Synthesis of N-substituted 3-ammomethylidenetetramic acids

Article abstract of DOI:10.1055/s-2005-916072

(S)-3-(Dimethylamino)methylidene-5-benzyltetramic acid derivatives 4a and 4b were prepared in three steps from N-protected (S)-3-phenylalanines 1a and 1b, respectively. Similarly, N-[N-(benzyloxycarbonyl)glycyl]grycine (1c) was transformed into the enamitione 4c. Acid-catalysed coupling of enaminones 4a-c with aliphatic, aromatic, and heteroaromatic primary amines 5-34 afforded the corresponding N(3′)-substituted 3-aminomethylidenetetramic acid derivatives 35-64 in 29-96% yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-916072

FEATURE ARTICLE
2969
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
Synthesis of
N
a
-Substitute
m
d 3-Aminomethylid
o
enetetramic
A
cids Pirc, David Bevk, Renata Jakše, Simon Rečnik, Ljubo Golič, Amalija Golobič, Anton Meden,
Branko Stanovnik,* Jurij Svete*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: branko.stanovnik@fkkt.uni-lj.si; E-mail: jurij.svete@fkkt.uni-lj.si
Received 30 May 2005; revised 18 July 2005
HO
Abstract: (S)-3-(Dimethylamino)methylidene-5-benzyltetramic
OH
O
O
N
acid derivatives 4a and 4b were prepared in three steps from N-pro-
tected (S)-3-phenylalanines 1a and 1b, respectively. Similarly,
N-[N-(benzyloxycarbonyl)glycyl]glycine (1c) was transformed into
the enaminone 4c. Acid-catalysed coupling of enaminones 4a–c
with aliphatic, aromatic, and heteroaromatic primary amines 5–34
afforded the corresponding N(3¢)-substituted 3-aminomethylidene-
tetramic acid derivatives 35–64 in 29–96% yields.
HN
HO
O
O
H
H
tenuazonic acid
(Alternaria tenius)
H
equisetin
(Fusarium equiseti)
Key words: amines, chiral pool, coupling, heterocycles, enami-
nones
O
OH
N
H
O
H
H
Tetramic acid (pyrrolidin-2,4-dione) derivatives have at-
tracted scientific interest for several decades. A great deal
of interest can be attributed to the fact, that the majority of
naturally occurring tetramic acids exhibit biological activ-
ity, such as antibiotic and antiviral activity. Since many of
naturally occurring tetramic acids exist as the 3-acyl de-
rivatives, preparation of this type of compounds repre-
sents an important target in synthetic organic chemistry.1
Such examples of naturally occurring 3-acyltetramic ac-
ids are tenuazonic acid,2 equisetin,3 a-cyclopiazonic acid,4
and physarorubinic acid5 (Figure 1).
α-cyclopiazonic acid
(Penicillium cyclopium)
N
H
OH
O
COOH
MeN
physarorubinic acid
O
(Physarium polycephalum)
HO
Figure 1 Some examples of naturally occurring 3-acyltetramic acid
derivatives
In the last two decades, a series of 2-substituted alkyl 3-
(dimethylamino)prop-2-enoates were prepared and used
as versatile reagents for the preparation of various hetero-
cyclic systems, functionalised heterocyclic compounds,
and natural product analogues.6 Just recently, the prope-
noate methodology has been employed in combinatorial
synthesis of dehydroalanine derivatives and heterocy-
cles.7 In extension, various chiral 3-(dimethylamino)prop-
2-enoate analogues were prepared from commercially
available enantiopure starting materials, such as L-pyro-
glutamic acid, tetrahydrofuran-2-one-5-carboxylic acid,
and (+)-camphor. These chiral enaminones were em-
ployed as the key intermediates in the preparation of func-
tionalized heterocycles, such as b-heteroarylalanine,
alaninol, and propane-1,2-diol derivatives, heterocyclic
analogs of dipeptides, and terpene-functionalised hetero-
cycles.6,8 In continuation of our work in the field of chiral
enaminones, we now report preparation of tetramic acid
derived enaminones and coupling reactions with primary
amines, which afforded the corresponding N(3¢)-substi-
tuted 3-(aminomethylidene)pyrrolidine-2,4-dione deriva-
tives 35–64 as aza-analogs of 3-formyl- (or 3-
hydroxymethylidene)-substituted tetramic acids.
First, (S)-5-benzyl-1-tert-butoxycarbonyl-4-hydroxy-2,5-
dihydropyrrol-2-one (3a)9a and (S)-5-benzyl-1-benzyl-
oxycarbonyl-4-hydroxy-2,5-dihydropyrrol-2-one (3b)9b
were prepared according to literature procedures in two
steps from (S)-N-tert-butoxycarbonyl-3-phenylalanine
(1a) and (S)-N-benzyloxycarbonyl-3-phenylalanine (1b),
respectively, via coupling of 1a,b with Meldrum’s acid in
the presence of N,N¢-dicyclohexylcarbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP), followed by ‘ring
switching’ transformation of the intermediates 2a,b in re-
fluxing ethyl acetate. Similarly, the analog 3c was
obtained in 93% overall yield from N-[N-(benzyloxycar-
bonyl)glycyl]glycine (1c). Finally, treatment of 1-acyltet-
ramic acids 3a–c with N,N-dimethylformamide dimethyl
acetal (DMFDMA) at 45–90 °C furnished the correspond-
ing 1-acyl- and 1-alkoxycarbonyl-3-[(E)-(dimethylami-
no)methylidene]pyrrolidine-2,4-diones 4a–c in 72–80%
yields (Scheme 1).
Once the desired enamino tetramic acid derivatives 4a–c
were synthesized, dimethylamine substitution reactions
were carried out with a variety of primary amines, such as
anilines 5–14, heteroarylamines 15–22, a-amino acid es-
SYNTHESIS 2005, No. 17, pp 2969–2988
Advanced online publication: 23.09.2005
DOI: 10.1055/s-2005-916072; Art ID: T07105SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

2970
S. Pirc et al.
FEATURE ARTICLE
Biographical Sketches
Samo Pirc was born in Kranj, Slove-
his studies under the supervision of
Professor Branko Stanovnik and re-
ceived his PhD in 2004. Currently, he
is working as a researcher at Lek Phar-
maceuticals d. d., a new Sandoz com-
pany, Ljubljana, Slovenia.
nia, in 1975. He studied chemistry at
the University of Ljubljana and re-
ceived his BSc in 2000. He continued
David Bevk was born in Ljubljana,
Slovenia, in 1977. In 2001, he ob-
tained his BSc degree in chemistry,
from the University of Ljubljana, Fac-
ulty of Chemistry and Chemical Tech-
nology. Since 2001 he is a PhD
student under the supervision of Pro-
fessor Branko Stanovnik.
Renata Jakše was born in Arbon,
Switzerland, in 1975. She studied
chemistry at the University of Ljublja-
na and received her Diploma in 1998,
and her PhD in 2003 under the super-
vision of Professor Branko Stanovnik.
She is currently working at Krka Phar-
maceuticals d. d., Novo mesto, Slove-
nia.
Simon Rečnik was born in Maribor,
Slovenia, in 1974. He studied chemis-
try at the University of Ljubljana and
received his BSc in 1998. He contin-
ued his research under the supervision
of Professor Jurij Svete and received
his PhD in 2002. Since then, he is a
Quality Manager at Lek Pharmaceuti-
cals d. d., a new Sandoz company,
Ljubljana, Slovenia.
Ljubo Golič was born in 1932 in
Vrenska gorca, Slovenia. He received
his Diploma in chemistry in 1956 and
his PhD in structural chemistry at the
University of Ljubljana in 1965. He
was a research student at the Universi-
ty of Glasgow in Professor Speak-
man's group. He continued his career
at the University of Ljubljana, where
he became a Full Professor in 1977.
His research interests lie in the field of
structural chemistry, with focus on
compounds with short hydrogen
bonds. Currently he is a Professor
Emeritus at University of Ljubljana.
Amalija Golobič was born in Novo
mesto, Slovenia, in 1969. She studied
chemistry at the University of Ljublja-
na and received her Diploma in 1992
and PhD degree in 1996. Since 2004
she is an Assistant Professor at the
University of Ljubljana. Her main re-
search interests are structure determi-
nation of coordination and organic
compounds in solid state by X-ray dif-
fraction of single crystals and structur-
al characterization of ceramics using
powder diffraction.
Anton Meden was born in Ljubljana,
Slovenia, in 1963. He studied Chemis-
try at the University of Ljubljana and
received his PhD in 1994. In 1995/
1996 he spent one year as a post-doc at
the Laboratory of Crystallography at
the ETH in Zurich. From 1995 to 2000
he was an Assistant Professor of
Chemistry at the Faculty of Chemistry
and Chemical Technology, University
of Ljubljana. Since 2001 until present
he is an Associate Professor and is re-
sponsible for the X-ray laboratory at
the same institution.
Branko Stanovnik was born in Br-
ezovica pri Ljubljani, Slovenia, in
1938. He received his Diploma in
chemistry in 1960 and his PhD in or-
ganic chemistry at the University of
Ljubljana in 1964. He became an As-
sociate Professor at that university in
1967 and Full Professor in 1972. He
was a postdoctoral fellow with the Na-
tional Research Council in Canada and
Visiting Professor in the USA and
Australia. He is a member of many ad-
visory boards and societies and the au-
thor of over 500 papers, reviews and
books. His research interests lie in the
field of heterocyclic chemistry, 1,3-di-
polar cycloadditions, asymmetric syn-
thesis, and natural products synthesis.
Jurij Svete was born in Ljubljana,
Slovenia in 1962. He received his Di-
ploma in chemistry in 1986 and his
PhD in 1990 under supervision of Pro-
fessor Stanovnik. He continued to
work as a researcher with the group of
Professor Stanovnik. In 1997 he spent
one year as a Humboldt Fellow at the
University of Stuttgart, Germany,
working with Professor Jäger on the
synthesis of iminopolyols from furan-
nitrile oxide cycloadducts. In 1996, he
became an Assistant Professor at the
University of Ljubljana and an Asso-
ciate Professor in 2001. His research
interests include synthesis of hetero-
cyclic compounds with emphasis on
chiral functionalized heterocycles,
stereoselective synthesis, chemistry of
enaminones, 1,3-dipolar cycloaddi-
tions, and combinatorial synthesis.
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2971
R1
N
R1
N
O
R2
O
R2
i
H
O
O
NMe2
NHR
4a–c
35/35'–64/64'
R1
R2
Compound
Isomer
(major or minor)
major
COOtBu
35a–64a
35'a–64'a
35b–64b
35'b–64'b
35c–64c
35'c–64'c
CH2Ph
CH2Ph
CH2Ph
CH2Ph
H
COOtBu
minor
major
minor
major
COOBn
COOBn
COCH2NHCOOBn
COCH2NHCOOBn
minor
H
Scheme 2 Reagents and conditions: (i) RNH2 (5–34), EtOH, 37%
HCl (1 equiv), 20–80 °C
enaminones 4a–c with primary amines proceeded under
relatively mild conditions. Typically, reactions were car-
ried out in ethanol with amine hydrochlorides or with free
amines in the presence of one equivalent of 37% hydro-
chloric acid at 20–80 °C to afford the corresponding sub-
stitution products as the E/Z-mixtures of the major
isomers 35–64 and the minor isomers 35¢–64¢ isomers
(Scheme 2, Table 1).
