Synthesis of heterocyclic compounds using amidines as their ene-1,1-diamine tautomers. I. Synthesis of 4,5-dihydro-3H-pyridin-2-one, 3,4-dihydropyrrol-2- one and 1,3-dihydropyrrol-2-one derivatives by the reaction of amidines with α,β-unsaturated esters

Article abstract of DOI:10.1002/jhet.5570420417

N-t-Butylacetamidines 1 on heating with methyl acrylate (2) at 200° gave the 4,5-dihydro-3H-pyridin-2-one derivatives 5. Michael addition of the acetamidines 1 as their ene-1,1-diamine tautomers 1′ to 2 and the subsequent cyclization of the adducts gave derivatives 5. Amidines 1 on reaction with trimethyl ethylenetricarboxylate (9) or dimethyl acetylenedicarboxylate (12) afforded 3,4-dihydropyrrol-2-one 11 or 1,3-dihydropyrrol-2-one derivatives 13.

Full text of DOI:10.1002/jhet.5570420417

May-Jun 2005
583
Synthesis of Heterocyclic Compounds Using Amidines as Their Ene-
1,1-diamine Tautomers. I. Synthesis of 4,5-Dihydro-3H-pyridin-2-one,
3,4-Dihydropyrrol-2-one and 1,3-Dihydropyrrol-2-one Derivatives by
the Reaction of Amidines with α,β-Unsaturated Esters
Kunio Ito*, Yoshiko Kizuka and Yuji Hirano
Department of Applied Chemistry, Faculty of Engineering,
Toyo University,
Kujirai, Kawagoe, Saitama 350-8585, Japan
Received August 30, 2004
N-t-Butylacetamidines 1 on heating with methyl acrylate (2) at 200˚ gave the 4,5-dihydro-3H-pyridin-2-
one derivatives 5. Michael addition of the acetamidines 1 as their ene-1,1-diamine tautomers 1' to 2 and the
subsequent cyclization of the adducts gave derivatives 5. Amidines 1 on reaction with trimethyl ethylenetri-
carboxylate (9) or dimethyl acetylenedicarboxylate (12) afforded 3,4-dihydropyrrol-2-one 11 or 1,3-dihy-
dropyrrol-2-one derivatives 13.
J. Heterocyclic Chem., 42, 583 (2005).
Reaction of amidines with electrophiles generally results
their N,C-tautomer ene-1,1-diamine, take place Michael
addition to α,β-unsaturated esters, and subsequently the
Michael adducts underwent cyclization with elimination of
alcohol to afforded 4,5-dihydro-3H-pyridin-2-one, 3,4-dihy-
dropyrrol-2-one, or 1,3-dihydropyrrol-2-one derivatives.
N-t-butylbenzylamidine (1a) was heated with methyl
acrylate (2) at 100˚ for 10 hours in diglyme. After the sol-
vent and low-boiling materials were removed under
reduced pressure, N-alkylated product 3a, formed by addi-
tion of the amidine via the N,N'-tautomer azaenamine, was
obtained in near quantitative yield (97 %).
in N-alkylated products, with reaction occurring via the N,N'-
tautomer azaenamine [1]. For C-alkylation in which the
amidines react via the N,C-tautomers ene-1,1-diamines,
there is only one report on the reaction of trisubstituted cyclic
amidine 1-methyl-2-benzyliminopyrrolidine [2]. There are
no reports in which C-alkylation products are obtained from
monosubstituted or disubstituted amidines. The present
study describes reaction between monosubstituted
acetamidines with a t-butyl group on the nitrogen atom and
α,β-unsaturated esters. We report that amidines, reacting as

584
K. Ito, Y. Kizuka and Y. Hirano
Vol. 42
Table 1
A solution of 3a in triglyme was heated in an autoclave
at 200˚ for 5 hours. 4,5-Dihydro-3H-pyridin-2-one deriva-
tive 5a, derived from C-alkylation of amidine 1a, was
obtained (60 %). The structure of 5a was confirmed by
elemental analysis, spectroscopic measurements, and
derivatization to known compound 6 [3].
Preparation of Compounds 5
1
2
Compound
R
R
Yield %
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
4-Cl-C H
H
H
H
79
68
71
59
53
40
14
40
19
32
39
6
4
4
4-Br-C H
6
4-MeO-C H
H
6
4
4-Me-C H
H
6
4
Ph-CH
H
H
H
2
Me
Et
H
H
5j
5k
Me
Me
-(CH ) -
2 5
As shown in Scheme 1, the reaction tends toward N-
alkylation at 100˚. At 200˚, however, the N-alkylated
product 3a undergoes the retro-Michael reaction. A small
amount of the N,C-tautomer of the amidine 1a, that is ene-
1,1-diamine 1'a, then reacts with 2 by Michael addition to
produce the C-alkylated product 4a. Subsequently,
cyclization with irreversible elimination of alcohol from
4a yields the product 5a. Thus, the reaction proceeds in
the direction of C-alkylation, producing the pyridin-2-one
derivative 5a.
2-benzyl-3-methyl-5,6-dihydro-3H-pyrimidin-4-one (8)
(65 %), derived from cyclization of the N-alkylated prod-
uct. Therefore, it is considered that ring formation on the
t-butyl nitrogen atom in 3 and 4 was controlled by the
steric hindrance due to the bulky t-butyl group, i.e., 5 was
exclusively produced in the case of 1.
