An efficient approach to chiral C8/C9-piperazino-substituted 1,4-benzodiazepin-2-ones as peptidomimetic scaffolds

Article abstract of DOI:10.1021/jo8015456

(Chemical Equation Presented) A promising way to interfere with biological processes is through the modulation of protein-protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.

Full text of DOI:10.1021/jo8015456

An Efficient Approach to Chiral C8/C9-Piperazino-Substituted
1,4-Benzodiazepin-2-ones as Peptidomimetic Scaffolds
Stefania Butini,†,‡ Emanuele Gabellieri,†,‡ Paul Brady Huleatt,†,‡ Giuseppe Campiani,*,†,‡
Silvia Franceschini,†,‡ Margherita Brindisi,†,‡ Sindu Ros,†,‡ Salvatore Sanna Coccone,†,‡
Isabella Fiorini,†,‡ Ettore Novellino,†, Gianluca Giorgi,§ and Sandra Gemma†,‡
European Research Centre for Drug DiscoVery and DeVelopment (NatSynDrugs), UniVersity of Siena,
Banchi di Sotto 55, 53100 Siena, Italy, Dipartimento Farmaco Chimico Tecnologico (DFCT), UniVersity of
Siena, Via Aldo Moro, 53100 Siena, Italy, Dipartimento di Chimica Farmaceutica e Tossicologica
(DCF&T), UniVersity of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy, and
Dipartimento di Chimica (DC), UniVersity of Siena, Via Aldo Moro 2, 53100 Siena, Italy
campiani@unisi.it
ReceiVed July 28, 2008
A promising way to interfere with biological processes is through the modulation of protein-protein
interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold
has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways
to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9
have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality
at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization
of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the
molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate
protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild
conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid
activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and
acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully
resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using
chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the
substrates.
Introduction
in cellular processes, the ability to interfere with such specific
interactions provides a powerful means of influencing the
function of selected proteins within the cell.
A minor fraction of the protein-protein interface residues
can account for the majority of the free energy of binding
betweenproteins.1Such“hotspots”arecommonatprotein-protein
interfaces2 and have been identified by combining X-ray
crystallography with site-directed mutagenesis.3,4 Thus, from a
pharmaceutical standpoint, cell-permeable small organic modu-
Many proteins exert their biological roles as components of
complexes, and their functions are often determined by specific
protein-protein interactions (PPIs). Because of their central role
* To whom correspondence should be addressed. Phone: 0039-0577-234172.
Fax: 0039-0577-234333.
† European Research Centre for Drug Discovery and Development (NatSyn-
Drugs).
‡ DFCT-University of Siena.
DCF&T-University of Napoli “FedericoII”.
(1) Clackson, T.; Wells, J. A. Science 1995, 267, 383–386.
(2) Bogan, A. A.; Thorn, K. S. J. Mol. Biol. 1998, 280, 1–9.
§ DC-University of Siena.
8458 J. Org. Chem. 2008, 73, 8458–8468
10.1021/jo8015456 CCC: $40.75 2008 American Chemical Society
Published on Web 10/10/2008

Piperazino-Substituted 1,4-Benzodiazepin-2-ones
lators of PPIs are highly desirable tools for both the study of
physiological cellular processes and the treatment of a number
of diseased states in which aberrant or inappropriate PPIs occur.
A molecular recognition event depends upon electrostatic and
steric complementarities at the ligand/receptor interface. For
small molecules this recognition surface is dictated by the
geometry of appended functional groups on a suitable scaffold,
matching protein surface features where shape and electrostatic
potential, hydrophobic patches,3b,5-8 and about 76% of all
hydrogen bonds in protein complexes5,9 are mainly associated
with side chains as key recognition elements in PPIs.10
ꢀ-Turns are often conserved during evolution, they represent
an important recognition element of peptides and proteins, and
are considered as initiation sites for protein folding. Conse-
quently, a great deal of scientific effort has been devoted to
classifying, designing, and synthesizing ꢀ-turn mimetics.11 Three
classes of peptidomimetics were defined:12 (i) class I mimetics
that often match the amide bond backbone, (ii) class II mimetics
that do not necessarily mimic the structure of the parent peptide,
and (iii) class III compounds based on replacing the amide
backbone of peptides by other templates or scaffolds. The
benzodiazepine (BDZ) scaffold represents a classic example of
class III peptidomimetics and is considered a protypical
privileged substructure.13 The term “privileged structure” was
first applied by Evans et al. to 1,4-benzodiazepine-2-ones able
to bind cholecystokinin, gastrin, and central BDZ receptor.14,15
There is a plethora of literature indicating the “pharmacoge-
nicity” of the BDZ scaffold and its therapeutic utility. Besides
the well-known anxiolytic,16 sedative,17 and anticonvulsant18
activities of the classic BDZs (e.g., diazepam, triazolam, or
midazolam), several 1,4-benzodiazepine derivatives demon-
strated activity as antitumor antibiotics,19 anti-HIV agents,20 and
antiarrhythmics.21 Furthermore, diverse 1,4-benzodiazepine
derivatives were also used as constrained dipeptide mimics or
nonpeptide scaffolds in the search for peptidomimetics either
as enzyme inhibitors22 or as ligands of G-protein coupled
receptors.23 More recently, the 1,4-benzodiazepine-2,5-dione
scaffold was also used as a PPI modulator.24
Given the importance of PPIs, the utility of peptidomimetics,
and the pharmacogenic profile of 1,4-benzodiazepin-2-ones, we
decided to further explore this scaffold with the aim of
identifying new molecular entities that match PPI motifs. In
particular, we focused our attention on fuctionalizing the BDZ
C8 and C9 positions with a piperazine ring. The distal piperazine
nitrogen atom represents an interaction point that in combination
with the BDZ scaffold could allow the reproduction of protein
secondary structures and/or hot-spots (PPI domains). In fact,
the piperazine ring is a common pharmacophore found in a large
number of drugs, it is regarded as a privileged structural element
for the enhancement of “drug-like” properties, and has been
used in the construction of peptidomimetic compounds and PPI
inhibitors.24c,25
Most of the BDZs described to date present either an
unsubstituted or C6/C7-substituted benzofused ring system due,
in part, to the facile incorporation of functionality at these
positions. On the contrary, examples of C8/C9-substituted 1,4-
benzodiazepines are scarce and an even smaller subset of these
examples bear groups that can be functionalized to generate
chemical diversity13 (e.g., amine, carboxylic functions, etc.),
although few examples are reported of chemical routes leading
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Butini et al.
CHART 1. C8/C9-Substituted 1,4-Benzodiazepin-2-ones
1a-i and 2a-c (R1 as defined in Tables 1 and 2)
enantiomeric purity of the synthesized BDZs was assessed by
NMR spectroscopy with use of chiral solvating agents (CSA).
Results and Discussion
The synthesis of the target BDZs 1a-i and 2a-c (Chart 1)
and of their intermediates (and byproducts) is described in
Schemes 1-5. The key intermediates for the synthesis of C8-
or C9-substituted BDZs (1a-i and 2a-c) were aminobenzophe-
nones 7a-c and 10a-c, respectively. Commercially available
benzoic acids 3a,b were chosen as suitable starting materials
to give access to these key intermediates. Accordingly, as
outlined in Scheme 1, compound 3a was transformed into the
corresponding benzoyl chloride28 and then reacted with phe-
nylmagnesium bromide to afford nitrobenzophenone 4a in 50%
overall yield. However, treatment of 3b under the same reaction
conditions did not afford the expected product 4b, but resulted
in the formation of the benzoic ester 5a, whose structure was
confirmed by X-ray analysis (Figure 1, SI).
SCHEME 1. Synthesis of Benzophenone 4a and Esters 5a,b
These data encouraged us to speculate about the reaction
mechanism leading to the formation of 5a from 3b. Accordingly,
we propose a multistep mechanism (Scheme 2) based on a
previously described single electron transfer (SET) reaction29
between nitroarenes and Grignard reagents as the initiating step.
Initially, the reaction between the acid chloride of 3b and the
Grignard reagent (Scheme 2, Step A) could generate a nitroarene
radical anion (A) and a phenyl radical through the SET reaction.
