Studies towards the synthesis of the benzodiazepine alkaloid auranthine. Synthesis of an acetylated derivative

Article abstract of DOI:10.1002/jhet.5570400103

Different approaches towards the synthesis of auranthine have been investigated. A completed synthesis of 3-[2-(4-oxo-3,4-dihydro-quinazolin-2-yl)- ethyl]-3,4-dihydro-1H-benzo[e][1,4]-diazepine-2,5-dione, an auranthine precursor, which after dehydration w

Full text of DOI:10.1002/jhet.5570400103

Jan-Feb 2003
Studies Towards the Synthesis of the Benzodiazepine Alkaloid
Auranthine. Synthesis of an Acetylated Derivative
Anette Witt [a], Annika Gustavsson [b] and Jan Bergman*
29
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and Södertörn University
College, Novum Research Park, SE-141 57 Huddinge, Sweden
[a]
[b]
Present address: Syntagon AB, SE-151 02 Södertälje, Sweden
Present address: Karo Bio AB, SE-141 57 Huddinge, Sweden
Received January 28, 2002
Received Revised September 19, 2002
Different approaches towards the synthesis of auranthine have been investigated. A completed synthesis
of 3-[2-(4-oxo-3,4-dihydro-quinazolin-2-yl)-ethyl]-3,4-dihydro-1H-benzo[e][1,4]-diazepine-2,5-dione, an
auranthine precursor, which after dehydration with 50% propylphosphonic acid anhydride solution in ethyl
acetate and DMA gave a C-acetyl derivative of auranthine. Additionally studies towards the synthesis of
fused quinazolinones yielded the C-acetylated pyrido[2,1-b]quinazolinones or butyric acid derivatives.
J. Heterocyclic Chem., 40, 29 (2003).
Introduction.
are available, but no synthesis of auranthine (4) has yet
been published. Here, we discuss attempts to synthesise
auranthine (4), as well as a completed synthesis of an
acetylated derivative, namely 15a,b.
One of the earliest fungal benzodiazepines to be charac-
terised was cyclopenin (1), produced by Penicillium
cyclopium, and biosynthesised from anthranilate and
phenylalanine [1]. Although 1 shows some structural simi-
larities with the antidepressant drug diazepam (2), it does
not appear to be biologically active. The knowledge of the
structural diversity of fungal benzodiazepines has been
broadened with the discovery of asperlicin (3), produced
by Aspergillus alliaceus, which is a potent cholecystokinin
antagonist [2]. During the isolation and characterisation of
nephrotoxins [3] and other metabolites from Penicillium
aurantiogriseum a new fungal benzodiazepine was
reported, auranthine (4) (Figure 1) [4], the structure of
which was deduced not only with spectroscopic methods
but also by biosynthetic studies [5a]. Recently, this alka-
loid was found by UV-guided screening of benzodiazepine
producing species in Penicillium [5b]. Several syntheses of
cyclopenin (1) [6], diazepam (2) [7] and asperlicin (3) [8]
Results and Discussion.
A retrosynthetic analysis of auranthine (4) reveals at
least three possible synthetic routes towards compound (4)
(Figure 2). One conceivable synthesis towards compounds
5 and 7 involves the aza-Wittig methodology [9], which is
a powerful tool in the synthesis of heterocycles containing
a C=N double bond. Dehydration of a quinazoline ring in
natural products [10] is very useful and dehydration of the
precursor 6 thus should represent an alternative route.
Figure 2
The benzodiazepine 9 [11] was easily prepared from the
inexpensive starting material isatoic anhydride (8) and glu-
tamic acid (Glu) according to Gates [7b] in 45% yield
(Scheme 1). Cyclisation to the pyrrolobenzodiazepine 10
was achieved by heating compound 9 in acetic anhydride
(Ac O) for a few minutes or in N,N-dimethylacetamide
2
(DMA) overnight (Scheme 1). Compound 10 was isolated in
57% or 25−40% yield, respectively. Compound 10 crys-
tallised readily from Ac O, and a second crop could be iso-
2
lated containing the N-acetylated compound 14a [12] in var-
ious amounts depending on the reaction time. When a longer
reaction time was used the amount of compound 14a
Figure 1

30
A. Witt, A. Gustavsson and J. Bergman
Vol. 40
Scheme 2
increased. When a simple experiment was performed, by
heating compound 10 in a small amount of Ac O, the sole
2
product was the N-acetylated compound 14a (Scheme 2).
When using DMA at reflux the non-cyclised product 14b
was isolated in 30% yield along with compound 10. The
non-cyclised adduct 14b could be synthesised in 95% yield,
by treating compound 10 with dimethylamine in water
(Scheme 2). When the pyrrolobenzodiazepine 10 was heated
with anthranilamide in diphenyl ether for 48 h the auranthine
precursor 6 was isolated in 94% yield (Scheme 1). When a
shorter reaction time was used the yield decreased.
Compound 6 could also be independently synthesised from
the quinazolinone adduct 11 [13]. As expected, compound 11
was easily decarboxylated to the protected acid 12 (Scheme
1). The N-protected aminoacid 12 could be isolated in 96%
yield and after removel of the acetyl group in 3 M HCl the
synthetic amino acid 13 was isolated in 64% yield. This
amino acid could be converted to the auranthine precursor 6
according to Gates [7b] in 59% yield. To sum up, the auran-
thine precursor 6 has been attained in 4 steps and in 24%
overall yield from 8 or in 36% overall yield from 11.
Several attempts, e.g. DCC, POCl or PCl , have been
3
3
made to cyclise compound 6 to auranthine (4) with almost
no success except for one type of reaction, which involved
peptide coupling, and the reagent selected was propylphos-
phonic acid anhydride (PRPA). When a mixture of the
auranthine precursor 6, 50% PRPA solution in ethyl
acetate and DMA was heated at reflux, a solid product
could be collected after 4 h (Scheme 3). This solid was
poorly soluble in all organic solvents and on the basis of
the spectral data we propose structure 15a or its tautomer
15b, i.e. a C-acetyl derivative of auranthine (4). When
using N,N-dimethylformamide (DMF), dimethyl sulfoxide
(DMSO) or N-methylpyrrolidone as solvent no such cycli-
sation occurred. The structural analysis of 15a,b indicated
the enol-imine structure 15a, but due to low solubility in
Scheme 1
DMSO-d , trifluoroacetic acid (TFA) was added and the
6
equilibrium might be influenced by this condition.
