Bronsted acid catalyzed friedel-crafts alkylation reactions of trifluoromethyl-α,β-ynones with indoles

Article abstract of DOI:10.1055/s-0032-1317485

The successful development of a Bronsted acid catalyzed Friedel-Crafts alkylation reaction between trifluoromethyl-α,β-ynones and indoles has been described. The reaction is catalyzed by benzoic acid (5 mol%), with the indoles adding to the carbonyl carbon of the trifluoromethyl-α,β- ynones producing the corresponding 1,2-addition products as trifluoromethyl propargyl alcohols in high yields. Furthermore, treatment of the product with indoles in the presence of trifluoroacetic acid (10 mol%) afforded trifluoromethyl-functionalized unsymmetrical bis(indolyl)propynes in high yields.

Full text of DOI:10.1055/s-0032-1317485

LETTER
▌2699
letter
Brønsted Acid Catalyzed Friedel–Crafts Alkylation Reactions of Trifluoro-
methyl-α,β-ynones with Indoles
Reactions of Trifluoromethyl-α,β-ynones with Indoles
Shigeru Sasaki,* Yuta Ikekame, Manabu Tanayama, Takayasu Yamauchi, Kimio Higashiyama
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan
Fax +81(3)54985768; E-mail: s-sasaki@hoshi.ac.jp
Received: 18.08.2012; Accepted after revision: 25.09.2012
trifluoromethyl-α,β-ynones and indoles, yielding synthet-
Abstract: The successful development of a Brønsted acid catalyzed
ic fluorine-containing indole derivatives.
Friedel–Crafts alkylation reaction between trifluoromethyl-α,β-
ynones and indoles has been described. The reaction is catalyzed by
Ph
O
benzoic acid (5 mol%), with the indoles adding to the carbonyl car-
bon of the trifluoromethyl-α,β-ynones producing the corresponding
1,2-addition products as trifluoromethyl propargyl alcohols in high
yields. Furthermore, treatment of the product with indoles in the
presence of trifluoroacetic acid (10 mol%) afforded trifluoro-
methyl-functionalized unsymmetrical bis(indolyl)propynes in high
yields.
Ph
CF3
1
O
Dy(OTf)3 (7.5 mol%)
i-PrPybox (5 mol%)
+
F3C
CH2Cl2, r.t.
N
H
N
3
H
Key words: Brønsted acid, trifluoromethyl-α,β-ynones, indoles,
trifluoromethyl propargyl alcohols, bis(indolyl)propynes
2
Scheme 1 The catalytic enantioselective FC alkylation of trifluoro-
methyl-α,β-enones with indoles
Trifluoromethylated compounds are an important class of
pharmaceutical and agrochemical materials because of
their interesting properties, such as their binding inter-
actions and bioavailability.1 Trifluoromethylated com-
pounds have been usefully applied to the synthesis of
organofluorine compounds, and various methods have
been developed for the introduction of the trifluoromethyl
moiety into organic compounds and building blocks.2
The reaction of trifluoromethyl-α,β-ynone 47a with indole
2 was chosen as a model reaction system to assess the be-
havior of ynone 4 in the proposed FC alkylation reaction.
Thus, indole 2 was reacted with 1.05 equivalents of ynone
4 in an optimization screen in the presence of several eas-
ily available acid catalysts (Table 1).
We initially examined the FC alkylation reaction using
Sc(OTf)3 and Dy(OTf)3/(S,S)-i-PrPybox as a catalyst in
dichloromethane (CH2Cl2) for 18 hours. Contrary to our
expectations, which were based on the successful FC al-
kylation reaction of indoles with trifluoromethyl-α,β-
enones (Scheme 1), this reaction proceeded to give the
1,2-addition product of indole 2 to the carbonyl carbon of
ynone 4, providing the trifluoromethyl propargyl alcohol
5 in low yield, none of the desired product (Table 1, en-
tries 1 and 2) and with no enantioselectivity (Table 1, en-
try 2).
