Enantioselective zirconium-catalyzed friedel-crafts alkylation of pyrrole with trifluoromethyl ketones

Article abstract of DOI:10.1021/ol802509m

(Chemical Equation Presented) The first catalytic enantioselective Friedel-Crafts alkylation of pyrrole with 2,2,2-trifluoroacetophenones to give pyrroles with a trifluoromethyl-substituted tertiary alcohol moiety bearing a quaternary stereogenic center i

Full text of DOI:10.1021/ol802509m

ORGANIC
LETTERS
2009
Vol. 11, No. 2
441-444
Enantioselective Zirconium-Catalyzed
Friedel-Crafts Alkylation of Pyrrole with
Trifluoromethyl Ketones
Gonzalo Blay, Isabel Fernández, Alicia Monleón, Jose´ R. Pedro,* and Carlos Vila
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Vale`ncia, Dr.
Moliner 50, E-46100 Burjassot (Vale`ncia), Spain
jose.r.pedro@uV.es
Received October 30, 2008
ABSTRACT
The first catalytic enantioselective Friedel-Crafts alkylation of pyrrole with 2,2,2-trifluoroacetophenones to give pyrroles with a trifluoromethyl-
substituted tertiary alcohol moiety bearing a quaternary stereogenic center is described. The reaction is achieved in the presence of a 3,3′-
dibromo-BINOL-Zr(IV) complex to give the expected products with high yields (up to 98%) and good enantioselectivities (up to 93% ee). The
absolute stereochemistry of the products has been determined by chemical correlation.
Recently, trifluoromethylated compounds have received
considerable attention, and they have diverse applications
in the areas of materials science, agrochemistry and biomedi-
cal chemistry due to their unique chemical, physical, and
biological properties.1 On the other hand, the catalytic
enantioselective construction of stereogenic tetrasubstituted
carbon centers is a very challenging goal and a matter of
current interest in organic chemistry.2 The emergence of
drugs such as Efavirenz (anti-HIV)3 or CJ-17,493 (neurokinin
1 receptor antagonist),4 two chiral R-trifluoromethyl tertiary
alcohols in which the CF3 moiety is located at a stereogenic
tetrasubstituted carbon atom, has stimulated investigation in
this area. In this context, two general strategies for the
synthesis of this type of R-trifluoromethyl tertiary alcohol
can be used. The first one is the trifluoromethylation of
carbonyl compounds.5 However, enantioselective trifluo-
(2) (a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J. C., Baro, A., Eds.; Wiley-VCH: Weinheim:
Germany, 2006. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
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(e) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473–1482. (f)
Trost, B. M.; Jiang, C. H. Synthesis 2006, 369–396. (g) Riant, O.;
Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873–888. (h) Cozzi, P. G.;
Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969–5994.
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M. E.; Parsons, R. L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore,
J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.;
Morgan, S. J.; Davis, W. P.; Confalone, P. M.; Chen, C.-Y.; Tillyer, R. D.;
Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G. J. Org.
Chem. 1998, 63, 8536–8543.
(1) (a) Organofluorine Compounds: Chemistry Applications; Hiyama,
T., Ed.; Springer: New York, 2000. (b) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, Germany, 2004. (c) Chambers, R. D.
Fluorine in Organic Chemistry; Blackwell: Oxford, U.K., 2004. (d) Shah,
P. A.; Westwell, D. J. Enzyme Inhib. Med. Chem. 2007, 22, 527–540. (e)
Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886. (f) Kirk,
K. L. Org. Process Res. DeV. 2008, 12, 305–321. (g) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV. 2008, 37, 320–330.
(h) Zhu, Y.; Zhao, P.; Cai, X.; Meng, W.-D.; Qing, F.-L. Polymer 2007,
48, 3116–3124. (i) Tsuchiya, K.; Shibasaki, Y.; Aoyagi, M.; Ueda, M.
Macromolecules 2006, 39, 3964–3966.
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Process Res. DeV. 2007, 11, 1015–1024.
10.1021/ol802509m CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society

