"Dry" and "wet" green synthesis of 2,2′ -disubstituted quinazolinones

Article abstract of DOI:10.1002/ejoc.200901052

An extremely convenient, environmentally benign spirocyclization under either aqueous or solventless conditions, developed for the preparation of spiro[cyclohexane-l,2′(l′H)-quinazolin]-4′(3′H)-one (3), has been utilized to convert α- and β-aminocarboxamides 5a, 5b, 6a-c and 9 and cycloalkanones 2-2b and alkanones 2c-e into 1,4-diazaspiro[4.5]decan- 2-one (10) and cis-, diexo- or diendo-2,2′-disub-stituted quinazolinones 5a, 5b, 7a-f and 8. diexo-Methylenebridged carboxamides 6a and 6b were treated "on water" with N-benzylpiperidinone (11) to afford spiropiperidinequinazolinones 12a and 12b. All these reactions were performed at room temperature, without any catalyst or co-solvent, and gave yields of up to 99%.

Full text of DOI:10.1002/ejoc.200901052

FULL PAPER
DOI: 10.1002/ejoc.200901052
“Dry” and “Wet” Green Synthesis of 2,2Ј-Disubstituted Quinazolinones
[a]
[a,b]
Ferenc Miklós and Ferenc Fülöp*
Keywords: Water chemistry / Spiro compounds / Nitrogen heterocycles / Green chemistry / Sustainable chemistry
An extremely convenient, environmentally benign spiro-
cyclization under either aqueous or solventless conditions,
developed for the preparation of spiro[cyclohexane-1,2Ј-
stituted quinazolinones 5a, 5b, 7a–f and 8. diexo-Methylene-
bridged carboxamides 6a and 6b were treated “on water”
with N-benzylpiperidinone (11) to afford spiropiperidine–
quinazolinones 12a and 12b. All these reactions were per-
formed at room temperature, without any catalyst or co-sol-
vent, and gave yields of up to 99%.
(
1ЈH)-quinazolin]-4Ј(3ЈH)-one (3), has been utilized to con-
vert α- and β-aminocarboxamides 5a, 5b, 6a–c and 9 and cy-
cloalkanones 2–2b and alkanones 2c–e into 1,4-diazaspiro-
[4.5]decan-2-one (10) and cis-, diexo- or diendo-2,2Ј-disub-
Introduction
heating of monosubstituted anthranilamides with cyclic
[
18]
ketones without solvent proved to be an effective method
for the preparation of spiroquinazolinones. The cyclization
The development of cleaner, safer and eco-friendly chem-
ical processes is an important goal for chemists in both aca-
[19]
of anthranilamide with ketones in absolute ethanol or in
[
1]
[2]
demia and industry. A number of strategies have been
produced for the synthesis of heterocyclic compounds, such
[20]
refluxing trifluoroethanol
is also known. For the prepa-
ration of spiro-1,2-dihydroquinazolin-4(3H)-ones, a new
as reactions performed in aqueous[ or solvent-free me-
3]
[4]
method has been introduced: the reductive cyclization of 2-
dia, mechanochemical mixing (grindstone and ball-mill
[21]
nitrobenzamides with carbonyl compounds.
Modifica-
[
5]
[6]
[7]
chemistry) or the use of ionic liquids or microwave or
tion of the Friedländler reaction of 2-aminobenzonitriles
[
8]
[9]
ultrasonic irradiation. The best solvent is “no solvent”.
[22]
with cyclohexanone in the prenes.
The Kaupp group pointed to the sustainable character of
gas–solid reactions in the absence of solvents and stressed
that they must be performed to completion with 100% yield Results and Discussion
of a single product. They demonstrated such favourable be-
We have developed efficient and environmentally benign
haviour in more than 1000 gas–solid and stoichiometric so-
methodology for the preparation of spiropiperidines.[ The
spirocyclization of carbocyclic 2-aminocarbohydrazides
with N-benzylpiperidinone in water at room temperature in
the absence of any additive led to 3Ј-aminospiropiperidine–
quinazolinones. All products precipitated from the reaction
mixture and were obtained in excellent yields. Simplifying
that system in the present work, we investigated the cy-
clocondensation of anthranilamide (1) and cyclohexanone
23]
lid–solid synthetic reactions.[10] The solid-state mechanism,
which involves phase rebuilding (anisotropic molecular mi-
grations within crystals), phase transformation and crystal
disintegration, is the basis for the technical design.[11] 2-Spi-
roquinazolinones are an important class of fused heterocy-
cles that have attracted significant interest in medicinal
chemistry, in view of their great variety of biological and
pharmaceutical activities.[
12]
Moreover, they are key inter-
(
2) at room temperature in aqueous medium (Method A).
mediates for the synthesis of cycloalkanone-2-carbox-
[
13]
[14]
[15]
It was somewhat surprising that spiroquinazoline 3 started
to precipitate from a stirred, stoichiometric mixture of 1
and 2 in water at room temperature after about 15 min
Scheme 1). Compound 3 was isolated in high yield the next
day by simple filtration.
