Efficient solid-phase synthesis of highly functionalized 1,4-benzodiazepin-5-one derivatives and related compounds by intramolecular aza-wittig reactions

Article abstract of DOI:10.1002/chem.200401112

Due to their widespread biological activities and favorable pharmacokinetic properties, benzodiazepines were among the first classes of small molecules to be synthesized on solid supports. Since then, there have been numerous reports on the synthesis of similar skeletons. We have employed the T1 triazene linker to yield 1,4-benzodiazepin-5-one. Starting from various substituted triazene resins, cleavage in the presence of an azide donor, such as trimethylsilylazide, gave rise to aryl azides. Intramolecular aza-Wittig reactions produced the appropriately functionalized N-heterocycles. By using this route, the natural product deoxyvasicinone and related compounds were prepared.

Full text of DOI:10.1002/chem.200401112

Efficient Solid-Phase Synthesis of Highly Functionalized 1,4-Benzodiazepin-
5-one Derivatives and Related Compounds by Intramolecular Aza–Wittig
Reactions**
Carmen Gil[a] and Stefan Brꢀse*[b]
Abstract: Due to their widespread bio-
logical activities and favorable pharma-
cokinetic properties, benzodiazepines
were among the first classes of small
molecules to be synthesized on solid
supports. Since then, there have been
numerous reports on the synthesis of
similar skeletons. We have employed
the T1 triazene linker to yield 1,4-ben-
zodiazepin-5-one. Starting from various
substituted triazene resins, cleavage in
the presence of an azide donor, such as
trimethylsilylazide, gave rise to aryl
azides. Intramolecular aza–Wittig reac-
tions produced the appropriately func-
tionalized N-heterocycles. By using this
route, the natural product deoxyvasici-
none and related compounds were pre-
pared.
Keywords: aza–Wittig reaction
·
benzodiazepines · heterocycles · sol-
id-phase synthesis · traceless linker
Introduction
diazepines represent an important class of molecules with a
broad range of biological activities. Many different types of
benzodiazepinones have been synthesized and their pharma-
cology has been extensively published.[7–9] In addition, the
1,4-benzodiazepin-2,5-dione core is found in a number of
natural products.[10,11]
The discovery of new drugs often begins with the modifica-
tion of natural products[1] and commonly known privileged
structures.[2] One example of this is the modification of the
azepine class of drugs. This scaffold is a prototype of a privi-
leged structure and is able to provide ligands for diverse re-
ceptors, such as cholecystokinin, gastrin, and central benzo-
diazepine receptors.[3] Diazepam, triazolam, and midazolam,
which contain the benzodiazepine moiety, are well-known
anxiolytic,[4] sedative,[5] and anticonvulsant drugs .[6] Benzo-
Due to their widespread biological activities and favor-
able pharmacokinetical properties,[12] benzodiazepines were
among the first classes of small molecules to be synthesized
on solid supports.[13–15] Since then, there have been numer-
ous reports of synthesis by using similar skeletons. The ini-
tial efforts to prepare libraries of this type focused on 1,4-
benzodiazepin-2-ones and 1,4-benzodiazepin-2,5-diones;[16]
however, there are also examples for the solid-supported
synthesis of 2,3-benzodiazepin-4-ones,[17] 1,4-benzodiazepin-
2,3-diones,[18] and pyrrolo[2,1-c][1,4]benzodiazepines.[19,20]
Substantial progress has been made in the field of hetero-
cyclic synthesis by use of the aza–Wittig methodology. This
has been utilized for the synthesis of five-, six-, and seven-
membered azaheterocycles. Several successful examples of
natural product synthesis, in which this cyclization reaction
was the key step, have been published.[21,22]
[a] Dr. C. Gil
The use of commercially available polymer-bound triphe-
nylphosphine for Wittig reactions enables the principles of
solid-phase synthesis to be combined with the application of
polymer-supported reagents.[23–26] The byproduct triphenyl-
phosphine oxide, derived from Wittig reactions in the so-
lution phase, is often difficult to separate from the end-prod-
uct. Following the use of a polymer-supported Wittig re-
agent, the triarylphosphine oxide remains attached to the
Kekulꢀ-Institut fꢁr Organische Chemie und Biochemie
Rheinischen Friedrich-Wilhelms-Universitꢂt
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
[b] Prof. Dr. S. Brꢂse
Institut fꢁr Organische Chemie, Universitꢂt Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax : (+49)721-608-8581
E-mail: braese@ioc.uka.de
[**] The IUPAC Chemset notation is used throughout this paper.
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DOI: 10.1002/chem.200401112
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FULL PAPER
resin, and can be separated only by filtration. After reduc-
tion, the triarylphosphine oxide is recycled with trichlorosi-
lane to give the phosphine (Scheme 1).[27] A triphenylphos-
phine reagent linked to a linear polystyrene has also been
synthesized for this purpose.[28]
Scheme 2. Synthesis of the triazene resins 3.
Scheme 1. Aza–Wittig reaction employing polymer-supported triphenyl-
phosphine.
In this paper, we employed the methodology described
above to obtain 1,4-benzodiazepin-5-one derivatives by
solid-phase methods, the solution synthesis of which was re-
ported by Eguchi and co-workers[29] In addition, the exten-
sion to deoxyvasicinone, one of the secondary metabolites
identified in Isatis tinctoria, is demonstrated.[30]
Scheme 3. Amide coupling on solid supports.
Results and Discussion
were reacted immediately with the azide transfer reagent
trimethylsilyl azide[35] to achieve the aryl azides 6{1–7,1} in
moderate yields (21–62%) (Scheme 4). Azide 6{1,2} was ob-
tained after the reaction of 3{1} with the methyl ester hydro-
chloride of l-proline 4{2} using the same method.
We chose to focus on the 1,4-benzodiazepin-5-one structure
as our first target, because a majority of the biologically
active benzodiazepines identified to date fall within this sub-
class. Recently, we successfully completed a benzotriazinone
synthesis by using polymer-bound triazenes that were cou-
pled with different amino acids and amines.[31,32] By using
this process, o-azidobenzoylamides were prepared by a post-
cleavage modification of polymer-bound triazenes.
Triazene carboxylate resins 3{1–7} were prepared on a
multigram scale by diazotation of the anthranilic acids
1{1–7} (Figure 1) with isoamyl nitrite, and a subsequent cou-
pling to the benzylamine resin 2 (Scheme 2).
Scheme 4. Cleavage and azide 6{1–7,1} formation.
The 1,4-benzodiazepin-5-ones were obtained by cycliza-
tion of the azides 6{1–7,1} and 6{1,2} with polymer-supported
triphenylphosphine, via the corresponding iminophosphor-
anes, at room temperature in toluene. They were heated at
1008C in the same solvent without further purification for 3
or 18 h to produce the intramolecular aza–Wittig products
7{1–7,1} and 7{1,2}, respectively. The desired benzodiaze-
pines were isolated in 68–99% yield and 68–94% purity
without any further purification (Scheme 5). The use of
polymer-supported triphenylphosphine provides a more sim-
plified purification procedure, relative to the corresponding
solution-phase method. The polymer-supported phosphine
oxides were easily removed through filtration.
Figure 1. Anthranilic acids 1 used for library production.
Secondary amines were synthesized to introduce a variety
of products with the 1,4-benzodiazepin-5-one core
(Figure 2). Following a reductive amination procedure using
NaBH4 as the reducing reagent (see Experimental Sec-
tion),[36] the methyl esters of three amino acids were com-
bined with four different aromatic aldehydes to give amines
4{3–8}. With these unpurified six amines 4{3–8}, the aryl
azides 6{1,3–8} were used for the synthesis of benzodiaze-
The triazene carboxylate resins 3{1–7} were then coupled
with the methyl ester hydrochloride of sarcosine (4{1}) by
using 2-chloro-1-methylpyridinium iodide as the coupling re-
agent[33,34] (Scheme 3). Triazene resin cleavage was achieved
by applying 5% TFA in dichloromethane at room tempera-
ture to obtain the corresponding diazonium salts. These salts
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C. Gil and S. Brꢂse
Scheme 6. Intramolecular aza–Wittig reaction.
tion as the key step.[39] Until now, no solid-phase approach
has been reported. Here, we present the synthesis of deoxy-
vasicinone on solid supports by using the T1 triazene linker
to obtain the corresponding azides, and the subsequent
solid-phase, intramolecular aza–Wittig reaction.
Scheme 5. Intramolecular aza–Wittig reaction.
Amides are less nucleophilic than amines. Therefore, the
Mukayama reagent 2-chloro-1-methylpyridinium iodide was
not efficient for the coupling of carboxylates to amides.
Moreover, the sensitivity of the triazene moiety to traces of
acid prevented the conventional transformation of carbox-
ylates into acid chlorides using sulfuryl chlorides, thionyl
chorides, or phosphoryl chlorides, due to trace amounts of
hydrogen chloride. The reagent combination of aryl phos-
phines/tetrachloromethane has been reported as an in situ
preparation of acyl chlorides.[40] Thus, the treatment of the
triazene carboxylate resin 3{1} with triphenylphosphine and
tetrachloromethane generated the acyl chlorides, which re-
acted in situ with the lactams 4{9–11} to obtain amides
5{1,9–11} (Scheme 7). The azides 6{1,9–11} were then ob-
tained in moderate yields (12–20%) by cleavage of the cor-
responding triazene resins 5{1,9–11} with TFA. Finally,
deoxyvasicinone 7{1,9} (n=1) and related heterocycles
7{1,10} (n=2) and 7{1,11} (n=3) were obtained by treat-
ment with triphenylphosphine polystyrene at 1008C for
132 h (Scheme 8).
