Facile synthesis of 6,12b-diaza-dibenzo[a,h]azulen-7-ones and benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-ones via CuI/l-proline catalyzed intramolecular N-arylation

Article abstract of DOI:10.1016/j.tetlet.2010.11.117

Facile intramolecular N-arylation catalyzed by CuI/l-proline has been developed to prepare 6,12b-diaza-dibenzo[a,h]azulen-7-ones and benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-ones in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.11.117

Tetrahedron Letters 52 (2011) 541–543
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of 6,12b-diaza-dibenzo[a,h]azulen-7-ones and
benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-ones via CuI/L-proline catalyzed
intramolecular N-arylation
⇑
Hong-Jun Wang , Yi Wang, Fatoumata Camara, William D. Paquette, Adam J. Csakai, John E. Mangette
Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), PO Box 15098, 26 Corporate Circle, Albany, NY 12212, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile intramolecular N-arylation catalyzed by CuI/L-proline has been developed to prepare 6,12b-diaza-
Received 27 September 2010
Revised 17 November 2010
Accepted 23 November 2010
Available online 27 November 2010
dibenzo[a,h]azulen-7-ones and benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-ones in good to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Privileged structures, such as 1,4-benzodiazepines, are impor-
tant in medicinal chemistry.1 In particular, 1,4-benzodiazepine-3-
ones have shown a wide range of biological activities as fibrinogen
receptor antagonists,2a–c protein kinase C activators,2d angiotensin
analogs,2e vasopressin V2 receptor agonists,2f mitochondrial F1F0
ATP hydrolase inhibitors,2g and b-turn mimetics.2h We became
interested in the ring-fused 1,4-benzodiazepine-3-ones, and to
our surprise, analogs such as indolodiazepines or pyrrolodiaze-
pines, had received little synthetic attention.3 Miyashiro et al. re-
R3
O
Me
N
N
H
R1
Me HN
I
I
1
2
R2
R3
O
Me
N
R1
R2
N
cently reported the synthesis of
a pyrrolodiazepine scaffold
through the N-arylation of methyl 1H-pyrrole-2-carboxylate and
2-fluorobenzonitrile, followed by reduction of the cyano group
and subsequent intramolecular cyclization.3a The reduction of the
benzonitrile intermediate required Raney Ni catalyzed hydrogena-
tion in 7 M ammonia in methanol, which may limit the application
of this method. We envisioned that an intramolecular cyclization
of intermediates, such as 2, might provide a more general ap-
proach. Compounds 2 can be easily prepared by acylation of N-
methyl-2-iodobenzylamine (Scheme 1). Herein, we report the
development of this intramolecular N-arylation to prepare a vari-
ety of 6,12b-diaza-dibenzo[a,h]azulen-7-ones and benzo[f]pyrrol-
3
Scheme 1.
N-arylation for the synthesis of pyrroloquinoxalines and indolo-
quinoxalines.4e On the other hand, recent research from Buchwald
and Ma demonstrated the use of CuI/diamino ligand5a or CuI/ami-
no acid5b,c systems to achieve efficient intermolecular N-arylation
of indoles or pyrroles.
As the starting point of this study, the iodo substrate 2a was pre-
pared in 88% yield by Py-Bop coupling of N-methyl-2-iodobenzyl-
amine and 1H-indole-2-carboxylic acid. Application of the
standard Buchwald conditions (CuI/trans-N,N0-dimethyl-1,2-cyclo-
hexanediamine), as shown in entry 1 of Table 1, led to an incom-
plete reaction with 31% of the desired product 3a, 50% of starting
material 2a and 19% of uncharacterized side products being
observed by HPLC analysis. In contrast, application of Ma’s
o[1,2-a][1,4]diazepin-4-ones using CuI/L-proline catalysis.
In the past two decades, significant progress has been made to
the Buchwald–Hartwig N-arylation, including a number of applica-
tions to the synthesis of various diazepines and quinoxalines.4 For
example, Ma and co-workers applied both CuI-catalyzed intermo-
lecular and intramolecular N-arylation of amino acid derivatives to
their synthesis of 1,4-benzodiazepine-3-ones, highlighted with a
modified procedure for the synthesis of SB-214857.4a,b Ferraccioli4c
and Beccalli4d reported the synthesis of diazepines through palla-
dium-catalyzed intramolecular N-arylation of primary amines.
Beccalli also studied the palladium-catalyzed intramolecular
CuI/L-proline conditions gave a clean transformation, and a simple
aqueous workup provided product 3a, which was determined to
be clean by NMR analysis (Table 1, entry 2).6
With this protocol in hand, we were able to examine the intra-
molecular N-arylation of selected iodo substrates as shown in
Tables 2 and 3. Non-substituted indole (Table 2, entry 1) and
indoles bearing electron-withdrawing substituents (entries 2–4)
⇑
Corresponding author. Tel.: +1 518 512 2000; fax: +1 518 512 2081.
