Efficient guanidine-catalyzed alkylation of indoles with fluoromethyl ketones in the presence of water

Article abstract of DOI:10.1021/ol9005079

A simple and efficient guanidine-catalyzed methodology for the direct preparation of trifluoromethyl-indolyl-phenylethanols in the presence of water is reported. This synthetically viable class of compounds is obtained in excellent yields (up to 98%) thro

Full text of DOI:10.1021/ol9005079

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2093-2096
Efficient Guanidine-Catalyzed Alkylation
of Indoles with Fluoromethyl Ketones in
the presence of Water
Marco Bandini* and Riccardo Sinisi
Dipartimento di Chimica “G. Ciamician”, Via Selmi 2, 40126 Bologna, Italy
marco.bandini@unibo.it
Received March 11, 2009
ABSTRACT
A simple and efficient guanidine-catalyzed methodology for the direct preparation of trifluoromethyl-indolyl-phenylethanols in the presence of
water is reported. This synthetically viable class of compounds is obtained in excellent yields (up to 98%) through Friedel-Crafts-type alkylation
of indoles with aromatic fluoromethyl ketones. Exceptional reaction scope of indoles and alkylating agents is described.
Aromatic organo-fluorine compounds are receiving a great
deal of attention in pharmaceutical, agrochemical and mate-
rial sciences, due to the unique features brought by the
fluorine atom/s to the physical and chemical features of the
molecule.1 In this scenario, indolyl rings and trifluoromethyl
groups are frequently combined in complex molecular
architectures.
Catalytic FC-type alkylations of indoles with trifluorom-
ethylcarbonyl compounds are practical and enable routes to
the creation of benzylic stereocenters.2 Despite the wide-
spread interest in these targets, at the present, organo-
metallic3a and metal-free3b,c catalyzed methodologies have
been mostly applied to activated 3,3,3-trifluoromethylpyru-
vates and only a handful of catalytic indole alkylations with
simple trifluoromethyl ketones and aldo-derivatives are
known.4
As a continuation of our ongoing interest in catalytic indole
functionalizations5 and use of simple trifluoromethyl ketones
for the construction of CF3-containing quaternary stereo-
centers,6 we envisioned a confluence of these topics as a
straighforward means for the preparation of a family of
(3) (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J.
Org. Chem. 2001, 66, 1009–1013. (b) To¨ro¨k, B.; Abid, M.; London, G.;
Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew.
Chem., Int. Ed. 2005, 44, 3086–3089. (c) Abid, M.; To¨ro¨k, B. Org. Lett.
2008, 10, 933–935.
(1) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical Frontiers of
Fluorine Chemistry; American Chemical Society: Washington, DC, 1996.
(b) Himaya, T. Organofluorine Compounds; Springer-Verlag: Berlin,
Feidelberg, 2001. (c) Paquette, L. Fluorine-Containing Reagents; Wiley-
VCH: Weinheim, 2007. (d) Ma, J.-A.; Cahard, J. Chem. ReV. 2004, 104,
6119–6146. (e) Ma, J.-A.; Cahard, J. J. Fluorine Chem. 2007, 128, 975–
996.
(4) (a) Abid, M.; To¨ro¨k, B. AdV. Synth. Catal. 2005, 347, 1797–1803.
(b) Zhang, G.-W.; Wang, L.; Nie, J.; Ma, J.-A. AdV. Synth. Catal. 2008,
350, 1457–1463.
(2) For representative reviews on catalytic FC-alkylations see: (a)
Jørgensen, K. A. Synthesis 2003, 1117–1125. (b) Bandini, M.; Melloni,
A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550–556. (c)
Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005,
1199–1222. (d) Poulsen, T. B.; Jørgensen, K. A. Chem. ReV. 2008, 108,
2903–2915. (e) Sheng, Y.-F.; Zhang, A. J.; Zheng, X.-J.; You, S.-L. Chin.
J. Org. Chem. 2008, 28, 605–616.
(5) (a) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.;
Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424–1425. (b) Bandini,
M.; Eichholzer, A.; Monari, M.; Piccinelli, F.; Umani-Ronchi, A. Eur. J.