Scheme 1 Reagents and conditions: (i) Meldrum’s acid, DMAP,
DCC, CH2Cl2, 0–20 °C, then washing with 1 M aq NaHSO4 (Ref.9);
(ii) EtOAc, reflux (Ref.9); (iii) DMFDMA, toluene, 80–90 °C (3a →
4a) or DMFDMA, CH2Cl2, reflux (3b → 4b)
ters 23–29, alkylamines 30–33, and hydroxylamine 34. In
this manner, a series of N-substituted 1-acyl-3-amino-
methylidenetetramic acid derivatives 35–64 were pre-
pared in 29–96% yields. All these couplings of
Table 1 Experimental and Physical Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢
Reactants
Product
2¢c
Method
Temp (°C) Time (h) CC
Yield (%) E:Z
Mp (°C)
145–147
84–85
–
–
–
–
–
93
–
–
2c
–
–
–
–
~100
~100
72
–
–
3c
–
–
–
–
–
133–136
128–130
oil
–
4a
–
–
–
–
100:0
100:0
100:0
52:48
53:47
56:44
93:7
84:16
85:15
44:56
55:45
60:40
58:42
54:46
–
4b
–
–
–
–
72
–
4c
–
–
–
–
80
148–149
57–60
4a + PhNH2·HCl (5)
4b + PhNH2·HCl (5)
4c + PhNH2·HCl (5)
4b + 4-MeC6H4NH2·HCl (6)
4c + 4-MeC6H4NH2·HCl (6)
4a + 4-NO2C6H4NH2 (7)
4b + 4-NO2C6H4NH2 (7)
4c + 4-NO2C6H4NH2 (7)
4c + 2-MeOC6H4NH2 (8)
4c + 3-MeOC6H4NH2 (9)
4a + 4-MeOC6H4NH2 (10)
35/35¢a
35/35¢b
35/35¢c
36/36¢b
36/36¢c
37/37¢a
37/37¢b
37/37¢c
38/38¢c
39/39¢c
40/40¢a
A
A
B
B
B
B
B
B
B
B
A
20
20
80
20
80
20
20
80
80
80
20
48
48
3
1:2a
2:1a
–
83
83
98–104
184–186
136–139
196–198
165–166
181–183
212–214b
200–202
179–182
56–61
95
48
–
71
1.5
–
95
18
48
3
–
77
–
79
–
90
3
–
87
3
–
87
24
1:2a
71
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2972
S. Pirc et al.
FEATURE ARTICLE
Table 1 Experimental and Physical Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Reactants
Product
40/40¢b
40/40¢c
41/41¢c
42/42¢c
43/43¢b
43/43¢c
44/44¢b
44/44¢c
Method
A
B
Temp (°C) Time (h) CC
Yield (%) E:Z
54:46
Mp (°C)
151–152
190–191
196–200
206–208
174–175
247–250
115–125
159–166
95–98
4b + 4-MeOC6H4NH2 (10)
4c + 4-MeOC6H4NH2 (10)
4c + 2-BrC6H4NH2 (11)
4c + 3-BrC6H4NH2 (12)
4b + 4-BrC6H4NH2 (13)
4c + 4-BrC6H4NH2 (13)
4b + 1-naphthylamine (14)
4c + 1-naphthylamine (14)
80
80
80
80
80
80
80
80
20
20
20
20
80
20
80
50
20
80
60
20
80
80
20
50
60
60
20
20
20
20
80
20
80
20
70
20
2
3
2
2
3
2
80:1c
–
82
84
85
88
89
90
93
84
48
48
74
63
91
46
43
76
77
29
73
43
79
93
88
35
53
89
93
84
90
46
79
96
88
92
95
53
59:41
60:40
62:38
84:16
86:14
49:51
60:40
46:54
0:100
0:100
42:58
58:42
45:55
57:43
42:58
30:70
100:0
42:58
51:49
44:56
56:44
76:24
60:40
19:81
46:54
50:50
18:82
43:57
52:48
59:41
53:47
60:40
51:49
45:55
36:64
B
–
B
–
B
–
B
–
A
B
60:1c
–
3
18
18
48
18
4a + 3-amino-5-methyl-1H-pyrazole (15) 45/45¢a
A
B
2:1a
–
4a + 5-amino-1H-tetrazole (16)
4b + 5-amino-1H-tetrazole (16)
4a + 3-amino-5-methylisoxazole (17)
4c + 3-amino-1H-indazole (18)
4a + 2-aminopyridine (19)
46a
145–153
187–198
67–70
46b
B
–
47/47¢a
48/48¢c
49/49¢a
49/49¢c
50/50¢a
50/50¢b
50c
A
B
1:1a
–
1.5
210–212b
67–69
A
A
A
B
48
9
2:1a
2:1a
1:0a
–
4c + 2-aminopyridine (19)
160–161
75–81
4a + aminopyrazine (20)
1
4b + aminopyrazine (20)
48
153–155
198–202b
56–64
4c + aminopyrazine (20)
A
A
A
B
2.5
1:0a
1:0a
1:0a
–
4a + 2-amino-4-methylpyrimidine (21)
4b + 2-amino-4-methylpyrimidine (21)
4b + 3-aminoquinoline (22)
4c + 3-aminoquinoline (22)
4a + HCl·H-Gly-OMe (23)
4c + HCl·H-Gly-OMe (23)
4a + HCl·H-L-Ala-OEt (24)
4a + HCl·H-L-Leu-OMe (25)
4b + HCl·H-L-Leu-OMe (25)
4a + HCl· H-L-Gla-di-OEt (26)
4a + HCl·H-L-Cys-OEt (27)
4b + HCl·H-L-Cys-OEt (27)
4c + HCl·H-L-Cys-OEt (27)
4b + HCl·H-L-Phe-OMe (28)
4c + HCl·H-L-Phe-OMe (28)
4b + HCl·H-L-Trp-OMe (29)
4a + HCl·H2NCH2CH2CO2Et (30)
4a + HCl·H2NCH2CN (31)
51/51¢a
51/51¢b
52/52¢b
52/52¢c
53/53¢a
53/53¢c
54/54¢a
55/55¢a
55/55¢b
56/56¢a
57/57¢a
57/57¢b
57/57¢c
58/58¢b
58/58¢c
59/59¢b
60/60¢a
61/61¢a
2
48
2
51–57
170–173
195–197b
115–125
194–198
111–124
112–115
35–44
B
3
–
Bd
B
24
4
–
–
A
A
A
A
A
A
A
A
A
A
A
B
4
1:0a
1:0a
2:1a
1:0a
1:0a
2:1a
2:1a
2:1a
3:1a
2:1a
1:0a
–
4
48
48
48
48
1
83–89
73–77
47–53
190–198b
39–46
48
1
63–66
48
6
78–84
128–130
147–153
24
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2973
Table 1 Experimental and Physical Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Reactants
Product
61/61¢b
61/61¢c
62/62¢b
63/63¢c
64a
Method
Temp (°C) Time (h) CC
Yield (%) E:Z
Mp (°C)
140–153
204–207
41–48
4b + HCl·H2NCH2CN (31)
4c + HCl·H2NCH2CN (31)
4b + PhCH2NH2·HCl (32)
4c + adamantylmethylamine (33)
4a + HCl·H2NOH (34)
4b + HCl·H2NOH (34)
4c + HCl·H2NOH (34)
B
B
A
B
Bd
B
B
20
80
20
80
20
20
80
24
2
–
87
94
84
55
62
71
73
43:57
–
88:12
51:49
61:39
100:0
100:0
89:11
48
2
1:0a
–
228–230
159–161
179–182
184–186
24
48
6
–
64b
–
64/64¢c
–
a EtOAc–hexanes.
b With decomposition.
c CHCl3–MeOH.
d Precipitation of the product occurred upon addition of water.
Structures of compounds 4, 35–64 were determined by pounds 4b, 40a, 57c, 59b, and 62b were confirmed by 13C
1
spectroscopic (IR, H and 13C NMR, MS, HRMS) meth- NMR and HRMS. The identity of compound 51b was
ods and by elemental analyses for C, H, and N (Tables 2– confirmed by HRMS.
5). Compounds 4b, 40a, 51b, 57c, 59b, and 62b were not
isolated in analytically pure form. The identities of com-
Table 2 Correlation of Chemical Shifts d of H–C(3¢) and H–N–C(3¢) Protons and Coupling Constants, JH(3¢),NH, with Configuration around
the Exocyclic C=C Double Bond in Compounds 35/35¢–64/64¢
Product
Solvent
d
H–C(3¢)
E-Isomer
H–N–C(3¢)
Z-Isomer
JH(3¢),NH (Hz)