In the next step, the phenyl radical attacks the oxygen atom of
the nitro group, forming a reactive intermediate (B) that by loss
of magnesium bromide phenolate (Step C) evolves to 4-chloro-
2-nitrosobenzoyl chloride (C).29 At this point we hypothesized
that the phenoxide anion formed in Step C could react with the
acid chloride functionality to form the phenylbenzoic ester (D).
However, we cannot rule out a concerted mechanism directly
leading to intermediate D from B involving an intramolecular
nucleophilic attack of the phenoxy-functionality of B on the
acyl chloride thus forming D.
Although Steps A-D are all plausible, the oxidation of the
nitroso group (Step E) remains speculative.
to nitro-26 or azido-derivatives27 that can be reduced to the
corresponding amino functionality.
Phenyl 3-chloro-2-nitrobenzoate (5b) was formed starting
from 3-chloro-2-nitrobenzoyl chloride (Scheme 1) only when
this latter was added to a solution of the Grignard reagent (an
excess of phenylmagnesium bromide was consequently present).
On the contrary, compound 5a was formed from 4-chloro-2-
nitrobenzoyl chloride even if the presence of an excess of
phenylmagnesium bromide was carefully avoided. Although we
do not have an exact explanation for the different reactivity of
the acid chlorides of compounds 3a and 3b toward phenylmag-
nesium bromide, the electronic and steric differences of the two
compounds are likely to play a pivotal role in the SET reaction.
In the following step of the synthetic pathway, the afore-
mentioned nitrobenzophenone 4a was used as the starting
material for the synthesis of key intermediates 7a-c (Scheme
3), while compounds 10a-c, necessary for the preparation of
benzodiazepines 2a-c, were synthesized following an alterna-
tive synthetic strategy (Scheme 4).
For the synthesis of the C8 and C9 piperazin-1-yl-substituted
1,4-benzodiazepine-2-ones 1a-i and 2a-c (Chart 1) presented
herein, a standard approach to the BDZ system was applied.
Specifically, N-acylation of an o-aminobenzophenone (7a,c,
10a,c, Schemes 1-5) with an activated L- or D-R-amino acid
derivative, followed by a ring closure event to form the BDZ
N4/C5 bond.
The coupling of amino acids with poorly reactive anilines
under mild conditions, while avoiding racemization, represented
the critical step of this synthetic method. To address this issue,
efficient amino acid activation was pursued exploiting the rapid
formation of acid chlorides, under low temperature and acid/
base free conditions, using triphenylphosphine and hexachlo-
roacetone. This procedure resulted in high reaction yields, did
not produce racemization, and was compatible with the acid-
sensitive protecting group in the reaction substrates. The
Benzophenone 4a was subjected to a nucleophilic aromatic
substitution reaction with N-protected piperazines at 100 °C in
a sealed tube for 24 h to obtain derivatives 6a-c (Scheme 3).
(26) (a) Kukla, M. J.; Breslin, H. J.; Pauwels, R.; Fedde, C. L.; Miranda,
M.; Scott, M. K.; Sherrill, R. G.; Raeymaekers, A.; Van Gelder, J.; Andries, K.;
Janssen, M. A. C.; De Clerq, E.; Janssen, P. A. J. J. Med. Chem. 1991, 34,
746–751. (b) Pfaendler, H. R.; Weisner, F. Heterocycles 1995, 40, 717–727.
(27) Ripka, W. C.; De Lucca, G. V.; Bach, A. C., II; Pottorf, R. S.; Blaney,
J. M. Tetrahedron 1993, 49, 3593–3608.
(28) Jung, J.-C.; Oh, S.; Kim, W-K.; Park, W.-K.; Kong, J. Y.; Park, O.-S.
J. Heterocycl. Chem. 2003, 40, 617–623.
(29) Dal Pozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163–178.
8460 J. Org. Chem. Vol. 73, No. 21, 2008

Piperazino-Substituted 1,4-Benzodiazepin-2-ones
SCHEME 2. Hypothesized Reaction Mechanism Leading to the Formation of 5a from 3b
SCHEME 3. Synthesis of Compounds 7a-c
piperazine to afford intermediates 10a and10b, respectively, each
in 10% yield over two steps.
Attempts to improve the yield by varying reaction conditions
(e.g., temperature, solvents, or using microwave irradiation)
failed to convey a substantial improvement. Probably, the low
reactivity of the benzophenone C4 halo substituents toward the
aromatic nucleophilic displacement could rely on the electron-
donating effect of the m-amino group. Consequently, we decided
to optimize the formation of the benzophenone 9 through an
alternative and less expensive procedure. Accordingly, ben-
zonitrile 11 was selected as the starting material and when
treated sequentially with phenylmagnesium bromide (2 equiv)
and aqueous acid provided the corresponding chloroaminoben-
zophenone 9b in 80% yield. Reaction of N-Bn-piperazine with
9b furnished 10c in 35% yield. Starting from 10b and 10c the
Boc-derivative 10a was obtained as previously described.
Scheme 5 describes the synthesis of target compounds 1a-i
and 2a-c. Attempts to directly couple Cbz-R-amino acids with
di-o-substituted anilines 7a,c by using a variety of peptide
coupling reagents failed due to a combination of the inherently
poor nucleophilicity and steric inaccessability of this aminoben-
zophenone nitrogen atom. Preprepared activated esters (e.g.,
p-nitrophenyl and hexafluorophenyl) of the aforementioned Cbz-
R-amino acids similarly failed to react with compound 7c.
Activation of a carboxylic acid can also be achieved through
conversion to the corresponding acyl chloride and several
methods are available for such reaction.31 However, the use of
protected R-amino acid chlorides has been limited as they tend
to undergo racemization (either during synthesis or subsequent
coupling) via azalactone-type intermediates and cleavage of
protecting groups can occur.31,32 Consequently, we turned our
attention to developing a method for the formation of Cbz-R-
amino acid chlorides in situ under mild conditions. Once formed,
these highly reactive intermediates would certainly react with
the sterically encumbered amines 7a,c.
The reduction of the nitro group of 6a-c was then performed
by using different methods depending upon the nature of the
piperazine protecting groups which had been chosen according
to the orthogonal protection strategy employed.
Reaction of 6a,b with tin(II) chloride in ethanol to obtain
7a,b failed, while successful reduction was achieved by using
Fe(0) in acidic ethanol, leading to the desired anilines 7a,b in
good yield. On the other hand, the reduction of compound 6c
to aniline 7c was performed by catalytic transfer hydrogenation
(Pd/C and cyclohexene). Boc-protected derivative 7c was also
accessed from the less expensive intermediate 7b, using Pd/C
and cyclohexene in the presence of (Boc)2O. Reduction of the
aromatic nitro group and simultaneous hydrogenolytic cleavage
of the Cbz group afforded the free piperazine, which was trapped
in situ with (Boc)2O.
Due to the undesired formation of the benzoic ester 5a
previously discussed (Scheme 2), a different synthetic strategy
was undertaken for the synthesis of 4-piperazinebenzophenones
10a-c (Scheme 4). An ortho-benzoylation of 3-bromoaniline
8 was effected with benzonitrile in the presence of boron
trichloride and aluminum trichloride30 affording benzophenone
9a, which was substituted with N-Boc-piperazine and N-Cbz-
It is known that rapid formation of acid chlorides under low
temperature and acid/base free conditions could be conveniently
achieved by using triphenylphosphine and a source of chloride
like carbon tetrachloride or hexachloroacetone33 and in a few
examples similar methodologies were applied to the formation
(31) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–
10852.
(32) Jass, P. A.; Rosso, V. W.; Racha, S.; Soundararajan, N.; Venit, J. J.;
Rusowicz, A.; Swaminathan, S.; Livshitz, J.; Dalaney, E. J. Tetrahedron 2003,
59, 9019–9029.
(30) Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. J. Am. Chem. Soc.
1978, 100, 4842–4852.
(33) (a) Lee, J. B. J. Am. Chem. Soc. 1966, 88, 3440–3441. (b) Villeneuve,
G. B.; Chan, T. H. Tetrahedron Lett. 1997, 38, 6489–6492.
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Butini et al.
