An unexpected three-component condensation leading to amino-(3-oxo-2,3- dihydro-1H-isoindol-1-ylidene)acetonitriles

Article abstract of DOI:10.1021/jo0486802

The reaction of 2-carboxybenzaldehyde with primary amines in the presence of cyanide leads to the formation of 2-substituted amino(3-oxo-2,3-dihydro-1H- isoindol-1-ylidene)acetonitriles. These compounds originate from the condensation of 2-carboxybenzalde

Full text of DOI:10.1021/jo0486802

SCHEME 1. Consecutive Reactions of Strecker
Products via a Nucleophilic Attack on the Nitrile
Carbon
An Unexpected Three-Component
Condensation Leading to Amino-
(3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)-
acetonitriles
Till Opatz* and Dorota Ferenc
Institut fu¨r Organische Chemie, Universita¨t Mainz,
Duesbergweg 10-14, 55128 Mainz, Germany
opatz@uni-mainz.de
Received July 30, 2004
SCHEME 2. Preparation of Compounds 5 and 7a
Abstract: The reaction of 2-carboxybenzaldehyde with
primary amines in the presence of cyanide leads to the
formation of 2-substituted amino(3-oxo-2,3-dihydro-1H-
isoindol-1-ylidene)acetonitriles. These compounds originate
from the condensation of 2-carboxybenzaldehyde with the
amine and two molecules of hydrogen cyanide and represent
a novel class of isoindolinones.
The Strecker reaction between an aldehyde, an amine,
and hydrogen cyanide is widely regarded as the first
multicomponent reaction (MCR).1 Its reliability, the
ready availability of the starting materials, and the
versatility of the resulting products make it a very
important process for the large-scale production of amino
acids, herbicides, and chelating agents, such as NTA and
EDTA. Although the Strecker reaction can be performed
on a wide variety of substrates, the presence of neighbor-
ing groups may lead to the formation of products other
than R-aminonitriles. In particular, the nitrile carbon is
susceptible to intra- or intermolecular nucleophilic
attack. Examples are the Bucherer-Bergs reaction2-4
and the analogous formation of dithiohydantoins from
R-aminonitriles and carbon disulfide,5 the ketone-medi-
ated hydration of R-aminonitriles,6 and the preparation
of 2-phenylimidazo[1,2-a]pyridin-3-amine (4) from 2-
aminopyridine, benzaldehyde, and cyanide (Scheme 1).7,8
During an attempt to prepare aminonitrile 6 from
2-carboxybenzaldehyde, methylamine hydrochloride, and
potassium cyanide in aqueous methanol, a yellow crys-
talline solid precipitated from the reaction mixture when
left to stand overnight at room temperature. Structural
course of the reaction critically depends on the pH of the
medium. If the reaction medium was acidified by the
addition of acetic acid, 2-methyl-3-oxoisoindoline-1-car-
bonitrile 5 was obtained instead (Scheme 2).
In contrast to the formation of 5, which results from
cyclodehydration of the Strecker product 6,9,10 the forma-
tion of 7a is less easy to understand. Formally, this
product results from the nucleophilic addition of a
molecule of HCN to the nitrile carbon of 6 and subsequent
cyclodehydration. The similar dimerization of HCN to the
highly reactive iminoacetonitrile has been proposed to
be the initial step in the formation of diaminomaleoni-
trile, the stable tetramer of HCN.11,12 In the case of the
addition of HCN to an R-aryl-substituted aminonitrile,
the resulting R-cyanoimine could tautomerize to the
thermodynamically more favorable 2,3-diaminocinna-
monitrile, although this would not explain the importance
of the ortho-carboxy group. An alternative for the forma-
tion of 7a is via the initial formation of 5, which, either
directly or after tautomerization to the ketenimine, is
nucleophilically attacked by a second cyanide ion. Indeed,
5 does react with KCN and acetic acid in methanol to
form 7a when heated; however, the conversion is poor,
and the reaction is too slow to account for the formation
1
elucidation by H and 13C NMR spectroscopy revealed
this precipitate to be a mixture of (2E)- and (2Z)-amino-
(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)aceto-
nitrile (7a). Experiments showed that elevated reaction
temperatures promote the formation of 7a, and that the
(1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27-45.
(2) Bergs, H. German Patent 566094, 1929; Chem. Abstr. 1933, 27,
1001.
(3) Bucherer, H. T.; Brandt, W. J. Prakt. Chem. 1934, 140, 129-
150.
