Quaternary Phosphonium Salts as Active Br?nsted Acid Catalysts for Friedel-Crafts Reactions

Article abstract of DOI:10.1021/acs.orglett.9b02108

A readily available quaternary phosphonium salt containing a trifluoroacetonyl group and a tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BAr^F₄^-) counterion was demonstrated to be a highly active Br?nsted acid catalyst for Friedel-Crafts-type reactions of an array of electron-rich heteroarenes and aniline derivatives with isatin-derived ketimines, even at 0.1 mol % catalyst loadings.

Full text of DOI:10.1021/acs.orglett.9b02108

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Quaternary Phosphonium Salts as Active Brønsted Acid Catalysts for
Friedel−Crafts Reactions
Lin Chen,† Ben-Xian Xiao,† Wei Du,† and Ying-Chun Chen*,†,‡
†Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education and Sichuan Research Center for Drug
Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
‡College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: A readily available quaternary phosphonium
salt containing a trifluoroacetonyl group and a tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate (BArF −) counterion was
4
demonstrated to be a highly active Brønsted acid catalyst for
Friedel−Crafts-type reactions of an array of electron-rich
heteroarenes and aniline derivatives with isatin-derived
ketimines, even at 0.1 mol % catalyst loadings.
rønsted acid, which can deliver a proton or possesses
hydrogen-bonding donor capacity, represents one of the
alcohols, and amides, commonly featuring heteroatom−hydro-
gen units, including O−H, N−H, and S−H moieties. In sharp
contrast, other types of functionalities, such as C−H units, were
rarely reported probably because of the weak acidity.5 As a
result, the discovery and development of novel Brønsted acid
catalyst systems with other types of hydrogen-bonding donor
capacity is of great significance, which might bring about
different experiences in catalytic processes and catalytic
efficiency.
B
most important organocatalysts in chemistry.1 A broad range of
organic compounds, as exemplified in Figure 1, have been
The Wittig reaction, condensation between phosphorus
ylides and carbonyl compounds, is one of the most important
methods for alkene synthesis.6 The active phosphorus ylide
species are generally prepared from quaternary phosphonium
salts (QPSs) by α-deprotonation under basic conditions. The
acidity of the α-CH group of phosphonium salts is much
stronger than that of normal C−H bond owing to electron-
withdrawing effect of the cationic group, especially by
introducing another functional group into the α-site, as
illustrated in Figure 2.7 Indeed, it has been noticed that
phosphonium salts could be potentially used as a novel type of
Brønsted acid catalysts,8 which have been previously identified
in acetal formation and deprotection processes owing to their
high acidity; however, very limited examples in catalytic organic
reactions have been reported to date.9
Figure 1. Some selected classic Brønsted acid catalysts.
extensively utilized and explored.2 Many of them show good
catalytic activities in many kinds of organic reactions, and
abundant examples in a highly stereoselective manner have been
reported by employing diverse chiral Brønsted acid systems.
Enhancing the acidity by introducing cationic or electron-
withdrawing groups is usually applied to facilitate the catalytic
efficiency of Brønsted acids.3 Nevertheless, some limitations,
such as tedious synthetic steps, low catalytic activity, high
catalyst loadings, and narrow substrate compatibility, remain to
be expanded. The recent design of highly acidic and confined
imidodiphosphorimidate catalysts by List showed that exploring
the new types of easily available Brønsted acid catalysts with
excellent activity is still a significant target for organic chemists
(Figure 1).4
Figure 2. Comparison of equilibrium acidities of typical acids and
quaternary phosphonium salts (in DMSO at 25 °C).
In general, as summarized in Figure 1, the Brønsted acid
catalysts’ acidic groups are supplied by a variety of organic acids
(carboxylic acids, phosphoric acids, sulfonic acids) and hydro-
gen-bonding donors, such as (thio)ureas, squaramides, (thiol)-
Received: June 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To explore this hypothesis, a few quaternary phosphonium
salts with different functional groups were prepared from Ph3P
and the corresponding halides (Table 1). As summarized in
Table 2. Kinetic Data for the Friedel−Crafts Reaction of
a
Ketimine 1a and Aniline 2b
Table 1. Preliminary Attempts of Using QPSs in Friedel−
a
Crafts Reactions
TOF1/2
k1/2
b
entry
catalyst (mol %)
t
1/2 (h)
(mol h−1
)
(M−1 h−1
)
1
2
3
(PhO)2P(O)OH (20)
Cu(MeCN)4BF4 (1)
P7 (10)
P7 (5)
P7 (1)
P7 (0.5)
P7 (0.2)
P7 (0.1)
1a decomposed
2.04
49
1.99
ND
ND
28.96
23.85
5.2
c
<5 min
<5 min
0.14
0.17
0.78
ND
ND
357
588
320
156
c
4
5
6
7
8
3.21
1.26
a
Reactions were performed using 1a (0.05 mmol), 2b (0.1 mmol),
b
b
entry QPS
2
time
entry QPS
2
time
the corresponding catalyst in CDCl3 (0.5 mL), which were monitored
b
by 1H NMR analysis. Data were given from calculations according to
1
2
3
4
5
P1
P2
P3
P4
P5
indole
indole
indole
indole
indole
ND
42 h
12 h
6
7
8
9
10
P3
P4
P6
P5
P7
PhNMe2
PhNMe2
PhNMe2
PhNMe2
PhNMe2
96 h
72 h
72 h
6 h
1
the fitting formula, which were obtained from the rate test by H
c
NMR and correlation data fitting. Not determined.