We next investigated this cyclization under solventless
conditions. After equivalent amounts of 1 and 2 had stirred
amides,
acridin-9-ones,
cis-3-azacepham analogues
[16]
and 1β-methylcarbapenem derivatives.
It has been re-
[
17]
ported
that the room-temperature treatment of anthra-
(
nilamide with cyclohexanone or cyclopentanone in ethanol
saturated with hydrogen chloride allows facile synthesis of
spiro[cycloalkane-1,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-ones. The
for 15 min, the initially heterogeneous reaction changed
[
[
a] Institute of Pharmaceutical Chemistry, University of Szeged,
Eötvös utca 6, 6720 Szeged, Hungary
Fax: +36-62-545-705
[24]
into a honey-like paste;
when left to stand for 2 d, this
resulted in crystalline 3 in 98–100% purity (Method B). Nu-
merous ways have been described in the literature to synthe-
size 3 from 1 and 2. A survey of some of the most useful
classical and modern methods for the preparation of
E-mail: fulop@pharm.u-szeged.hu
b] Stereochemistry Research Group of the Hungarian Academy of
Sciences
Eötvös utca 6, 6720 Szeged, Hungary
Eur. J. Org. Chem. 2010, 959–965
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
959

F. Miklós, F. Fülöp
FULL PAPER
Under solventless conditions, 5a, the cis-hexahydro de-
rivative of 3Ј,5Ј,6Ј,7Ј-tetrahydro[cyclohexane-1,2Ј-cyclopen-
[
31]
[25]
ta[d]pyrimidin]-4Ј(1ЈH)-one,
and 5b
were obtained
quantitatively.
It was recently reported that diendo-methylene- and di-
exo-epoxy-bridged tetrahydrospiroquinazolinones were pre-
pared from the corresponding 2-aminocarboxamides with
cycloalkanones in boiling ethanol without the use of any
Scheme 1.
[
32]
catalyst.
To extend those results, diexo-3-aminonorbornene-2-carb-
oxamide (6a) and ketones 2–2e were reacted under the
heterocycle 3 is presented in Table 1. Additionally, a com-
parison is made between the reaction conditions of known
procedures and our current synthetic approach.
“dry” conditions to give 2,2Ј-disubstituted quinazolinones
7a–f (Table 2).
Table 1. Synthesis of spiro[cyclohexane-1,2Ј(1ЈH)-quinazolin]-
Table 2. Solventless synthesis of diexo-2,2Ј-disubstituted quinazol-
inones 7a–f from 3-aminocarboxamide 6a with ketones 2–2e.
4
Ј(3ЈH)-one (3) from cyclohexanone (2) and anthranilamide (1)
(
Scheme 1).
In view of these interesting results and the relatively
[
25]
small numbers of reports describing the spirocyclization
[
26–28]
of saturated or partially saturated anthranilamides
with (cyclo)alkanones, we studied the condensation of cis-
[29]
hexahydroanthranilamide (4b)
and its cyclopentane
In all cases, during conventional magnetic stirring, con-
densation was carried out in a closed system to avoid the
escape of 2–2e. For the preparation of quinazolinones 7d–
f, alkanones 2c–e were applied in 100% excess, while cyclo-
alkanones 2–2b were used in equimolar amounts. The ex-
cess amounts of volatile reagents 2c–e were removed by
evaporation. Reactions were complete in 2 d at room tem-
perature, except for 7f, which was formed in a yield of 98%
in 10 d. It is noteworthy that when the same reaction condi-
tions were applied to the cyclization of the solid starting
compounds, that is, 6a and cyclooctanone or cyclododeca-
[
30]
homologue 4a with 2 (Scheme 2).
Scheme 2.
960
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 959–965

“Dry” and “Wet” Green Synthesis of 2,2Ј-Disubstituted Quinazolinones
none, no product was obtained. In the solid–solid system,
the condensations proceeded much more slowly than in the
liquid–solid system.[
5f]
On the other hand, it was observed that the solventless
spirocyclization of cyclohexanone (2) with diendo stereoiso-
mer 6b proceeded to afford methylene-bridged spiro com-
pound 8 in high yield after 2 d, as shown in Scheme 3.
Scheme 4.
Scheme 3.
Scheme 5.
It is presumed that the cyclizations of α- and β-amino-
amides with ketones under either aqueous or solventless
conditions take place without the formation of a Schiff azolinones 12a and 12c. After several days, the NMR spec-
[
33]
base; the intermediate carbinolamines (hemiaminals) are troscopic data indicated that the unsolidified mixture of 6a
[
38]
transformed into the 2,2Ј-disubstituted quinazolinones di- or 6c with N-benzylpiperidin-4-one (11) contained diexo-
rectly by the elimination of water. Under virtually dry con- methylene-bridged spiropiperidines in yields of not more
ditions, the presence of moisture and other impurities in the than ca. 50%. As the reactions of water-insoluble organic
[
24]
starting reagents,
and the continuously increasing compounds in aqueous suspensions have recently received
[
39]
amount of water formed as a byproduct, appear likely to a great deal of attention, and because of the special prop-
[
40]
promote the formation of the tetrahedral carbinolamine in- erties of water as compared with those of commonly em-
[
34]
termediate.
