Studies on isocyanides and related compounds; a facile synthesis of 4-phenyl-1-(2H)phthalazinone-2-alkanoic acid amides

Article abstract of DOI:10.1055/s-2001-9745

A convenient synthesis of the title compounds by means of the Ugi four-component condensation (Ugi 4-CC) is reported. The reaction between acetaldehyde azine (3a), 2-benzoylbenzoic acid (4), and cyclohexyl isocyanide (5) spontaneously afforded N-cyclohexy

Full text of DOI:10.1055/s-2001-9745

PAPER
85
Studies on Isocyanides and Related Compounds; A Facile Synthesis of
4
-Phenyl-1-(2H)phthalazinone-2-alkanoic Acid Amides
a
a
b
a
a1
Stefano Marcaccini,* Roberto Pepino, Cecilia Polo, M Cruz Pozo
a
CNR, Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni, Dipartimento di Chimica Organica "Ugo
Schiff", Università di Firenze, via Gino Capponi 9, 50121 Firenze, Italy
E-mail: marc@chimorg.unifi.it
b
Departamento de Química Orgánica, Facultad de Veterinaria, Universidad deExtremadura, Avenida de la Universidad s/n, 10071 Cáceres,
Spain
Received 7 June 2000; revised 11 September 2000
The usefulness of multi-component reactions of isocya-
Abstract: A convenient synthesis of the title compounds by means
nides in the synthesis of precursors of heterocyclic com-
of the Ugi four-component condensation (Ugi 4-CC) is reported.
The reaction between acetaldehyde azine (3a), 2-benzoylbenzoic
pounds has been largely proved.1
1, 12
1
1
acid (4), and cyclohexyl isocyanide (5) spontaneously afforded
N-cyclohexyl 2-(1,2-dihydro-1-oxo-4-phenylphthalazin-2-yl)pro-
pionamide (1a) upon loss of acetaldehyde from the intermediate
Ugi 4-CC adduct 6a. Starting from the less reactive azines 3c-f
arising from ketones, the Ugi 4-CC adducts 6c-f did not spontane-
ously cyclize, whereas phenylacetaldehyde azine (3b) afforded a
In continuation of our studies, we wish to report a novel
synthetic approach that allowed us to easily obtain a series
of N-cyclohexyl 4-phenyl-1-(2H)phthalazinone-2-al-
kanoic acid amides 1. The synthesis is based on the Ugi
13
four-component condensation (U-4CC) between azines
mixture of the Ugi 4-CC adduct 6b and cyclized product 1b. In all 3 (generated in situ by reacting carbonyl compounds 2 and
of the cases, the adducts 6b-f were easily cyclized to 1b-f in acidic hydrazine), 2-benzoylbenzoic acid (4), and cyclohexyl
medium.
isocyanide (5) and is summarized in the Scheme.
Key words: isocyanides, multi-component reactions, Ugi four-
component condensation (U-4CC), 1-(2H)phthalazinones, phthala-
zine ring synthesis
The reaction took place very easily with azines 3a, b aris-
ing from aldehydes. When acetaldehyde azine (3a) was
employed, the primary four-component adduct spontane-
ously cyclized to 1a with loss of acetaldehyde. By em-
ploying phenylacetaldehyde azine (3b),
a partial
As it is well-known, 2-acylbenzoic acids react with hydra-
zine to give 4-substituted 1-(2H)phthalazinones. By em-
ploying N-substituted hydrazines in the place of
hydrazine, 2,4-disubstituted 1-(2H)phthalazinones are ob-
cyclization took place. Consequently, a mixture of the pri-
mary 4-CC adduct 6b and the cyclization product 1b was
always obtained. By recrystallizing the mixture twice, we
were able to obtain the primary adduct 6b in a pure form,
but with considerable loss. Compound 6b was easily cy-
clized to 1b upon heating an ethanolic solution containing
hydrochloric acid. The overall yield was nevertheless low
because of the considerable loss due to the purification of
the starting material. Fortunately, compound 1b was ob-
tained in a satisfactory manner upon acidic treatment of
the crude reaction mixture. The physical and spectral data
are reported in Tables 1 and 2.
