A new approach for the synthesis of 2-substituted indole derivatives via Michael type adducts

Article abstract of DOI:10.1016/j.tet.2005.01.017

4,7-Dihydroindole undergoes regioselective alkylation at the 2-position of the indole nucleus through conjugate addition with α,β-unsaturated carbonyl compounds. The oxidation of the Michael adducts affords the corresponding 2-substituted indole derivatives which were characterized by spectroscopic methods.

Full text of DOI:10.1016/j.tet.2005.01.017

Tetrahedron 61 (2005) 2401–2405
A new approach for the synthesis of 2-substituted indole
derivatives via Michael type adducts
*
˘
¨
Huseyin C¸ avdar and Nurullah Sarac¸oglu
¨
Department of Chemistry, Faculty of Art and Sciences, Ataturk University, Erzurum 25240, Turkey
Received 5 October 2004; revised 4 December 2004; accepted 7 January 2005
Available online 27 January 2005
Abstract—4,7-Dihydroindole undergoes regioselective alkylation at the 2-position of the indole nucleus through conjugate addition with
a,b-unsaturated carbonyl compounds. The oxidation of the Michael adducts affords the corresponding 2-substituted indole derivatives which
were characterized by spectroscopic methods.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
benzoyl group and masking the indole nitrogen as a phenyl
sulfonyl or acyl.
The chemistry of indole is one of the most active areas of
heterocyclic chemistry. The indole moiety remains at the
forefront of biological and medicinal chemistry. The most
ubiquitous of the bioactive alkaloids known are based on the
indole nucleus.1 Since the 3-position of indole is the
preferred site for electrophilic substitution reaction, 3-alkyl
or acyl indoles are versatile intermediates for the synthesis
of a wide range of indole derivatives.2 The simple and direct
method for the synthesis of 3-alkylated indoles involve the
conjugate addition of indoles to a,b-unsaturated com-
pounds. 2-Substituted indoles are also potential inter-
mediates for many alkaloids and pharmacologically
important substances.3 While the methods for the
preparation of 3-substituted indoles are well established,
there is a need for yet easier access to 2-substituted indoles.
Generally restricted methods have been reported for the
preparation of 2-substituted indoles. a-Lithioindoles have
been used to prepare 2-haloindoles and to introduce a
variety of substituents by the reaction with appropriate
electrophiles such as aldehydes, ketones and chloformates.4
Another method for the synthesis of 2-substituted indoles
involves a-palladation at moderate temperature if C-3 is
occupied. The metallated products are allowed to react with
acrylates, other alkenes (Heck reaction) or carbon monoxide
in situ.5 Additionally, 2-methylindoles have been elaborated
into many 2-substituted indole derivatives using an allylic
bromination reaction.6 However, most of these methods
involve protection of the indole 3-position with an ester or
Indole (1) undergoes electrophilic substitution preferen-
tially at b(C3)-position whereas pyrrole (2) gives reaction at
a(C2)-position.7 The positional selectivity in these five-
membered systems is well explained by the stability of the
Wheland intermediates for electrophilic substitution. The
intermediate cations from b- for indole (1) and a- for
pyrrole (2) are the more stabilized. Michael reactions are
one of the most important carbon–carbon bond-forming
reactions in organic synthesis.8,9 We would like to disclose
herein our approach for synthesis of 2-substituted indole
derivatives with Michael type adducts. Our synthetic
strategy is based on a dipole change by transforming the
indole ring into a pyrrole derivative.
2. Results and discussion
Firstly, we carried out Birch reduction reaction of indole
with Li in liquid ammonia, which is a very powerful
reducing system, and which reduces the benzene ring but
not the pyrrole ring to form 4,7-dihydroindole (3) and
4,5,6,7-tetrahydroindole (4) (Scheme 1).10 We obtained a
mixture consisting of 3 and 4 in a 4:1 ratio, which could be
best separated by recrystallization, respectively. Since the
Keywords: Indole; Natural product; Michael reaction; Electrophilic
substitution; Bismuth nitrate; a,b-Unsaturated compound.
