Assembly of N-substituted pyrrolo[2, 1-c][1, 4]benzodiazepine-5, 11-diones via copper catalyzed aryl amination

Article abstract of DOI:10.1016/j.tet.2010.04.127

Copper-catalyzed amination of N-heterocycle derived aryl iodides followed by intramolecular con- densative cyclization afforded N-substituted pyrrolo[2 1-c][1, 4]-benzodiazepine-5, 11-diones with good yields. By varying primary amines and substituents at aromatic ring of aryl iodides, a wide range of these heterocycles were assembled.

Full text of DOI:10.1016/j.tet.2010.04.127

Tetrahedron 66 (2010) 5714e5718
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Assembly of N-substituted pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones via
copper catalyzed aryl amination
,
b
b,
*
Xu Lu a, Liu Shi a, Hui Zhang a , Yongwen Jiang , Dawei Ma
*
a Department of Chemistry, Shanghai University, Shanghai 200444, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2010
Received in revised form 28 April 2010
Accepted 29 April 2010
Available online 12 May 2010
Copper-catalyzed amination of N-heterocycle derived aryl iodides followed by intramolecular con-
densative cyclization afforded N-substituted pyrrolo[2,1-c][1,4]-benzodiazepine-5,11-diones with good
yields. By varying primary amines and substituents at aromatic ring of aryl iodides, a wide range of these
heterocycles were assembled.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Aryl amination
Coupling
Benzodiazepine
Heterocycles
Amides
1. Introduction
In recent years, a considerable number of reports1e7 have
revealed that pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (PBD)
is an important core structure for pharmaceutical design. The
successful examples include compound 1 (Fig. 1) that has growth
hormone releasing activity,1 protein PLK1 inhibitor 2,2 ST2806 (3)
that shows inhibitory activity to myeloid differentiation factor 88,3
as well as protein thioesterase 1 (APT1) inhibitor 4.4 Additionally,
PBDs have been used as the key intermediates for synthesis of
several natural antibiotics and designed antitumor agents.8
O
H
N
N
H
NH2
O
O
N
O
Me
O
N
N
1
N
OMe
H
N
O
HN
N
Since N-functionalization of PBDs plays a key role to obtain
diverse and bioactive derivatives, the development of powerful
methods for preparing N-substituted PBDs (A, Fig. 2) is highly de-
sired. Although direct alkylation of N-unsubstituted PBDs (B) is the
most popular and widely used method for synthesizing
N-substituted PBDs, it suffers from low yields when less reactive
alkylating reagents are used.3,4,9,10 In some cases special reactions
have to be employed to achieve this transformation.11 On the other
hand, methods for elaboration of N-unsubstituted PBDs are limited.
These tricyclic compounds have often been obtained via a conden-
sation/cyclization process of isatoic anhydrides (C) with proline
derivatives,9,12 or a reduction/cyclization process of nitro or azido
compounds D.10,13 In these cases multi-step synthesis is generally
H
N
N
N
O
F3C
2
O
O
O
H
N
H2N
N
O
N
H
NH
N
N
OH
H
H
O
NH2
3
(ST2806)
O
N
O
O
O
S
H
N
N
HN
S
O
O
O
C16H33-n
4
* Corresponding authors. E-mail address: madw@mail.sioc.ac.cn (D. Ma).
Figure 1. Some representative bioactive molecules with PBD core structure.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.127

X. Lu et al. / Tetrahedron 66 (2010) 5714e5718
5715
required because some starting materials are not conveniently
available (Fig. 2).
substrate. This change could inhibit the direct intermolecular
condensation with benzylamine. However, after coupling reaction
condensative cyclization turned to be slow and the direct coupling
product was isolated in 15% yield (entry 2). To solve this problem,
we acidified the coupling reaction mixture with 1 N HCl and then
heating the solution at 110 ꢀC. In this case 7a was isolated in 72%
During the studies on the synthesis of heterocycles via copper-
catalyzed cross-coupling reactions,14,15 we became interested in aryl
amination of aryl halides E that possess a proline core linked by an
amide bond. We envisaged that after the amination took place,
cyclization would occur via an intramolecular amide formation. This
approach would offer a diverse and efficient method for assembling
N-substituted PBDs using primary amines and aryl halides as the
starting materials (Fig. 2).
Table 2
Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones via coupling and sub-
sequent condensationa
Entry
Product (yield)b
Entry
Product (yield)b
R
O
H
N
O
MeO
OMe
OMe
OMe
N
Alkylation
R'
R'
N
N
Y
Y
O
H
O
O
H
N
B
O
A
N
1
2
Aryl amination
& cyclization?
N
N
O
7b (81%)
O
7c (80%)
R''O
O
R''O
O
H
N
X
Z
O
CF3
O
R'
R'
R'
O
N
N
Y
Y
O
O
E
O
O
C
O
O
D
: Z = NO2, N3
N
N
H
H
3
5
4
6
Figure 2. Possible approaches for assembling N-substituted PBDs.
