Chiral Pd-catalyzed enantioselective Friedel-Crafts reaction of indoles with γ,δ-unsaturated β-keto phosphonates

Article abstract of DOI:10.1016/j.tetlet.2011.04.084

The catalytic enantioselective Friedel-Crafts alkylation reaction promoted by chiral palladium complexes is described. The treatment of indoles with γ,δ-unsaturated β-keto phosphonates under the mild reaction conditions afforded the corresponding Friedel-

Full text of DOI:10.1016/j.tetlet.2011.04.084

Tetrahedron Letters 52 (2011) 3247–3249
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Chiral Pd-catalyzed enantioselective Friedel–Crafts reaction of indoles
with c,d-unsaturated b-keto phosphonates
⇑
Young Ku Kang, Bo Kyung Kwon, Joo Yang Mang, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic enantioselective Friedel–Crafts alkylation reaction promoted by chiral palladium complexes
is described. The treatment of indoles with ,d-unsaturated b-keto phosphonates under the mild reaction
conditions afforded the corresponding Friedel–Crafts alkylation adducts with excellent enantioselectivi-
Received 25 February 2011
Revised 14 April 2011
Accepted 20 April 2011
Available online 27 April 2011
c
ties (up to 99% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts reaction
Asymmetric catalysis
Chiral palladium catalysts
Indoles
c
,d-Unsaturated b-keto phosphonates
The Friedel–Crafts (FC) alkylation is important reaction for the
FC reaction of indoles with c,d-unsaturated b-keto phosphonates
formation of C–C bonds.1 The asymmetric FC reaction can afford
enantiomerically enriched alkylated arene products. The chemistry
of indole derivatives that are present in many substances com-
monly found in nature is a rapidly developing area because of their
importance in biochemical and medicinal application. Thus, the
development of asymmetric FC reaction of indole derivatives is
important in the synthesis of natural products2 and pharmacolog-
ical and biological active compounds.3 Over the past decade, tre-
mendous effort has been devoted to the development of catalytic
catalyzed by chiral palladium complexes has not been reported.
As part of research program related to the development of syn-
thetic methods for the enantioselective construction of stereogenic
carbon centers,7 we recently reported the catalytic electrophilic
amination, fluorination, Mannich reaction and Michael reaction
of active methines promoted by chiral palladium complexes with
excellent enantioselectivities.8 In this letter, we wish to describe
the enantioselective FC reaction of indoles with
c,d-unsaturated
b-keto phosphonates catalyzed by air- and moisture-stable chiral
enantioselective FC reaction of
a,b-unsaturated carbonyl com-
palladium complexes (Fig. 1).
To determine suitable reaction conditions for the catalytic
enantioselective FC reaction of indoles, we first examined FC reac-
pounds using chiral metal complexes1a–d and organocatalysts.1e–g
Chiral metal-catalyzed process usually required the bidentate che-
lating substrates such as b,
c
-unsaturated
a-ketoesters, glyoxylates,
tion of indole 3a with c,d-unsaturated b-keto phosphonates 2 in
alkylidene malonates and pyruvates, acyl phosphonates, 2-acyl
imidazoles, a0-hydroxy enones, enoylpyridine 1-oxide and thioes-
ters.4 In 2007, Kim and co-workers reported enantioselective FC
the presence of 5 mol % of dicationic palladium complexes 1 in
CH2Cl2 at room temperature (Table 1). We surveyed the effect of
structure of palladium complexes 1. High yields with good to
excellent enantioselectivities (85–96% ee) were observed for
structurally variable palladium catalysts (entries 1–6). Under the
reaction of indoles with c,d-unsaturated b-keto phosphonates cat-
alyzed by chiral Cu(OTf)2–Box complexes.5 There are still some
drawbacks in the previously reported procedures, such as high cat-
alyst loading and low temperatures for high enantioselectivity.