E-mail address: Hong-Jun.Wang@amriglobal.com (H.-J. Wang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.117

542
H.-J. Wang et al. / Tetrahedron Letters 52 (2011) 541–543
Table 1
Table 3
Reactions catalyzed with CuI/diamino ligand or CuI/amino acid
Synthesis of pyrrolodiazepine 3h and imidazodiazepine 3i through the cyclization of
iodo substrates
O
O
O
Me
N
O
X
N
CuI/ligand
HO
4
N
X
Me
Me HN
I
N
N
HN
H
Me HN
I
3a
Py-Bop
2a
I
2h, X =CH
2i, X = N
DIPEA, DMF
rt, overnight
1
Entry
Conditionsa
3ab
2ab
O
1
2
A
B
31%c
94%
50%c
0
Me
X
N
CuI, L-proline
N
a
Condition A: trans-N,N0-dimethyl-1,2-cyclohexanediamine (0.08 mmol), CuI
(0.02 mmol), 2a (0.2 mmol), K3PO4 (0.5 mmol), toluene (0.5 mL), 95 °C, 19 h. Con-
dition B: -proline (0.04 mmol), CuI (0.02 mmol), 2a (0.2 mmol), K2CO3 (0.4 mmol),
K2CO3, DMSO
95 °C, 19 h
3h
, X =CH
3i, X = N
L
DMSO (0.5 mL), 95 °C, 19 h.
b
Determined by HPLC analysis at UV 254 nm.
Toluene was evaporated before HPLC analysis.
c
Entry
X
Isolated yield of 2a
Isolated yield of 3b
1
2
CH
N
2h, 83%
2i, 81%
3h, 64%
3i, 82%
a
Table 2
Compound 1 (1.0 mmol), 4 (1.0 mmol), Py-Bop (1.2 mmol), DIPEA (2.0 mmol),
DMF (3 mL).
Synthesis of indolodiazepines through the cyclization of iodo substrates
b
L-Proline (0.04 mmol), CuI (0.02 mmol), 2 (0.2 mmol), K2CO3 (0.4 mmol), DMSO
R3
O
(0.5 mL).
Py-Bop
Me
N
N
DIPEA, DMF
H
R1
Me HN
2a-g
R3
indole acid
rt, overnight
I
I
1
Table 4
R2
Synthesis of indolodiazepines through the cyclization of bromo substrates
O
Me
O
Me
NH
Py-Bop
N
R1
CuI, L-proline
R1
R2
R1
N
DIPEA, DMF
N
R3
Me HN
K2CO3, DMSO
95 °C, 19–45 h
R2
Br
N
indole acid
rt, overnight
R2
Br
6a-f
3a-g
1
2
5a
, R = R = H
, R1 = CH3O, R2 = H
5b
O
1
2
Entry
R1
R2
R3
Isolated yield of 2a
Isolated yield of 3
5c
, R = H, R = F
Me
1
2
3
4
5
6
7
H
Cl
F
NO2
CH3
BnO
H
H
H
H
H
H
CH3O
H
H
H
Ph
H
H
H
2a, 88%
2b, 84%
2c, 88%
2d, 89%
2e, 96%
2f, 64%
2g, 97%
3a, 91%b,d
3b, 90%b,d
3c, 91%b,d
3d, 74%b,d
3e, 94%b,e
3f, 83%c,e
3g, 61%b,e
R3
CuI, L-proline
N
K2CO3, DMSO
120 °C, 24 h
3a-k
R1
R2
CH3O
a
Compound 1 (1.0 mmol), indole acid (1.0 mmol), Py-Bop (1.2 mmol), DIPEA
(2.0 mmol), DMF (3 mL).
Entry
R1
R2
R3
Isolated yield of 6a
Isolated yield of 3b
b
1
2
3
4
5
6
H
H
H
H
CH3O
H
H
H
H
H
H
F
H
Cl
F
CH3
H
H
6a, 83%
6b, 73%
6c, 87%
6d, 75%
6e, 42%
6f, 83%
3a, 93%
3b, 91%
3c, 90%
3e, 87%
3j, 85%
3k, 81%
L-Proline (0.04 mmol), CuI (0.02 mmol), 2 (0.2 mmol), K2CO3 (0.4 mmol), DMSO
(0.5 mL).
c
L-Proline (0.08 mmol), CuI (0.04 mmol), 2f (0.2 mmol), K2CO3 (0.6 mmol), DMSO
(1.5 mL).
d
19 h.
