Synthesis of fused heterocycles with a benzazepinone moiety via intramolecular Heck coupling

Article abstract of DOI:10.1016/j.tetlet.2005.09.122

The preparation of fused heterocycles with a benzazepinone moiety was realised via an intramolecular Heck coupling reaction either at position 2 or at position 3 of the heterocyclic system. This method allowed the synthesis of the pyrrolo[2,3-c]azepinone

Full text of DOI:10.1016/j.tetlet.2005.09.122

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8177–8179
Synthesis of fused heterocycles with a benzazepinone moiety
via intramolecular Heck coupling
*
´
Lionel Joucla, Aurelien Putey and Benoˆıt Joseph
ˆ
Laboratoire de Chimie Organique 1, UMR-CNRS 5181, Universite´ Claude Bernard–Lyon 1, Batiment 308 CPE Lyon,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
Received 1 August 2005; revised 16 September 2005; accepted 20 September 2005
Available online 6 October 2005
Abstract—The preparation of fused heterocycles with a benzazepinone moiety was realised via an intramolecular Heck coupling
reaction either at position 2 or at position 3 of the heterocyclic system. This method allowed the synthesis of the pyrrolo[2,3-c]azepi-
none core and Paullone derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
report in this letter, a general, mild and straightforward
procedure for the preparation of the benzazepinone
moiety, involving an intramolecular Heck type coupling
reaction.
In our ongoing project concerning the development of
new cyclin dependent kinase (CDK) inhibitors, we
became interested in the preparation of azepinoindole
derivatives. Indeed, these structures are closely related
to well-known pyrroloazepine moieties which are present
in a number of natural and synthetic products such as
Hymenialdisine,1 Latonduine2 and Paullones3 (Fig. 1).
2. Results and discussion
First, we investigated the cyclisation of compounds 1a–d
(Scheme 1), which were easily available by a peptidic
coupling (EDCI, DMAP) between the corresponding
indole-, pyrrolo[2,3-b]pyridine- or benzo[b]thiophene-3-
carboxylic acids and 2-iodobenzylamine followed by a
Boc protection of the amide.
Some of these molecules are interesting CDK and/or
GSK-3 (glycogen synthase kinase 3) inhibitors.4 We
O
N
NH2
N
H2N
R
N
Br
N
H
Latonduine A
R = H
Latonduine B
NH
O
Br
Boc
R = CO2H
N
H
N
H
O
N
H
R
Br
N
1a-d
Hymenialdisine
O
X
Y
O
I
R1
NH
Pd(OAc)2 (0.1 eq), PPh3 (0.2 eq)
Ag2CO3 (2 eq), DMF, 100˚C, 2 h
Paullones
N
H
O
Boc
R
N
Figure 1.
2a-d
X
Y
Keywords: Benzazepinone; Palladium; Heck; Cyclisation.
*
Corresponding author. Tel.: +33 472 448 135; fax: +33 472 431
214; e-mail: benoit.joseph@univ-lyon1.fr
Scheme 1.
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.122

8178
L. Joucla et al. / Tetrahedron Letters 46 (2005) 8177–8179
5
Table 2. Yield of compounds 4 obtained by Heck coupling reaction
´
As previously reported by Merour and co-workers for
the preparation of the six-membered ring analogues,
the Heck reaction was effective in the presence of a
Pd(OAc)2/PPh3 catalytic system and silver carbonate
as base. The reaction was performed in excellent yield
(Table 1) with 0.1 equiv of palladium catalyst in 2 h.
In the case of 1d, only 0.05equiv of Pd(OAc) 2 was
required to complete the reaction. This was certainly
due to a transition state involving a stabilisation of the
palladium species by the sulfur atom as suggested by
Lemaire and co-workers.6
3
R1
R2
Y
4
Yield (%)
a
3a
3b
3c
3d
3e
H
H
OMe
H
H
H
H
H
OMe
H
N-Boc
N-EOM
N-EOM
N-EOM
S
4a
4b
4c
4d
4e
/
96
93
96
82
a Degradation of 3a.
We then extended these conditions to 3c–e and obtained
excellent results (Table 2). For 3e, an increase from 0.05
to 0.075equiv of the amount of Pd(OAc) 2 did not
improve the yield.