In many reactions, significant rate enhance- ployed organic solvents, we decided to attempt to prepare
ments were observed in water as compared with organic 12a and 12b in aqueous medium (Scheme 6).
solvents. This acceleration has been attributed to many fac-
tors, including the hydrophobic effect, enhanced hydrogen
bonding in the transition state and the cohesive energy den-
[
35]
sity of water.
Following the above studies, we investigated the additive
effect of water in the slower condensation of 6a and 2e,
where steric resistance to formation of the carbinolamine
probably occurs. In the presence of a stoichiometric amount
of water, cyclization of amide 6a with diethyl ketone (2e) at
room temperature was complete in 6 d, giving rise to 7f in
a yield of 96%. It is important that the addition of either
substoichiometric (0.5 equiv.) or superstoichiometric (3 or
Scheme 6.
1
0 equiv.) amounts of water to the reaction mixture of 6a
and 2e did not lead to a beneficial effect on the reaction or diexo-3-amino-N-methylbicyclo[2.2.1]hept-5-ene-2-carb-
rate. oxamide (6c) was dissolved in water and N-benzylpiperidin-
diexo-3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxamide (6a)
In marked contrast with the latter observations, the for- 4-one (11) was added dropwise. During stirring at room
mation of tricyclic compounds 7d–f was accelerated in the temperature, spiropiperidine derivative 12a or 12b started
presence of a large excess of water. The reactions of to precipitate in about 30 min. After stirring for 24 h at am-
2.5 mmol of 6a with 5 mmol of 2c, 2d (solubility in water bient temperature, the precipitated diexo-methylene-bridged
at 20 °C 292 g/1000 mL) or 2e (solubility in water 50 g/ tetrahydro-2Ј,2ЈЈ-disubstituted quinazolinones were isolated
1
7
000 mL) “in” or “on” 5 mL of water gave quinazolinones by simple filtration. Under neutral conditions, the corre-
d–f in excellent yields and purities (Scheme 4). sponding spiropiperidones were obtained in yields of 78–
To investigate the limit of the solventless condensation/ 88%.
cyclization, we explored the above-mentioned strategies in
All of the 2,2Ј-disubstituted quinazolinones, 1,4-diaza-
the reaction of 2 with glycinamide (7)[ (Scheme 5).
36]
spiro[4.5]decane-2-one were characterized by IR,
[23,41] 1
H
[
23,42–46]
13
From the “dry” reaction mixture of commercially avail- NMR
and C NMR spectroscopy and elemental
able 2 and 9, a solid product, 1,4-diazaspiro[4.5]decan-2- analyses. 13C NMR spectroscopic data were in agreement
[
37]
13
one (10), was obtained in high yield in 3 days.
with literature data; compounds gave a C signal at 66–
Accordingly, the generality of the solvent-free reactions 78 ppm for a quaternary C-2. This shift appears reasonable
[19a]
was investigated for the synthesis of spiropiperidine–quin- for a –NHCR NH– system, where R is an alkyl group.
2
Eur. J. Org. Chem. 2010, 959–965
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
961

F. Miklós, F. Fülöp
FULL PAPER
2
4 h (7f) in a round-bottomed flask (25 mL) sealed with a teflon
Conclusions
cap, quinazolinones 7d–f precipitated. These were filtered off,
In conclusion, green approaches have been devised for washed with water (5 mL) and dried upon a porous plate at 100 °C.
the preparation of synthetically and pharmaceutically rel-
evant 2,2Ј-disubstitutedquinazolinones and spiropiper-
diexo-2,2Ј-Dimethyl-5,8-methano-2,3,4a,5,8,8a-hexahydroquinaz-
olin-4(1H)-one (7d): Yield: 0.36 g (75%). Colourless powder. M.p.
idines. In the presence of moisture and impurities in the
starting compounds, the solventless condensations of carb-
oxamides 4a, 4b, 6a, 6b and 9 with (partially) water-solu-
ble alkanones 2c–e or slightly water-soluble (i.e. cyclohex-
anone: 87 g/1000 mL at 20 °C) cycloalkanones 2, 2a and 2b
gave 1,4-diazaspiro[4.5]decan-2-one 10 and quinazolinones
2
2
29–233 °C (H O).
diexo-2-Ethyl-5,8-methano-2Ј-methyl-2,3,4a,5,8,8a-hexahydroquin-
azolin-4(1H)-one/diexo-2Ј-ethyl-5,8-methano-2-methyl-
2,3,4a,5,8,8a-hexahydroquinazolin-4(1H)-one (1:1; 7e): Yield: 0.38 g
(
75%). Colourless powder. M.p. 189–192 °C (H O).
2
diexo-2,2Ј-Diethyl-5,8-methano-2,3,4a,5,8,8a-hexahydroquinazolin-
5a, 5b and 7a–f. At ambient temperature, all of these reac-
4(1H)-one (7f): Yield: 0.38 g (95%). Colourless powder. M.p. 181–
tions, except that of 6a with 2, were complete in 48–72 h
without the need for any catalyst. On application of the
aqueous protocol (Method A) for the preparation of 7d–f,
significantly enhanced reaction rates were observed. From
the less water-soluble (12 g/1000 mL at 20 °C) N-benzylpip-
eridin-4-one (11) and bridged carboxamides 6a and 6b, spi-
1
83 °C (H O).
