New linearly and angularly fused quinazolinones: Synthesis through gold(I)-catalyzed cascade reactions and anticancer activities

Article abstract of DOI:10.1002/ejoc.201101822

A robust library-based approach to new fused quinazolinones by the development of gold(I)-catalyzed cascade reactions between 2- aminobenzohydrazides and alkynoic acids is documented. Selected compounds were administered to lung (A549) and breast cancer cells (MDA-MB-231 and MCF-7) in vitro and it was found that some successfully inhibited cell proliferation.

Full text of DOI:10.1002/ejoc.201101822

FULL PAPER
DOI: 10.1002/ejoc.201101822
New Linearly and Angularly Fused Quinazolinones: Synthesis through
Gold(I)-Catalyzed Cascade Reactions and Anticancer Activities
Nitin T. Patil,*[a] Pediredla G. V. V. Lakshmi,[a] Balasubramanian Sridhar,[b] Sujata Patra,[c]
Manika Pal Bhadra,[c] and Chitta Ranjan Patra*[c]
Keywords: Synthetic methods / Homogeneous catalysis / Gold / Cascade reactions / Nitrogen heterocycles / Antitumor
agents / Privileged structures
A robust library-based approach to new fused quinazolin-
ones by the development of gold(I)-catalyzed cascade reac-
tions between 2-aminobenzohydrazides and alkynoic acids is
documented. Selected compounds were administered to lung
(A549) and breast cancer cells (MDA-MB-231 and MCF-7) in
vitro and it was found that some successfully inhibited cell
proliferation.
tween alkynoic acids A and diamines B (Figure 1, path a),
leading to the synthesis of multiply substituted dihydro-
benzimidazoles and tetrahydroquinazolines.[9] The hypothesis
on which the current work was based involved the use of
readily available 2-aminobenzohydrazides C, which on
treatment with alkynoic acids A in the presence of gold cat-
alysts[10] might undergo cyclization cascades (Figure 1,
path b) to form either pyridazino- or diazepino-fused quin-
azolinones D (when X = H) or pyrrolo- or isoindolo-quin-
azolinones E (when X = Ar). Both the beauty and a main
challenge of the methodology reside in the wide chemical
diversity of products accessible through the design of 2-ami-
nobenzohydrazides C and alkynoic acids A with high re-
gioselectivity/diastereoselectivity. Although the scaffolds
D[11] and E[12] are known in the literature, to the best of
our knowledge there is no report on their identification as
privileged structures.
Introduction
Privileged structures[1] are important in chemical biology
or drug discovery for the identification of bioactive small
molecules.[2] Rather than being directed towards a single
biological target, libraries of privileged structures can be
used to identify new ligands for a variety of targets.[3] In
general, rigid polyheterocyclic core skeletons show binding
specificity towards certain biopolymers because of the “pre-
paid” entropic penalty, resulting from the limited confor-
mational flexibilities of the skeletons.[4] There is therefore
great demand for the synthesis of new privileged scaffolds
and for studies of their binding with various biopolymers.[5]
Here we wish to present our preliminary work on identifica-
tion of new small molecules such as pyridazino- or diazep-
ino-fused quinazolinones and pyrrolo- or isoindolo-fused
quinazolinones as antiproliferative as well as anticancer
agents against lung and breast cancer cell lines. The hetero-
cycles were accessed through one-pot[6] gold(I)-catalyzed
cascade reactions between alkynoic acids and 2-amino-
benzohydrazides.
As a part of our ongoing interest in the development
of metal-catalyzed cascade processes that rapidly generate
privileged scaffolds with high molecular complexity,[7] we
recently reported gold(I)-catalyzed cascade[8] reactions be-
[a] CPC Division, Indian Institute of Chemical Technology
(CSIR),
Hyderabad 500607, India
E-mail: nitin@iict.res.in
[b] Laboratory of X-ray Crystallography, Indian Institute of
Chemical Technology (CSIR),
Hyderabad 500607, India
[c] Department of Chemical Biology, Indian Institute of Chemical
Technology (CSIR),
Hyderabad 500607, India
E-mail: crpatra@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101822.
Figure 1. Strategies for accessing linearly/angularly fused quinazol-
inones.
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Gold-Catalyzed Cascade Reactions
azepino-quinazolinones 3i–o in 60–78% yields (Entries 9–
15). Dodec-3-ynoic acid (2c) was also found to be a good
substrate, although a slight decrease in yield was observed
(Entry 16).
Results and Discussion
Like in our previous investigations,[9a] the catalyst Ph3PAu-
OTf in DCE was found to be optimal.[13] An equimolar
mixture of 2-aminobenzohydrazide (1a, Table 1) and pent-
We next set out to investigate the reactivities of 2-amino-
4-ynoic acid (2a) in the presence of Ph3PAuOTf (5 mol-%) NЈ-arylbenzohydrazides. To begin with, 4a (Table 2) was
was heated in DCE at 80 °C for 12 h. The starting materials treated with 2a under the established reaction conditions.
were completely consumed, giving the required Interestingly, an angularly fused compound – 3a-methyl-4-
4a-methyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quinazol- (phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazol-
ine-2,10-dione (3a) in 62% isolated yield as a single re- ine-1,5-dione (6a) – was obtained.[15] This interesting switch
gioisomer (Table 1, Entry 1).[14] As can be judged from En- in regioselectivity arising through the presence of an aryl
tries 2–8, various 2-aminobenzohydrazides reacted well substituent on the benzohydrazide component allowed the
with 2a, giving the desired products in 55–72% yields. Even synthesis of several pyrrolo- or isoindolo-quinazolinones.
hex-5-ynoic acid (2b) was found to be reactive with 2- The scope of this cascade reaction was further studied and
aminobenzohydrazides 1a–g, giving the corresponding di- the results are shown in Table 2. From Entries 2–9 it can be
Table 1. Synthesis of pyridazino/diazepino-quinazolinones.[a]
[a] Reactions were performed in DCE (1 mL) with 1 (0.51 mmol), 2 (0.51 mmol), and Ph3PAuOTf catalyst (5 mol-%) at 80 °C for 12 h.
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FULL PAPER
Table 2. Synthesis of pyrrolo- and isoindolo-fused quinazolinones.[a]
[a] Reactions were performed in DCE (1 mL) with 4 (0.51 mmol), 2/5 (0.51 mmol), and Ph3PAuOTf catalyst (1 mol-%) at 100 °C for 24 h.
[b] The diastereomer 6pЈ was obtained in 15% yield.
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seen that a variety of 2-amino-NЈ-arylbenzohydrazides 4b– to speculate that these fused compounds could be regarded
i reacted well with pent-4-ynoic acid (2a) to give products as a privileged scaffold as well. We randomly selected ten
6b–i in high yields ranging from 87–98%. We further inves- compounds and the inhibitory cell proliferation effects of
tigated the scope of the alkynoic acids: both terminal and these molecules were studied. The compounds were admin-
internal alkynes with tethered carboxylic acid groups re- istered against lung (A549) and breast cancer (MDA-MB-
acted well with 2-amino-NЈ-arylbenzohydrazides to give the 231 and MCF-7) cell lines in a dose-dependent manner (2–
corresponding quinazolinones in good yields. Compound 20 μm) in a MTT assay (Figure 3). As shown in Figure 3
4a reacted well, for example, with 5a and 5b to give the (A), compounds 3d, 3e, 6a, 6c, 6e, 6g, and 6h were found
corresponding products 6j and 6k in 84% and 69% yields, to be most potent, showing significant inhibition of prolif-
respectively (Entries 10 and 11). Interestingly, 2-ethynyl- eration of lung cancer cells (A549). The most significant
benzoic acid (5c) was also found to be a good substrate, molecules are 3d and 3e, which show ca. 46% and ca. 53%
reacting with different 2-amino-NЈ-arylbenzohydrazides 4a, inhibition of A549 cell proliferation (IC50: 3d = ca. 25 μm
4b, 4c, and 4f to afford isoindolo-quinazolinones 6l–o in and 3e = ca. 2 μm). From Figure 3 (A) it can also be seen
55–75% yields (Entries 12–15).
that as the concentrations of the compounds are increased
Next, to gain insight into the matter of diastereoselectiv- from 2 μm to 20 μm, the inhibition of cell proliferation in-
ity, we treated 2,2Ј-disubstituted alkynoic acid 5d with 4a creases in a dose-dependent manner. Assays of inhibition
(Entry 16). Interestingly, diastereomer 6p was obtained as of cell proliferation by these compounds were next also car-
the major product (61% yield) and the other diastereomer ried out for breast cancer cell lines (MDA-MB-231 and
6pЈ was obtained as a minor one (15% yield). The relative MCF-7; Figure 3, B and C). Clearly one can judge that
stereochemistry of 6p was unambiguously verified by X-ray some compounds inhibited cell proliferation against those
crystallography (Figure 2). To explore further we treated 5a cell lines. It is evident from Figure 3 (A–C) that potent com-
with 4b, 4f, and 4i, which gave the corresponding products pounds show inhibition of proliferation not only of lung
6q, 6r, and 6s in 86, 82, and 60% yields, respectively (En- cancer cells but also breast cancer cells, and this demon-
tries 17–19). Finally, we tested the reactions of internal al- strates that these molecules might also find application for
kynes 2c and 2d with 4a and 4b to give the required prod- other cancers.
ucts 6t–v with 50–70% yields (Entries 20–22). It is worth
noting that the presence of a halo substituent on the 2-
aminobenzohydrazides had no significant influence on the
reactivity (Table 1 and Table 2). The halo-substituted mole-
cules can serve as versatile synthons enabling the introduc-
tion of various functional groups and expanding the avail-
ability of the targeted diverse libraries of products.
