An alternative approach towards novel heterocycle-fused 1, 4-diazepin-2-ones by an aromatic amidation protocol

Article abstract of DOI:10.1016/S0040-4020(03)01123-2

The synthesis of new 1,4-diazepin-2-one derivatives starting from glycine or alanine aminoacids is presented. The key cyclization step includes the PIFA mediated formation of N-acylnitrenium ions and their subsequent intramolecular trapping by an (hetero)aromatic ring. The so-promoted aromatic amidation process takes place without loss of enantiomeric purity when optically pure methoxyamide precursors are employed.

Full text of DOI:10.1016/S0040-4020(03)01123-2

Tetrahedron 59 (2003) 7103–7110
An alternative approach towards novel heterocycle-fused
1,4-diazepin-2-ones by an aromatic amidation protocol
*
Arkaitz Correa, M. Teresa Herrero, Imanol Tellitu, Esther Domınguez, Isabel Moreno
*
´
´
and Raul SanMartin
´ ´ ´
Departamento de Quımica Organica II, Facultad de Ciencias, Universidad del Paıs Vasco-Euskal Herriko Unibertsitatea (UPV/EHU)
Apdo. 644-48080 Bilbao, Spain.
Received 28 May 2003; accepted 15 July 2003
Abstract—The synthesis of new 1,4-diazepin-2-one derivatives starting from glycine or alanine aminoacids is presented. The key
cyclization step includes the PIFA mediated formation of N-acylnitrenium ions and their subsequent intramolecular trapping by an
(hetero)aromatic ring. The so-promoted aromatic amidation process takes place without loss of enantiomeric purity when optically pure
methoxyamide precursors are employed.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
anticonvulsant, and antihypnotic agents,9 selective
cholecystokinin (CCK) receptor subtype A or B antagonists,
platelet-activating factor antagonists,10 human immuno-
deficiency virus (HIV) transactivator Tat antagonists,11 and
reverse transcriptase inhibitors.12 Thus, intensive studies
have been done to discover new synthetic routes for the
access of this type of skeletons and modified ring systems
with potential new activities.13 In particular, heterocycle-
fused diazepine derivatives, such as triazolo-,14 thieno-,15
pyrrolo-,16 indolo-,17 and pyrido-diazepines18 have
exhibited new pharmacological activities.
In the last decades, the use of hypervalent iodine compounds
for synthetic purposes has increased considerably.1 The low
toxicity associated to this kind of reagents, and their ready
availability and easy handling, have allowed their appli-
cation to a number of important transformations. Besides,
their environmentally friendly nature also suggests future
applications in sustainable chemistry (green chemistry).
During the last years, our group has focussed on the search
for new applications of one of these reagents, PIFA,
[phenyliodine(III)bis-(trifluoroacetate)] for the synthesis of
different types of heterocycles. Thus, we have reported an
easy access to a series of phenanthridines,2 and heterocycle-
fused phenanthrenes and phenanthrenoids3 by the construc-
tion of the biaryl linkage.4 Later, we used the known ability
of PIFA to generate N-acylnitrenium ions from N-alkoxy-
amides5 to accomplish a facile entry to a series of
heterocycle-fused quinolinones.6 More recently, we have
prepared a series of isoindolinone and isoquinolin-2-one by
employing a novel PIFA promoted olefin amidohydroxyl-
ation process.7
Recently, and continuing our work on new N-containing
heterocyclic compounds, we have reported a preliminary
work describing the access to 1,4-benzodiazepin-2-ones.19
In the present paper we wish to describe our results in the
extension of the cited methodology to the preparation of
heterocycle-fused analogues that, in our opinion, would be
potential candidates of interest for SAR studies taking into
account the already mentioned pharmacological activities.
This approach is schematically summarized in Figure 1.
In this context, we decided to extend our research focussing
on developing a new approach to the preparation of
benzodiazepines. 1,4-Benzodiazepine derivatives have
widespread biological activities and are one of the most
important classes of bioavailable therapeutic agents.8
Examples have been reported that act as anxiolytic,
Keywords: hypervalent iodine; heterocycles; cyclizations; N-acylnitrenium;
diazepin-2-ones.
*
Corresponding authors. Tel.: þ34-94-601-5438; fax: þ34-94-601-2748;
Figure 1. Generation of the electrophilic N-acylnitrenium species and
intramolecular attack.
e-mail: qoptecoi@lg.ehu.es
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01123-2

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A. Correa et al. / Tetrahedron 59 (2003) 7103–7110
Most of the strategies developed for the synthesis of the
target skeleton 1 (route A in Scheme 1) require an amine
functionality, or any other nitrogen containing functional
group, directly connected to the aryl or the heteroaryl ring,
and a carbonyl functionality (as in 2a).20 This premise may
limit the access to derivatives with different substitution
pattern in the (hetero)aryl ring. Thus, we considered that the
application of the aromatic amidation methodology on
precursors of type 2b would allow us to construct the dashed
bond on simple non-functionalized arene or heteroaromatic
rings (route B in Scheme 1) thus avoiding the aromatic N-
functionality.
instead of BF3·OEt2, afforded the same product but in a
lower yield (30%).
The success of the explored aromatic amidation reaction via
formation of an N-acylnitrenium intermediate prompted us
to expand this methodology to the preparation of different
benzodiazepine derivatives. Therefore, as shown in
Scheme 3, the known derivative 4b was prepared21 in a
two steps sequence by protection of aminoester 3b22
followed by basic hydrolysis of the resulting derivative
7b, which was transformed into the required amide 5b by
the previously commented method. When the oxidative
cyclization conditions were applied to alkoxyamide 5b, the
desired benzodiazepine-2-one 6b was obtained. In this case,
the use of TFA as additive in the cyclization step provided
the optimum 70% yield.
Scheme 1. Retrosynthetic analysis for heterocycle-fused 1,4-diazepin-2-
ones.
2. Results and discussion
Since aminoacids are one of the most useful building blocks
for the preparation of 1,4-benzodiazepines, we firstly
employed the commercially available N-benzylglycine
(3a) as the starting material to develop the planned protocol.