Figure 2. Secondary amines used for library synthesis.
pines, according to the procedure described above. For com-
pounds 7{1,3–8}, the cyclization by an aza–Wittig reaction
requires heating at 1008C for 18 h (Scheme 6). A reduction
of
polystyryldiphenylphos-
phine oxide to polystyryldiphe-
nylphosphine was attempted
using trichlorosilane and N,N-
dimethylaniline at 1008C.[27]
This phosphine was later
reused for aza–Wittig synthe-
ses without producing a lower
yield. After reduction, the
resin was washed thoroughly
until trichlorosilane had been
completely eliminated. In this
way, the acid hydrolysis of 1,4-
Scheme 7. Synthesis of the azides 6{1,9–11}.
benzodiazepin-5-ones to 1,4-benzodiazepin-2,5-(1H)-dione
derivatives was avoided.[37]
We also applied this methodology to the synthesis of de-
oxyvasicinone and a few related compounds. This alkaloid
was isolated from Isatis tinctoria, and its synthesis by differ-
ent routes has already been described.[38] Amongst these, a
solution procedure published by Eguchi and co-workers em-
ployed a domino Staudinger/intramolecular aza–Wittig reac-
Scheme 8. Synthesis of deoxyvasicinone (7{1,9}) and related heterocycles.
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Benzodiazepinone Derivatives
FULL PAPER
THF, CH2Cl2, methanol, and pentane, and then dried under high
vacuum.
Conclusion
We have employed the T1 triazene linker[41] to yield aryl
azides that subsequently reacted with triphenylphosphine
polystyrene to give the appropriately functionalized N-het-
erocycles. It was proven that the solid-phase aza–Wittig re-
action provides an effective method to create a variety of
1,4-benzodiazepin-5-one or quinazoline derivatives. The nat-
ural product deoxyvasicinone and related compounds were
prepared using this method.
Triethylammonium 2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoate
3{1}: IR (KBr): n˜ =3600 (w, br, ps), 3061 (s, ps), 3027 (s, ps), 2930 (s, ps),
2847 (s, ps), 1944 (m, ps), 1874 (m, ps), 1804 (m, ps), 1739 (s), 1600 (s,
ps), 1493 (s, ps), 1451 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C93H100N4O2: C 85.55, H 7.71, N 4.28; found: C 84.65, H 8.67, N 4.27;
[42]
loading: 0.764 mmolgꢀ1
.
Triethylammonium 2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-bromo-
benzoate 3{2}: IR (KBr): n˜ =3647 (w, br, ps), 3027 (s, ps), 2912 (s, ps),
2870 (s, ps), 1943 (m, ps), 1871 (m, ps), 1803 (m, ps), 1739 (s), 1601 (s,
ps), 1493 (s, ps), 1451 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C103H109N4O2Br: C 81.75, H 7.25, N 3.66; found: C 83.40, H 7.28, N 2.86;
loading: 0.629 mmolgꢀ1
.
Triethylammonium
2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-iodo-
Experimental Section
benzoate 3{3}: IR (KBr): n˜ =3464 (w, br, ps), 3060 (s, ps), 3026 (s, ps),
2913 (s, ps), 2846 (s, ps), 1944 (m, ps), 1874 (m, ps), 1804 (m, ps), 1743
(s), 1601 (s, ps), 1493 (s, ps), 1451 cmꢀ1 (s, ps); elemental analysis calcd
(%) for C103H109N4O2I: C 79.31, H 7.03, N 3.55; found: C 81.77, H 7.19, N
General: 1H NMR: Bruker DP 300 (300 MHz), Bruker DP 400
(400 MHz); d=7.19 ppm for CHCl3. Description of signals: s=singlet,
bs=broad singlet, d=doublet, t=triplet, q=quartet, m=multiplet, mc=
centered multiplet, ca=complex area, dd=doublet of doublet, ddd=
doublet of dd, dt=doublet of triplets, dq=doublet of quartets, tt=triplet
of triplets. The spectra were analyzed according to first order. All cou-
pling constants are absolute values. Abbreviations for signals: Ar-H=ar-
omatic, Aliph-H=aliphatic. 13C NMR: Bruker DP 300 (75 MHz), Bruker
DP 400 (100 MHz); d=77.00 ppm for deuterochloroform. IR (infrared
spectroscopy): The resins were measured as KBr pellets by using a
Bruker IFS88 instrument; ps=polystyrene. MS (mass spectroscopy): EI-
HRMS (electronic ionization-high resolution mass spectroscopy) was per-
formed by using Kratos MS 50 (70 eV) and Thermo Quest Finnegan
MAT 95 XL (70 eV) instruments. GC (gas chromatography) analytical
(achiral stationary-phase): Hewlett–Packard HP 5890 Serie II 12 mꢄ
0.25 mm capillary column HP I (carrier gas N2). TLC (thin layer chroma-
tography): Silica gel-coated aluminium plates (Merck, silica gel 60, F254).
Detection under UV light at 254 nm. Elemental analysis: Elementar Var-
io EL analyzer at the Mikroanalytisches Labor des Instituts fꢁr Organi-
sche Chemie der Universitꢂt Bonn (Germany). Descriptions without
nominated temperature were conducted at room temperature (RT). Solid
materials (except resins) were powdered. Chemicals, solvents, reagents,
and chemicals were purchased from Aldrich, Fluka, Janssen, and Merck.
Merrifield resin (1–2% cross-linked, 200–400 mesh) was obtained from
CalBioChem-NovaBioChem with loading=1.06 mmolgꢀ1. To obtain the
molecular mass of the resin and to calculate the elemental analysis, the
following calculation must be performed, in which molar masssub is the
molecular mass of the fragment being substituted (e.g., Cl in the case of
Merrifield resin), and molar massadd is the molecular mass of the frag-
2.70; loading: 0.611 mmolgꢀ1
.
Triethylammonium 2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-chloro-
benzoate 3{4}: IR (KBr): n˜ =3456 (w, br, ps), 3026 (s, ps), 2923 (s, ps),
2870 (s, ps), 1943 (m, ps), 1872 (m, ps), 1803 (m, ps), 1741 (s), 1601 (s,
ps), 1493 (s, ps), 1452 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C95H101N4O2Cl: C 83.52, H 7.45, N 4.09; found: C 85.78, H 7.42, N 2.64;
loading: 0.555 mmolgꢀ1
.
Triethylammonium 2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-methyl-
benzoate 3{5}: IR (KBr): n˜ =3465 (w, br, ps), 3026 (s, ps), 2916 (s, ps),
2850 (s, ps), 1943 (m, ps), 1872 (m, ps), 1803 (m, ps), 1737 (s), 1601 (s,
ps), 1493 (s, ps), 1452 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C96H104N4O2: C 85.74, H 7.71, N 4.15; found: C 87.70, H 7.59, N 2.33;
loading: 0.460 mmolgꢀ1
.
Triethylammonium 2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-3-methyl-
benzoate 3{6}: IR (KBr): n˜ =3449 (w, br, ps), 3026 (s, ps), 2924 (s, ps),
2850 (s, ps), 1943 (m, ps), 1871 (m, ps), 1803 (m, ps), 1736 (s), 1602 (s,
ps), 1493 (s, ps), 1451 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C107H115N4O2: C 86.32, H 7.78, N 3.75; found: C 87.71, H 7.42, N 2.02;
loading: 0.390 mmolgꢀ1
.
Triethylammonium
2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-3,5-di-
chlorobenzoate 3{7}: IR (KBr): n˜ =3450 (w, br, ps), 3025 (s, ps), 2914 (s,
ps), 2850 (s, ps), 1944 (m, ps), 1871 (m, ps), 1802 (m, ps), 1736 (s), 1601
(s, ps), 1493 (s, ps), 1450 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C106H111N4O2Cl2: C 82.48, H 7.24, N 3.62; found: C 83.62, H 6.85, N 2.87;
loading: 0.631 mmolgꢀ1
.
General procedure for amine coupling (5{1–7,1} and 5{1,2}): Resin 3{1–7}
(1 equiv) and 2-chloro-1-methylpyridinium iodide (2 equiv) were sus-
pended in CH2Cl2 (80 mL), and then 20 equiv of NEt3 were added. The
corresponding amine 4{1–2} (3 equiv) was added after 15 min. The result-
ing mixture was stirred overnight at RT. The resin 5 was filtered off,
washed sequentially with THF, Et2O, MeOH, DMF, THF, CH2Cl2, metha-
nol, and pentane, and then dried under high vacuum.
ꢀ
ment being added (e.g., HN CH2Ph in case of resin 2):
1000
molar massnew
¼
ꢀðmolar masssubꢀmolar massaddÞ
loadingold
All resins were washed sequentially by using a vacuum reservoir connect-
ed to a sintered glass frit. Cleavage was conducted using a glass pipette
filled with glass wool. Evaporation of the solvent was achieved by using a
rotary vaporizer and/or a high vacuum (ca. 0.1 mbar). All solvents were
dried by usual methods and distilled under argon.
Methyl ester of (2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoylami-
nomethyl)acetic acid 5{1,1}: IR (KBr): n˜ =3647 (w, br, ps), 3467 (s, ps),
3025 (s, ps), 2934 (s, ps), 2800 (s, ps), 1944 (m, ps), 1872 (m, ps), 1804 (m,
ps), 1753 (s), 1650 (s), 1601 (s, ps), 1493 (s, ps), 1453 cmꢀ1 (s, ps); elemen-
tal analysis calcd (%) for C115H116N4O3: C 86.25, H 7.30, N 3.74; found: C
General washing procedure: Three times with (methanol, THF, pentane,
dichloromethane), once with (methanol, DMF, pentane, THF), and twice
with (pentane, dichloromethane, pentane).
85.49, H 7.71, N 2.62; loading: 0.537 mmolgꢀ1
.
Methyl ester of (2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-bromoben-
zoylaminomethyl)acetic acid 5{2,1}: IR (KBr): n˜ =3647 (w, br, ps), 3479
(s, ps), 3024 (s, ps), 2921 (s, ps), 2790 (s, ps), 1944 (m, ps), 1874 (m, ps),
1804 (m, ps), 1753 (s), 1654 (s), 1601 (s, ps), 1492 (s, ps), 1451 cmꢀ1 (s,
ps); elemental analysis calcd (%) for C137H137N4O3Br: C 83.65, H 7.02, N
General procedure for the synthesis of triazene resin T1 (3):[31] The an-
thranilic acid derivatives 1 (26.5 mmol, 5 equiv) were dissolved in THF
(50 mL) and cooled to ꢀ108C. BF3·Et2O (13.2 mL, 53 mmol, 10 equiv)
and isoamyl nitrite (7.5 mL, 53 mmol, 10 equiv) were added dropwise
under stirring for 5–15 min. The reaction mixture was stirred at ꢀ108C
for 1 h and then diluted with pyridine (25 mL) and DMF (25 mL). Ben-
zylamine resin 2 (5.0 g, 4.5 mmol, 1 equiv) was added and the resulting
mixture stirred at RT for 1 h. Resin 3 was filtered off, washed sequential-
ly with pyridine/DMF (1:1), THF/NEt3 (1:1), MeOH/NEt3 (1:1), DMF,
2.84; found: C 82.48, H 7.03, N 3.35; loading: 0.772 mmolgꢀ1
.
