An unusual polyheterocyclic diversity by the π-cyclisation of N-carbamoyliminium ion, with or without tandem N,N-acetal cleavage, from spiro(imidazolidinoquinazolinones)

Article abstract of DOI:10.1055/s-2008-1067032

Spiro(imidazolidinoquinazolinones), obtained easily in one step from 1-carbamoylisatins, are readily converted in three steps by successive N-alkylations and sodium borohydride regio-selective reduction into the corresponding hydroxyspirolactams. The latt

Full text of DOI:10.1055/s-2008-1067032

PAPER
1389
An Unusual Polyheterocyclic Diversity by the p-Cyclisation of N-Carbamoyl-
iminium Ion, with or without Tandem N,N-Acetal Cleavage, from Spiro(imi-
dazolidinoquinazolinones)
p
-Cyclisation of
N
n
-Carbamoyli
t
minium
h
Ions from
S
o
piro(imidazo
n
lidinoquinaz
y
olinones) Pesquet,a Adam Daïch,*a Servane Coste,b,1 Luc Van Hijftec
a
URCOM, EA 3221, UFR-ST de l'Université du Havre, 25 rue Philippe Lebon, B.P. 540, 76058 Le Havre Cedex, France
Fax +33(2)32744391; E-mail: adam.daich@univ-lehavre.fr
b
c
UC2M2 - IRCOF, SMS/UPRES, EA 3233, Université de Rouen, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France
Johnson & Johnson, Division of Janssen-Cilag, Campus de Maigremont, B.P. 615, 27106 Val-de-Reuil Cedex, France
Received 9 January 2008
R1
N
Bn
N
Abstract: Spiro(imidazolidinoquinazolinones), obtained easily in
one step from 1-carbamoylisatins, are readily converted in three
steps by successive N-alkylations and sodium borohydride regio-
selective reduction into the corresponding hydroxyspirolactams.
The latter are valuable platforms for further transformations via the
intermediacy of N-acyliminium species and have been applied to
the synthesis of original isoquinoloquinazoline, indoloquinazoline
and imidazoindole derivatives.
X = CH2, S
n = 0, 1 ; m = 0, 2
n
Ar
O
O
N
R1
N
X
m
Bn
Ar
c
Bn
O
IV
III
a
N
a
a
b
N
R1
O
O
R1
n
R1
N
Key words: p-cyclisation, cleavage, N-acyliminium ion, hydroxy
lactam, reduction, imidazolidine, quinazolinone
N
N
Bn
A
N
Bn
OH
Ar
m
Ar
II
OH
Ar = Ph, pyrrole
1 = H, Bn
X
R
The quinazolinone skeleton is a frequently encountered
heterocycle in many alkaloids2 and synthetic structures
showing many types of pharmaceutical activities as dem-
onstrated in recent exhaustive reviews.2,3 Aromatic
quinazolines have been shown to possess tyrosine kinase
inhibiting effects,4 are useful to inhibit tumour growth,
and exhibit other biological profiles including antiepilep-
tic and anticonvulsant activity.5 Others have also been
used, for example, in the treatment of tuberculosis6 as well
as benign prostatic hyperplasia.7 More importantly, sub-
stituted 3,4-dihydro-2(1H)-quinolinones have induced di-
rect inhibition of the Na+-dependant Ca2+ influx via the
Na+/Ca2+ exchanger in cardiomyocytes with high potency
and exerted a protective effect against myocardial ischem-
ic reperfusion injury.8 As a consequence, these scaffolds
are considered to be privileged structures for drug devel-
opment, and have accelerated the quest for new ring syn-
thesis methods.
In a recent contribution,9 we have reported a novel ap-
proach to the synthesis of 4,5-fused imidazolidin-2-ones
III and IV (Scheme 1) based on the action of TFAA–TFA
combination on properly substituted a-hydroxylactams I
and II derived from spirohydantoins. The key step of this
sequential reaction is based on the formation of the cyclic
N-acyliminium intermediate A, from which a transposi-
tion of the electronically rich group resulted in ring expan-
sion leading to a stable cyclic cation. The latter ultimately
loses one proton spontaneously to give the expected 4,5-
I
Scheme 1 Retrosynthetic scheme leading to 4,5-fused imidazoli-
din-2-ones III and IV via N-acyliminium chemistry
fused tricyclic and tetracyclic imidazolidin-2-ones. Dur-
ing these investigations, we have demonstrated also that
the tandem process seems to be easy, general, regiospecif-
ic and resulted in the formation of polyheterocyclic sys-
tems containing an imidazolidin-2-one nucleus in good to
excellent yields (67–99%).
While spirohydroxylactams of types I and II substituted at
the angular carbon C(5) with alkyl, arylalkyl, and aryl, de-
rived from spirohydantoin systems have been widely syn-
thesised and their behaviour in acid medium towards
intermolecular and intramolecular a-amidoalkylation
studied,9,10 heteroaryl spirohydroxylactams have not so
far been explored.
In this context and with our interest in the development of
synthetic methodologies toward original aza-heterocyclic
systems containing a quinazolinone ring fused to polycy-
clic skeletons with promising pharmaceutical properties,
we have chosen to explore hydroxylactams of type 1, de-
rived from spiro(imidazoloquinazolinones) (Scheme 2).
In particular, certain spiro(imidazoloquinazolinones) be-
longing to the quinazolinone family have been found to be
highly potent as aldose reductase inhibitors,11 but for ob-
scure reasons no additional intensive work has been done
on these spiro-systems since their discovery.
These substrates were chosen for the following reasons: 1)
no investigations using N-acyliminium ion chemistry
have been performed on this class of compounds; 2) the
results obtained in this study, could answer questions
SYNTHESIS 2008, No. 9, pp 1389–1396
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1067032; Art ID: Z01208SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

1390
A. Pesquet et al.
PAPER
yields of 49% and 47%, respectively, while 7c was iso-
lated in acceptable yield (66%). Using the published condi-
tions, we never isolated either 7a or 7b in yields indicated
by the authors or the relevant papers, which were of 69%
and 72%, respectively. The installation of the benzyl
group at the hydantoin N(1¢)-position of 7a–c was accom-
plished regiospecifically. Interestingly, since these kind
of substrates have three possible points of diversity, a
thorough study of the effects of solvent and base on regio-
selective N-alkylation of spiro(imidazoloquinazolinones)
has been discussed in different papers.15,17,18 After certain
optimisation work taking into account these consider-
ations, we have found that the best combination with
which to accomplish this reaction seems to be the use of
ethanolic potassium hydroxide at reflux for four hours.
Under these conditions, the N(1¢)-benzyl spirohydantoins
8a and 8c, being poorly soluble, crystallised out from the
solution while 8b, as an oily material, could not be isolat-
ed in pure form and decomposed slowly after a few days.
