Synthesis of 1,4-benzodiazepinones via palladium-catalysed allene carbopalladation/amination domino sequence Dedicated to Professor Maria José Calhorda in occasion of her 65th birthday.

Article abstract of DOI:10.1016/j.jorganchem.2013.11.010

Vinyl-substituted 1,4-benzodiazepinones were obtained in good yields (10 examples, 61-82% yield) via the reaction between N-allenyl anthranyl amides and aryl iodides under Pd(0) catalysis. This new single cycle catalytic domino transformation involves a C

Full text of DOI:10.1016/j.jorganchem.2013.11.010

Accepted Manuscript
Synthesis of 1,4-benzodiazepinones via palladium-catalysed allene carbopalladation /
amination domino sequence
Micol Rigamonti, Guillaume Prestat, Gianluigi Broggini, Giovanni Poli
PII:
S0022-328X(13)00808-5
10.1016/j.jorganchem.2013.11.010
JOM 18355
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 29 September 2013
Revised Date: 7 November 2013
Accepted Date: 10 November 2013
Please cite this article as: M. Rigamonti, G. Prestat, G. Broggini, G. Poli, Synthesis of 1,4-
benzodiazepinones via palladium-catalysed allene carbopalladation / amination domino sequence,
Journal of Organometallic Chemistry (2013), doi: 10.1016/j.jorganchem.2013.11.010.
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ACCEPTED MANUSCRIPT
Abstract
N-allenyl anthranyl amides and aryl iodides react to give vinyl-substituted benzodiazepinones.
This new Pd-catalyzed domino sequence involves a C-C followed by an N-C bond formation.

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Graphical Abstract
Synthesis of 1,4-benzodiazepinones via palladium-catalysed allene carbopalladation /
amination domino sequence
Micol Rigamonti,a,b† Guillaume Prestat,a‡ Gianluigi Broggini,b* and Giovanni Polia*
a Institut Parisien de Chimie Moléculaire UMR CNRS 7201, FR2769 Institut de Chimie
Moléculaire UPMC, 4 Place Jussieu, case 183, F-75005, Paris, France.
Fax: (+)33 (0)1 44 27 42 87
b Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11,
22100 Como, Italy;
N-allenyl anthranyl amides and aryl iodides react to give vinyl-substituted benzodiazepinones.
This new Pd-catalyzed domino sequence involves a C-C followed by an N-C bond formation.

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Highlights
Aryl iodides are required for a successful outcome of the reaction.
This Pd-catalysed domino sequence involves a C-C and an N-C bond formation.
The protection of the amino group was necessary for the Pd-catalysed domino reaction.

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Synthesis of 1,4-benzodiazepinones via palladium-
catalysed allene carbopalladation / amination domino
sequence
Micol Rigamonti,a,b† Guillaume Prestat,a‡ Gianluigi Broggini,b* and Giovanni Polia*
a UPMC, IPCM, UMR CNRS 7201, 4 place Jussieu, case 183, F-75252 Paris Cedex 05,
France.
b Dipartimento di Scienze Chimiche e Ambientali, Università dell’Insubria, via Valleggio 11,
22100 Como, Italy.
* Corresponding authors.
E-mail addresses:
gianluigi.broggini@uninsubria.it
giovanni.poli@upmc.fr
Dedication
Dedicated to Professor Maria José Calhorda in occasion of her 65th birthday.
†
Present address: Sintetica SA, via Penate 5, 6850 Mendrisio, Switzerland.
Present address: Université Paris Descartes, UMR 8601 CNRS, Laboratoire de Chimie et
‡
Biochimie Pharmacologiques et Toxicologiques, 45 rue des Saints-Pères, 75006 Paris,
France.

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Abstract
Vinyl-substituted 1,4-benzodiazepinones were obtained in good yields (10 examples, 61-82%
yield) via the reaction between N-allenyl anthranyl amides and aryl iodides under Pd(0)
catalysis. This new single cycle catalytic domino transformation involves a C-C followed by
an N-C bond formation.
Keywords
palladium
allene
domino reactions
carbopalladation
amination
1,4-benzodiazepinones

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1. Introduction
Since the discovery of chlordiazepoxide, by L. Sternbach, in the mid fifties, 1,4-
benzodiazepines became one of the most popular heterocyclic structures in the history of
drugs [1]. The benzodiazepine motif, found incorporated into a number of pharma molecules
such as CNS drugs [2], antibiotics [3], antithrombotics [4], anti-HIV drugs [5], as well as
peptidomimetics [6] is nowadays considered as a privileged structure [7].
In particular, the sub-set of 1,4-benzodiazepin-5-ones occupies an important role in
medicinal chemistry [8]. For example, tri- as well as tetra-cyclic systems containing the 1,4-
diazepin-5-one motif proved to be useful candidates for a wide array of therapeutic
applications [9,10]. The antihistaminic property of tarpane [11], the antibiotic activity of
abbeymycin [12], the anti-anxiety effect of flumazenil [13] and the anti-neurodegenerative
activity of bretazenil [14] represent remarkable examples (Figure 1).
Figure 1. Some examples of pharmacologically active polycyclic 1,4-benzodiazepinones.
Appropriate structural modifications of the above structures may lead to new analogues
endowed with interesting biological activities. Accordingly, the search for novel synthetic
approaches toward such heterocyclic structures is highly desirable.
Most of the reported methods to prepare 1,4-benzodiazepin-5-ones start from the readily
available isatoic anhydride [15]. Although useful solid supported variants of this approach
have been reported [16], these methods either require harsh pre-functionalisation conditions,
or are not atom economical.
In the context of our ongoing research directed toward the synthesis of heterocycles via
transition metal-catalysis, we recently directed our interest toward allenes [17]. These
previous studies led us to envision N-allenyl anthranil amides as suitable substrates for the
synthesis of α-styryl-substituted 1,4-benzodiazepin-5-ones via a pure domino [18] Pd(0)-

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catalysed carbopalladation / allylic amination process. This plan proved successful and the
present article describes details about this new strategy that widens the existing palladium-
based approaches toward 1,4-benzodiazepin-5-ones (Scheme 1) [19].
Scheme 1. Previously reported Pd-catalysed syntheses of 1,4-benzodiazepin-5-ones and the
present approach.
2. Results and discussion
The required N-allenyl amide cyclization precursor 1a was first prepared by DCC promoted
condensation between N-benzyl-(4-methylpenta-2,3-dienyl)-amine [17f] and N-tosyl
anthranilic acid [20] under standard conditions (Scheme 2) [21].
Scheme 2. Generation of the starting cyclization precursor.
Coupling between 1a and 4-iodotoluene (1.2 equivalents) to give the benzodiazepine 2a was
chosen as model reaction to investigate the planned carbopalladation / amination sequence
(Table 1).
Table 1
Optimization of the ring closing coupling between N-allenylamide 1a and 4-iodotoluene to
give 1,4-benzodiazepin-5-one 2a.

