InBr3: A versatile catalyst for the different types of Friedel-Crafts reactions

Article abstract of DOI:10.1021/jo9014613

(Chemical Equation Presented) Mild and efficient InBr₃-catalyzed Friedel-Crafts alkylation of heteroaromatic or electron-rich aromatic compounds with α-amido sulfones at room temperature in CH₂Cl₂ has been developed. The p

Full text of DOI:10.1021/jo9014613

pubs.acs.org/joc
InBr3: A Versatile Catalyst for the Different Types of
Friedel-Crafts Reactions
Ponnaboina Thirupathi and Sung Soo Kim*
Department of Chemistry, Inha University, Incheon 402-751, South Korea
sungsoo@inha.ac.kr
Received July 9, 2009
Mild and efficient InBr3-catalyzed Friedel-Crafts alkylation of heteroaromatic or electron-rich aromatic
compounds with R-amido sulfones at room temperature in CH2Cl2 has been developed. The products
undergo further Friedel-Crafts alkylation with heteroaromatic or electron-rich aromatic compounds
leading to unsymmetrical or bis-symmetrical triaryl methanes in good yield. R-Amido sulfones are
employed for the synthesis of the unsymmetrical and bis-symmetrical triaryl methanes. The use of mild
reaction condition, low catalytic loading, and high yield are the advantages of the present procedures.
Introduction
activities.3 The introduction of functionalized alkyl frame-
work at the 3-position in the indole system is a common
practice directed to the synthesis of biologically active com-
pounds.4 A variety of methods have been explored for the
Friedel-Crafts alkylation of indole due to its electron-rich
nature.5
Recently several workers have demonstrated that R-amido
sulfones 1 are useful precursors of N-acyliminium ions 2 that
can further react with several nucleophiles such as allylsi-
lanes, silyl ketene acetals, trimethylsilyl cyanide, and elec-
tron-rich aromatics leading to the corresponding adducts 3
(Scheme 1).6 Petrini and co-workers have demonstrated that
the Friedel-Crafts reactions of heteroaromatic indoles with
Friedel-Crafts alkylation is one of the most important
C-C bond-forming reactions in organic chemistry.1 These
reactions are usually assisted by either protic acid or Lewis
acid catalyst. Indoles and many of its derivatives are present in
numerous substances commonlyfoundinnature,2 aswellas in
the compounds that show pharmacological and biological
(1) For reviews of Friedel-Crafts alkylation reactions, see: (a) Olah, G. A.
Friedel-Crafts and Related Reactions; Wiley-Interscience: New York, 1964;
Vol. II, Part 1. (b) Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation
Chemistry: A Century of Discovery; Dekker: New York, 1984. (c) Olah, G. A.;
Krishnamurthi, R.; Prakash, G. K. S. Friedel-Crafts Alkylations in Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, UK, 1991. (d) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2004, 43, 550.
(2) (a) Jiang, B.; Yang C. G.; Wang, J. J. Org. Chem., 2002, 67, 1396-1398
and references cited therein. (b) Sundberg, R. J. The Chemistry of Indoles;
Academic: New York, 1970. (c) Kam, T. S. In Alkaloids, Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: Amsterdam, The
Netherlands, 1999; Vol. 4, p 285.
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DOI: 10.1021/jo9014613
r
Published on Web 09/21/2009
J. Org. Chem. 2009, 74, 7755–7761 7755
2009 American Chemical Society

