Synthesis of new melatonin analogues from dimers of azaindole and indole by use of Suzuki homocoupling

Article abstract of DOI:10.3987/COM-02-9695

N-{2-[3′-(2-Acetylaminoethyl)-1H,1′H-[5,5′]biindol-3-yl]- and N-{2-[1′-(2-acetylaminoethyl)-1′H-[5, 5′]biindol-1-yl]ethyl}acetamide (2,3) and their analogues in 7-azaindole series (4,5) were synthesized by palladium catalysed reaction starting from indole or 7-azaindole using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium, as catalyst.

Full text of DOI:10.3987/COM-02-9695

HETEROCYCLES, Vol. 60, No. 4, 2003, pp. 865 - 877
Received, 18th December, 2002, Accepted, 6th February, 2003, Published online, 10th February, 2003
SYNTHESIS OF NEW MELATONIN ANALOGUES FROM DIMERS OF
AZAINDOLE AND INDOLE BY USE OF SUZUKI HOMOCOUPLING
Jérôme Guillard, Carlos Larraya, and Marie-Claude Viaud-Massuard*
EA 3247 GRCHT Laboratoire de Chimie Organique, UFR des Sciences Pharmaceutiques, Université de
Tours, 31 Avenue de Monge, 37200 Tours - France. Phone : 33 247 36 72 27 ; Fax : 33 247 36 72 29 ;
E-mail : mcviaud@univ-tours.fr
Abstract-
N-{2-[3’-(2-Acetylaminoethyl)-1H,1’H-[5,5’]biindol-3-yl]-
and
N-{2-[1’-(2-
acetylaminoethyl)-1’H-[5,5’]biindol-1-yl]ethyl}acetamide (2,3) and their analogues in 7-azaindole
series (4,5) were synthesized by palladium catalysed reaction starting from indole or 7-azaindole
using [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium, as catalyst.
Melatonin (1), a pineal hormone, plays a major role in the regulation of seasonal cycles and the control of
1,2
3
circadian rhythms and has been the focus of considerable clinical interest. Two human melatonin
4,5
6
receptors have been cloned and defined as MT1 and MT2 receptors. These two receptors belong to the
family of seven-transmembrane domain G-protein-coupled receptors. Both receptors have similar binding
for melatonin and display similar rank orders for the binding of reference melatonin ligands despite 60%
homology between the two receptors. The synthesis of selective melatonin analogues is still a challenge,
it is why our attention has been focused on developing a catalytic approach to dimers of indoles (2,3) and
7-azaindoles (4,5) (Figure 1).
Figure 1
NHAc
R4
MeO
N
N
R3
H
1
R5
2
R2=R4= H and R3=R5= (CH2)2NHAc
R3=R5 = H and R2=R4= (CH2)2NHAc
R4
N
3
N
N
R2
R3
4
5
R2 = R4 = Me and R3=R5= (CH2)2NHAc
R3 = R5 = Me and R2=R4= (CH2)2NHAc
R5
N
N
R2
Palladium catalysed cross-coupling between aryl boronic acids and haloarenes or aryl triflates has been
7
8
shown to be a versatile method for the preparation of biaryls. Suzuki et al. recently reported the
preparation of cis-diborylalkene via its transition metal catalysed addition with tetraalkoxydiboron (6).
Moreover the alkoxydiboron (6) which is thermally stable and easily handled in air, has been shown to be

9,10
a useful boron nucleophile for the cross or homocoupling reaction with aryl halides.
Thus we have used this method for a one-pot preparation of symmetrical bi-indoles and bi-azaindoles via
a modified in situ Suzuki homocoupling reaction.
RESULTS AND DISCUSSION
Synthesis of N-{2-[ 3’-(2-acetylaminoethyl)-1H,1’H-[5,5’]biindol-3-yl]ethyl}acetamide (2)
The synthesis of 5-bromo-3-(N,N-dimethylamino)methylindole (7) was accomplished via Mannich’s
11
reaction with 5-bromoindole in the presence of formaldehyde and dimethylamine in acetic acid. Next,
treatment of 7 with methyl iodide in THF followed by a nucleophilic substitution with potassium cyanide
12
afforded the nitrile (8) in 52% overall yield from 5-bromoindole (Scheme 1).
Scheme 1
Br
+
CH2O 1.23 M
Me2NH
MeI, THF
rt, 12 h
Br
Br
NMe2
NMe3
I
N
CH3COOH
rt, 12 h
N
H
N
H
H
7
KCN, H2O
Br
CN
80°C, 12 h
N
52% for 3 steps
H
8
The homocoupling of (5-bromo-1H-indol-3-yl)acetonitrile (8) using borane (9) generated in situ gave the
corresponding dimer (10) in 53% yield, which was converted to the final compound (2) after
hydrogenation over Raney nickel and concomitant N-acetylation in 67% overall yield from 10
(Scheme 2).
Scheme 2
Me
Me
Me
Me
O
O
O
B
Me
Me
O
B
Me
Me
Me
Me
O
CN
6
Br
Me
Me
CN
PdCl2(dppf), KOAc
DMF, 2 h
B
O
N
N
H
H
8
9
H
N
8, PdCl2(dppf)
Na2CO3 2M
CN
NC
53% for 2 steps
N
10
H
H
H2, Ni Raney
N
Ac2O, AcONa, 60°C, 4 h
67%
NHAc
AcNH
2
N
H

