One-pot sequential Ti-/Cu-catalysis for tandem amidation/Ullmann-type cyclization: Synthesis of model benzodiazepine(di)ones promoted by microwave irradiation

Article abstract of DOI:10.1039/c2ob07063d

The application of sequential Ti-/Cu-catalysis in the model one-pot synthesis of benzodiazepine(di)ones promoted by microwave irradiation demonstrates the expediency of dual catalysis in coupling-cyclization methods useful for diversity-oriented synthesis

Full text of DOI:10.1039/c2ob07063d

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PAPER
One-pot sequential Ti-/Cu-catalysis for tandem amidation/Ullmann-type
cyclization: synthesis of model benzodiazepine(di)ones promoted by
microwave irradiation†
Leonardo Ciofi,a Andrea Trabocchi,*a Claudia Lalli,b Gloria Menchia and Antonio Guarnaa
Received 9th December 2011, Accepted 30th January 2012
DOI: 10.1039/c2ob07063d
The application of sequential Ti-/Cu-catalysis in the model one-pot synthesis of benzodiazepine(di)ones
promoted by microwave irradiation demonstrates the expediency of dual catalysis in coupling-cyclization
methods useful for diversity-oriented synthesis.
Introduction
The search for efficient and mild methodologies for the prep-
aration of heterocycles is a challenge of increasing impact for
chemists involved in the construction of organic molecules with
enhanced complexity and chemical diversity. From this point of
view, it is well recognized that the development of multi-bond
Scheme 1 Sequential catalytic approach to cyclic chemotypes.
forming protocols, such as multicomponent reactions,1 domino
reactions,2 or one-pot multi-step processes are important issues
for the construction of small molecules in diversity-oriented syn-
thesis from operational simplicity and assembly efficiency.3
Efforts in improving library generation are focusing on the con-
cepts of step economy and tandem catalysis, in order to proceed
rapidly with the generation of wide arrays of small molecule
collections. Tandem transformations are usually operated in one-
pot without the need for intermediate workups or purifications,
and recently, multicatalytic approaches have attracted growing
interest in this field.4 In multicatalytic processes, multiple dis-
tinct catalytic steps are executed during a single operation, in
either a tandem or sequential fashion. Although there has been
increasing recognition of the power of multicatalytic synthesis,
the number and range of examples disclosed in this area to date
is still limited.3h,5
envisaged the possibility of exploring a new Ti-/Cu-catalyzed
sequential one-pot process for the generation of 1,4-benzo-
diazepine-2,5-diones and 1,4-benzodiazepine-2-ones (Scheme 1).
The relevance of such heterocyclic compounds in medicinal
chemistry is remarkable, for instance the synthesis and analysis
of 12 melanocortin receptor agonists using the 1,4-benzo-
diazepine-2,5-dione template has been recently reported.6 These
heterocyclic compounds proved to possess anticonvulsant,
anxiolytic, and antitumor properties, as well as being antagonists
of cholecystokinin receptor (CCK), opiate receptor, and platelet
glycoprotein IIb–IIIa.7 In addition, the 1,4-benzodiazepine-2,5-
dione moiety appears in a number of natural products,8 and it
has been extensively studied in combinatorial chemistry as a
molecular platform for appendage diversity.9 We planned to
combine the concept of sequential catalytic processes to micro-
wave-assisted synthetic technique, as the interest to microwave-
assisted reactions has been increasing among organic and medic-
inal chemists in recent years, not only because these reactions
exhibit particular or unexpected reactivity in some cases, but
also because they are significantly useful for green chemistry.10
We envisioned the possibility of exploring catalyzed processes
for key coupling-cyclization steps in the generation of hetero-
cyclic chemotypes. Accordingly, it would be highly valuable
to develop sequential one-pot processes to achieve arrays of
heterocycles in a diversity-oriented manner. As a case study, we
aDepartment of Chemistry “Ugo Schiff”, University of Florence, Via
della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy.
E-mail: andrea.trabocchi@unifi.it; Fax: +39 055 457 3531; Tel: +39
055 457 3507
Results and discussion
bCentre de Recherche de Gif, Institut de Chimie des Substances
Naturelles CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex,
France
We initially explored the reactivity of N-(2-iodobenzoyl) proline
esters in the amidation reaction with butylamine using the Zr-cat-
alyzed process, as reported by Porco and collaborators.11 This
process is a straightforward route for the preparation of amides
†Electronic supplementary information (ESI) available: copies of 1H
and 13C NMR spectra. See DOI: 10.1039/c2ob07063d
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Table 1 Exploration of the reaction conditions for the first step of the
process
Table 2 Exploration of the reaction conditions for the second step of
the process
Conversion,a %
Entry
Catalyst
Additive
Solvent
Conversion,a %
Entry
Catalyst
Ligand
Base
1
2
3
4
5
6
7
—
—
—
—
HOAt
HYP
HYP
—
DMSO
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
0
0
20
0
89
91
0
1
2
3
4
5
Pd(OAc)2
(PPh3)2PdCl2
PdCl2
CuI (10% mol)
CuI (20% mol)
BINAP
—
Dppf
TCAb
TCAb
KOAc
KOAc
KOAc
K2CO3
K2CO3
0
10
0
43
68
Zr(OtBu)4
ZrCl4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
a Measured by 1H NMR. b Thiophene-2-carboxylic acid.