Following the route depicted in Scheme 2, carbamate 4a
was prepared directly from 3a by N-acylation with ethyl
chloroformate, and transformed into amide 5a using
methoxylamine hydrochloride and a combination of EDC,
HOBt and triethylamine in CH2Cl2.
Scheme 3. Reagents and conditions: (i) NaOH, ClCOOEt, THF/H2O, room
temperature (quant.); (ii) NaOH, THF/H2O, room temperature (96%);
(iii) NH2OMe·HCl, Et3N, EDC, HOBt, CH2Cl2, room temperature (75%);
(iv) PIFA, TFA, CH2Cl2, 08C (70%).
With these results in hand, we next focussed on the study of
the behaviour of a stereogenic centre under the stated
reaction conditions. So, optically pure amide (S)-5b was
prepared starting from enantiopure (S)-3b employing the
sequence expressed above for the racemic series.23 Finally,
as depicted in Scheme 4, the access to enantiopure
benzodiazepine-2-one (S)-6b was achieved without loss of
enantiomeric purity, treating the amide (S)-5b with PIFA.
Scheme 4. Reagents and conditions: (i) PIFA, TFA, CH2Cl2, 08C (70%).
Scheme 2. Reagents and conditions: (i) NaOH, ClCOOEt, THF/H2O, room
temperature (quant.); (ii) NH2OMe·HCl, Et3N, EDC, HOBt, CH2Cl2, room
temperature (87%); (iii) PIFA, BF3·OEt2, CH2Cl2, 2208C (60%).
Following our research on the PIFA mediated aromatic
amidation reaction as a useful tool for the construction of
new and highly valuable heterocyclic frameworks, we next
decided to expand this methodology to the preparation of
heterocycle-fused diazepine derivatives considering the
lack of general methods for the synthesis of this type of
compounds. Taking into account our previous results, and
encouraged by the known pharmacological activity of
some thieno-fused diazepines, such as clotiazepam,24
brotizolam25 and etizolam,26 and some pyrrolo-fused
As mentioned above, and in order to promote the key
cyclization step, PIFA was selected as the source of
hypervalent iodine to generate an electrophilic N-acyl-
nitrenium ion from amide 5a. By application of cyclization
conditions, using boron trifluoride etherate as additive,
benzodiazepine-2-one 6a was obtained in good yield (60%).
Conversely, the addition of TFA to the reaction medium,

A. Correa et al. / Tetrahedron 59 (2003) 7103–7110
7105
diazepines, such us antramicine and tomaimicine,27 we
selected the thiophene and the pyrrole rings as models for
the corresponding heterocycle-fused 1,4-diazepin-2-one
derivatives.
separately, with optically pure L-alanine methyl ester (10).
The resulting aminoester derivatives 3d,e were protected as
carbamates 7d,e and then hydrolyzed under basic conditions
to render the corresponding carboxylic acids 4d,e, which
were transformed into amides 5d,e in good overall yields.
When amides 5d,e were submitted to the oxidative
cyclization conditions using TFA as additive, 1,4-
thieno[2,3-f]diazepin-2-ones 6d and 6e were regio-
selectively obtained (55 and 76%, respectively) as a result
of an intramolecular attack of the N-acylnitrenium inter-
mediate onto the more nucleophilic 2-position of the
heteroaromatic ring.28 HPLC analysis of derivative (S)-6d
revealed that the oxidative cyclization process took place
without loss of enantiomeric purity.
So, as depicted in Scheme 5, we started with the reductive
amination of commercially available 2-thienocarboxalde-
hyde 8a with glycine methyl ester (9). The resulting
aminoester derivative 3c was protected as carbamate 7c
and then hydrolyzed under basic conditions to render the
corresponding carboxylic acid 4c, which was transformed
into amide 5c in good overall yield. Treatment of amide 5c
under a variety of experimental conditions (solvent,
temperature, additives,…) never rendered the desired
bicyclic compound 6c. Instead, complete degradation of
the starting material was confirmed.
As commented above, in order to investigate both the scope
of the presented methodology and its extension to other
fused heterocyclic systems, we faced the synthesis of
pyrrolodiazepinone derivatives. Similarly, amide 5f, which
was synthesized starting from commercially avalaible
1-methyl-2-pyrrolecarboxaldehyde (11) and glycine methyl
ester (9) (see Scheme 7), was submitted to the action of
PIFA. In this case, the corresponding novel pyrrolo[2,3-
f]diazepinone 6f was obtained in a moderate 33% yield after
studying a variety of reaction conditions (additive, tem-
perature, solvent,…). In particular, carrying out the reaction
using trifluoroethanol as solvent, instead of dichloro-
methane, at 08C afforded the best results.29
Scheme 5. Reagents and conditions: (i) Glycine methyl ester (9), Et3N,
NaBH3CN, room temperature (67%); (ii) NaOH, ClCOOEt, THF/H2O,
2208C (67%); (iii) LiOH, THF/H2O, room temperature (96%); (iv) NH2-
OMe·HCl, Et3N, EDC, HOBt, CH2Cl2, room temperature (71%).
Considering that the diminished nucleophilicity of the
3-position (versus the 2-position) in the thiophene ring
could be the reason for the latter result, a new attempt
starting from thienocarboxaldehyde 8b was accomplished
(see Scheme 6). Thus, aldehyde 8b was submitted to
reductive amination with glycine methyl ester (9) and,
Scheme 7. Reagents and conditions: (i) Glycine methyl ester (9), Et3N,
NaBH3CN, room temperature (49%); (ii) NaOH, ClCOOEt, THF/H2O,
2208C (97%); (iii) LiOH, THF/H2O, room temperature (94%); (iv) NH2-
OMe·HCl, Et3N, EDC, HOBt, CH2Cl2, room temperature (71%); (v) PIFA,
CF3CH2OH, 08C (33%).
3. Conclusions
A short and facile synthesis of new benzo-, thieno- and
pyrrolo-fused 1,4-diazepin-2-one derivatives is presented.