2
Method B: A mixture of 6a (0.76 g, 5.0 mmol) and ketone 2c, 2d
or 2e (10.0 mmol) was stirred for 15 min in a round-bottomed flask
(
10 mL) sealed with a teflon cap. After standing at room tempera-
ture for 2 d, the excess amount of 2c or 2d was removed by evapora-
tion under reduced pressure, whereas the excess amount of 2e was
ropiperidines 12a and 12c were formed in “on water” reac- evaporated off after 10 d. The purities of 2,2Ј-disubstituted quina-
1
tions. These methods include some important features, such zolinones 7d–f were established by H NMR measurements.
as the solvent-free medium, the use of water as a green sol-
vent and mild reaction conditions. Moreover, the experi-
mental procedures are very easy to carry out.
diexo-2,2Ј-Dimethyl-5,8-methano-2,3,4a,5,8,8a-hexahydroquinaz-
olin-4(1H)-one (7d): Yield: 99%. Colourless powder. M.p. 244–
246 °C. IR (KBr): ν˜ = 3287 (νNH), 3159 (νHNCO), 3062 (ν=CH), 1645
–
1 1
(
ν
CONH), 1573 (νC=C), 710 (ν=CH) cm . H NMR (400 MHz, [D
6
]-
DMSO): δ = 1.14–1.30 (m, 7 H, 2ϫCH and 9-H) 1.56 (d, J =
3
8
7
8
.9 Hz, 1 H, 9-H), 1.78 (d, J = 7.4 Hz, 1 H, 4a-H), 2.02 (d, J =
.9 Hz, 1 H, 1-NH), 2.61 (s, 8-H), 1 H, 3.08 (t, J = 7.4 Hz, 1 H,
a-H), 3.19 (s, 1 H, 5-H), 6.13 (dd, J = 2.8 Hz, J = 5.5 Hz, 1 H, 7-
Experimental Section
General: Melting points were determined with a Kofler apparatus
1
13
and are uncorrected. H NMR (400 Hz) and C NMR (100 MHz)
spectra were recorded with a Bruker Avance DRX 400 spectrome-
H), 6.24 (dd, J = 2.8 Hz, J = 5.5 Hz, 1 H, 6-H), 7.99 (s, 1 H, 3-
13
NH) ppm. C NMR (100 MHz, [D
3.8, 44.3, 47.2, 53.4, 66.5, 135.4, 138.1, 170.7 ppm. C11
192.26): calcd. C 68.72, H 8.39, N 14.57; found C 68.43, H 8.61,
6
]DMSO): δ = 27.5, 29.3, 41.5,
6
ter, with TMS as internal reference and [D ]DMSO as solvent.
4
(
16 2
H N O
FTIR spectra recordings were performed with a Perkin–Elmer 100
FTIR spectrometer. Elemental analyses were carried out with a
Perkin–Elmer 2400 elemental analyzer.
N 14.68.
diexo-2-Ethyl-5,8-methano-2Ј-methyl-2,3,4a,5,8,8a-hexahydroquin-
azolin-4(1H)-one/diexo-2Ј-ethyl-5,8-methano-2-methyl-2,3,4a,5,8,8a-
hexahydroquinazolin-4(1H)-one (1:1; 7e): Yield: 94%. Colourless
powder. M.p. 190–193 °C. IR (KBr): ν˜ = 3294 (νNH), 3166 (νHNCO),
Spiro[cyclohexane-1,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-one (3)
Method A: To a stirred mixture of 1 (1.36 g, 10.0 mmol) in water
(10 mL) was added cyclohexanone (2; 0.98 g, 10.0 mmol) in por-
–
1 1
3
(
CH
9
058 (ν=CH), 1643 (νCONH), 1573 (νC=C), 708 (δ=CH) cm . H NMR
400 MHz, [D ]DMSO): δ = 0.80 and 0.85 (t, J = 7.5 Hz, 3 H, 2-
), 1.14 and 1.19 (s, 1 H, 2-CH ), 1.22 (d, J = 8.7 Hz, 2 H,
CH and 9-H), 1.75 and 1.82 (d, J
= 7.3 Hz, 1 H, 4a-H), 2.04 (br. s, 2 H,1-NH) 2.63 (s, 2 H, 8-H),
.98 and 3.08 (d, J = 7.4 Hz, 1 H, 8a-H), 3.18 (s, 2 H, 5-H), 6.13
m, 2 H, 7-H), 6.24 (m, 2 H, 6-H), 7.85 and 8.04 (s, 1 H, 3-NH)
tions. After vigorous stirring at room temperature for 24 h in a
round-bottomed flask (25 mL) sealed with a teflon cap, spiro com-
pound 3 precipitated. It was filtered off, washed with water (5 mL)
and dried upon a porous plate at 100 °C. Yield: 1.79 g (83%). M.p.