The Friedel–Crafts (FC) alkylation reaction of indoles is
an interesting transformation because a number of biolog-
ically active indole alkaloid derivatives have been report-
ed in the literature.3
Recently, considerable interest has been focused on the
FC alkylation reaction of indoles with a variety of differ-
ent electrophiles.4 Consequently, several efficient meth-
ods have been developed by numerous research groups for
the synthesis of organofluorine compounds using the FC
alkylation reaction.5
In contrast, when the proposed FC alkylation was con-
ducted in the presence of a Brønsted acid catalyst, no re-
action was observed (Table 1, entries 3–5). In these cases,
indole 2 existed in the liquid phase at the reaction temper-
ature and was miscible8 with the ynone 4. Interestingly,
we found that the reaction proceeded at a much greater
rate in the absence of solvent, generating alcohol 5 in
higher yields, depending on the catalyst used (Table 1, en-
tries 6–8: 94%, 50%, and 90%, respectively). During the
optimization study, benzoic acid performed as an effec-
tive catalyst in the absence of solvent for the FC alkylation
reaction indole 1 with ynone 4.
In our previous work,6 we reported the catalytic enantio-
selective FC alkylation reaction of trifluoromethyl-α,β-
enone 1 with indole 2 to yield the corresponding 1,4-ad-
duct 3 (Scheme 1) through a Michael addition reaction. It
is worthy of note that the reaction proceeded cleanly and
no byproducts were observed. To the best of our knowl-
edge, however, there have been no reports in the literature
describing the FC alkylation reaction of indoles with tri-
fluoromethyl-α,β-ynones to yield the corresponding al-
kylation products. Herein, we describe the successful
development of a catalytic FC alkylation reaction between
Although 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) also
performed well, benzoic acid was selected as the optimum
catalyst going forward because it is relatively inexpen-
SYNLETT 2012, 23, 2699–2703
Advanced online publication: 18.10.2012
DOI: 10.1055/s-0032-1317485; Art ID: ST-2012-U0697-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2700
S. Sasaki et al.
LETTER
Table 1 Optimization of the Reaction Conditions
Table 2 The FC Alkylation Reactions of Indole 2 with Trifluoro-
methyl-α,β-ynone Derivatives 6a–f
O
O
OH
F3C
Ph
F3C
OH
F3C
F3C
R
Ph
4 (1.05 equiv)
catalyst (5 mol%)
r.t.
R
6a–f (1.05 equiv)
benzoic acid (5 mol%)
solvent, r.t.
+
N
+
H
N
5
H
N
H
7a–f
N
H
2
2
Entry Catalyst
Solvent
CH2Cl2
Time
Yield of 5
(%)a
Entry
6
R
Solvent
Time
(min)
7
Yield
(%)a
1
2b
3
4
5
6
7
8
Sc(OTf)3
18 h
18 h
18 h
18 h
18 h
1.5 h
2 h
40
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
4-MeC6H4
4-MeOC6H4
4-ClC6H4
none
60
150
80
7a
7b
7c
7d
7e
7f
77
87
90
91
93
81
Dy(OTf)3/(S,S)-i-PrPybox CH2Cl2
48d
n.r.e
n.r.e
n.r.e
94
none
HFIPc
CH2Cl2
CH2Cl2
CH2Cl2
none
CH2Cl2
phenol
4-MeOCOC6H4 CH2Cl2
150
20
benzoic acid
HFIP
4-NCC6H4
CH2Cl2
none
n-Bu
60
phenol
none
50
a Isolated yield.
benzoic acid
none
50 min 90
a Isolated yield.
Table 3 The FC Alkylation Reactions of Indoles 8a–g with Tri-
fluoromethyl-α,β-ynone 4
b The reaction was performed with 7.5 mol% Dy(OTf)3 and 5 mol%
(S,S)-i-Pr-Pybox.
c HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol.
d No enantioselectivity was observed (see Supporting Information).
e No reaction.
O
OH
F3C
F3C
Ph
Ph
R1
benzoic acid (5 mol%)
neat, r.t.
4 (1.05 equiv)
R2
sive, easy to treat, and easily obtained from a commercial
source.