Methyl ester of (2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-iodoben-
zoylaminomethyl)acetic acid 5{3,1}: IR (KBr): n˜ =3646 (w, br, ps), 3465
(s, ps), 3026 (s, ps), 2923 (s, ps), 2849 (s, ps), 1944 (m, ps), 1873 (m, ps),
1803 (m, ps), 1754 (s), 1650 (s), 1602 (s, ps), 1493 (s, ps), 1451 cmꢀ1 (s,
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C. Gil and S. Brꢂse
ps); elemental analysis calcd (%) for C140H140N4O3I: C 81.94, H 6.87, N
2.71; found: C 80.70, H 7.29, N 3.17; loading: 0.744 mmolgꢀ1
0.3H; anti-H-6), 7.56 (d, J(H6,H4)=2.0 Hz, 0.7H; syn-H-6), 7.63 (dd,
0.3H; anti-H-4), 7.65 ppm (dd, 0.7H; syn-H-4); 13C NMR (100 MHz,
CDCl3): d=34.1 (anti-NCH3), 37.5 (syn-NCH3), 48.5 (syn-NCH2), 52.3
(syn-OCH3), 52.4 (anti-NCH2), 52.4 (anti-OCH3), 88.2 (C-5), 120.4, 137.0,
139.4, (Ar-C), 129.6 (anti-C-2), 129.8 (syn-C-2), 136.3 (anti-C-1), 136.4
(syn-C-1), 167.0 (anti-CON), 167.3 (syn-CON), 169.0 (anti-COOCH3),
169.0 ppm (syn-COOCH3); EI-HRMS: m/z calcd for C11H11N4O3I:
373.9876; found: 373.9876; MS (EI): m/z (%): 374 (12) [M+], 272 (100);
yield: 62%.
.
Methyl ester of (2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-chloroben-
zoylaminomethyl)acetic acid 5{4,1}: IR (KBr): n˜ =3646 (w, br, ps), 3026
(s, ps), 2924 (s, ps), 2800 (s, ps), 1944 (m, ps), 1873 (m, ps), 1804 (m, ps),
1754 (s), 1657 (s), 1601 (s, ps), 1493 (s, ps), 1451 cmꢀ1 (s, ps); elemental
analysis calcd (%) for C153H153N4O3Cl: C 86.24, H 7.23, N 2.61; found: C
84.23, H 7.22, N 3.15; loading: 0.691 mmolgꢀ1
.
Methyl ester of (2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-5-methylben-
zoylaminomethyl)acetic acid 5{5,1}: IR (KBr): n˜ =3650 (w, br, ps), 3465
(s, ps), 3024 (s, ps), 2923 (s, ps), 2850 (s, ps), 1944 (m, ps), 1873 (m, ps),
1803 (m, ps), 1754 (s), 1650 (s), 1601 (s, ps), 1493 (s, ps), 1451 cmꢀ1 (s,
ps); elemental analysis calcd (%) for C183H185N4O3: C 88.33, H 7.49, N
N-(2-Azido-5-chlorobenzoyl)-N-methylglycine methyl ester 6{4,1}: Rf: 0.2
(Cyclohexane/AcOEt 3:1); 1H NMR (400 MHz, CDCl3): d=2.82 (s,
2.0H; syn-NCH3), 3.06 (s, 1.0H; anti-NCH3), 3.65 (s, 1.0H; anti-
COOCH3), 3.71 (s, 2.0H; syn-COOCH3), 3.80 (m, 0.7H; anti-NCH2),
4.21 (brs, 1.3H; syn-NCH2), 7.03 (d, J(H3,H4)=8.4 Hz, 0.3H; anti-H-3),
7.06 (d, J(H3,H4)=8.4 Hz, 0.7H; syn-H-3), 7.18 (d, J(H6,H4)=2.4 Hz,
0.3H; anti-H-6), 7.24 (d, J(H6,H4)=2.4 Hz, 0.7H; syn-H-6), 7.30 (dd,
0.3H; anti-H-4), 7.32 ppm (dd, 0.7H; syn-H-4); 13C NMR (100 MHz,
CDCl3): d=34.1 (anti-NCH3), 37.4 (syn-NCH3), 48.5 (syn-NCH2), 52.2
(syn-OCH3), 52.3 (anti-NCH2), 52.4 (anti-OCH3), 119.9, 128.3, 130.7 (Ar-
C), 129.0 (anti-C-2), 129.2 (syn-C-2), 130.59 (syn-C-5), 130.61 (anti-C-5),
135.0 (anti-C-1), 135.1 (syn-C-1), 167.3 (anti-CON), 167.5 (syn-CON),
168.9 (anti-COOCH3), 169.0 ppm (syn-COOCH3); EI-HRMS: m/z calcd
for C11H11N4O3Cl: 282.0520; found: 282.0527; MS (EI): m/z (%): 282/284
(12) [M+], 180/182 (100); yield: 44%.
2.24; found: C 87.70, H 7.59, N 2.33; loading: 0.460 mmolgꢀ1
.
Methyl ester of (2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-3-methylben-
zoylaminomethyl)acetic acid 5{6,1}: IR (KBr): n˜ =3648 (w, br, ps), 3444
(s, ps), 3029 (s, ps), 2847 (s, ps), 1944 (m, ps), 1872 (m, ps), 1804 (m, ps),
1755 (s), 1651 (s), 1602 (s, ps), 1495 (s, ps), 1455 cmꢀ1 (s, ps); elemental
analysis calcd (%) for C213H215N4O3: C 88.86, H 7.52, N 1.94; found: C
87.15, H 7.92, N 2.45; loading: 0.505 mmolgꢀ1
.
Methyl ester of (2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)-3,5-dichloro-
benzoylaminomethyl)-acetic acid 5{7,1}: IR (KBr): n˜ =3646 (w, br, ps),
3027 (s, ps), 2914 (s, ps), 2850 (s, ps), 1944 (m, ps), 1873 (m, ps), 1804 (m,
ps), 1755 (s), 1658 (s), 1602 (s, ps), 1494 (s, ps), 1452 cmꢀ1 (s, ps); elemen-
tal analysis calcd (%) for C137H136N4O3 Cl2: C 84.06, H 7.00, N 2.86;
N-(2-Azido-5-methylbenzoyl)-N-methylglycine methyl ester 6{5,1}: Rf: 0.1
(Cyclohexane/AcOEt 3:1); 1H NMR (400 MHz, CDCl3): d=2.22 (s,
1.0H; anti-CH3), 2.26 (s, 2.0H; syn-CH3), 2.48 (s, 2.0H; syn-NCH3), 3.07
(s, 1.0H; anti-NCH3), 3.63 (s, 1.0H; anti-COOCH3), 3.71 (s, 2.0H; syn-
COOCH3), 3.82 (m, 0.7H; anti-NCH2), 4.22 (brs, 1.3H; syn-NCH2), 6.97–
7.17 ppm (m, 3Ar-H); 13C NMR (100 MHz, CDCl3): d=20.6 (syn-CH3),
20.6 (anti-CH3), 33.9 (anti-NCH3), 37.5 (syn-NCH3), 48.4 (syn-NCH2),
52.1 (syn-OCH3), 52.2 (anti-OCH3), 52.4 (anti-NCH2), 118.3, 128.7, 131.2
(Ar-C), 127.5 (anti-C-2), 127.7 (syn-C-2), 133.5 (anti-C-5), 133.6 (syn-
C-5), 135.1 (syn-C-1), 135.2 (anti-C-1), 169.0 (anti-CON), 169.2 (syn-
CON), 169.2 (anti-COOCH3), 169.3 ppm (syn-COOCH3); EI-HRMS:
m/z calcd for C12H14N4O3: 262.1066; found: 262.1067; MS (EI): m/z (%):
262 (12) [M+], 161 (100); yield: 25%.
found: C 81.64, H 7.43, N 3.13; loading: 0.700 mmolgꢀ1
(2-(3-Benzyl-3-polystyrylmethyl-1-triazenyl)benzoyl-l-proline
.
methyl
ester 5{1,2}: IR (KBr): n˜ =3647 (w, br, ps), 3464 (s, ps), 3026 (s, ps), 2913
(s, ps), 2847 (s, ps), 1944 (m, ps), 1872 (m, ps), 1803 (m, ps), 1748 (s),
1644 (s), 1601 (s, ps), 1493 (s, ps), 1452 cmꢀ1 (s, ps); elemental analysis
calcd (%) for C156H157N4O3: C 87.74, H 7.41, N 2.61; found: C 86.41, H
8.13, N 2.67; loading: 0.551 mmolgꢀ1
.
General procedure for the generation of azides (6{1–7,1} and 6{1,2}): The
corresponding resin 5 was suspended in 5% TFA/CH2Cl2 at RT. After 5–
10 min, the mixture was filtered and trimethylsilylazide was added. The
solvents and the remnants of TFA and trimethylsilylazide were removed
by evaporation. The residue was purified by using flash chromatography,
eluting with a 3:1 cyclohexane/AcOEt system.