Scheme 3
Reagents and conditions: (a) i: Glu, Et N, water, rt, 48 h; ii: acetic acid,
3
reflux, 4-5 h, 45%; (b) Ac O, reflux, 5 min, 57% or DMA, reflux, 9h, 25-
2
40%; (c) anthranilamide, diphenyl ether, reflux, 48 h, 94%; (d) 20%
KOH, 90-100°, 2-3 h, add diluted H SO , 96%; (e) 3 M HCl, reflux,
2
4
overnight, 64%; (f) i: isatoic anhydride, Et N, water, rt, overnight; ii:
3
acetic acid, reflux, 3 h, 59%.

Jan-Feb 2003
Studies Towards the Synthesis of the Benzodiazepine Alkaloid Auranthine
31
Scheme 4
In a second approach to auranthine (4) the fused quina-
zolinone 7 or the fused benzodiazepine 5 was investigated
using the aza-Wittig methodology [9]. The quinazolinone
16 has been synthesised from the 2-azidobenzoyl deriva-
tives of glutarimide in boiling toluene [14], and also the
natural product, deoxyvacisinone 17a, has been obtained
from a 2-azidobenzoyl derivative of 2-pyrrolidinone
(Figure 3) [15]. Recently a synthesis of fused quinazoli-
nones, such as compound 17a and its homologue 17b, by
an azido-reductive cyclisation of the corresponding 2-azi-
dobenzoyl derivatives with TMS-NaI has been reported
[16]. Also, compounds 17a,b are readily available from
condensation of isatoic anhydride (8) with 2-pyrrolidone
and 2-piperidone, respectively [17].
Figure 3
Based on these products we prepared the glutarimide 18
[18], by condensation of N-Cbz-L-glutamine [19] using
N-hydroxysuccinimide and DCC in DMF at 0°. The glu-
tarimide 18 was easily deprotected with 45% HBr in acetic
acid to the hydrobromide salt 19 in 96% yield (Scheme 4)
[20]. o-Azidobenzoic acid was converted to the corre-
sponding acid chloride [21], which was allowed to react
with the glutarimide 18 in the presence of methyllithium as
a base to yield the azide 20 in 52% yield. Alternatively the
Reagents and conditions: (a) 45% HBr in acetic acid, 50°, 45 min, 96%;
(b) MeLi, -78°, 2-azidobenzoyl chloride, THF, overnight, 52%; (c) 21a; 2-
azidobenzoyl chloride, Et N, 40-50°, dioxane, overnight, 78% and 21b;
3
isatoic anhydride, Et N, 60°, 3 h, room temperature, overnight, 39%.
3
After all the set-backs, using aza-Wittig reactions we
decided to investigate the synthesis mentioned in the litera-
ture of the quinazolinone 16 [14]. The 2-azidobenzoyl deriv-
atives 23 was synthesised from glutarimide [24] and the acid
chloride of o-azidobenzoic acid [21] in the presence of
methyllithium as a base in 51% yield (Scheme 5).
Compound 23 was treated with TEP in boiling toluene. The
hydrobromide salt 19 in the presence triethylamine (Et N)
3
as a base afforded the azide 21a in 78% yield. The corre-
sponding amine 21b was obtained from isatoic anhydride
and the hydrobromide salt 19 with Et N in acetonitrile in
3
39% yield. The latter reaction is known between isatoic
anhydride and 3-aminopiperidin-2-one, which could be
cyclised in acetic acid or phosphorus pentoxide to a pyri-
dobenzodiazepine [22]. In a publication dealing with deriv-
atives of succinimide and glutarimide having a 4(3H)-
quinazolinone moiety in the α-position [23], the amine 21b
is mentioned as a not-characterised intermediate. Attempts
to cyclise compound 20 to a protected analogue of com-
pound 7 using aza-Wittig conditions such as triphenylphos-
phine or triethylphosphite (TEP) in boiling toluene or
xylene yielded a product in low amounts. A solid product
was isolated after recrystallisation from toluene/hexane,
and on the basis of the spectral data obtained we propose
structure 22 (Scheme 4). Compound 22 was also compared
with the N-acetylated acid 12 and the spectral data agreed
well. Attempts were made to cyclise the azide 21a, using
aza-Wittig conditions, or the amine 21b, using acetic acid,
heating or various dehydrating agents such as phosphorus
pentoxide, to compound 5 with no success.
1
H-nmr spectrum of the crude product pointed towards the
quinazolinone 16, but after work up, such as flash chro-
matography on silica gel, treatment with water or recrystalli-
sation from toluene/hexane, the sole product was the non-
cyclised compound 24. Thus, the ring-system in compound
16 seems to be very sensitive towards hydrolysis. Compound
24 was independently synthesised from anthranilamide and
glutaric anhydride in toluene at reflux [25].
The protected acid 12 and compound 24 can be consid-
ered as precursors to the fused quinazolinone 7, and many
attempts were made to cyclise compounds 12 and 24.
Thus, when 12 or 24 were heated with acetic anhydride at
reflux the cyclised products 25a,b could be isolated in
26% and 23% yield, respectively, after flash chroma-
tography on silica gel and recrystallisation from ethanol or
methanol (Scheme 6). Spectroscopic analysis, including
COSY, HMQC and HMBC experiments, provided

32
A. Witt, A. Gustavsson and J. Bergman
Vol. 40
Scheme 5
EXPERIMENTAL
General Aspects. NMR spectra were recorded on a Bruker
1
Avance DPX 300 spectrometer, operating at 300 MHz for H-
13
nmr and 75 MHz for C-nmr, respectively, or, where indicated,
on a JEOL (500 MHz) instrument, δ values are given in ppm. The
1
abbreviation, app t in H-nmr stands for apparent triplet.
