One-pot microwave-assisted selective azido reduction/tandem cyclization in condensed and solid phase with nickel boride

Article abstract of DOI:10.1055/s-0029-1216831

An efficient and inexpensive method using microwave-assisted irradiation with Ni₂B for the syntheses of aromatic amines, pyrrolobenzodiazepines as well as pyrroloquinazolinones was developed. This protocol was applied in the tandem resin-cleavage, azido reduction, and cyclization of compounds 3 and 5 that afforded substituted pyrrolo[2,1-c][1,4] benzodiazepines 4 and 6 in a one-pot manner. The microwave-assisted irradiation reactions enhanced yields with very short reaction times in contrast to the conventional thermal reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216831

PAPER
2163
One-Pot Microwave-Assisted Selective Azido Reduction/Tandem Cyclization
in Condensed and Solid Phase with Nickel Boride
M
icrowave-Assist
a
e
d
A
zido R
g
eduction/Tan
u
dem
C
ycliza
l
tion
w
i
a
th N
i
B
Shankaraiah,a Nagula Markandeya,b Marlene Espinoza-Moraga,a Claudia Arancibia,a Ahmed Kamal,*b
2
Leonardo Silva Santos*a
a
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
E-mail: lssantos@utalca.cl
b
Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27193189; E-mail: ahmedkamal@iict.res.in
Received 26 January 2009; revised 23 February 2009
way of main importance in hydrogenation processes, es-
Abstract: An efficient and inexpensive method using microwave-
pecially in selective hydrogenation reactions.9 Several of
these methodologies are not suitable if labile groups are
present during the reduction process. During the past few
assisted irradiation with Ni2B for the syntheses of aromatic amines,
pyrrolobenzodiazepines as well as pyrroloquinazolinones was de-
veloped. This protocol was applied in the tandem resin-cleavage,
azido reduction, and cyclization of compounds 3 and 5 that afforded years, we have investigated several synthetic strategies in-
substituted pyrrolo[2,1-c][1,4]benzodiazepines 4 and 6 in a one-pot
manner. The microwave-assisted irradiation reactions enhanced
yields with very short reaction times in contrast to the conventional
thermal reactions.
cluding solid-supported ones for the conversion of azido
and nitro aromatic compounds to the corresponding
amines.10
In such a scenario, microwave-assisted (MWA) approach
Key words: pyrrolo[2,1-c][1,4]benzodiazepines, pyrroloquinazoli-
has been applied in a variety of synthetic transformations
for time as well as energy-saving aspects.11,12a It is well
known that microwave-assisted irradiation is more selec-
tive in comparison to thermal reactions by favoring faster
reactions and preventing decomposition of reactants and
products.12b Despite its increasing importance and recent
usage, there are few reports on the application of MWA
for the reduction of azido and nitro groups.13 During the
course of PBD and pyrroloquinazolinone syntheses, we
noted that Ni2B was another choice to obtain such hetero-
cyclic compounds. The main advantage of using this pro-
tocol consists in producing compounds 4 and 6 from azido
derivatives 3 and 5 in a one-pot manner (Scheme 1).
nones, azido reductive cyclization, nickel boride, microwave irradi-
ation
The search towards efficient and mild methodologies for
the reduction of azido/nitro groups to amines continues to
challenge the chemists involved in the construction of or-
ganic molecules with enhanced complexity and functions.
A large number of organic azides have attracted much in-
terest not only as excellent protecting groups, but also as
key intermediates for the synthesis of medicinally active
compounds, such as carbohydrates, nucleosides, N-het-
erocycles, pyrrolo[2,1-c][1,4]benzodiazepines (PBDs),
lactams, fused pyrroloquinazolinones, quinolines, and cy-
clic imides.1 Several mild methodologies have been re-
ported for the reduction of aromatic azido derivatives into
the corresponding amines with the goal for the construc-
tion of heterocyclic moieties.2 A great number of reagents
have been described in the literature for azido group re-
ductions using borohydrides,3 triphenylphosphine,4 ben-
zyltriethylammonium tetrathiomolybdate,5 hexamethyl-
disilathiane,6 samarium iodide,7 radical initiators,8 and
others. Use of nickel boride is shown to be an alternative
PBDs are tricyclic low molecular weight compounds pro-
duced by various Streptomyces species, and are known to
exhibit the DNA-binding interactions with potent antitu-
mor or antibiotic activity.14 PBD-5,11-diones have also
been utilized as key intermediates in the synthesis of nat-
urally occurring and synthetically modified PBD imines
such as tomaymycin and chicamycin.15–17 Moreover, the
tricyclic ring system has been extensively utilized in the
preparation of a number of pharmaceutically important
moieties used as templates for the design and assembly of
O
H
N
N3
N3
COOMe
COOMe
H
N
N
N
R
O
O
O
O
3
4, R = H
6, R = OH
5
Scheme 1 Retrosynthetic analysis of pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones
SYNTHESIS 2009, No. 13, pp 2163–2170
x
x.
x
x
.