N-(2-Azido-3-methylbenzoyl)-N-methylglycine methyl ester 6{6,1}: Rf: 0.3
(Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=2.25 (s,
1.0H; anti-CH3), 2.28 (s, 2.0H; syn-CH3), 2.89 (s, 2.0H; syn-NCH3), 3.08
(s, 1.0H; anti-NCH3), 3.65 (s, 1.0H; anti-COOCH3), 3.72 (s, 2.0H; syn-
COOCH3), 3.88 (m, 0.7H; anti-NCH2), 4.25 (brs, 1.3H; syn-NCH2), 6.98–
7.14 ppm (m, 3Ar-H); 13C NMR (100 MHz, CDCl3): d=17.9 (syn-CH3),
17.9 (anti-CH3), 33.8 (anti-NCH3), 37.7 (syn-NCH3), 48.4 (syn-NCH2),
52.2 (syn-OCH3), 52.3 (anti-OCH3), 52.6 (anti-NCH2), 125.6, 125.9, 132.1
(Ar-C), 129.3 (anti-C-2), 129.8 (syn-C-2), 132.4 (syn-C-5), 132.4 (anti-
C-5), 134.3 (anti-C-1), 134.4 (syn-C-1), 169.0 (anti-CON), 169.1 (syn-
CON), 169.2 (syn-COOCH3), 169.2 ppm (anti-COOCH3); EI-HRMS:
m/z calcd for C12H14N4O3: 262.1066; found: 262.1065; MS (EI): m/z (%):
262 (4), [M+], 161 (100); yield: 21%.
N-(2-Azidobenzoyl)-N-methylglycine methyl ester 6{1,1}: Rf: 0.2 (Cyclo-
hexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=2.84 (s, 2.0H; syn-
NCH3), 3.08 (s, 1.0H; anti-NCH3), 3.63 (s, 1.0H; anti-COOCH3), 3.72 (s,
2.0H; syn-COOCH3), 3.80 (m, 0.7H; anti-NCH2), 4.23 (brs, 1.3H; syn-
NCH2), 7.50–7.12 ppm (m, 4Ar-H); 13C NMR (100 MHz, CDCl3): d=34.0
(anti-NCH3), 37.5 (syn-NCH3), 48.5 (syn-NCH2), 52.2 (syn-OCH3), 52.2
(anti-OCH3), 52.4 (anti-NCH2), 118.5, 125.1, 128.3, 130.6 (Ar-C), 127.7
(anti-C-2), 127.9 (syn-C-2), 136.3 (anti-C-1), 136.5 (syn-C-1), 169.1 (anti-
COOCH3), 169.2 ppm (syn-COOCH3); EI-HRMS: m/z calcd for
C11H12N4O3: 248.0909; found: 248.0915; MS (EI): m/z (%): 248 (12)
[M+], 147 (100); yield: 32%.
N-(2-Azido-5-bromobenzoyl)-N-methylglycine methyl ester 6{2,1}: Rf: 0.2
(Cyclohexane/AcOEt 3:1); 1H NMR (400 MHz, CDCl3): d=2.85 (s,
2.0H; syn-NCH3), 3.06 (s, 1.0H; anti-NCH3), 3.66 (s, 1.0H; anti-
COOCH3), 3.72 (s, 2.0H; syn-COOCH3), 3.80 (m, 0.7H; anti-NCH2),
4.20 (brs, 1.3H; syn-NCH2), 6.96–7.48 ppm (m, 3Ar-H); 13C NMR
(100 MHz, CDCl3): d=34.1 (anti-NCH3), 37.0 (syn-NCH3), 48.5 (syn-
NCH2), 52.2 (syn-OCH3), 52.3 (anti-NCH2), 52.4 (anti-OCH3), 117.9 (syn-
C-5), 118.0 (anti-C-5) 120.1, 131.1, 133.5, (Ar-C), 129.3 (anti-C-2), 129.5
(syn-C-2), 135.5 (anti-C-1), 135.7 (syn-C-1), 167.1 (anti-CON), 167.4 (syn-
CON), 168.9 (anti-COOCH3), 169.0 ppm (syn-COOCH3); EI-HRMS:
m/z calcd for C11H11N4O3Br: 326.0015; found: 326.0016; MS (EI): m/z
(%): 326/328 (8) [M+], 224/226 (100); yield: 46%.
N-(2-Azido-3,5-dichlorobenzoyl)-N-methylglycine methyl ester 6{7,1}: Rf:
0.4 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=2.87 (s,
2.0H; syn-NCH3), 3.07 (s, 1.0H; anti-NCH3), 3.67 (s, 1.0H; anti-
COOCH3), 3.72 (s, 2.0H; syn-COOCH3), 3.82 (m, 0.7H; anti-NCH2),
4.20 (brs, 1.3H; syn-NCH2), 7.08 (d, J=2.4 Hz, 0.3H; anti-H-4), 7.15 (d,
J=2.4 Hz, 0.7H; syn-H-4), 7.32 (d, 0.3H; anti-H-6), 7.35 ppm (d, J=
2.4 Hz, 0.7H; syn-H-6); 13C NMR (100 MHz, CDCl3): d=34.0 (anti-
NCH3), 37.5 (syn-NCH3), 48.5 (syn-NCH2), 52.3 (anti-NCH2), 52.3 (syn-
OCH3), 52.5 (anti-OCH3), 126.5, 131.1, 131.2, 131.5, 132.3 (Ar-C), 129.6
(anti-C-2), 129.7 (syn-C-2), 166.4 (anti-CON), 166.7 (syn-CON), 168.7
(anti-COOCH3), 168.8 ppm (syn-COOCH3); EI-HRMS: m/z calcd for
C11H10N4O3Cl2: 316.0130; found: 316.0129; MS (EI): m/z (%): 316/318 (4)
[M+], 215/217 (100); yield: 27%.
N-(2-Azido-5-iodobenzoyl)-N-methylglycine methyl ester 6{3,1}: Rf: 0.3
(Cyclohexane/AcOEt 3:1); 1H NMR (400 MHz, CDCl3): d=2.85 (s,
2.0H; syn-NCH3), 3.07 (s, 1.0H; anti-NCH3), 3.67 (s, 1.0H; anti-
COOCH3), 3.72 (s, 2.0H; syn-COOCH3), 3.80 (m, 0.7H; anti-NCH2),
4.20 (brs, 1.3H; syn-NCH2), 6.85 (d, J(H3,H4)=8.3 Hz, 0.3H; anti-H-3),
6.88 (d, J(H3,H4)=8.3 Hz, 0.7H; syn-H-3), 7.50 (d, J(H6,H4)=2.0 Hz,
N-(2-Azidobenzoyl)-l-proline methyl ester 6{1,2}: Rf: 0.1 (Cyclohexane/
AcOEt 2:1); [a]20 =ꢀ84.66 (CHCl3); 1H NMR (400 MHz, CDCl3): d=
1.78–2.30 (m, 4H; CH2CH2), 3.21–3.34 (m, 2H; NCH2), 3.44 (s, 0.75H;
anti-COOCH3), 3.72 (s, 2.25H; syn-COOCH3), 4.12 (dd, J=2.6, 8.2 Hz,
0.25H; anti-NCH), 4.61 (dd, J=3.9, 8.2 Hz, 0.75H; syn-NCH), 7.03–
2684
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2680 – 2688

Benzodiazepinone Derivatives
FULL PAPER
7.38 ppm (m, 4Ar-H); 13C NMR (100 MHz, CDCl3): d=22.9 (anti-CH2),
24.7 (syn-CH2), 29.5 (syn-CH2), 31.2 (anti-CH2), 46.3 (anti-NCH2), 48.3
(syn-NCH2), 52.1 (anti-OCH3), 52.2 (syn-OCH3), 58.4 (syn-NCH), 60.3
(anti-NCH), 118.5, 125.0, 128.2, 130.5 (Ar-C), 128.8 (anti-C-2), 129.1 (syn-
C-2), 136.3 (C-1), 166.9 (syn-CON), 167.1 (anti-CON), 172.4 ppm
(COOCH3); EI-HRMS: m/z calcd for C14H15N3O3: 274.0676; found:
274.1068; MS (EI): m/z (%): 274 (8) [M+], 187 (100); yield: 12%.
3,4-Dihydro-2-methoxy-4-methyl-5,9-dichloro-1,4-benzodiazepin-5(5H)-
one 7{7,1}: Rf: 0.1 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz,
CDCl3): d=3.15 (s, 3H; NCH3), 3.69 (s, 2H; CH2), 3.91 (s, 3H; OCH3),
7.47 (d, J=2.5 Hz, 1H; H-8), 7.75 ppm (d, 1H; H-6); 13C NMR
(100 MHz, CDCl3): d=36.6 (NCH3), 48.4 (CH2), 55.0 (OCH3), 128.8,
129.1, 129.6, 129.8, 131.9 (Ar-C), 140.4 (C-9a), 163.0 (COCH3), 165.7 ppm
(CO); EI-HRMS: m/z calcd for C11H10N2O2Cl2: 272.0119; found:
272.0115; MS (EI): m/z (%): 272/274 (100), [M+]; purity: 94% (by GC);
yield: 99%.
General procedure for the synthesis of 1,4-benzodiazepin-5-ones
(7{1–7,1} and 7{1,2}): The triphenylphosphine polystyrene (4 equiv) was
distended with dry toluene (8 mL) in a glass vial and was sealed under
argon. A solution of the corresponding azide 6 (1 equiv) in dry toluene
was injected into the suspension. The reaction mixture was shaken at RT
for 1 h, and then heated at 1008C for 3 and 18 h for 6{1–7,1} and 6{1,2},
respectively. After cooling, the resin was separated by filtration and
washed with dichloromethane. The filtrate was concentrated until dry to
give the benzodiazepines 7{1–7,1} and 7{1,2}.
11-Methoxy-1,2,3,11a-tetrahydro-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5-
one 7{1,2}: Rf: 0.1 (Cyclohexane/AcOEt 2:1); [a]20 =+524 (CHCl3);
1H NMR (400 MHz, CDCl3): d=1.93–1.97 (m, 4H; CH2CH2), 3.40–3.49
(m, 2H; NCH2), 3.82 (s, 3H; OCH3), 3.90–3.92 (m, 1H; NCH), 7.07–7.14
(m, 2Ar-H), 7.37 (t, J=1.6, 7.1 Hz, 1H), 7.92 ppm (dd, J=1.3, 7.9 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=23.9, 26.5 (CH2CH2), 46.8
(NCH2), 54.4 (OCH3), 54.4 (NCH), 124.1, 126.4, 130.2, 131.5 (Ar-C),
127.4 (C-5a), 144.1 (C-9a), 162.3 (COCH3), 165.7 ppm (CO); EI-HRMS:
m/z calcd for C13H14N2O2: 230.1055; found: 230.1057; MS (EI): m/z (%):
230 (88) [M+], 145 (100); purity: 83% (by GC); yield: 99%.