Synthesis of N-{2-[ 1’-(2-acetylaminoethyl)-1’H-[5,5’]biindol-1-yl]ethyl}acetamide (3)
The reaction of 5-bromoindole with sodium hydride followed by an addition of bromoacetonitrile
provided 11 in 73% yield. Using the method described above, dimer (12) was prepared in 2 steps from 10
in 37 % yield ; the nitrile group was then reduced to acetamide on Raney nickel in acetic anhydride to
give dimer (3) with a moderate yield (70%) (Scheme 3).
Scheme 3
Br
Br
BrCH2CN, NaH
DMF, rt, 15 h
N
H
N
73%
CN
11
CN
1) 6, PdCl2(dppf)
(CH2)2NHAc
KOAc, DMF, 2 h
2) 11, PdCl2(dppf)
Na2CO3, 2M
N
N
H2 (40 psi), Ni Raney
Ac2O, AcONa
rt, 18 h
37% within 2 steps
70%
12
N
3
N
(CH2)2NHAc
CN
Synthesis of N-{2-[ 3’-(2-acetylaminoethyl)-1,1’-dimethyl-1H,1’H-[5,5’]bi[pyrrolo[2,3-b]pyridin]-3-
yl]ethyl}acetamide (4)
The required 5-bromo-7-azaindole (15) was prepared in 4 steps from 7-azaindole. The first step involved
bromination with bromine in a mixture of t-butanol and water at room temperature to provide the
tribromo derivative (13) (85%). 3,3,5-Tribromo-2-oxo-1,3-dihydropyrrolo[2,3-d]pyridine (13) was then
13
treated with zinc in acetic acid to give 14 in 94% yield. Reduction of the amide function was realised
with the borane-tetrahydrofuran complex. The resulting indoline was oxidised by heating in acetic acid in
the presence of manganese triacetate to provide 7-azaindole (15) in a 50% overall yield (Scheme 4).
Scheme 4
Br
Br
Br2, t-BuOH
H2O, rt
Br
Zn, AcOH
rt
Br
N
N
94%
85%
N
O
N
N
N
O
H
H
H
13
14
1) BH3-THF, THF
0°C to rt
2) Mn(OAC)3, 2H2O
AcOH 75°C
Br
N
N
H
50%
15
Treatment of 15 with methyl iodide in the presence of sodium hydride in N,N-dimethylformamide lead to
product (16) in good yield (85%) which then underwent the modified Suzuki’s homocoupling described
above to give the corresponding dimer (17) in good yield (83%) (Scheme 5).

Scheme 5
Me
N
1) 6, PdCl2(dppf)
KOAc, DMF, 2 h
2) 16, PdCl2(dppf)
Na2CO3, 2M
N
Br
Br
MeI, NaH
DMF, rt, 3 h
N
N
N
N
83%
85%
H
15
16
Me
17
N
N
Me
14
According to the C-3 formylation of the indole ring descrided in the literature, we have also introduced
a formyl group regioselectively at the C-3 position of compound (18) under Vilsmeier-Haack conditions.
Subsequent chemical modifications converted the formyl group into N-ethylacetamide side chain. Indeed,
reaction of aldehyde (18) with ammonium acetate in nitromethane led to a nitrovinylic derivative.
Treatment of the latter one with sodium borohydride and silica gel in a mixture of chloroform and
2-propanol furnished the corresponding nitro compound. Next the amido group was obtained by catalytic
hydrogenation on Raney nickel in methanol followed by acetylation using acetic anhydride and pyridine
in dichloromethane. The expected amide (4) was prepared in 17% overall yield (Scheme 6).
Scheme 6
Me
Me
N
N
N
N
POCl3, DMF
98%
CHO
OHC
17
N
N
18
N
N
Me
Me
Me
1) MeNO2, AcONH4, 120°C, 4 h
2) i-PrOH, CHCl3, SiO2, NaBH4, rt, 20 min
3) MeOH, Ni Raney, H2 (40 psi), 60°C, 12 h
4) Ac2O, CH2Cl2, Pyridine
N
N
NHAc
17% within 4 steps
AcNH
N
N
4
Me
Synthesis of N-{2-[1’-(2-acetylaminoethyl)-1’H-[5,5’]bi[pyrrolo[2,3-b]pyridin]-1-yl]ethyl}acetamide
(5)
Compound (5) was prepared according to the synthetic sequence illustrated in Scheme 7. The first step
involved a reaction of 15 with sodium hydride followed by addition of bromoacetonitrile to generate
compound (19) in 55% yield. Homocoupling using tetra-alkoxydiboron (6) provided the corresponding
dimer (20). The reduction of the nitrile group using hydrogen on Raney nickel in acetic anhydride
afforded the desired dimer (5) in 31% yield. Low yield of the last step is explained by difficulties
encountered during the purification.

