Facile preparation of 3-amino-4-(arylamino)-1h-isochromen-1-ones by a new multicomponent reaction

Article abstract of DOI:10.1002/ejoc.200400685

Reactions between 2-formylbenzoic acid, various anilines and HCN result in the formation of 3-amino-4-(arylamino)-1H-isochromen-1-ones in high yield. The mechanism of this three-component condensation involves the intermediate formation of an α-aminonitrile and subsequent cyclization through nucleophilic attack of the ortho-carboxylate at the nitrile carbon. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400685

FULL PAPER
Facile Preparation of 3-Amino-4-(arylamino)-1H-isochromen-1-ones by a New
Multicomponent Reaction
Till Opatz*[a] and Dorota Ferenc[a]
Keywords: Multicomponent reactions / Heterocycles / Cyclization / Amines / Strecker reaction
Reactions between 2-formylbenzoic acid, various anilines
and HCN result in the formation of 3-amino-4-(arylamino)-
1H-isochromen-1-ones in high yield. The mechanism of this
three-component condensation involves the intermediate
formation of an α-aminonitrile and subsequent cyclization
through nucleophilic attack of the ortho-carboxylate at the
nitrile carbon.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
of acid, 2-substituted 3-oxoisoindoline-1-carbonitriles 1 are
formed through cyclodehydration of the intermediate α-
aminonitriles.[13] Products of the same type have been pre-
pared by Baum and Staveski from Schiff bases of methyl 2-
formylbenzoate (Scheme 1).[14]
Introduction
Multicomponent reactions (MCRs) are valuable tools for
the preparation of complex structures from simple starting
materials. In particular, they are well suited for the rapid
and highly atom-economical assembly of large compound
libraries. Consequently, the application of MCRs in the
drug discovery process has enjoyed considerable attention,
and the development of new MCRs is being pursued both
in industry and academia.[1,2] From the discovery of the
Strecker reaction in 1850,[3] the repertoire has expanded to
include a multitude of synthetic procedures, among them,
for example, the Hantzsch pyrrole and dihydropyridine syn-
thesis,[4,5] the Mannich reaction,[6] the Biginelli condensa-
tion,[7] the Passerini reaction,[8] and the Petasis reaction.[9]
Whereas a relatively large proportion of the known MCRs
are based on isonitriles, the prototype being the Ugi four-
component condensation,[10] only a few MCRs employ hy-
drogen cyanide as reactant. On the other hand, two HCN-
based reactions, the Strecker reaction and the related Buch-
erer–Bergs hydantoin synthesis,[11,12] are important indus-
trial processes used for the production of amino acids or
chelators such as EDTA or NTA on a 100000-ton scale.
Here we report on a novel three-component condensation
of 2-formylbenzoic acid with anilines and hydrogen cyanide
to afford 3-amino-4-(arylamino)-1H-isochromen-1-ones.
Scheme 1. Synthesis of amino(3-oxo-2,3-dihydro-1H-isoindol-1-yli-
dene)acetonitriles and 3-oxoisoindoline-1-carbonitriles.
Results and Discussion
Reactions between 2-formylbenzoic acid, amines and
HCN have turned out to be a surprisingly rich source of
different heterocyclic products. In the presence of an excess
Recently, we found that amino(3-oxo-2,3-dihydro-1H-
isoindol-1-ylidene)acetonitriles 3 can be obtained from 2-
formylbenzoic acid, HCN and α-unbranched primary am-
ines under neutral or basic conditions.[15] In contrast to the
formation of compounds 1, this reaction is rather sensitive
to the steric bulk of the amine component, even an isopro-
pyl group preventing the corresponding product from being
[a]
Institut für Organische Chemie, Johannes Gutenberg-Uni-
versität Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
Fax: +49-6131-39-24786,
E-mail: opatz@uni-mainz.de
Eur. J. Org. Chem. 2005, 817–821
DOI: 10.1002/ejoc.200400685
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
817

T. Opatz, D. Ferenc
FULL PAPER
formed. Consequently, treatment of 2-formylbenzoic acid tacked by the carboxy group to yield the O-acyl imidate 6,
with anilines does not yield compounds of type 3. In the followed by tautomerization to 4.