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Entry Catalytic Base
systema
T
Additive Solvent
Ligand Conversion Yield
(°C) (20%)
(0.05 M)
DMSO
(%)b
(%)c
1
A
NaH (1.2 eq.) rt,d
TBAB
-
84
46
55e
2
B
NaH (1.2 eq.) 50
-
CH3CN
dppf
75
27
(10%)
3
A
A
A
A
Cs2CO3 (2 eq.) 50
K2CO3 (2 eq.) 50
K2CO3 (2 eq.) 90
NaH (1.2 eq.) 50,d
90e
TBAB
TBAB
TBAB
TBAB
DMSO
DMSO
DMSO
DMSO
-
-
-
-
6
n.i.f
n.i.
n.i.
82
4
20
20
100
5
6g
7
A
-
90
TBAB
DMSO
-
0
-
a Catalytic system A: Pd(CH3CN)2Cl2 (5%), BuLi (10%); catalytic system B: Pd(OAc)2 (5%).
bConsumption of 1a as determined by 1H NMR spectroscopy. c Yields refer to isolated yields.
e
f
dTemperature for deprotonation of 1. Temperature for the cyclization reaction. not isolated.
gFlask 1: 1a (1.0 equiv.)/NaH (1.2 equiv.), DMSO, 50°C, 10 min. Flask 2: a) Pd(CH3CN)2Cl2
(5 mol%), DMSO, n-BuLi (10 mol %); b) ArI (1.2 equiv.), TBAB (20 mol%). Then, flask 2
into flask 1, 90 °C.
First, we investigated the feasibility of the reaction employing phosphine-free conditions. This
protocol was recently reported by some of us for the synthesis of γ-lactams via
carbopalladation / allylation of allenyl substrates [22, 17a]. Accordingly, the catalytically
active palladium species was generated by the addition of BuLi (10 mol%) to a solution of
Pd(CH3CN)2Cl2 (5 mol%) in DMSO. Then, 4-iodotoluene (1.2 equiv.), tetrabutyl ammonium
bromide (TBAB) (20 mol%) and a DMSO solution of the sodium amidate were added in
sequence (Entry 1). Although the conversion of the substrate was satisfactory, the expected
benzodiazepinone 2a was isolated in only moderate yields. Switching to Pd(OAc)2 / dppf as
catalytic system in acetonitrile, decreased dramatically the substrate conversion (Entry 2). We
thus decided to come back to the ligandless protocol, optimizing bases and temperatures. The
use of Cs2CO3 or K2CO3 was nearly ineffective either at 50 °C or at 90°C (entries 3-5).
Conversely, deprotonation of the allenylamide with NaH at 50 °C followed by heating at 90

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°C after the addition of the remaining reagents brought about a complete conversion together
with a remarkable increase of the yield (entry 6). Finally, a blank experiment omitting NaH
gave no product, thereby confirming the crucial role of that base for the success of the
reaction (entry 7).
With the optimized ligandless conditions in hand, the scope of the domino sequence was next
examined on 0.1 mmol scale reactions, reacting 1a with various aryl iodides (Table 2).
Electron-rich 2-, 3- and 4-iodoanisoles reacted smoothly, affording the expected
corresponding benzodiazepinones 2b-d in 63%, 63% and 73%, respectively. The reaction of
electron poor aryl iodides such as those bearing para positioned methoxycarbonyl, nitro, and
acetyl functions gave products 2e-g in satisfactory yields (61%, 71% and 68%, respectively).
The use of simple iodobenzene led to the expected benzodiazepinone 2h in 67% yield. The
heteroaromatic halide 3-iodopyridine afforded the expected product 2i in 70% yield. Finally,
the same protocol well sustained substitutions on the aromatic ring. Indeed, the N-allenyl 3-
methyl anthranyl amide 1b afforded uneventfully benzodiazepinone 2j (75%) [23].
The formation of 1,4-benzodiazepin-5-ones can be rationalized according to the mechanism
depicted in Scheme 3. First, the Pd(0) complex I [24] is generated from Pd(CH3CN)2Cl2 and
n-BuLi. After oxidative addition of the iodoarene to I, the thus formed PhPdI complex II
undergoes carbopalladation to give the η3-allyl complex IV via III. 7-Exo nucleophilic attack
by the sodium salt of the sulfonamide (or carbamate) nitrogen atom forms the
benzodiazepinone 2a and regenerates a Pd(0)-species, thereby closing the catalytic cycle.
Table 2
Scope of the domino sequence.a

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aFor the reaction conditions, see entry 6, Table 1. Yields refer to isolated products.
Not surprisingly, in all the cases studied, the carbopalladation / amination sequence was
totally regioselective, always yielding the desired 1,4-benzodiazepin-5-ones as the sole
products. Indeed, a 9-endo type attack on the unsubstituted terminus of the allyl moiety to
produce a benzo[1,5]diazoninone ring is expected to be much more disfavoured (Scheme 3).
Scheme 3. Mechanistic proposal for the carbopalladation/allylic amination domino sequence.
Finally, to ascertain that the above cyclization strategy could be satisfactorily carried out with
an N-protecting group synthetically more attractive than the tosyl function, the N-Boc 1c and
the N-nosyl analogs 1d [25] were synthesized and submitted to the same domino protocol as
above. Although the former derivative gave only a moderate yield of benzodiazepine, the N-
nosyl one smoothly cyclised in high yield (Table 3) [26].
Table 3
Validation of the domino process on the N-Boc and N-Ns derivatives.a
Entry
PG
BOC
Ns
Substrate
Product Yield (%)
1
2
48
80
1c
2k
2l
1d
aFor the rection conditions, see entry 6, Table 1. Yields refer to isolated products.

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3. Conclusion
We have developed an original approach to 1,4-benzodiazepin-5-ones starting from N-
allenamides of anthranilic acid. This was obtained designing a catalytic sequence wherein a
C-C and C-N carbon bond are created in a single synthetic operation. Besides their intrinsic
pharmacological interest, the obtained scaffolds represent an interesting DOS-compatible
platform [27] amenable to modular synthesis (via the use of differently substituted anthranilic
acids and/or allenyl moieties) as well as orthogonal protections. Furthermore, the vinyl moiety
of the products lends itself to easy post-cyclisation modifications.
4. Experimental section
4.1. General information
DMSO was distilled over CaH2 under reduced pressure. All other solvents were dried on a
MBraun solvent purification system MB SPS-800. Chemicals were purchased from Sigma
Aldrich and Acros Organics and used as received, unless stated.
All reactions were conducted under argon and glassware was flame-dried before use. Flash
chromatography was conducted on silica gel (0.040-0.063 mm). Analytical Thin Layer
Chromatography (TLC) were performed on Merck precoated 60 F254 plates. Melting points
were measured using a Stuart Scientific SMP3 apparatus. IR spectra were recorded on a
Bruker Tensor 27 (Pike) apparatus and only the strongest or the structurally most important
peaks were listed.
1H NMR (400 MHz) and 13C NMR (100 MHz) were recorded on a Bruker Avance 400
spectrometer (BBFO probe). Chemical shifts are reported in ppm relative to residual peak of
1
deuterated chloroform as internal standard. 13C NMR spectra are H-decoupled and the
determination of the multiplicities was achieved by the DEPT pulse sequence.
High resolution mass spectrometry was performed on a Thermo Fisher Scientific LTQ-
Orbitrap (ESI).
4.2. General procedure for the synthesis of N-protected allenyl amides
To a solution of N-benzyl-(4-methylpenta-2,3-dienyl)-amine [17f] (187 mg, 1 mmol, 1 equiv.)
in THF (9.3 mL, 0,1 M) were rapidly added under argon atmosphere the appropriate N-
protected-anthranylic acid (1.2 equiv.), DCC (248 mg, 1.2 equiv.) and DMAP (6.1 mg, 0.05
equiv.). The resulting mixture was stirred at room temperature overnight. The completion of
the reaction was verified by TLC. Cyclohexane (28 mL) was then added, the mixture was