The pure crystalline products 8a and 8c were isolated with
moderate yields of 46% and 47%, however, the yield
could be increased to 87% and 91%, respectively, by add-
ing the solids obtained from the precipitation observed
during the process as well as those obtained after the usual
work-up of the filtrate liquor containing also these prod-
ucts. Next, methylation at both the N(1)- and N(3¢)-posi-
tions of N-benzyl spirohydantoins 8a–c was achieved
successfully in moderate to excellent yields under PTC
conditions (anhydrous K2CO3 as a base and a mixture of
KI and 18-crown-6 as catalysts in anhydrous toluene at re-
flux for 24 h). Because of the difficulty encountered dur-
ing the isolation of the starting N-benzyl derivative 8b, the
alkylated product 9b was isolated as a crystalline solid af-
ter chromatographic separation in 51% yield calculated in
two steps from spirohydantoin 7b.
O
other
processes
via the
Bn and R
groups
O
N
N
N
N
N
N
Bn
?
Bn
N
OH
N
R
O
R
1
O
N-transposition
N
C-transposition
R
ion N-acyliminium
intermediate B
O
N
N
O
O
N
N
N
N
N
Bn
Bn
R = Bn, Ph, n-Pr
O
R
a
b
c
2
3
Scheme 2 N-Acyliminium intermediate B used as a novel platform
from which to access new and original scaffolds
raised during the synthesis of 4,5-fused imidazolidin-2-
ones reported earlier by us;9 and 3) as highlighted in
Scheme 2, the selection of different substituents (R = Bn,
Ph and n-Pr) at one nitrogen atom of the quinazoline ring
allows consideration of the stable N-acyliminium species
B. This would act as an aryl group or nitrogen atom scav-
enger after their transposition to provide interestingly sub-
stituted imidazobenzo[1,3]diazepines 2 or 3. In addition,
if the R group or the benzyl (Bn) acts as an internal nu-
cleophile, the process would produce original polyhetero-
cyclic systems such as fused quinazolinones that are
difficult to obtain through traditional approaches.
This study also constitutes a continuation of our efforts to-
wards the exploration of the synthetic opportunities arris-
ing from our previous studies on N-acyliminium
cyclisation in tandem with Grignard reaction,12 Pummerer
cyclisation,13 N-acyliminium ion isomerisation,14 and N-
acyliminium ion isomerisation/double alkyl transposi-
tion.15
The polyalkylated spirohydantoins 9a–c were then sub-
mitted to the reduction reaction to obtain the correspond-
ing 5¢-hydroxylactams 1a–c as the N-acyliminium cation
precursors (Scheme in Table 1). According to our reports
in this field,9,15 the reduction of spirohydantoins 9a–c was
carried out with a large excess of sodium borohydride (6
equiv) in anhydrous ethanol at reflux for 6–48 hours (the
reaction was monitored by TLC) to easily provide the ex-
pected hydroxyspirolactams 1a–c in 82–98% yields after
recrystallisation from ethanol.
Our study started with the synthesis of hydroxyspirolac-
tams 1a–c substituted at the N(3)-position of the quinazo-
line skeleton (Table 1). These substrates were prepared in
order to measure the impact of the substituent group on
both the reduction reaction as well as the cyclisation step
of these N-acyliminium precursors. The synthesis was
easily accomplished in five steps from the commercially
available isatin (4) and isocyanate derivatives 5a–c using
standard procedures.
Thus, the treatment of isatin (4) with isocyanates 5a–c ac-
cording to the protocol reported by Yamagishi et al.,16 re-
sulted in the installation of different substituents at the
N(3)-position. Products 6a (R = Bn) and 6b (R = Ph)
were described earlier,16,17 6c (R = n-Pr), as a new com-
pound, was isolated in 68% yield after purification by re-
All hydroxyspirolactams 1a–c were obtained as solids and
their structure assignments were made on the basis on
their IR, NMR (1H and 13C experiments including NOE
difference and DEPT Programs, respectively) as well as
1
elemental analysis. For instance, in the H NMR spectra
of hydroxyspirolactams 1a–c, the methylene protons of
the lateral functionality [N(1¢)CH2Ph; see Table 1 for the
structure numbering] appeared as an AB system with
chemical shifts at d = 4.02, 4.25, 4.13 ppm for pseudo
equatorial and d = 4.82, 4.62, 4.79 ppm for pseudo axial
protons, respectively. They also appeared as an AB sys-
tem in spirohydantoin 9a at d = 4.58 and 4.70 ppm (J = 14
Hz) but appeared as singlets in N(1¢)-benzyl spirohydan-
crystallisation
from
ethanol.
The
3-alkylated
spiro[imidazolidine-4¢,4(1H)-quinazoline]-2¢,2,5¢-triones
7a–c were then obtained by reaction of 6a–c with 2-ethyl-
2-isothiourea hydrobromide and triethylamine followed
by heating at 80 °C with 10% hydrochloric acid. The
products 7a and 7b were identical to those reported in the
literature16,17 (Table 1), and were isolated in moderate
Synthesis 2008, No. 9, 1389–1396 © Thieme Stuttgart · New York

PAPER
p-Cyclisation of N-Carbamoyliminium Ions from Spiro(imidazolidinoquinazolinones)
1391
Table 1 Five-Step Sequence Leading to Spirohydroxylactam Precursors of N-Acyliminium Species 1a–c
Product index
R
7, Yield (%)
8, Yield (%)
9, Yield (%)
Hydroxylactams 1
Time (h)
Yield (%)
a
b
c
Bn
49a
47a
66
46 (up to 87%)b
61
7
82
98
82
a,c
Ph
–
51d
>99
48
6
n-Pr
47 (up to 91%)b
a These products are reported in the literature.16,17
b Yields of products formed by precipitation. Yields in brackets correspond to products obtained after complete isolation.
c Spirohydantoin 8b, as an oily material, was not isolated in pure form.
d The yield over two steps starting from spirohydantoin 7b.
toin derivatives 9b and 9c (d = 4.49 and 4.76 ppm) used as of TFAA–TFA in precise equimolar amounts as men-
starting materials. This is due to the presence of a diaste- tioned by us9 and in a few cases by others18a,b [i.e., TFAA–
reotopic effect with a coupling constant of about J = 15 TFA (1:1) with a slight excess (1.3 equiv) of each reactant
Hz in all cases. The spectra also showed two doublets cor- relative to substrate, CH2Cl2, reflux, 24 h], gave the cyc-
responding to the coupling of the angular proton at C(5¢) lised product 10a, identified as 13(8H)-benzyl-5,15-
(d = 4.61, 4.75 and 4.49 ppm) and OH [CH(OH) geminal dimethylimidazo[4¢,5¢:3,4]isoquinolo[3,4-c]quinazoline-
coupling] with classical constants ranging from J = 6 to 6,14-dione, as a crystalline material in 56% yield after
7.8 Hz, which disappeared after D2O exchange. This phe- chromatographic purification. From this result, its seems
nomenon was absent in the spectra of their congener that the reaction occurred by direct attack on the N-
spirohydantoins 9a–c. A confirmation of these structures acyliminium intermediate Ba (Scheme 3) by the p-aro-
also came with their 13C NMR. In the latter, one additional matic system linked to the N(3) of the quinazolinone
ternary carbon C(5¢) appeared to the detriment of a quater- system, to provide the imidazole-fused isoquinolo-
nary carbon in the aromatic region corresponding to the quinazoline product 10a. This product formed via a 6-
carbonyl function in the starting hydantoins 9a–c. From endo-trig process, which was favored over the 5-endo-
these results, it is clear that the reduction reaction oc- trig, which could led to the spiropentacyclic product 11a.
curred regioselectively and cleanly without any traces of Also, in contrast to our first hypothesis highlighted in
by-products in very good yields.