Thirupathi and Kim
JOCArticle
SCHEME 1
SCHEME 2
R-amido sulfones catalyzed by montmorillonite K-10 give
the unexpected 3-(1-arylsulfonylalkyl)indoles.7 Moreover
3-(1-arylsulfonylalkyl)indoles have further scope for various
synthetic transformations.8
agents,17 suitable building blocks for generating dendrimers,18
and substrates for theoretical19 and biological20 studies. While
many methods have been reported for the preparation of
symmetrical triaryl methanes,21 the synthesis of unsymmetrical
derivatives is far less studied.22-24 We describe here a broad
scope of InBr3-catalyzed Friedel-Crafts alkylations that allow
the selective preparation of structurally diverse triaryl
methanes through sequential reactions with same or different
electron-rich aromatic compounds (Scheme 2; Table 1).
In recent years the utility of indium salts as Lewis acids in
organic synthesis has received a great deal of attention due to
the relatively low toxicity, stability in air and water, and
strong tolerance to oxygen- and nitrogen-containing sub-
strates.9 The application as Lewis acid catalyst to funda-
mental reactions such as Diels-Alder,10 Friedel-Crafts,11
Mukaiyama aldol,12 and Sakurai-Hosomi allylation reac-
tions13 has been extensively investigated.14 In continuation
of the development of useful synthetic methodology for C-C
bond-forming reactions,15 we report herein an efficient
InBr3-catalyzed Friedel-Crafts alkylation of heteroaro-
matic or electron-rich aromatic compounds with R-amido
sulfones. The products undergo further Friedel-Crafts al-
kylation with heteroaromatic or electron-rich aromatic com-
pounds giving rise to triaryl methanes.
Result and Discussion
We have carried out the reaction of R-amido sulfone 4 with
heteroaromatic indole 8 in CH2Cl2 in the presence of molec-
ular iodine that produces the desired 3-(1-arylsulfonylalkyl)-
indole in 58% yield (entry 1). In the absence of any catalyst
no product could be detected (entry 2). Then the Lewis acids
such as ZrOCl2 8H2O, Rh(acac)3, Co(acac)3, In(acac)3, and
3
Triaryl methanes display interesting properties and have
received a great deal of attention as leuco dyes,16 photochromic
InBr3 were screened (entries 3-7). InBr3 (10 mol %) is found
to be the most effective catalyst (entry 7). The effect of
various solvents also has been studied. CH2Cl2 is found to
be the solvent of choice in terms of yield and reaction time
(entry 12).
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(11a-e) to give the Friedel-Crafts alkylation products in
good yield. The methyl group at the 2-position of indoles
(entry 3 and 6) gives less yield than in case of the reaction of
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TABLE 1. Friedel-Crafts Alkylation of Heteroaromatic Indoles with R-Amido Sulfones under Various Reaction Conditionsa
entry
catalyst (mol %)
I2 (20)
solvent
reaction time (h)
isolated yield (%)b
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1,4-dioxane
THF
1,4-dioxane:H2O (3:1)
MeOH
H2O
6
12
8
12
12
12
4
10
8
4
4
5
6
8
10
7
12
58
NR
63
NR
NR
NR
89
67
73
89
90
70
83
61
44
40
trace
ZrOCl2 8H2O (10)
3
Rh(acac)3 (10)
Co(acac)3 (10)
In(acac)3 (10)
InBr3 (10)
InBr3 (3)
InBr3 (5)
InBr3 (15)
InBr3 (20)
10
11
12
InBr3 (10)
aReaction conditions: R-amido sulfone(1.0 mmol), heteroaromatic indole (1.1 mmol), and solvent(2.0 mL) at r.t. bYield of isolated product after flash
column chromatography.
a
TABLE 2. Friedel-Crafts Alkylation of Heteroaromatic Indoles with R-Amido Sulfones Catalyzed by InBr3
R-amido sulfone 10
entry
R1
R
Ar
indole 8
product 11
reaction time (h)
isolated yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2t-Butyl
CO2Bn
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
Ph
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
8a
8b
8c
8d
8e
8c
8a
8a
8a
8a
8a
8a
8a
8a
8a
11a
11b
11c
11d
11e
11f
11a
11a
11g
11h
11i
6
6
7
6
7
7
6
6
5
5
4
6
6
7
6
83
76
80
78
75
78
61
68
84
86
90
83
80
76
73
4-MePh
4-MeOPh
3-Me, 4-MeOPh
4-ClPh
3-ClPh
2-ClPh
C6H11
11j
11k
11l
11m
aReaction conditions: R-amido sulfone (1.0 mmol), indole (1.1 mmol), InBr3 (0.1 mmol), and CH2Cl2 (2.0 mL) at r.t. bYield of isolated product after
flash column chromatography.
indole-6-carboxylate (entry 5) with R-amido sulfone (R =
CO2Et, Ar = Ph, R1 = Ph) produce corresponding 3-(1-
arylsulfonylalkyl)indoles in 78% and 75% yield, respectively.
Indole 8a is used as a substrate to react with various R-amido
sulfones for the Friedel-Crafts alkylation reactions (Table 2,
entries 7-15). The alkoxy group in the carbamoyl moiety in
R-amido sulfones plays an important role for the yield of
product. Among the alkoxy groups OEt, O-tert-butyl, and
OBn in R-amido sulfones (entries 1, 6 and 7), the ethyloxy
(OEt) group is found to give the best result (entry 1). The
R-amido sulfones with an electron-donating group attached to
the benzene ring are able to undergo Friedel-Craftsalkylation
J. Org. Chem. Vol. 74, No. 20, 2009 7757