presence of an excess of acetic acid, the dehydrated Strecker
This MCR therefore has a certain similarity to the Buch-
products 1 were obtained instead. When the same reaction erer–Bergs reaction, with the ortho-carboxy group function-
was run with an equimolar mixture of aniline and acetic ing in place of the carbamate, though the final imidate–
acid, however, a yellow crystalline compound was obtained, amide rearrangement step does not take place. The reaction
with the same composition as the Strecker product as appears to be much less sensitive to the steric bulk of the
judged by mass spectrometry and elemental analysis, but amine component than the formation of compounds 3,
not showing any CϵN absorption in the IR spectrum. even N-methylaniline proving to be a suitable substrate. Al-
NMR analysis revealed this substance to be 3-amino-4- though the decisive role of the nature of the amine for the
(phenylamino)-1H-isochromen-1-one (4a). To explore the outcome of the reaction is not well understood, it may be
scope of this novel three-component condensation, a set of argued that the electrophilicity of the nitrile carbon in 5,
substituted anilines was subjected to the same conditions; and hence the aptitude for a nucleophilic attack by the car-
the results are listed in Table 1.
boxylate, is increased by an N-aryl substituent, thus favour-
ing the formation of compound 4. Alternatively, the higher
pKa of an alkyl-substituted amino group may give rise to a
zwitterionic structure of the aminonitrile 5, which adopts a
different conformation with the nitrile group turned away
from the potential nucleophile. At lower pH, however,
cyclodehydration of the intermediate aminonitrile to 3-
oxoisoindoline-1-carbonitriles 1 becomes the dominant pro-
cess.
Table 1. Preparation of 3-amino-4-(arylamino)-1H-isochromen-1-
ones.
The structural features of the unprecedented diaminoiso-
coumarin moiety in compounds 4 can be recognized in the
crystal structure of the p-tolyl derivative 4d (Figure 1). Ste-
ric repulsion between the protons at C(9) and N(11) with
Compound
Ar
R
Yield (%)
4a
4b
4c
4d
4e
4f
4
4h
4i
4j
4k
Ph
H
H
H
H
H
H
H
H
H
Me
H
82
75
60
82
88
78
81
74
87
64
56
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
3-MeO-C6H4
4-MeO-C6H4
4-CF3-C6H4
4-Br-C6H4
4-Cl-C6H4
Ph
2,4-Me2-C6H3
In all cases, the 3-amino-4-(arylamino)-1H-isochromen-
1-ones 4 could be isolated in high yield from the reaction
mixtures as stable yellow crystalline solids. The mechanism
of their formation can be interpreted as depicted in
Scheme 2. Firstly, a regular Strecker reaction at the alde-
hyde function takes place. Subsequently, the nitrile carbon
of the intermediate α-aminonitrile 5 is nucleophilically at-
Figure 1. ORTEP view of 4d at 193 K with the atomic numbering
scheme. Thermal ellipsoids are drawn at 50% probability.
Table 2. Selected bond lengths (Å) and angles (°) for 4d.
Bond lengths
Bond lengths
C(1)–C(2)
C(1)–C(10)
C(2)–N(11)
C(2)–O(3)
1.346(4) O(3)–C(4)
1.443(3) C(4)–C(5)
1.354(3) C(4)–O(13)
1.372(3) C(1)–N(13)
1.386(3)
1.439(4)
1.212(3)
1.426(3)
Bond angles
Bond angles
C(1)–C(2)–N(11)
C(1)–C(2)–O(3)
C(2)–C(1)–N(13)
126.9(2) C(2)–O(3)–C(4)
122.7(2) O(12)–C(4)–O(3)
117.6(2) O(12)–C(4)–C(5)
121.6(2)
115.1(2)
127.7(2)
Scheme 2. Proposed mechanism of the formation of compounds 4.
