Synthesis of novel pyrazole-based heterocycles via a copper(ii)-catalysed domino annulation

Article abstract of DOI:10.1039/c3ob41146j

Pyrazole-based β-aminonitriles and β-amino-carbaldehydes as bifunctional building blocks are introduced in a facile copper(ii)-catalysed one-pot domino generation of multiple N-containing heterobi- and tricycles. This streamlined synthetic approach permits easy access to novel pyrazole-fused imidazo- and pyrimido[1,2-c]pyrimidinones and to pyrazolo[3,4-d]pyrimidinone species with isolated yields up to 90%. The present study also reveals a unique amine-isocyanate coupling promotion via copper(ii)-based catalytic activation.

Full text of DOI:10.1039/c3ob41146j

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ARTICLE TYPE
Synthesis of novel pyrazole-based heterocycles
via a copper(II)-catalysed domino annulation
Márió Gyurisa,b, László G. Puskása, Gábor K. Tóthb, Iván Kanizsai*,a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Pyrazole-based -aminonitriles and -amino-carbaldehydes as bifunctional building blocks are introduced
in a facile copper(II)-catalysed one-pot domino generation of multiple N-containing heterobi- and
tricycles. This streamlined synthetic approach permits easy access to novel pyrazole-fused imidazo- and
pyrimido[1,2-c]pyrimidinones and to pyrazolo[3,4-d]pyrimidinone species with isolated yields up to 90%.
10 The present study also reveals a unique amine-isocyanate coupling promotion via copper(II)-based
catalytic activation.
In case of relatively weak aromatic nucleophiles (e.g. 5-
aminopyrazoles), the catalytic activation of the electrophilic
coupling partners may be needed to improve the efficiency.
Introduction
Domino transformations, as multi-step one-pot processes, are
effective tools in organic synthesis, allowing the formation of
15 several new bonds in a simple and elegant one-pot synthetic
operation, thereby providing access to various types of molecular
entities.1 In order to design and achieve efficient tandem
processes, polifunctional building blocks, such as -aminonitriles
are needed to be employed.1,2
50
20
The benefits of bifuncional -aminonitriles containing
pyrazole ring can be exploited in their use as valuable synthons in
the construction of multiple N-containing heterocycles, such as
tacrine analogues through the Friedländer reaction, or
pyrazolo[3,4-d]pyrimidines via
a
Dimroth rearrangement.3,4
25 (Figure 1).2 Moreover, concerning the medicinal chemistry
aspects, pyrazole scaffolds (e.g. Celebrex®) are of great
pharmaceutical interest due to their extensively studied biological
and medicinal properties, including selective COX-2 inhibition
and antiviral activities.10,11
Figure. 1 Applicability of -aminonitrile building blocks.
30
The common feature of these transformations is the amine-
electrophile coupling step, which depends on the correlated
chemical character of the reactants and determines the reaction
outcome. Reactivity profiles and parameters of several aromatic
N-nucleophiles in different chemical processes have already been
In the present article, we report a facile Lewis acid-catalysed
domino transformation of substituted 5-amino-1H-pyrazole-4-
55 carbonitriles and carbaldehydes with chloroalkyl isocyanates to
give novel pyrazolo[3,4-d]pyrimidine unit-based heterobi- and
tricycles. The study also points out the synthetic potential of
bifunctional building blocks to readily construct N,N-
multiheterocycles through rapid domino processes.
35 determined.5-9 It is to be noted, that we are not aware of previous
quantitative investigations on the nucleophilic behaviour of
amino-substituted pyrazole scaffolds reacted with isocyanates as
electrophile agents.
60 Results and Discussion
40 aAvidin Ltd., Alsó Kikötő sor 11, Szeged, Hungary, H-6726;
www.avidinbiotech.com Fax: (+ 36)-62-202-108;
Initial experiments were performed with 5-amino-1-phenyl-
1H-pyrazole-4-carbonitrile (1a) and 2-chloroethyl isocyanate (2a)
in order to adjust the reaction parameters. Starting material 1a
was synthetized on the basis of literature data (see Supporting
65 Information).12 Preliminary trials indicated that neither the
formation of the intermediate urea adduct 3a nor that of the cyclic
product 4a could be detected, even after either conventional or
Email:i.kanizsai@avidinbiotech.com
bDepartment of Medical Chemistry, Faculty of General Medicine,
University of Szeged, Dóm tér 8, Szeged, Hungary, H-6720
45 † Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 8
microwave heating, demonstrating the extremely low
min furnished the best result and led to adduct 3a in an isolated
nucleophilic character of the examined amino function (Table 1,
entries 1-4).
yield of 90% (Table 1, entry 15). Reactions were monitored at
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different temperatures in the range 25-100 °C; quantitative
DOI: 10.1039/C3OB41146J
Various Lewis acids were therefore tested in catalytic
conversions were observed at 80 °C with a 10 mol% catalyst
5
quantities to promote the amine-isocyanate coupling (Table 1, 20 load.
entries 5-15). Rapid microwave-aided optimization revealed that
Various basic additives were next examined in order to
the reaction was improved dramatically by copper(II) salts, which
led to the exclusive formation of urea adduct 3a. Among the
catalysts tested, Cu(OAc)2 was found to be the best, though
trigger the domino ring-closure process (4a, Table 1, entries 20-
30). Following completion of our study of copper-catalysed
isocyanate-amine coupling, the subsequent experiments were
10 CuCl2 and Cu(C5HF6O2)2 also exhibited noteworthy catalytic 25 focused on the one-pot sequence, and it was therefore not
efficiency (Table 1, entries 10-12). The dependence of the
coupling conversion on the quantity of Cu(OAc)2 applied was
examined in the range 5-40 mol% under microwave conditions.
Treatment of 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (1a)
15 with isocyanate 2a in the presence of 10 mol% Cu(OAc)2 for 5
considered necessary to isolate the urea intermediates. The use of
1.2 equivalents of Cs2CO3 in a one-pot fashion was found to be
the most effective way to obtain pyrazole-fused imidazo[1,2-
c]pyrimidinone 4a in a good yield (82%, Table 1, entry 30).
