Organocatalytic asymmetric friedel-crafts alkylation of indoles with simple α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol070309o

Figure presented The first general and highly enantioselective organocatalytic Friedel-Crafts alkylation of indoles with simple α,β-unsaturated ketones has been accomplished. Central to these studies has been the identification of a new catalyst amine salt, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis.

Full text of DOI:10.1021/ol070309o

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1403-1405
Organocatalytic Asymmetric
Friedel
−Crafts Alkylation of Indoles with
Simple
r,â
-Unsaturated Ketones
Giuseppe Bartoli, Marcella Bosco, Armando Carlone, Fabio Pesciaioli,
Letizia Sambri, and Paolo Melchiorre*
Dipartimento di Chimica Organica “A. Mangini”, Alma Mater Studiorum,
UniVersita` di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
pm@ms.fci.unibo.it
Received February 12, 2007
ABSTRACT
The first general and highly enantioselective organocatalytic Friedel−Crafts alkylation of indoles with simple
r
,
â
-unsaturated ketones has
been accomplished. Central to these studies has been the identification of a new catalyst amine salt, in which both the cation and the anion
are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis.
The indole framework represents a privileged structural motif
of established value in medicinal chemistry and complex
target synthesis.1 In this regard, the development of effective
asymmetric entries to indole architecture constitutes an
important research field. Over the past few years, the catalytic
enantioselective additions of indoles to unsaturated carbonyl
compounds, namely, known as Friedel-Crafts (F-C)-type
alkylations, have been the topic of particularly intensive
investigations.2 A number of highly selective metal-catalyzed
asymmetric F-C reactions of bidentate chelating carbonyls
have been developed,3 whereas in 2002 MacMillan and co-
workers4 first demonstrated the feasibility of organocatalytic
strategies based on LUMO lowering activation of R,â-
unsaturated aldehydes via the reversible formation of an
iminium ion with chiral imidazolidinones.5,6 Despite these
recent advances, just one efficient metal-catalyzed asym-
metric addition of indoles to monochelating ketones has been
reported recently by the group of Bandini and Umani-Ronchi,
affording the indolyl derivatives in moderate to good optical
purity but with important restrictions in substrate scope.7,8
Thus, the use of simple R,â-unsaturated ketones still remains
(4) (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172-1173. (b) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482-5487.
See also: (c) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura,
R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437-3440.
(5) For an excellent review on iminium ion activation, see: Lelais, G.;
MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79-87.
(6) For some leading examples that rely on different organocatalytic
strategies, see: (a) To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k,
M. S.; Mhadgut, C.; Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed.
2005, 44, 3086-3089. (b) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci,
A. Angew. Chem., Int. Ed. 2005, 44, 6576-6579. (c) Wang, Y.-Q.; Song,
J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156-8157.
(7) (a) Bandini, M.; Fagioli, M.; Melchiorre, P.; Umani-Ronchi, A.
Tetrahedron Lett. 2003, 44, 5846-5849. (b) Bandini, M.; Fagioli, M.;
Garavelli, M.; Melloni, A.; Trigari, V.; Umani-Ronchi, A. J. Org. Chem.
2004, 69, 7511-7518.
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996; p
175. (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-
VCH: Weinheim, 2003.
(2) For recent reviews on catalytic asymmetric Friedel-Crafts reactions,
see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int.
Ed. 2004, 43, 550-556. (b) Jørgensen, K. A. Synthesis 2003, 1117-1125.
(3) For selected examples, see: (a) Jensen, K. B.; Thorhauge, J.; Hazell,
R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160-163. (b)
Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem. Commun. 2001, 347-
348. (c) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030-9031. (d)
Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am.
Chem. Soc. 2003, 125, 10780-10781. (e) Palomo, C.; Oiarbide, M.; Kardak,
B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154-
4155. (f) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc.
2005, 127, 8942-8943.
10.1021/ol070309o CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/09/2007

