Highly enantioselective Friedel-Crafts alkylations of pyrroles and indoles with α′-hydroxy enones under Cu(II)-simple bis(oxazoline) catalysis

Article abstract of DOI:10.1021/ja0423217

Remarkably high and regular enantioselectivities are obtained in Friedel-Crafts alkylation reactions involving α-hydroxy enone templates and Cu(II)-bis(oxazoline) complexes as catalysts. The simple elaboration of adducts provides a route to enantioenriche

Full text of DOI:10.1021/ja0423217

Published on Web 03/02/2005
Highly Enantioselective Friedel-Crafts Alkylations of Pyrroles and Indoles
with r′-Hydroxy Enones under Cu(II)-Simple Bis(oxazoline) Catalysis
Claudio Palomo,* Mikel Oiarbide, Bharat G. Kardak, Jesu´s M. Garc´ıa,§ and Anthony Linden‡
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad del Pa´ıs Vasco,
Apdo. 1072, 20080 San Sebastia´n, Spain
Received December 21, 2004; E-mail: qoppanic@sc.ehu.es
Scheme 1. Alkene Templates 1-6 used in Asymmetric Catalytic
Friedel-Crafts Alkylations and the New Development Based on
Template 7 and Bis(oxazoline)-Cu(II) Catalysts
The Friedel-Crafts reaction of arenes with electron-deficient
alkenes is an important C-C bond-forming process in organic
synthesis.1 While asymmetric catalytic versions of this reaction
provide access to important enantioenriched aryl-substituted prod-
ucts, only a few examples of such processes are known:2 (a) the
reaction of enals 1 with pyrroles and indoles catalyzed by a chiral
secondary amine catalyst,3 and (b) the metal-catalyzed reactions
involving â,γ-unsaturated R-ketoesters 2,4 alkylidene malonates 3,5
and acyl phosphonates 4.6 Friedel-Crafts reactions with two
additional alkene templates, 5 and 6, have also been described7
but with more limited results. Yet, important restrictions apply to
substrate generality and reaction selectivity. Apparently, in metal-
catalyzed Friedel-Crafts reactions not only bidentate, chelating
Michael acceptors are required but also particularly effective metal-
substrate coordination is needed for optimum selectivity.8 Previous
observations from this laboratory in the context of Diels-Alder9
and conjugate addition10 reactions have shown the capability of
R′-hydroxy enones for metal-assisted activation, likely through
formation of 1,4-metal chelated species as the reactive intermediates.
On this basis, we pursued to validate such a 1,4-metal binding
hypothesis11 and, hence, increase the pool of available templates
for catalytic, asymmetric Friedel-Crafts reactions. Since the pyrrole
and indole skeletons are important substructures within natural
product isolates and medicinal agents,12these heteroarenes were
selected for the study. Initial screening reactions carried out with
enone 7a and N-methyl pyrrole 8 in the presence of 10 mol % of
a survey of chiral bis(oxazoline)-metal complexes in CH2Cl2 as
solvent, revealed 12 and 13 as the most effective.13 Using these
catalysts, Friedel-Crafts adduct 10a was formed in yields of 86
and 80% and, most notably, with 92 and 91% ee, respectively. With
the exception of â-aryl enones, such as 7g, which provided product
10g with modest enantioselectivity, good yields and excellent
enantiomeric excesses were obtained with a series of enones (7a-
f) which vary in the identity of the â-alkyl substituent (Table 1).
In some instances, small amounts of dialkylation product were
detected,14 which could be partially or totally suppressed by
lowering the temperature and increasing the mole equivalents of
8, respectively. The system also proved effective for the reactions
of N-H pyrrole 9 to give adducts 11.
Table 1. Friedel-Crafts Alkylation of N-methyl Pyrrole 8 and
Pyrrole 9 with Various R′-Hydroxy Enones 7 Catalyzed by
Complex 12a
enone 7
R
T,
°
C
time, h
product
yield, %b
ee, %c
a
PhCH2CH2
25
25
-20
-20
-20
0
2
2
2
10a
10a
11a
10b
11b
10c
10d
10e
10f
86
80
83
82
87
86
84
88
86
95
92
91d
90
b
CH3(CH2)5
6
96
0.5
20
4
18
12
24
91e
95
c
d
e
f
(CH3)2CH
c-C6H11
CH3CH2
(CH3)2CHCH2
Ph
25
97f
94
-20
-20
25
94f
68d
g
10g
a Reactions conducted at 0.5 mmol scale and 0.25 M substrate concentra-
tion. Mole ratio of arene:7:cat is 2:1:0.1. b Yield of isolated product after
column chromatography. c Determined by chiral HPLC. d Using catalyst 13.
e Using 6 molar equiv of 9. f Using 6 molar equiv of 8.