Scheme 1
.
Enantioselective F-C Reaction of Pyrrole with
Table 1. Optimization of Enantioselective F-C Reaction of 1
and 2a Catalyzed by Zr(IV)-BINOL Complexesa
2,2,2-Trifluoroacetophenone and BINOL-Type Ligands Used in
This Study
entry
solvent
L
t (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12d
13e
14f
15g
16h
17i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
dioxane
toluene
benzene
F-C6H5
benzene
benzene
benzene
benzene
benzene
benzene
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
1.5
1.5
3.5
1.2
2.2
17
20
22
1.5
1.5
1.2
3
1.5
2
1
2.5
1
92
98
93
90
89
64
42
34
99
97
98
91
96
96
87
87
99
10
8
59
9
43
48
66
66
85
90
80
74
78
76
78
78
78
a All reactions were performed with BINOL-type ligands L (0.05 mmol),
Zr(OtBu)4 (0.05 mmol), pyrrole (1.25 mmol), and 2,2,2-trifluoroacetophe-
none (0.25 mmol) in 2 mL of solvent at room temperature unless otherwise
stated. b Isolated yield of 3a after flash chromatography. c Determined by
HPLC using Chiralcel OD-H column. d Reaction temperature was 0 °C.
e Reaction temperature was 50 °C. f Reaction was performed with ligand
L3 (10 mol %) and Zr(OtBu)4 (10 mol %). g Reaction was performed with
ligand L3 (10 mol %). h Reaction was performed with 3 equiv of pyrrole.
i Reaction was performed with 10 equiv of pyrrole.
romethylation is difficult to achieve, and high enantiomeric
excesses are rarely reached except when the substrate is very
hindered.6 A second strategy would be the addition of carbon
nucleophiles to trifluoromethyl ketones. However, the forma-
tion of quaternary carbons via the addition of carbon
nucleophiles to ketones still constitutes a major challenge
in synthetic chemistry.2 So far, the use of trifluoromethyl
ketones as acceptors in enantioselective addition reactions
has been limited; the addition of organometallic zinc re-
agents7 and arylboronic acids8 and the Henry reaction being
among the few reported examples.9 To the best of our
knowledge, no catalytic enantioselective Friedel-Crafts
alkylation of aromatic substrates with trifluoromethyl ketones
has been reported so far, with the exception of few examples
with ethyl trifluoropyruvate.10 Herein we report the first
zirconium-catalyzed Friedel-Crafts alkylation of pyrrole
with 2,2,2-trifluoroacetophenones reaching enantioselectivi-
ties up to 93% ee.
The reaction of pyrrole 1 with 2,2,2-trifluoroacetophenone
2a was chosen to optimize the reaction conditions. BINOL-
type ligands11 and Zr(OtBu)4 in dichloromethane at room
temperature12 were evaluated as shown in the illustrated
reaction (Scheme 1), and the results are summarized in Table
1. We used an excess of 5 equiv of pyrrole with respect to
the trifluoromethyl ketone to avoid the formation of dialky-
lated products.13 With ligands L1-L5 the reaction was
completed in 1.5-3.5 h, giving product 3a with good yield
(89-98%) but low/moderate enantioselectivity (8-59% ee)
(entries 1-5), and the highly hindered 3,3′-disubstituted
BINOL L6 led to a lower yield (64% yield, 48% ee). Ligand
L3, having two bromine atoms at the 3,3′ positions, led to
the best result (93% yield, 59% ee) (entry 3). Next, we
screened different solvents using ligand L3. Ether-type
solvents (THF or dioxane) had a negative influence on the
catalytic activity, although they slightly improved the enan-
tioselectivity (entries 7 and 8). On the other hand, aromatic
(5) (a) Chang, Y.; Cai, C. Tetrahedron Lett. 2005, 46, 3161–3164. (b)
Roussel, S.; Billard, T.; Langlois, B. R.; Saint-James, L. Chem. Eur. J.
2005, 11, 939–944. (c) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem.
2003, 68, 4457–4463. (d) Langlois, B. R.; Billard, T. Synthesis 2003, 185–
194. (e) Joubert, J.; Roussel, S.; Christophe, C.; Billard, T.; Langlois, B. R.;
Vidal, T. Angew. Chem., Int. Ed. 2003, 42, 3133–3136. (f) Prakash, G. K. S.;
Hu, J.; Olah, G. A. Org. Lett. 2003, 5, 3253–3256. (g) Roussel, S.; Billard,
T.; Langlois, B. R.; Saint-James, L. Synthesis 2004, 2119–2122.
(6) (a) Langlois, B. R.; Billard, T.; Roussel, S. J. Fluorine Chem. 2005,
126, 173–179. (b) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6119–
6146.
(7) (a) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284–
287. (b) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355–8361. (c)
Jeon, S.-J.; Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416–16425.
(d) Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P.-O.; Tomassini, C. J.
Org. Chem. 2005, 70, 5733–5736. (e) Ni, M.; Wang, R.; Han, Z.-J.; Mao,
B.; Da, C.-S.; Liu, L.; Chen, C. AdV. Synth. Catal. 2005, 347, 1659–1665.
(f) Jeon, S.-J.; Li, H.; Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Org.
Chem. 2005, 70, 448–455. (g) Cozzi, P. G. Angew. Chem., Int. Ed. 2003,
42, 2895–2898. (h) Garc´ıa, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641–3644.
(i) Tomita, D.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005,
127, 4138–4139.
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279. (b) Brunel, J. M. Chem. ReV. 2005, 105, 857–898. (c) Shibasaki, M.;
Yoshikawa, N. Chem. ReV. 2002, 102, 2187–2210. (d) Saruhashi, K.;
Shibashaki, S. J. Am. Chem. Soc. 2006, 128, 11232–11235. (e) Ihori, Y.;
Yamashita, I.; Ishitani, H.; Kobayashi, H. J. Am. Chem. Soc. 2005, 127,
15528–15532. (f) Kobayashi, S.; Kobayashi, J.; Ishani, H.; Ueno, M. Chem.
Eur. J. 2002, 8, 4185–4190.
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Minnaard, A. J. Chem. Commun. 2006, 4093–4095.
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M.; Sinisi, R.; Umani-Ronchi, A. Chem. Commun. 2008, 4360–4362.
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J. Org. Chem. 2001, 66, 1009–1013. (b) Lyle, M. P. A.; Draper, N. D.;
Wilson, P. D. Org. Lett. 2005, 7, 901–904. (c) To¨ro¨k, B.; Abid, M.; London,
G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.; Yand, P.; Prakash, G. K. S.
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442
Org. Lett., Vol. 11, No. 2, 2009