* Corresponding author. Tel.: C90 442 2314425; fax: C90 442 2360948;
e-mail: nsarac@atauni.edu.tr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.017

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H. C¸ avdar, N. Sarac¸oglu / Tetrahedron 61 (2005) 2401–2405
2402
reaction of 3 with maleic anhydride (5) in CHCl3 gave
3-(4,7-dihydro-1H-indol-2-yl)-dihydro-furan-2,5-dione (6)
in a 73.5% (Scheme 2). For the next step, we attempted
the aromatization of the cyclohexadiene ring in 6 to obtain
the indole derivative 7. Whereas, the oxidation of 6 with
1 equiv of 1,2-dicyano-4,5-dichloroquinone (DDQ) gave a
complex reaction mixture, the indole derivative 8 was
obtained by reaction of 6 with 2 equiv of DDQ in a 90%.
Similarly, various a,b-unsaturated carbonyl compounds
such as diethyl azodicarboxylate (9), 1,3-diphenyl-prope-
none (10),11 2-cyclohexenone (11)11 and 2-cyclopentenone
(12)11 were reacted with 4,7-dihydroindole (3) in order to
Scheme 1.
reduction products are now pyrrole derivatives, we
investigated the Michael reaction of 4,7-dihydroindole (3)
with a,b-unsaturated carbonyl compounds (Table 1). The
Table 1. Michael addition of 4,7-dihydroindole (3) with some a,b-unsaturated compounds
Entry
Nucleophile
Electrophile
Catalyst
Oxidant
Product
Yield (%)a
5
3
3
8
1
–
90
13
2b
Bi(NO3)3
Bi(NO3)3
Bi(NO3)3
Bi(NO3)3
45
30
49
45
9
10
3
3
3
15
3
11
16
4
12
17
5
a Isolated yield.
b EtO2C–NH–NH–CO2Et (14)12 forms at entry 2.
Scheme 2.

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H. C¸ avdar, N. Sarac¸oglu / Tetrahedron 61 (2005) 2401–2405
2403
synthesize the corresponding indole derivatives. The
3. Experimental
3.1. General methods
Michael acceptors 9–12 failed to react with dihydroindole
3 under the present reaction conditions. Compound 3 was
treated with 1 mol of diethyl azodicarboxylate (9) in the
presence of a catalytic amount of Bi(NO3)39 as mild reagent
in CH2Cl2 to give a mixture of the corresponding Michael
adduct, indole derivative 13, reduction product 1412 of
diethyl azodicarboxylate (9) and the unreacted 3. Therefore,
the dihydroindole 3 reacted with 2 equiv of diethyl azodi-
carboxylate (9) in the presence of Bi(NO3)3 to furnish 13
and 14 in moderate yield. While 1 equiv of the diethyl
azodicarboxylate (9) is used as the Michael acceptor, the
rest serves as oxidation reagent. Next, the indole derivatives
15–17 were synthesized from the reaction of 3 with the
enones 10–12 in the presence of Bi(NO3)3 followed by
the oxidation of these formed Michael adducts with
p-benzoquinone (18) as the oxidation agent.
Solvents were concentrated at reduced pressure. Melting
points were determined on Buchi 539 capillary melting
apparatus and uncorrected. Infrared spectra were obtained
from KBr pellets or film on a Mattson 1000 FT-IR
1
spectrophotometer. H NMR and 13C NMR spectra were
recorded on 200 (50) and 400 (100)-MHz Varian spec-
trometer and are reported in d units with SiMe4 as internal
standard. Elemental analyses were carried out on a Carlo
Erba 1108 model CHNS-O analyser.
3.1.1. Birch reduction reaction of the indole (1). Liquid
ammonia (500 mL) was distilled under N2 into a predried,
three-necked flask. Then, the solution of the indole (1)
(25 g, 0.21 mol) in dry methanole (128 g, 4 mol) was added,
and the resulting solution was cooled to K35G5 8C and
stirred as mechanical. The resulting solution was treated
with Lithium metal (6 g, 0.84 mol) added in small pieces for
5–10 min, which reacted very rapidly. The resulting deep
blue solution was stirred at the same temperature for 60 min
and then the resulting mixture was allowed to warm to rt.
After the excess ammonia had evaporated, Et2O (200 mL),
NH4Cl (5 g) and H2O (300 mL) were carefully added to the
reaction mixture. The layers were separated, the aqueous
layer was extracted with Et2O (2!200 mL), and the
combined organic layers were washed with NaHCO3 (2!