2
0
0
9
Advanced online publication: 19.05.2009
DOI: 10.1055/s-0029-1216831; Art ID: M00709SS
© Georg Thieme Verlag Stuttgart · New York

2164
N. Shankaraiah et al.
PAPER
peptidomimetic agents,18 anxiolytic drugs,19 anticonvul- duction reactions were carried out using 1a–i and an
sants,20 herbicides,21 and anticancer agents.22
excess of Ni2B (3 equiv) in MeOH–HCl (1.0 M) for 10–
20 minutes at 60–70 °C. The corresponding amines 2a–i
was obtained in good yields (72–88%). The reactions
were monitored by the disappearance of starting material
as indicated by TLC and GC analysis. It was interesting to
observe that the substituted azido acid derivatives (entries
f and i) did not dimerize after reductions using the Ni2B
reagent system as observed previously.24 It was also inter-
esting to note that products 2c,d,f,g were selectively ob-
tained without any detected amount of debenzylated side
products.
Our investigation began by examining Ni2B in acidic me-
dia as a mild reaction condition for the conversion of azi-
do compounds to the corresponding amines through
thermal and MWA approaches. The structure of nickel
boride has remained unclear for the last 40 years, howev-
er, its annealing behavior was investigated and accepted
to lead to crystalline Ni2B.23 The nickel boride (Ni2B,
amorphous fine black granules) was freshly prepared by
mixing Ni(OAc)2 and NaBH4.23 Previously, Seltzman and
co-workers23d reported the reduction of iodine-substituted
arylnitro compounds to the corresponding amino deriva- Therefore, with aim to increase the yields along with the
tives with Ni2B. Table 1 summarizes the azido reductions shortening of the reaction times, we decided to explore the
with Ni2B. The azido starting materials 1a–i were synthe- microwave-assisted irradiation process as the heating
sized according to reported methods.10c–e Initially, the re- source for the conversion of aryl azides into amines. This
Table 1 Ni2B Reduction of Azido Derivatives to the Corresponding Amines
Ni2B
MeOH–HCl (1 M)
60–70 °C
N3
NH2
R
R
or
Ni2B
MeOH–HCl (1 M)
MW (70 W)
1a–i
2a–i
Entry
Substrate 1
Product 2a
Thermal reaction
MWA reaction
Time (min)
Time (min)
Yield (%)b
Yield (%)b
93
N3
NH2
a
b
c
10
82
77
88
80
75
1
1
1
1
1
Cl
Br
Cl
Br
N3
NH2
10
10
10
10
84
95
90
88
N3
NH2
BnO
Cl
BnO
Cl
N3
NH2
d
e
BnO
BnO
MeO2C
N3
MeO2C
NH2
Cl
Cl
OBn
OBn
NH2
N3
f
15
75
1
82
CO2H
CO2H
BnO
NH2
BnO
N3
g
h
i
10
15
20
80
75
72
1
1
1
90
88
80
MeO
HO
CO2Me
NH2
MeO
BnO
CO2Me
N3
MeO
HO
CO2Me
NH2
MeO
HO
CO2Me
N3
MeO
CO2H
MeO
CO2H
a All compounds were characterized by GC, 1H and 13C NMR, FT-IR, and EI-MS.
b Isolated yields.
Synthesis 2009, No. 13, 2163–2170 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Azido Reduction/Tandem Cyclization with Ni2B
2165
Table 2 Synthesis of PBD-5,11-diones 4a–d and Pyrroloquinazolinones 4e–h through Reductive Cyclization Using Ni2B
Ni2B
MeOH–HCl (1 M)
60–70 °C
O
H
N
N3
COOMe
H
R
R
or
Ni2B
N
N
MeOH–HCl (1 M)
MW (70 W)
O
O
4a–d
3a–d
Ni2B
MeOH–HCl (1 M)
60–70 °C
N3
N
O
N
R
R
or
Ni2B
N
MeOH–HCl (1 M)
MW (70 W)
O
O
3e–h
4e–h
Entry
Substrate 3
Product 4a
Thermal reaction
MWA reaction
Time (min)
Time (min)
Yield (%)b
Yield (%)b
90
O
H
N3
COOMe
N
H
a
20
72
76
80
75
2
2
2
2
N
N
O
O
O
O
H
N
N3
BnO
COOMe
BnO
H
b
c
20
23
30
88
90
85
N
MeO
N
MeO
O
O
H
N
MeO
MeO
N3 COOMe
MeO
MeO
H
N
N
O
O
O
H
N
N3
HO
COOM;e
HO
H
d
N
MeO
N
MeO
O
O
N3
N
O
e
f
15
20
20
15
82
80
75
72
2
2
2
2
92
90
80
85
N
N
O
O
BnO
N3
O
BnO
MeO
N
O
N
N
MeO
O
N3
N
O
O
g
h
N
N
O
Cl
N3
O
Cl
N
N
N
O
O
a All compounds were characterized by GC, 1H and 13C NMR, FT-IR and EI-MS.
b Isolated yields.