SCHEME 4. Synthesis of Compounds 10a-c
SCHEME 5. Synthesis of 1,4-Benzodiazepines 1a-i and 2a-ca
a For R, R1, and R2 see Tables 1 and 2.
of amino acid chlorides.34 Gratifyingly, under these conditions,
compounds 7a,c and 10a,b were converted into 13a-k and
14a-e. Optimal reaction conditions required the use of 3 equiv
of triphenylphosphine, 0.75 equiv of hexachloroacetone, and
1.5 equiv of N-protected amino acid in dichloromethane at 25
°C. Reaction yields are listed in Tables 1 and 2, and with few
exceptions they were higher than 90% for compounds of type
13 and 14. Moreover, enantiomeric excess (ee), determined for
the target compounds (see below and the Supporting Informa-
tion), indicated that no amino acid racemization occurred under
the above-described reaction conditions. This methodology
offers a valid alternative to the use of protected amino acid
fluorides which are needed to perform similar transformations.31,35
In the next steps of the synthetic pathway, deprotection
of Cbz-protected amino groups of 13a,b,d-k and 14b-e was
accomplished by hydrogenolysis, using cyclohexene and 10%
Pd/C in ethanol under reflux. During the hydrogenation step,
a simultaneous cyclization reaction produced the correspond-
ing Boc-protected benzodiazepines 15a,c-j and 16b-e and
the Bn-protected derivative 15b with yields ranging from 78%
to 80%.
Starting from compounds 13c and 14a, deprotection of the
Fmoc group in refluxing piperidine occurred with in situ
cyclization to afford 15b and 16a, respectively. For compounds
13h,j and 14c, which presented an additional benzyl group for
protection of the primary alcohol (Ser) or the phenolic hydroxyl
(Tyr) function, longer reaction times were required for complete
deprotection, which resulted in partial decomposition and a
lowering of the overall yield. Replacement of cyclohexene with
cyclohexadiene as the hydrogen donor shortened the reaction
time (12 h) but did not lead to improved yields. In the last step
of the synthesis, quantitative N-Boc-deprotection of 15a,c-j
and 16b-d was achieved by treatment with a freshly prepared
dry solution of 5% hydrochloric acid in methanol. This method
(34) (a) Lorca, M.; Kurosu, M. Synth. Commun. 2001, 31, 469–473. (b)
Miller, M. C.; Sood, A.; Spielvogel, B. F.; Hall, I. H. Anticancer Res. 1997, 17,
3299–3306.
(35) (a) Dourlat, J.; Liu, W.-Q.; Gresh, N.; Garbay, C. Bioorg. Med. Chem.
Lett. 2007, 17, 2527–2530. (b) Carpino, L. A.; Beyermann, M.; Wenschuh, H.;
Bienert, M. Acc. Chem. Res. 1996, 29, 268–274.
8462 J. Org. Chem. Vol. 73, No. 21, 2008

Piperazino-Substituted 1,4-Benzodiazepin-2-ones
TABLE 1. Coupling of N-Protected Amino Acids with Aminobenzophenones 7a,c Affording Amides 13a-k, Cyclization Products 15a-j, and
Deprotected 1,4-Benzodiazepines 1a-i As Described in Scheme 5
cleanly afforded the corresponding target compounds 1a-i and
2a-c as the hydrochloride salts.
strategy herein discussed is based on a mild chlorination
procedure applied to the synthesis of enantiopure amino acid
chlorides. By using this methodology, these highly reactive
intermediates could be prepared and coupled with poorly
reactive and hindered anilines, thus giving access to anilides
which were otherwise inaccessible. Moreoever, this coupling
took place without racemization as evidenced by the high ee
(g98%) determined for the BDZ products. The ee was
evaluated by means of an NMR method based on the use of
CSAs.
The ee of N-Boc protected benzodiazepines 15c-j and 16c-e
was determined by NMR spectroscopy by using Pirkle alcohol
(R)-trifluorobenzyl alcohol as the chiral solvating agent. Ap-
plying this methodology, the ee determined for compounds
15c-j and 16c-e proved to be g98%, thus confirming that no
racemization occurred during the synthetic process (further
details are given as Supporting Information).
Conclusions
Experimental Procedure
This work provides a new, mild, and efficient method for
the synthesis of C8/C9-piperazino-substituted 1,4-benzodi-
azepine peptidomimetic scaffolds potentially useful for the
synthesis of small-molecule PPI modulators. The synthetic
(3-Chloro-2-nitrophenyl)phenylmethanone (4a). 3-Chloro-2-
nitrobenzoic acid (3a) (3.04 g, 15.08 mmol) was converted into
the corresponding 3-chloro-2-nitrobenzoyl chloride as described in
J. Org. Chem. Vol. 73, No. 21, 2008 8463

Butini et al.
TABLE 2. Coupling of N-Protected Amino Acids with Aminobenzophenones 10a,c Affording Amides14a-e, Cyclization Products 16a-e, and
Deprotected 1,4-Benzodiazepines 2a-c As Described in Scheme 5
the literature,36 and this latter was dissolved in THF (100 mL) and
cooled to -10 °C. A solution of phenylmagnesium bromide (1 M
solution in THF, 15.08 mmol, 15.1 mL) was added dropwise over
a period of 10 min. The reaction mixture was stirred at 23 °C for
16 h; afterward it was poured into a 5% solution of HCl (100 mL)
and the aqueous phase was extracted with EtOAc (5 × 50 mL).
The combined organic extracts were washed with brine (50 mL)
and dried (Na2SO4) then the solvent was removed in vacuo. The
residue was purified by column chromatography (n-hexane/EtOAc
11:1) to afford, after recrystallization, the title compound as light
orange prisms (1.98 g, 50%). Mp (n-hexane) 65-67 °C [lit.37 mp
(isopropanol) 67-69 °C]. Anal. (C13H8ClNO3) C, H, N.
4-Chloro-2-nitrobenzoic Acid Phenyl Ester (5a). 4-Chloro-2-
nitrobenzoyl chloride (5.0 g, 2 mmol), prepared from 2-nitro-4-
chlorobenzoic acid (3b) as described in the literature,36 was
dissolved in THF (20 mL) and cooled to -10 °C. A solution of
phenylmagnesium bromide (1 equiv, 3 M in THF) was added
dropwise over a period of 10 min. The reaction mixture was stirred
at 23 °C for 5 h; afterward it was poured into a 5% solution of
HCl (100 mL) and extracted with EtOAc (5 × 50 mL). The
combined organic extracts were washed with brine (50 mL) and
dried then the solvent was removed in vacuo. The residue was
purified by column chromatography (n-hexane/EtOAc 11:1) to
afford, after recrystallization, the title compound as orange prisms
(2.3 g, 42%). Mp (n-hexane) 81-82 °C; 1H NMR (200 MHz,
CDCl3) δ 7.20 (m, 3H), 7.37 (m, 2H), 7.68 (dd, 1H, J ) 7.7, 1.8
Hz), 7.84-7.00 (d, 1H, J ) 8.4 Hz), 7.94 (s, 1H); 13C NMR (50
MHz, CDCl3) δ 121.0, 124.2, 125.0, 126.4, 129.5, 131.3, 133.0,
138.3, 150.2, 162.8; ESI MS m/z 300 (M + Na)+. Anal.
(C13H8ClNO4) C, H, N.
from 2-nitro-3-chlorobenzoic acid (3a) as described in the litera-
ture,36 over a period of 10 min. The reaction mixture was stirred
at room temperature for 6 h then poured into a 5% solution of HCl
(10 mL) and extracted with EtOAc (5 × 10 mL). The combined
organic extracts were washed with brine (10 mL) and dried then
the solvent was removed in vacuo. The residue was purified by
column chromatography (4:1, n-hexane/EtOAc; Rf 0.42) to afford
the title compound as an orange oil (300 mg, 27%). 1H NMR (200
MHz, CDCl3) δ 7.16-7.68 (m, 5H), 8.03 (m, 2H), 8.17 (d, J )
8.1 Hz, 1H). MS m/z 300 (M + Na)+. Anal. (C13H8ClNO4) C, H,
N.
