High-pressure accelerated asymmetric organocatalytic friedel-crafts alkylation of indoles with enones: Application to quaternary stereogenic centers construction

Article abstract of DOI:10.1021/ol300274u

An organocatalytic Friedel-Crafts alkylation of indoles with α,β-unsaturated ketones was found to be efficiently accelerated under high-pressure conditions with a low loading of chiral primary amine salts with good yield and enantioselectivity up to 90%. This approach also allows, for the first time, selected indole derivatives containing quaternary stereogenic centers to be obtained from prochiral β,β-disubstituted enones with an enantioselectivity up to 80%.

Full text of DOI:10.1021/ol300274u

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1540–1543
High-Pressure Accelerated Asymmetric
Organocatalytic FriedelꢀCrafts Alkylation
of Indoles with Enones: Application to
Quaternary Stereogenic Centers Construction
_
ꢀ
Dawid Łyzwa, Krzysztof Dudzinski, and Piotr Kwiatkowski*
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
pkwiat@chem.uw.edu.pl
Received February 3, 2012
ABSTRACT
An organocatalytic FriedelꢀCrafts alkylation of indoles with R,β-unsaturated ketones was found to be efficiently accelerated under high-pressure
conditions with a low loading of chiral primary amine salts with good yield and enantioselectivity up to 90%. This approach also allows, for the first
time, selected indole derivatives containing quaternary stereogenic centers to be obtained from prochiral β,β-disubstituted enones with an
enantioselectivity up to 80%.
Indole-containing motifs are very common in many
natural products, bioactive substances, and industrially
useful compounds.1 A large group of such molecules are
chiral, so the development of novel, efficient, and envi-
ronmentally friendly asymmetric synthetic methods re-
mains a very important area of indole chemistry. Of special
interest are derivatives with alkyl-type substituents in the
C-3 position of indole. Direct functionalization at this
position can be realized using FriedelꢀCrafts (FꢀC)
alkylation,2 e.g. with R,β-unsaturated carbonyl compounds,
very often with generation of a stereogenic center at the
benzylic position.
In recent years much attention has been focused on
asymmetric FꢀC reactions catalyzed by simple chiral
organic molecules.3 The iminium activation strategy4 de-
veloped by MacMillan5 is a very powerful approach for
FꢀC reactions of activated arenes with R,β-unsaturated
aldehydes.3,6 This methodology is also applicable for more
difficult FꢀC reactions with less reactive enones (due to
(4) (a) Brazier, J. B.; Tomkinson, N. C.O. Top. Curr. Chem. 2010,
€
291, 281. (b) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007,
107, 5416. (c) Lelais, G.; MacMillan, D.W. C. Aldrichimica Acta 2006,
39, 79.
(5) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243. (b) Paras, N. A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2001, 123, 4370.
(6) For selected, representative examples of FꢀC reactions of indoles
with enals via iminium activation, see: (a) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (b) Huang, Y.; Walji, A. M.;
Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.
(c) Li, C.-F.; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org.
Lett. 2007, 9, 1847. (d) Hong, L.; Wang, L.; Chen, C.; Zhang, B.; Wang,
R. Adv. Synth. Catal. 2009, 351, 772. (e) Galzerano, P.; Pesciaioli, F.;
Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009,
48, 7892. (f) Jin, S.; Li, C.; Ma, Y.; Kan, Y.; Zhang, Y. J.; Zhang, W. Org.
Biomol. Chem. 2010, 8, 4011. (g) Fu, N.; Zhang, L.; Li, J.; Luo, S.;
Cheng, J.-P Angew. Chem., Int. Ed. 2011, 50, 11451.
(1) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (b) Rahman, A.; Basha, A. Indole Alkaloids; Harwood Academic
Publishers: Amsterdam, 1998. (c) Majumdar, K. C., Chattopadhyay, S. K.,
Eds. Heterocycles in Natural Product Synthesis; Wiley-VCH: Weinheim,
2011.