Scheme 2, neither C- nor N-transposition, providing imi-
dazobenzo[1,3]diazepine 2a or 3a, respectively, occurred.
Ultimately, confirmation of the structure of the product
10a was made by an array of mono- and bidimensional
NMR studies. The 1H NMR spectra showed two AB sys-
tems characteristic of the methylene groups with usual
coupling constants of J = 15 and J = 16 Hz and one singlet
at d = 4.69 ppm attributed to the angular proton H(12b).
Furthermore, the 13C NMR and DEPT spectra of 10a were
in accordance with the above considerations since one ad-
ditional quaternary carbon appeared as a consequence of
the p-cyclisation process.
Because no body of literature on hydroxy quinazoline-
spiroimidazolidines regarding the reactivity of these func-
tionalities in acidic medium exists, the behaviour of a-hy-
droxyspirolactams of types 1a, 1b and 1c bearing one (1c)
or two (1a and 1b) nucleophiles was examined under the
influence of acid. For a better comparison of the results,
only the nature of the R group on the N(5)-position of the
quinazoline nuclei in hydoxyspirohydantoin substrates
1a–c was changed.
At the outset of our investigations, the hydroxyspirolac-
tam 1a (R = Bn) was chosen as a test compound for the
amidoalkylation transformation (Scheme 3). Thus, treat-
ment of this N-acyliminium precursor 1a with a mixture
Using the cyclisation protocol delineated in Scheme 3 on
hydroxyspirolactams 1b and 1c proved successful in both
Synthesis 2008, No. 9, 1389–1396 © Thieme Stuttgart · New York

1392
A. Pesquet et al.
PAPER
O
O
O
O
2
+
N
N
3
π-cyclisation
N
N 15
N
N
+
N
N
N
X
π-cyclisation
– H+
12b
N
11
10
12c
N
Ph
O
Ph
– H+
56%
N
N
N
6
N
N
O
N
O
O
O
O
Ba
Ba
10a
11a
–
HN
O
O
N
O
O
N
N
N
N
N
+
N
H
π-cyclisation
acid/base
61%
cleavage
N
N
N
N
N
N
– H+
N
+
O
O
O
10b
Db
Cb
Bb
O
O
N
O
O
N
N
+
N
N
N
N
N
+
N
N
cleavage
acid/base
58%
π-cyclisation
H
H
N
N
N
– H+
N
N
–
N
O
O
O
10c
Dc
Bc
Cc
Scheme 3 Mechanistic considerations of hydroxyspirolactams 1a–c conversion to isoquinoloquinazoline, indoloquinazoline and imidazo-
indole derivatives 10a–c
cases; in each case only one product was obtained with reaction mechanism illustrates two pathways that appear
yields of 61% and 58%, respectively. The products were possible, depending on the substituent
R group
identified as N-(N¢-methylcarboxamido)benzylamino-5- (Scheme 3). The initially formed N-acyliminium cation
methylindolo[1,2-c]quinazolin-6-one (10b) and 8-meth- Ba led to the p-cyclisation product 10a, the cationic spe-
yl-9-o-[N-methyl-N-(N¢-propylcarboxamido)amino]phe-
cies Bb and Bc generated in acidic medium afforded the
nylimidazo[4,3-a]isoindol-7-one (10c). Because neither indoloquinazoline and imidazoindole derivatives 10b and
spectroscopic analyses (1H and 13C NMR and DEPT pro- 10c as the sole reaction products. In both cases, the N-
grams), nor other analytical approaches, proved to be suf- acyliminium ions Bb and Bc undergo p-cationic cyclisa-
ficient to determine the structure of the formed tion via the 5-endo-trig process into the intermediates Cb
polyheterocyclic system exactly, a complementary single- and Cc followed by cleavage of the polycyclic N,N-acetal
crystal X-ray crystallographic analysis was carried out function into the mesoionic tertiary N-acyliminium spe-
(Figure 1). This unambiguously secured the identity of the cies Db and Dc. The observed products 10b and 10c are
product 10b.19
finally formed by tandem acid–base/elimination. During
these transformations, the different ways taken upon N,N-
aminal cleavage to form 10b and 10c could be due to the
constraint of the five-membered ring system being
formed. This result unambiguously confirms the impor-
tant role exerted by the neighbouring R group during the
cyclisation step.
Because no traces of products 2 or 3 were found in the re-
action mixture (examined by TLC at the end of the reac-
tion process before any purification), the suggested
In summary, spirohydantoins 9a–c, obtained through a
three-step sequence by reaction of N-carbamoylisatins
6a–c with 2-ethyl-2-isothiourea, followed by three N-
alkylation processes including, at the outset, one regiospe-
cific benzylation, have been shown to undergo sodium
borohydride reduction to give hydroxyspirolactams 1a–c
in good to excellent yields. The cyclisation of the latter
cyclic N-acyliminium precursors with a TFAA–TFA
combination in precise equimolar proportions, provides a
versatile, short synthesis of two categories of products
10a and 10b,c. The latter were obtained under mild con-
ditions and via an interesting p-cationic cyclisation either
with or without an associated cyclic transposition. The
Figure 1 ORTEP view of the molecular structure of 10b resulting key step of this transformation is based on the formation
from the cyclisation of hydroxy lactam 1b
of the cyclic N-acyliminium intermediates B, from which,
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PAPER
p-Cyclisation of N-Carbamoyliminium Ions from Spiro(imidazolidinoquinazolinones)
1393
Anal. Calcd for C17H14N4O3: C, 63.35; H, 4.38; N, 17.38. Found: C,
63.17; H, 4.22; N, 17.17.
in the case of Ba, the p-attack of the benzyl group led to
the imidazole-fused tetracyclic product 10a. Importantly,
the intermediates Cb and Cc obtained via the classical p-
cyclisation reaction of the phenyl and benzyl groups at-
tached to N(3) and N(1¢), respectively, provides a new
generation of N-amidoyliminium species Db and Dc,
which undergo an acid/base exchange leading to new
classes of products 10b and 10c.
3¢-Phenylspiro(imidazolidine-4,4¢-quinazoline)-2,2¢(1¢H),5-tri-
one (7b)
Obtained from the phenyl isocyanate (5b).
Yield: 47% (Lit.16,17 72%); brown solid; Rf = 0.12 (EtOAc); mp
>300 °C (Lit.16,17 >280 °C).
IR (KBr): 3345 (3 × NH), 1749 (C=O), 1722 (C=O), 1647 (C=O)
cm–1.
Finally, we have developed a new approach and docu-
mented the effectiveness of the readily available spiro(im-
idazoloquinazolinones) to provide useful heterocycles.
This approach capitalises on complementary regioselec-
tive transformations based on the N-acyliminium aryla-
tion allied (or not) with imidazolone or quinazolinone
opening via an interesting and original N,N-aminal func-
tion. The syntheses of more complex polyhydroxylated
targets using these methodologies are under investigation
in our laboratory and the results will be reported soon.