N
N
O
O
7d (85%)
7e (63%)
2. Results and discussion
With the above idea in mind, a coupling reaction between aryl
bromide 5a and benzylamine was conducted under our typical
reaction conditions (10 mol % CuI, 20 mol % L-proline, K2CO3, DMSO,
O
H
O
H
N
N
N
N
90 ꢀC).16 It was found that after coupling the desired tricyclic
product 7a was isolated in 52% yield, together with amide 8 in 22%
yield (Table 1, entry 1). The formation of 8 should be resulted from
the simple condensation of methyl ester 5a with benzylamine.
After failed in inhibiting this side reaction by tuning the reaction
conditions (using different bases and copper salts), we moved our
attention to employing sterically hindered i-butyl ester 5b as our
O
O
7g (76%)
95% ee
7f (82%)
91% ee
OTBS
O
H
N
O
N
H
7
8
N
N
O
7h (70%)
Table 1
O
N
97% ee
7i (46%)
Coupling of aryl halides 5 with benzylamine and subsequent cyclization under
different conditionsa
BocHN
N
X
1. [Cu], ligand, K2CO3, DMSO
+
PhCH2NH2
6a
O
H
2. 1 N HCl, 110 o
C
N
O
H
9
10
12
COOR
O
N
N
5a: X = Br, R = Me
5b: X = Br, R = i-Bu
5c: X = I, R = i-Bu
Ph
N
O
7k (63%)
O
O
H
7j (62%)
NHBn
N
Ph
Ph
+
O
H
O
H
N
N
N
MeO
MeO
CONHBn
O
8
11
O
7a
N
N
Me
7l (75%)
7m (75%)
O
O
Entry
Substrate
Catalystb
T (ꢀC)
Yield of 7ac (%)
1
2
3
4
5
5a
5b
5b
5b
5c
A
A
A
B
B
90
90
90
90
80
52d
55d
Ph
72
O
H
74 (80% ee)
78 (93% ee)
N
O
13
14
a
Reaction conditions: aryl halide (1 mmol), benzylamine (2.5 mmol), catalyst
N
Cl
7n (64%)
(0.1 mmol), K2CO3 (2 mmol), DMSO (1 mL), 24 h; then 1 N HCl, 110 ꢀC.
b
A: CuI/L-proline; B: Pre-synthesized complex by heating a mixture of Cu2O and
a
L
-proline in toluene.
Reaction conditions: 2-iodobenzamide (1 mmol), amine (2.5 mmol), catalyst
(0.2 mmol, pre-synthesized complex by heating a mixture of Cu2O and L-proline in
toluene), K2CO3 (2 mmol), DMSO (1 mL), 80 ꢀC, 24 h; then 1 N HCl, 110 ꢀC for 5 h.
c
Isolated yield.
d
The product was directly isolated from coupling reaction mixture, together with
b
8 in 22% yield (entry 1), or direct coupling product in 15% yield (entry 2).
Isolated yield.

5716
X. Lu et al. / Tetrahedron 66 (2010) 5714e5718
yield (entry 3). Using a pre-synthesized complex by heating
a mixture of Cu2O and -proline in toluene (its structure has not
for assembling ST2806 (3) that inhibits myeloid differentiation
L
factor 88.3
been fully established owing to technology issue) gave a similar
result (entry 4). At this moment we determined the optical purity of
our product, and were disappointedly found that the ee value of 7a
was only 80%. Since the coupling step might be responsible for the
undesired racemization, we decided to utilize aryl iodide 5c as the
coupling partner, and hoped that this substrate could react with
benzylamine at relatively low temperatures, thereby avoiding the
possible racemization. To our delight, reaction of 5c with benzyl-
amine completed at 80 ꢀC, affording 7a with 78% yield and 93% ee,
after cyclization at 110 ꢀC (entry 5). Further reducing reaction
temperatures led to low conversion at the coupling step.
3. Conclusions
In summary, we have discovered that copper-catalyzed amina-
tion of N-heterocycle derived aryl iodides followed by intra-
molecular condensative cyclization could afford N-substituted
pyrrolo[2,1-c][1,4]-benzodiazepine-5,11-diones with good yields.
A wide range of primary amines could be applied for this process,
thereby giving a reliable method for diverse synthesis of these
pharmaceutically important heterocycles.
The optimized reaction conditions were then tested by varying
primary amines and substituted aryl iodides, and the results are
summarized in Table 2. Four substituted benzyl amines bearing
either electronic donating or withdrawing groups proceeded
smoothly, giving the corresponding tricyclic products 7be7e in good
yields (entries 1e4). Allylamine, simple and functionalized alkyl
amines were compatible with these reaction conditions (entries
5e9). The additional functional groups in products 7f, 7i, and 7j
would allow further transformations to obtain other PBDs. Because
cyclopropanyl halides could easily undergo ring-opening,
introducing a N-cyclopropanyl group at PBDs is obviously forbidden,
and therefore an alternative method was developed recently.11 By
using our procedure, the same type of compounds could be
assembled from commercially available cyclopropan-amine (entry
10). The generality of our process was further demonstrated by
formation of PBDs 7le7o, through coupling of benzylamine and
substituted aryl iodides (entries 11e14). It is notable that products
7f, 7g, and 7h showed ee values of 91%, 95%, and 97%, respectively,
indicating that a slight racemization occurred in most cases.