Synthesis 2009, No. 13, 2163–2170 © Thieme Stuttgart · New York

2166
N. Shankaraiah et al.
PAPER
simple process and reaction conditions render particularly 30 minutes in condensed-phase, and 85–92% yields in 2
attractive for the efficient preparation of biologically and minutes in microwave-assisted reactions. As expected,
medicinally interesting molecules. The same reactions as azido derivatives 3a–d showed better results in the reduc-
depicted in Table 1 were carried out under MWA irradia- tion followed by cyclization to the corresponding PBD-
tion in a sealed vessel. Reaction times were reduced to one 5,11-diones 4a–d. In addition, fused pyrroloquinazolino-
minute for azides 2a–i, the yields (80–95%) were better nes (deoxyvasicinones) 4e–h were also synthesized effi-
than using thermal heating, as shown in Table 1. Further, ciently by using this Ni2B reagent system. These
it was also observed that applying the described protocol, derivatives 4e–h are particularly interesting compounds
temperatures of the reaction mixture inside the reaction as precursors for vasicinone and its derivatives that pos-
vessel reached values of 39 °C (1 min) and 52 °C (2 min) sess several pharmacological properties such as bron-
for MWA irradiation reductions applying a potency of 70 chodilation,25 antitumour,26 and antimycobacterial.27
W. These temperatures were lower than used in the ther-
Recently, we reported a versatile solid-phase combinato-
mal conditions, preventing in this way degradation of re-
rial approach for PBD-5,11-diones with high diversity of
actants and products, and favoring the enhancement of
a library of compounds, and in vitro activity against
yields.
Mycobacterium tuberculosis assays.28 In the same con-
Next, we performed the reactions using 3a–d10c–e as these text, a solid-phase approach was developed for reductive
compounds are interesting intermediates for PBD-5,11- cyclization of azido/nitro derivatives to the corresponding
dione syntheses. Table 2 summarizes the selective reduc- PBD-5,11-diones employing Al/NiCl2·6H2O and Al/
tion of 3a–d to amines followed by tandem cyclization af- NH4Cl in a two-steps manner.29 Thus, it is plausible to ex-
fording 4a–d in good to excellent yields (72–80%) in 20– pect that using MWA, compounds 6a–e might be obtained
Table 3 One-Pot Microwave-Assisted Solid-Phase Synthesis of PBD-5,11-diones by Reductive Cyclization and Resin Cleavage with Ni2B
Ni2B
CH2Cl2–MeOH–TFA
(2:1:0.5)
O
H
N
MW (70 W)
2 min
N3
H
COOMe
R
R
N
N
OH
O
O
O
5a–e
6a–e
Entry
Substrate 5
Product 6a
Time (min)
2
Yield (%)b
80
O
H
N
N3
COOMe
H
a
N
N
N
N
N
N
O
OH
O
O
O
H
N
N3
BnO
COOMe
H
b
c
2
2
2
2
73
64
78
81
N
MeO
O
OH
OH
OH
OH
O
O
O
H
N
N3
MeO
MeO
COOMe
H
N
O
O
O
O
H
N
N3
COOMe
H
d
e
N
O
O
O
O
H
N
N3
Cl
COOMe
H
N
O
O
O
a All compounds were characterized by 1H and 13C NMR, FT-IR and EI-MS.
b Isolated yields.
Synthesis 2009, No. 13, 2163–2170 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Azido Reduction/Tandem Cyclization with Ni2B
2167
by Ni2B reduction protocol from solid-supported 5a–e.10d
The C2-hydroxy substituted PBD-5,11-diones 6a–e were
obtained by a different protocol as used before. In the new
approach Ni2B was used with CH2Cl2–MeOH–TFA
(2:1:0.5) as solvent. After MWA irradiation (2 min) of the
mixture, 6a–e was obtained in good yields ranging from
64–81% and lower reaction times than described previ-
ously, as depicted in Table 3. The sequence of this one-pot
solid-phase synthesis of 6 by a reductive cyclization and
resin cleavage seems to follow resin cleavage and/or re-
duction and tandem ring-closing (Table 3).
(FAB and EI-MS) equipment. Column chromatography was per-
formed using silica gel (100–200 mesh). TLC analyses were per-
formed with silica gel plates using I2, KMnO4, and UV-lamp for
visualization. The final yields of the purified products were deter-
mined on the basis of loading of the polymeric support starting from
the Wang resin.