Thirupathi and Kim
JOCArticle
FIGURE 1. Plausible mechanism of InBr3-catalyzed Friedel-Crafts alkylation of R-amido sulfones with indoles.
FIGURE 2. 1H NMR of bis-indole 15 (R = 4-MePh).
smoothly and generate the corresponding products in very
good yield (entries 9-11). The reactions of p-, m-, and
o-chloro-R-amido sulfones with indole 8a give the correspond-
ing 3-(1-arylsulfonylalkyl)indoles in 83%, 80%, and 76%
yield, respectively (entries 12-14). The o-chloro isomer indi-
cates slight steric effects that are responsible for the lower yield
(entry 14). Cyclohexyl R-amido sulfone brings about the
corresponding 3-(1-arylsulfonylalkyl)indole derivative in good
yield (entry 15).
A plausible mechanism for the formation of 11 may start
from the N-acyliminium ion 12 that is formed by elimination
of arenesulfinic acid from the R-amido sulfone 10 by the
action of InBr3. Reaction of the strong electrophile 12 with
indole 8a gives the Fredel-Crafts product 13 (Figure 1).
InBr3 catalyzes the elimination of carbamate from 13 leading
to the second iminium ion 14.25 The iminium ion 14 then
reacts with indole 8a in a second Fredel-Crafts reaction
giving rise to bis-indole 15 through reversible reaction.
Formation of bis-indole 15 has been observed during the
course of the reaction that completely disappeared at the
end of the reaction. After 1.0 h of reaction time 15 (R =
4-MePh) was isolated and characterized by NMR analysis
(see Figure 2 and the Supporting Information). The arene-
sulfinic acid (ArSO2H) reacts with the second iminium ion 14
to afford the desired product 11 (Figure 1).
We have further examined the scope of the Friedel-Crafts
alkylation reactions using R-amido sulfones 16 with other
electron-rich aromatic compounds 17 and the results are
summarized in Table 3. The R-amido sulfone (R = Ph, Ar =
4-MePh) was treated with 1,2,4-trimethoxybenzene 17a to
afford the corresponding diarylsulfone 18a in excellent yield
(25) Ke, B.; Qin, Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett. 2005,
46, 1751.
7758 J. Org. Chem. Vol. 74, No. 20, 2009

