Reaction of indoles with aromatic fluoromethyl ketones: An efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K2CO3/n-Bu4PBr in water

Article abstract of DOI:10.3762/bjoc.16.71

A new, mild and efficient protocol for the synthesis of trifluoromethyl(indolyl)phenylmethanols by the reaction of indoles with a variety of aromatic fluoromethyl ketones in the presence of K₂CO₃ (15 mol %) and n-Bu₄PBr (15 mol %) in water. The desired products were obtained in good to excellent yields without requiring a column chromatographic purification. The reusability of the catalytic system and large-scale synthesis of indolyl(phenyl)methanols, which would further transform into biological active indole-derived compounds, are further advantages of this protocol.

Full text of DOI:10.3762/bjoc.16.71

Reaction of indoles with aromatic fluoromethyl ketones:
an efficient synthesis of trifluoromethyl(indolyl)phenyl-
methanols using K2CO3/n-Bu4PBr in water
Thanigaimalai Pillaiyar*1, Masoud Sedaghati1 and Gregor Schnakenburg2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 778–790.
1PharmaCenter Bonn, Pharmaceutical Institute, Department of
Pharmaceutical and Medicinal Chemistry, University of Bonn, An der
Immenburg 4, D-53121 Bonn, Germany and 2Institute of Inorganic
Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, D-53121
Bonn, Germany
doi:10.3762/bjoc.16.71
Received: 12 February 2020
Accepted: 02 April 2020
Published: 20 April 2020
Email:
This article is part of the thematic issue "Organo-fluorine chemistry V".
Guest Editor: D. O'Hagan
Thanigaimalai Pillaiyar* - thanigai@uni-bonn.de
* Corresponding author
© 2020 Pillaiyar et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
C–C-bond formation; C3-funtionalization of indole; diindolylmethane;
Friedel–Crafts reaction; indole; indole-3-carbinol; large-scale
synthesis; recyclability
Abstract
A new, mild and efficient protocol for the synthesis of trifluoromethyl(indolyl)phenylmethanols by the reaction of indoles with a
variety of aromatic fluoromethyl ketones in the presence of K2CO3 (15 mol %) and n-Bu4PBr (15 mol %) in water. The desired
products were obtained in good to excellent yields without requiring a column chromatographic purification. The reusability of the
catalytic system and large-scale synthesis of indolyl(phenyl)methanols, which would further transform into biological active indole-
derived compounds, are further advantages of this protocol.
Introduction
(1H-Indol-3-yl)methanols have emerged as versatile pre-elec- down product of glucobrassicin, which can be found in crucif-
trophiles for C–C functionalization at the position 3 of indoles erous vegetables [15], has a wide range of biomedical applica-
[1-4]. Friedel–Crafts alkylation of (1H-indol-3-yl)methanols tions as an anticancer [16], antioxidant, and antiatherogenic
with indoles has proven to be a powerful strategy for the prepa- agent [17].
ration of biologically important 3,3′-diindolylmethanes (DIMs)
[5-14]. Additionally, (1H-indol-3-yl)methanols have been used Organofluorine compounds have attracted much attention due
as key precursors for the construction of complex indole deriva- to their potential biological applications in medicinal and agri-
tives that would be useful in pharmaceuticals as drugs and agro- cultural sciences. Introducing fluoro groups into organic mole-
chemicals [2-14]. The simple (1H-indol-3-yl)methanol, a break- cules can dramatically influence their physiochemical and bio-
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Beilstein J. Org. Chem. 2020, 16, 778–790.
logical properties in comparison with non-fluorinated analogs tion of a large volume of waste liquids for the compound sepa-
[18] (see compounds I and II in Figure 1). Many pharmaceuti- ration and column chromatographic purification [24,25], and
cals and agrochemicals developed in recent decades have either moderate substrate scope of the reaction. Thus, finding an alter-
a fluorine atom or a trifluoromethyl group [19-22]. Given this, native method with broad substrate scope, functional group
the development of a method for the incorporation of fluorine or tolerance, and simple purification technique is highly desired.