(2) Bandini, M., Umani-Ronchi, A., Eds. Catalytic Asymmetric
Friedel-Crafts Alkylations; Wiley-VCH: Weinheim, 2009.
(3) For recent review on asymmetric organocatalytic FꢀC reactions,
see: (a) Terrasson, V.; de Figueiredo, R. M.; Campagne, J. M. Eur. J.
Org. Chem. 2010, 2635. (b) Marques-Lopez, E.; Diez-Martinez, A.;
Merino, P.; Herrera, R. P. Curr. Org. Chem. 2009, 13, 1585. (c) Bartoli,
G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449.
r
10.1021/ol300274u
Published on Web 03/07/2012
2012 American Chemical Society

Scheme 1. FriedelꢀCrafts Reaction of Indole with Enones
steric repulsions).7 Chen7b and Melchiorre7c demonstrated
that chiral primary amine salts derived from cinchona
alkloids are good catalysts for asymmetric FꢀC alkylation
of indoles with enones, although this reaction usually
requires a high catalyst concentration (20ꢀ30 mol %).
The existing literature contains only a few articles con-
cerning asymmetric organocatalytic FꢀC reactions with
R,β-unsaturated ketones catalyzed by chiral amines7 or
Brønsted acids8 and no information about asymmetric
FꢀC reactions with β,β-disubstituted enones, leading to
products with quaternary stereogenic centers.9
In our opinion, the reactivity problem of enones in
selected organocatalytic reactions can be overcome by
applying a high-pressure technique.10,11 We have recently
demonstrated the first example of significant pressure
influence on an organocatalytic reaction proceeding via
an iminium activation mode.12 We found that a combina-
tion of pressure and bifunctional catalysis with primary
amines remarkably accelerate enantioselective conjugate
addition of nitroalkanes to sterically congested β,β-disub-
stituted enones, allowing for the construction of quatern-
ary stereogenic centers with very high enantioselectivity.
Here, we demonstrate the significant influence of pres-
sure on FꢀC reactions of indoles with enones (Scheme 1)
catalyzed by salts of chiral primary amines.13 This is the
first example of pressure influence studies on an organo-
catalytic FꢀC reaction proceeding via an iminium activa-
tion mode.14 This technique also allows to synthesize
selected indole derivatives containing quaternary stereo-
genic centers from β,β-disubstituted enones.9
Figure 1. Organocatalysts examined in FꢀC alkylation.
alkaloids. Chen applied 30 mol % of 9-amino-9-deoxy-epi-
cinchonine (1f, Figure 1) with 2 equiv of TfOH and after
3 days isolated product 3a with 72% yield and 65% ee.
Melchiorre7c discovered a more efficient catalytic system
based on a primary amine derived from dihydroquinine
(20 mol %) and D-N-Boc-phenylglycine (40 mol %) as a
cocatalyst. After 1 day at 70 °C the product 3a was isolated
with 90% yield and 88% ee.
Our preliminary investigations of the model reaction
under 1 bar and 10 kbar at 50 °C with 5 mol % of simple
chiral primary amines 1aꢀf (Figure 1) and benzoic acid as
a cocatalyst indicate the strong effect of hydrostatic pres-
sure on the reaction rate (Table 1). In all cases the yield at
atmospheric pressure was very low (e6%), but under
10 kbar benzylidenoacetone conversion exceeds 70%. The
best results in terms of yield and enantioselectivity were
observed with 9-amino-9-deoxy-epi-cinchonine (1f) with
2 equiv of BzOH (entry 6, 95% yield and 83% ee at 10 kbar).
In contrast, the reaction under atmospheric pressure at
50 °C affords product 3a with only a 6% yield and
comparable enantioselectivity (82% ee).
For further investigations we selected amine 1f and
studied more attentively the influence of pressure (in the
1 barꢀ10 kbar range) on the reaction course. The results of
these investigations with 2 or 5 mol % of catalyst 1f 2BzOH
3
As a model reaction for our studies, we chose the
alkylation of indole with E-benzylidenoacetone (Table 1).
