General and easy access to 11-substituted 4-hydroxy-2,3,4,5-tetrahydro[1,4] diazepino[1,2-a]indol-1-one derivatives

Article abstract of DOI:10.1055/s-2006-950249

An efficient route to prepare the 4-hydroxy-2,3,4,5-tetrahydro[1,4] diazepino[1,2-a]indol-1-one scaffold is described. The key reactions of the synthesis are an iodolactonisation followed by a lactone-to-lactam rearrangement. Various 11-substituted deriva

Full text of DOI:10.1055/s-2006-950249

LETTER
2755
General and Easy Access to 11-Substituted 4-Hydroxy-2,3,4,5-tetrahy-
dro[1,4]diazepino[1,2-a]indol-1-one Derivatives
1
1-Substituted 4-H
u
ydroxy-2,3,4
r
,5-tetrah
é
ydro[1,4]d
l
iazepin
i
o[1,2-
a
e
]indole-1-
o
n
nes Putey, Guy Fournet, Benoît Joseph*
Laboratoire de Chimie Organique 1, UMR – CNRS 5181, Université Claude Bernard – Lyon 1, CPE – Bâtiment 308,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72431214; E-mail: benoit.joseph@univ-lyon1.fr
Received 27 July 2006
hyde with ethyl azidoacetate in the presence of MeONa
yielded the azidoacrylate, which was converted into in-
dole 1c by refluxing in xylene (overall yield 68%).5 N-Al-
lylation of indolic nitrogen 1 was carried out in the
Abstract: An efficient route to prepare the 4-hydroxy-2,3,4,5-tet-
rahydro[1,4]diazepino[1,2-a]indol-1-one scaffold is described. The
key reactions of the synthesis are an iodolactonisation followed by
a lactone-to-lactam rearrangement. Various 11-substituted deriva-
tives were obtained by palladium-mediated cross-coupling reac- presence of allyl bromide and an appropriate base such as
tions.
K2CO3 or NaH to afford 2 in good yield (2a: 94%, 2b:
94% and 2c: 88%). Saponification of esters 2 afforded ac-
ids 3 in 96–100% yield.
Key words: diazepinoindole, seven-membered ring, iodolactonisa-
tion, palladium
R3
I
R1
R2
R1
R2
O
Syntheses and reactivities of 1,4-diazepines fused with
five- and six-membered heterocyclic rings are well inves-
tigated.1 2,3,4,5-Tetrahydro[1,4]diazepino[1,2-a]indol-1-
one derivatives have received much less attention. One
series of compounds I has been reported as precursor of
serotonine antagonists (Figure 1).2,3 The synthesis of I is
achieved by ring closure of ethyl 1-(3-aminopropyl)-3-
substituted-indole-2-carboxylates.3
O
NH
N
N
O
I
OH
II
R1
R2
CO2H
N
As a part of an ongoing research work dedicated to the de-
sign of kinase inhibitors, we became interested in the de-
sign of new derivatives II. The retrosynthetic approach of
this series was based on an iodolactonisation of 1-allylin-
dole-2-carboxylic acids followed by a lactone-to-lactam
rearrangement as shown in Scheme 1.
Scheme 1 Retrosynthetic scheme for the synthesis of II
The iodolactonisation was investigated on model com-
pound 3a. The first reaction conditions using iodine (2
equiv) in CHCl3–H2O at 0 °C for 90 minutes afforded
compound 4a in 66% yield.6 Iodination of the position C-
3 of the indole part occurred in the same time. Increase of
the temperature reaction at 70 °C afforded 4a in a better
yield (84%). The second assay was performed on 3a in the
presence of N-iodosuccinimide (2.3 equiv) and 2,6-luti-
dine in CH2Cl2 at –20 °C.7 Compound 4a was again ob-
tained in good yield (81%).8 Iodolactonisation using N-
R3
R2
R1
R2
11
O
R1
O
NH
NH
N
N
4
I
OH
II
Figure 1 General formulae of I and II
We now report a direct and convenient procedure for the iodosuccinimide was applied to 3b and 3c to afford 4b and
access of 4-hydroxy-11-iodo-2,3,4,5-tetrahydro[1,4]diaz- 4c, respectively, in 94% and 67% yield. The treatment of
epino[1,2-a]indol-1-one skeleton (Scheme 2, Table 1) 3c with iodine at 0 °C afforded 4c in a disappointing 15%
followed by the functionalisation of the position C-11 via yield. In this case, 1-allyl-2,3-diiodo-6-methoxyindole
palladium-mediated cross-coupling reactions.
was isolated as the major product (41%).
The esters 1 were synthesised by adapting standard meth- Lactones 4 were finally converted into the desired lactams
ods. Compounds 1a4 and 1b were prepared from esterifi- 5. Once again, optimisation studies were required for this
cation of the commercially available acids in 92–98% rearrangement. Treatment of 4a with ammonia in meth-
yield. Treatment of commercially available p-anisalde- anol failed due to the low solubility of the starting materi-
al.6 Addition of DMF in the reaction mixture in order to
increase the solubility, unfortunately led to a partial con-
version even after three days and 5a9 was obtained in 46%
yield. By using THF instead of DMF, the reaction pro-
SYNLETT 2006, No. 17, pp 2755–2758
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950249; Art ID: G21206ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
6