Figure 1. Stereochemical model for the substrate-catalyst complex.
using catalyst 13,15 high enantiomeric excesses could be attained
(entry 6, from 85 to 93%; entry 9, from 85 to 96%). Importantly,
increasing the scale (entry 1) and lowering the catalyst loading to
5 and 2 mol % (entries 2 and 4), which represents the lowest
catalyst/substrate ratio employed in the asymmetric Friedel-Crafts
reaction,4 resulted in no significant loss of enantioselectivity and
yield. Finally,16 the reactions with differently substituted indoles
15-17 worked nicely.
Indole derivatives 14-17 worked as efficiently as pyrroles and
provided adducts 18-21 in good to excellent yields and enantio-
meric excesses (Table 2). While the typical reaction temperature
was either 0 or 25 °C, the catalytic system showed remarkable
performance even at refluxing conditions (40 °C) (entries 3 and
7). Enones bearing branched chains at the â position showed
attenuated reactivity and lower selectivity using catalyst 12, but
The sense of asymmetric induction observed in the above
reactions is consistent with the model shown in Figure 1, which
assumes a distorted square planar geometry around copper, as
previously disclosed in the literature for similar systems.17
§ Current address: Departamento de Qu´ımica Aplicada, Universidad Pu´blica
de Navarra, Campus de Arrosad´ıa, 31006 Pamplona, Spain.
‡ (X-ray analysis) Organisch-chemisches Institut der Universita¨t Zu¨rich, Win-
terthurerstrasse 190, CH-8057, Zu¨rich, Switzerland.
9
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J. AM. CHEM. SOC. 2005, 127, 4154-4155
10.1021/ja0423217 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Friedel-Crafts Alkylation of Indoles 14-17 with Various
R′-Hydroxy Enones 7 Catalyzed by Complex 12a
as 27 and 28, in high yields and excellent enantioselectivities.
Moreover, in these transformations, acetone is the only byproduct
formed, an additional aspect of the approach that is of practical
interest. In conclusion, R′-hydroxy enones 7 in combination with
commercially available bis(oxazoline)-Cu(OTf)2 catalysts signifi-
cantly expand the enantioselective Friedel-Crafts reaction.
Acknowledgment. We thank The University of the Basque
Country (UPV/EHU) and Ministerio de Educacio´n y Ciencia (MEC,
Spain) for financial support. A grant to B.G.K. from UPV/EHU is
acknowledged. This work is dedicated to Dr. Cecilia Sarasola.
entry
indole
enone 7, R
T,
°
C
time, h
product
yield, %b
ee, %c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
14
a
PhCH2CH2
0
25
reflux
0
25
25
reflux
25
25
0
3
3
18a
88
85
85
85
44g
68
81
32i
80
95
65i
89
96
86
95d
94e
98
Supporting Information Available: Complete experimental pro-
1
cedures, H and 13C spectra, HPLC chromatograms, crystallographic
0.5
12
48
24
4
36
24
48
3
b
c
CH3(CH2)5
(CH3)2CH
18b
18c
96f
85
data for S-2 (CIF), and an ORTEP diagram. This material is available
free of charge via the Internet at http://pubs.acs.org.
93h
95
References
d
c-C6H11
18d
85
96h
83j
98
(1) Olah, G. A.; Kishnamurti, R.; Prakash, G. K. S. In ComprehensiVe Organic
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Vol. 3, pp 293-339.
h
i
a
a
a
4-Cl-C6H4
CH3
PhCH2CH2 25
PhCH2CH2 25
PhCH2CH2 25
18h
18i
19a
20a
21a
0
(2) For a review, see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2004, 43, 550-556. See also: (b) Jørgensen, K. A.
Synthesis 2003, 1117-1125.