6
2
CH
3
3
-H), 1.40–1.61 (m, 6 H, 2-CH
2
3
O) (ref.[ 225 °C).
17]
2
28–230 °C (H
Method B: Stoichiometric amounts of 1 (1.36 g, 10.0 mmol) and 2
0.98 g, 10.0 mmol) were stirred for 15 min in a round-bottomed
2
2
(
(
13
ppm. C NMR (100 MHz, [D
6.1, 32.8 and 34.4, 39.6 and 39.9, 42.0 and 42.4, 44.9 (2ϫC), 47.8
and 47.9, 53.4 (2 ϫ C), 69.1 and 69.5, 135.9 (2 ϫ C), 138.6 and
38.7, 171.2 and 171.5 ppm. C12 O (206.29): calcd. C 69.87,
6
]DMSO): δ = 7.8 and 9.5, 25.7 and
flask (10 mL) sealed with a teflon cap. After standing at room tem-
2
1
perature for 2 d, the H NMR spectroscopic data on the solidified
product proved the presence of 3 in 98–100% purity. Colourless
powder. M.p. 225–228 °C. IR (KBr): ν˜ = 3367 (νNH), 3173 (νHNCO),
1
18 2
H N
H 8.80, N 13.58; found C 69.63, H 8.61, N 14.38.
647 (νCONH), 1610 (νC=C,Ar), 761 (νC=H,Ar) cm . 1H NMR
–1
1
diexo-2,2Ј-Diethyl-5,8-methano-2,3,4a,5,8,8a-hexahydroquinazolin-
6
(400 MHz, [D ]DMSO): δ = 1.06–1.88 (m, 10 H, 2–6-H), 6.55 (s, 1
4(1H)-one (7f): Yield: 98%. Colourless powder. M.p. 186–188 °C.
H, 1Ј-NH), 6.56–7.62 (m, 4 H, ArH), 7.84 (s, 1 H, 3Ј-NH) ppm.
1
3
IR (KBr): ν˜ = 3293 (νNH), 3196 (ν
), 3061 (ν=CH), 1635
C NMR (100 MHz, [D
2ϫC), 67.9, 114.5, 114.6, 116.5, 127.2, 133.2, 146.8, 163.4 ppm.
O (216.29): calcd. C 72.19; H 7.46; N 12.95; found C
2.25, H 7.62, N 12.81.
6
]DMSO): δ = 20.9 (2ϫC), 24.5, 37.2
HNCO
1 1
–
(
ν
CONH), 1572 (νC=C), 708 (δ=CH) cm . H NMR (400 MHz, [D
6
]-
), 0.82 (t, J =
), 1.22 (d, J = 8.6 Hz, 1 H, 9-H) 1.37–1.59
and 9-H), 1.78 (d, J = 7.2 Hz, 1 H, 4a-H),
.97 (br. s, 1 H, 1-NH), 2.64 (s, 1 H, 8-H), 3.02 (d, J = 7.2 Hz, 1
(
DMSO): δ = 0.77 (t, J = 7.4 Hz, 3 H, 2-CH
.4 Hz, 3 H, 2-CH CH
m, 5 H, 2-CH CH
2 3
CH
13 16 2
C H N
7
7
(
1
2
3
2
3
diexo-2-Ethyl(methyl)-2Ј-ethyl(methyl)-5,8-methano-2,3,4a,5,8,8a-
hexahydroquinazolin-4(1H)-ones (7d–7f)
H, 8a-H), 3.17 (s, 1 H, 5-H), 6.11 (dd, J = 2.9 Hz, J = 5.3 Hz, 1
H, 7-H), 6.24 (dd, J = 3.0 Hz, J = 5.2 Hz, 1 H, 6-H), 7.90 (s, 1 H,
3-NH) ppm. C NMR (100 MHz, [D
Method A: To a stirred solution of 6a (0.38 g, 2.5 mmol) in water
1
3
(5 mL) was added alkanone 2c, 2d or 2e (5.0 mmol) in portions at
6
]DMSO): δ = 7.7, 9.3, 30.2,
room temperature. After vigorous stirring for 5 h (7d), 19 h (7e) or
31.3, 42.8, 44.6, 45.4, 48.5, 53.3, 71.6, 136.2, 139.1, 171.9 ppm.
962
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 959–965

“Dry” and “Wet” Green Synthesis of 2,2Ј-Disubstituted Quinazolinones
1
C
13
H
20
N
2
O (220.32): calcd. C 70.87, H 9.15, N 12.72; found C
spiro compounds 10, 5a and 5b were determined by H NMR mea-
70.63, H 9.01, N 12.68.
surements.
