A rapid and efficient synthesis of a new pyrrolobenzodiazocines via an intramolecular Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tetlet.2009.07.145

New pyrrolobenzodiazocines 3 have been prepared by an intramolecular Friedel-Crafts process from pyrrolobenzoacrylamides 2. The cyclisation process involving a 1,4-intramolecular addition of a pyrrole onto acrylamide led to the formation of an eight-membe

Full text of DOI:10.1016/j.tetlet.2009.07.145

Tetrahedron Letters 50 (2009) 5884–5887
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A rapid and efficient synthesis of a new pyrrolobenzodiazocines
via an intramolecular Friedel–Crafts reaction
b
Samir BouzBouz a, , Morgane Sanselme
*
a Laboratoire de Chimie Organique UMR 6014 COBRA, CNRS-Université de Rouen, 22 Bd Gambetta, 76183 Rouen, France
b Unité de Croissance Cristalline et de Modélisation Moléculaire, UPRES EA 3233. Université de Rouen, 1 rue Lucien Tesnière, 76821 Mont-Saint-Aignan cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
New pyrrolobenzodiazocines 3 have been prepared by an intramolecular Friedel–Crafts process from pyr-
rolobenzoacrylamides 2. The cyclisation process involving a 1,4-intramolecular addition of a pyrrole onto
acrylamide led to the formation of an eight-membered ring.
Received 12 May 2009
Revised 28 July 2009
Accepted 29 July 2009
Available online 3 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolobenzodiazocine
Intramolecular
Friedel–Crafts
Cyclisation
Pyrrole
Acrylamide
Eight-membered ring
The synthesis of new heterocyclic systems with biological activ-
ity is a major challenge for chemists.1 A great number of medium-
sized heterocyclic compounds such as 1,4-benzodiazepines are
biologically important as these products are active on the CNS.2
Eight-membered heterocyclic compounds are also of impor-
tance as for example, amino heterocyclic eight-membered ring
natural products, such as buflavine exhibit adrenolytic and anti-
serotonin activities.3,4 If seven-membered rings can be synthesised
easily, eight-membered heterocycles are more difficult to construct
as high energy activation is needed to close the ring due to
torsional strains, transannular interactions and also to Pfizer
strains.5 However, pyrrolobenzodiazocines can be formed by the
construction of the eight-membered ring. Up-to-date only six pyr-
rolobenzodiazocines were described and can be classified in three
classes: pyrrolo[1,2-e][1,5] benzodiazocines6 which were synthes-
ised by lactamisation, pyrrolo-[2,1-c][1,4]-benzodiazocines7 which
were obtained by a Dieckman reaction and pyrrolo[1,2-b][2,5] ben-
zodiazocines which were formed by using either a Ugi MCR reac-
Here, we would like to report an efficient and rapid access to
pyrrolo[1,2-f][1,6]-benzodiazocines 3 from the amino phenylpyr-
role 112 via acrylamides intermediates 2 taking advantage of the
nucleophilicity of the pyrrole group to form one of the C–C bond
of the eight-membered ring of the pyrrolobenzodiazocines.
Thus, after condensation of 1a with acryloyl chloride (Et3N,
CH2Cl2, 0 °C), 2a was obtained in good yield (87%). The cyclisation
step of 2a to 3a was then examined and the screening of different
Lewis acids was achieved in order to obtain the best yield in 3a.
The best Lewis acid revealed to be AlCl3.13 When 2a was treated
with AlCl3 (2 equiv) in CH2Cl2 (c = 0.005 M),14 at rt for 1 h, 3a15
was isolated in 67% yield (Table 1, entry 1). The reaction is gen-
eral and the results are reported in Table 1. Compounds 3b–e15
were, respectively, obtained in good yields from 1b–e (Table 1,
entries 2–5). We have to point that for compound 3f16 (59%),
the reaction has been performed in acetonitrile for 16 h at rt
(Table 1, entry 6). An X-ray diffraction analysis of 3a17 showed
that the eight-membered ring system has a boat conformation
(Figs. 1 and 2).
tion,8
a a a reductive
lactamisation,9 Mannich reaction10 or
amination11 (Scheme 1).
It is worth noting that for compound 3f, two isomers were ob-
served by 1H NMR and 13C NMR spectra in a ratio 6:1, due to an
atropoisomeric effect.18
The cyclisation of compounds 2 is probably due to the activa-
tion of the carbonyl group of the acrylamide by AlCl3 producing
intermediate A. Then, an intramolecular 1,4-addition of the pyrrole
group onto the activated Michael intermediate takes place to pro-
* Corresponding author.