Figure 3. A–C: The new heterocyclic scaffolds significantly inhibit
the proliferation of lung cancer cells (A: A549) and breast cancer
cells (B: MDA-MB-231 and C: MCF-7). C = control, D = DMSO.
The data are statistically significant with pՅ0.05. The me-
ansϮSDs of three separate experiments, each performed in tripli-
cate, were calculated.
Although detailed medicinal chemistry investigation
awaits further studies, these results do confirm the utility
Figure 2. X-ray crystal structure of 6p (ORTEP diagram).
of this methodology for rapid access to structurally rigid
Having established a library-based approach to linearly azaheterocyclic scaffolds capable of diversification into a
and angularly fused quinazolinones, we set out to screen range of molecules suitable for biological screening and
those molecules for cell proliferation against lung and which might display activities appropriate for further inves-
breast cancer cell lines. The fact that quinazolinones are an tigation as potential leads for medicinal chemistry programs
important class of heterocycles in pharmacology[12] led us or as potential biological probes for chemical biology.
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8-Bromo-4a-methyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quin-
azoline-2,10-dione (3c): Pale yellow solid (60% yield); m.p. 206–
208 °C. Rf = 0.39 (DCM/MeOH 95:05). 1H NMR (CDCl3, [D6]-
Conclusions
We have identified pyridazino- or diazepino-quinazoli-
nones and pyrrolo- or isoindolo-quinazolinones as privi- DMSO, 300 MHz): δ = 7.79 (s, 1 H), 7.31 (dd, J = 8.5, 1.8 Hz, 1
H), 6.65 (d, J = 8.5 Hz, 1 H), 2.68–2.58 (m, 1 H), 2.40–2.20 (m, 2
H), 2.02–1.93 (m, 1 H), 1.52 (s, 3 H) ppm. 13C NMR (CDCl3, [D6]-
DMSO, 75 MHz): δ = 170.4, 156.0, 144.4, 135.6, 129.3, 116.7,
leged scaffolds in a drug discovery program. These scaffolds
were easily accessed through gold(I)-catalyzed cascade reac-
tions between 2-aminobenzohydrazides and alkynoic acids.
Some of the compounds inhibited cell proliferation of lung
(A549) and breast cancer cells (MDA-MB-231 and MCF-
7) in vitro, so these findings demonstrate that the scaffolds
could prove an interesting starting point for finding leads
in lung and breast cancer therapies.
114.4, 109.0, 73.8, 36.0, 28.7, 23.7 ppm. IR (KBr): ν
= 3299,
˜
max
3185, 3087, 2925, 1691, 1648, 1611, 1502, 1448, 1360, 1259, 1169,
1122, 890, 817, 769, 702, 624, 572 cm–1. HRMS: calcd. for
C12H12N3O2BrNa [M + Na]+· 332.0010; found 331.9997.
8-Chloro-4a,6-dimethyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quin-
azoline-2,10-dione (3d): Pale yellow solid (65% yield); m.p. 216–
218 °C. Rf = 0.36 (DCM/MeOH 95:05). 1H NMR (CDCl3, [D6]-
DMSO, 300 MHz): δ = 10.03 (br. s, 1 H), 7.53 (s, 1 H), 7.12 (s, 1
H), 6.09 (br. s, 1 H), 2.67–2.54 (m, 2 H), 2.29–2.22 (m, 1 H), 2.18
(s, 3 H), 2.02–1.92 (m, 1 H), 1.50 (s, 3 H) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δ = 171.1, 156.7, 142.7, 133.7, 126.0, 123.9,
Experimental Section
General Procedure for Pyridazino- or Diazepino-Fused Quinazolin-
ones: See Table 1. The 2-aminobenzohydrazide 1 (0.51 mmol), the
alkynoic acid 2 (0.51 mmol), and the Ph3PAuCl/AgOTf catalyst
(5 mol-%) in DCE (1 mL) were placed in a screw-cap vial contain-
ing a stirring bar. The reaction vial was fitted with a cap, evacuated,
filled with nitrogen, and heated with stirring at 80 °C for 12 h. The
reaction mixture was allowed to cool to ambient temperature, di-
luted with ethyl acetate, and filtered through a plug of silica gel.
The filtrate was concentrated and the obtained residue was purified
by silica gel column chromatography with hexane/ethyl acetate or
DCM/MeOH as eluent to afford the analytically pure compound
3.
121.2, 114.3, 74.4, 35.9, 29.0, 24.5, 16.6 ppm. IR (KBr): ν
=
˜
max
3339, 3178, 3094, 2973, 2918, 2850, 1690, 1649, 1598, 1505, 1464,
1425, 711, 641, 579, 551, 516, 433 cm–1. HRMS: calcd. for
C13H15N3O2Cl [M + H]+· 280.0852; found 280.0850.
4a,6,8-Trimethyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quinazol-
ine-2,10-dione (3e): Pale yellow solid (55% yield); m.p. 210–212 °C.
Rf = 0.29 (DCM/MeOH 95:05). 1H NMR (CDCl3, [D6]DMSO,
300 MHz): δ = 9.75 (br. s, 1 H), 7.42 (s, 1 H), 6.98 (s, 1 H), 5.60
(br. s, 1 H), 2.70–2.60 (m, 1 H), 2.33–2.01 (m, 9 H), 1.50 (s, 3
H) ppm. 13C NMR (CDCl3, [D6]DMSO, 75 MHz): δ = 170.6,
157.5, 141.1, 135.2, 126.4, 124.8, 123.0, 113.2, 73.7, 35.8, 28.9, 23.6,
General Procedure for Pyrrolo- or Isoindolo-Fused Quinazolinones:
See Table 2. The 2-amino-NЈ-arylbenzohydrazide 4 (0.51 mmol),
the alkynoic acid 5/2 (0.51 mmol), and the Ph3PAuCl/AgOTf cata-
lyst (1 mol-%) in DCE (1 mL) were placed in a screw-cap vial con-
taining a stirring bar. The reaction vial was fitted with a cap, evacu-
ated, filled with nitrogen, and heated with stirring at 100 °C for
24 h. The reaction mixture was allowed to cool to ambient tem-
perature, diluted with ethyl acetate, and filtered through a plug of
silica gel. The filtrate was concentrated and the obtained residue
was purified by silica gel column chromatography with hexane/
ethyl acetate as eluent to afford the analytically pure compound 6.
19.8, 16.6 ppm. IR (KBr): ν
= 3341, 3183, 2972, 2920, 1689,
˜
max
1648, 1594, 1477, 1427, 1357, 1278, 1221, 1172, 1118, 1087, 1012,
975, 868, 777, 642, 582, 434 cm–1. HRMS: calcd. for C14H18N3O2
[M + H]+· 260.1399; found 260.1410.
