged archi-
tectural units frequently found in pharmaceuticals and bioactive
molecules.2−4 For example, Letrozole, Vorozole, and para-
phenyl-substituted diindolylmethanes (C-DIMs) have proven
to be very effective drugs in the treatment of cancer (Scheme
1). The absolute configurations of these molecules or their
Scheme 1. Pharmaceutically Relevant Triarylmethanes
derivatives are shown to further modulate the biological
activities.2a,c,e It is therefore of high importance to introduce
asymmetry at the methanetriyl group in the heteroaryl-
substituted triarylmethane molecules with high enantiocontrol.
However, the enantioselective synthesis of triarylmethanes has
until recently remained a challenge and only a few examples
have been reported.5 In addition, the enantioselective synthesis
of pyrrolyl-substituted triarylmethanes has not been developed.
Friedel−Crafts-type arylations of diarylmethanols or diaryl-
methylamines have been the most common method for the
synthesis of unsymmetric triarylmethanes.4,5b,6 However, only
one enantioselective protocol toward the synthesis of bis-
(indolyl)methanes has been reported by You and co-workers
with only moderate enantioselectivities (Scheme 2).5b
Compared with You’s work, the synthesis of enantioenriched
pyrrolyl-substituted triarylmethanes 1 is more challenging since
pyrroles always give lower enantioselectivities than indoles in
enantioselective Friedel−Crafts alkylations.7 It is probably
because of the higher reactivity of pyrroles and the difficulty
in enantiofacial differentiation caused by the smaller size of the
pyrroles.
Recently, imidodiphosphoric acids have been first reported
by List and co-workers as new efficient chiral Brønsted acids in
catalytic enantioselective reactions.8 We have also reported
Received: December 19, 2013
Published: February 3, 2014
© 2014 American Chemical Society
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Letter
their syntheses and applications, independently (Scheme 2).9 In
view of the efficiency of imidodiphosphoric acids in
enantioselective transformations of small substrates,8a,b we
expected that this new type of chiral Brønsted acids could also
promote the Friedel−Crafts reactions of pyrrole with high
enantioselectivities. Herein, we will first report the enantiose-
lective synthesis of pyrrolyl-substituted triarylmethanes 1
through chiral imidodiphosphoric acids catalyzed Friedel−
Crafts reactions of pyrrole with trimethylsilyl protected 3-
arylindolylmethanols with high enantioselectivities and a low
catalyst loading (Scheme 2). Moreover, this strategy was also
expanded to the synthesis of bis(indolyl)triarylmethanes 2
successfully with high enantioselectivities.
could also promote the dehydration of other molecules of 5
and the subsequent addition of pyrrole 6. This possible
problem could not only consume unprotected substrate 5 and
lead to a lower yield but also result in a decrease of the ee value
of product 1a. Thus, protecting the hydroxyl group with the
trimethylsilyl group might largely prevent these disadvantages
from happening. An improvement to 88% ee was observed
when the solvent was changed from toluene to tetrahydrofuran
(THF) (Table 1, entry 8). Lowering of the reaction
temperature further improved the chemo- and enantioselectiv-
ity (Table 1, entries 9 and 10) until the reaction was below −20
°C (Table 1, entry 11). Thus, the best result was observed
when the reaction was run at −20 °C in THF by using 5 mol %
of catalyst 3a (Table 1, entry 10).
We initially investigated our triarylmethane synthesis strategy
by using 3-indolylphenylmethanol 5 and pyrrole 6 in the
presence of 5 mol % of catalyst 3 or 4 in toluene (Table 1).
Under our optimized conditions (Table 1, entry 10), we
observed a broad scope with respect to the trimethylsilyl
protected 3-arylindolylmethanols 5 (Scheme 3). Substrates
a
Table 1. Optimization of the Reaction Conditions
Scheme 3. Scope of Synthesis of 1-(Aryl)-1-(indolyl)-1-
a
(pyrrolyl)methanes 1
yield
b
ee
c
entry
R
cat.
solvent
toluene
temp, t
rt, 0.5 h
(%)
(%)
1
H
3a
3b
3c
4
60
55
42
56
74
73
73
80
86
90
63
65
43
11
33
80
77
83
88
88
90
90
2
H
toluene
toluene
toluene
toluene
CH2Cl2
rt, 0.5 h
rt, 6 h
3
H
4
H
rt, 0.5 h
rt, 0.5 h
rt, 2 h
5
TMS
TMS
TMS
TMS
TMS
TMS
TMS
3a
3a
3a
3a
3a
3a
3a
6
7
1,4-dioxane rt, 35 h
8
THF
THF
THF
THF
rt, 18 h
9
0 °C, 33 h
−20 °C, 40 h
−30 °C, >72 h
10
11
a
Reactions were performed with 0.1 mmol of 5, 0.1 mmol of 6, and 5
mol % of the catalyst in 1 mL of solvent. Yield of the isolated product.