E-Isomer
Z-Isomer
E-Isomer
Z-Isomer
35/35¢a
35/35¢b
35/35¢ca,b
36/36¢b
36/36¢c
37/37¢a
37/37¢b
37/37¢c
38/38¢c
39/39¢c
40/40¢a
40/40¢b
40/40¢c
41/41¢c
42/42¢c
43/43¢b
43/43¢c
44/44¢b
44/44¢c
CDCl3
7.95
7.97
8.33
7.93
8.29
7.96
7.99
8.42
8.57
8.40
7.85
7.87
8.23
8.63
8.35
7.90
8.30
8.09
8.53
8.13
8.14
10.94
10.91
11.21
10.89
11.27
11.32
11.55
11.32
11.39
11.28
11.33
11.39
11.82
11.48
11.29
11.36
11.53
11.80
11.44
11.27
11.39
11.46
12.34
13.6
12.2
0
13.9
13.9
0
CDCl3
c
DMSO-d6
CDCl3
–
8.11
13.9
0
14.3
–
c
d
DMSO-d6
CDCl3
–
–
8.12
8.14
11.05
11.01
11.35
11.28
11.14
10.94
10.91
11.23
11.30
11.25
10.91
11.3
0
13.2
13.6
0
CDCl3
c
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
–
0
8.65
13.9
0
13.9
0
c
–
8.03
8.04
13.7
13.6
0
14.1
13.9
0
CDCl3
c
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
–
c
–
12.1
0
13.6
0
c
–
8.07
11.7
0
13.6
c
d
d
DMSO-d6
CDCl3
–
–
–
8.28
8.55
11.12
11.81
11.9
12.8
13.6
14.3
DMSO-d6
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2974
S. Pirc et al.
FEATURE ARTICLE
Table 2 Correlation of Chemical Shifts d of H–C(3¢) and H–N–C(3¢) Protons and Coupling Constants, JH(3¢),NH, with Configuration around
the Exocyclic C=C Double Bond in Compounds 35/35¢–64/64¢ (continued)
Product
Solvent
d
H–C(3¢)
E-Isomer
H–N–C(3¢)
Z-Isomer
JH(3¢),NH (Hz)
E-Isomer
Z-Isomer
E-Isomer
Z-Isomer
45/45¢a
46a
CDCl3
8.23
–
8.46
8.00
8.02
8.09
11.17
11.48
11.48
–
0
–
13.9
0
DMSO-d6
DMSO-d6
CDCl3
d
d
46b
–
–
–
–
–
47/47¢a
48/48¢c
49/49¢a
49/49¢c
50/50¢a
50/50¢b
50c
7.81
8.34
8.68
8.81
8.62
8.65
8.67
8.67
8.70
8.09
8.45
7.36
7.89
7.42
7.36
10.62
11.71
11.00
10.89
11.97
11.31
11.59
11.31
11.39
11.75
11.06
11.11
11.47
11.76
9.65
9.97
9.85
9.67
9.75
9.71
9.86
9.90
10.07
9.80
9.94
9.89
9.74
0
13.6
0
c
DMSO-d6
CDCl3
–
0
8.90
8.88
8.79
8.81
–
12.8
0
12.8
d
d
DMSO-d6
CDCl3
–
–
11.09
11.06
–
11.7
11.2
0
12.8
12.8
–
CDCl3
DMSO-d6
CDCl3
51/51¢a
51/51¢b
52/52¢b
52/52¢c
53/53¢a
53/53¢c
54/54¢a
55/55¢ab
55/55¢b
56/56¢a
57/57¢a
57/57¢b
57/57¢c
58/58¢b
58/58¢c
59/59¢b
60/60¢ab
61/61¢a
61/61¢b
61/61¢c
62/62¢b
63/63¢c
64ab
8.84
8.87
8.28
8.57
7.55
8.01
7.63
7.51
7.53
7.53
7.58
7.60
7.85
10.78
10.77
11.12
11.42
9.28
9.66
9.40
9.25
9.25
9.28
9.38
9.37
9.57
9.38
9.43
9.46
9.28
9.36
9.31
13.2
12.8
0
13.4
13.2
13.6
14.3
13.9
0
CDCl3
CDCl3
DMSO-d6
CDCl3
13.2
0
DMSO-d6
CDCl3
0
12.8
0
14.3
14.2
14.2
14.3
13.9
14.0
14.3
13.8
0
CDCl3
c
CDCl3
–
0
CDCl3
7.37
7.43
0
CDCl3
0
c
CDCl3
–
0
CDCl3
7.73
0
c
c
CDCl3
–
–
0
c
c
CDCl3
–
–
0
c
c
CDCl3
–
–
0
13.9
14.3
13.9
13.2
CDCl3
7.43
7.60
7.62
8.02
7.64
7.67
7.66
14.0
d
d
CDCl3
–
–
d
d
CDCl3
–
–
c
d
d
CDCl3
–
–
10.00
9.87
0
0
–
c
CDCl3
–
7.68
7.91
–
9.41
9.54
–
14.3
15.1
–
DMSO-d6
CDCl3
7.82
7.47
9.94
14.7
0
12.27
12.27
11.29
c
64b
CDCl3
–
–
–
0
–
d
d
64/64¢c
DMSO-d6
7.65
7.79
–
0
–
a Structure was determined by X-ray diffraction.
b The Z/E-configuration was determined by HMBC spectroscopy.
c Overlapped with other signals.
d NH exchanged.
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2975
Table 3 Analytical, MS, and IR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢
Producta
2¢c
EI-MS (m/z)
EI-HRMS (m/z)
IR (KBr/film)
cm–1
[a]D
–
20
–
3408, 3012, 2939, 1724, 1711, 1679, 1662, 1644,
1566, 1401, 1267, 1022, 812, 742
2c
–
3386, 3322, 1718, 1702, 1675, 1528, 1379, 1287,
1262, 1208, 1160, 695
–
3c
290 (M+)
Calcd: 290.090272
Found: 290.091020
3338, 1735, 1718, 1702, 1664, 1632, 1410, 1278,
1181, 970
–
4a
4b
4c
344 (M+)
Calcd: 344.173608
Found: 344.175100
3450, 1767, 1695, 1653, 1616, 1341, 1281, 1255,
1150, 1093, 779, 704
–165b
–124b
–
378 (M+)
Calcd: 378.157957
Found: 378.158550
3458, 1767, 1700, 1659, 1616, 1442, 1380, 1302,
1095, 989, 701
345 (M+)
Calcd: 345.132471
Found: 345.133300
3424, 2933, 1726, 1681, 1641, 1497, 1433, 1397,
1073, 908, 754, 697, 662
35/35¢a
35/35¢b
–
3436, 2978, 1769, 1706, 1664, 1628, 1587, 1484,
1298, 1156, 756
–276b
–277b
426 (M+)
Calcd: 426.157957
Found: 426.159050
3448, 3220, 1774, 1710, 1665, 1628, 1586, 1484,
1447, 1382, 1349, 1291, 1140, 990, 755, 699
35/35¢c
36/36¢b
36/36¢c
–
3312, 1721, 1672, 1645, 1488, 1320, 1262, 1212,
1170, 973, 888, 756
–
–
3428, 1770, 1715, 1667, 1616, 1580, 1485, 1375,
1298, 1218, 998, 698
–286b
–
407 (M+)
Calcd: 407.148121
Found: 407.149250
3329, 1720, 1681, 1653, 1624, 1484, 1307, 1262,
1244, 1218, 1057, 830
37/37¢a
37/37¢b
438 (MH+, FAB)
3108, 1773, 1668, 1632, 1589, 1509, 1481, 1344,
1292, 1224, 1154, 1110, 750
–350b
–291b
–
3446, 1774, 1716, 1675, 1659, 1628, 1587, 1511,
1483, 1346, 1291, 1221, 1110, 993, 971, 852, 757,
700
37/37¢c
38/38¢c
39/39¢c
40/40¢a
–
3293, 1728, 1709, 1675, 1624, 1589, 1532, 1298,
1257, 855
–
–
3341, 1716, 1690, 1658, 1624, 1589, 1548, 1470,
1385, 1314, 1246, 755
–
–
3314, 1726, 1680, 1589, 1385, 1294, 1249, 1046,
756, 697
–
423 (MH+, FAB)
3431, 2976, 2932, 1767, 1734, 1705, 1657, 1627,
1588, 1519, 1485, 1348, 1300, 1253, 1156, 1031,
831, 701
–242b
40/40¢b
40/40¢c
41/41¢c
–
–
–
3470, 2361, 1776, 1713, 1660, 1626, 1588, 1519,
1485, 1377, 1298, 1251, 1179, 835, 698
–284b
3370, 1715, 1662, 1633, 1481, 1310, 1250, 1163,
1051, 837, 751
–
–
3415, 1734, 1725, 1699, 1662, 1622, 1572, 1456,
1391, 1311, 1223
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2976
S. Pirc et al.
FEATURE ARTICLE
Table 3 Analytical, MS, and IR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Producta
42/42¢c
43/43¢b
43/43¢c
44/44¢b
44/44¢c
45/45¢a
46a
EI-MS (m/z)
EI-HRMS (m/z)
IR (KBr/film)
cm–1
[a]D
–
20
–
–
–
–
–
–
3350, 1728, 1710, 1686, 1662, 1625, 1578, 1385,
1323, 992, 768
3422, 1764, 1713, 1668, 1652, 1618, 1575, 147,8
1376, 1293, 1216, 1072, 995, 698
–245b
–
3294, 1707, 1675, 1614, 1474, 1384, 1256, 1011,
778, 702
3464, 1771, 1698, 1654, 1639, 1615, 1596, 1493,
1379, 1341, 1300, 1263, 751, 701
–236b
–
3310, 1721, 1702, 1687, 1646, 1616, 1596, 1396,
1308, 1256, 770
3274, 2978, 1765, 1708, 1664, 1624, 1347, 1299,
1254, 1154, 777, 701
–231b
–210c
384 (M+)
3116, 1760, 1698, 1632, 1503, 1286, 1153, 842, 702
385 (MH+, FAB)
46b
–
3447, 3119, 1759, 1697, 1662, 1628, 1586, 1499,
1384, 1272, 1228, 701
–139c
–206b
–
47/47¢a
48/48¢c
49/49¢a
49/49¢c
50/50¢a
50/50¢b
50c
398 (MH+, FAB)
2978, 2932, 1771, 1711, 1676, 1630, 1597, 1467,
1428, 1400, 1368, 1345, 1279, 1156, 787, 701
–
–
–
–
–
–
–
3424, 3191, 1730, 1693, 1661, 1638, 1510, 1401,
1349, 1225, 1003
2978, 2931, 1769, 1708, 1674, 1625, 1567, 1474,
1425, 1278, 1230, 1150, 1064, 778, 701
–242b
–
3322, 1737 (C=O), 1674, 1620, 1567, 1427, 1272,
1245, 1210, 1163, 889, 791
3470, 1769, 1709, 1677, 1621, 1529, 1397, 1281,
1247, 1144, 702
–269b
–223b
–
3264, 1770, 1732, 1711, 1684, 1613, 1527, 1387,
1287, 1244, 1145, 1062, 968, 785, 701
3322, 1717, 1682, 1615, 1528, 1400, 1246, 1168,
1058, 792
51/51¢a
51/51¢b
3419, 2979, 1773, 1713, 1687, 1623, 1553, 1455,
1395, 1276, 1246, 1157, 1068, 789, 702
–226b
–163b
442 (M+)
Calcd: 442.164105
Found: 442.165080
3446, 1777, 1715, 1686, 1621, 1552, 1455, 1381,
1275, 1245, 994, 700
52/52¢b
52/52¢c
53/53¢a
53/53¢c
54/54¢a
–
–
–
–
3436, 1765, 1689, 1665, 1627, 1592, 1341, 1268,
1228, 1112, 996, 698
–286b
–
3428, 1731, 1717, 1700, 1668, 1629, 1512, 1332,
1230, 761
3447, 3257, 2976, 1758, 1720, 1697, 1654, 1497,
1344, 1159, 702
–111b
–
3304, 1740, 1685, 1649, 1492, 1258, 1214, 1172,
701
417 (MH+)
Calcd: 417.202562
Found: 417.203950
3226, 2975, 1766, 1742, 1702, 1659, 1620, 1493,
1349, 1282,1141, 1064, 846, 700
–62.8b
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2977
Table 3 Analytical, MS, and IR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Producta
55/55¢a
55/55¢b
56/56¢a
57/57¢a
57/57¢b
EI-MS (m/z)
EI-HRMS (m/z)
IR (KBr/film)
cm–1
[a]D
20
–
–
–
–
3458, 2959, 1747, 1703, 1665, 1620, 1491, 1307,
1152, 752, 698
–120b
–90.7b
–110b
–160b
–112b
3472, 2957, 1771, 1745, 1709, 1666, 1619, 1493,
1382, 1349, 1297, 1267, 1141, 1001, 745, 700
3244, 2978, 1762, 1737, 1699, 1655, 1638, 1346,
1281, 1159, 700
3464, 2979, 1758, 1701, 1664, 1615, 1494, 1307,
1156, 845, 789, 755, 701
482 (M+)
Calcd: 482.152496
Found: 482.152350
3446, 1769, 1741, 1706, 1666, 1615, 1495, 1382,
1348, 1296, 1263, 1193, 1097, 700
57/57¢c
58/58¢b
58/58¢c
59/59¢b
449 (M+)
Calcd: 449.125672
Found: 449.126110
3433, 1727, 1665, 1614, 1493, 1395, 1244, 1169,
698
–22.0b
–194b
–149b
–234b
512 (M+)
Calcd: 512.194737
Found: 512.196050
3473, 3030, 1770, 1745, 1708, 1665, 1618, 1495,
1455, 1381, 1349, 1296, 1096, 999, 748, 700
479 (M+)
Calcd: 479.169251
Found: 479.170530
3420, 1726, 1667, 1617, 1493, 1397, 1243, 1172,
701
551 (M+)
Calcd: 551.205636
Found: 551.207050
3328, 1762, 1696, 1661, 1615, 1493, 1349, 1296,
1268, 1096, 743, 700
60/60¢a
61/61¢a
–
3455, 2977, 1758, 1738, 1697, 1651, 1489, 1347,
1068, 982, 843, 700
–67.5b
–80.9b
356 (MH+, FAB)
711 (M2H+, FAB)
1066 (M3H+, FAB)
3276, 1278, 1758, 1698, 1653, 1633, 1493, 1349,
1253, 1157, 1097, 700
61/61¢b
389 (M+)
3436, 3624, 1763, 1697, 1657, 1495, 1381, 1346,
1294, 1267, 1068, 702.