818
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 817–821

3-Amino-4-(arylamino)-1H-isochromen-1-ones by a New Multicomponent Reaction
FULL PAPER
sured with a Dr. Tottoli apparatus (Büchi) and are uncorrected. All
compounds showed decomposition rather than melting at the given
temperatures.
the ortho-protons of the aniline ring results in a twisted ge-
ometry with an angle of 70° between the ring planes. As
would be expected, the C(1)=C(2) bond (1.346 Å) shows
double bond character and all other bond lengths and
angles are within the normal ranges (Table 2). The mole-
cules form a network of inversion symmetric dimers with
N(11)–H(11A)···O(12)Ј and N(13)–H(13)···N(11)ЈЈ hydro-
gen bonds.
Compounds 4 present a hydrogen bond “donor-ac-
ceptor-acceptor” pattern similar to that found in cytosine,
so the ability to form Watson–Crick-type base pairs with
guanine might be anticipated (Figure 2). It should be noted
that the sp3-hybridized oxygen O3 is not expected to show
a preference for an H-bond donor located outside the ring
plane.[16,17] Investigations on this issue are underway in our
laboratory.
General Procedure: The corresponding aniline (20 mmol), acetic
acid (1.14 mL, 20 mmol) and potassium cyanide (0.78 g, 12 mmol)
were added to a stirred solution of 2-formylbenzoic acid (1.50 g,
10 mmol) in methanol (25 mL). The resulting mixture was heated
to reflux for 3 h. After cooling, the crystalline product was col-
lected by filtration, washed with water and methanol and dried
over P4O10. In cases of incomplete or lacking crystallization, water
and CH2Cl2 (30 mL each) were added to the residue, the organic
layer was separated, washed with satd. aq. NaHCO3 and dried with
Na2SO4, and the solvent was removed in vacuo. The resulting resi-
due was purified by flash chromatography or recrystallization.
3-Amino-4-phenylamino-1H-isochromen-1-one (4a): Yellow crystals
(2.08 g, 82%), m.p. 131 °C (dec.), Rf (cyclohexane/EtOAc/CH2Cl2
2:1:1) = 0.48. 1H NMR (300 MHz, [D6]DMSO), COSY (400 MHz,
[D6]DMSO): δ = 6.50–6.62 (m, 5 H, NH2, 2Ј,6Ј-H, 4Ј-H), 6.80 (s,
1 H, NH), 7.02–7.11 (m, 4 H, 5-H, 7-H, 3Ј,5Ј-H), 7.52 (ddd, J =
8.3, 7.2, 1.3 Hz, 1 H, 6-H), 7.92 ppm (pseudo-d, J = 7.9 Hz, 1 H,
8-H). 13C NMR (75.5 MHz, [D6]DMSO), HMQC, HMBC (400/
100.6 MHz, [D6]DMSO): δ = 90.5 (C-4), 112.7 (C-2Ј,6Ј), 113.9 (C-
8a), 116.7 (C-4Ј), 119.6 (C-5), 122.1 (C-7), 128.9 (C-3Ј,5Ј), 129.2
(C-8), 134.8 (C-6), 141.7 (C-4a), 147.7 (C-1Ј), 156.0 (C-3),
160.3 ppm (CO). IR (KBr): ν = 3474, 3375, 3300, 1728, 1653, 1605,
˜
1586, 1497, 1483, 1304, 766, 756, 696 cm–1. FD-MS (m/z): 252.2
(100) [M]+, 504.7 (5) [2M]+. C15H12N2O2 (252.27): calcd. C 71.42,
H 4.79, N 11.10; found C 71.61, H 4.93, N 11.24.
