New derivatives and ring systems of annulated pyrrolobenzo[1,4]diazepines

Article abstract of DOI:10.1016/j.tet.2007.12.044

(S)-11-Thioxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5(10H)-one was subsequently reacted with amino acid esters and base to give new 6:7:5:5, 6:7:5:6, and 6:5:7:7 ring systems. The 6:7:5:5 ring system, (S)-11,12,13,13a-tetrahydro-2H

Full text of DOI:10.1016/j.tet.2007.12.044

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2048e2056
www.elsevier.com/locate/tet
New derivatives and ring systems of annulated
pyrrolobenzo[1,4]diazepines
a
Andreas Schmidt a, , Anika Sabine Lindner ,
*
Abbas Gholipour Shilabin a, Martin Nieger b
a Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
b Laboratory of Inorganic Chemistry, 00014 University of Helsinki, Finland
Received 1 November 2007; received in revised form 17 December 2007; accepted 20 December 2007
Available online 14 January 2008
Abstract
(S)-11-Thioxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5(10H)-one was subsequently reacted with amino acid esters
and base to give new 6:7:5:5, 6:7:5:6, and 6:5:7:7 ring systems. The 6:7:5:5 ring system, (S)-11,12,13,13a-tetrahydro-2H-benzo[e]imidazo[2,1-
c]pyrrolo[1,2-a][1,4]diazepine-3,9-dione, exhibits a considerable CH-acidity at position 2, which was exploited in Knoevenagel reactions,
a Wittig reaction, enol ester formations, and methylations.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Knoevenagel reactions; Circumdatin; Pyrrolobenzodiazepine
1. Introduction
was postulated recently as structure of Circumdatin A 1 and
B 2 from Aspergillus species16 (Scheme 1).
Benzodiazepines form a well-known and widely applied
class of biologically active compounds1 and are representa-
tives of the family of privileged structures.2 In the area of
molecular recognition considerable efforts have been devoted
to the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines (PBDs)
that can recognize and bind to specific sequences of DNA.
They are potential regulators of gene expression with possible
application as therapeutic agents in the treatment of genetic
disorders including cancer.3 Furthermore, they can be used
as affinity-cleavage reagents in molecular biology.4 The PBD
ring system is also found in natural antitumor antibiotics from
Streptomyces species such as Anthramycin,5 Tomaymycine,6
Abbeymycin,7 Chicamycin A,8 DC-81,9 Mazethramycin,10
Neothramycin A and B,11 Prothracarcin,12 Sibanomicin,13
Sibiromycin,14 and Porothramycin B.15 A pentacyclic system
O
O
R
N
R
N
H
N
N
H
N
N
O
O
OH
O
OMe
MeO
1: R = OMe
2: R = H
3: R = OMe
4: R = H
Scheme 1. The Circumdatins A, B, D, E.
All naturally occurring compounds possess the (S)-configura-
tion at the a-carbon atom of the pyrrolidine ring [i.e., C(11a)],
which causes an isohelicity with the minor groove of the dou-
ble-stranded B-form of DNA. In continuation of our interest in
alkaloids and model compounds of alkaloid structures,17 nucleo-
base betaines,18 and ionic heteroaromatics19 we became inter-
ested in this class of compounds and synthesized some model
* Corresponding author. Fax: þ49 (0)5323 722858.
E-mail address: schmidt@ioc.tu-clausthal.de (A. Schmidt).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.044

A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
2049
compounds of the proposed betainic structures of Circumdatin A
and B.26 We report here the syntheses and reactions of first repre-
sentatives of the new 6:7:5:5 ring system 3,9,11,12,13,13a-hexa-
hydro-2H-benzo[e]imidazo[2,1-c]pyrrolo[1,2-a][1,4]diazepine,
its 6:7:5:6 derivative, 2,3,4,10,12,13,14,14a-octahydrobenzo[e]-
pyrimido[2,1-c]pyrrolo[1,2-a][1,4]diazepine, and its 6:7:5:7
derivative, 5,8a,13b-triaza-benzo[g]cyclohepta[e]azulene. The
6:5:7:6 ring system is the partial structure of the Circumdatin
familyof alkaloidsfromAspergillus speciessuchas Circumdatin
D 3 and E 4,20,21 as well as of numerous other natural products
such as the Benzomalvins AeC, Asperlicins, Sclerogenin,20
and nonpeptidal cholecystokinin antagonists from microbial
sources.21,22
butanoate hydrochloride, and ethyl 5-amino-pentanoate hydro-
chloride, respectively, in the presence of HgCl2 and triethyl-
amine to the corresponding iminoesters 7aed in high yields.
Signals were observed between d¼5.30 and 5.72 ppm in the
1H NMR spectra taken in CDCl3, suggesting secondary amine
protons which are not involved in tautomerism in solution.
Indicative for the N(10)]C(11)eNH partial structure, HH-
COSY experiments showed correlations between these NH
groups and the CH2 groups of the side chains. This is in con-
trast to other derivatives which we described earlier.25,26 The
structure of 7b was also confirmed by an X-ray single crystal
analysis which is shown in Figure 1. Single crystals were
obtained by slow evaporation of 7b in MeOH. Intermolecular
hydrogen bonds were detected between N(71)eH and
C(1)]O [H/O distance¼209(1) pm; crystallographic num-
bering] and between C(6)eH and C(74)]O [H/O distance¼
236 pm]; close contacts were measured between C(11)eH and
N(8)eH [H/N distance¼248 pm].
2. Results and discussion
2.1. Syntheses and spectroscopic features
Ring closure of 7aec was easily accomplished by 2 N
NaOH in a mixture of dioxane/water (2:1) at room tempera-
ture. Thus, the new 6:7:5:5, 6:7:5:6, and 6:7:5:7 ring systems
8aec were obtained in excellent yields. Tetracycle 8a was also
prepared on reaction of 7a with sodium hydride in anhydrous
DMF at room temperature. Using starting material 7d under
analogous reaction conditions resulted in the formation of
carboxylic acid 9 instead of the expected 6:7:5:8 ring system.
Single crystals of 8a were obtained by slow evaporation of
a saturated solution in acetone. The compound crystallized
monoclinic. The results of the X-ray single crystal structure
analysis including the crystallographic numbering are shown
in Figure 2. The pyrrolobenzodiazepine ring system adopts
a twisted conformation with the seven-membered ring in
Reaction of the benzo[e]pyrrolo[1,2-a][1,4]diazepine 5
from Isatis indigotica23 with Lawesson’s reagent in toluene
gave monothiolactam 6a24 or dithiolactam 6b depending on
the reaction conditions (Scheme 2). Thus, higher temperatures
gave high yields of dithiolactam 6b while lower temperatures
resulted in monothiolactam 6a as the exclusive reaction
product.
O
X
Lawesson´s
reagent
N
N
toluene, reflux
H
O
H
S
N
N
H
H
5
6a: X = O
6b: X = S
[6a] A)
O
N
O
N
[7a]
H
NH
B)
H
N
N
N
O
O
n
7a: n=1
7b: n=2
7c: n=3
7d: n=4
8a
OEt
[7b]
B)
[7c]
B)
[7d] B)
O
O
O
N
N
N
H
NH
H
N
H
N
N
N
N
O
O
O
4
9
8b
8c
OH
Scheme 2. Synthesis of new ring systems starting from monothiolactam 6a.
Reaction conditions: (A) EtOOCe(CH2)neNHþ3 Clꢀ, HgCl2, NEt3; (B) (1)
NaOH, dioxane, H2O; (2) HCl.
Monothiolactam 6a reacted with glycine ethyl ester hydro-
chloride, b-alanine ethyl ester hydrochloride, ethyl 4-amino-
Figure 1.

