A convenient two-step synthesis of amino acid derived chiral 3-substituted [1,4]benzodiazepin-2-ones

Article abstract of DOI:10.1055/s-2005-869950

A new two-step route to chiral 3-substituted [1,4]benzodiazepin-2-ones is described, which involves the coupling of 2-nitrobenzyl bromide with a series of amino acids, followed by diazepine ring formation with Fe/AcOH at 110 °C. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-2005-869950

PAPER
1881
A Convenient Two-Step Synthesis of Amino Acid Derived Chiral 3-Substituted
[1,4]Benzodiazepin-2-ones1
A
C
onven
i
ient
T
w
t
o-Ste
p
e
Synthesis
o
n
f
A
mino
A
c
d
id
D
erivative
r
s
a Kumar Mishra, Gautam Panda*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, UP, India
Fax +91(522)2223405; fax +91(522)2223938; E-mail: bapi.rm@yahoo.com; E-mail: gautam_panda@lycos.com
Received 14 December 2004; revised 9 March 2005
Cl
Abstract: A new two-step route to chiral 3-substituted [1,4]benzo-
CH3
O
O
diazepin-2-ones is described, which involves the coupling of 2-ni-
trobenzyl bromide with a series of amino acids, followed by
diazepine ring formation with Fe/AcOH at 110 °C.
N
Cl
H
O
NH
N
N
NHBoc
Key words: 3-substituted [1,4]benzodiazepin-2-ones, pyrrolo[2,1-
c][1,4]benzodiazepin-2-ones, iron/acetic acid, amino acids, chiral
N
Cl
2
CONH2
1
[1,4]Benzodiazepine scaffolds are considered among the
most important structures for drug discovery,2 being a ma-
jor structural feature in a range of drugs such as opiate an-
tagonists,3 anti-inflammatory agents,3,4 anti-HIV agents,5
anti-arrhythmics,6 anxiolytics, antibiotics, anticonvul-
sants,7 hypnotics, and vasopressin receptor antagonists.8
Moreover, a diverse range of [1,4]benzodiazepines are
used as constrained dipeptide mimics or non-peptide scaf-
folds for peptidomimetics.9 Recently, g-secretase inhibi-
tors 1 and 2 were also reported. Another well-known
member of the benzodiazepine family is pyrrolo[2,1-
c][1,4]benzodiazepines (PBDs). Research on PBDs is of
considerable interest due to their potential as anti-tumor
agents, gene regulators, and DNA probes.10 The PBD ring
systems are also produced by various Streptomyces spe-
cies, and include anthramycin (3), porothramycin B (4),
tomaymycin (5), chicamycin A (6), and abbeymycin (7).
OR3
H
OCH3
H
R4
N
N
HO
H
N
R1
N
H3CO
CH3
CON
R2
O
O
3 Anthramycin (R4 = CH3, R3 = R2 = R1 = H)
4 Porothramycin B (R4 = H, R3 = R2 = R1 = CH3)
5 Tomaymycin
H
H
OCH3
H
OCH3
H
N
N
HO
N
N
H3CO
OH
OH
O
O
6 Chicamycin A
7 Abbeymycin
Figure 1 Biologically active [1,4]benzodiazepines and PBDs.
There are some limitations to the reported methodologies
for the synthesis of [1,4]benzodiazepines and [1,4]ox-
azepin-7-ones.5 Selective reduction of diamides5b,c can of-
ten be difficult, while cyclization with p-toluenesulfonic
acid under reflux conditions5d results in dehydration prod-
ucts. Moreover, the cyclization under DCC/DMAP condi-
tions can be problematic when multiple hydroxy and ester
functionalities are present.5e This prompted us to investi-
gate alternative methodologies for the synthesis of novel
[1,4]benzodiazepines. We envisioned a direct access to
chiral 3-substituted-[1,4]benzodiazepin-2-ones 8 from
amino acid derived esters 9. Ester 9 will be obtained from
2-nitrobenzyl bromide 10 and chiral amino methyl esters
11 (Scheme 1).
trobenzyl bromide in the presence of i-Pr2NEt and DMF
to furnish 2-nitrobenzyl protected methyl ester derivatives
13a–i in moderate to good yield (62–85%). It is interest-
ing to note that the unprotected amino functionality of
glutamine (12f, CH2CH2CONH2) and tryptophan (12i)
did not react with 2-nitrobenzyl bromide. All the isolated
compounds were characterized by their 1H, 13C NMR, and
mass spectrum. In the mass spectra of all the compounds,
13a–i, a fragmentation peak at 136 appeared due to the p-
NO2C6H4CH2 group.
NO2
Br
H
N
O
NH2
OCH3
R
10
Initially, we performed the synthesis of [1,4]benzodiaz-
epines following, essentially, the steps given in Scheme 2.
The commercially available methyl ester derivative of
amino acid hydrochlorides 12a–i were reacted with 2-ni-
O
+
R
NH
R
N
H
OCH3
H2N
8
9
O
11
SYNTHESIS 2005, No. 11, pp 1881–1887
Advanced online publication: 20.06.2005
x
x.
x
x
.
2
0
0
5
Scheme 1 Retrosynthesis of [1,4]benzodiazepines.
DOI: 10.1055/s-2005-869950; Art ID: Z23804SS
© Georg Thieme Verlag Stuttgart · New York

1882
J. K. Mishra, G. Panda
PAPER
H
O
H
O
N
NH2
N
N
NO2
COOMe
CH3
v
iv
CH3
vi
COOMe
CH3
N
NH
N
CH3
Boc
16
Boc
15
Boc
17a
14
iii
NO2
NO2
Br
CH3
H
COOMe
CH3
i
+
HCl⋅H2N
COOCH3
N
H
10
13a
H
N
O
NO2
NO2
Br
i
R
COOCH3
H
ii
+
R
N
R
HCl⋅H2N
COOCH3
12a–i
Structure of R
NH
17a–i
Fe/AcOH
H
10
Entry
13a–i
DIPEA/DMF
Yield ( %)
Yield ( %)
a
-CH3
-CH2CH(CH3)2
-CH2SCH2
73
80
80
78
b
c
85
75
80
83
-CH2
d
e
84
84
-CH2
OBn
f
84
84
81
80
-CH2CH2CONH2
g
-CH2COOCH3
-CH2CH2SCH3
H2C
h
i
62
83
84
80
N
H
Scheme 2 Reagents and conditions: i) i-Pr2NEt, DMF, r.t., 2 h; ii) Fe, AcOH, reflux, 30 min; iii) Boc2O, CH2Cl2, r.t., 12 h; iv) Pd/C, H2, r.t.,
1 h; v) HOBt, toluene, reflux, 24 h; vi) 50% TFA, CH2Cl2, r.t., 0.5 h.