In a similar reaction to that between 1a and 2, the
N-alkylated product 10a was obtained by stirring an ether
solution of 1a and trimethyl ethylenetricarboxylate (9) for
2 hours at room temperature (93 %). When a diglyme
solution of the obtained 10a was heated at 150˚ for 3 hours,
the 3,4-dihydropyrrol-2-one derivative 11a was obtained
(89 %). Separately, when a diglyme solution of the ami-
dine 1a and 9 was heated at 150˚ for 3 hours, 11a was
obtained in a yield of 87 % (Scheme 2). The results for
preparation of various 3,4-dihydropyrrol-2-one derivatives
The existence of the ene-1,1-diamine tautomer 1' was
confirmed by the method of Pfau and Ribière [4].
1
Observation of the H-nmr spectrum of N-t-butylbenzy-
lamidine (1a) in CD OD revealed that the methylene sin-
3
glet (δ = 3.44) intensity fell by 80% after 5 minutes at
room temperature because of deuteration, and completely
disappeared after 30 minutes. This indicates that there is a
very fast tautomeric equilibrium between the azaenamine
and ene-1,1-diamine in the monosubstituted acetamidine,
as in the case between imine and secondary enamine.
The product 5a was also directly obtained by heating 1a
and 2 at 200˚. When a triglyme solution of 1a and 2 was
heated with stirring in an autoclave at 200˚ for 5 hours, 5a
was obtained in 79 % yield. Table 1 shows the results of
preparation of various 4,5-dihydro-3H-pyridin-2-one
derivatives 5, obtained from reaction between N-t-butylac-
1
etamidines 1 and methyl acrylate (2). When R was aryl
groups for compounds 5a-5e, the pyridin-2-one derivatives
5 were obtained by comparatively higher yield compared
with the case of alkyl groups. This result is due to the fact
that the conjugation of double bond and aryl groups shifted
the tautomeric equilibrium in the direction of the ene-1,1-
diamine form 1' in some measure.
Heating of N-t-butylbenzamidine or N-methylbenzyl-
amidine with 2 at 200˚ showed a contrasting result to heat-
ing of 1 with 2. Reaction of N-t-butylbenzamidine with 2
gave N-alkylated product 7 (40 %), and cyclization prod-
ucts such as pyrimidinone derivatives could not be
isolated. Reaction of N-methylbenzylamidine with 2 gave

May-Jun 2005
Synthesis of Heterocyclic Compounds Using Amidines
585
further purification. Trimethyl ethylenetricarboxylate (9) was
obtained according to the method of Hall and Ykman [6].
Methyl 3-[1-(N-t-Butylamino)-2-phenylethylidene]aminopropi-
onate (3a).
A solution containing N-t-butylbenzylamidine (1a) (9.50 g, 50.0
mmoles) and methyl acrylate (2) (6.46 g, 75.0 mmoles) in diglyme
(100 ml) was heated 100˚ for 10 hours. The solvent and the low
boiling materials were removed under reduced pressure (at 0.15
mmHg), maintaining the bath temperature below 100˚, leaving
13.40 g (97 %) of N-alkylation product 3a as a pale yellow liquid.
1
This product obtained was of satisfactory purity as judged by H
Table 2
Preparation of Compounds 11 and 13
nmr spectroscopy, which was used without further purification; ir
-1
1
(liquid film): 3411, 1736, 1647, 1600, 1525, 1504, 1444 cm ;
H
nmr: δ 1.27 (9H, s, C(CH ) ), 2.53 and 3.47 (each 2H, t, J=6.6 Hz,
3 3
1
2
Compound
R
R
Reaction
Time [h]
Yield
[%]
CH ), 3.48 (2H, s, CH ), 3.63 (1H, br s, NH), 3.65 (3H, s,
2
2
+
CO CH ), 7.17-7.32 (5H, m, aromatic); ms: m/z 276 (M ).
2
3
Anal. Calcd. for C H N O : C, 69.53; H, 8.75; N, 10.14.
Found: C, 69.08; H, 9.22; N, 10.28.
16 24
2 2
11a
11b
11c
11d
11e
11f
Ph
4-Cl-C H
H
H
H
H
H
3
3
3
3
3
3
3
3
3
3
3
2
2
4
7
87
71
72
88
56
51
50
50
66
68
58
65
76
24
15
6
4
4
4-Br-C H
6
Conversion to 4,5-Dihydro-3H-pyridin-2-one Derivative 5a of
N-Alkylation Product 3a.
4-MeO-C H
6
4
4-Me-C H
6
4
Ph-CH
H
H
A solution of N-alkylation product 3a (5.53 g, 20.0 mmoles) in
triglyme (40 ml) was heated with stirring at 200˚ for 5 hours in an
autoclave. The reaction mixture was cooled, and the precipitated
product 5a was collected by filtration and washed with carbon
tetrachloride. Evaporation of the combined filtrates under
reduced pressure and recrystallization of residual solid from a
small amount of carbon tetrachloride, gave an additional amount
of 5a. The total yield of 5a was 2.94 g (60 %), mp 202.5-205.0˚.
2
11g
11j
H
Me
Ph
Me
—
—
—
—
—
—
—
13a
13b
13c
13d
13e
13f
13i
4-Cl-C H
6
4
4-Br-C H
6
4
4-MeO-C H
6
4
4-Me-C H
6
4
Ph-CH
Et
2
Derivatization to 6 by Hydrolysis of 5a.
To a solution of 5a (2.44 g, 10.0 mmoles) in 1,4-dioxane (10
ml) were added acetic acid (5.0 ml) and water (5.0 ml), and this
mixture was heated under reflux for 50 hours. The resulting solu-
tion was concentrated under reduced pressure. To the residue
was added 4 N aqueous sodium hydroxide, and the alkaline solu-
tion was extracted with chloroform (3 x 20 ml). The combined
organic extracts were dried over anhydrous sodium sulfate and
evaporated, leaving 0.87 g (46 %) of 3-phenyl-2,6-piperidine-
dione (6) as white needles. An analytical sample was prepared
by recrystallization from ethyl acetate: mp 143.0-144.5˚ (refer-
11 obtained from reaction of 1 and 9 are shown in Table 2.