(4) Bucherer, H. T.; Steiner, W. J. Prakt. Chem. 1934, 140, 291-
316.
(5) Chubb, F. L.; Edward, J. T. Can. J. Chem. 1981, 59, 2724-2728.
(6) Lagriffoul, P.-H.; Tadros, Z.; Taillades, J.; Commeyras, A. J.
Chem. Soc., Perkin Trans. 2 1992, 1279-1285.
(7) Astik, R. R.; Thaker, K. A. J. Indian Chem. Soc. 1981, 58, 1013-
1014.
(8) Schmitt, M.; Bourguignon, J.-J.; Barlin, G. B.; Davies, L. P. Aust.
J. Chem. 1997, 50, 719-725.
(9) Welch, W. M. J. Org. Chem. 1982, 47, 886-888.
(10) Baum, J. S.; Staveski, M. M. Synth. Commun. 1989, 19, 2283-
2292.
(11) Ferris, J. P.; Bonner, D. B.; Lotz, W. J. Am. Chem. Soc. 1972,
94, 6968-6974.
(12) Evans, R. A.; Lorencak, P.; Ha, T.-K.; Wentrup, C. J. Am. Chem.
Soc. 1991, 113, 7261-7276.
10.1021/jo0486802 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/26/2004
8496
J. Org. Chem. 2004, 69, 8496-8499

TABLE 1. Preparation of Amino(2-alkyl-3-oxo-2,3-
TABLE 2. Selected Bond Lengths (Å) and Angles (deg)
dihydro-1H-isoindol-1-ylidene)acetonitriles
for (Z)-7f
N(1)-C(2)
1.412
1.353
1.375
1.428
C(19)-N(20)
C(2)-C(3)
N(1)-C(9)
C(9)-O(21)
1.143
1.467
1.373
1.226
C(2)-C(17)
C(17)-N(18)
C(17)-C(19)
N(1)-C(2)-C(3)
N(1)-C(2)-C(17)
105.73
125.42
C(2)-C(17)-N(18)
C(2)-C(17)-C(19)
127.67
118.74
entry product
R
methoda
yield (%)
53
Z/E
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
Me
A
A
B
B
B
B
B
B
3.1:1
Et
29 (Z), 9 (E) 3.2:1
moiety (Table 2), is in good accordance with the corre-
sponding values found in N-(2-amino-1,2-dicyanovinyl)-
acetamide by Booth et al.13
n-Bu
21
29
4.6:1
4.5:1
i-Pent
i-Pr
Bn
44 (Z)
In all of the experiments, minor amounts of the (E)-
isomers were formed, as well. In the case of compounds
7b and 7g, both isomers were separated and purified by
column chromatography and crystallization. Not surpris-
ingly, the NMR signal of the proton at C(4) in (E)-7g
showed a very strong NOE enhancement of 28% upon
irradiation of the amino protons. The small distance
between the amino group and the aromatic ortho-
hydrogen in the (E)-isomer also accounts for the pre-
dominant formation of the sterically less-demanding (Z)-
product. When the pure isomers (E)-7b and (Z)-7b were
heated to 90 °C in DMSO-d6, the slow equilibration of
the double-bond geometry could be observed in both
cases, resulting in a 3.8:1 mixture in favor of the (Z)-
isomer. Whether the mechanism of this reaction involves
a tautomerization to the R-cyanoimine or an addition-
elimination sequence remains to be investigated. Al-
though the relative mobility of the (E)-isomers on TLC
is always slightly higher, the best way to distinguish
between the isomers is the 1H chemical shift of the amino
group in DMSO-d6; the NH2 protons of the (Z)-isomers
constantly resonate at ∼0.20 ppm downfield.
7g
7h
3-pyr-CH2-
PhCH2CH2-
37 (Z), 9 (E) 4.0:1
40
5.2:1
a Method A: 2 equiv of amine hydrochloride and 2.2 equiv of
KCN. Method B: 2 equiv of amine, 2 equiv of AcOH, and 2.2 equiv
of KCN.
FIGURE 1. Crystal structure of (Z)-7f with the atomic
numbering scheme. Thermal ellipsoids are drawn at 50%
probability.
In summary, a three-component condensation leading
to a novel class of isoindolinones has been found. Al-
though the yield of the reactions was only moderate, the
synthesis from readily available 2-carboxybenzaldehyde
is simple and makes these remarkable amino(alkylidene)-
acetonitriles interesting starting materials for the prepa-
ration of more complex heterocycles.
of 7a under the original experimental conditions. In
addition, lactam 5 could not be detected if the reaction
proceeded in a neutral or an alkaline medium. To explore
the scope of the reaction, a set of R-unbranched primary
amines were subjected to the reaction. In all cases,
compounds of 7 were obtained in moderate yield (Table
1).