Therefore, the development of alternative catalysts for enantiose-
2+
lective FC reactions between indoles and
c,d-unsaturated b-keto
Ar2
P
Pd
1a : Ar = Ph, X = BF4
phosphonates would be highly desirable. Recently, the efficient
examples of the enantioselective reactions catalyzed by chiral pal-
ladium complexes were reported.6 To the best of our knowledge,
_
OH2
1b : Ar = Ph, X = OTf
2X
1c : Ar = Ph, X = PF6
1d : Ar = Ph, X = SbF6
P
NCMe
Ar2
1e : Ar = 4-methylphenyl , X = BF4
1f : Ar= 3,5-dimethylphenyl , X = BF4
⇑
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
Figure 1. Structures of chiral palladium catalysts.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.084

3248
Y. K. Kang et al. / Tetrahedron Letters 52 (2011) 3247–3249
Table 1
Optimization of the reaction conditions
O
O
H
O
O
N
cat. 1 (5 mol%)
P(OR)2
+
P(OR)2
solvent, rt
HN
2
3a
4
Entry
Cat.
Solvent
2, R
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1c
1c
1c
1c
1c
1c
1c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
AcOEt
Acetone
THF
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2b, Et
2c, i-Pr
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2
2
2
2
2
2
2.5
4
24
60
48
48
36
4a, 95
4a, 92
4a, 98
4a, 93
4a, 90
4a, 94
4b, 94
4c, 96
4a, 95
4a, 70
4a, 60
4a, 71
4a, 74
93
91
96
85
91
86
93
85
73
95
81
99
95
Toluene
a
Isolated yield.
b
Enantiopurity was determined by chiral HPLC analysis using chiral column (Chiralpak AS for 4a and 4c Chiralcel OD–H for 4b).
Table 2
Catalytic enantioselective Friedel–Crafts reaction of indoles with
c,d-unsaturated b-keto phosphonates
R2
R3
R1
O
O
O
O
N
cat. 1c (5 mol%)
P(OMe)2
+
P(OMe)2
R1
solvent, rt
R2
N
2
R3
3
4
3a, R2 = H, R3 = H
2a, R1 = Me
3b, R2 = Me, R3 = H
3c, R2 = OMe, R3 = H
3d, R2 = Br, R3 = H
3e, R2 = H, R3 = Me
3f, R2 = Br, R3 = Me
2b, R1 = Et
2c, R1 = n-Pr
2d, R1 = CH2CH2Ph
2e, R1 = Ph
Entry
2
3
Solvent
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
3a
3c
3d
3e
3a
3a
3a
THF
Toluene
THF
THF
THF
48
96
20
72
72
72
20
96
34
72
24
36
72
4a, 71
4d, 79
4e, 92
4f, 75
4g, 71
4h, 86
4i, 94
4j, 95
4k, 98
4l, 95
4m, 78
4n, 68
N.R.
99
99
93
99
93
93
85
93
93
85
90
99
—
5c
6c
7
THF
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
THF
8c
9
10c
11
12
13
THF
THF
a
Isolated yield.
b
Enantiopurity was determined by HPLC analysis using chiral columns (Chiralpak AS for 4a, 4i and 4h, Chiralpak AS–H for 4k and 4l, Whelk-01 for 4d, Chiralcel OD–H for
4e, Chiralhyun–Leu for 4j, Chiralpak AD–H for 4f and 4g, IA for 4m and 4n).
c
Cat. 1a was used instead of cat. 1c.
standard reaction conditions, catalyst 1c gave better enantioselec-
tivity (96% ee, entry 3). We studied the effect of the ester group of
phosphonates 2 using Pd catalyst 1c in CH2Cl2 (entries 3, 7 and 8).
Dimethyl 2-oxo-pent-3-enylphosphonate (2a) showed the best
enantioselectivity (entry 3). Next, we examined the reaction in var-
ious solvents (entries 3 and 9–13). The use of CH2Cl2, THF, toluene
and EtOAc gave the good results, whereas the FC reaction in MeOH
and acetone gave lower enantioselectivities (entries 3 and 9–13).