J-Values are given in Hz. IR spectra were recorded on a Perkin-
Elmer 1600 FT-IR instrument. Elemental analyses were per-
formed by H. Kolbe, Mikroanalytisches Laboratorium, Mülheim
an der Ruhr, Germany. HRMS analyses were performed by E.
Nilsson, University of Lund, Sweden. Melting points were deter-
mined on a Büchi Melting Point B-545 (capillary method) and
are uncorrected. All solvents were purified by distillation or were
of HPLC grade. Flash chromatography was done on silica gel 60
(230−400 mesh ASTM, Merck), TLC analyses were run on
evidence for the structures 25a,b. Interestingly, from a
structural point of view, compounds 25a,b show some
similarities with the known acetyl derivative 15a,b. The
methylene protons conjugated to the imine in the naturally
occurring pyrrolo[2,1-b]quinazolinone 17a and its homo-
logue 17b react readily with electrophiles [26]. The
formylquinazolinone derivatives of compounds 17a,b
have been investigated [27], and three tautomeric forms
may exist, namely oxo-imine (A), enol-imine (B) and oxo-
enamine (C) forms (Figure 4). In agreement with our
results the six-membered formylquinazolinone exists
mainly in the oxo-enamine form (C) [27].
Merck Silica Gel 60 F
plates.
254
3-(2,5-Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-
yl)propionic Acid (9).
Triethylamine (43.5 g, 0.43 mol) was added to a mixture of
isatoic anhydride (31.9 g, 0.20 mol) and glutamic acid (28.8 g,
0.20 mol) in water (400 mL). The mixture was stirred at room
temperature for 48 h, whereupon the completely homogeneous
solution was concentrated under reduced pressure to a dark
oil. The oily residue was then heated at reflux in glacial acetic
acid (200 mL) for 4.5 h. The solution was concentrated and
poured onto ice/water (~400 mL). Crystalline material was
collected and dried to give compound 9 (21.7 g, 45%) as a
beige solid, mp 220−222° (Lit. [11] mp 220−222°); ir (KBr):
Scheme 6
-1
1
3161w, 1745, 1684, 1644, 1483, 1411, 1191, 761 cm ; H-
nmr (DMSO-d ): δ 1.72−1.88 (1H, m, CH ), 1.93−2.10 (1H,
6
2
m, CH ), 2.29−2.42 (2H, m, CH ), 3.63−3.76 (1H, m, CH),
2
2
7.10 (1H, d, J 7.9, ArH), 7.22 (1H, dd, J 7.8, 7.2, ArH), 7.51
(1H, ddd, J 8.1, 7.2, 1.4, ArH), 7.74 (1H, dd, J 7.8, 1.1, ArH),
8.47 (1H, d, J 5.5, NH), 10.39 (1H, s, NH), 12.08 (1H, br s,
13
COOH); C-nmr (DMSO-d ) δ 23.2 (t), 29.9 (t), 51.0 (d),
6
121.0 (d), 124.0 (d), 126.3 (s), 130.4 (d), 132.2 (d), 136.6 (s),
167.8 (s), 171.4 (s), 174.0 (s).
1H-Pyrrolo-[2,1-c][1,4]benzodiazepine-1,4,10-trione (10).
In conclusion, a C-acetyl analogue of auranthine has
been achieved in 5 steps and 5% yield from isatoic anhy-
dride (8) or 7% yield from compound 11. Synthetic
approaches towards fused quinazolinones, such as 7 or 16,
yielded butyric acid derivatives 22 and 24.
The acid 9 (6.19 g, 25 mmol) was heated at reflux for 5 min-
utes in acetic anhydride (100 mL). The solution obtained was
allowed to stand overnight, and the white crystals were collected
and dried to give compound 10 (3.29 g, 57%), mp 245−247°; ir
-1
1
(KBr): 3279s, 2952, 1763s, 1693, 1478, 1349, 755 cm ; H-nmr
(DMSO-d ): δ 1.98−2.18 (1H, m, CH ), 2.38−2.64 (3H, m, CH ),
6
2
2
4.66 (1H, d, J 8.2, CH), 7.17 (1H, d, J 7.8, ArH), 7.28 (1H, dd, J
8.0, 7.1, ArH), 7.61 (1H, ddd, J 8.1, 7.2, 1.6, ArH), 7.81 (1H, dd,
13
J 7.9, 1.4, ArH), 10.71 (1H, s, NH); C-nmr (DMSO-d ) δ 17.7
6
(t), 30.9 (t), 55.9 (d), 121.6 (d), 124.3 (d), 125.7 (s), 131.3 (d),
133.6 (d), 136.6 (s), 164.0 (s), 169.6 (s), 173.2 (s).
Anal. Calcd. for C
H N O : C, 62.60; H, 4.38; N, 12.17.
12 10 2 3
Found: C, 62.48; H, 4.46; N, 12.08.
5-Acetyl-1H-pyrrolo-[2,1-c][1,4]benzodiazepine-1,4,10-trione
( 14a).
Compound 10 (350 mg, 1.5 mmol) was heated at reflux for 2 h
in acetic anhydride (5 mL). The white crystals formed were col-
lected and dried to give compound 14a (160 mg, 39%), mp 204−
Figure 4.

Jan-Feb 2003
Studies Towards the Synthesis of the Benzodiazepine Alkaloid Auranthine
33
205° (Lit. [12] 110−111°); ir (KBr): 1769, 1713, 1335, 1192, 758,
Method A.