4. Experimental
4.1. General remarks
All solvents were purified and dried prior to use. Optical rota-
tions were measured by used a PerkineElmer 241MC polarimeter
in the solvent indicated. 1H NMR spectra were recorded at Bruker
Avance 300 MHz, and 13C NMR spectra were recorded at Bruker
Avance 400 MHz, and assigned in parts per million (
chemical shifts were given on the scale (ppm) and were refer-
d
). 1H NMR
d
enced to internal TMS. Reference peaks for chloroform in 13C NMR
spectra were set at 77.0 ppm. Low-resolution mass spectra were
recorded on a GILENT5973 instrument (EI) and a LCMS-2010EV
instrument (ESI). High-resolution mass spectra were recorded on
an IonSpec 4.7 Tesla FTMS instrument. Silica gel plate GF254 were
used for thin layer chromatography (TLC) and silica gel H or
300e400 mesh were used for flash column chromatography. En-
antiomeric excesses were determined by HPLC using a Daicel
CH1RALPARK AD-H column (wavelength¼254 or 214 nm) with
hexane/i-PrOH as the eluent.
Finally, we attempted to change the pyrrolidine unit of PBDs 7
via employing other cyclic amino acid derived aryl iodides. As
indicated in Table 3, three 4-hydroxy-
products were obtained with 50e66% yields (entries 1e3), while
piperidine fused product 10 was produced in 65% yield (entry 4).
L
-proline embodied tricyclic
4.2. General procedure for the synthesis of N-substituted
pyrrolo[2,1-c][1,4]benzodiazepine- 5,11-diones
An oven-dried Schlenk tube was charged with an appropriate
amine (2.5 mmol), aryl iodide (1 mmol), copper catalyst (34 mg,
0.2 mmol, pre-synthesized by heating a mixture of Cu2O and
Table 3
Synthesis of other tricyclic compounds via coupling and subsequent condensationa
Entry
Product (yield)b
Entry
Product (yield)b
L-proline in toluene), and K2CO3 (276 mg, 2 mmol). The tube was
evacuated and backfilled with argon (three times), and then DMSO
(1.0 mL) was added. The reaction mixture was stirred at 80 ꢀC for
24 h. After cooling, 1 mL of 1 N HCl was added and then the mixture
was stirred at 110 ꢀC for 5 h. The mixture was partitioned between
water and ethyl acetate. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel chro-
matography to give the desired product.
BocHN
CO2Bu-t
O
O
N
H
N
H
1
2
N
N
O
Cl
OTBS
OTBS
O
9b (66%)
9a (50%)
MeO
OMe
OMe
Ph
4.2.1. (S)-10-Benzyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]dia-
zepine-5,11(10H,11aH)-dione (7a). 1H NMR (300 MHz, CDCl3)
d 7.90
3
4
O
N
O
N
(d, J¼7.8 Hz, 1H), 7.40 (t, J¼7.8 Hz, 1H), 7.32e7.15 (m, 8H), 5.17 (d,
J¼15.6 Hz, 1H), 5.00 (d, J¼15.9 Hz, 1H), 4.20e4.18 (m, 1H),
3.87e3.79 (m, 1H), 3.64e3.55 (m, 1H), 2.81e2.77 (m, 1H), 2.17e2.00
MeO
MeO
H
N
N
O
OTBS
9c (60%)
10 (65%)
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 169.5, 165.1, 139.8, 136.9,
O
a
131.9, 130.5, 130.3, 128.7 (2C), 127.3, 126.8 (2C), 125.9, 122.3, 57.2,
52.4, 46.6, 26.8, 23.8; EIMS m/z 306 (Mþ); HRMS (EI) calcd for
C19H18N2O2 (Mþ) 306.1368, found 306.1365. HPLC: CH1RALPARK
AD-H 0.46 cmꢁ25 cm; detected at 214 nm; n-hexane/i-propanol:
80/20; flow: 0.7 mL/min; retention time: 17.5 min (minor),
Reaction conditions: 2-iodobenzamide (1 mmol), amine (2.5 mmol), catalyst
(0.2 mmol, pre-synthesized complex by heating a mixture of Cu2O and L-proline in
toluene), K2CO3 (2 mmol), DMSO (1 mL), 80 ꢀC, 24 h; then 1 N HCl, 110 ꢀC for 5 h.
b
Isolated yield.
Noteworthy is that some of our products are potential building
blocks for elaboration of the known bioactive compounds. For
example, 7i could be transferred to growth hormone releaser 1;1 9a
could be converted into APT1 inhibitor 4;4 while 9b could be used
25.6 min (major), ee¼93%. [
a
]
23.4 þ366.8 (c 1.00, CHCl3).
D
4.2.2. (S)-10-(4-Methoxybenzyl)-2,3-dihydro-1H-benzo[e]pyrrolo
[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (7b). 1H NMR (300 MHz,

X. Lu et al. / Tetrahedron 66 (2010) 5714e5718
5717
CDCl3)
d
7.86 (d, J¼7.8 Hz, 1H), 7.39 (t, J¼6.0 Hz, 1H), 7.25e7.20 (m,
(Mþ) 258.1368, found 258.1364; HPLC: CH1RALPARK AD-H
0.46 cmꢁ25 cm; detected at 214 nm; n-hexane/i-propanol: 80/20;
flow: 0.7 mL/min; retention time: 10.1 min (minor), 14.5 min (ma-
2H), 7.06 (d, J¼8.7 Hz, 2H), 6.78 (d, J¼9.0 Hz, 2H), 5.02 (s, 2H),
4.15e4.13 (m, 1H), 3.83e3.75 (m, 1H), 3.70 (s, 3H), 3.60e3.51 (m,
1H), 2.77e2.73 (m, 1H), 2.20e2.13 (m, 1H), 2.10e2.00 (m, 2H); 13C
jor), ee¼95%. [
a
]
24.7 þ529.1 (c 1.00, CHCl3).
