Synthesis of 1,4-benzodiazepine-3,5-diones

Article abstract of DOI:10.1021/jo049169b

Even though benzodiazepines have a strong position in medicinal chemistry, very few synthetic routes to 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have ever been published and the claimed products have often been poorly characterized. Through the present wor

Full text of DOI:10.1021/jo049169b

Syn th esis of 1,4-Ben zod ia zep in e-3,5-d ion es
Per Wiklund,† Mark Rogers-Evans,‡ and J an Bergman*,†
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and So¨derto¨rn University
College, Novum Research Park, SE-141 57 Huddinge, Sweden, and F. Hoffmann-La Roche Ltd,
Pharmaceuticals Division, Lead Generation, PRBC-CI, Bldg 65/ 416, CH-4070 Basel, Switzerland
jabe@biosci.ki.se
Received May 17, 2004
Even though benzodiazepines have a strong position in medicinal chemistry, very few synthetic
routes to 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have ever been published and the claimed
products have often been poorly characterized. Through the present work several 1H-1,4-
benzodiazepine-3,5(2H,4H)-diones have become available from N-carbamoylmethylanthranilic acids.
The required ring closures were achieved only when the amino groups of the starting materials
were substituted with electron withdrawing groups such as acetyl, alkyloxycarbonyl, or nitroso.
During the synthetic work a novel ring contraction rearrangement from a 1-nitroso-1H-1,4-
benzodiazepine-3,5(2H,4H)-dione to a 3H-quinazoline-4-one was observed. The proposed mechanism
involves elimination of HNO followed by a proton-mediated loss of CO. The 1-nitrosated
1,4-benzodiazepinediones could be separately denitrosated to the corresponding amino compounds.
In tr od u ction
Despite the fact that thousands of 1,4-benzodiazepi-
nones have been synthesized, analyzed, and tested for
bioactivity since the initial discovery of the sedative and
tranquilizing effects of chlordiazepoxide in 1958, followed
by the patent for diazepam (1) in 1963,1 only a few
examples of the isomeric 1H-1,4-benzodiazepine-3,5-
(2H,4H)-diones (2 and 3) are to be found in the literature.
The dehydrogenated parent compounds 4 are still un-
known.2 The first benzodiazepine ever reported, com-
pound 5,3 was of this type, but the assigned structure
was subsequently disproved in favor of the benzoxazinone
6.4 In this paper we present syntheses of, and structural
evidence for, compounds of the types 2 and 3, and
describe reactions of molecules of these types.
The most general synthetic approach to 1,4-benzodi-
azepine-3,5-diones yet reported involves DCC mediated
ring closure of N-carboxymethylanthranilamides. This
procedure has been purported to yield compounds 3a 5 and
3b-d .6 However, in our hands this method failed to yield
any products which would be consistent with seven-
membered rings. The products appeared to be polymeric.
The reported data on these products are sketchy at best,
and serious doubt arose about the claimed syntheses of
3a -d . There are also a couple of brilliant approaches to
these systems, which are alas limited to very specific
targets, i.e., compounds 77 and 8.8 There are also two
patents which include claims on 1,4-benzodiazepin-2,5-
diones.9,10 They both involve substances with large sub-
stituents on N4 as exemplified by compound 9. This
† Karolinska Institute and So¨derto¨rn University College.
‡ F. Hoffmann-La Roche Ltd.
(1) Sternbach, L. H. J . Med. Chem. 1979, 22, 1-7.
(2) Walser, A.; Fryer, R. I. Chem. Heterocycl. Compd. (Chichester,
U.K.) 1991, 50, 631-848.
(7) Heindel, N. D.; Lemke, T. F.; Harless, H. R.; Brydia, L. E. Proc.
W. Va. Acad. Sci. 1966, 38, 250-255. Heindel, N. D.; Lemke, T. F. J .
Heterocycl. Chem. 1966, 3, 389-390. Heindel, N. D.; Fish, V. B.; Lemke,
T. F. J . Org. Chem. 1968, 33, 3997-4004. Heindel, N. D.; Fives, W.
P.; Lemke, T. F.; Rowe, J . E.; Snady, H. W.; Carrano, R. A. J . Med.
Chem. 1971, 14, 1233-1235.
(8) Mustafa, M. E.-S.; Takaoka, A.; Ishikawa, N. Bull. Soc. Chim.
Fr. 1986, 944-954. Ishikawa, N.; Takaoka, A. Daikin Industries, Ltd.,
J apan, J P 62178574; Chem. Abstr. 1987, 108, 75435.
(3) Ga¨rtner, S. J ustus Liebigs Ann. Chem. 1904, 332, 226-245.
(4) Gilman, N. W.; Blount, J . F.; Fryer, R. I. J . Org. Chem. 1976,
41, 737-739.
(5) Osman, A. N.; El-Gendy, A. A.; Omar, R. H.; Wagdy, L.; Omar,
A. H. Boll. Chim. Farm. 2002, 141, 8-14.
(6) Stavropoulos, G.; Theodoropoulos, D. J . Heterocycl. Chem. 1977,
14, 1139-1143.
10.1021/jo049169b CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/24/2004
J . Org. Chem. 2004, 69, 6371-6376
6371

Wiklund et al.
rather insoluble product that is presumably stabilized by
internal hydrogen bonds. The product could be purified
by boiling in acetonitrile followed by filtration, and it was
very resistant to hydrolysis (water in warm DMSO).
The anhydrides 11 and 12 could not be forced to cyclize,
which is not surprising as this would require attack from
a poorly nucleophilic amide onto a deactivated (and
hindered) anhydride. However, after treatment of 10 with
acetic anhydride and base, a low yield of the ring closed
and N1-acetylated product 2a could be isolated. Thus it
was clear that an electron withdrawing substituent on
N1, as would be expected, will enable ring closure. The
1H NMR spectrum of 2a showed an imide N-H signal
at 11.15 ppm and an AB-type doublet of a doublet from
the methylene protons (in DMSO-d6).