trifluoromethyl group into organic molecules perhaps remains a
current challenge in organic chemistry methodology. For exam- In our continuous effort of synthesizing indole derivatives [29-
ple, trifluoromethyl-substituted (1H-indol-3-yl)methanol deriva- 31], herein, we report an efficient synthesis of multiple halogen-
tives were reported for their promising anti-HIV inhibitory ac- substituted (1H-indol-3-yl)methanol derivatives in the presence
tivities [23], see for example compounds III and IV (Figure 1). of potassium carbonate and tetrabutylphophonium bromide,
However, these compounds were synthesized from multiple which mediate the reaction in water through the formation of
synthetic routes with the involvement of air sensitive condi- the interface between organic and aqueous phases. The advanta-
tions.
geous of this reaction include high yields, no column chroma-
tography, broad substrate scope, multiscale synthesis, and re-
Trifluoromethyl-substituted (1H-indol-3-yl)methanol deriva- cyclable of the catalyst (Figure 2C).
tives can be synthesized by Friedel–Crafts hydroxyalkylation
reactions of indoles with trifluoromethyl ketones in the pres- Results and Discussion
ence of either Lewis/Bronsted acid catalysts. Bandini et al. re- The optimization studies were carried out with model sub-
ported the trifluoromethyl hydroxyalkylation of indoles cata- strates 5-methoxyindole (1a, 3.4 mmol) and 2,2,2-trifluoroace-
lyzed by an organic base 2-tert-butyl-1,1,3,3-tetramethyl- tophenone (2a, 3.70 mmol) in water (5 mL, see Table 1 for
guanidine (TMG), also known as Barton's base, in excellent results). Using water as a solvent has the advantage that the
yields (Figure 2A) [24]. Recently, Liu and co-workers reported formed product 3a would not be soluble, which makes the
this reaction in the presence of cesium carbonate in acetonitrile purification easier through a simple filtration. In a first attempt,
(Figure 2B) [25]. Dinuclear zinc [26], cinchonidine catalysts, the reaction did not initiate at all without any base or catalyst
and solvent-free conditions [27] have been also utilized for this (Table 1, entry 1). Next, we investigated the reaction in the
reaction. The base-catalyzed reaction has a benefit because it presence of 20 mol % of base such as NaOH (Table 1, entry 2)
may avoid the formation of diindolylmethane and biindoles as or KOH (Table 1, entry 3). However, no product was formed
byproducts [28].
(Table 1, entries 2 and 3), and it was observerd that reactant 2a
separated from the aqueous phase. This makes us add quater-
Although these methods were useful, they have limitations and nary salts into the reaction, which could make the interface be-
drawbacks, which are the use of organic solvents [24], difficul- tween organic and aqueous phase. Very interestingly, the com-
ties in recyclability of the catalyst [24,25], multiple reaction bination of 20 mol % of tetrabutylammonium bromide (TBAB)
steps involving air sensitive/unhydrous conditions [23], genera- and NaOH (20 mol %) yielded the desired product, 2,2,2-
Figure 1: Structures of trifluoromethylated compounds and their biological activities.
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Beilstein J. Org. Chem. 2020, 16, 778–790.
Figure 2: Synthetic approaches toward hydroxyalkylation of indole.
Table 1: Optimization of reaction conditions for the preparation of 2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol (3a).a
Entry
Base (mol %)
Catalyst (mol %)
Time (h)
Yield (%)b
1
–
–
24
24
24
15
15
24
15
12
15
15
15
15
0
2
NaOH (20)
KOH (20)
NaOH (20)
NaOH (20)
–
–
0
3
–
0
4
TBAB (20)
TBPB (20)
TBPB (20)
TBPB (20)
TBPB (20)
TBPB (20)
TBPB (20)
TBPB (20)
TBPB (20)
93
96
0
5
6
7
KOH (20)
K2CO3 (20)
CS2CO3 (20)
K3PO4 (20)
K2HPO4 (20)
Na5P3O10 (20)
91
97
81
89
70
76
8
9
10
11
12
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Table 1: Optimization of reaction conditions for the preparation of 2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol (3a).a (continued)
13
14
15
16
17
K2CO3 (20)
K2CO3 (20)
K2CO3 (15)
K2CO3 (10)
K2CO3 (5)
TBAC (20)
TBAF (20)
TBPB (15)
TBPB (10)
TBPB (5)
15
15
12
18
24
72
61
>99 (94)c
90
69
aReaction conditions: 1a (500 mg, 3.4 mmol) and 2a (524 µL, 3.70 mmol) were used in H2O (5 mL) at room temperature. bIsolated yields. cObtained
yield in tap water.