When a diglyme solution of 1 and dimethyl acetylenedi-
carboxylate (12) was heated at 150˚, 1,3-dihydropyrrol-2-
one derivatives 13 were obtained (Scheme 3, Table 2). The
structures of 11 and 13 were confirmed on the basis of their
microanalyses and spectral data. Both compounds 11 and
13 were prepared by reaction via the N,C-tautomer of the
1
amidines 1, that is, ene-1,1-diamine 1'. When R was aryl
-1
ence [3a], mp 142-143˚); ir: 3405, 1716, 1697, 1492, 1454 cm ;
groups for compounds 11a-11e and 13a-13e, as well as the
case of pyridin-2-one derivatives 5, pyrrol-2-one derivatives
11 and 13 were obtained in somewhat higher yield.
1
H nmr: δ 2.17-2.32 (2H, m, CH CH CO), 2.64 (1H, ddd,
2
2
J=17.8, 9.3, 5.4 Hz, CH CO), 2.70 (1H, dt, J=17.8, 5.6 Hz,
2
CH CO), 3.78 (1H, dd, J=9.3, 5.4 Hz, CH), 7.19-7.39 (5H, m,
2
+
aromatic), 8.44 (1H, br s, NH); ms: m/z 189 (M ).
EXPERIMENTAL
Anal. Calcd. for C H NO : C, 69.83; H, 5.86; N, 7.40.
11 11
2
Found: C, 69.66; H, 5.93; N, 7.39.
The ir and the H nmr spectra of this compound are in com-
plete agreement with the spectra of the sample synthesized
according to the method of the reference [3b].
1
All melting points are uncorrected. The ir spectra were
recorded on a Horiba FT-720 spectrometer in potassium bromide
pellets unless otherwise noted. The H nmr data were obtained
1
with a JEOL JNM-EX400 (400 MHz) spectrometer in deuterio-
chloroform by using tetramethylsilane as an internal standard.
Mass spectra were measured with a Shimadzu GCMS-QP5050A
spectrometer at 70 eV of ionization energy by use of a direct-inlet
system. Elemental analyses were performed by using a Perkin-
Elmer 2400 II CHN Analyzer.
N-t-Butylacetamidines 1, N-t-Butylbenzamidine, and N-
methylbenzylamidine were prepared by the method of Cooper
and Partridge [5]. Methyl acrylate (2) and dimethyl acetylenedi-
carboxylate (12) were commercially available and used without
Methyl 3-[(N-t-Butylamino)benzylidene]aminopropionate (7).
A solution containing N-t-butylbenzamidine (5.29 g, 30.0
mmoles) and methyl acrylate (2) (3.10 g, 36.0 mmoles) in
triglyme (60 ml) was heated with stirring at 200˚ for 5 hours in an
autoclave. Removal of the solvent under reduced pressure and
distillation of the residue gave 3.87 g (49 %) of 7, which on
standing crystallized. An analytical sample was prepared by
recrystallization from hexane: bp 117-119˚ (0.35 mmHg), mp
-1
1
43.0-44.0˚; ir: 3375, 1728, 1635, 1600, 1523, 1439 cm ;
H

586
K. Ito, Y. Kizuka and Y. Hirano
Vol. 42
nmr: δ 1.39 (9H, s, C(CH ) ), 2.45 and 3.28 (each 2H, t, J=6.8
6-t-Butylamino-5-(4-methoxyphenyl)-4,5-dihydro-3H-pyridin-
2-one (5d).
3 3
Hz, CH ), 3.63 (3H, s, CO CH ), 3.81 (1H, br s, NH), 7.21-7.39
2
2
3
+
(5H, m, aromatic); ms: m/z 262 (M ).
This compound was obtained as white needles, mp 150.0-
Anal. Calcd. for C H N O : C, 68.67; H, 8.45; N, 10.68.
15 22
2 2
-1
1
151.0˚; ir: 3249, 1639, 1606, 1545, 1510, 1469, 1392 cm ;
H
Found: C, 69.06; H, 8.53; N, 10.87.
nmr: δ 1.39 (9H, s, C(CH ) ), 2.07 and 2.15 (each 1H, m, CH ),
3 3
2
2.40-2.54 (2H, m, CH ), 3.46 (1H, dd, J=8.9, 5.1 Hz, CH), 3.82
2-Benzyl-3-methyl-5,6-dihydro-3H-pyrimidin-4-one (8).
2
(3H, s, OCH ), 5.06 (1H, br s, NH), 6.92 and 7.12 (each 2H, d,
J=8.8 Hz, aromatic); ms: m/z 274 (M ).
3
A solution containing N-methylbenzylamidine (4.45 g, 30.0
mmoles) and methyl acrylate (2) (3.10 g, 36.0 mmoles) in triglyme
(60 ml) was heated with stirring at 200˚ for 5 hours in an autoclave.
Removal of the solvent under reduced pressure and distillation of
the residue gave 3.96 g (65 %) of 8, which on standing crystallized.
An analytical sample was prepared by recrystallization from car-
bon tetrachloride: bp 148-150˚ (1.15 mmHg), mp 67.3-68.2˚; ir:
+
Anal. Calcd. for C H N O : C, 70.04; H, 8.08; N, 1021.
16 22
2 2
Found: C, 70.48; H, 8.17; N, 10.12.
6-t-Butylamino-5-(4-methylphenyl)-4,5-dihydro-3H-pyridin-2-
one (5e).
