Friedel-Crafts reaction of indole derivatives using the iminium salt generated by the oxidation of amino ketene silyl acetal

Article abstract of DOI:10.3987/COM-08-S(F)66

Friedel-Crafts reaction of various indole derivatives proceeded with the iminium salt generated by the oxidation of amino ketene silyl acetal to give the addition products in good yields. Further reaction of the introduced glycine moiety of the adducts wi

Full text of DOI:10.3987/COM-08-S(F)66

HETEROCYCLES, Vol. 77, No. 2, 2009
767
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 767 – 772. © The Japan Institute of Heterocyclic Chemistry
Received, 28th July, 2008, Accepted, 26th September, 2008, Published online, 29th September, 2008
DOI: 10.3987/COM-08-S(F)66
FRIEDEL-CRAFTS REACTION OF INDOLE DERIVATIVES USING
THE IMINIUM SALT GENERATED BY THE OXIDATION OF AMINO
KETENE SILYL ACETAL
Takuya Iwao and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering
Mie University, Tsu, Mie 514-8507, Japan. E-mail: mshimizu@chem.mie-u.ac.jp
Abstract – Friedel-Crafts reaction of various indole derivatives proceeded with
the iminium salt generated by the oxidation of amino ketene silyl acetal to give
the addition products in good yields. Further reaction of the introduced glycine
moiety of the adducts with the second nucleophiles provided double nucleophilic
addition products.
Intriguing reactivity of the iminim salts generated by the oxidation of aluminum enolate derivatives has
enabled the use of α-imino esters as acceptors of two nucleophiles (eq 1).1 Generation of iminium species
by the oxidation of the intermediary enolates was extended to the use of amino ketene silyl acetal, readily
isolable enolate derivatives as starting materials, and this methodology offers a simple approach to a
variety of α-amino esters in a short step (eq 2).2
Et2AlCl , EtAlCl2
(PhCOO)2
+
Et
R
PMP
PMP
Et
R
PMP
N
N
N
Nu-
(1)
CO2Et
-
EtCN, -20 oC to rt
CO2Et
R
CO2Et
Nu
PhCO2
+
NBn2
NBn2
CO2Et
OEt
OTMS
DDQ
RMgX
(2)
Bn2N
ArO-
R
CO2Et
Scheme 1.
-----------------------------------
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

768
HETEROCYCLES, Vol. 77, No. 2, 2009
Indole skeletons are often found in many of biologically active compounds such as tryptophan,
indomethacin, and dragmacidin derivatives, and several methodologies have been reported to
functionalize indoles.3 When these iminium salts are used as electrophiles, this methodology offers a
regio- and chemoselective introduction of a glycine moiety into indoles. Further treatment of this adduct
.
with a second nucleophile in the presence of BF3 Et2O induces displacement of the dibenzylamino moiety
to give a double nucleophilic addition product (4).4
NBn2
CO2Et
Nu
CO2Et
N
Bn2N
OEt
DDQ
.
2
R
Nu-, BF3 Et2O
OTMS
N
N
1
R
3
R
4
Scheme 2.
The initial examination was carried out to find optimum Friedel–Crafts reaction conditions using
1-methylindole (2b) as nucleophile, and Table 1 summarizes the results.
Table 1. Friedel-Crafts Reaction of 1-Methylindole (2b) with the Iminium Salt under Various Conditionsa
NBn2
oxidant
CO2Et
N
(1.0 equiv)
OEt
Bn2N
CO2Et
Me
(1.1 equiv)
2b
solvent, -78 oC to rt, 12 to 14 h
OTMS
N
N
N
1
Me
Me
Me
4b
5
Entry
Oxidant
NCS
Solvent
EtCN
EtCN
EtCN
EtCN
EtCN
CH2Cl2
PhMe
DMF
Additive (equiv)
none
4b (%)b
5 (%)b
1
2
32
22
0
0
20
37
42
0
NBS
NIS
none
3
none
4
I2
none
0
5
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
none
99
96
88
99
67
38
31
6
none
0
7
none
0
8
none
.
BF3 Et2O (0.5)
.
BF3 Et2O (1.0)
0
9
EtCN
EtCN
EtCN
0
10
11
12
18
.
BF3 Et2O (2.0)