1H NMR (200 MHz, DMSO-d6): d = 6.88–7.07 (m, 2 H, HAr and
NH), 7.20–7.41 (m, 9 H, HAr and NH), 9.98 (br s, 1 H, NH).
13C NMR (50.3 MHz, DMSO-d6): d = 87.0 (Cq), 113.9 (CHAr),
121.4 (CHAr), 126.2 (CHAr), 127.1 (CHAr), 127.3 (2 × CHAr), 128.6
(2 × CHAr), 130.7 (CHAr), 136.2 [Cq(Ar)], 138.6 [Cq(Ar)], 141.8
[Cq(Ar)], 151.2 (C=O), 151.7 [C(2)=O], 170.9 [C(4)=O].
Anal. Calcd for C16H12N4O3: C, 62.33; H, 3.92; N, 18.17. Found: C,
62.12; H, 3.78; N, 18.02.
3¢-Propylspiro(imidazoline-4,4¢-quinazoline)-2,2¢(1¢H),5-trione
(7c)
Melting points were taken with a capillary melting point apparatus
and are uncorrected. The infrared (IR) absorption spectra were de-
termined as dispersions in KBr discs and are indicated in cm–1. The
1H and 13C NMR spectra were recorded as solutions in CDCl3 or
DMSO-d6 at 200 or 300 MHz (1H) and 50.3 or 75 MHz (13C), re-
spectively, and chemical shifts (d) are expressed in ppm relative to
TMS as internal standard. Thin layer chromatography (TLC) was
performed using silica gel analytical plates (F254) of 0.25 mm thick-
ness; detection was facilitated by UV light at 254 or 365 nm or using
p-anisaldehyde. The analytical results of elemental analysis are
within 0.4% of theoretical values and were obtained from INSA in-
stitution at Rouen, 76130 Mt-St-Aignan, France.
Obtained from the n-propyl isocyanate (5c), recrystallised from
EtOH.
Yield: 66%; brown solid; Rf = 0.32 (cyclohexane–EtOAc, 1:1); mp
279 °C.
IR (KBr): 3232 (3 × NH), 1769 (C=O), 1722 (C=O), 1666 (C=O)
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.81 (t, J = 7 Hz, 3 H, CH3),
1.50–1.61 (m, 2 H, CH2), 2.76–2.90 (m, 1 H, CH2), 3.23–3.38 (m,
1 H, CH2), 6.86 (dd, J = 1.6, 8.6 Hz, 1 H, HAr), 6.94–7.04 (m, 2 H,
HAr), 7.25–7.33 (m, 1 H, HAr), 9.19 (br s, 1 H, NH), 9.89 (br s, 1 H,
NH), 11.3 (br s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 11.5 (CH3), 22.4 (CH2), 44.8
(CH2), 78.2 (Cq), 114.2 [Cq(Ar)], 116.2 (CHAr), 122.0 (CHAr), 125.1
(CHAr), 130.6 (CHAr), 136.6 [Cq(Ar)], 151.2 (C=O), 155.5 [C(2)=O],
173.7 [C(4)=O].
Synthesis of Spirohydantoins 7a–c; General Procedure
To a stirred solution of isatin (4; 10.3 g, 70 mmol) in anhydrous
DMF (70 mL) was added Et3N (9.8 mL, 70 mmol). After stirring for
15 min, the appropriate isocyanate 5 (70 mmol) was added dropwise
at 0 °C and the reaction was stirred for an additional 1 h. The yellow
solid formed (6) was collected by filtration and washed successively
with H2O and Et2O. To a crude mixture of carbamoylisatin 6 (20
mmol) and Et3N (3.1 mL, 22 mmol) in anhydrous THF (100 mL)
was added in one portion S-ethylisothiouronium bromide (3.7 g, 20
mmol). After stirring at r.t. for 24 h, the solution was concentrated
under reduced pressure. The crude solid was then diluted with HCl
(10%, 50 mL) and heated at 80 °C for 24 h then cooled to r.t. The
resulting solid 7 was filtered, triturated with Et2O and recrystallised
from EtOH.
Anal. Calcd for C13H14N4O3: C, 56.93; H, 5.14; N, 20.43. Found: C,
56.80; H, 5.00; N, 20.29.
Synthesis of Benzylspirohydantoins 8a–c; General Procedure
To a stirred mixture of spirohydantoins (7a–c; 10 mmol) and KOH
(0.56 g, 10 mmol) in anhydrous EtOH (70 mL) was added, drop-
wise, benzyl bromide (1.2 mL, 10 mmol) in anhydrous EtOH (30
mL). The mixture was then refluxed for 4 h under stirring then
cooled to r.t. The solution was concentrated under reduced pressure
to provide a residue which was purified by flash chromatography on
silica gel (cyclohexane–EtOAc, 4:1).
3¢-Benzylspiro(imidazolidine-4,4¢-quinazoline)-2,2¢(1¢H),5-tri-
one (7a)
Obtained from the benzyl isocyanate (5a).
1,3¢-Dibenzylspiro(imidazolidine-4,4¢-quinazoline)-2,2¢(1¢H),5-
trione (8a)
Yield: 46%; pale-yellow solid; Rf = 0.66 (cyclohexane–EtOAc,
2:3); mp 203 °C.
Yield: 49% (Lit.16,17 69%); yellow solid; Rf = 0.28 (EtOAc); mp
>300 °C (Lit.16,17 >280 °C).
IR (KBr): 3248 (2 × NH), 1793 (C=O), 1721 (C=O), 1664 (C=O)
IR (KBr): 3242 (3 × NH), 1787 (C=O), 1723 (C=O), 1660 (C=O)
cm–1.
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 4.26 (d, J = 16 Hz, 1 H, CH2),
4.37 (d, J = 15 Hz, 1 H, CH2), 4.52 (d, J = 16 Hz, 1 H, CH2), 4.54
(d, J = 16 Hz, 1 H, CH2), 6.87–6.99 (m, 3 H, HAr), 7.15–7.30 (m,
11 H, HAr), 9.56 (br s, 1 H, NH), 10.12 (br s, 1 H, NH).
1H NMR (200 MHz, DMSO-d6): d = 4.25 (d, J = 16 Hz, 1 H, CH2),
4.60 (d, J = 16 Hz, 1 H, CH2), 6.89–7.01 (m, 2 H, HAr), 7.26 (m,
7 H, HAr), 9.14 (br s, 1 H, NH), 10.02 (br s, 1 H, NH), 11.22 (br s,
1 H, NH).
13C NMR (50.3 MHz, DMSO-d6): d = 40.8 (CH2), 41.6 (CH2), 77.0
(Cq), 114.4 (CHAr), 116.0 [Cq(Ar)], 122.0 (CHAr), 124.8 (CHAr),
126.9 (CHAr), 127.2 (2 × CHAr), 127.7 (2 × CHAr), 127.8 (CHAr),
128.1 (2 × CHAr), 128.7 (2 × CHAr), 130.7 (CHAr), 136.2 [Cq(Ar)],
13C NMR (50.3 MHz, DMSO-d6): d = 40.8 (CH2), 78.2 (Cq), 114.2
(CHAr), 116.3 [Cq(Ar)], 121.9 (CHAr), 125.0 (CHAr), 126.7 (CHAr),
127.2 (2 × CHAr), 128.0 (2 × CHAr), 130.5 (CHAr), 136.5 [Cq(Ar)],
138.4 [Cq(Ar)], 151.5 (C=O), 155.5 [C(2)=O], 173.2 [C(4)=O].