Scheme 7
Br
Br
BrCH2CN, NaH
DMF, rt, 15 h
N
N
55%
N
N
H
15
19
CN
CN
(CH2)2NHAc
1) 6, PdCl2(dppf)
KOAc, DMF, 2 h
2) 18, PdCl2(dppf)
Na2CO3, 2M
H2 (40 psi), Ni Raney
Ac2O, AcONa
60°C, 12 h
N
N
N
N
31%
61%
20
N
N
N
N
5
(CH2)2NHAc
CN
In conclusion, this paper reports the synthesis of an analogue of melatonin which possess an 7-azaindole
or an indole skeleton. As a result of these syntheses, we have developed several new procedures allowing
access to the dimers using a modified in situ Suzuki homocoupling.
EXPERIMENTAL
Melting points are uncorrected. 1H-NMR and 13C-NMR spectra were recorded on a Bruker AM-300 WB
(300 MHz). The coupling constants are recorded in Hz and the chemical shifts are reported in ppm
(δ, ppm) downfield from TMS which was used a internal standard. IR spectra were obtained with a
Perkin-Elmer FT Paragon 1000 PC. MS spectra were registered on a Perkin-Elmer SCIEX API 3000
spectrometer. Reaction products were purified by flash chromatography using silica gel (Merck 230-400
mesh). Analytical TLC was carried out on silica gel F254 plates. All anhydrous reactions were performed
in oven-dried glassware under an atmosphere of argon. Anhydrous solvents were transferred via syringe.
5-(Bromo-1H-indol-3-yl)acetonitrile (8)
Dimethylamine (2.12 mL, 16.83 mmol) and formaldehyde (13.70 mL 1.23 M solution, 16.83 mmol) were
respectively added to a solution of acetic acid at 5°C. The mixture was stirred an additional time (5 min)
with continued cooling. After, the 5-bromoindole (3 g, 15.30 mmol) was added and the mixture was
stirred for 12 h, allowing the temperature to increase slowly at room rt. After cooling at 0°C, the mixture
was basified using 10% sodium hydroxide solution (16 mL). The white precipitate that separated was
filtered under vacuum and dried. The product (7) without purification, was then taken up in THF (50 mL)
under an inert atmosphere and methyl iodide (2.4 g, 16.83 mmol) was added at 0°C. The solution which
resulted was stirred at rt for 12 h. The solvent was removed in vacuo and the crude residue was taken up
in 5% aqueous sodium hydroxide (30 mL) and potassuim cyanid (9.94 g, 153 mmol) was added. The
mixture was heated slowly at 80°C during 12 h, cooled at rt and then extracted with ethyl acetate. The

combined organic extracts were dried over anhydrous MgSO , filtered and concentrated in vacuo. The
4
residue was purified by flash chromatography on silica gel (eluent : light petroleum/ethyl acetate, 1/1) to
-1
give compound (8) (1.86 g, 52% within 3 steps) as a colourless oil : IR (film) ν : 3377, 2915, 2249 cm .
1H-NMR (CDCl3) δ : 3.72 (s, 2H, CH2CN), 7.11 (d, 1H, J = 2.2 Hz, H2), 7.20 (d, 1H, J =8.7 Hz, H7), 7.28
(dd, 1H, J = 8.7 Hz, J = 1.7 Hz, H6), 7.67 (d, 1H, J = 1.7 Hz, H4), 8.52 (s, 1H, NH). 13C-NMR (CDCl3) δ :
14.6 (CH2CN), 104.3 (C3), 113.6 (C2), 118.6 (Cq), 121.0 (CH), 121.1 (Cq), 124.7 (CH), 126.1 (CH),
79
81
128.0 (C7a), 135.3 (C5). MS (IS) m/z : 235 (M+1 for Br) m/z = 237 (M+1 for Br). Anal. Calcd for
C H N Br : C, 51.09 ; H, 3.00 ; N, 11.92 ; Br, 33.99. Found : C,51.06 ; H,2.98 ; N,11.89 ; Br, 33.95.
10 7 2
(3’-Cyanomethyl-1H,1’H-[5,5’]biindol-3-yl)acetonitrile (10)
Under an inert atmosphere, bis(pinacolato)diborane (6) (0.32 g, 1.27 mmol), potassium acetate (0.25 g,
2.55 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.07 g, 0.01 mmol) were
added to a stirred solution of 7 (0.2 g , 0.85 mmol) in dry DMF (5 mL). The mixture was stirred at 80°C
under nitrogen for
2
h. After cooling the solution to rt,
8
(0.4 g, 1.7 mmol),
[1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.07 g, 0.01 mmol) and 2 M Na CO (2.25
2
3
mL, 4.25 mmol) were added and the mixture was stirred at 80°C under nitrogen overnight. The solution
was cooled to rt, the product was extracted with dichloromethane (15 mL) and washed with water (15
mL), brine and dried over anhydrous MgSO . Finally, purification by flash chromatography on silica gel
4
using 40% ethyl acetate in light petroleum as eluent gave 140 mg (53%) of (3’-cyanomethyl-1H,1’H-
[5,5’]biindol-3-yl)acetonitrile (10) as white needles. mp 206-207°C (pentane). IR (KBr) ν : 3405, 2918,
1
-1
2250 cm . H-NMR (CDCl3) δ : 3.87 (s, 4H, CH2CN), 7.23 (s, 2H, H2), 7.44 (d, 2H, J = 8.5 Hz, H7),
7.54 (dd, 2H, J = 8.5 Hz, J =1.4 Hz, H6), 7.77 (d, 2H, J = 1.4 Hz, H4), 8.41 (s, 2H, NH). 13C-NMR
(CDCl3) δ : 14.4 (2xCH2CN), 103.3 (2xC3), 111.8 (2xC2), 118.3 (2xCH), 120.3 (2xCN), 123.2 (2xCH),
123.7 (2xCH), 126.5 (2xCq), 134.7 (2xCq), 135.4 (2xCq). MS (IS) m/z = 311 (M+1). Anal. Calcd for
C H N : C, 77.40 ; H, 4.55 ; N, 18.05. Found : C,77.61 ; H,4.58 ; N, 18.12.
20 14 4
N-{2-[ 3’-(2-Acetylaminoethyl)-1H,1’H-[5,5’]biindol-3-yl]ethyl}acetamide (2)
A solution of compound (10) (0.12 g, 0.39 mmol) in acetic anhydride (30 mL) was hydrogenated over
Raney nickel (0.01 g) in the presence of sodium acetate (0.13 g, 1.56 mmol) for 4 h at 60°C. The reaction
was cooled to rt and the catalyst was filtered on Celite and the filtrate concentrated in vacuo. The residue
was taken up in dichloromethane, washed with water and dried over anhydrous MgSO . After removal of
4
the solvent, the crude residue was chromatographed over silica gel (eluent : ethyl acetate/methanol : 9/1)
to afford 2 (0.105 g, 67%) as a white solid. mp 237-238°C (pentane). IR (KBr) ν : 3406, 3260, 2925,
1
-1
1629 cm . H-NMR (CD3OD) δ : 1.91 (s, 6H, COCH3), 2.99 (t, 4H, J = 7.2 Hz, H1’), 3.51 (t, 4H,
J = 7.2 Hz, H2’), 7.09 (s, 2H, H2), 7.38 (d, 2H, J = 8.2 Hz, H7), 7.44 (dd, 2H, J = 8.2 Hz, J = 1.5 Hz, H6),