This novel approach takes place through the generation of
electrophilic N-acylnitrenium species by PIFA, which are
intramolecularly trapped by the nucleophilic ring to
complete an aromatic amidation reaction. In the presented
methodology it is noteworthy the complete (when applied)
regioselectivity achieved in the key cyclization step and the
lack of racemization throughout the process when starting
from optically pure precursors.
Scheme 6. Reagents and conditions: (i) Glycine methyl ester (9) (or
L-alanine methyl ester 10 for 3e), Et3N, NaBH3CN, room temperature (50%
for 3d; 88% for 3e); (ii) NaOH, ClCOOEt, THF/H2O, 2208C (92% for 7d;
92% for 7e); (iii) LiOH, THF/H2O, room temperature (89% for 4d; 92% for
4e); (iv) NH2OMe·HCl, Et3N, EDC, HOBt, CH2Cl2, room temperature
(72% for 5d; 76% for 5e); (v) PIFA, TFA, CH2Cl2, 08C (55% for 6d; 76%
for 6e).

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A. Correa et al. / Tetrahedron 59 (2003) 7103–7110
4. Experimental
nate (3e). According to the typical procedure aminoester 3e
was obtained from 3-thienocarboxaldehyde (8b) and (S)-
alanine methyl ester hydrochloride (10) in 88% yield as a
chromatographycally pure yellowish oil after purification by
Melting points were measured in a Bu¨chi apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin–
Elmer R-1420 infrared spectrophotometer as KBr plates or
as neat liquids and peaks are reported in cm21. NMR spectra
were recorded on a Bruker ACE-250 instrument (250 MHz
1
column chromatography (hexanes/EtOAc, 6:4). H NMR
(CDCl3): 1.31 (d, J¼7.1 Hz, 3H, CH3), 1.87 (bs, 1H, NH),
3.39 (q, J¼7.1 Hz, 1H, CH), 3.69 (d, J¼13.1 Hz, 1H,
CHaHb), 3.72 (s, 3H, OCH3), 3.82 (d, J¼13.1 Hz, 1H,
CHaHb), 7.03–7.29 (m, 3H, Harom); 13C NMR (CDCl3):
18.7, 46.5, 51.4, 55.3, 121.4, 125.3, 126.1, 127.1, 175.6; IR
(neat): 3326, 1734; MS (EI) m/z (%): 200 (11), 199 (Mþ, 1),
140 (39), 112 (13), 97 (100), 53 (9). HRMS: calcd for
C9H13NO2S 199.0667, found 199.0669; [a]2D0¼228.4 (c
0.11, CH2Cl2).
1
for H and 62.83 MHz for 13C) at 208C unless otherwise
stated. Chemical shifts (d) were measured in ppm relative to
1
chloroform (d¼7.26 for H or 77.00 for 13C) as internal
standard. Coupling constants, J, are reported in hertz. DEPT
experiments were used to assist with the assignation of the
signals. Combustion analyses were performed on a Perkin–
Elmer 2400 CHN apparatus, and HRMS spectra were
recorded at the University of Vigo on a VG Autospec M
instrument.
4.1.5. Methyl N-[(N0-methyl-2-pyrrolylmethyl)amino]-
acetate (3f). According to the typical procedure aminoester
3f was obtained from 1-methyl-2-pyrrolocarboxaldehyde
(11) and glycine methyl ester (9) in 49% yield as a
chromatographycally pure pale brown oil after purification
by column chromatography (hexanes/EtOAc, 5:5). 1H NMR
(CDCl3): 1.83 (bs, 1H, NH), 3.41 (s, 2H, CH2COO), 3.65 (s,
3H, OCH3), 3.72 (s, 3H, NCH3), 3.75 (s, 2H, ArCH2), 6.03–
6.05 (m, 2H, Harom), 6.59–6.72 (m, 1H, Harom); 13C NMR
(CDCl3): 33.5, 44.5, 49.2, 51.6, 106.3, 108.4, 122.5, 129.83,
172.9; IR (neat): 3320, 1750; MS (EI) m/z (%): 182 (Mþ, 9),
109 (25), 97 (18), 94 (100), 93 (10), 53 (11). HRMS: calcd
for C9H14N2O2 182.1055, found 182.1057.
4.1. Typical procedure for the reductive amination
reaction. Preparation of aminoesters 3b–f
4.1.1. Synthesis of (S)-methyl 2-(benzylamino)-propio-
nate [(S)-3b]. Triethylamine (4.7 mL, 33.9 mmol) was
added to a solution of benzaldehyde (3.0 g, 28.3 mmol)
and (S)-alanine methyl ester hydrochloride (4.7 g,
33.9 mmol) in CH2Cl2 (80 mL) and the mixture was stirred
for 3 h at room temperature. Then, NaBH3CN (2.8 g,
42.4 mmol) was added in three portions and the mixture
was stirred until total conversion of the starting material.
Water (30 mL) was added, the organic phase was separated
and the aqueous layer was extracted with CH2Cl2
(3£20 mL). The combined organic extracts were dried
over sodium sulfate, and, after evaporation of the solvent,
the residue was subjected to flash chromatography (hexanes/
EtOAc, 6:4) yielding aminoester (S)-3b as a pale yellow oil
(76%).22
4.2. Typical procedure for the preparation of
carbamates 4a and 7b–f
4.2.1. Synthesis of (S)-methyl 2-(N-benzyl-N-ethoxy-
carbonylamino)propionate (7b). A solution of ethyl
chloroformate (0.56 mL, 4.0 mmol) in THF (5 mL) was
added dropwise to a cold solution (2208C) of aminoester
(S)-3b in 5 mL of the same solvent. After the addition of
half of the ethyl chloroformate, a solution of NaOH
(186 mg, 4.7 mmol) in THF/H2O (3 mL, 3:7) was added.
When the addition of chloroformate was finished, the
temperature was raised to room temperature and stirring was
continued for 2 h. Then, pH was adjusted to 2 with HCl aq
10%, and the mixture was extracted with Et2O (3£5 mL).