2050
A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
was formed on treatment of 8a with bromine and triphenylphos-
phine in good yields (Scheme 4). Reaction with butyraldehyde
then yielded 12. Bromination of 8a with NBS and AIBN,
however, resulted in the formation of 2-bromo derivative 13 as
intensely yellow colored compound, which is unstable on
storage. Under these conditions, the chiral C11a-position of
the pyrrolobenzodiazepine partial structure is oxidized.
O
N
PPh3 / Br2 + Et3N
Benzene / CCl4
8a
H
N
N
O
NBS, AIBN
P
Ph
Ph
Ph
Figure 2.
11
a boat conformation. Accordingly, the dihedral angles of
N11BeC3AeC3BeN6A (crystallographic numbering) and
C11AeC7AeC7eN6A are ꢀ63.2(2)ꢁ and 42.4(2)ꢁ, respec-
tively. Moreover, torsion angles of ꢀ2.2(2)ꢁ [C3BeN6Ae
C7eC7A] and ꢀ177.3(1)ꢁ [C7eC7AeC11AeN11B] were
determined. The bond distance of C3AeN3 is 127.4(2) pm
which corresponds to imino C(sp2)]N(sp2) double bond.
The C3AeC3B bond is a single bond with a bond length of
150.0(2) pm. A close intermolecular contact was measured
between C(11)eH and O(7) [H/O distance¼245 pm].
The new ring system 8a has a CH-acidic methylene group in
the imidazoline ring. Thus, acetone in the presence of K2CO3 at
reflux temperature furnished the Knoevenagel product 10a in
good yield (Scheme 3). Treatment of 8a with cyclohexanone
under analogous conditions gave 10b, and cyclopentanone
gave 10c. Under these conditions, however, almost complete
racemization occurred.
Toluene (abs.)
O
O
N
H
N
O
N
O
N
Br
13
H
N
O
N
H
12
Scheme 4.
Additional functionalizations of 8a were achieved on
Einhorn reaction with benzoyl chloride in pyridine and di-
chloromethane, which resulted in the formation of ester 14a
(Scheme 5). Under analogous reaction conditions acetyl
chloride reacted to 14b, which could not be isolated in pure
form. However, peaks at m/z¼297, 282, and 254 in mass
spectrometry could be assigned to the proposed structure,
which obviously decomposed during the work-up procedure
8a
O
R1
R2
base
O
O
O
N
N
N
1. pyridine /CH2Cl2
8a
H
2. benzoyl chloride
H
H
N
N
N
N
N
N
O
O
O
14a
H
O
Me
O
Me
10a
N
10c
H
1. LDA,THF
2. MeI
N
N
1. pyridine /CH2Cl2
2. acetyl chloride
O
O
10b
N
O
Scheme 3. Exploiting the CH-acidity of ring system 8a.
N
H
N
N
H
N
O
These reactions could also be performed as domino cyclo-
condensation reactions to afford 10a and 10b in one step start-
ing from monothiolactam 6a, or, alternatively, using n-BuLi in
THF. An alternative approach to exocyclic double bonds in
position 2 of 8a was the reaction via Wittig ylide 11, which
N
H
O
O
14b
15
Scheme 5. Acylations and methylations of 8a.

A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
2051
3
˚
to reconstitute dilactam 5. Methylation of 8a resulted in the for-
mation of 15, as proved by HSQC- and HMBC-NMR-measure-
ments. In HMBC-analysis couplings between C-2 at 68.5 ppm
and the methyl groups at 1.37 and 1.44 ppm were found.
We then tried to introduce a keto group in position 2 of 8a.
Thus, thiolactam 6a was reacted with anhydrous NH3 and
HgCl2 to yield 16 which we described earlier25 (Scheme 6).
Reaction with oxalyl chloride at ꢀ78 ꢁC in the presence of
triethylamine lead to 17, which proved to be an unstable com-
pound. After a short period of time, dilactam 5 reconstituted.
V¼1626.11(7) A , Z¼4, r(calcd)¼1.288 Mg mꢀ3, F(000)¼
672, m¼0.090 mmꢀ1, 15,194 reflections (2qmax¼55ꢁ) mea-
sured on a Nonius Kappa-CCD diffractometer at 123(2) K
˚
using Mo Ka radiation (l¼0.71073 A), 3687 unique
[Rint¼0.040] used for structure solution (Direct Methods,
SHELXS-9727a) and refinement (full-matrix least-squares on
F2, SHELXL-9727b) with 211 parameters and 1 restraint,
H-atoms with a riding model, R1 (I>2s(I))¼0.031, wR2
(all data)¼0.074, largest diff. peak and hole 0.196 and
ꢀ0.193 e Aꢀ3. The absolute configuration could not be deter-
˚
mined reliably (x¼ꢀ0.5(8), racemic twin).27c
O
NH3 (g)
N
3.2.2. Compound 8a
Colorless crystals, C14H13N3O2, M¼255.27, crystalsize0.40ꢂ
6a
HgCl2, NEt3, THF
H
N
NH2
0.30ꢂ0.20 mm, monoclinic, space group P21 (no. 4): a¼
ꢁ
˚
˚
˚
9.3330(2) A, b¼7.0934(2) A, c¼9.9247(3) A, b¼114.714(1) ,
16
V¼596.86(3) A , Z¼2, r(calcd)¼1.420 Mg mꢀ3, F(000)¼268,
3
˚
1. NEt3, CH2Cl2, rt
2. (COCl)2, -78 °C
m¼0.098 mmꢀ1, 5713 reflections (2qmax¼55ꢁ) measured on
a Nonius Kappa-CCD diffractometer at 123(2) K using Mo Ka
˚
O
radiation (l¼0.71073 A), 2197 unique [Rint¼0.023] used for
N
structure solution (Direct Methods, SHELXS-9727a) and refine-
ment (full-matrix least-squares on F2, SHELXL-9727b) with 172
parameters and 1 restraint, H-atoms with a riding model, R1
(I>2s(I))¼0.028, wR2 (all data)¼0.069, largest diff. peak and
H
N
N
O
hole 0.129 and ꢀ0.215 e Aꢀ3. The absolute configuration could
O
˚
17
not be determined reliably (x¼ꢀ0.1(10)).27c
Scheme 6.
Crystallographic data (excluding structure factors) for the
structures reported in this work have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-664431 (7b) and CCDC-664432 (8a).
Copies of the data can be obtained free of charge on application
to The Director, CCDC, 12 Union Road, Cambridge DB2 1EZ,
UK (fax: þ44 (1223) 336033; e-mail: deposit@ccdc.cam.ac.uk).
In summary, we present three new ring systems as deriva-
tives of natural products, and functionalizations to either po-
tentially biologically active compounds or starting materials
for further derivatizations.
3. Experimental
3.3. (S)-2,3-Dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]-
diazepine-5,11(10H,11aH)-dithione (6b)
3.1. General
The H and 13C NMR spectra were recorded on Bruker
1
A mixture of dilactam 5 (2.16 g, 10 mmol) and Lawesson’s
reagent (2.02 g, 5 mmol) in toluene was stirred overnight at
room temperature and then refluxed for 6 h. Evaporation of
the solvent in vacuo gave a solid residue, which was purified
by flash chromatography [silica, CH2Cl2/acetone (100:1)] to
give monothiolactam 6a as yellow solid (Rf¼0.05) and pure
dithiolactam 6b as a dark yellow solid (Rf¼0.4).
ARX-400 and DPX-200 spectrometers and were taken in
CDCl3 and DMSO-d6 at 200 and 400 MHz at 20 ꢁC. The
chemical shifts are reported in parts per million relative to in-
ternal tetramethylsilane (d¼0.00). Multiplicities are described
by using the following abbreviations: s¼singlet, d¼doublet,
t¼triplet, q¼quadruplet, h¼heptet, m¼multiplet, br¼broad.
The mass spectra (EIMS) were measured with a Hewlett-
Packard HP 5989B or a Varian SAT2100T with GC3900.
Melting points are uncorrected. The CHN analyses were per-
formed in the Institute of Technical Chemistry of the Clausthal
University of Technology.