4a,5-Dimethyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quinazoline-
2,10-dione (3f): Pale yellow solid (72 % yield); m.p. 128–130 °C
(ref.[11] m.p. 133–135 °C); Rf = 0.30 (EtOAc 100 %). 1H NMR
(CDCl3, [D6]DMSO, 400 MHz): δ = 7.83 (d, J = 6.7 Hz, 1 H), 7.40
(t, J = 7.5 Hz, 1 H), 6.86 (t, J = 7.5 Hz, 1 H), 6.78 (d, J = 8.4 Hz,
1 H), 2.93 (s, 3 H), 2.66–2.58 (m, 2 H), 2.42–2.35 (m, 1 H), 2.22–
2.19 (m, 1 H), 1.47 (s, 3 H). 13C NMR ([D6]DMSO, 75 MHz): δ =
169.7, 156.9, 146.5, 134.3, 127.4, 118.1, 113.7, 113.3, 79.1, 33.7,
4a-Methyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quinazoline-
2,10-dione (3a): White solid (62% yield); m.p. 173–175 °C (ref.[11]
m.p. 183–185 °C); Rf = 0.35 (DCM/MeOH 95:05). 1H NMR
(CDCl3, [D6]DMSO, 300 MHz): δ = 9.87 (br. s, 1 H), 7.68 (d, J =
7.7 Hz, 1 H), 7.24 (t, J = 7.5 Hz, 1 H), 6.75–6.69 (m, 3 H), 2.69–
2.59 (m, 1 H), 2.41–2.24 (m, 2 H), 2.01–1.92 (m, 1 H), 1.52 (s, 3
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 171.2, 157.8, 145.9,
133.8, 127.4, 117.9, 114.9, 113.1, 74.2, 36.4, 29.0, 24.4 ppm. IR
32.3, 28.4, 19.8 ppm. IR (KBr): ν
= 3189, 2925, 1651, 1605,
˜
max
1470, 1430, 1037, 962, 869, 836, 778, 756, 705, 554, 509 cm–1
.
HRMS: calcd. for C13H16N3O2 [M + H]+· 246.1242; found
246.1236.
7,8-Dimethoxy-4a-methyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]-
quinazoline-2,10-dione (3g): Pale yellow solid (66% yield); m.p. 190–
192 °C (ref.[11] m.p. 198–200 °C); Rf = 0.41 (EtOAc/MeOH 95:05).
1H NMR (CDCl3, [D6]DMSO, 300 MHz): δ = 7.19 (s, 1 H), 6.27
(s, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 2.72–2.61 (m, 1 H), 2.38–2.30
(m, 2 H), 2.02–1.95 (m, 1 H), 1.50 (s, 3 H) ppm. 13C NMR ([D6]
DMSO, 75 MHz): δ = 171.2, 158.3, 154.3, 141.9, 141.8, 109.6,
(KBr): ν
= 3293, 3212, 2970, 1687, 1649, 1516, 1020, 973, 882,
˜
max
841, 758, 687 cm–1. HRMS: calcd. for C12H14N3O2 [M + H]+·
232.1086; found 232.1090.
4a,8-Dimethyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quinazoline-
2,10-dione (3b): White solid (58% yield); m.p. 110–112 °C (ref.[11]
m.p. 182–185 °C); Rf = 0.36 (DCM/MeOH 95:05). 1H NMR
(CDCl3, [D6]DMSO, 300 MHz): δ = 9.90 (br. s, 1 H), 7.48 (s, 1 H),
7.06 (d, J = 7.9 Hz, 1 H), 6.63 (d, J = 8.3 Hz, 1 H), 2.67–2.56 (m,
1 H), 2.39–2.31 (m, 1 H), 2.28–2.22 (m, 4 H), 1.98–1.88 (m, 1 H),
1.48 (s, 3 H) ppm. 13C NMR (CDCl3, [D6]DMSO, 75 MHz): δ =
170.4, 157.2, 143.1, 134.1, 126.9, 126.7, 114.8, 112.8, 73.7, 36.0,
104.5, 98.3, 74.4, 55.9, 55.5, 36.3, 29.1, 23.9 ppm. IR (KBr): ν
˜
max
= 3436, 2929, 1656, 1607, 1511, 1473, 1384, 1276, 1220, 1106, 1007,
877, 772, 556 cm–1. HRMS: calcd. for C14H17N3O4Na [M + Na]+·
314.1116; found 314.1129.
8-Methoxy-4a-methyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quin-
azoline-2,10-dione (3h): Pale yellow semisolid (70% yield). Rf = 0.25
28.7, 23.2, 19.8 ppm. IR (KBr): ν
= 3294, 2973, 2922, 1648, (EtOAc 100%). 1H NMR (CDCl3, [D6]DMSO, 500 MHz): δ = 7.22
˜
max
1509, 1420, 1448, 1355, 1268, 1227, 1152, 1172, 1124, 1086, 1030,
978, 911, 821, 776, 735, 697, 578, 534 cm–1. HRMS: calcd. for 8.7 Hz, 1 H), 3.75 (s, 3 H), 2.69–2.62 (m, 1 H), 2.38–2.26 (m, 3 H),
C13H16N3O2 [M + H]+· 246.1242; found 246.1238. 1.49 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 171.1,
(d, J = 2.6 Hz, 1 H), 6.88 (dd, J = 8.7, 2.6 Hz, 1 H), 6.69 (d, J =
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Gold-Catalyzed Cascade Reactions
157.5, 151.9, 140.1, 121.8, 116.7, 113.9, 109.9, 74.4, 55.4, 36.4, 29.0,
5a,6-Dimethyl-4,5,5a,6-tetrahydro-[1,2]diazepino[7,1-b]quinazoline-
2,11(1H,3H)-dione (3n): Pale yellow semisolid (70% yield). Rf =
0.41 (hexane/EtOAc 50:50). 1H NMR (CDCl3, [D6]DMSO,
500 MHz): δ = 9.44 (br. s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.40 (t,
J = 7.0 Hz, 1 H), 6.83 (t, J = 7.0 Hz, 1 H), 6.77 (d, J = 9.0 Hz, 1
H), 2.93 (s, 3 H), 2.28–2.09 (m, 3 H), 1.87–1.79 (m, 2 H), 1.74–1.66
(m, 1 H), 1.59 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
176.4, 161.7, 147.4, 134.7, 128.0, 118.0, 114.7, 113.7, 79.7, 33.4,
17.2 ppm. IR (film): ν
= 3305, 2929, 1660, 1504, 1441, 1361,
˜
max
1275, 1226, 1154, 1117, 1032, 825, 772, 639, 551 cm–1. HRMS:
calcd. for C13H15N3O3Na [M + Na]+· 284.1011; found 284.1009.
5a-Methyl-4,5,5a,6-tetrahydro-[1,2]diazepino[7,1-b]quinazoline-
2,11(1H,3H)-dione (3i): White solid (78% yield); m.p. 262–264 °C.
Rf = 0.43 (DCM/MeOH 95:05). 1H NMR (CDCl3, [D6]DMSO,
300 MHz): δ = 9.40 (br. s, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.24 (t,
J = 7.9 Hz, 1 H), 6.70–6.65 (m, 2 H), 2.42–2.32 (m, 1 H), 2.21–
2.11 (m, 2 H), 1.84–1.79 (m, 1 H), 1.74–1.66 (m, 2 H), 1.50 (s, 3
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 176.8, 162.0, 146.2,
134.1, 127.8, 117.1, 114.6, 112.5, 74.3, 38.0, 33.7, 23.4, 18.4 ppm.
31.9, 20.8, 17.6 ppm. IR (film): ν
= 3322, 3197, 3101, 2936,
˜
max
1682, 1605, 1492, 1452, 1432, 1386, 1307, 1202, 1177, 1120, 1042,
983, 930, 861, 783, 751, 661, 577, 514 cm–1. HRMS: calcd. for
C14H18N3O2 [M + H]+· 260.1399; found 260.1391.
IR (KBr): ν
= 3291, 3196, 2926, 1647, 1520, 1483, 1451, 1390,
˜
8,9-Dimethoxy-5a-methyl-4,5,5a,6-tetrahydro-[1,2]diazepino[7,1-b]-
quinazoline-2,11(1H,3H)-dione (3o): Pale yellow solid (70% yield);
m.p. 218–220 °C. Rf = 0.37 (EtOAc/MeOH 95:05). 1H NMR
(CDCl3, [D6]DMSO, 300 MHz): δ = 9.24 (br. s, 1 H), 7.15 (s, 1 H),
6.25 (s, 1 H), 3.82 (s, 3 H), 3.77 (s, 3 H), 2.44–2.34 (m, 1 H), 2.27–
2.12 (m, 2 H), 1.86–1.63 (m, 3 H), 1.49 (s, 3 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 177.0, 161.9, 154.5, 142.1, 141.5, 109.8,
103.9, 97.8, 74.5, 55.8, 55.4, 37.6, 33.9, 23.4, 18.5 ppm. IR (KBr):
max
1343, 1277, 1182, 1144, 1097, 984, 855, 765, 694, 605, 576 cm–1.