3,4-Dihydro-2-methoxy-4-methyl-1,4-benzodiazepin-5(5H)-one 7{1,1}: Rf:
0.02 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=3.20 (s,
3H, NCH3), 3.67 (s, 2H; CH2), 3.84 (s, 3H; OCH3), 6.90–7.87 ppm (m,
4Ar-H); 13C NMR (100 MHz, CDCl3): d=36.4 (NCH3), 48.3 (CH2), 54.4
(OCH3), 120.5 (C-5a), 124.3, 126.0, 130.7, 131.5 (Ar-C), 144.7 (C-9a),
162.8 (COCH3), 167.8 ppm (CO); MS (EI): m/z (%): 204 (8) [M+], 190
(100); purity: 68% (by GC); yield: 68%.
General procedure for the reductive amination (4{3–8}): The methyl
ester hydrochlorides of the amino acids (1.5 equiv) were dissolved in
MeOH and cooled to 08C. Triethylamine (1.5 equiv) was added to this
solution, then the reaction mixture was stirred for 10 min and allowed to
warm up to room temperature. The aldehydes (1 equiv) were added and
the reaction mixtures were stirred for 12 h at room temperature. The sol-
utions were cooled to 08C and NaBH4 (2 equiv) was added portionwise
to the reaction mixtures over a period of 30 min. After stirring for 2 h at
08C and for 1 h at room temperature, the reaction mixtures were acidi-
fied with 10% aqueous NaHSO4 and ether was added (25 mL). The
phases were then separated. The organic phases were washed with 10%
aqueous NaHSO4 and the combined aqueous layers were carefully neu-
tralized with solid sodium carbonate. The latter were extracted with
ether (3ꢄ10 mL). The combined ether layers were dried over sodium sul-
fate and evaporated to achieve the amines 4{3–8}.
3,4-Dihydro-2-methoxy-4-methyl-7-bromo-1,4-benzodiazepin-5(5H)-one
7{2,1}: Rf: 0.2 (Cyclohexane/AcOEt 4:3); 1H NMR (400 MHz, CDCl3):
d=3.14 (s, 3H; NCH3), 3.67 (s, 2H; CH2), 3.83 (s, 3H; OCH3), 6.95 (d, J-
(H9,H8)=8.4 Hz, 1H; H-9), 7.45 (dd, 1H; H-8), 7.98 ppm (d, J-
(H6,H8)=2.5 Hz, 1H; H-6); 13C NMR (100 MHz, CDCl3): d=36.5
(NCH3), 48.3 (CH2), 54.6 (OCH3), 117.4 (C-7), 128.0, 133.3, 134.5 (Ar-C),
129.0 (C-5a), 143.8 (C-9a), 163.0 (COCH3), 166.5 ppm (CO); MS (EI):
m/z (%): 282/284 (100) [M+]; purity: 83% (by GC); yield: 99%.
3,4-Dihydro-2-methoxy-4-methyl-7-iodo-1,4-benzodiazepin-5(5H)-one
7{3,1}: Rf: 0.3 (Cyclohexane/AcOEt 4:3); 1H NMR (400 MHz, CDCl3):
d=3.14 (s, 3H; NCH3), 3.66 (s, 2H; CH2), 3.83 (s, 3H; OCH3), 6.82 (d, J-
(H9,H8)=8.4 Hz, 1H; H-9), 7.64 (dd, 1H; H-8), 8.16 ppm (d, J-
(H6,H8)=2.0 Hz, 1H; H-6); 13C NMR (100 MHz, CDCl3): d=36.5
(NCH3), 48.4 (CH2), 54.6 (OCH3), 88.1 (C-7), 128.1, 139.3, 140.3 (Ar-C),
129.3 (C-5a), 144.4 (C-9a), 163.1 (COCH3), 166.3 ppm (CO); MS (EI):
m/z (%): 330 (100) [M+]; purity: 88% (by GC); yield: 93%.
Methyl ester of (4-methoxybenzylamino)acetic acid 4{3}: Rf: 0.1 (Cyclo-
hexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=2.97 (brs, 1H;
NH), 3.35 (s, 2H; NCH2COOMe), 3.64 (s, 3H; OCH3), 3.70 (s, 2H;
PhCH2N), 3.71 (s, 3H; COOCH3), 6.78 (d, J=8.7 Hz, 2H; Ar-H),
7.17 ppm (d, 2H; Ar-H); 13C NMR (100 MHz, CDCl3): d=49.2
(NCH2COOMe), 51.8 (COOCH3), 52.3 (PhCH2N), 55.2 (OCH3), 113.9,
129.6, 130.5, 158.9 (Ar-C), 172.6 ppm (COOCH3); EI-HRMS: m/z calcd
for C11H15NO3: 209.1052; found: 209.1047; MS (EI): m/z (%): 209 (4),
[M+], 121 (100); purity: 94% (by GC); yield: 85%.
3,4-Dihydro-2-methoxy-4-methyl-7-chloro-1,4-benzodiazepin-5(5H)-one
7{4,1}: Rf: 0.3 (Cyclohexane/AcOEt 4:3); 1H NMR (400 MHz, CDCl3):
d=3.14 (s, 3H; NCH3), 3.67 (s, 2H; CH2), 3.83 (s, 3H; OCH3), 7.02 (d, J-
(H9,H8)=8.4 Hz, 1H; H-9), 7.31 (dd, 1H; H-8), 7.83 ppm (d, J-
(H6,H8)=2.4 Hz, 1H; H-6); 13C NMR (100 MHz, CDCl3): d=36.4
(NCH3), 48.3 (CH2), 54.6 (OCH3), 127.7, 130.6, 131.6 (Ar-C), 128.7 (C-7),
129.8 (C-5a), 143.3 (C-9a), 163.0 (COCH3), 166.6 ppm (CO); MS (EI):
m/z (%): 238/240 (90) [M+], 180/182 (100); purity: 83% (by GC); yield:
99%.
Methyl ester of (3,4-dimethoxybenzylamino)acetic acid 4{4}: Rf: 0.1 (Cy-
clohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=1.77 (brs, 1H;
NH), 3.34 (s, 2H; NCH2COOMe), 3.66 (s, 3H; COOCH3), 3.67 (s, 2H;
PhCH2N), 3.79 (s, 3H; OCH3), 3.81 (s, 3H; OCH3), 6.73–6.83 ppm (m,
3H; Ar-H); 13C NMR (100 MHz, CDCl3): d=49.8 (NCH2COOMe), 51.7
(COOCH3), 53.1 (PhCH2N), 55.9 (OCH3), 55.9 (OCH3), 111.1, 111.5,
120.4, 132.0, 148.3, 149.1 (Ar-C), 172.9 ppm (COOCH3); EI-HRMS: m/z
calcd for C12H17NO4: 239.1158; found: 239.1159; MS (EI): m/z (%): 239
(12) [M+], 151 (100); purity: 93% (by GC); yield: 33%.
3,4-Dihydro-2-methoxy-4,7-dimethyl-1,4-benzodiazepin-5(5H)-one 7{5,1}:
Rf: 0.2 (Cyclohexane/AcOEt 4:3); 1H NMR (400 MHz, CDCl3): d=2.29
(s, 3H; CH3), 3.14 (s, 3H; NCH3), 3.66 (s, 2H; CH2), 3.82 (s, 3H; OCH3),
6.97 (d, J(H9,H8)=8.0 Hz, 1H; H-9), 7.17 (dd, 1H; H-8), 7.66 ppm (d, J-
(H6,H8)=1.7 Hz, 1H; H-6); 13C NMR (100 MHz, CDCl3): d=20.7
(CH3), 36.3 (NCH3), 48.4 (CH2), 54.3 (OCH3), 126.0, 130.7, 132.5 (Ar-C),
127.1 (C-5a), 134.0 (C-7), 142.4 (C-9a), 162.5 (COCH3), 168.0 ppm (CO);
MS (EI): m/z (%): 218 (68) [M+], 160 (100); purity: 72% (by GC);
yield: 98%.
Methyl ester of (4-phenylbenzylamino)acetic acid 4{5}: Rf: 0.1 (Cyclohex-
ane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=2.06 (brs, 1H; NH),
3.37 (s, 2H; NCH2COOMe), 3.65 (s, 3H; COOCH3), 3.76 (s, 2H;
PhCH2N), 7.22–7.51 ppm (m, 9H; Ar-H); 13C NMR (100 MHz, CDCl3):
d=49.9 (NCH2COOMe), 51.7 (COOCH3), 52.9 (PhCH2N), 127.0, 127.2,
128.7, 128.7, 138.5, 140.2, 140.9 (Ar-C), 172.8 ppm (COOCH3); EI-
HRMS: m/z calcd for C16H17NO2: 255.1259; found: 255.1256; MS (EI):
m/z (%): 255 (8) [M+], 167 (100); purity: 97% (by GC); yield: 64%.
3,4-Dihydro-2-methoxy-4,9-methyl-1,4-benzodiazepin-5(5H)-one 7{6,1}:
Rf: 0.04 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=2.26
(s, 3H; CH3), 3.15 (s, 3H; NCH3), 3.66 (s, 2H; CH2), 3.85 (s, 3H; OCH3),
7.02 (t, J=7.5 Hz, 1H; H-7), 7.24 (d, 1H; H-8), 7.69 ppm (d, 1H; H-6);
13C NMR (100 MHz, CDCl3): d=18.4 (CH3), 36.3 (NCH3), 48.3 (CH2),
54.2 (OCH3), 124.0, 128.4, 132.6 (Ar-C), 127.5 (C-5a), 133.4 (C-7), 143.1
(C-9a), 161.2 (COCH3), 168.2 ppm (CO); MS (EI): m/z (%): 218 (100)
[M+]; EI-HRMS: m/z calcd for C12H14N2O2: 218.1055; found: 218.1056;
purity: 74% (by GC); yield: 93%.