Scheme 2
.
Enantioselective F-C Reaction of Pyrrole with
Scheme 3. Reaction of 4,7-Dihydroindole (4) with 2a
Trifluoromethyl Ketones Catalyzed by L3-Zr(OtBu)4
hydrocarbons (toluene, benzene, or fluorobenzene) improved
both the catalytic activity and the enantioselectivity (entries
9-11). The best result was obtained using benzene as solvent
(97% yield, 90% ee) (entry 10). Lowering the temperature
to 0 °C or increasing the temperature to 50 °C had a negative
effect on the enantioselectivity, resulting in 74% ee (entry
12) and 78% ee (entry 13), respectively. A catalyst loading
reduction to 10 mol % also had a deleterious effect on the
reaction, compound 3a being obtained in 96% yield and 76%
ee (entry 14). As conditions of choice, we used L3-Zr(OtBu)4
in benzene, at room temperature, a catalyst loading of 20
mol %, and an excess of 5 equiv of pyrrole. An excess of 3
or 10 equiv of pyrrole had also a deleterious effect on the
reaction (entries 16 and 17).
ence of groups such as Br or CN (entries 8 and 9) lowered
the enantiomeric excess of the products. Nevertheless these
products could be obtained with high ee after recrystalliza-
tion. The presence of a substituent on the para and meta
positions of the aromatic ring in compound 2 did not affect
either the reactivity or the enantioselectivity of the reaction
(entries 2, 4, and 6 vs entries 10-12). However, the reaction
with o-methyltrifluoroacetophenone took place with very low
yield (5%), and the ee of the alkylation product dropped to
72%, indicating the existence of a steric effect caused by
the ortho substituent. Finally, 2′,2′,2′,3,4-pentafluoroac-
etophenone (2m) and 3,4-dichloro-2′,2′,2′-trifluoroacetophe-
none (2n), with two additional substituents on the aromatic
ring, could also serve as substrates in this reaction, giving
the corresponding alkylated pyrroles in excellent yields and
with good enantioselectivities (entries 13 and 14). Unfortu-
nately, the reaction with aliphatic trifluoromethyl ketone 2p
(entry 15) took place with good yield (92%) but poor
enantioselectivity (21% ee).
Table 2. Substrate Scope of Enantioselective F-C Reaction of
Pyrrole (1) with Trifluoromethyl Ketones 2 Catalyzed by
L3-Zr(OtBu)4 According to Scheme 2a
The effects of pyrrole substitution were also evaluated
under the optimized conditions. N-Methylpyrrole led to
mixtures of mono- and dialkylated products with poor
enantioselectivity (ca. 50% ee), and 2-ethylpyrrole led to the
C5 reaction product with excellent yield (95%) but very low
enantioselectivity (22%). However, 4,7-dihydroindole (4),
which can be considered as a disubstituted pyrrole, reacted
with 2a with excellent yield and good enantioselectivity to
give the C2-alkylated indole 5 (Scheme 3) after oxidation
with p-benzoquinone (92% overall yield for the two steps,
72% ee).14
The absolute stereochemistry of compound 3a was deter-
mined by chemical transformation into the literature-known
compound 6.15 This was accomplished by an oxidation
procedure in analogy to the oxidative cleavage of furans.13,16
Thus pyrrole 3a was oxidized to the Mosher acid amide 6
upon treatment with NaIO4 in the presence of RuCl3 (Scheme
4). By comparison of the optical rotation, the absolute
stereochemistry of the prepared compound 6, and therefore
of compound 3a, was determined to be of the R-configura-