The best yield of compounds 7a and 7b could be
obtained if the amine hydrochloride was used (method
A), whereas the longer-chain amines were most suitably
employed in combination with acetic acid (method B). For
instance, the preparation of 7b, according to method B,
resulted in a yield of only 24%, and method A gave only
13% of 7h. Sterically more demanding R-branched pri-
mary amines, such as isopropylamine, gave only trace
amounts of the corresponding products, which are prob-
ably destabilized by unfavorable interactions between the
amine side chains, the oxygen, and the amino or cyano
group. To investigate the structural features of the
unusual heterocyclic core of compounds 7, an X-ray
crystallographic analysis of the N-benzyl derivative, (Z)-
7f, was performed (Figure 1).
The steric repulsion between the hydrogens at C(4) and
C(19) results in a slight twist of the exocyclic aminoac-
etonitrile moiety against the plane of the bicyclic π-sys-
tem by an angle of 6°, whereas the length of the exocyclic
double bond is normal (1.353 Å). This value, as well as
the bond distances and angles in the aminoacetonitrile
Experimental Section
2-Methyl-3-oxoisoindoline-1-carbonitrile (5). To a stirred
solution of 2-carboxybenzaldehyde (3.0 g, 20 mmol) in methanol
(50 mL) were added methylamine hydrochloride (2.70 g, 40
mmol), potassium cyanide (1.69 g, 26 mmol), and acetic acid (2.28
mL, 40 mmol). The reaction mixture was heated to reflux for 3
h, and after it cooled, the mixture was partitioned between water
and CH2Cl2; the organic layer was separated, washed with
aqueous NaHCO3, and dried over Na2SO4, and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography (cyclohexane/ethyl acetate, 1:1) to yield 5 as
colorless crystals (2.19 g, 64%): mp 108-110 °C; IR (KBr) ν 3433
(br), 2891, 1698, 1472, 1427, 1386, 1320, 1058, 747, 691 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ 3.13 (s, 3H, CH3), 6.00 (s, 1H,
CHN), 7.64 (pseudo-t, J ) 7.4 Hz, 1H), 7.71-7.79 (m, 2H), 7.86
(pseudo-d, J ) 7.4 Hz, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ
27.7 (CH3), 51.2 (C1), 115.9 (CN), 123.3 (d), 123.6 (d), 130.1 (d),
130.7 (s), 132.7 (d), 137.4 (s), 166.3 (CO); FD-MS (m/z) M+ 172.1
(13) Al-Azmi, A.; Booth, B. L.; Pritchard, R. G.; Proenc¸a, F. J. R. P.
J. Chem. Soc., Perkin Trans. 1 2001, 485-486.
J. Org. Chem, Vol. 69, No. 24, 2004 8497

(100). Anal. Calcd for C10H8N2O: C, 69.76; H, 4.68; N, 16.27.
Found: C, 69.55; H, 4.62; N, 16.15.
22 mmol), and acetic acid (1.14 mL, 20 mmol). The reaction
mixture was heated to reflux for 4 h, and after it was cooled,
the mixture was partitioned between water and CH2Cl2; the
organic layer was separated, washed with aqueous NaHCO3, and
dried over Na2SO4, and the solvent was removed in vacuo. The
crude product was purified by flash chromatography (cyclohex-
ane/ethyl acetate/CH2Cl2, 2:1:4) to yield a 4.6:1 mixture of (Z)-
and (E)-7c (515 mg, 21%) as yellow crystals: Rf (cyclohexane/
EtOAc, 2:1) ) 0.39 (E,Z); IR (KBr) ν 3422 (br), 3330, 3222, 2960,
2206, 1671, 1629, 1473, 1312, 1096, 765, 699 cm-1. Signals of
the (Z)-isomer: 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J )
7.3 Hz, 3H, CH3), 1.16 (sextet, J ) 7.3 Hz, 2H, γ-CH2), 1.51,
(quintet, J ) 7.3 Hz, 2H, â-CH2), 4.07 (t, J ) 7.3 Hz, 2H, NCH2),
5.80 (br s, 2H, NH2), 7.48 (dt, Jt ) 7.4 Hz, Jd ) 0.9 Hz, 1H, H5),
7.68 (ddd, J ) 8.2, 7.4, 1.3 Hz, 1H, H6), 7.76 (ddd, J ) 7.4, 1.3,
Amino(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylid-
ene)acetonitrile (7a). To a stirred solution of 2-carboxyben-
zaldehyde (1.5 g, 10 mmol) and methylamine hydrochloride (1.35
g, 20 mmol) in methanol (25 mL) was added potassium cyanide
(1.43 g, 22 mmol), and the mixture was heated to reflux for 3.5
h. After 2.5 h, the formation of yellow crystals could be observed.