Figure 2. Possible hydrogen bonds between compounds 4 and gua-
nine
3-Amino-4-(2-tolylamino)-1H-isochromen-1-one (4b): Yellow crys-
tals (2.00 g, 75%), m.p. 150 °C (dec.), Rf (cyclohexane/EtOAc 2:1)
= 0.55. 1H NMR (300 MHz, [D6]DMSO): δ = 2.32 (s, 3 H, Me),
6.09 (s, 1 H, NH), 6.18 (dd, J = 8.1, 1.1 Hz, 1 H, 6Ј-H), 6.48–6.55
(m, 3 H, NH2, 4Ј-H), 6.83 (d-pseudo-t, Jt = 8, Jd = 1.7 Hz, 5Ј-H),
6.94–7.10 (m, 3 H, 5-H, 7-H, 3Ј-H), 7.49 (ddd, J = 8.1, 7.2, 1.4 Hz,
1 H, 6-H), 7.92 ppm (pseudo-d, J = 8.1 Hz, 8-H). 13C NMR
(75.5 MHz, [D6]DMSO): δ = 17.8 (Me), 90.5 (C-4), 110.3 (C-6Ј),
113.9 (C-8a), 116.6 (C-4Ј), 119.7 (C-5), 122.1 (C-7), 122.2 (C-2Ј),
126.5 (C-5Ј), 129.2 (C-8), 130.0 (C-3Ј), 134.7 (C-6), 141.7 (C-4a),
Conclusions
In summary, a novel three-component condensation of
2-formylbenzoic acid with anilines and hydrocyanic acid
has been found. The reaction furnishes 3-amino-4-(arylam-
ino)-1H-isochromen-1-ones in high yield. The ease of their
preparation from readily available chemicals should make
these compounds attractive starting materials for the prepa-
ration of fused heterocycles.
145.1 (C-1Ј), 155.9 (C-3), 160.4 ppm (CO). IR (KBr): ν = 3476,
˜
3397, 3326, 1729, 1641, 1604, 1550, 1503, 1484, 1268, 984, 763,
750 cm–1. FD-MS (m/z): 266.4 (100) [M]+, 533.0 (5) [2M]+.
C16H14N2O2 (266.29): C 72.16, H 5.30, N 10.52; found C 71.97, H
5.26, N 10.34.
Experimental Section
3-Amino-4-(3-tolylamino)-1H-isochromen-1-one (4c): The product
was purified by flash chromatography on silica gel with cyclohex-
ane/EtOAc 5:2 as the eluent. Yellow crystals (1.61 g, 60%), m.p.
152 °C (dec.), Rf (cyclohexane/EtOAc 2:1) = 0.51. 1H NMR
(300 MHz, [D6]DMSO): δ = 2.15 (s, 3 H, Me), 6.34–6.44 (m, 3 H,
2Ј-H, 4Ј-H, 6Ј-H), 6.52 (s, 2 H, NH2), 6.72 (s, 1 H, NH), 6.93 (t, J
= 7.9 Hz, 1 H, 5Ј-H), 7.04–7.11 (m, 2 H, 5-H, 7-H), 7.51 (ddd, J =
8.1, 7.2, 1.4 Hz, 1 H, 6-H), 7.90 ppm (pseudo-d, J = 7.8 Hz, 8-H).
13C NMR (75.5 MHz, [D6]DMSO): δ = 21.2 (Me), 90.6 (C-4),
110.0 (C-6Ј), 113.3 (C-2Ј), 113.9 (C-8a), 117.7 (C-4Ј), 119.7 (C-5),
122.1 (C-7), 128.8 (C-5Ј), 129.2 (C-8), 134.8 (C-6), 137.9 (C-3Ј),
141.8 (C-4a), 147.8 (C-1Ј), 156.0 (C-3), 160.3 ppm (CO). IR (KBr):
All reactions were carried out in dried glassware under argon unless
stated otherwise. Methanol was dried with magnesium and distilled
and stored under nitrogen. Analytical TLC was performed on alu-
minium backed TLC plates coated with aluminium oxide N/UV254
(Macherey–Nagel). Compounds were viewed under UV light
(254 nm) and/or by dipping the plates in an alkaline KMnO4 solu-
tion and heating. Column chromatography was performed on silica
gel (40–63 µm, E. Merck). NMR spectra were recorded with
Bruker AC 300 or AMX 400 spectrometers; chemical shifts were
referenced to the residual solvent peak ([D6]DMSO, δH = 2.50 ppm,
δC = 39.43 ppm). Coupling constants were partly determined by
Lorentz–Gauss transformation. 13C NMR spectra were recorded
with broad-band 1H decoupling; if necessary, signals were assigned
through DEPT-135, gs-COSY-90, gs-HMQC and gs-HMBC spec-
tra. FD-MS spectra were recorded with a Finnigan MAT 95 (de-
sorption voltage 5 kV, heater current 10 mAmin–1), the signals of
the 13C isotopomers are not given. IR spectra were measured with a
Perkin–Elmer 1760X FTIR spectrometer. Elemental analyses were
performed with a CHN Rapid (Heraeus). Melting points were mea-
ν = 3463, 3342, 1714, 1632, 1606, 1553, 1481, 1330, 1158, 1294,
˜
771 cm–1. FD-MS (m/z): 266.4 (100) [M]+, 533.0 (3) [2M]+.