4-Chloroaniline (2a); Typical Procedure
1-Azido-4-chlorobenzene (1a; 50 mg, 0.326 mmol) was dissolved
in MeOH (2.0 mL), and then Ni2B (76 mg, 0.980 mmol) and aq 1 M
HCl (1.0 mL) were added. This reaction mixture was heated to
60 °C and stirred for 10 min. Progress of the reaction was monitored
by the disappearance of starting material as indicated by TLC and
GC analysis. The same reaction was also performed with micro-
wave-assisted irradiation at 70 W using CEM Discover LabMate
equipment in a closed vessel with the temperature monitored by a
built-in infrared sensor for 1 min at 39 °C with cooling. The result-
ing mixture was filtered, and then the MeOH was evaporated under
vacuum. Then, H2O (10 mL) was added to the mixture and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4), rotaevaporated under reduced pressure to afford pure
compound 2a; yield: thermal, 34 mg (82%); MWA, 38 mg (93%);
mp 70–71 °C.
In conclusion, an efficient MWA methodology employing
Ni2B for the preparation of aromatic amines, pyrroloben-
zodiazepines as well as pyrroloquinazolinones has been
developed. The nickel boride reagent is easy to prepare,
inexpensive, safe to handle, stable, and not pyrophoric,
and no inert atmosphere is required. Interestingly, the
microwave-assisted irradiation reactions enhanced yields
with very short reaction times in contrast to the conven-
tional thermal reactions. The reaction conditions are par-
ticularly attractive and are an example of green chemistry
approach. The possibility of performing reactions in a
very short time period by MWA energy with the reaction
mixture can be considered green chemistry (reducing en-
ergy consumption, time savings, increasing efficiency,
water as solvent). This work is also an example of pre-
venting major adverse effects to the environment due to
the consumption of energy for heating and cooling, and
use of eco-friendly solvent like water. Several groups
have tried to overcome these problems by seeking effi-
cient methods that use alternative energy sources such as
ultrasound or microwave irradiation to facilitate chemical
reactions. If one compares the energy efficiency of con-
ventional oil-bath synthesis (heating by conduction and
convection currents), and microwave-assisted reactions, it
can be noted that for most chemical transformations a sig-
nificant energy saving (up to 80-fold) can be expected us-
ing microwaves as an energy source on a laboratory
scale.30
FT-IR (KBr): 3477, 3375, 3198, 1880, 1618, 1509, 1288, 1180,
1079, 1015, 647, 546 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.12 (d, J = 8.87 Hz, 2 H), 6.63 (d,
J = 8.87 Hz, 2 H), 3.67 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 116.5, 123.7, 129.5, 144.8.
EI-MS: m/z = 127 [M+].
4-Bromoaniline (2b)
Yield: thermal, 77%; MWA, 84%.
Mp 60–62 °C. Spectroscopic and physical data are in agreement
with those described in the literature.31
4-Benzyloxyaniline (2c)
Yield: thermal, 88%; MWA, 95%; mp 44–46 °C.
FT-IR: (KBr): 3411, 3373, 3287, 3204, 2897, 2847, 1632, 1591,
1462, 918, 827, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28–7.46 (m, 5 H), 6.83 (d, J =
8.73 Hz, 2 H), 6.66 (d, J = 8.73 Hz, 2 H), 4.51 (s, 2 H), 3.44 (br s, 2
H).
13C NMR (75 MHz, CDCl3): d = 152.1, 141.1, 137.3, 128.7, 128.1,
127.4, 117.1, 116.8, 70.6.
EI-MS: m/z = 199 [M+].
Commercially available chemical reagents were used without fur-
ther purification. Anhyd THF, CH2Cl2, MeOH, and DMF were pre-
pared by distillation under N2 over sodium/benzophenone, CaH2,
Na/P2O5, and CaH2/molecular sieves, respectively. Solvents for ex-
traction and column chromatography were distilled prior to use.
Wang resin (0.8–1.0 mmol/g, 100–200 mesh, 1% DVB) was pur-
chased from Lancaster. NaN3 was handled with care for the prepa-
ration of various substituted azido derivatives by wearing safety
glasses, facemask, gloves, and reactions were performed in a fume
hood. All the microwave reactions were performed in CEM Discov-
er LabMate equipment in a closed vessel (built-in infrared sensor)
with cooling system. IR spectra were recorded as thin films on KBr
discs and the wave numbers are expressed in cm–1. All the polymer-
bound intermediates were monitored by FT-IR spectra. Melting
points were measured with an electrothermal apparatus and are un-
corrected. 1H and 13C NMR spectra were recorded on Varian Gem-
ini 200, Bruker WH Avance 300, and Varian Unity 400 MHz
spectrometers using TMS as the internal standard. Chemical shifts
are reported in parts per million (ppm) downfield from TMS. Cou-
pling constants are reported in hertz (Hz). Mass spectra were re-
corded on a Quattro-LC ESI-MS, and on a LSIMS-VG-Autospec
4-Benzyloxy-3-chloroaniline (2d)
Yield: thermal, 80%; MWA, 90%; mp 57–58 °C.