2756
A. Putey et al.
LETTER
Table 1 Reaction Yields for Compounds 2–5
Compd
R1
R2
Yield of 2 (%) Yield of 3 (%) Yield of 4 (%)
Yield of 5 (%)
I2
NIS
81
1a
H
H
94
94
88
100
96
66
68
79
81
a
1b
OMe
H
H
–
94
1c
OMe
98
15
67
a Not tested.
I
I
R1
R2
O
R1
R2
R1
R2
R1
R2
O
iii
iv
i
CO2R
CO2R
NH
N
N
N
O
N
H
1a, 1b R = Et, 1c R = Me
I
OH
5a, 5b, 5c
4a, 4b, 4c
2a R = Et
2b R = Et
2c R = Me
ii
3a, 3b, 3c R = H
Scheme 2 Reagents and conditions: i) allylbromide (2.0 equiv), K2CO3, MeCN, reflux, 60 h (1a) or NaH, DMF, 0 °C to r.t., 15 h (1b,c); ii)
NaOH, EtOH–H2O, reflux, 1 h (2a) or LiOH·H2O, EtOH or MeOH, reflux, 18 h (2b,c); iii) I2 (2 equiv), aq NaHCO3, CHCl3–H2O, 0 °C, 90 min
or NIS (2.3 equiv), 2,6-lutidine (1.5 equiv), CH2Cl2, –20 °C, 3 h 30; iv) NH3 (g), MeOH–THF, r.t., 48 h for 5a and 24 h for 5b and 5c.
ceeded in 48 hours affording 5a in 68% yield. Following acid afforded products 7 and 8, respectively, in 56% and
the same conditions, 4b and 4c gave 5b and 5c in 79–81% 58% yield. We observed that the starting material 5a was
yield. Without methanol, no reaction occurred and start- not totally soluble in the solvent system (toluene–ethanol)
ing material was recovered. According to the synthesis used. Therefore, we decided to replace it by a mixture of
described above, the preparation of several grams of 5a DME–H2O.12 In this case, we performed the coupling re-
was easily performed for further biological and methodol- action with tetrakis(triphenylphosphine)palladium (5
ogy studies.
mol%), arylboronic acid (1.1 equiv) and Na2CO3 in
DME–H2O at 85 °C in 3–5 hours (Method B) leading to
11-aryl derivatives 6–9 in high yield (Scheme 3 and
Table 2).
Taking advantage of iodine on the indole ring, introduc-
tion of a substituent on the position C-11 by palladium
coupling reactions could be expected.
We replaced Pd(PPh3)4 by 10% Pd/C described as a suit-
able alternative to the ‘classical’ homogeneous condi-
I
Ar
O
O
i
Table 2 Suzuki Coupling Yields of Compounds 6–9
NH
NH
N
N
Method
Compd
Ar
Yield (%)a
OH
OH
5a
6–9
A
6
6
6
7
7
7
8
8
9
Ph
43
86
88
56
82
20
58
75
81
Scheme 3 Reagents and conditions: i) Method A: Pd(PPh3)4 (10
mol%), ArB(OH)2 (1.5 equiv), aq NaHCO3, toluene–EtOH, reflux, 15
h; Method B: Pd(PPh3)4 (5 mol%), ArB(OH)2 (1.1 equiv), Na2CO3,
DME–H2O, 85 °C, 3–5 h; Method C: 10% Pd/C, ArB(OH)2 (2.0
equiv), Na2CO3, DME–H2O, 85 °C, 4 h.
B
Ph
C
Ph
A
2-Furanyl
2-Furanyl
2-Furanyl
2-Thienyl
2-Thienyl
4-MeOC6H4
B
We first performed the Suzuki coupling reaction
(Scheme 3) between phenylboronic acid and our model
compound 5a in the presence of freshly prepared tet-
rakis(triphenylphosphine)palladium (10 mol%), aqueous
NaHCO3 in toluene–ethanol at reflux (Method A).10 Com-
pound 611 was isolated in 43% yield but the reaction was
not completed. We noticed that the substitution of phenyl-
boronic acid by 2-furanylboronic acid or 2-thienylboronic
C
A
B
B
a Isolated yield.
Synlett 2006, No. 17, 2755–2758 © Thieme Stuttgart · New York