30 Table 1 Microwave-aided optimization of the model reaction.
N
Cl
CN
CN
N
O
Lewis acid
Cl
base
W
O
N
N
H
N
N
N
+ OCN
NH2
N
H
solvent
W
N
N
N
H
Ph
Ph
Ph
1a
2a
3a
4a
Intermediate 3a
Product 4a
Entry
Solvent
Catalyst
Base
Yield [%]a
Entry
Solvent
Catalyst
Base
TEA
Yield [%]f
1
2
DMF
Toluene
MeCN
DMF
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0b
0c
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
DMF
DMF
MeCN
MeCN
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
–
–
–
–
17g
18g
DABCO
TEA
3
–
0c
18g
4
–
0c
DABCO
DABCO
DBU
16g
5
DMF
AgOTf
In(OTf)3
Me2SnCl2
InCl3
0d
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
33h
6
DMF
0d
traceh
traceh
traceh
10h
7
DMF
0d
tBuOK
K3PO4
TEA
8
DMF
0d
9
DMF
FeCl3*6H2O
CuCl2
0d
10
11
12
13
14
15
DMF
70d
66d
81d
81d
0d
DIPEA
DABCO
NaOAc
K2CO3
NaOMe
Cs2CO3
13h
DMF
Cu(C5HF6O2)2
Cu(OAc)2
45h
DMF
traceh
traceh
40h
MeCN
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMF/H2O
DMF
–
90e
82h
a Isolated yield of 3a after flash chromatography.
b Reaction conditions: 1a (1 mmol), 2a (3 equiv.), DMF (1.5 mL), 150 °C, 1 day.
c Reaction conditions: 1a (1 mmol), 2a (3 equiv.), solvent (1.5 mL), W: 300 W, 150 °C, 30 min.
35 d Reaction conditions: 1a (1 mmol), 2a (1.5 equiv.), catalyst (20 mol%), solvent (1.5 mL), W: 150 W, 80 °C, 5 min.
e Optimized reaction conditions: 1a (1 mmol), 2a (1.5 equiv.), Cu(OAc)2 (10 mol%), 4Å MS powder (100 mg), dry DMF (1.5 mL), W: 150 W, 80 °C, 5
min.
f Isolated yield of 4a after flash chromatography.
g Reaction conditions: 1a (1 mmol), 2a (3 equiv.), solvent (1.5 mL), base (3 equiv.), W: 250 W, 125 °C, 20 min.
h
40 Reaction conditions: 1a (1 mmol), 2a (1.5 equiv.), Cu(OAc)2 (10 mol%), 4Å MS powder (100 mg), solvent (1.5 mL), W1: 150 W, 80 °C, 5 min; then
base (1.2 equiv.), W2: 150 W, 100 °C, 5 min.
A comparative study of microwave versus conventional
heating surprisingly revealed similar efficiencies in terms of
reaction time, applied temperature and yield. In both cases, the
45 amine-isocyanate coupling was completed in 5 min at 80 °C, with
full conversion. Subsequent Cs2CO3-induced domino annulation
was achieved in an additional 5 min at 100 °C, affording 4a with
an overall yield of 82%.
2
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Organic & Biomolecular Chemistry
Interestingly, the use of tertiary amines without Cu(OAc)2 in
the reaction between 1a and 2a yielded tricyclic target compound
4a in low yields (22-26%, Table 1, entries 16-19). The reaction 20 domino ring-closure, subsequent Cs2CO3 addition and a further 5
isocyanates 2a and 2b in the presence of 10 mol% Cu(OAc)2
under thermal conditions (80 °C, 5 min, dry DMF). To induce the
View Article Online
DOI: 10.1039/C3OB41146J
might proceed via
a
tertiary amine-isocyanate activated
min at 100 °C afforded pyrazole-fused imidazo- and
pyrimido[1,2-c]pyrimidinones 4a-i and 5a-i, in yields of 77-90%
(Table 2, entries 1-18). The substitution pattern of the starting
materials 1a-i did not have an appreciable effect on the reaction
25 outcome.
5
complex,13 but the open-chain intermediate 3a could not be
detected in the reaction mixture.14
Table 2 Synthesis of tricyclic products 4a-i and 5a-i.
O
N
1. 10 mol% Cu(OAc)2
n
n
R
80 °C, 5 min
CN
N
N
N
2. 1.2 equiv. Cs2CO3
100 °C, 5 min
Cl
O
O
n
N
+
OCN
N
N
Cl
N
4Å MS powder
dry DMF
NH2
n
OCN
N
N
N
H
H
2a: n=1
2b: n=2
R
CHO
Ph
Ar
Ar
4a-i
5a-i
2a: n=1
2b: n=2
10 mol% Cu(OAc)2
Cl
n
1a-i
N
4Å MS powder
dry DMF
NH2
Entry
1
Product
Yield [%]a,b
N
Ar
100 °C, 15 min
Ph
R
N
n = 1,2
4a
82
6: R = Me
7: R = Ph
O
N
N
N
2
3
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
85
82
81
79
80
84
77
86
85
83
80
79
80
90
85
82
80
Ph
8a (81%), 8b (76%): R = Me
9a (78%), 9b (75%): R = Ph
Scheme 1 Transformation of -aminocarbaldehydes.
4
OMe
Experiments were then performed to reveal whether -
aminocarbaldehydes as bifunctional building blocks can be
30 subjected to a copper(II)-catalysed domino transformation with
5
6
chloroalkyl isocyanates. Starting materials
6
and
7
were
aza-
synthetized via Vilsmeier-Haack reaction
a
–
7
functionalization – chemoselective reduction strategy based on
reported data.15 With the previously described two-step, one-pot
35 concept, reactions between -aminocarbaldehydes 6 and 7 and
chloroalkyl isocyanates 2a and 2b were also investigated.