FT-IR (KBr): 3409, 3301, 3208, 3061, 3032, 2911, 2859, 1627,
1509, 1272, 1225, 1012, 921, 855, 747, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.47 (d, J = 7.46 Hz, 2 H), 7.40 (t,
J = 7.46 Hz, 2 H), 7.29 (t, J = 7.47 Hz, 1 H), 6.81 (d, J = 8.76 Hz, 1
H), 6.77 (d, J = 3.27 Hz, 1 H), 6.52 (dd, J = 8.72, 3.12 Hz, 1 H), 5.11
(s, 2 H), 3.46 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 146.9, 141.5, 138.8, 128.4, 128.3,
127.5, 124.3, 116.9, 117.2, 113.9, 72.1.
EI-MS: m/z = 233 [M+].
Methyl 5-Amino-2-chlorobenzoate (2e)
Yield: thermal, 75%; MWA, 88%; mp 68–70 °C.
FT-IR (KBr): 3458, 3366, 3228, 3010, 2947, 2838, 1727, 1628,
1611, 1488, 1444, 1334, 1044, 988, 788, 656 cm–1.
Synthesis 2009, No. 13, 2163–2170 © Thieme Stuttgart · New York

2168
N. Shankaraiah et al.
PAPER
1H NMR (200 MHz, CDCl3): d = 7.22 (d, J = 8.48 Hz, 1 H), 7.16 (d,
J = 3.32 Hz, 1 H), 6.77 (dd, J = 8.48, 3.21 Hz, 1 H), 3.96 (s, 3 H),
3.77 (br s, 2 H).
13C NMR (50 MHz, CDCl3): d = 167.1, 146.7, 132.6, 131.1, 122.2,
119.2, 117.8, 52.9.
was maintained at 52 °C with (CEM Discover LabMate) cooling.
The solvent was evaporated, neutralized to pH 7 with sat. aq 5%
NaHCO3 solution, and then extracted with EtOAc (3 × 25 mL). The
combined organic phases were washed with brine (20 mL), dried
(Na2SO4) and evaporated under reduced pressure. The crude prod-
uct thus obtained was purified by column chromatography over a
silica gel (60–120 mesh) employing EtOAc–hexane (75:25) as elu-
ent to afford 4a; yield: thermal, 56 g (72%); MWA, 71 g (90%); mp
218–219 °C; [a]D23 +201 (c 1.0, MeOH).
EI-MS: m/z = 185 [M+].
2-Amino-3-(benzyloxy)benzoic Acid (2f)
2-Azido-3-(benzyloxy)benzoic acid (1f; 0.050 g, 0.185 mmol) was
dissolved in MeOH (2.0 mL), then Ni2B (0.070 g, 0.557 mmol) and
aq 1 M HCl (1.0 mL) were added. This reaction mixture was heated
to 60 °C and stirred for 10 min. The resulting mixture was filtered
and the MeOH was evaporated under vacuum. Then, H2O (10 mL)
was added to the residue and extracted with CH2Cl2 (10 mL). Next,
the aqueous layer was carefully neutralized with aq 5% NaHCO3
until pH 7.0. The aqueous solution was extracted with EtOAc
(3 × 20 mL), dried (Na2SO4), rotaevaporated under reduced pres-
sure to afford the pure compound 2f as a brown solid; yield: ther-
mal, 33 mg (75%); MWA, 37 mg (82%); mp 141–142 °C.
FT-IR (KBr): 3223, 2952, 2873, 1688, 1625, 1476, 1449, 1413,
1268, 1213, 1154, 1103 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.22 (br s, 1 H), 8.01 (d, J = 8.03
Hz, 1 H), 7.45 (t, J = 8.03, 7.03 Hz, 1 H), 7.21–7.28 (m, 1 H), 7.05
(d, J = 8.03 Hz, 1 H), 4.07 (d, J = 6.57 Hz, 1 H), 3.75–3.86 (m, 1 H),
3.51–3.65 (m, 1 H), 2.71–2.82 (m, 1 H), 1.85–2.15 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 171.2, 163.3, 135.1, 132.2, 130.8,
124.3, 123.0, 121.0, 56.8, 46.8, 26.1, 23.2.
EI-MS: m/z = 216 [M+].