F IGURE 1. Compounds 3a (R2 ) Et)5 and 3b-d (b, R2 ) Ph;
c, R2 ) Bn; d , R2 ) p-toluyl),6 7 (Rx and Ry combinations of H,
Me, OMe, F, Cl, Br, and I),7 8,8 and compounds similar to 99,10
appear in the literature.
buspirone like molecule, and analogues with other atoms
in the 1-position (C, O, S), have been reported to have
high affinities for the 5-HT1A receptor9,11 and the opioid
σ-receptor.10
Resu lts a n d Discu ssion
In the initial investigations it was examined how
2-(carbamoylmethylamino)benzoic acid (10) could be
converted into 1,4-benzodiazepinediones. The acid 10
readily formed anhydrides, i.e., activated forms of the
carboxy functionality, proven by the transformation into
the mixed anhydride 11 and the symmetric anhydride
12, both of which are previously unknown.
When the precursor 10 was treated with chlorofor-
mates and triethylamine in refluxing acetonitrile, the
ring closed products 2b-d were formed. The reaction
with ethyl chloroformate produced compound 2b in a 66%
yield. Similarly, reactions with methyl and benzyl chlo-
roformate yielded 2c and 2d , respectively, albeit in lower
yields. The methylene protons of these compounds dis-
played themselves as broad humps in the 1H NMR
spectra, and the imide NH gave sharp singlets at around
11.2 ppm (in DMSO-d6).
All attempts to remove the N-ethyloxycarbonyl func-
tion of compound 2b failed even under conditions as
harsh as HBr in hot acetic acid, conditions which have
been reported to work for deprotection of an N-ethyloxy-
carbonyl-substituted tetrahydroquinoline.12 Compound
2b could easily be alkylated to form the N4-ethylated
compound 13, of which an HMBC spectrum was obtained
proving the cyclic structure. Compound 13 could also be
prepared by ring synthesis from the amide 14 (Scheme
1), which in turn was prepared from the ester 15 by
aminolysis. The required ester was easily prepared by a
selective Fischer esterification of N-carboxymethylan-
thranilic acid.13,14
The mixed anhydride approach was further pursued
and a novel scheme for preparation of 1,4-benzodiazepine-
3,5-diones was devised in which the system is activated
for ring closure by a nitroso group attached to N1
(Scheme 1). Introduction of nitroso groups was found to
be possible even on strongly deactivated secondary
The nucleophilicity of the carboxylate ion of the start-
ing material is increased by the electron donating amine
functionality in the ortho position, which explains the
ready formation of the anhydride 12. As soon as one
molecule is activated by the coupling reagent (Mukaiya-
ma’s reagent), it is attacked by another (unactivated)
molecule. The reaction is driven by the formation of the
(9) Tatsuoka, T.; Nomura, K. Suntory Ltd., J apan, EP 444924;
Chem. Abstr. 1991, 115, 232303.
(10) Tatsuoka, T.; Nomura, K.; Shibata, M.; Kawai, M. Suntory, Ltd.,
J apan, EP 463810; Chem. Abstr. 1992, 116, 214540.
(11) Anzini, M.; Corelli, F.; Cagnotto, A.; Skorupska, M. Med. Chem.
Res. 1993, 3, 249-256.
(12) Cacchi, S.; Palmieri, G. Tetrahedron 1983, 39, 3373-3383.
(13) Vorla¨nder, D.; von Schilling, R. Ber. Dtsch. Chem. Ges. 1900,
33, 553-554.
(14) Wiklund, P.; Bergman, J . Tetrahedron Lett. 2004, 45, 969-972.
6372 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of 1,4-Benzodiazepine-3,5-diones
SCHEME 1. Syn th esis of th e Ben zod ia zep in ed ion e
3a by Nitr osa tion , Rin g Closu r e, a n d
Den itr osa tion a
F IGURE 2. ORTEP drawing of the X-ray structure of 18.
SCHEME 2
a
Reagents and conditions: (a) EtNH2, rt, (b) isoamyl nitrite,
cat. TFA in PhMe at rt, (c) EtNH2, rt, (d) Et3N in MeCN followed
by ClCOOEt, heating, (e) TFA/urea, heating in EtOAc.
rivatives have not previously been used in the ring
synthesis of seven-membered rings.
Denitrosation of 18 to 3a was achieved by heating in
EtOAc with TFA, using urea as a scavenger. Alterna-
tively it could also be performed by heating with tin
chloride dihydrate. The physical characteristics of 3a do
not match the previously reported data,5 and it therefore
seems clear that this is in fact a novel compound.
amines. Deprotection of the nitrosamine to the free amine
(denitrosation) could be preformed with acidic condi-
tions,15 or reductively removed with SnCl2. The N-nitroso
group can thus function as a protective group with an
Umpolung effect due to its strongly electron withdrawing
character. N-Nitroso chemistry has been utilized through-
out the history of organic chemistry, but the discovery
of the biochemical importance of NO16 combined with the
well-known carcinogenic effects of N-nitroso compounds17
has led to a renewed interest in the field. A recent
example is a study on nitrosation of amidines.18
Perkin and Riley found that the nitrosamine 19 gives
1H-quinoxaline-2-one (20) when heated in alcohols, ben-
zene, or acetic acid (Scheme 2).21 No mechanistic expla-
nation was given, but the transformation could be
brought about by denitrosation followed by oxidation
(dehydrogenation), or more likely a direct elimination of
HNO (variously known as nitrosyl, nitroxyl, nitrosylhy-
dride, etc.).22 There are a few known nitrosyl donating
compounds, one of which is Angeli’s salt (Na2N2O3).23
Recent results have suggested that HNO has biological
effects, and this has prompted investigations into the
mechanism of decay of Angeli’s salt into HNO and NO.24
The structural similarities between 18 and 19 are obvi-
ous, and therefore 18 was heated in acetic acid in the
hope of achieving elimination. However, in this case the
reaction did not yield the expected seven-membered ring
4a (Scheme 3), but rather a compound lacking one
carbonyl signal in the 13C NMR spectrum. It was deter-
mined that a ring contraction with loss of CO had
occurred and that the product was in fact the known
quinazolinone 21.25 Scheme 3 shows a plausible mecha-
nism for this rearrangement.