2
tained. Alternatively, these product can be obtained by
reacting 4-substituted 1-(2H)phthalazinones with reactive
2
halides in the presence of bases. This method has been
employed for the synthesis of 4-substituted alkyl
1
-(2H)phthalazinone-2-acetates which are the starting
products for the preparation of the corresponding acids
and their functional derivatives such as amides and hy-
3
-7
drazides. A straightforward synthesis of the amides has
been achieved by employing N,N-diethyl chloroacet-
With the less reactive azines of ketones 3c-f, the reaction
was slower and required longer reaction periods. In this
case, the adducts 6c-f did not cyclize spontaneously.
8
amide as alkylating agent. A variety of biological activi-
8
8
5
ties such as hypnotic, anticonvulsive, antibacterial,
5
6
6
antifungal, antianaphilactic, nootropic, and inhibition
4
of the aldose reductase has been reported for these com- Since we were unable to purify the hydrazones 6c-f, we
pounds.
performed the cyclization on the crude products. The cy-
clization was achieved upon heating in acidic aqueous
medium and afforded the desired products 1c-f in satis-
factory yields. As expected, we were unable to isolate the
intermediate hydrazides 7.
A limitation of the above synthetic method lies in the poor
availability of a-haloacid derivatives. Consequently, the
1
2
4
-substituted 1-(2H)phthalazinones bearing -CR R COX
1 2
groups (R = alkyl or aralkyl, R = H, alkyl or aralkyl,
In conclusion, the present synthesis allowed us to obtain
the title compounds in a very simple manner. The substi-
X = OR, NHR, NR ) in position 2 appear to be not easily
obtainable.
2
3
tution pattern on the sp carbon atom linked across the po-
The synthesis of 4-substituted alkyl 1-(2H)phthalazinone-
sition 2 of the phthalazinone ring and the carbamoyl group
can be easily changed by choosing suitable carbonyl com-
pounds.
2
-acetates can also be accomplished by reacting 2-acyl-
9
,10
benzoic acids with alkyl hydrazinoacetates. Since hy-
drazinoesters are less available than the corresponding
haloesters, this method suffers from severe limitations.
Synthesis 2001, No. 1, 85–88 ISSN 0039-7881 © Thieme Stuttgart · New York

8
6
S. Marcaccini et al.
PAPER
N-Cyclohexyl-2-(1,2-dihydro-1-oxo-4-phenylphthalazin-2-
R
N
1
equiv N2H4·H2O
MeOH or EtOH
R1
R
yl)propionamide (1a)
O
N
R
A well-stirred solution of acetaldehyde (2a, 0.97 g, 22 mmol) and
hydrazine hydrate (0.55 g, 11 mmol) in MeOH (30 mL) was treated
with finely powdered 2-benzoylbenzoic acid (4, 2.49 g, 11 mmol)
and cyclohexyl isocyanide (5, 1.20 g, 11 mmol). The reaction mix-
ture was stirred for 8 h at r.t. and then filtered to give 1a. The mother
R1
R1
R
2
3
3
, c-C6H11NC (5)
r. t., EtOH or MeOH
-48 h
R1
liquors were evaporated to dryness and the residue stirred with Et O
R1
2
CO2H
O
R
(25 mL) to give another crop of 1a. The crude product was recrys-
tallized from DMF/EtOH (15 mL, 1:2) to give pure 1a (3.35 g).
8
N
N
CONHc-C6H11
O
N-Cyclohexyl-2-(1,2-dihydro-1-oxo-4-phenylphthalazin-2-yl)-
3-phenylpropionamide (1b)
Ph
Ph
4
Finely powdered 2-benzoylbenzoic acid (4, 2.49 g, 11 mmol) and
cyclohexyl isocyanide (5, 1.20 g, 11 mmol) were added to a well-
stirred solution of phenylacetaldehyde (2b, 2.64 g, 22 mmoles) and
hydrazine hydrate (0.55 g, 11 mmol) in MeOH (30mL). After a few
minutes, the formation of a precipitate was observed. The reaction
mixture was stirred for 24 h and then evaporated to dryness. The
residue was dissolved in the minimal amount of boiling EtOH and
the resulting solution cooled, treated with 6 N HCl (3 mL), and then
refluxed again for 5 min. The resulting mixture was ice-cooled and
filtered. The collected solid product was recrystallized from EtOH
to give 1b (3.73 g).