Org. Chem. 2007, 291, 7–2920. (c) Bandini, M.; Eichholzer, A.; Tragni,
M.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2008, 47, 3238–3241.
(6) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem. Commun. 2008,
4360–4362.
10.1021/ol9005079 CCC: $40.75
Published on Web 04/13/2009
 2009 American Chemical Society

important synthetic building blocks such as 2,2,2-trifluoro-
1-(1H-indol-3-yl)-1-phenylethanols 3 under mild catalytic
conditions.7
Table 1. Optimization of the Reaction Parametersa
Selective catalytic addition of an indolyl nucleus to simple
carbonyl compounds (aldehydes and ketones), still represents
a quite unexplored field if we consider the challenging
isolation of unstable indol-3-ylcarbinols under acidic condi-
tions.8,9
entry
cat (%)
solvent
1a/2a
yield 3aa (%)b
The present working idea deals with the use of catalytic
amounts of organic base, as an alternative to conventional
acid catalysis, to activate the indolyl core toward FC-
functionalization, with the concomitant minimization of bis-
indolylmethane formation (Scheme 1).8
1
2
3
4
5
6
7
8
InBr3 (10)
FeCl3 (10)
BF3·Et2O (10)
pTSA (10)
pyridine (10)
TEA (10)
DIPEA (10)
Quinine (10)
TMG (10)
tBuTMG (10)
tBuTMG (5)
tBuTMG (5)
tBuTMG (2)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
H2O
5/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
10
8
27
10
c
-
9
11
c
-
9
98
98
98
98
94
Scheme 1
.
Conventional vs Not-Conventional Activation Modes
in Catalytic FC-Alkylations of Indoles
10
11
12
13
5/1
1.1/1
1.1/1
1.1/1
H2O
a Reactions were carried out open to the air and with no precautions
taken to exclude moisture, unless otherwise specified. In the absence of
catalyst the reaction could not proceed at all. b Isolated yields after flash
chromatography. c No reaction.
and Barton’s base-tBuTMG (2-tBu-1,1,3,3-tetramethylguani-
dine, pKa ) 14)12 (1a:2a ratio: 5:1, 16 h, entries 9, 10) led
to 3aa in quantitative yield. Then, in order to discriminate
between these bases, a further survey of reaction parameters
such as catalyst loading, reaction time and reagent ratio was
performed. From this investigation, tBuTMG (5 mol %)
emerged as the catalyst of choice enabling the isolation of
3aa in quantitative yield even with indole:ketone ratio of
1.1:1.13
Pointing toward sustainability, we envisioned the pos-
sibility to run the present FC reaction in the presence of
water.14 Interestingly, although no detailed kinetic investiga-
tions were undertaken, comparable reaction rates with organic
media and in the presence of water were observed (entries
11 and 12). Finally, it was possible to lower the loading of
the catalyst up to 2 mol %, mantaining comparable chemical
outputs (entry 13). Although the reaction seemed to occur
in the concentrated organic phase constituted by the reagents,
the presence of water assisted the reaction course causing
the precipitation of the product 3.15,16
In this context, we have recently documented5b,c the
suitability of basic indole-activation (pKa values of N-H
indole range between 12.36 and 19.50),10 in catalytic FC
chemistry.
As a proof of concept, we surveyed a range of organic
bases as well as acid additives in the condensation of 1a
with 2a as the model reaction partners. A summary of results
is reported in Table 1.
As expected, classical Lewis (entries 1-3) and Brønsted11
(i.e., pTSA, entry 4) acid catalysts for FC alkylations
furnished the desired indole-3-carbynol 3aa in low yields
(e27%), leading to variable amounts of side products/
reactions such as bis-indolylmethanes and oxidative dimer-
ization of 1a. Unacceptable chemical outcomes were also
observed with moderately basic pyridine and aliphatic tertiary
amines (i.e., TEA, DIPEA, quinine), but delightfully, cata-
lytic amounts of TMG (tetramethylguanidine, pKa ) 13.6)12
(13) For reviews regarding the use of guanidine in organic synthesis
see: (a) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737–752. (b) Leow,
D.; Tan, C.-H. Chem. Asian J. 2009, 4, 488–507.