FT-IR: (KBr): 3491, 3348, 3064, 3029, 2922, 2866, 1673, 1612,
1577, 1463, 1399, 1275, 1214, 1158, 1087, 1041, 902, 845, 796
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47 (d, J = 9.29 Hz, 1 H), 7.26–
7.36 (m, 5 H), 6.86 (d, J = 8.80 Hz, 1 H), 6.72 (br s, 1 H), 6.49 (t,
J = 7.82, 8.31 Hz, 1 H), 5.64 (br s, 1 H), 5.00 (s, 2 H).
13C NMR (50 MHz, CDCl3): d = 174.4, 173.1, 146.1, 142.4, 136.6,
128.2, 123.6, 115.0, 114.5, 109.6, 76.9, 70.7, 22.6.
EI-MS: m/z = 243 [M+].
(11aS)-8-(Benzyloxy)-7-methoxy-2,3,5,10,11,11a-hexahydro-
1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (4b)
Yield: thermal, 76%; MWA, 88%; mp 172–173 °C; [a]D23 +239
(c 1.0, MeOH).
FT-IR (KBr): 3356, 2962, 2928, 2844, 1679, 1636, 1601, 1519,
1441, 1288, 1177, 1121, 1022, 883, 756, 697 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.81 (s, 1 H), 7.26–7.40 (m, 6 H),
6.49 (s, 1 H), 5.10 (s, 2 H), 4.00 (d, J = 6.44 Hz, 1 H), 3.91 (s, 3 H),
3.47–3.78 (m, 2 H), 2.63–2.71 (m, 1 H), 1.90–2.05 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 170.8, 165.0, 149.4, 146.6, 135.7,
129.4, 128.5, 128.0, 127.1, 119.4, 112.3, 105.8, 76.9, 76.6, 708,
56.7, 56.1, 47.2, 26.1, 23.5.
Methyl 2-Amino-4-(benzyloxy)-5-methoxybenzoate (2g)
Yield: thermal, 80%; MWA, 90%; mp 131–132 °C.
FT-IR (KBr): 3468, 3356, 3030, 2947, 1676, 1617, 1587, 1560,
1514, 1462, 1426, 1384, 1303, 1258, 1200, 1170, 992, 872, 835,
740, 695 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.24–7.39 (m, 6 H), 6.08 (s, 1 H),
5.08 (s, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 1.26 (d, J = 15.86 Hz, 2 H).
EI-MS: m/z = 352 [M+].
(11aS)-7,8-Dimethoxy-2,3,5,10,11,11a-hexahydro-1H-pyrro-
lo[2,1-c][1,4]benzodiazepine-5,11-dione (4c)
Yield: thermal, 80%; MWA, 90%; mp 178–180 °C; [a]D23 +303
(c 1.0, MeOH).
1H NMR (400 MHz, CDCl3): d = 8.71 (br s, 1 H), 7.42 (s, 1 H), 6.48
(s, 1 H), 4.03–4.10 (m, 1 H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.72–3.82
(m, 1 H), 3.52–3.65 (m, 1 H), 2.70–2.78 (m, 1 H), 1.98–2.06 (m, 3
H).
EI-MS: m/z = 287 [M+].
Methyl 2-Amino-4-hydroxy-5-methoxybenzoate (2h)
Yield: thermal, 75%; MWA, 88%; mp 148–149 °C.
FT-IR (KBr): 3410, 3304, 3000, 2958, 2850, 1670, 1598, 1576,
1508, 1446, 1302, 1231, 1175, 1061, 1023, 952, 869, 843, 784, 629,
448 cm–1.
13C NMR (50 MHz, CDCl3): d = 190.6, 184.8, 171.6, 165.7, 149.3,
138.5, 131.4, 123.3, 96.5, 76.3, 75.6, 66.7, 45.6, 43.0.
1H NMR (200 MHz, CDCl3): d = 7.22 (s, 1 H), 6.15 (s, 1 H), 5.48
EI-MS: m/z = 276 [M+].
(br s, 2 H), 3.84 (s, 3 H), 3.83 (s, 3 H).
(11aS)-8-Hydroxy-7-methoxy-2,3,5,10,11,11a-hexahydro-1H-
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (4d)
Yield: thermal, 75%; MWA, 85%; mp 254–255 °C; [a]D23 +276
(c 0.5, MeOH).
EI-MS: m/z =197 [M+].
Amino-4-hydroxy-5-methoxybenzoic Acid (2i)
Yield: thermal, 72%; MWA, 80%; mp 169–171 °C.
FT-IR (KBr): 2960, 2925, 2843, 1683, 1631, 1607, 1521, 1438,
1284, 1204, 1173, 1115, 1060, 1025, 884, 757 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.80 (br s, 1 H), 7.40 (s, 1 H), 6.50
(s, 1 H), 6.00–6.10 (br s, 1 H), 4.00–4.10 (m, 1 H), 3.95 (s, 3 H),
3.70–3.80 (m, 1 H), 3.55–3.65 (m, 1 H), 2.70–2.80 (m, 1 H), 1.90–
2.10 (m, 3 H).