The unprotected amino functionality of 13a derived from in 13a–i should not participate in this reaction. We tested
2-nitrobenzyl bromide and the methyl ester of L-alanine, various reagents and it was observed that treatment of
was converted into its Boc-derivative 14 and the nitro 13a–i with Fe/AcOH at 110 °C for 30 minutes gave
group was reduced to an amine moiety 15 upon hydroge- [1,4]benzodiazepine derivatives in excellent yield (78–
nation over Pd/C. The coveted [1,4]benzodiazepine ring 84%).
cyclization was performed by refluxing 15 with HOBt in
toluene for 24 hours. Finally the Boc group was removed
after reaction with 50% TFA in CH2Cl2 to furnish 17a.
After successful preparation of [1,4]benzodiazepine de-
rivatives from the methyl esters of 9 amino acids, we
wanted to explore our strategy in the synthesis of pyrro-
Although the four-step sequence allowed us to access lo[2,1-c][1,4]benzodiazepines (PBDs) from substituted
[1,4]benzodiazepines, the sequence involves expensive proline derivatives. Treatment of 2-nitrobenzyl bromide
reagents like Boc2O, Pd/C, and protection and deprotec- in the presence of i-Pr2NEt and DMF with substituted pro-
tion of the amino functionality. A shorter sequence was lines 18, 21, and 25 furnished 2-nitrobenzyl protected pro-
desirable for a more facile access to a diverse range of line derivatives 19, 22, and 26 (68–87%). It is noteworthy
benzodiazepine derivatives.
that the hydroxyl group of 25 did not react with 2-ni-
trobenzyl bromide 10. Treatment of 19, 22, and 26 with
Fe/AcOH gave PBDs in excellent yields (78–89%). Inter-
estingly, the amino group derived in situ from 22 did not
react with the carbonyl group of pyroglutamate to furnish
24.
With this in mind, we looked for a reagent, that would
convert the nitro functionality of 13a–i into its amino de-
rivatives in situ, and hence react with the -COOCH3 group
of 13a–i to furnish benzodiazepine derivatives. At the
same time, the secondary amine functionality -NH present
Synthesis 2005, No. 11, 1881–1887 © Thieme Stuttgart · New York

PAPER
A Convenient Two-Step Synthesis of Amino Acid Derivatives
1883
H
N
O
NO2
H
NO2
Br
i
ii
+
78%
68%
N
N
COOCH3
N
H
COOCH3
10
10
20
19
18
H
N
O
NO2
Br
NO2
N
O
H
ii
i
+
N
O 84%
90%
H3COOC
N
N
H
N
COOCH3
23
24
Not isolated
21
O
H3COOC
22
H
O
HO
NO2
NO2
Br
N
ii
89%
H
i
OH
+
COOCH3
N
87%
N
H
N
OH
H3COOC
27
10
25
26
Scheme 3 Reagents and conditions: i) i-Pr2NEt, DMF, r.t., 2 h; ii) Fe, AcOH, reflux, 30 min.
4.09 (d, 1 H, J = 14.4 Hz, ArCHH), 3.95 (d, 1 H, J = 14.4 Hz,
ArCHH), 3.68 (s, 3 H, OCH3), 3.36 (q, 1 H, J1 = J2 = 7 Hz,
NCHC=O), 1.33 (d, 3 H, J = 6 Hz, CH3).
MS: m/z (%) = 239 (100) [M+ + 1], 179 (50) [M+ – COOCH3].
In conclusion, we have described an efficient method to
synthesize a diverse range of [1,4]benzodiazepine skele-
tons in only two synthetic steps – coupling of 2-nitroben-
zyl bromide with a diverse range of chiral amino acids and
cyclization with Fe/AcOH. All the isolated benzodiaz-
epines are chiral with a high optical purity (90–98% ee).
Our synthetic scheme is more convenient and gave a new
series of high yielding PBDs, which can be extended into
other ring systems after some modifications. Work in this
direction is currently underway.
Anal. Calcd for C11H14N2O4: C, 55.46; H, 5.92; N, 11.76. Found: C,
55.66; H, 5.99; N, 11.86.
4-Methyl-2-(2-nitrobenzylamino)pentanoic Acid Methyl Ester
(13b)
Yield: 80% (73 mg); brown liquid; Rf 0.5 (EtOAc–hexane, 1:9).
IR (neat): 3455, 2957, 1734, 1636, 1529, 1464, 1350, 1201 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.81 (d, 1 H, J = 8 Hz, ArH), 7.48
(d, 1 H, J = 8 Hz, ArH), 7.47 (t, 1 H, J = 7 Hz, ArH), 7.34 (t, 1 , J = 7
Hz, ArH), 4.00 (d, 1 H, J = 14.4 Hz, ArCHH), 3.82 (d, 1 H, J = 14.4
Hz, ArCHH), 3.60 (s, 3 H, OCH3), 3.19 (t, 1 H, J = 6Hz, NCHC=O),
1.70–1.64 [m, 1 H, CH(CH3)2], 1.36 (t, 2 H, J = 7.2 Hz, CH2), 0.80
[d, 3 H, J = 6.6 Hz, (CH3)2], 0.75 [d, 3 H, J = 6.6 Hz, (CH3)2].
Melting points are uncorrected. Silica gel 60–120 mesh was used
for column chromatography. The organic layers were dried over an-
hydrous Na2SO4. IR spectra were recorded using a Perkin Elmer
Spectrum RX I FTIR spectrophotometer on a KBr disc or neat. 1H
NMR and 13C NMR spectra were recorded in CDCl3 at 25 °C with
TMS as internal standard on a Bruker DPX-200 FT spectrometers
(chemical shifts in d values, J in Hz). The ESMS were recorded
through direct flow injections in Merck M-8000 LCMS system and
FABMS spectra were recorded on JEOL/ SX-102 spectrometer. El-
emental analyses were performed on Elementar’s Vario EL III mi-
croanalyzer. The enantiomeric excess was determined by HPLC
with chiral column (LiChroCART® 250-4 ChiraDex®).
MS: m/z (%) = 281 (100) [M+ + 1], 238 (40) [M+ – CH(CH3)2], 206
(30) [M+ – COOCH3].
Anal. Calcd for C14H20N2O4: C, 59.99; H, 7.19; N, 9.99. Found: C,
59.75; H, 7.41; N, 9.89.
3-Benzylsulfanyl-2-(2-nitrobenzylamino)propionic Acid
Methyl Ester (13c)
Yield: 141 mg (85%); yellow semi-solid; Rf 0.5 (EtOAc–hexane,
1:9).