-1
1
716 cm ; H-nmr (DMSO-d ): δ 2.00−2.24 (1H, m, CH ), 2.38−
6
2
A mixture of anthranilamide (9.15 g, 67 mmol) and compound
10 (9.01 g, 39 mmol) was heated at reflux in diphenyl ether (100
mL) for 48 h. The mixture was cooled and diluted with diethyl
ether (100 mL). The brown crystalline material obtained was col-
lected, washed with diethyl ether and dried to give compound 6
(12,8 g, 94%), mp 330° (dec.); ir (KBr): 3171, 3047, 2925, 1688,
2.74 (3H, m, CH ), 2.59 (3H, s, CH ), 4.77 (1H, d, J 8.4, CH),
2
3
7.39 (1H, d, J 8.0, ArH), 7.56 (1H, app t, J 7.5, ArH), 7.68 (1H,
13
dd, J 8.1, 7.0, ArH), 7.77 (1H, d, J 7.6, ArH); C-nmr (DMSO-
d ) δ 18.2 (t), 27.3 (q), 31.2 (t), 59.7 (d), 128.3 (d), 129.8 (d),
6
130.1 (d), 131.1 (s), 132.0 (d), 134.3 (s), 164.1 (s), 170.6 (s),
172.3 (s), 173.2 (s).
-1
1
1666, 1618, 751 cm ; H-nmr (DMSO-d ): δ 1.98−2.15 (1H, m,
6
CH ), 2.22−2.38 (1H, m, CH ), 2.63−2.86 (2H, m, CH ), 3.77−
3.91 (1H, m, CH), 7.10 (1H, d, J 8.1, ArH), 7.22 (1H, app t, J 7.5,
ArH), 7.39−7.57 (3H, m, ArH), 7.71−7.79 (2H, m, ArH), 8.05
3-(2,5-Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)-
N,N-dimethylpropionamide (14b).
2
2
2
A solution of dimethylamine in water (6 mL, 60%) was added
to compound 10 (460 mg, 2.0 mmol), and the reaction mixture
was maintained at room temperature for 3 h and then neutralised
with 2 M HCl. The resulting precipitate was collected and
washed with water to give compound 14b (520 mg, 95%) as a
white solid, mp 254−257°; ir (KBr): 3209, 3111, 1677, 1628,
(1H, d, J 7.8, ArH), 8.54 (1H, d, J 5.5, NH), 10.41 (1H, s, NH),
13
12.09 (1H, s, NH); C-nmr (DMSO-d ): δ 24.6 (t), 30.5 (t), 51.2
6
(d), 120.9 (s), 121.0 (d), 124.0 (d), 125.7 (d), 126.0 (d), 126.3 (s),
126.7 (d), 130.4 (d), 132.2 (d), 134.3 (d), 136.7 (s). 148.7 (s),
156.6 (s), 161.7 (s), 167.9 (s), 171.5 (s).
Anal. Calcd. for C
H N O : C, 65.51; H, 4.63; N, 16.08.
-1
1
19 16 4 3
1408, 1156, 754 cm ; H-nmr (DMSO-d ): δ 1.73−1.90 (1H, m,
6
Found: C, 65.45; H, 4.57; N, 16.01.
CH ), 1.93−2.08 (1H, m, CH ), 2.40 (2H, t, J 7.2, CH ), 2.77
2
2
2
(3H, s, CH ), 2.91 (3H, s, CH ), 3.66−3.78 (1H, m, CH), 7.09
(1H, d, J 8.1, ArH), 7.21 (1H, app t, J 7.5, ArH), 7.51 (1H, app t,
Method B.
3
3
Triethylamine (400 mg, 4.0 mmol) was added to a mixture of
isatoic anhydride (372 mg, 2.3 mmol) and compound 13 (500
mg, 2.0 mmol) in water (25 mL). The mixture was stirred at room
temperature overnight. The solution was concentrated under
reduced pressure to a semisolid, which was heated at reflux in
glacial acetic acid (15 mL) for 3 h. The white precipitate formed
was collected and dried to give compound 6 (250 mg, 35%). The
mother liquor was poured onto ice/water to give additional 6 (168
mg, 24%). Total yield 59%, mp 334° (dec.). The spectral data of
6 were identical with those mentioned above.
J 7.3, ArH), 7.73 (1H, d, J 7.6, ArH), 8.45 (1H, d, J 5.4, NH),
13
10.37 (1H, s, NH); C-nmr (DMSO-d ) δ 23.4 (t), 28.6 (t), 34.8
6
(q), 36.5 (q), 51.2 (d), 120.9 (d), 123.9 (d), 126.3 (s), 130.4 (d),
132.2 (d), 136.6 (s), 167.8 (s), 171.4 (s), 171.6 (s).
2-Acetylamino-4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyric
Acid (12).
Compound 11 [13] (10.1 g, 26 mmol) was heated to 90−100° in
aqueous 20% KOH (100 mL) for 2 h. Thus the solution was acid-
ified with dilute H SO and the resulting precipitate collected and
2
4
dried to give compound 12 (7.18 g, 96%) as a white solid, mp
262−264° (dec.); ir (KBr): 3229s, 1679, 1610, 1301, 1250, 767
Acetylated Auranthine (15a,b).
50% Propylphosphonic acid anhydride solution in ethyl
acetate (4 mL) was added to a mixture of compound 6 (1.18 g,
3.4 mmol) in DMA (25 mL). The mixture was heated to reflux
for 4 h. After 2 h a solid precipitate appeared, which was col-
lected and dried to give compound 15a,b (250 mg, 20%) as a
grey solid, mp > 410°; ir (KBr): 3452w, 3246, 1687, 1640, 1399,
-1
1
cm ; H-nmr (DMSO-d ): δ 1.86 (3H, s, CH ), 1.92−2.08 (1H,
6
3
m, CH ), 2.18−2.34 (1H, m, CH ), 2.69 (2H, app t, J 7.7, CH ),
2
2
2
4.21−4.33 (1H, m, CH), 7.46 (1H, dd, J 7.8, 7.2, ArH), 7.59 (1H,
d, J 8.1, ArH), 7.78 (1H, dd, J 8.3, 7.0, ArH), 8.07 (1H, d, J 7.9,
ArH), 8.21 (1H, d, J 7.8, NH), 12.19 (1H, s, NH), 12.62 (1H, br s,
13
COOH); C-nmr (DMSO-d ): δ 22.4 (q), 28.0 (t), 30.7 (t), 51.3
6
-1
1
1280, 772 cm ; H-nmr (500 MHz, DMSO-d /TFA(~1/4)): δ
6
(d), 120.8 (s), 125.7 (d), 126.1 (d), 126.5 (d), 134.4 (d), 148.3 (s),
2.47 (3H, s, CH ), 3.09−3.17 (1H, m, CH ), 3.88 (1H, d, J 15.1,
+
3
2
156.7 (s), 161.6 (s), 169.4 (s), 173.4 (s); HRMS (FAB): [M+H]
CH ), 4.66 (1H, dd, J 10.7, 3.0, CH), 7.01 (1H, d, J 7.8, ArH),
2
for C H N O requires M, 290.1141. Found: m/z 290.1162.