[3-(4-Benzylpiperazin-1-yl)-2-nitrophenyl]phenylmethanone
(6a). 3-Chloro-2-nitrobenzophenone (4a) (234 mg, 0.89 mmol) was
dissolved in 1-benzylpiperazine (1 mL, 5.75 mmol) and the resulting
mixture was stirred at 100 °C in a sealed tube for 48 h. After cooling
to 23 °C, the mixture was partitioned between EtOAc (10 mL) and
water (5 mL). The organic phase was separated and dried then the
solvent was removed in vacuo. The residue was purified by column
chromatography (n-hexane/EtOAc 1:1; Rf 0.23) to afford, after
recrystallization, the title compound as yellow prisms (200 mg,
56%) and the unreacted starting material was recovered. Mp (n-
1
hexane) 122-124 °C; H NMR (200 MHz, CDCl3) δ 2.56-2.60
(m, 4H), 3.06-3.11 (m, 4H), 3.55 (s, 2H), 7.11 (d, 1H, J ) 7.0
Hz), 7.27-7.37 (m, 6H), 7.41-7.52 (m, 3H), 7.60 (m, 1H), 7.80
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 52.4, 53.3, 63.2, 123.4,
124.5, 127.4, 128.5, 128.8, 129.4, 130.2, 131.4, 134.0, 134.9, 136.0,
138.1, 144.8, 146.0, 193.3; ESI-MS m/z 424 (M + Na)+, 402 (M
+ H)+. Anal. (C24H23N3O3) C, H, N.
[3-(4-Benzyloxycarbonylpiperazin-1-yl)-2-nitrophenyl]phenyl-
methanone (6b). 3-Chloro-2-nitrobenzophenone (3a) (3.26 g, 12.47
mmol) was dissolved in 1-benzyloxycarbonylpiperazine (10 mL,
39.75 mmol) and the resulting mixture was stirred at 100 °C in a
sealed tube for 48 h. After cooling, the mixture was partitioned
between EtOAc (100 mL) and water (50 mL). The organic phase
was separated and dried then the solvent was removed in vacuo.
The residue was purified by column chromatography (n-hexane/
EtOAc 1:1; Rf 0.33) to afford the title compound as yellow prisms
3-Chloro-2-nitrobenzoic Acid Phenyl Ester (5b). To a solution
of phenylmagnesium bromide (1 equiv, 3 M in THF) was added
3-chloro-2-nitrobenzoyl chloride (846 mg, 3.44 mmol), prepared
(36) Roy, A. D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382–
385.
(37) Walsh, D. A.; Moran, H. W.; Shamblee, D. A.; Welstead, W. J. J.; Nolan,
J. C.; Sancilio, L. F.; Graff, G. J. Med. Chem. 1990, 33, 2296–2304.
8464 J. Org. Chem. Vol. 73, No. 21, 2008

Piperazino-Substituted 1,4-Benzodiazepin-2-ones
(2.80 g, 50%) and the unreacted starting material was recovered.
Mp (n-hexane) 126-128 °C; H NMR (200 MHz, CDCl3) δ 3.02
purified by column chromatography (n-hexane/EtOAc 3:1; Rf 0.43)
to afford, after recrystallization, the title compound in 84% yield
(1.14 g).
1
(m, 4H), 3.62 (m, 4H), 5.15 (s, 2H), 7.18-7.25 (m, 1H), 7.30-7.41
(m, 6H), 7.42-7.52 (m, 3H), 7.59 (m, 1H), 7.80 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 44.3, 52.6, 67.6, 124.8, 125.1, 128.2, 128.4,
128.8, 128.9, 130.3, 131.5, 134.2, 134.8, 135.9, 136.8, 145.7, 155.4
(2C), 193.1; ESI-MS m/z 468 (M + Na)+. HRMS calcd for
From 6b: To a suspension of 3-(4-benzyloxycarbonylpiperazin-
1-yl)-2-nitrobenzophenone (6b) (2.84 g, 6.38 mmol) in ethanol (60
mL) were added cyclohexene (20 mL), di-tert-butyldicarbonate
(2.09 g, 9.58 mmol), and 10% palladium on carbon (250 mg). The
reaction mixture was heated under reflux under an argon atmosphere
for 48 h, cooled, and filtered then the solvent was removed in vacuo.
The residue was purified as described above to afford the title
compound (2.28 g, 92%) as yellow prisms. Mp (n-hexane) 117-119
[(C25H23N3O5)
(C25H23N3O5) C, H, N.
+
Na]+ 468.1530, found 468.1529. Anal.
[3-(4-tert-Butoxycarbonylpiperazin-1-yl)-2-nitrophenyl]phe-
nylmethanone (6c). A mixture of 3-chloro-2-nitrobenzophenone
(4a) (1.40 g, 5.35 mmol) and 1-tert-butoxycarbonylpiperazine (2.80
g, 15.03 mmol) was heated to 100 °C in a sealed tube for 48 h.
After cooling to 23 °C, the mixture was partitioned between EtOAc
(50 mL) and water (30 mL). The organic phase was separated and
dried then the solvent was removed in vacuo. The residue was
purified by column chromatography (n-hexane/EtOAc 3:1; Rf 0.17)
to afford the title compound as a bright orange oil (1.46 g, 66%)
1
°C; H NMR (200 MHz, CDCl3) δ 1.46 (s, 9H), 2.90 (br, 6H),
4.08 (br, 2H), 6.49 (t, 1H, J ) 8.0 Hz), 6.63 (br, 2H), 7.07 (d, 1H,
J ) 8.0 Hz), 7.20 (d, 1H, J ) 8.0 Hz), 7.33-7.47 (m, 3H),
7.55-7.59 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 28.7, 48.6, 51.6,
80.1, 114.7, 118.3, 124.9, 128.3, 129.3, 130.8, 131.2, 139.8, 140.5,
146.9, 155.0, 199.4; ESI-MS m/z 420 (M + K)+, 404 (M + Na)+,
382 (M + H)+. Anal. (C22H27N3O3) C, H, N.
1
(4-Bromo-2-aminophenyl)phenylmethanone (9a). To a stirred
solution of boron trichloride (1 M solution in THF, 5.8 mmol, 5.8
mL) in dichloroethane was added a solution of 2-bromoaniline (0.63
mL, 5.8 mmol) dropwise under ice cooling. To the resulting solution
were added benzonitrile (1.18 mL, 11.6 mmol) and aluminum
trichloride (770 mg, 6.38 mmol) and within 20 min of stirring at
23 °C, the aluminum trichloride was completely dissolved. Sub-
sequently, the solution was heated under reflux for 6 h, then cooled
in ice and 2 N HCl was added dropwise under stirring. The resulting
mixure was warmed to 80 °C for 1 h, then cooled to 23 °C and
extracted with dichloromethane (5 × 50 mL). The combined organic
extracts were washed with brine (100 mL) and dried then the solvent
was removed in vacuo. The residue was purified by column
chromatography (n-hexane/EtOAc 10:1; Rf 0.53) to afford the title
compound (5.5 g, 34%) as a brownish solid. Mp (n-hexane) 90-92
and the unreacted starting material was recovered. H NMR (200
MHz, CDCl3) δ 1.45 (s, 9H), 2.98 (m, 4H), 3.52 (m, 4H), 7.16 (d,
1H, J ) 8.0 Hz), 7.33-7.58 (m, 5H), 7.77 (d, 2H, J ) 8.0 Hz);
13C NMR (75 MHz, CDCl3) δ 28.6, 44.2, 52.5, 80.2, 124.5, 125.0,
128.8, 130.3, 131.5, 134.1, 134.8, 135.9, 145.5, 145.8, 154.9, 193.2;
ESI-MS m/z 450 (M + K)+, 434 (M + Na)+. Anal. (C22H25N3O5)
C, H, N.