Coupling of the Amino Acid Methyl Ester with 2-Nitrobenzyl
Bromide; General Procedure
To o-nitrobenzyl bromide (100 mg, 0.46 mmol), amino acid methyl
ester hydrochloride (0.68 mmol) in anhyd DMF (10 mL) was added
i-Pr2NEt (0.24 mL, 1.38 mmol) and the reaction mixture was stirred
for 2 h at r.t. After extracting with EtOAc (3 × 50 mL), the organic
layer was washed with water (3 × 20 mL), and dried. The crude
product was purified by chromatography (silica gel; hexane–
EtOAc) to furnish the coupled product.
IR (neat): 2951, 1737, 1526, 1453, 1347, 1204, 1171 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.94 (d, 1 H, J = 7.6 Hz, ArH),
7.61 (d, 1 H, J = 7.6 Hz, ArH), 7.57 (d, 1 H, J = 7.7 Hz, ArH), 7.43
(d, 1 H, J = 7.7 Hz, ArH), 7.29–7.25 (m, 5 H, ArH), 4.09 (d, 1 H,
J = 14.8 Hz, ArCHH), 3.95 (d, 1 H, J = 14.8 Hz, ArCHH), 3.69 (s,
5 H, OCH3, SCH2Ph), 3.40 (t, 1 H, J = 6.6 Hz, CHCH2), 2.72 (dd, 2
H, J1 = 6.6 Hz, J2 = 5 Hz, CH2SCH2Ph), 2.10 (br s, 1 H, NH).
2-(2-Nitrobenzylamino)propionic Acid Methyl Ester (13a)
Yield: 80 mg (73%); brown oil; Rf 0.4 (EtOAc–hexane, 1:9).
IR (neat): 2952, 1735, 1528, 1447, 1350, 1206, 1155 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.93 (d, 1 H, J = 8 Hz, ArH),
7.64–7.53 (m, 2 H, J = 7.8 Hz, ArH), 7.42 (t, 1 H, J = 7.8 Hz, ArH),
MS: m/z (%) = 361 (100) [M+ + 1], 284 (10) [M+ – C6H5], 269 (30)
[M+ – CH2C6H5].
Anal. Calcd for C18H20N2O4S: C, 59.98; H, 5.59; N, 7.77. Found: C,
59.85; H, 5.61; N, 7.78.
Synthesis 2005, No. 11, 1881–1887 © Thieme Stuttgart · New York

1884
J. K. Mishra, G. Panda
PAPER
2-(2-Nitrobenzylamino)-3-phenylpropionic Acid Methyl Ester
(13d)
4-Methylsulfanyl-2-(2-nitrobenzylamino)butyric Acid Methyl
Ester (13h)
Yield: 108 mg (75%); brown viscous liquid; Rf 0.5 (EtOAc–hexane,
Yield: 85 mg (62%); yellow viscous liquid; Rf 0.4 (EtOAc–hex-
1:9).
ane,1:9).
IR (neat): 2950, 1736, 1527, 1446, 1348, 1203, 1174 cm–1.
IR (neat): 2919, 1734, 1528, 1438, 1349, 1202, 1167 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.89 (d, 1 H, J = 8.2 Hz, ArH),
7.47 (d, 2 H, J = 8 Hz, ArH), 7.29–7.16 (m, 4 H, ArH), 7.13 (d, 2 H,
J = 8 Hz, ArH), 4.09 (d, 1 H, J = 15 Hz, ArCHHN), 3.92 (d, 1 H,
J = 15 Hz, ArCHHN), 3.64 (s, 3 H, OCH3), 3.49 (dd, 1 H, J1 = 6.2
Hz, J2 = 7.2 Hz, NCHCH2Ph), 2.98 (dd, 1 H, J1 = 6.2 Hz, J2 = 15
Hz, PhCHH), 2.93 (dd, 1 H, J1 = 6.2 Hz, J2 = 15 Hz, PhCHH), 1.98
(br s, 1 H, NH).
1H NMR (CDCl3, 200 MHz): d = 7.82 (d, 1 H, J = 7.8 Hz, ArH),
7.51–7.44 (m, 2 H, ArH), 7.37–7.29 (m, 2 H, ArH), 4.04 (d, 1 H,
J = 14.8 Hz, ArCHH), 3.88 (d, 1 H, J = 14.8 Hz, ArCHH), 3.62 (s,
3 H, OCH3), 3.31–3.29 (m, 1 H, NCHC=O), 2.55–2.47 (m, 2 H,
CH2S), 2.00 (s, 3 H, CH3), 1.99–1.80 (m, 2 H, CH2CH2), 1.77 (br s,
1 H, NH).
MS: m/z (%) = 299 (60) [M+ + 1], 284 (40) [M+ – CH3], 251 (30)
MS: m/z (%) = 315 (100) [M+ + 1], 255 (70) [M+ – COOCH3], 237
[M+ – SCH3], 223 (50) [M+ –CH2CH2SCH3].
(20) [M+ – C6H5], 223 (60) [M+ – CH2C6H5].
Anal. Calcd for C13H18N2O4S: C, 52.33; H, 6.08; N, 9.39. Found: C,
52.55; H, 6.31; N, 9.22.
Anal. Calcd for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C,
64.36; H, 5.66; N, 8.80.
3-(1H-Indol-3-yl)-2-(2-nitrobenzylamino)propionic Acid
Methyl Ester (13i)
Yield: 136 mg (83%); brownish viscous oil; Rf 0.4 (EtOAc–hexane,
3-(4-Benzyloxyphenyl)-2-(2-nitrobenzylamino)propionic Acid
Methyl Ester (13e)
Yield: 80 mg, 84%; brown semi-solid; Rf 0.5 (EtOAc–hexane, 1:9).
3:7).
IR (neat): 2954, 1722, 1590, 1430, 1350, 1206, 1132 cm–1.
IR (neat): 3410, 1731, 1525, 1453, 1346, 1207 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.89 (d, 1 H, J = 7.8 Hz, ArH),
7.48–7.25 (m, 8 H, ArH), 7.05 (d, 2 H, J = 8.6 Hz, ArH), 6.87 (d, 2
H, J = 8.6 Hz, ArH), 5.04 (s, 2 H, C6H5CH2O), 4.09 (d, 1 H, J = 14.0
Hz, ArCHH), 3.91 (d, 1 H, J = 14.0 Hz, ArCHH), 3.64 (s, 3 H,
OCH3), 3.45 (t, 1 H, J = 7 Hz, NCHC=O), 2.93–2.86 (m, 2 H,
CHCH2), 1.93 (br s, 1 H, NH).