The ester 16 was prepared from 15 by nitrosation with
isoamyl nitrite, a very fast reaction catalyzed by a very
small quantity of TFA. Aminolysis with aqueous ethyl-
amine at room temperature then converted 16 into the
ethylamide 17. The nitrosation followed by aminolysis
gave an 82% overall yield with a very simple work up
procedure. Ring closure to the benzodiazepinedione 18
was performed with ethyl chloroformate and Et3N in
MeCN. In standard peptide coupling by the mixed
anhydride method only 1 equiv of base is normally used.19
In this case the reaction stopped at the anhydride stage
if additional base was not added. The structure of 18 was
determined by X-ray crystallography (Figure 2). Although
there is a published work on conformational analysis of
N-nitrosohexahydro-1,4-diazepine-5-ones,20 N-nitroso de-
(15) Williams, D. L. H. Nitrosation; Cambridge University Press:
Cambridge, 1988.
(16) Williams, D. L. H. Org. Biomol. Chem. 2003, 1, 441-449.
(17) Brown, J . L. Occup. Med.: State of the Art Rev. 1999, 14, 839-
848.
(18) Loeppky, R. N.; Yu, H. J . Org. Chem. 2004, 69, 3015-3024.
(19) Hruby, V. J .; Meyer, J .-P. In Bioorganic Chemistry, Peptides
and Proteins; Hecht, S. M., Ed.; Oxford University Press: Oxford, New
York, 1998; pp 27-64.
(20) Senthilkumar, U. P.; J eyaraman, R.; Murray, R. W.; Singh, M.
J . Org. Chem. 1992, 57, 6006-6014.
(21) Perkin, W. H.; Riley, G. C. J . Chem. Soc. 1923, 123, 2399-
2408.
(22) Bonner, F. T. Methods Enzymol. 1996, 268, 50-57. Bonner, F.
T.; Stedman, G. In Methods in Nitric Oxide Research; Stamler, J . S.,
Ed.; J ohn Wiley and Sons Ltd.: London, 1996; pp 3-18.
(23) Bonner, F. T.; Baruch, R. Inorg. Chem. 1974, 14, 558-563.
(24) Dutton, A. S.; Fukuto, J . M.; Houk, K. N. J . Am. Chem. Soc.
2004, 126, 3795-3800.
J . Org. Chem, Vol. 69, No. 19, 2004 6373

Wiklund et al.
SCHEME 3. P r op osed Mech a n ism for Rin g Con tr a ction Rea r r a n gem en t
SCHEME 4. Syn th esis of th e Ben zod ia zep in d ion e
3ba
by N-nitrosation. The latter method of Umpolung gave
the 1-nitroso-1H-1,4-benzodiazepine-3,5(2H,4H)-diones
18 and 24. Denitrosation under acidic conditions, exem-
plified on 18, or under reductive conditions, exemplified
on 24, gave access to the 1H-1,4-benzodiazepine-3,5-
(2H,4H)-diones 3a and 3b, respectively. Preparations of
these compounds have previously appeared in the litera-
ture, but the current data indicate these results to be in
error. Furthermore, it was discovered that compound 18
rearranged to a six-membered system on heating in acetic
acid. The proposed mechanism for this novel rearrange-
ment involves the 1,4-benzodiazepine-3,5(2H,4H)-dione
intermediate 4a . If correct, this suggests that such seven-
membered structures are not stable.
a
Reagents and conditions: (a) isoamyl nitrite at rt, (b) Et3N/
ClCOOEt at rt, (c) heating with SnCl2 in EtOAc.
As would be expected, ester aminolysis according to
Scheme 1 did not work well when a less basic/nucleophilic
amine, such as aniline, was utilized. Hence there was a
need for a procedure where an acetamide derivative could
be introduced on a derivative of an anthranilic acid. To
this end methyl anthranilate was reacted with chloro-
acetanilide (2-chloro-N-phenylacetamide). The latter was
prepared in situ in MeCN/NaHCO3 which was also the
medium for the following substitution reaction. Although
requiring a long reaction time this procedure has the
definite advantage that the highly lachrymatory and skin
irritating chloroacetanilide does not need to be handled
at all outside the reaction vessel. The resulting ester (22)
was hydrolyzed to the starting material 23 in quantita-
tive yield. The direct approach of reacting anthranilic acid
with chloroacetanilide under the same conditions also
gave this product, but of inferior purity and after a
cumbersome workup. A one-pot nitrosation/ring closure
of 23 afforded the benzodiazepinedione 24 in good yield
(71%). Also in this case it was necessary to add 2 equiv
or more of base to achieve cyclization of the mixed
anhydride, but the reaction proceeded at room temper-
ature. The spectral properties of the product bear very
close similarities with those of the ethyl-substituted
compound 18 (e.g., IR 1705/1702, 1659/1641, 1463/1466
cm-1). In this case prolonged heating in acetic acid did
not yield a ring-contracted product, but a complex
mixture of degraded material. Reductive denitrosation
with SnCl2 afforded 3b, the spectral properties of which
are very similar to those of its ethyl-substituted homo-
logue 3a . The characteristics of 3b do not match the
previously reported data.6 As mentioned above the previ-
ously prepared material is likely to be polymeric.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded at 300 and 75 MHz.
respectively, in DMSO-d6 or CDCl3 with the solvent signals
as reference.26 Coupling constants (J ) are given in Hz. All
column flash chromatography was performed with HPFC
(High Performance Flash Chromatography) on 60 Å prepacked
silica columns.