The yellow suspension was poured onto ice, and the yellow solid
was collected by filtration to yield 7a (967 mg, 49%) as a mixture
of isomers. The filtrate was extracted with ether; the organic
layer was separated and dried over Na2SO4, and the solvent was
removed in vacuo to yield another portion of 7a (93 mg, 4.7%):
Rf (cyclohexane/EtOAc, 3:2) ) 0.15 (Z), 0.31 (E); IR (KBr) ν 3442,
3313, 3209, 2214, 1706, 1632, 1474, 1428, 1312, 1268, 1090, 767,
692 cm-1; FD-MS (m/z) M+ 199.1 (100). Anal. Calcd for
C11H9N3O: C, 66.32; H, 4.55; N, 21.09. Found: C, 66.42; H, 4.35;
N, 21.09. For NMR spectroscopic analysis, the (Z)-isomer was
purified by recrystallization (EtOAc/petroleum ether): 1H NMR,
COSY (400 MHz, DMSO-d6) δ 3.51 (s, 3H, CH3), 5.80 (br s, 2H,
NH2), 7.46 (dt, Jt ) 7.4 Hz, Jd ) 0.9 Hz, 1H, H5), 7.65 (ddd, J )
8.2, 7.4, 1.3 Hz, 1H, H6), 7.74 (ddd, J ) 7.4, 1.3, 0.9 Hz, 1H,
H4), 8.14 (dt, Jd ) 8.2 Hz, Jt ) 0.9 Hz, 1H, H7); 13C NMR,
HMQC, HMBC (100.6 MHz, DMSO-d6) δ 28.8 (CH3), 101.2 (C-
NH2), 117.7 (CN), 120.0 (C7), 123.0 (C4), 123.9 (C1), 126.8 (C3a),
127.8 (C5), 132.1 (C6), 133.8 (C7a), 165.4 (CO). Signals of the
(E)-isomer (from the spectrum of the E/Z mixture): 1H NMR
(300 MHz, DMSO-d6) δ 3.45 (s, 3H, CH3), 5.65 (br s, 2H, NH2),
7.51 (dt, Jt ) 7.4 Hz, Jd ) 0.9 Hz, 1H, H5), 7.67 (ddd, J ) 7.9,
7.4, 1.3 Hz, 1H, H6), 7.77 (ddd, J ) 7.4, 1.3, 0.9 Hz, 1H, H4),
8.14 (dt, Jd ) 7.9 Hz, Jt ) 0.9 Hz, 1H, H7); 13C NMR (75.5 MHz,
DMSO-d6) δ 28.0 (CH3), 101.6 (C-NH2), 117.0 (CN), 122.8 (C4),
124.1 (C7), 127.2, 127.9 (C1, C3a), 128.7 (C5), 132.1 (C6), 133.5
(C7a), 164.9 (CO).
0.9 Hz, 1H, H4), 8.21 (dt, Jd ) 8.2 Hz, Jt ) 0.9 Hz, 1H, H7); 13
C
NMR, DEPT (75.5 MHz, DMSO-d6) δ 13.5 (CH3), 19.1 (γ-CH2),
31.4 (â-CH2), 40.0 (NCH2), 100.7 (C-NH2), 117.9 (CN), 120.2
(C7), 123.2 (C4), 123.5 (C1), 126.8 (C3a), 128.0 (C5), 132.4 (C6),
134.4 (C7a), 165.7 (CO). Signals of the (E)-isomer: 1H NMR (300
MHz, DMSO-d6) δ 0.89 (t, J ) 7.3 Hz, 3H, CH3), 1.28 (sextet, J
) 7.3 Hz, 2H, γ-CH2), 1.60 (quintet, J ) 7.3 Hz, 2H, â-CH2),
4.01 (t, J ) 7.3 Hz, 2H, NCH2), 5.59 (br s, 2H, NH2), 7.53 (dt, Jt
) 7.4 Hz, Jd ) 0.9 Hz, 1H, H5), 7.78 (ddd, J ) 7.4, 1.3, 0.9 Hz,
1H, H4), 8.18 (dt, Jt ) 0.9 Hz, 1H, H7). The signal of H6 was
completely obscured by the corresponding signal of the (Z)-
isomer; J6,7 could not be determined from the signal of H7 due
to a partial overlap with the H7 resonance of the (Z)-isomer:
13C NMR, DEPT (75.5 MHz, DMSO-d6) δ 13.5 (CH3), 19.1 (γ-
CH2), 30.9 (â-CH2), 39.5 (NCH2), 101.1 (C-NH2), 116.8 (CN),
122.8 (C4), 124.6 (C7), 126.97 (C1, C3a), 127.04 (C3a, C1), 128.8
(C5), 132.2 (C6), 133.8 (C7a), 165.0 (CO); FD-MS (m/z) M+ 241.2
(100). Anal. Calcd for C14H15N3O: C, 69.69; H, 6.27; N, 17.41.