45 h.
e
a
Compound 5 (1.0 mmol), indole acid (1.0 mmol), Py-Bop (1.2 mmol), DIPEA
(2.0 mmol), DMF (3 mL).
provided complete conversions after overnight heating at 95 °C.
Electron-donating substituents on the indole ring slowed down
the cyclization, and extended heating times were required to drive
the reaction to completion (entries 5–7). Due to solubility issues,
b
L-Proline (0.08 mmol), CuI (0.04 mmol), 6 (0.2 mmol), K2CO3 (0.4 mmol), DMSO
(0.5 mL).
more solvent (1.5 mL DMSO) and catalyst (0.4 equiv of L-proline,
0.2 equiv of CuI) were used to complete the transformation of sub-
strate 2f (entry 6). We were pleased to see the standard conditions
worked well on the pyrrole substrate 2h and the imidazole
substrate 2i, leading to pyrrolodiazepine 3h (64%, Table 3, entry
1) and imidazodiazepine 3i (82%, Table 3, entry 2), respectively.
Further expanding the usefulness of this protocol, we were able
to develop conditions to include bromo substrates (Tables 4 and 5).
Under the standard conditions (0.1 equiv of CuI, 0.2 equiv of
overcome this drop in reaction rate, we increased the catalyst load-
ing to 0.2 equiv of CuI/0.4 equiv of L-proline, and were delighted to
see the reaction went to completion after heating at 120 °C for 24 h
(Table 4, entry 1). These conditions were found to tolerate a variety
of electron-donating or electron-withdrawing substituents on the
indole ring or the bromo benzene ring (entries 2–6). Similar to
the iodo substrates, cyclization of the bromo pyrrole substrate 6g
or the bromo imidazole substrate 6h provided pyrrolodiazepine
3h (63%, Table 5, entry 1) and imidazodiazepine 3i (85%, Table 5,
entry 2), respectively.
L-proline, 2 equiv of K2CO3, 95 °C, 19 h), only 15% of bromo
substrate 6a was converted to the corresponding product 3a. To

H.-J. Wang et al. / Tetrahedron Letters 52 (2011) 541–543
543
Table 5
References and notes
Synthesis of pyrrolodiazepine 3h and imidazodiazepine 3i through the cyclization of
bromo substrates
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
2. (a) Miller, W. H.; Ku, T. W.; Ali, F. E.; Bondinell, W. E.; Calvo, R. R.;
Davis, L. D.; Erhard, K. F.; Hall, L. B.; Huffman, W. F.; Keenan, R. M.;
Kwon, C.; Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Takata, D. T.;
Yuan, C.-K. Tetrahedron Lett. 1995, 36, 9433; (b) Samanen, J. M.; Ali, F. E.;
Barton, L. S.; Bondinell, W. E.; Burgess, J. L.; Callahan, J. F.; Calvo, R. R.;
Chen, W.; Chen, L.; Erhard, K.; Feuerstein, G.; Heys, R.; Hwang, S.-M.;
Jakas, D. R.; Keenan, R. M.; Ku, T. W.; Kwon, C.; Newlander, K. A.;
Nichols, A.; Parker, M.; Peishoff, C. E.; Rhodes, G.; Ross, S.; Shu, A.;
Simpson, R.; Takata, D.; Yellin, T. O.; Uzsinskas, I.; Venslavsky, J. W.;
Yuan, C.-K.; Huffman, W. F. J. Med. Chem. 1996, 39, 4867; (c) Keenan, R.
M.; Callahan, J. F.; Samanen, J. M.; Bondinell, W. E.; Calvo, R. R.; Chen,
L.; DeBrosse, C.; Eggleston, D. S.; Haltiwanger, R. C.; Hwang, S. M.; Jakas,
D. R.; Ku, T. W.; Miller, W. H.; Newlander, K. A.; Nichols, A.; Parker, M.
F.; Southhall, L. S.; Uzinskas, I.; Vasko-Moser, J. A.; Venslavsky, J. W.;
Wong, A. S.; Huffman, W. F. J. Med. Chem. 1999, 42, 545; (d) Ma, D.;
Wang, G.; Wang, S.; Kozikowski, A. P.; Lewin, N. E.; Blumberg, P. M.
Bioorg. Med. Chem. Lett. 1999, 9, 1371; (e) Rosenstrom, U.; Sköld, C.;
Lindeberg, G.; Botros, M.; Nyberg, F.; Karlen, A.; Hallberg, A. J. Med.
Chem. 2004, 47, 859; (f) Yokoyama, K.; Suzuki, R.; Kondo, T.; Kondo, A.;
Kobayashi, H. WO 2006054560.; (g) Ding, C. Z.; Hamann, L. G.; Stein, P.
