Solid-Phase Synthesis of 3,4,5-Substituted 1,5-Benzodiazepin-2-ones

Article abstract of DOI:10.1021/jo981620+

The preparation of 3,4,5-substituted 8-carboxamido-1,5-benzodiazepin-2-ones using a solid-phase synthetic method is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the aryl fluoride with either an α- or β-substituted β-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group is accomplished in the presence of SnCl₂?H₂O. Hydrolysis of the ester is carried out in the presence of a heterogeneous mixture of 1 N NaOH/THF (1:1). The resulting aniline acid is cyclized to form the benzodiazepinone skeleton with DIC and HOBt. Selective alkylation at the N-5 position of the benzodiazepinone is accomplished with alkyl halides in the presence of K₂CO₃ in acetone. The desired products are cleaved from solid supports and obtained in 46-98% isolated yields.

Full text of DOI:10.1021/jo981620+

3060
J . Org. Chem. 1999, 64, 3060-3065
Solid -P h a se Syn th esis of 3,4,5-Su bstitu ted
1,5-Ben zod ia zep in -2-on es†
J ung Lee,* Diane Gauthier, and Ralph A. Rivero
The R.W. J ohnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477
Received August 10, 1998
The preparation of 3,4,5-substituted 8-carboxamido-1,5-benzodiazepin-2-ones using a solid-phase
synthetic method is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the
acid group. Aromatic substitution of the aryl fluoride with either an R- or â-substituted â-amino
ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group is
accomplished in the presence of SnCl2‚H2O. Hydrolysis of the ester is carried out in the presence
of a heterogeneous mixture of 1 N NaOH/THF (1:1). The resulting aniline acid is cyclized to form
the benzodiazepinone skeleton with DIC and HOBt. Selective alkylation at the N-5 position of the
benzodiazepinone is accomplished with alkyl halides in the presence of K2CO3 in acetone. The desired
products are cleaved from solid supports and obtained in 46-98% isolated yields.
In tr od u ction
(five-member heterocycle),3b 1-alkyl-2-alkylthiobenzimi-
dazole (five-member heterocycle),3c and quinoxalin-2-ones
(six-member heterocycle)3d from a common intermediate,
the resin-bound 4-fluoro-3-nitrobenzoic acid. Now, we are
pleased to report the solid-phase synthesis of 3,4,5-trisub-
stitued 8-carboxamido-1,5-benzodiazepin-2-ones, seven-
memebered heterocycles, from a common intermediate.4
Benzodiazepines5 have been an important pharma-
cophore in the pharmaceutical industry. The therapeutic
applications of benzodiazepines include anxiolytics,6a
antiarrhythmics,6b vasopressin antagonists,6c HIV reverse
transcriptase inhibitors,6d and cholecystokinin antag-
onists.6e In fact, the first heterocyclic templates prepared
on a solid support were 1,4-benzodiazepines.7 Since then
there have been numerous reports on the synthesis of
similar skeletons.8 To test the feasibility of preparing the
1,5-benzodiazepin-2-ones 1 on a solid support, we tar-
geted the preparation 35 compounds with variation of
three diversity elements.
During the last 6 years, development of solid-phase
synthetic methods has been a major focus for many
chemists.1 The ability to synthesize a large number of
small molecules in a short period of time has facilitated
the high-throughput screening programs in most phar-
maceutical companies. Even though the addition of new
compounds has accelerated tremendously, the important
issue of creating the diversity of the chemical libraries
still remains. In developing a solid-phase synthetic
method for a heterocycle, one would be able to make
thousands of molecules, but the essential scaffold remains
the same. Having structural diversity in chemical librar-
ies would provide a better chance of finding a novel ligand
during high-throughput screening. Therefore, the devel-
opment of a solid-phase synthetic method that could be
used to prepare a variety of chemical templates remains
as an important task. Previously, Gallop and co-workers
have demonstrated this approach in one example.2 In
their work, a resin-bound imine intermediate has been
used to prepare a variety of chemical templates, such as
pyrrolidines,2a thiazolidinones,2b and â-lactams.2c More
recently, we have reported along with Phillips and co-
workers the solid-phase synthesis of benzimidazoles (five-
member heterocycle),3a 1,3-dialkylbenzimidazole-2-ones
* To whom correspondence should be addressed. Tel: (215)-628-
5228. Fax: (215)-628-3297. E-mail: jlee@prius.jnj.com.
† Dedicated to Professor Satoru Masamune on the occasion of his
70th birthday.
Resu lts a n d Discu ssion
(1) (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gordon, E. M. J . Med. Chem. 1994, 37, 1233-1251. (b) Thompson, L.
A.; Ellman, J . A. Chem. Rev. 1996, 96, 555-600. (c) Balkenhohl, F.;
von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2288-2337. (d) Terett, N. K.; Gardner, M.;
Gordon, D. W.; Kobylecki, R. J .; Steele, J . Tetrahedron 1995, 51, 8135-
8173. (e) See the entire issue: Chem. Rev. 1997, 97, 347-509.
(2) (a) Murphy, M. M.: Schullek, J . R.; Gordon, E. M.; Gallop, M.
A. J . Am. Chem. Soc. 1995, 117, 7029-7030. (b) Holmes, C. P.; Chinn,
J . P.; Look, G. C.; Gordon, E. M.; Gallop, M. A. J . Org. Chem. 1995,
60, 7328-7333. (c) Ruhland, B.; Bhandari, A.; Gordon, E. M.; Gallop,
M. A. J . Am. Chem. Soc. 1996, 118, 253-254.
(3) (a) Phillips, G. W.; Wei, G. P. Tetrahedron Lett. 1996, 37, 4887-
4890. (b) Phillips, G. W.; Wei, G. P. Tetrahedron Lett. 1998, 39, 179-
182. (c) Lee, J .; Gauthier, D.; Rivero, R. A. Tetrahedron Lett. 1998, 39,
201-204. (d) Lee, J .; Murray, W. V.; Rivero, R. A. J . Org. Chem. 1997,
62, 3874-3879. See also: Morales, G. A.; Corbett, J . W.; DeGrado, W.
F. J . Org. Chem. 1998, 63, 1172-1177.
Our synthetic strategy involved a route similar to the
one reported previously and is shown in Scheme 1.3d We
initially decided to attach the phenyl ring of the benzo-
diazepinone to a solid support and then build the
heterocyclic ring on the support. The attachment of the
phenyl ring to the solid support was to be accomplished
(4) While this manuscript was being reviewed, a paper appeared
on the solid-phase synthesis of benzodiazepinones, which employed a
similar route with commercially available but limited â-amino acids
instead of the readily available â-amino esters as described in the
text: Schwarz, M. K.; Tumelty, D.; Gallop, M. A. Tetrahedron Lett.
1998, 39, 8397-8400.
(5) (a) Archer, G. A.; Sternbach, L. H. Chem. Rev. 1968, 68, 747-
784. (b) Sternbach, L. H. Prog. Drug Res. 1978, 22, 229-266.