<5 min
<5 min
Moreover, continuous reduction of the catalyst loadings still
guaranteed good catalytic efficiency (entry 7), even using 0.1
mol % of P7 (entry 8).
<5 min
a
Reactions were performed using 1a (0.1 mmol), ArH 2 (0.2 mmol),
QPS P (20 mol %) in CHCl3 (1 mL) at rt. Full conversion, detected
b
Subsequently, we explored the substrate scope and limitations
of the FC reaction of ketimines 1 from isatins and N,N-
disubstituted anilines. The reactions were conducted at a 0.1
mmol scale, thus a diluted solution of P7 (1 mol %) in DCE was
added for accuracy. As summarized in Table 3, the ketimine with
an N-MOM group exhibited excellent reactivity, and a
by TLC analysis.
Table 1, their catalytic efficacy (20 mol %) was examined in a
Friedel−Crafts (FC) reaction of isatin-derived ketimine 1a and
indole 2a in chloroform at room temperature.10 Salt P1 derived
from benzyl bromide showed inert activity (pKa = 17.4, entry
1);7 full conversion was observed by using the salt P2 from 4-
nitrobenzyl bromide (pKa = 11.0, entry 2).7 As expected, the
reaction was significantly improved by using salt P3 with an α-
ester group (entry 3), and the reaction completed in less than 5
min with salt P4 or P5 (relatively unstable) with a stronger
electron-withdrawing group (entries 4 and 5). Subsequently, the
less reactive N,N-dimethylaniline 2b was employed in the
reaction with ketimine 1a.11 QPSs P3, P4, and P6 also worked
well, though a long time was required (entries 6−8). P5
exhibited higher catalytic activity (entry 9). Phosphonium salt
P7 containing a tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
Table 3. Friedel−Crafts Reactions of Ketimines 1 and
Anilines 2 Catalyzed by Salt P7
b
entry
R1
R2
Me
MOM
Bn
R3
R4
yield (%)
c
1
H
H
H
7-F
5-Br
6-Cl
6-Br
5-Me
7-Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
−(CH2)4−
−(CH2)5−
Et
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3b, 95
3c, 99
3d, 99
3e, 99
3f, 89
3g, 92
3h, 92
3i, 96
3j, 91
3k, 99
3l, 98
3m, 99
3n, 99
3o, 98
counterion (BArF −) had much better stability, and dramatically
improved catalytic activity was observed (entry 10).
4
2
3
d
Inspired by the above experiments, we further evaluated salt
P7 in the FC reaction of ketimine 1a and N,N-dimethylaniline
2b under various loadings in CDCl3 at room temperature. The
half-life for the reaction (t1/2), turnover frequency (TOF), and
second-order rate constant (k) were determined by monitoring
the reaction via H NMR spectroscopy analysis. The results
are summarized in Table 2. For comparison, diphenyl phosphate
was found to be a poor catalyst and caused the decomposition of
ketimine 1a (pKa = 1.85; Table 2, entry 1).13 As a common
Lewis acid, Cu(CH3CN)4BF4 showed high efficiency at 1 mol %
loadings, and the reaction half-life is about 2 h. Whereas very
rapid conversion was observed with salt P7 at 10 or 5 mol %
loadings (entries 3 and 4), experimental data showed that P7 is
almost 10 times more effective than the Cu(I) salt at 1 mol %
loadings (entry 5 vs entry 2). An excellent TOF number (588
mol h−1) was calculated with 0.5 mol % of salt P7 (entry 6).
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
12
1
10
11
12
H
H
H
H
Et
Ph
Ph
e
13
e
14
a
Unless noted otherwise, reactions were performed using 1 (0.1
b
mmol), 2 (0.2 mmol), P7 (1 mol %) in DCE (1 mL) for 4 h. Yield
of the isolated product. For 2 h. With 5 mol % of P7, for 8 h. In 5
c
d
e
min.
B
DOI: 10.1021/acs.orglett.9b02108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
quantitative yield was obtained within 6 h (Table 1, entry 2).