14 16
3 4
7.11 (1H, app t, J 7.8, ArH), 7.37 (1H, ddd, J 8.2, 7.3, 1.3, ArH),
7.46 (1H, dd, J 8.2, 7.3, ArH), 7.66 (1H, d, J 8.0, ArH), 7.69−
2-Amino-4-(4-oxo-3,4-dihydroquinazolin-2-yl)-butyric Acid
(13).
7.77 (2H, m, ArH), 8.06 (1H, d, J 7.9, ArH), 9.62 (1H, s, NH);
13
C-nmr (125 MHz, DMSO-d /TFA(~1/4)): δ 18.4 (q), 30.8 (t),
6
Compound 12 (5.00 g, 17 mmol) in 3 M HCl (100 mL) was
heated at reflux overnight. The solution was concentrated under
reduced pressure to give 13-hydrochloride salt, which was dis-
solved in water and neutralised with 2 M NaOH. The precipitate
was collected and dried to give the amino acid 13 (2.75 g, 64%)
as a white solid, mp 271° (dec.); ir (KBr): 3036, 1662, 1630,
59.9 (d), 110.3 (s), 121.6 (s), 121.9 (d), 124.2 (d), 127.3 (d),
128.3 (s), 129.6 (d), 131.1 (d), 133.8 (d), 136.0 (d), 138.4 (s),
138.8 (d), 140.7 (s), 156.0 (s), 156.9 (s), 162.1 (s), 167.8 (s),
+
171.1 (s); HRMS (FAB): [M+H] for C
H N O requires M,
21 17 4 3
373.1300. Found: m/z 373.1303.
Anal. Calcd. for C
H N O : C, 67.73; H, 4.33; N, 15.05.
-1
1
21 16 4 3
1487, 1328, 774 cm ; H-nmr (DMSO-d /TFA(4/1)): δ 2.21−
2.48 (2H, m, CH ), 2.97−3.23 (2H, m, CH ), 3.92−4.07 (1H, m,
6
Found: C, 67.82; H, 4.27; N, 14.96.
2
2
CH), 7.56 (1H, dd, J 7.9, 7.3, ArH), 7.67 (1H, d, J 8.1, ArH), 7.84
[1-(2-Azidobenzoyl)-2,6-dioxo-piperidin-3-yl]carbamic Acid
Benzyl Ester (20).
(1H, ddd, J 8.4, 7.2, 1.2, ArH), 8.12 (1H, dd, J 7.9, 0.8, ArH),
13
8.37 (3H, br s); C-nmr (DMSO-d /TFA(4/1)): δ 29.1 (t), 29.8
6
Methyllithium (1.6 mL, 1.6 M in diethyl ether) was added at
−78° to a solution of compound 18 [18] (620 mg, 2.4 mmol) in
(t), 53.0 (d), 121.1 (d), 121.2 (s), 128.3 (d), 130.1 (d), 137.5 (d),
139.9 (s), 161.1 (s), 163.1 (s), 171.8 (s).
dry THF (20 mL) under N . The solution was stirred for 30 min-
2
utes and o-azidobenzoyl chloride (530 mg, 2.9 mmol) [21] was
added in dry THF (7 mL). The reaction mixture was allowed to
3-[2-(4-Oxo-3,4-dihydroquinazolin-2-yl)-ethyl]-3,4-dihydro-1H-
benzo[e][1,4]diazepine-2,5-dione (6).

34
A. Witt, A. Gustavsson and J. Bergman
Vol. 40
reach room temperature overnight and poured into water and
extracted with ethyl acetate (30 mL × 3). The combined organic
the mother liquor was purified by flash chomatography (60 %
ethyl acetate in hexane) to give more 23 (590 mg, 23%) as a light
yellow solid: total yield, 51%; mp 153° (dec.); ir (KBr): 2970,
2896, 2134, 1736, 1702, 1679, 1592, 1474, 1348, 1264, 1179,
extracts were dried (Na SO ) and concentrated under reduced
2
4
pressure to afford an oily residue, which was purified by flash
chromatography (50% ethyl acetate in hexane as eluent) to give
the azide 20 (497 mg, 52%) as a light yellow solid; ir (KBr):
3385, 3032, 2952, 2129, 1754, 1712, 1691, 1595, 1481, 1296,
-1
1
1145, 938, 776 cm ; H-nmr (DMSO-d ): δ 2.00 (2H, quintet, J
6
6.5, CH ), 2.75 (4H, t, J 6.5, CH ), 7.33 (1H, app t, J 7.6, ArH),
2
2
7.47 (1H, d, J 8.1, ArH), 7.75 (1H, ddd, J 8.4, 7.0, 1.4, ArH), 7.95
-1
1
13
1228, 697 cm ; H-nmr (DMSO-d ): δ 1.95−2.32 (2H, m, CH ),
(1H, dd, J 7.9, 1.4, ArH); C-nmr (DMSO-d ): δ 19.7 (t), 31.7
6
2
6
2.70−2.87 (1H, m, CH ), 3.03−3.23 (1H, m, CH ), 4.64−4.79
(t), 120.9 (d), 122.9 (s), 125.3 (d), 132.7 (d), 135.9 (d), 140.0 (s),
2
2
+
(1H, m, CH), 5.06 (2H, s, CH ), 7.24−7.44 (6H, m, ArH/NH),
168.5 (s), 172.6 (s); HRMS (FAB): [M+H] for C H N O
2
12 11
4
3
7.48 (1H, d, J 8.1, ArH), 7.76 (1H, ddd, J 8.4, 7.0, 1.4, ArH), 7.84
(1H, d, J 8.7, ArH), 7.97 (1H, d, J 7.9, ArH); C-mnr (DMSO-
requires M, 259.0831. Found: m/z 259.0854.