1-Acetyl-1H-1,4-ben zod ia zep in e-3,5(2H,4H)-d ion e (2a ).
2-(Carbamoylmethylamino)benzoic acid27 (0.99 g, 5.0 mmol)
was refluxed in THF (20 mL) with diisopropylethylamine (2.8
mL, 16 mmol) and acetic anhydride (1.5 mL, 16 mmol) for 5
h. The reaction mixture was filtered while hot, and the filtrate
was thoroughly evaporated in vacuo (25 mmHg, 70 °C) until
a semisolid material remained. This material was crystallized
from MeCN to yield a yellow tinted white crystalline material
(0.20 g, 18%); mp 201-202 °C (from MeCN); IR νmax 3213,
1729, 1655, 1601 cm-1; 1H NMR (DMSO-d6) δ 1.93 (3H, s), 4.10
(1H, d, J ) 16.9), 4.91 (1H, d, J ) 16.9), 7.54-7.59 (2H, m),
7.73 (1H, m), 8.00 (1H, dd, J ) 1.1, 7.2), 11.15 (1H, s); 13C
NMR (DMSO-d6) δ 21.8 (CH3), 51.8 (CH2), 127.4 (CH), 128.5
(CH), 129.1 (C), 132.6 (CH), 134.2 (CH), 140.8 (C), 164.8 (C),
169.2 (C), 172.3 (C). Anal. Calcd for C11H10N2O3 (218.21): C,
60.55; H, 4.62; N, 12.84. Found: C, 60.43; H, 4.45; N, 12.91.
1-Eth yloxycar bon yl-1H-1,4-ben zodiazepin e-3,5(2H,4H)-
d ion e (2b). 2-(Carbamoylmethylamino)benzoic acid27 (2.0 g,
10.2 mmol) was refluxed in MeCN (20 mL) with Et3N (5.0 mL,
36 mmol) for 15 min. Ethyl chloroformate (2.0 mL, 21 mmol)
was added dropwise and the reflux then continued for 75 min.
The reaction mixture was poured on 5% citric acid (aq, 50 mL)
and diluted with crushed ice (to a total volume of 100 mL).
After 1 h the solid product was filtered off, washed with water,
and dried to yield an off-white solid (1.63 g, 66%); mp 180 °C
(from PhMe); IR νmax several peaks at 3187-2893, 1725, 1655
cm-1; 1H NMR (DMSO-d6) δ 1.14 (3H, br s), 4.12 (2H, apparent
br d), 4.45 (2H, very br s), 7.44-7.51 (2H, m), 7.67 (1H, m),
7.98 (1H, d, J ) 7.2), 11.18 (1H, s); 13C NMR (DMSO-d6) δ
14.2 (CH3), 53.2 (CH2), 62.3 (CH2), 127.5 (CH), 127.6 (C), 132.1
(CH), 133.5 (CH), 140.0 (C), 153.6 (C), 164.8 (C), 172.1 (C).
Anal. Calcd for C12H12N2O4 (248.23): C, 58.06; H, 4.87; N,
11.29. Found: C, 58.54; H, 4.80; N, 11.12.
Con clu sion s
Through this work we have shown that synthesis of
1H-1,4-benzodiazepine-3,5(2H,4H)-diones from N-car-
bamoylmethylanthranilic acids is feasible if the electron
distribution of the starting materials is reversed by
electron withdrawing substituents on the secondary
amino groups. This could be achieved by N-acylation, or
1-Me t h y lo x y c a r b o n y l-1H -1,4-b e n zo d ia ze p in e -3,5-
(2H,4H)-d ion e (2c). The same procedure as for 2b, but with
(25) Maillard, J .; Benard, M.; Vincent, M.; Vo Van, T.; J olly, R.;
Morin, R.; Menillet, C.; Benharkate, M. Chim. Ther. 1967, 2, 202-
212.
(26) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J . Org. Chem. 1997,
62, 7512-7515.
(27) Lempert, K.; Doleschall, G. Chem. Ber. 1963, 96, 1271-1276.
6374 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of 1,4-Benzodiazepine-3,5-diones
MeOCOCl (2.0 mL, 26 mmol) and 2 h reaction time yielded a
powder (0.82 g, 60%); mp 151 °C; IR νmax 3395, 3184, 1791,
1700, 1653, 1576 cm-1; 1H NMR (DMSO-d6) δ 1.28 (9H, s), 3.87
(2H, d, J ) 4.9), 6.61-6.70 (2H, m), 7.25 (1H, br s), 7.51 (1H,
m), 7.57 (1H, br s), 7.71 (1H, dd, J ) 1.5, 8.3), 8.09 (1H, t, J )
4.9); 13C NMR (DMSO-d6) δ 26.2 (C), 45.0 (CH2), 107.9 (C),
112.2 (CH), 115.1 (CH), 132.0 (CH), 136.8 (CH), 151.2 (C),
164.1 (C), 170.3 (C), 174.1 (C). Anal. Calcd for C14H18N2O4: C,
60.42; H, 6.52; N, 10.07. Found: C, 60.43; H, 6.42; N, 10.16.