Yield of 6b: 0.41 g (34%); mp: 254 ꢁC. 1H NMR (400 MHz,
DMSO-d6): d¼1.92e2.05 (m, 1H, 2-H), 2.14e2.38 (m, 2H, 1,2-
H), 2.82e2.92 (m, 1H, 1-H), 3.64e3.79 (m, 1H, 3-H),
3.89e3.99 (m, 1H, 3-H), 4.59 (d, J¼7.04 Hz, 1H, 11a-H),
7.22 (d, J¼8.02 Hz, 1H, 9-H), 7.31 (t, J¼7.49 Hz, 1H, 7-H),
7.54 (td, J¼7.73, 1.10 Hz, 1H, 8-H), 8.12 (dd, J¼8.02,
7.49 Hz, 1H, 6-H), 12.61 (br s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): d¼22.9 (C-2), 29.6 (C-1), 55.1 (C-3), 65.3
(C-11a), 122.1, 125.9, 132.2, 133.0, 134.7, 135.2, 190.2 (CS),
200.1 (CS). IR (KBr): ~n ¼ ¼ 576, 658, 773, 825, 978, 1046,
1158, 1188, 1371, 1482, 1520, 1599, 2924, 3068, 3105, 3424.
MS: 248 (100) [M], 179 (23), 136 (10), 71 (100).
3.2. X-ray crystal structure analysis of 7b and 8a
3.2.1. Compound 7b
Colorless crystals, C17H21N3O3, M¼315.37, crystal size
0.40ꢂ0.30ꢂ0.10 mm, orthorhombic, space group P212121
˚
˚
˚
(no. 19): a¼8.4072(2) A, b¼12.5881(3) A, c¼15.3652(4) A,

2052
A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
Anal. Calcd for C12H12N2S2 (248.37): C, 58.1; H, 4.9; N,
11.3. Found: C, 57.6; H, 4.9; N, 11.3.
4.27 (q, J¼7.1 Hz, 2H, CH2CH3), 5.74 (br s, 1H, NH), 7.04e
7.12 (m, 2H, 8-H, 9-H), 7.36e7.44 (m, 1H, 7-H), 7.40 (ddd,
J¼8.1, 7.2, 1.6 Hz, 1H, 6-H). 13C NMR (50 MHz, CDCl3):
d¼14.2 (CH2CH3), 23.6 (C-2), 26.6 (C-1), 33.0 (COCH2),
36.7 (NHCH2), 46.4 (C-3), 54.4 (C-11a), 60.9 (CH2CH3),
122.4, 126.5, 126.6, 130.1, 131.6, 146.7, 156.2 (C-11), 166.9
(CO), 171.0 (CO2). IR (KBr): ~n ¼ 3283 ðNHÞ, 3059, 2973,
2870, 1728, 1603, 1524, 1465, 1342, 1174, 1032. GCeMS
(70 eV) m/z (%): 315 (100) [Mþ], 270 (19), 242 (52), 215
(14), 200 (19), 172 (28), 146 (34), 118 (15), 70 (31).
3.4. General procedure for preparation of the
pyrrolobenzo[1,4]diazepin-5-ones (7aed)
To a suspension of thiolactam 6a (0.232 g, 1.0 mmol) and
HgCl2 (0.272 g, 1.0 mmol) in acetonitrile (30 mL) was first
added the amino acid ethyl ester hydrochloride (1.5 mmol)
and then Et3N (1.0 mL) at room temperature. The mixture
was then refluxed for 2e3 h (monitored by TLC), during
which time the color changed to black. After cooling, the
resulting mixture was filtered through a plug of Celite which
was then washed with chloroform. The filtrate was subse-
quently treated with a saturated NaHCO3 solution (20 mL)
and a solution of Na2S2O3 (20 mL). The solvents were then
removed under reduced pressure to give the crude products
which were finally recrystallized.
Anal. Calcd for C17H21N3O3 (315.37): C, 64.7; H, 6.7; N,
13.3. Found: C, 64.6; H, 6.5; N, 13.3.
3.4.3. (S)-Ethyl 4-(5-oxo-2,3,5,11a-tetrahydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepin-11-ylamino)-
butanoate (7c)
Using 4-aminobutyric ethyl ester hydrochloride as starting
material gave 7c as a red oil.
Yield: 0.36 g (98%). 1H NMR (200 MHz, CDCl3): d¼1.27 (t,
J¼7.1 Hz, 3H, CH2CH3), 1.90e1.98 (m, 2H, 14-H), 2.08e2.32
(m, 4H, 1-H, 2-H), 2.48 (t, J¼6.7 Hz, 2H, 15-H), 3.32e3.62 (m,
3H, 3-H, 13-H), 3.80e3.91 (m, 1H, 3-H), 4.01 (dd, J¼7.6,
2.1 Hz, 1H, 11a-H), 4.15 (q, J¼7.1 Hz, 2H, CH2CH3), 5.74
(br s, 1H, NH), 7.02e7.12 (m, 2H, 8-H, 9-H), 7.39 (ddd,
J¼7.4, 1.7 Hz, 1H, 7-H), 7.92 (dd, J¼7.4, 1.3 Hz, 1H, 6-H).
13C NMR (50 MHz, CDCl3): d¼12.3 (CH2CH3), 21.4 (C-2),
21.8 (C-1), 24.7 (C-13), 30.5 (C-14), 40.1 (C-12), 44.6 (C-3),
52.6 (C-11a), 58.9 (CH2CH3), 120.3, 124.6, 124.8, 128.1,
129.7, 133.6 (Carom.), 154.7 (C-11), 164.7 (C]O), 172.7
(C]O). IR (NaCl): ~n ¼ 3355, 2980, 1730, 1608, 1462, 1416,
1216, 1034, 761. LCeMS (ESI): 330.1821 (100) [M].
Anal. Calcd for C18H23N3O3 (329.29): C, 65.6; H, 7.0; N,
12.7. Found: C, 65.7; H, 7.0; N, 12.5.
3.4.1. (S)-Ethyl 2-(5-oxo-2,3,5,11a-tetrahydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepin-11-ylamino)-
acetate (7a)
Using glycine ethyl ester hydrochloride as starting material
gave an oil. By addition of diethyl ether (15 mL) and stirring
for 10 min at room temperature, the crude product was
obtained as a pale yellow solid which was filtered off and
washed with diethyl ether. Recrystallization from EtOAc/
petrol afforded pale yellow crystals.
Yield: 0.25 g (83%); mp: 89e91 ꢁC; [a]D20 þ717.2 (c 1.0,
1
CHCl3). H NMR (400 MHz, CDCl3): d¼1.32 (t, J¼7.1 Hz,
3H, CH2CH3), 2.04e2.18 (m, 2H, 2-H), 2.22e2.38 (m, 2H,
1-H), 3.54e3.61 (m, 1H, 3-H), 3.86e3.92 (m, 1H, 3-H), 4.06
(dd, J¼7.8, 1.9 Hz, 1H, 11a-H), 4.10e4.27 (m, 2H, NHCH2),
4.27 (q, J¼7.1 Hz, 2H, CH2CH3), 5.46 (br s, 1H, NH),
7.08e7.12 (m, 2H, 8-H, 9-H), 7.38e7.42 (m, 1H, 7-H), 7.96
(dd, J¼8.3, 1.7 Hz, 1H, 6-H). 13C NMR (100 MHz, CDCl3):
d¼14.6 (CH2CH3), 24.2 (C-2), 27.2 (C-1), 43.7 (NHCH2),
46.9 (C-3), 54.5 (C-11a), 62.1 (CH2CH3), 123.1, 127.0,
127.2, 130.5, 132.0, 147.0, 156.2 (C-11), 166.9 (CO), 171.0
(CO). IR (KBr): ~n ¼ 3312 ðNHÞ, 3055, 2976, 1784, 1620,
1593, 1541, 1461, 1277, 1199. GCeMS (70 eV) m/z (%): 301
(100) [Mþ], 255 (42), 226 (10), 186 (13), 158 (25), 131 (14),
102 (16), 70 (17).