HRMS: calcd. for C13H16N3O2 [M + H]+· 246.1242; found
246.1238.
5a,9-Dimethyl-4,5,5a,6-tetrahydro-[1,2]diazepino[7,1-b]quinazoline-
2,11(1H,3H)-dione (3j): White solid (73% yield); m.p. 243–245 °C.
Rf = 0.49 (EtOAc 100 %). 1H NMR (CDCl3, [D6]DMSO,
500 MHz): δ = 9.32 (br. s, 1 H), 7.50 (s, 1 H), 7.05 (d, J = 9.0 Hz,
1 H), 6.60 (d, J = 8.0 Hz, 1 H), 2.40–2.35 (m, 1 H), 2.24 (s, 3 H),
2.17–2.12 (m, 2 H), 1.85–1.81 (m, 1 H), 1.73–1.65 (m, 2 H), 1.49
(s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 176.8, 162.1,
144.0, 135.0, 127.5, 125.9, 114.8, 112.5, 74.3, 38.0, 33.8, 23.4, 19.9,
ν
max = 3326, 3178, 3089, 2931, 1639, 1505, 1455, 1415, 1384, 1280,
˜
1241, 1174, 1081, 1049, 1027, 917, 860, 820, 796, 769, 741, 641, 584,
504 cm–1. HRMS: calcd. for C15H19N3O4Na [M + Na]+· 328.1273;
found 328.1287.
18.5 ppm. IR (KBr): ν
= 3314, 3247, 3112, 2931, 2864, 1654,
˜
max
4a-Octyl-3,4,4a,5-tetrahydro-1H-pyridazino[6,1-b]quinazoline-2,10-
dione (3p): Pale yellow semisolid (49% yield). Rf = 0.26 (hexane/
EtOAc 50:50). H NMR (CDCl3, [D6]DMSO, 300 MHz): δ = 7.67
(d, J = 7.9 Hz, 1 H), 7.23 (t, J = 7.9 Hz, 1 H), 6.73–6.68 (m, 3 H),
2.69–2.60 (m, 1 H), 2.32–2.25 (m, 2 H), 2.04–1.89 (m, 2 H), 1.74–
1.66 (m, 1 H), 1.38–1.20 (m, 12 H), 0.85 (t, J = 6.7 Hz, 3 H) ppm.
13C NMR ([D6]DMSO, 75 MHz): δ = 171.2, 158.3, 145.9, 133.8,
126.7, 126.3, 117.4, 114.4, 76.5, 36.9, 31.2, 28.9, 28.8, 28.6, 28.5,
1520, 1447, 1417, 1386, 1355, 1274, 1205, 1161, 983, 902, 828, 783,
753, 580, 546 cm–1. HRMS: calcd. for C14H17N3O2Na [M + Na]+·
282.1218; found 282.1230.
1
9-Bromo-5a-methyl-4,5,5a,6-tetrahydro-[1,2]diazepino[7,1-b]quin-
azoline-2,11(1H,3H)-dione (3k): White solid (61% yield); m.p. 260–
262 °C. Rf = 0.44 (EtOAc 100%). H NMR (CDCl3, [D6]DMSO,
300 MHz): δ = 9.41 (br. s, 1 H), 7.83–7.78 (m, 1 H), 7.29 (dd, J =
8.5, 2.0 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 2.45–2.35 (m, 1 H),
2.22–2.10 (m, 2 H), 1.86–1.69 (m, 3 H), 1.52 (s, 3 H) ppm. 13C
NMR ([D6]DMSO, 75 MHz): δ = 176.8, 160.8, 145.2, 136.5, 129.7,
1
25.9, 25.2, 22.1, 13.9 ppm. IR (film): νmax = 3305, 2927, 2854, 1646,
˜
1513, 1485, 1460, 1348, 1220, 1167, 1104, 1029, 970, 821, 754, 693,
606, 536 cm–1. HRMS: calcd. for C19H28N3O2 [M + H]+· 330.2181;
found 330.2187.
117.1, 114.0, 108.0, 74.5, 38.1, 33.7, 23.3, 18.4 ppm. IR (KBr): ν
˜
max
= 3305, 3110, 2930, 1686, 1652, 1610, 1497, 1478, 1384, 1340, 1265,
1165, 1133, 956, 826, 780, 689, 639, 570, 537 cm–1. HRMS: calcd.
for C13H14N3O2BrNa [M + Na]+· 346.0167; found 346.0152.
3a-Methyl-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quin-
azoline-1,5-dione (6a): Pale yellow solid (94 % yield); m.p. 190–
192 °C. Rf = 0.50 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
1
DMSO, 300 MHz): δ = 8.23 (d, J = 8.1 Hz, 1 H), 8.07 (br. s, 1 H),
7.98 (d, J = 7.5 Hz, 1 H), 7.59 (t, J = 7.3 Hz, 1 H), 7.26 (t, J =
7.5 Hz, 1 H), 7.14 (t, J = 7.5 Hz, 2 H), 6.83–6.75 (m, 3 H), 2.73–
2.41 (m, 3 H), 2.27–2.20 (m, 1 H), 1.59 (s, 3 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 172.2, 162.5, 148.6, 135.6, 133.8, 128.8,
127.9, 124.7, 119.8, 119.3, 118.8, 112.3 80.9, 29.9, 29.6, 22.4 ppm.
9-Chloro-5a,7-dimethyl-4,5,5a,6-tetrahydro-[1,2]diazepino[7,1-b]quin-
azoline-2,11(1H,3H)-dione (3l): White solid (66% yield); m.p. 246–
248 °C. Rf = 0.48 (EtOAc 100%). H NMR (CDCl3, [D6]DMSO,
500 MHz): δ = 9.42 (br. s, 1 H), 7.55 (s, 1 H), 7.11 (s, 1 H), 6.06
(br. s, 1 H), 2.41–2.35 (m, 1 H), 2.22–2.19 (m, 1 H), 2.16 (s, 3 H),
1.84–1.79 (m, 1 H), 1.76–1.72 (m, 1 H), 1.57 (s, 3 H) ppm. 13C
NMR ([D6]DMSO, 75 MHz): δ = 176.8, 161.2, 143.0, 134.0, 125.9,
124.4, 120.8, 113.6, 74.6, 37.9, 33.8, 23.0, 18.4, 16.8 ppm. IR (KBr):
1
IR (KBr): ν
= 3267, 3022, 1719, 1659, 1600, 1489, 1383, 1339,
˜
max
1220, 1174, 1079, 977, 893, 811, 755, 692, 650, 496 cm–1. HRMS:
calcd. for C18H18N3O2 [M + H]+· 308.1399; found 308.1399.
ν
max = 3324, 3223, 3125, 2939, 1685, 1655, 1509, 1470, 1438, 1395,
˜
1360, 1264, 1214, 1168, 1098, 1032, 886, 782, 699, 598 cm–1
.
Note: The reaction between the 2-aminobenzohydrazide and the
keto-acid has been reported[11] to give the linearly fused compound.
However, we found that the structure reported in this paper is erro-
neous and that it is in fact angularly fused. The results were con-
firmed by examination of melting points, by superimposable IR
and 1H NMR spectra, and by X-ray crystallography of the samples
obtained by the literature method and by our method.
HRMS: calcd. for C14H16ClN3O2Na [M + Na]+· 316.0828; found
316.0826.
5a,7,9-Trimethyl-4,5,5a,6-tetrahydro-[1,2]diazepino[7,1-b]quinazol-
ine-2,11(1H,3H)-dione (3m): White solid (60% yield); m.p. 218–
1
220 °C. Rf = 0.50 (EtOAc 100%). H NMR (CDCl3, [D6]DMSO,
300 MHz): δ = 9.25 (br. s, 1 H), 7.44 (s, 1 H), 6.97 (s, 1 H), 2.47–
2.35 (m, 1 H), 2.26–2.18 (m, 5 H), 2.13 (s, 3 H), 1.86–1.70 (m, 3
H), 1.57 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 176.9, 7-Bromo-3a-methyl-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]-
162.3, 141.9, 135.8, 125.8, 125.3, 123.1, 112.8, 74.4, 37.8, 33.8, 23.1,
quinazoline-1,5-dione (6b): White solid (97 % yield); m.p. 198–
1
19.9, 18.5, 16.8 ppm. IR (KBr): ν = 3342, 3210, 3123, 2935, 200 °C. Rf = 0.60 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
˜
max
1651, 1619, 1512, 1478, 1438, 1391, 1356, 1334, 1274, 1216, 1099,
1031, 880, 785, 724, 678, 640, 597, 567, 529 cm–1. HRMS: calcd.
for C15H20N3O2 [M + H]+· 274.1555; found 274.1557.