an important challenge for the asymmetric F-C alkylations
of indoles.
results.8a Considering the inherent problems of forming
congested iminium ions from ketones, we questioned whether
primary amines, owing to their reduced steric requirements,
might be suitable for enone activation.11-13
In this paper, we document the first efficient asymmetric
organocatalytic addition of indoles to simple enones,8 a
general and operationally trivial protocol that allows rapid
access to a broad range of highly enantioenriched â-indolyl
derivatives (up to 96% ee). In particular, the successful
application of the iminium ion activation strategy to enone
substrates was achieved by developing a new catalytic amine
salt, in which both the cation and the anion are chiral.9
The proposed organocatalytic F-C alkylation strategy was
first examined by reacting indole 1 with trans-4-phenyl-3-
buten-2-one 2a in the presence of a series of chiral amine
salts as the catalysts (Table 1). Interestingly, secondary
Preliminary studies confirmed that TFA salts of primary
amines A and B were able to promote the reaction with good
catalytic efficiency but with low levels of enantioselectivity
(entries 2 and 3). Notably, the use of TFA salts of the easily
available 9-amino(9-deoxy)epi-hydroquinine C, which was
very recently described as an effective catalyst for enone
activation,12,13 afforded promising stereoinduction, albeit not
yet satisfactory. We speculated that the nature of the
counteranion is the crucial factor for the optimization of the
catalyst efficiency. With this consideration in mind, a survey
of various salts of the chiral primary amine C was performed.
An extensive screen of the acidic additives, besides
establishing the beneficial effect of a 1:2 ratio of amine C
to a cocatalyst (entries 4 and 5), revealed that the use of
N-Boc glycine as an achiral counteranion gave the product
3a with high enantiomeric excess (85% ee, entry 8) albeit
at the expense of reactivity. Considering that asymmetric
counterion-directed catalysis (ACDC)9 has recently been
recognized as an efficient strategy for enantioselective
transformations, we evaluated the efficiency of catalytic salts
derived from the combination of C with a series of
N-protected L-amino acids. The absence of a protecting group
in the amino acid had a deleterious effect on the catalytic
activity (entry 9), whereas the variation of the chiral
architecture had a substantial impact on reactivity but a
minimal impact on stereoselectivity (entries 10-14). Surpris-
Table 1. Selected Screening Resultsa
conversion ee
entry
amine
acidic additive
(%)b
(%)c
1
2
3
4
5
6
7
L-proline
-
TFA
TFA
TFA
TFAd
pTSA
CF3SO3H
0
85
73
44
23
20
18
-
-16
29
65
61
A
B
C
C
C
C
59
31
8
9
C
C
C
C
C
C
C
C
C
C
R: H
PG: Boc
PG: H
<5
0
7
85
-
R: Ph
R: t-Bu
R: Bn
R: Bn
R: Bn
R: Ph
R: Ph
R: Ph
R: Ph
10
11
12
13
14
15e
16f
17f,g
PG: Boc
PG: Boc
PG: Cbz
PG: Fmoc
PG: Boc
PG: Boc
PG: Boc
PG: Boc
89
90
85
86
90
92
93
87
8
10
<5
16
18
21
>95
(9) During our studies, the successful application of a similar ACDC
tactic for the enantioselective hydrogenation of simple enones was described.
See: (a) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368-
13369. See also: (b) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45,
4193-4195.
(10) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 2458-2460. (b) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2006, 128, 12662-12663. For selected examples using
other secondary chiral amines, see: (c) Halland, N.; Hansen, T.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2003, 42, 4955-4957. (d) Halland, N.; Aburel,
P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272-1276. (e)
Hanessian, S.; Shao, Z.; Warrier, J. S. Org. Lett. 2006, 8, 4787-4790.
(11) For recent use of primary amine salts in asymmetric iminium
catalysis with unsaturated ketones, see: Kim, H.; Yen, C.; Preston, P.; Chin,
J. Org. Lett. 2006, 8, 5239-5242. See also ref 9a.
(12) During our studies, the TFA salt of 9-amino(9-deoxy)epi-quinine
was reported to be an excellent catalyst for the asymmetric conjugate
addition of carbon-centered nucleophiles to R,â-unsaturated ketones: (a)
Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.;
Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389-392.
(b) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen,
Y.-C. Org. Lett. 2007, 9, 413-415.
(13) After our original submission, the asymmetric alkylation of indoles
with unsaturated ketones catalyzed by 30 mol % of the CF3SO3H salt of
9-amino(9-deoxy)epi-quinine was reported, affording moderate to good
levels of enantioselectivity (ee’s ranging from 47% to 89%). See: (a) Chen,
W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol.
Chem. 2007, 5, 816-821.
a
For additional studied catalysts, additives, and conditions, see the
Supporting Information. b Determined by 1H NMR of the crude mixture. c
ee of 3a was determined by HPLC analysis. d 20 mol % of TFA. e Racemic
N-Boc phenylglycine (Boc-Phg-OH) was used. f (D)-Boc-Phg-OH was
g
used. 70 °C reaction temperature.
amines such as L-proline (entry 1) and the MacMillan second-
generation imidazolidinone catalyst, which has previously
enabled highly enantioselective nucleophilic addition to R,â-
unsaturated ketones via iminium ion catalysis,10 afforded poor
(8) For an organocatalytic indole alkylation with enones promoted by
an achiral amine, see: (a) Li, D.-P.; Guo, Y.-C.; Ding, Y.; Xiao, W.-J.
Chem. Commun. 2006, 799-801. In this report, an initial attempt to perform
an asymmetric version using the MacMillan second-generation imidazoli-
dinone afforded poor selectivity (28% ee). Recently, a low selective (up to
29 % ee) addition of indole to chalcone promoted by D-camphorsulfonic
acid was reported. See: (b) Zhou, W.; Xu, L.-W.; Li, L.; Yang, L.; Xia,
C.-G. Eur. J. Org. Chem. 2006, 5225-5227. See also ref 13.
1404
Org. Lett., Vol. 9, No. 7, 2007