The combined organic extracts were dried over sodium
sulfate and concentrated in vacuum to yield aminoester 7b
4.1.2. Methyl [N-(2-thienylmethyl)amino]acetate (3c).
According to the typical procedure aminoester 3c was
obtained from 2-thienocarboxaldehyde (8a) and glycine
methyl ester (9) in 67% yield as a chromatographycally pure
pale brown oil after purification by column chromatography
(hexanes/EtOAc, 5:5). 1H NMR (CDCl3): 2.05 (bs, 1H,
NH), 3.40 (s, 2H, CH2COO), 3.68 (s, 3H, OCH3), 3.97 (s,
2H, ArCH2), 6.90–7.19 (m, 3H, Harom); 13C NMR (CDCl3):
43.3, 49.0, 51.4, 124.4, 124.9, 126.3, 142.8, 172.3; IR (neat):
3337, 1740; MS (EI) m/z (%): 185 (Mþ, 4), 126 (12), 112
(47), 97 (100), 53 (10). HRMS: calcd for C8H11NO2S
185.0510, found 185.0512.
1
as a colorless oil (quantitative). H NMR (328C) (CDCl3):
1.22 (t, J¼7.0 Hz, 3H, OCH2CH3), 1.35 (d, J¼7.0 Hz, 3H,
CHCH3), 3.63 (s, 3H, OMe), 4.18 (q, J¼7.0 Hz, 2H, OCH2),
4.49–4.63 (m, 3H, NCH2þCH-Me), 7.23–7.34 (m, 5H,
Harom); 13C NMR (CDCl3, mixture of rotamers): 14.1, 14.9,
15.5, 49.1, 50.3, 51.6, 54.6, 61.3, 126.7, 127.5, 128.0, 137.6,
138.0, 156.0, 172.0; IR (neat): 1746, 1702 cm21; MS (EI)
m/z (%): 265 (Mþ, 1), 206 (39), 192 (8), 178 (36), 92 (9), 91
(100). HRMS: calcd for C14H19NO4 265.1314, found
265.1316; [a]2D0¼239.7 (c 1.10, CH2Cl2); ee: 99%
4.1.3. Methyl N-(3-thienylmethyl)aminoacetate (3d).
According to the typical procedure aminoester 3d was
obtained from 3-thienocarboxaldehyde (8b) and glycine
methyl ester (9) in 50% yield as a chromatographycally pure
pale brown oil after purification by column chromatography
(hexanes/EtOAc, 7:3). 1H NMR (CDCl3): 2.32 (bs, 1H,
NH), 3.38 (s, 2H, CH2COO), 3.67 (s, 3H, OCH3), 3.78 (s,
2H, ArCH2), 7.00–7.25 (m, 3H, Harom); 13C NMR (CDCl3):
47.8, 49.5, 51.6, 121.9, 125.7, 127.4, 140.1, 172.6; IR (neat):
3420, 1750; MS (EI) m/z (%): 185 (Mþ, 9), 126 (23), 112
(30), 97 (100), 53 (9). HRMS: calcd for C8H11NO2S
185.0510, found 185.0513.
(Chiralcel
OJ,
Hex/i-PrOH,
96:4,
0.8 mL/min,
tR¼21.75 min).
4.2.2. N-Benzyl-N-ethoxycarbonylglycine (4a). Accord-
ing to the typical procedure carbamate 4a was obtained from
N-benzylglycine (3a) in quantitative yield as a colorless oil.
1H NMR (CDCl3, rotamer mixture 50:50): 1.24–1.33 (m,
3H, OCH2CH3), 3.90 and 3.98 (s, total 2H, CH2CO2H),
4.1.4. (S)-Methyl 2-[N-(3-thienylmethyl)amino]-propio-

A. Correa et al. / Tetrahedron 59 (2003) 7103–7110
7107
4.17–4.28 (m, 2H, OCH2), 4.56 and 4.58 (s, total 2H,
PhCH2), 6.90 (bs, 1H, COOH), 7.21–7.35 (m, 5H, Harom);
13C NMR (CDCl3): 14.4, 46.9, 47.3, 50.9, 51.1, 62.2, 62.3,
127.6, 128.0, 128.6, 136.4, 156.7, 157.0 173.9, 174.0; IR
(neat): 3130, 1725, 1712, 1702; MS (EI) m/z (%): 237 (Mþ,
5), 164 (60), 118 (13), 91 (100). HRMS: calcd for
C12H15NO4 237.1001, found 237.0991.
6.00–6.06 (m, 2H, Harom), 6.58–6.61 (m, 1H, Harom); 13C
NMR (CDCl3): 14.5, 33.6, 42.5, 45.7, 45.9, 51.9, 61.7, 61.9,
106.6, 106.7, 110.5, 110.6, 123.6, 126.3, 126.6, 155.9,
170.0; IR (neat): 1760, 1710; MS (EI) m/z (%): 254 (Mþ,
26), 181 (32), 94 (100), 93 (8), 82 (15). HRMS: calcd for
C12H18N2O4 254.1267, found 254.1265.
4.3. Typical procedure for the hydrolysis of N-protected
aminoesters. Synthesis of aminoacids 4b–f
4.2.3. Methyl N-ethoxycarbonyl-N-(2-thienylmethyl)-
aminoacetate (7c). According to the typical procedure
carbamate 7c was obtained from aminoester 3c in 67% yield
as a chromatographycally pure yellowish oil after purifi-
cation by column chromatography (hexanes/EtOAc, 6:4).
1H NMR (CDCl3, rotamer mixture 50:50): 1.19–1.34 (m,
3H, OCH2CH3), 3.69 (s, 3H, OCH3), 3.91 and 3.98 (s, total
2H, CH2CO2), 4.12–4.26 (m, 2H, OCH2), 4.66 and 4.71 (s,
total 2H, ArCH2), 6.90–6.96 (m, 2H, Harom), 7.23–7.25 (m,
1H, Harom); 13C NMR (CDCl3): 14.5, 45.7, 45.9, 46.9, 47.1,
52.0, 61.9, 62.1, 125.6, 125.7, 126.5, 126.6, 126.9, 139.4,
139.5, 155.9, 156.0, 169.9, 170.0; IR (neat): 1751, 1704; MS
(EI) m/z (%): 257 (Mþ, 7), 184 (50), 124 (15), 97 (100), 53
(9). HRMS: calcd for C11H15NO4S 257.0722, found
257.0723.