—
a Measured by 1H NMR.
Table 3 Exploration of the reaction conditions for the second step of
the process
from unactivated esters and amines using a catalytic system com-
prising group (IV) metal alkoxides in conjunction with additives,
including 1-hydroxy-7-azabenzotriazole (HOAt), which was
found to be general and of wide applicability using a variety of
structurally diverse esters and amines.
Control experiments using proline derivative 1 as the substrate
showed the reaction did not occur in the absence of the catalyst
both in toluene and DMSO (Table 1, entries 1–2). We found this
reaction to proceed sluggishly with Zr(OtBu)4 using this sub-
strate, with only 20% conversion after 2 h at 120 °C (entry 3).
We moved then on the cheaper and easier to handle ZrCl4 and
Ti(OiPr)4, and whereas ZrCl4 did not lead to any product, even
with the use of 2-hydroxypyridine (HYP) as an additive, the
application of Ti(OiPr)4 resulted in the successful conversion to
the desired amide. No improvements in presence of the additive
were observed (entries 4–6), and a test reaction in DMSO failed
to succeed, thus impairing the application of the two-steps
process in the same solvent (entry 7).
A possible reason for Ti(OiPr)4 showing better catalytic
activity compared to Zr(OtBu)4 could be less hindrance of the
former towards the bulky o-iodobenzoyl-proline ethyl ester used
as the starting material. The choice of ethyl esters as substrates
was due to the high reactivity of the corresponding methyl
derivatives, which provided the trans-esterified isopropyl ester
derivatives in significant amounts. Thus, a putative ligand
exchange process with the organometallic species resulted in a
capping reaction towards the desired amidation process. In fact,
the isopropyl ester does not proceed in the amidation reaction
due to high hindrance displayed by this ester, as reported.11
Ethyl ester substrates proved to work without any trans-
esterification side reactions even at high temperatures (120 °C),
thus giving the desired products in good yields.
Yield,
%
Cmpd
X
R1
R2
R3
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CO –(CH2)3–
CO –(CH2)3–
CO –(CH2)3–
CO –(CH2)3–
CO –(CH2)3–
CO –(CH2)3–
CO –(CH2)3–
CO
CO
CO
CO CH2Ph
CH2 –(CH2)3–
CH2 –(CH2)3–
CH2 Ac
CH2CH2CH2CH3 63
CH2CH(CH3)3
CH2Ph
CH2CHvCH2
CH2CH2OCH3
67
56
62
42
CH2CH(OCH3)2 45
CH2CH2OH 19
CH2CH(CH3)3 CH2CH2CH2CH3 18
H
H
H
CH(CH3)3
CH2Ph
H
CH2CH2CH2CH3 28
CH2CH2CH2CH3 24
CH2CHvCH2
CH2CH2CH2CH3 43
CH2CHvCH2 18
CH2CH2CH2CH3 60
CH2CHvCH2 53
26
H
H
CH2 Ac
The sequential one-pot process proved to work successfully,
as the Cu-catalyzed reaction was found not to be altered by the
presence of Ti(OiPr)4. Specifically, the two-steps process con-
sisted of carrying out the first process in a concentrated toluene
solution, followed by addition to the more diluted DMSO
solution containing the second catalytic system. The presence of
toluene in the solvent mixture, although in lower amounts with
respect to DMSO, did not affect the outcome of the second step.
The one-pot process was analyzed for its scope on an array of
substrates as reported in Table 3. N-(2-Iodobenzoyl)proline ethyl
ester proved to succeed in giving the title benzodiazepinediones
3–8 for aliphatic amines, allylamine and benzylamine, with
overall yields ranging from 42 to 67%. When aminoethanol was
used as the amino component, the yield for the corresponding
compound 9 dropped to 19%, possibly due to the coordinating
For the cyclization step consisting of the N-arylation process,
both Cu- and Pd-based catalysts were taken into account, as
reported (Table 2).12 Poor yields were observed for the Pd-based
catalytic process, whereas an Ullmann-type reaction catalyzed by
CuI was optimal when used in an amount of 20% and in the
presence of 40% mol equivalents of thiophene-2-carboxylic acid
as a ligand for copper.
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role of the hydroxyl group towards copper, thus impairing the
cyclization step. Also, N-(2-iodobenzoyl)amino esters deriva-
tives from primary amino acids such as phenylalanine, leucine
and valine gave benzodiazepinediones 10–12 in poor yields
ranging from 18 to 28%, respectively, suggesting the amide
proton as an interfering element in the cyclization process pro-
moted by copper. Accordingly, when the capped N-acetyl-N′-(2-
iodobenzyl)glycine ethyl ester not bearing any amide protons
was taken into account, the corresponding benzodiazepinones
16–17 were achieved in 53 and 60% yield by reacting with allyl-
amine and butylamine, respectively. The dual catalytic one-pot
process was assayed on N-(2′-iodobenzyl)proline ethyl ester as
an example of tertiary amine, to probe the compatibility of the
method with a different substrate. The reaction with butylamine
resulted in the corresponding benzodiazepinone 14 in 60%, thus
indicating full compatibility also with tertiary amines. Neverthe-
less, the amine reactant proved to play a role in the successful
outcome of the process, as bulky amines and substrates posses-
sing a β-branched hindrance, such as t-butylamine, cyclohexyl-
amine and cyclopropylamine, failed to work. Accordingly, it has
to be mentioned that amidation reaction needs fine tuning to give
best yields, as reported,11 specifically in varying solvent, concen-
tration and additives depending on selected starting esters and
amines. In our process, with aim to extend the concept on library
development, we found important to select a unique protocol for
different substrates and reagents which however gave good
overall yields and proved to work in a sequential fashion with
the subsequent arylation reaction.