beige crystalline material (0.69 g, 30%); mp 108-110 °C; IR
ν
max 3519, 3473, 3045, 2897, 1707, 1662 cm-1; 1H NMR (DMSO-
d6) δ 3.66 (3H, br s), 4.45 (2H, very br s), 7.45-7.52 (2H, m),
7.67 (1H, m), 7.98 (1H, dd, J ) 1.1, 7.5), 11.18 (1H, s); 13C
NMR (DMSO-d6) δ 53.3 (CH2), 53.5 (CH3), 127.59 (CH), 127.65
(CH), 128.4 (C), 132.2 (CH), 133.6 (CH), 139.8 (C), 154.1 (C),
164.8 (C), 172.1 (C). Anal. Calcd for C11H10N2O4: C, 56.41; H,
4.30; N, 11.96. Found: C, 56.42; H, 4.61; N, 11.54.
2-(Ca r b a m oylm et h yla m in o)b en zoic Acid An h yd r id e
(12). 2-(Carbamoylmethylamino)benzoic acid27 (2.0 g, 10.2
mmol) and 2-chloro-1-methylpyridinium iodide (3.04 g, 12.0
mmol) were heated at refluxed in dry THF (40 mL) with Et3N
(2.0 mL) for 1 h. After the mixture was cooled to room
temperature, water (20 mL) was added and the solid product
was filtered off. After washing with MeCN (2 × 10 mL) a pale
yellow fine powder was obtained (1.70 g, 92%); mp 169-170
°C; IR νmax 3382, 3180, 1756, 1742, 1674, 1649, 1611, 1574
1-B e n zy lo x y c a r b o n y l-1H -1,4-b e n zo d ia ze p in e -3,5-
(2H,4H)-d ion e (2d ). 2-(Carbamoylmethylamino)benzoic acid27
(2.0 g, 10.2 mmol) was refluxed in MeCN (40 mL) with Et3N
(3.0 mL, 22 mmol) for 15 min. Benzyl chloroformate (3.0 mL,
21 mmol) was added dropwise and the reflux then continued
for 16 h. The reaction mixture was poured on 10% citric acid
(aq, 100 mL) and extracted with Et2O (2 × 100 mL). The
combined extracts were washed with sat. NaHCO3 (50 mL),
water (50 mL), and brine (50 mL). The solution was dried (Na2-
SO4), filtered through a plug of silica, and evaporated to form
a solid material that could be triturated with diisopropyl ether
(0.96 g, 31%); mp 122-122.5 °C; IR νmax 3368, 3193, 1663,
1
cm-1; H NMR (DMSO-d6) δ 3.88 (4H, d, J ) 4.9), 6.64-6.71
(4H, m), 7.25 (2H, br s), 7.53 (2H, m), 7.55 (2H, br s), 7.87
(2H, dd, J ) 1.5, 8.1), 8.09 (2H, t, J ) 4.9); 13C NMR (DMSO-
d6) δ 45.1 (CH2), 108.0 (C), 112.2 (CH), 115.2 (CH), 132.1 (CH),
136.6 (CH), 151.1 (C), 164.2 (C), 170.4 (C). Anal. Calcd for
1
1576, 1251, 1221 cm-1; H NMR (DMSO-d6) δ 4.50 (2H, very
br s), 2.10 (2H, br s), 7.20-7.38 (5H, m), 7.46-7.51 (2H, m),
7.67 (1H, m), 7.98 (1H, d, J ) 7.9), 11.20 (1H, s); 13C NMR
(DMSO-d6) δ 53.4 (CH2), 67.5 (CH2), 127.4 (CH), 127.6 (CH),
127.8 (CH), 128.0 (CH), 128.4 (C), 128.5 (CH), 132.2 (CH),
133.6 (CH), 136.0 (C), 153.5 (C), 164.8 (C), 172.1 (C). Anal.
Calcd for C17H14N2O4 (310.30): C, 65.80; H, 4.55; N, 9.03.
Found: C, 65.69; H, 4.57; N, 8.83.
C18H18N4O5 (370.36): C, 58.37; H, 4.90; N, 15.13. Found: C,
58.01; H, 4.95; N, 15.30. MS (ESI) m/z 369 [M - H]-.
4-E t h yl-1-et h yloxyca r b on yl-1H -1,4-b en zod ia zep in e-
3,5(2H,4H)-d ion e (13). Meth od 1: Compound 2b (2.0 g, 8.0
mmol) was dissolved in DMF (10 mL) and NaH (0.35 g, 60%
in mineral oil, 8.8 mmol) was added. The reaction flask was
cooled by immersion in an ice bath and EtBr (1.5 mL, 20 mmol)
was added. The mixture was stirred at 0-25 °C for 4 h and
then poured on water (50 mL). The material gained by
extraction with Et2O was purified by silica column flash
chromatography, eluting with diisopropyl ether, to give a white
solid (1.56 g, 71%). Meth od 2: Et3N (0.70 mL, 5.0 mmol) was
added to compound 14 (1.11 g, 5.00 mmol) in MeCN (10 mL)
and the mixture was heated at reflux for 5 min. Ethyl
chloroformate (1.5 mL, 16 mmol) was added, followed by
another portion of Et3N (1.5 mL, 11 mmol). Gas evolved (CO2).