[3-(4-Benzylpiperazin-1-yl)-2-aminophenyl]phenylmetha-
none (7a). To a solution of 3-(4-benzylpiperazinyl)-2-nitroben-
zophenone (6a) (763 mg, 1.901 mmol) in ethanol (5 mL), glacial
acetic acid (5 mL), water (1 mL) and 6 M HCl (0.1 mL) was added
iron powder (740 mg, 13.25 mmol). The resulting heterogeneous
mixture was heated under reflux for 30 min, poured into water (20
mL), and filtered through a bed of Celite, which was subsequently
washed with dichloromethane (10 mL). The aqueous filtrate was
extracted with dichloromethane (5 × 10 mL) and the organic phases
were combined, washed with 10% NaHCO3 solution (10 mL), water
(10 mL), and brine (10 mL) and dried. The solvent was removed
in vacuo and the residue was purified by column chromatography
(n-hexane /EtOAc 1:1; Rf 0.60) to afford, after recrystallization,
the title compound as bright yellow prisms (693 mg, 98%). Mp
°C [lit.38 mp (diluted alcohol) 88-90 °C]; H NMR (300 MHz,
1
CDCl3) δ 6.16 (br, 2H), 6.72 (d, 1H, J ) 7.3 Hz), 6.93 (s, 1H),
7.29 (d, 1H, J ) 7.0 Hz), 7.43-7.62 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 118.1, 119.2, 119.4, 128.1, 128.7, 131.0, 138.3, 139.9,
154.4 (2C), 199.6; ESI-MS m/z 276 (M + H)+. HRMS calcd for
[(C13H10BrNO)
(C13H10BrNO) C, H, N.
+
H]+ 276.0019, found 276.0018. Anal.
1
(n-hexane) 115-116 °C; H NMR (200 MHz, CDCl3) δ 2.63 (br,
(4-Chloro-2-aminophenyl)phenylmethanone (9b). To a stirred
solution of 2-amino-4-chlorobenzonitrile (1.55 g, 1.01 mmol) in
THF (30 mL) was added a solution of phenylmagnesium bromide
(2.5 equiv, 3 M in THF) dropwise over a period of 10 min. The
reaction mixture was stirred at 23 °C for 16 h; afterward it was
poured into a 5% solution of HCl (100 mL) and the resulting
mixture was heated under reflux for 3 h. The phases were separated,
and the aqueous phase was extracted with dichloromethane (3 ×
50 mL). The combined organic extracts were dried then the solvent
was removed in vacuo. The residue was purified by column
chromatography (n-hexane/EtOAc 5:1) to afford the title compound
(1.79 g, 80%). Analytical data were identical to those reported in
the literature.39
[4-(4-tert-Butoxycarbonylpiperazin-1-yl)-2-aminophenyl]phe-
nylmethanone (10a). From 9a: A mixture of 4-bromo-2-ami-
nobenzophenone (9a) (225 mg, 0.81 mmol) and 1-tert-butoxycar-
bonylpiperazine (761 mg, 4 mmol) was heated to 130 °C in a sealed
tube for 48 h. After cooling to 23 °C, the mixture was partitioned
between EtOAc (50 mL) and H2O (30 mL). The organic phase
was separated and dried then the solvent was removed in vacuo.
The residue was purified by column chromatography (n-hexane/
EtOAc 2:1; Rf 0.32) to afford the title compound as a bright orange
oil (91 mg, 30%) and the unreacted starting material was recovered.
4H), 2.95 (m, 4H), 3.61 (s, 2H), 6.59 (t, 1H, J ) 8.0 Hz), 6.65 (br,
2H), 7.15-7.51 (m, 10H), 7.60-7.65 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 51.6, 54.1, 63.4, 114.6, 118.1, 124.9, 127.4, 128.2, 128.5,
129.3, 129.5, 130.4, 131.1, 138.2, 140.2, 140.6, 147.1, 199.5; ESI-
MS m/z 394 (M + Na)+, 372 (M + H)+. HRMS calcd for
[(C24H25N3O)
+
Na]+ 394.1890, found 394.1893. Anal.
(C24H25N3O) C, H, N.
[3-(4-Benzyloxycarbonylpiperazin-1-yl)-2-aminophenyl]phe-
nylmethanone (7b). Starting from 6b (1.11 g, 2.49 mmol), the title
compound was obtained as described for 7a. After purification by
column chromatography (n-hexane/EtOAc 2:1; Rf 0.37) and re-
crystallization the title compound was obtained as bright yellow
prisms (774 mg, 75%). Mp (n-hexane) 122-123 °C; 1H NMR (200
MHz, CDCl3) δ 3.02 (br, 6H), 4.20 (br, 2H), 5.19 (s, 2H), 6.56 (t,
1H, J ) 8.0 Hz), 6.66 (br, 2H), 7.12 (d, 1H, J ) 8.0 Hz), 7.27 (d,
1H, J ) 8.0 Hz), 7.30-7.51 (m, 8H), 7.63 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 44.8, 51.5, 67.5, 114.7, 118.4, 124.9, 128.2, 128.3,
128.3, 128.8, 129.3, 130.9, 131.2, 136.9, 139.6, 140.4, 155.5, 199.5.
ESI-MS m/z 454 (M + K)+, 438 (M + Na)+, 416 (M + H)+.
HRMS calcd for [(C25H25N3O3) + Na]+ 438.1788, found 438.1792.
Anal. (C25H25N3O3) C, H, N.
[3-(4-tert-Butoxycarbonylpiperazin-1-yl)-2-aminophenyl]phe-
nylmethanone (7c). From 6c: To a solution of 3-(4-tert-butoxy-
carbonylpiperazin-1-yl)-2-nitrobenzophenone (6c) (1.46 g, 3.55
mmol) in ethanol (20 mL) and cyclohexene (10 mL) was added
10% palladium on carbon. The resulting suspension was heated
under reflux under an argon atmosphere for 16 h, cooled, and
filtered. The solvent was removed in vacuo and the residue was
(38) Koelsch, C. F. J. Am. Chem. Soc. 1944, 66, 1983–1984.
(39) Carter, M. C.; Alber, D. G.; Baxter, R. C.; Bithell, S. K.; Budworth, J.;
Chubb, A.; Cockerill, G. S.; Dowdell, V. C. L.; Henderson, E. A.; Keegan, S. J.;
Kelsey, R. D.; Lockyer, M. J.; Stables, J. N.; Wilson, L. J.; Powell, K. L. J. Med.
Chem. 2006, 49, 2311–2319.
J. Org. Chem. Vol. 73, No. 21, 2008 8465

Butini et al.
From 10b: To a suspension of [4-(4-benzyloxycarbonylpiper-
azin-1-yl)-2-aminophenyl]phenylmethanone (10b) (1.6 g, 3.85
mmol) in ethanol (50 mL) was added cyclohexene (20 mL), di-
tert-butyldicarbonate (1.26 g, 5.57 mmol), and 10% palladium on
carbon (250 mg). The reaction was heated under reflux under argon
for 48 h, cooled, and filtered then the solvent was removed in vacuo.
The residue was purified as described above to afford the title
compound (1.3 g, 88%).
2-(Benzyloxycarbonylamino)-N-[2-benzoyl-6-(4-tert-butoxy-
carbonylpiperazin-1-yl)phenyl]acetamide (13a). Compound 13a
was prepared following the above-described general procedure and
after purification by column chromatography (n-hexane /EtOAc 2:1;
1
Rf 0.59) was obtained as a colorless oil (343 mg, 86%). H NMR
(200 MHz, CDCl3) δ 1.48 (s, 9H), 2.77 (br, 4H), 3.53 (br, 4H),
3.82 (d, 2H, J ) 5.9 Hz), 5.09 (s, 2H), 5.48 (m, 1H), 7.08-7.49
(m, 10H), 7.53 (m, 1H), 7.87 (d, 2H, J ) 7.2 Hz), 8.75 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 28.7, 44.5, 45.4, 52.0, 67.5, 80.2,
122.9, 125.2, 125.6, 128.4, 128.5 (2C), 128.8, 129.4, 130.6, 133.0,
133.7, 136.2, 137.0, 145.4, 154.9, 156.9, 167.9, 195.6; ESI-MS m/z
1167 (2 M + Na)+, 611 (M + K)+, 595 (M + Na)+, 573 (M +
H)+. Anal. (C32H36N4O6) C, H, N.