100 mL), dried (MgSO4), filtered, and concentrated. The 1H
NMR of the residue showed that the formation of 3 and 4 in
a 4:1 ratio. The residue (23 g) was recrystallized with
CH2Cl2/hexane to give the dihydroindole 3 (19 g, 75%) as a
colourless crystals, mp: 35–36 8C (lit.10 mp 37–39 8C).
Further the recrystalliztion of the residue furnished the
tetrahydroindole 4 (4.10 g, 16%) as a pale yellow crystals
from hexane; mp 53–54 8C (lit.10 mp 54–55 8C); For 4,7-
dihydro-1H-indole (3): 1H NMR (200 MHz, CDCl3): d 7.70
(m, NH, 1H), 6.72 (t, JZ2.5 Hz, A part of AB system,
]CH, H-2, 1H), 6.07 (t, JZ2.5 Hz, B part of AB system,
]CH, H-3, 1H), 5.95 (bd, JZ10.1 Hz, A part of AB
system, ]CH, H-5 or H-6, 1H), 5.87 (bd, JZ10.1 Hz, B
part of AB system, ]CH, H-5 or H-6, 1H), 3.30 (bs, H-4
and H-7, CH2, 4H); 13C NMR (50 MHz, CDCl3): d 128.00,
127.93, 125.98, 118.28, 115.88, 108.77, 27.01, 26.02; IR
(CH2Cl2, cmK1): 3364, 3018, 2856, 2825, 1651, 1555,
1362, 1324, 1208, 1150, 1085, 958. For 4,5,6,7-tetrahydro-
1H-indole (4): 1H NMR (200 MHz, CDCl3): d 7.72 (m, NH,
1H), 6.66 (t, JZ2.6 Hz, A part of AB system, ]CH, H-2,
1H), 6.03 (t, JZ2.6 Hz, B part of AB system, ]CH, H-3,
The structures of the products were determined by 1H NMR,
13C NMR, IR and elemental analysis. The Michael addition
product 6 was characterized by the presence of NH signals
at d 8.38 ppm, olefinic protons and C3-H in pyrrole ring at
5.88–5.32 ppm (3H), allylic proton at 4.39 ppm (dd, JZ9.4,
7.7 Hz). Furthermore CH2 protons in the anhydride ring
gave rise to a resolved the AB system. While the A part (low
field) of the AB system showed at 3.43 ppm (dd, JZ18.7,
9.4 Hz), the B part of the system and the CH2 protons in the
cyclohexadiene ring coincided at 3.33–3.15 ppm. Notably,
NOE experiments for C3-H in all indole derivatives (8, 13,
15, 16, 17) showed that a NOE between the aromatic C4-H
and C3-H in the five-membered ring but not observed NOE
between the C3-H and the NH protons. Thus, the reaction
of the dihydroindole 3 with the Michael acceptors results in
2-substitution of the indole nucleus. This observed regio-
selectivity shows that the attack of the dihydroindole 3 to
the unsaturated compound occurs at the C-2 position. The
reaction of the dihydroindole 3 with the a,b-unsaturated
compounds probably proceeds through an intermediate 20
as depicted in Scheme 3. In the last step, the oxidation of the
Michael addition products gives the corresponding indole
derivatives.
1H), 2.64–2.55 (m, CH2, 4H), 1.93–1.73 (m, CH2, 4H); 13
C
NMR (50 MHz, CDCl3): d 128.97, 118.90, 117.73, 109.44,
26.02, 25.61, 25.04, 24.88; IR (CH2Cl2, cmK1): 3370, 3093,
2923, 2846, 1673, 1596, 1542, 1442, 1311, 1203, 1133,
1079, 1056, 910, 833.
3.1.2. 3-(4,7-Dihydro-1H-indol-2-yl)-dihydro-furan-2,5-
dione (6). A solution of 4,7-dihydroindole (3) (300 mg,
2.50 mmol) and freshly sublimed maleic anhydride
(247 mg, 2.50 mmol) in 20 mL CHCl3 was stirred at room
temperature for 2 days. After removal of the solvent, the
residue was filtered on a short silica gel column (5 g) eluting
with CHCl3 (200 mL) to give 400 mg (73.5%) of the title
Scheme 3.