1H NMR (CDCl3, 200 MHz): d = 8.11 (br s, 1 H, NH), 7.83 (d, 1 H,
J = 7.6 Hz, ArH), 7.49 (d, 1 H, J = 7.8 Hz, ArH), 7.42 (d, 1 H, J =
7.6 Hz, ArH), 7.32 (d, 1 H, J = 8.6 Hz, ArH), 7.11 (d, 1 H, J = 7.7
Hz, ArH), 7.02 (d, 2 H, J = 7.6 Hz, ArH), 4.11 (d, 1 H, J = 14.8 Hz,
ArCHH), 3.92 (d, 1 H, J = 14.8 Hz, ArCHH), 3.65 (s, 3 H, OCH3),
3.60 (t, 1 H, J = 7 Hz, CHN), 3.16 (dd, 1 H, J1 = 6Hz, J2 = 12 Hz,
ArCHCH), 3.13 (dd, 1 H, J1 = 6 Hz, J2 = 12 Hz, ArCHCH), 2.01 (br
s, 1 H, NH).
MS: m/z (%) = 421 (100) [M+ + 1], 361 (40) [M+ – COOCH3], 344
(30) [M+ – C6H5], 331 (20) [M+ – CH2C6H5].
MS: m/z (%) = 354 (100) [M+ + 1], 307 (60) [M+ – NO2].
Anal. Calcd for C24H24N2O5: C, 68.56; H, 5.75; N, 6.66. Found: C,
68.78; H, 5.71; N, 6.39.
1-(2-Nitrobenzyl)pyrrolidine-2-carboxylic Acid Methyl Ester
(19)
Yield: 83 mg, 68%; yellow liquid; Rf 0.4 (EtOAc–hexane, 1:9).
IR (neat): 2954, 1737, 1527, 1442, 1355, 1201 cm–1.
4-Carbamoyl-2-(2-nitrobenzylamino)butyric Acid Methyl
Ester (13f)
Yield: 110mg (81%); brownish semi-solid; Rf 0.4 (EtOAc–hexane,
2:8).
1H NMR (CDCl3, 200 MHz): d = 7.85 (d, 1 H, J = 8 Hz, ArH), 7.73
(d, 1 H, J = 7.6 Hz, ArH), 7.55 (t, 1 H, J = 7.6 Hz, ArH), 7.38 (t, 1
H, J = 7.6 Hz, ArH), 4.13 (d, 1 H, J = 15 Hz, ArCHH), 4.03 (d, 1 H,
J = 15 Hz, ArCHH), 3.64 (s, 3 H, OCH3), 3.40 (dd, 1 H, J1 = 4.8 Hz,
J2 = 8.4 Hz, NCHC=O), 3.05–2.95 (m, 1 H, NCH), 2.50–2.38 (m, 1
H, NCH), 2.23–1.77 (series of m, 4 H, CH2CH2).
IR (neat): 2955, 1742, 1696, 1527, 1439, 1349, 1212 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.89 (dd, 1 H, J1 = 7.6 Hz, J2 = 7.6
Hz, ArH), 7.53–7.37 (m, 3 H, ArH), 5.05 (d, 1 H, J = 16 Hz,
ArCH2), 4.47 (d, 1 H, J = 16 Hz, ArCH2), 4.08 (dd, 1 H, J1 = 3.2 Hz,
J2 = 8 Hz, NCH), 3.63 (s, 3 H, OCH3), 3.57 (s, 1 H, NH), 2.48–2.26
(m, 4 H, CH2CH2).
MS: m/z (%) = 265 (100) [M+ + 1], 218 (20) [M+ – NO2], 206 (25)
[M+ – COOCH3].
MS: m/z (%) = 295 (40) [M+ + 1], 235 (60) [M+ – COOCH3], 251
(20) [M+ – CONH2].
Anal. Calcd for C13H16N2O4: C, 59.08; H, 6.10; N, 10.60. Found: C,
60.00; H, 6.15; N, 10.54.
Anal. Calcd for C13H17N3O5: C, 52.88; H, 5.80; N, 14.23. Found: C,
52.15; H, 5.81; N, 14.66.
1-(2-Nitrobenzyl)-5-oxopyrrolidine-2-carboxylic Acid Methyl
Ester (22)
Yield: 109 mg (84%); brown liquid; Rf 0.4 (EtOAc–hexane, 1:9).
IR (neat): 2955, 1742, 1696, 1527, 1441, 1350, 1214 cm–1.
2-(2-Nitrobenzylamino)succinic Acid Dimethyl Ester (13g)
Yield: 110 mg (80%); brown liquid; Rf 0.4 (EtOAc–hexane, 1:9).
IR (neat): 3436, 2365, 1737, 1527, 1440, 1352 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.96 (d, 1 H, J = 8 Hz, ArH), 7.58
(d, 1 H, J = 7.8 Hz, ArH), 7.54 (d, 1 H, J = 7.8 Hz, ArH), 7.46 (d, 1
H, J = 8 Hz, ArH), 5.12 (d, 1 H, J = 16 Hz, ArCHH), 4.54 (d, 1 H,
J = 16 Hz, ArCHH), 4.16 (dd, 1 H, J1 = 3.2 Hz, J2 = 8 Hz,
NCHC=O), 3.70 (s, 3 H, OCH3), 2.55–2.16 (series of m, 4 H,
CH2CH2).
1H NMR (CDCl3, 200 MHz): d = 7.84 (d, 1 H, J = 7.8 Hz, ArH),
7.52 (d, 1 H, J = 7.6 Hz, ArH), 7.47 (d, 1 H, J = 7.8 Hz, ArH), 7.36
(d, 1 H, J = 7.6 Hz, ArH), 4.10 (d, 1 H, J = 14.2 Hz, ArCHH), 3.94
(d, 1 H, J = 14.2 Hz, ArCHH), 3.78 (t, 1 H, J = 6 Hz, CHN), 3.64 (s,
3 H, OCH3), 3.61 (s, 3 H, OCH3), 2.72 (dd, 1 H, J1 = 6 Hz, J2 = 12
Hz, CHHCOO), 2.63 (dd, 1 H, J1 = 6 Hz, J2 = 12 Hz, CHHCOO),
2.20 (br s, 1 H, NH).
MS: m/z (%) = 279 (50) [M+ + 1], 219 (40) [M+ – COOCH3], 235
(30) [M+ – NO2].
MS: m/z (%) = 297 (30) [M+ + 1], 238 (40) [M+ – COOCH3].
Anal. Calcd for C13H14N2O5: C, 56.11; H, 5.07; N, 10.07. Found: C,
57.00; H, 5.75; N, 10.80.
Anal. Calcd for C13H16N2O6: C, 52.70; H, 5.44; N, 9.46. Found: C,
52.65; H, 5.66; N, 9.66.
Synthesis 2005, No. 11, 1881–1887 © Thieme Stuttgart · New York

PAPER
A Convenient Two-Step Synthesis of Amino Acid Derivatives
IR (neat): 3437, 3252, 3027, 2824, 1671, 1489, 1384 cm–1.
1885
4-Hydroxy-1-(2-nitrobenzyl)pyrrolidine-2-carboxylic Acid
Methyl Ester (26)
Yield: 112 mg (87%); brownish semi-solid; Rf 0.5 (EtOAc–hexane,
2:8).