(7) For a recent elegant example of Zr-catalyzed stereoselective addition
of pyrrole to trifluoromethyl ketones see: Blay, G.; Ferna´ndez, I.; Monleo´n,
A.; Pedro, J. R.; Vila, C. Org. Lett. 2009, 11, 441–444.
(14) For representative examples of FC-alkylations in water see: (a)
Manabe, K.; Aoyama, N.; Mikami, K. AdV. Synth. Catal. 2001, 343, 174–
176. (b) Zhuang, W.; Jørgensen, K. A. Chem. Commun. 2002, 1336–1337.
(c) Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8, 4939–4942. For a
comprehensive review on C-C bond forming processes in water see: Li,
C.-J. Chem. ReV. 2005, 105, 3095–3166, and references therein.
(15) (a) Klijn, J. E.; Engberts, B. F. N. Nature (London) 2005, 435,
746–747. (b) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem.,
Int. Ed. 2006, 45, 8100–8102. (c) Hayashi, Y. Angew. Chem., Int. Ed. 2006,
(8) (a) Remers, W. A. In Indoles, Heterocyclic Compounds; Houlihan,
W. J., Ed.; John Wiley & Sons: London, 1972. (b) Indoles; Sudberg, R. J.,
Ed.; Academic Press: London, 1996
(9) For a leading study see: Li, H.; Wang, Y.-Q.; Deng, L. Org. Lett.
.
2006, 8, 4063–4065
.
(10) Yagil, G. Tetrahedron 1967, 23, 2855–2861.
(11) During the submission of the manuscript an enantioselective
arylation of trifluomethyl ketones (CH2Cl2) was described in the presence
of BINOL-derived chiral phosphoric acids: Nie, J.; Zhang, G.-W.; Wang,
L.; Fu, A.; Zheng, Y.; Ma, J.-A. Chem. Commun. 2009, DOI: 10.1039/
b900474b.
45, 8103–8104
.
(16) Although in many cases camparable results in terms of reaction
rate and isoltated yield were obtained in water or under neat conditions,
the presence of water became fundamental when fluoroketones (i.e., 2d,
2e) were employed.
(12) The reported pKa values refer to the conjugated acids.
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Org. Lett., Vol. 11, No. 10, 2009

With optimal reaction conditions in hand (tBuTMG, 2 mol
%, H2O, 16 h, rt), we assessed the scope of electrophilic
agents by reacting a range of trifluoromethyl ketones (2b-g)
with 1a and the results are listed in Table 2.
ethanone (2h) to the tBuTMG-catalyzed condensation with
1a. Satisfyingly, the desired difluoro-compound 3ah was
isolated in 66% yield (entry 7).
Great scope of indoles was finally documented by the runs
collected in Table 3. Here a number of commercially
Table 2. Scope of Fluoromethylaryl Ketones 2 in the
tBuTMG-Catalyzed Alkylation of 1a
Table 3. Proving the Scope of Indoles in the
tBuTMG-Catalyzed Alkylation Process with 2a
entry
indole
product
yield 3 (%)a
1
2
3
4
5
6
7
8
1b, X: 5-F, R: H
1c, X: 5-Br, R: H
1d, X: 5-CN, R: H
1e, X: 5-NO2, R: H
1f, X: 6-F, R: H
1g, X: 6-Cl, R: H
1h, X: 5-OMe, R: H
1i, X: 5-OBn, R: H
1j, X: 2-Me, R: H
1k, X: 2-Me/7-Br, R: H
1l, X: 7-Me, R: H
1m, X: H, R: Me
1n, 7-azaindole
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
98
98
98
98
98
94
98
66
86
75
98
sb
96c
9
10
11
12
13
a Isolated yields after flash chromatography. b No reaction. c With 5
mol % of catalyst. Dioxane:H2O 9:1 was used as the solvent.
available substituted indoles were reacted with 2a under the
best reaction conditions.