3.4.4. (S)-Ethyl 5-(5-oxo-2,3,5,11a-tetrahydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepin-11-ylamino)-
pentanoate (7d)
Using 5-aminovaleric ethyl ester hydrochloride gave a red
oil.
Yield: 0.68 g (99%); [a]2D0 þ424.1 (c 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): d¼1.27 (t, J¼7.1 Hz, 3H, CH2CH3),
1.66e1.70 (m, 4H, 2-H, 14-H), 1.74e1.80 (m, 1H, 1-H),
2.05e2.17 (m, 2H, 15-H), 2.30e2.41 (m, 3H, 16-H, 1-H),
3.32e3.47 (m, 2H, 13-H), 3.50e3.64 (m, 1H, 3-H), 3.81e
3.93 (m, 1H, 3-H), 4.02 (dd, J¼7.1, 2.1 Hz, 1H, 11a-H), 4.14
(q, J¼7.1 Hz, 2H, CH2CH3), 5.21 (br s, 1H, NH), 7.02e7.11
(m, 2H, 7-H, 9-H), 7.39 (ddd, J¼7.6, 1.8 Hz, 1H, 8-H), 7.9
(dd, J¼7.87 Hz, 1H, 6-H). 13C NMR (50 MHz, CDCl3):
d¼14.2 (CH2CH3), 21.9 (C-15), 23.8 (C-2), 26.6 (C-1), 28.3
(C-14), 33.6 (C-16), 40.9 (C-13), 46.4 (C-3), 54.4 (C-11a),
60.5 (CH2CH3), 122.1, 126.5, 126.7, 129.8, 130.0, 131.5
(Carom.), 156.3 (C-11), 166.6 (C]O), 173.9 (C]O). IR
(NaCl): 3347, 2939, 1731, 1607, 1539, 1461, 1415, 1162,
1110, 1034, 763. MS: 343 (100) [Mþ], 298 (30), 256 (100),
242 (60), 229 (90), 199 (50), 160 (70), 70 (75).
Anal. Calcd for C16H19N3O3 (301.34): C, 63.8; H, 6.3; N,
13.9. Found: C, 63.7; H, 6.1; N, 13.5.
3.4.2. (S)-Ethyl 3-(5-oxo-2,3,5,11a-hexahydro-1H-
benzo[e]pyrrolo-[1,2-a][1,4]diazepin-11-ylamino)-
propanoate (7b)
Using b-alanine ethyl ester hydrochloride as starting mate-
rial afforded a solid which was recrystallized from benzene to
yield 7b as colorless crystals.
Yield: 0.222 g (70%); mp: 122e124 ꢁC; [a]D20 þ878.5 (c 1.0,
CHCl3). 1H NMR (200 MHz, CDCl3): d¼1.28 (t, J¼7.1 Hz, 3H,
CH2CH3), 1.93e2.35 (m, 4H, 1-H, 2-H), 2.64e2.71 (m, 2H,
COCH2), 3.48e3.62 (m, 1H, 3-H), 3.57e3.74 (m, 2H,
NHCH2), 3.81e3.92 (m, 1H, 3-H), 4.00e4.05 (m, 1H, 11a-H),
Anal. Calcd for C19H25N3O3: C, 66.45; H, 7.34; N, 12.24.
Found: C, 66.61; H, 6.92; N, 12.83.

A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
2053
3.5. General procedure for the preparation of 1,3-imidazole-,
1,3-pyrimidine-, and 1,3-diazepin-4-one-pyrrolo-
benzo[1,4]diazepin-5-ones (8 and 9)
Anal. Calcd for C15H15N3O2 (269.30): C, 66.9; H, 5.6; N,
15.6. Found: C, 66.6; H, 5.7; N, 15.2.
3.5.3. (5bS)-2,3,4,5b,6,7,8-Octahydro-5,8a,13b-triaza-
benzo[g]cyclohepta[e]-azulene-1,8-dione (8c)
Using 7c gave a solid which was recrystallized from EtOH/
2-propanol to yield 8c as colorless crystals.
To a solution of the cycloamidine ethyl esters 7aed (1.505,
1.575, 1.560 g (5.0 mmol) and 0.343 g (1.0 mmol)) in a mixture
of dioxane/water (2:1) (50 mL) was added a solution of NaOH
(2 N) (3.0 mL) at 0 ꢁC. The reaction mixture was then stirred
for 30 min at room temperature after removing the ice bath,
and then acidified to pH¼3 with HCl (0.5 N) at 0 ꢁC. Compound
8a was purified by extraction with chloroform (2ꢂ50 mL), dry-
ing of the combined organic layers over Na2SO4, and evapora-
tion of the solvent under reduced pressure. The resulting
solids were extracted with dichloromethane (50 mL) to remove
impurities. The aqueous layers were evaporated in vacuo to give
solids which were extracted with methanol. After distillation of
the solvent 8b and 8c were obtained as colorless solids, respec-
tively, and 9 as pale yellow oil.
Yield: 1.01 g (67%); mp: 210 ꢁC. 1H NMR (200 MHz,
DMSO-d6): d¼1.81e2.01 (m, 4H, 7-H, 3-H), 2.02e2.29 (m,
1H, 6-H), 2.40 (t, J¼7.5 Hz, 2H, 2-H), 2.63e2.82 (m, 1H,
6-H), 3.38e3.71 (m, 4H, 4-H, 8-H), 4.51 (d, J¼7.6 Hz, 1H,
5b-H), 7.38e7.48 (m, 1H, 13-H), 7.60e7.79 (m, 2H, 11-H,
12-H), 7.83 (d, J¼7.6 Hz, 1H, 10-H). 13C NMR (50 MHz,
DMSO-d6): d¼22.7 (C-7), 23.0 (C-6), 25.5 (C-3), 30.5 (C-2),
42.2 (C-8), 46.5 (C-4), 55.4 (C-5b), 124.3, 126.6, 128.0,
129.9, 132.0, 134.0 (Carom.), 162.6 (C-5a), 163.7 (C]O),
174.1 (C]O). IR (NaCl): ~n ¼ 3435, 2881, 1725, 1669, 1634,
1482, 1449, 1415, 1354, 1268, 1225, 1177, 892, 798, 764,
697. GCeMS (70 eV) m/z (%): 283 (100) [Mþ1].
Anal. Calcd for C16H17N3O2 (283.88): C, 67.8; H, 6.0; N,
14.8. Found: C, 67.6; H, 6.0; N, 14.7.
3.5.1. (S)-11,12,13,13a-Tetrahydro-2H-benzo[e]imidazo-
[2,1-c]pyrrolo[1,2-a][1,4]diazepine-3,9-dione (8a)
Using 7a afforded a solid which was recrystallized from
acetone to yield 8a as pale yellow crystals.
3.5.4. (S)-(5-Oxo-2,3,5,11a-tetrahydro-1H-benzo[e]pyrrolo-
[1,2-a][1,4]diazepin-11-ylamino)pentanoic acid (9)
Using 7d gave a solid which was recrystallized from EtOH/
2-propanol to yield 9 as faintly yellow oil.