10.1021/jo981620+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/14/1999

Synthesis of Trisubstituted 1,5-Benzodiazepin-2-ones
J . Org. Chem., Vol. 64, No. 9, 1999 3061
Sch em e 1
As shown in Scheme 1, a substituent at the â position
of the â-amino ester transforms to the substituent at
C-4 position of the benzodiazepinones. We anticipated
that the presence of a bulky group at the C-4 position
of the benzodiazepinones would cause difficulty in al-
kylation at the N-5 position due to possible steric hin-
drance. Therefore, for the preparation of either R- or
â-substituted â-amino esters, we concentrated mostly on
the R-substituted â-amino esters. After considering the
preexisting abundance of starting materials, we chose to
prepare the R-substituted â-amino esters from ethyl
cyanoacetate and aldehydes. The preparation involved
two steps as shown in Scheme 2. The Knoevenagel
condensation10 of ethyl cyanoacetate 2 and aldehydes,
and subsequent reduction of the resulting acrylic nitrile
3 with Pearlman’s catalyst gave the desired R-substituted
â-amino esters 4 from 43% to 59% overall yields. Surpris-
ingly, the route described above has not been used to
prepare R-substituted â-amino esters to our knowledge.12
Full investigation of the synthetic route will be reported
elsewhere.13
Sch em e 2
With the â-amino esters in hand, the solid-phase syn-
thesis began with removal of the Fmoc-protecting group
from Rink-Amide resin with DMF/piperidine (1:1), as
shown in the Scheme 3. 4-Fluoro-3-nitrobenzoic acid was
then attached to the resultant amino-resin using O-(7-
azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-
fluorophosphate (HATU) and N,N′-diisopropylethylamine
(DIEA). Portions of the product resin 6 were equally
divided into seven parts. Each portion of resin was then
allowed to react with seven different â-amino esters.
Hindered â-substituted â-amino esters, such as ethyl
3-aminobutyrate and methyl 3-amino-3-phenylpropi-
onate, were chosen to observe the effects of any steric
hindrance during the course of the synthesis. Aromatic
substitution of the activated aryl fluoride 6 with â-amino
ester was accomplished in the presence of DIEA in DMF
for 3 days.
through the acid function of 4-fluoro-3-nitrobenzoic acid.9
In our previous paper,3d we had used R-amino esters to
form the basic skeleton of the six-membered ring of
quinoxalinones. Therefore, utilizing â-amino esters seemed
to be the obvious choice to construct the basic skeleton
of the seven-membered benzodiazepinones. Because not
many substituted â-amino esters were commercially
available, we decided to employ a simple route10 to
prepare a variety of R-substituted â-amino esters, as
shown in Scheme 2. After the aromatic substitution of
the aryl fluoride with the â-amino ester, the stage was
set for the formation of the heterocyclic ring of the
benzodiazepinones. The reduction of the aryl nitro group
and subsequent intramolecular cyclization11 of the result-
ing amine with the ester would give the skeleton of
benzodiazepinones. Alkylation at the N-5 position of the
skeleton with alkyl halides would result in the introduc-
tion of one more diversity element in the core structure.
To verify the extent of aromatic substitution, small
portions of the resins 7 were treated with 95% TFA for a
period of 50 min. The cleaved products were separated
from the resins and concentrated. The concentrated
products were initially analyzed by LC and then purified
by flash chromatography. The initial LC analysis indi-
cated that no starting materials were observed, and the
products 8 were greater than 90% pure in all cases. The
crude products were then purified by flash chromatog-
raphy. The purified products were analyzed by LC, MS,
(6) (a) Wright, W. B.; Brabander, H. J .; Greenblatt, E. N.; Day, I.
P.; Hardy, R. A. J . Med. Chem. 1978, 21, 1087-1089. (b) Selnick, H.
G.; Liverton, N. J .; Baldwin, J . J .; Butcher, J . W.; Claremon, D. A.;
Elliotte, J . M.; Freidinger, R. M.; King, S. A.; Libby, B. E.; McIntyre,
C. J .; Pribush, D. A.; Remy, D. C.; Smith, G. R.; Tebben, A. J .;
J urkiewicz, N. K.; Lynch, J . J .; Salata, J . J .; Sanguinetti, M. C.; Siegal,
P. K. S.; Slaughter, D. E.; Vyas, K. J . Med. Chem. 1997, 40, 3865-
3868. (c) Albright, J . D.; Feich, M. F.; Santos, E. G. D.; Dusza, J . P.;
Sum, F.-W.; Venkatesan, A. M.; Coupet, J .; Chan, P. S.; Ru, X.;
Mazandarani, H.; Bailey, T. J . Med. Chem. 1998, 41, 2442-2444. (d)
Breslin, H. J .; Kukla, M. J .; Ludovici, D. W.; Mohrbacher, R.; Ho, W.;
Miranda, M.; Rodgers, J . D.; Hitchens, T. K.; Leo, G.; Gauthier, D. A.;
Ho, C. Y.; Scott, M. K.; De Clercq, E.; Pauwels, R.; Andries, K.; J anssen,
M. A. C.; J anssen, P. A. J . Med. Chem. 1995, 38, 771-793. (e) Castro,
J . L.; Broughton, H. B.; Russell, M. G. N.; Rathbone, D.; Watt, A. P.;
Ball, R. G.; Chapman, K. L.; Patel, S.; Smith, A. J .; Marshall, G. R.;
Matassa, V. G. J . Med. Chem. 1997, 40, 2491-2501.
1
and H and 13C NMR. In all cases, the analysis confirmed
(10) For the Knoevenagel condensation of aldehydes with ethyl
cyanoacetate, see: Gardner, P. D.; Brandon, R. I. J . Org. Chem. 1957,
22, 1704-1705. J ones, G. Org. React. 1967, 15, 204-599. For
a
complete reduction of an acrylic nitrile to an alkylamine with a borane
reagent, see: Weinhardt, K.; Wallach, M. B.; Marx, M. J . Med. Chem.
1985, 28, 694-698. With H2/PtO2, see: Cowen, F. M. J . Org. Chem.
1955, 20, 287-294.
(11) (a) Parker, K. A.; Dermatakis, A. J . Org. Chem. 1997, 62, 4164-
4167. (b) Fray, M. J .; Cooper, K.; Parry, M. J .; Richardson, K.; Steele,
J . J . Med. Chem. 1995, 38, 3514-3523. (c) Floyd, D. M.; Moquin, R.
V.; Atwal, K. S.; Ahmed, S. Z.; Spergel, S. H.; Gougoutas, J . Z.; Malley,
M. F. J . Org. Chem. 1990, 55, 5572-5579. (d) Mayer, J . P.; Zhang, J .;
Bjergarde, K.; Lenz, D. M.; Gaudino, J . J . Tetrahedron Lett. 1996, 37,
8081-8084. (e) van Niel, M. B.; Freedman, S. B.; Matassa, V. G.; Patel,
S.; Penqilley, R. P.; Smith, A. J . Bioorg. Med. Chem. Lett. 1995, 5,
1421-1426. (f) Levai, A.; Puzicha, G. Synthetic Comm. 1985, 15, 623-
632.