trifluoro-1-(1H-indol-3-yl)ethan-1-ol (3a) in 93% yield Having the optimized conditions in hand, the substrate scope of
(Table 1, entry 4). The product 3a was isolated by filtration and the reaction was explored. At first, different trifluoromethyl ke-
confirmed by NMR and X-ray crystallography analysis (CCDC- tones were investigated, and the results are summarized in
1973322, see Supporting Information File 1 for detailed crystal- Table 2. Trifluoroacetophenones having a halogen substituent at
lographic data). It is noteworthy to mention that the formation the para-position of the phenyl ring such as p-F (2b), p-Cl (2c),
of the product was even increased in the presence of tetra- and p-Br (2d) provided the corresponding trifluoro-1-(1H-indol-
butylphosphonium bromide (TBPB) to 96% (Table 1, entry 5). 3-yl)ethan-1-ols 3b, 3c, and 3d in 97, 92 and 89% yields, re-
On the other hand, the reaction did not initiate only with TBPB spectively. Similarly, trifluoroacetophenones having a p-methyl
(Table 1, entry 6). It indicates that quaternary salts mediate the (2e) and p-methoxy (2f) group at the phenyl ring resulted in 3e,
reaction in the presence of a base through the formation of the and 3f with excellent yields of 98 and 93%, respectively. These
interface between the organic and aqueous phase.
results suggest that the electronic properties of the substituent
on the phenyl ring of the trifluoroacetophenones did not signifi-
As a next step, different bases were investigated by using cantly influence the yield of the reaction.
TBPB. In the presence of KOH and the Cs2CO3, the formation
of the product was reduced to 91% (Table 1, entry 7) and 81% The trifluoromethyl ketones having electron-rich heteroaro-
(Table 1, entry 9), respectively, while it was increased to 97% matics such as 2-(trifluoroacetyl)furan (2g) and 2-(trifluoro-
(Table 1, entry 8) in the presence of K2CO3. The reaction in the acetyl)thiophene (2h) gave the desired products 3g (97%) and
presence of tripotassium phosphate base (Table 1, entry 10; 3h (98%) in excellent yields.
89%), dipotassium phosphate base (Table 1, entry 11; 70%) or
sodium triphosphate (Table 1, entry 12; 76%) did not improve Next, the role of fluorine in the reactants was explored by
the yield. These results suggest that K2CO3 is the best catalyst subjecting the reaction of 2,2-difluoro-1-phenylethan-1-one (2i)
for the reaction among the bases investigated.
with 1a. The desired product 3i was obtained in 63% yield.
However, no product was formed when the reaction was carried
To find the best catalytic system, other quaternary salts were out with 2-fluoro-1-phenylethan-1-one (2j) or acetophenone
invested in the reaction. When tetrabutylammonium chloride (2k). The reason could be due to either reducing the electrophi-
(TBAC) or tetrabutylammonium fluoride (TBAF) was em- licity of the ketone or the presence of enolizable protons in
ployed in the presence of K2CO3, the formation of the product α-position to the keto group in basic medium. Supporting this
was reduced to 72% (Table 1, entry 13) and 61% (Table 1, entry hypothesis, the reaction of 1a with 1,1,1-trifluoro-3-phenyl-2-
14), respectively. These results suggest that the combination of propanone (2l), which has a 3-methylene group also did not
K2CO3/TBPB could be the best catalytic system for this reac- proceed at all.
tion.