–63.9b
390 (MH+, FAB)
779 (M2H+, FAB)
Calcd: 389.137556
Found: 389.138650
61/61¢c
62/62¢b
356 (M+)
3350, 3147, 1724, 1673, 1585, 1495, 1429, 1395,
1251, 1179, 700
–
357 (MH+, FAB)
713 (M2H+, FAB)
440 (M+)
Calcd: 440.173608
Found: 440.175250
3251, 1768, 1708, 1660, 162, 1488, 1455, 1382,
1340, 1297, 1209, 1076, 742, 698
–69.8b
63/63¢c
64a
–
–
–
–
3341, 2902, 1727, 1681, 1661, 1593, 1489, 1397,
1251, 1167, 697
–
3420, 3109, 2985, 1756, 1600, 1431, 1351, 1323,
1152, 994, 845, 700
–168c
–112b
–
64b
3071, 1760, 1607, 1496, 1389, 1356, 1313,
1286,1237, 967, 775, 697
64/64¢c
3312, 1726, 1660, 1516, 1422, 1400, 1236, 1064,
981, 879, 756, 699
a Satisfactory microanalyses obtained: C 0.43; H 0.37; N 0.36. Exceptions: 57/57¢c, N –0.57; 59/59¢b, N –0.65; 62/62¢b, N –1.07.
b c = 0.50, CHCl3.
c c = 0.50, DMSO.
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2978
S. Pirc et al.
FEATURE ARTICLE
Table 4 1H NMR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢
Product
Solvent
1H NMR, d
2¢c
DMSO-d6
1.48 (6 H, s, 2 Me), 3.17 (6 H, s, NMe2), 3.64 (2 H, d, J = 6.0 Hz, CH2NH), 4.14 (2 H, d, J = 4.5 Hz, CH2NH), 5.06
(2 H, s, PhCH2O), 6.93–7.00 (2 H, m, 2 H of pyridine), 7.25–7.40 (5 H, m, Ph), 7.61 (1 H, t, J = 6.0 Hz, CH2NH),
7.65 (1 H, t, J = 4.5 Hz, CH2NH), 8.19–8.24 (2 H, m, 2 H of pyridine), 13.28 (1 H, br s, NH pyridine)
2c
3c
4a
DMSO-d6
DMSO-d6
CDCl3
1.64 (6 H, s, 2 Me), 3.67 (2 H, d, J = 5.7 Hz, CH2NH), 4.47 (2 H, d, J = 5.0 Hz, CH2NH), 5.05 (2 H, s, PhCH2O),
7.27–7.39 (5 H, m, Ph), 7.54 (1 H, t, J = 5.7 Hz, CH2NH), 8.09 (1 H, t, J = 5.0 Hz, CH2NH)
4.19 (2 H, s, 5-CH2), 4.24 (2 H, d, J = 6.0 Hz, CH2NH), 4.99 (1 H, s, 3–H), 5.04 (2 H, s, PhCH2O), 7.27–7.39 (5 H,
m, Ph), 7.42 (1 H, t, J = 6.0 Hz, CH2NH), 12.51 (1 H, br s, OH)
1.59 (9 H, s, t-Bu), 3.25 (1 H, dd, J = 3.0, 13.6 Hz, 1 H of PhCH2CH), 3.25 (3 H, s, NMe), 3.37 (1 H, dd, J = 5.7,
13.6 Hz, 1 H of PhCH2CH), 3.61 (3 H, s, NMe), 4.34 (1 H, br s, PhCH2CH), 7.04–7.11 (2 H, m, 2 H of Ph), 7.14–
7.23 (4 H, m, 3 H of Ph, CH=)
4b
CDCl3
3.22 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.26 (3 H, s, NMe), 3.36 (1 H, dd, J = 5.7, 13.9 Hz, 1 H of
PhCH2CH), 3.60 (3 H, s, NMe), 4.41 (1 H, br s, PhCH2CH), 5.35 (2 H, s, PhCH2O), 6.90–6.98 (2 H, m, 2 H of Ph),
7.08–7.15 (3 H, m, 3 H of Ph), 7.30–7.42 (4 H, m, 3 H of Ph, CH=), 7.45–7.51 (2 H, m, 2 H of Ph)
4c
CDCl3
3.39 (3 H, s, NMe), 3.76 (3 H, s, NMe), 4.02 (2 H, s, 5-CH2), 4.62 (2 H, d, J = 5.7 Hz, CH2NH), 5.14 (2 H, s,
PhCH2O), 5.55 (1 H, s, CH2NH), 7.29–7.43 (6 H, m, Ph, CH=)
4c
DMSO-d6
CDCl3
3.41 (3 H, s, NMe), 3.64 (3 H, s, NMe), 3.88 (2 H, s, 5-CH2), 4.33 (2 H, d, J = 6.0 Hz, CH2NH), 5.05 (2 H, s,
PhCH2O), 7.27–7.39 (5 H, m, Ph), 7.43 (1 H, t, J = 6.0 Hz, CH2NH), 7.55 (1 H, s, CH=)
35/35¢a
Major E-Isomer: 1.62 (9 H, s, t-Bu), 3.33 (1 H, dd, J = 3.2, 13.8 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 6.0, 13.8
Hz, 1 H of PhCH2CH), 4.54 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 7.05–7.10 (2 H, m, 2 H of Ph), 7.10–7.30 (6 H,
m, 6 H of Ph), 7.35–7.46 (2 H, m, 2 H of Ph), 7.95 (1 H, d, J = 13.6 Hz, NHCH=), 11.27 (1 H, d, J = 13.2 Hz,
NHCH=)
Minor Z-Isomer: 1.63 (9 H, s, t-Bu), 3.33 (1 H, dd, J = 2.9, 13.8 Hz, 1 H of PhCH2CH), 3.44 (1 H, dd, J = 5.8, 13.8
Hz, 1 H of PhCH2CH), 4.48 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 8.13 (1 H, d, J = 13.9 Hz, NHCH=), 10.94 (1 H,
d, J = 13.6 Hz, NHCH=)
35/35¢b
CDCl3
Major E-Isomer: 3.24–3.35 (1 H, m, 1 H of PhCH2CH), 3.40 (1 H, dd, J = 5.3, 13.9 Hz, 1 H of PhCH2CH), 4.58 (1
H, dd, J = 2.6, 5.3 Hz, PhCH2CH), 5.38 (2 H, s, PhCH2O), 6.86–7.00 (2 H, m, 2 H of Ph), 7.05–7.16 (4 H, m, 4 H
of Ph), 7.16–7.30 (2 H, m, 2 H of Ph), 7.32–7.46 (5 H, m, 5 H of Ph), 7.46–7.55 (2 H, m, 2 H of Ph), 7.97 (1 H, d,
J = 12.2 Hz, NHCH=), 11.32 (1 H, d, J = 12.0 Hz, NHCH=)
Minor Z-Isomer: 4.52 (1 H, dd, J = 2.6, 5.3 Hz, PhCH2CH), 5.36 (1 H, d, J = 12.4 Hz, 1 H of PhCH2O), 5.42 (1 H,
d, J = 12.4 Hz, 1 H of PhCH2O), 8.14 (1 H, d, J = 13.9 Hz, NHCH=), 10.91 (1 H, d, J = 13.8 Hz, NHCH=)
35/35¢c
36/36¢b
DMSO-d6
Major E-Isomer: 4.06 (2 H, s, 5-CH2), 4.40 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O), 7.24–7.40 (6 H,
m, 6 H of Ph), 7.40–7.48 (2 H, m, 2 H of Ph), 7.50 (1 H, t, J = 6.0 Hz, CH2NH), 7.59–7.65 (2 H, m, 2 H of Ph), 8.33
(1 H, br s, NHCH=), 11.55 (1 H, br s, NHCH=)
Minor Z-Isomer: 11.21 (1 H, br s, NHCH=)
CDCl3
Major E-Isomer: 2.36 (3 H, s, Me), 3.29 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.39 (1 H, dd, J = 5.7, 13.9
Hz, 1 H of PhCH2CH), 4.58 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.38 (2 H, s, PHCH2O), 6.89–6.97 (2 H, m, 2 H
of Ph), 7.05–7.16 (5 H, m, 5 H of Ph), 7.18–7.24 (2 H, m, 2 H of Ph), 7.31–7.44 (3 H, m, 3 H of Ph), 7.47–7.53 (2
H, m, 2 H of Ph), 7.93 (1 H, d, J = 13.9 Hz, NHCH=), 11.32 (1 H, d, J = 13.6 Hz, NHCH=)
Minor Z-Isomer: 2.34 (3 H, s, Me), 4.52 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.40 (2 H, s, PHCH2O), 8.11 (1 H, d,
J = 14.3 Hz, NHCH=), 10.89 (1 H, d, J = 14.0 Hz, NHCH=)
36/36¢c
37/37¢a
DMSO-d6
Major E-Isomer: 2.31 (3 H, s, Me), 4.04 (2 H, s, 5-CH2), 4.39 (2 H, d, J = 6.4 Hz, CH2NH), 5.06 (2 H, s, PhCH2O),
7.21–7.27 (2 H, m, 2 H of Ar), 7.28–7.41 (5 H, m, Ph), 7.46–7.53 (3 H, m, 2 H of Ar, CH2NH), 8.29 (1 H, s,
NHCH=), 11.39 (1 H, br s, NHCH=)
Minor Z-Isomer: 4.02 (2 H, s, 5-CH2), NH exchanged
CDCl3
Major E-Isomer: 1.63 (9 H, s, t-Bu), 3.33 (1 H, dd, J = 3.0, 13.6 Hz, 1 H of PhCH2CH), 3.42 (1 H, dd, J = 6.0, 13.9
Hz, 1 H of PhCH2CH), 4.58 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 7.02–7.08 (2 H, m, 2 H of Ph), 7.14–7.27 (3 H,
m, 3 H of Ph), 7.28–7.35 (2 H, m, 2 H of Ar), 7.96 (1 H, br d, J = 11.3 Hz, NHCH=), 8.25–8.34 (2 H, m, 2 H of Ar),
11.28 (1 H, br d, J = 11.3 Hz, NHCH=)
Minor Z-Isomer: 1.64 (9 H, s, t-Bu), 4.53 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 8.12 (1 H, d, J = 13.2 Hz, NHCH=),