This particular reaction was investigated by Chen7b and
Melchiorre7c with primary amines derived from cinchona
(11) For examples of enantioselective organocatalytic reactions un-
der high pressure, see: (a) Matsumoto, K.; Uchida, T. Chem. Lett. 1981,
1673. (b) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.; Mataumoto,
K. J. Org. Chem. 1988, 53, 1157. (c) Misumi, Y.; Bulman, R. A.;
Matsumoto, K. Heterocycles 2002, 56, 599. (d) Sekiguchi, Y.; Sasaoka,
A.; Shimomoto, A.; Fujioka, S.; Kotsuki, H. Synlett 2003, 1655.
(e) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc.
2003, 125, 11208. (f) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N.
Tetrahedron Lett. 2004, 45, 4353.(g) Mimoto, A.; Nakano, K.; Ichikawa,
Y.; Kotsuki, H. Heterocycles 2010, 80, 799. (h) Mori, K.; Yamauchi, T.;
Maddaluno, J.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Synlett 2011, 2080.
(i) For recent review, see: Toma, S.; Sebesta, R.; Meciarova, M. Curr. Org.
Chem. 2011, 15, 2257.
(7) (a) Van Li, D.-P.; Guo, Y.-C.; Ding, Y.; Xiao, W.-J. Chem.
Commun. 2006, 799. (b) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.;
Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2007, 5, 816. (c) Bartoli, G.;
Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org.
Lett. 2007, 9, 1403. (d) Hong, L.; Sun, L.; Liu, C.; Wang, L.; Wong, K.;
Wang, R. Chem.;Eur. J. 2009, 15, 11105.
(8) (a) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M.
Angew. Chem., Int. Ed. 2008, 47, 593. (b) Tang, H.-Y.; Lu, A.-D.; Zhou,
Z.-H.; Zhao, G.-F.; He, L.-N.; Tang, C.-C. Eur. J. Org. Chem. 2008,
1406. (c) Sakamoto, T.; Itoh, J.; Mori, K.; Akiyama, A. Org. Biomol.
Chem. 2010, 8, 5448. (d) For review, see: You, S.-L.; Cai, Q.; Zeng, M.
Chem. Soc. Rev. 2009, 38, 2190.
(9) (a) Christoffers, J., Baro, A., Eds. Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis; Wiley-VCH: Weinheim,
2005. (b) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(10) (a) Van Eldik, R., Klarner, F. G.; Eds. High Pressure Chemistry:
Synthetic Mechanistic and Supercritical Applications; Wiley-VCH:
Weinheim, 2002. (b) Matsumoto, K., Acheson, R. M., Eds. Organic Synth-
esis at High Pressure; Wiley: New York, 1991. (c) Jurczak, J., Baranowski,
B., Eds. High Pressure Chemical Synthesis; Elsevier: Amsterdam, 1989.
(12) Kwiatkowski, P.; Dudzinski, K.; Lyzwa, D. Org. Lett. 2011, 13,
3624.
(13) For a review on organocatalysis with primary amines, see:
(a) Jiang, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354. (b) Xu, L.-W.;
Luo, J.; Lu, Y. Chem. Commun. 2009, 1807. (c) Peng, F.; Shao, Z. J. Mol.
Catal. A: Chem. 2008, 285, 1. (d) Chen, Y.-C. Synlett 2008, 1919.
(14) For other selected examples of FꢀC type reactions under high-
pressure conditions, see: (a) Kotsuki, H.; Hayashida, K.; Shimanouchi,
T.; Nishizawa, H. J. Org. Chem. 1996, 61, 984. (b) Kotsuki, H.;
Teraguchi, T.; Shimomoto, N.; Ochi, M. Tetrahedron Lett. 1996, 37,
3727. (c) Harrington, P.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949.
(d) Harrington, P.; Kerr, M. A. Can. J. Chem. 1998, 76, 1256.