Found: C, 69.55; H, 6.29; N, 17.25.
Amino[2-(3-methylbutyl)-3-oxo-2,3-dihydro-1H-isoindol-
1-ylidene]acetonitrile (7d). The preparation of 7d was carried
out in the manner described for 7c using isopentylamine (2.32
mL) as the amine component. The eluent for flash chromatog-
raphy was cyclohexane/ethyl acetate/CH2Cl2, 2:1:2. Yellow crys-
tals of 7d (733 mg, 29%) were obtained as a 4.5:1 mixture of
diastereomers (Z/E): Rf (cyclohexane/EtOAc, 1:1) ) 0.69 (Z), 0.79
(E); IR (KBr) ν 3410 (br), 3334, 3231, 2957, 2206, 1673, 1625,
1474, 1371, 1311, 1281, 1098, 766, 698 cm-1; 1H NMR (300 MHz,
DMSO-d6) δ 0.86 (d, J ) 6.4 Hz, 6H, CH3Z), 0.91 (d, J ) 6.4 Hz,
1.3H, CH3E), 1.34-1.63 (m, 3.7H, γ-CHE+Z, â-CH2E+Z), 4.04 (t, J
) 7.7 Hz, 0.5H, NCH2E), 4.09 (t, J ) 7.2 Hz, 2H, NCH2Z), 5.58
(br s, 0.4H, NH2E), 5.79 (br s, 2H, NH2Z), 7.48 (dt, Jt ) 7.4 Hz,
Jd ) 0.9 Hz, 1H, H5Z), 7.53 (dt, Jt ) 7.4 Hz, Jd ) 0.9 Hz, 0.2H,
H5E), 7.63-7.71 (m, 1.2 H, H6E+Z), contained in this multiplet,
7.67 (ddd, J ) 8.2, 7.4, 1.3 Hz, 1H, H6Z), 7.76 (ddd, J ) 7.4, 1.3,
0.9 Hz, 1H, H4Z), 7.77 (ddd, J ) 7.4, 1.3, 0.9 Hz, 0.2H, H4E),
8.18 (dt, Jd ) 7.9 Hz, Jt ) 0.9 Hz, 0.2H, H7E), 8.21 (dt, Jd ) 8.2
Hz, Jt ) 0.9 Hz, 1H, H7Z); 13C NMR, DEPT (75.5 MHz, DMSO-
d6) (signals of (Z)-isomer) δ 22.3 (CH3), 25.2 (γ-CH), 38.2, 38.8
(â-CH2, NCH2), 100.7 (C-NH2), 117.9 (CN), 120.2 (C7), 123.2
(C4), 123.6 (C1), 126.8 (C3a), 128.0 (C5), 132.4 (C6), 134.4 (C7a),
165.6 (CO); 13C NMR, DEPT (75.5 MHz, DMSO-d6) (signals of
(E)-isomer) δ 22.3 (CH3), 25.5 (γ-CH), 37.6, 38.4 (â-CH2, NCH2),
101.2 (C-NH2), 116.9 (CN), 122.8 (C4), 124.6 (C7), 126.9, 127.1
(C1, C3a), 128.8 (C5), 132.2 (C6), 133.9 (C7a), 165.0 (CO); FD-
MS (m/z) M+ 255.2 (100), [2M]+ 510.8 (4). Anal. Calcd for
Amino(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)-
acetonitrile (7b). To a stirred solution of 2-carboxybenzalde-
hyde (1.5 g, 10 mmol) and ethylamine hydrochloride (1.63 g, 20
mmol) in methanol (25 mL) was added potassium cyanide (1.43
g, 22 mmol), and the mixture was heated to reflux for 4.5 h.