O
6
6
a,b
1 a,b
-
RCHOa
1% (1a)
8
R1
R
HCl, H2O
H2N
EtOH, r. t. or ∆
N
O
CONHc-C6H11
5
min - 15 h
6
b-f
O
Ph
The Ugi 4-CC adduct 6b was obtained by means of a different
work-up: compounds 3b, 4, and 5 were allowed to react as de-
scribed above. The solid that precipitated in the reaction medium
was collected by filtration and recrystallized twice from EtOH to
give 6b (1.84 g, 37%); mp: 171-173 °C.
7
R1
O
R
-
1
IR (KBr): n = 3365 (NH), 1670 (CO), 1656 (CO) cm .
1
b-f
N
N
CONHc-C6H11
Anal. Calcd for C H N O (571.72): C, 77.73; H, 6.52; N, 7.35.
5
9-75%
37 37
3
3
Found: C, 78.05; H, 6.71; N, 7.27.
Ph
1
N-Cyclohexyl-1-(1,2-dihydro-1-oxo-4-phenylphthalazin-2-yl)-
1-cyclopentanecarboxamide (1c); Typical Procedure
a
If R = PhCH , the spontaneous cyclization took place partially.
2
A solution of the cyclopentanone (2c, 1.85 g, 22 mmol) and hydra-
zine hydrate (0.55 g, 11 mmol) in MeOH (30 mL) was stirred at r.t.
for 20 min. Finely powdered 2-benzoylbenzoic acid (4, 2.49 g,
11 mmol) and a solution of cyclohexyl isocyanide (5, 1.20 g,
R1
R–R1
1
a
,2,3,6,7
R
1
1 mmol) in MeOH (10 mL) were added to the above solution. The
CH
3
H
H
reaction mixture was stirred for 48 h and then evaporated to dryness.
The gummy white residue was stirred with EtOH (20 mL) and the
b
c
d
e
f
C
6
H
5
CH
2
resulting solution was treated with 37% HCl (10 mL) and H O
2
(13 mL). The resulting mixture was refluxed for 30 min and then
CH (CH ) CH
2
2
2
2
2
2
cooled and filtered to give 1c. The mother liquors were evaporated
almost to dryness and the residue stirred with Et O (30 mL). The
CH
CH
(CH
CH
2
)
3
CH
2
2
resulting suspension was filtered to give another crop of 1c. The
collected crude product was recrystallized from EtOH to give pure
2
OCH
2
CH
2
1
c (2.70 g).
CH CH N(COCH )CH CH
2
2
3
2
2
N-Cyclohexyl-1-(1,2-dihydro-1-oxo-4-phenylphthalazin-2-yl)1-
cyclohexanecarboxamide (1d)
Compound 1d was obtained by employing cyclohexanone (2d,
Scheme
2
.16 g) in the place of cyclopentanone (2c). Yield: 3.12 g after re-
crystallization from i-PrOH.
N-Cyclohexyl-4-(1,2-dihydro-1-oxo-4-phenylphthalazin-2-yl)-
Mps were determined in open capillary tubes using a Büchi 512
4
-tetrahydropyrancarboxamide (1e)
Compound 1e was obtained by employing tetrahydropyran-4-one
2e, 2.20 g) in the place of cyclopentanone (2c). Yield: 3.37 g after
melting point apparatus and are uncorrected. IR spectra were re-
1
corded on a Perkin-Elmer 881 spectrophotometer for KBr discs. H
(
NMR spectra were recorded on a Varian Gemini 200 apparatus at
recrystallization from EtOH/DMF (17 mL, 1:2).