(e) Kwiatkowski, P.; Wojaczynska, E.; Jurczak, J. Tetrahedron: Asymmetry
2003, 14, 3643. (f) Emmett, M. R.; Kerr, M. A. Org. Lett. 2011, 13, 4180.
Org. Lett., Vol. 14, No. 6, 2012
1541

Table 1. Catalyst Screening in the Model Reactiona
Table 2. Optimization of FꢀC Reaction of Indole with 2aa
a Reaction conditions: 2a (c = 0.5 mol/L, 0.5ꢀ2 mmol scale), indole
(1.2 equiv) in toluene, 10 kbar, 50 °C, 20 h (or 1 bar, 50 °C, 20 h).
b Determined by GC analysis. c Determined by HPLC analysis using
AD-H column. d 66% ee at 1 bar. e 91% ee at 1 bar. f Isolated yield.
a Reaction conditions: 2a (0.5 mmol, c = 0.5 mol/L), indole
(0.6 mmol), amine 1 (5 mol %), benzoic acid (10 or 5 mol %) in toluene
(ca. 1 mL), 10 kbar, 50 °C, 20 h (or 1 bar, 50 °C, 20 h). b Determined by
GC analysis with internal standard. c Determined by HPLC analysis
using Chiralpak AD-H column. d 82% ee at 1 bar.
Figure 2. Effect of pressure on the reaction of 2a with indole.
Figure 3. Products of high pressure reaction of indole with
simple enones catalyzed by 1f 2BzOH (isolated yield given).
3
at 50 °C are shown in Figure 2. Under 6 kbar we observed the
highest enantioselectivity (increase from 82 to 88% ee) and
yield in the range of 45ꢀ75%. Under higher pressure (8ꢀ10
kbar) we improved the yield (64ꢀ95%) but slightly de-
creased the enantioselectivity (83ꢀ84% ee at 10 kbar).
We also investigated the model reaction with various
acid additives and a lower catalyst loading under 10 kbar
(Table 2). Use of stronger acids (e.g., salicylic, TCA, and D-
N-Boc-phenylglycine) increased catalyst activity but re-
sulted in decreased ee (entries 2ꢀ4). The reaction can be
effectively catalyzed even by 0.5 mol % of 1f and salicylic
acid (1.5 mol %) with a 75% yield and 71% ee (entry 10).15
The best results in terms of enantioselectivity was obtained
with amine 1f and 2ꢀ2.5 equiv of benzoic acid (entries 5
and 6). A higher excess of BzOH increased catalyst activity
but slightly decreased enantioselectivity (entries 7ꢀ9).
Finally, to demonstrate the scope of the FꢀC reaction
of indole with different simple acyclic E-enones and cyclo-
hexenonewe applied9ꢀ10kbarofpressureand 2 mol % of
1f with 2ꢀ2.5 equiv of benzoic acid (Figure 3; see products
3bꢀd). For more hindered acyclic enones with isopropyl in
the β-position and ethyl or isobutyl connected to the
carbonyl group we increased the catalyst loading to
5 mol % (products 3eꢀg). By comparison, product 3f
was obtained with a 56% yield and 20 mol % of Mel-
chiorrecatalystafter 3daysat70°C.7c Underhigh-pressure
conditions and 5 mol % of 1f 2BzOH we obtained the
3
product 3f in 86% yield and 90% ee.
In this project special attention was focused on reactions
of indole with various β,β-disubstituted enones, enabling
the generation of quaternary stereogenic centers.9,16 For
preliminary studies we chose the reaction of indole with
enone E-4a containing an alkyl and electron-withdrawing
group in the β-positions (Table 3). Application of 10 mol %
of 1f and 20 mol % of benzoic acid resulted in a modest
(16) To the best of our knowledge, only one example of an intramo-
lecular organocatalytic FꢀC reaction of pyrroles with β,β-disubstituted
enals has been reported in the literature: Banwell, M. G.; Beck, D. A. S.;
Willis, A. C. ARKIVOC 2006, 163.
(15) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem.
Soc. Rev. 2012, 41, 2406.