When the process was carried out with pre-mixing of the two
catalysts and all the reactants in a challenging fully one-pot oper-
ation, the two-steps reaction failed to produce the title bicyclic
compound. This was probably due to inactivation of the first
reaction step by the presence of the copper moiety. Moreover,
the fully one-pot process was impaired by the solvent system, as
the two steps required different solvents (see method develop-
ment). Interestingly, a side-reaction consisting of the oxidation of
the amine to the corresponding aldehyde was observed in low
yield, possibly resulting from the Cu-catalyzed deamination
process of the intermediate imine species in DMSO, similarly to
a reported mechanism for the Cu-catalyzed aerobic oxidation of
amines.13
possessing polar hydrogen atoms as of secondary amides and
hydroxyl groups. Successful sequential application of Ti(OiPr)4
and CuI catalysts in a two-step process is a first evidence which
may suggest further exploration towards other synthetic appli-
cations promoted by such catalysts. Efforts towards the explora-
tion of new combinations of catalysts for dual or more complex
syntheses are of great interest with aim to access more sustain-
able processes, taking advantage of the concepts of green chem-
istry and step-economy in multistep syntheses.
Experimental
General methods
NMR spectra were acquired on a Varian Inova 400 spectrometer
1
running at 400 and 100 MHz for H and 13C, respectively and
on a Varian Gemini 200 spectrometer, running at 200 and
1
50 MHz for H and 13C, respectively. Chemical shifts (δ) are
reported in ppm relative to residual solvent signals (CHCl3,
1
7.26 ppm for H NMR; CDCl3, 77.0 ppm for 13C NMR). The
following abbreviations are used to indicate the multiplicity in
1H NMR spectra: s, singlet; d, doublet; t, triplet; m, multiplet;
br, broad signal. 13C NMR spectra were acquired on a broad
band decoupled mode. ESI mass spectra were carried out on a
ion-trap double quadrupole mass spectrometer using electrospray
(ES+) ionization technique. Chromatographic separations were
performed on silica gel using flash-column techniques. Analyti-
cal grade solvents and commercially available reagents were
used without further purification.
(A) Representative procedure for N-(2-iodobenzoyl)amino
acid ethyl esters. 2-Iodobenzoic acid (1.2 eq.) was dissolved in
CH2Cl2 and SOCl2 (10 eq.) was added at rt. The mixture was
refluxed for 1 h, then the solvent was evaporated. The crude was
dissolved in CH2Cl2, and evaporated again for complete removal
of thionyl chloride. Meanwhile, amino acid ethyl ester hydro-
chloride (1 eq.) was suspended in CH2Cl2 and put in an ice bath.
Triethylamine (2 eq.) was added dropwise to achieve complete
dissolution of the product. Then, the resulting acyl chloride was
dissolved in dry CH2Cl2 and added dropwise at 0 °C to the solu-
tion containing the proline derivative. The reaction mixture was
allowed to return to rt and stirred for 16 h, then washed with 5%
HCl, 5% NaHCO3 and brine. Organic phases were combined,
dried over anhydrous Na2SO4, filtered and evaporated. Flash-
column chromatography purification (1 : 1 EtOAc–petroleum
ether) afforded pure N-(2-iodobenzoyl)amino acid ethyl ester
(5.4 g, 14.3 mmol, 55% for proline as the amino acid substrate).
Conclusions
In conclusion, we reported on a one-pot method for the gener-
ation of benzodiazepine(di)ones, which are relevant heterocycles
for medicinal chemistry, starting from the corresponding amino
ester derivatives as a benchmark for validating the sequential
combination of Ti-catalyzed amidation and the Cu-catalyzed N-
arylation reactions. When the two catalysts were added simul-
taneously, the process proved not to be working, as the amine
reactant of the first step resulted in partial Cu-mediated oxidation
to the corresponding aldehyde, in agreement with similar pro-
cesses reported in the literature. Nevertheless, the multicatalytic
one-pot process proved to work nicely on a sequential fashion
for diverse substrates, giving the title product in 42–67% overall
yield when a proline derivative was used as the substrate. It was
ascertained that the process could not be used with substrates
(B) General procedure for the synthesis of N-(2-iodobenzyl)
amino acid ethyl ester. Amino acid ethyl ester hydrochloride
(1 eq.) was suspended in CH3CN (40 ml mmol−1) and anhy-
drous K2CO3 (6 eq.) was added. 2-Iodobenzyl bromide (1 eq.)
was added and reaction mixture was refluxed o.n., then allowed
to return to rt. The resulting suspension was filtered through
Celite and evaporated to give a crude that was subjected to flash-
column chromatography (EtOAc–petroleum ether 1 : 1) to afford
pure product.