In summary, we have developed an efficient strategy to
access 2-substituted indole derivatives starting from indole.
Further applications of this chemistry are currently in
progress.

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H. C¸ avdar, N. Sarac¸oglu / Tetrahedron 61 (2005) 2401–2405
2404
compound 6. The crystallization of the residue from CHCl3/
hexane gave dark yellow powder; mp 145–146 8C: 1H NMR
(200 MHz, CDCl3): d 8.38 (m, NH, 1H), 5.88–5.82 (m,
]CH, pyrrole and cyclohexadiene ring, 3H), 4.39 (dd, JZ
9.4, 7.7 Hz, CH, 1H), 3.43 (dd, JZ18.7, 9.4 Hz, A part of
AB system, CH2, 1H), 3.33–3.15 (m, CH2, 5H); 13C NMR
(50 MHz, CDCl3): d 173.51, 170.95, 128.11, 127.55,
124.56, 123.23, 116.57, 107.16, 41.78, 36.29, 26.65,
25.81; IR (CH2Cl2, cmK1): 3401, 3031, 2861, 2831, 1859,
1774, 1604, 1411, 1272, 1234, 1149, 1072, 1002. Anal.
calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C,
67.03; H, 5.04; N, 6.39.
A solution of 4,7-dihydroindole (3) (300 mg, 2.52 mmol),
1,3-diphenyl-propenone (10) (132 mg, 0.63 mmol) and
Bi(NO3)3 (219 mg, 0.45 mmol) in 2 mL CH2Cl2 was stirred
at room temperature for 16 h. After the solvent was
evaporated, the residue was filtered on a short silica gel
column (5 g) eluting with CH2Cl2 (100 mL). The crude
product (432 mg, 1.32 mmol) and 147 mg (1.32 mmol)
p-benzoquinone were dissolved in CH2Cl2 (20 mL) and
stirred at room temperature for 24 h. Reaction mixture was
diluted with CH2Cl2 (100 mL), and the organic phase was
washed with NaOH (2!50 mL, 10%), washed with water
(2!50 mL) and dried over MgSO4. After removal of the
solvent, the residue was purified on a silica gel column
(50 g) eluting with ethyl acetate/hexane (5%) to give 40 mg
of unreacted 1,3-diphenyl-propenone (10) as the first
fraction. Further elution with ethyl acetate/hexane (5%)
furnished the product 15: (242 mg, 30%) yellow crystals
from CH2Cl2/hexane; mp 124–125 8C; 1H NMR (200 MHz,
CDCl3): d 8.23 (m, NH, 1H), 8.02–7.97 (m, 2H), 7.63–7.50
(m, 4H), 7.48–7.23 (m, 6H), 7.15–7.00 (m, 2H), 6.20 (m,
]CH, H3, 1H), 4.96 (dd, JZ7.7 Hz, 5.5 Hz, CH, 1H), 3.92
(dd, JZ17.7, 7.7 Hz, A part of AB system, CH2, 1H), 3.70
(dd, JZ17.7, 5.5 Hz, B part of AB system, CH2, 1H); 13C
NMR (50 MHz, CDCl3): d 200.56, 144.26, 143.66, 138.80,
138.14, 135.41, 130.81, 130.69, 130.17, 130.12, 129.13,
123.51, 122.07, 121.63, 114.63, 112,62, 101.96, 46.92,
41.76; IR (CH2Cl2, cmK1): 3392, 3046, 2923, 2869, 1684,
1600, 1458, 1346, 1292, 1253, 1223, 992, 753, 700. Anal.
calcd for C23H19NO: C, 84.89; H, 5.89; N, 4.30. Found: C,
85.01; H, 5.74; N, 4.41.