Interestingly, a copper(II)-induced single cyclisation process was
observed both under microwave conditions and on conventional
heating, furnishing pyrazolo[3,4-d]pyrimidin-6(5H)-ones 8a, 8b,
40 9a and 9b exclusively, instead of the anticipated tricycle (Scheme
1). It should be mentioned that the presence of Cs2CO3 led to
complex reaction mixtures, whereas in the absence of the
copper(II)-salt no reaction occurred. This transformation can be
regarded as an easy and elegant access route to pyrazolo[3,4-
45 d]pyrimidin-6(5H)-one frameworks.16
Possible catalytic cycles of the copper-catalyzed amine-
isocyanate coupling and the following domino processes are
depicted in Scheme 2. Considerable interest has been
demonstrated in copper-mediated transformations due to their
50 wide-ranging applicability, including C-N, C-O and C-C bond
formation reactions.17 Theoretical and experimental studies on
intermediate copper(II)-isocyanate complexes in a copper(II)-
catalysed urethane formation were earlier described, and such
intermediates might explain the specific activator effect on the
55 above-mentioned coupling process.18,19
8
9
10
11
12
13
14
15
16
17
18
Cl
5f
Cl
F
4g
5g
4h
5h
4i
F
5i
a Isolated yields of 4a-i and 5a-i after flash chromatography.
In pathway A, copper(II) is introduced as a dinuclear core in
complex I, leading to cyclic conjugation and a reduced electron
density on the isocyanate carbon.20 The attack by the 5-
aminopyrazole derivative on the activated NCO carbon provides
60 access to the amino-imidate-copper transition state II. An
intramolecular N→N H-shift, followed by the release of copper,
leads to urea adduct V.
10 b Reaction conditions: 1a-i (1 mmol), 2a or 2b (1.5 equiv.), Cu(OAc)2
(10 mol%), 4Å MS powder (100 mg), dry DMF (1.5 mL), 80 °C, 5 min;
then Cs2CO3 (1.2 equiv.), 100 °C, 5 min.
The well-established protocol was then adopted to synthetize a
15 series of pyrazole-based tricyclic analogues (Table 2). -
Aminonitriles 1a-i possessing electron-donating and/or electron-
withdrawing groups were successfully reacted with chloroalkyl
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Organic & Biomolecular Chemistry
Page 4 of 8
Ar
R
X
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N
DOI: 10.1039/C3OB41146J
N
Cl
Cl
NH2
N
+
C
+
n
NH2
n
N
R
+
N
O
O
C
H
N
n
Cu
L
O
C
N
Cl
X
Ar 1,6,7
H
pathway A
pathway B
n-2 HN
NH
Ar
Ar
+
Ln-2Cu
CuLn-2
N
N
Cl
n
2
OCN
X
Cl
N
C
+
O
N
N
LnCuII
LnCuII
X
X
R
n
H2N
R
R
N
N
I
III
Ar
LnCuII
R
X
Cl
Cl
H
N
O
O
H
Cu
Ln-2
n
n
N
N
C
N
H
N
H
Cl
n
Cl
Ar
O
N
HN
NH
Ln-2Cu
CuLn-2
R
X
Ar
XX
Ar
n
N
N
HN
N
C
N
H
O
Ar
N
N
Cl
O
N
R
R
N
N
n
N
H
H
LnCuII
LnCuII
N
Ar
V
IV
II
X
R
LnCuII
CuLn-2
HN
Cl
Cl
X=C
Cs2CO3
X=C
HO
no base
N
O
R
n
+
CN
n
route C
route D
N
O
N
O
N
N
H
N
N
N
H
Ar
Ar
VIII
VI
LnCuII
LnCuII
Cl
Cl
+
Cl
HO
N
N
n
H
n
R
n
n
R
N
N
N
N
N
- H2O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
H
H
Ar
Ar
Ar
Ar
and
8 and 9
4
5
VII
IX
Scheme 2 Possible catalytic cycles for copper-catalysed domino annulations.
Pathway B shows an alternative route, incorporating the amine
As regards -aminocarbaldehydes 6 and 7, a copper salt-
5
and the isocyanate in a single copper-centred complex (III).21
The ‘cage-like’ shape provides the requisite proximity between
the amine and the coordinated isocyanate. The attack by the
amino group on the activated carbon (IV), the subsequent N→N
20 generated electron shift leads to activation of the formyl group,
thereby improving the reactivity (VIII) and initiating the
spontaneous ring-closure reaction in the absence of base (route
D). Subsequent tautomeric equilibrium, followed by water
elimination, provides pyrazolo[3,4-d]pyrimidin-6(5H)-one 8 or 9
25 and inhibits the in situ formation of the third ring, as displayed in
Scheme 1.
10 H-shift and the degradation of the copper complex generates urea
intermediate V.
Intermediate V undergoes deprotonation, which induces an
intramolecular nucleophilic attack on the nitrile carbon atom
(route C). The base-induced first ring-closure gives reactive
15 amino-imidate species VII, which undergo a further annulation
via an intramolecular SN2 reaction, affording target compounds 4
or 5.
Conclusions
In conclusion, we have described here an efficient copper(II)-
catalysed two-step one-pot domino process for the rapid synthesis
30 of novel N,N-multiheterocycles. The copper(II)-acetate-promoted
amine-isocyanate coupling and Cs2CO3-induced one-pot domino
4
| Journal Name, [year], [vol], 00–00
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Organic & Biomolecular Chemistry
ring-closure process afforded 18 novel pyrazole-fused imidazo-
7-(4-methoxyphenyl)-6,7-dihydro-2H-imidazo[1,2-c]pyr-
and pyrimido[1,2-c]pyrimidinone scaffolds, with isolated yields
of up to 90%. Copper(II)-acetate was also introduced as catalyst
azolo[4,3-e]pyrimidin-5(3H)-one (4b). White crystalline, (232
View Article Online
mg, 82%), mp 197-199 °C, C14H13N5O2; Elemental analysis:
DOI: 10.1039/C3OB41146J
in the reactions of -aminocarbaldehydes and chloroalkyl 60 Calcd.: C, 59.36; H, 4.63; N, 24.72; O, 11.30; Found: C, 59.34;
5
isocyanates, furnishing pyrazolo[3,4-d]pyrimidin-6(5H)-ones via
a cyclocondensation procedure.