(C) Representative procedure for microwave-assisted synthesis
of benzodiazepine(di)ones. Reactions were performed on
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0.2–0.5 mmol scale. Starting material (1 eq.) was dissolved in
dry toluene (1 M) in a flame-dried, sealed microwave vial under
N2 atmosphere. Amine (1.1 eq.) and Ti(OiPr)4 (0.1 eq.) were
added in this order and the vessel was heated for 2 h at 120 °C
in a microwave reactor. Meanwhile, in another vial a suspension
of anhydrous K2CO3 (2 eq.), CuI (0.2 eq.) and thiophene-2-car-
boxylic acid (0.4 eq.) in DMSO (0.1 M) was degassed in a
Schlenk line and put under N2 atmosphere. Then, the reaction
mixture was added via syringe and the suspension was heated
for 2 h at 150 °C in a microwave reactor. The resulting suspen-
sion was then diluted with EtOAc (10×), and washed with 5%
HCl and brine. Flash chromatography purification (1 : 3 EtOAc–
petroleum ether) afforded pure products as yellow, orange or
brown oils.
anhydrous CH2Cl2 (25 ml) and triethylamine (1.65 ml,
11.8 mmol) was added. Acetyl chloride (462 μl, 6.50 mmol)
was added dropwise at 0 °C, then the reaction mixture was
allowed to stir at rt under N2 atmosphere for 16 h. The resulting
solution was washed with 5% HCl, 5% NaHCO3 and brine.
Flash chromatography purification (1 : 1 EtOAc–petroleum
1
ether) afforded a yellowish oil (1.17 g, 3.23 mmol, 55%). H
NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.87 (d, J = 7.9
Hz, 1 × 0.72 H, major), 7.81 (d, J = 7.9 Hz, 1 × 0.28 H), 7.37
(t, J = 7.6 Hz, 1 × 0.72 H, major), 7.30 (t, J = 7.5 Hz, 1 × 0.28
H, minor), 7.23 (dd, J1 = 1.4 Hz, J2 = 7.7 Hz, 1 × 0.28 H,
minor), 7.15 (d, J = 7.6 Hz, 1 × 0.72 H, major), 7.02 (t, J = 7.6
Hz, 1 × 0.72 H, major), 6.96 (t, J = 7.5 Hz, 1 × 0.72 H, major),
4.72 (s, 2 × 0.28 H, minor), 4.56 (s, 2 × 0.72 H, major), 4.18
(q, J = 7.1 Hz, 2 H, major and minor superimposed), 4.05 (s, 2 ×
0.72 H, major), 3.94 (s, 2 × 0.28 H, minor), 2.15 (s, 3 × 0.72 H,
major), 2.14 (m, 3 × 0.28 H, minor), 1.26 (t, J = 7.1 Hz, 3 H,
major and minor superimposed). 13C NMR δ (75 MHz, CDCl3,
mixture of rotamers): 171.7 and 171.2 (s), 169.0 and 168.8 (s),
139.9 and 139.5 (d), 138.7 and 137.7 (s), 129.5 and 129.2 (d),
128.7 and 128.5 (d), 127.1 (d), 99.2 and 97.7 (s), 61.6 and 61.2
(t), 58.3 and 54.1 (t), 49.6 and 47.4 (t), 21.5 and 21.3 (q), 14.2
(q). ESI-MSMS m/z (%): 361 [M+, 2], 315 [M+ − ethoxy, 100]
286 [M+ − ethoxycarbonyl, 5], 217 [iodobenzyl, 9]. Elemental
analysis calcd (%) for C13H16INO3: C 43.23, H 4.47, N 3.88;
found C 43.31, H 4.54, N 3.72.
(S)-Ethyl 1-(2-iodobenzoyl)pyrrolidine-2-carboxylate (1)
Prepared in 55% yield according to general procedure A. [α]D24
1
−136.9 (c 1.1, CHCl3). H NMR (400 MHz, CDCl3) mixture of
rotamers δ 7.90 (m, 1 H), 7.22 (m, 3 H), 4.77 (dd, J1 = 8.4 Hz,
J2 = 3.8 Hz, 0.19 H, minor), 4.67 (dd, J1 = 8.6 Hz, J2 = 4.5 Hz,
0.81 H, major), 4.25 (qd, J1 = 7.2 Hz, J2 = 2.0 Hz, 0.65 H,
major) and 4.00 (qd, J1 = 7.1 Hz, J2 = 3.2 Hz, 0.35 H, minor),
4.08 (dd, J1 = 2.4 Hz, J2 = 8.5 Hz, 2 × 0.35 H, minor) and 3.79
(m, 2 × 0.65 H, major), 3.31–3.24 (m, 1 H), 2.37–2.23 (m, 1 H),
2.13–1.89 (m, 2 H), 1.31 (t, J = 7.1 Hz, 3 × 0.65 H, major) and
1.12 (t, J = 7.1, 3 × 0.35 H, minor). 13C NMR (50 MHz, CDCl3)
mixture of rotamers δ 171.8 and 171.7 (s), 168.9 (s), 142.9 and
141.4 (s), 139.l and 138.9 (d), 130.7 and 130.3 (d), 128.3 and
128.0 (d), 127.8 and 127.2 (d), 92.2 and 91.6 (s), 61.3 and 61.2
(t), 61.0 and 58.6 (d), 48.7 and 46.2 (t), 31.2 and 29.5 (t),
24.7 and 22.8 (t), 14.1 and 14.0 (q). ESI-MSMS m/z (%) 374
[M+ + 1, 20], 327 [M+ − ethoxy, 100], 300 [M+ − ethoxycarbo-
nyl, 96]. Elemental analysis calcd (%) for C14H16INO3: C 45.06,
H 4.32, N 3.75; found C 45.14, H 4.34, N 3.67.