Thirupathi and Kim
JOCArticle
TABLE 3. Friedel-Crafts Alkylation of Electron-Rich Aromatic
We propose a plausible mechanism that could explain
the formation of compounds 23 in the following manner
(Figure 3). InBr3 catalyzes the formation of N-acylimi-
nium ion 12 by elimination of arenesulfinic acid
(ArSO2H) from the R-amido sulfones 10. Reaction of
the strong electrophiles 12 with electron-rich arene 17
gives the Fredel-Crafts products 24. The elimination of
carbamate from 24 by InBr3 may lead to formation of
oxonium ions 25. The oxonium ions 25 can react with
arenesulfinic acid (ArSO2H) to produce the diaryl sul-
fones 18. The diaryl sulfones 18 in presence of InBr3 result
in the second oxonium ions 26 that react with indole 8 in a
second Fredel-Crafts reaction to afford triaryl methanes
23.26,27
a
Compounds with R-Amido Sulfones Catalyzed by InBr3
R-amido sulfone 16
isolated
arene 17 product 18 yield (%)b,c
entry
Ar
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-MePh Ph
4-MePh Ph
4-MePh Ph
4-MePh Ph
17a
17b
17c
17d
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
18a
18b
18c
18d
18e
18f
18g
18h
18i
18j
18k
18l
18m
18n
18o
18p
92
80
87
90
86
89
90
92
92
87
90
87
83
85
81
79
Conclusion
Ph
Ph
Ph
4-MeOPh
In conclusion, we have demonstrated InBr3-catalyzed
Friedel-Crafts alkylations of heteroaromatic or electron-
rich aromatic compounds with R-amido sulfones. The
catalyst system also allows a controlled double electrophi-
lic aromatic substitution that provides access to unsymme-
trical and bis-symmetrical triaryl methanes with wide
structural diversity. R-Amido sulfones are employed for
the first time in the synthesis of the unsymmetrical and bis-
symmetrical triaryl methanes. Further investigation of the
reaction under other reaction conditions is currently in
progress.
4-MePh 4-MePh
4-MePh 4-MeOPh
4-MePh 3-Me,4-MeOPh
4-MePh 4-NO2Ph
4-MePh 4-ClPh
4-MePh 3-ClPh
4-MePh 2-ClPh
4-MePh PhCH2CH2
4-MePh C6H11
4-MePh (CH3)2CHCH2
aReaction conditions: R-amido sulfone (1.0 mmol), aromatic com-
pounds (1.1 mmol), InBr3 (0.1 mmol), and CH2Cl2 (2.0 mL) at r.t. bYield
of isolated product after flash column chromatography. cAll the reaction
times were 2.5 h except for entries 2, 6, 11, and 14-16 that took 3.0 h.
(26) The electron-rich arene (e.g., indole or 1,2,4-trimethoxybenzene)
having various resonance structures (I to X). The active resonance structures
are II, V, and VII for the addition reaction.
(entry 1). The synthetic utility of the method is further
demonstrated by the reaction of R-amido sulfone (R = Ph,
Ar = 4-MePh) with electron-rich aromatic compounds such
as 1,3-dimethoxy-, 1,2,3-trimethoxy-, and 1,3,5-trimethox-
ybenzene for formation of aryl sulfones (entries 2-4). The
reactions of various R-amido sulfones containing electron-
donating or electron-withdrawing groups attached to the
benzene ring with 1,2,4-trimethoxybenzene produce (1-al-
kyl-1-aryl)methylphenyl or tolylsulfones in excellent yield
(entries 5-13). The reactions of aralkyl, cyclic and acyclic
aliphatic R-amido sulfones with 1,2,4-trimethoxybenzene
give the corresponding (1-alkyl-1-aryl)methyl tolylsulfones
in 85%, 81%, and 79%, respectively (entries 14-16).
Table 4 shows the Friedel-Crafts alkylation reaction of
diaryl sulfones with nucleophilic arene partners. Both hetero-
aromatic and electron-rich aromatic compounds prove to be
very effective to afford the Friedel-Crafts substitution pro-
ducts in good yield as a single regioisomer. The reactions of
diaryl sulfones 21 with heteroaromatic indole 22 give corre-
sponding unsymmetrical triaryl methane in 68%, 61%, and
63% yield, respectively (entries 1-3). Similarly, unsubstituted,
methoxy- and chloro-substituted diaryl sulfones were also
reacted smoothly with 1,2,4-trimethoxybenzene to afford the
corresponding bis-symmetrical triaryl methanes in good yield
(entries 5-8). The reactions of o- and p-chloro diarylsufones
with 1,2,4-trimethoxybenzene gave corresponding products in
56% and 64% yield, respectively (entries 7 and 8).The o-chloro
isomer shows less yield, which might be due to the steric and
electronic effects of the chlorine substituent (entry 7).
The deprotonation of arenesulfinic acid (X) leads to the formation of
sulfinate ion. This shows two resonance structures, O-sulfinate (XI) and
S-sulfinate (XII). The S-sulfinate (XII) could be more nucleophilic than
O-sulfinate (XI).
In the synthesis of triaryl methanes, the addition of carbanion (II or V)
derived from electron-rich arene is more favorable than S-sulfinate (XII)
from arenesulfinic acid. This may be due to the higher nucleophilicity
of the II or V.
(27) Kice, J. C.; Large, G. B. J. Am. Chem. Soc. 1968, 90, 4069.
J. Org. Chem. Vol. 74, No. 20, 2009 7759