From 10c: To a suspension of [4-(4-benzylpiperazin-1-yl)-2-
aminophenyl]phenylmethanone (10c) (510 mg, 1.37 mmol) in
ethanol (20 mL) were added cyclohexene (20 mL) and 10%
palladium on carbon (50 mg). The reaction was heated under reflux
under argon for 16 h, cooled, and filtered, then di-tert-butyldicar-
bonate (382 mg, 2.02 mmol) was added and the solution was heated
under reflux for an additional 3 h. The solvent was removed in
vacuo, the residue was purified as described above to afford the
2-(Benzyloxycarbonylamino)-N-[2-benzoyl-6-(4-benzylpiper-
azin-1-yl)phenyl]acetamide (13b). The title compound was pre-
pared following the above-described general procedure and after
purification by column chromatography (n-hexane/EtOAc 1:1) was
1
title compound (396 mg, 76%). H NMR (300 MHz, CDCl3) δ
1
1.46 (s, 9H), 3.30 (m, 4H), 3.50 (m, 4H), 6.02 (d, 1H, J ) 2.3 Hz),
6.15 (dd, 1H, J ) 9.1, 2.3 Hz), 6.30 (br, 2H), 7.33 (d, 1H, J ) 9.1
Hz), 7.39-7.48 (m, 3H), 7.55 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 28.6, 43.1, 47.2, 80.4, 99.6, 103.9, 111.0, 128.2, 128.9, 130.4,
136.9, 141.2, 153.6, 154.8, 154.9, 197.2; ESI-MS m/z 420 (M +
K)+, 404 (M + Na)+, 382 (M + H)+. Anal. (C22H27N3O3) C, H,
N.
obtained as a colorless oil (320 mg, 45%). H NMR (200 MHz,
CDCl3) δ 2.63 (br, 4H), 2.89 (br, 4H), 3.54 (s, 2H), 3.87 (d, 2H, J
) 5.8 Hz), 5.13 (s, 2H), 5.49 (m, 1H), 7.10-7.54 (m, 16H), 7.88
(d, 2H, J ) 7.1 Hz), 8.65 (br s, 1H); 13C NMR (75 MHz, CDCl3)
δ 45.3, 52.1, 53.8, 63.3, 67.4, 122.9, 125.2, 125.4, 127.4, 128.2,
128.3, 128.4, 128.5, 128.6, 128.8, 129.3, 129.4, 130.5, 133.3, 136.3,
137.2, 138.2, 145.5, 156.6, 167.3, 195.4; ESI-MS m/z 601 (M +
K)+, 585 (M + Na)+, 563 (M + H)+. Anal. (C34H34N4O4) C, H,
N.
[4-(4-Benzyloxycarbonylpiperazin-1-yl)-2-aminophenyl]phe-
nylmethanone (10b). A mixture of 4-bromo-2-aminobenzophenone
(9a) (2.5 g, 9.1 mmol) and 1-benzyloxycarbonylpiperazine (8.7 mL,
45.4 mmol) was stirred at 130 °C in a sealed tube for 48 h. After
cooling, the mixture was partitioned between EtOAc (100 mL) and
water (50 mL). The organic phase was separated and dried then
the solvent was removed in vacuo. The residue was purified by
column chromatography (n-hexane/EtOAc 2:1; Rf 0.21) to afford
the title compound as a thick yellow oil (1.1 g, 33%) and the
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-N-[2-benzoyl-6-
(4-benzylpiperazin-1-yl)phenyl]acetamide (13c). The title com-
pound was prepared following the above-described general proce-
dure and after purification by column chromatography (n-hexane/
EtOAc 1:1; Rf 0.30) was obtained as a colorless oil (308 mg, 75%).
1H NMR (200 MHz, CDCl3) δ 2.54 (br, 4H), 2.85 (br, 4H), 3.42
(s, 2H), 3.96 (d, 2H, J ) 5.5 Hz), 4.23 (m, 1H), 4.40 (m, 2H), 5.90
(m, 1H), 7.08-7.62 (m, 17H), 7.77 (d, 2H, J ) 7.4 Hz), 7.98 (d,
2H, J ) 7.4 Hz), 8.87 (br, 1H); 13C NMR (75 MHz, CDCl3) δ
45.3, 47.3, 52.2, 53.8, 63.2, 67.8, 120.3, 123.0, 125.2, 125.4, 127.3,
128.0, 128.4, 128.5, 129.3, 130.6, 132.9, 133.4, 137.2, 138.1, 141.5,
144.0, 145.5, 156.7, 167.3, 195.5; ESI-MS m/z 689 (M + K)+,
673 (M + Na)+, 651 (M + H)+. Anal. (C41H38N4O4) C, H, N.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-N-[2-benzoyl-5-
(4-benzylpiperazin-1-yl)phenyl]acetamide (14a). Compound 14a
was prepared following the above-described general procedure and
after purification by column chromatography (n-hexane/EtOAc 2:1;
1
unreacted starting material was recovered. H NMR (300 MHz,
CDCl3) δ 3.25 (m, 4H), 3.63 (m, 4H), 5.16 (s, 2H), 6.01 (d, 1H, J
) 2.3 Hz), 6.12 (dd, 1H, J ) 8.5, 2.3 Hz), 6.31 (br, 2H), 7.30-7.46
(m, 9H), 7.59 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 43.6, 47.2,
67.2, 99.8, 104.0, 111.1, 128.2 (2C), 128.4, 128.8, 128.9, 130.5,
136.7, 136.9, 141.2, 153.5, 154.8, 155.4, 197.3; ESI-MS m/z 454
(M + K)+, 438 (M + Na)+, 416 (M + H)+. Anal. (C25H25N3O3)
C, H, N.
[4-(4-Benzylpiperazin-1-yl)-2-aminophenyl]phenylmetha-
none (10c). 4-Chloro-2-aminobenzophenone (9b) (1.41 g, 6.1
mmol) was dissolved in 1-benzylpiperazine (5.7 mL, 30 mmol) and
the resulting mixture was stirred at 130 °C in a sealed tube for
48 h. After cooling, the mixture was partitioned between EtOAc
(100 mL) and water (50 mL). The organic phase was separated
and dried then the solvent was removed in vacuo. The residue was
purified by column chromatography (n-hexane/EtOAc 3:1) to afford
the title compound as a yellow low-melting solid (0.77 g, 33%)
1
Rf 0.38) was obtained as a waxy yellow solid (381 mg, 91%). H
NMR (300 MHz, CDCl3) δ 2.91 (br, 2H), 3.48 (br, 2H), 3.89 (br,
4H), 4.05-4.41 (m, 7H), 5.83 (br, 1H), 6.43 (br, 1H), 7.22-7.74
(m, 18H), 8.28 (s, 1H), 12.10 (br, 1H), 13.00 (br, 1H); 13C NMR
(75 MHz, CDCl3) δ 44.5, 46.0, 47.4, 51.0, 61.2, 67.8, 106.0, 108.0,
114.7, 120.1, 125.5, 127.3, 127.7, 127.9, 128.4, 129.5, 129.7, 130.6,
131.8 (2C), 136.9, 139.4, 141.5, 143.1, 144.1, 153.3, 157.0, 169.2,
198.4; ESI-MS m/z 689 (M + K)+, 673 (M + Na)+, 651 (M +
H)+. HRMS calcd for [(C41H38N4O4) + H]+ 651.2966, found
651.2964. Anal. (C41H38N4O4) C, H, N.
1
and the unreacted starting material was recovered. H NMR (300
MHz, CDCl3) δ 2.56 (m, 4H), 3.33 (m, 4H), 3.55 (s, 2H), 6.01 (d,
1H, J ) 2.3 Hz), 6.14 (dd, 1H, J ) 8.3, 2.3 Hz), 6.19 (br, 2H),
7.16-7.46 (m, 9H), 7.53 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
47.2, 53.0, 63.3, 99.3, 103.8, 110.6, 127.5, 128.2, 128.6, 128.9,
129.4, 130.3, 136.9, 138.1, 141.4, 153.7, 155.2, 197.1; ESI-MS m/z
394 (M + Na)+, 372 (M + H)+. Anal. (C24H25N3O) C, H, N.
General Procedure for Preparation of compounds 13a-k
and 14a-e. A stirred solution of protected amino acid (0.94 mmol)
and triphenylphosphine (1.88 mmol) in dry dichloromethane (10
mL) was cooled to -10 °C and hexachloroacetone (0.75 equiv)
was added dropwise. After 15 min, a solution of the appropriate
protected benzophenones (0.63 mmol) in dichloromethane (2 mL)
was added. The reaction mixture was stirred at -10 °C for 30 min,
warmed to 23 °C, and washed with 10% NaHCO3 solution (10
mL). The aqueous phase was extracted with dichloromethane (2 ×
5 mL), the organic extracts were combined and dried, then the
solvent was removed in vacuo. The residue was purified by column
chromatography, using a mixture of n-hexane/EtOAc as the eluent.