IR (neat): 3423, 2952, 1711, 1527, 1439, 1353, 1183 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.81 (d, 1 H, J = 8 Hz, ArH), 7.64
(d, 1 H, J = 8 Hz, ArH), 7.54 (t, 1 H, J = 8 Hz, ArH), 7.43 (t, 1 H,
J = 8 Hz, ArH), 4.40 (t, 1 H, J = 5 Hz, CHN), 4.15 (s, 2 H, ArCH2),
3.73–3.72 (m, 1 H, CHOH), 3.64 (s, 3 H, OCH3), 3.25 (dd, 1 H,
J1 = 5 Hz, J2 = 11 Hz, CHHN), 2.51 (dd, 1 H, J1 = 5 Hz, J2 = 11 Hz,
CHHN), 2.25–2.11 (m, 2 H, CH2), 1.94 (br s, 1 H, OH).
1H NMR (CDCl3, 200 MHz): d = 8.14 (br s, 1 H, NH), 7.27 (d, 2 H,
J = 7.8 Hz, ArH), 7.17 (t, 1 H, J = 7.8 Hz, ArH), 6.99 (d, 1 H, J =
7.6 Hz, ArH), 4.13 (d, 1 H, J = 13 Hz, ArCHH), 3.89 (d, 1 H, J = 13
Hz, ArCHH), 3.57 (q, 1 H, J1 = J2 = 7 Hz, NHCHO), 1.90 (s, 1 H,
NH), 1.31 (d, 3 H, J = 6.6 Hz, CH3).
MS: m/z (%) = 177 (100) [M+ + 1], 161 (50) [M+ – CH3].
Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C,
68.00; H, 6.77; N, 14.97.
Cyclization of 13a–i with Fe/AcOH; General Procedure
Compound 13a–i (0.54 mmol) was taken in AcOH (5 mL) and the
temperature of the reaction mixture was raised to 50 °C. Fe powder
(75 mg, 1.33 mmol) was added and refluxed at 110 °C for 30 min.
The mixture was filtered through celite, washed with AcOH (3 × 10
mL) and AcOH washings were concentrated in vacuo. The crude
product was extracted with EtOAc (3 × 15 mL), washed with water
(2 × 20 mL), brine (2 × 20 mL), dried over Na2SO4 and the com-
bined organic phase was concentrated in vacuo. The residue was pu-
rified by column chromatography (silica gel; EtOAc–hexane, 1:1)
to furnish the cyclized product.
MS: m/z (%) = 281 (100) [M+ + 1], 263 (20) [M+ – OH], 221 (50)
[M+ – COOCH3]
Anal. Calcd for C13H16N2O5: C, 55.71; H, 5.75; N, 9.99. Found: C,
55.31; H, 5.68; N, 9.75.
2-[tert-Butoxycarbonyl(2-nitrobenzyl)amino]propionic Acid
Methyl Ester (14)
Compound 13a (2.42 g, 10.16 mmol) and Boc2O (3.32 g, 15.25
mmol) were added to anhyd CH2Cl2 (40 mL) and the resulting solu-
tion was stirred for 12 h at r.t. After the usual work up, column chro-
matography furnished 14 (3.00 g, 87%)as a brown semi-solid;
Rf 0.7 (EtOAc–hexane, 1:9).
3-Isobutyl-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one (17b)
20
Yield: 90 mg, 78%; yellow white solid; mp 118 °C (CH2Cl2); [a]D
+1.43 (c 0.7, CH2Cl2); 95% ee
2-[(2-Aminobenzyl)-tert-butoxycarbonylamino]propionic Acid
Methyl Ester (15)
Rf 0.4 (EtOAc–hexane, 1:1).
Compound 14 (3 g, 8.87 mmol) and Pd/C (100 mg) were added to
MeOH (40 mL), and the solution was hydrogenated for 3 h. The
mixture was filtered through celite and washed with MeOH. The or-
ganic layer was concentrated to dryness and the residue was puri-
fied by column chromatography (EtOAc–hexane) to furnish 15 (2.0
g, 66%) as brown semi-solid; Rf 0.6 (EtOAc–hexane, 1:9).
1H NMR (CDCl3, 200 MHz): d = 6.90 (t, 1 H, J = 7.8 Hz, ArH), 6.86
(d, 1 H, J = 7.8 Hz, ArH), 6.66–6.60 (m, 2 H, ArH), 4.50 (d, 1 H, J
= 13.6 Hz, ArCHH), 4.10 (d, 1 H, J = 13.6 Hz, ArCHH), 3.80 (m, 1
H, NCHC=O), 3.57 (s, 3 H, OCH3), 1.37 [s, 9 H, (CH3)3], 1.17 (d, 3
H, J = 6.6, CH3).
IR (neat): 3432, 1593, 1384, 1351, 1282 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.70 (br s, 1 H, NH), 7.23 (d, 1 H,
J = 7.8 Hz, ArH), 7.21 (t, 1 H, J = 7.6 Hz, ArH), 7.06 (t, 1 H, J = 7.6
Hz, ArH), 6.94 (d, 1 H, J = 7.8 Hz, ArH), 4.02 (d, 1 H, J = 13.0 Hz,
ArCHH), 3.81 (d, 1 H, J = 13.0Hz, ArCHH), 3.41 (t, 1 H, J = 7 Hz,
NCHC=O), 2.36 (br s, 1 H, NH), 1.73–1.62 (m, 2 H, CH2), 1.40–
1.33 [m, 1 H, CH(CH3)2], 0.76 [d, 6 H, J = 6.2 Hz, (CH3)2].
13C NMR (CDCl3, 50 MHz): d = 176.0 (C=O), 138.1 (ArC), 131.6
(ArC), 129.9 (ArCH), 129.0 (ArCH), 125.6 (ArCH), 121.2 (ArCH),
56.8 (ArCH2), 49.2 (NCHC=O), 40.5 (CH2), 25.1 [CH(CH3)2], 23.3
(CH3), 22.5 (CH3).
MS: m/z (%) = 309 (100) [M+ + 1], 249 (40) [M+ – COOCH3].
MS: m/z (%) = 219 (80) [M+ + 1], 176 (50) [M+ – CH(CH3)2].
3-Methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-
carboxylic Acid tert-Butyl Ester (16)
Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C,
72.00; H, 8.46; N, 12.80.
Compound 15 (400 mg, 1.29 mmol) and HOBt (105 mg, 0.77
mmol) were added to anhyd toluene (20 mL) and the resulting solu-
tion was refluxed for 24 h. The mixture was extracted with EtOAc
(3 × 20 mL), and concentrated to dryness; the residue was purified
by column chromatography (silica gel; EtOAc–hexane) to furnish
16 (220 mg, 61%) as a brown solid; Rf 0.4 (EtOAc–hexane, 3:7); mp
152 °C (CH2Cl2).