3.1.3. 3-(1H-Indol-2-yl)-furan-2,5-dione (8). To a stirred
solution of 6 (152 mg, 0.71 mmol) in 10 mL of dry benzene
(CAUTION-CARCINOGENIC) was added a solution of
DDQ (355 mg, 1.54 mmol). After the addition was
complete, stirring was continued for 1 h at room tempera-
ture. The solvent was evaporated and residue was filtered on
a short silica gel column (5 g) eluting with CH2Cl2
(100 mL). The residue (148 mg, 99%) was recrystallized
from ethyl acetate/hexane to give 8 as dark brown powder
(135 mg, 90%); mp 223–224 8C: 1H NMR (200 MHz,
CD3COCD3): d 11.00 (m, NH, 1H), 7.71 (d, JZ7.7 Hz, A
part of AB system, 1H), 7.55 (d, JZ1.5 Hz, H-3, 1H), 7.48
(d, JZ7.7 Hz, A part of AB system, 1H), 7.31 (bt, JZ
7.7 Hz, A part of AB system, 1H), 7.12 (s, 1H), 7.11 (d, JZ
7.7 Hz, B part of AB system, 1H); 13C NMR (50 MHz,
CD3COCD3): d 167.61, 167.25, 142.13, 141.26, 131.02,
129.94, 128.94, 125.20, 123.74, 123.45, 121.40, 116.35,
114.76, 114.06; IR (CH2Cl2, cmK1): 3394, 1835, 1766,
1619, 1511, 1411, 1280, 1241, 1141, 910. Anal. calcd for
C12H7NO3: C, 67.61; H, 3.31; N, 6.57. Found: C, 67.04; H,
3.26; N, 6.69.
3.1.6. 3-(1H-Indol-2-yl)-cyclohexanone (16). A solution of
4,7-dihydroindole (3) (100 mg, 0.84 mmol), 2-cyclo-
hexenone (11) (81 mg, 0.84 mmol) and Bi(NO3)3 (73 mg,
0.30 mmol) in 2 mL CH2Cl2 was stirred at room tempera-
ture for 16 h. After the solvent was evaporated, the residue
was filtered on a short silica gel column (5 g) eluting with
CH2Cl2 (100 mL). The crude product (181 mg, 0.82 mmol)
and p-benzoquinone (98 mg, 0.90 mmol) were dissolved in
CH2Cl2 (20 mL) and stirred at room temperature for 24 h.
Reaction mixture was diluted with CH2Cl2 (100 mL), and
the organic phase was washed with NaOH (2!50 mL,
10%), washed with water (2!50 mL) and dried over
MgSO4. After removal of the solvent, the residue was
filtered on a silica gel column (45 g) eluting with ethyl
acetate/hexane (20%) to give 90 mg (49%) as a dark brown
powder which was recrystallized from CH2Cl2/hexane; mp
3.1.4. Reaction of 4,7-dihydroindole (3) diethyl azo-
dicarboxylate (9). A solution of 4,7-dihydroindole (3)
(179 mg, 1.50 mmol), diethyl azodicarboxylate (9)
(502 mg, 3.01 mmol) and Bi(NO3)3 (117 mg, 0.24 mmol)
in 2 mL CH2Cl2 was stirred at room temperature for 16 h.
The residue was filtered on a silica gel column (60 g) eluting
with ethyl acetate/hexane (5%) to give the indole derivative
13, which was crystallized from CH2Cl2/hexane (140 mg,
45%, dark grey powders, mp: 115–116 8C. Further elution
with ethyl acetate/hexane (40%) furnished the product 14:
(140 mg, 40%) colourless powder from CH2Cl2/hexane; mp
119–120 8C (lit.12 mp 128–130 8C); For 13: 1H NMR
(200 MHz, CDCl3): d 9.76 (m, NH, 1H), 7.51 (bd, JZ
6.6 Hz, 1H), 7.31 (bd, JZ7.7 Hz, 1H), 7.26–7.06 (m, 2H),
6.12 (m, ]CH, H-3, 1H), 4.37–4.15 (m, CH2, 4H), 1.36–
1.17 (m, CH3, 6H); 13C NMR (50 MHz, CDCl3): d 157.75,
156.08, 135.26, 129.07, 123.36, 123.22, 122.11, 121.91,
121.83, 112.86, 65.64, 64.70, 16.38 (2C); IR (CH2Cl2,
cmK1): 3324, 3062, 2993, 2931, 1720, 1627, 1604, 1558,
1465, 1380, 1319, 1249, 1172, 1072, 1010. Anal. calcd for
C14H17N3O4: C, 57.72; H, 5.88; N, 14.42. Found: C, 57.56;
1
148–149 8C; H NMR (200 MHz, CDCl3): d 8.10 (m, NH,
1H), 7.56 (bd, JZ6.5 Hz, 1H), 7.32 (bd, JZ8.0 Hz, 1H),
7.20–7.05 (m, 2H), 6.28 (bs, ]CH, H3, 1H), 3.26 (pentet,
JZ4.8 Hz, CH, 1H), 2.85–1.75 (m, CH2, 8H); 13C NMR
(50 MHz, CDCl3): d 212.26, 143.32, 137.84, 130.35,
123.66, 122.19, 121.90, 112.57, 100.86, 49.06, 43.28,
39.73, 33.23, 26.67; IR (CH2Cl2, cmK1): 3340, 3054,
2939, 2861, 1704, 1643, 1596, 1550, 1457, 1419, 1349,
1311, 1234, 1172, 1141. Anal. calcd for C14H15NO: C,
78.84; H, 7.09; N, 6.57. Found: C, 79.01; H, 6.97; N, 6.71.