11.05 (1 H, d, J = 13.2 Hz, NHCH=)
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2979
Table 4 1H NMR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Product
Solvent
CDCl3
1H NMR, d
37/37¢b
Major Z-Isomer: 3.31 (1 H, dd, J = 2.7, 13.9 Hz, 1 H of PhCH2CH), 3.42 (1 H, dd, J = 5.7, 13.9 Hz, 1 H of
PhCH2CH), 4.58 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.38 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 5.43 (1 H, d,
J = 12.1 Hz, 1 H of PhCH2O), 6.88–6.95 (2 H, m, 2 H of Ph), 7.10–7.16 (3 H, m, 3 H of Ph), 7.22–7.28 (2 H, m, 2
H of Ar), 7.36–7.46 (3 H, m, 3 H of Ph), 7.48–7.53 (2 H, m, 2 H of Ph), 8.14 (1 H, d, J = 13.6 Hz, NHCH=), 8.25–
8.35 (2 H, m, 2 H of Ar), 11.01 (1 H, d, J = 13.9 Hz, NHCH=)
Minor E-Isomer: 3.30 (1 H, dd, J = 2.6, 13.9 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 5.7, 13.9 Hz, 1 H of
PhCH2CH), 4.64 (1 H, dd, J = 3.0, 5.8 Hz, PhCH2CH), 5.40 (2 H, s, PhCH2O), 7.30–7.36 (2 H, m, 2 H of Ar), 7.99
(1 H, s, NHCH=), 11.33 (1 H, br s, NHCH=)
37/37¢c
38/38¢c
DMSO-d6
DMSO-d6
Major E-Isomer: 4.10 (2 H, s, 5-CH2), 4.41 (2 H, d, J = 5.7 Hz, CH2NH), 5.06 (2 H, s, PhCH2O), 7.28–7.42 (5 H,
m, Ph), 7.53 (1 H, t, J = 5.7 Hz, CH2NH), 7.85–7.94 (2 H, m, 2 H of Ph), 8.23–8.30 (2 H, m, 2 H of Ph), 8.42 (1 H,
br s, NHCH=), 11.39 (1 H, br s, NHCH=)
Minor Z-Isomer: 11.35 (1 H, br s, NHCH=)
Major E-Isomer: 3.94 (3 H, s, OMe), 4.10 (2 H, s, 5-CH2), 4.38 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O),
6.99–7.09 (1 H, m, 1 H of Ar), 7.19 (1 H, dd, J = 1.3, 8.3 Hz, 1 H of Ar), 7.22–7.41 (6 H, m, Ph, 1 H of Ar), 7.49 (1
H, t, J = 6.0 Hz, CH2NH), 7.78–7.89 (1 H, m, 1 H of Ar), 8.57 (1 H, d, J = 13.9 Hz, NHCH=), 11.82 (1 H, d, J = 13.9
Hz, NHCH=)
Minor Z-Isomer: 4.03 (2 H, s, 5-CH2), 4.42 (2 H, d, J = 6.0 Hz, CH2NH), 7.53 (1 H, t, J = 6.0 Hz, CH2NH), 8.65 (1
H, d, J = 13.9 Hz, NHCH=), 11.28 (1 H, d, J = 13.9 Hz, NHCH=)
39/39¢c
40/40¢a
DMSO-d6
Major E-isomer: 3.80 (3 H, s, OMe), 4.06 (2 H, s, 5-CH2), 4.40 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O),
6.84 (1 H, dd, J = 2.4, 8.1 Hz, 1 H of Ar), 7.17 (1 H, dd, J = 1.8, 7.9 Hz, 1 H of Ar), 7.28 (1 H, t, J = 2.3 Hz, 1 H of
Ar), 7.29–7.40 (6 H, m, Ph, 1 H of Ar), 7.50 (1 H, t, J = 6.0 Hz, CH2NH), 8.40 (1 H, br s, NHCH=), 11.48 (1 H, br
s, NHCH=)
Minor Z-Isomer: 11.14 (1 H, br s, NHCH=)
CDCl3
Major E-Isomer: 1.61 (9 H, s, t-Bu), 3.32 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.40 (1 H, dd, J = 6.0, 13.6
Hz, 1 H of PhCH2CH), 3.82 (3 H, s, OMe), 4.52 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 6.87–6.96 (2 H, m, 2 H of
Ar), 7.03–7.23 (7 H, m, Ph, 2 H of Ar), 7.85 (1 H, d, J = 13.7 Hz, NHCH=), 11.29 (1 H, d, J = 13.8 Hz, NHCH=)
Minor Z-Isomer: 1.62 (9 H, s, t-Bu), 3.33 (1 H, dd, J = 2.9, 13.9 Hz, 1 H of PhCH2CH), 3.43 (1 H, dd, J = 5.7, 13.9
Hz, 1 H of PhCH2CH), 3.80 (3 H, s, OMe), 4.46 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 8.03 (1 H, d, J = 14.1 Hz,
NHCH=), 10.94 (1 H, d, J = 14.1, NHCH=)
40/40¢b
CDCl3
Major E-Isomer: 3.29 (1 H, dd, J = 2.8, 13.8 Hz, 1 H of PhCH2CH), 3.39 (1 H, dd, J = 5.7, 13.7 Hz, 1 H of
PhCH2CH), 3.82 (3 H, s, OMe), 4.57 (1 H, dd, J = 3.0, 5.8 Hz, PhCH2CH), 5.38 (2 H, s, PhCH2O), 6.88–6.97 (4 H,
m, 4 H of Ph), 7.04–7.16 (5 H, m, 3 H of Ph, 2 H of Ar), 7.31–7.45 (3 H, m, 3 H of Ph), 7.47–7.53 (2 H, m, 2 H of
Ar), 7.87 (1 H, d, J = 13.6 Hz, NHCH=), 11.36 (1 H, d, J = 13.6 Hz, NHCH=)
Minor Z-Isomer: 3.30 (1 H, dd, J = 2.7, 13.9 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 5.6, 13.9 Hz, 1 H of
PhCH2CH), 3.81 (3 H, s, OMe), 4.51 (1 H, dd, J = 2.9, 5.7 Hz, PhCH2CH), 5.35 (1 H, d, J = 12.4 Hz, 1 H of
PhCH2O), 5.42 (1 H, d, J = 12.4 Hz, 1 H of PhCH2O), 8.04 (1 H, d, J = 13.9 Hz, NHCH=), 10.91 (1 H, d, J = 14.0
Hz, NHCH=)
40/40¢c
41/41¢c
DMSO-d6
DMSO-d6
Major E-Isomer: 3.77 (3 H, s, OMe), 4.04 (2 H, s, 5-CH2), 4.39 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O),
6.96–7.03 (2 H, m, 2 H of Ar), 7.27–7.40 (5 H, m, Ph), 7.49 (1 H, t, J = 6.0 Hz, CH2NH), 7.53–7.60 (2 H, m, 2 H of
Ar), 8.23 (1 H, br s, NHCH=), 11.53 (1 H, br s, NHCH=)
Minor Z-Isomer: 11.23 (1 H, br s, NHCH=)
Major E-Isomer: 4.15 (2 H, s, 5-CH2), 4.39 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O), 7.19–7.27 (1 H,
m, 1 H of Ar), 7.28–7.40 (5 H, m, Ph), 7.44–7.58 (2 H, m, CH2NH, 1 H of Ar), 7.77 (1 H, dd, J = 1.1, 8.0 Hz, 1 H
of Ar), 7.92–8.02 (1 H, m, 1 H of Ar), 8.63 (1 H, br, NHCH=), 11.80 (1 H, d, J = 12.1 Hz, NHCH=)
Minor Z-Isomer: 4.07 (2 H, s, 5-CH2), 4.42 (2 H, d, J = 6.0 Hz, CH2NH), 5.05 (2 H, s, PhCH2O), 11.30 (1 H, d,
J = 13.6 Hz, NHCH=)
42/42¢c
43/43¢b
DMSO-d6
Major E-Isomer: 4.07 (2 H, s, 5-CH2), 4.40 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O), 7.24–7.42 (6 H,
m, Ph, 1 H of Ar), 7.42–7.48 (1 H, m, 1 H of Ar), 7.51 (1 H, t, J = 6.0 Hz, CH2NH), 7.59–7.68 (1 H, m, 1 H of Ar),
7.94–7.98 (1 H, m, 1 H of Ar), 8.35 (1 H, br s, NHCH=), 11.44 (1 H, br s, NHCH=)
Minor Z-Isomer: 11.25 (1 H, br s, NHCH=)
CDCl3
Major E-isomer: 3.29 (1 H, dd, J = 3.0, 13.8 Hz, 1 H of PhCH2CH), 3.39 (1 H, dd, J = 5.9, 13.8 Hz, 1 H of
PhCH2CH), 4.59 (1 H, dd, J = 3.0, 5.8 Hz, PhCH2CH), 5.38 (2 H, s, PhCH2O), 6.89–6.95 (2 H, m, 2 H of Ph), 7.05–
7.10 (2 H, m, 2 H of Ar), 7.10–7.15 (3 H, m, 3 H of Ph), 7.31–7.45 (3 H, m, 3 H of Ph), 7.47–7.52 (2 H, m, 2 H of
Ph), 7.52–7.57 (2 H, m, 2 H of Ar), 7.90 (1 H, d, J = 11.7 Hz, NHCH=), 11.27 (1 H, d, J = 11.7 Hz, NHCH=)
Minor Z-Isomer: 3.30 (1 H, dd, J = 2.7, 13.8 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 4.9, 13.8 Hz, 1 H of
PhCH2CH), 4.53 (1 H, dd, J = 2.8, 5.7 Hz, PhCH2CH), 5.36 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 5.42 (1 H, d,
J = 12.1 Hz, 1 H of PhCH2O), 8.07 (1 H, d, J = 13.6 Hz, NHCH=), 10.91 (1 H, d, J = 13.6 Hz, NHCH=)