This compound was obtained as white needles, mp 180.0-
181.0˚; ir: 3252, 1647, 1601, 1547, 1510, 1471, 1450, 1390
-1
1
1685, 1655, 1458, 1365, 1296 cm ; H nmr: δ 2.48 and 3.64 (each
2H, t, J=7.3 Hz, CH ), 3.06 (3H, s, NCH ), 3.82 (2H, s, CH ),
2
3
2
-1
1
cm ; H nmr: δ 1.39 (9H, s, C(CH ) ), 2.08 and 2.16 (each 1H,
3 3
+
7.24-7.35 (5H, m, aromatic); ms: m/z 202 (M ).
Anal. Calcd. for C H N O: C, 71.26; H, 6.98; N, 13.85.
m, CH ), 2.36 (3H, s, CH ), 2.40-2.54 (2H, m, CH ), 3.47 (1H,
2
3
2
12 14
2
dd, J=9.3, 5.1 Hz, CH), 4.99 (1H, br s, NH), 7.09 and 7.19 (each
Found: C, 70.91; H, 7.00; N, 13.82.
+
2H, d, J=8.1 Hz, aromatic); ms: m/z 258 (M ).
Anal. Calcd. for C H N O: C, 74.38; H, 8.58; N, 10.84.
4,5-Dihydro-3H-pyridin-2-ones 5.
16 22
2
Found: C, 74.08; H, 8.81; N, 11.32.
A solution containing N-t-butylacetamidines 1 (30 mmoles) and
methyl acrylate (2) (36.0 mmoles) in triglyme (60 ml) was heated
with stirring at 200˚ for 5 hours in an autoclave. The reaction mix-
ture was cooled, and the precipitated product was collected by fil-
tration and washed with carbon tetrachloride. Evaporation of com-
bined filtrates under reduced pressure and recrystallization of the
residual solid from a small amount of carbon tetrachloride, gave an
additional amount of product 5. All the products obtained were of
5-Benzyl-6-t-butylamino-4,5-dihydro-3H-pyridin-2-one (5f).
This compound was obtained as a white powder, mp 184.5-
185.0˚; ir: 3249, 1635, 1599, 1545, 1500, 1475, 1456, 1392
-1
1
cm
; H nmr: δ 1.27 (9H, s, C(CH ) ), 1.85 and 2.02 (each 1H,
3 3
m, CH ), 2.43-2.61 (3H, m, CH and CH), 2.85 (1H, dd, J=13.6,
2
2
6.8 Hz, CH ), 2.91 (1H, dd, J=13.6, 9.3 Hz, CH ), 5.09 (1H, br s,
2
2
+
NH), 7.17-7.35 (5H, m, aromatic); ms: m/z 258 (M ).
Anal. Calcd. for C H N O: C, 74.38; H, 8.58; N, 10.84.
1
satisfactory purity as judged by H nmr spectroscopy. Samples for
analysis were recrystallized from chloroform.
16 22
2
Found: C, 74.50; H, 8.68; N, 10.90.
6-t-Butylamino-5-phenyl-4,5-dihydro-3H-pyridin-2-one (5a).
This compound was obtained as white scales, mp 204.5-
6-t-Butylamino-4,5-dihydro-3H-pyridin-2-one (5g).
This compound was obtained as a white powder, mp 219.0-
220.0˚; ir: 3276, 1651, 1585, 1527, 1473, 1448, 1421, 1390
-1
1
205.0˚; ir: 3273, 1649, 1577, 1520, 1469, 1444, 1392 cm ;
H
nmr: δ 1.39 (9H, s, C(CH ) ), 2.11 and 2.21 (each 1H, m, CH ),
-1
1
3 3
2
cm ; H nmr: δ 1.46 (9H, s, C(CH ) ), 1.88 (2H, quin, J=6.6 Hz,
3 3
2.42-2.56 (2H, m, CH ), 3.51 (1H, dd, J=9.3, 5.1 Hz, CH), 4.93
2
CH ), 2.34 and 2.40 (each 2H, t, J=6.6 Hz, CH ), 6.35 (1H, br s,
2
2
+
(1H, br s, NH), 7.20-7.42 (5H, m, aromatic); ms: m/z 244 (M ).
+
NH); ms: m/z 168 (M ).
Anal. Calcd. for C H N O: C, 73.74; H, 8.25; N, 11.47.
15 20
2
Anal. Calcd. for C H N O: C, 64.25; H, 9.59; N, 16.65.
9
16 2
Found: C, 73.59; H, 8.32; N, 11.37.
Found: C, 64.13; H, 9.72; N, 16.50.
6-t-Butylamino-5-(4-chlorophenyl)-4,5-dihydro-3H-pyridin-2-
one (5b).
6-t-Butylamino-5-methyl-4,5-dihydro-3H-pyridin-2-one (5h).
This compound was obtained as a white powder, mp 180.0-
180.5˚; ir: 3253, 1639, 1601, 1547, 1500, 1473, 1451, 1398
This compound was obtained as a white powder, mp 171.0-
-1
1
172.0˚; ir: 3271, 1645, 1583, 1537, 1500, 1448, 1387 cm ;
H
-1
1
cm ; H nmr: δ 1.26 (3H, d, J=7.3 Hz, CH ), 1.46 (9H, s,
3
nmr: δ 1.41 (9H, s, C(CH ) ), 2.05 and 2.20 (each 1H, m, CH ),
3 3
2
C(CH ) ), 1.69 and 2.00 (each 1H, m, CH ), 2.37-2.55 (3H, m,
3 3
2
2.42-2.47 (2H, m, CH ), 3.51 (1H, dd, J=8.3, 5.1 Hz, CH), 4.99
+
2
CH and CH), 5.85 (1H, br s, NH); ms: m/z 182 (M ).