E-mail address: samir.bouzbouz@univ-rouen.fr (S. BouzBouz).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.145

S. BouzBouz, M. Sanselme / Tetrahedron Letters 50 (2009) 5884–5887
5885
H
O
H
O
N
N
N
N
R2
HO
CO2Me
R1
Dieckman reaction7
Pyrrolo[2,1-c][1,4]benzodiazocine
lactamisation 6
Pyrrolo[1,2-e][1,5]benzodiazocine
O
H
R1
O
O
R
N
N
N
N
R2
N
H
N
N
lactamisation9
Mannich and amination
reductrice10, 11
Ugi MCR reaction8
Pyrrolo[1,2-b][2,5]benzodiazocine
Scheme 1. Different classes of pyrrolobenzodiazocines.
Table 1
Synthesis of different pyrrolo[1,2-f][1,6]-benzodiazocines
H
O
H
O
N
R2
N
R2
NH2
Acryloyl chloride or
methacryloyl chloride
AlCl3, 25 °C
R1
R1
R1
CH2Cl2 or CH3CN
N
Et3N, CH2Cl2, 0 °C
N
N
2
1
3
Entry
Aminopyrrole 1
Acrylamide 2 (yield)
Pyrrolobenzodiazocine 3 (yield)
H
O
H
O
NH2
N
N
1
N
N
N
1a
2a (87%)
3a (67%)
H
N
O
H
O
NH2
N
MeO
N
MeO
MeO
2
3
4
N
N
1b
2b (91%)
3b (64%)
H
N
O
H
N
O
NH2
Cl
Cl
Cl
N
N
N
1c
2c (85%)
3c (72%)
H
N
O
H
N
O
NH2
N
F
F
F
N
N
1d
2d (80%)
3d (61%)
(continued on next page)

5886
S. BouzBouz, M. Sanselme / Tetrahedron Letters 50 (2009) 5884–5887
Table 1 (continued)
Entry
Aminopyrrole 1
Acrylamide 2 (yield)
Pyrrolobenzodiazocine 3 (yield)
H
N
O
H
N
O
NH2
N
5
N
N
Me
Me
Me
1e
2e (82%)
3e (75%)
H
N
O
H
N
O
NH2
Me
Me
6
N
N
N
1a
2f (88%)
3f (67%)
duce B which, after an 1,3-prototropy, leads to C and after hydro-
lysis, 3 can be isolated.
C-C bond
formation
R
+
R
_
N
_
N
H
Mol-B
AlCl3
AlCl3
+
O
O
N
N
H
B
H
A
R
N
_
Mol-A
R
H2O
N
AlCl3
O
N
+
O
N
H
C
H
3
Mol-C
In order to prove that intermediate C is formed in the reaction
media, a 1H NMR19 study was achieved on 2e. When 2e was treated
with AlCl3 in CD2Cl2, after 5 min, it was observed by 1H NMR that
2e disappeared and that a stable intermediate was formed. This
intermediate corresponds to C as the treatment of 3e with AlCl3
led to the same intermediate.
Figure 1. ORTEP representation of three molecules constitutive of the asymmetric
unit of 3,4-dihydro-pyrrolo[1,2-f][1,6]-benzodiazocin-2-one (3a).
In summary, we have described that pyrrolobenzodiazocines
can be obtained in good yields from pyrroloacrylamides when trea-
ted with AlCl3, involving an intramolecular Friedel–Crafts cyclisa-
tion. Further investigations of this efficient intramolecular
cyclisation are in progress in our laboratory and the results will
be reported in due course.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.145.
References and notes
1. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; . Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield,
J. J. Med. Chem. 1988, 31, 2235; (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893.
Figure 2. Superimposition of the three molecules of the Asymmetric Unit of 3a. The
molecules labelled ‘A’ (green) and ‘C’ (violet) are quite the same whereas the
molecule labelled ‘B’ (grey) exhibits
arrangement.
a significant difference on the eight-ring
2. Wang, J.-Y.; Guo, X.-F.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem
2008, 73, 1979. and references cited therein.

S. BouzBouz, M. Sanselme / Tetrahedron Letters 50 (2009) 5884–5887
5887
3. (a) Vedejs, E.; Galante, R. J.; Goekjian, P. G. J. Am. Chem. Soc. 1998, 120, 3613; (b)
Stillings, M. R.; Freeman, S.; Myers, P. L.; Readhead, M. J.; Welbourn, A. P.;
Rance, M. J.; Atkinson, D. C. J. Med. Chem. 1985, 28, 225; (c) Basil, B.; Coffee, E. C.
J.; Gell, D. L.; Maxwell, D. R.; Sheffield, D. J.; Wooldridge, K. R. H. J. Med. Chem.