FT-IR (KBr): 3485, 3324, 1710, 1576, 1508, 1441, 1384, 1297
cm–1.
1H NMR (200 MHz, CDCl3): d = 7.26 (s, 1 H), 6.19 (s, 1 H), 5.55
(br s, 2 H), 3.92 (s, 3 H).
EI-MS: m/z = 183 [M+].
13C NMR (50 MHz, CDCl3) d = 175.1, 170.1, 155.1, 149.5, 135.8,
122.5, 117.0, 112.8, 61.5, 60.7, 51.7, 30.7, 28.2.
EI-MS: m/z = 262 [M+].
(11aS)-2,3,5,10,11,11a-Hexahydro-1H-pyrrolo[2,1-c][1,4]ben-
zodiazepine-5,11-dione (4a); Typical Procedure
To a stirred solution of compound 3a (0.100 g, 0.364 mmol) in
MeOH (2.0 mL) and Ni2B (0.137 g, 1.094 mmol) was added aq 1 M
HCl (1.0 mL). The reaction mixture was heated to 60 °C followed
by stirring for 20–30 min and the same amount of the reaction was
repeated in microwave irradiation at 70 W for 2 min; temperature
1,2,3,9-Tetrahydropyrrolo[2,1-b]quinazolin-9-one (4e)
Yield: thermal, 82%; MWA, 92%; mp 104–106 °C.
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Microwave-Assisted Azido Reduction/Tandem Cyclization with Ni2B
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1H NMR (300 MHz, CDCl3): d = 8.24 (dd, J = 1.5, 8.3 Hz, 1 H),
7.57–7.70 (m, 2 H), 7.38–7.52 (m, 1 H), 4.16–4.21 (t, J = 7.5 Hz, 2
H), 3.12–3.18 (t, J = 7.5 Hz, 2 H), 2.24–2.34 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 172.1, 166.3, 152.8, 146.7, 138.1,
131.2, 129.9, 119.4, 112.7, 108.5, 80.1, 70.2, 68.9, 56.9, 55.3, 40.3,
38.2.
EI-MS: m/z = 186 [M+].
EI-MS: m/z = 368 [M+].
6-(Benzyloxy)-7-methoxy-1,2,3,9-tetrahydropyrrolo[2,1-
b]quinazolin-9-one (4f)
Yield: thermal, 80%; MWA, 90%; mp 157–158 °C.
(2R,11aS)-2-Hydroxy-7,8-dimethoxy-1,2,3,10,11,11a-hexahy-
dro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (6c)
Yield: 64%; [a]D23 +138 (c 1.0, MeOH).
FT-IR (KBr): 2955, 2931, 2849, 1662, 1611, 1501, 1453, 1401,
1371, 1288, 1261, 1175, 1137, 1076, 1028, 846, 777 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.53 (s, 1 H), 7.25–7.46 (m, 5 H),
7.00 (s, 1 H), 5.22 (s, 2 H), 4.16 (t, J = 7.34 Hz, 2 H), 3.99 (s, 3 H),
3.10 (t, J = 7.34, 8.08 Hz, 2 H), 2.18–2.34 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 176.8, 173.1, 168.4, 164.5, 155.4,
148.0, 147.4, 146.7, 133.3, 128.3, 125.0, 115.6, 89.9, 75.3, 65.7,
51.6, 49.1, 39.1, 31.5.
1H NMR (400 MHz, CDCl3 + DMSO-d6): d = 8.98 (s, 1 H), 7.47 (s,
1 H), 6.63 (s, 1 H), 4.61 (d, J = 5.78 Hz, 1 H), 4.41 (m, 1 H), 4.17
(t, J = 4.08 Hz, 1 H), 4.08 (d, J = 6.78 Hz, 1 H), 3.84 (s, 3 H), 3.86
(s, 3 H), 3.45–3.60 (m, 1 H), 3.65–3.85 (m, 1 H), 1.93–2.98 (m, 1
H).
13C NMR (50 MHz, DMSO-d6): d = 170.8, 165.1, 152.5, 146.1,
131.7, 118.6, 112.2, 104.8, 67.8, 57.2, 56.8, 54.2, 34.2.
EI-MS: m/z = 292 [M+].
ESI-MS: m/z = 323 [M + H]+.
(2R,11aS)- 2-Hydroxy-8-methyl-1,2,3,10,11,11a-hexahydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (6d)
Yield: 78%; [a]D23 +189 (c 1.0, MeOH).