2-(Benzyloxycarbonylamino)-N-[2-benzoyl-5-(4-tert-butoxy-
carbonylpiperazin-1-yl)phenyl]acetamide (14b). Compound 14b
was prepared following the above-described general procedure and
after purification by column chromatography (n-hexane/EtOAc 2:1;
1
Rf 0.20) was obtained as a colorless oil (400 mg, 89%). H NMR
(300 MHz, CDCl3) δ 1.46 (s, 9H), 3.38 (m, 4H), 3.55 (m, 4H),
4.09 (d, 2H, J ) 5.4 Hz), 5.14 (s, 2H), 5.75 (br, 1H), 6.44 (d, 1H,
J ) 9.1 Hz), 7.27-7.56 (m, 11H), 8.33 (s, 1H), 12.2 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 28.6, 43.4, 45.9, 46.9, 67.5, 80.5, 104.8,
107.3, 113.2, 128.3, 128.4, 128.7, 129.4, 129.9, 131.5, 136.5, 136.9,
140.0, 143.4, 154.8, 154.9, 156.8, 168.9, 198.3;.ESI-MS m/z 595
(M + Na)+, 573 (M + H)+. Anal. (C32H36N4O6) C, H, N.
The characterization data of compounds 13d-k and14c-e are
available as Supporting Information.
General Procedure for Preparation of Compounds 15a-j
and 16a-e. To a degassed solution of Cbz-derivatives 13 or 14
8466 J. Org. Chem. Vol. 73, No. 21, 2008

Piperazino-Substituted 1,4-Benzodiazepin-2-ones
(0.48 mmol) and cyclohexene or 1,4-cyclohexadiene (10 mL) in
ethanol (10 mL) was added 10% palladium on carbon (30 mg).
The reaction mixture was heated under reflux until the reaction
was complete (the reaction was monitored by TLC or ESI-MS and
was typically complete within 24-48 h). The catalyst was removed
by filtration through a bed of Celite and the solvent was removed
in vacuo.
9-(4-tert-Butoxycarbonylpiperazinyl)-5-phenyl-1,3-dihydro-
benzo[e][1,4]diazepin-2-one (15a). Compound 15a was prepared
following the above-described general procedure and after purifica-
tion by column chromatography (n-hexane/EtOAc 2:1; Rf 0.44) and
recrystallization the title compound was obtained as colorless prisms
(126 mg, 53%). Mp (n-hexane) 216-218 °C; 1H NMR (200 MHz,
CDCl3) δ 1.48 (s, 9H), 2.87 (br, 4H), 3.46-3.73 (m, 4H), 4.32 (br,
2H), 7.10 (m, 2H), 7.25-7.43 (m, 4H), 7.50 (m, 2H), 8.24 (br,
1H); 13C NMR (75 MHz, CDCl3) δ 28.7, 44.3, 52.2, 57.4, 80.4,
123.0, 123.6, 127.6, 127.8, 128.4, 130.0, 130.5, 134.0, 139.8, 142.9,
154.9, 170.9 (2C); ESI-MS m/z 863 (2 M + Na)+, 459 (M + K)+,
443 (M + Na)+, 421 (M + H)+. Anal. (C24H28N4O3) C, H, N.
9-(4-Benzylpiperazinyl)-5-phenyl-1,3-dihydrobenzo[e][1,4]dia-
zepin-2-one (15b). From 13b: Compound 15b was prepared
following the above-described general procedure and after purifica-
tion by column chromatography (n-hexane/EtOAc 4:1) was obtained
in 75% yield (180 mg).
general procedure and after purification by column chromatog-
raphy (n-hexane/EtOAc 2:1) was obtained as amorphous white
solid (61 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 1.51 (s, 9H),
3.32 (m, 4H), 3.61 (m, 4H), 3.85 (t, 1H, J ) 6.9 Hz), 4.26 (m,
1H), 4.43 (m, 1H), 6.46 (d, 1H, J ) 2.2 Hz), 6.68 (dd, 1H, J )
8.8, 2.2 Hz), 7.2 (d, 1H, J ) 8.8 Hz), 7.36-7.46 (m, 4H), 7.56
(d, 2H, J ) 7.3 Hz), 8.38 (s, 1H); 13C NMR (100 MHz, CD3OD)
δ 27.3, 43.0, 61.6, 64.6, 80.1, 104.9, 110.5, 118.0, 127.8, 129.7,
130.2, 132.4, 139.3, 140.4, 153.4, 155.0, 170.2, 171.4; ESI-MS
m/z 489 (M + K)+, 451 (M + H)+; [R]20D -21.9 (c 0.2, CH3OH).
Anal. (C25H30N4O4) C, H, N. From the reaction mixture was
also recovered as a byproduct the (+)-(3R)-3-(benzyloxyme-
thyl)-5-phenyl-8-(4-tert-butoxycarbonylpiperazin-1-yl)-1,3-
dihydrobenzo[e][1,4]diazepin-2-one (40 mg, 21%) as a colorless
1
low-melting solid. H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H),
3.27 (m, 4H), 3.58 (m, 4H), 3.92 (t, 1H, J ) 6.7 Hz), 4.18 (dd,
1H, J ) 6.4, 6.1 Hz), 4.46 (dd, 1H, J ) 9.3, 7.0 Hz), 4.71 (s,
2H), 6.45 (d, 1H, J ) 2.0 Hz), 6.64 (dd, 1H, J ) 8.8, 2.0 Hz),
7.15 (d, 1H, J ) 8.8 Hz), 7.24-7.44 (m, 8H), 7.54 (m, 2H),
8.48 (s, 1H); 13C NMR (75 MHz, CD3OD) δ 27.5, 44.3, 63.3,
70.2, 73.4, 80.4, 105.1, 110.8, 118.3, 127.5, 127.7, 128.1, 128.2,
129.9, 130.6, 132.6, 138.5, 139.6, 140.6, 153.6, 155.2, 169.9,
171.5; ESI-MS m/z 563 (M + Na)+, 541 (M + H)+; [R]20D +15.2
(c 0.1, CH3OH). Anal. (C32H36N4O4) C, H, N. Following the
same procedure, (S)-(+)-16c was obtained as a colorless oil (50
From 13c: To a solution of N-Fmoc protected anilide 13c (488
mg, 0.75 mmol) in dichloromethane (10 mL) was added piperidine
(1 mL). The reaction mixture was stirred under reflux for 24 h.
After this time the solvent was removed in vacuo and the residue
was purified by column chromatography (n-hexane/EtOAc 4:1) and
recrystallization to afford the title compound as colorless prisms
mg, 46%). [R]20 +21.5 (c 0.3, CH3OH). Anal. (C25H30N4O4)
D
C, H, N. From the reaction mixture was also recovered as a
byproduct the (-)-(3S)-3-(benzyloxymethyl)-5-phenyl-8-(4-tert-
butoxycarbonylpiperazin-1-yl)-1,3-dihydrobenzo[e][1,4]diazepin-
2-one (20 mg, 31%). [R]20 -15.8 (c 0.2, CH3OH). ESI-MS,
D
1H and 13C NMR data of both compounds were identical with
those described above. Anal. (C32H36N4O4) C, H, N.
1
(58 mg, 30%). Mp (n-hexane) 216-218 °C; H NMR (200 MHz,
CDCl3) δ 2.68 (br, 4H), 2.96 (m, 4H), 3.60 (s, 2H), 4.31 (s, 2H),
7.08 (m, 2H), 7.25-7.43 (m, 9H), 7.51 (m, 2H), 8.24 (br, 1H); 13
C
The characterization data of compounds 15d-j and16b,d-e are
available as Supporting Information.
NMR (100 MHz, CDCl3) δ 52.1, 53.4, 57.3,. 63.1, 122.7, 123.2,
127.1, 127.2, 127.3, 128.1, 128.3, 129.3, 129.7, 130.2, 133.9, 137.8,
139.7, 143.0, 170.6, 170.7; ESI-MS m/z 433 (M + Na)+, 411 (M
+ H)+. Anal. (C26H26N4O) C, H, N.