Synthesis 2008, No. 9, 1389–1396 © Thieme Stuttgart · New York

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A. Pesquet et al.
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136.6 [Cq(Ar)], 138.0 [Cq(Ar)], 151.6 (C=O), 154.7 [C(2)=O], 171.4
[C(4)=O].
1-Benzyl-1¢,3-dimethyl-3¢-phenylspiro(imidazolidine-4,4¢-
quinazoline)-2,2¢,5-trione (9b)
Obtained from spirohydantoin 8b.
Anal. Calcd for C24H20N4O3: C, 69.89; H, 4.89; N, 13.58. Found: C,
69.76; H, 4.69; N, 13.33.
Yield: 51% (2 steps from 7b); colourless solid; Rf = 0.67 (cyclohex-
ane–EtOAc, 2:3); mp 187 °C.
1-Benzyl-3¢-phenylspiro(imidazolidine-4,4¢-quinazoline)-
2,2¢(1¢H),5-trione (8b)
Because this product was not isolated in pure form, the crude oily
mixture obtained at the end of the reaction was used in the next step.
IR (KBr): 1783 (C=O), 1725 (C=O), 1664 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.80 (s, 3 H, CH3), 3.43 (s, 3 H,
CH3), 4.49 (s, 2 H, CH2), 6.78 (dd, J = 1.6, 8.6 Hz, 1 H, HAr), 6.96–
7.22 (m, 11 H, HAr), 7.35–7.40 (m, 2 H, HAr).
13C NMR (50.3 MHz, CDCl3): d = 25.4 (CH3), 30.4 (CH3), 42.6
(CH2), 80.8 (Cq), 114.1 (CHAr), 114.2 (CHAr), 123.0 (CHAr), 125.4
(CHAr), 125.7 (CHAr), 127.9 (CHAr), 128.3 (2 × CHAr), 128.7
(2 × CHAr), 128.9 (CHAr), 129.1 (CHAr), 131.4 (CHAr), 131.5
(CHAr), 135.1 [2 × Cq(Ar)], 136.7 [Cq(Ar)], 139.2 [Cq(Ar)], 152.3
(C=O), 154.2 [C(2)=O], 170.1 [C(4)=O].
1-Benzyl-3¢-propylspiro(imidazolidine-4,4¢-quinazoline)-
2,2¢(1¢H),5-trione (8c)
Yield: 47%; colourless solid; Rf = 0.64 (cyclohexane–EtOAc, 1:1);
mp 192 °C.
IR (KBr): 3228 (2 × NH), 1788 (C=O), 1722 (C=O), 1664 (C=O)
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.61 (t, J = 7 Hz, 3 H, CH3),
1.40–1.53 (m, 2 H, CH2), 2.69–2.83 (m, 1 H, CH2), 2.94–3.09 (m,
1 H, CH2), 4.66 (s, 2 H, CH2), 6.84–7.00 (m, 3 H, HAr), 7.25–7.37
(m, 6 H, HAr), 9.56 (br s, 1 H, NH), 9.97 (br s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 11.1 (CH3), 22.0 (CH2), 41.8
(CH2), 44.6 (CH2), 77.0 (Cq), 114.2 (CHAr), 115.8 [Cq(Ar)], 121.8
(CHAr), 125.1 (CHAr), 127.9 (CHAr), 128.0 (2 × CHAr), 128.7
(2 × CHAr), 130.6 (CHAr), 136.3 [Cq(Ar)], 136.6 [Cq(Ar)], 150.9
(C=O), 154.6 [C(2)=O], 171.7 [C(4)=O].
Anal. Calcd for C25H22N4O3: C, 70.41; H, 5.20; N, 13.14. Found: C,
70.29; H, 5.05; N, 13.02.
1-Benzyl-1¢,3-dimethyl-3¢-propylspiro(imidazolidine-4,4¢-
quinazoline)-2,2¢,5-trione (9c)
Obtained from N3-benzylspirohydantoin 8c.
Yield: 100%; colourless solid; Rf = 0.56 (cyclohexane–EtOAc, 1:1);
mp 163 °C.
IR (KBr): 1781 (C=O), 1724 (C=O), 1666 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.58 (t, J = 7 Hz, 3 H, CH3), 1.18–
1.59 (m, 2 H, CH2), 2.60 (s, 3 H, CH3), 2.70–2.85 (m, 1 H, CH2),
2.96–3.09 (m, 1 H, CH2), 3.36 (s, 3 H, CH3), 4.76 (s, 2 H, CH2),
6.70 (dd, J = 1.6, 8.6 Hz, 1 H, HAr), 6.92 (dd, J = 1.6, 8.6 Hz, 2 H,
HAr), 7.29–7.44 (m, 6 H, HAr).
Anal. Calcd for C20H20N4O3: C, 65.92; H, 5.53; N, 15.38. Found: C,
65.81; H, 5.42; N, 15.41.
Synthesis of Polysubstituted Spirohydantoins 9a–c; General
Procedure
To a stirred mixture of benzylspirohydantoins (8a–c; 50 mmol) and
18-crown-6 ether (1% w/w) in anhydrous toluene (50 mL) were
added solid K2CO3 (1.72 g, 125 mmol) and anhydrous KI (0.1
equiv). After stirring for 15 min, MeI (150 mmol, 0.93 mL) in an-
hydrous toluene (15 mL) was added dropwise over a period of 30
min. The mixture was refluxed for 24 h under stirring and then
cooled to r.t. After filtration over a short column of Celite, the or-
ganic layer was concentrated under reduced pressure to provide a
colourless oil which was purified by flash column chromatography
on silica gel (cyclohexane–EtOAc, 1:4).
13C NMR (75 MHz, CDCl3): d = 11.2 (CH3), 21.5 (CH2), 24.8
(CH3), 30.1 (CH3), 42.9 (CH2), 46.6 (CH2), 79.8 (Cq), 113.7 (CHAr),
114.3 [Cq(Ar)], 122.6 (CHAr), 125.0 (CHAr), 128.3 (CHAr), 128.8
(2 × CHAr), 128.9 (2 × CHAr), 131.2 (CHAr), 135.5 [Cq(Ar)], 138.9
[Cq(Ar)], 151.9 (C=O), 154.2 [C(2)=O], 170.6 [C(4)=O].
Anal. Calcd for C22H24N4O3: C, 67.33; H, 6.16; N, 14.28. Found: C,
67.20; H, 6.04; N, 14.15.
Synthesis of Spirohydroxylactams 1a–c; General Procedure
To a well-stirred solution of spirohydantoins (9a–c; 4 mmol) in an-
hydrous EtOH (40 mL) was added, in portions at r.t., NaBH4 (0.91
g, 24 mmol) over a period of 10 min. The mixture was stirred under
reflux for 6–48 h (the reaction was monitored by TLC using CH2Cl2
as eluent), cooled to r.t. and concentrated under reduced pressure.