13
4-(4-Oxo-3,4-dihydroquinazolin-2-yl)butyric Acid (24).
d ): δ 23.4 (t), 31.3 (t), 51.2 (d), 65.6 (t), 120.8 (d), 122.7 (s),
6
125.3 (d), 127.7 (d), 127.8 (d), 128.3 (d), 132.8 (d), 136.0 (d),
Triethyl phosphite (380 mg, 2.3 mmol) was added to a mix-
136.8 (s), 140.2 (s), 156.1 (s), 167.8 (s), 171.3 (s), 171.8 (s);
ture of compound 23 (520 mg, 2.0 mmol) in toluene (25 mL, dis-
+
HRMS (FAB): [M+H] for C
H N O requires M, 408.1308.
tilled from Na) under N and at room temperature. The mixture
20 18 5 5
2
Found: m/z 408.1319.
was heated to 70° for 1 h and then heated at reflux for additional
2 h. The cooled solution was concentrated under reduced pres-
sure to afford a yellow solid, which was treated with a small
amount of water to give compound 24 (360 mg, 77%) as a white
solid, mp 275−277° (Lit. [25a] >250°); ir (KBr): 3043, 2897,
2-Azido-N-(2,6-dioxo-piperidin-3-yl)benzamide (21a).
2-Azidobenzoic acid (590 mg, 3.6 mmol) and thionyl chloride
(3.26 g, 27 mmol) were heated at 80° for 2 h under N [21]. The
2
-1
mixture was cooled to room temperature, and the excess of
thionyl chloride was removed under reduced pressure. The
residue was dissolved in dioxane (5 mL) and then added to a
stirred mixture of the hydrobromide salt 19 (630 mg, 3.0 mmol)
and triethylamine (460 mg, 4.5 mmol) in dioxane (20 mL). After
stirring at 40−50° overnight, the mixture was filtered through
Celite and concentrated under reduced pressure to afford a yellow
solid, which was purified by flash chromatography (1% methanol
in chloroform) to give the azide 21a (640 mg, 78%) as a white
solid, mp 180−181° (dec.); ir (KBr): 3316, 3202, 3094, 2142,
1713, 1684, 1613, 1474, 1335, 1190, 1010, 906, 776 cm ;
1
H-nmr (DMSO-d ): δ 1.96 (2H, quintet, J 7.4, CH ), 2.32 (2H,
6
2
t, J 7.4, CH ), 2.63 (2H, t, J 7.4, CH ), 7.45 (1H, ddd, J 8.0, 6.9,
2
2
1.1, ArH), 7.59 (1H, d, J 7.8, ArH), 7.76 (1H, ddd, J 8.4, 6.9,
1.5, ArH), 8.07 (1H, dd, J 7.9, 1.2, ArH), 12.15 (2H, br s,
13
NH/COOH); C-nmr (DMSO-d ): δ 21.8 (t), 32.8 (t), 33.5 (t),
6
120.9 (s), 125.7 (d), 126.0 (d), 126.8 (d), 134.2 (d), 148.8 (s),
156.8 (s), 161.8 (s), 174.1 (s).
2-Benzyloxycarbonylamino-4-(4-oxo-3,4-dihydroquinazolin-2-
yl)butyric Acid (22).
-1
1
1711, 1652, 1533, 1202, 752 cm ; H-nmr (DMSO-d ): δ 1.95−
6
2.20 (2H, m, CH ), 2.48−2.65 (1H, m, CH ), 2.69−2.89 (1H, m,
Compound 22 was prepared similarly to compound 24 using
compound 20 (170 mg, 0.42 mmol), but the mixture was heated
at reflux for 6 h and compound 22 was recrystallised from
toluene/hexane in 38% yield as a beige solid; ir (KBr): 3289,
2
2
CH ), 4.68−2.86 (1H, m, CH), 7.28 (1H, ddd, J 7.6, 7.5, 0.7,
2
ArH), 7.37 (1H, d, J 7.8, ArH), 7.56 (1H, ddd, J 7.8, 7.6, 1.5,
ArH), 7.63 (1H, dd, J 7.6, 1.4, ArH), 8.65 (1H, d, J 8.1, NH),
13
-1
1
10.87 (1H, s, NH); C-nmr (DMSO-d ): δ 24.1 (t), 30.9 (t), 49.7
3034, 2920, 1723, 1686, 1610, 1538, 1260, 775 cm ; H-nmr
(DMSO-d ): δ 1.90−2.14 (2H, m, CH ), 2.22−2.44 (2H, m, CH ),
6
(d), 119.9 (d), 124.9 (d), 127.4 (s), 129.9 (d), 131.8 (d), 136.8 (s),
6
2
2
+
165.2 (s), 171.9 (s), 172.9 (s); HRMS (FAB): [M+H] for
4.46−4.59 (1H, m, CH), 5.04 (2H, s, CH ), 7.23−7.44 (5H, m,
2
C
H N O requires M, 274.0940. Found: m/z 274.0935.
ArH/NH), 7.50 (1H, app t, J 7.5, ArH), 7.63 (1H, d, J 8.0, ArH),
12 12 5 3
7.71 (1H, d, J 7.6, ArH), 7.81 (1H, app t, J 7.1, ArH), 8.10 (1H, d,
2-Amino-N-(2,6-dioxo-piperidin-3-yl)benzamide (21b).