+
N
R3
R1
R2
To further expand the scope of our new FC alkylation re-
action, indole 2 was reacted with 1.05 equivalents of a va-
riety of different ynone derivatives 6a–f7 under the
optimized conditions (Table 2).
9a–g
N
R3
8a–g
Entry
8
R1
R2
R3
Temp Time 9
(h)
Yield
(%)a
Pleasingly, the desired 1,2-addition products 7a–f were
successfully formed in high yields in all cases. Trifluoro-
methyl-α,β-ynone derivatives containing strongly elec-
tron-donating substituents at the para position of the
aromatic ring showed slightly lower levels of reactivity (R
= 4-MeC6H4, 4-MeOC6H4; Table 2, entries 1 and 2) rela-
tive to ynone 4 likely because of the resulting increase in
the electron density at the trifluoromethyl carbonyl car-
bon. Interestingly, the trifluoromethyl-α,β-ynone deriva-
tives containing electron-withdrawing substituents
directly linked to the para position of the aromatic ring
(e.g., 6c–e) were all solid at room temperature and could
therefore not be effectively mixed under the reaction con-
ditions and required the presence of a solvent. Conse-
quently, an extended reaction time was required to obtain
the products in good yields.
1
2
3
4
5
6
7
8a
8b
8c
8d
8d
8e
8e
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
r.t.
r.t.
r.t.
r.t.
0.25 9a 98
0.5 9b 95
OMe
Br
22
22
9c 96
CO2Me
CO2Me
CN
9d n.r.b
9d 61
70 °C 24
r.t. 20
70 °C 20
9e n.r.b
CN
9e complex
mixture
8
9
8f
H
H
Me
H
H
r.t.
16
24
9f 97
9g 89
8g
Me r.t.
We continued to investigate the scope and limitations of
the optimized FC alkylation reaction by applying the op-
a Isolated yield.
b No reaction.
Synlett 2012, 23, 2699–2703
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reactions of Trifluoromethyl-α,β-ynones with Indoles
2701
timized reactions conditions to the reaction a variety of The reaction of trifluoromethyl propargyl alcohol 5 with
different indole derivatives 8a–g with ynone 4 (Table 3).
1.5 equivalents of 5-methylindole (8a) was chosen as a
model reaction system for optimizing the reaction condi-
tion using a variety of different acid catalysts (Table 4).
In the majority of cases, the reactions provided the desired
trifluoromethyl propargyl alcohol derivatives 9a–g in
good yields, except for 5-cyanoindole (8e) in Table 3, en-
tries 6 and 7. In addition, the presence of electron-donat-
ing groups at the C-5 position of the indole skeleton (R1 =
Me and MeO; Table 3, entries 1 and 3) appeared to have
a beneficial effect on the reaction, resulting in higher
yields over a shorter reaction time.
Table 4 Optimization of the Reaction Conditions of 512 with 8a
OH
F3C
Ph
H
N
Ph
CF3
N
H
5
acid catalyst
solvent, r.t.
In contrast, substrates containing electron-withdrawing
groups (R1 = Br and CO2Me; Table 3, entries 3–5) at the
C-5 position of the indole skeleton had an adverse impact
on the reactivity, resulting in the requirement for extended
reactions times and a higher reaction temperature (70 °C)
to deliver adequate yields. Unfortunately, however, the
use of 5-cyanoindole (8e) in the FC alkylation reaction at
70 °C resulted only in a complex mixture instead of the
desired product. Furthermore, 2-methylindole (8f) and N-
methylindole (8g) both required extended reaction times
to obtain the desired 1,2-addition products in good yield
(Table 3, entries 8 and 9). The reaction of 3-methylindole
(8h) with 4 proceed as anticipated to give the 1,2-addition
product at the 2-position of the 3-methylindole (Scheme
2).
Me
+
Me
NH
10
N
H
8a (1.5 equiv)
Entry Catalyst (mol%) Solvent
Time
Yield of 10 (%)a
1
2
3
4
5
6
7
8
PTSA (5)
TFA (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
7 d
24 h
38 h
24 h
38 h
20 h
20 h
18 h
32
35
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
74
59
11
CCl4
n.r.b
n.r.b
98
O
Me
F3C
F3C
DMF
Ph
OH
CHCl3
4 (1.05 equiv)
benzoic acid (5 mol%)
no solvent, r.t., 2 d
N
Me
+
a Isolated yield.