The scope of ketones was further extended with mixed halogen-
Next, the amount of catalytic system K2CO3/TBPB was substituted, pentafluoro or heptafluoro ketones such as
reduced from 20 mol % to 15 mol % to see if there any change 2-chloro-2,2-difluoro-1-phenylethan-1-one (2m), 2,2,3,3,3-
in the yield. As indicated in Table 1, entry 15, the product 3a pentafluoro-1-phenylpropan-1-one (2n) and 2,2,3,3,4,4,4-hepta-
was isolated in >99%. However, further reduction to 10 mol % fluoro-1-phenylbutan-1-one (2o). All these reactions provided
or 5 mol % slowed the reaction rate, and only 90% (Table 1, the corresponding products (3m: 94%, 3n: 93%, 3o: 90%) in
entry 16) or 69% (Table 1, entry 17) of 3a was isolated. These excellent yields.
results suggest that the combination of K2CO3 (15 mol %)/n-
Bu4PBr (15 mol %) is a suitable and efficient catalytic system Next, the scope of substituted indoles was studied with tri-
for this reaction.
fluoromethyl ketone 2a, and the results are shown in Table 3. In
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Table 2: Substrate scope of the reaction with ketones.a
Ketones
Multihalogen-substituted
hydroxylakylated indoles
Mp (°C)
Purity (%)b
Yield (%)c
135–136
(135)d [24]
>99%
(98)e [24]
99
2a
3a [24]
115–116
153–154
172–173
130–131
98
99
97
99
97%
2b
2c
2d
2e
3b
92
3c
89
3d
98
3e
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Table 2: Substrate scope of the reaction with ketones.a (continued)
151–152
98
93
2f
3f
3g
3h
158–159
99
97
2g
148–149
97
98
2h
185–186
96
63
2i
3i
–
–
0
2j
3j
–
–
0
2k
3k
–
–
0
2l
3l
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Table 2: Substrate scope of the reaction with ketones.a (continued)
158–159
168–169
161–163
98
97
97
94
93
90
2m
3m
3n
3o
2n
2o
aReaction conditions: 1 (3.4 mmol) and 2 (3.75 mmol) in water (5 mL). bPurity was determined by HPLC coupled to a UV diode array detector (DAD)
at 220−400 nm. cIsolated yields. dReported melting points. eReported yields.
Table 3: Substrate scope of the reaction with indoles.a
Indoles
Trifluoromethly substituted
hydroxylakylated indoles
Mp (°C)
Purity (%)b
Yield (%)c
122–124
(75)d [25]
96
(95)e [25]
98
1b
3p
160–161
99
79
1c
3q
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Table 3: Substrate scope of the reaction with indoles.a (continued)
192–193
97
99
99
90
1d
3r
94
(98)e [24]
112–113
1e
3s
90–91
(90)d [24]
96
(98)e [24]
1f
3t
3u
3v
3w
3x
165–166
227–228
239–240
98
97
99
97
91
92
97
1g
1h
1i
185–186
185d [24]
90
86e [24]
1j
aReaction conditions: 1 (3.4 mmol) and 2 (3.75 mmol) in water (5 mL). bPurity was determined by HPLC coupled to a UV diode array detector (DAD)
at 220−400 nm. cIsolated yields. dReported melting points. eReported yields.
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the case of a simple indole (1b), the corresponding product 3p produce the product 3a in excellent to good yields up to
was isolated in 96% yield. Indoles bearing electron-donating 4 cycles (99–84%). In the fifth cycle, the yield of 3a was
groups (i.e., methoxy, 1c,d) and electron-withdrawing groups reduced to 67%. This could be due to the dilution of the catalyt-
(i.e., F, 1e,f) at different positions of indoles were well toler- ic system in each cycle.
ated and delivered the desired fluorinated indol-3-yl-1-
phenylethanols (3q–t) in excellent yields in the range from 3-Indolylmethanols are versatile pre-electrophiles for C–C func-
79–96%. The reaction of 3a with different azaindoles (4-. 5-, 6-, tionalization at the 3-position of indoles. Particularly, the
and 7-azaindoles, 1g–j) provided the corresponding products in Friedel–Crafts alkylation of 3-indolylmethanols with indoles
the range from 91–97% yield (3u–x).