2
(1H, br s, NH), 7.15 and 7.37 (each 2H, d, J=8.3 Hz, aromatic);
Anal. Calcd. for C H N O: C, 64.90; H, 9.95; N, 15.37.
10 18
2
+
ms: m/z 278 (M ).
Found: C, 65.90; H, 10.23; N, 15.27.
Anal. Calcd. for C H ClN O: C, 64.63; H, 6.87; N, 10.05.
15 19
2
6-t-Butylamino-5-ethyl-4,5-dihydro-3H-pyridin-2-one (5i).
This compound was obtained as a white powder, mp 184.0-
Found: C, 64.65; H, 6.95; N, 10.13.
5-(4-Bromophenyl)-6-t-butylamino-4,5-dihydro-3H-pyridin-2-
one (5c).
-1
184.5˚; ir: 3252, 1643, 1592, 1547, 1500, 1475, 1452, 1394 cm ;
1
H nmr: δ 0.99 (3H, t, J=7.4 Hz, CH ), 1.47 (9H, s, C(CH ) ), 1.54
3
3 3
This compound was obtained as a white powder, mp 186.5-
–1.71 (2H, m, CH ), 1.82, 1.95 and 2.12 (each 1H, m, CH and CH),
2
2
-1
1
187.0˚; ir: 3255, 1641, 1595, 1545, 1500, 1456, 1392 cm ;
H
+
2.38-2.51 (2H, m, CH ), 5.66 (1H, br s, NH); ms: m/z 196 (M ).
2
nmr: δ 1.41 (9H, s, C(CH ) ), 2.02 and 2.19 (each 1H, m, CH ),
Anal. Calcd. for C H N O: C, 67.31; H, 10.27; N, 14.27.
3 3
2
11 20
2
2.39 (2H, t, J=6.6 Hz, CH ), 3.52 (1H, dd, J=7.8, 5.1 Hz, CH),
Found: C, 67.01; H, 10.48; N, 14.07.
2
5.20 (1H, br s, NH), 7.09 and 7.51 (each 2H, d, J=8.3 Hz, aro-
6-t-Butylamino-5,5-dimethyl-4,5-dihydro-3H-pyridin-2-one
(5j).
+
matic); ms: m/z 322 and 324 (M ).
Anal. Calcd. for C H BrN O: C, 55.74; H, 5.92; N, 8.67.
15 19
2
Found: C, 55.38; H, 6.00; N, 9.00.
This compound was obtained as a white powder, mp 181.0-

May-Jun 2005
Synthesis of Heterocyclic Compounds Using Amidines
587
-1
1
182.0˚; ir: 3336, 1738, 1647, 1558, 1514, 1469, 1444 cm ; H nmr:
δ 1.24 (6H, s, 2CH ), 1.46 (9H, s, C(CH ) ), 1.75 and 2.51 (each 2H,
Anal. Calcd. for C H N O : C, 63.32; H, 6.71; N, 7.77.
Found: C, 63.46; H, 6.88; N, 7.74.
19 24
2 5
3
3 3
+
t, J=6.8 Hz, CH ), 5.27 (1H, br s, NH); ms: m/z 196 (M ).
2
Dimethyl 2-[5-t-Butylamino-4-(4-chlorophenyl)-2-oxo-3,4-dihy-
dro-2H-pyrrol-3-yl]malonate (11b).
Anal. Calcd. for C H N O: C, 67.31; H, 10.27; N, 14.27.
11 20
2
Found: C, 67.30; H, 10.55; N, 14.38.
This compound was obtained as white prisms, mp 139.5-
140.5˚; ir: 3294, 1755, 1736, 1703, 1574, 1529, 1491, 1438
1-t-Butylamino-2-azaspiro[5,5]undec-1-en-3-one (5k).
-1
1
cm ; H nmr: δ 1.41 (9H, s, C(CH ) ), 3.01 (1H, dd, J=5.6, 4.6
3 3
This compound was obtained as a white powder, mp 193.5-
Hz, CH), 3.46 and 3.71 (each 3H, s, CO CH ), 4.15 (1H, d, J=4.6
-1
1
2
3
194.5˚; ir: 3342, 1639, 1552, 1502, 1477, 1442 cm ; H nmr: δ
1.46 (9H, s, C(CH ) ), 1.45-1.73 (10H, m, (CH ) ), 1.86 and 2.47
Hz, CH), 4.37 (1H, d, J=5.6 Hz, CH), 5.04 (1H, br s, NH), 7.07
3 3
2 5
+
and 7.35 (each 2H, d, J=8.5 Hz, aromatic); ms: m/z 394 (M ).
+
(each 2H, t, J=6.8 Hz, CH ), 5.45 (1H, br s, NH); ms: m/z 236 (M ).
2
Anal. Calcd. for C H ClN O : C, 57.80; H, 5.87; N, 7.09.
19 23
2 5
Anal. Calcd. for C H N O: C, 71.14; H, 10.23; N, 11.85.
14 24
2
Found: C, 57.42; H, 5.92; N, 7.03.
Found: C, 71.11; H, 10.52; N, 11.99.
Dimethyl 2-[4-(4-Bromophenyl)-5-t-butylamino-2-oxo-3,4-
dihydro-2H-pyrrol-3-yl]malonate (11c).
Trimethyl 2-[1-(N-t-Butylamino)-2-phenylethylidene])amino-
1,1,2-ethanetricarboxylate (10a).
This compound was obtained as white needles, mp 168.0-
168.5˚; ir: 3294, 1755, 1736, 1703, 1576, 1527, 1489, 1437 cm ;
To a stirred solution of N-t-butylbenzylamidine (1a) (2.85 g,
15.0 mmoles) in ether (30 ml) at room temperature was added
dropwise a solution of trimethyl ethylenetricarboxylate (9)
(3.03 g 15.0 mmoles) in ether (30 ml) during 15 minutes. When
the reaction mixture was further stirred for 30 minutes at room
temperature a white precipitate began to separate from solution.