15
16
17
2
2
2
93
97
98
(3) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
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2002, 124, 1172-1173. (c) Paras, N. A.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 7894-7895.
a Reactions conducted at 0.5 mmol scale and 0.25 M substrate concentra-
tion. Mole ratio of indole:7:cat is 2:1:0.1. b Yield of isolated product after
column chromatography. c Determined by chiral HPLC. d Reaction con-
ducted at 10 mmol scale. e Using 5 mol % catalyst loading. f Using 2 mol
% catalyst loading. g Only 25% of unreacted enone 7c recovered. h Using
catalyst 13. i Yield not optimized. j Using 30 mol % cat 13.
(4) Jensen, K. B.; Thorhauge, J.; Mazell, R.-G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 160-163.
(5) (a) Zhuang, W.; Hausen, T.; Jørgensen, K. A. Chem. Commun. 2001, 347-
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Am. Chem. Soc. 2003, 125, 10780-10781.
Scheme 2. Elaboration of Adducts into Enantioenriched Pyrrole-
and Indole-Substituted Aldehydes, Carboxylic Acids, and Ketones
(7) (a) Bandini, M.; Fagioli, P.; Garavelli, M.; Melloni, A.; Trigari, V.; Umani-
Ronchi, A. J. Org. Chem. 2004, 69, 7511-7518. (b) Bandini, M.; Melloni,
A.; Tommasi, S.; Umani-Ronchi, A. HelV. Chim. Acta 2003, 86, 3753-
3763.
(8) Widely used, chelating N-enoyl-2-oxazolidinones in combination with Cu-
(II)-BOX catalysts seemed to be totally ineffective; for example, unaltered
starting materials are recovered after 2 days of stirring a mixture of
N-methyl pyrrole and N-crotonyl-2-oxazolidinone in the presence of 10
mol % Cu(II)-t-BOX catalyst.
(9) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M.; Gonza´lez, A.; Arceo, E. J. Am.
Chem. Soc. 2003, 125, 13942-13943.
(10) Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Go´mez-Bengoa, E.;
Garc´ıa, J. M. J. Am. Chem. Soc. 2004, 126, 9188-9189.
(11) Hypothetically, the 1,4-metal arrangement resulting from the coordination
of templates 2 and 4 with the catalyst is advantageous over the 1,5-metal
arrangement encountered in other typical bidentate templates, such as 3.
Also, see ref 8.
(12) (a) Sundberg, R. D. Pyrroles and Their Benzo Derivatives: Synthesis and
Applications. In ComprehensiVe Heterocyclic Chemistry; Katrizky, A. R.,
Rees, C. W., Eds.; Pergamon: Oxford, 1984, Vol. 4, pp 313-376. (b)
Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559-590. (c) Toyota, M.; Ihara,
N. Nat. Prod. Rep. 1998, 15, 327-340.
(13) Other solvents, such as THF, Et2O, or toluene, tested using catalyst 12
led to slightly lower selectivity, while the reaction did not proceed at all
in acetonitrile. See the Supporting Information for details.
(14) Enone/yield of dialkylated 8: 7b/4%, 7d/14%, 7f/8% (See SI for details).
(15) For enhancement of enantiomeric excess by ligand distortion, see: (a)
Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875-5878. (b)
Lipkowitz, K. B.; Schefzick, S.; Avnir, D. J. Am. Chem. Soc. 2001, 123,
6710-6711.
The potential of this catalytic approach is best demonstrated by
the versatile elaboration of adducts through oxidative cleavage of
the ketol moiety. For example, adducts 10a,c and 18a, after
sequential reduction and oxidative diol cleavage, afforded aldehydes
22, 23, and 24, which were characterized as the corresponding
alcohols. Alternatively, 18 could be transformed directly into
carboxylic acids and, hence, esters 25 and 26 of high enantiomeric
purity.18 Of importance, a sequential alkyllithium addition to the
carbonyl group in 18, followed by treatment with NaIO4, constituted
a practical entry to the otherwise elusive ketone derivatives, such
(16) Under the conditions reported, no reaction was observed between enone
7a and other types of arenes tested, such as anisole and 3-dimethylami-
noanisole.
(17) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335 and
references therein. (b) Thorhauge, J.; Roberson, M.; Hazell, R. G.;
Jørgensen, K. A. Chem.sEur. J. 2002, 8, 1888-1898.
(18) For assessment of the enantiomeric purity and the absolute configuration
of the products, see the Supporting Information.
JA0423217
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