The absolute configuration of 4a was established by comparison
of the optical rotation and chiral HPLC analysis with previously re-
ported values.5
With optimal reaction condition in hand, we studied the gener-
ality of the enantioselective FC reaction of various indoles 3 with
c
,d-unsaturated b-keto phosphonates 2.9 As it can be seen by the
results summarized in Table 2, the corresponding alkylated prod-
ucts 4a–4n were obtained in high yields with enantioselectivities

Y. K. Kang et al. / Tetrahedron Letters 52 (2011) 3247–3249
3249
R4
N
R4
N
O
O
O
O
cat. 1c (5 mol%)
P(OMe)2
+
P(OMe)2
*
THF, rt, 2 h
5a, R4 = H
5b, R4 = Me
2a
6a, 72%, 99% ee
6b, 78%, 95% ee
Scheme 1.
J. Am. Chem. Soc. 2005, 127, 4154; (h) Bandini, M.; Fagioli, M.; Melchiorre, P.;
Melloni, A.; Umani-Ronchi, A. Tetrahedron Lett. 2003, 44, 5843; (i) Bandini, M.;
Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Helv. Chim. Acta 2003, 86, 3753; (j)
Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc.
2003, 125, 10780; (k) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu,
R. J. Am. Chem. Soc. 2007, 129, 10029; (l) Takenaka, N.; Abell, J. P.; Yamamoto, H.
J. Am. Chem. Soc. 2007, 129, 742.
(85–99% ee). The best enantioselectivity of FC adducts 4d and 4k
was obtained in toluene, and FC adducts 4i, 4j and 4l was obtained
in CH2Cl2. On the other hand, dimethyl 2-oxo-4-phenyl-but-3-eny-
lphosphonate (2e) could not be alkylated with indole (3a) under
optimal reaction conditions (Table 2, entry 13).
Furthermore, indole derivatives 5 were also used as substrate in
this FC reaction with dimethyl 2-oxo-pent-3-enylphosphonate
(2a). It was found that the corresponding products 6 were obtained
in high yields with excellent enantioselectivities (Scheme 1).
In conclusion, we have developed an efficient catalytic FC reac-
5. Yang, H.; Hong, Y.-T.; Kim, S. Org. Lett. 2007, 9, 2281.
6. For recent selected examples of the enantioselective reactions catalyzed by
chiral palladium complexes, see: (a) Lectard, S.; Hamashima, Y.; Sodeoka, M.
Adv. Synth. Catal. 2010, 352, 2708; (b) Sodeoka, M.; Hamashima, Y. Chem.
Commun. 2009, 5787; (c) Hamashima, Y.; Sasamoto, N.; Umebayashi, N.;
Sodeoka, M. Chem. Asian J. 2008, 3, 1443; (d) Hamashima, Y.; Sasamoto, N.;
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7. (a) Yoon, S. J.; Kang, Y. K.; Kim, D. Y. Synlett 2011, 420; (b) Moon, H. W.;
Kim, D. Y. Bull. Korean Chem. Soc. 2011, 32, 291; (c) Kang, Y. K.; Kim, S. M.;
Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847; (d) Kang, S. H.; Kim, D. Y. Adv.
Synth. Catal. 2010, 352, 2783; (e) Lee, J. H.; Kim, D. Y. Synthesis 2010, 1860;
(f) Moon, H. W.; Kim, D. Y. Tetrahedron Lett. 2010, 51, 2906; (g) Lee, J. H.;
Kim, D. Y. Adv. Synth. Catal. 2009, 351, 1779; (h) Kang, Y. K.; Kim, D. Y. J.
Org. Chem. 2009, 74, 5734; (i) Moon, H. W.; Cho, M. J.; Kim, D. Y.
Tetrahedron Lett. 2009, 50, 4896; (j) Kwon, B. K.; Kim, S. M.; Kim, D. Y. J.