(7) Bunin, B. A.; Ellman, J . A. J . Am. Chem. Soc. 1992, 114, 10997-
10998.
(8) (a) Bhalay, G.; Blaney, P.; Palmer, V. H.; Baxter, A. D. Tetra-
hedron Lett. 1997, 38, 8375-8378. (b) Boojamra, C. G.; Burow, K. M.;
Thompson, L. A.; Ellman, J . A. J . Org. Chem. 1997, 62, 1240-1256.
Boojamra, C. G.; Burow, K. M.; Ellman, J . A. J . Org. Chem. 1995, 60,
5742-5743. Plunkett, M. J .; Ellman, J . A. J . Am. Chem. Soc. 1995,
117, 3306-3307. (c) Mayer, J . P.; Zhang, J .; Bjergarde, K.; Lenz, D.
M.; Gaudino, J . J . Tetrahedron Lett. 1996, 37, 8081-8084. (d) Goff, D.
A.; Zuckermann, R. N. J . Org. Chem. 1995, 60, 5744-5745.
(9) Dankwardt, S. M.; Newman, S. R.; Krstenansky, J . L. Tetrahe-
dron Lett. 1995, 36, 4923-4926.
(12) (a) Cole, D. Tetrahedron 1994, 50, 9517-9582. (b) Griffith, O.
W. Annu. Rev. Biochem. 1986, 55, 855-878. (c) Cardillo, G.; Tomasini,
C. Chem. Soc. Rev. 1996, 25, 117-128.
(13) Lee, J .; Rivero, R. Manuscript in preparation.

3062 J . Org. Chem., Vol. 64, No. 9, 1999
Lee et al.
Sch em e 3a
a
Key: (a) DMF/piperidine (1:1); (b) (4-F-3-NO2)PhCO2H, HATU, DIEA, DMF; (c) H2NCH(R2)CH(R1)CO2R, DIEA, DMF; (d) SnCl2‚H2O,
DMF; (e) 1 N NaOH; THF (1:1); (f) DIC, HOBt, DMF; (g) R3CH2Br, K2CO3, CH3COCH3, 55 °C; (h) TFA/H2O (95:5).
the structure of the desired product 8, and the yields
ranged from 71 to 96%.
matography. The subsequent analysis of the purified ma-
terials indicated that a complete intramolecular cycliza-
tion occurred in all seven cases and the disubstituted 1,5-
benzodiazepin-2-ones 10 were obtained in 55-88% yields.
The aryl nitro group of the resin 7 was then reduced
with SnCl2‚H2O.14 To verify the completion of the reduc-
tion, samples of the resins were subjected to the same
TFA treatments as before. The crude products were
analyzed by LC and MS. The analysis of the products
indicated complete reduction of the nitro group. As
expected, the intramolecular cyclization observed in the
quinoxalinone case did not spontaneously occur at this
time. At this point we considered two alternatives for the
intramolecular cyclization to form the seven-membered
ring.11 One possibility involved two steps: initial hy-
drolysis of the ester to form a free acid and then cycliza-
tion of the aniline acid with a coupling agent. The other
possibility involved direct cyclization of the aniline ester
to form the seven-membered ring. Since the latter pos-
sibility requires only one step, we focused on the direct
cyclization. All attempts11 with aid of acid, base, heat,
or use of various solvents were unfruitful. Even the use
of sodium tert-butoxide at 60 °C in THF11d did not produce
the cyclized product. Thus, we turned to the other alter-
native. After some experiments, we found refluxing the
resin in a heterogeneous mixture (1:1) of 1 N NaOH and
THF for 24 h provided clean hydrolysis of the ester. The
product was analyzed after cleaving from the resin. The
characterization of the product with LC, MS, and 1H
NMR confirmed the hydrolysis, and the product was
obtained in almost quantitative yield. To our delight, the
next step involving the intramolecular cyclization of the
aniline acid with 1,3-diisopropylcarbodiimide (DIC) and
1-hydroxybenzotriazole (HOBt) proceeded without any
problems. To verify the completion of the cyclization, sam-
ples of the resins were subjected to the same TFA treat-
ment as before. As before, the crude products were initial-
ly analyzed by LC and MS and purified by flash chro-
Once the basic skeleton of 1,5-benzodiazepin-2-ones
had been prepared, additional diversity was added to N-5
position of the benzodiazepinones. As we have done
previously with quinoxalinones,3d the resins containing
the benzodiazepinones 9 were treated with alkyl halides.
The five-alkyl halides consisted of benzyl bromide, methyl
4-(bromomethyl)benzoate, 1-bromomethyl-3-methoxyben-
zene, 2-(bromomethyl)naphthalene, and 4-nitrobenzyl
bromide. After the resins were treated with the alkyl
halides in the presence of K2CO3 in refluxing acetone for
24 h, the products were cleaved from the resins using
the standard cleavage conditions. The crude products
were concentrated and then analyzed by LC and MS. In
all samples, no dialkylation products were observed. But
as expected, when the C-4 position of the benzodiazepi-
none contained a phenyl group, a trace of unreacted
starting material was observed in most of the LC spectra.
Interestingly, no variance in reactivity was observed
between electron-donating and -withdrawing alkyl ha-
lides.
The crude products were subsequently purified by flash
chromatography. The chromatographed products were
again analyzed by LC, MS, and 1H and 13C NMR to
confirm structure and purity. The desired products,
shown in Table 1, were obtained in 46-98% yields. It is
worthy to note that after eight synthetic steps on a solid
support 98% yields were obtained in some cases. It
certainly demonstrates the efficiency and feasibility of
the solid-phase synthetic method developed.
In summary, we have demonstrated that 3,4,5-trisub-
stituted 8-carboxamido-1,5-benzodiazepin-2-ones can be
prepared on a solid support from common building blocks
such as â-amino esters and alkyl halides. So far, we have
demonstrated that three different heterocycles could be
derived from a common intermediate, the resin-bound
(14) Meyers, H. V.; Dilley, G. J .; Durgin, T. L.; Powers, T. S.;
Winssinger, N. A.; Zhu, H.; Pavia, M. R. Mol. Diversity, 1995, 1, 13-
20.

Synthesis of Trisubstituted 1,5-Benzodiazepin-2-ones
J . Org. Chem., Vol. 64, No. 9, 1999 3063
Ta ble 1. 3,4,5-Su bstitu ted
8-Ca r boxa m id o-1,5-ben zod ia zep in -2-on es
pressure. To the crude solid was then added 200 mL of hexane.
The yellow solids were filtered, washed with hexane (3 × 50
mL), and dried to obtain 24.9 g (99% yield) of the R,â-
unsaturated ester 3a : mp 90-92 °C; 1H NMR (300 MHz,
CDCl3) δ 8.21 (1H, s), 8.03 (2H, dd, J ) 8.7, 7.0 Hz), 7.20 (2H,
t, J ) 8.6 Hz), 4.39 (2H, q, J ) 7.2, 14.2 Hz), 1.40 (3H, t, J )
7.0 Hz); 13C NMR (75 MHz, DMSO) δ 163.6, 162.3, 153.9,
133.4, 127.7, 116.7, 116.4, 102.5, 62.7, 14.1.