H, 4.66; N, 24.70; O, 11.32; 1H NMR (500 MHz, CDCl3): 3.55
(t, J = 8.4 Hz, 2H), 3.70 (t, J = 8.4 Hz, 2H), 3.86 (s, 3H), 5.34 (s,
1H), 6.99 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.90 (s,
1H); 13C NMR (125.7 MHz, CDCl3):  37.9, 46.1, 55.5, 88.5,
65 112.7, 114.5, 125.7, 130.5, 142.1, 143.0, 158.0, 159.4; MS (ES,
pos. mode) m/z = 284.1 [M + H]+.
Experimental Section
General procedure for the synthesis of products 4a-i and 5a-i
To a mixture of 4-amino-1-aryl-1H-pyrazole-4-carbonitrile
8-(4-methoxyphenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]-
pyrimido[1,2-c]pyrimidin-6(2H)-one (5b). Pale-brown powder,
(240 mg, 81%), mp 189-190 °C, C15H15N5O2; Elemental analysis:
70 Calcd.: C, 60.60; H, 5.09; N, 23.56; O, 10.76; Found: C, 60.62;
10 1a-i (1 mmol), chloroalkyl isocyanate 2a or 2b (1.5 mmol) and
4Å molecular sieve powder (100 mg) in 1.5 mL of dry DMF,
anhydrous Cu(OAc)2 (18 mg, 10 mol%) was added. The reaction
vessel was placed in a preheated oil bath at 80 °C, and the
contents were stirred for 5 min, monitored by TLC (eluent: n-
15 hexane/EtOAc (1:1)). The resulting dark mixture was cooled
down to room temperature. Cs2CO3 (423 mg, 1.2 mmol) was
added, the reaction vessel was placed in a preheated oil bath at
100 °C and the mixture was stirred for an additional 5 min,
monitored by TLC (eluent: n-hexane/EtOAc (1:2)). The
20 suspension was then poured into ice and extracted with EtOAc
(2×30 mL). The combined organic phases were extracted with
brine (2×30 mL), dried over anhydrous Na2SO4, filtered and
evaporated in vacuo. The crude product 4a-i or 5a-i was purified
by flash chromatography, using n-hexane/EtOAc (1:1) as eluent.
25 Note: In the event of microwave irradiation, the following
settings were applied: a standard 10 mL microwave vial; 1. W
power1 (150 W), T1 (80 °C), t1 (5 min), ramping time (15 s); 2.
W power2 (150 W), T2 (100 °C), t2 (5 min), ramping time (20 s).
1
H, 5.06; N, 23.59; O, 10.74; H NMR (500 MHz, DMSO-d6):
1.76 (bs, 2H), 3.15 (bs, 2H), 3.40 (bs, 2H), 7.04-7.12 (m, 3H),
7.38 (d, J = 8.6 Hz, 2H),8.20 (s, 1H); 13C NMR (125.7 MHz,
DMSO-d6): 21.5, 39.5 (CH2, overlapped with DMSO signal),
75 48.0, 55.5, 89.6, 112.8, 114.5, 125.4, 130.4, 141.7, 146.2, 152.7,
159.4; MS (ES, pos. mode) m/z = 298.1 [M + H]+.
7-(2-ethylphenyl)-6,7-dihydro-2H-imidazo[1,2-c]pyrazolo-
[4,3-e]pyrimidin-5(3H)-one (4c). White powder, (222 mg, 79%),
mp 162-164 °C, C15H15N5O; Elemental analysis: Calcd.: C,
80 64.04; H, 5.37; N, 24.90; O, 5.69; Found: C, 64.01; H, 5.40; N,
24.87; O, 5.71; 1H NMR (500 MHz, DMSO-d6): 1.03 (t, J = 7.5
Hz, 3H), 2.34 (q, J = 7.4 Hz, 2H), 3.26 (t, J = 7.8 Hz, 2H), 3.45
(t, J = 7.4 Hz, 2H), 7.24 (s, 1H), 7.38-7.39 (m, 2H), 7.43-7.54 (m,
2H); 8.25 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6):  14.3,
85 23.2, 37.8, 45.9, 87.5, 112.9, 126.8, 127.3, 129.6, 130.4, 135.9,
140.9, 142.2, 144.2, 157.6; MS (ES, pos. mode) m/z = 282.1 [M +
H]+.
30
1-(2-chloroethyl)-3-(4-cyano-1-phenyl-1H-pyrazol-5-yl)-
urea (3a). White powder, (260 mg, 90%), mp 142-144 °C,
C13H12ClN5O; Elemental analysis: Calcd.: C, 53.89; H, 4.17; Cl,
12.24; N, 24.17; O, 5.52; Found: C, 53.92; H, 4.15; Cl, 12.27; N,
8-(2-ethylphenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]pyr-
imido[1,2-c]pyrimidin-6(2H)-one (5c). White powder, (236 mg,
90 80%), mp 127-128 °C, C16H17N5O; Elemental analysis: Calcd.: C,
65.07; H, 5.80; N, 23.71; O, 5.42; Found: C, 65.09; H, 5.82; N,
23.68; O, 5.39; 1H NMR (500 MHz, DMSO-d6): 1.06 (t, J = 6.9
Hz, 3H), 1.65 (bs, 2H), 2.37 (d, J = 7.1 Hz, 2H), 3.06 (bs, 2H),
3.35 (bs, 2H), 6.99 (s, 1H), 7.22-7.40 (m, 2H), 7.40-7.56 (m, 2H);
95 8.23 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6):  14.4, 21.5,
23.1, 39.5 (CH2, overlapped with DMSO signal), 48.0, 89.0,
112.9, 126.4, 126.8, 129.5, 130.2, 135.6, 141.1, 141.7, 147.4,
152.4; MS (ES, pos. mode) m/z = 296.1 [M + H]+.