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filtered over a celite pad and then concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel eluting with cyclohexane/AcOEt 7:3.
4.2.1.
N-Benzyl-N-(4-methylpenta-2,3-dienyl)-2-(4-methylphenylsulfonamido)benzamide
(1a) - White solid. (Yield: 70%). M.p.: 107-109 °C. IR (neat) 1620, 1597, 1337, 1164, 737
1
cm-1. Mixture of two rotamers in a 3.1:1 ratio. H-NMR: (400 MHz, CDCl3): 1.75 (6H, s),
2.20-2.50 (3H, m), 3.13 (2H, s br), 4.64 (2H, s br), 4.73-4.90 (1H, m), 6.70-7.80 (13H, m),
8.41 (1H, s br) (major rotamer); 1.75 (6H, s), 2.20-2.50 (3H, m), 3.96 (2H, s br), 4.17 (2H, s
br), 4.85-5.10 (1H, m), 6.70-7.80 (13H, m), 8.57 (1H, s br) (minor rotamer). 13C-NMR (100
MHz, CDCl3): 20.6 (q), 21.6 (q), 47.0 (t), 47.4 (t), 85.1 (d), 98.7 (s), 124.3 (d), 126.2 (d),
126.9 (s), 127.3 (d), 127.8 (d), 128.1 (d), 129.1 (d), 129.7 (d), 130.2 (d), 131.3 (d), 134.9 (s),
136.6 (s), 143.7 (s), 153.8 (s), 170.1 (s), 203.2 (s) (major rotamer); 20.6 (q), 21.9 (q), 47.0 (t),
47.4 (t), 85.1 (d), 98.7 (s), 123.9 (d), 126.2 (d), 126.9 (s), 127.3 (d), 127.8 (d), 128.2 (d),
129.1 (d), 129.7 (d), 130.2 (d), 131.5 (d), 134.9 (s), 136.4 (s), 144.8 (s), 153.8 (s), 167.6 (s),
203.2 (s) (minor rotamer). HRMS (ESI +): Calcd. for C27H28N2NaO3S1 (M+Na+): 483.17128,
found: 483.17051.
4.2.2.N-Benzyl-3-methyl-N-(4-methylpenta-2,3-dienyl)-2-(4-
methylphenylsulfonamido)benzamide (1b) - Colorless oil. (Yield: 60%). IR (neat) 1614,
1451, 1164 cm-1. Mixture of two rotamers in a 2.5:1 ratio. 1H-NMR: (400 MHz, CDCl3): 1.74
(6H, d, J = 2.7 Hz), 2.30 (3H, s), 2.33 (3H, s), 3.45 (2H, d, J = 4.7), 4.62 (2H, s), 4.92 (1H,
dddd, J = 4.7, 4.7, 2.7, 2.7 Hz), 7.00 (2H, d, J = 8.0 Hz), 7.01-7.50 (8H, m), 7.54 (2H, d, J =
8.0 Hz), 7.96 (1H, s br) (major rotamer); 1.65 (6H, d, J = 2.5 Hz), 2.29 (3H, s), 2.46 (3H, s),
3.96 (2H, d, J = 5.8 Hz), 4.38 (2H, s), 4.99-5.09 (1H, m), 7.01-7.50 (10H, m), 7.75 (2H, d, J =
8.0 Hz), 7.86 (1H, s br) (minor rotamer). 13C-NMR (100 MHz, CDCl3): 19.6 (q), 20.9 (q),
21.7 (q), 47.9 (t), 48.3 (t), 85.5 (d), 98.2 (s), 125.4 (d), 126.6 (d),127.2 (d), 127.9 (d), 128.9
(d), 129.6 (d), 129.7 (d), 133.6 (d), 133.7 (s), 134.0 (s), 136.9 (s), 137.4 (s), 139.8 (s), 143.7
(s), 170.8 (s), 203.3 (s) (major rotamer); 19.6 (q), 20.6 (q), 21.9 (q), 45.5 (t), 52.7 (t), 84.6 (d),
96.5 (s), 124.6 (d), 126.9 (d), 127.2 (d), 127.9 (d), 129.2 (d), 129.6 (d), 129.9 (d), 133.6 (d),
133.7 (s), 134.0 (s), 136.9 (s), 137.4 (s), 139.8 (s), 144.0 (s), 171.3 (s), 203.7 (s) (minor
rotamer). HRMS (ESI +): Calcd. for C28H30N2NaO3S1 (M+Na+): 497.18693, found:
497.18587.

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4.2.3. Tert-butyl 2-[benzyl(4-methylpenta-2,3-dienyl)carbamoyl]phenylcarbamate (1c) -
White solid (Yield: 58%). M.p.: 98-100 °C. IR (neat) 1728, 1626, 1516, 1157 cm-1. Mixture
1
of two rotamers in a 2:1 ratio. H-NMR: (400 MHz, CDCl3): 1.52 (9H, s), 1.75 (6H, s), 3.74
(2H, s br), 4.80 (2H, s br), 4.85-5.00 (1H, m), 6.80-7.40 (8H, m), 7.70-8.25 (2H, m) (major
rotamer); 1.52 (9H, s), 1.75 (6H, s), 4.04 (2H, s br), 4.57 (2H, s br), 5.00-5.20 (1H, m), 6.80-
7.40 (8H, m), 7.70-8.25 (2H, m) (minor rotamer). 13C-NMR (100 MHz, CDCl3): 20.7 (q),
28.7 (q), 47.4 (t), 48.0 (t), 80.7 (s), 85.4 (d), 98.6 (s), 121.4 (d), 122.3 (d), 124.6 (s), 126.9 (d),
127.9 (d), 128.4 (s), 129.0 (d), 130.9 (d), 137.2 (s), 153.2 (s), 170.8 (s), 203.0 (s). HRMS (ESI
+): Calcd. for C25H30N2NaO3S (M+Na+): 429.21486, found: 429.21436.
4.2.4. N-Benzyl-N-(4-methylpenta-2,3-dienyl)-2-(4-nitrophenylsulfonamido)benzamide (1d) -
Yellow solid. (Yield: 62%). M.p.: 70-72 °C. IR (neat) 1619, 1531, 1348, 1170 cm-1. Mixture
of two rotamers in a 3.9:1 ratio. 1H-NMR: (400 MHz, CDCl3): 1.75 (6H, s br), 3.20 (2H, s br),
4.62 (2H, s br), 4.70-4.90 (1H, m), 7.00-8.40 (13H, m), 8.80 (1H, s br) (major rotamer); 1.75
(6H, s br), 3.96 (2H, s br), 4.29 (2H, s br), 4.85-5.05 (1H, m), 7.00-8.40 (13H, m), 9.0 (1H, s
br) (minor rotamer). 13C-NMR (100 MHz, CDCl3): 20.6 (q), 47.0 (t), 47.6 (t), 84.8 (d), 99.4
(s), 124.2 (d), 124.6 (d), 125.1 (d), 126.9 (s), 127.6 (d), 128.6 (d), 129.3 (d), 130.0 (d), 131.7
(d), 134.6 (d), 135.6 (s), 136.6 (s), 145.2 (s), 150.2 (s), 169.7 (s), 203.3 (s). HRMS (ESI +):
Calcd. for C26H25N3NaO5S1 (M+Na+): 514.14071, found: 514.13935
4.3. General procedure for the Pd-catalysed domino sequence
NaH (4.8 mg, 0.12 mmol, 1.2 equiv., 60% dispersion in mineral oil) was added to a solution
of the appropriate N-protected allenyl amide (0.1 mmol, 1 eq.) in freshly distilled DMSO (1.6
mL) under Ar atmosphere. The resulting mixture was stirred at 50 °C for 10 min. In another
flask, n-butyllithium (10 mL, 0.02 mmol, 20 mol%, 2.0 M solution in hexanes) was added
dropwise to a solution of PdCl2(CH3CN)2 in freshly distilled DMSO under argon atmosphere.
The resulting solution, initially yellow, became dark orange. The appropriate aromatic iodide
(0.12 mmol, 1.2 equiv.) and tetrabutylammonium bromide (6.4 mg, 0.02 mmol, 20 mol%)
were then successively added, and the solution containing the deprotonated amide was added
via cannula. The resulting mixture was stirred at 90 °C. The completion of the reaction was
monitored by TLC (about 2 h) and the reaction was quenched with a saturated solution of
NH4Cl. The aqueous layer was extracted with CH2Cl2, the combined organic layers were
washed with a saturated solution of NaCl, dried on MgSO4 and concentrated in vacuo. The