The mixture was heated at reflux for 75 min, followed by the
same workup as in the first method to give the product in 74%
yield; mp 74 °C; IR νmax several peaks at 3187-2893, 1722,
1657, 1600, 1218, 765 cm-1; 1H NMR (DMSO-d6) δ 1.05-1.21
(6H, m), 3.86 (2H, q, J ) 6.8), 4.13 (2H, q, J ) 7.2), 4.58 (2H,
br s), 7.44-7.49 (2H, m), 7.66 (1H, m), 8.01 (1H, d, J ) 8.3);
13C NMR (DMSO-d6) δ 13.0 (CH3), 14.2 (CH3), 54.7 (CH2), 62.3
(CH2), 126.6 (CH), 127.2 (CH), 129.0 (C), 132.9 (CH), 133.3
(CH), 139.9 (C), 153.3 (C), 165.2 (C), 172.2 (C). Anal. Calcd
for C14H16N2O4 (276.29): C, 60.86; H, 5.84; N, 10.14. Found:
C, 61.05; H, 5.83; N, 10.38.
4-Eth yl-1H-1,4-ben zod ia zep in e-3,5(2H,4H)-d ion e (3a ).
Compound 18 (0.35 g, 1.5 mmol) was dissolved in EtOAc (50
mL) and heated at reflux with urea (0.36 g, 6.0 mmol) and
TFA (1.5 mL) for 16 h. The solution was then washed with 2
M NaOH (50 mL), followed by water (50 mL). The two
combined aqueous layers were extracted with EtOAc (2 × 25
mL). The three combined organic layers were washed with
brine (100 mL), dried (Na2SO4), and evaporated. The residue
was purified by flash chromatography (0-50% EtOAc in
hexane) to yield a white crystalline solid (0.20 g, 65%); mp
95.5-96 °C (from heptane); IR νmax 3352, 1703, 1594, 1510
1
cm-1; H NMR (CDCl3) δ 1.24 (3H, t, J ) 7.2), 3.91 (2H, s),
3.94 (2H, q, J ) 7.2), 4.63 (1H, br s), 6.80 (1H, dd, J ) 1.1,
7.9), 6.96 (1H, m), 7.34 (1H, m), 8.26 (1H, dd, J ) 1.9, 8.3);
13C NMR (CDCl3) δ 13.8 (CH3), 40.7 (CH2), 52.4 (CH2), 117.6
(CH), 117.8 (C), 120.2 (CH), 134.0, (CH), 134.7 (CH), 149.3 (C),
168.0 (C), 169.4 (C). Anal. Calcd for C11H12N2O2 (204.23): C,
64.69; H, 5.92; N, 13.72. Found: C, 64.30; H, 5.76; N, 13.61.
+
MS (ESI) m/z 205 [M + H]+, 177 [M + H - C2H5]
.
4-P h en yl-1H-1,4-ben zodiazepin e-3,5(2H,4H)-dion e (3b).
Compound 24 (1.41 g, 5.00 mmol) was dissolved in EtOAc (20
mL). SnCl2‚2H2O (2.26 g, 10.0 mmol) was added and the
mixture heated to reflux for 1 h. The mixture was filtered by
suction through a plug of aluminum oxide (basic, activity 1).
The plug was thoroughly rinsed with EtOAc. The filtrate was
evaporated in vacuo to give the solid product (0.91 g, 72%);
mp 159 °C (from diisopropyl ether); IR νmax 3325, 1700, 1639,
2-(Eth oxyca r bon ylm eth yla m in o)ben zoic Acid (14). N-
Ethoxycarbonylmethylanthranilic acid13,14 (4.48 g, 20.0 mmol)
was dissolved in EtNH2 (20 mL 70% aq), and the solution was
kept at 25 °C for 24 h. The mixture was poured on crushed ice
and acidified with concd HCl (25 mL) leading to precipitation
of the product. The solid formed was filtered off and dried (4.42
g, 99%); mp 203 °C; IR νmax 3396, 3283, 1647, 1580, 1516, 1244,
1
1605 cm-1; H NMR (CDCl3) δ 4.03 (2H, s), 4.95 (1H, very br
739 cm-1 1H NMR (DMSO-d6) δ 1.02 (3H, t, J ) 7.2), 3.12
;
s), 6.79 (1H, dd, J ) 0.8, 8.3), 6.95 (1H, m), 7.17-7.20 (2H,
m), 7.34-7.48 (4H, m), 8.20 (1H, dd, J ) 1.5, 8.3); 13C NMR
(CDCl3) δ 52.0 (CH2), 117.1 (C), 117.8 (CH), 120.0 (CH), 128.4
(CH), 128.6 (CH), 129.4 (CH), 134.4 (CH, 134.8 (CH), 138.8
(C), 149.7 (C), 168.2 (C), 169.6 (C). Anal. Calcd for C15H12N2O2
(252.09): C, 71.42; H, 4.79; N, 11.10. Found: C, 71.20; H, 4.82;
N, 11.15.
(2H, m), 3.78 (2H, s), 6.50 (1H, d, J ) 8.2), 6.59 (1H, t, J )
8.2), 7.36 (1H, m), 7.80 (1H, dd, J ) 1.5, 7.9), 8.02 (1H, t, J )
5.3), 12.60 (1H, br s); 13C NMR (DMSO-d6) δ 14.7 (CH3), 33.4
(CH2), 45.8 (CH2), 110.7 (C), 111.3 (CH), 114.6 (CH), 131.7
(CH), 134.4 (CH), 150.2 (C), 168.6 (C), 169.6 (C). Anal. Calcd
for C11H14N2O3 (222.24): C, 59.45; H, 6.35; N, 12.61. Found:
C, 59.07; H, 6.32; N, 12.29.