Eth yl 2-Cyan o-3-(4-m eth oxy)ph en yl-2-pr open oate (3b).
Using the same procedure, from 14.1 mL (116 mmol) of
4-methoxybenzaldehyde, 25.3 g (94% yield) of 3b was obtained
as a yellow solid: mp 81-82 °C; 1H NMR (300 MHz, CDCl3) δ
8.15 (1H, s), 7.99 (2H, d, J ) 8.8 Hz), 6.98 (2H, J ) 8.8 Hz),
4.36 (2H, q, J ) 7.1, 14.3 Hz), 3.89 (3H, s), 1.39 (3H, t, J ) 7.2
Hz); 13C NMR (75 MHz, DMSO) δ 163.6, 162.9, 154.2, 133.5,
124.2, 116.1, 114.6, 99.2, 62.3, 55.5, 14.1.
Eth yl r-(Am in om eth yl)-4-flu or oh yd r ocin n a m a te (4a ).
To 6.58 g (30 mmol) of 3a were added 80 mL of ethanol, 4.0
mL of the concentrated hydrochloride, and 658 mg of Pd(OH)2
(20 wt % Pd on carbon). The suspension was hydrogenated
for 3 days. After 3 days, the crude reaction solution was
concentrated under the reduced pressure. To the concentrated
crude were then added 125 mL of CH2Cl2 and 200 mL of 1 N
HCl. After separation of the organic layer, the aqueous layer
was washed with 2 × 100 mL of CH2Cl2 and neutralized with
a saturated solution of NaHCO3. The neutralized solution was
back-extracted with 3 × 100 mL of ethyl acetate. The combined
organic layer was dried over Na2SO4 and concentrated to
obtain 3.4 g (43% yield) of a yellow oil: 1H NMR (300 MHz,
CD3OD) δ 7.24 (2H, dd, J ) 5.5, 8.5 Hz), 7.03 (2H, t, J ) 8.5
Hz), 4.15 (2H, q, J ) 7.1, 14.0 Hz), 3.18-2.89 (5H, m), 1.18
(3H, t, J ) 7.1 Hz).
isolated
R1
R2
R3
yielda (%)
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
87
75
74
67
54
68
54
52
64
64
63
58
46
93
52
97
98
98
85
89
67
65
72
74
77
51
63
53
63
47
59
66
63
64
64
H
H
H
H
4-CO2MePh
3-OMePh
2-naphthyl
4-NO2Ph
Ph
4-CO2MePh
3-OMePh
2-naphthyl
4-NO2Ph
Ph
4-CO2MePh
3-OMePh
2-naphthyl
4-NO2Ph
Ph
CH3
CH3
CH3
CH3
CH3
Ph
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
H
H
H
H
4-CO2MePh
3-OMePh
2-naphthyl
4-NO2Ph
Ph
12s
12t
12u
12v
12w
12x
12y
12z
12a a
12a b
12a c
12a d
12a e
12a f
12a g
12a h
12a i
CH2(4-OMe)Ph
CH2(4-OMe)Ph
CH2(4-OMe)Ph
CH2(4-OMe)Ph
CH2(4-OMe)Ph
CH2(4-F)Ph
H
H
H
H
H
4-CO2MePh
3-OMePh
2-naphthyl
4-NO2Ph
Ph
H
CH2(4-F)Ph
CH2(4-F)Ph
CH2(4-F)Ph
CH2(4-F)Ph
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
H
H
H
H
H
H
H
H
4-CO2MePh
3-OMePh
2-naphthyl
4-NO2Ph
Ph
4-CO2MePh
3-OMePh
2-naphthyl
4-NO2Ph
Eth yl r-(Am in om eth yl)-4-m eth oxyh ydr ocin n am ate (4b).
Using the same procedure, from 11.6 g (50 mmol) of 3b, 7.5 g
(63% yield) of a reddish oil was obtained: 1H NMR (300 MHz,
CD3OD) δ 7.09 (2H, d, J ) 8.5 Hz), 6.82 (2H, d, J ) 8.5), 4.07
(2H, q, J ) 7.2, 14.3 Hz), 3.74 (3H, s), 2.76 (5H, m), 1.15 (3H,
t, J ) 7.2 Hz).
H
a
Yields are based on support-bound starting material 5.
Atta ch m en t of 4-F lu or o-3-n itr oben zoic Acid to Rin k
Am id e Resin . To 20 g of the Rink Amide resin (Novabiochem,
0.67 mmol/g) was added a solution containing 60 mL of each
DMF and piperidine at room temperature. The suspension was
allowed to mix at room temperature for 50 min. After 50 min,
the supernatant was removed. The resin was washed with
DMF, MeOH, CH2Cl2, and Et2O, and then dried in vacuo. To
the dried resin were added 9.92 g (53.6 mmol) of 4-fluoro-3-
nitrobenzoic acid, 20.4 g (53.6 mmol) of HATU, 18.7 mL (107
mmol) of DIEA, and 100 mL of dry DMF at room temperature.
The suspension was allowed to mix at room temperature
overnight. The next day, the supernatant was removed. The
resin was washed with DMF, MeOH, CH2Cl2, and Et2O and
then dried in vacuo.
4-fluoro-3-nitrobenzoic acid. The heterocycles consist of
five-membered (benzimidazole), six-membered (quinox-
alinones), and seven-membered (benzodiazepinones) rings.
By simple manipulation of building blocks, one can
prepare distinctively different heterocyclic templates
using essentially one solid-phase synthetic method. Ad-
ditional templates could be prepared by manipulating
different building blocks. These efforts are currently in
progress and will be reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r e for Ar om a tic Su bstitu tion of th e
Ar yl F lu or id e w ith â-Am in o Ester s. To each 1 g (approxi-
mately 0.67 mmol) of the above resin was added 4 equiv of
either R- or â-substituted â-amino ester (â-alanine ethyl ester
HCl, ethyl 3-aminobutyrate, methyl 3-amino-3-phenylpropi-
onate, ethyl 3-amino-2-phenylpropionate, ethyl 3-amino-2-ben-
zylpropionate, ethyl 3-amino-2-(4-methoxy)benzylpropionate,
ethyl 3-amino-2-(4-fluoro)benzylpropionate, ethyl 2-amino-
methyl-4-methylpentanoate), 8 equiv of DIEA, and 5 mL of
DMF at room temperature. The suspensions were allowed to
mix at room temperature for 3 days. After 3 days, supernatants
were removed. The resins were washed with DMF, MeOH,
CH2Cl2, and Et2O and dried in vacuo. From each of the seven
resins, 100 mg was removed to analyze the intermediates. To
each 100 mg of the resin was added 1 mL of a solution con-
taining 950 µL of TFA and 50 µL of H2O at ice-bath temper-
ature. The mixtures were slowly warmed to room temperature
and allowed to mix for 50 min. After 50 min, the supernatants
were removed, and the resins were washed with MeOH (3 ×
2 mL). The combined supernatants were concentrated under
a stream of nitrogen. The concentrated samples were further
dried in vacuo. The crude samples were analyzed by LC and
Reagents were purchased from Aldrich, Lancaster, Pfaltz
& Bauer, TCI America, Novabiochem, and Bachem Biosciences
and used without further purification. 1H and 13C NMR spectra
were collected on Bruker AC-300 or DMX 400 FT NMR
spectrometers. Chemical shifts are reported with respect to
tetramethylsilane (TMS) δH,C ) 0.0 ppm. Spectra were ac-
quired at ambient temperature using DMSO-d6, CD3OD, or
CDCl3. Mass spectral analyses were performed on a Fisons
instrument (Hewlett-Packard HPLC driven electrospray MS
instrument). Analytical HPLC analyses were performed on a
Hewlett-Packard liquid chromatography system (YMC column,
4 mm × 50 mm, 4 µm C18, 1.0 mL/min, 8 min gradient from
95% aqueous media (0.1% TFA) to 95% CH3CN (0.1% TFA),
220 and 260 nm).