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2980
S. Pirc et al.
FEATURE ARTICLE
Table 4 1H NMR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Product
Solvent
1H NMR, d
43/43¢c
DMSO-d6
Major E-Isomer: 4.06 (2 H, s, 5-CH2), 4.39 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O), 7.28–7.41 (5 H,
m, Ph), 7.50 (1 H, t, J = 6.0 Hz, CH2NH), 7.61 (4 H, s, 4 H of Ar), 8.30 (1 H, br s, NHCH=), 11.39 (1 H, br s,
NHCH=)
Minor Z-Isomer: 4.04 (2 H, s, 5-CH2), 5.05 (2 H, s, PhCH2O), NH exchanged
44/44¢b
CDCl3
Major Z-Isomer: 3.35 (1 H, dd, J = 3.0, 13.8 Hz, 1 H of PhCH2CH), 3.46 (1 H, dd, J = 5.7, 13.8 Hz, 1 H of
PhCH2CH), 4.57 (1 H, dd, J = 3.0, 5.6 Hz, PhCH2CH), 5.39 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 5.44 (1 H, d,
J = 12.2 Hz, 1 H of PhCH2O), 6.91–7.01 (2 H, m, 2 H of Ph), 7.09–7.16 (3 H, m, 3 H of Ph), 7.32–7.73 (9 H, m, Ph,
4 H of Ar), 7.76–7.84 (1 H, m, 1 H of Ar), 7.85–8.06 (2 H, m, 2 H of Ar), 8.28 (1 H, d, J = 13.6 Hz, NHCH=), 11.12
(1 H, d, J = 13.4 Hz, NHCH=)
Minor E-Isomer: 3.33 (1 H, dd, J = 3.0, 13.8 Hz, 1 H of PhCH2CH), 3.42 (1 H, dd, J = 5.7, 13.8 Hz, 1 H of
PhCH2CH), 4.67 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.41 (2 H, s, PhCH2O), 8.09 (1 H, d, J = 11.9 Hz, NHCH=),
11.46 (1 H, br, NHCH=)
44/44¢c
45/45¢a
DMSO-d6
Major E-Isomer: 4.17 (2 H, s, 5-CH2), 4.40 (2 H, d, J = 6.0 Hz, CH2NH), 5.07 (2 H, s, PhCH2O), 7.26–7.42 (5 H,
m, Ph), 7.51 (1 H, t, J = 6.0 Hz, CH2NH), 7.54–7.78 (3 H, m, 3 H of Ar), 7.79–8.81 (4 H, m, 4 H of Ar), 8.53 (1 H,
d, J = 12.8 Hz, NHCH=), 12.34 (1 H, d, J = 12.8 Hz, NHCH=)
Minor Z-Isomer: 4.08 (2 H, s, 5-CH2), 4.48 (2 H, d, J = 6.0 Hz, CH2NH), 5.08 (1 H, s, PhCH2O), 8.55 (1 H, d,
J = 14.3 Hz, NHCH=), 11.81 (1 H, d, J = 14.3 Hz, NHCH=)
CDCl3
Major Z-Isomer: 1.62 (9 H, s, t-Bu), 2.31 (3 H, d, J = 0.7 Hz, Me), 3.30–3.44 (2 H, m, PhCH2CH), 4.48 (1 H, dd,
J = 3.0, 5.7 Hz, PhCH2CH), 5.81 (1 H, d, J = 0.7 Hz, 1 H of Het), 7.03–7.09 (2 H, m, 2 H of Ph), 7.13–7.22 (3 H,
m, 3 H of Ph), 8.46 (1 H, d, J = 13.9 Hz, NHCH=), 11.12 (1 H, br s, NH of Het), 11.17 (1 H, d, J = 13.9 Hz, NHCH=)
Minor E-Isomer: 1.61 (9 H, s, t-Bu), 2.33 (3 H, d, J = 0.8 Hz, Me), 4.52 (1 H, dd, J = 3.4, 5.7 Hz, PhCH2CH), 5.89
(1 H, d, J = 0.8 Hz, 1 H of Het), 8.23 (1 H, br s, NHCH=), 11.48 (1 H, br s, NHCH=)
46a
DMSO-d6
DMSO-d6
CDCl3
1.54 (9 H, s, t-Bu), 3.20 (1 H, dd, J = 2.6, 13.9 Hz, 1 H of PhCH2CH), 3.31 (1 H, dd, J = 6.0, 13.9 Hz, 1 H of
PhCH2CH), 4.56 (1 H, dd, J = 2.6, 6.0 Hz, PhCH2CH), 6.92–7.02 (2 H, m, 2 H of Ph), 7.11–7.30 (3 H, m, 3 H of
Ph), 8.00 (1 H, br s, NHCH=), 11.48 (1 H, br s, NHCH=), HN(1¢) exchanged
46b
3.20 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.28 (1 H, dd, J = 6.0, 13.9 Hz, 1 H of PhCH2CH), 4.64 (1 H,
dd, J = 3.0, 6.0 Hz, PhCH2CH), 5.35 (2 H, s, PhCH2O), 6.84–6.92 (2 H, m, 2 H of Ph), 7.12–7.18 (3 H, m, 3 H of
Ph), 7.34–7.53 (5 H, m, Ph), 8.02 (1 H, br s, NHCH=), NHCH= and HN(1¢) exchanged
47/47¢a
Major Z-Isomer: 1.62 (9 H, s, t-Bu), 2.41 (3 H, d, J = 0.8 Hz, Me), 3.32 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH),
3.42 (1 H, dd, J = 6.0, 13.9 Hz, 1 H of PhCH2CH), 4.50 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 5.88 (1 H, q, J = 0.8
Hz, 1 H of Het), 7.01–7.07 (2 H, m, 2 H of Ph), 7.13–7.24 (3 H, m, 3 H of Ph), 8.09 (1 H, d, J = 13.6 Hz, NHCH=),
10.62 (1 H, d, J = 13.2 Hz, NHCH=)
Minor E-Isomer: 1.62 (9 H, s, t-Bu), 2.44 (3 H, d, J = 0.8 Hz, Me), 3.40 (1 H, dd, J = 6.0, 13.8 Hz, 1 H of PhCH2CH),
4.55 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 5.99 (1 H, q, J = 0.8 Hz, 1 H of Het), 7.81 (1 H, s, NHCH=), 10.89 (1 H,
br s, NHCH=)
48/48¢c
49/49¢a
DMSO-d6
Major E-Isomer: 4.09 (2 H, s, 5-CH2), 4.42 (2 H, d, J = 5.3 Hz, CH2NH), 5.07 (2 H, s, PhCH2O), 7.16–7.23 (1 H,
m, 1 H of Het), 7.28–7.40 (5 H, m, Ph), 7.40–7.47 (1 H, m, 1 H of Het), 7.48–7.57 (2 H, m, 1 H of Het, CH2NH),
7.92–7.98 (1 H, m, 1 H of Het), 8.34 (1 H, br s, NHCH=), 11.97 (1 H, br s, NHCH=), 13.12 (1 H, s, NH of Het)
Minor Z-Isomer: 11.71 (1 H, br s, NHCH=)
CDCl3
Major Z-Isomer: 1.63 (9 H, s, t-Bu), 3.34 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.43 (1 H, dd, J = 5.7, 13.9
Hz, 1 H of PhCH2CH), 4.49 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 6.86 (1 H, ddd, J = 0.8, 0.9, 8.1 Hz, 1 H of Het),
7.04–7.09 (2 H, m, 2 H of Ph), 7.09–7.23 (4 H, m, 3 H of Ph, 1 H of Het), 7.68 (1 H, ddd, J = 1.9, 7.4, 8.1 Hz, 1 H
of Het), 8.36–8.40 (1 H, m, 1 H of Het), 8.90 (1 H, d, J = 12.8 Hz, NHCH=), 11.00 (1 H, d, J = 13.2 Hz, NHCH=)
Minor E-isomer: 1.62 (9 H, s, t-Bu), 3.33 (1 H, dd, J = 3.4, 13.9 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 5.9, 13.9
Hz, 1 H of PhCH2CH), 4.55 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 7.00 (1 H, ddd, J = 0.8, 0.9, 8.1 Hz, 1 H of Het),
7.73 (1 H, ddd, J = 1.9, 7.4, 8.1 Hz, 1 H of Het), 8.68 (1 H, d, J = 12.8 Hz, NHCH=), 11.31 (1 H, d, J = 12.8 Hz,
NHCH=)
49/49¢c
DMSO-d6
Major E-Isomer: 4.08 (2 H, s, 5-CH2), 4.41 (2 H, d, J = 5.7 Hz, CH2NH), 5.06 (2 H, s, PhCH2O), 7.24–7.42 (6 H,
m, Ph, 1 H of Het), 7.52 (1 H, t, J = 5.7 Hz, CH2NH), 7.65–7.72 (1 H, m, 1 H of Het), 7.86–7.94 (1 H, m, 1 H of
Het), 8.42–8.48 (1 H, m, 1 H of Het), 8.81 (1 H, br s, NHCH=), 11.59 (1 H, br s, NHCH=)
Minor Z-Isomer: 4.08 (2 H, s, 5-CH2), 4.44 (2 H, d, J = 6.0 Hz, CH2NH), 7.52 (1 H, t, J = 6.0 Hz, CH2NH), 8.88 (1
H, s, NHCH=), NH exchanged
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2981
Table 4 1H NMR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Product
Solvent
CDCl3
1H NMR, d
50/50¢a
Major Z-Isomer: 1.64 (9 H, s, t-Bu), 3.34 (1 H, dd, J = 2.6, 13.9 Hz, 1 H of PhCH2CH), 3.44 (1 H, dd, J = 6.0, 13.9
Hz, 1 H of PhCH2CH), 4.53 (1 H, dd, J = 2.6, 5.7 Hz, PhCH2CH), 7.04–7.08 (2 H, m, 2 H of Ph), 7.12–7.24 (3 H,
m, 3 H of Ph), 8.30 (1 H, d, J = 1.5 Hz, 1 H of Het), 8.33 (1 H, dd, J = 1.5, 2.5 Hz, 1 H of Het), 8.40 (1 H, d, J = 2.5
Hz, 1 H of Het), 8.79 (1 H, d, J = 12.8 Hz, NHCH=), 11.09 (1 H, d, J = 12.8 Hz, NHCH=)
Minor E-Isomer: 1.62 (9 H, s, t-Bu), 3.42 (1 H, dd, J = 6.2, 13.9 Hz, 1 H of PhCH2CH), 4.59 (1 H, dd, J = 3.0, 6.0
Hz, PhCH2CH), 8.34 (1 H, dd, J = 1.5, 2.6 Hz, 1 H of Het), 8.42–8.44 (2 H, m, 2 H of Het), 8.62 (1 H, d, J = 11.7
Hz, NHCH=), 11.31 (1 H, d, J = 11.9 Hz, NHCH=)
50/50¢b
CDCl3
Major Z-Isomer: 3.32 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.42 (1 H, dd, J = 5.7, 13.9 Hz, 1 H of
PhCH2CH), 4.58 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.38 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 5.43 (1 H, d,
J = 12.1 Hz, 1 H of PhCH2O), 6.87–6.95 (2 H, m, 2 H of Ph), 7.08–7.16 (3 H, m, 3 H of Ph), 7.33–7.46 (3 H, m, 3
H of Ph), 7.48–7.54 (2 H, m, 2 H of Ph), 8.31 (1 H, d, J = 1.9 Hz, 1 H of Het), 8.32–8.36 (1 H, m, 1 H of Het), 8.41
(1 H, d, J = 2.6 Hz, 1 H of Het), 8.81 (1 H, d, J = 12.8 Hz, NHCH=), 11.06 (1 H, d, J = 12.6 Hz, NHCH=)
Minor E-Isomer: 3.31 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 6.0, 13.9 Hz, 1 H of
PhCH2CH), 4.64 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.40 (2 H, s, PHCH2O), 8.43–8.46 (2 H, m, 2 H of Het), 8.65
(1 H, d, J = 11.2 Hz, NHCH=), 11.39 (1 H, br d, J = 11.3 Hz, NHCH=)
50c
DMSO-d6