D
NMR (100 MHz, CDCl3)
d 169.3, 164.9, 158.7, 139.6, 131.8, 130.5,
130.0, 128.9, 128.1 (2C), 125.7, 122.4, 113.9 (2C), 57.1, 55.0, 51.4, 46.5,
4.2.8. (S)-10-(Cyclopropylmethyl)-2,3-dihydro-1H-benzo[e]pyrrolo
26.6, 23.7; EIMS m/z 336 (Mþ); HRMS (EI) calcd for C20H20N2O3
[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (7h). 1H NMR (300 MHz,
(Mþ) 336.1474, found 336.1464. [
a
]
23.7 þ245.8 (c 1.00, CHCl3).
CDCl3)
d
7.93 (dd, J¼7.8,1.5 Hz, 1H), 7.52 (t, J¼7.9 Hz, 1H), 7.36e7.29
D
(m, 2H), 4.07 (d, J¼7.5 Hz, 1H), 4.03 (d, J¼7.5 Hz, 1H), 3.86e3.78 (m,
1H), 3.64e3.52 (m, 2H), 2.75e2.69 (m, 1H), 2.19e2.09 (m, 1H),
2.06e1.95 (m, 2H), 1.01e0.82 (m, 1H), 0.47e0.38 (m, 2H), 0.23e0.12
4.2.3. (S)-10-(3,4,5-Trimethoxybenzyl)-2,3-dihydro-1H-benzo[e]pyr-
rolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione NMR
(7c). 1H
(300 MHz, CDCl3)
d
7.91 (d, J¼6.3 Hz, 1H), 7.45 (t, J¼8.1 Hz, 1H),
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 169.1, 165.0, 139.5, 131.7, 131.2,
7.31e7.25 (m, 2H), 6.32 (s, 2H), 5.17 (d, J¼15.9 Hz, 1H), 4.96 (d,
J¼15.6 Hz, 1H), 4.20e4.18 (m, 1H), 3.82e3.76 (m, 1H), 3.78 (s, 9H),
3.63e3.50 (m, 1H), 2.80e2.76 (m, 1H), 2.18e1.98 (m, 3H); 13C NMR
130.0,125.8,123.1, 57.2, 52.6, 46.4, 26.5, 23.8,10.0, 4.3, 3.5; EIMS m/z
270 (Mþ); HRMS (EI) calcd for C16H18N2O2 (Mþ) 270.1368, found
270.1370; HPLC: CH1RALPARK AD-H 0.46 cmꢁ25 cm; detected at
214 nm; n-hexane/i-propanol: 80/20; flow: 0.7 mL/min; retention
(100 MHz, CDCl3) d 169.2, 164.6, 152.9 (2C), 139.1, 136.5, 132.1, 131.6,
130.4, 129.7, 125.6, 122.0, 103.0 (2C), 60.3, 56.8, 55.6 (2C), 51.4, 46.1,
time: 10.3 min (minor), 15.9 min (major), ee¼97%. [
a]
24.4 þ431.9 (c
D
26.2, 23.3; ESI-MS m/z 397.3 (MþH)þ; HRMS (ESI) calcd for
1.00, CHCl3).
24.8
C22H24N2Na1O5 (MþNa)þ 419.1582, found 419.1577. [
(c 1.00, CHCl3).
a
]
þ279.2
D
4.2.9. (S)-10-(3-(tert-Butyldimethylsilyloxy)propyl)-2,3-dihydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (7i). 1H
4.2.4. (S)-10-(Benzo[d][1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-
NMR (300 MHz, CDCl3)
d
7.94 (d, J¼7.5 Hz,1H), 7.54 (t, J¼7.5 Hz,1H),
benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (7d). 1H
7.40e7.30 (m, 2H), 4.35e4.25 (m, 1H), 4.07 (d, J¼5.7 Hz, 1H),
3.86e3.81 (m, 2H), 3.63e3.55 (m, 3H), 2.78e2.73 (m, 1H),
2.20e2.10 (m, 1H), 2.08e1.98 (m, 2H), 1.95e1.86 (m, 1H), 1.84e1.73
(m, 1H), 0.89 (s, 9H), 0.045 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
NMR (300 MHz, CDCl3)
d
7.89 (dd, J¼7.8, 1.2 Hz, 1H), 7.42 (td, J¼8.1,
1.8 Hz, 1H), 7.29e7.22(m, 2H), 6.71e6.59 (m, 3H), 5.98 (s, 2H), 5.04
(d, J¼15.6 Hz, 1H), 4.92 (J¼15.6 Hz, 1H), 4.16e4.14 (m, 1H),
3.85e3.78 (m, 1H), 3.62e3.53 (m, 1H), 2.78e2.73 (m, 1H), 2.19e1.99
CDCl3)
d 169.2, 165.0, 139.7, 131.9, 130.7, 130.1, 126.0, 122.6, 59.9,
(m, 3H); 13C NMR (100 MHz, CDCl3)
d
169.4, 165.0, 147.9, 146.8,
57.3, 46.5, 45.3, 31.0, 26.6, 25.7 (3C), 23.8,18.1, ꢂ5.6 (2C). ESI-MS m/z
139.6, 131.9, 130.8, 130.5, 130.2, 125.9, 122.3, 120.2, 108.3, 107.5,
389.2 (MþH)þ; HRMS (EI) calcd for C21H32N2O3Si (Mþ) 388.2182,
101.0, 57.2, 52.0, 46.6, 26.7, 23.8; EIMS m/z 350 (Mþ); HRMS (EI)
found 388.2177. [
a
]
D
24.8 þ284.5 (c 1.00, CHCl3).