3-Benzylsulfanylmethyl-1,3,4,5-tetrahydrobenzo[e][1,4]diaz-
epin-2-one 17c
Yield: 100 mg (80%); yellow solid; mp 136 °C (CH2Cl2); [a]D
–2.29 (c 0.7, CH2Cl2); 92% ee; Rf 0.4 (EtOAc–hexane, 2:8).
20
IR (neat): 3426, 3251, 1669, 1590, 1393, 1281 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.44 (br s, 1 H, NH), 7.23–7.02
(m, 8 H, ArH), 6.90 (d, 1 H, J = 7.6 Hz, ArH), 3.96 (d, 1 H, J = 13.6
Hz, ArCHHN), 3.77 (d, 1 H, J = 13.6 Hz, ArCHHN), 3.61 (s, 2 H,
SCH2Ph), 3.36 (dd, 1 H, J1 = 5.4 Hz, J2 = 6.9 Hz, NHCHC=O), 2.85
(dd, 1 H, J1 = 5.2 Hz, J2 = 14 Hz, SCHH), 2.69 (dd, 1 H, J1 = 5.2 Hz,
J2 = 14 Hz, SCHH), 2.25 (br s, 1 H, NH).
13C NMR (CDCl3, 50 MHz): d = 173.9 (C=O), 138.7 (ArC), 137.5
(ArC), 131.6 (ArC), 129.8 (ArCH), 129.1 (ArCH), 129.0 (ArCH),
128.8 (ArCH), 127.4 (ArCH), 125.7 (ArCH), 121.2 (ArCH), 58.7
(ArCH2N), 49.5 (PhCH2), 37.6 (CHN), 34.0 (CH2SCH2).
IR (neat): 3451, 3079, 2926, 2856, 2363, 1657, 753 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.40 (br s, 1 H, NH), 7.20 (d, 2 H,
J = 7.8 Hz, ArH), 7.16 (t, 1 H, J = 7.8 Hz, ArH), 6.86 (d, 1 H, J =
7.8 Hz, ArH), 4.12 (d, 1 H, J = 13 Hz, ArCHH), 3.88 (d, 1 H, J = 13
Hz, ArCHH), 4.01 (q, 1 H, J1 = J2 = 7 Hz, NCHC=O), 1.30 (d, 1 H,
J = 6.6 Hz, CH3), 1.18 [s, 9 H, (CH3)3].
MS: m/z (%) = 277 (40) [M+ + 1], 175 (60) [M+ – OCOOC(CH3)3].
3-Methyl-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one (17a);
Boc Group Removal from 16
To a stirred solution of 16 in anhyd CH2Cl2 was added 50% TFA in
CH2Cl2 and the mixture was stirred at r.t. for 0.5 h. After the usual
work-up and column chromatography 17a (100mg, 80%) was iso-
lated as a white solid; mp 174 °C (CH2Cl2); 97% ee; Rf 0.5 (EtOAc–
hexane, 3:7).
MS: m/z (%) = 299 (50) [M+ + 1], 222 (40) [M+ – C6H5], 208 (20)
[M+ – CH2C6H5], 176 (30) [M+ – SCH2C6H5] .
Anal. Calcd for C17H18N2OS: C, 68.42; H, 6.08; N, 9.39. Found: C,
68.27; H, 6.66; N, 9.59.
Synthesis 2005, No. 11, 1881–1887 © Thieme Stuttgart · New York

1886
J. K. Mishra, G. Panda
PAPER
3-Benzyl-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one (17d)
Yield: 100 mg (83%); mp 171 °C (CH2Cl2); yellow-white solid;
[a]D20 –29.43 (c 0.7, CH2Cl2); 90% ee; Rf 0.4 (EtOAc–hexane, 1:1).
(2-Oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)ace-
tic Acid Methyl Ester (17g)
Yield: 100 mg (84%); mp 134 °C (CH2Cl2), white solid; [a]D
+13.43 (c 0.7, CH2Cl2); 96% ee; Rf 0.4 (EtOAc–hexane, 6:4).
20
IR (neat): 3429, 1659, 1593, 1484, 1384, 1351, 1284 cm–1
.
IR (neat): 3309, 1721, 1684, 1592, 1366, 1187 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.05 (br s, 1 H, NH), 7.31–7.07
(series of m, 8 H, ArH), 6.94 (d, 1 H, J = 7.8 Hz, ArH), 4.11 (d, 1
H, J = 13.8 Hz, ArCHH), 3.83 (d, 1 H, J = 13.8 Hz, ArCHH), 3.71
(dd, 1 H, J1 = 5.6 Hz, J2 = 6.8 Hz, NCHC=O), 3.23 (dd, 1 H, J1 =
5.6 Hz, J2 = 6.8 Hz, PhCHH), 2.91 (dd, 1 H, J1 = 5.6 Hz, J2 = 6.8
Hz, PhCHH).
13C NMR (CDCl3, 50 MHz): d = 174.2 (C=O), 138.5 (ArC), 137.6
(ArC), 131.6 (ArC), 129.8 (CH), 129.0 (CH), 128.8 (CH), 126.9
(CH), 125.7 (CH), 121.1 (CH), 60.2 (ArCHH), 49.5 (NCHC=O),
38.1 (PhCH2).
1H NMR (CDCl3, 200 MHz): d = 8.71 (br s, 1 H, NH), 7.32–7.22
(m, 2 H, ArH), 7.15 (d, 1 H, J = 7 Hz, ArH), 7.01 (d, 1 H, J = 7 Hz,
ArH), 4.11 (d, 1 H, J = 13.8 Hz, ArCHH), 3.91 (d, 1 H, J = 13.8 Hz,
ArCHH), 3.87 (t, 1H , J = 7 Hz, C=OCHN), 3.65 (s, 3 H, OCH3),
2.88 (dd, 1 H, J1 = 6 Hz, J2 = 15.2 Hz, ArCHHCH), 2.71 (dd, 1 H,
J1 = 6 Hz, J2 = 15.2 Hz, ArCHHCH), 2.56 (br s, 1 H, NH).
13C NMR (CDCl3, 50 MHz): d = 175.0 (C=O), 172.0 (C=O), 138.0
(ArC), 130.8 (ArC), 130.0 (ArCH), 129.8 (ArCH), 125.0 (ArCH),
120.9 (ArCH), 55.0 (ArCH2), 52.3 (NCHC=O), 49.8 (OCH3), 36.2
(CH2C=O).
MS: m/z (%) = 253 (60) [M+ + 1], 175 (100) [M+ – C6H5], 162 (40)
[M+ – CH2C6H5].
MS: m/z (%) = 235 (100) [M+ + 1], 175 (20) [M+ – COOCH3], 161
(30) [M+ – CH2COOCH3].
Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C,
77.00; H, 6.79; N, 11.00.
Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found: C,
62.33; H, 6.09; N, 11.54.
3-(4-Benzyloxybenzyl)-1,3,4,5-tetrahydrobenzo[e][1,4]di-
azepin-2-one (17e)
Yield: 102 mg (84%); mp 152 °C (CH2Cl2); white solid; [a]D
+2.86 (c 0.7, CH2Cl2); 98% ee; Rf 0.4 (EtOAc–hexane, 8:2).
3-(2-Methylsulfanylethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]di-
azepin-2-one (17h)
Yield: 100 mg (84%); mp 112 °C (CH2Cl2); White solid; [a]D
+16.33 (c 0.6, CH2Cl2); 95% ee; Rf 0.4 (EtOAc–hexane, 6:4).
20
20
1H NMR (CDCl3, 200 MHz): d = 8.16 (br s, 1 H, NH), 7.38–7.24
(m, 7 H), 7.15 (d, 1 H, J = 8 Hz, ArH), 7.11 (d, 2 H, J = 8.6 Hz,
ArH), 6.94 (d, 1 H, J = 7.8 Hz, ArH), 6.85 (d, 2 H, J = 8.6 Hz, ArH),
4.99 (s, 2 H, C6H5CH2O), 4.06 (d, 1 H, J = 13.6 Hz, ArCHHN), 3.83
(d, 1 H, J = 13.6 Hz, ArCHHN), 3.66 (dd, 1 H, J1 = 5.2 Hz, J2 = 8
Hz, NCHC=O), 3.17 (dd, 1 H, J1 = 5.2 Hz, J2 = 13.6 Hz, ArCHH),
2.85 (dd, 1 H, J1 = 5.2 Hz, J2 = 13.6 Hz, ArCHH), 1.83 (br s, 1 H,
NH).
13C NMR (CDCl3, 50 MHz): d = 174 (C=O), 148 (ArC), 139.6
(ArC), 132 (ArC), 123 (ArCH), 121 (ArCH), 116 (ArCH), 116
(ArCH), 115 (ArCH), 114 (ArCH), 112 (ArCH), 56 (ArCH2O), 42
(ArCH2N), 34 (CHN).
IR (neat): 2822, 1665, 1588, 1389, 1277, 1156 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.54 (br s, 1 H, NH), 7.26 (d, 1 H,
J = 7.8 Hz, ArH), 7.24 (t, 1 H, J = 7.8 Hz, ArH), 7.15 (t, 1 H, J = 7.8
Hz, ArH), 7.02 (d, 1 H, J = 7.6 Hz, ArH), 4.09 (d, 1 H, J = 13.4 Hz,
ArCHH), 3.89 (d, 1 H, J = 13.4 Hz, ArCHH), 3.58 (t, 1 H, J = 6.6
Hz, NCHC=O), 2.62–2.54 (m, 2 H, CH2S), 2.22–2.15 (m, 2 H,
CH2CH2S), 2.05 (s, 3 H, SCH3), 1.88–1.81 (m, 1 H, NH).
MS: m/z (%) = 237 (100) [M+ + 1], 221 (15) [M+ – CH3], 189 (30)
[M+ – SCH3], 162 (30) [M+ – CH2CH2SCH3].
Anal. Calcd for C12H16N2OS: C, 60.98; H, 6.82; N, 11.85. Found:
C, 61.20; H, 6.65; N, 11.87.
MS: m/z (%) = 359 (60) [M+ + 1], 281 (30) [M+ – C6H5], 267 (40)
[M+ – CH2C6H5].
3-(1H-Indol-3-ylmethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]di-
Anal. Calcd for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82. Found: C,
77.80; H, 6.46; N, 8.25.
azepin-2-one (17i)
Yield: 100 mg (80%); mp 145 °C; brown solid (CH2Cl2); [a]D
+11.67 (c 0.6, CH2Cl2); 94% ee; Rf 0.4 (MeOH–CHCl3, 1:9).
20
3-(2-Oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-
yl)propionamide (17f)
Yield: 100 mg (84%); white solid; mp 194 °C (CHCl3); [a]D
+47.57 (c 0.7, CH2Cl2); 99% ee; Rf 0.6 (MeOH–CHCl3, 1:9).
IR (neat): 3298, 1670, 1588, 1488, 1384, 1353 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.54 (br s, 1 H, NH), 8.24 (s, 1 H,
NH), 7.55 (d, 1 H, J = 7.8 Hz, ArH), 7.28–6.99 (series of m, 7 H,
ArH), 6.88 (d, 1 H, J = 7.6 Hz, ArH), 4.02 (d, 1 H, J = 14 Hz,
ArCHH), 3.80 (d, 1 H, J = 14 Hz, ArCHH), 3.77 (d, 1 H, J = 8 Hz,
C=OCHN), 3.36 (dd, 1 H, J1 = 5.4 Hz, J2 = 14.2 Hz, CHHCH), 3.11
(dd, 1 H, J1 = 5.4 Hz, J2 = 14.2 Hz, CHHCH), 2.76 (br s, 1 H, NH).
13C NMR (CDCl3, 50 MHz): d = 174.8 (C=O), 137.7 (ArC), 136.5
(ArC), 131.3 (ArC), 129.8 (CH), 129.0 (CH), 127.9 (C), 125.6
(CH), 123.9 (CH), 122.3 (CH), 121.2 (CH), 119.7 (CH), 119.2
(CH), 111.8 (ArC), 111.6 (CH), 59.4 (ArCH2N), 49.5 (ArCH2), 27.6
(ArCH2).
20
IR (neat): 3212, 1674, 1598, 1388, 1354, 1279, 1188 cm–1.
1H NMR (CDCl3, 200 MHz): d = 9.13 (br s, 1 H, NH), 7.40 (d, 1 H,
J = 7.6 Hz, ArH), 7.37 (d, 1 H, J = 7.4 Hz, ArH), 7.24 (d, 1 H, J =
7.6 Hz, ArH), 7.13 (d, 1 H, J = 7.4 Hz, ArH), 4.27 (d, 1 H, J = 14.2
Hz, ArCHH), 4.26 (d, 1 H, J = 14.2 Hz, ArCHH), 4.17 (d, 1 H, J =
6.6 Hz, CHN), 2.67–2.03 (series of m, 4 H, CH2CH2).
13C NMR (CDCl3, 50 MHz): d = 173.8 (C=O), 169.9 (C=O), 137.4
(ArC), 130.7 (CH), 129.9 (CH), 127.6 (ArC), 126.6 (CH), 122.5
(CH), 58.3 (ArCH2), 44.9 (CHC=O), 30.3 (CH2C=O), 19.1
(CH2CH2).
MS: m/z (%) = 292 (40) [M+ + 1].