C16H14N2O2 (266.29): C 72.16, H 5.30, N 10.52; found C 71.89, H
5.38, N 10.41.
3-Amino-4-(4-tolylamino)-1H-isochromen-1-one (4d): The reaction
time was only 45 min. Yellow crystals (2.18 g, 82%), m.p. 156–
163 °C (dec.), Rf (cyclohexane/EtOAc 2:1) = 0.38. 1H NMR
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Opatz, D. Ferenc
FULL PAPER
(300 MHz, [D6]DMSO), COSY (400 MHz, [D6]DMSO): δ = 2.14
NMR (75.5 MHz, [D6]DMSO): δ = 89.9 (C-4), 107.3 (C-4Ј), 113.9
(s, 3 H, Me), 6.46–6.51 (m, 4 H, NH2, 2Ј,6Ј-H), 6.60 (s, 1 H, NH), (C-8a), 114.7 (C-2Ј,6Ј), 119.3 (C-5), 122.1 (C-7), 129.3 (C-8), 131.4
6.86 (AAЈ part of AAЈXXЈ, 2 H, 3Ј,5Ј-H), 7.02–7.09 (m, 2 H, 5-H,
7-H), 7.49 (ddd, J = 8.2, 7.1, 1.3 Hz, 1 H, 6-H), 7.90 ppm (pseudo-
d, J = 7.7 Hz, 1 H, 8-H). 13C NMR (75.5 MHz, [D6]DMSO),
(C-3Ј,5Ј), 134.9 (C-6), 141.3 (C-4a), 147.1 (C-1Ј), 156.0 (C-3),
160.2 ppm (CO). IR (KBr): ν = 3459, 3367, 1709, 1652, 1606, 1554,
˜
1490, 1330, 1288, 815, 764 cm–1. FD-MS (m/z): 330.4 (100) [M]+,
HMQC, HMBC (100.6 MHz, [D6]DMSO): δ = 20.0 (Me), 91.0 (C- 332.4 (71). C15H11BrN2O2 (331.16): C 54.40, H 3.35, N 8.46; found
4), 112.8 (C-2Ј,6Ј), 114.0 (C-8a), 119.7 (C-5), 122.0 (C-7), 125.1 (C-
4Ј), 129.2 (C-8), 129.3 (C-3Ј,5Ј), 134.7 (C-6), 141.7 (C-4a), 145.3
C 54.21, H 3.33, N 8.34.
3-Amino-4-(4-chlorophenylamino)-1H-isochromen-1-one (4i): Yellow
crystals (2.49 g, 87%), m.p. 168 °C (dec.), Rf (cyclohexane/EtOAc
(C-1Ј), 156.0 (C-3), 160.3 ppm (CO). IR (KBr): ν = 3460, 3369,
˜
3284, 1724, 1650, 1606, 1516, 1482, 1295, 811, 757, 697 cm–1. FD-
MS (m/z): 266.3 (100) [M]+, 532.8 (3) [2M]+. C16H14N2O2 (266.29):
C 72.16, H, 5.30, N 10.52; found C 72.34, H 5.23, N 10.65.