After the reaction mixture was cooled, it was partitioned between
water and CH2Cl2; the organic layer was separated, washed with
aqueous NaHCO3, and dried over Na2SO4, and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography (cyclohexane/ethyl acetate/CH2Cl2, 1:1:2) to
yield the (Z)-isomer (609 mg, 29%, yellow crystals) and the (E)-
isomer (188 mg, 9%, yellow crystals). (Z)-Isomer: mp 143 °C dec;
Rf (cyclohexane/EtOAc, 1:1) ) 0.49; IR (KBr) ν 3391, 3339, 3245,
2983, 2216, 1685, 1627, 1475, 1316, 1093, 762, 696 cm-1 1H
;
NMR (300 MHz, DMSO-d6) δ 1.12 (t, J ) 7.2 Hz, 3H, CH3), 4.10
(q, J ) 7.2 Hz, 2H, CH2), 5.81 (br s, 2H, NH2), 7.49 (dt, Jt ) 7.4
Hz, Jd ) 0.9 Hz, 1H, H5), 7.69 (ddd, J ) 8.1, 7.4, 1.3 Hz, 1H,
H6), 7.76 (ddd, J ) 7.4, 1.3, 0.9 Hz, 1H, H4), 8.21 (dt, Jd ) 8.1
Hz, Jt ) 0.9 Hz, 1H, H7); 13C NMR (75.5 MHz, DMSO-d6) δ 15.0
(CH3), 35.5 (CH2), 100.6 (C-NH2), 117.9 (CN), 120.2 (C7), 123.1
(C4), 123.4 (C1), 126.9 (C3a), 127.9 (C5), 132.3 (C6), 134.4 (C7a),
165.3 (CO); FD-MS (m/z) M+ 213.1 (100). Anal. Calcd for
C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.84; H,
5.20; N, 19.50. (E)-Isomer: mp 124 °C dec; Rf (cyclohexane/
EtOAc, 1:1) ) 0.55; IR (KBr) ν 3440 (br), 3382, 3300, 3207, 2211,
1682, 1397, 1364, 1098, 771, 699 cm-1 1H NMR (300 MHz,
;
DMSO-d6) δ 1.21 (t, J ) 7.2 Hz, 3H, CH3), 4.07 (q, J ) 7.2 Hz,
2H, CH2), 5.61 (br s, 2H, NH2), 7.54 (dt, Jt ) 7.4 Hz, Jd ) 0.9
Hz, 1H, H5), 7.70 (ddd, J ) 7.9, 7.4, 1.3 Hz, 1H, H6), 7.79 (ddd,
J ) 7.4, 1.3, 0.9 Hz, 1H, H4), 8.19 (dt, Jd ) 7.9 Hz, Jt ) 0.9 Hz,
1H, H7); 13C NMR, HMQC, HMBC (100.6 MHz, DMSO-d6) δ
14.6 (CH3), 34.8 (CH2), 101.0 (C-NH2), 116.8 (CN), 122.8 (C4),
124.6 (C7), 126.8 (C1), 127.2 (C3a), 128.8 (C5), 132.2 (C6), 133.9
(C7a), 164.8 (CO); FD-MS (m/z) M+ 213.3 (100). Anal. Calcd for
C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.58; H,
5.21; N, 19.57.
C
15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.50; H,
6.79; N, 16.22. (Note, the superscripts E and Z denote signals
of the corresponding isomers.) The (Z)-isomer could be purified
by recrystallization from ethyl acetate/petroleum ether. Yellow
crystals were obtained: mp 131.5-132.5 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.34-1.46 (m, 3H, γ-CH, â-CH2). For all other
signals, see the 1H NMR spectrum of the isomeric mixture: FD-
MS (m/z) M+ 255.4 (100), [2M]+ 510.9 (8).