(S)-10-Butyl-1,2,3,11a-tetrahydro-10H-benzo[e]pyrrolo[1,2-a]
[1,4]diazepine-5,11-dione (3)
Prepared according to general procedure C in 63% yield.
C16H20N2O2: C 70.56, H 7.40, N 10.29; found C 70.71, H 7.49,
N 10.11. NMR data as reported.14
(S)-10-Isobutyl-1,2,3,11a-tetrahydro-10H-benzo[e]pyrrolo[1,2-a]
[1,4]diazepine-5,11-dione (4)
(S)-Ethyl 1-(2-iodobenzyl)pyrrolidine-2-carboxylate (18)
Prepared according to general procedure C in 67% yield. [α]D25
+97.8 (c 0.7, CHCl3). H NMR (400 MHz, CDCl3) δ 7.87 (dd,
Prepared in 96% yield according to general procedure B. [α]D24
−38.3 (c 4.8, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.80
(d, J = 7.9 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.30 (t, J = 7.5
Hz, 1 H), 6.92 (t, J = 7.6 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H),
3.94 (part A of AB system, J = 4.1 Hz, 1 H), 3.74 (part B of AB
system, J = 14.0 Hz, 1 H), 3.43 (m, 1 H), 3.07 (m, 1 H), 2.53
(m, 1 H), 2.15 (m, 1 H), 2.01–1.88 (m, 2 H), 1.85–1.78 (m, 1
H), 1.24 (t, J = 7.1 Hz, 3 H). 13C NMR δ 173.9 (s), 141.0 (d),
139.1 (d), 130.3 (d), 128.5 (d), 128.0 (d), 99.8 (d), 65.3 (t), 62.1
(d), 60.4 (t), 53.0 (t), 29.3 (t), 23.3 (t), 21.4 (q). ESI-MSMS m/z
(%): 360 [M+ + 1, 4], 332 [free acid + 1, 16] 286 [M+ − ethoxy-
carbonyl, 100], 217 [iodobenzyl, 19]. Elemental analysis calcd
(%) for C14H18INO2: C 46.81, H 5.05, N 3.90; found C 46.90,
H 5.14, N 3.77.
1
J1 = 7.8, J2 = 1.6 Hz, 1 H), 7.50 (td, J1 = 7.4 Hz, J2 = 1.7 Hz, 1
H), 7.31 (dd, J1 = 7.6 Hz, J2 = 1.0, 1 H), 7.27 (d, J = 7.5 Hz, 1
H), 4.30 (dd, J = 13.7, 9.2 Hz, 1 H), 4.03 (dd, J1 = 7.6 Hz, J2 =
2.1, 1 H), 3.79 (m, 1 H), 3.56 (m, 1 H), 3.33 (dd, J1 = 13.7, J2 =
5.7 Hz, 1 H), 2.72 (m, 1 H), 2.13 (m, 1 H), 1.99 (m, 2 H), 1.70
(m, 2 H), 0.78 (d, J = 6.7 Hz, 3 H), 0.72 (d, J = 6.7 Hz, 3 H).
13C NMR (50 MHz, CDCl3) δ 169.1 (s), 164.6 (s), 131.8 (d),
130.1 (d), 125.8 (d), 122.9 (d), 110.2 (d), 57.5 (d), 54.2 (t), 46.4
(t), 37.0 (t), 26.9 (t), 23.8 (d), 20.1 (q), 19.4 (q). ESI-MSMS m/z
(%): 273 [M+ + 1, 100], 217 [M+ + 1-iBu, 78], 174
[M+ + 1-Pro, 12]. Elemental analysis calcd (%) for C16H20N2O2:
C 70.56, H 7.40, N 10.29; found C 70.67, H 7.44, N 10.11.
(S)-10-Benzyl-1,2,3,11a-tetrahydro-10H-benzo[e]pyrrolo[1,2-a]
Ethyl 2-(N-(2-iodobenzyl)acetamido)acetate (19)
[1,4]diazepine-5,11-dione (5)
N-2-Iodobenzoyl glycine ethyl ester was prepared according to
general procedure B from glycine ethyl ester hydrochloride in
83% yield. The precursor (1.89 g, 5.91 mmol) was dissolved in
Prepared according to general procedure C in 56% yield.