DMSO, 500 MHz): δ = 8.20 (d, J = 7.9 Hz, 1 H), 8.12 (br. s, 1 H),
8.08 (d, J = 2.9 Hz, 1 H), 7.70 (dd, J = 8.9, 2.9 Hz, 1 H), 7.15 (t,
J = 7.9 Hz, 2 H), 6.80–6.77 (m, 3 H), 2.70–2.57 (m, 2 H), 2.49–
Eur. J. Org. Chem. 2012, 1790–1799
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1795

N. T. Patil, C. R. Patra et al.
FULL PAPER
2.69–2.64 (m, 2 H), 2.55–2.44 (m, 1 H), 2.31–2.23 (m, 1 H), 1.66
(s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 172.2, 162.0,
145.3, 135.7, 133.9, 132.6, 128.6, 128.1, 124.9, 121.3, 120.0, 119.0,
113.9, 107.4, 81.2, 29.9, 29.7, 22.8 ppm. IR (KBr): ν
= 3345,
˜
max
3299, 3067, 2984, 1713, 1677, 1594, 1483, 1378, 1329, 1297, 1218,
1123, 1014, 835, 760, 797, 681, 636, 564, 498, 438 cm–1. HRMS:
calcd. for C18H17N3O2Br [M + H]+· 386.0504; found 386.0508.
4-(3-Methoxyphenylamino)-3a-methyl-2,3,3a,4-tetrahydropyrrolo-
[1,2-a]quinazoline-1,5-dione (6g): Pale yellow solid (87% yield); m.p.
182–184 °C. Rf = 0.38 (hexane/EtOAc 50:50). 1H NMR (CDCl3,
[D6]DMSO, 500 MHz): δ = 8.22 (d, J = 7.9 Hz, 1 H), 8.05 (br. s, 1
H), 7.98 (d, J = 7.9 Hz, 1 H), 7.59 (t, J = 6.9 Hz, 1 H), 7.26 (t, J
= 6.9 Hz, 1 H), 7.03 (t, J = 7.9 Hz, 1 H), 6.40 (d, J = 7.9 Hz, 1 H),
6.35–6.31 (m, 2 H), 3.72 (s, 3 H), 2.69–2.41 (m, 3 H), 2.24–2.20 (m,
1 H), 1.57 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
172.1, 162.5, 160.1, 150.0, 135.6, 133.8, 129.7, 127.9, 124.6, 119.8,
118.8, 105.0, 104.6, 98.4, 80.9, 54.7, 29.8, 29.5, 22.3 ppm. IR (KBr):
2.43 (m, 1 H), 2.28–2.24 (m, 1 H), 1.60 (s, 3 H) ppm. 13C NMR
([D6]DMSO, 75 MHz): δ = 172.1, 161.1, 148.2, 136.3, 134.8, 130.0,
128.7, 121.8, 120.6, 119.3, 116.5, 112.3, 80.9, 30.0, 29.5, 22.4 ppm.
IR (KBr): ν
= 3297, 3019, 2962, 1718, 1673, 1599, 1483, 1425,
˜
max
1378, 1329, 1208, 1077, 895, 828, 746, 697, 650, 532, 495 cm–1
.
HRMS: calcd. for C18H16N3O2BrNa [M + Na]+· 408.0323; found
408.0347.
3a,7-Methyl-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quin-
azoline-1,5-dione (6c): White solid (98% yield); m.p. 189–191 °C.
Rf = 0.53 (hexane/EtOAc 50:50). 1H NMR (CDCl3, [D6]DMSO,
300 MHz): δ = 8.09 (d, J = 8.3 Hz, 1 H), 8.01 (br. s, 1 H), 7.77 (s,
1 H), 7.39 (d, J = 8.3 Hz, 1 H), 7.13 (t, J = 7.7 Hz, 2 H), 6.81–6.74
(m, 3 H), 2.70–2.46 (m, 3 H), 2.40 (s, 3 H), 2.25–2.18 (m, 1 H),
1.57 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 172.0,
162.6, 148.6, 134.4, 134.1, 133.3, 128.8, 127.9, 119.7, 119.3, 118.7,
ν
max = 3255, 3032, 2972, 1721, 1660, 1600, 1524, 1487, 1383, 1338,
˜
1261, 1201, 1157, 1080, 1036, 990, 832, 762, 692, 654, 571, 522,
484 cm–1. HRMS: calcd. for C19H20N3O3[M + H]+· 338.1504;
found 338.1514.
4-(4-Chlorophenylamino)-3a-methyl-2,3,3a,4-tetrahydropyrrolo-
[1,2-a]quinazoline-1,5-dione (6h): Pale yellow solid (97% yield); m.p.
208–210 °C. Rf = 0.31 (hexane/EtOAc 70:30). 1H NMR (CDCl3,
[D6]DMSO, 300 MHz): δ = 8.30 (br. s, 1 H), 8.23 (d, J = 7.9 Hz, 1
H) 7.98 (d, J = 7.5 Hz, 1 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.27 (t, J =
7.5 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 2 H), 6.80 (d, J = 7.7 Hz, 2 H),
2.72–2.57 (m, 2 H), 2.45–2.34 (m, 1 H), 2.27–2.14 (m, 1 H), 1.57
(s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 172.1, 162.4,
147.6, 135.6, 133.8, 128.5, 127.9, 124.6, 122.7, 119.8, 118.6, 114.0,
112.3, 80.9, 29.9, 29.6, 22.3, 20.4 ppm. IR (KBr): ν
= 3257,
˜
max
3123, 3043, 2974, 1696, 1603, 1501, 1381, 1315, 1245, 1201, 1145,
1081, 1043, 980, 866, 828, 785, 743, 681, 600, 532, 495 cm–1
.
HRMS: calcd. for C19H20N3O2 [M + H]+· 322.1555; found
322.1566.
3a-Methyl-4-(p-tolylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quin-
azoline-1,5-dione (6d): White solid (91% yield); m.p. 160–162 °C.
Rf = 0.57 (hexane/EtOAc 70:30). 1H NMR (CDCl3, [D6]DMSO,
500 MHz): δ = 8.22 (d, J = 7.8 Hz, 1 H), 8.01 (d, J = 7.8 Hz, 1 H),
7.61–7.59 (m, 1 H), 7.28 (t, J = 7.8 Hz, 1 H), 6.98 (d, J = 7.8 Hz,
2 H), 6.75 (d, J = 7.8 Hz, 2 H) 2.73–2.59 (m, 2 H), 2.55–2.48 (m,
1 H), 2.26–2.21 (m, 4 H), 1.59 (s, 3 H) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 172.4, 162.6, 146.3, 135.7, 133.9, 129.4, 128.1, 128.0,
124.9, 119.9, 119.0, 112.5, 81.0, 30.0, 29.7, 22.5, 20.2 ppm. IR
80.8, 29.9, 29.5, 22.3 ppm. IR (KBr): ν
= 3264, 2972, 2925,
˜
max
1717, 1656, 1596, 1490, 1382, 1338, 1296, 1231, 1170, 1129, 1086,
973, 829, 766, 697, 633, 600, 503 cm–1. HRMS: calcd. for
C18H17N3O2Cl [M + H]+· 342.1009; found 342.1010.
3a-Methyl-4-[3-(trifluoromethyl)phenylamino]-2,3,3a,4-tetrahydro-
pyrrolo[1,2-a]quinazoline-1,5-dione (6i): Pale yellow solid (98%
yield); m.p. 216–218 °C. Rf = 0.48 (hexane/EtOAc 70:30). 1H NMR
(CDCl3, [D6]DMSO, 300 MHz): δ = 8.61 (br. s, 1 H), 8.25 (d, J =
7.9 Hz, 1 H), 7.99 (d, J = 7.3 Hz, 1 H), 7.61 (t, J = 8.3 Hz, 1 H),
7.32–7.25 (m, 2 H), 7.08–7.02 (m, 3 H), 2.71–2.58 (m, 2 H), 2.45–
2.18 (m, 2 H), 1.59 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz):
δ = 172.1, 162.6, 149.4, 135.7, 133.9, 130.1, 129.9, 129.5, 128.0,
126.0, 124.7, 122.4, 119.8, 118.5, 115.9, 115.6, 115.5, 108.5, 108.4,
(KBr): νmax = 3424, 3270, 3078, 2920, 1725, 1619, 1603, 1515, 1486,
˜
1468, 1382, 1298, 1080, 983, 813, 757, 691, 640, 511, 499 cm–1
.