The reaction mixture was further stirred at room temperature.
After 2 hours, the crystalline solid was collected by filtration to
give 4.46 g of N-alkylation product 10a. Evaporation of the fil-
trate yielded an additional 0.99 g of 10a. The total yield of 10a
was 5.45 g (93 %), as pale yellow needles. An analytical sam-
ple was prepared by further recrystallization from ether: mp
-1
1
H nmr: δ 1.41 (9H, s, C(CH ) ), 3.00 (1H, dd, J=5.4, 4.6 Hz, CH),
3 3
3.47 and 3.71 (each 3H, s, CO CH ), 4.14 (1H, d, J=4.6 Hz, CH),
2
3
4.35 (1H, d, J=5.4 Hz, CH), 5.14 (1H, br s, NH), 7.01 and 7.50
+
(each 2H, d, J=8.3 Hz, aromatic); ms: m/z 438 and 440 (M ).
Anal. Calcd. for C H BrN O : C, 51.95; H, 5.28; N, 6.38.
19 23
2 5
Found: C, 52.24; H, 5.42; N, 6.39.
Dimethyl 2-[5-t-Butylamino-4-(4-methoxyphenyl)-2-oxo-3,4-
dihydro-2H-pyrrol-3-yl]malonate (11d).
This compound was obtained as white needles, mp 147.0-
-1
1
148.0˚; ir: 3238, 1736, 1703, 1579, 1541, 1510, 1458 cm ;
H
-1
1
101.0-101.5˚; ir: 3400, 1747, 1726, 1620, 1529, 1437 cm ;
H
nmr: δ 1.41 (9H, s, C(CH ) ), 3.05 (1H, dd, J=5.9, 4.9 Hz, CH),
3 3
nmr: δ 1.20 (9H, s, C(CH ) ), 3.67 (3H, s, CO CH ), 3.68 (5H,
3 3
2
3
3.42 (3H, s, OCH ), 3.70 and 3.81 (each 3H, s, CO CH ), 4.13
3
2
3
s, CO CH and CH ), 3.73 (3H, s, CO CH ), 3.78 (1H, br s,
2
3
2
2
3
(1H, d, J=4.9 Hz, CH), 4.32 (1H, d, J=5.9 Hz, CH), 5.09 (1H, br
NH), 4.20 and 4.83 (each 1H, d, J=9.3 Hz, CH), 7.18-7.30 (5H,
s, NH), 6.89 and 7.03 (each 2H, d, J=8.7 Hz,, aromatic); ms: m/z
+
m, aromatic); ms: m/z 392 (M ).
+
390 (M ).
Anal. Calcd. for C H N O : C, 61.21; H, 7.19; N, 7.14.
20 28
2 4
Anal. Calcd. for C H N O : C, 61.53; H, 6.71; N, 7.18.
20 26
2 6
Found: C, 61.16; H, 7.15; N, 7.16.
Found: C, 61.88; H, 6.92; N, 7.22.
Conversion to 3,4-Dihydropyrrol-2-one derivative 11a of N-
Alkylation Product 10a.
Dimethyl 2-[5-t-Butylamino-4-(4-methylphenyl)-2-oxo-3,4-
dihydro-2H-pyrrol-3-yl]malonate (11e).
A solution of N-alkylation product 10a (3.04 g, 8.0 mmoles)
in diglyme (16 ml) was heated with stirring at 150˚ for 3 hours.
The solvent was removed under reduced pressure and the resid-
ual solid was recrystallized from carbon tetrachloride to give
2.57 g (89 %) of 11a as a white powdery solid, mp 146.5-150.0˚.
This compound was obtained as white needles, mp 168.5-
-1
1
169.5˚; ir: 3240, 1749, 1697, 1591, 1545, 1514, 1431 cm ;
H
nmr: δ 1.40 (9H, s, C(CH ) ), 2.35 (3H, s, CH ), 3.07 (1H, dd,
3 3
3
J=5.9, 4.9 Hz, CH), 3.40 and 3.70 (each 3H, s, CO CH ), 4.13
2
3
(1H, d, J=4.9 Hz, CH), 4.33 (1H, d, J=5.9 Hz, CH), 5.05 (1H, br
3,4-Dihydropyrrol-2-ones 11.
s, NH), 6.99 and 7.17 (each 2H, d, J=8.1 Hz, aromatic); ms: m/z
+
374 (M ).
A solution containing N-t-butylacetamidines 1 (10.0 mmoles)
and trimethyl ethylenetricarboxylate (9) (10.5 mmoles) in
diglyme (20 ml) was heated with stirring at 150˚ for 3 hours.
After removal of the solvent under reduced pressure, the resid-
ual solid was recrystallized from carbon tetrachloride to give
11. All the products obtained were of satisfactory purity as
Anal. Calcd. for C H N O : C, 64.15; H, 7.00; N, 7.48.
20 26
2 5
Found: C, 64.24; H, 7.22; N, 7.44.
Dimethyl 2-(4-Benzyl-5-t-butylamino-2-oxo-3,4-dihydro-2H-
pyrrol-3-yl)-malonate (11f).
This compound was obtained as white needles, mp 189.0-
1
judged by H nmr spectroscopy. Analytical samples were pre-
-1
1
190.5˚; ir: 3230, 1759, 1738, 1697, 1595, 1522, 1446 cm ;
H
pared by recrystallization from monoglyme.
nmr: δ 1.24 (9H, s, C(CH ) ), 2.62 (1H, dd, J=13.7, 11.2 Hz,
3 3
CH ), 2.81 (1H, t, J=4.4 Hz, CH), 3.29 (1H, dd, J=13.7, 4.4 Hz,
Dimethyl 2-(5-t-Butylamino-2-oxo-4-phenyl-3,4-dihydro-2H-
pyrrol-3-yl)-malonate (11a).