The results listed in Table 3 entries 1-6 represent one of
the strong points of the methodology. In fact, indolyl-rings
bearing electron-withdrawing substituents (i.e., CN, NO2) are
generally recognized as unwilling substrates for FC-alkyla-
tion reactions.18 On the contrary, the present tBuTMG-
catalyzed methodology allowed electron-deficient indoles
(1b-g) to be readily transformed into the corresponding
fluorinated indol-3-yl-1-phenylethanols (3ba-3ga) in excel-
lent yield.19 Electron-dontating groups at C-2, C-5 and C-7
positions are also well tolerated (yield 66-98%), with the
possibility to further extend the protocol to the FC-reluctant
7-azaindole 1n (yield: 96%, entry 13).20
a Isolated yields after flash chromatography. b Reaction time 48 h, 1a:
2g ) 5:1.
High tolerance toward aryl-substitution of the fluoroketone
was highlighted by the excellent yields obtained with ketones
2b-e (entries 1-4). Interestingly, while the introduction of
a sterically demanding substituent (i.e., PivNH-, 2f) close
to the carbonyl group led a decreased isolated yield in the
final product (yield ) 60%, entry 5), trifluoromethyl ketone
2g bearing electron-rich heteroaryl unit (i.e., thiophene)
proved to be a competent candidate for the alkylation of 1a
(yield ) 98%, entry 6).17
Finally, N-methylindole proved to be inert under optimal
reaction conditions (entry 12), stressing the existence of a
key NH-base interaction in the present FC-alkylation meth-
odology.
(18) For representative examples see: (a) Bandini, M.; Cozzi, P. G.;
Melchiorre, P.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 5386–5389. (b)
Moran, J.; Suen, T.; Beauchemin, A. M. J. Org. Chem. 2006, 71, 676–679.
(c) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.-Eur. J.
2008, 14, 3630–3636.
Finally, the role of the fluorine atoms in the reaction
outcome was clarified by subjecting R,R-difluoro-1-phenyl
(19) Also pyrroles were found suitable substrates for the present
tBuTMG-catalyzed methodology. As an example the condensation of
2,4-dimethylpyrrole with 2a (tBuTMG 5 mol%, 16 h, rt) led to the
corresponding 1-(3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-phenyle-
thanol in 75% yield.
(17) Limitation of the protocol comprises the use of enolizable aliphatic
trifluoromethyl ketones that resulted unreactive under best reaction param-
eters.
(20) Popowycz, F.; Routier, S.; Joseph, B.; Me´rour, J.-Y. Tetrahedron
2007, 63, 1031–1067.
Org. Lett., Vol. 11, No. 10, 2009
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The process was also carried out on a multigram scale.
Here, the loading of the tBuTMG was lowered up to 1.0
mol %, obtaining 3aa in 94% yield after 72 h reaction time.21
The rigorous use of a 1:1 (1a:2a) mixture allowed the final
product to be isolated by filtration without the need for
organic solvents both in the reaction course and workup
procedure (Scheme 2).
scope and mildness of the reaction parameters emerged from
the survey of substrates. Attempts to develop an enantiose-
lective version of the present protocol and to extend the
method to aldehydes and enolizable ketones are currently
underway in our laboratories.
Acknowledgment. We acknowledge the MIUR (Rome),
FIRB Project (Progettazione, preparazione e valutazione
biologica e farmacologica di nuove molecole organiche quali
potenziali farmaci innovativi), Consorzio C.I.N.M.P.I.S.
(Bari), and University of Bologna.
Scheme 2
.
tBuTMG-Catalyzed Multigram Scale FC-Alkylation
of 1a with 2a
Supporting Information Available: Experimental pro-
cedures, 1H/13C/19F-NMR spectra and full spectroscopic data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL9005079
(21) General procedure for multigram scale FC-alkylation. A sample
vial containing distilled water (4.0 mL) was charged with 1a (5.7 mmol,
672 mg), ketone 2a (1.0 g, 5.7 mmol) and 9.8 mg of tBuTMG (1.0 mol
%). The reaction was vigorously stirred at the room temperature for 72 h.
Pure product 3aa was recovered by filtration, washed with water (5 mL),
and dried under vacuum (1.55 g, yield: 94%).
In conclusion, we have documented an unprecedented
practical and efficient tBuTMG-catalyzed addition of indoles
to fluoromethylaryl ketones in the presence of water. Wide
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Org. Lett., Vol. 11, No. 10, 2009