diendo- and diexo-5Ј,8Ј-Methano-4Јa,5Ј,8Ј,8Јa-tetra-hydrospiro-
cycloalkane-1,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-ones (7a–c and 8)
1,4-Diazaspiro[4.5]decan-2-one (10): Yield: 96%. Colourless pow-
der. M.p. 115–118 °C (ref.[
37a]
118–119 °C). IR (KBr): ν˜ = 3279
[
–1 1
(ν
NH), 3186 (νHNCO), 1690 (νCONH) cm . H NMR (400 MHz, [D
6
]-
Method B: Stoichiometric amounts of 6a or 6b (5.0 mmol) and cy-
cloalkanone 2, 2a or 2b (5.0 mmol) were stirred for 15 min in a
round-bottomed flask (10 mL) sealed with a teflon cap. After
standing at room temperature for 2 d, the purities of solidified 2-
DMSO): δ = 1.19–1.59 (m, 10 H, 5–9-H), 2.81 (br. s, 1 H, 3-NH),
13
3
.14 (s, 2 H, 3-H), 8.33 (s, 1 H, 1-NH) ppm. C NMR (100 MHz,
]DMSO): δ = 22.3 (2 ϫ C), 24.7, 37.6 (2 ϫ C), 48.2, 75.1,
75.3 ppm. C O (154.21): calcd. C 62.31, H 9.15, N 18.17;
[
D
6
1
8 14 2
H N
1
spiroquinazolinones 7a–c and 8 were determined by H NMR mea-
found C 62.01, H 9.02, N 18.45.
surements.
cis-Hexahydrospiro[cyclohexane-1,2Ј-cyclopenta[d]pyrimidin]-
diexo-5Ј,8Ј-Methano-4Јa,5Ј,8Ј,8Јa-tetrahydrospiro[cyclohexane-
4
Ј(1ЈH)-one (5a): Yield: 97%. Colourless powder. M.p. 195–197 °C.
1
,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-one (7a): Yield: 99 %. Colourless
–1 1
IR (KBr): ν˜ = 3263 (νNH), 3166 (νHNCO), 1651 (νCONH) cm . H
NMR (400 MHz, [D ]DMSO): δ = 1.04–1.74 (m, 13 H, 2–6-H and
Ј-7Ј-H), 1.74 (d, J = 9.6 Hz, 1 H, 1Ј-NH), 1.80–2.02 (m, 3 H, 5Ј
and 7Ј-H), 2.22 (m, 1 H, 4Јa-H), 3.44 (m, 1 H, 7Јa-H), 7.58 (s, 1
powder. M.p. 232–234 °C. IR (KBr): ν˜ = 3298 (νNH), 3164 (νHNCO),
6
–
1 1
3
058 (ν=CH), 1668 (νCONH), 1572 (νC=C), 701 (δ=CH) cm . H
NMR (400 MHz, [D ]DMSO): δ = 1.23 (d, J = 9.0 Hz, 1 H, 9Ј-H),
.10–1.82 (m, 11 H, 2–6-H and 9Ј-H), 1.79 (d, J = 6.8 Hz, 1 H,
5
6
1
4
6
5
7
2
1
1
13
H, 4Ј-NH) ppm. C NMR (100 MHz, [D
4.0, 26.0, 30.1, 34.2, 36.4, 39.3, 44.8, 52.0, 69.5, 172.7 ppm.
O (208.31): calcd. C 69.19, H 9.68, N 13.45; found C
9.18, H 9.48, N 13.55.
6
]DMSO): δ = 22.3, 22.9,
aЈ-H), 1.87 (br. s, 1 H, 1-NH), 2.66 (s, 1 H, 8Ј-H), 2.99 (d, J =
.8 Hz, 1 H, 8Јa-H), 3.19 (s, 1 H, 5Ј-H), 6.13 (dd, J = 2.8 Hz, J =
.4 Hz, 1 H, 7Ј-H), 6.23 (dd, J = 2.7 Hz, J = 5.4 Hz, 1 H, 6Ј-H),
]DMSO): δ =
1.2, 22.1, 25.0, 35.7, 37.3, 42.0, 43.8, 44.4, 47.2, 52.6, 68.0, 135.6,
38.0, 170.9 ppm. C14 O (232.33): calcd. C 72.38, H 8.68, N
2.06; found C 72.60, H 8.91, N 12.15.
2
12 20 2
C H N
6
.89 (s, 1 H, 3Ј-NH) ppm. 13C NMR (100 MHz, [D
6
cis-Hexahydrospiro[cyclohexane-1,2Ј(1ЈH)-quinazolin]-4Ј(1ЈH)-one
[
25b]
(
5b): Yield: 99 %. Colourless powder. M.p. 150–152 °C (ref.