Yield: 1.084 g (85%); mp: 199e201 ꢁC; [a]D20 þ130.5 (c 1.0,
1
CHCl3). H NMR (200 MHz, CDCl3): d¼1.98e2.31 (m, 3H,
4-H, 5-H), 2.84e2.98 (m, 1H, 4-H), 3.60e3.68 (m, 1H, 6-H),
3.82e3.93 (m, 1H, 6-H), 4.32e4.35 (m, 2H, 2-H), 4.41e4.45
(m, 1H, 3b-H), 7.41 (ddd, J¼7.9, 7.4, 1.4 Hz, 1H, 10-H),
7.54e7.63 (m, 1H, 9-H), 7.69 (dd, J¼7.9, 1.1 Hz, 1H, 11-H),
7.99 (dd, J¼7.8, 1.4 Hz, 1H, 8-H). 13C NMR (50 MHz,
CDCl3): d¼23.3 (C-5), 26.0 (C-4), 47.3 (C-6), 53.9 (C-3b),
59.0 (C-2), 122.3, 126.4, 127.8, 129.5, 130.4, 131.1 (Carom.),
162.8 (C-3a), 164.0 (CO), 177.4 (CO). IR (KBr): ~n ¼ 2959,
2876, 1749, 1624, 1465, 1340, 1220, 1170, 1026. GCeMS
(70 eV) m/z (%): 255 (100) [Mþ], 226 (25), 198 (14), 184
(16), 172 (16), 158 (34), 130 (36), 103 (31), 69 (23).
Yield: 0.252 g (81%); [a]2D0 þ194.0 (c 1.0, MeOH). 1H NMR
(400 MHz, CDCl3): d¼1.51e1.70 (m, 4H, 14-H, 15-H), 1.93e
2.02 (m, 2H, 2-H), 2.17e2.24 (m, 1H, 1-H), 2.27e2.30 (m, 1H,
16-H), 2.32e2.39 (m, 1H, 16-H), 2.75e2.83 (m, 1H, 1-H),
3.37e3.45 (m, 1H, 3-H), 3.65e3.69 (m, 2H, 13-H, 3-H),
3.78e3.87 (m, 1H, 13-H), 4.52 (d, J¼8.0 Hz, 1H, 11a-H),
7.41e7.46 (m, 1H, 9-H), 7.62e7.69 (m, 2H, 7-H, 8-H), 7.83
(dd, J¼7.8, 1.2 Hz, 1H, 6-H), 10.17 (s, 1H, OH), 11.89 (s, 1H,
NH). 13C NMR (100 MHz, CDCl3): d¼21.5 (C-15), 23.1
(C-2), 25.7 (C-1), 26.9 (C-14), 33.3 (C-16), 42.8 (C-13), 46.5
(C-3), 55.5 (C-11a), 124.4, 126.6, 128.1, 130.0, 132.1, 134.3,
162.5 (C-11), 163.8 (CO), 173.3 (CO). IR (KBr): ~n ¼ 3396,
1718, 1632, 1260, 1218, 1364, 1205, 1106, 764. GCeMS
(70 eV) m/z (%): 315 (100) [Mþ], 297 (10), 256 (80), 242
(60), 229 (55), 187 (25), 160 (55), 70 (75).
Anal. Calcd for C14H13N3O2 (255.27): C, 65.3; H, 5.1; N,
16.5. Found: C, 65.4; H, 5.1; N, 16.1.
3.5.2. (S)-2,3,12,13,14,14a-Hexahydrobenzo[e]pyrimido-
[2,1-c]pyrrolo[1,2-a][1,4]diazepine-4,10-dione (8b)
Using 7b gave a solid which was recrystallized from EtOH/
2-propanol to yield 8b as colorless crystals.
Anal. Calcd for C17H21N3O2 (315.37): C, 64.7; H, 6.7; N,
13.3. Found: C, 64.8; H, 6.4; N, 13.7.
Yield: 1.049 g (78%); mp: 194e196 ꢁC; [a]D20 þ485.2 (c 1.0,
1
CH3OH). H NMR (400 MHz, DMSO-d6): d¼1.87e2.12 (m,
3.6. General procedure for the preparation of the diazepines
(10aec)
3H, 5-H, 6-H), 2.36e2.48 (m, 3H, 3-H, 5-H), 3.33e3.38 (m,
1H, 7-H), 3.43 (t, J¼6.9 Hz, 2H, 2-H), 3.57e3.64 (m, 1H, 7-
H), 3.91 (d, J¼7.6 Hz, 1H, 4b-H), 6.96e7.00 (m, 2H, 11-H,
12-H), 7.36 (td, J¼7.7, 1.1 Hz, 1H, 10-H), 7.70 (dd, J¼7.7,
1.3 Hz, 1H, 9-H). 13C NMR (100 MHz, DMSO-d6): d¼24.1
(C-6), 26.7 (C-5), 35.1 (C-3), 38.5 (C-2), 47.1 (C-7), 55.1
(C-4b), 121.7, 127.2, 127.5, 130.4, 132.0, 148.6, 158.1 (C-4a),
166.2 (CO), 175.4 (CO). IR (KBr): ~n ¼ 2967, 2873, 1693,
1630, 1455, 1394, 1257, 1202. GCeMS (70 eV) m/z (%): 270
(100) [Mþþ1], 240 (8), 216 (26), 201 (13), 172 (17), 146 (9),
103 (8), 63 (11).
To a solution of cycloamidine ethyl ester 7a (0.301 g,
1.0 mmol) in THF (20 mL) was added K2CO3 (0.5 g) and
the corresponding ketone (1.0 mL) at room temperature. The
mixture was then heated at reflux for 4e6 h (monitoring by
TLC). After cooling, the solids were filtered off and the
filtrates were evaporated in vacuo. The resulting solids were
subjected to flash column chromatography [silica gel,
EtOAc/petrol (1:1)] to afford the compounds 10aec as faintly
yellow solids or oily products.

2054
A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
3.6.1. 2-(Propan-2-ylidene)-11,12,13,13a-tetrahydro-2H-
benzo[e]imidazo][2,1-c]pyrrolo[1,2-a][1,4]diazepine-3,9-
dione (10a)
Anal. Calcd for C19H19N3O2 (321.37): C, 71.0; H, 6.0; N,
13.1. Found: C, 70.9; H, 6.0; N, 13.2.
Acetone was used. Yield: 0.23 g (78%); mp: 214e217 ꢁC;
[a]2D0 ꢀ4.8 (c 0.5, CHCl3). 1H NMR (200 MHz, CDCl3):
d¼1.96e2.27 (m, 3H, 4,5-H), 2.32 (s, 3H, CH3), 2.46 (s, 3H,
CH3), 2.95e3.08 (m, 1H, 4-H), 3.62e3.89 (m, 2H, 6-H),
4.46e4.50 (m, 1H, 3b-H), 7.38 (ddd, J¼7.9, 7.4, 1.4 Hz, 1H,
10-H), 7.57 (ddd, J¼8.0, 7.4, 1.3 Hz, 1H, 9-H), 7.69 (dd,
J¼7.9, 1.3 Hz, 1H, 11-H), 7.99 (dd, J¼8.0, 1.4 Hz, 1H, 8-H).
13C NMR (50 MHz, CDCl3): d¼19.8 (CH3), 22.7 (CH3), 23.4
(C-5), 26.0 (C-4), 47.2 (C-6), 53.6 (C-3b), 123.5, 126.9, 128.9,
131.2, 131.3, 131.9, 136.0, 153.4, 156.4 (C-3a), 165.1 (CO),
166.2 (CO). IR (KBr): ~n ¼ 2942, 2869, 1709, 1641, 1459,
1395, 1334, 1234, 1155, 1064. GCeMS (70 eV) m/z (%): 295
(100) [Mþ], 280 (31), 227 (14), 199 (17), 130 (30), 102 (34).
Anal. Calcd for C17H17N3O2 (295.34): C, 69.1; H, 5.8; N,
14.2. Found: C, 68.8; H, 5.9; N, 14.1.
3.7. 2-(Triphenyl-l5-phosphanylidene)-3b,4,5,6-tetrahydro-2H-
3,6a,11b-triaza-benzo[g]cyclopenta[e]azulene-1,7-dione (11)
A solution of triphenylphosphine (0.131 g, 0.5 mmol) in dry
benzene (10 mL) was cooled to 10 ꢁC. With stirring, a solution
of bromine (26 mL, 0.5 mmol) in carbon tetrachloride (2 mL)
was added during 10 min. When the addition was complete, a
solution of triethylamine (0.17 mL, 1.2 mmol) and tetracyclic
imidazole (150 mg, 0.5 mmol) in benzene/THF (1:1) (6 mL)
was added at once. The solution was refluxed for 10 min. The
solid (triethylammonium bromide) was filtered off and the sol-
vent was removed by distillation to leave a red oil which solid-
ified upon addition of n-pentane. The crude product was purified
by column chromatography using EA/acetone as a solvent to
give the product as a yellow colored solid.