13
7.79 (d, 2H, J = 1.5 Hz, H4). C-NMR (CD3OD) δ : 21.2 (2xCOCH3), 24.9 (2xC1’), 40.4 (2xC2’), 110.9
(2xC2), 112.2 (2xC3), 116.1 (2xC7), 121.6 (2xCH), 122.5 (2xCH), 127.9 (2xCq), 133.7 (2xCq), 135.9
(2xCq), 171.9 (2xCO). MS (IS) m/z = 403 (M+1). Anal. Calcd for C H N : C, 83.50 ; H, 7.64 ; N,
22 24 2
8.85. Found : C, 83.8 ; H, 7.58 ; N, 8.83.
(5-Bromoindo-1-yl)acetonitrile (11)
Under an inert atmosphere, sodium hydride (60% in oil, 0.18 g, 7.65 mmol) was added to a stirred
solution of 5-bromoindole (1 g, 5.10 mmol) in N,N-dimethylformamide 99.8% (25 mL) at 0°C during 30
min. The addition was finished, the mixture was stirred an additional time (30 min) under continued
cooling. After, the bromoacetonitrile (1.22 mL, 10.20 mmol) was added dropwise and the mixture was
stirred for 12 h, allowing the temperature to increase at rt. Then water was added, the product was
extracted with dichloromethane, purified by flash chromatography on silica gel (eluent : light
petroleum/ethyl acetate : 85/15) to give compound (11) (0.78 g, 65%) as yellow solid. mp 94-95°C
1
-1
(pentane). IR (KBr) ν : 2967, 2258 cm . H-NMR (CDCl3) δ : 4.97 (s, 2H, CH2CN), 6.55 (dd, 1H, J = 3.5
Hz, J = 0.2 Hz, H3), 7.09 (d, 1H, J = 3.5 Hz, H2), 7.23 (d, 1H, J = 8.5 Hz, H7), 7.39 (dd, 1H, J = 8.5 Hz, J =
13
1.7 Hz, H6), 7.78 (d, 1H, J = 1.7 Hz, H4). C-NMR (CDCl3) δ : 34.8 (CH2CN), 104.1 (C3), 110.6 (C2),
114.4 (Cq), 114.6 (Cq), 124.5 (CH), 126.2 (CH), 128.7 (CH), 131 (Cq), 134.8 (Cq). MS (IS) m/z = 235
(M+1, for 79Br), m/z = 237 (M+1, for 81Br). Anal. Calcd for C H N Br : C, 51.09 ; H, 3.00 ; N, 11.92 ;
10 7 2
Br, 33.99. Found : C, 51.20 ; H, 2.98 ; N,11.90 ; Br, 34.01.
(1’-Cyanomethyl-1’H-[5,5’]biindol-1-yl)acetonitrile (12)
Under an inert atmosphere, bis(pinacolato)diborane (6) (0.32 g, 1.27 mmol), potassium acetate (0.25 g,
2.55 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.07 g, 0.01 mmol) were
added to a stirred solution of 11 (0.2 g , 0.85 mmol) in dry DMF (5 mL). The mixture was stirred at 80°C
under nitrogen for
2
h. After cooling the solution to rt, 11 (0.4 g, 1.7 mmol),
[1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.07 g, 0.01 mmol) and 2 M Na CO (2.25
2
3
mL, 4.25 mmol) were added and the mixture was stirred at 80°C, under nitrogen overnight. The solution
was cooled to rt, the product was extracted with dichloromethane (15 mL) and washed with water (15
mL), brine and dried over anhydrous MgSO . Finally, purification by flash chromatography on silica gel
4
using 30% ethyl acetate in light petroleum as eluent gave 140 mg (53%) of (1’-cyanomethyl-1’H-
[5,5’]biindol-1-yl)acetonitrile (12) as white needles. mp 201-202°C (pentane). IR (KBr) ν : 2913, 2252
1
cm-1. H-NMR (DMSO-d6) δ : 5.55 (s, 4H, CH2CN), 6.59 (d, 2H, J = 3.2 Hz, H3),7.44(d,2H, J = 3.2 Hz,
H2), 7.56 (dd, 2H, J = 8.7 Hz, J = 1.7 Hz, H6), 7.65 (d, 2H, J = 8.7 Hz, H7), 7.85 (d, 2H, J = 1.7 Hz, H4).
13C (DMSO-d6) δ : 34.4 (2xCH2CN), 103.8 (2xC3), 110.9 (2xC2), 117.5 (2xCq), 119.8 (2xC7), 122.7