Methyl ester of benzylaminoacetic acid 4{6}: Rf: 0.2 (Cyclohexane/AcOEt
2:1); 1H NMR (400 MHz, CDCl3): d=2.34 (brs, 1H; NH), 3.35 (s, 2H;
NCH2COOMe), 3.65 (s, 3H; COOCH3), 3.74 (s, 2H; PhCH2N), 7.21–
7.36 ppm (m, 5H; Ar-H); 13C NMR (100 MHz, CDCl3): d=49.8
(NCH2COOMe), 51.7 (COOCH3), 53.2 (PhCH2N), 127.2, 128.3, 128.4,
139.2 (Ar-C), 172.7 ppm (COOCH3); MS (EI): m/z (%): 179 (4) [M+], 91
(100); EI-HRMS: m/z calcd for C10H13NO2: 179.0946; found: 179.0946;
purity: 53% (by GC), yield: 43%.
Chem. Eur. J. 2005, 11, 2680 – 2688
www.chemeurj.org
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2685

C. Gil and S. Brꢂse
Methyl ester of 2-(4-methoxybenzylamino)propionic acid 4{7}: Rf: 0.3
(Cyclohexane/AcOEt 2:1); [a]20 =ꢀ2.68 (CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.23 (d, J=7.1 Hz, 3H; CH3), 2.33 (brs, 1H; NH), 3.31 (c,
1H; CH), 3.64 (s, 3H; OCH3), 3.64 (s, 2H; PhCH2N), 3.70 (s, 3H;
COOCH3), 6.76 (d, J=8.7 Hz, 2H; Ar-H), 7.16 ppm (d, 2H; Ar-H);
13C NMR (100 MHz, CDCl3): d=18.96 (CH3), 51.2 (PhCH2N), 51.7
(COOCH3), 55.2 (CH), 55.7 (OCH3), 113.8, 129.5, 131.6, 158.8 (Ar-C),
176.0 ppm (COOCH3); EI-HRMS: m/z calcd for C12H17NO3: 223.12;
found: 223.12; MS (EI): m/z (%): 223 (4) [M+], 121 (100); purity: 97%
(by GC); yield: 37%.
the remnants of TFA and trimethylsilylazide were removed by evapora-
tion. The residue was purified by performing flash chromatography, elut-
ing with a 3:1 cyclohexane/AcOEt system.
Methyl ester of [(2-azidobenzoyl)(4-methoxybenzyl)amino]acetic acid
6{1,3}: Rf: 0.3 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3):
d=3.56, 3.68, 3.72, 3.74 (8Aliph-H), 4.30 (s, 2H; NCH2Ph), 6.77–
7.39 ppm (m, 8Ar-H); 13C NMR (100 MHz, CDCl3): d=45.1 (syn-
NCH2Ph), 48.1 (anti-NCH2Ph), 48.7 (anti-CH2COOCH3), 52.1 (anti-
COOCH3), 52.2 (syn-COOCH3), 52.8 (syn-CH2COOCH3), 55.3 (OCH3),
114.1, 114.2, 118.4, 118.7, 125.1, 125.1, 128.2, 128.2, 129.1, 129.8, 130.6,
130.7, 136.3, 136.8, 159.3, 159.4 (Ar-C), 162.3 (syn-COOCH3), 169.0 (anti-
COOCH3), 169.3 (syn-NCO), 169.3 ppm (anti-NCO); yield: 55%.
Methyl ester of 2-(4-methoxybenzylamino)-3-phenylpropionic acid 4{8}:
Rf: 0.2 (Cyclohexane/AcOEt 2:1); [a]20 =ꢀ0.07 (CHCl3); 1H NMR
(400 MHz, CDCl3): d=2.84 (brs, 1H; NH), 2.88 (d, J=6.9 Hz, 2H;
CHCH2Ph), 3.45 (t, 1H; CH), 3.52 (s, 3H; OCH3), 3.52 (s, 2H;
PhCH2N), 3.65 (s, 3H; COOCH3), 6.69–7.19 ppm (m, 9H; Ar-H);
13C NMR (100 MHz, CDCl3): d=39.5 (CHCH2Ph), 51.3 (PhCH2N), 51.6
(COOCH3), 61.8 (CH), 55.2 (OCH3), 113.8, 126.7, 128.4, 129.2, 129.5,
131.1, 137.2, 158.8 (Ar-C), 174.6 ppm (COOCH3); EI-HRMS: m/z calcd
for C18H21NO3: 299.1521; found: 299.1506; MS (EI): m/z (%): 299 (4)
[M+], 121 (100); purity: 98% (by GC); yield: 64%.
Methyl ester of [(2-azidobenzoyl)(3,4-dimethoxybenzyl)amino]acetic acid
6{1,4}: Rf: 0.2 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3):
d=3.56, 3.68, 3.78, 3.81, 3.83 (11Aliph-H), 4.30 (s, 2H; NCH2Ph), 6.64–
7.38 ppm (m, 7Ar-H); 13C NMR (100 MHz, CDCl3): d=48.4 (anti-
CH2COOCH3), 48.7 (syn-CH2COOCH3), 52.1 (syn-COOCH3), 52.2 (anti-
COOCH3), 53.2 (NCH2Ph), 55.8 (syn-OCH3), 55.8 (anti-OCH3), 55.9
(syn-OCH3), 55.9 (anti-OCH3), 110.7, 111,0, 111.2, 111.4, 118.5, 118.7,
120.2, 120.9, 125.1, 125.2, 127.8, 127.8, 127.8, 128.1, 128.2, 128.5, 130.6,
130.7, 136.2, 136.6, 148.7, 148.9, 149.4, 149.4 (Ar-C), 169.0 (anti-NCO),
169.3 (syn-NCO), 169.3 (syn-COOCH3), 169.4 ppm (anti-COOCH3); MS
(FAB): m/z (%): 385 (26) [M+], 307 (100); yield: 37%.
General procedure for the amine coupling (5{1,3–8}): Resin 3{1}
(1 equiv) and 2-chloro-1-methylpyridinium iodide (2 equiv) were sus-
pended in 80 mL of CH2Cl2, after which NEt3 (20 equiv) was added. The
corresponding amine 4{3–8} (3 equiv) was added after 15 min. The result-
ing mixture was stirred overnight at RT. The resin 5{1,3–8} was filtered
off, washed sequentially with THF, Et2O, MeOH, DMF, THF, CH2Cl2,
methanol, and pentane, and was dried under high vacuum.
Methyl ester of [(2-azidobenzoyl)(4-phenylbenzyl)amino]acetic acid
6{1,5}: Rf: 0.5 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3):
d=3.56, 3.68, 3.71 (5 Aliph-H), 4.41 (s, 2H; NCH2Ph), 7.07–7.53 ppm (m,
13Ar-H); 13C NMR (100 MHz, CDCl3): d=48.5 (anti-CH2COOCH3),
49.07 (syn-CH2COOCH3), 52.2 (syn-COOCH3), 52.2 (anti-COOCH3),
53.1 (NCH2Ph), 118.5, 118.7, 125.1, 125.2, 127.0, 127.0, 127.4, 127.5, 127.5,
128.1, 128.2, 128.3, 128.8, 130.7, 130.7, 134.4, 135.0, 136.3, 136.8, 140.4,
140.7, 140.7, 141.0 (Ar-C), 169.1 (anti-NCO), 169.3 (syn-NCO), 169.4
(anti-COOCH3), 169.5 ppm (syn-COOCH3); yield: 20%.
Methyl ester of [(2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoyl)(4-
methoxybenzyl)amino]acetic acid 5{1,3}: IR (KBr): n˜ =3647 (w, br, ps),
3476 (s, ps), 3026 (s, ps), 2927 (s, ps), 2850 (s, ps), 1945 (m, ps), 1874 (m,
ps), 1805 (m, ps), 1754 (s), 1650 (s), 1601 (s, ps), 1493 (s, ps), 1452 cmꢀ1
(s, ps); elemental analysis calcd (%) for C147H147N4O4: C 86.83, H 7.28, N
2.74; found: C 84.71, H 6.98, N 3.31; loading: 0.774 mmolgꢀ1
.
Methyl ester of [(2-azidobenzoyl)benzylamino]acetic acid 6{1,6}: Rf: 0.3
(Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=3.55 (s, 2H;
CH2COOCH3), 3.67 (s, 3H; COOCH3), 4.37 (s, 2H; NCH2Ph), 7.07–
7.32 ppm (m, 9Ar-H); 13C NMR (100 MHz, CDCl3): d=48.7 (anti-
CH2COOCH3), 48.9 (syn-CH2COOCH3), 52.1 (anti-COOCH3), 52.1 (syn-
COOCH3), 53.3 (NCH2Ph), 118.4, 118,6, 125.0, 125.1, 126.9, 127.6, 127.7,
127.9, 127.9, 128.2, 128.3, 128.5, 128.7, 128.7, 128.8, 130.6, 130.6, 131.4,
135.4, 135.9, 136.3, 136.8 (Ar-C), 169.0 (anti-NCO), 169.2 (syn-NCO),
169.3 (anti-COOCH3), 169.4 ppm (syn-COOCH3); yield: 16%.
Methyl ester of [(2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoyl)(3,4-
dimethoxybenzyl)amino]acetic acid 5{1,4}: IR (KBr): n˜ =3647 (w, br, ps),
3479 (s, ps), 3026 (s, ps), 2927 (s, ps), 2850 (s, ps), 1945 (m, ps), 1873 (m,
ps), 1803 (m, ps), 1751 (s), 1651 (s), 1601 (s, ps), 1493 (s, ps), 1454 cmꢀ1
(s, ps); elemental analysis calcd (%) for C148H149N4O5: C 86.15, H 7.27, N
2.70; found: C 84.24, H 7.28, N 3.63; loading: 0.898 mmolgꢀ1
.