The N-benzyl ketimine was less reactive, and 5 mol % catalyst
loadings were required for complete conversion after 8 h (entry
3). In addition, a number of ketimines with either electron-
withdrawing or electron-donating groups on the aromatic ring
were well-tolerated under the catalysis of 1 mol % of P7 (entries
4−9). On the other hand, other N,N-dialkyl-substituted anilines
were very compatible, too (entries 10−12). It is noteworthy that
both triphenylamine and N-methyl diphenylamine showed
remarkable reactivity, and complete conversions were attained
in only 5 min (entries 13 and 14).
catalysis of either P4 (20 mol %) or P7 (1 mol %) in the
presence of equal equivalents of a bulky tertiary amine base
DIPEA (pKa of its salt = 11.3). As outlined in Scheme 2, the FC
Scheme 2. Catalytic Mechanism Exploration
The FC alkylation reactions of a variety of electron-rich
heteroarenes were further studied under the catalysis of 0.1 mol
% of P7. As summarized in Table 4, diversely substituted indoles
Table 4. Friedel−Crafts Reactions of Ketimine 1a and
a
Various Heteroarenes
yield
b
b
entry
ArH
indole
2-Me-indole
5-Me-indole
6-Me-indole
7-Me-indole
yield (%)
entry
ArH
(%)
c
1
2
3
4
5
3a, 87 (96)
3p, 86
6
7
8
9
10
5-Br-indole
6-F-indole
7-azaindole
2-Et-furan
3t, 88
3u, 97
3v, 84
3w, 85
3x, 78
3q, 94
3r, 97
3s, 91
reaction was found to be completely prohibited in both cases. In
addition, 1H NMR analysis showed that the key acidic α-CH2 (δ
6.40 ppm) of salt P4 disappeared after DIPEA was added, and
two new peaks (δ 10.30 and 4.41 ppm) were obviously
generated. It suggested that apparent interaction occurred
between the acidic α-CH2 group of phosphonium salt P4 and
DIPEA, probably generating the ylide species,16 which further
verified the rationality of its acidic α-CH2 group for the observed
Brønsted acid catalysis.
Finally, we explored the potential asymmetric FC reaction. A
few chiral phosphonium salts P8−11 with diverse chiral
structures were easily prepared and applied in the reaction of
ketimine 1a and indole 2a. As illustrated in Scheme 3, excellent
reactivity was observed even at 0.1 mol % catalyst loadings in all
2-Et-thiophene
a
Unless noted otherwise, reactions were performed with 1a (0.1
mmol), heteroarene 2 (0.2 mmol), P7 (0.1 mol %) in DCE (1 mL)
b
c
for 30 min. Yield of the isolated product. Data in parentheses was
obtained at a 1.0 mmol scale after 1 h.
exhibited outstanding reactivity with ketimine 1a, and the
corresponding FC products were generally isolated in high
yields after 30 min (Table 4, entries 1−7), even at a larger scale
(entry 1). In addition, 7-azaindole could afford the correspond-
ing FC product in a good yield (entry 8). Moreover, high
reactivity was observed for both 2-ethylfuran and 2-ethyl-
thiophene (entries 9 and 10).
As illustrated in Scheme 1, apart from the Mannich-type FC
reaction, good reactivity was observed in the Michael addition-
Scheme 3. Preliminary Asymmetric Attempts with Diverse
Chiral Phosphonium Salts
Scheme 1. Friedel−Crafts Reactions of Enones and Indoles
type FC reaction of either indole 2a or 1-methylindole 2aa with
chalcone 4a in EtOAc14 catalyzed by salt P7 at ambient
temperature, though higher loadings were required.15 Interest-
ingly, even enone 4b bearing a labile α′-bromomethyl group was
well-compatible, delivering the FC product 5c in a high yield.
To get more insights into the catalytic mechanism, we
investigated the reaction of ketimine 1a and aniline 2b under the
C
DOI: 10.1021/acs.orglett.9b02108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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4
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02108.
Complete experimental procedures and characterization
of the products; kinetic data for the Friedel−Crafts
1
reaction monitored by H NMR analysis; NMR spectra
(PDF)
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(b) Karanam, P.; Reddy, G. M.; Lin, W. Synlett 2018, 29, 2608.
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(8) Sereda, O.; Tabassum, S.; Wilhelm, R. Lewis Acid Organo-
catalysts. In Asymmetric Organocatalysis; List, B., Ed.; Springer: Berlin,
2009; p 86.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ycchen@scu.edu.cn.
ORCID
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2001, 57, 5991. (b) Hon, Y.-S.; Lee, C.-F. Tetrahedron Lett. 1999, 40,
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Ying-Chun Chen: 0000-0003-1902-0979
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the NSFC
(21772126).
■
(13) Scherrer, R. A.; Donovan, S. F. Anal. Chem. 2009, 81, 2768.
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DOI: 10.1021/acs.orglett.9b02108
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