2
CH ), 3.39 (1H, dt, J=11.2, 4.4 Hz, CH), 3.68 and 3.79 (each 3H,
2
s, CO CH ), 4.13 (1H, d, J=4.4 Hz, CH), 4.89 (1H, br s, NH),
2
3
This compound was obtained as a white powder, mp 149.5-
151.0˚; ir: 3240, 1757, 1738, 1703, 1657, 1579, 1531, 1437
+
7.25-7.40 (5H, m, aromatic); ms: m/z 374 (M ).
Anal. Calcd. for C H N O : C, 64.15; H, 7.00; N, 7.48.
-1
1
20 26
2 5
cm ; H nmr: δ 1.41 (9H, s, C(CH ) ), 3.09 (1H, dd, J=5.9, 4.9
3 3
Found: C, 64.08; H, 7.01; N, 7.49.
Hz, CH), 3.39 and 3.70 (each 3H, s, CO CH ), 4.14 (1H, d,
2
3
J=4.9 Hz, CH), 4.37 (1H, d, J=5.9 Hz, CH), 5.08 (1H, br s, NH),
7.10-7.39 (5H, m, aromatic); ms: m/z 360 (M ).
Dimethyl 2-(5-t-Butylamino-2-oxo-3,4-dihydro-2H-pyrrol-3-
yl)malonate (11g).
+

588
K. Ito, Y. Kizuka and Y. Hirano
Vol. 42
This compound was obtained as white needles, mp 173.0-
174.0˚; ir: 3234, 1741, 1699, 1597, 1520, 1490, 1465, 1437 cm ;
Methyl [5-t-Butylamino-4-(4-methoxyphenyl)-2-oxo-1,2-dihy-
dropyrrol-3-ylidene]acetate (13d).
-1
1
H nmr: δ 1.46 (9H, s, C(CH ) ), 2.88 (1H, dd, J=13.0, 6.3 Hz,
3 3
This compound was obtained as dark red needles, mp 207.0-
CH ), 2.91 (1H, dd, J=13.0, 7.8 Hz, CH ), 3.10 (1H, ddd, J=7.8,
2
2
-1 1
207.5; ir: 3413, 1693, 1664, 1587, 1533, 1439 cm ; H nmr: δ 1.54
(9H, s, C(CH ) ), 3.80 and 3.81 (each 3H, s, OCH or CO CH ),
6.3, 5.4, Hz, CH), 3.69 and 3.76 (each 3H, s, CO CH ), 4.01 (1H,
2
3
3 3
3
2
3
+
d, J=5.4 Hz, CH), 6.71 (1H, br s, NH); ms: m/z 284 (M ).
5.69 (1H, br s, NH), 5.94 (1H, s, CH), 6.95 and 7.31 (each 2H, d,
Anal. Calcd. for C H N O : C, 54.92; H, 7.09; N, 9.85.
+
13 20
2 5
J=8.8 Hz, aromatic) 9.00 (1H, br s, NH); ms: m/z 330 (M ).
Found: C, 55.18; H, 7.10; N, 9.75.
Anal. Calcd. for C H N O : C, 65.44; H, 6.71; N, 8.48.
18 22
2 4
Found: C, 65.64; H, 6.73; N, 8.55.
Dimethyl 2-(5-t-Butylamino-4,4-dimethyl-2-oxo-3,4-dihydro-
2H-pyrrol-3-yl)-malonate (11j).
Methyl [5-t-Butylamino-4-(4-methylphenyl)-2-oxo-1,2-dihy-
dropyrrol-3-ylidene]acetate (13e).
This compound was obtained as white needles, mp 176.0-
-1
1
177.0˚; ir: 3294, 1747, 1693, 1572, 1531, 1460, 1435 cm ;
H
This compound was obtained as red needles, mp 204.5-205.0˚;
nmr: δ 1.17 and 1.39 (each 3H, s, CH ), 1.49 (9H, s, C(CH ) ),
-1
1
3
3 3
ir: 3396, 1690, 1657, 1583, 1533, 1442 cm ; H nmr: δ 1.54
(9H, s, C(CH ) ), 2.34 (3H, s, CH ), 3.80 (3H, s, CO CH ), 5.79
3.20 and 3.61 (each 1H, d, J=10.6 Hz, CH), 3.75 and 3.80 (each
3 3
3
2
3
+
3H, s, CO CH ), 5.84 (1H, br s, NH); ms: m/z 312 (M ).
2
3
(1H, br s, NH), 5.94 (1H, s, CH), 7.21 and 7.29 (each 2H, d, J=8.1
Hz, aromatic) 9.02 (1H, br s, NH); ms: m/z 314 (M ).
Anal. Calcd. for C H N O : C, 57.68; H, 7.74; N, 8.97.
+
15 24
2 5
Found: C, 57.76; H, 7.85; N, 9.02.
Anal. Calcd. for C H N O : C, 68.77; H, 7.05; N, 8.91.
18 22
2 3
Found: C, 68.72; H, 7.13; N, 8.93.
1,3-Dihydropyrrol-2-ons 13.
Methyl (4-Benzyl-5-t-butylamino-2-oxo-1,2-dihydropyrrol-3-
ylidene)acetate (13f).
