Catalytic enantioselective conjugate addition of indoles to simple α,β-unsaturated ketones

Article abstract of DOI:10.1016/S0040-4039(03)01400-X

Chiral [Al(salen)Cl] complex (10 mol%) in the presence of 2,6-lutidine (10 mol%) was found to be effective in catalysing the enantioselective Friedel-Crafts-type conjugate addition of indoles (3) to (E)-arylcrotyl ketones (2), furnishing the corresponding

Full text of DOI:10.1016/S0040-4039(03)01400-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5843–5846
Catalytic enantioselective conjugate addition of indoles to simple
a,b-unsaturated ketones
Marco Bandini,* Matteo Fagioli, Paolo Melchiorre, Alfonso Melloni and Achille Umani-Ronchi*
Dipartimento di Chimica ‘G. Ciamician’, Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 27 January 2003; revised 4 June 2003; accepted 5 June 2003
Abstract—Chiral [Al(salen)Cl] complex (10 mol%) in the presence of 2,6-lutidine (10 mol%) was found to be effective in catalysing
the enantioselective Friedel–Crafts-type conjugate addition of indoles (3) to (E)-arylcrotyl ketones (2), furnishing the correspond-
ing b-indolyl ketones in excellent yield and high enantioselectivity (ee up to 89%).
© 2003 Elsevier Ltd. All rights reserved.
The catalytic asymmetric alkylation of aromatic and
heteroaromatic compounds is a valuable method for
the synthesis of highly functionalised enantiomerically
enriched molecules. Since the pioneering study pub-
lished by Casnati and Casiraghi on the enantioselective
ortho-hydroxy alkylation of phenol with aldehydes,1
many efforts have been devoted to the exploitation of
new catalytic stereocontrolled Friedel–Crafts proce-
dures.2 Of particular relevance are the asymmetric 1,2-
additions and 1,4-additions of electron-rich aromatic
compounds to carbonyls mediated by chiral Lewis acids
(by homogeneous3 as well as heterogeneous catalysis4)
and by optically active organic catalysts.5
Despite numerous and significant advances in this field,
the asymmetric catalytic Friedel–Crafts-type conjugate
addition of aromatic compounds to simple a,b-unsatu-
rated ketones still represents a considerable synthetic
challenge. In fact, the steric similarity of the two car-
bonyl substituents renders the stereodifferentiation of
the two faces of the unsaturated ketones a difficult task.
As a continuation of our previous study on the InBr3
catalysed addition of indoles to enones,6 we now
describe the first stereoselective version of this process
employing the commercially available chiral (R,R)-
[Al(salen)Cl] complex (Fig. 1, 1) as the catalyst.7
Our initial attempts were carried out using (E)-enones
2a–c and 2-methylindole (3a) in the presence of 10
mol% of 1 in toluene at room temperature. The data
Figure 1.
Scheme 1. Asymmetric conjugate addition reaction catalysed by [Al(salen)Cl] (1).
Keywords: aluminium; asymmetric catalysis; indole; ketones; Michael reaction.
* Corresponding authors. E-mail: bandini@ciam.unibo.it; umani@ciam.unibo.it
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01400-X