7-(2,4-dimethylphenyl)-6,7-dihydro-2H-imidazo[1,2-c]-
100 pyrazolo[4,3-e]pyrimidin-5(3H)-one (4d). White powder, (236
mg, 84%), mp 203-205 °C, C15H15N5O; Elemental analysis:
Calcd.: C, 64.04; H, 5.37; N, 24.90; O, 5.69; Found: C, 64.02; H,
5.39; N, 24.88; O, 5.71;1H NMR (500 MHz, DMSO-d6): 1.99
(s, 3H), 2.33 (s, 3H), 3.21-3.37 (m, 2H), 3.44-3.60 (m, 2H), 7.09-
105 7.34 (m, 4H), 8.23 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6):
16.8, 20.7, 37.8, 45.8, 87.3, 112.9, 126.8, 127.3, 131.6, 134.1,
134.9, 139.7, 142.3, 144.0, 157.6; MS (ES, pos. mode) m/z =
282.1 [M + H]+.
1
24.15; O, 5.50; H NMR (500 MHz, DMSO-d6): 3.35 (bs, 2H),
35 3.56 (bs, 2H), 6.94 (s, 1H), 7.29-7.76 (broad s, 4H), 8.17 (s, 1H),
8.91 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6): 41.5, 43.9,
88.4, 113.2, 124.4, 128.7, 129.4, 137.4, 142.1, 142.2, 153.8; MS
(ES, pos. mode) m/z = 290.1 [M + H]+.
7-phenyl-6,7-dihydro-2H-imidazo[1,2-c]pyrazolo[4,3-e]-
40 pyrimidin-5(3H)-one (4a). White crystalline, (207 mg, 82%), mp
185-187 °C, C13H11N5O; Elemental analysis: Calcd.: C, 61.65; H,
4.38; N, 27.65; O, 6.32; Found: C, 61.63; H, 4.36; N, 27.68; O,
6.34; 1H NMR (500 MHz, DMSO-d6): 3.39 (t, J = 7.5 Hz, 2H),
3.68 (t, J = 7.5 Hz, 2H), 7.31 (s, 1H), 7.45-7.57 (m, 5H), 8.28 (s,
45 1H); 13C NMR (125.7 MHz, DMSO-d6): ; 37.9, 46.1, 88.8,
112.6, 124.0, 128.9, 129.5, 137.7, 142.5, 143.1, 157.9; MS (ES,
pos. mode) m/z = 254.1 [M + H]+.
8-phenyl-3,4,7,8-tetrahydropyrazolo[4,3-e]pyrimido[1,2-
c]pyrimidin-6(2H)-one (5a). Pale-brown powder, (227 mg, 85%),
50 mp 179-180 °C, C14H13N5O; Elemental analysis: Calcd.: C,
62.91; H, 4.90; N, 26.20; O, 5.99; Found: C, 62.93; H, 4.93; N,
8-(2,4-dimethylphenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]-
110 pyrimido[1,2-c]pyrimidin-6(2H)-one (5d). White powder, (227
mg, 77%), mp 165-166 °C, C16H17N5O; Elemental analysis:
Calcd.: C, 65.07; H, 5.80; N, 23.71; O, 5.42; Found: C, 65.04; H,
1
26.17; O, 5.97; H NMR (500 MHz, DMSO-d6): 1.78 (s, 2H),
3.16 (s, 2H), 3.44 (s, 2H), 7.10 (s, 1H), 7.42-7.66 (m, 5H), 8.25
(s, 1H); 13C NMR (125.7 MHz, DMSO-d6):  21.5, 48.1, 90.0,
55 112.7, 123.8, 128.9, 129.4, 137.5, 142.1, 146.4, 152.6; MS (ES,
pos. mode) m/z = 268.1 [M + H]+.
1
5.84; N, 23.67; O, 5.45; H NMR (500 MHz, DMSO-d6): 1.61-
1.77 (m, 2H), 2.02 (s, 3H), 2.32 (s, 3H), 3.01-3.14 (m, 2H), 3.33-
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Organic & Biomolecular Chemistry
Page 6 of 8
3.47 (m, 2H), 6.95 (s, 1H), 7.07-7.26 (m, 3H), 8.21 (s, 1H); 13C
NMR (125.7 MHz, DMSO-d6): 17.0, 20.7, 21.5, 39.5 (CH2,
overlapped with DMSO signal), 48.0, 88.7, 113.0, 126.5, 126.9, 60 80%), mp 133-134 °C, C14H11F2N5O; Elemental analysis: Calcd.:
8-(2,4-difluorophenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]pyr-
imido[1,2-c]pyrimidin-6(2H)-one (5g). White powder, (242 mg,
View Article Online
DOI: 10.1039/C3OB41146J
131.7, 133.8, 135.1, 139.5, 141.7, 147.3, 152.4; MS (ES, pos.
mode) m/z = 296.1 [M + H]+.
7-(4-chlorophenyl)-6,7-dihydro-2H-imidazo[1,2-c]pyrazolo-
[4,3-e]pyrimidin-5(3H)-one (4e). Light yellow powder, (247 mg,
C, 55.45; H, 3.66; F, 12.53; N, 23.09; O, 5.28; Found: C, 55.43;
H, 3.64; F, 12.55; N, 23.10; O, 5.29; 1H NMR (500 MHz,
DMSO-d6): 1.81 (bs, 2H), 3.12 (bs, 2H), 3.58 (bs, 2H), 7.02 (s,
1H), 7.23-7.30 (m, 1H), 7.50-7.64 (m, 2H), 8.29 (s, 1H); 13C
5
86%), mp 202-204 °C, C13H10ClN5O; Elemental analysis: Calcd.: 65 NMR (125.7 MHz, DMSO-d6): 21.6, 39.5 (CH2, overlapped
C, 54.27; H, 3.50; Cl, 12.32; N, 24.34; O, 5.56; Found: C, 54.29;
with DMSO signal) 48.0, 88.6, 105.2, 105.4, 105.6, 112.2, 112.3,
112.6, 122.1, 122.2, 129.9, 130.0, 142.7, 148.2, 151.8, 155.5,
155.6, 157.5, 157.6, 161.4, 161.5, 163.4, 163.5; MS (ES, pos.
mode) m/z = 304.1 [M + H]+.