C19H18N2O2: C 74.49, H 5.92, N 9.14; found C 74.56, H 6.00,
N 9.01. NMR data as reported.14,15
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(S)-10-Allyl-1,2,3,11a-tetrahydro-10H-benzo[e]pyrrolo[1,2-a]
[1,4]diazepine-5,11-dione (6)
118.8 (d), 118.5 (d), 55.3 (d), 54.9 (t), 46.9 (t), 38.7 (t), 28.2 (t),
19.9 (q, 2 C). ESI-MSMS m/z (%): 285 [M+ + Na − CH3, 100].
Elemental analysis calcd (%) C20H22N2O2: C 74.51, H 6.88, N
8.69; found C 74.59, H 6.95, N 8.61.
Prepared according to general procedure C in 62% yield.
C15H16N2O2: C 70.29, H 6.29, N 10.93; found C 70.41, H 6.35,
N 10.77. NMR data as reported.15,16
(S)-1-Butyl-3-isopropyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-
(S)-10-(2-Methoxy-ethyl)-1,2,3,11a-tetrahydro-10H-benzo[e]
pyrrolo[1,2-a][1,4]diazepine-5,11-dione (7)
2,5-dione (11)
Prepared according to general procedure C in 28% yield. [α]D26
−65.3 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.40
(dd, J1 = 7.8 Hz, J2 = 1.4 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 1 H),
6.67 (d, J = 8.4 Hz, 1 H), 6.56 (t, J = 7.4 Hz, 1 H), 6.00 (br, 1
H), 4.32 (dd, J1 = 8.3 Hz, J2 = 7.3 Hz, 1 H), 3.26 (m, 2 H), 2.20
(sextuplet, J = 6.8 Hz, 1 H), 1.64 (m, 2 H), 1.33 (m, 2 H), 1.01
(d, J = 6.8 Hz, 6 H), 0.91 (t, J = 7.4 Hz, 3 H). 13C NMR
(50 MHz, CDCl3) δ 171.1 (s), 169.8 (s), 149.9 (s), 133.1 (d),
127.6 (d, 2 C), 114.5 (d), 111.6 (d), 58.7 (d), 42.7 (t), 39.3 (d),
31.6 (t), 31.3 (t), 20.4 (q), 20.0 (q), 19.3 (q). ESI-MSMS m/z
(%): 275 [M+ + 1, 36], 245 [M+ + 1 − C2H6, 100], 231 [M+ −
iPr, 65]. Elemental analysis calcd (%) for C16H22N2O2: C 70.04,
H 8.08, N 10.21; found C 70.10, H 8.11, N 10.18.
Prepared according to general procedure C in 42% yield.
C15H18N2O3: C 65.68, H 6.61, N 10.21; found C 65.79, H 6.70,
N 10.09. NMR data as reported.17
(S)-10-(2,2-Dimethoxy-ethyl)-1,2,3,11a-tetrahydro-10H-benzo[e]
pyrrolo[1,2-a][1,4]diazepine-5,11-dione (8)
Prepared according to general procedure C in 45% yield. [α]D24
+54.3 (c 1.7, CHCl3). 1H NMR δ 7.88 (d, J = 8.1 Hz, 1 H), 7.49
(d, J = 3.6 Hz, 2 H), 7.29 (m, 1 H), 4.61 (dd, J1 = 4.7 Hz, J2 =
6.4 Hz, 1 H), 4.11 (dd, J1 = 14.0 Hz, J2 = 6.5 Hz, 1 H), 4.06
(dd, J1 = 7.7 Hz, J2 = 2.0 Hz, 1 H), 3.78 (m, 2 H), 3.55 (m, 1
H), 3.36 (s, 3 H), 3.27 (s, 3 H), 2.69 (m, 1 H), 2.13 (m, 1 H),
2.00 (m, 3 H). 13C NMR (50 MHz, CDCl3) δ 169.4 (s), 165.0
(s), 139.9 (s), 132.0 (d), 130.9 (s), 129.9 (d), 126.0 (d), 123.6
(d), 101.7 (d), 57.2 (d), 55.2 (q), 54.7 (q), 51.6 (t), 46.5 (t), 26.6
(t), 23.9 (t). ESI-MSMS m/z (%): 327 [M+ + Na, 100], 295
[M+ + Na − MeOH, 57]. Elemental analysis calcd (%) for
C16H20N2O4: C 63.14, H 6.62, N 9.20; found C 63.21, H 6.64,
N 9.01.
(S)-3-Benzyl-1-butyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (12)
Prepared according to general procedure C in 24% yield. [α]D27
−7.8 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3) δH 7.75
(d, J = 7.2 Hz, 2 H), 7.51 (t, J = 7.4 Hz, 1 H),7.43 (t, J = 7.2
Hz, 2 H), 7.29 (m, 4 H), 6.95 (d, J = 7.8 Hz, 1 H), 5.65 (brs,
1 H), 4.76 (dd, J = 13.9 Hz, J = 8.2 Hz, 1 H), 3.17 (m, 4 H),
1.30 (m, 2 H), 1.19 (m, 2 H), 0.85 (t, J = 7.3 Hz, 3 H). 13C
NMR (50 MHz, CDCl3) δC 170.4 (s), 166.9 (s), 137.4 (s), 136.7
(s), 133.7 (d), 131.8 (d), 129.3 (d), 129.0 (d), 128.7 (d), 128.6
(d), 126.7 (d), 55.2 (d), 39.3 (t), 31.6 (t), 31.3 (t), 19.9 (t), 13.7
(q). ESI-MSMS m/z (%): 324 [M+ + 1, 31], 251 [M+ − butyla-
mine, 100]. Elemental analysis calcd (%) for C20H22N2O2: C
74.51, H 6.88, N 8.69; found C 74.64, H 7.00, N 8.63.