Thus, the 2-regioisomers 3a–d were synthesised accord-
ing to the procedure applied for compounds 1a–d. We
attempted to perform the intramolecular Heck coupling
on position 3 of heterocycles, as reported in the litera-
ture for five- or six-membered rings.8
As only a few examples of palladium coupling were de-
scribed on pyrrole derivatives so far,8b,9 we eventually
applied these conditions (0.05equiv of Pd(OAc) 2) to
the synthesis of compound 6, related to the structure
of Latonduine (Scheme 3). The cyclisation of 5 afforded
611 in 59% yield (40% of starting material recovered),
and was then improved up to 70% (26% of starting
material recovered) when 0.1 equiv of Pd(OAc)2 was
used.
When the cyclisation conditions described above were
applied to compound 3a, the latter underwent a
complete degradation after 24 h (Scheme 2). Therefore,
we decided to protect the indole nitrogen with an
electron donating group (–EOM = –CH2OCH2CH3),
as reported for the inter- or intramolecular cyclisation
of nitrogen heterocycles.8,9 The resulting protected
indole 3b was then submitted to the Heck coupling reac-
tion and afforded the desired product 4b10 in an excellent
96% yield. In addition, we were pleased to observe that
the cyclisation occurred with only 0.05equiv of
Pd(OAc)2 in 1 h compared to the reported intramolecu-
lar cyclisations of heterocycles.8
This methodology can also be extended to the synthesis
of Paullone series (Scheme 3).12 Actually, N-electron
withdrawing protecting groups such as Boc or SO2Ph
prevented cyclisation (Table 3, entry 1). However,
N-Me and N-EOM compounds 7b and 7c allowed the
intramolecular cyclisation with excellent yield (Table 3,
entry 2–3). As recently reported for palladium-mediated
methodologies,13 our synthetic strategy allows the prep-
aration of N-unprotected derivatives (via final deprotec-
tion of EOM groups). This represents a convenient
Table 1. Yield of compounds 2 obtained by Heck coupling reaction
1
R
X
Y
2
Yield (%)
1a
1b
1c
1d
H
OMe
H
CH
CH
N
N-SO2Ph
N-SO2Ph
N-SO2Ph
S
2a7
2b
2c
92
96
86
100a
I
Pd(OAc)2 (0.1 eq)
PPh3 (0.2 eq)
Ag2CO3 (2 eq)
DMF, 100˚C, 1 h
H
CH
2d
a 0.05equiv of Pd(OAc) 2 was used.
N
N
Boc
70%
N
N
EOM O
5
Boc
EOM
O
6
I
Pd(OAc)2 (0.1 eq)
PPh3 (0.2 eq)
R1
O
O
Ag2CO3 (2 eq)
DMF, 100˚C, 0.5 h
N
N
R2
R2
Y
Boc
N
R2
N
N
O
3a-d
R1
I
R1
7
8
Pd(OAc)2 (0.05 eq), PPh3 (0.1 eq)
Ag2CO3 (2 eq), DMF, 100˚C, 1 h
Scheme 3.
R1
Table 3. Yield of compounds 8 obtained by Heck coupling reaction
7
R1
R2
8
Yield (%)
N
R2
Y
a
7a
7b
7c
Me
Me
EOM
Boc
Me
EOM
8a
8b
8c
/
Boc
O
89
92
4a-d
Scheme 2.
a Degradation of 7a.

L. Joucla et al. / Tetrahedron Letters 46 (2005) 8177–8179
8179
(2CH), 128.7 (C+2CH), 129.7 (C), 130.3 (CH), 133.4
(CH), 134.2 (CH), 135.7 (C), 136.5 (C), 138.6 (C), 141.9
(C), 151.1 (CO), 162.7 (CO); HRMS (EI) m/z calcd for
C27H24N2O5S: 488.1406; found: 488.1408.
alternative to Fischer indole synthesis which is the most
useful route to Paullones used so far.3
8. (a) Kozikowski, A. P.; Ma, D. Tetrahedron Lett. 1991, 32,
3317–3320; (b) Beccalli, E. M.; Broggini, G.; Martinelli,
M.; Paladino, G.; Zoni, C. Eur. J. Org. Chem. 2005, 10,
2091–2096.
9. (a) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897–2900;
(b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 8050–8057.
3. Conclusion
In summary, we have shown that Pd(OAc)2/PPh3/
Ag2CO3 is a mild, fast and efficient high yielding cata-
lytic system for the synthesis of fused heterocycles with
a benzazepinone moiety. This methodology can be
applied to heterocycles such as indole, pyrrolo[2,3-b]pyr-
idine, benzo[b]thiophene or pyrrole. In addition, we
proposed a simple and novel synthetic route to pyr-
rolo[2,3-c]azepinone and indolo[3,2-d]benzazepinone
ring systems. Further studies are under investigation in
order to obtain new Paullone analogues and will be
published in due course.