Amino(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylid-
ene)acetonitrile (7f). The preparation of 7f was carried out in
the manner described for 7c using benzylamine (2.2 mL) as the
amine component. The eluent for flash chromatography was
cyclohexane/ethyl acetate/CH2Cl2, 3:1:1. (Z)-7f (1.20 g, 44%) was
Amino(2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)-
acetonitrile (7c). To a stirred solution of 2-carboxybenzalde-
hyde (1.5 g, 10 mmol) in methanol (25 mL) were added
n-butylamine (1.98 mL, 20 mmol), potassium cyanide (1.43 g,
8498 J. Org. Chem., Vol. 69, No. 24, 2004

obtained as yellow crystals: mp 138 °C dec; Rf (cyclohexane/
EtOAc, 3:2) ) 0.64; IR (KBr) ν 3444, 3335, 3219, 2214, 1696,
1685, 1636, 1612, 1473, 1342, 1313, 1294, 1175, 1159, 984, 764,
signal at 8.20 ppm (H7) by 28%. Irradiation at 5.34 ppm (CH2)
enhanced the signals at 8.37 (H2′, 10%) and 7.45 ppm (H4′,
7%): 13C NMR (75.5 MHz, DMSO-d6) δ 41.1 (CH2), 102.2 (C-
NH2), 116.6 (CN), 123.2, 123.5 (C4, C5′), 124.5 (C7), 125.9, 126.6
(C1, C3a), 129.0 (C5), 132.6 (C6), 132.8 (C3′), 133.8 (C4′), 134.0
(C7a), 147.6, 148.2 (C2′, C6′), 165.5 (CO); ESI-MS (m/z) [M +
H]+ 277.3 (100). Anal. Calcd for C16H12N4O: C, 69.55; H, 4.38;
N, 20.28. Found: C, 69.53; H, 4.34; N, 20.12.
1
743, 710 cm-1; H NMR (300 MHz, DMSO-d6) δ 5.34 (br s, 2H,
CH2), 5.76 (br s, 2H, NH2), 7.11 (pseudo-d, J ) 7.2 Hz, 2H, o-Ph),
7.19-7.34 (m, 3H, m/p-Ph), 7.53 (dt, Jt ) 7.4 Hz, Jd ) 0.9 Hz,
1H, H5), 7.72 (ddd, J ) 8.2, 7.4, 1.3 Hz, 1H, H6), 7.85 (ddd, J )
7.4, 1.3, 0.9 Hz, 1H, H4), 8.21 (dt, Jd ) 8.2 Hz, Jt ) 0.9 Hz, 1H,
H7); 13C NMR (75.5 MHz, DMSO-d6) δ 43.7 (CH2), 101.2 (C-
NH2), 117.6 (CN), 120.3 (C7), 122.9 (C1), 123.5 (C4), 126.1 (o-
Ph), 126.4 (C3a), 127.1 (p-Ph), 128.1 (C5), 128.5 (m-Ph), 132.7
(C6), 134.5 (C7a), 137.6 (i-Ph), 166.0 (CO); FD-MS (m/z) M+ 275.4
(100). Anal. Calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26.
Found: C, 74.28; H, 4.87; N, 15.18.
(2Z)-Amino[3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoin-
dol-1-ylidene]acetonitrile (7h). The preparation of 7h was
carried out in the manner described for 7c using 2-phenethyl-
amine (2.52 mL) as the amine component. The eluent for flash
chromatography was cyclohexane/ethyl acetate/CH2Cl2, 3:2:2.
Yellow crystals of 7h (1.16 g, 40%) were obtained as a 5.2:1
mixture of diastereomers (Z/E): Rf (cyclohexane/EtOAc, 1:1) )
0.67 (Z), 0.77 (E); FD-MS (m/z) M+ 289.3 (100), [2M]+ 578.8 (27).
Anal. Calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found:
C, 74.49; H, 5.24; N, 14.30. The pure (Z)-isomer could be obtained
by recrystallization from ethyl acetate/petroleum ether: mp 150
°C dec; IR (KBr) ν 3382, 3325, 3251, 2209, 1694, 1684, 1650,
Amino[3-oxo-2-(pyridin-3-ylmethyl)-2,3-dihydro-1H-isoin-
dol-1-ylidene]acetonitrile (7g). The preparation of 7g was
carried out in the manner described for 7c using 3-picolylamine
(2.04 mL) as the amine component. The eluent for flash
chromatography was cyclohexane/ethyl acetate, 6:1. (Z)-7g (1.01
g, 37%) and (E)-7g (251 mg, 9%) were obtained as yellow crystals.
