Biphenylphosphine-palladium(II) complexes-catalyzed Friedel-Crafts reaction for the synthesis of α-amino and α-hydroxy indolylacetates and diindolylacetates

Article abstract of DOI:10.1055/s-2001-16802

Biphenylphosphine-palladium(II) complexes-catalyzed Friedel-Crafts reaction of N-methylindol with imino and carbonyl compounds afforded α-amino and α-hydroxy substituted indolylacetates and diindolylacetates in good yields.

Full text of DOI:10.1055/s-2001-16802

LETTER
1443
Biphenylphosphine-Palladium(II) Complexes-Catalyzed Friedel-Crafts
Reaction for the Synthesis of -Amino and -Hydroxy Indolylacetates and
Diindolylacetates
Jian Hao, Sonia Taktak, Kousuke Aikawa, Yukinori Yusa, Manabu Hatano, Koichi Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan
Fax +81-3-5734-2776; E-mail: kmikami@o.cc.titech.ac.jp
Received 26 February 2001
Abstract: Biphenylphosphine-palladium(II) complexes-catalyzed
Friedel-Crafts reaction of N-methylindol with imino and carbonyl
compounds afforded -amino and -hydroxy substituted indolyl-
acetates and diindolylacetates in good yields.
PPh2
Pd
Y
Y
PPh2
HX
Key words: biphenylphosphine, palladium complexes, Friedel-
Crafts reaction, indoles
X
CO2Et
BIPHEP-Pd (II)
OEt
+
H
N
Me
O
N
Me
As one of the most important methodologies for carbon-
carbon bond formation, the Friedel-Crafts reaction has
been received great attention for several decades.1 The
Lewis acid catalyzed versions of alkylation and acylation
reactions have been well developed in recent years.2 How-
ever, the Friedel-Crafts additions of imines and aldehydes
which would lead to the formation of -amino and -hy-
droxy acids of biological interests have not been well in-
vestigated yet.3 Recent contribution by Johannsen for the
asymmetric synthesis of indol -amino acetic acid deriva-
tives via CuPF6-catalyzed Friedel-Crafts reactions of in-
dol and N-tosyl imine has just been reported,4 However, to
the best of our knowledge, the palladium(II)-catalyzed
Friedel-Crafts reaction of N-methylindole with glyoxy-
lates, which would lead to the formation of -hydroxy in-
dolylacetates, has not been reported yet.
1
2
3
BIPHEP-Pd (II) (6a) (X = O, NBn)
2: X = O, NBn, NTs.
BIPHEP-Pd (II): 6a, 6b.
CO2Et
N
N
Me
Me
4
Scheme 1
LA
HO
O
CO2Et
OEt
+
H
In our research on the transition metal-catalyzed glyoxy-
late-ene reaction, the palladium(II) species have been
shown to give good catalytic activity.5 This promoted us
to further explore the possibility of palladium(II) catalysts
in other carbon-carbon bond forming reactions. Herein,
we report biphenylphosphine (BIPHEP)6- palladium(II)
complexes-catalyzed Friedel-Crafts reaction of N-meth-
ylindole with glyoxylate and their imine counterparts,
which give us an easy access to the biologically interest-
ing molecules, such as -hydroxy indolylacetates, -ami-
no indolylacetates, and diindolyl acetates (Scheme 1).
N
O
Me
N
Me
3a
1
2a
CO2Et
CO2Et
1
+
N
N
Me
N
Me
Me
4
7
Our initial effort on [Pd(CH3CN)2(BIPHEP)2](SbF6)2 (6a)
catalyzed addition reaction of N-methylindole to glyoxy-
late at room temperature in dichloroethane was failed to
give the -hydroxy indolylacetates (3a) (Table, entry 2).
Instead, the diindolyl acetate (4a) was obtained in 95%
yield. The reaction should go through the -hydroxy in-
dolylacetate (3a), but the subsequent dehydroxylation and
addition of another equivalent of indole rapidly took place
to form the diindolylacetate. Dehydroxylation might arise
from the high sensitivity of -hydroxy indolylacetate (3a)
Scheme 2
to the Lewis acid. 3-Alkylidene-3H-indolium cation 7 is
considered to be formed during this reaction catalyzed by
6a.7 This intermediate is electrophilic enough to react
with another equivalent of indole to form the diindolylac-
etate (4) in high yield (Scheme 2). Thus, we employed the
neutral palladium(II) complex, such as Pd(CH3CN)2Cl2
(5) and Pd(BIPHEP)(OCOCF3)2 (6b), instead of the cat-
Synlett 2001, No. 9, 1443–1445 ISSN 0936-5214 © Thieme Stuttgart · New York