H2O (40 mL) was added and the mixture was extracted into CH2Cl2
(2 × 30 mL). The organic layers were combined, dried over MgSO4
and concentrated under reduced pressure to provide a colourless
solid which was recrystallised from a suitable solvent to give 5-hy-
droxyspiroimidazolidin-2-ones 1a–c in good to excellent yields.
1,3¢-Dibenzyl-1¢,3-dimethylspiro(imidazolidine-4,4¢-quinazo-
line)-2,2¢,5-trione (9a)
Obtained from benzylspirohydantoin 8a.
Yield: 60%; pale-yellow solid; Rf = 0.89 (cyclohexane–EtOAc,
2:3); mp 92 °C.
IR (KBr): 1781 (C=O), 1725 (C=O), 1662 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.20 (s, 3 H, CH3), 3.45 (s, 3 H,
CH3), 3.92 (d, J = 16 Hz, 1 H, CH2), 4.58 (d, J = 14 Hz, 1 H, CH2),
4.70 (d, J = 14 Hz, 1 H, CH2), 4.91 (d, J = 16 Hz, 1 H, CH2), 6.63
(d, J = 7.8 Hz, 1 H, HAr), 6.89–7.07 (m, 4 H, HAr), 7.18–7.22 (m,
3 H, HAr), 7.30–7.42 (m, 6 H, HAr).
13C NMR (75 MHz, CDCl3): d = 24.9 (CH3), 30.7 (CH3), 42.9
(CH2), 48.3 (CH2), 80.2 (Cq), 114.0 (CHAr), 122.8 (CHAr), 124.8
(CHAr), 127.6 (CHAr), 128.1 (2 × CHAr), 128.4 (2 × CHAr), 128.5
(CHAr), 128.9 (2 × CHAr), 129.2 (2 × CHAr), 131.3 (CHAr), 135.8
[2 × Cq(Ar)], 137.4 [2 × Cq(Ar)], 152.8 (C=O), 154.2 [C(2)=O], 170.5
[C(4)=O].
1,3¢-Dibenzyl-1¢,5-dihydro-5-hydroxy-1¢,3-dimethylspiro(imi-
dazolidine-4,4¢-quinazoline)-2,2¢-dione (1a)
Obtained from spirohydantoin 9a.
Yield: 82%; colourless crystals; Rf = 0.78 (cyclohexane–EtOAc,
2:3); mp 114 °C.
IR (KBr): 3343 (OH), 1704 (C=O), 1656 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.38 (s, 3 H, CH3), 3.25 (d, J = 7.8
Hz, 1 H, OH), 3.37 (s, 3 H, CH3), 4.02 (d, J = 15 Hz, 1 H, CH2),
4.49 (d, J = 16 Hz, 1 H, CH2), 4.61 (d, J = 7.8 Hz, 1 H, CH), 4.82
(d, J = 15 Hz, 1 H, CH2), 5.02 (d, J = 16 Hz, 1 H, CH2), 6.78–7.01
(m, 2 H, HAr), 7.19–7.30 (m, 12 H, HAr).
Anal. Calcd for C26H24N4O3: C, 70.89; H, 5.49; N, 12.72. Found: C,
70.73; H, 5.28; N, 12.66.
13C NMR (50.3 MHz, CDCl3): d = 27.1 (CH3), 30.7 (CH3), 44.3
(CH2), 48.4 (CH2), 80.8 (Cq), 87.4 (CH), 121.3 (CHAr), 122.7
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PAPER
p-Cyclisation of N-Carbamoyliminium Ions from Spiro(imidazolidinoquinazolinones)
1395
[Cq(Ar)], 125.0 (CHAr), 127.1 (CHAr), 127.5 (2 × CHAr), 127.6
(CHAr), 128.4 (2 × CHAr), 128.5 (2 × CHAr), 128.7 (2 × CHAr),
128.9 (CHAr), 130.2 (CHAr), 136.6 [Cq(Ar)], 137.8 [Cq(Ar)], 138.9
[Cq(Ar)], 154.8 (C=O), 157.9 (C=O).
8H-13-Benzyl-5,15-dimethylimidazo[4¢,5¢:3,4]isoquinolo[3,4-
c]quinazoline-6,14-dione (10a)
Obtained from spirohydroxylactam 1a.
Yield: 56%; colourless solid; Rf = 0.61 (cyclohexane–EtOAc, 2:3);
Anal. Calcd for C26H26N4O3: C, 70.57; H, 5.92; N, 12.66. Found: C,
70.41; H, 5.78; N, 12.57.
mp 215 °C.
IR (KBr): 1688 (C=O), 1655 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.62 (s, 3 H, CH3), 3.29 (s, 3 H,
CH3), 3.48 (d, J = 16 Hz, 1 H, CH2), 4.05 (d, J = 15 Hz, 1 H, CH2),
4.69 (s, 1 H, CH), 5.03 (d, J = 16 Hz, 1 H, CH2), 5.33 (d, J = 15 Hz,
1 H, CH2), 6.82 (d, J = 7.8 Hz, 1 H, HAr), 6.96–7.11 (m, 4 H, HAr),
7.20–7.43 (m, 8 H, HAr).
13C NMR (50.3 MHz, CDCl3): d = 25.3 (CH3), 30.2 (CH3), 41.3
(CH2), 44.6 (CH2), 63.4 (CH), 76.9 (Cq), 112.9 (CHAr), 120.1
[Cq(Ar)], 122.7 (CHAr), 126.4 (CHAr), 127.2 (CHAr), 127.3 (CHAr),
127.8 (CHAr), 128.3 (2 × CHAr), 128.7 (CHAr), 128.9 (2 × CHAr),
130.1 (CHAr), 130.3 (CHAr), 131.0 [Cq(Ar)], 136.9 [Cq(Ar)], 137.8
[Cq(Ar)], 138.0 [Cq(Ar)], 151.6 (C=O), 157.6 (C=O).
1-Benzyl-1¢,5-dihydro-5-hydroxy-1¢,3-dimethyl-3¢-phenyl-
spiro(imidazolidine-4,4¢-quinazoline)-2,2¢-dione (1b)
Obtained from spirohydantoin 9b.
Yield: 98%; colourless crystals; Rf = 0.62 (cyclohexane–EtOAc,
2:3); mp 117 °C.
IR (KBr): 3323 (OH), 1702 (C=O), 1654 (C=O) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.45 (s, 3 H, CH3), 3.29 (s, 3 H,
CH3), 4.25 (d, J = 15 Hz, 1 H, CH2), 4.61 (d, J = 15 Hz, 1 H, CH2),
4.75 (s, 1 H, CH), 6.94–7.11 (m, 6 H, HAr), 7.20–7.45 (m, 8 H, HAr),
7.61 (br s, 1 H, OH).
13C NMR (50.3 MHz, CDCl3): d = 27.3 (CH3), 30.7 (CH3), 44.2
(CH2), 81.0 (Cq), 87.0 (CH), 113.8 (CHAr), 122.8 (CHAr), 123.6
[Cq(Ar)], 124.2 (CHAr), 127.4 (CHAr), 127.6 (CHAr), 128.2 (CHAr),
128.4 (2 × CHAr), 128.5 (2 × CHAr), 128.7 (CHAr), 128.8 (CHAr),
129.9 (CHAr), 130.1 (CHAr), 137.12 [Cq(Ar)], 138.2 [Cq(Ar)], 138.3
[Cq(Ar)], 154.9 (C=O), 157.9 (C=O).