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crude product was purified by flash chromatography on silica gel eluting with
cyclohexane/AcOEt 8:2.
4.3.1.
4-Benzyl-2-(2-methyl-1-p-tolylprop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2a) - Colorless oil. Yield: 82%. IR (neat) 1650, 1351, 1161,
1
716, 660 cm-1. H-NMR: (400 MHz, CDCl3): 1.41 (3H, s), 1.80 (3H, s), 2.33 (3H, s), 2.43
(3H, s), 3.06 (1H, dd, J = 15.3, 4.3), 3.33 (1H, dd, J = 15.3, 12.5), 3.74 (1H, A part of AB
system, J = 14.7 Hz), 3.81 (3H, s), 4.62 (1H, B part of AB system, J = 14.7 Hz),5.38 (1H, dd,
J = 12.5, 4.3), 6.33 (1H, d, J = 8.0, 0.9 Hz), 6.60-6.95 (1H, m), 7.03 (1H, ddd, J = 8.0, 7.8, 1.7
Hz), 7.10-7.17 (2H, m), 7.22 (1H, ddd, J = 7.8, 7.8, 0.9 Hz), 7.27-7.37 (7H, m), 7.42-7.47
(2H, m), 7.54 (1H, dd, J = 7.8, 1.7 Hz), 7.67-7.87 (1H, m); 13C-NMR (100 MHz, CDCl3):
19.4 (q), 21.4 (q), 21.9 (q), 22.8 (q), 48.9 (t), 49.5 (t), 64.3 (d), 127.6 (d), 128.2 (d), 128.3 (d),
128.8 (d), 129.2 (d), 129.8 (d), 130.1 (d), 131.1 (d), 131.3 (s), 133.6 (d), 133.7 (s), 134.1 (s),
134.2 (s), 136.6 (s), 136.7 (s), 137.0 (s), 143.9 (s), 168.0 (s).HRMS (ESI +): Calcd. for
C34H34N2NaO3S1 (M+H+): 551.23629, found: 551.23544.
4.3.2. Tert-butyl 4-benzyl-2-(2-methyl-1-p-tolylprop-1-enyl)-5-oxo-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-1-carboxylate (2k) - Colorless oil (Yield: 48%). IR (neat) 1725, 1630,
1156 cm-1. 1H-NMR: (400 MHz, CDCl3): 1.33 (9H, s), 1.49 (3H, s), 1.69 (3H, s), 2.34 (3H, s),
3.19-3.24 (1H, m), 3.41-3.49 (1H, m), 4.70 (1H, A part of AB system, J = 14.2 Hz), 5.03 (1H,
B part of AB system, J = 14.2 Hz), 5.35-5.42 (1H, m), 5.52-5.60 (1H, m), 6.30-6.40 (1H, m),
6.70-7.50 (10H, m), 7.55-7.61 (1H, m). 13C-NMR: (100 MHz, CDCl3): 21.4 (q), 22.7 (q), 28.5
(q), 49.5 (t), 50.4 (t), 63.1 (d), 80.8 (s), 126.6 (d), 128.2 (d), 128.6 (d), 128.7 (d), 129.1 (d),
129.2 (d), 130.0 (d), 130.6 (d), 133.4 (s), 136.7 (s), 137.5 (s), 147.5 (s), 156.1 (s), 168.0 (s).
HRMS: Calcd. For C32H36N2NaO3 (M+Na+): 519.26181, found: 519.26114.
4-Benzyl-2-(2-methyl-1-p-tolylprop-1-enyl)-1-(4-nitrophenylsulfonyl)-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2l) - Colorless oil. (Yield: 80%). IR (neat) 1652, 1530,
1350, 1176, 668, 616 cm-1. 1H-NMR: (400 MHz, CDCl3): 1.44 (3H, s), 1.87 (3H, s), 2.35 (3H,
s), 3.14 (1H, dd, J = 15.5, 4.4 Hz), 3.36 (1H, dd, J = 15.5, 12.3 Hz), 3.88 (1H, A part of AB
system, J = 14.5 Hz), 4.64 (B part of AB system, J = 14.5 Hz), 5.48 (1H, dd, J = 12.3, 4.4
Hz), 6.31 (1H, dd, J = 8.1, 1.0 Hz), 6.25-6.50 (1H, s br), 6.60-6.90 (1H, s br), 6.56 (1H, d, J =
9.0 Hz), 7.06 (1H, ddd, J = 8.1, , 7.8, 1.7 Hz), 7.13-7.18 (2H, m), 7.23-7.41 (6H, m), 7.50
(1H, dd, J = 7.8, 1.7 Hz), 15.2 (2H, d, J = 8.9 Hz), 8.28 (2H, d, J = 8.9 Hz). 13C-NMR (100