(S)-10-(2-Hydroxy-ethyl)-1,2,3,11a-tetrahydro-10H-benzo[e]
pyrrolo[1,2-a][1,4]diazepine-5,11-dione (9)
Prepared according to general procedure C in 19% yield. 1H
NMR (400 MHz, CDCl3) δ 7.87 (dd, J1 = 7.8 Hz, J2 = 1.6 Hz,
1 H), 7.51–7.46 (m, 1 H), 7.37–7.35 (m, 1 H), 7.31–7.29
(m, 1 H), 4.08–3.94 (m, 2 H), 3.90–3.84 (m, 2 H), 3.82–3.74
(m, 2 H), 3.56–3.49 (m, 1 H), 2.70–2.65 (m, 1 H), 2.04–1.92
(m, 4 H). 13C NMR (50 MHz, CDCl3) δ 170.3 (s), 165.1 (s),
139.9 (s), 132.1 (d), 130.5 (d), 130.1 (d), 126.1 (d), 123.1 (s),
61.2 (t), 57.4 (d), 52.6 (t), 46.6 (t), 40.9 (t), 23.0 (t), 21.5 (t).
[α]2D6 +2.6 (c 0.4, CHCl3). ESI-MSMS m/z (%): 261 [M+ + 1,
15], 243 [M+ − H2O, 82]. Elemental analysis calcd (%) for
C14H16N2O3: C 64.60, H 6.20, N 10.76; found C 64.71, H 6.24,
N 10.67.
1-Allyl-4-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (13)
Prepared according to general procedure C in 26% yield. 1H
NMR (400 MHz, CDCl3) δ 7.86 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1
H), 7.41 (td, J1 = 7.8 Hz, J2 = 1.6 Hz, 1 H), 7.25 (m, 7 H), 5.79
(m, 1 H), 5.29 (d, part A of the AB system, J = 14.8 Hz, 1 H),
5.10 (m, 2 H), 4.44 (dd, part A of the ABX system, J1 = 16.0
Hz, J2 = 5.2 Hz, 1 H), 4.31 (dd, part B of the ABX system, J1 =
16.0 Hz, J2 = 5.2 Hz, 1 H), 4.28 (d, part B of the AB system,
J = 14.8 Hz, 1 H), 3.83 (d, part A of the AB system, J = 14.6
Hz, 1 H), 3.62 (d, part B of the AB system, J = 14.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3) δ 167.7 (s), 162.3 (s), 140.3 (s),
136.2 (s), 132.9 (d), 132.1 (d), 131.0 (d), 129.2 (d), 128.7 (d),
128.5 (d), 128.3 (d), 127.9 (d), 125.9 (d), 123.5 (d), 121.4 (d),
117.5 (t), 51.3 (t), 50.5 (t, 2 C). ESI-MSMS m/z (%): 306 [M+,
44]. Elemental analysis calcd (%) for C19H18N2O2: C 74.49, H
5.92, N 9.14; found C 74.54, H 5.99, N 9.03.
(S)-3-Benzyl-1-isobutyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-
2,5-dione (10)
Prepared according to general procedure C in 18% yield. [α]D25
−10.2 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.74
(d, J = 7.1 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.30 (m, 2 H),
6.97 (br, 1 H), 4.80 (m, 1 H), 3.27 (m, 1 H), 3.08 (m, 1 H), 2.99
(m, 2 H),1.65–1.57 (m, 4 H), 1.25–1.21 (m, 1 H), 0.78 (d, J =
6.7 Hz, 3 H), 0.76 (d, J = 6.7 Hz, 3 H). 13C NMR (50 MHz,
CDCl3) δ 170.6 (s), 167.1 (s), 136.7 (s), 134.4 (s), 131.8 (d),
129.3 (s), 128.8 (d), 128.7 (d), 128.6 (d), 127.0 (d), 125.8 (s),
2784 | Org. Biomol. Chem., 2012, 10, 2780–2786
This journal is © The Royal Society of Chemistry 2012

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(S)-10-Butyl-1,2,3,5,10,11a-hexahydro-benzo[e]pyrrolo[1,2-a]
[1,4]diazepin-11-one (14)
major), 2.19 (s, 3 × 0.25 H, minor), 2.12 (s, 3 × 0.75 H, major).