(2xCH), 129.9 (2xCH), 130.1 (2xCq), 134.8 (2xCq), 135.7 (2xCq). MS (IS) m/z = 311 (M+1). Anal. Calcd
for C H N : C, 77.40 ; H, 4.55 ; N, 18.05. Found : C, 77.86 ; H, 4.62 ; N, 18.20.
20 14 4
N-{2-[ 1’-(2-Acetylaminoethyl)-1’H-[5,5’]biindol-1-yl]ethyl}acetamide (3)
A solution of compound (12) (0.12 g, 0.39 mmol) in acetic anhydride (30 mL) was hydrogenated (40 psi)
over Raney nickel (0.01 g) in the presence of sodium acetate (0.13 g, 1.56 mmol) for 4 h at 60°C. The
reaction was cooled to rt and the catalyst was filtered on Celite and the filtrate concentrated in vacuo. The
residue was taken up in dichloromethane, washed with water and dried over anhydrous MgSO . After
4
removal of the solvent, the crude residue was chromatographed over silica gel (eluent : ethyl
acetate/methanol : 9/1) to afford 3 (0.11 g, 70%) as a white solid. mp 236-237°C (pentane). IR (KBr)
1
ν : 3273, 2929, 1637 cm-1. H-NMR (DMSO-d6) δ : 1.77 (s, 6H, COCH3), 3.40 (t, 4H, J = 6.2 Hz, H2’),
4.24 (t, 4H, J = 6.2 Hz, H1’), 6.47 (d, 2H, J = 3.4 Hz, H3), 7.33 (d, 2H, J = 3.4 Hz, H2), 7.45 (dd, 2H,
J = 8.5 Hz, J = 1.5 Hz, H6), 7.51 (d, 2H, J = 8.5 Hz, H7), 7.78 (d, 2H, J = 1.5 Hz, H4), 7.99 (t, 2H,
13
J = 5.3 Hz, NHAc). C (DMSO-d6) δ : 23.4 (2xCOCH3), 40 (2xC1’), 45.8 (2xC2’), 100.8 (2xC3), 110.7
(2xC2), 119.2 (2C4), 121.7 (2xC6) 129.8 (2xCH), 130.1 (2xC7a), 134.7 (2xCq), 135.8 (2xCq), 170.3
(2xCO). MS (IS) m/z = 403 (M+1). ). Anal. Calcd for C H N O : C, 71.62 ; H, 6.51 ; N, 13.92. Found :
24 26 4 2
C, 71.34 ; H, 6.66 ; N, 13.68.
5-Bromo-1H-pyrrolo[2,3-b]pyridine (15)
Under an inert atmosphere, a solution of borane-tetrahydrofuran complex (37.6 mL, 1 M solution in THF,
37.6 mmol) was added dropwise to a suspension of 5-bromo-1,3-dihydro-2-oxopyrrolo[2,3-b]pyridine
11
(14) (2.00 g, 9.4 mmol) in dry THF (30 mL) at 0°C. After all complex was added, the mixture was
stirred an additional time (35 min) at rt. The solvent was then removed under reduced pressure. The
residue was dilued with a solution of hydrochloric acid (20 mL, 6 M) and heated until the complete
dissolution of the solid. After cooling at 10°C, the mixture was basified using 10% sodium hydroxide
solution until pH = 9 and extracted with ethyl acetate. The combined extracts were dried over anhydrous
MgSO . Removal of the solvent in vacuo, the product was dissolved in acetic acid (20 mL) and the
4
resulting solution was added to a suspension of manganese triacetate (4.1 g, 15.28 mmol) in acetic acid
(20 mL). After, the mixture was heated at 75°C for 45 min and the solvent was removed under reduced
pressure. The crude was taken up in water, basified with saturated hydrogenocarbonate solution and
extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO . Removal of the
4
solvent in vacuo, the product was purified by flash chromatography on silica gel (eluent : light
petroleum/ethyl acetate : 8/2) to afford compound (15) (0.92 g, 50% within 2 steps) as a yellow solid. mp
1
176-177°C (pentane). IR (KBr) ν : 3300-3000 cm-1. H-NMR (CDCl3) δ : 6.39 (d, 1H, J= 2.9 Hz, H3),
7.30 (d, 1H, J = 2.9 Hz, H2), 8.01 (d, 1H, J = 2.2 Hz, H4), 8.29 (d, 1H, J = 2.2 Hz, H6), 10.9 (s, 1H, NH).