4.3.1. Synthesis of (S)-N-benzyl-N-ethoxycarbonyl-
alanine (4b). LiOH (49 mg, 1.2 mmol) was added to a
solution of aminoester 7b (155 mg, 0.6 mmol) in THF/H2O
(12 mL, 4:1). The mixture was stirred at room temperature
until conversion was complete. Then, the solution was
treated with HCl (5% aq.) and extracted with EtOAc
(3£5 mL). The organic extracts were dried over sodium
sulfate and the solvent was evaporated under reduced
pressure to afford carboxylic acid 4b (96%).21
4.3.2. N-Ethoxycarbonyl-N-(2-thienylmethyl)glyine (4c).
According to the typical procedure carboxylic acid 4c was
obtained from aminoester 7c in 96% yield as a chromato-
graphycally pure yellowish oil after purification by column
1
4.2.4. Methyl N-ethoxycarbonyl-N-(3-thienyl-methyl)-
aminoacetate (7d). According to the typical procedure
carbamate 7d was obtained from aminoester 3d in 92%
yield as a chromatographycally pure yellowish oil after
purification by column chromatography (hexanes/EtOAc,
chromatography (hexanes/EtOAc, 7:3). H NMR (CDCl3,
rotamer mixture 50:50): 1.15–1.29 (m, 3H, CH3), 3.92 and
4.00 (s, total 2H, CH2CO2H), 4.12–4.20 (m, 2H, OCH2),
4.64 and 4.68 (s, total 2H, CH2N), 6.88–6.93 (m, 2H,
Harom), 7.18–7.22 (m, 1H, Harom), 11.0 (bs, 1H, OH); 13C
NMR (CDCl3): 14.5, 45.9, 46.7, 47.1, 62.2, 62.5, 125.8,
125.9, 126.7, 127.1, 139.1, 156.1, 156.4, 174.2, 174.4; IR
(neat): 3107, 1710, 1690; MS (EI) m/z (%): 243 (Mþ, 15),
184 (15), 170 (53), 124 (26), 112 (9), 97 (100), 53 (10).
HRMS: calcd for C10H13NO4S 243.0565, found 243.0569.
1
6:4). H NMR (CDCl3, rotamer mixture 50:50): 1.18–1.34
(m, 3H, OCH2CH3), 3.67 (s, 3H, OCH3), 3.85 and 3.93 (s,
total 2H, CH2CO2CH3), 4.10–4.23 (m, 2H, OCH2), 4.51
and 4.54 (s, total 2H, CH2N), 6.94–7.27 (m, 3H, Harom); 13
C
NMR (CDCl3): 14.5, 46.3, 46.4, 47.1, 47.4, 51.9, 61.7, 61.9,
122.6, 123.1, 126.3, 127.1, 127.6, 137.6, 137.7, 156.1,
156.3, 170.0, 170.1; IR (neat): 1760, 1710; MS (EI) m/z (%):
257 (Mþ, 15), 184 (33), 124 (12), 97 (100), 53 (8). HRMS:
calcd for C11H15NO4S 257.0722, found 257.0724.
4.3.3. N-Ethoxycarbonyl-N-(3-thienylmethyl)glycine
(4d). According to the typical procedure carboxylic acid
4d was obtained from aminoester 7d in 89% yield as
yellowish oil, which was used in the following step without
further purification. 1H NMR (CDCl3, rotamer mixture
50:50): 1.24–1.33 (m, 3H, CH3), 3.90 and 3.98 (s, total 2H,
CH2CO2H), 4.14–4.27 (m, 2H, OCH2), 4.53 and 4.56 (s,
total 2H, CH2N), 6.96–7.00 (m, 1H, Harom), 7.15–7.21 (m,
1H, Harom), 7.28–7.31 (m, 1H, Harom), 8.45 (bs, 1H, OH);
13C NMR (CDCl3): 14.5, 46.4, 46.9, 47.4, 62.1, 62.3, 122.9,
123.3, 126.5, 126.6, 127.2, 127.7, 137.4, 156.3, 156.7,
174.6, 174.8; IR (neat): 3100, 1740, 1700; MS (EI) m/z (%):
243 (Mþ, 24), 184 (10), 170 (36), 124 (19), 98 (13), 97
(100), 53 (9). HRMS: calcd for C10H13NO4S 243.0565,
found 243.0565.
4.2.5. (S)-Methyl 2-[N-ethoxycarbonyl-N-(3-thienyl-
methyl)]aminopropionate (7e). According to the typical
procedure carbamate 7e was obtained from aminoester 3e in
92% yield as a chromatographycally pure pale yellow oil
after purification by column chromatography (hexanes/
1
EtOAc, 6:4). H NMR (CDCl3): 1.21 (t, J¼7.1 Hz, 3H,
OCH2CH3), 1.34 (d, J¼7.1 Hz, 3H, CHCH3), 3.60 (s, 3H,
OCH3), 4.18 (q, J¼7.1 Hz, 2H, OCH2), 4.34–4.59 (m, 3H,
NCH2þCHCH3), 7.00–7.25 (m, 3H, Harom); 13C NMR
(CDCl3): 14.4, 15.1, 15.6, 44.6, 45.7, 51.9, 54.6, 61.6, 121.8,
122.5, 125.7, 127.1, 127.6, 138.7, 139.2, 156.0, 172.3; IR
(neat): 1744, 1699; MS (EI) m/z (%): 271 (Mþ, 6), 212 (14),
184 (17), 97 (100), 53 (8). HRMS: calcd for C12H17NO4S
271.0887, found 271.0888; [a]2D0¼214.8 (c 0.12, CH2Cl2).