20 2
H N
1
48–149 °C). IR (KBr): ν˜ = 3254 (νNH), 3168 (νHNCO), 1646
–
1 1
(
ν
CONH) cm . H NMR (400 MHz, [D
6
]DMSO): δ = 1.02–1.71 (m,
diexo-5Ј,8Ј-Methano-4Јa,5Ј,8Ј,8Јa-tetrahydrospiro[cyclopentane-
,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-one (7b): Yield: 99 %. Colourless
powder. M.p. 239–241 °C. IR (KBr): ν˜ = 3282 (νNH), 3155 (νHNCO),
17 H, 2–6-H and 5Ј-8Ј-H), 1.79 (d, J = 12.9 Hz, 1 H, 1Ј-NH), 1.91
1
(
(
dt, J = 4.2 Hz, J = 11.8 Hz, 1 H, 4Јa-H), 2.01 (m, 1 H, 5Ј-H), 3.13
m, 1 H, 8Јa-H), 7.40 (s, 1 H, 4Ј-NH) ppm. C NMR (100 MHz,
13
–
1 1
3
058 (ν=CH), 1641 (νCONH), 1572 (νC=C), 708 (δ=CH) cm . H
NMR (400 MHz, [D ]DMSO): δ = 1.23 (d, J = 8.6 Hz, 1 H, 9Ј-H),
.38–1.69 (m, 7 H, 2–5-H and 9Ј-H), 1.69–1.92 (m, 2 H, 2–5-H),
.76 (d, J = 7.4 Hz, 1 H, 4aЈ-H), 2.10 (br. s, 1 H, 1-NH), 2.63 (s, 1
[D
6
]DMSO): δ = 20.6, 22.6, 23.1, 25.6, 25.9, 26.0, 30.6, 37.0, 40.6,
6
4
3.3, 45.3, 69.2, 173.5 ppm. C13 O (222.33): calcd. C 70.23,
22 2
H N
1
1
H 9.97, N 12.60; found C 69.98, H 9.68, N 12.55.
diexo-1-Benzyl-(3Ј-methyl)-5Ј,8Ј-methano-4Јa,5Ј,8Ј,8Јa-tetrahydro-
spiro[piperidine-4,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-ones (12a and 12b):
To a stirred solution of β-aminocarboxamide 6a or 6c (5.0 mmol)
in water (10 mL) was added 1-benzyl-4-piperidinone (11; 0.95 g,
H, 8Ј-H), 3.05 (d, J = 7.4 Hz, 1 H, 8Јa-H), 3.20 (s, 1 H, 5Ј-H), 6.14
dd, J = 2.7 Hz, J = 5.6 Hz, 1 H, 7Ј-H), 6.24 (dd, J = 2.7 Hz, J =
.6 Hz, 1 H, 6Ј-H), 8.12 (s, 1 H, 3Ј-NH) ppm. 13C NMR (100 MHz,
]DMSO): δ = 21.9, 23.3, 37.3, 38.5, 41.9, 43.8, 44.3, 47.1, 53.8,
7.0, 135.6, 137.9, 171.1 ppm. C13 O (218.30): calcd. C 71.53,
(
5
[D
6
5.0 mmol) in portions at room temperature. After vigorous stirring
7
18 2
H N
for 24 h in a round-bottomed flask (25 mL) sealed with a teflon
cap, product 12a or 12b precipitated. It was filtered off, washed
with water (10 mL) and dried upon a porous plate at 100 °C.
H 8.31, N 12.83; found C 71.60, H 8.11, N 12.75.
diexo-5Ј,8Ј-Methano-4Јa,5Ј,8Ј,8Јa-tetrahydrospiro[cycloheptane-
1,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-one (7c): Yield: 98%. Colourless pow-
diexo-1-Benzyl-5Ј,8Ј-methano-4Јa,5Ј,8Ј,8Јa-tetrahydrospiro[piper-
idine-4,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-one (12a): Yield: 1.42 g (88%).
der. M.p. 212–214 °C. IR (KBr): ν˜ = 3303 (νNH), 3158 (νHNCO),
061 (ν=CH), 1634 (νCONH), 1569 (νC=C), 695 (δ=CH) cm 1. 1H
NMR (400 MHz, [D ]DMSO): δ = 1.22 (d, J = 8.9 Hz, 1 H, 9Ј-H),
.38–1.75 (m, 13 H, 2–7-H and 9Ј-H), 1.76 (d, J = 6.8 Hz, 1 H,
–
3
Colourless powder. M.p. 225–228 °C (H
2
O). IR (KBr): ν˜ = 3301
6
(
(
ν
γ
NH), 3172 (νHNCO), 3059 (ν=CH), 1635 (νCONH), 1573 (νC=C), 734
=CH,Ar), 701 (δ=CH) cm . H NMR (400 MHz, [D ]DMSO): δ =
6
1
4
7
5
7
2
1
9
–
1 1
aЈ-H), 1.83 (br. s, 1 H, 1-NH), 2.64 (s, 1 H, 8Ј-H), 3.00 (d, J =
.0 Hz, 1 H, 8Јa-H), 3.19 (s, 1 H, 5Ј-H), 6.13 (dd, J = 2.6 Hz, J =
1
1
.23 (d, J = 8.9 Hz, 1 H, 9Ј-H), 1.43–1.54 (m, 2 H, 3-H and 5-H),
.56 (d, J = 8.7 Hz, 1 H, 9Ј-H), 1.68–1.94 (m, 2 H, 3-H and 5-H),
.6 Hz, 1 H, 7Ј-H), 6.23 (dd, J = 2.6 Hz, J = 5.6 Hz, 1 H, 6Ј-H),
.99 (s, 1 H, 3Ј-NH) ppm. 1 C NMR (100 MHz, [D
3
1.78 (d, J = 7.6 Hz, 1 H, 4aЈ-H), 1.87 (d, J = 9.9 Hz, 1 H, 1Ј-NH),
6
]DMSO): δ =
2.22–2.57 (m, 4 H, 2-H and 6-H), 2.66 (s, 1 H, 8Ј-H), 2.99 (t, J =
8.3 Hz, 1 H, 8Јa-H), 3.20 (s, 1 H, 5Ј-H), 3.44 (s, 2 H, benzyl-H),
6.13 (dd, J = 2.9 Hz, J = 5.6 Hz, 1 H, 7Ј-H), 6.23 (dd, J = 2.9 Hz,
1.2, 21.4, 28.9, 29.0, 38.6, 41.7, 42.0, 43.8, 44.4, 47.3, 53.1, 72.1,
35.6, 138.1, 171.0 ppm. C15 O (246.36): calcd. C 73.13; H
.00; N 11.37; found C 72.90, H 8.81, N 11.55.