1
2:1) = 0.44. H NMR (300 MHz, [D6]DMSO): δ = 6.53–6.62 (m,
4 H, NH2, 2Ј,6Ј-H), 6.99–7.12 (m, 5 H, NH, 5-H, 7-H, 3Ј,5Ј-H),
7.52 (ddd, J = 8.2, 7.1, 1.4 Hz, 1 H, 6-H), 7.91 ppm (ddd, J = 7.9,
1.4, 0.6 Hz, 1 H, 8-H). 13C NMR (75.5 MHz, [D6]DMSO): δ = 90.0
(C-4), 113.9 (C-8a), 114.2 (C-2Ј,6Ј), 119.4 (C-5), 119.9 (C-4Ј), 122.1
(C-7), 128.6 (C-3Ј,5Ј), 129.3 (C-8), 134.9 (C-6), 141.4 (C-4a), 146.8
3-Amino-4-(3-methoxyphenylamino)-1H-isochromen-1-one (4e): Yel-
low crystals (2.49 g, 88%), m.p. 163 °C (dec.), Rf (cyclohexane/
1
EtOAc 2:1) = 0.53. H NMR (300 MHz, [D6]DMSO): δ = 3.63 (s,
3 H, OMe), 6.13–6.22 (m, 3 H, 2Ј-H, 4Ј-H, 6Ј-H), 6.53 (s, 2 H,
NH2), 6.82 (s, 1 H, NH), 6.95 (t, J = 8.1 Hz, 1 H, 5Ј-H), 7.04–7.11
(m, 2 H, 5-H, 7-H), 7.51 (ddd, J = 8.3, 7.1, 1.4 Hz, 1 H, 6-H),
7.90 ppm (ddd, J = 7.9, 1.4, 0.6 Hz, 8-H). 13C NMR (75.5 MHz,
[D6]DMSO): δ = 54.6 (OMe), 90.5 (C-4), 98.8 (C-2Ј), 102.1, 105.6
(C-4Ј, C-6Ј), 113.9 (C-8a), 119.6 (C-5), 122.1 (C-7), 129.2 (C-8),
129.6 (C-5Ј), 134.8 (C-6), 141.6 (C-4a), 149.2 (C-1Ј), 156.0 (C-3),
(C-1Ј), 156.0 (C-3), 160.2 ppm (CO). IR (KBr): ν = 3430, 1723,
˜
1650, 1608, 1556, 1495, 1305, 1089, 816, 766 cm–1. FD-MS (m/z):
286.4 (100) [M]+, 288.4 (34). C15H11ClN2O2 (286.71): C 62.84, H
3.87, N 9.77; found C 63.01, H 3.76, N 9.62.
3-Amino-4-(methylphenylamino)-1H-isochromen-1-one (4j): The
product was purified by flash chromatography on silica gel with
cyclohexane/EtOAc 3:1 as the eluent. Yellow crystals (1.71 g, 64%),
160.27, 160.31 ppm (CO, C-3Ј). IR (KBr): ν = 3409, 3374, 3319,
˜
1
m.p. 163 °C (dec.), Rf (cyclohexane/EtOAc 2:1) = 0.69. H NMR
1714, 1645, 1626, 1551, 1494, 1162, 1093, 845, 748 cm–1. FD-MS
(m/z): 282.4 (100) [M]+. C16H14N2O3 (282.29): C 68.07, H 5.00, N
9.92; found C 67.96, H 5.09, N 9.97.