H
b n.r. = no reaction.
Ph
9h 57%
N
H
Initially, alcohol 5 was reacted with 5-methylindole (8a)
in the presence of p-toluenesulfonic acid (PTSA) (5
mol%) in CH2Cl2 at ambient temperature for seven days,
affording the unsymmetrical bis(indolyl)propyne 1013 in
low yield (Table 4, entry1) together with many other un-
identified compounds. It is worthy of note that many un-
identified compounds were generated when sulfonic acids
were used as the catalyst. This was attributed to the strong
acidity of the catalysts which may have led to the decom-
position of the starting materials and the product 10, giv-
ing rise to the observed lower yields. We then turned our
attention to the acidity of catalyst and selected trifluoro-
acetic acid (TFA, 5 mol%). When TFA was used as the
catalyst in the reaction, only the desired bis(indolyl)pro-
pyne 10 and residual starting materials could be detected
in the product mixture (Table 4, entry 2). We proceeded to
increase the amount of TFA to 10 mol% and found that the
yield of the bis(indolyl)propyne 10 increased to 98%
when the solvent was also changed to CHCl3 and the reac-
tion was conducted at ambient temperature for 18 hours
(Table 4, entry 8).
8h
Scheme 2 The reaction of 3-methylindole (8h) with trifluoromethyl-
α,β-ynone 4
It is worthy of note that the reaction of carbonyl com-
pounds with indoles in the presence of the acid catalyst af-
forded the corresponding bis(indolyl) derivatives9 via a
highly resonance-stabilized cation on the indole group.10
In contrast, the reaction of trifluoromethyl-α,β-ynones
with indoles in the presence of the benzoic acid catalyst
provided the trifluoromethyl-functionalized propargyl al-
cohol derivatives. Bis(indolyl)propynes were not ob-
tained in the current study because the trifluoromethyl
moiety effectively destabilized the α-carbocation as a con-
sequence of its strong electron-withdrawing nature.11 It
was therefore envisaged that the use of a trifluoroacetic
acid catalyst more acidic than benzoic acid would over-
come this issue and allow for the synthesis of trifluoro-
methyl-functionalized
unsymmetrical
bis(indolyl)-
propynes. We proceeded to investigate the possibility of
achieving this transformation using a standard reaction
system.
With the optimized conditions in hand for the synthesis of
a trifluoromethyl-functionalized unsymmetrical bis(in-
dolyl)propyne, we proceeded to further evaluate the scope
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2699–2703

2702
S. Sasaki et al.
LETTER
of the reaction and examined the performance of a variety manipulate this understanding to allow for the selective
of other indole derivatives 1 and 8b–g in the reaction with synthesis of trifluoromethyl-functionalized unsymmetri-
trifluoromethyl propargyl alcohol 5 in CHCl3 in the pres- cal bis(indolyl)propynes. The current methodologies are
ence of TFA (10 mol%) at ambient temperature (Table 5). particularly well suited for the introduction of trifluoro-
methyl moieties and indole skeletons because they are
Table 5 Synthesis of the Trifluoromethyl-Functionalized Unsym-
metrical Bis(indolyl)propynes 11a–g
facile procedures which provide high yields of the desired
products. Furthermore, these structural classes enjoy sig-
nificant application in the fields of biochemical, biomedi-
OH
F3C
Ph
cal, and pharmaceutical research, and it is envisaged that
the current methodologies will be of significant use to re-
searchers in these areas.
R3
R2
N
N
Ph
CF3
H
5
TFA (10 mol%)
Acknowledgment
+
CHCl3, r.t.
R1
R1
This work was supported in part by The Science Research Promoti-
on Fund from The Promotion and Mutual Aid Corporation for Pri-
vate Schools of Japan.