4.3.4. (S)-N-Ethoxycarbonyl-N-(3-thienylmethyl)-
alanine (4e). According to the typical procedure carboxylic
acid 4e was obtained from aminoester 7e in 92% yield as a
chromatographycally pure pale orange oil after purification
by column chromatography (hexanes/EtOAc, 6:4). 1H NMR
(CDCl3, rotamer mixture 50:50): 1.24 (t, J¼7.1 Hz, 3H,
OCH2CH3), 1.38 (d, J¼7.1 Hz, 3H, CHCH3), 4.18 (q,
J¼7.1 Hz, 2H, OCH2), 4.33–4.65 (m, 3H, CHCH3þCH2N),
7.02–7.28 (m, 3H, Harom), 9.00 (bs, 1H, OH); 13C NMR
(CDCl3): 13.9, 14.1, 14.7, 15.3, 45.1, 45.8, 54.6, 54.8, 61.8,
121.7, 122.3, 126.8, 127.3, 138.3, 138.8, 156.1, 176.2; IR
(neat): 3102, 1710, 1698; MS (EI) m/z (%): 257 (Mþ, 3),
4.2.6. Methyl N-ethoxycarbonyl-N-(N0-methyl-2-pyr-
rolylmethyl)aminoacetate (7f). According to the typical
procedure carbamate 7f was obtained from aminoester 3f in
97% yield as a chromatographycally pure pale yellow oil
after purification by column chromatography (hexanes/
1
EtOAc, 7:3). H NMR (CDCl3, rotamer mixture 50:50):
1.19–1.42 (m, 3H, OCH2CH3), 3.58 (s, 3H, OCH3), 3.65 (s,
3H, NCH3), 3.83 and 3.87 (s, total 2H, CH2CO2CH3), 4.11–
4.28 (m, 2H, OCH2), 4.56 and 4.57 (s, total 2H, CH2N),

7108
A. Correa et al. / Tetrahedron 59 (2003) 7103–7110
184 (11), 98 (14), 97 (100), 53 (12). HRMS: calcd for
C11H15NO4S 257.0722, found 257.0724; [a]2D0¼261.6 (c
0.05, CH2Cl2).
4.4.3. N0-Ethoxycarbonyl-N0-(2-thienylmethyl)amino-N-
methoxyacetamide (5c). According to the typical pro-
cedure amide 5c was obtained from aminoacid 4c in 71%
yield as a white solid after crystallization from methanol.
4.3.5. N-Ethoxycarbonyl-N-[N0-methyl-(2-pyrrolyl-
methyl)]glycine (4f). According to the typical procedure
carboxylic acid 4f was obtained from aminoester 7f in 94%
yield as a pale brown oil. 1H NMR (CDCl3, rotamer mixture
50:50): 1.21–1.36 (m, 3H, OCH2CH3), 3.57 (s, 3H, NCH3),
3.88 and 3.92 (s, total 2H, CH2CO2H), 4.15–4.30 (m, 2H,
OCH2), 4.57 and 4.59 (s, total 2H, CH2N), 6.03–6.12 (m,
2H, Harom), 6.55–6.62 (m, 1H, Harom), 10.49 (bs, 1H, OH);
13C NMR (CDCl3): 14.4, 14.5, 33.6, 33.7, 42.4, 42.6, 45.5,
45.7, 62.0, 62.3, 106.7, 106.8, 110.8, 123.7, 126.3, 156.1,
156.2, 174.8; IR (neat): 3100, 1700, 1690. Due to its labile
nature, this compound was quickly transformed into the
corresponding amide.
Mp: 92–938C (MeOH); H NMR (CDCl3, 328C): 1.32 (t,
1
J¼7.1 Hz, 3H, CH3), 3.69 (s, 3H, OCH3), 3.89 (s, 2H,
CH2NH), 4.24 (q, J¼7.1 Hz, 2H, OCH2), 4.71 (s, 2H,
CH2N), 6.93–6.99 (m, 2H, Harom), 7.23–7.26 (m, 1H,
Harom), 8.92 (bs, 1H, NH); 13C NMR (CDCl3): 14.5, 46.5,
48.4, 62.5, 64.3, 125.8, 126.7, 127.1, 138.9, 156.5, 166.7; IR
(KBr): 3200, 1710, 1680; MS (EI) m/z (%): 240 (Mþ232,
12), 197 (44), 138 (15), 124 (48), 112 (20), 97 (100), 85
(21), 56 (24), 53 (15). Anal. calcd for C11H16N2O4S: C,
48.52; H, 5.92; N, 10.29. Found: C, 48.56; H, 6.00; N, 10.25.
4.4.4. N0-Ethoxycarbonyl-N0-(3-thienylmethyl)amino-N-
methoxyacetamide (5d). According to the typical pro-
cedure amide 5d was obtained from aminoacid 4d in 72%
yield as a white solid after crystallization from ether. Mp:
79–808C (Et2O); 1H NMR (CDCl3, 378C): 1.26 (t,
J¼7.1 Hz, 3H, CH3), 3.67 (s, 3H, OCH3), 3.84 (s, 2H,
CH2NH), 4.17 (q, J¼7.1 Hz, 2H, OCH2), 4.53 (s, 2H,
CH2N), 6.98–7.28 (m, 3H, Harom), 9.02 (bs, 1H, NH); 13C
NMR (CDCl3): 14.5, 46.7, 48.3 62.2, 64.2, 123.2, 126.5,
127.2, 137.4, 156.7, 166.8; IR (KBr): 3200, 1710, 1680; MS
(EI) m/z (%): 272 (Mþ, 1), 240 (2), 184 (21), 97 (100).
HRMS: calcd for C11H16N2O4S 272.0831, found 272.0829.
4.4. Typical procedure for the synthesis of N-methoxy-
amides 5a–f
4.4.1. Synthesis of 2-[(N0-benzyl-N0-ethoxycarbonyl-
amino)]-N-methoxyacetamide (5a). A solution of EDC
(0.90 mg, 4.7 mmol) and HOBt (0.59 g, 5.0 mmol) in
CH2Cl2 (8 mL) was added to a suspension of aminoacid
4a (740 mg, 3.1 mmol), NH2OMe·HCl (312 mg, 3.7 mmol)
and Et3N (0.52 mL, 3.7 mmol) in the same solvent (8 mL).