13C-NMR (CDCl3) δ : 100 (C3), 111. 1 (Cq), 121.9 (Cq), 126.5 (CH), 130.9 (CH), 142.4 (CH), 146.6
(Cq). MS (IS) m/z = 198 (M+1). Anal. Calcd for C H N Br : C, 42.67 ; H, 2.56 ; N, 14.22 ; Br, 40.55.
7 5 2
Found : C, 42.81 ; H, 2.55 ; N, 14.48 ; Br, 40.49.
5-Bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (16)
Under an inert atmosphere, sodium hydride (60% in oil, 0.36 g, 15.23 mmol) was added to a stirred
solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15) (2.00 g, 10.15 mmol) in N,N-dimethylformamide
(75 mL) at 0°C for 30 min. Then the mixture was stirred an additional time (30 min) under continued
cooling. Then methyl iodide (2.16 g, 15.23 mmol) was added dropwise and the mixture was stirred for
12 h, allowing the temperature to increase at rt. Then, water was added and the product was extracted
with dichloromethane, purified by flash chromatography on silica gel (eluent : light petroleum/ethyl
acetate : 9/1) to give 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (16) (1.37 g, 63%) as yellow oil. IR
(film) ν : 1590 cm-1. 1H-NMR (CDCl3) δ : 3.73 (s, 3H, NCH3), 6.25 (d, 1H, J = 3.4 Hz, H3), 7.05 (d, 1H,
13
J = 3.4 Hz, H2), 7.86 (d, 1H, J = 2.0 Hz, H4), 8.26 (d, 1H, J = 2.0 Hz, H6). C-NMR (CDCl3) δ : 31.7
(NCH3), 99.2 (C3), 111.9 (Cq), 122.3 (Cq), 130.8 (CH), 130.9 (CH), 143.5 (CH), 146.4 (Cq). MS (IS) m/z
79
81
= 211 (M+1 for Br), m/z = 213 (M+1 for Br). Anal. Calcd for C H N Br : C, 45.53 ; H, 3.34 ; N,
8 7 2
13.27; Br, 37.86. Found : C, 45.89 ; H, 3.20 ; N, 13.39; Br, 37.78.
1,1’-Dimethyl-1H,1’H-[5,5’]bi[pyrrolo[2,3-b]pyridinyl] (17)
Under an inert atmosphere, bis(pinacolato)diborane (6) (0.58 g, 2.27 mmol), potassium acetate (0.56 g,
5.68 mmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.15 g, 0.19 mmol) were
added to a stirred solution of 16 (0.4 g , 1.89 mmol) in dry DMF (5 mL). The mixture was stirred at 80°C
under nitrogen for 2 h. After cooling the solution to rt, 16 (0.8 g, 3.78 mmol), [1,1’-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.15 g, 0.19 mmol) and 2 M Na CO (4.72 mL,
2
3
9.45 mmol) were added and the mixture was stirred at 80°C, under nitrogen for 12 h. The solution was
cooled to rt, the product was extracted with dichloromethane (15 mL) and washed with water (15 mL),
brine and dried over anhydrous MgSO . Finally, purification by flash chromatography on silica gel using
4
ethyl acetate as eluent gave 0.41 g (83%) of 1,1’-dimethyl-1H,1’H-[5,5’]bi[pyrrolo[2,3-b]pyridinyl] (17)
as colourless oil. IR (film) ν : 1596 cm-1. 1H-NMR (CDCl3) δ : 3.94 (s, 6H, NCH3), 6.51 (d, 2H, J = 3.4
13
Hz, H3), 7.21 (d, 2H, J = 3.4 Hz, H2), 8.10 (d, 2H, J = 2 Hz, H4), 8.59 (d, 2H, J = 2 Hz, H6). C-NMR
(CDCl3) δ : 31.7 (2xNCH3), 99.9 (2xC3), 121.4 (2xCq), 127.9 (2xCH), 128.2 (2xCq), 130.2 (2xCH),
142.9 (2xCH), 147.6 (2xCq). MS (IS) m/z = 263 (M+1). Anal. Calcd for C H N : C, 73.26 ; H, 5.38 ;
16 14 4
N, 21.36. Found : C, 73.48 ; H, 5.40 ; N, 21.51.
1,1’-Dimethyl-1H,1’H-[5,5’]bi[pyrrolo[2,3-b]pyridinyl]-3,3’-dicarbaldehyde (18)