R2
NH
11a–g
N
R3
1, 8b–g (1.5 equiv)
Supporting Information for this article is available online at
Entry 1 or 8 R1
R2
R3
Time 11
Yield (%)a
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
1
2
3
4
5
6
7
1
H
H
H
H
H
18 h
18 h
22 h
5 d
11a
82
95
98
84
91
97
79
References and Notes
8b
8c
8d
8e
8f
8g
OMe
Br
H
11b
11c
11d
11e
11f
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H
CO2Me
CN
H
H
H
H
H
5 d
Me
H
H
16 h
24 h
(c) Kitazume, T.; Yamazaki, T. Experimental Methods in
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H
Me
11g
a Isolated yield.
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In all cases, the reactions provided the desired corre-
sponding trifluoromethyl-functionalized unsymmetrical
bis(indolyl)propynes 11a–g. Furthermore, the electronics
of the indole system did not appear to have a significant
impact on the yield of the reaction, with indole derivatives
bearing either electron-donating or electron-withdrawing
groups providing the corresponding products in good
yield. Electron-withdrawing substituents at the C-5 posi-
tion of the indole skeleton, however, had an adverse im-
pact on the rate of the reaction, with extended reaction
times being required to deliver high yields (Table 5, en-
tries 4 and 5).
In summary, we have demonstrated that benzoic acid can
efficiently facilitate the FC reaction between trifluoro-
methyl-α,β-ynones and indoles. The FC reaction occurred
via a 1,2-addition of the 3-position of the indole to the car-
bonyl carbon of a trifluoromethyl-functionalized propar-
gyl alcohol in high yields. Furthermore, we also achieved
a novel facile synthesis of trifluoromethyl-functionalized
unsymmetrical bis(indolyl)propynes using TFA as a cata-
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acid catalysts on the stability of the α-carbocation and
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yl-functionalized propargyl alcohols and unsymmetrical
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Synlett 2012, 23, 2699–2703
© Georg Thieme Verlag Stuttgart · New York

LETTER
(e) Wang, T.; Zhang, G.-W.; Teng, Y.; Nie, J.; Zheng, Y.;
Reactions of Trifluoromethyl-α,β-ynones with Indoles
2703
needed), then was stirred for 10 min. Then benzoic acid (5
mol%, 25 μmol, 3 mg) was added in one portion. After
completion of reaction as indicated by TLC, the mixture was
purified by silica gel chromatography directly.
1,1,1-Trifluoro-2-(1H-indol-3-yl)-4-phenylbut-3-yn-2-ol
(5)
Purification by silica gel chromatography (CHCl3–MeOH,
29:1) gave white solid (mp 134–136 °C). 1H NMR (400
MHz, CDCl3): δ = 3.11 (s, 1 H), 7.20 (ddd, J = 7.5, 7.0, 1.2
Hz, 1 H), 7.25 (ddd, J = 7.5, 7.0, 1.2 Hz, 1 H), 7.23–7.24 (m,
4 H), 7.52–7.56 (m, 3 H), 8.02 (d, J = 8.0 Hz, 1 H), 8.29 (s,
1 H). 13C NMR (100 MHz, CDCl3): δ = 71.01 (q, J = 34.3
Hz), 84.50, 87.12, 111.41, 111.51, 120.54, 121.04, 121.13,
122.66, 123.94 (q, J = 285.5 Hz), 124.80, 128.20, 129.39,
132.03, 136.53. 19F NMR (376.5 MHz, CDCl3): δ = –71.6.
IR (KBr): 3425, 3360, 2240 cm–1. HRMS (EI): m/z calcd for
C18H12F3NO: 319.1184; found: 319.1208. Anal. Calcd for
C18H12F3NO: C, 68.57; H, 3.84; N, 4.44. Found: C, 68.87; H,
3.91; N, 4.50.
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43, 74. (d) Aristov, S. A.; Vasil’ev, A. V.; Fukin, G. K.;
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(8) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.;
Machado, P. Chem. Rev. 2009, 109, 4140.