Syn th esis of r-Su bstitu ted â-Am in o Ester s. Eth yl
2-Cya n o-3-(4-flu or o)p h en yl-2-p r op en oa te (3a ). To 12.3 mL
(116 mmol) of ethyl cyanoacetate were added 140 mL of
toluene, 1.52 mL of piperidine, and 12.4 mL (116 mmol) of
4-fluorobenzaldehyde at room temperature. The suspension
was allowed to reflux overnight. The next day, the suspension
was cooled, and the solvent was removed under the reduced

3064 J . Org. Chem., Vol. 64, No. 9, 1999
Lee et al.
MS and then purified by flash chromatography. The purified
products were weighed and analyzed by LC, MS, and 1H and
13C NMR.
121.7, 115.0, 62.0 (61.9), 51.6 (50.9), 43.8 (43.2), 36.7, 28.3
(28.0), 16.7 (16.4), 14.6 (14.5), 11.8 (11.7); MS (ESI) m/z 338
(M + H
+).
Gen er a l P r oced u r e for Red u ction for th e Ar yl Nitr o
Gr ou p . Hyd r olysis of ester a n d Cycliza tion . To each 900
mg (approximately 0.60 mmol) of the resin bound nitro ester
were added 1.78 g (9.4 mmol) of SnCl2‚H2O and 5.0 mL of DMF
at room temperature. The suspensions were allowed to mix
at room temperature overnight. The next day, the superna-
tants were removed. The resins were washed with DMF,
MeOH, CH2Cl2, and Et2O and dried in vacuo. From each of
the seven resins, 100 mg was removed to analyze the inter-
mediates. To each 800 mg (approximately 0.54 mmol) of the
resin-bound aniline ester was added 10 mL of a heterogeneous
mixture of 1 N NaOH/THF (1:1). The suspension was slowly
heated to 55 °C and allowed to mix at 55 °C overnight. The
next day, the supernatants were removed, and the resins were
washed with H2O until the filtrate was neutral. The resins
were further washed with DMF, MeOH, CH2Cl2, and Et2O and
dried in vacuo. From each of the seven resins, 100 mg was
removed to analyze the intermediates. To each 700 mg
(approximately 0.47 mmol) of the resin bound aniline acid were
added 5 mL of DMF, 294 µL (1.88 mmol) of DIC, and 254 mg
(1.88 mmol) of HOBt at room temperature. The suspensions
were allowed to mix at room temperature overnight. The next
day, the supernatants were removed, and the resins were
washed with DMF, MeOH, CH2Cl2, and Et2O. After the resins
were dried, 100 mg from each of the seven resins was removed
to analyze the cyclized product. To each 100 mg of the resin
was added 1 mL of a solution containing 950 µL of TFA and
50 µL of H2O at ice-bath temperature. The mixtures were
slowly warmed to room temperature and allowed to mix for
50 min at room temperature. After 50 min, supernatants were
removed, and the resins were washed with MeOH (3 × 2 mL).
The combined supernatants were concentrated under a stream
of nitrogen, and the concentrated samples were further dried
in vacuo. The dried samples were purified by flash chroma-
tography. The products were weighed and analyzed by LC, MS,
and 1H and 13C NMR.
8-Car boxam ido-1,5-ben zodiazepin -2-on e (10a). The crude
product was purified by flash chromatography (CHCl3/EtOH,
8:1) to obtain 17 mg (88% yield) of a white solid: mp >230 °C;
HPLC tR 1.3 min; 1H NMR (300 MHz, CD3OD) δ 7.43 (2H, m),
6.75 (1H, d, J ) 8.9 Hz), 3.62 (2H, t, J ) 5.3 Hz), 2.67 (2H, t,
J ) 5.3 Hz); 13C NMR (75 MHz, CD3OD) δ 176.2, 171.8, 144.4,
125.8, 124.5, 123.9, 123.9, 119.3, 45.2, 37.7; MS (ESI) m/z 206
(M + H+).
4-Meth yl-8-car boxam ido-1,5-ben zodiazepin -2-on e (10b).
The crude product was purified by flash chromatography
(CHCl3/EtOH, 8:1) to obtain 18 mg (76% yield) of a clear oil:
HPLC tR 3.2 min; 1H NMR (300 MHz, CD3OD) δ 7.46 (2H, m),
6.84 (1H, d, J ) 8.2 Hz), 3.97 (1H, m), 2.62 (1H, dd, J ) 3.2,
13.6 Hz), 2.45 (1H, dd, J ) 7.5, 13.6 Hz), 1.32 (3H, d, J ) 6.3
Hz); 13C NMR (75 MHz, CD3OD) δ 175.0, 171.8, 144.3, 126.1,
126.1, 124.9, 123.7, 120.3, 53.9, 42.9, 23.7; MS (ESI) m/z 219
(M + H+).
N-(2-Nitr o-4-ca r boxa m id o)p h en yl-â-a la n in e Eth yl Es-
ter (8a ). From 100 mg of the resin (before the cleavage of the
product) was obtained 18 mg (96% yield) of a yellow solid: mp
1
195-197 °C; HPLC tR 5.2 min; H NMR (300 MHz, DMSO) δ
8.65 (1H, d, J ) 1.9 Hz), 8.45 (1H, t, J ) 5.8 Hz), 8.02 (2H,
m), 7.30 (1H, s), 7.15 (1H, d, J ) 9.2 Hz), 4.08 (2H, q, J ) 7.1,
14.3 Hz), 3.67 (2H, m), 2.70 (2H, t, J ) 6.6 Hz), 1.18 (3H, t, J
) 7.2 Hz); 13C NMR (75 MHz, DMSO) δ 173.0, 167.7, 147.9,
136.7, 132.4, 128.2, 122.7, 115.8, 61.9, 34.9, 15.8; MS (ESI)
m/z 282 (M + H+).