Anal. Calcd for C26H24N4O2: C, 73.56; H, 5.70; N, 13.20. Found: C,
73.39; H, 5.56; N, 13.05.
N-(N¢-Methylcarboxamido)benzylamino-5-methylindolo[1,2-
c]quinazolin-6-one (10b)
Obtained from spirohydroxylactam 1b.
Anal. Calcd for C25H24N4O3: C, 70.08; H, 5.65; N, 13.08. Found: C,
69.85; H, 5.54; N, 13.12.
Yield: 61%; colourless solid; Rf = 0.71 (cyclohexane–EtOAc, 2:3);
mp 236 °C.
IR (KBr): 3389 (NH), 1692 (C=O), 1649 (C=O) cm–1.
1-Benzyl-1¢,5-dihydro-5-hydroxy-1¢,3-dimethyl-3¢-propyl-
spiro(imidazolidine-4,4¢-quinazoline)-2,2¢-dione (1c)
Obtained from spirohydantoin 9c.
1H NMR (200 MHz, CDCl3): d = 2.73 (d, J = 5 Hz, 3 H, CH3), 3.54
(s, 3 H, CH3), 4.60 (d, J = 13 Hz, 1 H, CH2), 4.85 (q, J = 5 Hz, 1 H,
NH), 5.27 (d, J = 13 Hz, 1 H, CH2), 7.02–7.23 (m, 10 H, HAr), 7.45
(td, J = 1.6, 8.6 Hz, 1 H, HAr), 7.98 (dd, J = 1.6, 7.8 Hz, 1 H, HAr),
8.44–8.52 (m, 1 H, HAr).
13C NMR (50.3 MHz, CDCl3): d = 27.7 (CH3), 30.1 (CH3), 52.1
(CH2), 114.2 (CHAr), 114.6 (Cq=), 115.9 (CHAr), 117.9 (CHAr),
123.8 (CHAr), 123.9 (CHAr), 124.4 (CHAr), 124.5 (CHAr), 127.4
(Cq), 127.5 (CHAr), 127.8 (Cq), 128.2 (2 × CHAr), 129.7 (2 × CHAr),
129.8 (CHAr), 132.0 (Cq), 135.4 (Cq), 138.3 (2 × Cq), 147.4 (C=O),
158.1 (C=O).
Yield: 82%; colourless crystals; Rf = 0.52 (cyclohexane–EtOAc,
1:1); mp 164 °C.
IR (KBr): 3327 (OH), 1699 (C=O), 1649 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.75 (t, J = 7 Hz, 3 H, CH3), 1.22–
1.34 (m, 1 H, CH2), 1.67–1.77 (m, 1 H, CH2), 2.71 (s, 3 H, CH3),
2.85–3.05 (m, 1 H, CH2), 3.17 (s, 3 H, CH3), 3.33–3.52 (m, 1 H,
CH2), 4.13 (d, J = 15 Hz, 1 H, CH2), 4.49 (d, J = 6 Hz, 1 H, OH),
4.66 (d, J = 6 Hz, 1 H, CH), 4.79 (d, J = 15 Hz, 1 H, CH2), 6.74–
6.97 (m, 3 H, HAr), 7.18–7.29 (m, 6 H, HAr).
13C NMR (75 MHz, CDCl3): d = 11.7 (CH3), 22.6 (CH2), 26.9
(CH3), 30.2 (CH3), 44.3 (CH2), 47.7 (CH2), 80.7 (Cq), 87.5 (CH),
113.2 (CHAr), 121.1 [Cq(Ar)], 122.4 (CHAr), 124.9 (CHAr), 127.6
(CHAr), 128.4 (2 × CHAr), 128.6 (2 × CHAr), 130.1 (CHAr), 136.8
[Cq(Ar)], 137.9 [Cq(Ar)], 154.1 (C=O), 158.1 (C=O).
Anal. Calcd for C25H22N4O2: C, 73.15; H, 5.40; N, 13.65. Found: C,
73.02; H, 5.15; N, 13.49.
8-Methyl-9-o-[N-methyl-N-(N¢-propylcarboxamido)ami-
no]phenylimidazo[4,3-a]isoindol-7-one (10c)
Obtained from spirohydroxylactam 1c.
Anal. Calcd for C22H26N4O3: C, 66.99; H, 6.64; N, 14.20. Found: C,
66.76; H, 6.49; N, 14.05.
Yield: 58%; yellow oil; Rf = 0.50 (cyclohexane–EtOAc, 1:1); mp
87 °C (product 10c crystallizes in the refrigerator after several
days).
Acid-Mediated Cyclisation of Spirohydroxylactams 1a–c; Gen-
eral Procedure
IR (KBr): 3054 (NH), 1698 (C=O), 1655 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.37 (t, J = 7 Hz, 3 H, CH3), 1.04–
1.29 (m, 3 H, CH2 and NH), 2.85–2.99 (m, 1 H, CH2), 3.09 (s, 3 H,
CH3), 3.40 (s, 3 H, CH3), 3.72–3.86 (m, 1 H, CH2), 4.77 (d, J = 16
Hz, 1 H, CH2), 4.97 (d, J = 16 Hz, 1 H, CH2), 7.17–7.33 (m, 8 H,
HAr).
13C NMR (75 MHz, CDCl3): d = 10.3 (CH3), 21.0 (CH2), 28.7
(CH3), 37.5 (CH3), 45.5 (CH2), 49.4 (CH2), 121.6 (CHAr), 121.9
(Cq=), 122.3 (Cq=), 124.7 (CHAr), 125.5 (CHAr), 126.7 (2 × CHAr),
127.6 (CHAr), 128.6 [Cq(Ar)], 128.7 (2 × CHAr), 136.4 [2 × Cq(Ar)],
143.1 [Cq(Ar)], 153.4 (C=O), 165.5 (C=O).
To a well-stirred, cold solution of spirolactams 1a–c (1 mmol) in
anhydrous CH2Cl2 (10 mL), was added, dropwise, a solution of
TFAA (0.18 mL, 1.3 mmol) and TFA (0.096 mL, 1.3 mmol) in an-
hydrous CH2Cl2 (10 mL). After heating at reflux for 24 h under stir-
ring, the reaction mixture was diluted carefully with H2O (25 mL)
and neutralised with cold 10% NaHCO3. The solution was extracted
with CH2Cl2 (2 × 10 mL) and the organic layer was washed with
H2O (2 × 10 mL), brine (2 × 10 mL), separated, dried over MgSO4
and evaporated in vacuo. The resulting residue was purified by flash
chromatography on silica gel column (cyclohexane–EtOAc, 1:3) to
give the cyclic products 10a–c as crystalline materials.
Anal. Calcd for C22H24N4O2: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.03; H, 6.23; N, 14.64.
Synthesis 2008, No. 9, 1389–1396 © Thieme Stuttgart · New York

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A. Pesquet et al.
PAPER
(10) For representative papers in this field, see: (a)Carrera, J. M.
Jr.; Garvey, D. S. J. Heterocycl. Chem. 1992, 29, 847.