13
J 7.3, ArH), 12.22 (2H, br s, NH/COOH); C-nmr (DMSO-d ):
6
The hydrobromide salt 19 (0.71 g, 3.4 mmol) and triethylamine
(0.69 g, 6.8 mmol) were dissolved in acetonitrile (30 mL) and
heated at 60°. Isatoic anhydride (0.66 g, 4.0 mmol) was added and
after 3 additional hours at 60° the solution was allowed to stand
overnight at ambient temperature. The precipitate obtained was
collected and dried to give the amine 21b (320 mg, 39%) as a
solid with a bluish tinge, mp 235° (dec.) (Lit. [23] mp 197−201°);
ir (KBr): 3462, 3342, 3191, 3105, 1699, 1634, 1506, 1210, 754
δ 28.1 (t), 30.2 (t), 53.6 (d), 65.5 (t), 121.2 (s), 125.7 (d), 126.4
(d), 127.0 (d), 127.5 (d), 127.7 (d), 128.3 (d),134.4 (d), 136.9 (s),
148.4 (s), 155.8 (s), 157.2 (s), 161.6 (s), 173.6 (s).
N-Acetyl-N-(6-acetyl-9,11-dioxo-5,8,9,11-tetrahydro-7H-pyrido-
[2,1-b]quinazolin-8-yl)acetamide (25a).
Compound 12 (4.46 g, 15 mmol) was heated at reflux in acetic
anhydride (110 mL) for 3 h. The solution was concentrated under
reduced pressure to yield a dark oil, and the oily residue was flash
chromatographed (ethyl acetate) and recrystallised in ethanol to
give compound 25a (1.40 g, 26%) as yellow needles, mp 194−
195°; ir (KBr): 3380w, 1747, 1689, 1637, 1577, 1417, 1275,
-1
1
cm ; H-nmr (DMSO-d ): δ 1.87−2.22 (2H, m, CH ), 2.50−2.89
6
2
(2H, m, CH ), 4.66−4.83 (1H, m, CH), 6.42 (2H, br s, NH ), 6.53
2
2
(1H, dd, J 7.7, 7.1, ArH), 6.71 (1H, d, J 7.9, ArH), 7.16 (1H, ddd,
J 8.2, 7.0, 1.2, ArH), 7.51 (1H, d, J 8.0, ArH), 8.46 (1H, d, J 8.3,
13
-1
1
NH), 10.83 (1H, s, NH); C-nmr (DMSO-d ): δ 24.2 (t), 31.0 (t),
1226, 971, 759 cm ; H-nmr (DMSO-d ): δ 2.29 (3H, s, CH ),
6
6
3
49.1 (d), 114.0 (s), 114.5 (d), 116.4 (d), 128.1 (d), 132.0 (d), 149.8
(s), 168.7 (s), 172.4 (s), 173.0 (s).
2.45 (6H, s, 2×CH ), 2.95 (1H, dd, J 14.2, 6.8, CH ), 3.09 (1H,
3
2
dd, J 14.2, 12.7, CH ), 5.10 (1H, dd, J 12.7, 6.8, CH), 7.45 (1H,
2
ddd, J 8.0, 7.0, 1.0, ArH), 7.76 (1H, ddd, J 8.6, 7.1, 1.6, ArH),
1-(2-Azidobenzoyl)piperidine-2,6-dione (23).
7.83 (1H, d, J 8.0, ArH), 8.00 (1H, dd, J 7.8, 1.4, ArH), 13.62
13
Compound 23 was prepared similarly to compound 20 using
(1H, s, NH); C-nmr (DMSO-d ): δ 23.4 (t), 26.3 (q), 28.8 (q),
6
glutarimide [24]. A white solid (720 mg, 28%) was collected and
56.7 (d), 90.9 (s), 118.8 (s), 122.8 (d), 126.0 (d), 126.7 (d), 134.0

Jan-Feb 2003
Studies Towards the Synthesis of the Benzodiazepine Alkaloid Auranthine
35
[7a]
M. Ishikura, M. Mori, T. Ikeda, M. Terashima and Y.
(d), 136.4 (s), 145.6 (s), 157.9 (s), 168.0 (s), 172.8 (s), 198.1 (s);
+
Ban, J. Org. Chem., 47, 2456 (1982); [b] M. Gates, J. Org. Chem.,
45, 1675 (1980).
HRMS (FAB): [M+H] for C
H N O requires M, 356.1246.
18 18 3 5
Found: m/z 356.1260.
[8]
F. He, B. M. Foxman and B. B. Snider, J. Am. Chem.
Anal. Calcd. for C
H N O : C, 60.84; H, 4.82; N, 11.83.
18 17 3 5
Soc., 120, 6417 (1998).
Found: C, 60.69; H, 4.92; N, 11.67.
[9]
For reviews on heterocyclic syntheses by aza-Wittig
6-Acetyl-7,8-dihydro-5H-pyrido[2,1-b]quinazoline-9,11-dione
(25b).
reaction, see: [a] H. Wamhoff, G. Rechardt and S. Stölben, Adv. in
Heterocycl. Chem., 64, 174 (1996); [b] P. Molina and M. J. Vilaplana,
Synthesis (Spec. Issue), 1197 (1994); [c] S. Eguchi, Y. Matsushita
and K. Yamashita, Org. Prep. Proced. Int., 24, 209 (1992).
Compound 24 (1.19 g, 5.0 mol) was heated at reflux in acetic
anhydride (45 mL) for 16 h. The solution was concentrated under
reduced pressure to yield a dark oil, and the oily residue was flash
chromatographed (75 % ethyl acetate in hexane) and recrys-
tallised in methanol to give compound 25b (290 mg, 23%) as a
light yellow solid, mp 181−183°; ir (KBr): 1725, 1701, 1630,
[10]
For recent reviews on quinazoline alkaloids, see: [a] J. P.
Michael, Nat. Prod. Rep., 18, 543 (2001); [b] S. Johne, in
nd
nd
Supplements to the 2 supplements to the 2 Edition of Rodd’s
Chemistry of Carbon Compounds, Vol. IV I/J, M. Sainsbury, ed,
Elsevier, Amsterdam, 2000, pp 203−231; [c] S. Johne, in
-1
1
1579, 1407, 1277, 1122, 963, 757 cm ; H-nmr (DMSO-d ): δ
nd
6
Supplements to the 2 Edition of Rodd’s Chemistry of Carbon
2.27 (3H, s, CH ), 2.63−2.74 (2H, m, CH ), 2.74−2.85 (2H, m,
3
2
Compounds, Vol. IV I/J, M. F. Ansell, ed, Elsevier, Amsterdam,
1995, pp 223−240.