1970, 13, 403.
s, 1H), 6.14 (br s, 1H), 6.03 (br s, 1H), 3.84 (s, 3H), 3.17 (dtapp, J = 15.2 and
9.6 Hz, 1H), 2.85–2.61 (m, 1H), 2.70–2.60 (m, 1H), 2.41 (m, 1H). 13C NMR
(CDCl3, 75 MHz) d: 175.2 (s), 159.6 (s), 135.1 (s), 131.7 (s), 131.6 (s), 128.5 (d),
123.5 (d), 113.9 (d), 112.3 (d), 108.9 (d), 108.6 (d), 55.8 (q), 31.6 (t), 22.5 (t). IR
(neat)
m
(cmÀ1): 3174 (NH), 1661 (CO). HRMS calcd: 242.1055 [(EI+),
4. Viladomat, F.; Bastida, J. E.; Codina, C.; Campbell, W. E.; Mathee, S.
Phytochemistry 1995, 40, 307.
M = C14H14N2O2], Found: 242.1054Spectral data for 9-chloro-3,4-dihydro-
pyrrolo[1,2-f][1,6]-benzodiazocin-2-one (3c). Yellow solid mp = 189–194 °C;
1H NMR (CDCl3, 300 MHz) d: 8.57 (br s, 1H, NH), 7.25 (br s, 2H), 7.14 (br s, 1H),
6.40 (br s, 1H), 6.06 (br s, 1H), 5.94 (br s, 1H), 3.15 (dtapp, J = 15.2 and 9.6 Hz,
1H), 2.70 (ddapp, J = 15.2 and 9.0 Hz, 1H), 2.51 (dtapp, J = 12.0 and 9.4 Hz, 1H),
2.31 (m, 1H), 13C NMR (CDCl3, 75 MHz) d: 175.4 (s), 137.3 (s), 135.3 (s), 134.0
(s), 131.6 (s), 128.7 (d), 128.4 (d), 127.4 (d), 123.4 (d), 109.5 (d), 109.3 (d), 31.6
5. (a) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Chem. Eur. J. 2007, 13,
6452; (b) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Org. Lett. 2005, 7,
2723; (c) Spring, D. R.; Krishnan, S.; Blackwell, H. E.; Schreiber, S. L. J. Am. Chem.
Soc. 2002, 124, 1354; (d) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14,
95.
6. Aiello, E.; Dattolo, G.; Cirrincione, G.; Almerico, A. M.; D’Asdia, I. J. Heterocycl.
Chem. 1981, 18, 1153.
(t), 22.4 (t). IR (neat) m
(cmÀ1): 3174 (NH), 1666 (CO). HRMS calcd: 246.0560
[(EI+), M = C13H11N2OCl], Found: 246.0567.
7. Koriatopoulou, K.; Karousis, N.; Varvounis, G. Tetrahedron 2008, 64,
10009.
8. Potapov, V. V.; Fetisova, N. A.; Nikitin, A. V.; Ivachtchenko, A. V. Tetrahedron
Lett. 2009, 50, 2790.
Spectral data for 9-fluoro-3,4-dihydro-pyrrolo[1,2-f][1,6]-benzodiazocin-2-one
(3d). Yellow solide mp = 161–165 °C; 1H NMR (CDCl3, 300 MHz) d: 8.75 (s, 1H,
NH), 7.41 (dd, J = 8.8 and 5.6 Hz, 1H), 7.10 (td, J = 8.2 and 2.8 Hz, 1H), 6.97 (dd,
J = 8.7 and 2.8 Hz, 1H), 6.51 (br s, 1H), 6.15 (t, J = 3.0 Hz, 1H), 6.04 (br s, 1H),
3.16 (dtapp, J = 15.4 and 9.6 Hz, 1H), 2.81 (ddapp, J = 15.1 and 9.6 Hz, 1H), 2.62
(dtapp, J = 13.2 and 9.4 Hz, 1H), 2.45 (m, 1H). 13C NMR (CDCl3, 75 MHz) d: 175.5
(s), 163.4 and 160.0 two peaks (s, C–F), 135.8 and 135.7 two peaks (s, Caro),
134.9 and 134.8 two peaks (s, Caro), 131.6 (s), 129.0 and 128.9 two peaks (d,
Caro), 123.5 (d), 115.3 and 115.0 two peaks (d, Caro), 114.5 and 114.2 two peaks
9. Korakas, D.; Varvounis, G. J. Heterocycl. Chem. 1994, 31, 1317.
10. Nakamura, A.; Kamiya, S. Chem. Pharm. Bull. 1974, 22, 2142.
11. De Martino, G.; Massa, S.; Scalzo, M.; Giuliano, R.; Artico, M. J. Chem. Soc., Perkin
Trans. 1 1972, 2504.