Thirupathi and Kim
JOCArticle
TABLE 4. Synthesis of Triaryl Methanes from Diaryl Methylsulfonesa,b
diaryl sulfone 21
entry
Ar
Ph
4-MePh
4-MePh
Ph
4-MePh
4-MePh
4-MePh
4-MePh
Ar1
Ar2
Ar3 22
product 23
isolated yields (%)c
1
2
3
4
5
6
7
8
4-MeOPh
4-MeOPh
4-MeOPh
Ph
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
indole
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
indole
indole
23a
23a
23a
23b
23b
23c
23d
23e
68
61
63
65
59
67
56d
64
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
1,2,4-(OCH3)3C6H3
Ph
4-MeOPh
2-ClPh
4-ClPh
aReaction conditions: diaryl sulfone (1.0 mmol), heteroaromatic indole or electron-rich aromatic compound (1.1 mmol), InBr3 (0.1 mmol), and
CH2Cl2 (2.0 mL) at r.t. bReaction time is 6.0 h. cYield of isolated product after flash column chromatography. dIsolated yield after 7.0 h of reaction time.
FIGURE 3. Plausible mechanism of InBr3-catalyzed Friedel-Crafts alkylation of R-amido sulfone with electron-rich aromatic compounds
and synthesis of triarylmethanes.
Experimental Section
TLC. After completion, the reaction was quenched with
distilled water (5 mL) and the mixture was extracted with
EtOAc (5 mL). The combined organic portions were washed
with water (5 mL) and saturated aqueous NH4Cl (5 mL), dried
over anhydrous Na2SO4, and concentrated under vacuum.
The crude product was subjected to flash column chromatog-
raphy (silica gel, hexane-EtOAc, 4:1 to 3:1) to obtain the pure
product.
A. Experimental Procedure for the Friedal-Crafts Alkyla-
tion of Heteroaroamtic or Electron-Rich Aromatic Compounds.
InBr3 (10 mol %) was added to a solution of R-amido sulfones
(1 mmol) and heteroaroamtic indoles or electron-rich aro-
matic compounds in CH2Cl2 (2 mL) under nitrogen. The
mixture was stirred at r.t. and the reaction was monitored by
7760 J. Org. Chem. Vol. 74, No. 20, 2009

Thirupathi and Kim
JOCArticle
1
11a: brown solid; H NMR (400 MHz, CDCl3) δ 8.63 (d,
J = 6.5 Hz, 1H), 7.56 (s, 1H), 7.50-7.40 (m, 5H), 7.23-7.19
(m, 4H), 7.06-6.99 (m, 4H), 5.68 (s, 1H), 2.25 (s, 3H); 13C NMR
(50 MHz, CDCl3) δ 144.3, 135.4, 135.1, 133.4, 130.0, 129.2,
129.1, 128.8, 128.3, 126.9, 124.9, 122.2, 119.8, 118.1, 111.5,
106.8, 69.0, 21.4.7
aqueous NH4Cl (5 mL), dried over anhydrous Na2SO4, and
concentrated under vacuum. The crude product was subjected
to flash column chromatography (silica gel, hexane-EtOAc,
4:1 to 3:1) to obtain the pure product.
23a: white solid, mp 179-180 °C; 1H NMR (400 MHz,
CDCl3) δ 7.96 (br s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.25 (d,
J = 7.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 3H), 6.99 (t, J = 7.4 Hz,
1H), 6.80 (d, J = 7.2 Hz, 2H), 6.61 (s, 1H), 6.58 (d, J = 7.6 Hz,
1H), 5.98 (s, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 3.59 (s,
3H); 13C NMR (50 MHz, CDCl3) δ 157.7, 151.2, 147.9, 142.9,
136.8, 136.4, 129.7, 127.1, 124.7, 123.8, 121.9, 120.2, 120.1, 119.2,
114.3, 113.4, 111.0, 98.2, 57.0, 56.6, 56.1, 55.2, 40.0; HRMS-EI
(m/z) [M]þ calcd for C25H25NO4 403.1784, found 403.1786.
18a: white solid, mp 110-111 °C; 1H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H),
7.56 (d, J = 7.5 Hz, 2H), 7.36-7.33 (m, 3H), 7.19 (d, J = 7.2 Hz,
2H), 6.62 (d, J = 7.5 Hz, 1H), 6.32 (s, 1H), 6.03 (s, 1H), 3.82 (s,
3H), 3.54 (s, 3H), 2.40 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
160.9, 157.9, 144.1, 136.0, 133.7, 130.8, 130.2, 129.0, 128.5 128.2,
114.3, 104.7, 98.3, 66.4, 55.4, 55.3, 21.6; HRMS-EI (m/z) [M]þ
calcd for C22H22O4S 382.1239, found 382.1263.
B. Experimental Procedure for the Synthesis of Triaryl
Methanes. To a mixture of diaryl sulfone (1 mmol) and
heteroaromatic indole or electron-rich aromatic compound
(1.1 mmol) in CH2Cl2 (2 mL) under nitrogen, InBr3 (10 mol %)
was added and stirred for 6.0 h at r.t. The progress of the
reaction mixture was monitored by TLC. After completion of
the reaction, the mixture was quenched with distilled water
(5 mL) and then extracted with EtOAc (5 mL). The combined
organic portions were washed with water (5 mL) and saturated
Acknowledgment. The authors thank The Centre for Bio-
logical Modulators of the KRICT for financial support. We
also acknowledge the assistance by BK21 provided by Korea
Research Council.
Supporting Information Available: Experimental procedure
and characterization data of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 20, 2009 7761