ACCEPTED MANUSCRIPT
MHz, CDCl3): 19.5 (q), 21.4 (q), 22.8 (q), 49.0 (t), 49.8 (t), 65.5 (d), 124.7 (d), 128.4 (d),
128.6 (d), 128.8 (d), 129.0 (d), 129.3 (d), 129.9 (d), 131.3 (d), 132.2 (s), 132.9 (s), 133.2 (d),
134.2 (s), 136.3 (s), 136.6 (s), 136.9 (s), 144.7 (s), 150.4 (s), 167.5 (s). HRMS (ESI +): Calcd.
for C33H31N3NaO5S (M+Na+): 604.18766, found: 604.18677.
4.3.3.
4-Benzyl-2-(1-(2-methoxyphenyl)-2-methylprop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)one (2b) - Colorless oil (Yield: 73%). IR (neat) 1651, 1466,
1351, 1159, 718, 658 cm-1. Mixture of two atropoisomers in a 1.1:1 ratio. H-NMR: (400
MHz, CDCl3): 1.43 (3H, s), 1.80 (3H, s ), 2.43 (3H, s), 3.07 (1H, dd, J = 15.3, 4.0 Hz), 3.34
(1H, dd, J = 15.3, 12.5 Hz), 3.52 (3H, s br, minor atropoisomer) 3.70-3.85 (1H, m), 3.94 (3H,
s br, major atropoisomer), 4.63 (1H, d, J = 14.7 Hz),5.39 (1H, dd, J = 12.5, 4.0 Hz) 5.90-6.10
(1H, m), 6.35-6.40 (1H, m), 6.78 (1H, dd, J = 7.8, 1.8 Hz), 7.00-7.25 (5H, m), 7.27-7.57 (9H,
m); 13C-NMR (100 MHz, CDCl3): 19.3 (q), 21.9 (q), 22.8 (q), 48.9 (t), 49.5 (t), 55.5 (q, minor
atropoisomer), 55.8 (q), major atropoisomer), 64.1 (d), 127.6 (d), 128.2 (d), 128.4 (d), 128.8
(d), 129.2 (d), 129.8 (d), 130.1 (d), 131.2 (d), 131.3 (s), 133.5 (d), 133.6 (d), 134.0 (s), 134.1
(s), 136.6 (s), 137.0 (s), 141.0 (s), 144.0 (s), 168.0 (s). HRMS (ESI +): Calcd. for
C34H34N2NaO4S1 (M+Na+): 589.21315, found: 589.21208.
4.3.4.
4-Benzyl-2-(1-(3-methoxyphenyl)-2-methylprop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2c)
Colorless oil. (Yield: 63%). IR (neat) 1651, 1351, 1159, 718, 658 cm-1. 1H-NMR: (400 MHz,
CDCl3): 1.40 (3H, s), 1.80 (3H, s), 2.42 (3H, s), 3.11 (1H, dd, J = 15.8, 4.5 Hz), 3.15 (3H, s),
3.49 (1H, dd, J = 15.8, 12.3 Hz), 3.66 (1H, A part of AB system, J = 14.7 Hz), 4.56 (B part of
AB system, J = 14.7 Hz), 5.40 (1H, dd, J = 12.3, 4.5 Hz), 6.09 (1H, d, J = 8.1), 6.56 (1H, d, J
= 9.0 Hz), 6.90-7.50 (m, 14H), 7.56 (1H, d, J = 7.6 Hz). 13C-NMR (100 MHz, CDCl3): 19.5
(q), 21.9 (q), 22.8 (q), 48.9 (t), 49.5 (t), 54.8 (q), 64.6 (d), 110.6 (d), 121.4 (d), 127.6 (d),
128.1 (d), 128.3 (d), 128.5 (s), 128.7 (d), 128.9 (d), 129.1 (d), 129.7 (d), 130.1 (d), 130.5 (s),
131.1 (d), 131.3 (s), 133.7 (d), 134.1 (s), 134.6 (d), 134.7 (s), 136.9 (s), 137.2 (s), 143.8 (s),
157.3 (s), 168.2 (s). HRMS (ESI +): Calcd. for C34H34N2NaO4S1 (M+Na+): 589.21315, found:
589.21202.
4.3.5.
4-Benzyl-2-(1-(4-methoxyphenyl)-2-methylprop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2d) - Colorless oil (Yield: 63% ). IR (neat) 1651, 1509,
1350, 1244, 1172 cm-1. 1H-NMR: (400 MHz, CDCl3): 1.41 (3H, s), 1.80 (3H, s), 2.43 (3H, s),

ACCEPTED MANUSCRIPT
3.06 (1H, dd, J = 15.3, 4.3), 3.32 (1H, dd, J = 15.3, 12.4), 3.75 (1H, A part of AB system, J =
14.7 Hz), 3.81 (3H, s), 4.62 (1H, B part of AB system, J = 14.7 Hz), 5.38 (1H, dd, J = 12.4,
4.3 Hz), 6.20-6.60 (2H, m), 6.41 (1H, dd, J = 7.9, 1.1 Hz), 6.80-7.10 (1H, m), 7.09 (1H, ddd,
J = 7.9, 7.6, 1.7 Hz), 7.11-7.15 (2H, m), 7.23 (1H, ddd, J = 7.6, 7.6, 1.1 Hz), 7.27-7.37 (6H,
m), 7.42-7.47 (2H, m), 7.55 (1H, dd, J = 7.6, 1.7 Hz); 13C-NMR (100 MHz, CDCl3): 19.4 (q),
21.9 (q), 22.8 (q), 48.9 (t), 49.5 (t), 55.7 (q), 64.3 (d), 127.6 (d), 128.2 (d), 128.4 (d), 128.8
(d), 129.2 (d), 129.8 (d), 130.1 (d), 131.2 (d), 131.8 (s), 132.0 (s), 133.3 (s), 133.6 (d), 134.1
(s), 134.2 (s), 136.6 (s), 136.9 (s), 144.0 (s), 158.9 (s), 168.0 (s). HRMS (ESI +): Calcd. for
C34H34N2NaO4S1 (M+Na+): 589.21315, found: 589.21188.
4.3.6. Methyl 4-[1-(4-benzyl-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin2-yl)-
2-methylprop-1-enyl]benzoate (2e) - Colorless oil (Yield: 68%). IR (neat) 1722, 1651, 1276,
1
711, 659 cm-1. H-NMR: (400 MHz, CDCl3): 1.38 (3H, s), 1.81 (3H, s), 2.43 (3H, s), 3.10
(1H, dd, J = 15.3, 4.2), 3.34 (1H, dd, J = 15.3, 12.5 Hz), 3.79 (1H, A part of AB system, J =
14.7 Hz), 3.94 (3H, s), 4.61 (1H, B part of AB system, J = 14.7 Hz), 5.39 (1H, dd, J = 12.5,
4.2 Hz), 6.29 (1H, d, J = 8.0 Hz), 6.52 (1H, s br), 7.02 (1H, ddd, J = 8.0, 7.6, 1.7 Hz), 7.10-
7.15 (2H, m), 7.22 (1H, ddd, J = 7.7, 7.6, 1.0 Hz), 7.27-7.37 (5H, m), 7.40-7.47 (2H, m), 7.54
(1H, dd, J = 7.7, 1.7 Hz), 7.50-7.85 (2H, m), 8.05-8.35 (1H, m). 13C-NMR (100 MHz,
CDCl3): 19.4 (q), 21.9 (q), 22.7 (q), 48.9 (t), 49.5 (t), 52.4 (q), 64.0 (d), 127.6 (d), 128.3 (d),
128.6 (d), 128.9 (d), 129.0 (s), 129.2 (d), 130.1 (d), 130.2 (d), 131.4 (d), 132.1 (s), 133.1 (s),
133.2 (d), 133.8 (s), 134.0 (s), 136.3 (s), 136.8 (s), 144.2 (s), 144.9 (s), 167.4 (s), 167.9 (s).
HRMS (ESI +): Calcd. for C35H34N2NaO4S (M+Na+): 617.20806, found: 617.20659.
4.3.7.
4-Benzyl-2-(2-methyl-1-(4-nitrophenyl)prop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2f) - Colorless oil. (Yield: 61%). IR (neat) 1652, 1518,
1
1346 cm-1. H-NMR: (400 MHz, CDCl3): 1.39 (3H, s), 1.81 (3H, s), 2.44 (3H, s), 3.12 (1H,
dd, J = 15.3, 4.2 Hz), 3.33 (1H, dd, J = 15.3, 12.6 Hz), 3.82 (1H, A part of AB system, J =
14.7 Hz), 4.61 (B part of AB system, J = 14.7 Hz), 5.39 (1H, dd, J = 12.6, 4.2 Hz), 6.30 (1H,
dd, J = 8.0, 1.0 Hz), 6.38-6.95 (1H, m), 7.05 (1H, ddd, J =8.0, 7.6, 1.6 Hz), 7.11-7.15 (2H,
m), 7.21-7.45 (6H, m), 7.40-7.45 (2H, m), 7.57 (1H, dd, J = 7.6, 1.6 Hz), 7.59-8.65 (3H, m)
13C-NMR (100 MHz, CDCl3): 19.5 (q), 22.0 (q), 22.8 (q), 48.8 (t), 49.6 (t), 63.9 (d), 127.6
(d), 128.3 (d), 128.7 (d), 128.9 (d), 129.3 (d), 130.2 (d), 130.4 (d), 131.4 (d), 132.3 (s), 132.8
(d), 133.1 (s), 133.7 (s), 134.1 (s), 136.0 (s), 136.7 (s), 144.4 (s), 147.3 (s), 167.7 (s). HRMS
(ESI +): Calcd. for C33H31N3NaO5S (M+Na+): 604.18766, found: 604.18638.

