Catalytic enantioselective friedel-crafts alkylations of indoles with α′-phosphoric enones

Article abstract of DOI:10.1021/ol070548b

The C₂-symmetric bis(oxazoline) copper(II) complex proves to be an excellent catalyst in the Friedel-Crafts alkylation of indoles with α′-phosphoric enones. The enantioselectivities of this reaction are obtained in up to 98% ee.

Full text of DOI:10.1021/ol070548b

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2281-2284
Catalytic Enantioselective Friedel
Alkylations of Indoles with
r′-Phosphoric Enones
−Crafts
Hyeyeon Yang, Young-Taek Hong, and Sunggak Kim*
Center for Molecular Design & Synthesis and Department of Chemistry,
School of Molecular Science, Korea AdVanced Institute of Science and Technology,
Daejeon 305-701, Korea
skim@kaist.ac.kr
Received March 4, 2007
ABSTRACT
The C2-symmetric bis(oxazoline) copper(II) complex proves to be an excellent catalyst in the Friedel−Crafts alkylation of indoles with r′-
phosphoric enones. The enantioselectivities of this reaction are obtained in up to 98% ee.
The Friedel-Crafts reactions are very important and useful
for carbon-carbon bond formations. Their catalytic enan-
tioselective reactions have attracted a great deal of recent
attention owing to easy access to optically active aryl-
substituted products from readily available starting materials.1
Two approaches involving chiral secondary amine-catalyzed2
and the chiral metal-catalyzed reactions are very promising.
The latter process usually requires the substrates being
capable of chelating to the chiral metal complexes. Previously
reported templates for this purpose include â,γ-unsaturated
R-ketoesters,3 alkylidene malonates,4 R,â-unsaturated acyl
phosphates,5 R′-hydroxy enones,6 R,â-unsaturated 2-acyl-
imidazoles,7 and nitroalkenes.8
On the basis of the well-known synthetic usefulness of
â-keto phosphonates,9 we have been interested in utilizing
â-keto phosphonate moieties for chelating to the chiral Lewis
acids. Since the indole skeleton is an important substructure
(4) (a) Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem. Commun. 2001,
347-348. (b) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030-
9031. (c) Zhou, J.; Tang, Y. Chem. Commun. 2004, 432-433. (d) Zhou,
J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309-
1320.
(5) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J.
J. Am. Chem. Soc. 2003, 125, 10780-10781.
(1) For reviews, see: (a) Jørgensen, K. A. Synthesis 2003, 1117-1125.
(b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
2004, 43, 550-556.
(6) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garc´ıa, J. M.; Linden, A.
J. Am. Chem. Soc. 2005, 127, 4154-4155.
(7) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005,
127, 8942-8943.
(2) (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.
(8) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006,
71, 75-80.
(9) (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
(b) Nangia, A.; Prasuna, G. Tetrahedron 1996, 52, 3435-3450. (c) Wiemer,
D. F. Tetrahedron 1997, 53, 16609-16644.
(3) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 160-163.
10.1021/ol070548b CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/11/2007