(300 MHz, [D6]DMSO): δ = 3.16 (s, 3 H, Me), 6.60–6.66 (m, 3 H,
2Ј,6Ј-H, 4Ј-H), 6.70–6.74 (m, 3 H, NH2, 5-H), this multiplet con-
taining 6.71 (br.s, 2 H, NH2), 6.71 (pseudo-d, J = 8.3 Hz, 1 H, 5-
H), 7.04–7.16 (m, 3 H, 7-H, 3Ј,5Ј-H), 7.48 (ddd, J = 8.3, 7.1,
1.4 Hz, 1 H, 6-H), 7.94 ppm (ddd, J = 7.9, 1.4, 0.6 Hz, 1 H, 8-H).
13C NMR (75.5 MHz, [D6]DMSO): δ = 37.2 (Me), 96.4 (C-4),
111.8 (C-2Ј,6Ј), 114.1 (C-8a), 116.2 (C-4Ј), 119.0 (C-5), 122.1 (C-
7), 128.9 (C-3Ј,5Ј), 129.6 (C-8), 134.9 (C-6), 140.8 (C-4a), 148.0 (C-
3-Amino-4-(4-methoxyphenylamino)-1H-isochromen-1-one (4f): Yel-
low crystals (2.21 g, 78%), m.p. 167 °C (dec.), Rf (cyclohexane/
1
EtOAc 2:1) = 0.56. H NMR (300 MHz, [D6]DMSO): δ = 3.62 (s,
3 H, OMe), 6.45–6.55 (m, 5 H, NH, NH2, 2Ј,6Ј-H), 6.70 (AAЈ part
of AAЈBBЈ, 2 H, 3Ј,5Ј-H), 7.04–7.10 (m, 2 H, 5-H, 7-H), 7.50 (ddd,
J = 8.3, 7.0, 1.3 Hz, 1 H, 6-H), 7.90 ppm (dd, J = 8.3, 1.3 Hz, 1 H,
8-H). 13C NMR (75.5 MHz, [D6]DMSO): δ = 55.2 (OMe), 91.5 (C-
4), 113.6, 114.6 (C-2Ј,6Ј, C-3Ј,5Ј), 114.0 (C-8a), 119.7 (C-5), 122.0
(C-7), 129.2 (C-8), 134.7 (C-6), 141.6, 141.8 (C-4a, C-1Ј), 151.3 (C-
1Ј), 155.8 (C-3), 160.2 ppm (CO). IR (KBr): ν = 3472, 3337, 1746,
˜
1640, 1603, 1548, 1483, 1494, 1318, 763, 752 cm–1. FD-MS (m/z):
266.5 (100) [M]+. C16H14N2O2 (266.29): C 72.16, H 5.30, N 10.52;
found C 72.36, H 5.38, N 10.57.
4Ј), 156.1 (C-3), 160.3 ppm (CO). IR (KBr): ν = 3433, 3379, 3292,
˜
3-Amino-4-(2,4-dimethylphenylamino)-1H-isochromen-1-one (4k):
Yellow crystals (1.58 g, 56%), m.p. 151 °C (dec.), Rf (cyclohexane/
EtOAc 2:1) = 0.59. H NMR (300 MHz, [D6]DMSO): δ = 2.12 (s,
1718, 1647, 1606, 1511, 1483, 1233, 1032, 825, 754 cm–1. FD-MS
(m/z) = 282.4 (100) [M+]. C16H14N2O3 (282.29): C 68.07, H 5.00,
N 9.92; found C 68.09, H 4.96, N 9.97.