Under an inert atmosphere, phosphorus oxychloride (2.99 mL, 32.1 mmol) was added to
N,N-dimethylformamide (40 mL) at 0°C. After 10 min of stirring, a solution of compound (17) (0.42 g,
1.6 mmol) in N,N-dimethylformamide (5 mL) was added. The reaction was stirred for 30 min at 0°C,
then heated at rt during 3 h. Then the solvent was removed under reduced pressure and the residue diluted
with water. After extraction with ethyl acetate, the organic layers were dried over anhydrous MgSO and
4
evaporated in vacuo. The crude mixture was purified by flash chromatography (eluent: ethyl acetate) to
1
provide 18 (0.5 g, 98%) as a white solid. mp > 245 °C (pentane). IR (KBr) ν : 1655 cm-1. H-NMR
(CDCl3) δ : 4.02 (s, 6H, NCH3), 7.91 (s, 2H, H2), 8.69 (d, 2H, J = 2.0 Hz, H4), 8.80 (d, 2H, J = 2.0 Hz,
H6), 10.12 (s, 1H, CHO). 13C-NMR (CDCl3) δ : 32.6 (2xNCH3), 116.7 (2xCq), 118.1 (2xCq), 129.7
(2xCH), 130.7 (2xCq), 139.9 (2xCH), 145.1 (2xCH), 147.8 (2xCq), 184.8 (2xCO). MS (IS) m/z = 319
(M+1). Anal. Calcd for C H N O : C, 67.92 ; H, 4.43 ; N, 17.60. Found : C, 68.02 ; H, 4.38 ; N,
18 14 4 2
17.62.
N-{2-[3’-(2-Acetylaminoethyl)-1,1’dimethyl-1H,1’H-[5,5’]bi[pyrrolo[2,3-b]pyridin]-3-yl]ethyl}-
acetamide (4)
To a solution of aldehyde (18) (0.48 g, 1.60 mmol) in nitromethane (20 mL) was added to ammonium
acetate (0.61 g, 8 mmol) and then the mixture was stirred at 120°C during 4 h. After cooling and dilution
with dichloromethane, the mixture was hydrolysed and extracted. The organic layers were dried over
anhydrous MgSO and concentrated in vacuo. The crude nitrovinyl compound obtained which was used
4
without further purification in the next step. Thus, to a stirred solution of nitro compound in a mixture of
isopropanol (35 mL) and chloroform (100 mL) was added at rt under inert atmosphere silica gel 230-400
mesh (0.81 g). To this suspension was added portionwise sodium borohydride (0.3 g, 8 mmol) and then,
the mixture was stirred at rt during 12 h. After this time, this mixture was filtered on Celite and filtrate
was concentrated in vacuo. The crude compound obtained was used without further purification in the
next step. Thus the satured nitro compound (0.85g, 2.43 mmol) was dissolved in methanol (4 mL). To
this solution was added Raney nickel (0.015 g) and the mixture was hydrogenated (40 psi) in a Parr
shaker at 60°C during 6 h. The catalyst was filtered off and the solvent was removed under reduced
pressure. The crude amino derivative was obtained as a yellow oil which was used without purification in
the next step. Under an inert atmosphere, the crude aminoderivative was dissolved in dichloromethane
(20 mL), pyridine (20 ml) and acetic anhydride (0.45 mL, 4.8 mmol) at 0°C. The mixture was stirred
during 12 h at rt before hydrolysis. The aqueous phase was neutralised with saturated
hydrogenocarbonate and extracted with dichloromethane. The organics layers were dried over anhydrous
MgSO , the solvent was removed under reduced pressure. The crude mixture was purified by flash
4
chromatography (eluent : ethyl acetate/methanol 95/5) to provide compound (4) (0.12 g, 5% within 4
1
steps) as a brown oil. IR (film) ν 3406, 3260, 2925, 1629 cm-1. H-NMR (CD3OD) δ : 1.95 (s, 6H,