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M. Bandini et al. / Tetrahedron Letters 44 (2003) 5843–5846
Table 1. Screening of amines as possible additives for the
[Al(salen)Cl] catalysed conjugate addition of indole 3a (1.5
equiv.) to 2c (1 equiv.)a
A considerable increase of stereoselectivity of the pro-
cess was achieved by using aluminium-coordinating
amines in catalytic amount.9 In Table 1, we summarise
the chemical and optical outcomes of the 1-4 addition
of 3a to 2c employing 10 mol% of 1 in the presence of
a range of amines. The use of 10 mol%10 of additive
generally reduced the rate of the process. However, the
stereoselection significantly increased up to 79% ee
when 2,6-dimethylpyridine (2,6-lutidine, lut) was
utilised (yield 65%, entry 5).11 On the contrary, by
adding the sterically congested 2,6-ditbutylpyridine
(2,6-ditBu-py) a significant drop in stereoinduction was
observed (ee=29% entry 6, Table 1).
Entry
Additive (%)
t (h)
4ca (%)b
Ee (%)c
1
2
3
4
5
6
None
24
48
48
48
48
80
70
54
65
65
59
55 (R)
71 (R)
76 (R)
77 (R)
79 (R)
29 (R)
Aniline (10)
Pyridine (10)
Et3N (10)
2,6-Lutidine (10)
2,6-ditBu-pyridine (10) 48
a All the reactions were carried out in anhydrous toluene at room
temperature.
b Isolated yield after flash chromatography.
The key role of the amines could be rationalised by
assuming their coordination on the aluminium centre of
1 leading to a new catalytic species [Al(salen)Cl]/amine.
In this context, 1H NMR studies of equimolar solutions
of [Al(salen)Cl] and amine (i.e. Et3N or lut, dry
CD2Cl2, rt) confirmed a quantitative complexation
between additive and aluminium complex 1,12 while
analogous experiments carried out in the presence of
2,6-ditBu-py did not show any significant base–alu-
minium interaction.
c Determined by chiral HPLC analysis with Chiralcel OD column.
reported in Scheme 1 show that the highest enantiose-
lectivity was achieved when an aromatic group in the
ketone’s skeleton is bound to the carbonyl moiety, and
a small aliphatic group R% is linked to the CꢀC double
bond (2c).8 In the latter case, the b-indolyl ketone was
isolated in 80% yield and 55% ee.
Table 2. Stereoselective addition of indoles to (E)-enones catalysed by [Al(salen)Cl]/lut complexa
Entry
Enone
Indole
Product
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
2c
2c
2c
2d
2e
2f
2g
2g
2h
2h
2i
3a
3b
3c
3a
3a
3a
3a
3a
3a
3a
3a
3b
3a
4ca
4cb
4cc
4da
4ea
4fa
4ga
4ga
4ha
4ha
4ia
48d
35
41
80
58
96
98
68e
92
78f
90
67
95
84 (R)
64 (R)
65 (R)
73 (R)
49 (R)
78 (R)
80 (R)
89 (R)
78 (R)
86 (R)
88 (R)
80 (R)g
77 (R)
9
10
11
12
13
2i
2j
4ib
4ja
a All the reactions were carried out in anhydrous toluene at room temperature for 48 h unless otherwise specified.
b Isolated yield after flash chromatography.
c Determined by chiral HPLC analysis with Chiralcel OD column. The absolute configuration was assigned R by assuming, for all the indoles
tested, the same spatial stereodifferentiation induced by (R,R)-1 (Fig. 3).
d The reaction was carried out at 0°C (72 h reaction time).
e The reaction was carried out at −15°C (96 h reaction time).
f The reaction was carried out at −20°C (72 h reaction time).
g The reaction was carried out in the presence of 20 mol% of catalytic system.

M. Bandini et al. / Tetrahedron Letters 44 (2003) 5843–5846
5845
Figure 2. Mechanism hypothesis for the [Al(salen)Cl]/amine catalysed 1,4-addition.
Figure 3. (a) 5/TFA (20 mol%), H2O/iPrOH, −30°C. (b) PhMgBr/Et2O/0°C. (c) MnO2/CH2Cl2/rt.
dazolidinone 6 (Fig. 3).15 The (R)-indolyl aldehyde 4ld
(ee=55%) was then reacted with PhMgBr in Et2O at
0°C to obtain 4%ld in 98% yield and 60:40 diastereoiso-
meric ratio. Finally, the desired ketone (R)-4cd was
easily synthesised by oxidation of 4%ld with MnO2 [ee=
55%, [h]D=+6.4 (c=0.9 CHCl3)].
To prove the generality of the method, a range of
(E)-arylcrotyl ketones (2d–j, 1 equiv.) was synthesised13
and reacted with indoles 3a–c (1.5 equiv.) in the pres-
ence of 10 mol% of the complex 1/lut prepared in situ
(Table 2). The protocol furnished excellent chemical
yields and high ee’s with a,b-unsaturated ketones bear-
ing electron poor aromatic rings (2f–j). In these cases,
in fact, the enantioselectivity was good-ranging from 77
to 89%.
In summary, this study demonstrates the effectiveness
of chiral [Al(salen)Cl]/amine complexes as catalysts for
the enantioselective Friedel–Crafts-type conjugate addi-
tion of indoles to (E)-arylcrotyl ketones. This simple
process provides easy access to a large library of highly
functionalised b-indolyl ketones possessing a stereocen-
tre in the b-position in excellent yields and high enan-
tiomeric excesses. Studies addressed towards the
comprehension of the reaction mechanism are currently
under investigation.
Although the mechanistic details of the present reaction
are still under investigation, a working model involving
a crucial stereocontrolled formation of an intermediate
octahedral Schiff base–aluminium enolate 5 can be
supposed (Fig. 2).14
The absolute configuration of the adduct 4cb [ee=64%,
[h]D=+7.4 (c 1 CHCl3), Table 2, entry 2] was assigned
R by comparison of both optical rotation value and
chiral HPLC retention times of the compound 4cd
(obtained by NH-methylation of 4cb) with the same
adduct synthesised in three steps starting from the
enantioselective organocatalytic FC alkylation of 3d
with (E)-crotonaldehyde 4l using the MacMillan’s imi-
Typical experimental procedure: [Al(salen)Cl] (18 mg,
0.03 mmol) and 2,6-lutidine (3.5 mL, 0.03 mmol) were
added to anhydrous toluene (1 mL) and the mixture
was stirred for about 5 min at room temperature, then
2g (54 mg, 0.3 mmol) was added to the solution fol-
lowed by 3a (59 mg, 0.45 mmol). During the reaction