HRMS: calcd. for C19H19N3O2Na [M + Na]+· 344.1375; found
344.1386.
4-(3-Chlorophenylamino)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]-
quinazoline-1,5-dione (6e): Pale yellow solid (97% yield); m.p. 217–
80.9, 30.0, 29.6, 22.2 ppm. IR (KBr): ν
= 3262, 3049, 2964,
1
˜
max
219 °C. Rf = 0.49 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
1720, 1653, 1606, 1534, 1485, 1388, 1335, 1229, 1162, 1119, 1069,
986, 876, 803, 760, 703, 658, 577, 521 cm–1. HRMS: calcd. for
C19H16N3O2F3Na [M + Na]+· 398.1092; found 398.1077.
DMSO, 500 MHz): δ = 8.41 (br. s, 1 H), 8.24 (d, J = 8.9 Hz, 1 H),
7.98 (d, J = 7.9 Hz, 1 H), 7.60 (t, J = 7.9 Hz, 1 H), 7.27 (t, J =
7.9 Hz, 1 H), 7.09 (t, J = 7.9 Hz, 1 H), 6.81 (s, 1 H), 6.73 (d, J =
7.9 Hz, 2 H), 2.70–2.55 (m, 2 H), 2.43–2.36 (m, 1 H), 2.26–2.22 (m,
1 H), 1.57 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
172.1, 162.5, 150.3, 135.7, 133.9, 133.6, 130.5, 128.0, 124.6, 119.7,
119.0, 118.5, 111.8, 111.1, 80.9, 30.0, 29.6, 22.2 ppm. IR (KBr):
3aЈ-Methyl-4Ј-(phenylamino)-3aЈ,4Ј-dihydro-1ЈH-spiro[cyclopent-
ane-1,2Ј-pyrrolo[1,2-a]quinazoline]-1Ј,5Ј(3ЈH)-dione (6j): Pale yellow
solid (84 % yield); m.p. 180–182 °C. Rf = 0.56 (hexane/EtOAc
1
70:30). H NMR (CDCl3, [D6]DMSO, 300 MHz): δ = 8.23 (d, J =
ν
max = 3247, 3076, 3035, 2978, 1721, 1660, 1595, 1479, 1381, 1339,
˜
8.1 Hz, 1 H), 8.01–7.97 (m, 2 H), 7.60 (t, J = 8.3 Hz, 1 H), 7.27 (t,
J = 7.3 Hz, 1 H), 7.14 (t, J = 7.9 Hz, 2 H), 6.78 (t, J = 7.7 Hz, 2
H), 2.43–2.39 (m, 1 H), 2.26–2.17 (m, 2 H), 2.07–1.49 (m, 10
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 172.6, 162.2, 148.7,
135.5, 133.6, 128.8, 127.7, 124.9, 120.2, 119.7, 119.4, 112.3, 83.2,
1307, 1226, 1168, 1123, 1076, 987, 885, 850, 802, 759, 684, 603,
522, 440 cm–1. HRMS: calcd. for C18H17N3O2Cl [M + H]+·
342.1009; found 342.1012.
4-(2-Bromophenylamino)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]-
quinazoline-1,5-dione (6f): Pale yellow solid (87% yield); m.p. 204–
206 °C. Rf = 0.43 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
DMSO, 300 MHz): δ = 8.27 (d, J = 8.3 Hz, 1 H), 8.07 (d, J =
7.5 Hz, 1 H), 7.62 (t, J = 8.3 Hz, 1 H), 7.49 (dd, J = 7.5, 1.5 Hz, 1
H), 7.29 (t, J = 7.5 Hz, 1 H), 7.16 (t, J = 8.3 Hz, 1 H), 6.88 (d, J
37.1, 29.9, 28.7, 28.5, 28.3, 27.2, 22.8 ppm. IR (KBr): νmax = 3278,
˜
2952, 2866, 1709, 1665, 1601, 1489, 1378, 1337, 1231, 1164, 1055,
1026, 969, 881, 755, 693, 495 cm– 1 . HRMS: calcd. for
C22H23N3O2Na [M + Na]+· 384.1687; found 384.1700.
1
3aЈ-Methyl-4Ј-(phenylamino)-3aЈ,4Ј-dihydro-1ЈH-spiro[cyclohexane-
= 8.3 Hz, 1 H), 6.81 (dt, J = 7.5, 1.5 Hz, 1 H), 6.49 (br. s, 1 H), 1,2Ј-pyrrolo[1,2-a]quinazoline]-1Ј,5Ј(3ЈH)-dione (6k): Pale yellow so-
1796 Eur. J. Org. Chem. 2012, 1790–1799
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Gold-Catalyzed Cascade Reactions
lid (69% yield); m.p. 215–217 °C. Rf = 0.51 (hexane/EtOAc 70:30).
δ = 162.7, 144.4, 134.9, 134.2, 133.5, 132.4, 130.3, 129.8, 128.2,
1H NMR (CDCl3, [D6]DMSO, 500 MHz): δ = 8.18 (d, J = 7.9 Hz, 128.0, 125.7, 125.0, 123.9, 121.9, 121.2, 119.6, 113.4, 107.2, 79.7,
1 H), 8.00 (d, J = 7.9 Hz, 1 H), 7.82 (br. s, 1 H), 7.60 (t, J = 7.9 Hz,
23.3 ppm. IR (KBr): ν
= 3412, 3294, 3059, 2929, 1714, 1683,
˜
max
1 H), 7.27 (t, J = 6.9 Hz, 1 H), 7.15 (t, J = 7.9 Hz, 2 H), 6.80 (t, J 1605, 1488, 1461, 1378, 1319, 1288, 1188, 1168, 1021, 963, 807,
= 7.9 Hz, 3 H), 2.39–2.36 (m, 1 H), 2.23–2.20 (m, 1 H), 1.86–1.75 759, 692, 649, 508 cm–1. HRMS: calcd. for C22H16N3O2BrNa [M
(m, 4 H), 1.70–1.49 (m, 9 H) ppm. 13C NMR ([D6]DMSO, + Na]+· 456.0330; found 456.0343.
75 MHz): δ = 176.5, 162.6, 148.5, 135.3, 133.7, 128.9, 127.8, 125.1,
(2R,3aR)-2-(4-Isobutylphenyl)-2,3a-dimethyl-4-(phenylamino)-
2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione (6p): White
120.9, 119.7, 119.4, 112.2, 78.7, 44.3, 40.5, 34.9, 33.6, 25.5, 24.7,
21.5, 21.3 ppm. IR (KBr): ν
= 3416, 3254, 2925, 2854, 1718,
˜
max
solid (60 % yield); m.p. 222–224 °C. Rf = 0.54 (hexane/EtOAc
70:30). 1H NMR (CDCl3, 500 MHz): δ = 8.34 (d, J = 7.9 Hz, 1 H),
8.11 (d, J = 7.9 Hz, 1 H), 7.66 (t, J = 6.9 Hz, 1 H), 7.33 (t, J =
7.9 Hz, 1 H), 7.27 (d, J = 7.9 Hz, 2 H), 7.13–7.06 (m, 4 H), 6.84
(t, J = 6.9 Hz, 1 H), 6.74 (d, J = 7.9 Hz, 2 H), 6.32 (br. s, 1 H),
3.08–3.05 (m, 1 H), 2.43–2.37 (m, 3 H), 1.88–1.79 (m, 1 H), 1.78
(s, 3 H) 1.73 (s, 3 H), 0.88 (d, J = 5.9 Hz, 6 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 176.1, 147.3, 141.3, 140.4, 135.9, 134.1,
129.3, 129.0, 128.6, 125.8, 125.4, 121.7, 121.2, 113.7, 79.1, 48.3,
1653, 1602, 1489, 1465, 1446, 1375, 1331, 1250, 1224, 1153, 1079,
1030, 965, 884, 766, 696, 668, 582, 534, 498 cm–1. HRMS: calcd.
for C23H25N3O2Na [M + Na]+· 398.1844; found 398.1845.