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4.3.8.
2-[1-(4-Acetylphenyl)-2-methylprop-1-enyl]-4-benzyl-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2g) - Colorless oil (Yield: 71%). IR (neat) 1682, 1650,
1350, 1158, 714, 660 cm-1. 1H-NMR: (400 MHz, CDCl3): 1.39 (3H, s), 1.81 (3H, s), 2.43 (3H,
s), 2.62 (3H, s), 3.11 (1H, dd, J = 15.2, 4.2 Hz), 3.34 (1H, dd, J = 15.2, 12.5 Hz), 3.79 (1H, A
part of AB system, J = 14.6 Hz), 4.61 (1H, B part of AB system, J = 14.6 Hz), 5.39 (1H, dd, J
= 12.5, 4.2 Hz), 6.26 (1H, dd, J = 8.1, 0.9 Hz), 6.40-6.75 (1H, br s), 6.99 (1H, ddd, J = 8.1,
7.6, 1.7 Hz), 7.13 (2H, m), 7.22 (1H, ddd, J = 7.6, 7.6, 0.9 Hz), 7.27-7.38 (5H, m), 7.41-7.46
13
(2H, m), 7.55 (1H, dd, J = 7.6, 1.7 Hz), 7.55-7.80 (2H, br s), 7.80-8.30 (1H, s br). C-NMR
(100 MHz, CDCl3): 19.4 (q), 21.9 (q), 22.7 (q), 27.0 (q), 48.9 (t), 49.5 (t), 64.0 (d), 127.6 (d),
128.3 (d), 128.6 (d), 128.9 (d), 129.2 (d), 130.1 (d), 130.2 (d), 131.2 (d), 132.1 (s), 133.1 (d),
133.8 (s), 134.1 (s), 136.0 (s), 136.3 (s), 144.2 (s), 145.2 (s), 167.8 (s), 198.2 (s). HRMS (ESI
+): Calcd. for C35H34N2NaO4S (M+Na+): 601.21315, found: 601.21187.
4.3.9.
4-Benzyl-2-(2-methyl-1-phenylprop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2h) - White oil. (Yield: 67%). IR (neat) 1651, 1351, 1160,
1
703, 658 cm-1. H-NMR: (400 MHz, CDCl3): 1.40 (3H, s), 1.82 (3H, s), 2.43 (3H, s), 3.08
(1H, dd, J = 15.3, 4.2), 3.35 (1H, ddd, J = 15.3, 12.4, 0.8), 3.75 (1H, A part of AB system, J =
14.7 Hz), 4.62 (1H, B part of AB system, J = 14.7 Hz), 5.40 (1H, dd, J = 12.4, 4.2 Hz), 6.30
(2H, dd, J = 8.1, 1.1 Hz), 6.45 (1H, s br), 6.90-7.05 (1H, m), 7.03 (1H, ddd, J = 8.1, 7.6, 1.7
Hz), 7.11-7.16 (2H, m), 7.18-1.25 (1H, m), 7.21 (1H, ddd, J = 7.6, 7.6, 1.1),7.27-7.37 (5H,
m), 7.42-7.60 (4H, m), 7.54 (1H, dd, J = 7.6, 1.7 Hz); 13C-NMR (100 MHz, CDCl3): 19.4 (q),
21.9 (q), 22.8 (q), 48.9 (t), 49.5 (t), 64.2 (d), 127.0 (d), 127.6 (d), 128.2 (d), 128.8 (d), 129.2
(d), 129.8 (d), 130.1 (d), 131.2 (d), 131.4 (s), 133.5 (d), 133.8 (s), 134.0 (s), 136.6 (s), 137.0
(s), 139.7 (s), 144.0. (s), 168.0 (s). HRMS (ESI +): Calcd. for C33H32N2NaO3S1 (M+Na+):
559.20258, found: 559.20159.
4.3.10.
4-Benzyl-2-(2-methyl-1-pyridin-2-yl)prop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2i) - Colorless oil. (Yield: 70%) IR (neat) 1651, 1351,
1
1159, 712, 658 cm-1. H-NMR: (400 MHz, CDCl3): 1.40 (3H, s), 1.81 (3H, s), 2.43 (3H, s),
3.10 (1H, dd, J = 15.3, 4.2), 3.25-3.33 (1H, m), 3.86 (1H, A part of AB system, J = 14.7 Hz),
4.59 (1H, B part of AB system, J = 14.7 Hz), 5.34-5.40 (1H, m), 6.32 (1H, s br), 7.08-7.14
(3H, m), 7.17-7.40 (8H, m), 7.41-7.48 (2H, m), 7.51-7.58 (1H, m), 7.60-8.40 (1H, m), 8.52
(1H, d, J = 4.3 Hz). 13C-NMR (100 MHz, CDCl3): 19.5 (q), 21.9 (q), 22.9 (q), 48.7 (t), 49.6

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(t), 63.9 (d), 127.6 (d), 128.3 (d), 128.2 (d), 128.8 (d), 129.1 (s), 129.3 (d), 130.2 (d), 130.3
(d), 130.4 (d), 131.2 (s), 131.5 (d), 132.8 (s), 133.0 (s), 133.7 (d), 134.0 (s), 134.4 (s), 136.1
(s), 136.7 (s), 144.3 (s), 167.8 (s). HRMS (ESI +): Calcd. for C32H31N3NaO3S1 (M+Na+):
560.19783, found: 560.19650.
4.3.11.
4-Benzyl-9-methyl-2-(2-methyl-1-p-tolylprop-1-enyl)-1-tosyl-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (2j) - Colorless oil (Yield: 75%). IR (neat) 1651, 1351,
1162, 700, 658 cm-1.1H-NMR: (400 MHz, CDCl3): 1.48 (3H, s), 1.57 (3H, s), 1.95 (3H, s),
2.32 (3H, s), 2.46 (3H, s), 3.00 (1H, dd, J = 15.2, 3.7), 3.18 (1H, A part of AB system, J =
14.9 Hz), 3.59 (1H, dd, J = 15.2, 12.2 Hz), 4.69 (1H, A part of AB system, J = 14.9 Hz), 5.36
(1H, dd, J = 12.2, 3.6 Hz), 6.40-6.80 (1H, m), 6.90-7.05 (2H, m), 7.10-7.15 (2H, m), 7.16-
7.22 (1H, m), 7.23-7.35 (6H, m), 7. 38 (2H, d, J = 8.2 Hz), 7.50-7.55 (1H, m), 7.63 (2H, d, J =
8.2 Hz); 13C-NMR (100 MHz, CDCl3): 18.7 (q), 20.2 (q), 21.4 (q), 21.9 (q), 23.6 (q), 48.8 (t),
49.8 (t), 64.6 (d), 128.1 (d), 128.4 (d), 128.5 (d), 128.7 (d), 129.1 (d), 130.2 (d), 132.3 (s),
133.8 (s), 134.1 (s), 134.6 (d), 135.0 (s), 136.1 (s), 136.8 (s), 137.0 (s), 143.5 (s), 144.1 (s),
168.5 (s). HRMS (ESI +): Calcd. for C35H36N2NaO3S1 (M+Na+): 587.23388, found:
587.23221.
Acknowledgements
The authors thank UPMC, CNRS and Università dell’Insubria for financial support.
Appendix A. Supplementary data
1H-NMR and 13C-NMR spectra of compounds 1a-d and 2a-j can be found at DOI:
References
[1] E. Shorterm A Historical Dictionary of Psychiatry, Oxford University Press, New York, 2005.
[2] R.M. McKernan, T.W. Rosahl, D.S. Reynolds, C. Sur, K.A. Wafford, J.R. Atack, S. Farrar, J. Myers, G.
Cook, P. Ferris, L. Garrett, L. Bristow, G. Marshall, A. Macaulay, N. Brown, O. Howell, K.W. Moore,
R.W. Carling, L.J. Street, J.L. Castro, C.I. Ragan, G.R. Dawson, P.J. Whiting, Nature Neuroscience 3
(2000) 587-592.
[3] (a) W. Leimgruber, V. Stefanovic, F. Schenker, A. Karr, J. Berger, J. Am. Chem. Soc. 87 (1965) 5793-
5795;
(b) D.E. Thurston, D.S. Bose, Chem. Rev. 1994, 94, 433-465.