HETEROCYCLES, Vol. 77, No. 2, 2009
769
aReaction was carried out according to the typical procedure (Ref. 5). bIsolated yield.
Regarding the oxidation reagent, use of NCS and NBS gave the adduct (4b) in low yields (Entries 1 and
2), whereas NIS and iodine effected the formation of the 1:2 addition product (5) (Entries 3 and 4). The
best yield of the adduct (4b) was obtained, when DDQ was used in EtCN or DMF, where the by-product
.
(5) was not formed (Entries 5 and 8). The use of BF3 Et2O did not noticeably accelerate the addition, but
induced the formation of the 1:2 addition product (5) (Entries 9 ~ 11). Under the optimum reaction
conditions found for the addition of 1-methylindole a variety of indoles were subjected to the
Friedel–Crafts reaction, and the representative results are shown in Scheme 2.
NBn2
OEt
Bn2N
indole (1.0 eq)
DDQ (1.1 eq),
EtCN, -78 oC ~ rt, 12 h
CO2Et
R'
R'
OTMS
N
1
R
4
NBn2
NBn2
CO Et
NBn2
CO2Et
NBn2
CO2Et
NBn2
Me
CO2Et
R'
2
CO2Et
N
N
H
N
Br
N
N
R
TIPS
H
4i 72%
4k: R' = NO2
17%
>99%
73%
39%
13%
4f: R' = NO2
4g: R' = Br
4h: R = OMe
4a: R = H
11%
4n 0%
NBn2
CO2Et
NBn2
4l: R' = Br
71%
81%
4b: R = Me
4c: R = Bn
4d: R = TIPS
4e: R = Ts
Me
4m: R' = OMe
5%
CO2Et
N
Br
N
94%
0%
TIPS
4j 67%
4o 0%
Scheme 2.
Regarding the substituent at the nitrogen of indole, methyl and triisopropylsilyl (TIPS) groups effected
the addition efficiently (4b, d), whereas p-toluenesulfonyl (Ts) inhibited the product formation in the
absence of a Lewis acid (4e). 1-TIPS derivatives having a 5- or 6-substituent were next examined, and the
bromo and methoxy derivatives gave the adduct in good yields (4g, h), while the 5-nitro derivative
suppressed the addition reaction (4f). Except for the case with 6-bromoindole (4i), N-unprotected
derivatives did not serve as good nucleophiles in the present system, and the adducts were obtained in low
yields (4a, k, l, m). 3-Methylindoles did not participate in the addition reaction with the present iminium
salt (4n, o).