Methyl ester of [(2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoyl)(4-
phenylbenzyl)amino]acetic acid 5{1,5}: IR (KBr): n˜ =3645 (w, br, ps),
3622 (s, ps), 3025 (s, ps), 2926 (s, ps), 2850 (s, ps), 1944 (m, ps), 1872 (m,
ps), 1802 (m, ps), 1748 (s), 1649 (s), 1601 (s, ps), 1493 (s, ps), 1452 cmꢀ1
(s, ps); elemental analysis calcd (%) for C186H183N4O3: C 88.58, H 7.31, N
Methyl ester of 2-[(2-azidobenzoyl)(4-methoxybenzyl)amino]propionic
acid 6{1,7}: Rf: 0.3 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz,
CDCl3): d=1.34 (d, 2H, J=7.1 Hz; CH3), 3.75 (s, 3H; COOCH3), 3.76 (s,
3H; OCH3), 4.30 (NCH2Ph), 6.78–7.79 ppm (m, 8Ar-H); 13C NMR
(100 MHz, CDCl3): d=12.8 (syn-CH3), 14.0 (anti-CH3), 39.0 (syn-
NCH2Ph), 42.9 (anti-NCH2Ph), 52.2 (syn-COOCH3), 52.2 (anti-
COOCH3), 55.2 (OCH3), 57.0 (CH), 113.7, 113,9, 118.5, 125.0, 126.8,
127.6, 127.9, 128.4, 128.9, 130.4, 130.5, 136.2, 136.6, 158.7, 159.2 (Ar-C),
167.8 (syn-COOCH3), 169.4 (anti-COOCH3), 171.6 ppm (NCO); MS
(FAB): m/z (%): 369 (28) [M+], 219 (100); yield: 15%.
2.21; found: C 86.84, H 7.55, N 2.57; loading: 0.578 mmolgꢀ1
.
Methyl ester of [(2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoyl)ben-
zylamino]acetic acid 5{1,6}: IR (KBr): n˜ =3648 (w, br, ps), 3026 (s, ps),
2922 (s, ps), 2847 (s, ps), 1944 (m, ps), 1871 (m, ps), 1803 (m, ps), 1753
(s), 1652 (s), 1601 (s, ps), 1493 (s, ps), 1453 cmꢀ1 (s, ps); elemental analy-
sis calcd (%) for C185H184N4O3: C 88.48, H 7.38, N 2.22; found: C 85.92,
H 6.74, N 2.12; loading: 0.462 mmolgꢀ1
.
Methyl ester of 2-[(2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoyl)-
(4-methoxybenzyl)amino]propionic acid 5{1,7}: IR (KBr): n˜ =3652 (w, br,
ps), 3466 (s, ps), 3026 (s, ps), 2928 (s, ps), 2850 (s, ps), 1944 (m, ps), 1873
(m, ps), 1796 (m, ps), 1743 (s), 1642 (s), 1601 (s, ps), 1493 (s, ps),
1453 cmꢀ1 (s, ps); elemental analysis calcd (%) for C154H153N4O4: C 87.10,
Methyl ester of 2-[(2-azidobenzoyl)(4-methoxybenzyl)amino]-3-phenyl-
propionic acid 6{1,8}: Rf: 0.3 (Cyclohexane/AcOEt 2:1); 1H NMR
(400 MHz, CDCl3): d=3.69 (s, 3H; COOCH3), 3.73 (s, 3H; OCH3), 6.66–
7.34 ppm (m, 13Ar-H); 13C NMR (100 MHz, CDCl3): d=39.0 (CHCH2),
42.9 (NCH2Ph), 52.2 (syn-COOCH3), 53.4 (anti-COOCH3), 55.2 (syn-
OCH3), 55.3 (anti-OCH3), 113.8, 118.5, 125.0, 126.7, 127.2, 127.6, 128.0,
128.3, 129.4, 129.8, 129.9, 130.4, 136.2, 159.3 (Ar-C), 167.8 (COOCH3),
168.7 (anti-NCO), 170.4 ppm (syn-NCO); yield: 5%.
H 7.26, N 2.62; found: C 86.54, H 7.35, N 3.57; loading: 0.923 mmolgꢀ1
.
Methyl ester of 2-[(2-(3-benzyl-3-polystyrylmethyl-1-triazenyl)benzoyl)-
(4-methoxybenzyl)amino]-3-phenylpropionic acid 5{1,8}: IR (KBr): n˜ =
3646 (w, br, ps), 3458 (s, ps), 3026 (s, ps), 2928 (s, ps), 2851 (s, ps), 1944
(m, ps), 1872 (m, ps), 1796 (m, ps), 1741 (s), 1640 (s), 1601 (s, ps), 1493
(s, ps), 1453 cmꢀ1 (s, ps); elemental analysis calcd (%) for C154H153N4O4:
C 87.10, H 7.26, N 2.62; found: C 85.96, H 7.44, N 3.55; loading:
General procedure for the synthesis of 1,4-benzodiazepin-5-ones
(7{1,3–8}): The triphenylphosphine polystyrene (4 equiv) was distended
with dry toluene (8 mL) in a glass vial and was sealed under argon. A so-
lution of the azide 6{1,3–8} (1 equiv) in dry toluene was injected into the
suspension. The reaction mixture was shaken at RT for 1 h and then
heated at 1008C for 18 h. After cooling, the resin was separated by filtra-
tion and washed with dichloromethane. The filtrate was concentrated
until dry to give the benzodiazepines 7{1,3–8}.
0.900 mmolgꢀ1
.
General procedure for the generation of azides (6{1,3–8}): The resin
5{1,3–8} was suspended in 5% TFA/CH2Cl2 at RT. After 5–10 min, the
mixture was filtered, and trimethylsilylazide was added. The solvents and
2686
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2680 – 2688

Benzodiazepinone Derivatives
FULL PAPER
2-Methoxy-4-(4-methoxybenzyl)-3,4-dihydrobenzo[e][1,4]diazepin-5-one
7{1,3}: Rf: 0.1 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3):
d=3.68 (s, 2H, NCH2), 3.71 (s, 3H, PhOCH3), 3.72 (s, 3H, OCH3), 4.69
(s, 2H, NCH2Ph), 6.78–7.96 ppm (m, 8Ar-H); 13C NMR (100 MHz,
CDCl3): d=45.8 (NCH2), 51.1 (NCH2Ph), 54.2 (OCH3), 55.3 (PhOCH3),
114.1, 124.4, 126.1, 128.8, 129.6, 131.0, 131.7, 135.8, 144.9, 159.3 (Ar-C),
163.3 (COCH3), 167.8 ppm (CO); EI-HRMS: m/z calcd for C18H18N2O3:
310.1317; found: 310.1315; MS (EI): m/z (%): 310 (24) [M+], 201 (100);
yield: 98%.
C 88.94, H 7.50, N 2.26; found: C 87.68, H 7.57, N 2.49; loading:
0.512 mmolgꢀ1
.
General procedure for the generation of azides (6{1,9–12}): The resin
5{1,9–12} was suspended in 5% TFA/CH2Cl2 at RT. After 5–10 min, the
mixture was filtered and trimethylsilylazide was added. The solvents and
the remnants of TFA and trimethylsilylazide were removed by evapora-
tion. The residue was purified by performing flash chromatography, elut-
ing with a 3:1 cyclohexane/AcOEt system.
1-(2-Azidobenzoyl)pyrrolidin-2-one 6{1,9}: Rf: 0.4 (Cyclohexane/AcOEt
2:1); 1H NMR (400 MHz, CDCl3): d=2.06 (q, 2H, CH2), 2.41 (t, J=
8.2 Hz, 2H; COCH2), 3.90 (t, J=7.0 Hz, 2H; NCH2), 7.11 (m, 2Ar-H),
7.21 (d, J=7.5 Hz, 1Ar-H), 7.39 ppm (t, J=7.7 Hz, 1Ar-H); 13C NMR
(100 MHz, CDCl3): d=17.4 (CH2), 33.0 (COCH2), 45.5 (NCH2), 118.1,
124.7, 128.3, 131.2, 137.2 (Ar-C), 167.3 (CON), 174.1 ppm (COCH2); EI-
HRMS: m/z calcd for C11H10N4O2: 230.0804, found: 230.0802; MS (EI):
m/z (%): 230 (18) [M+], 116 (100); yield: 12%.
4-(3,4-Dimethoxybenzyl)-2-methoxy-3,4-dihydrobenzo[e][1,4]diazepin-5-
one 7{1,4}: Rf: 0.03 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz,
CDCl3): d=3.60 (s, 2H; NCH2), 3.78 (s, 3H; PhOCH3), 3.79 (s, 3H;
PhOCH3), 3.68 (s, 3H; OCH3), 4.60 (s, 2H; NCH2Ph), 6.73–8.22 ppm (m,
7Ar-H); 13C NMR (100 MHz, CDCl3): d=45.7 (NCH2), 51.5 (NCH2Ph),
54.2 (OCH3), 55.9 (PhOCH3), 55.9 (PhOCH3), 111.1, 111.4, 120.8, 124.4,
126.2, 129.0, 132.5, 144.9, 148.8, 149.3 (Ar-C), 163.3 (COCH3), 167.9 ppm
(CO); EI-HRMS: m/z calcd for C19H20N2O4: 340.1423; found: 340.1426;
MS (EI): m/z (%): 340 (16) [M+], 201 (100).
1-(2-Azidobenzoyl)piperidin-2-one 6{1,10}: Rf: 0.5 (Cyclohexane/AcOEt
2:1); 1H NMR (400 MHz, CDCl3): d=1.79–1.91 (m, 4H; CH2CH2), 2.46
(t, J=6.4 Hz, 2H; COCH2), 3.78 (t, J=6.2 Hz, 2H; NCH2), 7.04 (d, J=
8.1 Hz, 1Ar-H), 7.10 (t, J=7.5 Hz, 1Ar-H), 7.26 (d, J=7.7 Hz, 1Ar-H),
7.34 ppm (t, J=7.3 Hz, 1Ar-H); 13C NMR (100 MHz, CDCl3): d=20.8,
22.5 (CH2), 34.3 (COCH2), 44.9 (NCH2), 118.1, 125.0, 128.4, 130.8, 135.9
(Ar-C), 170.2 (CON), 172.8 ppm (COCH2); EI-HRMS: m/z calcd for
C12H12N4O2: 244.0906, found: 244.0955; MS (EI): m/z (%): 244 (4) [M+],
117 (100); yield: 17%.
2-Methoxy-4-(4-phenylbenzyl)-3,4-dihydrobenzo[e][1,4]diazepin-5-one
7{1,5}: Rf: 0.1 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3):
d=3.64 (s, 2H; NCH2), 3.67 (s, 3H; OCH3), 4.79 (s, 2H; NCH2Ph), 6.89–
7.96 ppm (m, 13Ar-H); 13C NMR (100 MHz, CDCl3): d=46.1 (NCH2),
51.5 (NCH2Ph), 54.2 (OCH3), 124.5, 126.2, 127.0, 127.4, 128.6, 128.8,
131.0, 131.8, 135.8, 140.7, 145.0 (Ar-C), 163.2 (COCH3), 168.0 ppm (CO).