2-(Ca r b a m oylm et h yla m in o)b en zoyl P iva loyl An h y-
d r id e (11). 2-(Carbamoylmethylamino)benzoic acid27 (0.99 g,
5.0 mmol) in DMF (10 mL) was treated with NaH (0.20 g 60%
in mineral oil, 5.0 mmol), the solution was cooled to 0 °C, and
pivaloyl chloride (0.61 mL, 5.0 mmol) was added. The mixture
was stirred for 15 min at 0-25 °C, and then poured on water
(50 mL). The solid formed was collected and washed with water
followed by Et2O. After drying, this gave a light yellow fine
2-(Eth oxyca r bon ylm eth yln itr osoa m in o)ben zoic Acid
(16). N-Ethoxycarbonylmethylanthranilic acid13,14 (4.48 g, 20.0
mmol) was suspended in toluene (40 mL). Isoamyl nitrite (3.0
mL, 22 mmol) was added followed by a small drop of TFA.
The mixture was stirred for 1 h and the solution was passed
through a plug of silica to which the product bound. The
toluene was rinsed out of the silica with hexane after which
the product could be eluted with Et2O. The Et2O-filtrate was
J . Org. Chem, Vol. 69, No. 19, 2004 6375

Wiklund et al.
thoroughly evaporated in vacuo to form an oil (used without
further purification in the following transformation). Addition
of toluene and evaporation again gave a yellowish white
crystalline solid (4.55 g, 90%); mp 101-102 °C (from toluene/
hexane); IR νmax 1750, 1698, 1599, 1422 cm-1; 1H NMR (CDCl3)
δ 1.29 (3H, t, J ) 7.2), 4.26 (2H, q, J ) 7.2), 4.59 (2H, s), 7.62
(1H, m), 7.69 (1H, dd, J ) 1.5, 7.9), 7.76 (1H, m), 8.20 (1H,
dd, J ) 1.5, 7.9); 13C NMR (CDCl3) δ 14.2 (CH3), 50.3 (CH2),
62.0 (CH2), 125.8 (C), 128.9 (CH), 129.9 (CH), 132.6 (CH), 134.6
(CH), 141.5 (C), 166.3 (C), 170.0 (C). Anal. Calcd for C11H12N2O5
(252.22): C, 52.38; H, 4.80; N, 11.11. Found: C, 52.38; H, 4.72;
N, 10.96. MS (ESI) m/z: 251 [M - H]-, 221 [M - H - NO]-.
2-(Eth ylca r ba m oylm eth yln itr osoa m in o)ben zoic Acid
(17). The oil of compound 16 was dissolved in EtNH2 (20 mL
70% aq), and the solution was kept at 25 °C for 24 h. The
mixture was poured on crushed ice and acidified with concd
HCl (20 mL). On standing, and oil formed which solidified after
several hours. The beige solid was collected and dried (4.12 g,
82% from N-ethoxycarbonylmethylanthranilic acid); mp 120-
1.2, 7.9), 8.41 (1H, s); 13C NMR (DMSO-d6) δ 14.5 (CH3), 41.2
(CH2), 121.6 (C), 126.0 (CH), 126.9 (CH), 127.1 (CH), 134.2
(CH), 147.8 (CH), 148.0 (C), 160.0 (C).
2-[[2-Oxo-2-(p h en yla m in o)eth yl]a m in o]ben zoic Acid
Meth yl Ester (22). Aniline (20 mL, 0.22 mol) was dissolved
in MeCN (100 mL) containing NaHCO3 (50 g, 0.60 mol).
Chloroacetyl chloride (16 mL, 0.22 mol) was added in portions
during 15 min, after which methyl anthranilate (20 mL, 0.15
mol) was added. The mixture was then heated to reflux for 70
h. The flask was cooled to room temperature and the contents
was poured into ice-water (400 mL). The solid that eventually
formed was collected and recrystallized from MeOH to yield a
white powder (15.06 g, 24%); mp 137-139 °C (lit.13 mp 140-
142 °C); IR νmax 3385, 3278, 1672, 1597 cm-1; 1H NMR (DMSO-
d6) δ 3.83 (3H, s), 4.08 (2H, d, J ) 5.3), 6.61-6.66 (2H, m),
7.06 (1H, m), 7.30-7.35 (2H, m), 7.42 (1H, m), 7.60-7.63 (2H,
m), 7.83 (1H, dd, J ) 1.5, 8.3), 8.15 (1H, t, J ) 5.3), 10.17 (1H,
s); 13C NMR (DMSO-d6) δ 46.2 (CH2), 51.5 (CH3), 109.8 (C),
111.7 (CH), 114.9 (CH), 119.2 (CH), 123.3 (CH), 128.8 (CH),
131.1 (CH), 134.8 (CH), 138.8 (C), 149.8 (C), 167.8 (C), 167.9
(C).
1
122 °C; IR νmax 1677, 1623, 1600, 1570, 1461, 1441 cm-1; H
NMR (DMSO-d6) δ 0.99 (3H, t, J ) 7.2), 3.06 (2H, m), 4.52
(2H, s), 7.59-7.81 (3H, m), 7.95 (1H, dd, J ) 1.2, 7.7), 8.18
(1H, t, J ) 5.1), 13.3 (1H, br s); 13C NMR (DMSO-d6) δ 14.5
(CH3), 33.6 (CH2), 51.2 (CH2), 126.9 (CH), 128.0 (C), 129.1 (CH),
130.7 (CH), 132.8 (CH), 140.5 (C), 164.6 (C), 167.0 (C). Anal.
Calcd for C11H13N3O4 (251.24): C, 52.59; H, 5.22; N, 16.73.
Found: C, 52.57; H, 5.17; N, 16.56. MS (ESI) m/z 250 [M -
H]-, 220 [M - H - NO]-.