Yield: 0.186 g (72%). 1H NMR (400 MHz, CDCl3):
d¼1.94e1.99 (m, 1H, 5-H), 2.11e2.23 (m, 2H, 4,5-H),
2.92e2.99 (m, 1H, 4-H), 3.69e3.76 (m, 1H, 6-H), 3.78e3.84
(m, 1H, 6-H), 4.51 (dd, J¼7.9, 3.8 Hz, 1H, 3b-H), 7.31 (ddd,
J¼7.8, 7.5, 1.1 Hz, 1H, 10-H), 7.52 (ddd, J¼8.4, 7.2, 1.5 Hz,
1H, 9-H), 7.55e7.60 (m, 6H, Ph), 7.66e7.70 (m, 3H, Ph),
7.76e7.81 (m, 6H, Ph), 7.99 (dd, J¼7.8, 1.6 Hz, 1H, 11-H),
8.11 (dd, J¼8.2, 1.0 Hz, 1H, 8-H). 13C NMR (100 MHz,
CDCl3): d¼24.1 (C-5), 26.8 (C-4), 47.7 (C-6), 60.8 (C-3b),
123.8, 124.5, 124.8, 125.9, 128.9, 129.0, 129.4, 129.5, 131.4,
131.7, 132.4, 132.5, 132.6, 133.4, 133.5, 133.9, 134.5, 134.6,
142.3, 142.5, 166.3 (CO), 171.6 (CO). MS (70 eV) m/z (%):
515 (100).
3.6.2. 2-Cyclohexylidene-11,12,13,13a-tetrahydro-2H-
benzo[e]imidazo[2,1-c]pyrrolo[1,2-a][1,4]diazepine-3,9-
dione (10b)
Cyclohexanone was used. Yield: 0.24 g (71%); mp: 161e
1
164 ꢁC; [a]D20 0 (c 0.5, CHCl3). H NMR (200 MHz, CDCl3):
d¼1.65e1.82 (m, 6H, 3ꢂCH2), 1.95e2.31 (m, 3H, 4,5-H),
2.79e2.85 (m, 2H, CH2), 2.94e3.05 (m, 1H, 4-H), 3.07e3.15
(m, 2H, CH2), 3.62e3.89 (m, 2H, 6-H), 4.44e4.50 (m, 1H,
3b-H), 7.38 (ddd, J¼7.9, 7.5, 1.4 Hz, 1H, 10-H), 7.57 (ddd,
J¼8.0, 7.5, 1.3 Hz, 1H, 9-H), 7.69 (dd, J¼7.9, 1.3 Hz, 1H,
11-H), 7.98 (dd, J¼8.0, 1.4 Hz, 1H, 8-H). 13C NMR (50 MHz,
CDCl3): d¼23.4 (C-5), 26.0 (C-4), 26.1 (CH2), 28.2 (2ꢂCH2),
28.7 (CH2), 31.7 (CH2), 47.2 (C-6), 53.6 (C-3b), 123.5, 126.9,
128.9, 131.2, 131.3, 131.8, 133.4, 156.4, 161.3 (C-3a), 165.2
(CO), 166.7 (CO). IR (KBr): ~n ¼ 2934, 2853, 1715, 1651,
1459, 1396, 1284, 1173. GCeMS (70 eV) m/z (%): 335 (100)
[Mþ], 307 (7), 227 (14), 281 (27), 255 (13), 199 (11), 130
(15), 102 (20).
3.8. 2-Butylidene-11,12,13,13a-tetrahydro-2H-benzo-
[e]imidazo[2,1-c]pyrrolo[1,2-a][1,4]diazepine-3,9-dione (12)
A mixture of the ylide 11 (0.515 g, 1 mmol) and n-butanal
(1.0 mL) in anhydrous toluene (30 mL) was heated at 70 ꢁC
overnight under nitrogen gas. After cooling, the toluene was
evaporated under reduced pressure and the residue was puri-
fied by flash column chromatography using EA/PE (1:1).
Yield: 0.21 g (68%). 1H NMR (200 MHz, CDCl3): d¼1.22e
1.30 (m, 3H, CH3), 1.54e1.66 (m, 2H, CH2), 2.06e2.30 (m, 3H,
4,5-H), 2.64 (q, J¼7.7 Hz, 2H, CH2), 2.99e3.05 (m, 1H, 4-H),
3.65e3.72 (m, 1H, 6-H), 3.80e3.89 (m, 1H, 6-H), 4.47e4.52
(m, 1H, 3b-H), 6.79 (t, J¼7.7 Hz, 1H, CH), 7.40 (ddd, J¼7.6,
7.5, 1.2 Hz, 1H, 10-H), 7.59 (ddd, J¼8.2, 7.3, 1.5 Hz, 1H,
9-H), 7.74 (dd, J¼8.1, 1.1 Hz, 1H, 11-H), 8.00 (dd, J¼7.8,
1.5 Hz, 1H, 8-H).
Anal. Calcd for C20H21N3O2 (335.40): C, 71.6; H, 6.3; N,
12.5. Found: C, 71.7; H, 6.2; N, 12.3.
3.6.3. 2-Cyclopentylidene-11,12,13,13a-tetrahydro-2H-
benzo[e]imidazo[2,1-c]pyrrolo[1,2-a][1,4]diazepine-3,9-
dione (10c)
Cyclopentanonewas used. Yield: 0.09 g (28%); [a]2D0 þ4.5 (c
1
0.5, CHCl3). H NMR (200 MHz, CDCl3): d¼1.70e1.79 (m,
1H, 5-H), 1.80e1.97 (m, 4H, 2ꢂCH2), 1.99e2.11 (m, 1H, 5-
H), 2.13e2.23 (m, 2H, CH2), 2.26e2.10 (m, 1H, 4-H), 2.87e
3.08 (m, 3H, 4-H, CH2), 3.61e3.69 (m, 1H, 6-H), 3.71e3.77
(m, 1H, 6-H), 4.41e4.53 (m, 1H, 3b-H), 7.34e7.45 (m, 1H,
12-H), 7.53e7.62 (m, 1H, 10-H), 7.75e7.79 (m, 1H, 11-H),
7.96e8.01 (m, 1H, 9-H). 13C NMR (50 MHz, CDCl3): d¼23.4
(C-5), 25.4 (C-4), 26.0 (CH2), 26.5 (CH2), 33.8 (CH2), 41.9
(CH2), 47.2 (C-6), 53.6 (C-3b), 121.0, 123.4, 126.8, 128.8,
131.3, 131.9, 132.9, 157.1 (C-2), 164.4 (C-3a), 165.2 (CO),
166.0 (CO). IR (KBr): ~n ¼ 3229, 2958, 2877, 1717, 1637,
1461, 1396, 1338, 1165, 763, 735. GCeMS (70 eV) m/z (%):
321 (100) [Mþ], 216 (20), 187 (15), 146 (30), 130 (30), 70 (100).