13C NMR (50 MHz, CDCl3) δ 169.4 (s), 165.9 (s), 142.2 (s),
132.4 (s), 130.9 (d), 129.9 (d), 129.6 (d), 127.0 (d), 122.0 (d),
118.1 (t), 50.8 (t), 50.4 (t), 46.3 (t), 21.7 (q). ESI-MSMS m/z
(%): 245 [M+ + 1, 100], 203 [M+ + 1 − CH3CO, 58], 146
[M+ + 1 − acetylglycine, 100]. Elemental analysis calcd (%) for
C14H16N2O2: C 68.83, H 6.60, N 11.47; found C 68.91, H 6.71,
N 11.36.
Prepared according to general procedure C in 43% yield. [α]D26
+289.7 (c 1.3, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.35
(t, J = 7.2 Hz, 2 H), 7.20 (m, 2 H), 4.20 (m, 1 H), 3.82 (d, part
A of the AB system, J = 10.9 Hz, 1 H), 3.54 (m, 2 H), 3.40 (d,
part B of the AB system, J = 10.9 Hz, 1 H), 3.12 (m, 2 H), 2.41
(m, 1 H), 2.06 (m, 1 H), 1.87 (m, 1 H), 1.72 (m, 1 H), 1.60
(m, 1 H), 1.47 (m, 1 H), 1.30 (m, 2 H), 0.87 (t, J = 7.4 Hz, 3 H).
13C NMR (50 MHz, CDCl3) δ 169.8 (s), 142.5 (s), 133.1 (s),
129.7 (d), 128.9 (d), 126.0 (d), 122.1 (d), 61.1 (d), 54.0 (t), 53.6
(t), 48.1 (t), 32.3 (t), 30.6 (t), 23.9 (t), 20.4 (t), 13.7 (q).
ESI-MSMS m/z (%): 259 [M+ + 1, 4], 231 [M+ + 1 − CO, 23],
162 [M+ + 1 − proline, 100]. Elemental analysis calcd (%) for
C16H22N2O: C 74.38, H 8.58, N 10.84; found C 74.51, H 8.62,
N 10.77.
Acknowledgements
Fondazione Roma, CINMPIS, and MIUR are acknowledged for
financial support.
Notes and references
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(S)-10-Allyl-1,2,3,5,10,11a-hexahydro-benzo[e]pyrrolo[1,2-a][1,4]
diazepin-11-one (15)
Prepared according to general procedure C in 18% yield. [α]D26
1
+271.6 (c 0.8, CHCl3). H NMR (400 MHz, CDCl3) δ 7.35 (m,
2 H), 7.22 (m, 2 H), 5.90 (m, 1 H), 5.15 (m, 2 H), 4.49 (m, 2 H),
3.85 (d, part A of the AB system, J = 11.0 Hz, 1 H), 3.62 (dd, J1
= 7.8 Hz, J2 = 2.0 Hz, 1 H), 3.41 (d, part B of the AB system,
J = 11.0 Hz, 1 H), 3.13 (dd, J1 = 8.5 Hz, J2 = 1.9 Hz, 1 H), 2.50
(dd, J1 = 17.4 Hz, J2 = 9.2 Hz, 1 H), 2.44 (m, 1 H), 2.07
(m, 1 H), 1.90 (m, 1 H), 1.76 (m, 1 H). 13C NMR (50 MHz,
CDCl3) δ 169.7 (s), 142.6 (s), 133.5 (d), 132.5 (s), 129.7 (d),
128.9 (d), 126.2 (d), 122.0 (d), 117.4 (t), 61.2 (d), 53.9 (t), 53.6
(t), 51.1 (t), 24.0 (t), 23.9 (t). ESI-MSMS m/z (%): 243 [M+ + 1,
22], 215 [M+ + 1 − CO, 56], 146 [M+ + 1 − proline, 100].
Elemental analysis calcd (%) for C15H18N2O: C 74.35, H 7.49,
N 11.56; found C 74.44, H 7.64, N 11.49.
4-Acetyl-1-butyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-
one (16)
Prepared according to general procedure C in 60% yield. 1H
NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.46–7.19
(m, 4 H), 4.58–4.42 (m, 2 H), 4.06–3.84 (m, 4 H), 2.17 (s, 3 ×
0.47 H, minor), 2.11 (s, 3 × 0.53 H, major), 1.49 (m, 2 H), 1.26
(m, 2 H), 0.85 (m, 3 H). 13C NMR (50 MHz, CDCl3) δ 169.4
(s), 165.9 (s), 141.9 (s), 130.9 (s), 130.0 (d), 129.6 (d), 126.9
(d), 122.1 (d), 50.9 (t), 47.1 (t), 46.3 (t), 29.9 (t), 21.7 (t), 20.1
(q), 13.6 (q). ESI-MSMS m/z (%): 261 [M+ + 1, 12], 219 [M+ +
1 − CH3CO, 20], 162 [M+ + 1 − acetylglycine, 100]. Elemental
analysis calcd (%) for C15H20N2O2: C 69.20, H 7.74, N 10.76;
found C 69.31, H 7.80, N 10.65.
4-Acetyl-1-allyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-
one (17)
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(m, 4 H), 5.81 (m, 1 H), 5.14 (m, 2 H), 4.54 (s, 2 H), 4.43
(m, 2 H), 4.07 (s, 2 × 0.25 H, minor), 3.93 (s, 2 × 0.75 H,
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This journal is © The Royal Society of Chemistry 2012