N -(2-Nit r o-4-ca r b oxa m id o)p h e n yl-3-m e t h ylp r op io-
n a te Eth yl Ester (8b). From 100 mg of the resin (before the
cleavage of the product) was obtained 19 mg (96% yield) of a
1
yellow oil: HPLC tR 5.5 min; H NMR (300 MHz, CD3OD) δ
8.75 (1H,s), 8.46 (1H, d, J ) 7.8 Hz), 7.99 (1H, d, J ) 9.1 Hz),
7.13 (1H, d, J ) 9.1 Hz), 4.31 (1H, m), 4.14 (2H, q, J ) 7.2,
14.4 Hz), 2.70 (2H, d, J ) 5.8 Hz), 1.38 (3H, d, J ) 6.5 Hz),
1.23 (3H, t, J ) 7.1 Hz); 13C NMR (75 MHz, CD3OD) δ 172.7,
170.2, 147.4, 136.0, 132.6, 128.3, 121.6, 115.3, 61.9, 47.0 (46.9),
41.6, 20.4, 14.5; MS (ESI) m/z 296 (M + H+).
N -(2-Nit r o-4-ca r b oxa m id o)p h e n yl-3-p h e n ylp r op io-
n a te Meth yl Ester (8c). From 100 mg of the resin (before
the cleavage of the product) was obtained 20 mg (83% yield)
of a yellow oil: HPLC tR 6.0 min; 1H NMR (300 MHz, CD3OD)
δ 9.08 (1H, d, J ) 6.7 Hz), 8.76 (1H, s), 7.83 (1H, d, J ) 8.9
Hz), 7.42-7.24 (5H, m), 6.86 (1H, d, J ) 9.1 Hz), 5.21 (1H, q,
J ) 6.4, 12.9 Hz), 3.65 (3H, s), 3.17 (2H, d, J ) 6.1 Hz); 13C
NMR (75 MHz, CD3OD) δ 171.0, 168.6, 145.7, 140.3, 134.1,
131.6, 128.6, 127.5, 126.4, 125.9, 120.8, 114.7, 54.1, 54.0, 50.9,
41.4; MS (ESI) m/z 344 (M + H+).
N -(2-Nit r o-4-ca r b oxa m id o)p h e n yl-2-p h e n ylp r op io-
n a te Eth yl Ester (8d ). From 100 mg of the resin (before the
cleavage of the product) was obtained 19 mg (76% yield) of a
1
yellow oil: HPLC tR 6.4 min; H NMR (300 MHz, CD3OD) δ
8.70 (1H, d, J ) 1.7 Hz), 7.93 (1H, dd, J ) 2.2, 9.2 Hz), 7.36-
7.27 (5H, m), 7.07 (1H, d, J ) 9.2 Hz), 4.23-4.05 (4H, m), 3.78
(1H, q, J ) 9.8, 16.6 Hz), 1.18 (3H, t, J ) 7.2 Hz); 13C NMR
(75 MHz, CD3OD) δ 173.8, 170.2, 148.0, 137.6, 135.9, 132.6,
130.0, 129.2, 129.0, 128.1, 121.8, 115.1, 62.4, 52.0, 46.5, 14.3;
MS (ESI) m/z 358 (M + H+).
N-(2-Nitr o-4-ca r boxa m id o)p h en yl-2-((4-m eth oxy)ben -
zyl)p r op ion a te Eth yl Ester (8e). From 100 mg of the resin
(before the cleavage of the product) was obtained 19 mg (71%
1
yield) of a yellow oil: HPLC tR 6.5 min; H NMR (300 MHz,
CD3OD) δ 8.73 (1H, d, J ) 2.1 Hz), 8.50 (1H, m), 7.93 (1H, dd,
J ) 2.0, 9.0 Hz), 7.12 (2H, d, J ) 8.5 Hz), 6.90 (1H, J ) 9.1
Hz), 6.83 (1H, d, J ) 8.6 Hz), 4.08 (2H, q, J ) 7.0, 14.2 Hz),
3.76 (3H, s), 3.73-3.55 (2H, m), 3.12-2.81 (3H, m), 1.15 (3H,
t, J ) 7.0 Hz); 13C NMR (75 MHz, CD3OD) δ 173.8, 168.7,
158.6, 146.4, 134.4, 131.2, 129.9, 129.5, 126.6, 120.3, 113.5,
60.6, 54.2, 43.4, 34.6, 12.9; MS (ESI) m/z 402 (M + H+).
N-(2-Nitr o-4-ca r boxa m id o)p h en yl-2-((4-flu or o)ben zyl)-
p r op ion a te Eth yl Ester (8f). From 100 mg of the resin
(before the cleavage of the product) was obtained 19 mg (76%
4-P h en yl-8-car boxam ido-1,5-ben zodiazepin -2-on e (10c).
The crude product was purified by flash chromatography
(CHCl3/EtOH, 8:1) to obtain 16 mg (75% yield) of a white
solid: mp >230 °C; HPLC tR 4.6 min; 1H NMR (300 MHz,
DMSO) δ 9.60 (1H, s), 7.67 (1H, s), 7.44-7.24 (6H, m), 7.06
(1H, s), 6.91 (1H, d, J ) 8.9 Hz), 6.40 (1H, d, J ) 2.9 Hz), 4.97
(1H, m), 2.76-2.50 (2H, m); 13C NMR (75 MHz, DMSO) δ
171.9, 169.1, 146.0, 143.8, 130.0, 128.9, 127.9, 127.0, 126.0,
125.6, 124.1, 120.2, 61.5, 44.2; MS (ESI) m/z 282 (M + H+).
1
yield) of a yellow oil: HPLC tR 6.7 min; H NMR (300 MHz,
CD3OD) δ 8.73 (1H, d, J ) 2.1 Hz), 8.50 (1H, m), 7.25-6.88
(5H, m), 4.07 (2H, q, J ) 7.0, 14.2 Hz), 3.67-3.59 (2H, m),
3.12-2.88 (3H, m), 1.13 (3H, m); 13C NMR (75 MHz, CD3OD)
δ 173.6, 168.7, 146.4, 134.4, 132.0, 131.3, 130.3, 126.6, 120.4,
119.7, 114.8, 114.6, 113.5, 60.6, 51.0, 43.6, 34.5, 12.9; MS (ESI)
m/z 390 (M + H+).
N-(2-Nitr o-4-ca r boxa m id o)p h en yl-2-(2-isobu tyl)p r op i-
on a te Eth yl Ester (8 g). From 100 mg of the resin (before
the cleavage of the product) was obtained 19 mg (76% yield)
of a yellow oil: HPLC tR 6.6 min; 1H NMR (300 MHz, CD3OD)
δ 8.74 (1H, d, J ) 2.1 Hz), 8.44 (1H, m), 7.99 (1H, dd, J ) 2.1,
9.0 Hz), 7.09 (1H, dd, J ) 1.7, 9.1 Hz), 4.15 (2H, q, J ) 7.2,
14.5 Hz), 3.68 (2H, m), 2.76 (1H, m), 1.85 (1H, m), 1.55 (1H,
m), 1.36-1.21 (4H, m), 1.03-0.93 (6H, m); 13C NMR (75 MHz,
CD3OD) δ 175.6 (175.2), 168.9, 148.1, 136.0, 132.7, 128.1,
3-P h en yl-8-car boxam ido-1,5-ben zodiazepin -2-on e (10d).