4-Benzyl-2-methoxy-3,4-dihydrobenzo[e][1,4]diazepin-5-one 7{1,6}: Rf:
0.1 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=3.61 (s,
2H; NCH2), 3.67 (s, 3H; OCH3), 4.76 (s, 2H; NCH2Ph), 6.86–7.73 ppm
(m, 9Ar-H); 13C NMR (100 MHz, CDCl3): d=46.0 (NCH2), 51.7
(NCH2Ph), 54.2 (OCH3), 1117.6, 124.4, 128.1, 128.5, 128.6, 131.0, 131.5,
136.1, 144.9 (Ar-C), 167.2 ppm (CO).
1-(2-Azidobenzoyl)azepan-2-one 6{1,11}: Rf: 0.5 (Cyclohexane/AcOEt
2:1); 1H NMR (400 MHz, CDCl3): d=1.77 (m, 6H; CH2CH2CH2), 2.59
(m, 2H; COCH2), 3.94 (m, 2H; NCH2), 7.04 (d, J=8.1 Hz, 1Ar-H), 7.09
(t, J=7.5 Hz, 1Ar-H), 7.21 (d, J=7.7 Hz, 1Ar-H), 7.32 ppm (t, J=8.1 Hz,
1Ar-H); 13C NMR (100 MHz, CDCl3): d=23.6, 28.6, 29.5 (CH2), 39.0
(COCH2), 43.8 (NCH2), 118.1, 124.9, 128.0, 130.5, 135.6 (Ar-C), 169.5
(CON), 176.9 ppm (COCH2); EI-HRMS: m/z calcd for C14H15N3O2:
258.1117, found: 258.1116; MS (EI): m/z (%): 258 (4) [M+], 230 (100);
yield: 20%.
2-Methoxy-4-(4-methoxybenzyl)-3-methyl-3,4-dihydrobenzo[e]-
[1,4]diazepin-5-one 7{1,7}: Rf: 0.1 (Cyclohexane/AcOEt 2:1); [a]20
=
ꢀ3.61 (CHCl3); 1H NMR (400 MHz, CDCl3): d=1.38 (d, J=7.0 Hz, 3H,
CH3), 3.64 (s, 3H, PhOCH3), 3.72 (s, 3H, OCH3), 4.45 (c, 1H, CH), 6.65–
7.21 ppm (m, 8Ar-H).
General procedure for the synthesis of 1,4-benzodiazepin-5-ones
(7{1,9–11}): The triphenylphosphine polystyrene (4 equiv) was distended
with dry toluene (8 mL) in a glass vial sealed under argon. A solution of
the azide 6{1,9–11} (1 equiv) in dry toluene was injected into the suspen-
sion. The reaction mixture was shaken at RT for 1 h and then heated at
1008C for 132 h. After cooling, the resin was separated by filtration and
washed with dichloromethane. The filtrate was concentrated to dryness
to give the benzodiazepines 7{1,9–11}.
3-Benzyl-2-methoxy-4-(4-methoxybenzyl)-3,4-dihydrobenzo[e]-
[1,4]diazepin-5-one 7{1,8}: Rf: 0.03 (Cyclohexane/AcOEt 2:1); [a]20
=
ꢀ0.05 (CHCl3); 1H NMR (400 MHz, CDCl3): d=3.51 (s, 3H; PhOCH3),
3.72 (s, 3H; OCH3), 6.72–8.03 ppm (m, 13Ar-H); 13C NMR (100 MHz,
CDCl3): d=34.5 (CH2Ph), 52.9 (NCH2Ph), 54.0 (OCH3), 55.2 (CH), 61.3
(PhOMe), 113.9, 120.7, 124.5, 126.9, 128.5, 128.7, 128.8, 129.8, 131.0,
136.1, 139.3, 143.3, 159.2 (Ar-C), 163.2 (COCH3), 166.8 ppm (CO); EI-
HRMS: m/z calcd for C25H24N3O3: 400.1787; found: 400.1787; MS (EI):
m/z (%): 400 (12) [M+], 201 (100).
2,3-Dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one
(deoxyvasicinone)
7{1,9}: Rf: 0.03 (Cyclohexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3):
d=2.21 (q, 2H; NCH2CH2CH2), 3.10 (t, J=7.8 Hz, 2H; NCH2CH2CH2),
4.13 (t, J=7.1 Hz, 2H; NCH2CH2CH2), 7.35–8.22 ppm (m, 4Ar-H);
General procedure for the coupling via acid chlorides (5{1,9–11}): A mix-
ture of triphenylphosphine (3 equiv), resin 3{1} (1 equiv), lactams 4{9–11}
(2 equiv), diisopropylethylamine (4 equiv), and carbon tetrachloride
(3 equiv) was heated at reflux in THF for 5 h. After cooling, the resin
5{1,9–11} was filtered off, washed sequentially with THF, Et2O, MeOH,
DMF, THF, CH2Cl2, methanol, and pentane, and was dried under high
vacuum.
13C NMR
(100 MHz,
CDCl3):
d=19.5
(NCH2CH2CH2),
32.5
(NCH2CH2CH2), 46.5 (NCH2CH2CH2), 120.5, 126.2, 126.4, 126.7, 134.1,
149.1 (Ar-C), 159.4 (CO), 160.9 ppm (N=C); EI-HRMS: m/z calcd for
C11H10N2O: calcd 186.0793; found: 186.0789; MS (EI): m/z (%): 186 (90)
[M+], 185 (100); purity: 82% (by GC); yield: 99%.
(2-(3-Benzyl-3-polystyrylmethyl-1-triazenyl)benzoylpyrrolidin-2-one
5{1,9}: IR (KBr): n˜ =3647 (s, ps), 3620 (w, ps), 3061 (w, br, ps), 2951 (w,
br, ps), 1944 (m, ps), 1872 (m, ps), 1800 (m, ps), 1751 (s), 1679 (s), 1601
(s, ps), 1494 (s, ps), 1461 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C181H180N4O2: C 88.98, H 7.42, N 2.28; found: C 87.34, H 7.86, N 2.46;
6,7,8,9-Tetrahydropyrido[2,1-b]quinazolin-11-one 7{1,10}: Rf: 0.1 (Cyclo-
hexane/AcOEt 2:1); 1H NMR (400 MHz, CDCl3): d=1.87 (q, 2H;
NCH2CH2CH2CH2), 1.93 (q, 2H; NCH2CH2CH2CH2), 2.93 (t, J=6.6 Hz,
2H; NCH2CH2CH2CH2), 4.00 (t, J=6.0 Hz, 2H; NCH2CH2CH2CH2),
7.25–8.19 ppm (m, 4Ar-H); 13C NMR (100 MHz, CDCl3): d=19.3
loading: 0.501 mmolgꢀ1
.
(NCH2CH2CH2CH2),
22.0
(NCH2CH2CH2CH2),
31.8
(NCH2CH2CH2CH2), 42.2 (NCH2CH2CH2CH2), 120.4, 126.0, 126.3, 126.6,
134.1, 147.3 (Ar-C), 154.9 (CO), 162.1 ppm (N=C); EI-HRMS: m/z calcd
for C12H12N2O: 200.095; found: 200.095; MS (EI): m/z (%): 200 (100)
[M+]; purity: 96% (by GC); yield: 99%.
(2-(3-Benzyl-3-polystyrylmethyl-1-triazenyl)benzoylpiperidin-2-one
5{1,10}: IR (KBr): n˜ =3649 (s, ps), 3621 (w, ps), 3026 (s, ps), 2926 (w, br,
ps), 1944 (m, ps), 1872 (m, ps), 1802 (m, ps), 1713 (s), 1679 (s), 1601 (s,
ps), 1493 (s, ps), 1452 cmꢀ1 (s, ps); elemental analysis calcd (%) for
C
182H182N4O2: C 88.96, H 7.46, N 2.27; found: C 86.33, H 8.02, N 2.32;
7,8,9,10-Tetrahydro-6H-azepino[2,1-b]quinazolin-12-one 7{1,11}: Rf: 0.2
(Cyclohexane/AcOEt 2:1); H NMR (400 MHz, CDCl3): d=1.77 (m, 6H;
loading: 0.462 mmolgꢀ1
.
1
(2-(3-Benzyl-3-polystyrylmethyl-1-triazenyl)benzoylazepan-2-one 5{1,11}:
IR (KBr): n˜ =3645 (s, ps), 3620 (w, ps), 3026 (s, ps), 2926 (w, br, ps), 1944
(m, ps), 1873 (m, ps), 1802 (m, ps), 1713 (s), 1679 (s), 1601 (s, ps), 1493
(s, ps), 1452 cmꢀ1 (s, ps); elemental analysis calcd (%) for C183H184N4O2:
NCH2CH2CH2CH2CH2), 3.00 (m, 2H; NCH2CH2CH2CH2CH2), 4.31 (m,
2H; NCH2CH2CH2CH2CH2), 7.20–8.19 ppm (m, 4Ar-H); 13C NMR
(100 MHz, CDCl3): d=25.4, 28.1, 29.57 (NCH2CH2CH2CH2CH2), 37.7
(NCH2CH2CH2CH2CH2), 42.9 (NCH2CH2CH2CH2CH2), 120.2, 126.3,
Chem. Eur. J. 2005, 11, 2680 – 2688
www.chemeurj.org
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2687

C. Gil and S. Brꢂse
126.7, 127.0, 134.1, 147.4 (Ar-C), 159.7 (CO), 161.9 ppm (N=C); EI-
HRMS: m/z calcd for C13H14N2O: 214.1106; found: 214.1107; MS (EI)
m/z (%): 214 (100) [M+]; purity: 91% (by GC); yield: 99%.
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Acknowledgment
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Our research was supported by the Deutsche Forschungsgemeinschaft
(BR1750-2/3), the Fonds der Chemischen Industrie, and by a Marie
Curie Fellowship (to CG) of the European Community program “Im-
proving Human Research Potential and the Socio-economic Knowledge
Base” (Contract No. HPMF-CT-2002-01644).
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Received: November 4, 2004
Published online: February 25, 2005
2688
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2680 – 2688