1
H, 5.97; N, 14.30. For 14: H NMR (200 MHz, CDCl3): d
6.62 (m, NH, 2H), 4.20 (q, JZ7.1 Hz, OCH2, 4H), 1.27 (t,
JZ7.1 Hz, CH3, 6H); 13C NMR (50 MHz, CDCl3): d
158.73, 64.25, 16.39; IR (CH2Cl2, cmK1): 3301, 2993,
1712, 1519, 1380, 1326, 1241, 1072.
3.1.7. 3-(1H-Indol-2-yl)-cyclopentanone (17). A solution
of 4,7-dihydroindole (3) (200 mg, 1.68 mmol), 2-cyclo-
pentenone (12) (146 mg, 1.68 mmol) and Bi(NO3)3
(146 mg, 0.37 mmol) in 2 mL CH2Cl2 was stirred at room
temperature for 16 h. After the solvent was evaporated, the
3.1.5. 3-(1H-Indol-2-yl)-1,3-diphenyl-propan-1-one (15).

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H. C¸ avdar, N. Sarac¸oglu / Tetrahedron 61 (2005) 2401–2405
2405
3. (a) Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.; Bornmann,
W. G. J. Org. Chem. 1987, 52, 347. (b) Hashimoto, C.;
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residue was filtered on a short silica gel column (5 g) eluting
with CH2Cl2 (100 mL). The crude product (350 mg,
1.74 mmol) and p-benzoquinone (206 mg, 1.91 mmol)
were dissolved in CH2Cl2 (20 mL) and stirred at room
temperature for 24 h. Reaction mixture was diluted with
CH2Cl2 (100 mL), and the organic phase was washed with
NaOH (2!50 mL, 10%), washed with water (2!50 mL)
and dried over MgSO4. After removal of the solvent, the
residue was filtered on a silica gel column (45 g) eluting
with ethyl acetate/hexane (20%) gave 150 mg (45%) as a
dark brown powder which was recrystallized from CH2Cl2/
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1
hexane; mp 100–101 8C; H NMR (200 MHz, CDCl3): d
8.21 (bs, NH, 1H), 7.58 (bd, JZ8.2 Hz, 1H), 7.33 (bd, JZ
7.4 Hz, 1H), 7.23–7.08 (m, 2H), 6.30 (bs, ]CH, H3, 1H),
3.59–3.51 (m, CH, 1H), 2.77–2.05 (m, CH2, 6H); 13C NMR
(50 MHz, CDCl3): d 219.82, 142.69, 138.18, 130.34,
123.71, 122.19, 121.96, 112.59, 100.78, 46.56, 40.00,
37.58, 31.54; IR (CH2Cl2, cmK1): 3384, 3061, 2961,
2906, 1738, 1630, 1461, 1407, 1300, 1246, 1153, 1015.
Anal. calcd for C13H13NO: C, 78.36; H, 6.58; N 7.03.
Found: C, 78.48; H, 6.44; 6.90.
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68, 4594.
Acknowledgements
The authors are indebted to the Department of Chemistry
and Atatu¨rk University for financial support.
References and notes
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