A solution containing N-t-butylacetamidines 1 (20.0 mmoles)
and dimethyl acetylenedicarboxylate (12) (20.0 mmoles) in
diglyme (40 ml) was heated with stirring at 150˚ for the time indi-
cated in Table 2. After removal of the solvent under reduced
pressure, the residue was recrystallized from ethyl
acetate–hexane to give 13. All the products obtained were of sat-
This compound was obtained as orange needles, mp 192.5-
-1
1
193.5˚; ir: 3406, 1693, 1662, 1587, 1550, 1437 cm ; H nmr: δ
1.27 (9H, s, C(CH ) ), 3.59 (2H, s, CH ), 3.77 (3H, s, CO CH ),
3 3
2
2
3
4.79 (1H, br s, NH), 5.89 (1H, s, CH), 7.19-7.31 (5H, m, aro-
1
isfactory purity as judged by H nmr spectroscopy. Samples for
analysis were recrystallized from monoglyme.
+
matic), 8.69 (1H, br s, NH); ms: m/z 314 (M ).
Anal. Calcd. for C H N O : C, 68.77; H, 7.05; N, 8.91.
18 22
2 3
Found: C, 69.08; H, 7.27; N, 9.02.
Methyl (5-t-Butylamino-2-oxo-4-phenyl-1,2-dihydropyrrol-3-
ylidene)acetate (13a).
Methyl (5-t-Butylamino-4-ethyl-2-oxo-1,2-dihydropyrrol-3-yli-
dene)acetate (13i).
This compound was obtained as dark red prisms, mp 189.0-
-1
1
189.5˚; ir: 3411, 1668, 1579, 1523, 1442 cm ; H nmr: δ 1.55
This compound was obtained as orange needles, mp 180.0-
(9H, s, C(CH ) ), 3.80 (3H, s, CO CH ), 5.85 (1H, br s, NH),
-1
1
3 3
2
3
180.5˚; ir: 3413, 1682, 1658, 1585, 1543, 1437 cm ; H nmr: δ
1.02 (3H, t, J=7.6 Hz, CH ), 1.54 (9H, s, C(CH ) ), 2.14 (2H, q,
5.94 (1H, s, CH), 7.17-7.27 and 7.37-7.42 (5H, m, aromatic) 9.05
3
3 3
+
(1H, br s, NH); ms: m/z 300 (M ).
J=7.6 Hz, CH ), 3.77 (3H, s, CO CH ), 5.20 (1H, br s, NH), 5.82
2
2
3
Anal. Calcd. for C H N O : C, 67.98; H, 6.71; N, 9.33.
+
17 20
2
3
(1H, s, CH), 8.72 (1H, br s, NH); ms: m/z 252 (M ).
Found: C, 67.80; H, 6.77; N, 9.47.
Anal. Calcd. for C H N O : C, 61.88; H, 7.99; N, 11.10.
13 20
2 3
Found: C, 62.00; H, 8.04; N, 10.99.
Methyl [5-t-Butylamino-4-(4-chlorophenyl)-2-oxo-1,2-dihy-
dropyrrol-3-ylidene]acetate (13b).
This compound was obtained as as red needles, mp 222.0-
REFERENCES AND NOTES
-1
1
222.5˚; ir: 3400, 1689, 1670, 1597, 1523, 1437 cm ; H nmr: δ
1.56 (9H, s, C(CH ) ), 3.81 (3H, s, CO CH ), 5.75 (1H, br s,
3 3
2
3
[1a] A. L. Weis, Synthesis, 528 (1985); [b] K. A. Gupta, A. K.
Saxena and P. C. Jain, Synthesis, 905 (1981); [c] M. Langlois, C. Guilloneau,
T. V. Van, R. Jolly and J. Maillard, J. Heterocyclic Chem., 20, 393 (1983); [d]
A. L. Weis and D. Zamir, J. Org. Chem., 52, 3421 (1987); [e] C. Kashima,
M. Shimizu and Y. Omote, J. Heterocyclic Chem., 26, 251 (1989).
[2] M. Pfau, M. Chiriacescu and G. Revial, Tetrahedron Lett., 34,
327 (1993).
[3a] J. A. Elvidge, R. P. Linstead and A. M. Salaman, J. Chem.
Soc., 208 (1959); [b] T. Połon´ski, J. Chem. Soc., Perkin Trans. I, 639
(1988).
[4] M. Pfau and C. Ribière, J. Chem. Soc., Chem. Commun., 66
(1970).
[5] F. C. Cooper and M. W. Partridge, in Organic Syntheses, Coll
Vol 4, A. H. Blatt, ed, John Wiley & Sons, New York, NY, 1963, p 769.
[6] H. K. Hall Jr. and P. Ykman, J. Am. Chem. Soc., 97, 800
(1975).
NH), 5.93 (1H, s, CH), 7.35 (4H, s, aromatic) 9.09 (1H, br s,
+
NH); ms: m/z 334 (M ).
Anal. Calcd. for C H ClN O : C, 60.99; H, 5.72; N, 8.37.
17 19
2 3
Found: C, 60.75; H, 5.80; N, 8.26.
Methyl [4-(4-Bromophenyl)-5-t-butylamino-2-oxo-1,2-dihy-
dropyrrol-3-ylidene]acetate (13c).
This compound was obtained as light red needles, mp 227.5-
-1
1
228.5˚; ir: 3415, 1692, 1672, 1597, 1522, 1439 cm ; H nmr: δ
1.56 (9H, s, C(CH ) ), 3.81 (3H, s, CO CH ), 5.78 (1H, br s,
3 3
2
3
NH), 5.92 (1H, s, CH), 7.28 and 7.49 (each 2H, d, J=8.5 Hz, aro-
+
matic) 9.08 (1H, br s, NH); ms: m/z 378 and 380 (M ).
Anal. Calcd. for C H BrN O : C, 53.84; H, 5.05; N, 7.39.
17 19
2 3
Found: C, 53.97; H, 5.04; N, 7.36.