12. Compounds 1b–d were prepared in two steps from commercially available 4-
methoxy or 4-chloro or 4-fluoro 2-nitrophenylaniline by thermal condensation
with 2,5-dimethoxytetrahydrofurane in glacial acetic acid to give 1-(4-
methoxy or 4-chloro or 4-fluoro 2-nitrophenyl)-1H-pyrrole, which was then
reduced with ethanolic hydrazine hydrate in the presence of Raney nickel.
Amine 1e was prepared by reduction of 1-(6-methyl 2-nitrophenyl)-1H-
pyrrole in an ethanolic aqueous ammonium chloride solution in the presence
of zinc. Amine 1a is commercially available from Aldrich.
13. Bouzbouz, S. Unpublished results.
(d, Caro), 109.2 (d), 109.0 (d), 31.6 (t), 22.3 (t). IR (neat)
1683 (CO).
m
(cmÀ1): 3185 (NH),
16. Spectral data for 3-methyl-3,4-dihydro-pyrrolo[1,2-f][1,6]-benzodiazocin-2-
one (3f). 1H NMR (CDCl3, 300 MHz) d: 8.43 (br s, 0.15H, NH), 8.35 (br s, 0.85H,
NH), 7.45–7.12 (m, 4H), 6.67 (br s, 0.15H), 6.44 (br s, 0.85H), 6.15 (t, J = 3.02 Hz,
0.15H), 6.08 (t, J = 3.02 Hz, 0.85H), 6.03 (br s, 0.15H), 5.94 (br s, 0.85H), 2.95–
2.65 (m, 3H), 1.12 (d, J = 5.8 Hz, 0.45H), 1.05 (d, J = 5.8 Hz, 2.55H). 13C NMR
major diastereoisomer (CDCl3, 75 MHz) d: 178.1 (s), 139.2 (s), 133.7 (s), 131.4
(s), 128.6 (d), 128.3 (d), 127.4 (d), 127.3 (d), 123.7 (d), 109.5 (d), 108.7 (d), 33.4
14. General procedure:
acrylamide
a flame-dried round-bottomed flask was charged with
2
(1 equiv) in solvent (c = 5 Â 10À3 M). AlCl3 (2 equiv) was
(d), 32.9 (t), 17.1 (q). IR (neat) m
(cmÀ1): 3188 (NH), 1697 (CO). MS m/z: 226
(78), 211 (4) 197 (11), 183 (21), 169 (100), 156 (11), 143 (2), 129 (3), 115 (4),
91 (5), 77 (7), 65 (6).
subsequently added as
a
solid, producing
a
yellow solution which was
stirred at 25 °C. After disappearance of starting material (TLC), the solution
was hydrolysed by H2O, extracted (CH2Cl2) and concentrated in vacuo. The
residue was purified by chromatography on silica gel (CH2Cl2/EtOAc).
17. Crystallographic data for 3a reported in this manuscript have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 728234 Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(+44) 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk).
15. Spectral data for 3,4-dihydro-pyrrolo[1,2-f][1,6]-benzodiazocin-2-one (3a).
Yellow crystal mp = 140–143 °C; 1H NMR (CDCl3, 300 MHz) d: 7.75 (s, 1H,
NH), 7.45 (m, 3H), 7.26 (s, 1H), 6.55 (br s, 1H), 6.17 (br s, 1H), 6.07 (br s, 1H),
3.18 (dtapp, J = 15.2 and 9.6 Hz, 1H), 2.85–2.78 (m, 1H), 2.70–2.60 (m, 1H), 2.42
(m, 1H). 13C NMR (CDCl3, 75 MHz) d: 175.0 (s), 138.9 (s), 134,2 (s), 131.6 (s),
128.8 (d), 128.6 (d), 127.9 (d), 127.5 (d), 123.4 (d), 109.3 (d), 109.0 (d), 31.5 (t),
18. The interconversion of atropoisomers was characterised by a 1HNMR study of
compound 3f in DMSO-d6 at seven different temperatures from 293 to 352 K.
These spectra show the broadening of the signals with increasing temperature,
there is also the reduction in the intensity of signals from the minor
atropoisomer their dispartion up to 352 K.
22.6 (t). IR (neat)
m
(cmÀ1): 3190 (NH), 1697 (CO). MS m/z: 212 (100), 195 (3),
183 (38), 169 (89), 156 (21), 143 (3), 129 (4), 115 (5), 91 (7), 77 (6), 65 (6).
Spectral data for 9-methoxy-3,4-dihydro-pyrrolo[1,2-f][1,6]-benzodiazocin-2-
one (3b). White solid mp = 215–218 °C; 1H NMR (CDCl3, 300 MHz) d: 7.99 (s,
1H, NH), 7.35 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.77 (br s, 1H), 6.51 (br
19. The spectra of compounds 2e and 3e and the spectra of the reaction followed
by NMR are in the Supplementary data.