2
00 MHz in CDCl solutions. All the chemicals were employed as
3
N-Cyclohexyl 1-Acetyl-4-(1,2-dihydro-1-oxo-4-phenylphthal-
azin-2-yl)-4-piperidinecarboxamide (1f)
A solution of 1-acetyl-4-piperidone (2f, 3.11 g, 22 mmol) in EtOH
supplied. Cyclohexyl isocyanide (5) was prepared according to lit-
erature procedures.14,15
(
20 mL) was stirred at r.t. with hydrazine hydrate (0.55 g, 11 mmol)
for 20 min. Finely powdered 2-benzoylbenzoic acid (4, 2.49 g,
1 mmol) and cyclohexyl isocyanide (5, 1.20 g, 11 mmol) were
1
Synthesis 2001, No. 1, 85–88 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Studies on Isocyanides and Related Compounds
Elemental Analysis
87
Table 1 Compounds 1a-f Prepared
Product
Yield %
Mp °C
Formula
MW
Found
Calculated
H
C
H
N
C
N
1
1
1
1
1
1
a
b
c
d
e
f
81
75
59
66
71
67
229-230
200-201
174-175
178-179
226-227
232-234
C H N O
375.47
451.57
415.54
429.57
431.54
472.59
73.78
77.41
75.21
75.31
72.08
71.17
6.66
6.68
7.22
7.01
6.98
6.93
11.37
9.09
10.01
9.99
10.05
11.60
73.57
77.14
75.15
75.49
72.37
71.16
6.71
6.47
7.03
7.27
6.77
6.82
11.19
9.31
10.11
9.78
9.74
11.86
2
3
25
3
2
2
2
2
3
3
C H N O
2
9
29
3
C H N O
2
6
29
3
C H N O
2
7
31
3
C H N O
2
6
29
3
C H N O
2
8
32
4
Table 2 Spectral Data of Compounds 1a−f
1
13
Prod-
uct
IR (KBr)
n (cm )
H-NMR(200MHz, CDCl /TMS)
C-NMR (50 MHz, CDCl /TMS)
3
3
−
1
d, J (Hz)
d
1a
3261 (NH),
0.99-1.95 (m, 10 Hcyclohexane), 1.70 (d, 3 H, J = 7.4,
15.78 (CH ), 24.45, 25.40, 32.67 (CH ), 48.03
3 2
1
651 (CO)
CH ), 3.76 (m, 1 H, 1-Hcyclohexane), 5.75 (q, 1 H, J =
(CHcyclohexane), 56.63 (NCHCO), 126.60, 127.21,
128.37, 129.04, 129.31, 131.36, 132.99 (CHarom),
127.79, 128.37 (Carom), 134.81 (CaromCON), 147.21
3
7
.4, CH CH), 6.31 (d, 1 H, J = 7.8, NH), 7.47-8.58
3
(
m, 9 Harom)
(
C=N), 159.16 (CCON), 168.93 (CCONH)
1b
3365 (NH),
670, 1656
CO)
0.93-1.80 (m, 10 Hcyclohexane), 3.58 (m, 2 H, CH Ph),
24.47, 25.47, 32.70 (CH ), 35.93 (CH Ph), 48.13
2
2
2
1
(
3.77 (m, 1 H, 1-Hcyclohexane), 5.93 (dd, 1 H, J = 6.4,
9.0, CHCO), 6.29 (d, 1 H, J = 6.6, NH), 7.10-8.50
(CHcyclohexane), 62.10 (NCHCO), 126.30, 126.59,
127.26, 128.15, 128.38, 129.05, 129.28, 131.31,
132.96 (CHarom), 127.61, 128.97 (Carom), 134.81,
(
m, 14 Harom)
1
37.35 (CaromCON), 147.35 (C=N), 159.68
(
CCON), 168.14 (CCONH)
1c
3325 (NH),
658, 1637
CO)
0.98-1.96 (m, 10 Hcyclohexane and 8 Hcyclopentane), 3.80
(m, 1 H, 1-Hcyclohexane), 5.68 (d, 1 H, J = 7.8, NH),
24.19, 24.69, 25.48, 32.80, 35.83 (CH ), 48.25
(CHcyclohexane), 77.85 (NCCO), 126.18, 127.14,
128.38, 128.87, 129.34, 131.03, 132.77 (CHarom),
2
1
(
7.53-8.54 (m, 9 Harom
)
1
28.58, 128.69 (Carom), 135.27 (CaromCON), 145.57
(
C=N), 158.88 (CCON), 171.34 (CCONH)
1d
3301 (NH),
659, 1636
CO)
0.97-2.72 (m, 20 Hcyclohexane), 3.80 (m, 1 H,
1-Hcyclohexane), 5.75 (d, 1 H, J = 8.2, NH), 7.52-8.51
(m,
22.38, 24.69, 25.46, 25.49, 25.95, 32.20, 32.82
1
(
(CH ), 48.18 (CHcyclohexane), 70.42 (NCCO), 125.98,
2
127.17, 128.37, 128.79, 129.37, 130.90, 132.70