1542
Org. Lett., Vol. 14, No. 6, 2012

Table 3. Model FꢀC Reaction of Indole with β,β-Disubstituted
Enone 4a: Construction of Quaternary Stereogenic Centera
Scheme 2. Determination of Absolute Configuration
of 1f and 20ꢀ25 mol % of salicylic acid (or 25 mol % of
BzOH for 5g and 5h). Combining the high-pressure tech-
nique and aminocatalysis works well with various
E-enones having an alkyl and a carboalkoxy group in the
β-position with enantioselectivities up to 80% (Figure 4).
The reaction is also possible with β,β-dialkyl substituted
enones but with low enantioselectivity. Acceptable yields
and moderate enantiomeric excesses were obtained with
cyclic 3-methylcyclohexenone (see product 5h).
Products 5aꢀf are crystalline, and simple crystallization
can improve their optical purity (e.g., for 5b 96% ee and ca.
50% yield after single crystallization; recrystallization ee
>99%). We found that high pressure accelerates Meyers’
lactamization of (þ)-5b with cis-aminoindanol 1g to pro-
vide diastereomerically pure compound 6(Scheme2). Based
on X-ray crystallographic analysis of 6 we assigned the
absolute configuration of products 5aꢀg obtained in the
FꢀC reaction with catalyst 1f.
a Reaction conditions:4a (0.3mmol, c= 0.5 mol/L), indole (0.45 mmol),
1f (10 mol %), acid (20 mol %) in toluene (ca. 0.5 mL), 10 kbar, 50 °C,
20 h. b Determined by GC analysis with internal standard. c Determined
by HPLC analysis using IA column. d Isolated yield. e 10% yield and 45% ee
at 1 bar (50 °C, 20 h); in other cases yield e5%. f Z-isomer of 4a was used.
In conclusion, we have demonstrated that hydrostatic
pressure has a significant effect on the rate of organocata-
lytic FriedelꢀCrafts alkylation of indoles with enones pro-
ceeding via an iminium activation mode. The reaction with
simple enones is effectively catalyzed under 8ꢀ10 kbar by
0.5ꢀ5 mol % of chiral primary amines derived from
cinchona alkaloids and weak acid cocatalysts with good
enantioselectivity (83ꢀ90%). Such a catalytic system is
almost nonactive under atmospheric pressure. We have also
presented for the first time promising results of the organo-
catalytic FꢀC reaction with prochiral sterically hindered
β,β-disubstituted enones, which under high pressure allows
for the formation of indole derivatives containing all-carbon
quaternary stereogenic centers with good yields and
48ꢀ80% enantioselectivity.
Figure 4. Products of high-pressure organocatalytic indole
alkylation with β,β-disubstituted enones (isolated yield given).
yield and promising enantioselectivity (entry 1). A
considerably better yield and a similar level of enantios-
electivity (∼75% ee) were observed with slightly stronger
acids, e.g. salicylic or Boc-D-Phg-OH (entries 2 and 3). By
comparison, the yield under atmospheric pressure and
50 °C with the same catalytic systems did not exceed 5%.
Combining stronger acids and high pressure resulted in a
drop in enantioselectivity (e.g., 19% ee with TCA, entry 4).
To summarize, the most promising results in terms of yield
and enantioselectivity were observed with salicylic acid
under 10 kbar (entry 2). The use of isomeric Z-4a enone
resulted in the opposite direction of asymmetric induction
and in a moderate yield and ee (entry 11).
Acknowledgment. We are grateful to the Polish National
Science Centre (Grant No. N N204 145740) and the
Foundation for Polish Science for financial support. Many
thanks to Professor Janusz Jurczak (University of Warsaw
and Polish Academy of Sciences) for his help and en-
couragement.
Supporting Information Available. Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The FꢀC reaction was also tested with other β,β-di-
The authors declare no competing financial interest.
substituted enones and indole in the presence of 10 mol %
Org. Lett., Vol. 14, No. 6, 2012
1543