1444
J. Hao et al.
Table Addition of N-Methyl-Indole to Ethyl Glyoxylate 8
LETTER
HO
CO2Et
O
CO2Et
+
10 mol% Pd (II)
OEt
+
H
N
Me
O
N
Me
N
Me
N
Me
1
2a
3a
4
Yield (%)
Temp (oC)
Entry
Pd (II)
Pd(CH3CN)2Cl2 (5)
Time (hr)
Sol
3a
4
-
CH2ClCH2Cl
1
2
rt
rt
18
12
96
-
[Pd(CH3CN)2(BIPHEP)](SbF6)2 (6a) CH2ClCH2Cl
[Pd(CH3CN)2(BIPHEP)](SbF6)2 (6a) CH2Cl2
95
53
3
-78 - rt
18
32
[Pd(CH3CN)2(BIPHEP)](SbF6)2 (6a)
[Pd(CH3CN)2(BIPHEP)](SbF6)2 (6a)
Pd(BIPHEP)(OCOCF3)2 (6b)
4
5
6
7
Toluene
rt
rt
rt
rt
18
20
24
24
52
13
15
45
28
82
-
BTF1
Toluene
Pd(BIPHEP)(OCOCF3)2 (6b)
-
CH2ClCH2Cl
1BTF = Benzotrifluoride
ionic complex (6a). The reaction was well controlled to
offer 3a in 96% yield in dichloroethane without observa-
tion of 4 (entry 1). It’s worthy to mention that the product
radio (3a vs 4) is also affected by solvents and reaction
temperature. Polar solvents, such as CH2Cl2 and
CH2ClCH2Cl, provided good solubility to palladium com-
plex 6a and afforded the diindol product (4). Less polar
solvent, such as toluene, provided the -hydroxy indoly-
lacetate 3a. Lower reaction temperature could also reduce
the possibility of dehydroxylation. For example, in the
case catalyzed by the complex 6a, -hydroxy indolylace-
tate (3a) was obtained in 32% yield when the reaction was
carried out from 78 °C to room temperature (entry 3).
Pd(BIPHEP)(OCOCF3)2 also showed good selectivity to
offer 3a in dichloroethane at room temperature (entry 7).
ArHN
NAr
CO2Et
10 mol% 6
OEt
+
H
CH2ClCH2Cl
rt, 18hr
N
Me
O
N
Me
1
2b: Ar = Bn
2c: Ar = Ts
3b: Yield: 97%
3c, Yield: 96%
60 o
C
24 hr
Ar = Bn
CO2Et
N
Me
N
Me
4, 53%
Further investigation shows that this palladium(II)-cata-
lyzed Friedel-Crafts reaction is also applicable to the imi-
ne counterparts. The Pd(CH3CN)2Cl2 does not work well
in this addition reaction of indole to N-benzyl imine at am-
bient temperature. It should be mentioned that the palladi-
um cationic complex 6a is effective to the less
electrophlic imine, such as N-benzyl imine (Scheme 3).9
Deamination followed by addition of one more equivalent
of indole to form the diindolylacetate (4) was not ob-
served when the reaction was carried out at room temper-
ature. However, in the case of 2b, deamination occurred
when the reaction was carried out at 60 °C, and diindoly-
lacetate 4 was obtained in 53% for 24 h. No deamination
was observed in the case of 2c even at 60 °C.
Scheme 3
References and Notes
(1) Reviews: (a) Smith, M, B. Organic Synthesis; McGraw-Hill:
New York, 1994; pp 1313. (b) Heaney, H. Comprehensive
Organic Synthesis; Pergamon Press: Oxford, 1991; Vol. 2, pp
733. (c) Roberts, R. M.; Khalaf, A. A. Friedel-Crafts
Alkylation Chemistry. A Century of Discovery; Dekker: New
York, 1984. (d) Olah, G. A. Friedel-Crafts Chemistry; Wiley-
Interscience: New York, 1973.
(2) Reviews: (a) Yamamoto, H. Ed., Lewis Acids in Organic
Synthesis; Wiley-VCH: Weinheim, 2001. (b) Santelli, M.;
Pons, J.-M. Lewis Acids and Selectivity in Organic Synthesis;
CRC Press: Boca Raton, New York, London, Tokyo, 1996.
(c) Mikami, K.; Nakai, T. Asymmetric Lewis Acid Catalysts.
Kagaku Zoukan 1995, 124, 177. (d) Schinzer, D. Selectivities