7-(3-fluorophenyl)-6,7-dihydro-2H-imidazo[1,2-c]pyrazolo-
[4,3-e]pyrimidin-5(3H)-one (4h). White powder, (244 mg, 90%),
mp 178-179 °C, C13H10FN5O; Elemental analysis: Calcd.: C,
57.56; H, 3.72; F, 7.00; N, 25.82; O, 5.90; Found: C, 57.58; H,
3.70; F, 7.02; N, 25.80; O, 5.90; 1H NMR (500 MHz, DMSO-d6):
10 H, 3.48; Cl, 12.34; N, 24.32; O, 5.58; 1H NMR (500 MHz,
DMSO-d6): 3.42 (t, J = 8.0 Hz, 2H), 3.76 (t, J = 7.6 Hz, 2H),
7.34 (s, 1H), 7.54-7.63 (m, 4H), 8.29 (s, 1H); 13C NMR (125.7
MHz, DMSO-d6): 37.9, 46.0, 88.5, 112.5, 125.7, 129.5, 133.3,
136.7, 142.7, 143.3, 157.6; MS (ES, pos. mode) m/z = 288.0 [M +
15 H]+.
70
8-(4-chlorophenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]pyr-
imido[1,2-c]pyrimidin-6(2H)-one (5e). Pale-yellow powder, (256
mg, 85%), mp 216-218 °C, C14H12ClN5O; Elemental analysis: 75 3.43 (t, J = 7.9 Hz, 2H), 3.79 (t, J = 7.9 Hz, 2H), 7.29-7.47 (m,
Calcd.: C, 55.73; H, 4.01; Cl, 11.75; N, 23.21; O, 5.30; Found: C,
20 55.70; H, 4.04; Cl, 11.73; N, 23.23; O, 5.32; 1H NMR (500 MHz,
DMSO-d6): 1.79-1.88 (m, 2H), 3.14-3.21 (m, 2H), 3.48-3.57
(m, 2H), 7.12 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6
Hz, 2H), 8.27 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6): 21.5,
48.1, 89.9, 112.6, 125.5, 129.5, 133.3, 136.5, 142.3, 146.6, 152.4;
25 MS (ES, pos. mode) m/z = 302.1 [M + H]+.
4H), 7.54-7.63 (m, 1H), 8.31 (s, 1H); 13C NMR (125.7 MHz,
DMSO-d6): 38.0, 46.0, 88.6, 111.2, 111.4, 112.5, 115.7, 115.8,
120.0, 131.2, 131.3, 139.1, 139.2, 142.8, 143.4, 157.6, 161.0,
162.9; MS (ES, pos. mode) m/z = 272.1 [M + H]+.
80
8-(3-fluorophenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]pyr-
imido[1,2-c]pyrimidin-6(2H)-one (5h). Pale-yellow powder,
(242 mg, 85%), mp 195-196 °C, C14H12FN5O; Elemental
analysis: Calcd.: C, 58.94; H, 4.24; F, 6.66; N, 24.55; O, 5.61;
7-(3-chlorophenyl)-6,7-dihydro-2H-imidazo[1,2-c]pyrazolo-
[4,3-e]pyrimidin-5(3H)-one (4f). White powder, (238 mg, 83%),
1
Found: C, 58.92; H, 4.26; F, 6.66; N, 24.53; O, 5.63; H NMR
mp 188-189 °C, C13H10ClN5O; Elemental analysis: Calcd.: C, 85 (500 MHz, DMSO-d6): 1.84 (bs, 2H), 3.18 (bs, 2H), 3.54 (bs,
54.27; H, 3.50; Cl, 12.32; N, 24.34; O, 5.56; Found: C, 54.29; H,
30 3.48; Cl, 12.34; N, 24.33; O, 5.57; H NMR (500 MHz, DMSO-
2H), 7.15 (s, 1H), 7.30-7.41 (m, 3H), 7.55-7.64 (m, 1H), 8.28 (s,
1H); 13C NMR (125.7 MHz, DMSO-d6): 21.5, 39.5 (CH2,
overlapped with DMSO signal), 48.1, 90.0, 111.1, 111.3, 112.5,
115.7, 115.9, 119.8, 131.2, 131.3, 138.8, 138.9, 142.4, 146.7,
1
d6): 3.43 (t, J = 7.6 Hz, 2H), 3.80 (t, J = 7.3 Hz, 2H), 7.37 (s,
1H), 7.46-7.71 (m, 4H), 8.31 (s, 1H); 13C NMR (125.7 MHz,
DMSO-d6): 38.0, 46.0, 88.5, 112.5, 122.6, 123.8, 128.8, 131.1, 90 152.5, 160.9, 162.9; MS (ES, pos. mode) m/z = 286.1 [M + H]+.
133.5, 139.0, 142.9, 143.4, 157.6; MS (ES, pos. mode) m/z =
7-(2-chlorophenyl)-6,7-dihydro-2H-imidazo[1,2-c]pyrazolo-
[4,3-e]pyrimidin-5(3H)-one (4i). Pale-yellow powder, (232 mg,
82%), mp 227-229 °C, C13H10ClN5O; Elemental analysis: Calcd.:
C, 54.27; H, 3.50; Cl, 12.32; N, 24.34; O, 5.56; Found: C, 54.25;
35 288.1 [M + H]+.
8-(3-chlorophenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]pyr-
imido[1,2-c]pyrimidin-6(2H)-one (5f). White powder, (241 mg,
80%), mp 196-198 °C, C14H12ClN5O; Elemental analysis: Calcd.: 95 H, 3.52; Cl, 12.30; N, 24.36; O, 5.54; 1H NMR (500 MHz,
C, 55.73; H, 4.01; Cl, 11.75; N, 23.21; O, 5.30; Found: C, 55.71;
40 H, 4.03; Cl, 11.78; N, 23.19; O, 5.31; 1H NMR (500 MHz,
DMSO-d6): 1.84 (bs, 2H), 3.19 (bs, 2H), 3.56 (bs, 2H), 7.16 (s,
1H), 7.47 (d, J = 7.0 Hz, 1H), 7.52-7.61 (m, 3H), 8.29 (s, 1H);
DMSO-d6): 3.32 (CH2, overlapped with DMSO signal, 2H),
3.61 (t, J = 8.0 Hz, 2H), 7.27 (s, 1H), 7.48-7.55 (m, 1H), 7.55-
7.61 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H); 13C NMR
(125.7 MHz, DMSO-d6): 37.8, 45.5, 86.8, 112.7, 128.3, 129.8,
13C NMR (125.7 MHz, DMSO-d6): 21.5, 39.5 (CH2, overlapped 100 130.2, 130.4, 131.8, 135.2, 142.9, 144.6, 156.9; MS (ES, pos.
with DMSO signal), 48.0, 90.0, 112.5, 122.4, 123.6, 128.8, 131.1,
45 133.5, 138.7, 142.4, 146.7, 152.4; MS (ES, pos. mode) m/z =
302.1 [M + H]+.
mode) m/z = 288.1 [M + H]+.