Then, the mixture was cooled (08C) and Et3N (0.65 mL,
4.7 mmol) was added dropwise. After stirring for 2 h,
temperature was raised to room temperature and stirring was
continued until the conversion was complete. Then, the
solution was washed with water, dried over sodium sulfate,
and the solvent was evaporated at reduced pressure. The
resulting residue was column chromatographed (hexanes/
EtOAc, 5:5) to afford amide 5a as a colorless oil which was
4.4.5. (S)-2-[N0-Ethoxycarbonyl-N0-(3-thienylmethyl)-
amino]-N-methoxypropionamide [(S)-5e]. According to
the typical procedure amide (S)-5e was obtained from
aminoacid (S)-4e in 76% yield as a chromatographycally
pure pale yellow oil after purification by column chroma-
1
tography (hexanes/EtOAc, 5:5). H NMR (CDCl3, 378C):
1.25 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.34 (d, J¼7.1 Hz, 3H,
CHCH3), 3.64 (s, 3H, OCH3), 4.19 (q, J¼7.1 Hz, 2H, OCH2),
4.39–4.57 (m, 3H, CH2NþCHCH3), 7.0–7.25 (m, 3H,
Harom), 8.94 (bs, 1H, NH); 13C NMR (CDCl3): 13.8, 14.6,
42.9, 52.2, 63.7, 121.9, 125.5, 127.0, 139.2, 156.6, 168.8; IR
(neat): 3229, 1690, 1685; MS (EI) m/z (%): 254 (Mþ232, 1),
212 (10), 97 (100), 53 (10); [a]2D0¼282.6 (c 0.05, CH2Cl2).
1
crystallized from ether (87%). Mp: 72–748C (Et2O); H
NMR (CDCl3, rotamer mixture 50:50): 1.30 (t, J¼7.1 Hz,
3H, OCH2CH3), 3.69 (s, 3H, NOMe), 3.79 (bs, 2H, CO–
CH2–N), 4.23 (q, J¼7.1 Hz, 2H, OCH2), 4.57 (s, 2H, Ph–
CH2), 7.26–7.37 (m, 5H, Harom), 8.34 and 9.09 (bs, total 1H,
NH); 13C NMR (CDCl3): 14.1, 46.6, 47.0, 51.0, 61.7, 63.5,
127.2, 127.6, 128.0, 136.5, 156.3, 156.5, 166.1, 166.3; IR
(KBr): 3221, 1703, 1679; MS (EI) m/z (%): 192 (Mþ274),
178 (5), 118 (5), 91 (100), 65 (13). Anal. calcd for
C13H18N2O4: C, 58.63; H, 6.81; N, 10.52. Found: C, 58.69;
H, 6.61; N, 10.66.
4.4.6. N0-Ethoxycarbonyl-N0-(1-methyl-2-pyrrolyl-
methyl)amino-N-methoxyacetamide (5f). According to
the typical procedure amide 5f was obtained from
aminoacid 4f in 71% yield as a chromatographycally pure
pale yellow oil after purification by column chromatography
4.4.2. (S)-2-(N0-benzyl-N0-ethoxycarbonylamino)-N-
methoxypropionamide [(S)-5b]. According to the typical
procedure amide (S)-5b was obtained from aminoacid (S)-
4b in 75% yield as a chromatographycally pure pale yellow
oil after purification by column chromatography (hexanes/
(hexanes/EtOAc, 3:7). H NMR (CDCl3, (378C): 1.28 (t,
1
J¼7.1 Hz, 3H, CH3), 3.57 (s, 3H, NCH3), 3.67 (s, 3H,
OCH3), 3.80 (s, 2H, CH2NH), 4.21 (q, J¼7.1 Hz, 2H,
OCH2), 4.57 (s, 2H, CH2N), 6.02–6.11 (m, 2H, Harom),
6.57–6.61 (m, 1H, Harom), 8.46 (bs, 1H, NH); 13C NMR
(CDCl3): 14.2, 33.5, 42.5, 45.1, 61.6, 63.8, 106.5, 110.3,
123.2, 156.1, 166.1, 171.0; IR (neat): 3200, 1710, 1680; MS
(EI) m/z (%): 254 (Mþ215, 2), 226 (14), 194 (20), 121 (14),
97 (12), 95 (19), 94 (100), 83 (13), 82 (17), 53 (10).
1
EtOAc, 3:7). H NMR (CDCl3, 328C): 1.24 (t, J¼7.0 Hz,
3H, OCH2CH3), 1.33 (d, J¼7.1 Hz, 3H, CH–CH3), 3.67 (s,
3H, NOMe), 4.20 (q, J¼7.0 Hz, 2H, OCH2), 4.39–4.45 (m,
2H, Ph–CHaHbþCH–Me), 4.62 (d, J¼16.2 Hz, 1H, Ph–
CHaHb), 7.29–7.31 (m, 5H, Harom), 8.89 (bs, 1H, NH); 13
C
NMR (CDCl3, 328C): 13.9, 14.7, 48.2, 52.8, 61.4, 63.3,
126.5, 126.6, 127.9, 138.4, 156.5, 169.2; IR (neat): 3228,
1699, 1672; MS (EI) m/z (%): 234 (Mþ246, 21), 207 (11),
206 (79), 178 (20), 91 (100); [a]2D0¼285.8 (c 0.01, CH2Cl2);
ee: 99% (Chiralcel OD, hexanes/i-PrOH, 95:5, 0.7 mL/min,
tR¼25.02 min).