CH ), 7.43 (1H, ddd, J 7.9, 7.1, 0.8, ArH), 7.74 (1H, ddd, J 8.7,
2
7.1, 1.7, ArH), 8.00 (1H, dd, J 7.8, 1.6, ArH), 8.22 (1H, d, J 8.5,
[11]
770 (1969).
[12]
A. Ermili and G. Filacchioni, Ann. Chim. (Rome), 59,
13
ArH), 13.78 (1H, s, NH); C-nmr (DMSO-d ): δ 18.6 (t), 28.6
6
(q), 32.8 (t), 93.3 (s), 118.6 (s), 122.6 (d), 125.7 (d), 126.6 (d),
133.9 (d), 136.7 (s), 146.5 (s), 157.9 (s), 170.4 (s), 197.6 (s).
European Patent. 0 353 778 A2 (Zo & CO., Ltd), 1990;
Chem. Abstr., 113, 40740 (1990).
Anal. Calcd. for C
Found: C, 65.60; H, 4.65; N, 10.92.
H N O : C, 65.62; H, 4.72; N, 10.93.
[13]
[14]
A. Witt, J. Bergman, Tetrahedron, 56, 7245 (2000).
A. -B. N. Luheshi, S. M. Salem, R. K. Smalley, P. D.
14 12 2 3
Kennewell and R. Westwood, Tetrahedron Lett., 31, 6561 (1990).
[15a] H. Takeuchi, S. Hagiwara and S. Eguchi, Tetrahedron,
45, 6375 (1989); [b] H. Takeuchi and S. Eguchi, Tetrahedron Lett.,
30, 3313 (1989).
Acknowledgement.
We thank Dr. Hans Wallberg for his help with the structure elu-
cidation of compound 15a,b.
[16]
A. Kamel, K. V. Ramana and M. V. Rao, J. Org. Chem.,
66, 997 (2001).
REFERENCES AND NOTES
[17]
[18]
[19]
[20]
[21]
E. Späth and N. Platzer, Berichte, 68, 2221 (1935).
H. Zahn and E. T. J. Fölsche, Chem. Ber., 102, 2158 (1969).
M. Bergmann and L. Zervas, Berichte., 65, 1192 (1932).
T. Polon´ski, J. Chem. Soc., Perkin Trans. 1, 639 (1988).
M. A. Ardakani, R. K. Smalley and R. H. Smith, J.
[1a]
Bracken, A. Pocker and H. Raistrick, Biochem. J., 57, 587 (1954).
[2a] M. A. Goetz, M. Lopez, R. L. Monaghan, R. S. L.
M. Luckner, Eur. J. Biochem., 2, 74 (1967); [b] A.
Chem. Soc., Perkin Trans. 1, 2501 (1983).
[22] M. Oklobdzˇija, G. Comisso, E. Decorte, T. Fajdiga, G.
Gratton, F. Moimas, R. Toso, and V. Sunjic´, J. Heterocyclic Chem.,
20, 1329 (1983).
Chang, V. J. Lotti and T. B. Chen, J. Antibiot., 38, 1633 (1985); [b] J.
M. Liesch, O. D. Hensens, J. P. Springer, R. S. L. Chang and V. J.
Lotti, J. Antibiot., 38, 1638 (1985); [c] H. H. Sun, S. J. Byard and R.
Copper, J. Antibiot., 47, 599 (1994).
ˇ
[23]
N. Å. Jönsson, L. Mikiver, U. Selberg, Acta Pharm.
[3a]
K. M. Macgeorge and P. G. Mantle, Mycopathologia,
Suec., 431 (1972).
112, 139 (1990); [b] S. E. Yeulet, P. G. Mantle, M. S. Rudge and J. B.
Greig, Mycopathologia, 102, 21 (1988); [c] J. M. Barnes, P. K. C.
Austwick, R. L. Carter, F. V. Flynn, G. C. Peristianis and W. N.
Aldridge, Lancet, 671 (1977).
[24]
E. C. Kornfeld, R. G. Jones and T. V. Parke, J. Am.
Chem. Soc., 71, 150 (1949).
[25a] C. O. Usifoh, Sci. Pharm., 68, 275 (2000); [b] J. -W.
Chern, J. -C. Lo, H. -M. Lin, F. -C. Cheng and C. O. Usifoh, Chin.
Pharm. J., 51, 31 (1999).
[26a] A. D. Dunn and K. I. Kinnear, J. Heterocyclic Chem.,
21, 603 (1984); [b] M. P. Jain, V. N. Gupta, C. K. Atal, K. K. Joshi
and C. V. S. Subrahmanyam, Indian Drugs, 23, 505 (1986).
[27a] Á. Horváth, I. Hermecz, M. Pongor-Csákvári, Z.
Mészáros, J. Kökösi, G. Tóth and Á. Szöllõsy, J. Heterocyclic Chem.,
21, 219 (1984); [b] K. Horváth, J. Kökösi and I. Hermecz, J. Chem.
Soc., Perkin Trans. 2, 1613 (1989).
[4]
R. N. Sheppard, J. Chem. Soc., Perkin Trans. 1, 1891 (1986).
[5a] S. E. Yeulet and P. G. Mantle, FEMS Microbiol. Lett.,
S. E. Yeulet, P. G. Mantle, J. N. Bilton, H. S. Rzepa and
41, 207 (1987); [b] L. T. Ostenfeld, K. Frydenvang and J. C. Frisvad,
Biochem. Syst. Ecol. 28, 881 (2000).
[6a]
R. P. Rhee and J. D. White, J. Org. Chem., 42, 3650
(1977); [b] J. D. White, W. E. Haefliger and M. J. Dimsdale,
Tetrahedron, 26, 233 (1970); [c] P. K. Martin, H. Rappoport, H. W.
Smith and J. L. Wong, J. Org. Chem., 34, 1359 (1969).