3.9. 2-Bromo-12,13-dihydro-3H-benzo[e]imidazo[2,1-c]-
pyrrolo[1,2-a][1,4]diazepine-3,9(11H)-dione (13)
To a solution of the tetracyclic imidazole 8a (0.255 g,
1 mmol) in carbon tetrachloride (12 mL) was added N-bromo-
succinimide (0.178 g, 1 mmol) and AIBN. The mixture was
heated at reflux temperature for 12 h. After cooling, the solid
was filtered off and the filtrate was evaporated in vacuo to give

A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
2055
Yield: 59 mg (21%); [a]2D0 þ78.2 (c 0.5, CHCl3). H NMR
(400 MHz, CDCl3): d¼1.37 (s, 3H, CH3), 1.44 (s, 3H, CH3),
2.03e2.08 (m, 1H, 5-H), 2.10e2.24 (m, 2H, 4-H, 5-H), 2.85e
2.92 (m, 1H, 4-H), 3.60e3.68 (m, 1H, 6-H), 3.81e3.88
(m, 1H, 6-H), 4.42 (dd, J¼7.6, 2.3 Hz, 1H, 3b-H), 7.46e7.41
(m, 1H, 10-H), 7.53e7.58 (m, 1H, 11-H), 7.60e7.65 (m, 1H,
12-H), 7.90e7.96 (m, 1H, 9-H). 13C NMR (100 MHz,
CDCl3): d¼23.3 (C-5), 23.7 (CH3), 24.1 (CH3), 26.0 (C-4),
47.3 (C-3b), 53.9 (C-6), 68.5 (C-2), 123.3, 127.2, 128.7,
130.8, 131.2, 132.1 (6Carom.), 159.7 (C-3a), 165.2 (C]O),
183.4 (C]O). IR (NaCl): ~n ¼ 3385, 2977, 2880, 1745, 1638,
1461, 1392, 1340, 1285, 1226, 1165, 1135, 1085, 915, 864,
734. MS: 283 (70) [Mþ], 255 (15), 240 (10), 186 (70), 117
(90), 102 (15), 90 (30), 84 (30), 70 (50).
1
a brownish oil. The crude product was then subjected to flash
column chromatography [silica gel, EtOAc/petroleum ether
(1:3)] to afford the compound 13 as intensely yellow solid
which is unstable.
1
Yield: 70 mg (21%). H NMR (200 MHz, CDCl3): d¼2.11
(m, 2H, 5-H), 3.42 (t, J¼7.7 Hz, 2H, 4-H), 4.16 (t, J¼7.7 Hz,
2H, 6-H), 7.35 (td, J¼7.7, 1.15 Hz, 1H, 10-H), 7.64 (td, J¼7.8,
1.9 Hz, 1H, 9-H), 8.25 (dd, J¼8.1, 1.8 Hz, 1H, 12-H), 8.72
(dd, J¼8.5, 1.0 Hz, 1H, 8-H). IR (KBr): ~n ¼ 2923, 1752,
1678, 1648, 1489, 1447, 1385, 1360, 1207, 1148, 1022, 985,
751. MS (70 eV) m/z (%): 333/331 (80) [M], 224 (100), 198
(30), 170 (28), 142 (29), 130 (40), 102 (70), 76 (75).
3.10. (S)-9-Oxo-11,12,13,13a-tetrahydro-9H-benzo[e]-
imidazo[2,1-c]pyrrolo[1,2-a][1,4]diazepin-3-yl benzoate (14a)
HREIMS calcd for C16H17N3O2þHþ: 283.1399; found:
283.1400.
To a solution of 8a (0.255 g, 1.0 mmol) in 10 mL of abs
dichloromethane was added 0.5 mL abs pyridine. At room
temperature 0.12 mL (1.0 mmol) freshly distilled benzoyl chlo-
ride was added dropwise. The reaction was stirred for 2 h at this
temperature (monitored by TLC). The reaction mixturewas then
evaporated in vacuo to give a brownish oil which was subjected
to flash column chromatography [silica gel, EtOAc/petrol (1:1)]
to afford the compound 14a as dark yellow solid.
Yield: 180 mg (51%); mp: 156e159 ꢁC; [a]D20 þ172.4 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): d¼2.07e2.14 (m, 1H, 5-
H), 2.21e2.30 (m, 1H, 5-H), 2.32e2.41 (m, 1H, 4-H), 3.10e
3.16 (m, 1H, 6-H), 3.65e3.72 (m, 1H, 6-H), 3.84e3.90 (m,
1H, 6-H), 4.59 (dd, J¼8.1, 3.2 Hz, 1H, 3b-H), 7.22 (s, 1H, 2-
H), 7.46e7.54 (m, 4H, 8-H, 10-H, b-benzoyl), 7.58e7.61 (m,
1H, Harom.), 7.62e7.68 (m, 1H, g-benzoyl), 8.05 (dd, J¼8.2,
1.2 Hz, 2H, a-benzoyl), 8.11 (dd, J¼7.7, 1.7 Hz, 1H, 9-H).
13C NMR (100 MHz, CDCl3): d¼23.8 (C-5), 26.9 (C-4), 47.5
(C-6), 53.9 (C-3b), 114.8 (C-2), 123.4, 127.7, 127.9, 128.9
(2C), 130.3 (2C), 130.4, 131.3, 131.6, 131.8, 134.4, (Carom.),
137.7 (C-1), 143.1 (C-3a), 161.7 (CO), 164.5 (CO). IR (KBr):
~n ¼ 2972, 1745, 1638, 1602, 1556, 1527, 1462, 1417, 1250,
1223, 1180, 1116, 1082, 800, 757, 704. MS: 359 (15) [Mþ],
256 (10), 105 (100), 96 (15), 77 (50), 64 (95). HRESIMS calcd
for C21H17N3O3þNaþMeCN: 423.1434; found: 423.1470.
Anal. Calcd for C21H17N3O3 (359.13): C, 70.1; H, 4.7; N,
11.6. Found: C, 69.8; H, 4.4; N, 11.4.
3.12. 11,12,13,13a-Tetrahydro-2H-benzo[e]imidazo[2,1-c]-
pyrrolo[1,2-a][1,4]diazepine-2,3,9-trione (17)
To a suspension of 15 (0.215 g, 1.0 mmol) in 10 mL of abs
dichloromethane was added 0.55 mL of triethylamine at
room temperature. After cooling to ꢀ78 ꢁC, oxalyl chloride
(0.104 mL, 1.2 mmol) was added dropwise to the mixture,
whereupon the color changed to orange. After stirring for 2 h
at this temperature the reaction mixture was quenched with
water. The organic layer was separated, washed with water,
anddriedoverNa2SO4. Evaporationofthesolventgavearesidue
which was subjected to flash column chromatography [silica
gel, EtOAc/petrol (1:1)] to afford the compound 16 as yellow
solid which decomposed rapidly so that we were prevented
from a characterization. MS (70 eV) of a freshly prepared sam-
ple: m/z (%): 269 (10) [Mþ], 216 (15), 160 (15), 146 (15), 102
(20), 92 (40), 70 (100). After a short period of time, dilactam
5 reconstituted as evidenced by MS and NMR measurements.
References and notes
1. (a) Da Settimo, F.; Taliani, S.; Trincavelli, M. L.; Montali, M.; Martini, C.
Curr. Med. Chem. 2007, 14, 2680; (b) Lueddens, H.; Korpi, E. R. Handbook
ofContemporaryNeuropharmacology; John WileyandSons:NewYork, NY,
2007; Vol. 2, p 93; (c) Bacon, E. R.; Chatterjee, S.; Williams, M. Comprehen-
sive Medicinal Chemistry II; Elsevier: Amsterdam, 2006; Vol. 6, p 139.
2. Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudiniere,
R. F. J. Comb. Chem. 2000, 2, 513.
3.11. 2,2-Dimethyl-11,12,13,13a-tetrahydro-2H-benzo[e]-
imidazo[2,1-c]pyrrolo[1,2-a][1,4]diazepine-3,9-dione (15)
3. (a) Kamal, A.; Khan, M. N. A.; Reddy, K. S.; Ahmed, S. K.; Kumar,
M. S.; Juvekar, A.; Sen, S.; Zingde, S. Bioorg. Med. Chem. Lett. 2007,
17, 5345; (b) Antonow, D.; Cooper, N.; Howard, P. W.; Thurston, D. E.