(9) For selected examples, see: (a) Yadav, J. S.; Reddy, B. V. S.;
Murthy, C. V. S. R.; Kumar, G. M.; Madan, C. Synthesis
2001, 783. (b) Bandgar, B. P.; Shaikh, K. A. Tetrahedron
Lett. 2003, 44, 1959. (c) Zhang, Z.-H.; Yin, L.; Wang, Y.-M.
Synthesis 2005, 1949. (d) Deb, M. L.; Bhuyan, P. J.
Tetrahedron Lett. 2006, 47, 1441. (e) Sobhani, S.; Safaei,
M.; Hasaninejad, A. R.; Rezazadeh, S. J. Organomet. Chem.
2009, 694, 3027. (f) Praveen, C.; Dheenkumar, P.;
Muralidharan, D.; Perumal, P. T. Bioorg. Med. Chem. Lett.
2010, 20, 7292. (g) Patil, V. D.; Dere, G. B.; Rege, P. A.;
Patil, J. J. Synth. Commun. 2011, 41, 736.
(13) General Procedure for the Synthesis of Unsymmetrical
Bis(indolyl) Propynes
To a solution of trifluoromethyl propargyl alcohol derivative
5 (0.5 mmol) in CHCl3 (2 mL) were added indoles (1.5
equiv, 0.75 mmol) and TFA (10 mol%, 50 μmol, 6 mg) at r.t.
The reaction mixture was stirred until the disappearance of
trifluoromethyl propargyl alcohol derivatives as observed by
TLC. The reaction mixture was quenched with an aq sat.
NaHCO3 solution (2 mL), and the organic layer was
separated. The aqueous layer was extracted 3 times with
CHCl3. The combined organic layer was dried with anhyd
Na2SO4 and then evaporated. The residue was purified by
column chromatography.
5-Methyl-3-[1,1,1-trifluoro-2-(1H-indol-3-yl)-4-
phenylbut-3-yn-2-yl]-1H-indole (10)
(10) Kogan, N. A. Chemistry of Heterocyclic Compounds;
Springer: New York, 1980, 373–376.
Purification by silica gel chromatography (CHCl3) gave a
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 1 H),
6.97–7.04 (m, 2 H), 7.13–7.19 (m, 1 H), 7.19–7.21 (m, 1 H),
7.21–7.24 (m, 2 H), 7.26–7.31 (m, 3 H), 7.35 (d, J = 8.1 Hz,
1 H), 7.45–7.49 (m, 2 H), 7.56 (s, 1 H), 7.75 (d, J = 8.1 Hz,
1 H), 8.00 (s, 1 H), 8.09 (s, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 21.56, 46.52 (q, J = 31.0 Hz), 85.14, 86.23,
110.91, 111.14, 111.24, 111.85, 119.70, 120.85, 121.29,
122.09, 122.53, 123.82, 124.33, 124.46, 125.87, 126.07,
126.15 (q, J = 284.6 Hz), 128.22, 128.47, 128.88, 131.74,
134.77, 136.45. 19F NMR (376.5 MHz, CDCl3): δ = –71.54.
IR (KBr): 3413, 2235 cm–1. ESI-HRMS: m/z calcd for
C27H18F3N2: 427.1422; found: 427.1419.
(11) (a) Allen, A. D.; Kanagasabapathy, V. M.; Tidwell, T. T.
J. Am. Chem. Soc. 1986, 108, 3470. (b) Allen, A. D.;
Colomvakos, J. D.; Tee, O. S.; Tidwell, T. T. J. Org. Chem.
1994, 59, 7185. (c) Allen, A. D.; Fujio, M.; Mohammed, N.;
Tidwell, T. T.; Tsuji, Y. J. Org. Chem. 1997, 62, 246.
(12) General Procedure for the Synthesis of Propargyl
Alcohols
The reaction was performed in a 3 mL V-vial equipped with
Teflon-coated magnetic stirrer bar and screw cap. The V-vial
was charged with indole (0.5 mmol), trifluoromethyl-α,β-
ynone (1.05 equiv, 0.525 mmol), and CH2Cl2 (0.5 mL; as
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Synlett 2012, 23, 2699–2703

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