Determined by HPLC analysis on a Chiralcel AD-H column.
b
c
Imidodiphosphoric acid catalyst 3 or 4 could promote the
dehydration of substrate 5 and generate an alkylidene-
indolenine intermediate10 which could form a stable chiral
ion pair A with the chiral imidodiphosphoric acid.8a,11,12 This
chiral ion pair may add the nucleophilic reagent pyrrole in a
regio- and stereoselective fashion. Since the C-2 position of
pyrrole 6 was more nucleophilic,13 it attacked substrate 5 at the
C-2 position and produced triarylmethane 1a as the main
product. Interestingly, catalyst 3a derived from two (R)-BINOL
frameworks with different 3,3′-substituents gave a higher yield
and enantioselectivity (60% yield, 65% ee, Table 1, entry 1)
than other symmetric imidodiphosphoric acid catalysts (Table
1, entries 2−4). Our first notable improvement was the use of a
trimethylsilyl protection group on 3-arylindolylmethanols. This
change resulted in a dramatic increase in the chemo- and
enantioselectivity of the reaction (74% yield, 80% ee, Table 1,
entry 5). Besides, the trimethylsilyl protected 3-arylindolyl-
methanol substrates are easy to store since they are less
sensitive to air and light compared with the unprotected 3-
arylindolylmethanols. It might be because the weak acidity of
the H atom on the hydroxyl group in unprotected substrate 5
a
Reactions were performed with 0.1 mmol of 5, 0.1 mmol of 6, and 5
mol % of catalyst 3a in 1 mL of THF at −20 °C. Yield of the isolated
product. Ee value was determined by HPLC analysis on Chiralcel AD-
b
H or OD-H column. Reactions were run at 40 °C with 1 mol % of
catalyst 3a. c The reaction was carried out on a 1 g (2.7 mmol) scale of
5p.
bearing either electron-withdrawing (5b−j) or electron-
donating groups (5k and 5l) on the phenyl moiety reacted to
form the corresponding triarylmethanes 1b−l in high yields
with excellent enantioselectivities (71−91% yield, 86−96% ee).
The substrate 5m, containing the naphthyl substituent, also
reacted smoothly and afforded the triarylmethanes 1m in high
yield with good enantioselectivity (90% yield, 86% ee). Besides,
we were pleased to find that the reaction of substrate 5i could
proceed with 1 mol % of catalyst 3a under an increased reaction
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Letter
temperature (40 °C) and generated triarylmethane 1i in high
yield with excellent ee (91% yield, 96% ee). Further, variation
of the indole substituents was also tested (Scheme 3, 5n−p)
with 1 mol % of catalyst 3a at 40 °C. An electron-withdrawing
group on the 5-position of indole slightly decreased the
enantioselectivity (Scheme 3, 1n). Electron-donating substitu-
ents on the 5-position of the indole rings were more favorable,
and triarylmethanes 1o and 1p were synthesized in high yields
(96% and 95%) with excellent enantioselectivities (96% ee). As
illustrated in the synthesis of enantioenriched triarylmethane
1p, the method is also amenable to gram scale.
Our next challenge was to apply this method to synthesize
enantioenriched triarylmethanes 2. Although similar work has
been reported by You and co-workers by using chiral
phosphoric acid catalysts and different substrates (3-indolyl)-
methanamines, only moderate ee values (45 to 68% ee) were
obtained.5b Gratifyingly, imidodiphosphoric acid catalyst 3a was
found to be more effective and triarylmethanes 2 have been
synthesized with high enantioselectivities. When a range of
substituted 1-methyl-indoles 7 were selected as the nucleophilic
reagents, their more nucleophilic C-3 positions13 attacked
substrates 5 and produced triarylmethanes 2 as the main
products. The reaction conditions were optimized, and the best
result was obtained in a 1,4-dioxane at 15 °C with 1 mol % of
catalyst 3a. The scope of the substrates was explored under the
optimized reaction conditions. Substrates with electron-with-
drawing or -donating groups at the ortho or meta position of the
phenyl rings gave rise to the triarylmethane products in good
yields with high levels of enantioselectivities (Scheme 4, 2a−k,
62−99% yield, 88−95% ee), including the highly symmetric
triarylmethanes 2a, 2g, and 2h. Substrates with substituents on
the para position of the phenyl rings and other substitution
patterns also underwent Friedel−Crafts reactions to yield
triarylmethanes 2l−n in high yields with good enantioselectiv-
ities (87−95% yield, 74−85% ee). Besides, in these processes,
our catalyst loading (1 mol %) was much lower than that
reported by You et al. (5 mol %). Combined with the high
enantioselectivities, our reaction was more efficient and the
imidodiphosphoric acid catalyst showed more extraordinary
chiral-control ability compared with the phosphoric acid
catalyst.5b
The absolute configuration of the optically active 2b was
established to be R by X-ray crystallographic analysis (Figure
1).14 It is noteworthy that the highly enantioselective synthesis
Scheme 4. Scope of Synthesis of 1-(Aryl)-1,1′-
a
bis(indolyl)methanes 2
Figure 1. X-ray crystallographic structure of enantiopure triaryl-
methane 2b.