J. Comb. Chem. 2007, 9, 437; (c) Kamal, A.; Reddy, D. R.; Reddy,
P. S. M. M. Bioorg. Med. Chem. Lett. 2007, 17, 803; (d) Kamal, A.;
Shankaraiah, N.; Devaiah, V.; Reddy, K. L. Tetrahedron Lett. 2006, 47,
6553; (e) Kang, G.-D.; Howard, P. W.; Thurston, D. E. Chem. Commun.
2003, 1688; (f) Cooper, N.; Hagan, D. R.; Tiberghien, A.; Ademefun,
T.; Matthews, C. S.; Howard, P. W.; Thurston, D. E. Chem. Commun.
2002, 1764; (g) Kamal, A.; Ramu, R.; Khanna, G. B. R.; Saxena,
A. K.; Shanmugavel, M.; Pandita, R. M. ARKIVOC 2005, III, 83; (h)
Hurley, L. H.; Boyed, F. L. TIPS 1988, 9, 402; (i) Zhilina, Z. V.; Ziemba,
A. J.; Trent, J. O.; Reed, M. W.; Gorn, V.; Zhov, Q.; Duan, W.; Hurley, L.;
Ebbinghaus, S. W. Bioconjugate Chem. 2004, 15, 1182; (j) Kumar, R.;
Lown, J. W. Mini-Rev. Med. Chem. 2003, 3, 323.
Under an inert gas atmosphere 0.22 mL (1.5 mmol) of diiso-
propylamine in 5 mL abs THF was cooled to ꢀ78 ꢁC. At this
temperature 0.61 mL of n-BuLi (1.5 mmol, c¼2.45 mol/L in
hexane) was added dropwise. This mixture was stirred at room
temperature for 30 min. After cooling to ꢀ78 ꢁC a solution of
0.255 g (1 mmol) 8a in 10 mL abs THF was added dropwise.
After 1 h 0.34 mL (3 mmol) iodomethane was added. The reac-
tion mixture was stirred for 1 h at ꢀ78 ꢁC and 2 h at room tem-
perature. After evaporation of the solvent, the residue was
purified by column chromatography using EA to afford 15 as
yellow oil. The compound is unstable.

2056
A. Schmidt et al. / Tetrahedron 64 (2008) 2048e2056
4. Dervan, P. B. Science 1986, 232, 464.
16. Rahbaek, L.; Breinhold, J.; Frisvad, J. C.; Christophersen, C. J. Org.
Chem. 1999, 64, 1689.
5. (a) Leimgruber, W.; Stefanovic, V.; Schenker, F.; Karr, A.; Berger, J.
J. Am. Chem. Soc. 1965, 87, 5791; (b) Leimgruber, W.; Batcho, A. D.;
Schenker, F. J. Am. Chem. Soc. 1965, 87, 5793; (c) Arora, S. K. Acta
Crystallogr. 1979, B35, 2945.
6. (a) Arima, K.; Kohsaka, M.; Tamura, J.; Imanaka, H.; Sakai, H. J. Antibiot.
1972, 25, 437; (b) Nishioka, Y.; Beppu, T.; Kohsaka, M.; Arima, K. J. Anti-
biot. 1972, 25, 660; (c) Tazuka, Z.; Takaya, T. J. Antibiot. 1983, 36, 142.
7. Hochlowski, J. E.; Andres, W. W.; Theriault, R. J.; Jackson, M.;
McAlpine, J. B. J. Antibiot. 1987, 40, 145.
17. (a) Schmidt, A.; Topp, M.; Mordhorst, T.; Schneider, O. Tetrahedron
2007, 63, 1842; (b) Schmidt, A.; Mordhorst, T.; Nieger, M. Nat. Prod.
Res. 2005, 19, 541; (c) Schmidt, A.; Mordhorst, T. ARKIVOC 2003,
XIV, 233; (d) Schmidt, A.; Habeck, T.; Kindermann, M. K.; Nieger, M.
J. Org. Chem. 2003, 68, 5977.
´
18. Schmidt, A.; Lindner, A.; Nieger, M.; Ruiz Delgado, M. C.; Ramırez, F. J.
Org. Biomol. Chem. 2006, 4, 3056.
19. (a) Schmidt, A.; Habeck, T.; Lindner, A. S.; Snovydovych, B.; Namyslo,
J. C.; Adam, A.; Gjikaj, M. J. Org. Chem. 2007, 72, 2236; (b) Schmidt,
8. Konishi, M.; Ohkuma, H.; Naruse, N.; Kawaguchi, H. J. Antibiot. 1984,
37, 200.
A.; Snovydovych, B.; Habeck, T.; Drottboom, P.; Gjikaj, M.; Adam, A.
¨
9. Kyowa Hakko Kogyo Co. Ltd. Jpn Kokai Tokyo Koho JP 58180487, 21
Oct 1983; Chem. Abstr. 1984, 100, 173150.
Eur. J. Org. Chem. 2007, 4909; (c) Schmidt, A.; Habeck, T.; Snovydo-
vych, B.; Eisfeld, W. Org. Lett. 2007, 9, 3515; (d) Schmidt, A.; Mordhorst,
T.; Nieger, M. Synthesis 2006, 3987.
10. Kunimoto, S.; Masuda, T.; Kanbayashi, N.; Hamada, M.; Naganawa, H.;
Miamota, M.; Takeuchi, T.; Umezawa, H. J. Antibiot. 1980, 33, 665.
11. (a) Takeuchi, T.; Miamota, M.; Ishizuka, M.; Naganawa, H.; Kondo, S.;
Hamada, M.; Umezawa, H. J. Antibiot. 1976, 29, 93; (b) Miyamoto, M.;
Kondo, S.; Naganawa, H.; Maeda, K.; Ohno, M.; Umezawa, H. J. Antibiot.
1977, 30, 340.
20. Rahbaek, L.; Breinholt, J. J. Nat. Prod. 1999, 62, 904.
21. Grieder, A.; Thomas, A. W. Synthesis 2003, 1707.
22. Bock, M. G.; DiPardo, R. M.; Pitzenberger, S. M.; Homnick, C. F.;
Springer, J. P.; Freidinger, R. M. J. Org. Chem. 1987, 52, 1644.
23. Wu, X.; Liu, Y.; Sheng, W.; Sun, J.; Qin, G. Planta Med. 1997, 63, 55.
24. Kamal, A.; Howard, P. W.; Reddy, B. S. N.; Thurston, D. E. Tetrahedron
1997, 53, 3223.
12. Shimizu, K.-I.; Kawamoto, I.; Tomita, F.; Morimoto, M.; Fujimoto, K.
J. Antibiot. 1982, 35, 972.
13. (a) Hara, M.; Tamaoki,T.; Yoshida, M.;Morimoto, M.;Nakano, H. J. Antibiot.
1988, 51, 702; (b) Itoh, J.; Watabe, H.-O.; Ishii, S.; Gomi, S.; Nagasawa, M.;
Yamamoto, H.;Shomura,T.;Sezaki,M.;Kondo, S. J. Antibiot. 1988, 41, 1281.
14. Leber, J. D.; Hoover, J. R. E.; Holden, K. G.; Johnson, R. K.; Hecht, S. M.
J. Am. Chem. Soc. 1988, 110, 2992.
25. Schmidt, A.; Gholipour Shilabin, A.; Nieger, M. Heterocycles 2005, 65,
625.
26. Schmidt, A.; Gholipour Shilabin, A.; Namyslo, J. C.; Nieger, M.;
Hemmen, S. Eur. J. Org. Chem. 2005, 1781.
27. (a) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467; (b) Sheldrick,
15. Tsunkawa, M.; Kamei, H.; Konishi, M.; Miyaki, T.; Oki, T.; Kawakuchi,
H. J. Antibiot. 1988, 41, 1366.
G. M. Univ. Gottingen, 1997. (c) Flack, H. D. Acta Crystallogr. 1983,
A39, 876.
¨