10. Selected data for 4b. Mp 104–106 °C (EtOAc/PE); 1H
NMR (300 MHz, DMSO-d6): d 1.03 (t, 3H, J = 7.2 Hz,
CH3), 1.47 (s, 9H, 3CH3), 3.34–3.54 (m, 2H, CH2), 4.26
(d, 1H, J = 15.1 Hz, CH2), 5.09 (d, 1H, J = 15.1 Hz, CH2),
5.92 (d, 1H, J = 10.7 Hz, CH2), 6.05(d, 1H, J = 10.7 Hz,
CH2), 7.32 (t, 1H, J = 7.7 Hz, HAr), 7.44–7.63 (m, 4H,
H
H
Ar), 7.83 (d, 1H, J = 8.5Hz, H Ar), 8.03–8.06 (m, 2H,
Ar); 13C NMR (75MHz, CDCl 3): d 15.2 (CH3), 28.2
(3CH3), 48.9 (CH2), 64.2 (CH2), 74.3 (CH2), 83.5(C),
111.9 (CH), 121.3 (C), 122.1 (2CH), 124.6 (C), 126.3 (CH),
127.3 (CH), 128.3 (CH), 128.5(CH), 128.7 (C), 129.4 (C),
132.9 (C), 136.1 (C), 139.8 (C), 150.8 (CO), 161.6 (CO);
HRMS (EI) m/z calcd for C24H26N2O4: 406.1893; found:
406.1894.
Acknowledgements
This research work was supported by a Grant from the
`
´
Ministere de lÕEnseignement Superieur et de la Recher-
11. Selected data for 6. Mp 77–79 °C (EtOH); 1H NMR
(300 MHz, CDCl3): d 1.19 (t, 3H, J = 7.2 Hz, CH3), 1.50
(s, 9H, 3CH3), 3.55–3.59 (m, 2H, CH2), 4.24 (d, 1H,
J = 14.7 Hz, CH2), 5.11 (d, 1H, J = 14.7 Hz, CH2), 5.54
(d, 1H, J = 9.5Hz, CH 2), 6.09 (d, 1H, J = 9.5Hz, CH 2),
6.55 (d, 1H, J = 2.8 Hz, HPyr), 7.22 (d, 1H, J = 2.8 Hz,
HPyr), 7.27–7.69 (m, 4H, HAr); 13C NMR (75MHz,
CDCl3): d 15.1 (CH3), 28.1 (3CH3), 48.9 (CH2), 64.6
(CH2), 78.3 (CH2), 82.9 (C), 107.7 (CH), 123.5(C), 127.0
(CH), 127.3 (CH), 128.2 (CH), 128.6 (CH), 129.2 (CH),
130.8 (C), 133.7 (C), 135.0 (C), 151.2 (CO), 161.2 (CO);
HRMS (EI) m/z calcd for C20H24N2O4: 356.1736; found:
356.1735.
che to L.J. and A.P.
References and notes
1. Cimino, G.; De Rosa, S.; De Stephano, S.; Mazzarella, L.;
Puliti, R.; Sodano, G. Tetrahedron Lett. 1982, 23, 767–768.
2. Linington, R. G.; Williams, D. E.; Tahir, A.; Van Soest,
R.; Andersen, R. J. Org. Lett. 2003, 5, 2735–2738.
3. Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.;
Gussio, R.; Sausville, A. A.; Meijer, L.; Kunick, C. J.
Med. Chem. 1999, 42, 2909–2919.
12. Selected data for 8b and 8c. Compound 8b: mp 145–
4. (a) Knockaert, M.; Greengard, P.; Meijer, L. Trends
Pharmacol. Sci. 2002, 23, 417–425; (b) Meijer, L.; Flajolet,
M.; Greengard, P. Trends Pharmacol. Sci. 2004, 25, 471–
480.