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[4] (a) D.E. Thurston, “Advances in the Study of Pyrrolo[2,1-c][1,4]-benzodiazepine (PBD) Antitumor
Antibiotics”, in Molecular Aspects of Anticancer Drug-DNA Interactions, vol. 1 (Eds.: D. Neidle, M. J.
Waring), The Macmillan Press Ltd., London, 1993, pp. 54-88;
(b) J.M. Samanen, F.E. Ali, L.S. Barton, W.E. Bondinell, J.L. Burgess, J.F. Callahan, R.R. Calvo, W. Chen,
L. Chen, K. Erhard, G. Feuerstein, R. Heys, S.-M. Hwang, D.R. Jakas, R.M. Keenan, T.W. Ku, C. Kwon,
C.-P. Lee, W.H. Miller, K.A. Newlander, A. Nichols, M. Parker, C.E. Peishoff, G. Rhodes, S. Ross, A.
Shu, R. Simpson, D. Takata, T.O. Yellin, I. Uzsinskas, J.W. Venslavsky, C.-K. Yuan, W.F. Huffman, J.
Med. Chem. 39 (1996) 4867-4870.
[5] (a) E. DeClerq, Antiviral Res. 38 (1998) 153-224;
(b) K.A. Parker, C.A. Coburn, J. Org. Chem. 57 (1992) 97-100;
(c) M.J. Kukla, H.J. Breslin, C.J. Diamond, P.P. Grous, C.Y. Ho, M.Miranda, J.D. Rodgers, R.G. Sherrill,
E. De Clercq, R. Pauwels, K. Andries, L.J. Moens, M.A. C. Janssen, P.A. J. Janssen, J. Med. Chem. 34
(1991) 3187-3197.
[6] (a) R.M. Keenan, J.F. Callahan, J.M. Samanene, W.E. Bondinell, R.R. Calvo, L. Chen, C. DeBrosse, D.S.
Eggleston, R.C. Haltiwanger, S.M. Hwang, D.R. Jakas, T.W. Ku, W.H. Miller, K.A. Newlander, A.
Nichols, M.F. Parker, L.S. Southhall, I. Uzinskas, J.A. Vasko-Moser, J.W. Venslavsky, A.S. Wong, W.F.
Huffman, J. Med. Chem. 42 (1999) 545-559;
(b) P. Verdié, G. Subra, L. Feliu, P. Sanchez, G. Bergé, G. Garcin, J. Martinez, J. Comb. Chem. 9 (2007)
254-262;
(c) M.D. Cummings, C. Schubert, D.J. Parks, R.R. Calvo, L.V. LaFrance, J. Lattanze, K.L. Milkiewicz, T.
Lu, Chem. Biol. Drug. Des. 67 (2006) 201-205;
(d) N. Cabedo, X. Pannecoucke, J.-C. Quirion, Eur. J. Org. Chem. (2005) 1590-1596.
[7] L. Costantino, D. Barlocco, Curr. Med. Chem. 13 (2006) 65-85.
[8] A. Walser, R.I. Fryer, in Chemistry of heterocyclic compounds. Bicyclic diazepines (Eds.: E.C. Taylor, A.
Weissberger); Wiley; Chichester, UK, 1991; Vol. 50, p. 431.
[9] For examples of tricyclic 1,4-benzodiazepin-5-ones, see: (a) L.P. Tardibono, M.J. Miller, Org. Lett. 11
(2009) 1575-1578;
(b) G. Broggini, G. Molteni, A. Terraneo, G. Zecchi, Tetrahedron 55 (1999) 14803-14806;
(c) T. Wang, A. S. Lui, I.S. Cloudsale, Org. Lett. 1 (1999) 1835-1839;
(d) Q. Zhou, W. Duan, D. Simmons, Y. Shayo, M.A. Raymond, R.T. Dorr, L.H. Hurley, J. Am. Chem. Soc.
123 (2001) 4865-4866;
(e) I.A. O’Neil, S. Thompson, S.B. Kalindjian, T.C. Jenkins, Tetrahedron Lett. 44 (2003) 7809-7812;
(f) G.A. Kraus, A. Melekhov, Tetrahedron 54 (1998) 11749-11754;
(g) D.J. Skalitzky, J.T. Marakovits, K.A. Maegley, A.E. Ekker, X.-H. Yu, Z. Hostomsky, S.E. Webber,
B.W. Eastman, R. Almassay, J. Li, N.J. Curtin, D.R. Newell, A.H. Calvert, R.J. Griffin, B.T. Golding, J.
Med. Chem. 46 (2003) 210-213.
[10] For examples of tetracyclic 1,4-benzodiazepin-5-ones, see: (a) G. Broggini, I. De Marchi, M. Martinelli, G.
Paladino, T. Pilati, A. Terraneo, Synthesis (2005) 2246-2252;
(b) D.K. Mohapatra, P.K. Maity, M. Shabab, M.I. Khan, Bioorg. Med. Chem. Lett. 19 (2009) 5241-5245;
(c) L. Basolo, E.M. Beccalli, E. Borsini, G. Broggini, M. Khansaa, M. Rigamonti, Eur. J. Org. Chem.
(2010) 1694-1703;
(d) C.S. Chambers, N. Patel, K. Hemming, Tetrahedron Lett. 51 (2010) 4859-4861.
[11] For papers concerning tarpane, see: (a) A.R. Hanze, R.E. Strube, M.E. Greig, J. Med. Chem., 6 (1963) 767-
771;
(b) F. Hunziker, H. Lauener, J. Smutz, Arzneim.-Forsh., 13 (1963) 324;
(c) E. Waldvogel, G. Schwarb, J.-M. Bastian, J.-P. Bourquin, Helv. Chim. Acta. 59 (1976) 866-877.
[12] For papers concerning abbeymicin, see: (a) P. G. Baraldi, G. Balboni, B. Cacciari, A. Guiotto, S.
Manfredini, R. Romagnoli, G. Spalluto, D.E. Thurston, P.W. Howard, N. Bianchi, C. Rutigliano, C.
Mischiati, R. Gambari, J. Med. Chem. 42 (1999) 5131-5141;
(b) A. Kamal, E. Laxman, N. Laxman, N.V. Rao, Bioorg. Med. Chem. Lett. 10 (2000) 2311-2313.
[13] For papers concerning flumazenil, see: (a) W. Frostl and L. Maitre, Pharmacopsych. 22 (1989) 54-56;