calcd for C20H18N2O4 (Mþ) 350.1267, found 350.1270. [
(c 1.00, CHCl3).
a]
24.0 þ339.4
D
4.2.10. (S)-tert-Butyl-2-(5,11-dioxo-2,3-dihydro-1H-benzo[e]pyrrolo
[1,2-a][1,4]diazepin-10(5H,11H,11aH)-yl)ethylcarbamate
(7j). 1H
NMR (300 MHz, CDCl3)
J¼7.6 Hz, 1H), 7.39e7.27 (m, 2H), 4.81 (br s, 1H), 4.13e3.95 (m, 2H),
3.93e3.78 (m, 2H), 3.60e3.51 (m, 1H), 3.37 (m, 2H), 2.73e2.68 (m,
1H), 2.18e2.10 (m, 1H), 2.08e1.93 (m, 2H), 1.40 (s, 9H); 13C NMR
4.2.5. (S)-10-(4-(Trifluoromethyl)benzyl)-2,3-dihydro-1H-benzo[e]-
pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (7e). 1H NMR
d
7.91 (dd, J¼7.8, 1.5 Hz, 1H), 7.54 (t,
(300 MHz, CDCl3)
d
7.91 (d, J¼6.3 Hz,1H), 7.55 (d, J¼8.4 Hz, 2H), 7.43 (t,
J¼8.1 Hz, 1H), 7.31e7.26 (m, 3H), 7.18 (d, J¼8.1 Hz, 1H), 5.21 (d,
J¼15.9 Hz,1H), 5.08 (d, J¼16.2 Hz,1H), 4.22 (d, J¼5.7 Hz,1H), 3.85e3.79
(m, 1H), 3.64e3.55 (m, 1H), 2.78e2.70 (m, 1H), 2.77e1.99 (m, 3H); 13C
(100 MHz, CDCl3)
d 169.1, 164.5, 155.4, 139.2, 131.8, 130.0, 129.8,
125.5, 122.0, 78.9, 56.7, 48.2, 46.1, 38.8, 27.8 (3C), 26.1, 23.3; EIMS m/
NMR (100 MHz, CDCl3)
d
169.6, 164.9, 141.1 (q, J¼1.3 Hz, 1C), 139.4,
z 359 (Mþ); HRMS (EI) calcd for C19H25N3O4 (Mþ) 359.1845, found
132.1, 130.4 (J¼7.4 Hz, 2C), 129.4 (q, J¼32.4 Hz, 1C), 126.9 (2C), 126.1,
125.6 (q, J¼3.7 Hz, 2C), 123.9 (q, J¼271 Hz, 1C), 121.9; 57.1, 51.9, 46.6,
26.7, 23.7; EIMS m/z 374 (Mþ); HRMS (EI) calcd for C20H17F3N2O2 (Mþ)
359.1848. [
a
]
24.8 þ332.8 (c 1.00, CHCl3).
D
4.2.11. (S)-10-Cyclopropyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a]-
374.1242, found 350.1245. [
a
]
24.2 þ260.1 (c 1.00, CHCl3).
[1,4]diazepine-5,11(10H,11aH)-dione (7k). 1H NMR (300 MHz,
D
CDCl3)
d
7.86 (dd, J¼7.6, 1.5 Hz, 1H), 7.53 (t, J¼7.8 Hz, 1H), 7.37 (d,
4.2.6. (S)-10-Allyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]dia-
zepine-5,11(10H,11aH)-dione (7f). 1H NMR (300 MHz, CDCl3)
7.92
J¼8.4 Hz, 1H), 7.27 (m, 1H), 4.03e4.01 (m, 1H), 3.79e3.73 (m, 1H),
3.60e3.50 (m, 1H), 3.18e3.11 (m, 1H), 2.79e2.74 (m, 1H), 2.09e1.92
(m, 3H), 1.33e1.14 (m, 1H), 0.88e0.65 (m, 2H), 0.23e0.14 (m., 1H);
d
(dd, J¼8.1, 1.5 Hz, 1H), 7.49 (t, J¼6.0 Hz, 1H), 7.37e7.27 (m, 2H),
5.97e5.87 (m, 1H), 5.22e5.16 (m, 2H), 4.59 (dd, J¼16.2, 5.1 Hz, 1H),
4.35 (dd, J¼16.2, 5.4 Hz, 1H), 4.12e4.09 (m, 1H), 3.86e3.78 (m, 1H),
3.62e3.53 (m, 1H), 2.77e2.72 (m, 1H), 2.18e1.97 (m, 3H); 13C NMR
13C NMR (100 MHz, CDCl3)
d 172.0, 165.4, 140.1, 131.6, 129.8, 129.7,
125.2, 122.9, 58.0, 46.6, 30.3, 26.5, 23.6, 11.5, 7.4; ESI-MS m/z 257.2
(MþH)þ; HRMS (EI) calcd for C15H16N2O2 (Mþ) 256.1212, found
(100 MHz, CDCl3)
d
169.0, 165.1, 139.9, 133.3, 132.0, 130.3, 130.2, 125.8,
256.1212. [
a]
24.8 þ362.2 (c 1.00, CHCl3).