8-(2-chlorophenyl)-3,4,7,8-tetrahydropyrazolo[4,3-e]pyr-
imido[1,2-c]pyrimidin-6(2H)-one (5i). White crystalline, (241
mg, 80%), mp 197-198 °C, C14H12ClN5O; Elemental analysis:
7-(2,4-difluorophenyl)-6,7-dihydro-2H-imidazo[1,2-
c]pyrazolo-[4,3-e]pyrimidin-5(3H)-one (4g). White powder, (228 105 Calcd.: C, 55.73; H, 4.01; Cl, 11.75; N, 23.21; O, 5.30; Found: C,
mg, 79%), mp 183-184 °C, C13H9F2N5O; Elemental analysis:
50 Calcd.: C, 53.98; H, 3.14; F, 13.14; N, 24.21; O, 5.53; Found: C,
53.96; H, 3.16; F, 13.12; N, 24.23; O, 5.51; H NMR (500 MHz,
55.73; H, 4.03; Cl, 11.73; N, 23.23; O, 5.32; 1H NMR (500 MHz,
DMSO-d6): 1.72 (bs, 2H), 3.08 (bs, 2H), 3.49 (bs, 2H), 6.99 (s,
1H), 7.46-7.53 (m, 2H), 7.54-7.61 (m, 1H), 7.69 (d, J = 7.7 Hz,
1H), 8.28 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6): 21.6,
1
DMSO-d6): 3.37 (t, J = 7.6 Hz, 2H), 3.75 (t, J = 8.0 Hz, 2H),
7.21-7.35 (m, 2H), 7.51-7.60 (m, 1H), 7.62-7.71 (m, 1H), 8.30 (s, 110 39.5 (CH2, overlapped with DMSO signal), 47.9, 88.5, 112.7,
1H); 13C NMR (125.7 MHz, DMSO-d6): 37.9, 45.7, 86.9,
55 105.2, 105.4, 105.6, 112.3, 112.5, 112.6, 122.4, 122.5, 129.8,
129.9, 143.2, 144.8, 155.5, 155.7, 156.9, 157.6, 157.7, 161.4,
161.5, 163.4, 163.5; MS (ES, pos. mode) m/z = 290.1 [M + H]+.
128.1, 129.7, 130.2, 130.4, 131.7, 134.9, 142.4, 147.9, 152.0; MS
(ES, pos. mode) m/z = 302.1 [M + H]+.
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 8
Organic & Biomolecular Chemistry
General procedure for the synthesis of products 8a, 8b, 9a
and 9b
MHz, DMSO-d6): 31.2, 42.6, 50.0, 103.7, 120.2, 126.0, 127.1,
60 129.1, 129.9, 130.4, 138.2, 146.3, 149.4, 153.5, 158.2; MS (ES,
View Article Online
DOI: 10.1039/C3OB41146J
pos. mode) m/z = 364.1 [M + H]+.
To a mixture of -aminocarbaldehyde 5 or 6 (1 mmol),
Acknowledgements
chloroalkyl isocyanate 2a or 2b (1.5 mmol) and 4Å molecular
sieve powder (100 mg) in 1.5 mL of dry DMF, anhydrous
Cu(OAc)2 (18 mg, 10 mol%) was added. The reaction vessel was
placed in a preheated oil bath at 100 °C and the contents were
stirred for 15 min, monitored by TLC (eluent: n-hexane/EtOAc
(2:3)). The suspension was then poured into ice and extracted
5
This work was supported by the grants from the National
Innovation Agency (NIH): GOP-1.3.1-11/b-2011-0002 and
65 TÉT_10-1-2011-0376 for AVIDIN Ltd.
Notes and references
10 with EtOAc (2×30 mL). The combined organic phases were
extracted with brine (2×30 mL), dried over anhydrous Na2SO4,
filtered and evaporated in vacuo. The crude product 8a, 8b, 9a or
9b was purified by flash chromatography using n-hexane/EtOAc
(2:3) as eluent.
15 Note: In the event of microwave irradiation, the following
settings were applied: a standard 10 mL microwave vial; W
power (150 W), T (100 °C), t (15 min), ramping time (20 s).
1
For reviews on domino reactions, see: a) L. F. Tietze, G. Brasche, K.
Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH,
Weinheim, 2005, ISBN: 978-3-527-29060-4; b) L. F. Tietze, Chem.
Rev., 1996, 96, 115; c) A. Padwa, S. K. Bur, Tetrahedron, 2007, 63,
5341; d) S. K. Bur, A. Padwa, Adv. Heterocycl. Chem., 2007, 94, 1.
For selected reports on -aminonitrile-based transformations, see: a)
E. P. Papadopoulos, J. Heterocycl. Chem., 1980, 17, 1553, b) E. P.
Papadopoulos, J. Heterocycl. Chem., 1984, 21, 1411,.c) F. Fülöp, H.
Wamhoff, P. Sohár, Synthesis, 1995, 7, 863, d) C.-Y. Shiau, J.-W.
Chern, J.-H. Tien, K.-C. Liu, J. Heterocycl. Chem., 1989, 26, 595, e)
S. Ma, J. Li, Y. Sun, J. Zhao, X. Zhao, X. Yang, L. Zhang, L. Wang,
Z. Zhou, Tetrahedron, 2006, 62, 7999; f) N. H. Metwally, F. M.
Abdelrazek, Synth. Commun., 2005, 35, 2481; g) A. D. Roy, A.