COCH3), 3.01 (t, 4H, J = 6.8 Hz, H1’), 3.60 (t, 4H, J = 6.8 Hz, H2’), 3.89 (s, 6H, NCH3), 5.71 (s, 2H,
13
NHCH3), 7.07 (s, 2H, H2), 8.05 (d, 2H, J = 2 Hz, H4), 8.57 (d, 2H, J = 2 Hz, H6). C-NMR (CD3OD) δ :
24 (2xCOCH3), 26.1 (2xC1’), 31.8 (2xNCH3), 40.6 (2xC2’), 110.7 (2xCq), 120.6 (2xCq), 126.1 (2xCH),
127.7 (2xCq), 128.0 (2xCH), 134.8 (2xCq), 142.9 (2xCH), 170.5 (2xCO). MS (IS) m/z = 433 (M+1).
Anal. Calcd for C H N O : C, 66.65 ; H, 6.52 ; N, 19.43. Found : C, 66.80 ; H, 6.69 ; N, 19.40.
24 28 6 2
(5-Bromopyrrolo[2,3-b]pyridin-1-yl)acetonitrile (19)
Under an inert atmosphere, sodium hydride (60% in oil, 0.18 g, 7.58 mmol) was added to a stirred
solution of 5-bromoindole (1 g, 5.07 mmol) in N,N-dimethylformamide (25 mL) at 0°C during 30 min.
Then the mixture was stirred an additional time (30 min) with continued cooling. After, the
bromoacetonitrile (0.71 mL, 10.14 mmol) was added dropwise and the mixture was stirred for 12 h,
allowing the temperature to increase at rt. Then water was added, the product was extracted with
dichloromethane, purified by flash chromatography on silica gel (eluent : light petroleum/ethyl acetate :
8/2) to give compound (19) (0.66 g, 54%) as yellow solid. mp 84-85°C (pentane). IR (KBr)
1
ν : 2252 cm-1. H-NMR (CDCl3) δ : 5.18 (s, 2H, CH2CN), 6.50 (d, 1H, J = 3.7 Hz, H3), 7.29 (d, 1H,
13
J = 3.7 Hz, H2), 8.02 (d, 1H, J = 1.9 Hz, H4), 8.35 (d, 1H, J = 1.9 Hz, H6). C-NMR (CDCl3) δ : 32.4
(CH2CN), 102.3 (C3), 113.3 (Cq), 114.9 (Cq), 122.4 (Cq), 128.4 (C2), 131.9 (C4), 144.7 (C6), 145.9 (C7a).
MS (IS) m/z = 236 (M+1 for 79Br), m/z = 238 (M+1 for 81Br). Anal. Calcd for C H N Br : C, 45.79 ; H,
9 6 3
2.56 ; N, 17.80 ; Br, 33.85. Found : C, 45.74 ; H, 2.55 ; N, 17.78 ; Br, 33.81.
1’-Cyanomethyl-1’H-[5,5’]bi[pyrrolo[2,3-b]pyridin]-1-yl)acetonitrile (20)
Under an inert atmosphere, bis(pinacolato)diborane (6) (0.23 g, 0.91 mmol), potassium acetate (0.22 g,
2.28 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.06 g, 0.01 mmol) were
added to a stirred solution of 19 (0.18 g , 0.76 mmol) in dry DMF (5 mL). The mixture was stirred at
80°C under nitrogen for 2 h. After cooling the solution to rt, 19 (0.36 g, 1.52 mmol),
[1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.06 g, 0.01 mmol) and 2 M Na CO
2
3
(1.9 mL, 3.81 mmol) were added and the mixture was stirred at 80°C under nitrogen for 12 h. The
solution was cooled to rt, the product was extracted with dichloromethane (15 mL) and washed with
water (15 mL), brine and dried over anhydrous MgSO . Finally, purification by flash chromatography on
4
silica gel using 30% ethyl acetate in light petroleum as eluent gave 0.16 g (67%) of 1’-cyanomethyl-1’H-
[5,5’]bi[pyrrolo[2,3-b]pyridin]-1-yl)acetonitrile (20) as a white solid. mp > 240°C (pentane). IR (KBr) ν :
2923, 2248 cm-1. 1H-NMR (DMSO-d6) δ : 5.52 (s, 4H, CH2CN), 6.65 (d, 2H, J = 3.6 Hz, H3), 7.68 (d, 2H,
13
J = 3.6 Hz, H2), 8.34 (d, 2H, J = 2.2 Hz, H4), 8.67 (d, 2H, J = 2.2 Hz, H6). C-NMR (DMSO-d6) δ : 33
(2xCH2CN), 102.3 (2xC3), 117.4 (2xCq), 121.2 (2xCq), 128.5 (2xCq), 128.7 (2xC2), 130.5 (2xC4), 143.3

(2xC6), 147.1 (2xC7a). MS (IS) m/z = 313 (M+1). Anal. Calcd for C H N : C, 69.22 ; H, 3.87 ; N,
18 12 6
26.91. Found : C, 69.31 ; H, 3.84 ; N, 27.01.
N-{2-[1’-(2-acetylaminoethyl)-1’H-[5,5’]bi[pyrrolo[2,3-b]pyridin]-1-yl]ethyl}acetamide (5)
A solution of compound (20) (0.15 g, 0.48 mmol) in acetic anhydride (5 mL) was hydrogenated over
Raney nickel (0.01 g) in the presence of sodium acetate (0.16 g, 1.92 mmol) for 18 h at 60°C. The
reaction was cooled to rt and the catalyst was filtered on Celite and the filtrate concentrated in vacuo. The
residue was taken up in dichloromethane, washed with water and dried over anhydrous MgSO . After
4
removal of the solvent, the crude residue was chromatographed over silica gel (eluent : ethyl
acetate/methanol : 9/1) to afford 5 (0.06 g, 31%) as a white solid. mp 230-231°C (pentane). IR (KBr)
ν : 3296, 2920, 1639 cm-1. 1H-NMR (DMSO-d6) δ : 1.77 (s, 6H, COCH3), 3.48 (q, 4H, J = 6.1 Hz, H2’),
4.35 (t, 4H, J = 6.1 Hz, H1’), 6.52 (d, 2H, J = 3.4 Hz, H3), 7.55 (d, 2H, J = 3.4 Hz, H2), 8.01 (t, 2H,
J = 6.1 Hz, NHAc), 8.25 (d, 2H, J = 1.8 Hz, H4), 8.58 (d, 2H, J = 1.8 Hz, H6). 13C-NMR (DMSO-d6)
δ : 23.4 (2xCOCH3), 39.7 (2xC1’), 44.5 (2xC2’), 100.1 (2xC3), 121.1 (2xCq), 127.6 (2xC2), 128.0 (2xCq),
131.1 (2xC4), 142.3 (2xC6), 147.3 (2xC7a), 170.3 (2xCO). MS (IS) m/z = 405 (M+1). ). Anal. Calcd for
C H N O : C, 65.33 ; H, 5.98 ; N, 20.77. Found : C, 65.2 ; H, 5.93 ; N, 20.61.
22 24 6 2
ACKNOWLEDGEMENTS
We are grateful to A.D.I.R. Company (Courbevoie, France) for its multiform support.
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