D
122.1, 117.3, 57.2, 51.7, 46.7, 26.7, 23.8; EIMS m/z 256 (Mþ); HRMS (EI)
calcd for C15H16N2O2 (Mþ) 256.1212, found 256.1218; HPLC:
CH1RALPARK AD-H0.46 cmꢁ25 cm; detected at214 nm; n-hexane/i-
propanol: 80/20; flow: 0.7 mL/min; retention time: 10.9 min (minor),
4.2.12. (S)-10-Benzyl-7-methyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-
a][1,4]diazepine-5,11(10H,11aH)-dione (7l). 1H NMR (300 MHz,
CDCl3)
d
7.69 (s, 1H), 7.29e7.07 (m, 7H), 5.11 (d, J¼15.6 Hz, 1H), 5.01
15.6 min (major), ee¼91%. [
a]
D
24.8 þ465.1 (c 1.00, CHCl3).
(d, J¼15.9 Hz, 1H), 4.17 (d, J¼5.4 Hz, 1H), 3.81 (t, J¼9.3 Hz, 1H),
3.62e3.53 (m, 1H), 2.78e2.74 (m, 1H), 2.33 (s, 3H), 2.18e2.00 (m,
4.2.7. (S)-10-Propyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]dia-
zepine-5,11(10H,11aH)-dione (7g). 1H NMR (300 MHz, CDCl3)
7.92
3H); 13C NMR (100 MHz, CDCl3)
d 169.0, 164.8, 136.9, 136.6, 135.4,
d
132.3, 129.9, 129.8, 128.2 (2C), 126.8, 126.3 (2C), 121.7, 56.8, 51.8,
(d, J¼7.5 Hz, 1H), 7.52 (t, J¼7.8 Hz, 1H), 7.33e7.27 (m, 2H), 4.25e4.15
(m, 1H), 4.05e4.02 (m, 1H), 3.85e3.77(m, 1H), 3.66e3.51 (m, 2H),
2.75e2.70 (m, 1H), 2.18e2.08 (m, 1H), 2.04e1.92 (m, 2H), 1.67e1.41
46.1, 26.3, 23.4, 20.2; EIMS m/z 320 (Mþ); HRMS (EI) calcd for
25.0
C20H20N2O2 (Mþ) 320.1525, found 320.1523. [
CHCl3).
a]
þ336.8 (c 1.00,
D
(m, 2H), 0.82 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 169.3,
165.1, 139.4, 131.9, 131.2, 130.2, 125.8, 122.6, 57.4, 49.8, 46.5, 26.7,
4.2.13. (S)-10-Benzyl-7,8-dimethoxy-2,3-dihydro-1H-benzo[e]pyr-
rolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione NMR
(7m). 1H
23.9, 21.2, 11.1; EIMS m/z 258 (Mþ); HRMS (EI) calcd for C15H18N2O2

5718
X. Lu et al. / Tetrahedron 66 (2010) 5714e5718
(300 MHz, CDCl3)
d
7.34e7.21 (m, 6H), 6.60 (s, 1H), 5.26 (d,
2.94e2.87 (m, 1H), 2.11e2.02 (m, 1H), 0.87 (s, 9H), 0.11 (s, 6H); 13C
NMR (100 MHz, CDCl3) 168.9,165.0,153.0,151.1,146.5,136.6,133.1,
132.5, 122.0, 110.8, 105.0, 103.2 (2C), 69.2, 60.3, 55.9, 55.7 (2C), 55.6
J¼15.6 Hz, 1H), 4.80 (J¼15.3 Hz, 1H), 4.20e4.27 (m, 1H), 3.90 (s, 3H),
d
3.83e3.76 (m, 1H), 3.64 (s, 3H), 3.62e3.55 (m, 1H), 2.81e2.77 (m,
1H), 2.20e1.99 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
169.5, 165.0,
(2C), 55.5, 53.2, 52.0, 35.2, 25.2 (3C), 17.5, ꢂ5.3 (2C); ESI-MS m/z
151.4, 146.6, 137.5, 133.9, 128.8 (2C), 127.5, 127.0 (2C), 122.8, 111.2,
105.2, 57.4, 56.0, 55.8, 52.6, 46.6, 26.7, 23.8; ESI-MS m/z 367.3
(MþH)þ; HRMS (ESI) calcd for C21H22N2NaO4 (MþNa)þ 389.1478,
587.2 (MþH)þ; HRMS (EI) calcd for C30H42N2O8Si (Mþ) 586.2710,
23.7
found 587.2783. [
a
]
þ133.8 (c 1.00, CHCl3).