Subramanian, R. Roy, J. Org. Chem., 2006, 71, 382; h) M. D'hooghe,
S. Mangelinckx, E. Persyn, W. Van Brabandt, N. De Kimpe, J. Org.
Chem., 2006, 71, 4232; i) S. Mangelinckx, M. D'hooghe, S. Peeters,
N. De Kimpe, Synthesis, 2009, 1105; j) S. Catak, M. D’hooghe, T.
Verstraelen, K. Hemelsoet, A. Van Nieuwenhove, H.-J. Ha, M.
Waroquier, N. De Kimpe, V. Van Speybroeck, J. Org. Chem., 2010,
75, 4530; k) K. Weber, S. Kuklinski, P. Gmeiner, Org. Lett., 2000, 2,
647; l) M. Preiml, K. Hillmayer, N. Klempier, Tetrahedron Lett.,
2003, 44, 5057; m) M. Winkler, L. Martínková, A. C. Knall, S.
Krahulec, N. Klempier, Tetrahedron, 2005, 61, 4249.
70
75
80
85
2
5-(2-chloroethyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyr-
20 imidin-6(5H)-one (8a). White crystalline, (233 mg, 81%), mp
193-194 °C, C14H13ClN4O; Elemental analysis: Calcd.: C, 58.24;
H, 4.54; Cl, 12.28; N, 19.40; O, 5.54; Found: C, 58.22; H, 4.55;
1
Cl, 12.26; N, 19.42; O, 5.55; H NMR (500 MHz, DMSO-d6):
2.43 (s, 3H), 4.01 (t, J = 5.6 Hz, 2H), 4.31 (t, J = 5.6 Hz, 2H),
25 7.26 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 8.00 (d, J = 8.0
Hz, 2H), 9.10 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6): 12.2,
41.9, 53.2, 106.0, 119.7, 125.6, 129.0, 138.2, 146.3, 148.8, 153.6,
157.7; MS (ES, pos. mode) m/z = 289.1 [M + H]+.
5-(3-chloropropyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]-
30 pyrimidin-6(5H)-one (8b). Pale-yellow powder, (229 mg, 76%),
mp 171-172 °C, C15H15ClN4O; Elemental analysis: Calcd.: C,
59.51; H, 4.99; Cl, 11.71; N, 18.51; O, 5.28; Found: C, 59.52; H,
90 3 For selected reports on 5-amino-1H-pyrazole-4-carbonitrile-based
transformations, see: a) F. Da Settimo, G. Primofiore, C. La Motta, S.
Taliani, F. Simorini, A. M. Marini, L. Mugnaini, A. Lavecchia, E.
Novellino, D. Tuscano, C. Martini, J. Med. Chem., 2005, 48, 5162;
(b) M. C. Witschel, H. W. Höffken, M. Seet, L. Parra, T. Mietzner, F.
1
4.98; Cl, 11.72; N, 18.50; O, 5.28; H NMR (500 MHz, DMSO-
95
100
105
110
115
120
Thater, R. Niggeweg, F. Röhl, B. Illarionov, F. Rohdich, J. Kaiser,
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d6): 2.15-2.24 (m, 2H), 2.41 (s, 3H), 3.71 (t, J = 6.4 Hz, 2H),
35 4.09 (t, J = 6.9 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6
Hz, 2H), 8.10 (d, J = 7.9 Hz, 2H), 9.12 (s, 1H); 13C NMR (125.7
MHz, DMSO-d6): 12.2, 31.2, 42.5, 49.7, 106.1, 119.5, 125.4,
129.0, 138.4, 146.2, 148.3, 153.8, 157.6; MS (ES, pos. mode) m/z
= 303.1 [M + H]+.
40
5-(2-chloroethyl)-1,3-diphenyl-1H-pyrazolo[3,4-d]pyr-
imidin-6(5H)-one (9a). White crystalline, (273 mg, 78%), mp
178-179 °C, C19H15ClN4O; Elemental analysis: Calcd.: C, 65.05;
H, 4.31; Cl, 10.11; N, 15.97; O, 4.56; Found: C, 65.03; H, 4.33;
4
1
Cl, 10.10; N, 15.999; O, 4.55; H NMR (500 MHz, DMSO-d6):
45 4.02 (t, J = 6.1 Hz, 2H), 4.42 (t, J = 5.8 Hz, 2H), 7.32 (t, J = 7.1
Hz, 1H), 7.49-7.61 (m, 5H), 8.01 (d, J = 6.9 Hz, 2H), 8.18 (d, J =
8.1 Hz, 2H), 9.50 (s, 1H); 13C NMR (125.7 MHz, DMSO-d6):
41.7, 52.8, 103.6, 120.4, 126.1, 127.0, 129.1, 129.2, 130.1,
130.2, 138.1, 146.4, 149.8, 153.3, 158.2; MS (ES, pos. mode) m/z
50 = 351.1 [M + H]+.
5-(3-chloropropyl)-1,3-diphenyl-1H-pyrazolo[3,4-d]pyr-
imidin-6(5H)-one (9b). Yellow powder, (273 mg, 75%), mp 187-
188 °C, C20H17ClN4O; Elemental analysis: Calcd.: C, 65.84; H,
4.70; Cl, 9.72; N, 15.36; O, 4.39; Found: C, 65.82; H, 4.72; Cl,
5
6
T. Kanzian, T. A. Nigst, A. Maier, S. Pichl, H. Mayr, Eur. J. Org.
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Timken, J. Chem. Soc., Perkin Trans. 2, 1999, 1433.
1
55 9.70; N, 15.37; O, 4.38; H NMR (500 MHz, DMSO-d6): 2.19-
7
8
9
2.30 (m, 2H), 3.74 (t, J = 6.3 Hz, 2H), 4.19 (t, J = 7.0 Hz, 2H),
7.31 (t, J = 7.3 Hz, 1H), 7.48-7.61 (m, 5H), 8.02 (d, J = 6.8 Hz,
2H), 8.19 (d, J = 7.7 Hz, 2H), 9.42 (s, 1H); 13C NMR (125.7
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Organic & Biomolecular Chemistry
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