has become a useful method for the preparation of 3,3'-, and
3,6'-DIMs, which are known to possess a wide variety of bio-
We applied the developed protocol to reactions of other hetero- logical activities, including anti-inflammatory, and anticancer
cyclic systems such as indazole (4), benzimidazole (5), effects. Therefore, we decided to synthesize DIMs from 3a,
carbazole (6), benzofuran (7), and benzothiophene (8) with ke- which reacted with indole (1b) or 2-phenylindole (1k) in the
tone 2a (Figure 3). However, no desired products are formed.
presence of Ga(OTf)3 in ACN at room temperature or at 80 °C
as reported by Y. Ling et al. [32]. As indicated in Scheme 2, the
As a next step, this protocol is employed in the large-scale prep- desired unsymmetrical 3,3'-DIM (9: 81%) and 3,6'-DIM (10:
aration of 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-phenylethan-1- 77%) with quaternary center were afforded in good yields.
ols. We performed gram-scale reactions of 5-methoxyindole Besides, the protocol reported by S. Sasaki et al. [33] was also
(1a, 6.8 mmol) with 2,2,2-trifluoroacetophenone (2a, 7.5 mmol) employed for the synthesis of 3,3'-DIMs in good yield, see for
or of indole (1b, 8.5 mmol) with 2a (9.4 mmol, Scheme 1). In example product 11 (80%, Scheme 2).
both reactions, the desired products are achieved in excellent
yields (3a: 2.14 g, 98%; 3b: 2.39 g, 96%).
Next, a plausible mechanism for the preparation of multi-
halogen-alkylated 1-(1H-indol-3-yl)-1-phenylethan-1-ols is pro-
The recyclability of the catalytic system n-Bu4PBr/K2CO3 of posed as indicated in Scheme 3. Based on the literature [34],
this protocol was investigated in the preparation of 3a using 1a this reaction initiates by the formation of n-Bu4P+KCO3− salt
(3.40 mmol), 2a (3.70 mmol), K2CO3 (0.5 mmol) and (A) from the interaction of n-Bu4PBr and K2CO3. Intermediate
n-Bu4PBr (0.5 mmol) in distilled water (5 mL) at room temper- A makes a hydrogen bond interaction with the NH of the
ature for 12 h (Figure 4). The product 3a was filtered after 5-methoxyindole (1a) and form the adduct B. This interaction
completion of the reaction. The resulting filtrate was recovered, assists 1a reacting with an electrophilic ketone (2a) to form the
washed with ethyl acetate to remove any organic impurities, and intermediate D via C–C bond formation (C). Re-aromatization
reused for the next cycle. This procedure was followed for each of D generates E, which then protonates to form the desired
cycle. Interestingly, the catalytic system was efficient to product 3a by excluding A for the next catalytic cycle.
Figure 3: Structures of heterocycles that did not react with ketone 2a.
Scheme 1: Gram-scale synthesis of 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-phenylethan-1-ols (3a and 3p).
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Beilstein J. Org. Chem. 2020, 16, 778–790.
Figure 4: Recyclability of the catalytic system n-Bu4PBr/K2CO3 for the preparation of 2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)-1-phenylethan-1-ol
(3a).
Scheme 2: Synthesis of trifluoromethylated unsymmetrical 3,3'- and 3,6'-DIMs (9–11).
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Beilstein J. Org. Chem. 2020, 16, 778–790.
Scheme 3: Proposed mechanism for the preparation of 3a as an example.
Further, to prove this hypothesis the following control experi- tance of electrophilicity of ketones, different enolizable and
ments were performed. The reaction of 1-methylindole (1l) with nonenolizable ketones were screened with the reaction of
2a failed to provide the product (Scheme 4). It suggests that the 5-methoxyindole (1a). The enolizable ketones 2j–l failed to
indole having a free NH-functionality is important to interact provide the products (see Table 2). Similarly, nonenolizable ke-
with the base, thereby initiating the reaction. To find the impor- tones 2p and 2q (Scheme 4) failed to provide the products. This
Scheme 4: Control experiments.
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Beilstein J. Org. Chem. 2020, 16, 778–790.
observation suggests that the multihalogen-substitution en-
hanced the electrophilicity of the ketone for the Friedel–Crafts
hydroxyalkylation reaction of indole.
Preprint
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2020.17.v1
Conclusion
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Acknowledgements
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