6a-Methyl-6-(phenylamino)-6,6a-dihydroisoindolo[2,1-a]quinazoline-
5,11-dione (6l): Pale yellow solid (55% yield); m.p. 207–210 °C. Rf
= 0.55 (hexane/EtOAc 70:30). 1H NMR (CDCl3, [D6]DMSO,
500 MHz): δ = 8.18 (br. s, 1 H), 8.11 (d, J = 7.9 Hz, 1 H), 8.04 (d,
J = 6.9 Hz, 1 H), 7.89–7.84 (m, 2 H), 7.70 (t, J = 7.9 Hz, 1 H),
7.51 (t, J = 6.9 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.34 (t, J =
7.9 Hz, 1 H), 6.91 (t, J = 7.9 Hz, 2 H), 6.62 (t, J = 6.9 Hz, 1 H),
6.40 (d, J = 7.9 Hz, 2 H), 1.87 (s, 3 H) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 164.8, 163.2, 148.1, 143.7, 134.9, 134.0, 133.5, 130.1,
129.7, 128.5, 128.1, 125.6, 125.5, 123.7, 121.7, 119.5, 119.4, 112.3,
46.9, 44.8, 30.1, 26.5, 25.4, 22.3 ppm. IR (KBr): νmax = 3275, 3021,
˜
2955, 2866, 1924, 1719, 1673, 1604, 1487, 1468, 1331, 1309, 1224,
1170, 1128, 1048, 970, 851, 763, 754, 692, 500 cm–1. HRMS: calcd.
for C29H32N3O2 [M + H]+· 454.2494; found 454.2514.
(2S,3aR)-2-(4-Isobutylphenyl)-2,3a-dimethyl-4-(phenylamino)-
2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione (6pЈ): Pale
yellow semisolid (15% yield). Rf = 0.49 (hexane/EtOAc 70:30). H
79.6, 22.9 ppm. IR (KBr): ν
= 3264, 2925, 1714, 1664, 1601,
˜
max
1488, 1374, 1316, 1252, 1167, 1094, 971, 884, 760, 698, 662, 626,
614, 566, 495 cm–1. HRMS: calcd. for C22H17N3O2Na [M + Na]+·
378.1218; found 378.1224.
1
NMR (CDCl3, [D6]DMSO, 500 MHz): δ = 8.43 (br. s, 1 H), 8.29
(d, J = 8.0 Hz, 1 H), 7.96 (d, J = 7.0 Hz, 1 H), 7.75 (t, J = 8.0 Hz,
1 H), 7.41–7.36 (m, 3 H), 7.20–7.15 (m, 4 H), 6.86 (d, J = 8.0 Hz,
2 H), 6.79 (t, J = 7.0 Hz, 1 H), 2.87–2.85 (m, 1 H), 2.43–2.41 (m,
3 H), 1.85–1.76 (m, 1 H), 1.50 (s, 3 H), 1.15 (s, 3 H), 0.83 (d, J =
7.0 Hz, 6 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 174.2,
162.3, 148.5, 141.1, 139.7, 135.0, 133.9, 129.3, 128.9, 127.9, 125.5,
125.2, 120.5, 119.4, 119.3, 112.3, 78.4, 48.6, 46.1, 44.0, 29.4, 27.6,
3-Bromo-6a-methyl-6-(phenylamino)-6,6a-dihydroisoindolo[2,1-a]-
quinazoline-5,11-dione (6m): White solid (75 % yield); m.p. 219–
221 °C. Rf = 0.52 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
DMSO, 500 MHz): δ = 8.15–8.14 (m, 1 H), 8.10 (br. s, 1 H), 8.06
(d, J = 9.0 Hz, 1 H), 7.90 (d, J = 7.0 Hz, 1 H), 7.85 (d, J = 7.0 Hz,
1 H), 7.80–7.78 (m, 1 H), 7.51 (t, J = 7.0 Hz, 1 H), 7.45 (t, J =
7.0 Hz, 1 H), 6.92 (t, J = 7.0 Hz, 2 H), 6.65 (t, J = 7.0 Hz, 1 H),
6.39 (d, J = 8.0 Hz, 2 H), 1.88 (s, 3 H) ppm. 13C NMR ([D6]DMSO,
75 MHz): δ = 164.7, 162.0, 147.8, 143.5, 136.6, 134.1, 133.6, 130.2,
129.4, 128.5, 125.6, 123.8, 121.3, 119.4, 117.4, 112.2, 79.6,
1
22.7, 22.1 ppm. IR (film): ν
= 3326, 3178, 3089, 2931, 1639,
˜
max
1505, 1455, 1415, 1384, 1280, 1241, 1174, 1081, 1049, 1027, 917,
860, 820, 796, 769, 741, 641, 610, 584, 504 cm–1. HRMS: calcd. for
C29H31N3O2Na [M + Na]+· 476.2314; found 476.2318.
23.1 ppm. IR (KBr): ν
= 3314, 3058, 2971, 2924, 2852, 1842,
˜
max
1802, 1779, 1714, 1678, 1602, 1479, 1438, 1366, 1270, 1242, 1166,
1098, 1070, 889, 820, 764, 747, 688, 661, 575, 470 cm–1. HRMS:
calcd. for C22H16N3O2BrNa [M + Na]+· 456.0324; found 456.0334.
7Ј-Bromo-3aЈ-methyl-4Ј-(phenylamino)-3aЈ,4Ј-dihydro-1ЈH-spiro[cy-
clopentane-1,2Ј-pyrrolo[1,2-a]quinazoline]-1Ј,5Ј(3ЈH)-dione (6q):
Pale yellow solid (86% yield); m.p. 205–207 °C. Rf = 0.70 (hexane/
1
EtOAc 70:30). H NMR (CDCl3, [D6]DMSO, 500 MHz): δ = 8.18
3,6a-Dimethyl-6-(phenylamino)-6,6a-dihydroisoindolo[2,1-a]quinaz-
oline-5,11-dione (6n): Pale yellow solid (71 % yield); m.p. 192–
(d, J = 8.1 Hz, 1 H), 8.10–8.07 (m, 2 H), 7.70 (dd, J = 8.1, 2.0 Hz,
1 H), 7.14 (t, J = 8.1 Hz, 2 H), 6.81 (t, J = 7.2 Hz, 3 H), 2.45–2.38
(m, 1 H), 2.25–2.17 (m, 1 H), 2.04–1.99 (m, 1 H), 1.90–1.82 (m, 2
H), 1.74–1.53 (m, 8 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ
= 177.1, 161.3, 148.3, 136.4, 134.6, 130.1, 128.9, 122.5, 121.2, 119.5,
116.8, 112.2, 78.8, 49.9, 44.7, 38.2, 25.3, 24.7, 24.4 ppm. IR (KBr):
1
194 °C. Rf = 0.48 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
DMSO, 500 MHz): δ = 8.00 (d, J = 8.0 Hz, 1 H), 7.88 (d, J =
8.0 Hz, 1 H), 7.85 (br. s, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.60 (s, 1
H), 7.49–7.47 (m, 2 H), 7.41–7.38 (m, 1 H), 6.91 (t, J = 8.0 Hz, 2
H), 6.65 (t, J = 7.0 Hz, 1 H), 6.40 (d, J = 7.0 Hz, 2 H), 2.44 (s, 3
H), 1.85 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 164.7,
163.3, 148.1, 143.7, 134.9, 134.6, 133.3, 132.5, 130.0, 129.8, 128.5,
127.9, 125.5, 123.6, 121.6, 119.3, 112.2, 79.5, 22.8, 20.5 ppm. IR
ν
max = 3413, 3293, 3057, 2945, 2857, 1714, 1673, 1603, 1476, 1439,
˜
1376, 1272, 1243, 1170, 1052, 1027, 885, 836, 777, 746, 690, 540,
494 cm–1. HRMS: calcd. for C22H23N3O2Br [M + H]+· 440.0974;
found 440.0983.
(KBr): νmax = 3299, 3262, 3029, 2924, 2856, 1724, 1683, 1605, 1503,
˜
1468, 1448, 1423, 1372, 1316, 1284, 1172, 1099, 1070, 901, 815,
771, 754, 691, 539, 495 cm–1. HRMS: calcd. for C23H19N3O2Na [M
+ Na]+· 392.1369; found 392.1356.