in both natural products10 and therapeutic agents,11 we studied
the asymmetric Friedel-Crafts alkylation of indoles with R′-
phosphoric enones using chiral catalyst [{(S)-In-Box}Cu-
(OTf)2] 1a. This reaction exhibited good chemical yields and
high enantioselectivities (up to 98% ee).
was not significant with the exception of a diphenylphosphine
oxide derivative (63% ee) as shown in eq 3.
The enantioselective Friedel-Crafts alkylations of indoles
with several structurally different R′-phosphoric enones 2
using 1a (20 mol %) in dichloromethane are summarized in
Table 2. In most cases, the reaction gave the desired products
Table 2. Cu(II)-Catalyzed Friedel-Crafts Alkylations of
Indoles with R′-Phosphoric Enone 2a
To search for highly efficient chiral metal complexes, the
reaction was carried out with enone 2a and indole in the
presence of a variety of chiral bis(oxazoline)-metal com-
plexes. It was found that 1a gave the best result (at 0 °C,
98% yield, 86% ee) in terms of yield and enantioselectivity,
whereas 1b gave a low enantiomeric excess (at 0 °C, 95%
yield, 35% ee). It is also noteworthy that the Friedel-Crafts
reaction with 1c3,4a,12 slowed down dramatically. Treatment
of 2a with 3a and 1c in dichloromethane at 0 °C for 5 days
afforded 4a in 34% yield (31% ee) along with recovery of
2a (59%).
entry
2
3
temp [°C]
time [h]
yield [%]
ee [%]b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
2a
2a
2a
2b
2c
2a
2a
2d
2d
2d
2d
2d
2d
3a
3a
3a
3a
3a
3a
3b
3c
3a
3a
3a
3a
3b
3b
0
0
-40
-78
0
8
8
72
120
24
120
60
144
18
72
72
120
96
98 (4a)
98 (4a)
98 (4a)
98 (4a)
98 (4b)
62 (4c)
98 (4d)
39 (4e)
95 (4f)
96 (4f)
98 (4f)
99 (4f)
90 (4g)
95 (4g)
86
88c
94
95
90
86
86
82
86
96
97c
96
88
94
The effect of the solvent was briefly examined as shown
in Table 1. Among the solvents employed in this study,
0
0
0
0
Table 1. Effect of Solvent in the Friedel-Crafts Alkylations
-40
-40
-78
0
-40
504
entry
solvent
time [h]
yield [%]
ee [%]b
a All reactions were carried out on a 0.1 mmol scale with 20 mol %
catalyst. b Enantiomeric excesses were determined by chiral HPLC. c The
reaction was carried out in the presence of MS 4 Å.
1
2
3
4
5
Et2O
CHCl3
THF
toluene
CH2Cl2
18
8
18
18
8
95
93
46
83
98
78
66
78
84
86
in high yields and excellent enantioselectivities but the
reactions with isopropyl-substituted R′-phosphoric enone 2c
(entry 6) and N-allyl-substituted indole 3c (entry 8) were
slow and gave the products in low yields. The enantio-
selectivities ranged from 82% ee to 97% ee and the use of
molecular sieves 4 Å as an additive increased the enantio-
meric excess to a small extent (entries 2 and 11).13
a All reactions were carried out on a 0.1 mmol scale with 20 mol %
catalyst. b Enantiomeric excesses were determined by chiral HPLC.
dichloromethane gave the best result (entry 5) and toluene
was also equally effective (entry 4). We next studied how
structurally different phosphonate groups could influence the
enantioselectivities of the reaction but found that the effect
(11) (a) Dillard, R. D.; Bach, N. J.; Draheim, S. E.; Berry, D. R.; Carlson,
D. G. J. Med. Chem. 1996, 39, 5119-5136. (b) Rawson, D. J.; Dack, K.
N.; Dickinson, R. P.; James, K. Biorg. Med. Chem. Lett. 2002, 12, 125-
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1964.
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Soc. 2000, 122, 12517-12522. (b) Zhuang, W.; Gathergood, N.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009-1013.
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67, 547-552.
2282
Org. Lett., Vol. 9, No. 12, 2007