The crude product was purified by flash chromatography
(CHCl3/EtOH, 8:1) to obtain 16 mg (68% yield) of a white
solid: mp >230 °C; HPLC tR 4.6 min; 1H NMR (300 MHz,
DMSO) δ 9.64 (1H, s), 7.60 (1H, s), 7.37-7.21 (6H, m), 7.00
(1H, s), 6.66 (1H, d, J ) 8.4 Hz), 6.39 (1H, s), 3.99 (1H, d, J )
6.6 Hz), 3.77 (1H, m), 3.57 (1H, m); 13C NMR (75 MHz, DMSO)
δ 174.4, 169.3, 143.8, 139.9, 130.3, 129.8, 128.4, 125.4, 125.3,
125.0, 124.3, 118.7, 53.0, 50.0; MS (ESI) m/z 282 (M + H+).

Synthesis of Trisubstituted 1,5-Benzodiazepin-2-ones
J . Org. Chem., Vol. 64, No. 9, 1999 3065
3-(4-F lu or oben zyl)-8-ca r boxa m id o-1,5-ben zod ia zep in -
2-on e (10e). The crude product was purified by flash chro-
matography (CHCl3/EtOH, 8:1) to obtain 12 mg (55% yield) of
167.2, 142.1, 138.4, 133.9, 128.2, 127.9, 127.5, 126.8, 123.8,
122.0, 121.5, 60.0, 56.0, 53.2, 41.1, 16.3; MS (ESI) m/z 310 (M
+ H+).
1
a clear oil: HPLC tR 5.1 min; H NMR (300 MHz, CD3OD) δ
4-P h en yl-5-ben zyl-8-ca r boxa m id o-1,5-ben zod ia zep in -
2-on e (12k ). The crude product was purified by flash chro-
matography (CHCl3/EtOH, 8:1) to obtain 16 mg (63% yield) of
7.45 (2H, m), 7.24 (2H, m), 6.98 (2H, t, J ) 8.7 Hz), 6.73 (1H,
d, J ) 8.7 Hz), 3.53-3.30 (2H, m), 3.10-2.95 (2H, m), 2.67
(1H, dd, J ) 8.5, 13.5 Hz); 13C NMR (75 MHz, CD3OD) δ 175.4,
170.4, 163.1, 159.9, 143.1, 134.9 (134.9), 130.4, 130.3, 124.4,
122.9, 122.4 (122.4), 117.4, 114.7, 114.4, 56.8, 32.7, 16.9; MS
(ESI) m/z 314 (M + H+).
1
a white solid: mp >230 °C; HPLC tR 5.91 min; H NMR (400
MHz, DMSO) δ 9.78 (1H, s), 7.84 (1H, s), 7.56-7.15 (13H, m),
7.04 (1H, d, J ) 8.3 Hz), 4.91 (1H, dd, J ) 4.9, 10.6 Hz), 4.25-
4.09 (2H, AB, J ) 15.5 Hz), 2.73-2.45 (2H, m); 13C NMR (100
MHz, DMSO) δ 170.6, 167.2, 142.7, 141.3, 137.9, 133.2, 128.6,
128.3, 127.8, 127.4, 126.8, 126.6, 124.1, 121.9, 121.8, 68.7, 54.0,
41.4; MS (ESI) m/z 372 (M + H+).
3-(4-Meth oxy)ben zyl-8-car boxam ido-1,5-ben zodiazepin -
2-on e (10f). The crude product was purified by flash chroma-
tography (CHCl3/EtOH, 8:1) to obtain 14 mg (69% yield) of a
clear oil: HPLC tR 4.9 min; 1H NMR (300 MHz, CD3OD) δ 7.42
(2H, m), 7.09 (2H, d, J ) 8.5 Hz), 6.76 (2H, d, J ) 8.5 Hz),
6.72 (1H, d, J ) 8.2 Hz), 3.73 (3H, s), 3.53 (1H, d, J ) 2.1,
12.5 Hz), 3.30 (1H, m), 3.05-2.88 (2H, m), 2.60 (1H, dd, J )
8.9, 13.4 Hz); 13C NMR (75 MHz, CD3OD) δ 177.2, 159.8, 144.7,
132.3, 131.1, 125.8, 123.8, 118.8, 114.9, 58.3, 55.7, 34.1, 18.4;
MS (ESI) m/z 326 (M + H+).
3-P h en yl-5-ben zyl-8-ca r boxa m id o-1,5-ben zod ia zep in -
2-on e (12p ). The crude product was purified by flash chro-
matography (CHCl3/EtOH, 8:1) to obtain 24 mg (97% yield) of
1
a white solid: mp >230 °C; HPLC tR 6.07 min; H NMR (400
MHz, DMSO) δ 9.83 (1H, s), 7.83 (1H, s), 7.59-7.17 (13H, m),
7.08 (1H, d, J ) 9.1 Hz), 4.53-4.29 (2H, AB, J ) 15.1 Hz),
3.95-3.82 (2H, m), 3.41 (1H, dd, J ) 5.2, 10.3 Hz); 13C NMR
(100 MHz, DMSO) δ 172.3, 167.2, 144.1, 137.9, 136.8, 131.8,
129.4, 128.4, 127.9, 127.6, 127.4, 127.0, 124.3, 122.0, 119.2,
117.4, 61.7, 56.1, 47.5; MS (ESI) m/z 372 (M + H+).
3-Isobu tyl-8-car boxam ido-1,5-ben zodiazepin -2-on e (10g).
The crude product was purified by flash chromatography
(CHCl3/EtOH, 8:1) to obtain 13 mg (55% yield) of a clear oil:
HPLC tR 4.5 min; 1H NMR (300 MHz, CD3OD) δ 7.42 (2H, m),
6.69 (1H, d, J ) 8.3 Hz), 3.50 (2H, m), 2.51 (1H, m), 1.80-
3-(4-Meth oxy)ben zyl-5-ben zyl-8-ca r boxa m id o-1,5-ben -
zod ia zep in -2-on e (12u ). The crude product was purified by
flash chromatography (CHCl3/EtOH, 8:1) to obtain 19 mg (67%
yield) of a white solid: mp 189-191 °C; HPLC tR 6.27 min; 1H
NMR (400 MHz, DMSO) δ 9.65 (1H, s), 7.79 (1H, s), 7.52 (1H,
dd, J ) 2.0, 8.4 Hz), 7.44 (1H, d, J ) 2.0 Hz), 7.29-7.01 (9H,
m), 6.76 (2H, d, J ) 8.6 Hz), 4.48-4.14 (2H, AB, J ) 14.9 Hz),
3.34 (1H, m), 3.22 (1H, dd, J ) 5.6, 10.3 Hz), 2.90 (1H, dd, J
) 7.1, 13.7 Hz), 2.75 (1H, m), 2.38 (1H, dd, J ) 7.1, 13.7 Hz);
13C NMR (100 MHz, DMSO) δ 173.5, 167.2, 157.5, 144.5, 137.9,
131.9, 131.5, 129.9, 128.4, 128.2, 127.6, 127.4, 126.9, 126.3,
124.4, 121.9, 119.4, 113.5, 61.3, 56.1, 54.9, 43.0, 32.7; MS (ESI)
m/z 416 (M + H+).