MS: m/z (%) = 233 (60) [M+ + 1], 189 (70) [M+ – CONH2], 175 (40)
1,2,3,5,10,11a-Hexahydrobenzo[e]pyrrolo[1,2-a][1,4]diazepin-
[M+ – CONH2CH2].
11-one (20)
20
Yield: 90 mg (78%); mp 135 °C (CH2Cl2); white solid; [a]D
+30.28 (c 0.7, CH2Cl2), 97% ee; Rf 0.4 (EtOAc–hexane, 1:1).
Anal. Calcd for C12H15N3O2: C, 61.79; H, 6.48; N, 18.01. Found: C,
61.22; H, 6.58; N, 18.68.
IR (neat): 3192, 1660, 1601, 1482, 1383, 1291, 1142 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.79 (br s, 1 H, NH), 7.33 (d, 1 H,
J = 7.8 Hz, ArH), 7.29 (d, 1 H, J = 7.8 Hz, ArH), 7.16 (d, 1 H, J =
8 Hz, ArH), 7.01 (d, 1 H, J = 8 Hz, ArH), 3.95 (d, 1 H, J = 11.6 Hz,
Synthesis 2005, No. 11, 1881–1887 © Thieme Stuttgart · New York

PAPER
A Convenient Two-Step Synthesis of Amino Acid Derivatives
1887
ArCHH), 3.63 (t, 1 H, J = 8 Hz, NCHC=O), 3.59 (d, 1 H, J = 11.6
Hz, ArCHH), 3.07–3.03 (m, 1 H, CHN), 2.63–2.45 (series of m, 2
H, CHNCH), 2.01–1.77 (series of m, 3 H, CH2CH).
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
65.85; H, 6.01; N, 12.13.
13C NMR (CDCl3, 50 MHz): d = 173.1 (C=O), 138.3 (ArC), 131.2
(ArC), 130.2 (ArCH), 129.1 (ArCH), 125.8 (ArCH), 121.6 (ArCH),
61.9 (ArCH2), 54.9 (NCHC=O), 54.3 (CH2N), 24.7 (CH2), 24.1
(CH2).
Acknowledgment
This research project was supported by Department of Science and
Technology (SR/FTP/CSA-05/2002), New Delhi, India. One of the
authors (JKM) gratefully acknowledges the financial support in the
form of fellowship (JRF) from CSIR, India.
MS: m/z (%) = 203 (100) [M+ + 1].
Anal. Calcd for C12H14N2OC: 71.26; H, 6.98; N, 13.85. Found: C,
72.01; H, 7.18; N, 13.65.
References
1,5,10,11a-Tetrahydro-2H-benzo[e]pyrrolo[1,2-a][1,4]di-
azepine-3,11-dione (23)
(1) CDRI communication number 6708.
Yield: 105 mg (90%); yellow solid; mp 181 °C (CH2Cl2), [a]D20 +60
(c 0.7, CH2Cl2), 97% ee; Rf 0.4 (EtOAc–hexane, 7:3).
(2) (a) Hurley, L. H.; Boyd, F. L. Trends Pharmacol. Sci. 1988,
9, 402. (b) Hurley, L. H. J. Med. Chem. 1989, 32, 2027.
(c) Thurston, D. E.; Thompson, A. S. Chem. Br. 1990, 26,
767.
IR (neat): 3428, 2363, 1593, 1384, 1353 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.53 (br s, 1 H, NH), 7.39 (d, 1 H,
J = 7.8 Hz, ArH), 7.36 (d, 1 H, J = 7.6 Hz, ArH), 7.24 (d, 1 H,
J = 7.8 Hz, ArH), 7.10 (d, 1 H, J = 7.6 Hz, ArH), 4.76 (d, 1 H,
J = 14.2 Hz, ArCHH), 4.26 (d, 1 H, J = 14.2 Hz, ArCHH), 4.17 (t,
1 H, J = 8 Hz, O=CCHN), 2.68–2.03 (series of m, 4 H, CH2CH2).
13C NMR (CDCl3, 50 MHz): d = 173.8 (C=O), 169.6 (C=O), 137.2
(ArC), 130.8 (ArCH), 129.9 (ArCH), 127.8 (ArC), 126.8 (ArCH),
122.4 (ArCH), 58.2 (ArCH2), 44.9 (O = CCHN), 30.2 (CH2C=O),
19.2 (CH2CH).
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MS: m/z (%) = 217 (100) [M+ + 1].
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C,
66.55; H, 5.31; N, 12.55.
2-Hydroxy-1,2,3,5,10,11a-hexahydrobenzo[e]pyrrolo[1,2-
a][1,4]diazepin-11-one (27)
Yield: 105 mg (89%); brownish semi-solid; [a]D20 +22.17 (c 1.2,
CH2Cl2), 93% ee; Rf 0.5 (EtOAc–hexane, 9:1).
IR (neat): 3393, 1664, 1593, 1385, 1280, 1252, 1093 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.53 (br s, 1 H, NH), 7.23 (d, 1 H,
J = 7.2 Hz, ArH), 7.17 (d, 1 H, J = 7.2 Hz, ArH), 7.05 (d, 1 H,
J = 7.6 Hz, ArH), 6.88 (d, 1 H, J = 7.6 Hz, ArH), 4.40 (t, 1 H,
J = 4.8 Hz, O=CCHN), 3.83 (d, 1 H, J = 11.4 Hz, ArCHH), 3.68
(dd, 1 H, J1 = 5.6 Hz, J2 = 7.0 Hz, OHCH), 3.44 (d, 1 H, J = 11.4
Hz, ArCHH), 2.98 (br s, 1 H, OH), 2.93–2.87 (m, 1 H, CHHN), 2.80
(dd, 1 H, J1 = 8.2 Hz, J2 = 13 Hz, CHHCH2), 2.68–2.61 (m, 1 H,
CHHN), 1.68 (dd, 1 H, J1 = 8.2 Hz, J2 = 13 Hz, CHHCH2).
13C NMR (CDCl3, 50 MHz): d = 172 (C=O), 138.0 (ArC), 130.8
(ArC), 130.5 (CH), 129.3 (CH), 126.1 (CH), 121.7 (CH), 71.7
(C=OCHN), 62.5 (ArCH2), 60.7 (OHCH), 54.2 (CH2N), 35.6
(CH2).
(10) Thurston, D. E. Advances in the Study of Pyrrolo[2,1-
c][1,4]benzodiazepine (PBD) Antitumour Antibiotics, In
Molecular Aspects of Anticancer Drug-DNA Interactions,
Vol. 1; Neidle, S.; Waring, M. J., Eds.; Macmillan Press Ltd:
London, 1993, 54.
MS: m/z (%) = 219 (100) [M+ + 1], 201 (55) [M+ – OH].
Synthesis 2005, No. 11, 1881–1887 © Thieme Stuttgart · New York