4.11 (2 H, s, 5-CH2), 4.41 (2 H, d, J = 6.0 Hz, CH2NH), 5.06 (2 H, s, PhCH2O), 7.27–7.41 (5 H, m, Ph), 7.53 (1 H,
t, J = 6.0 Hz, CH2NH), 8.50 (1 H, dd, J = 1.2, 2.6 Hz, 1 H of Het), 8.52 (1 H, d, J = 2.6 Hz, 1 H of Het), 8.67 (1 H,
br s, NHCH=), 8.99 (1 H, s, 1 H of Het), 11.75 (1 H, br s, NHCH=)
51/51¢a
CDCl3
Major Z-Isomer: 1.63 (9 H, s, t-Bu), 2.47 (3 H, d, J = 0.4 Hz, Me), 3.34 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH),
3.44 (1 H, dd, J = 5.7, 13.9 Hz, 1 H of PhCH2CH), 4.51 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 6.93 (1 H, dd, J = 0.5,
5.0 Hz, 1 H of Het), 7.03–7.08 (2 H, m, 2 H of Ph), 7.10–7.23 (3 H, m, 3 H of Ph), 8.38 (1 H, d, J = 5.0 Hz, 1 H of
Het), 8.84 (1 H, d, J = 13.4 Hz, NHCH=), 10.78 (1 H, d, J = 13.6 Hz, NHCH=)
Minor E-Isomer: 1.62 (9 H, s, t-Bu), 2.49 (3 H, d, J = 0.4 Hz, Me), 3.33 (1 H, dd, J = 3.1, 13.8 Hz, 1 H of PhCH2CH),
3.42 (1 H, dd, J = 5.4, 13.9 Hz, 1 H of PhCH2CH), 4.55 (1 H, dd, J = 3.1, 5.7 Hz, PhCH2CH), 6.96 (1 H, dd, J = 0.5,
5.0 Hz, 1 H of Het), 8.42 (1 H, d, J = 5.0 Hz, 1 H of Het), 8.67 (1 H, d, J = 13.2 Hz, NHCH=), 11.06 (1 H, d, J = 13.1
Hz, NHCH=)
51/51¢b
52/52¢b
52/52¢c
CDCl3
Major E-Isomer: 2.50 (3 H, s, Me), 3.31 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 5.7, 13.9
Hz, 1 H of PhCH2CH), 4.61 (1 H, dd, J = 3.0, 5.8 Hz, PhCH2CH), 5.39 (2 H, s, PhCH2O), 8.42 (1 H, d, J = 5.1 Hz,
1 H of Het), 8.70 (1 H, d, J = 12.8 Hz, NHCH=), 11.11 (1 H, d, J = 12.4 Hz, NHCH=)
Minor Z-Isomer: 2.47 (3 H, s, Me), 3.32 (1 H, dd, J = 2.6, 13.8 Hz, 1 H of PhCH2CH), 3.42 (1 H, dd, J = 5.7, 13.8
Hz, 1 H of PhCH2CH), 4.56 (1 H, dd, J = 2.9, 5.7 Hz, PhCH2CH), 5.37 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 5.42
(1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 6.88–7.00 (3 H, m, 2 H of Ph, 1 H of Het), 7.08–7.15 (3 H, m, 3 H of Ph),
7.31–7.46 (3 H, m, 3 H of Ph), 7.48–7.54 (2 H, m, 2 H of Ph), 8.39 (1 H, d, J = 5.1 Hz, 1 H of Het), 8.87 (1 H, d,
J = 13.2 Hz, NHCH=), 10.77 (1 H, d, J = 13.2 Hz, NHCH=)
CDCl3
Major Z-Isomer: 3.35 (1 H, dd, J = 3.0, 13.8 Hz, 1 H of PhCH2CH), 3.46 (1 H, dd, J = 5.7, 13.8 Hz, 1 H of
PhCH2CH), 4.57 (1 H, dd, J = 3.0, 5.6 Hz, PhCH2CH), 5.39 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 5.44 (1 H, d,
J = 12.2 Hz, 1 H of PhCH2O), 6.91–7.01 (2 H, m, 2 H of Ph), 7.09–7.16 (3 H, m, 3 H of Ph), 7.32–7.73 (9 H, m, Ph,
4 H of Ar), 7.76–7.84 (1 H, m, 1 H of Ar), 7.85–8.06 (2 H, m, 2 H of Ar), 8.28 (1 H, d, J = 13.6 Hz, NHCH=), 11.12
(1 H, d, J = 13.4 Hz, NHCH=)
Minor E-Isomer: 3.33 (1 H, dd, J = 3.0, 13.8 Hz, 1 H of PhCH2CH), 3.42 (1 H, dd, J = 5.7, 13.8 Hz, 1 H of
PhCH2CH), 4.67 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.41 (2 H, s, PhCH2O), 8.09 (1 H, s, NHCH=), 11.47 (1 H,
br s, NHCH=)
DMSO-d6
Major E-Isomer: 4.12 (2 H, s, 5-CH2), 4.40 (2 H, d, J = 6.0 Hz, CH2NH), 5.07 (2 H, s, PhCH2O), 7.27–7.42 (5 H,
m, Ph), 7.51 (1 H, t, J = 6.0 Hz, CH2NH), 7.61–7.70 (1 H, m, 1 H of Het), 7.71–7.80 (1 H, m, 1 H of Het), 7.95–
8.06 (2 H, m, 2 H of Het), 8.45 (1 H, d, J = 13.2 Hz, NHCH=), 8.64 (1 H, s, 1 H of Het), 9.17 (1 H, t, J = 2.6 Hz, 1
H of Het), 11.76 (1 H, d, J = 13.6 Hz, NHCH=)
Minor Z-Isomer: 4.08 (2 H, s, 5-CH2), 4.45 (2 H, d, J = 6.0 Hz, CH2NH), 7.54 (1 H, t, J = 6.0 Hz, CH2NH), 8.57 (1
H, d, J = 14.3 Hz, NHCH=), 11.42 (1 H, d, J = 14.3 Hz, NHCH=)
53/53¢a
53/53¢c
CDCl3
Major E-Isomer: 1.59 (9 H, s, t-Bu), 3.28 (1 H, dd, J = 3.0, 13.6 Hz, 1 H of PhCH2CH), 3.37 (1 H, dd, J = 6.0, 13.6
Hz, 1 H of PhCH2CH), 3.81 (3 H, s, OMe), 4.11 (2 H, s, CH2NH), 4.46 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 7.01–
7.09 (2 H, m, 2 H of Ph), 7.12–7.23 (3 H, m, 3 H of Ph), 7.36 (1 H, br s, NHCH=), 9.65 (1 H, br s, NHCH=)
Minor Z-Isomer: 3.38 (1 H, dd, J = 6.0, 13.6 Hz, 1 H of PhCH2CH), 3.77 (3 H, s, OMe), 4.04–4.08 (2 H, m, CH2NH),
4.41 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 7.55 (1 H, d, J = 13.9 Hz, NHCH=), 9.28 (1 H, br, NHCH=)
DMSO-d6
Major E-Isomer: 3.69 (3 H, s, OMe), 3.98 (2 H, s, 5-CH2), 4.34 (2 H, d, J = 6.0 Hz, CH2NH), 4.36 (2 H, d, J = 4.9
Hz, CH2CO2Me), 5.05 (2 H, s, PhCH2O), 7.25–7.40 (5 H, m, Ph), 7.44 (1 H, t, J = 6.0 Hz, CH2NH), 7.89 (1 H, br s,
NHCH=), 9.97 (1 H, br s, NHCH=)
Minor Z-Isomer: 3.95 (2 H, s, 5-CH2), 7.47 (1 H, t, J = 6.0 Hz, CH2NH), 8.01 (1 H, br s, NHCH=), 9.66 (1 H, br s,
NHCH=)
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2982
S. Pirc et al.
FEATURE ARTICLE
Table 4 1H NMR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Product
Solvent
CDCl3
1H NMR, d
54/54¢a
Major Z-Isomer: 1.29 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.52 (3 H, d, J = 7.2 Hz, CHCH3), 1.62 (9 H, s, t-Bu), 3.30 (1
H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.41 (1 H, dd, J = 6.0, 13.9 Hz, 1 H of PhCH2CH), 4.01–4.15 (1 H, m,
NHCHCOO), 4.21 (2 H, q, J = 7.2 Hz, OCH2CH3), 4.42 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 7.03–7.12 (2 H, m,
2 H of Ph), 7.13–7.25 (3 H, m, 3 H of Ph), 7.63 (1 H, d, J = 14.3 Hz, NHCH=), 9.40 (1 H, br dd, J = 7.9, 14.3 Hz,
NHCH=)
Minor E-Isomer: 1.33 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.58 (3 H, d, J = 7.2 Hz, CHCH3), 1.61 (9 H, s, t-Bu), 4.26 (2
H, d, J = 7.2 Hz, OCH2CH3), 4.45 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 7.42 (1 H, br d, J = 12.8 Hz, NHCH=), 9.85
(1 H, br, NHCH=)
55/55¢a
CDCl3
Major Z-Isomer: 0.87 (3 H, d, J = 7.2 Hz, CHCH3), 1.61 (9 H, s, t-Bu), 3.26 (1 H, dd, J = 3.6, 13.6 Hz, 1 H of
PhCH2CH), 3.39 (1 H, dd, J = 5.7, 13.6 Hz, 1 H of PhCH2CH), 3.74 (3 H, s, OMe), 3.89–3.98 (1 H, m, NHCHCOO),
4.41 (1 H, dd, J = 3.4, 5.7 Hz, PhCH2CH), 7.51 (1 H, d, J = 14.2 Hz, NHCH=), 9.25 (1 H, br, NHCH=)
Minor E-Isomer: 0.92 (3 H, d, J = 6.8 Hz, CHCH3), 0.94 (3 H, d, J = 6.8 Hz, CHCH3), 1.59 (9 H, s, t-Bu), 1.56–1.63
[1 H, m, CH(CH3)2], 1.66–1.83 (2 H, m, CHCH2CH), 3.28 (1 H, dd, J = 3.0, 13.6 Hz, 1 H of PhCH2CH), 3.37 (1 H,
dd, J = 6.0, 13.6 Hz, 1 H of PhCH2CH), 3.79 (3 H, s, OMe), 3.96–4.06 (1 H, m, NHCHCOO), 4.45 (1 H, dd, J = 3.0,
5.7 Hz, PhCH2CH), 7.01–7.09 (2 H, m, 2 H of Ph), 7.11–7.22 (3 H, m, 3 H of Ph), 7.36 (1 H, br s, NHCH=), 9.67
(1 H, br s, NHCH=)
55/55¢b
CDCl3
Z-Isomer: 0.85–0.96 [6 H, m, CH(CH3)2], 1.37–1.50 [1 H, m, CH(CH3)2], 1.60–1.79 (2 H, m, CHCH2CH), 3.25 (1
H, dd, J = 3.7, 13.9 Hz, 1 H of PhCH2CH), 3.37 (1 H, dd, J = 5.6, 13.8 Hz, 1 H of PhCH2CH), 3.75 (3 H, s, OMe),
3.95 (1 H, ddd, J = 4.9, 9.0, 9.0 Hz, NHCHCOO), 4.47 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.33 (1 H, d, J = 12.4
Hz, 1 H of PhCH2O), 5.38 (1 H, d, J = 12.4 Hz, 1 H of PhCH2O), 6.88–6.96 (2 H, m, 2 H of Ph), 7.06–7.14 (3 H,
m, 3 H of Ph), 7.30–7.44 (3 H, m, 3 H of Ph), 7.45–7.51 (2 H, m, 2 H of Ph), 7.53 (1 H, d, J = 14.2 Hz, NHCH=),
9.25 (1 H, br dd, J = 9.0, 14.2 Hz, NHCH=)
E-Isomer: 3.24 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.36 (1 H, dd, J = 6.0, 13.9 Hz, 1 H of PhCH2CH),
3.98–4.07 (1 H, m, NHCHCOO), 4.51 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 5.36 (2 H, s, PhCH2O), 9.75 (1 H, br
s, NHCH=)
56/56¢a
57/57¢a
57/57¢b
CDCl3
CDCl3
CDCl3
Major Z-Isomer: 1.27 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.29 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.60 (9 H, s, t-Bu), 1.91–