D
found 389.1472. [
a
]
24.9 þ231.4 (c 1.00, CHCl3).
4.2.19. 5-Benzyl-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]dia-
zepine-6,12(5H,6aH)-dione (10). 1H NMR (300 MHz, CDCl3)
7.81
D
d
4.2.14. (S)-10-Benzyl-7-chloro-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-
(dd, J¼7.5, 1.5 Hz, 1H), 7.39 (td, J¼7.6, 1.5 Hz, 1H), 7.31e7.11 (m, 7H),
5.07 (s, 2H), 4.54 (dt, J¼13.5, 3.6 Hz, 1H), 4.31(dd, J¼6.6, 2.7 Hz, 1H),
2.91 (td, J¼13.2, 3.6 Hz, 1H), 2.28e2.21 (m, 1H), 2.10e1.96 (m, 1H),
1.87e1.81 (m, 1H), 1.73e1.66 (m, 2H), 1.62e1.46 (m, 1H); 13C NMR
a][1,4]diazepine-5,11(10H,11aH)-dione (7n). 1H NMR (300 MHz,
CDCl3)
d
7.87 (d, J¼2.4 Hz, 1H), 7.36e7.24 (m, 4H), 7.13 (m, 3H), 5.14
(d, J¼15.9 Hz, 1H), 4.99 (d, J¼15.6 Hz, 1H), 4.18 (m, 1H), 3.82e3.79
(m, 1H), 3.61e3.57 (m, 1H), 2.80e2.73 (m, 1H), 2.15e2.01 (m, 3H);
(100 MHz, CDCl3)
d 169.7, 168.5, 140.0, 137.0, 131.7, 130.2, 130.1,
13C NMR (100 MHz, CDCl3)
d
168.7, 163.3, 137.8, 136.1, 131.5, 131.4,
128.7 (2C), 127.3, 126.7 (2C), 125.9, 121.2, 51.2 (2C), 40.3, 23.6, 23.2,
19.2; EIMS m/z 320 (Mþ); HRMS (EI) calcd for C20H20N2O2 (Mþ)
320.1525, found 320.1521.
131.1, 129.6 (2C), 128.4, 127.0 (2C), 126.3, 123.2, 56.7, 51.8, 46.3, 26.3,
23.3; EIMS m/z 340 (Mþ); HRMS (EI) calcd for C19H17ClN2O2 (Mþ)
340.0979, found 340.0981. [
a]
25.0 þ192.7 (c 1.00, CHCl3).
D
Acknowledgements
4.2.15. (S)-10-Benzyl-7-fluoro-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-
a][1,4]diazepine-5,11(10H,11aH)-dione (7o). 1H NMR (300 MHz,
The authors are grateful to the Chinese Academy of Sciences and
the National Natural Science Foundation of China (grant 20921091
and 20872156) for their financial support.
CDCl3)
d
7.58 (dd, J¼9.0, 2.8 Hz, 1H), 7.32e7.06 (m, 7H), 5.13 (d,
J¼15.9 Hz, 1H), 4.98 (d, J¼15.9 Hz, 1H), 4.18 (m, 1H), 3.85e3.78 (m,
1H), 3.63e3.53 (m, 1H), 2.80e2.69 (m, 1H), 2.17e2.01 (m, 3H); 13C
NMR (100 MHz, CDCl3)
d
168.8, 163.3, 159.2 (d, J¼247.1 Hz, 1C),
References and notes
136.2, 135.5 (d, J¼2.9 Hz, 1C), 131.9 (d, J¼7.5 Hz, 1C), 128.3 (2C),
127.0, 126.3 (2C), 123.8 (d, J¼8.2 Hz, 1C), 118.7 (d, J¼23.1 Hz, 1C),
116.1 (d, J¼24.0 Hz, 1C), 56.8, 52.0, 46.3, 26.3, 23.3; EIMS m/z 324
(Mþ); HRMS (EI) calcd for C19H17FN2O2 (Mþ) 324.1274, found
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G. U.S. Patent 6,864,250, 2005.
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WO2006021544.
3. Fantò, N.; Gallo, G.; Ciacci, A.; Semproni, M.; Vignola, D.; Quaglia, M.; Bombardi,
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324.1273. [
a]
25.0 þ181.9 (c 1.00, CHCl3).
D
4.2.16. tert-Butyl-2-((2R,11aS)-2-(tert-butyldimethylsilyloxy)-7-
chloro-5,11-dioxo-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]dia-
zepin-10(5H,11H,11aH)-yl)ethylcarbamate (9a). 1H NMR (300 MHz,
CDCl3)
d
7.89 (s, 1H), 7.51 (d, J¼8.4 Hz, 1H), 7.38 (d, J¼8.4 Hz, 1H),
4.81e4.78 (m, 1H), 4.62e4.55 (m, 1H), 4.19e4.15 (m, 1H), 4.06e3.86
(m, 2H), 3.78e3.72 (dd, J¼12.0, 5.4 Hz 1H), 3.60e3.54 (dd, J¼12.6,
5.1 Hz, 1H), 3.39e3.33 (m, 2H), 2.88e2.81 (m, 1H), 2.07e1.98 (m,
1H),1.39 (s, 9H), 0.87 (s, 9H), 0.10 (s, 6H); 13C NMR (100 MHz, CDCl3)
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S. J. Comb. Chem. 2007, 9, 29.