of triarylmethanes 2 would provide more opportunities for
further biological activity studies of the analogs of cancer
treating drug C-DIMs (Scheme 1).3
In summary, we have disclosed the chiral imidodiphosphoric
acids catalyzed highly efficient and enantioselective Friedel−
Crafts-type alkylations for the construction of two different
types of chiral triarylmethanes 1 and 2. The novel imido-
diphosphoric acid catalyst 3a derived from two (R)-BINOL
frameworks with different 3,3′-substituents developed in our
previous work showed excellent catalytic activity and stereo-
controlled ability in both of these two catalyses. A range of
highly enantioenriched and versatile triarylmethanes 1 and 2
were synthesized in high yields (up to 99%) with excellent
enantioselectivities (up to 96% and 95% ee, respectively) with a
low catalyst loading (as low as 1 mol %) unprecedentedly.
Remarkably, enantioenriched triarylmethanes 1 have been
synthesized for the first time. We believe that the protocol
presented in this work will be appealing to practitioners of
medicinal chemistry. Studies aimed at further exploration of the
synthetic potential of this approach are currently underway.
a
Reactions were performed with 0.1 mmol of 5, 0.1 mmol of 7, and 1
mol % of catalyst 3a in 2 mL of 1,4-dioxane at 15 °C. Yield of the
isolated product. Ee value was determined by HPLC analysis on
Chiralcel AD-H or OD-H column.
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Letter
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ASSOCIATED CONTENT
* Supporting Information
Single crystal X-ray crystallography data for triarylmethane 2b,
experimental procedures, and complete characterizations
(NMR spectra, HPLC traces of both racemic and enantioen-
riched triarylmethanes products, and HRMS). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
̌
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́ ́
I.; List, B. Nature 2012, 483, 315. (b) Liao, S.; Coric, I.;
(8) (a) Coric,
Wang, Q.; List, B. J. Am. Chem. Soc. 2012, 134, 10765. (c) Kim, J. H.;
̌
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Coric, I.; Vellalath, S.; List, B. Angew. Chem., Int. Ed. 2013, 52, 4474.
AUTHOR INFORMATION
Corresponding Authors
■
(9) (a) Chen, Y.-Y.; Jiang, Y.-J.; Fan, Y.-S.; Sha, D.; Wang, Q.; Zhang,
G.; Zheng, L.; Zhang, S. Tetrahedron: Asymmetry 2012, 23, 904.
(b) Wu, K.; Jiang, Y. J.; Fan, Y. S.; Sha, D.; Zhang, S. Chem.Eur. J.
2013, 19, 474. (c) An, D.; Fan, Y.-S.; Gao, Y.; Zhu, Z.-Q.; Zheng, L.-
Y.; Zhang, S. Eur. J. Org. Chem. 2014, 301.
*E-mail: jiangyijun@jlu.edu.cn.
*E-mail: suoqin@jlu.edu.cn.
Notes
(10) Palmieri, A.; Petrini, M.; Shaikh, R. R. Org. Biomol. Chem. 2010,
8, 1259.
The authors declare no competing financial interest.
(11) (a) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M.
Angew. Chem., Int. Ed. 2008, 47, 593. (b) Guo, Q.-X.; Peng, Y.-G.;
Zhang, J.-W.; Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett. 2009, 11, 4620.
(c) Sun, F.-L.; Zeng, M.; Gu, Q.; You, S.-L. Chem.Eur. J. 2009, 15,
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(g) Song, L.; Guo, Q.-X.; Li, X.-C.; Tian, J.; Peng, Y.-G. Angew. Chem.,
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21202059), the China Postdoctoral Science Foundation
(2013M541287), and the Jilin Province Science & Technology
Development Program (20100538, 20110436, 201215033) for
financial support.
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Int. Ed. 2012, 51, 1899. (h) Coric, I.; Kim, J. H.; Vlaar, T.; Patil, M.;
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