2-[[2-Oxo-2-(p h en yla m in o)et h yl]a m in o]b en zoic Acid
(23). Compound 22 (8.53 g, 30.0 mmol) in water (50 mL) and
MeOH (50 mL) was heated to a boil with NaOH (1.3 g, 33
mmol). After letting the mixture cool to room temperature, it
was filtered and acidified with concd HCl. The white product
formed was collected and dried (8.07 g, 100%); mp 226 °C (lit.13
235 dec); IR νmax 3381, 3265, 1662, 1599 cm-1 1H NMR
;
4-E t h yl-1-n it r oso-1H -1,4-b en zod ia zep in e-3,5(2H ,4H )-
d ion e (18). Compound 17 (2.52 g, 10.00 mmol) was dissolved
in MeCN (20 mL). Et3N (1.5 mL, 11 mmol) was added and the
mixture was stirred 15 min. Ethyl chloroformate (1.5 mL, 16
mmol) was added and the stirring continued at room temper-
ature for 15 min. The mixture was then heated at reflux for 2
h. The mixture was cooled to room temperature and poured
into citric acid (10%, 100 mL). After addition of crushed ice
an oil separated out. Eventually the oil solidified and could
be collected and dried. The brown solid was heated in diiso-
propyl ether, upon which the product dissolved, leaving the
dark material unsolved. Evaporation of the liquid phase gave
an oil that slowly crystallized to yield a light yellow solid (1.32
g, 54%); mp 118-119 °C (CHCl3/hexane 1:1); IR νmax 1702,
(DMSO-d6) δ 4.09 (2H, s), 6.58-6.62 (2H, m), 7.05 (1H, m),
7.28-7.40 (3H, m), 7.62-7.65 (2H, m), 7.82 (1H, dd, J ) 1.5,
7.9), 10.35 (1H, s), 12.63 (1H, br s); 13C NMR (DMSO-d6 CDCl3)
δ 46.3 (CH2), 110.7 (C), 111.4 (CH), 114.7 (CH), 119.2 (CH),
123.3 (CH), 128.8 (CH), 131.7 (CH), 134.5 (CH), 138.9 (CH),
150.1 (CH), 168.0 (C), 169.7 (C).
1-Nitr oso-4-p h en yl-1H-1,4-ben zod ia zep in e-3,5(2H,4H)-
d ion e (24). Compound 23 (2.70 g, 10.00 mmol) was stirred in
toluene (40 mL) and MeCN (20 mL) with isoamyl nitrite (1.5
mL, 11 mmol) for 1 h (on which the starting material had fully
dissolved). Et3N (1.5 mL, 11 mmol) was added and after 5 min
ethyl chloroformate (1.5 mL, 16 mmol) was added and the
stirring continued at room temperature for 15 min. Another
portion of Et3N was added and the mixture was stirred for 1
h at room temperature. The mixture was poured into citric
acid (10%, 50 mL) in a separatory funnel. After shaking, the
aqueous phase was discarded and the organic phase washed
with sat. NaHCO3. The product precipitated from the solution
on standing (1.99 g, 71%); mp 189-190 °C (from 95% EtOH);
IR νmax 1704, 1659, 1599, 1463, 1248, 1133, 1100 cm-1; 1H NMR
(CDCl3) δ 5.02 (2H, s), 7.07-7.10 (2H, m), 7.38-7.49 (3H, m),
7.62 (1H, m), 7.79-7.82 (2H, m), 8.40 (1H, dd, J ) 0.8, 8.4);
13C NMR (CDCl3) δ 48.7 (CH2), 122.2 (CH), 124.7 (C), 128.4
(CH), 128.8 (CH), 129.2 (CH), 129.5 (CH), 134.9 (CH), 135.0
(CH), 137.9 (C), 140.0 (C), 165.0 (C), 166.1 (C). Anal. Calcd
for C15H11N3O3 (281.27): C, 64.05; H, 3.94; N, 14.94. Found:
C, 63.87; H, 3.90; N, 15.0.
1
1641, 1598, 1466, 1447; H NMR (CDCl3) δ 1.24 (3H, t, J )
7.1), 3.96 (2H, q, J ) 7.1), 7.57-7.62 (1H, m), 7.72-7.74 (2H,
m), 8.43 (1H, d, J ) 7.9); 13C NMR (CDCl3) δ 13.4 (CH3), 41.1
(CH2), 48.7 (CH2), 121.8 (CH), 125.0 (C), 128.9 (CH), 134.6
(CH), 134.7 (CH), 139.8 (C), 164.6 (C), 166.0 (C). Anal. Calcd
for C11H11N3O3 (233.22): C, 56.65; H, 4.75; N, 18.02; O, 20.58.
Found: C, 56.48; H, 4.72; N, 17.95. MS (ESI) m/z 251 [M +
NH4]+, 234 [M + H]+ 204 [M + H - NO]+ 176 [M + H - NO
,
,
- C2H5]+. The structure was confirmed by single-crystal X-ray
crystallography.
3-Eth yl-3H-qu in a zolin e-4-on e (21). Compound 18 (0.70
g, 3.0 mmol) was heated at reflux in AcOH (20 mL) for 15 h.
The solvent was evaporated in vacuo and the residual material
was purified on a silica flash column, eluting first with 10-
35% EtOAc in hexane then with 60-80% EtOAc in hexane.
The product (0.33 g, 63%) was isolated from the latter elution
portion; mp 99-100 °C (from diisopropyl ether) (lit.25 mp 99-
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for compound 18 in CIF format and 1H and 13C
NMR data for compounds 3a , 3b, 21, 22, and 23. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
101 °C); IR νmax 1668, 1608, 1471, 1371, 1248 cm-1; H NMR
(DMSO-d6) δ 1.28 (3H, t, J ) 7.2), 4.01 (2H, q, J ) 7.2), 7.54
(1H, m), 7.67 (1H, d, J ) 7.9), 7.81 (1H, m), 8.15 (1H, dd, J )
J O049169B
6376 J . Org. Chem., Vol. 69, No. 19, 2004