22 2
H N
J = 5.6 Hz, 1 H, 6Ј-H), 7.19–7.33 (m, 5 H, Ar-H), 7.93 (s, 1 H, 3Ј-
1
3
diendo-5Ј,8Ј-Methano-4Јa,5Ј,8Ј,8Јa-tetrahydrospiro[cyclohexane-
,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-one (8): Yield: 97%. Colourless pow-
NH) ppm. C NMR (100 MHz, [D ]DMSO): δ = 35.1, 36.7, 42.0,
6
1
43.8, 44.4, 47.1, 48.5, 49.3, 52.5, 61.9, 66.6, 126.7, 128.1 (2ϫC),
[32]
der. M.p. 240–243 °C (ref. 243–244 °C). The analytical and spec-
128.7 (2ϫC), 135.6, 138.0, 138.7, 171.0 ppm. C H N O (323.44):
2
0
25
3
troscopic data on 8 were identical to those in the literature.[
32]
calcd. C 74.27, H 7.79, N 12.99; found C 74.38, H 7.58, N 12.65.
1
,4-Diazaspiro[4.5]decan-2-one (9) and cis-Hexahydrospiro[cyclo-
diexo-1-Benzyl-3Ј-methyl-5Ј,8Ј-methano-4Јa,5Ј,8Ј,8Јa-tetrahydro-
spiro[piperidine-4,2Ј(1ЈH)-quinazolin]-4Ј(3ЈH)-one (12b): Yield:
hexane-1,2Ј-cycloalka[d]pyrimidin]-4Ј(1ЈH)-ones (5a and 5b): Stoi-
chiometric amounts of 4a, 4b or glycinamide 9[ (5.0 mmol) and
cyclohexanone (2; 0.49 g, 5.0 mmol) were stirred for 15 min in a
round-bottomed flask (10 mL) sealed with a teflon cap. The reac-
tion mixture of 4a or 4b and 2 was left to stand at room tempera-
ture for 2 d, and that of 9 and 2 for 3 d. The purities of solidified
36]
1.31 g (78%). Colourless powder. M.p. 162–164 °C (H
2
O). IR
(KBr): ν˜ = 3316 (νNH), 3061 (ν=CH), 1617 (νC=O), 1572 (νC=C), 746
–
1 1
6
(γ=CH,Ar), 701 (δ=CH) cm . H NMR (400 MHz, [D ]DMSO): δ =
1.22 (d, J = 8.8 Hz, 1 H, 9Ј-H), 1.54–1.78 (m, 4 H, 3-H, 5-H and
9Ј-H), 1.81 (d, J = 7.2 Hz, 1 H, 4aЈ-H), 1.96 (d, J = 10.2 Hz, 1 H,
Eur. J. Org. Chem. 2010, 959–965
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
963

F. Miklós, F. Fülöp
FULL PAPER
1
Ј-NH), 2.05–2.65 (m, 5 H, 2-H, 6-H and 3-H), 2.71 (s, 1 H, 8Ј- [10] a) G. Kaupp, J. Schmeyers, J. Boy, Tetrahedron 2000, 56, 6899;
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3
b) G. Kaupp, Top. Curr. Chem. 2005, 254, 91; c) G. Kaupp,
CrystEngComm 2003, 5, 117.
H, 5Ј-H), 3.46 (s, 2 H, benzyl-H), 6.14 (dd, J = 2.4 Hz, J = 5.2 Hz,
H, 7Ј-H), 6.24 (dd, J = 2.5 Hz, J = 5.3 Hz, 1 H, 6Ј-H), 7.18–7.38
[
[
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1
3
(
3
1
m, 5 H, Ar-H) ppm. C NMR (100 MHz, [D
6
]DMSO): δ = 26.6,
0.3, 34.6, 42.5, 43.8, 45.3, 47.2, 49.1, 49.3, 51.1, 61.9, 71.3, 126.8,
28.1 (2ϫC), 128.8 (2ϫC), 135.7, 138.0, 138.7, 170.0 ppm.
O (337.47): calcd. C 74.74, H 8.06, N 12.45; found C
4.39, H 7.78, N 12.65.
21 27 3
C H N
7
Acknowledgments
We are grateful to the Hungarian Research Foundation (OTKA
Nos. K75433 and T049407) for financial support.
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Received: September 14, 2009
Published Online: December 22, 2009
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