1H NMR (400 MHz, CDCl3): d = 10.31 (br s, 1 H), 7.75 (s, 1 H),
7.23 (d, J = 7.32 Hz, 1 H), 6.95 (d, J = 7.32 Hz, 1 H), 4.93 (d, J =
5.58 Hz, 1 H), 4.41 (m, 1 H), 4.16 (t, J = 8.08 Hz, 1 H), 3.74 (m, 1
H), 3.50–3.60 (m, 1 H), 2.71–2.82 (m, 1 H), 2.37 (s, 2 H), 1.97–2.07
(m, 2 H).
2-Methyl-6,7,8,9-tetrahydro[2,1-b]quinazoline-11-one (4g)
Yield: thermal, 75%; MWA, 80%; mp 119–121 °C.
1H NMR (200 MHz, CDCl3): d = 8.01 (s, 1 H), 7.55 (s, 2 H), 4.12
(t, J = 5.07 Hz; 2 H), 3.08 (t, J = 5.0 Hz, 2 H), 2.51 (s, 3 H), 1.90–
2.20 (m, 4 H).
EI-MS: m/z = 214 [M+].
13C NMR (75 MHz, CDCl3): d = 172.1, 166.2, 143.8, 134.7, 1231.4,
128.0, 124.6, 118.6, 67.3, 57.9, 51.2, 34.6, 22.0.
EI-MS: m/z = 246 [M+].
3-Chloro-6,7,8,9-tetrahydro[2,1-b]quinazoline-11-one (4h)
Yield: thermal, 72%; MWA, 85%; mp 132–133 °C.
1H NMR (200 MHz, CDCl3): d = 8.24 (d, J = 6.56 Hz, 1 H), 7.66 (s,
1 H), 7.47 (d, J = 6.65 Hz, 1 H), 4.04 (t, J = 7.42 Hz, 2 H), 3.03 (t,
J = 8.0 Hz, 2 H), 1.95–2.10 (m, 4 H).
(2R,11aS)-8-Chloro-2-hydroxy-1,2,3,10,11,11a-hexahydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (6e)
Yield: 81%; [a]D23 –88 (c 1.0, MeOH).
EI-MS: m/z = 234 [M+].
1H NMR (400 MHz, CDCl3): d = 10.51 (br s, 1 H), 7.78 (d, J = 4.89
Hz, 1 H), 7.09 (m, 2 H), 4.00–4.05 (m, 1 H), 3.65 (m, 1 H), 3.43 (m,
1 H), 3.01, (br s, 1 H), 2.61 (m, 1 H), 1.95 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 170.3, 164.4, 137.5, 131.8, 130.9,
125.3, 124.9, 119.8, 56.3, 46.9, 25.8, 23.1.
(2R,11aS)-2-Hydroxy-1,2,3,10,11,11a-hexahydro-5H-pyrro-
lo[2,1-c][1,4]benzodiazepine-5,11-dione (6a); Typical Proce-
dure
To a suspension of resin 5a (0.200 g, 0.72 mmol/g) in CH2Cl2 (4.0
mL) and MeOH (2.0 mL) was added TFA (1.0 mL) and Ni2B (0.272
g, 2.16 mmol). Then the microwave-assisted reaction was per-
formed at 70 W using a CEM Discover LabMate equipment in a
closed vessel with the temperature monitored by a built-in infrared
sensor for 2 min at 52 °C with cooling. The final product was then
filtered through a glass funnel, and the filtrate was neutralized with
sat. aq NaHCO3 until pH 7. The organic layer was separated and
dried (Na2SO4). The crude product was purified by preparative TLC
using EtOAc–hexane (9:1) as eluent to give 6a (80%) as a semi-
solid; yield: 17 mg (80%); [a]D23 +252 (c 1.0, MeOH).
EI-MS: m/z = 266 [M+].
Acknowledgment
L.S.S. thanks FONDECYT (Project 1085308), IFS (F/4195-1) and
Organisation for the Prohibition of Chemical Weapons for support
of research activity. PBCT (PSD-50) and Universidad de Talca
were also acknowledged for financial support to S.N. and M.E.M.
1H NMR (200 MHz, DMSO-d6): d = 10.20 (br s, 1 H), 7.85–8.00
(m, 1 H), 7.40–7.50 (m, 1 H), 7.08–7.26 (m, 2 H), 4.60–4.70 (m, 1
H), 4.40–4.55 (m, 1 H), 4.10–4.26 (m, 1 H), 3.85–3.95 (m, 1 H),
3.50–3.62 (m, 1 H), 2.78–2.95 (m, 1 H), 2.00–2.10 (m, 1 H).
13C NMR (50 MHz, DMSO-d6): d = 169.6, 165.0, 135.3, 131.2,
128.2, 125.4, 123.4, 120.5, 67.1, 54.7, 53.3, 33.8.
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Synthesis 2009, No. 13, 2163–2170 © Thieme Stuttgart · New York