3-(4-F lu or o)ben zyl-5-ben zyl-8-ca r boxa m id o-1,5-ben zo-
d ia zep in -2-on e (12z). The crude product was purified by flash
chromatography (CHCl3/EtOH, 8:1) to obtain 14 mg (51% yield)
of a white solid: mp 189-191 °C; HPLC tR 6.41 min; 1H NMR
(400 MHz, DMSO) δ 9.68 (1H, s), 7.78 (1H, s), 7.53 (1H, dd, J
) 2.0, 8.4 Hz), 7.44 (1H, d, J ) 2.1 Hz), 7.29-6.95 (11H, m),
4.47-4.17 (2H, AB, J ) 14.9 Hz), 3.37 (1H, m), 3.24 (1H, m),
2.94 (1H, dd, J ) 7.4, 13.6 Hz), 2.79 (1H, dd, J ) 5.9, 12.5
Hz), 2.44 (1H, dd, J ) 6.3, 13.6 Hz); 13C NMR (100 MHz,
DMSO) δ 173.3, 167.2, 144.4, 137.9, 135.8, 135.8, 131.8, 130.8,
130.7, 128.6, 128.1, 127.6, 127.4, 126.9, 124.4, 121.9, 119.4,
117.5, 114.9, 114.7, 61.2, 56.1, 42.8, 32.7; MS (ESI) m/z 404
(M + H+).
1.47 (3H, m), 0.95 (3H, dd, J ) 3.7, 6.6 Hz), 0.87 (3H, m); 13
C
NMR (75 MHz, CD3OD) δ 176.4 (176.3), 170.5, 142.8, 142.7,
124.0, 122.1, 121.4, 121.4, 121.3, 116.5, 116.4, 53.0 (53.0), 43.1
(42.8), 31.5 (31.0), 27.1 (25.2), 15.7 (14.6), 10.0 (9.5); MS (ESI)
m/z 262 (M + H+).
Gen er a l P r oced u r e for Alk yla tion a t th e N-5 P osition
of th e Ben zod ia zep in on e w ith Alk yl Ha lid es. To each 100
mg (approximately 67 µmol) of the cyclized resins were added
20 equiv (1.34 mmol) of alkyl halides (benzyl bromide, methyl
4-(bromomethyl)benzoate, 1-bromomethyl-3-methoxybenzene,
2-(bromomethyl)naphthalene, 4-nitrobenzyl bromide), 185 mg
(1.34 mmol) of K2CO3, and 1.5 mL of acetone at room
temperature. The mixtures were then heated at 55 °C over-
night. The next day, the mixtures were cooled to room
temperature, and supernatants were separated from the
resins. The resins were washed with acetone, H2O, DMF, CH2-
Cl2, and Et2O and then dried in vacuo. To each resin was then
added 2 mL of a solution containing 1.9 mL of TFA and 0.1
mL of H2O at ice-bath temperature. The mixtures were slowly
warmed to room temperature and allowed to mix 50 min at
room temperature. After 50 min, supernatants were separated,
and the resins were washed with MeOH (3 × 2 mL). The
combined supernatants were concentrated under a stream of
nitrogen. The concentrated samples were further dried in
vacuo. The crude products were initially analyzed by LC and
MS and then purified by flash chromatography. The purified
products were weighed and analyzed by LC, MS and 1H and
13C NMR.
3-Isobu tyl-5-ben zyl-8-ca r boxa m id o-1,5-ben zod ia zep in -
2-on e (12a e). The crude product was purified by flash chro-
matography (CHCl3/EtOH, 8:1) to obtain 14 mg (59% yield) of
1
a white solid: mp 224-226 °C; HPLC tR 6.32 min; H NMR
5-Ben zyl-8-car boxam ido-1,5-ben zodiazepin -2-on e (12a).
The crude product was purified by flash chromatography
(CHCl3/EtOH, 8:1) to obtain 17 mg (87% yield) of a white
solid: mp 203-205 °C; HPLC tR 5.12 min; 1H NMR (400 MHz,
DMSO) δ 9.60 (1H, s), 7.79-7.04 (10H, m), 4.38 (2H, s), 3.45
(2H, t, J ) 6.5 Hz), 2.39 (2H, t, J ) 6.5 Hz); 13C NMR (100
MHz, DMSO) δ 172.4, 167.2, 144.0, 138.0, 131.8, 128.4, 127.6,
127.1, 126.9, 124.2, 121.8, 119.3, 56.2, 54.8, 33.6; MS (ESI)
m/z 296 (M + H+).
(400 MHz, DMSO) δ 9.58 (1H, s), 7.80 (1H, s), 7.53 (1H, dd, J
) 1.8, 8.4 Hz), 7.46 (1H, d, J ) 2.0 Hz), 7.32-7.04 (7H, m),
4.50-4.24 (2H, AB, J ) 15.0 Hz), 3.35 (2H, m), 2.34 (1H, dd,
J ) 7.4, 13.6 Hz), 1.73 (1H, m), 1.35 (1H, m), 0.74 (6H, m); 13
C
NMR (100 MHz, DMSO) δ 174.2 (174.1), 167.2, 144.6, 138.1,
132.0, 128.4, 127.6, 127.4, 126.9, 124.3, 124.2, 121.7, 119.1,
119.1, 59.1 (58.8), 56.5 (56.4), 46.0 (45.8), 32.9 (32.7), 27.5,
(24.7), 17.3 (15.1), 11.3 (10.8); MS (ESI) m/z 352 (M + H+).
For analytical data of 12b-e, g-j, l-o, q-t, v-y, a a -a d ,
a f-a i, see the Supporting Information.
Ack n ow led gm en t. We wish to thank Bruce Mary-
4-Meth yl-5-ben zyl-8-ca r boxa m id o-1,5-ben zod ia zep in -
2-on e (12f). The crude product was purified by flash chroma-
tography (CHCl3/EtOH, 8:1) to obtain 14 mg (68% yield) of a
anoff for reviewing the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Analytical data for
28 benzodiazepinones and 1H NMR spectra of the 35 benzo-
diazepinones are available. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
white solid: mp >230 °C; HPLC tR 5.24 min; H NMR (400
MHz, DMSO) δ 9.61 (1H, s), 7.80 (1H, s), 7.51 (1H, dd, J )
2.1, 8.4 Hz), 7.44 (1H, d, J ) 2.1 Hz), 7.26-7.09 (7H, m), 4.50-
4.35 (2H, AB, J ) 15.2 Hz), 3.92 (1H, m), 2.39-2.13 (2H, m),
1.08 (3H, d, J ) 6.0 Hz); 13C NMR (100 MHz, DMSO) δ 171.8,
J O981620+