Fluorine Chem. 2009, 130, 259; (k) Oh, Y.; Kim, S. M.; Kim, D. Y. Tetrahedron
Lett. 2009, 50, 4674; (l) Kang, S. H.; Kim, D. Y. Bull. Korean Chem. Soc. 2009,
30, 1439; (m) Kwon, B. K.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 1441;
(n) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 249;
(o) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659; (p) Jung, S. H.; Kim,
D. Y. Tetrahedron Lett. 2008, 49, 5527; (q) Park, E. J.; Kim, M. H.; Kim, D. Y. J.
Org. Chem. 2004, 69, 6897; (r) Kim, D. Y.; Choi, Y. J.; Park, H. Y.; Joung, C. U.;
Koh, K. O.; Mang, J. Y.; Jung, K.-Y. Synth. Commun. 2003, 33, 435; (s) Kim, D.
Y.; Park, E. J. Org. Lett. 2002, 4, 545; (t) Kim, D. Y.; Huh, S. C.; Kim, S. M.
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tion of indoles to c,d-unsaturated b-keto phosphonates using air-
and moisture-stable chiral palladium complexes at room tempera-
ture. The desired d-indolyl b-keto phosphonates 4 were obtained in
high yields, and excellent enantioselectivities (85–99% ee) were
observed for all the substrates examined in this work. We believe
that this report provides a practical method for the preparation
of chiral c-indolyl b-keto phosphonate derivatives, and the avail-
ability of these compounds should facilitate biochemical and
medicinal studies in various fields.
Acknowledgments
Following are results of a study on the ‘Human Resource Devel-
opment Center for Economic Region Leading Industry’ Project, sup-
ported by the Ministry of Education, Science Technology (MEST)
and the National Research Foundation of Korea (NRF).
References and notes
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Bull. Korean Chem. Soc. 2008, 29, 2093; (e) Lee, J. H.; Bang, H. T.; Kim, D. Y. Synlett
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43, 550; (c) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005,
1199; (d) Poulsen, T. B.; Jrgensen, K. A. Chem. Rev. 2008, 108, 2903; (e) Tsogoeva,
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Chem. 2010, 2635; Bandini, M.; Umani-Ronchi, A. Catalytic Asymmetric Friedel–
Crafts Alkylations; Wiley-VCH: Weinheim, 2009; (i) Zeng, M.; You, S.-L. Synlett
2010, 1289.
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9. Typical procedure: To
a stirred solution of (E)-dimethyl 2-oxopent-3-
enylphosphonate (2a, 57.6 mg, 0.3 mmol), Pd-catalyst 1c (16.2 mg,
0.015 mmol) in THF (1.5 mL) was added indole (3a, 41.1 mg, 0.36 mmol) at
room temperature. The reaction mixture was stirred for 48 h at room
temperature. The reaction was diluted with EtOAc (10 mL), then washed with
sat. NH4Cl. The organic layer was dried over anhydrous MgSO4, filtered,
concentrated, and purified by flash column chromatography (EtOAc/Hex:15/1)
to afford (S)-dimethyl 4-(1H-indol-3-yl)-2-oxopentylphosphonate (4a, 71%,
65.9 mg). ½a 2D6:3
ꢀ
= –55.4 (c = 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) d 1.39 (d,
J = 6.9 Hz, 3H), 2.89 (dd, J = 8.1, 16.1 Hz, 1H), 3.00 (d, J = 22.4 Hz, 2H), 3.12 (dd,
J = 5.9, 16.1 Hz, 1H), 3.55–3.66 (m, 1H), 3.70 (d, J = 11.6 Hz, 3H), 3.73 (d,
J = 10.8 Hz, 3H), 6.99 (d, J = 2.4 Hz, 1H), 7.07–7.24 (m, 2H), 7.35 (d, J = 7.8 Hz,
1H), 7.64 (d, J = 7.6 Hz, 1H), 8.30 (br s, 1H); 13C MNR (50 MHz, CDCl3) d 21.1,
26.7, 41.6 (J = 127.5 Hz), 51.7, 53.0 (d, J = 6.1 Hz), 111.3, 119.1, 119.3, 120.4,
121.3, 122.0, 126.2, 136.5, 201.5 (J = 7.0 Hz); MS (ESI): m/z = 310.1 [M+H]+; HPLC
(80:20, n-hexane/i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AS column, tR = 20.0
(minor), 21.5 min (major), 99% ee.