D.; Pudzianowski, A. T. WO 2003106628.; (h) Rosenstroem, U.; Sköld, C.;
Lindeberg, G.; Botros, M.; Nyberg, F.; Karlen, A.; Hallberg, A. J. Med.
Chem. 2006, 49, 6133.
O
O
X
HO
4
Me
X
N
N
HN
H
Me HN
Br
Br
Py-Bop
6g
6h, X = N
, X =CH
5a
DIPEA, DMF
rt, overnight
O
Me
X
N
CuI, L-proline
N
K2CO3, DMSO
120 °C, 24 h
3h, X =CH
3i
, X = N
Entry
X
Isolated yield of 6a
Isolated yield of 3b
1
2
CH
N
6g, 89%
6h, 86%
3h, 63%
3i, 85%
3. (a) Miyashiro, J.; Woods, K. W.; Park, C. H.; Liu, X.; Shi, Y.; Johnson, E. F.; Bouska,
J. J.; Olson, A. M.; Luo, Y.; Fry, E. H.; Giranda, V. L.; Penning, T. D. Bioorg. Med.
Chem. Lett. 2009, 19, 4050; (b) Cheeseman, G. W. H.; Eccleshall, S. A. J. Heterocycl.
Chem. 1986, 23, 65.
a
Compound 5a (1.0 mmol), 4 (1.0 mmol), Py-Bop (1.2 mmol), DIPEA (2.0 mmol),
DMF (3 mL).
b
L
-Proline (0.08 mmol), CuI (0.04 mmol), 6 (0.2 mmol), K2CO3 (0.4 mmol), DMSO
4. (a) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583; (b) Wang, H.; Jiang, Y.; Gao, K.; Ma, D.
Tetrahedron 2009, 65, 8956; (c) Catellani, M.; Catucci, C.; Celentano, G.;
Ferraccioli, R. Synlett 2001, 803; (d) Beccalli, E. M.; Broggini, G.; Paladino, G.;
Zoni, C. Tetrahedron 2005, 61, 61; (e) Abbiati, G.; Beccalli, E. M.; Broggini, G.;
Paladino, G.; Rossi, E. Synthesis 2005, 2881.
5. (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684;
(b) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164; (c) Yuan, Q.; Ma, D. J.
Org. Chem. 2008, 73, 5159.
(0.5 mL).
In conclusion, we have developed facile procedures for the
synthesis of 6,12b-diaza-dibenzo[a,h]azulen-7-ones and benzo
[f]pyrrolo[1,2-a][1,4]diazepin-4-ones via CuI/ -proline catalyzed
intramolecular N-arylation. In the presence of 0.2 equiv of -proline
and 0.1 equiv of CuI, cyclization of the iodo substrates proceeds
smoothly to completion after heating at 95 °C for 19–45 h, giving
the desired products in good to excellent yields. Cyclization of
the bromo substrates requires higher temperature (120 °C) and
L
L
6. General
dibenzo[a,h]azulen-7-one (3a):
(0.0038 g, 0.020 mmol),
procedure
for
the
A
synthesis
of
5,6-dihydro-6,12b-diaza-
mixture of 2a (0.078 g, 0.20 mmol), CuI
L
-proline (0.0046 g, 0.040 mmol) and K2CO3
(0.055 g, 0.40 mmol) in DMSO (0.5 mL) was heated at 95 °C under
nitrogen atmosphere for 19 h. After this time, the reaction mixture was
cooled to room temperature, diluted with EtOAc (75 mL), washed with
water (3 ꢀ 10 mL) and satd aq NaCl (15 mL), dried over anhydrous
MgSO4, and filtered. The solvent was evaporated under reduced pressure
to give the product 3a (0.048 g, 91%), which was determined to be clean
by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) d 7.77 (d, J = 8.0 Hz, 1H),
7.75–7.71 (m, 2H), 7.50 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 7.45 (dd, J = 7.5,
1.5 Hz, 1H), 7.37 (d, J = 0.5 Hz, 1H), 7.36–7.31 (m, 2H), 7.27–7.24 (m, 1H),
4.67 (d, J = 15.0 Hz, 1H), 3.90 (d, J = 15.0 Hz, 1H), 3.23 (s, 3H); 13C NMR
catalyst loading (0.4 equiv of L-proline and 0.2 equiv of CuI), lead-
ing to the desired products in good to excellent yields.
Acknowledgments
The authors thank Dr. Keith D. Barnes and Dr. R. Jason Herr of
AMRI for helpful discussions and suggestions during the course
of this study.
(125 MHz, CDCl3)
d 162.1, 137.7, 136.8, 135.2, 132.6, 129.2, 128.4, 127.6,
126.3, 124.6, 124.2, 122.5, 121.8, 111.9, 109.7, 51.3, 35.0; MS (ESI) m/z
261 [MꢁH]ꢁ.