(CHarom), 128.41, 128.88 (Carom), 135.34 (Carom-
CON), 145.63 (C=N), 159.23 (CCON), 172.01
9
Harom
)
(
CCONH)
1
e
f
3313 (NH),
666, 1639
CO)
1.00-1.95 (m, 10 Hcyclohexane), 2.40-2.76 (m, 4 H,
OCH CH ), 3.74-3.98 (m, 5 H, 1-H and
24.66, 25.43, 32.41, 32.77 (CH ), 48.35 (CH
2
cyclohex-
1
(
), 64.31 (2 CH O), 67.62 (NCCO), 126.25,
2
2
2
cyclo-hexane
ane
4 H, OCH ), 5.85 (d, 1 H, J = 7.6, NH), 7.52-8.51
127.15, 128.44, 128.99, 129.29, 131.22, 133.00
(CHarom), 128.76 (Carom), 135.02 (CaromCON),
2
(
m, 9 Harom
)
1
46.19 (C=N), 159.32 (CCON), 170.72 (CCONH)
1
3311 (NH),
660, 1629
CO)
0.99-2.80 (m, 14 H, 10 Hcyclohexane and 4 H,
21.27 (CH ), 24.67, 25.39, 31.66, 32.01, 32.73
3
1
NCH CH ), 2.09 (s, 3 H, CH ), 3.36-4.20 (m, 5 H,
(CH ), 37.97, 43.05 (CH N), 48.44 (CHcyclohexane),
2
2
3
2
2
(
1-Hcyclohexane and 4 H, NCH ), 5.68 (d, 1 H, J = 8.2,
68.03 (NCCO), 126.35, 127.17, 128.50, 129.13,
2
NH), 7.52-8.51 (m, 9 Harom
)
129.23, 131.39, 133.15 (CHarom), 128.50, 128.62
(
(
Carom), 134.84 (CaromCON), 146.50 (C=N), 159.14
CCON), 168.62 (NCOCH ), 170.72 (CCONH)
3
Synthesis 2001, No. 1, 85–88 ISSN 0039-7881 © Thieme Stuttgart · New York

8
8
S. Marcaccini et al.
PAPER
added to the above solution. The reaction mixture was allowed to
stand for 48 h at r.t., and then treated under stirring with 37% HCl
(11) Review: Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int.
1993, 25, 141.
(
10 mL) and H O until incipient turbidity. The resulting emulsion
Bossio, R.; Marcaccini, S.; Papaleo, S.; Pepino, R. J.
Heterocycl. Chem. 1994, 31, 397.
Bossio, R.; Marcaccini, S.; Pepino, R. Synthesis 1994, 765.
Bossio, R.; Marcaccini, S.; Pepino, R.; Paoli, P. J. Heterocycl.
Chem. 1994, 31, 729.
2
was stirred for 15 h at r.t. and the supernatant liquid transferred to a
round-bottomed flask. The gummy white residue was stirred with
H O (30 mL) and Et O (20 mL) to give a suspension, which was fil-
2
2
tered to give 1f. The mother liquors were evaporated almost to dry-
ness and the residue stirred with H O (20 mL) and Et O (15 mL) to
give a suspension, which was filtered to give another crop of 1f. The
crude product was recrystallized from EtOH to give pure 1f
Bossio, R.; Marcaccini, S.; Pepino, R. J. Heterocycl. Chem.
1995, 32, 1115.
Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T. J. Chem.
Soc., Perkin Trans. 1 1996, 229.
2
2
(
3.48 g).
Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T. J. Org.
Chem. 1996, 61, 2202.
Bossio, R.; Fernández Marcos, C.; Marcaccini, S.; Pepino, R.
Tetrahedron Lett. 1997, 38, 2519.
Bossio, R.; Fernández Marcos, C.; Marcaccini, S.; Pepino, R.
Heterocycles 1997, 45, 1589.
Bossio, R.; Fernández Marcos, C.; Marcaccini, S.; Pepino, R.
Synthesis 1997, 1389.
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Article Identifier:
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1
Synthesis 2001, No. 1, 85–88 ISSN 0039-7881 © Thieme Stuttgart · New York