LETTER
11-Substituted 4-Hydroxy-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones
2757
tions.13 In this case, ligands and additives are generally not
required for efficient transformations, and catalyst remov-
al is easily performed by simple filtration. Just changing
the Pd system, we carried out the reaction between 5a and
phenylboronic acid (Method C). The result was very en-
couraging because compound 6 was isolated in 88% yield.
Unfortunately, when we applied the same conditions to 2-
furanylboronic acid, the yield decreased from 82% to only
20% yield.
(6) Grunewald, G. L.; Dahanukar, V. H. J. Heterocycl. Chem.
1994, 31, 1609.
(7) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc.
2003, 125, 7822.
(8) Typical Procedure for Iodolactonisation.
Under a N2 atmosphere, to a solution of 1-allyl-1H-indole-2-
carboxylic acid (3a, 1.49 g, 7.4 mmol) in anhyd CH2Cl2 (90
mL), was added at –20 °C, 2,6-lutidine (1.30 mL, 11.1
mmol, 1.5 equiv) and NIS (3.83 g, 17.0 mmol, 2.3 equiv).
The solution was stirred at –20 °C for 3.5 h. The reaction
mixture was extracted with CH2Cl2 (2 × 20 mL). The
organic phase was washed with 1 M HCl solution (10 mL),
sat. aq solution of Na2S2O3 (2 × 30 mL), brine solution
(2 × 30 mL), and sat. aq solution of NaHCO3. The organic
phases were combined, dried over Na2SO4 and evaporated in
vacuo. The crude solid was purified by recrystallisation from
CH2Cl2 to afford 4a (2.73 g, 81%) as a white solid; mp
169 °C (dec., CH2Cl2). IR (KBr): 3020, 2950, 1710, 1100,
750 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.42 (dd, 1 H,
J = 8.7, 10.6 Hz, CH2I), 3.59 (dd, 1 H, J = 4.4, 10.6 Hz,
CH2I), 4.27 (dd, 1 H, J = 9.0, 12.8 Hz, NCH2), 4.74 (dd, 1 H,
J = 3.3, 12.8 Hz, NCH2), 4.80–4.89 (m, 1 H, CH), 7.31 (t, 1
H, J = 8.0 Hz, Har), 7.36 (d, 1 H, J = 8.0 Hz, Har), 7.50 (t, 1
H, J = 8.0 Hz, Har), 7.62 (d, 1 H, J = 8.0 Hz, Har). 13C NMR
(75 MHz, CDCl3): d = 1.1 (CH2I), 44.9 (NCH2), 68.9 (C),
76.2 (CH), 110.4 (CH), 121.9 (C), 122.7 (CH), 124.2 (CH),
127.8 (CH), 131.1 (C), 136.8 (C), 157.4 (CO). ESI-MS:
m/z = 454 [M + H]+. Anal. Calcd for C12H9I2NO2: C, 31.82;
H, 2.00; N, 3.09. Found: C, 32.11; H, 2.13; N, 2.95.
(9) Typical Procedure for Lactam Formation.
In a last part, other ‘classical’ palladium coupling reac-
tions were performed on 5a in order to obtain a large range
of functionalised derivatives (Scheme 4). Thus, Sono-
gashira coupling reaction on 5a was carried out with 1-
pentyne to produce 10 in 63% yield.14 Heck reaction of 5a
with an excess of methyl acrylate led to 11 in 87% yield.15
In spite of multiple attempts, the Stille reaction of 5a with
allyltributyltin failed.16
CO2Me
O
O
i
ii
NH
NH
5a
N
N
A solution of iodolactone 4a (3.60 g, 7.95 mmol) in anhyd
MeOH (60 mL) and anhyd THF (30 mL) was added
dropwise over a period of 20 min to an ice-cold sat. NH3 in
MeOH solution (30 mL). The reaction mixture was allowed
to warm up to r.t. for 48 h. The solvents were then removed
by evaporation and the crude residue was purified by
recrystallisation from EtOAc–EtOH to afford 5a (1.75 g,
64%) as a white solid. The filtrate was then purified by flash
chromatography on silica gel (CH2Cl2–MeOH, 94:6) to give
0.11 g of 5a (overall yield 68%) as a white solid; mp 199 °C
(dec., EtOAc–EtOH). IR (KBr): 3410, 3320–3200, 3060,
2920, 1635, 1515, 1090, 745 cm–1. 1H NMR (300 MHz,
DMSO-d6): d = 2.73–2.80 (m, 1 H, CH2NH), 3.15–3.21 (m,