(Z)-Isomer: mp 133 °C dec; Rf (EtOAc) ) 0.42; IR (KBr) ν 3348,
3133 (br), 2206, 1684, 1635, 1611, 1478, 1431, 1344, 1319, 1281,
1159, 983, 768, 710 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 5.39
(br s, 2H, CH2), 5.85 (br s, 2H, NH2), 7.31 (ddd, J ) 7.9, 4.8, 0.9
Hz, 1H, H5′), 7.44 (ddd, J ) 7.9, 2.4, 1.7 Hz, 1H, H4′), 7.53 (dt,
Jt ) 7.4 Hz, Jd ) 0.9 Hz, 1H, H5), 7.72 (ddd, J ) 8.1, 7.4, 1.3
Hz, 1H, H6), 7.85 (ddd, J ) 7.4, 1.3, 0.9 Hz, 1H, H4), 8.21 (dt,
Jd ) 8.1 Hz, Jt ) 0.9 Hz, 1H, H7), 8.42 (dd, J ) 2.4, 0.9 Hz, 1H,
H2′), 8.44 (dd, J ) 4.8, 1.7 Hz, 1H, H6′); 13C NMR (75.5 MHz,
DMSO-d6) δ 41.5 (CH2), 101.2 (C-NH2), 117.5 (CN), 120.3 (C7),
123.1 (C1), 123.5 (C4, C5′), 126.3 (C3a), 128.2 (C5), 132.8 (C6),
133.2 (C3′), 134.0 (C4′), 134.5 (C7a), 147.9, 148.4 (C2′, C6′), 166.0
(CO); ESI-MS (m/z) [M + H]+ 277.3 (100). Anal. Calcd for
C16H12N4O: C, 69.55; H, 4.38; N, 20.28. Found: C, 69.65; H,
4.40; N, 20.20. (E)-Isomer: mp 128 °C dec; Rf (EtOAc) ) 0.54;
IR (KBr) ν 3407, 3329, 3221, 2214, 1673, 1645, 1472, 1436, 1428,
1632, 1615, 1474, 1343, 1314, 1249, 1149, 762, 750, 698 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ 2.83 (pseudo-t, J ) 7.5 Hz, 2H,
PhCH2), 4.31 (pseudo-t, J ) 7.5 Hz, 2H, NCH2), 5.87 (br s, 2H,
NH2), 7.11-7.26 (m, 5H, Ph), 7.48 (dt, Jt ) 7.4 Hz, Jd ) 0.9 Hz,
1H, H5), 7.68 (ddd, J ) 8.1, 7.4, 1.3 Hz, 1H, H6), 7.71 (ddd, J )
7.4, 1.3, 0.9 Hz, 1H, H4), 8.23 (dt, Jd ) 8.1 Hz, Jt ) 0.9 Hz, 1H,
H7); 13C NMR (75.5 MHz, DMSO-d6) δ 35.3 (PhCH2), 41.8
(NCH2), 100.6 (C-NH2), 117.9 (CN), 120.3 (C7), 123.2 (C4), 124.4
(C1), 126.2 (p-Ph), 126.8 (C3a), 128.1 (C5), 128.2, 128.6 (o/m-
Ph), 132.4 (C6), 134.4 (C7a), 138.2 (i-Ph), 165.6 (CO).
Acknowledgment. This work was supported by the
Fonds der Chemischen Industrie. The help of Dr. D.
Schollmeyer (crystallographic analysis of compound
(Z)-7f) and H. Kolshorn (NMR experiments and chemi-
cal shift simulations) is gratefully acknowledged.
1
1392, 1345, 1276, 781, 764, 713, 698 cm-1; H NMR (300 MHz,
DMSO-d6) δ 5.34 (br s, 2H, CH2), 5.69 (br s, 2H, NH2), 7.35 (ddd,
J ) 7.9, 4.8, 0.9 Hz, 1H, H5′), 7.45 (ddd, J ) 7.9, 2.4, 1.7 Hz,
1H, H4′), 7.60 (dt, Jt ) 7.4 Hz, Jd ) 0.9 Hz, 1H, H5), 7.75 (ddd,
J ) 7.9, 7.4, 1.3 Hz, 1H, H6), 7.89 (ddd, J ) 7.4, 1.3, 0.9 Hz, 1H,
H4), 8.20 (dt, Jd ) 7.9 Hz, Jt ) 0.9 Hz, 1H, H7), 8.37 (dd, J )
2.4, 0.9 Hz, 1H, H2′), 8.47 (dd, J ) 4.8, 1.7 Hz, 1H, H6′).
Irradiation (transient NOE) at 5.69 ppm (NH2) enhanced the
Supporting Information Available: 1H and 13C NMR
spectra of compounds 5, 7a-d, and 7f-h, as well as the X-ray
crystallographic data of (Z)-7f. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0486802
J. Org. Chem, Vol. 69, No. 24, 2004 8499