5846
M. Bandini et al. / Tetrahedron Letters 44 (2003) 5843–5846
the colour of the solution turned red–orange. After 48
h stirring, the reaction was quenched with a saturated
solution of NaHCO3 (5 mL), the two layers were
separated and the aqueous phase was extracted with
Et2O (3×5 mL). Finally, the collected organic phases
were dried over Na2SO4 and concentrated under
reduced pressure to give a pale orange oil, which was
then purified by flash chromatography (silica gel, cyclo-
hexane/Et2O 85/15, Rf=0.3). The (R)-4ga was isolated
as a pale yellow viscous oil (92 mg, 98% yield) in 80%
ee. Chiral analysis was carried out by HPLC (Chiralcel
OD iPrOH/hexane (20:80), flow rate 0.7 mL min−1, 225
nm; tr-(S)=11.44 min, tr-(R)=15.11 min); [h]D=−54 (c
0.98 in CHCl3). Analytical data for 4ga: IR (Nujol)
w=3398, 3055, 2963, 1695, 1587, 1456, 1091 cm−1; MS
(70 eV): m/z (%): 311 (20) [M+], 281 (18), 253 (10), 207
(82), 191 (15), 158 (100), 139 (22), 130 (18), 111 (12), 75
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352–4361; (g)
Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030–
9031.
4. Corma, A.; Garc´ıa, H.; Moussaif, A.; Sabater, M. J.;
Zniber, R.; Redouane, A. Chem. Commun. 2002, 1058–
1059.
5. (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370–4371; (b) Austin, J. F.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2002, 124, 1172–1173; (c) Paras,
N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 7894–7895.
6. (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre,
P.; Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67,
3700–3704; (b) Bandini, M.; Fagioli, M.; Melloni, A.;
Umani-Ronchi, A. Synthesis 2003, 397–402.
7. Chiral aluminium Schiff base complexes have been shown
to be effective catalysts in several asymmetric processes:
(a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
1998, 120, 5315–5316; (b) Myers, J. K.; Jacobsen, E. N.
J. Am. Chem. Soc. 1999, 121, 8959–8960; (c) Evans, D.
A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew.
Chem., Int. Ed. 2001, 40, 1884–1888; (d) Sammis, G. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442–4443.
8. The use of cyclic enones such as 2-cyclopenten-1-one and
2-cyclohexen-1-one furnished the desired indolyl deriva-
tives only in traces.
1
(9); H NMR (200 MHz, CDCl3, 25°C, TMS): l=8.4
(br, 1H), 7.77–7.81 (m, 2H), 7.65–7.69 (m, 1H), 7.23–
7.36 (m, 4H), 7.06–7.14 (m, 2H), 3.73 (q, J=7.0 Hz,
1H), 3.43–3.55 (m, 1H), 3.30 (dd, J=7.0 Hz, J=16.2
Hz, 1H), 2.38 (s, 3H), 1.50 (d, J=7.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3, 25°C, TMS): l=198.86,
160.19, 139.10, 135.47, 130.36, 129.37, 128.63, 120.63,
118.91, 118.87, 115.10, 110.53, 45.50, 27.43, 21.02,
11.88.
9. The role of pyridine as an additive in metallo-salen
catalysed asymmetric cyclopropanation of olefins was
recently discussed: Miller, J. A.; Jin, W.; Nguyen, S. T.
Angew. Chem., Int. Ed. 2002, 41, 2953–2956.
Acknowledgements
10. The use of a stoichiometric amount of amine was taken
into account as well. However, in this case, the 1-4
adduct was isolated after 48 h in low yield (i.e. Et3N 100
mol%, 18% yield, 66% ee).
We thank F.I.R.B., M.I.U.R. (Rome) ‘Progetto
Stereoselezione in Chimica Organica. Metodologie ed
Applicazioni’ and University of Bologna (funds for
selected research topics) for the financial support of this
research.
11. It is also notable that by using an excess of enone 2c (1.5
equiv.) with respect to the indole 3a (1 equiv.), 4ca was
obtained with a comparable enantiomeric excess (77%)
but with a significantly higher yield (87%).
12. Comparison of diagnostic 1H NMR signals of commer-
cial 1 and 1·Et3N in brackets (CD2Cl2, rt, 300 MHz):
8.34[7.80] (2H, CHꢁN), 7.58[7.41] (2H, Ar), 7.18[7.03]
(2H, Ar).
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