1 H, CH2NH), 4.18–4.29 (m, 2 H, NCH2 and CH), 4.43–4.49
(m, 1 H, NCH2), 5.38 (d, 1 H, J = 3.4 Hz, OH), 7.19 (t, 1 H,
J = 7.9 Hz, Har), 7.35 (t, 1 H, J = 7.9 Hz, Har), 7.39 (d, 1 H,
J = 7.9 Hz, Har), 7.58 (d, 1 H, J = 7.9 Hz, Har), 8.30 (t, 1 H,
J = 5.5 Hz, NH). 13C NMR (75 MHz, DMSO-d6): d = 45.3
(CH2), 48.7 (CH2), 61.3 (CI), 69.5 (CH), 111.0 (CH), 120.8
(CH), 121.7 (CH), 124.6 (CH), 129.2 (C), 133.4 (C), 137.2
(C), 164.0 (CO). ESI-MS: m/z = 343 [M + H]+. Anal. Calcd
for C12H11IN2O2: C, 42.13; H, 3.24; N, 8.19. Found: C,
41.87; H, 3.12; N, 8.05.
OH
OH
10
11
Scheme 4 Reagents and conditions: i) PdCl2(PPh3)2 (10 mol%), CuI
(10 mol%), 1-pentyne (7 equiv), Et3N, DMF, 45 °C, 4 h, 63%; ii)
Pd(OAc)2 (10 mol%), PPh3 (20 mol%), methyl acrylate (10 equiv),
Et3N, DMF, 90 °C, 5 h, 87%.
In summary, we developed an efficient and straightfor-
ward route to original 4-hydroxy-11-iodo-2,3,4,5-tetrahy-
dro[1,4]diazepino[1,2-a]indol-1-one derivatives. Several
substituents on position C-11 were introduced by Suzuki,
Sonogashira and Heck reactions. The compounds de-
scribed here are currently under evaluation for their ki-
nase-inhibitory activities and the biological results will be
reported in due course.
Acknowledgment
This research work was supported by a grant from the Ministère de
l’Enseignement Supérieur et de la Recherche to A.P.
(10) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457.
References and Notes
(1) Katritzky, A. R.; Jain, R.; Akhmedova, R.; Xu, Y.-J.
ARKIVOC 2003, (ix), 4.
(2) Reynolds, B. E.; Carson, J. R. Ger. Offen. 1,928,726, 1969;
Chem. Abstr. 1970, 72, 55528v.
(3) Hendi, S. B.; Basanagoudar, L. D. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1981, 20, 288.
(4) Fagan, G. P.; Chapleo, C. B.; Lane, A. C.; Myers, M.; Roach,
A. G.; Smith, C. F. C.; Stillings, M. R.; Welbourn, A. P. J.
Med. Chem. 1988, 31, 944.
(11) Physical Data of Compound 6.
Mp >210 °C (washing EtOAc). IR (KBr): 3420, 3310–3250,
3070, 2980, 1640, 1550, 1490, 1085, 750, 700 cm–1. 1H
NMR (300 MHz, DMSO-d6): d = 2.82–2.91 (m, 1 H,
CH2NH), 3.20–3.30 (m, 1 H, CH2NH), 4.25–4.30 (m, 2 H,
NCH2 and CH), 4.42–4.48 (m, 1 H, NCH2), 5.38 (d, 1 H,
J = 3.4 Hz, OH), 7.12 (t, 1 H, J = 7.5 Hz, Har), 7.29–7.64 (m,
8 H, Har), 8.25 (t, 1 H, J = 5.9 Hz, NH). 13C NMR (75 MHz,
DMSO-d6): d = 45.3 (CH2), 47.9 (CH2), 69.6 (CH), 110.5
(CH), 118.4 (C), 119.9 (CH), 120.3 (CH), 123.8 (CH), 125.4
(C), 126.4 (CH), 128.1 (2 CH), 129.7 (2 CH), 129.9 (C),
(5) Coowar, D.; Bouissac, J.; Hanbali, M.; Paschaki, M.;
Mohier, E.; Luu, B. J. Med. Chem. 2004, 47, 6270.
Synlett 2006, No. 17, 2755–2758 © Thieme Stuttgart · New York

2758
A. Putey et al.
LETTER
133.7 (C), 136.3 (C), 164.8 (CO). ESI-MS: m/z = 293 [M +
H]+. Anal. Calcd for C18H16N2O2: C, 73.96; H, 5.52; N, 9.58.
Found: C, 74.33; H, 5.67; N, 9.63.
(14) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Sonogashira, K. J. Organomet. Chem.
2002, 653, 46.
(12) Witulski, B.; Azcon, J. R.; Alayrac, C.; Arnautu, A.; Collot,
V.; Rault, S. Synthesis 2005, 771.
(13) Felpin, F.-X. J. Org. Chem. 2005, 70, 8575.
(15) (a) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320.
(b) Heck, R. F. Org. React. 1982, 27, 345.
(16) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100,
3636. (b) Espinet, P.; Echaverren, A. M. Angew. Chem. Int.
Ed. 2004, 43, 4707.
Synlett 2006, No. 17, 2755–2758 © Thieme Stuttgart · New York