1
146 °C (EtOAc/PE); H NMR (300 MHz, CDCl3): d 3.07
(d, 1H, J = 13.9 Hz, CH2), 3.35(s, 3H, CH ), 3.91 (s, 3H,
3
CH3), 3.97 (d, 1H, J = 13.9 Hz, CH2), 7.20 (t, 1H,
J = 7.0 Hz, HAr), 7.28–7.49 (m, 5H, HAr), 7.55 (d, 1H,
J = 7.8 Hz, HAr), 7.73 (d, 1H, J = 7.9 Hz, HAr); 13C NMR
(75MHz, CDCl 3): d 31.9 (CH3), 32.4 (CH2), 37.7 (CH3),
109.8 (CH), 112.4 (C), 118.8 (CH), 120.1 (CH), 122.9
(CH), 124.4 (CH), 124.8 (CH), 125.1 (C), 125.7 (C), 128.1
(CH), 128.7 (CH), 133.8 (C), 139.3 (C), 141.8 (C), 172.9
(CO); HRMS (EI) m/z calcd for C18H16N2O: 276.1263;
found: 276.1264. Compound 8c: mp 102–103 °C (EtOAc/
PE); 1H NMR (300 MHz, CDCl3): d 1.16 (t, 3H,
J = 7.0 Hz, CH3), 1.25(t, 3H, J = 7.0 Hz, CH3), 3.11
(d, 1H, J = 13.6 Hz, CH2), 3.41–3.51 (m, 1H, CH2), 3.56–
3.70 (m, 3H, CH2), 3.96 (d, 1H, J = 13.6 Hz, CH2), 4.73
(d, 1H, J = 10.0 Hz, CH2), 5.39 (d, 1H, J = 10.0 Hz, CH2),
5.57 (s, 2H, CH2), 7.21–7.48 (m, 4H, HAr), 7.54 (d, 1H,
J = 8.3 Hz, HAr), 7.73 (d, 1H, J = 7.9 Hz, HAr), 7.88 (d,
1H, J = 7.9 Hz, HAr), 7.95(br d, 1H, J = 7.6 Hz, HAr);
13C NMR (75MHz, CDCl 3): d 15.2 (CH3), 15.3 (CH3),
32.6 (CH2), 64.3 (CH2), 64.6 (CH2), 73.9 (CH2), 78.9
(CH2), 110.3 (CH), 112.9 (C), 118.9 (CH), 121.0 (CH),
123.5(CH), 124.8 (CH), 125.3 (C), 126.0 (CH), 126.2 (C),
128.6 (CH), 129.0 (CH), 134.2 (C), 139.2 (C), 140.8 (C),
172.7 (CO); HRMS (EI) m/z calcd for C22H24N2O3:
364.1787; found: 364.1788.
´
5. Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Merour, J.-Y.
Synthesis 2000, 549–556.
6. (a) Fournier Dit Chabert, J.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 2002, 43, 1829–1833; (b) Fournier Dit
Chabert, J.; Joucla, L.; David, E.; Lemaire, M. Tetra-
hedron 2004, 60, 3221–3230.
7. Example of Heck reaction, preparation of 2a: A mixture of
1a (154 mg, 0.25 mmol), triphenylphosphine (13 mg,
0.05mmol), palladium acetate (5.6 mg, 0.025mmol) and
silver carbonate (138 mg, 0.5mmol) in anhydrous DMF
(5mL) was vigorously stirred at 100 °C for 2 h. After
cooling to room temperature, the solvent was removed
under reduced pressure. The residue was taken up in
dichloromethane and filtered over CeliteÒ, rinsed with
dichloromethane. The solvent was evaporated in vacuo
and the crude residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl
acetate 9:1) to give 2a (112 mg, 92%). Mp 154 °C dec.
(Et2O); 1H NMR (300 MHz, CDCl3): d 1.51 (s, 9H,
3CH3), 3.66 (d, 1H, J = 14.5Hz, CH 2), 5.09 (d, 1H,
J = 14.5Hz, CH 2), 7.12 (br d, 2H, J = 8.5Hz, H Ar), 7.20
(t, 2H, J = 8.5Hz, H Ar), 7.37–7.58 (m, 6H, HAr), 7.97–
8.00 (m, 1H, HAr), 8.16 (br d, 1H, J = 7.7 Hz, HAr), 8.34
(d, 1H, J = 8.3 Hz, HAr); 13C NMR (75MHz, CDCl 3): d
28.1 (3CH3), 47.8 (CH2), 83.8 (C), 117.6 (CH), 121.7 (C),
122.8 (CH), 126.0 (CH), 126.5(2CH), 126.6 (CH), 127.5
´
´
13. (a) Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J.
Org. Chem. 2002, 67, 1199–1207; (b) Bremner, J. B.;
Sengpracha, W. Tetrahedron 2005, 61, 5489–5498.