770
HETEROCYCLES, Vol. 77, No. 2, 2009
As indicated in Table 1, under certain conditions a 1:2 addition product (5) was formed as a by-product,
and therefore, we next examined the subsequent nucleophilic displacement of the dibenzylamino moiety
of the adduct (6). Table 2 summarizes the results.
.
Table 2. Second Addition to the Adduct (4b) in the Presence of BF3 Et2Oa
Nu
NBn2
CO2Et
.
Nu- (2.0 eq), BF3 OEt2 (2.0 eq)
CO2Et
CH2Cl2, rt, 8 h
N
N
Me
Me
4b
6
Yield (%)b
Entry
Yield (%)b
Entry
1
Nucleophile
Nucleophile
Product (6)
Product (6)
OMe
CO2Et
OMe
OEt
MeO
OMe
CO2Et
66
CO2Et
CO2Et
78
3
OTMS
N
MeO
OMe
Me
N
6a
Me
OEt
6c
53c
CO2Et
SnBu3
53
4
EtOH
2
N
N
Me
Me
6d
6b
a Reaction was carried out according to the typical procedure (Ref. 6). b Isolated yield. c PPTS was used instead of
.
BF3 OEt2.
CO2Et
CO2Et
OEt
N
.
Bn2N
(1.0 eq)
OEt
DDQ (1.1 eq),
(5.0 eq), BF3 OEt2 (2.0 eq)
OTMS
Me
CH2Cl2, -78 oC to rt, 8 h
CH2Cl2, rt, 14 h
OTMS
N
1
Me
87%
6a
After a series of experiments, the best conditions were found for the addition of ketene silyl acetal derived
from ethyl isobutyrate, and the adduct (6a) was obtained in 78% yield (Entry 1). Under these conditions,
allyltrimethylsilane, and 1,3,5-trimethoxybenzene gave the adducts (6a, b) in moderate yields (Entries 2
and 3). Replacement of the dibenzylamino group with ethanol was effected by pyridinium
p-toluenesulfonate to give the ethoxy derivative (6d) in moderate yield (Entry 4). A one-pot
transformation was also carried out using five equivalents of the second nucleophile. In this case the
adduct (6a) was obtained in 87% yield.
A possible reaction mechanism is depicted in Scheme 3. First, oxidation of the amino ketene silyl acetal
(1) with DDQ gives the iminium salt (A), which in turn is attacked by indole to give the Friedel-Crafts

HETEROCYCLES, Vol. 77, No. 2, 2009
771
.
adduct (4b). This adduct is further activated with BF3 Et2O to give the second iminium salt (B). This
species would be responsible for the attack of the second nucleophile such as ketene silyl acetal to give
the double addition product (6).
Bn2N
Bn2N
Cl
OEt
CO2Et
CN
+
N
NBn2
O
Me
Bn2N
1
OEt
O
DDQ
Cl
ArO-
Si
CN
OSi
CO2Et
Cl
O
OTMS
O
A
Cl
CN
NC
NBn2
Nu
CO2Et
BF3
CO2Et
Bn2N
.
BF3 Et2O
CO2Et
X-
Nu-
CO2Et
N
MeN
- NBn2
N
Me
+
MeN
Me
4b
6
B
Scheme 3.
In conclusion, we have found that even in the absence of acid promoters, a facile Friedel-Crafts reaction
of indoles proceeded with the iminium salt generated by the oxidation of amino ketene silyl acetal. The
Friedel–Crafts adduct was further subjected to the second addition reaction to give the double addition
products in good yields. Since a variety of bioactive compounds have indole skeletons and this reaction
enables a simple introduction of the glycine moiety into indoles, the present methodology offers a useful
addition to the existing functionalization of indoles.
REFERENCES AND NOTES
1. (a) Y. Niwa and M. Shimizu, J. Am. Chem. Soc., 2003, 125, 3720. (b) M. Shimizu and Y. Niwa,
Tetrahedron Lett., 2001, 42, 2829. (c) Y. Niwa, K. Takayama, and M. Shimizu, Bull. Chem. Soc.
Jpn., 2002, 75, 1819. (d) Y. Niwa, K. Takayama, and M. Shimizu, Tetrahedron Lett., 2001, 42, 5473.
(e) M. Shimizu, Y. Niwa, T. Nagai, and I. Hachiya, Heterocycles, 2007, 72, 127.
2. (a) M. Shimizu, H. Itou, and M. Miura, J. Am. Chem. Soc., 2005, 127, 3296. (b) M. Shimizu, Pure
Appl. Chem., 2006, 78, 1867.
3. M. Bandini, A. Melloni, S. Tommasi, and A, Umani-Ronchi, Synlett, 2005, 1199, and references
cited therein.
4. (a) S. Shirakawa and S. Kobayashi, Org. Lett., 2006, 8, 4939. (b) R. Ballini, A. Palmieri, M. Petrini,
and E. Torregiani, Org. Lett., 2006, 8, 4093. (c) D. L. Comins and E. D. Stroud, Tetrahedron Lett.,
1986, 27, 1869.