4.5. Typical procedure for the synthesis of 1,4-diazepin-
2-ones 6
4.5.1. Synthesis of (3S)-4-ethoxycarbonyl-1-methoxy-3-
methyl-1,3,4,5-tetrahydro-2H-[1,4]benzodiazepin-2-one
(6b). A solution of TFA (0.07 mL, 0.91 mmol) and PIFA

A. Correa et al. / Tetrahedron 59 (2003) 7103–7110
7109
(169 mg, 0.39 mmol) in 8 mL of CH2Cl2 was added at 08C
to a solution of amide 5b (100 mg, 0.36 mmol) in 7 mL of
the same solvent, and the new solution was stirred until total
consumption of the starting material (tlc, hexanes/EtOAc,
7:3). Then, the mixture was washed with Na2CO3 (10% aq)
(1£4 mL), dried over sodium sulfate, filtered, and the
solvent was evaporated at reduced pressure. The resulting
residue was purified by column chromatography (hexanes/
EtOAc, 7:3) to afford benzodiazepine 6b as a yellowish oil
(70%).19
14.5, 24.8, 48.4, 64.3, 62.8, 64.3, 82.6, 154.0, 130.0, 143.6,
163.7, 169.2; IR (neat): 1720, 1690. This compound
suffered complete degradation under MS conditions.
Acknowledgements
Financial support from the University of the Basque
Country (9/UPV 41.310-13656/2001) and the Spanish
Ministry of Science and Technology (MCYT BQU 2001-
0313) is gratefully acknowledged. M. T. H. thanks the
Ministry of Science and Technology (MCYT) for a
predoctoral scholarship.
4.5.2. 4-Ethoxycarbonyl-1-methoxy-1,3,4,5-tetrahydro-
2H-[1,4]benzodiazepin-2-one (6a). Benzodiazepine 6a
was obtained in 60% yield from amide 5a following the
procedure described for 6b but using BF3·OEt2 instead of
TFA and working at 2208C. Purification was carried out by
column chromatography (hexanes/EtOAc, 7:3) to afford
benzodiazepine 6a as a yellowish oil.19
References
4.5.3. 4-Ethoxycarbonyl-1-methoxy-1,3,4,5-tetrahydro-
2H-1,4-thieno[3,2-f]diazepin-2-one (6d). Following the
procedure described for 6b, diazepine 6d was obtained in
55% yield from 5d as a chromatographycally pure pale
brown oil after purification by column chromatography
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1
(hexanes/EtOAc, 7:3). H NMR (CDCl3, 378C): 1.27 (t,
J¼7.1 Hz, 3H, CH2CH3), 3.83 (s, 3H, OCH3), 4.16–4.2 (m,
4H, CH2NþCH2CH3), 4.66–4.72 (m, 2H, CH2CON), 6.70
(d, J¼5.5 Hz, 1H, Harom), 6.99 (d, J¼5.5 Hz, 1H, Harom);
13C NMR (CDCl3): 14.5, 47.1, 50.3, 62.3, 63.0, 119.1,
126.2, 122.0, 138.8, 155.4, 167.8; IR (neat): 1710; MS (EI)
m/z (%): 270 (Mþ, 49), 209 (39), 142 (11), 141 (100), 139
(16), 138 (64), 126 (12), 115 (64), 110 (11), 43 (19), 42 (17).
HRMS: calcd for C11H14N2O4S 270.0674, found 270.0676.
´
2. Moreno, I.; Tellitu, I.; Etayo, J.; SanMartin, R.; Domınguez, E.
4.5.4. 3-(S)-4-Ethoxycarbonyl-1-methoxy-3-methyl-
1,3,4,5-tetrahydro-2H-1,4-thieno[3,2-f]diazepin-2-one
(6e). Following the procedure described for 6b, compound
6e was obtained in 76% yield from 5e as a chromato-
graphycally pure pale brown oil after purification by column
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3. (a) Moreno, I.; Tellitu, I.; SanMartin, R.; Badıa, D.; Carrillo,
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L.; Domınguez, E. Tetrahedron Lett. 1999, 40, 5067–5070.
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´
(b) Moreno, I.; Tellitu, I.; SanMartin, R.; Domınguez, E.
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Domınguez, E.; SanMartin, R. Eur. J. Org. Chem. 2002,
1
chromatography (hexanes/EtOAc, 7:3). H NMR (CDCl3,
378C): 1.26 (t, J¼7.1 Hz, 3H, CH2CH3), 1.47 (d, J¼7.1 Hz,
3H, CHCH3), 3.86 (s, 3H, OCH3), 4.17 (q, J¼7.1 Hz, 2H,
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139.2, 155.7, 168.3; IR (neat): 1710, 1706; MS (EI) m/z (%):
284 (Mþ, 18), 256 (31), 141 (100), 112 (27), 111 (84), 110
(68), 97 (11), 83 (14), 70 (18), 58 (12). HRMS: calcd for
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(4.97 g/100 mL, CH2Cl2); ee: 97% (Chiralcel OD, hexane-
s/iPrOH 98:2, 0.9 mL/min, tR¼41.99).
2126–2135.
4. A review about the applications of hypervalent iodine reagents
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Herrero, M. T.; SanMartin, R.; Domınguez, E. Curr. Org.
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´
´
(b) Herrero, M. T.; Tellitu, I.; Domınguez, E.; Hernandez,
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7. Serna, S.; Tellitu, I.; Domınguez, E.; Moreno, I.; SanMartin,
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tetrahydro-2H-1,4-pyrrolo[2,3-f]diazepin-2-one
(6f).
Following the procedure described for 6b, compound 6f
was obtained in 33% yield from 5f as a chromatography-
cally pure pale orange oil after purification by column
1
chromatography (hexanes/EtOAc, 7:3). H NMR (CDCl3):
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1.27 (t, J¼7.1 Hz, 3H, CH2CH3), 2.85 (s, 3H, NCH3), 3.70
(s, 3H, OCH3), 3.82 (d, J¼13.9 Hz, 1H, CHaHb), 3.97 (d,
J¼13.9 Hz, 1H, CHaHb), 4.15 (m, 3H, OCH2þCHcCHd),
4.44 (d, J¼18.2 Hz, 1H, CHcCHd), 6.33 (d, J¼5.9 Hz, 1H,
Harom), 6.90 (d, J¼5.9 Hz, 1H, Harom); 13C NMR (CDCl3):
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´
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´
¨
427–432.
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´
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