General Procedure for Preparation of Compounds 1a-h
and 2a-c. A 0.1 N dry solution of hydrochloric acid in methanol
was prepared by carefully adding acetyl chloride (0.3 mmol) to
dry methanol (3 mL). The resulting solution was added to Boc-
protected derivatives 15 or 16 (0.15 mmol) dissolved in dry
methanol (3 mL) and the reaction mixture was placed at the
rotavapor and kept at 60 °C until complete removal of the solvent
(10 min). Addition and evaporation of the methanolic solution of
hydrochloric acid was repeated (usually three times) until complete
disappearance of the starting material as monitored by TLC or ESI-
MS. The solvent was removed in vacuo to afford the title
compounds as their corresponding hydrochloride salts.
9-(Piperazin-1-yl)-5-phenyl-1,3-dihydrobenzo[e][1,4]diazepin-
2-one (1a). Following the above-described general procedure, the
title compound was obtained in quantitative yield, and as a bright
yellow amorphous solid. 1H NMR (200 MHz, CD3OD) δ 3.30 (br,
4H), 3.50 (br, 4H), 4.50 (br, 2H), 7.25 (d, 1H, J ) 8.1, Hz), 7.45
(m, 1H), 7.68 (m, 4H), 7.82-7.91 (m, 2H); 13C NMR (50 MHz,
CD3OD) δ 44.9, 52.6, 126.8, 130.3, 130.7, 132.4, 133.2, 133.5,
136.6, 137.8, 144.8, 168.9, 179.5; ESI-MS m/z 321 (M + H)+.
Anal. (C19H20N4O) C, H, N.
3-Methyl-5-phenyl-9-(4-tert-butoxycarbonylpiperazin-1-yl)-
1,3-dihydrobenzo[e][1,4]diazepin-2-one (15c). Compound (R)-
(-)-15c was prepared following the above-described general
procedure and after purification by column chromatography (n-
hexane/EtOAc 1:1; Rf 0.39) and recrystallization was obtained as
yellow prisms (182 mg, 62%). Mp (n-hexane) 115-117 °C dec;
1H NMR (200 MHz, CDCl3) δ 1.48 (s, 9H), 1.76 (d, 3H, J ) 7.0
Hz), 2.75 (br, 2H), 3.02 (m, 2H), 3.46-3.74 (m, 5H), 7.10 (m,
2H), 7.26 (m, 1H), 7.31-7.42 (m, 3H), 7.50 (m, 2H), 8.26 (br,
1H); 13C NMR (50 MHz, CDCl3) δ 17.2, 28.4, 43.9, 51.9, 59.3,
80.1, 122.5, 123.1, 127.1, 127.7, 128.1, 129.8, 130.1, 133.5, 139.5,
142.6, 154.6, 168.1, 171.6; ESI-MS m/z 891 (2 M + Na)+, 473
(M + K)+, 457 (M + Na)+, 435 (M + H)+; [R]20 -47.6 (c 0.9,
D
CH3OH). Anal. (C25H30N4O3) C, H, N. Following the same
procedure, (S)-(+)-15c was obtained as a colorless oil (182 mg,
1
63%). [R]20 +47.7 (c 0.2, CH3OH). ESI-MS, H and 13C NMR
D
data of (S)-15c were identical with those obtained for (R)-15c.
8-(4-Benzylpiperazin-1-yl)-5-phenyl-1,3-dihydrobenzo[e][1,4]-
diazepin-2-one (16a). The title compound was prepared following
the above-described general procedure and after purification by
column chromatography (EtOAc 1:1; Rf 0.36) was obtained as a
The characterization data of compounds 1b-h are available as
Supporting Information.
3-(2-Carboxyethyl)-5-phenyl-9-(piperazin-1-yl)-1,3-dihydro-
benzo[e][1,4]diazepin-2-one (1i). To solution of (R)-15j (50 mg,
0.1 mmol) in dry 1,4-dioxane (3 mL) was added a 0.1 N solution
of HCl in 1,4-dioxane (3 mL). The reaction mixture was stirred on
a rotavapor at 60 °C for 10 min, then was monitored by TLC or
ESI-MS. The solvent was removed in vacuo to afford the
hydrochloride salt of (R)-(+)-1i as a bright yellow amorphous solid
(42.0 mg, 99%). 1H NMR (200 MHz, D2O) δ 2.42-2.61 (m, 4H),
3.05 (m, 2H), 3.28-3.54 (m, 6H), 4.22 (m, 1H), 7.17 (d, 1H, J )
7.1 Hz), 7.33 (m, 1H), 7.49-7.56 (m, 4H), 7.69-7.76 (m, 2H);
13C NMR (75 MHz, CD3OD) δ 22.4, 30.0, 43.6, 59.7, 123.3, 125.8,
129.3, 129.4, 131.2, 131.9, 132.6, 135.6, 136.6, 143.7, 167.8, 175.1,
1
colorless amorphous solid (78 mg, 44%). H NMR (300 MHz,
CDCl3) δ 2.58 (m, 4H), 3.31 (m, 4H), 3.56 (s, 2H), 4.29 (s, 2H),
6.48 (s, 1H), 6.61 (d, 1H, J ) 8.8 Hz), 7.11 (d, 1H, J ) 8.8.Hz),
7.25-7.41 (m, 10H), 7.53 (d, 1H, J ) 7.4 Hz), 9.05 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 47.6, 53.0, 57.0, 63.1, 105.2, 110.3,
117.9, 127.5, 128.3, 128.6, 129.5, 130.1, 130.2, 132.9, 137.7, 140.2,
140.5, 153.2, 171.4, 172.0; ESI-MS m/z 433 (M + Na)+, 411 (M
+ H)+. Anal. (C26H26N4O) C, H, N.
3-(Hydroxymethyl)-5-phenyl-8-(4-tert-butoxycarbonylpiper-
azin-1-yl)-1,3-dihydrobenzo[e][1,4]diazepin-2-one (16c). Com-
pound (R)-(-)-16c was prepared following the above-described
J. Org. Chem. Vol. 73, No. 21, 2008 8467

Butini et al.
178.4; ESI-MS m/z 393 (M + H)+; [R]20 +234 (c 0.3, CH3OH).
Supporting Information Available: X-ray crystallography;
determination of enantiomeric purity by chiral solvating
agents; general experimental methods; characterization data
of compounds13d-k, 14c-e, 15d-j, 16b,d,e, 1b-h, and
2b,c; copies of 1H and 13C NMR spectra of new compounds;
and elemental analyses. This material is available free of
charge via the Internet at http://pubs.acs.org. The crystal-
lographic data of compound 5a was deposited at the
Cambridge Crystallographic Data Centre with deposit num-
bers CCDC 688413. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax (+44) 1223-336-033;
or e-mail deposit@ccdc.cam.ac.uk).
D
Anal. (C22H24N4O3) C, H, N. Following the same procedure, (S)-
(-)-1i was obtained in quantitative yield as a bright yellow
1
amorphous solid; [R]20 -238 (c 0.4, CH3OH). ESI-MS, H and
D
13C NMR data of (S)-1i were identical to those obtained for (R)-1i.
HRMS calcd for [(C22H24N4O3) + H]+ 393.1921, found 393.1919.
Anal. (C22H24N4O3) C, H, N.
8-(4-Piperazin-1-yl)-5-phenyl-1,3-dihydrobenzo[e][1,4]diazepin-
2-one (2a). Following the above-described general procedure, the
title compound was obtained in quantitative yield as a bright yellow
1
amorphous solid. H NMR (200 MHz, CD3OD) δ 3.40 (m, 4H),
3.85 (m, 4H), 4.34 (s, 2H), 6.84 (s, 1H), 7.01 (d, 1H, J ) 8.0, Hz),
7.25 (d, 1H, J ) 8.0, Hz), 7.40-7.73 (m, 5H); 13C NMR (75 MHz,
CD3OD) δ. 42.9, 43.6, 50.5, 104.4, 111.3, 111.4, 129.4, 131.8,
132.9, 134.8, 137.5, 144.4, 156.0, 167.8, 175.8; ESI-MS m/z 321
(M + H)+. Anal. (C19H20N4O) C, H, N.
The characterization data of compounds 2b,c are available as
Supporting Information.
Acknowledgment. The authors acknowledge MIUR PRIN
for financial support.
JO8015456
8468 J. Org. Chem. Vol. 73, No. 21, 2008