1
3 H, 4Ј-Me), 2.29 (s, 3 H, 2Ј-Me), 5.92 (s, 1 H, NH), 6.07 (d, J =
8.1 Hz, 1 H, 6Ј-H), 6.49 (br.s, 2 H, NH2), 6.64 (dd, J = 8.1, 2.2 Hz,
1 H, 5Ј-H), 6.85 (d, J = 2.2 Hz, 3Ј-H), 6.95 (pseudo-d, J = 8.3 Hz,
1 H, 5-H), 7.07 (ddd, J = 8.1, 7.1, 1.3 Hz, 1 H, 7-H), 7.50 (ddd, J
= 8.3, 7.1, 1.4 Hz, 1 H, 6-H), 7.91 ppm (dd, J = 8.1, 1.4 Hz, 1 H,
8-H). 13C NMR (75.5 MHz, [D6]DMSO): δ = 17.7 (2Ј-Me), 19.9
(4Ј-Me), 90.9 (C-4), 110.5 (C-6Ј), 113.9 (C-8a), 119.8 (C-5), 122.0
(C-7), 122.2 (C-2Ј), 124.9 (C-4Ј), 126.7 (C-5Ј), 129.1 (C-8), 130.8
(C-3Ј), 134.7 (C-6), 141.8 (C-4a), 142.7 (C-1Ј), 155.9 (C-3),
3-Amino-4-[4-(trifluoromethyl)phenylamino]-1H-isochromen-1-one
(4g): The product was purified by recrystallization from ethyl ace-
tate/cyclohexane. Yellow crystals (2.58 g, 81%), m.p. 152 °C (dec.),
Rf (cyclohexane/EtOAc 2:1)
=
0.40. 1H NMR (300 MHz,
[D6]DMSO): δ = 6.66–6.72 (m, 4 H, NH2, 2Ј,6Ј-H), 7.00 (pseudo-
d, J = 8.1 Hz, 1 H, 5-H), 7.08 (ddd, J = 8.1, 7.1, 1.1 Hz, 1 H, 7-
H), 7.38 (AAЈ part of AAЈXXЈ, 2 H, 3Ј,5Ј-H), 7.47 (s, 1 H, NH),
7.53 (ddd, J = 8.1, 7.1, 1.3 Hz, 1 H, 6-H), 7.92 ppm (pseudo-d, J
= 8.1 Hz, 1 H, 8-H). 13C NMR (75.5 MHz, [D6]DMSO): δ = 89.1
160.4 ppm (CO). IR (KBr): ν = 3462, 1728, 1645, 1608, 1553, 1508,
˜
2
1482, 1332, 1299, 761 cm–1. FD-MS (m/z): 280.4 (100) [M]+, 560.9
(5) [2M]+. C17H16N2O2 (280.32): C 72.84, H 5.75, N 9.99; found C
72.92, H 5.68, N 10.11.
(C-4), 112.4 (br., C-2Ј,6Ј), 113.9 (C-8a), 116.6 (q, J(C,F) = 32 Hz,
1
C-4Ј), 119.2 (C-5), 122.2 (C-7), 125.2 (q, JC,F = 270 Hz, CF3),
3
126.2 (q, JC,F = 3.4 Hz, C-3Ј,5Ј), 129.4 (C-8), 135.0 (C-6), 141.2
(C-4a), 151.2 (C-1Ј), 155.9 (C-3), 160.2 ppm (CO). IR (KBr): ν =
˜
CCDC-251052 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
3369, 1713, 1652, 1619, 1485, 1329, 1158, 1110, 1067, 830 cm–1.
FD-MS (m/z): 320.4 (100) [M]+. C16H11F3N2O2 (320.27): C 60.00,
H 3.46, N 8.75; found C 59.77, H 3.71, N 8.51.
3-Amino-4-(4-bromophenylamino)-1H-isochromen-1-one (4h): Yel-
low crystals (2.45 g, 74%), m.p. 138 °C (dec.), Rf (cyclohexane/
EtOAc 2:1) = 0.26. 1H NMR (300 MHz, [D6]DMSO): δ = 6.53
(AAЈ part of AAЈXXЈ, 2 H, 2Ј,6Ј-H), 6.61 (br.s, 2 H, NH2), 7.00–
7.04 (m, 2 H, NH, 5-H), 7.07 (ddd, J = 8.1, 7.1, 1.0 Hz, 1 H, 7-H),
Acknowledgments
This work was supported by the Fonds der Chemischen Industrie.
7.19 (XXЈ part of AAЈXXЈ, 2 H, 3Ј,5Ј-H), 7.53 (ddd, J = 8.1, 7.1, We thank Dr. H. Detert for kindly providing several anilines, H.
1.3 Hz, 1 H, 6-H), 7.90 ppm (pseudo-d, J = 8.1 Hz, 1 H, 8-H). 13C Kolshorn for the NMR spectroscopic analyses, and Dr. D.
820
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 817–821

3-Amino-4-(arylamino)-1H-isochromen-1-ones by a New Multicomponent Reaction
FULL PAPER
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Received: September 29, 2004
Eur. J. Org. Chem. 2005, 817–821
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