4Ј-(2-Bromophenylamino)-3aЈ-methyl-3aЈ,4Ј-dihydro-1ЈH-spiro[cy-
clopentane-1,2Ј-pyrrolo[1,2-a]quinazoline]-1Ј,5Ј(3ЈH)-dione (6r):
Pale yellow solid (82% yield); m.p. 200–202 °C. Rf = 0.70 (hexane/
1
6-(2-Bromophenylamino)-6a-methyl-6,6a-dihydroisoindolo[2,1-a]- EtOAc 70:30). H NMR (CDCl3, [D6]DMSO, 300 MHz): δ = 8.18
quinazoline-5,11-dione (6o): White solid (75 % yield); m.p. 262–
264 °C. Rf = 0.60 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
DMSO, 500 MHz): δ = 8.12 (d, J = 8.0 Hz, 1 H), 8.05 (d, J =
(d, J = 8.1 Hz, 1 H), 8.10–8.06 (m, 2 H), 7.71–7.69 (m, 1 H), 7.14
(t, J = 8.1 Hz, 2 H), 6.79–6.77 (m, 3 H), 2.44–2.38 (m, 1 H), 2.26–
2.22 (m, 1 H), 2.08–1.99 (m, 1 H), 1.90–1.80 (m, 2 H), 1.74–1.53
1
8.0 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 7.0 Hz, 1 H), (m, 8 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 176.9, 133.8,
7.72–7.69 (m, 1 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.44 (t, J = 7.0 Hz, 132.6, 128.5, 127.9, 125.0, 123.2, 121.2, 120.5, 115.0, 113.7, 112.5,
1 H), 7.39–7.34 (m, 3 H), 6.72 (t, J = 7.0 Hz, 1 H), 6.60 (t, J = 107.3, 78.9, 49.8, 44.5, 39.6, 38.6, 38.1, 25.3, 24.7 ppm. IR (KBr):
7.0 Hz, 1 H), 1.92 (s, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz):
νmax = 3293, 2931, 2863, 1689, 1591, 1478, 1370, 1329, 1296, 1224,
˜
Eur. J. Org. Chem. 2012, 1790–1799
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1797

N. T. Patil, C. R. Patra et al.
FULL PAPER
1155, 1018, 970, 874, 752, 679, 634, 566, 494 cm–1. HRMS: calcd.
Acknowledgments
for C22H22N3O2BrNa [M + Na]+· 462.0793; found 462.0800.
N. T. P. gratefully acknowledges financial support from the Depart-
ment of Science and Technology (DST), New Delhi. P. G. V. V. L.
thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, for a fellowship. C. R. P. is thankful to the DST for the
award of a Ramanujan fellowship grant and to CSIR (SIP0011) for
financial assistance.
3aЈ-Methyl-4Ј-(3-trifluoromethyl)phenylamino-3aЈ,4Ј-dihydro-1ЈH-
spiro[cyclopentane-1,2Ј-pyrrolo[1,2-a]quinazoline]-1Ј,5Ј(3ЈH)-dione
(6s): White solid (60% yield); m.p. 258–260 °C. Rf = 0.65 (hexane/
1
EtOAc 70:30). H NMR (CDCl3, [D6]DMSO, 500 MHz): δ = 8.56
(br. s, 1 H), 8.23 (d, J = 8.2 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H),
7.62 (t, J = 7.5 Hz, 1 H), 7.30–7.27 (m, 2 H), 7.06–6.99 (m, 3 H),
2.34–2.32 (m, 1 H), 2.13–2.03 (m, 1 H), 1.92–1.82 (m, 3 H), 1.76–
1.63 (m, 8 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 177.2,
162.8, 149.4, 135.5, 134.1, 130.3, 130.1, 129.8, 129.6, 128.1, 125.2,
120.8, 119.3, 116.0, 115.8, 108.3, 108.2, 78.9, 49.9, 44.9, 36.3, 25.4,
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= 3255, 3053, 2955,
˜
max
2863, 1705, 1657, 1601, 1538, 1484, 1468, 1427, 1377, 1332, 1231,
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HRMS: calcd. for C23H22N3O2F3Na [M + Na]+· 452.1562; found
452.1548.
3a-Octyl-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinaz-
oline-1,5-dione (6t): White solid (55% yield); m.p. 138–140 °C. Rf
= 0.67 (hexane/EtOAc 70:30). 1H NMR (CDCl3, [D6]DMSO,
300 MHz): δ = 8.15–8.09 (m, 2 H), 7.96 (d, J = 7.3 Hz, 1 H), 7.60
(t, J = 8.3 Hz, 1 H), 7.28 (t, J = 7.3 Hz, 1 H), 7.14 (t, J = 7.7 Hz,
2 H), 6.80–6.74 (m, 3 H), 2.64–2.57 (m, 2 H), 2.31–2.23 (m, 1 H),
2.07–1.99 (m, 1 H), 1.86–1.78 (m, 1 H), 1.26–1.18 (m, 13 H), 0.85
(t, J = 6.9 Hz, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ =
172.6, 162.2, 148.7, 135.5, 133.6, 128.8, 127.7, 124.9, 120.2, 119.7,
119.4, 112.3, 83.1, 37.1, 31.1, 29.9, 28.7, 28.5, 28.3, 27.2, 22.8, 22.0,
13.8 ppm. IR (KBr): ν
= 3260, 3106, 3020, 2924, 2853, 1717,
˜
max
1659, 1601, 1489, 1464, 1389, 1338, 1311, 1217, 1173, 975, 892,
851, 752, 692, 650, 535, 501 cm–1. HRMS: calcd. for C25H32N3O2
[M + H]+· 406.2494; found 406.2475.
3a-Ethyl-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinaz-
oline-1,5-dione (6u): Pale red solid (50% yield); m.p. 192–194 °C.
Rf = 0.49 (hexane/EtOAc 70:30). 1H NMR (CDCl3, [D6]DMSO,
300 MHz): δ = 8.16 (d, J = 8.3 Hz, 1 H), 7.98 (d, J = 6.9 Hz, 1 H),
7.93 (br. s, 1 H), 7.60 (t, J = 8.3 Hz, 1 H), 7.28 (t, J = 7.3 Hz, 1
H), 7.15 (t, J = 7.3 Hz, 3 H), 6.79 (t, J = 7.7 Hz, 2 H), 2.65–2.60
(m, 1 H), 2.55–2.54 (m, 1 H), 2.49–2.43 (m, 1 H), 2.32–2.23 (m, 1
H), 2.12–2.05 (m, 1 H), 1.96–1.87 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 172.7, 162.2, 148.7,
135.5, 133.7, 128.9, 127.7, 124.9, 120.3, 119.7, 119.4, 112.3, 83.5,
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30.1, 29.9, 26.7, 7.9 ppm. IR (KBr): νmax = 3327, 3254, 3033, 2963,
˜
1719, 1646, 1603, 1489, 1393, 1343, 1302, 1242, 1170, 1114, 1027,
854, 755, 692, 654, 497 cm–1. HRMS: calcd. for C19H19N3O2Na [M
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7-Bromo-3a-ethyl-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]-
quinazoline-1,5-dione (6v): Pale yellow solid (70% yield); m.p. 108–
110 °C. Rf = 0.55 (hexane/EtOAc 70:30). H NMR (CDCl3, [D6]-
DMSO, 500 MHz): δ = 8.14 (d, J = 9.0 Hz, 2 H), 8.09 (br. s, 1 H),
7.71 (dd, J = 9.0, 3.0 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 2 H), 6.82–6.80
(m, 3 H), 2.66–2.60 (m, 2 H), 2.54–2.47 (m, 1 H), 2.33–2.28 (m, 1
H), 2.14–2.08 (m, 1 H), 1.97–1.89 (m, 1 H), 0.89 (t, J = 8.0 Hz, 3
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 172.7, 160.9, 148.4,
136.4, 134.8, 129.9, 128.9, 122.3, 121.5, 119.5, 116.8, 112.3, 83.5,
1
30.3, 29.9, 26.9, 7.9 ppm. IR (KBr): νmax = 3272, 2967, 2928, 1716,
˜
1666, 1600, 1482, 1423, 1380, 1325, 1241, 1172, 1071, 859, 825,
752, 695, 660, 497 cm–1. HRMS: calcd. for C19H18N3O2BrNa [M
+ Na]+· 422.0475; found 422.0476.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, analytical and spectral data for
newly synthesized compounds.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1790–1799

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[13] See the Supporting Information for optimization studies.
[14] CCDC-843564 (for 3a), -843565 (for 6a), -843566 (for 3i), and
-843567 (for 6p) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[15] Interestingly, in the present case only 1 mol-% Ph3PAuOTf was
found to be enough to afford products with high yields. How-
ever, a higher temperature (100 °C) and longer reaction time
(24 h) were necessary. This observation is in contrast with the
results described in Table 1, in which the use of 5 mol-% cata-
lyst was optimal under heating conditions (80 °C) for 12 h.
This difference is probably due to the inhibition of Au catalyst
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Published Online: February 6, 2012
Eur. J. Org. Chem. 2012, 1790–1799
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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