(b) Liao, Z.-K.; Kohn, H. J. Org. Chem. 1985, 50, 1884; and
references cited therein from the same authors.
Acknowledgment
We are grateful to Johnson & Johnson, Pharmaceutical R&D,
Division of Janssen-Cilag, for support of this research. We are also
grateful to the Region of Haute Normandie, France for a Regional
Industrial Graduate Fellowship, attributed to A.P.
(c) Marquez, V. E.; Twanmoh, L.-M.; Wood, H. B. Jr.;
Driscoll, J. S. J. Org. Chem. 1978, 37, 2558.
(11) (a) Yamagishi, M.; Ozaki, K. I.; Yamada, Y.; Da-Te, T.;
Okamura, K.; Suzuki, M. Chem. Pharm. Bull. 1991, 39,
1694. (b) Yamagishi, M.; Yamada, Y.; Ozaki, K. I.; Asao,
M.; Shimizu, R.; Suzuki, M.; Matsumoto, M.; Matsuoka, Y.;
Matsumoto, K. J. Med. Chem. 1992, 35, 2085.
References
(1) Present address: CEA Saclay, INSTN-UESMS, 91191 Gif
sur Yvette Cedex, France
(12) (a) Daïch, A.; Marchalín, Š.; Pigeon, P.; Decroix, B.
Tetrahedron Lett. 1998, 39, 9187. (b) Chihab-Eddine, A.;
Daïch, A.; Jilale, A.; Decroix, B. Tetrahedron Lett. 2001, 42,
573. (c) Chihab-Eddine, A.; Daïch, A.; Jilale, A.; Decroix,
B. Heterocycles 2002, 58, 449.
(2) For representative reviews, see: (a) Bergman, J. The
Alkaloids 1983, 21, 29. (b) Michael, J. P. Nat. Prod. Rep.
2000, 17, 603. (c) Michael, J. P. Nat. Prod. Rep. 2001, 18,
543. (d) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7,
659.
(13) Hucher, N.; Decroix, B.; Daïch, A. Org. Lett. 2000, 2, 1201.
(14) (a) Hucher, N.; Decroix, B.; Daïch, A. J. Org. Chem. 2001,
66, 4695. (b) Cul, A.; Chihab-Eddine, A.; Pesquet, A.;
Marchalín, Š.; Daïch, A. J. Heterocycl. Chem. 2003, 40,
499. (c) Fogain-Ninkam, A.; Daïch, A.; Decroix, B.;
Netchitaïlo, P. Eur. J. Org. Chem. 2003, 4273. (d) Hucher,
N.; Pesquet, A.; Netchitaïlo, P.; Daïch, A. Eur. J. Org.
Chem. 2005, 2758.
(3) (a) da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz.
Chem. Soc. 2001, 12, 273. (b) Reddy, P. S.; Vasantha, T.
Heterocycles 2003, 60, 183. (c) Hamid, A.; Elomri, A.;
Daïch, A. Tetrahedron Lett. 2006, 47, 1777; and references
cited therein. (d) Carpenter, R. D.; Lam, K. S.; Kurth, M. J.
J. Org. Chem. 2007, 72, 284.
(4) (a) Hennequin, L. F.; Thomas, A. P.; Johnstone, C.; Stokes,
E. S. E.; Plé, P. A.; Lohmann, J.-J. M.; Ogilvie, D. J.; Dukes,
M.; Wedge, S. R.; Curwen, J. O.; Kendrew, J.;
van der Brempt, C. L. J. Med. Chem. 1999, 42, 5369.
(b) Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9,
69; and references cited therein. (c) Martínez-Vitturro, C.
M.; Domínguez, D. Tetrahedron Lett. 2007, 48, 1023.
(5) (a) Jones, T. R.; Thornton, T. J.; Flinn, A.; Jackman, A. L.;
Newell, D. R.; Calvert, A. H. J. Med. Chem. 1989, 32, 847.
(b) Malawska, B. Curr. Top. Med. Chem. 2005, 5, 69; and
references cited therein.
(15) Pesquet, A.; Daïch, A.; Decroix, B.; Van Hijfte, L. Org.
Biomol. Chem. 2005, 3, 3937.
(16) (a) Yamagishi, M.; Ozaki, K. I.; Ohmizu, H.; Yamada, Y.;
Suzuki, M. Chem. Pharm. Bull. 1990, 38, 2926.
(b) Yamagishi, M.; Yamada, Y.; Ozaki, K. I.; Tani, J.;
Suzuki, M. Chem. Pharm. Bull. 1991, 39, 626.
(c) Yamagishi, M.; Ozaki, K. I.; Yamada, Y.; Da-Te, T.;
Okamura, K.; Suzuki, M. Chem. Pharm. Bull. 1991, 39,
1694.
(17) Yamagishi, M.; Yamada, Y.; Ozaki, K. I.; Asao, M.;
Shimizu, R.; Suzuki, M.; Matsumoto, M.; Matsuoka, Y.;
Mataumoto, K. J. Med. Chem. 1992, 35, 2085.
(6) Kuneš, J.; Bazant, J.; Pour, M.; Waisser, K.; Šlosárek, M.;
Janota, J. Farmaco 2000, 55, 725.
(7) Meyer, M. D.; Altenbach, R. J.; Bai, H.; Basha, F. Z.;
Carroll, W. A.; Kerwin, J. F. Jr.; Lebold, S. A.; Lee, E.; Pratt,
J. K.; Sippy, K. B.; Tietje, K.; Wendt, M. D.; Brune, M. E.;
Buckner, S. A.; Hancock, A. A.; Drizin, I. J. Med. Chem.
2001, 44, 1971.
(8) (a) Hasegawa, H.; Muraoka, M.; Matsui, K.; Kojima, A.
Bioorg. Med. Chem. Lett. 2003, 13, 3471. (b) Hasegawa,
H.; Muraoka, M.; Ohmori, M.; Matsui, K.; Kojima, A.
Bioorg. Med. Chem. 2005, 13, 3721. (c) Hasegawa, H.;
Muraoka, M.; Ohmori, M.; Matsui, K.; Kojima, A. Chem.
Pharm. Bull. 2005, 53, 1236.
(18) (a) Kohn, H.; Liao, Z.-K. J. Org. Chem. 1982, 47, 2787.
(b) Liao, Z.-K.; Kohn, H. J. Org. Chem. 1984, 49, 3812.
(c) Liao, Z.-K.; Kohn, H. J. Org. Chem. 1984, 49, 4745.
(d) Salazar, L.; Rubido, J.; Espada, M.; Pedregal, C.; Trigo,
G.; Elguero, J. J. Heterocycl. Chem. 1986, 23, 481.
(e) Yamagishi, M.; Yamada, Y.; Ozaki, K. I.; Da-Te, T.;
Okamura, K.; Suzuki, M.; Mataumoto, K. J. Org. Chem.
1992, 57, 1568.
(19) Full crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre; CCDC reference
number 637457 for product 10b. Copies of the data can be
obtained free of charge at the following address:
http://www.ccdc.cam.ac.uk.
(9) Pesquet, A.; Daïch, A.; Van Hijfte, L. J. Org. Chem. 2006,
71, 5303.
Synthesis 2008, No. 9, 1389–1396 © Thieme Stuttgart · New York