ingly, employing the racemic or the opposite enantiomeric
counterion formed the same enantiomeric product 3a with
very similar selectivity although with slightly different
reactivity (entries 14-16).14 On the basis of these studies,
D-N-Boc phenylglycine was chosen for further investigations
as it proved to be superior with regard to enantioselectivity
and catalytic efficiency. Interestingly, the ee remained very
high even at 70 °C, at which temperature the reaction reached
completion after 24 h (entry 17).
entries 12 and 14), a class of substrates which, to our
knowledge, have not yet been recognized as suitable for
iminium ion activation.
The presented organocatalytic tactic is also general with
respect to indole architecture, as electronic modification of
the aromatic ring can be accomplished without affecting the
efficiency of the system (Table 3, ee’s ranging from 92% to
94%).
After optimizing the standard reaction parameters, the
scope of this new organocatalytic F-C indole alkylation was
explored using the conditions reported in Table 2: there
Table 3. Organocatalytic Alkylation of Substituted Indoles
with 2ea
Table 2. Organocatalytic Alkylation of Indole 1 with Simple
Enonesa
indole substituents
temp time
yielda
(%)
eeb
(%)
entry
X
Y
Z
(°C)
(h)
1
2
3c
4
5
6
H
H
H
H
H
CH3
H
H, 1
rt
rt
rt
40
rt
96
24
72
96
40
48
3e (91)
5a (87)
5a (84)
5b (74)
5c (76)
5d (<5)
93
94
94
92
93
62
CH3 H, 4a
CH3 H, 4a
H
H
H
temp time
yielda
(%)
eeb
(%)
entry
R1
R2
(°C)
(h)
Cl, 4b
MeO, 4c
H, 4d
1
2c
3
4
5
6
7c
8
Ph
Ph
Me, 2a
Me, 2a
Me, 2b
Me, 2c
Me, 2d
70
70
70
70
40
rt
24
60
24
48
70
96
90
96
66
70
72
96
72
90
3a (90) 88
3a (76) 88
3b (92) 89
3c (92) 84
3d (98) 87d
3e (91) 93
3e (87) 92
3f (67)
3g (99) 95
3h (65) 78
70
p-ClC6H4
2-thienyl
Me
CH3(CH2)4 Me, 2e
CH3(CH2)4 Me, 2e
a
Isolated yield. b Determined by HPLC analysis. c 10 mol % of C and
20 mol % of Boc-D-Phg-OH were employed.
40
rt
As a limitation of the approach, it is worth noting that
substitution on the indolic nitrogen had a detrimental effect
on both reactivity and selectivity (entry 6). This feature has
already been observed in other organocatalytic F-C alky-
lations of indoles believed to proceed via a dual activation
mechanism.6a,b
In summary, we have disclosed the first general and highly
enantioselective organocatalytic Friedel-Crafts alkylation of
indoles with simple R,â-unsaturated ketones. Central to these
studies has been the identification of a new catalyst amine
salt, in which both the cation and the anion are chiral, that
exhibits high reactivity and selectivity for iminium ion
catalysis. A full account of this survey, providing detailed
mechanistic investigations, will be forthcoming.
Ph(CH2)2
COOEt
Me, 2f
Me, 2g
(CH2)3, 2h
Et, 2i
Ph, 2j
Et, 2k
Ph, 2l
93d
9
50
40
70
70
50
70
10
11
12
13
14
Ph
Ph
Me
Me
3i (56)
3j (78)
3k (76) 96
95
82
3l (94)
70d
Isolated yield. b Determined by HPLC analysis. c 10 mol % of C and
a
d
20 mol % of Boc-D-Phg-OH were employed. Absolute configuration
determined by comparison of the specific optical rotations with those
reported in the literature.
appears to be significant tolerance toward steric and elec-
tronic demands of the â-olefin substituent to enable access
to a broad variety of highly enantioenriched â-indolyl ketones
(entries 1-10).
Importantly, it is possible to decrease the catalyst loading
to 10 mol % without affecting the efficiency of the system
(entries 2 and 7); the products were isolated in high yield
and enantioselectivity, increasing accordingly the reaction
time.
Acknowledgment. This work was carried out in the
framework of the National Project “Stereoselezione in Sintesi
Organica” supported by MIUR, Rome, and the FIRB
National Project “Progettazione, preparazione e valutazione
farmacologica di nuove molecole organiche quali potenziali
farmaci innovativi”.
Variation in the steric contribution of the R2 ketone
substituents (entries 11 and 13) reveals that the more
encumbered ethyl group engenders higher selectivity, albeit
with slightly lower reactivity.15 Notably, our organocatalytic
protocol is also effective with aromatic ketones (R2 ) Ph,
Supporting Information Available: Catalysts and condi-
tions screening studies, experimental procedures, and full
characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL070309O
(14) Theoretical studies based on DFT calculations to understand the
origin of these phenomena (e.g., the absence of a marked matched-
mismatched catalyst ion pair combination) are now underway.
(15) The use of a more encumbered R2 group resulted in lower
reactivity: R2 ) c-hexyl, 23% yield, 81% ee after 96 h at 70 °C.
Org. Lett., Vol. 9, No. 7, 2007
1405