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HETEROCYCLES, Vol. 77, No. 2, 2009
5. A typical procedure for the preparation of ethyl 2-dibenzylamino-2-(1-methylindolyl)acetate (4b) is
as follows: Under an argon atmosphere, 1-ethoxy-2-dibenzylamino-1-trimethylsiloxyethylene (1)
(0.20 mL, 0.10 mmol, 0.5 M in CH2Cl2) and a solution of 1-methylindole (2b) (13.1 mg, 0.10 mmol)
in DMF were successively added to a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
o
(25.0 mg, 0.11 mmol) in DMF (1.0 mL) at –78 C. The reaction mixture was allowed to warm to
ambient temperature with stirring for 14 h. The reaction was quenched with sat. aq. NaHCO3, and the
whole mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by
preparative
TLC
on
silica
gel
(EtOAc/n-hexane
=
1/4)
to
give
ethyl
2-dibenzylamino-2-(1-methylindolyl)acetate (4b) (>99%, 41.2 mg) as a colourless oil. 1H NMR (500
MHz, CDCl3) δ: 1.32 (t, J = 7.3 Hz, 3H), 3.67 (d, J = 13.7 Hz, 2H), 3.74 (s, 3H), 3.92 (d, J = 13.7 Hz,
2H), 4.21 (dq, J = 7.2, 10.7 Hz, 1H), 4.34 (dq, J = 7.2, 10.7 Hz, 1H), 4.87 (s, 1H), 7.08-7.12 (m, 3H),
7.20-7.34 (m, 11H), 7.50-7.51 (m, 1H); 13C NMR (126 MHz, CDCl3) δ : 14.5, 32.8, 54.4, 58.6, 60.3,
109.2, 109.5, 119.3, 121.8, 126.8, 127.6, 128.1, 128.8, 129.1, 137.1, 140.0, 172.4; IR (neat) 3439,
2838, 1727, 1640, 1544, 1452, 1370, 1027, 968, 740, 699, 566, 501 cm-1.
6. A typical procedure for the preparation of diethyl 2,2-dimethyl-3-(1-methylindolyl)succinate (6a) is
as
follows:
Under
an
argon
atmosphere,
to
a
solution
of
ethyl
2-dibenzylamino-2-(1-methylindolyl)acetate (4b) (30.5 mg, 0.074 mmol) in CH2Cl2 (1.0 mL) were
added successively a solution of 1-ethoxy-2-methyl-1-trimethylsiloxypropan-1-ene (28.3 mg, 0.148
.
mmol) in CH2Cl2 (1.5 mL) and BF3 Et2O (0.148 ml, 0.148 mmol, 1.0 M in CH2Cl2) at rt. The reaction
mixture was allowed to stand at rt for 5 h. The reaction was quenched with sat. aq. NaHCO3, and the
whole mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by
preparative TLC on silica gel (developed first with EtOAc/n-hexane = 1/4 and then with
CH2Cl2/n-hexane = 1/3) to give diethyl 2,2-dimethyl-3-(1-methylindolyl)succinate (6a) (78%, 18.1
mg) as a colourless oil. 1H NMR (500 MHz, CDCl3) δ: 1.17-1.26 (m, 9H), 1.36 (s, 3H), 3.78 (s, 3H),
4.03-4.19 (m, 4H), 4.42 (s, 1H), 7.09-7.13 (m, 2H), 7.21-7.30 (m, 2H), 7.59-7.61 (m, 1H); 13C NMR
(126 MHz, CDCl3) δ : 14.1, 14.1, 21.2, 25.1, 32.9, 45.7, 48.7, 60.5, 60.7, 107.9, 109.2, 119.2, 119.3,
121.5, 128.4, 129.1, 136.5, 173.3, 177,3; IR (neat) 2948, 1729, 1446, 1216, 1152, 1025, 883, 770,
697, 522, 417 cm-1.