in Lewis Acid Promoted Reaction; Kluwer Academic
Publishers: Dordrecht, Boston, London, 1988.
In summary, the biphenylphosphine-palladium(II)-cata-
lyzed Friedel-Crafts reaction has been developed for the
efficient synthesis of -hydroxy indolylacetate, -amino
indolylacetate and diindolyl acetate.
Synlett 2001, No. 9, 1443–1445 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Biphenylphosphine-Palladium(II) Complexes-Catalyzed Friedel-Crafts Reaction
1445
(3) Erker, G.; van der Zeijden, A. A. H. Angew. Chem. Int. Ed.
Engl. 1990, 29, 512. Also see: Ichii, A.; Kojima, J.; Mikami,
K. Org. Lett. 1999, 1, 2013.
acetate = 2:1, solvent was then evaporated off by evaporator
after reaction was finished, residue was purified by column
chromatography with elution of hexane/ethyl acetate = 4/1 to
afford the product as light yellow oil for 3a and light pink oil
for 4. 1H NMR (CDCl3, 300 MHz) for 3a: (ppm) = 1.24 (t,
(4) Johannsen, M. Chem. Commun. 1999, 2233.
(5) Hao, J.; Hatano, M.; Mikami, K. Organic Lett. 2000, 2, 4059.
(6) Chirally flexible biphenylphosphine (BIPHEP) ligands for
catalytic asymmetric synthesis: Mikami, K.; Korenaga, T.;
Terada, M.; Ohkuma, T.; Pham, T.; Noyori, R. Angew. Chem.
Int. Ed. 1999, 38, 495. Also see the use of this novel ligands:
(a) BIPHEP-Ru complexes: Mikami, K.; Aikawa, K.;
Korenaga, T. Organic Lett. 2000, 2, 0000. (b) BIPHEP-Pd
complexes: Ogasawara, M.; Yoshida, K.; Hayashi, T.
Organometallics 2000, 19, 1567. (c) BIPHEP-Pt complexes:
Tudor, M. D.; Becker, J. J.; White, P. S.; Gagné, M. R.
Organometallics 2000, 19, 4376.
3H, CH3, JCH
= 7.2 Hz), 3.30 (b, 1H, OH), 3.76 (s, 3H,
,CH
3
NCH3), 4.19 (dq,22H, CH2, JCH
3 = 7.2 Hz), 5.45 (s, 1H,
,CH
2
CH), 7.12 (s, 1H, 2-H), 7.14-7.73 (m, 4H, Ar). For 4:
(ppm) = 1.31 (t, 3H, CH3, JCH
NCH3), 4.26 (q, 2H, CH2, JCH
= 7.2 Hz), 3.74 (s, 6H,
,CH
3
2 = 7.2 Hz), 5.55 (s, 1H,
,CH
CH), 7.06 (s, 2H, 2-H), 7.14-7.713(m, 8H, Ar).
2
(9) 1H NMR (CDCl3, 300 MHz) for 3b: (ppm) = 1.23 (t, 3H,
CH3, JCH
= 7.2 Hz), 2.25 (b, 1H, NH), 3.76 (s, 3H,
,CH
3
NCH3), 3.842(s, 2H, CH2-Ph), 4.19 (dq, 2H, CH2,
JCH = 7.2 Hz), 4.71 (s, 1H, CH), 7.10 (s, 1H, 2-H), 7.12-
,CH
2
3
(7) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry,
3rd Ed.; Chapman & Hall, 1995, pp 312.
7.72 (m, 9H, Ar). For 3c: (ppm) = 1.12 (t, 3H, CH3,
JCH = 7.5 Hz), 2.35 (s, 3H, CH3-Ph), 3.65 (s, 6H, NCH3),
,CH
3
2
(8) General Procedure: To a solution of BIPHEP-Pd (II) complex
(0.025 mmol, 10 mol% of ethyl glyoxylate) and 50 mg 4Å MS
in 2 mL of dried solvent was added of ethyl glyoxylate (0.25
mmol in 2 mL dried solvent) and N-methyl indole (0.25 mmol
to 0.50 mmol in 2 mL solvent) subsequently under the
protection of argon atmosphere. This yellow solution was then
stirred at certain reaction temperature for certain time,
Reaction was monitored by TLC with elution of hexane/ethyl
4.02 (dq, 2H, CH2, JCH
= 7.5 Hz), 5.32 (d, 1H, CH,
,CH
3
2
J
CH-NH = 8.4 Hz), 5.69 (d, 1H, NH, JNH-CH = 8.4 Hz), 6.92 (s,
1H, 2-H), 7.04-7.63 (m, 8H, Ar).
Article Identifier:
1437-2096,E;2001,0,09,1443,1445,ftx,en;Y00501ST.pdf
Synlett 2001, No. 9, 1443–1445 ISSN 0936-5214 © Thieme Stuttgart · New York