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(b) R.F. Anton, H. Myrick, A.M. Baros, P.K. Latham, P.K. Randall, T.M. Wright, S.H. Stewart, R. Waid,
R. Malcolm, J. Clin. Psycopharm. 29 (2009) 334-342;
(c) M. Wallner, R.W. Olsen, Br. J. Pharmacol. 154 (2008) 288-298.
[14] For papers concerning bretazenil, see: A.G. Katsifis, M.E. McPhee, F. Mattner and D.D. Ridley, Aust. J.
Chem. 52 (1999) 1061-1069.
[15] (a) A. Jackson, B.B. Guilbert, S.D. Plant, J. Goggi, M.R. Battle, J.L. Woodcraft, A. Gaeta, C.L. Jones, D.R.
Bouvet, P.A. Jones, D.M. O’Shea, P.H. Zheng, S.L. Brwn, A.L. Ewan, W. Trigg, Bioorg. Med. Chem. Lett.
23 (2013) 821-826;
(b) R.L. Clark, C.J. Clements, M.P. Barrett, S.P. Mackay, R.P. Rathnam, G. Owusu-Dapaah, J. Spencer, J.
K. Huggan, Bioorg. Med. Chem. 20 (2012) 6019-6033;
(c) K. Sorra, K. Mukkanti, S. Pusuluri, Tetrahedron 68 (2012) 2001-2006;
(d) B. Pettersson, V. Hasimbegovic, J. Bergman, J. Org. Chem. 76 (2011) 1554-1561;
(e) K. Brahma, A.K. Sasmal, C. Chowdhury, Org. Biomol. Chem. 9 (2011) 8422-8429;
(f) M. Biel, P. Deck, A. Giannis, H. Waldmann, Chem. Eur. J. 12 (2006) 4121-4143;
(g) A. W. Thomas, Bioorg. Med. Chem. Lett. 12 (2002) 1881-1884;
(h) V. Santagada, E. Perissutti, F. Fiorino, B. Vivenzio, G. Caliendo, Tetrahedron Lett. 42 (2001) 2397-
2400.
[16] a) S.-C. Lee, S.B. Park, Chem. Commun. (2007) 3714-3716;
(b) S. Braese, C. Gil, Chem. Eur. J. 11 (2005) 2680-2688.
[17] (a) C. Kammerer, G. Prestat, D. Madec, G. Poli, Chem. Eur. J. 15 (2009) 4224-4227;
(b) E.M. Beccalli, G. Broggini, F. Clerici, S. Galli, C. Kammerer, M. Rigamonti, S. Sottocornola, Org. Lett.
11 (2009) 1563-1566;
(c) A.M. Manzo, A.D. Perboni, G. Broggini, M. Rigamonti, Tetrahedron Lett. 50 (2009) 4696-4699;
(d) G. Broggini, S. Galli, M. Rigamonti, S. Sottocornola, G. Zecchi, Tetrahedron Lett. 50 (2009) 1447-
1449;
(e) E.M. Beccalli, A. Bernasconi, E. Borsini, G. Broggini, M. Rigamonti, G. Zecchi, J. Org. Chem. 75
(2010) 6923-6932;
(f) A. Boutier, C. Kammerer-Pentier, N. Krause, G. Prestat, G. Poli, Chem. Eur. J. 18 (2012) 3840-3844;
(g) G. Broggini, E. Borsini, A. Fasana, G. Poli, F. Liron, Eur. J. Org. Chem. (2012) 3617-3624;
(h) C. Kammerer-Pentier, A. Diez Martinez, J. Oble, G. Prestat, P. Merino, G. Poli, J. Organomet. Chem.
714 (2012) 53-59.
[18] (a) G. Poli, G. Giambastiani, J. Org. Chem. 67 (2002) 9456-9459;
(b) G. Prestat, G. Poli, Chemtracts-Org. Chem. 17 (2004) 97.
[19] (a) E.M. Beccalli, G. Broggini, G. Paladino, A. Penoni, C. Zoni, J. Org. Chem. 69 (2004) 5627-5630;
(b) J.D. Neukom, A.S. Aquino, J.P. Wolfe, Org. Lett. 13 (2011) 2196-2199;
See also: (c) E.M. Beccalli, G. Broggini, G. Paladino, C. Zoni, Tetrahedron 61 (2005) 61-68.
[20] M.D. Surman, M.J. Mulvihill, M.J. Miller, Org. Lett. 4 (2002) 139-141.
[21] We exclusively worked with gem-dimethyl substituted allenes, as in our previous related study concerning
Pd-catalyzed allene cyclizations (ref 17a) only this type of allenes gave clean and reliable results.
[22] This protocol, found after a thorough study, is a superior method to obtain a very active underligated Pd(0)
species and in our hands favorably compared with all the other tested methods to generate zerovalent
palladium.
[23] Not unexpectedly, use of aryl bromides for this protocol was not effective. See for example reaction 1 →
12 in ref 17a.
[24] Square brackets around the metal atom are intended to render implicit the dative ligands. For example,
complex I will likely form surrounded by some loosely coordinated DMSO molecules.
[25] Contrary to the too robust tosyl function, the nosyl function is known to be easily cleaved under
nucleophilic aromatic substitution conditions (i.e. mercaptoethanol / DBU).
[26] Attempted preparation of the corresponding N-SES derivative failed.
[27] DOS: Diversity oriented Organic Synthesis: S.L. Schreiber, Science 287 (2000) 1964-1969.

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Synthesis of 1,4-benzodiazepinones via palladium-catalysed allene
carbopalladation / amination domino sequence
Micol Rigamonti,a,b Guillaume Prestat,a† Gianluigi Broggini,b* and Giovanni Poli,a*
Contents
General information
Spectral data
1
2-17
General information:
DMSO was distilled over CaH2 under reduced pressure. All other solvents were dried on an
MBraun solvent purification system MB SPS-800. Chemicals were purchased from Sigma Aldrich
and Acros Organics and used as received, unless stated.
All reactions were conducted under argon and glassware was flame-dried before use. Flash
chromatography was conducted on silica gel (0.040-0.063 mm). Analytical Thin Layer
Chromatography (TLC) were performed on Merck precoated 60 F254 plates. Melting points were
measured using a Stuart Scientific SMP3 apparatus. IR spectra were recorded on a Bruker Tensor
27 (Pike) apparatus and only the strongest or the structurally most important peaks were listed.
1H NMR (400 MHz) and 13C NMR (100 MHz) were recorded on a Bruker Avance 400
spectrometer (BBFO probe). Chemical shifts are reported in ppm relative to residual peak of
deuterated chloroform as internal standard. 13C NMR spectra are 1H-decoupled and the
determination of the multiplicities was achieved by the DEPT pulse sequence.
High resolution mass spectrometry was performed on a Thermo Fisher Scientific LTQ-Orbitrap
(ESI).
1

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1H spectrum of compound 1a
Ts
•
NH
N
O
13C spectrum of compound 1a
Ts
•
1H spectrum of compound XY
NH
N
O
2

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1H spectrum of compound 1b
Ts
NH
•
N
O
13C spectrum of compound 1b
Ts
•
NH
N
O
3

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1H spectrum of compound 1c
Boc
NH
•
N
O
13C spectrum of compound 1c
Boc
NH
•
N
O
4

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1H spectrum of compound 1d
Ns
•
NH
N
O
13C spectrum of compound 1d
Ns
•
NH
N
O
5

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1H spectrum of compound 2a
Ts
O
N
N
13C spectrum of compound 2a
Ts
N
N
O
6

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1H spectrum of compound 2k
Boc
N
N
O
13C spectrum of compound 2k
Boc
N
N
O
7

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1H spectrum of compound 2l
Ns
N
N
O
13C spectrum of compound 2l
Ns
N
N
O
8

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1H spectrum of compound 2b
O
Ts
O
N
N
13C spectrum of compound 2b
O
Ts
N
N
O
9