6. Grigg, R.; Cook, A. WO2005121073.
7. Kossakowski, J.; Zawadowski, T.; Turlo, J. Acta Pol. Pharm. 1997, 54, 483.
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Howard, P. W.; Thurston, D. E. Chem. Commun. 2002, 1764; (b) Kamal, A. J. Org.
Chem. 1991, 56, 2237.
9. Ludolph, B.; Waldmann, H. Tetrahedron Lett. 2009, 50, 3148.
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11. Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabé, F. J. Am. Chem. Soc.
2007, 129, 44.
d
168.4, 163.7, 155.4, 137.7, 131.9, 131.3, 130.5, 129.6, 123.6, 79.1, 69.1,
55.6, 53.3, 48.4, 38.6, 35.1, 27.8 (3C), 25.2 (3C), 17.5, ꢂ5.3 (2C); ESI-
MS m/z 546 (MþNa)þ; HRMS (ESI) calcd for C25H38ClN3O5SiNa
25.0
(MþNa)þ 546.2167, found 546.2162. [
a
]
þ174.2 (c 1.00, CHCl3).
D
12. Kamal, A.; Reddy, B. S. N.; Reddy, G. S. K. Synlett 1999, 1251.
13. (a) Kamal, A.; Markandeya, N.; Shankaraiah, N.; Reddy, C. R.; Prabhakar, S.;
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Shankaraiah, N.; Markandeya, N.; Espinoza-Moraga, M.; Arancibia, C.; Kamal,
A.; Santos, L. S. Synthesis 2009, 13, 2163.
14. (a) Ma, D.; Geng, Q.; Zhang, H.; Jiang, Y. Angew. Chem., Int. Ed. 2010, 49, 1291; (b)
Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int. Ed. 2009,
48, 4222; (c) Diao, X.; Wang, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 7974; (d)
Li, L.; Wang, M.; Zhang, X.; Jiang, Y.; Ma, D. Org. Lett. 2009, 11, 1309; (e) Wang,
B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10, 2761; (f) Chen, Y.; Wang,
Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625; (g) Yuan, Q.; Ma, D. J. Org. Chem. 2008,
73, 5159; (h) Lu, B.; Wang, B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337; (i)
Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291; (j) Chen, Y.; Xie, X.; Ma, D. J.
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15. For selected recent examples from other groups, see: (a) Martin, R.; Rodríguez,
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4.2.17. tert-Butyl2-((2R,11aS)-2-(tert-butyldimethylsilyloxy)-5,11-di-
oxo-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10
(5H,11H,11aH)-yl)acetate (9b). 1H NMR (300 MHz, CDCl3)
d 7.93 (dd,
J¼7.8, 1.5 Hz, 1H), 7.52 (t, J¼7.8 Hz, 1H), 7.34 (t, J¼7.5 Hz, 1H), 7.19 (d,
J¼8.1 Hz, 1H), 4.61e4.55 (m, 2H), 4.27 (dd, J¼8.1, 3.6 Hz, 1H),
4.15e4.10 (m, 1H), 3.80 (dd, J¼12.0, 5.4 Hz, 1H), 3.56 (dd, J¼12.0,
5.4 Hz, 1H), 2.90e2.83 (m, 1H), 2.09e2.00 (m, 1H), 1.48 (s, 9H), 0.87
(s, 9H), 0.09 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 169.3, 167.7, 165.5,
139.6, 132.3, 130.3, 129.3, 126.1, 121.7, 82.4, 69.4, 55.8, 53.6, 52.0,
35.5, 27.9 (3C), 25.6 (3C), 17.9, ꢂ4.8 (2C); ESI-MS m/z 461.1 (MþH)þ;
HRMS (EI) calcd for C24H36N2O5Si (M)þ 460.2393, found 460.2393.
[
a]
23.7 þ400.7 (c 1.00, CHCl3).
D
4.2.18. (2R,11aS)-2-(tert-Butyldimethylsilyloxy)-7,8-dimethoxy-10-
(3,4,5-trimethoxybenzyl)-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]
diazepine-5,11(10H,11aH)-dione (9c). 1H NMR (300 MHz, CDCl3)
d
7.33 (s, 1H), 6.66 (s, 1H), 6.38 (s, 2H), 5.07 (d, J¼15.6 Hz, 1H), 4.90
(d, J¼15.6 Hz, 1H), 4.63e4.58 (m, 1H), 4.33e4.29 (m, 1H), 3.82 (s,
3H), 3.69 (s, 9H), 3.76e3.61 (m, 1H), 3.63 (s, 3H), 3.64e3.59 (m, 1H),
16. (a) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453; (b) Zhang, H.; Cai, Q.; Ma,
D. J. Org. Chem. 2005, 70, 5164; (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.