tion, and for the rest of the products it was assigned on the
assumption of a uniform reaction mechanism.
entry
2
R
t (h)
3
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2b
2c
Ph
1.5
1.5
1
1
1
1.3
1
1
2
1
3a
3b
3c
3d 99
3e
3f
97
98
95
90
87
87
86
93
85
88
p-MeC6H4
p-EtC6H4
2d p-MeOC6H4
2e
2f
p-MeSC6H4
p-FC6H4
p-ClC6H4
84
98
99
2g
3g
2h p-BrC6H4
2i
2j
2k m-MeOC6H4
2l m-FC6H4
2m 3,4-F2C6H3
2n 3,4-Cl2C6H3
2p Et
3h 99 (70)d
77 (97)d
72 (94)d
85
86
80
63
68
p-CNC6H4
m-MeC6H4
3i
3j
94 (73)d
93
1
2
1
1
3k 96
3l 94
3m 96
3n 96
3p 92
1.2
21
a All reactions were performed with ligand L3 (0.05 mmol), Zr(OtBu)4
(0.05 mmol), pyrrole (1.25 mmol), and trifluoromethyl ketone 2 (0.25 mmol)
in benzene (2 mL) at room temperature unless otherwise stated. b Isolated
yield after flash chromatography. c Determined by HPLC analysis using
Chiralcel OD-H column. d In parenthesis, yield and ee of the product
obtained from the mother liquors after crystallization of a nearly racemic
mixture.
In summary, we have demonstrated the use of a zirco-
nium(IV)/BINOL catalyst in a Friedel-Crafts reaction of
unprotected pyrrole with a variety of differently substituted
To explore the scope of the reaction various substituted
2,2,2-trifluoroacetophenones 2a-n were reacted with pyrrole
(1) (Scheme 2, Table 2). In all the cases, the reaction
provided the expected products 3a-n with good to high
enantiomeric excesses (up to 93%). The presence of electron-
donating groups (Me, Et, MeO, MeS) or electron-withdraw-
ing-groups (F, Cl) in the aromatic ring had little influence
on the enantioselectivity (entries 2-7). However, the pres-
(14) (a) C¸ avdar, H.; Sarac¸oglu, N. Tetrahedron 2005, 61, 2401–2405.
(b) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249–2252. (c) Blay,
G.; Ferna´ndez, I.; Pedro, J. R.; Vila, C. Tetrahedron Lett. 2007, 48, 6731–
6734.
(15) Ohta, H.; Miyamae, Y.; Kimura, Y. Chem. Lett. 1989, 379–380.
(16) Kohler, F.; Gais, H.-J.; Raabe, G. Org. Lett. 2007, 9, 1231–1234
.
Org. Lett., Vol. 11, No. 2, 2009
443

protecting groups in pyrrole alkylations also enhances the
efficiency by which substituted pyrroles may be synthesized.
We are currently directing our efforts toward enhancing the
scope and enantioselectivity of this method, the elucidation
of the mechanism, and the rationalization of the origin of
the stereochemistry.
Scheme 4
.
Determination of Absolute Stereochemistry of
Compound 3a
Acknowledgment. Financial support from the Ministerio
de Educacio´n y Ciencia and FEDER (Grant CTQ 2006-
14199/BQU) is acknowledged. C.V. thanks the Generalitat
Valenciana for a predoctoral grant.
2,2,2-trifluoroacetophenones to give pyrroles with a triflu-
oromethyl substituted tertiary alcohol moiety. The reaction
takes place with good enantioselectivities (up to 93%) and
high isolated yields (up to 98%). Additional advantages are
the use of ligands that are commercially available in both
enantiomeric forms (hence providing access to both enan-
tiomeric products) and a simple experimental procedure at
room temperature. Further, the avoidance of using N-
Supporting Information Available: Experimental pro-
cedures, characterization data and copies of NMR spectra,
and chiral analysis for compounds 3a-n, 5, and 6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802509M
444
Org. Lett., Vol. 11, No. 2, 2009