The effect of indole derivatives was next evaluated under
similar conditions. The enantioselectivity was influenced by
either substituents of enone 2 or the reaction temperature.
Generally, 5-methoxy-1H-indole 3d reacted with enone 2
to give 4 in excellent yields and high enantiomeric excesses
(Table 3). Indoles substituted with electron-donating sub-
hydride (1.1 equiv) in THF followed by the addition of
lithium aluminum hydride (3 equiv) afforded 7 (eq 7).14
Compared with the optical rotation value of 7 and the
previously known compound, the absolute configuration
could be assigned as (S), indicating that the stereocenter was
not affected during transformations.6
Table 3. Cu(II)-Catalyzed Friedel-Crafts Alkylations of
Substituted Indoles with 2
Similarly, 4g was converted into 8 in 95% yield. The
dephosphonylation method makes the present approach very
attractive. The Friedel-Crafts alkylation with R′-phosphoric
enones complements those of simple aliphatic enones, which
have difficulty in achieving high enantiomeric excesses.15
The Horner-Emmons reaction of the Friedel-Crafts adduct
4 was performed by the known method.16 Treatment of 4g
with benzaldehyde and potassium carbonate in ethanol at
room temperature for 9 h afforded enone 9 in 93% yield
(Scheme 1).
entry
2
3
temp [°C]
time [h]
yield [%]
ee [%]a
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2d
2d
2d
3d
3d
3e
3f
3g
3d
3d
3d
0
-40
0
5
48
48
48
48
8
90 (4h)
90 (4h)
86 (4i)
85 (4j)
95 (4k)
99 (4l)
95 (4l)
92 (4l)
90
95
88
86
90
91
97
98b
0
0
0
-40
-40
18
18
Scheme 1. Conversion of â-Keto Phosphonate 4g into Ketone
8 and Enone 9
a Enantiomeric excesses were determined by chiral HPLC. b The reaction
was carried out in the presence of MS 4 Å.
stituents (3d and 3g) reacted with enone 2 in a highly
enantioselective manner and the rate of reaction was ac-
celerated (entries 1 and 6). Indoles substituted with electron-
withdrawing substituents (3e and 3f) also gave the desired
products in high yields, but the reaction slowed down (entries
3 and 4). As compared to indole 3d (entry 1), indole 3g with
a methoxy group at C(4) was somewhat less reactive but a
good level of enantioselectivity was still observed (entry 5).
The use of 4 Å molecular sieves was found to be marginal
(entry 8) and the temperature effect was more noticeable.
Furthermore, N-methylpyrrole worked as efficiently as indole
derivatives (eq 6).
The mechanism for chiral Cu(II)-bis(oxazoline)-catalyzed
enantioselective reactions has been well studied.17 The
asymmetric induction observed in the present Friedel-Crafts
To establish the absolute configuration of the Friedel-
Crafts adduct 4, we examined a chemical correlation between
the Friedel-Crafts adduct 4f having 92% ee and the
previously known compound 7.6 Treatment of 4f with sodium
(13) (a) Hanson, R. M.; Shapless, K. B. J. Org. Chem. 1986, 51, 1922-
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1991, 113, 106-113. (c) Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J.
Org. Chem. 1996, 61, 346-355.
Figure 1. Stereochemical model for the substrate-catalyst com-
plex.
Org. Lett., Vol. 9, No. 12, 2007
2283

reactions is consistent with the model shown in Figure 1,
which assumes a distorted square-planar geometry around
copper. Apparently, the indanyl ring would block the (Re)-
face approach by indole derivatives.
In summary, the R′-phosphoric enones, which have â-keto
phosphate as a template, are highly efficient for the enan-
tioselective Friedel-Crafts alkylations catalyzed by catalyst
[{(S)-In-Box}Cu(OTf)2] 1a and complement the previously
reported templates. The Friedel-Crafts adducts can be
converted into the corresponding methyl ketones and R,â-
unsaturated ketones. Further studies on the catalytic enan-
tioselective Michael reactions associated with R′-phosphoric
enone templates are in progress.
Acknowledgment. We are grateful to the CMDS,
KEPCO, and BK21 for financial support.
(14) (a) Oh, D. Y.; Hong, J. E.; Shin, W. S.; Jang, W. B. J. Org. Chem.
1996, 61, 2199-2201. (b) Oh, D. Y.; Lee, S. Y.; Hong, J. E.; Jang, W. B.
Tetrahedron Lett. 1997, 38, 4567-4570. (c) Oh, D. Y.; Lee, S. Y.; Lee,
C.-W. J. Org. Chem. 1999, 64, 7017-7022.
(15) Bandini, M.; Fagioli, M.; Garavelli, M.; Melloni, A.; Trigari, V.;
Umani-Ronchi, A. J. Org. Chem. 2004, 69, 7511-7518.
(16) Lee, H. K.; Kim, E.-K.; Pak, C. S. Tetrahedron Lett. 2002, 43,
9641-9644.
(17) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-
335. (b) Thorhauge, J.; Roberson, M.; Hazell, R. G.; Jørgensen, K. A. Chem.
Eur. J. 2002, 8, 1888-1898.
Supporting Information Available: General experimen-
tal procedures and full characterization of compounds 2-9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070548B
2284
Org. Lett., Vol. 9, No. 12, 2007