2.06 (1 H, m, 1 H of CH2CH2CO2Et), 2.15–2.40 (3 H, m, CH2CH2CO2Et, 1 H of CH2CH2CO2Et), 3.27 (1 H, dd,
J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.39 (1 H, dd, J = 5.7, 13.6 Hz, 1 H of PhCH2CH), 4.03–4.19 (1 H, m, NHCH-
COO), 4.15 (2 H, q, J = 7.2 Hz, OCH2CH3), 4.21 (2 H, q, J = 7.2 Hz, OCH2CH3), 4.42 (1 H, dd, J = 3.0, 5.7 Hz,
PhCH2CH), 7.02–7.09 (2 H, m, 2 H of Ph), 7.11–7.23 (3 H, m, 3 H of Ph), 7.53 (1 H, d, J = 14.3 Hz, NHCH=), 9.28
(1 H, br dd, J = 9.4, 14.2 Hz, NHCH=)
Minor E-Isomer: 1.59 (9 H, s, t-Bu), 4.45 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 7.37 (1 H, br s, NHCH=), 9.71 (1
H, br s, NHCH=)
Major Z-Isomer: 1.29 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.50 (1 H, t, J = 9.1 Hz, SH), 1.61 (9 H, s, t-Bu), 2.81–3.04
(2 H, m, CH2SH), 3.27 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.40 (1 H, dd, J = 5.7, 13.9 Hz, 1 H of
PhCH2CH), 3.97–4.05 (1 H, m, NHCHCOO), 4.24 (2 H, q, J = 7.2 Hz, OCH2CH3), 4.43 (1 H, dd, J = 3.0, 5.7 Hz,
PhCH2CH), 7.02–7.09 (2 H, m, 2 H of Ph), 7.11–7.22 (3 H, m, 3 H of Ph), 7.58 (1 H, d, J = 13.9 Hz, NHCH=), 9.38
(1 H, br dd, J = 9.4, 13.5 Hz, NHCH=)
Minor E-Isomer: 1.33 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.60 (9 H, s, t-Bu), 3.29 (1 H, dd, J = 3.0, 13.8 Hz, 1 H of
PhCH2CH), 3.39 (1 H, dd, J = 5.7, 13.8 Hz, 1 H of PhCH2CH), 4.09–4.15 (1 H, m, NHCHCOO), 4.26–4.34 (2 H,
m, OCH2CH3), 4.47 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 7.43 (1 H, br s, NHCH=), 9.86 (1 H, br s, NHCH=)
Major E-Isomer: 1.34 (3 H, t, J = 7.2 Hz, OCH2CH3), 3.27 (1 H, dd, J = 2.9, 13.9 Hz, 1 H of PhCH2CH), 4.08–4.16
(1 H, m, NHCHCOO), 4.27–4.35 (2 H, m, OCH2CH3), 4.53 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 5.34 (1 H, d,
J = 12.4 Hz, 1 H of PhCH2O), 5.40 (1 H, d, J = 12.4 Hz, 1 H of PhCH2O), 9.90 (1 H, br s, NHCH=)
Minor Z-Isomer: 1.29 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.51 (1 H, t, J = 9.1 Hz, SH), 2.87–3.09 (2 H, m, CH2SH),
3.25 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.38 (1 H, dd, J = 5.6, 13.9 Hz, 1 H of PhCH2CH), 3.98–4.06 (1
H, m, NHCHCOO), 4.25 (2 H, q, J = 7.2 Hz, OCH2CH3), 4.49 (1 H, dd, J = 2.9, 5.6 Hz, PhCH2CH), 5.34 (1 H, d,
J = 12.4 Hz, 1 H of PhCH2O), 5.40 (1 H, d, J = 12.4 Hz, 1 H of PhCH2O), 6.86–6.95 (2 H, m, 2 H of Ph), 7.05–7.14
(3 H, m, 3 H of Ph), 7.30–7.44 (3 H, m, 3 H of Ph), 7.44–7.52 (2 H, m, 2 H of Ph), 7.60 (1 H, d, J = 14.0 Hz,
NHCH=), 9.37 (1 H, br dd, J = 8.7, 14.0 Hz, NHCH=)
57/57¢c
CDCl3
Major E-Isomer: 1.34 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.56 (1 H, t, J = 9.0 Hz, CH2SH), 3.03–3.11 (2 H, m, CH2SH),
4.14 (2 H, s, 5-CH2), 4.17–4.26 (1 H, m, NHCHCH2), 4.32 (2 H, q, J = 7.2 Hz, OCH2CH3), 4.60–4.67 (2 H, m,
CH2NH), 5.14 (2 H, s, PhCH2O), 5.52 (1 H, br s, CH2NH), 7.30–7.40 (5 H, m, Ph), 7.73 (1 H, br s, NHCH=), 10.07
(1 H, br s, NHCH=)
Minor Z-Isomer: 1.34 (3 H, t, J = 7.2 Hz, OCH2CH3), 4.10 (2 H, s, 5-CH2), 4.28–4.37 (2 H, m, OCH2CH3), 7.85 (1
H, d, J = 14.3 Hz, NHCH=), 9.57 (1 H, br, NHCH=)
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2983
Table 4 1H NMR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Product
Solvent
CDCl3
1H NMR, d
58/58¢b
Major E-Isomer: 3.04 (1 H, dd, J = 8.7, 13.9 Hz, 1 H of PhCH2CHNH), 3.15–3.31 (2 H, m, 1 H of PhCH2CH, 1 H
of PhCH2CHNH), 3.33 (1 H, dd, J = 5.9, 13.9 Hz, 1 H of PhCH2CH), 3.82 (3 H, s, OMe), 4.13–4.23 (1 H, m, NH-
CHCOO), 4.49 (1 H, dd, J = 3.0, 6.0 Hz, PhCH2CH), 5.33 (2 H, s, PhCH2O), 6.85–6.92 (2 H, m, 2 H of Ph), 6.94–
7.01 (1 H, m, 1 H of Ph), 7.03–7.21 (5 H, m, 5 H of Ph), 7.23–7.52 (8 H, m, 7 H of Ph, NHCH=), 9.80 (1 H, br s,
NHCH=)
Minor Z-Isomer: 2.94 (1 H, dd, J = 8.8, 13.9 Hz, 1 H of PhCH2CHNH), 3.34 (1 H, dd, J = 5.9, 13.9 Hz, 1 H of
PhCH2CH), 3.76 (3 H, s, OMe), 4.06–4.16 (1 H, m, NHCHCOO), 4.41 (1 H, dd, J = 2.9, 5.7 Hz, PhCH2CH), 5.33
(1 H, d, J = 12.4 Hz, 1 H of PhCH2O), 5.38 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 9.38 (1 H, dd, J = 9.4, 13.8 Hz,
NHCH=)
58/58¢c
59/59¢b
CDCl3
CDCl3
Major E-Isomer: 3.07 (1 H, dd, J = 9.1, 13.7 Hz, 1 H of PhCH2CH), 3.34 (1 H, dd, J = 4.2, 13.9 Hz, 1 H of
PhCH2CH), 3.83 (3 H, s, OMe), 4.08 (2 H, s, 5–CH2), 4.27 (1 H, m, PhCH2CH), 4.58 (2 H, d, J = 5.6 Hz, CH2NH),
5.13 (2 H, s, PhCH2O), 5.50 (1 H, br s, CH2NH), 7.10–7.17 (2 H, m, 2 H of Ph), 7.28–7.44 (9 H, m, 8 H of Ph,
NHCH=), 9.94 (1 H, br s, NHCH=)
Minor Z-Isomer: 4.03 (2 H, s, 5-CH2), 4.63 (2 H, d, J = 6.0 Hz, CH2NH), 5.15 (2 H, s, PhCH2O), 9.43 (1 H, br s,
NHCH=)
Z-Isomer: 3.06–3.25 (2 H, m, CH2), 3.28–3.50 (2 H, m, CH2), 3.74 (3 H, s, OMe), 4.15 (1 H, deg dt, J = 3.8, 8.7 Hz,
CHCO2Me), 4.42 (1 H, dd, J = 3.0, 5.6 Hz, PhCH2CH), 5.27–5.41 (2 H, m, PhCH2O), 6.61 (1 H, d, J = 2.3 Hz, 1 H
of Het), 6.84–6.89 (1 H, m, 1H of Ar), 6.92–6.99 (2 H, m, 2 H of Ph), 7.03–7.23 (5 H, m, 3 H of Ph, 2 H of Het),
7.31–7.41 (4 H, m, 3 H of Ph, 1 H of Het), 7.42–7.51 (3 H, m, 2 H of Ph, NHCH=), 8.02 (1 H, s, NH of indole), 9.46
(1 H, dd, J = 9.4, 13.9 Hz, NHCH=)
E-Isomer: 3.82 (3 H, s, OMe), 4.20–4.28 (1 H, m, CHCO2Me), 4.44 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 9.89 (1
H, br s, NHCH=)
60/60¢a
CDCl3
Major Z-Isomer: 1.26 (3 H, t, J = 7.2 Hz, OCH2CH3), 1.59 (9 H, s, t-Bu), 2.57 (2 H, t, J = 6.0 Hz, CH2COO), 3.27
(1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.38 (1 H, dd, J = 5.3, 13.9 Hz, 1 H of PhCH2CH), 3.55–3.67 (2 H,
m, NHCH2), 4.16 (2 H, q, J = 7.2 Hz, OCH2CH3), 4.38 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 7.01–7.09 (2 H, m, 2
H of Ph), 7.13–7.22 (3 H, m, 3 H of Ph), 7.64 (1 H, d, J = 14.3 Hz, NHCH=), 9.28 (1 H, br, NHCH=)
Minor E-Isomer: 1.28 (3 H, t, J = 7.2 Hz, OCH2CH3), 2.62 (2 H, t, J = 6.0 Hz, CH2COO), 3.26 (1 H, dd, J = 3.0,
13.6 Hz, 1 H of PhCH2CH), 3.36 (1 H, dd, J = 5.3, 13.6 Hz, 1 H of PhCH2CH), 4.20 (2 H, q, J = 7.2 Hz, OCH2CH3),
4.42 (1 H, dd, J = 3.0, 5.7 Hz, PhCH2CH), 7.43 (1 H, d, J = 14.0 Hz, NHCH=), 9.74 (1 H, br, NHCH=)
61/61¢a
61/61¢b
CDCl3
CDCl3
Major Z-Isomer: 1.59 (9 H, s, t-Bu), 3.27–3.32 (2 H, m, PhCH2CH), 4.27–4.37 (1 H, m, PhCH2CH), 4.38–4.44 (2
H, m, CH2CN), 7.01–7.07 (2 H, m, 2 H of Ph), 7.14–7.25 (3 H, m, 3 H of Ph), 7.67 (1 H, d, J = 13.9 Hz, NHCH=),
9.36 (1 H, br, NHCH=)
Minor E-Isomer: 1.60 (9 H, s, t-Bu), 4.46–4.50 (2 H, m, CH2CN), 7.60 (1 H, s, NHCH=)
Major Z-Isomer: 3.21–3.37 (2 H, m, PhCH2CH), 4.23–4.29 (2 H, m, CH2CN), 4.48 (1 H, dd, J = 3.4, 5.4 Hz,
PhCH2CH), 5.30 (2 H, s, PhCH2O), 6.84–6.94 (2 H, m, 2 H of Ph), 7.08–7.18 (3 H, m, 3 H of Ph), 7.32–7.50 (5 H,
m, Ph), 7.66 (1 H, d, J = 13.2 Hz, NHCH=), 9.31 (1 H, br, NHCH=)
Minor E-Isomer: 4.30 (2 H, d, J = 1.6 Hz, CH2CN), 4.54 (1 H, dd, J = 3.3, 5.8 Hz, PhCH2CH), 5.35 (2 H, s,
PhCH2O), 7.62 (1 H, s, NHCH=)
61/61¢c
62/62¢b
CDCl3
CDCl3
Major E-Isomer: 3.97 (2 H, s, 5-CH2), 4.35 (2 H, d, J = 6.0 Hz, CH2NH), 4.61 (2 H, s, CH2CN), 5.05 (2 H, s,
PhCH2O), 7.27–7.39 (5 H, m, Ph), 7.47 (1 H, t, J = 6.0 Hz, CH2NH), 8.02 (1 H, s, NHCH=), 10.00 (1 H, br s,
NHCH=)
Minor Z-Isomer: 3.95 (2 H, s, 5-CH2)
Z-Isomer: 3.25 (1 H, dd, J = 3.0, 13.8 Hz, 1 H of PhCH2CH), 3.37 (1 H, dd, J = 5.6, 13.8 Hz, 1 H of PhCH2CH),
4.43–4.55 (3 H, m, PhCH2CH, PhCH2NH), 5.30 (1 H, d, J = 12.1 Hz, 1 H of PhCH2O), 5.37 (1 H, d, J = 12.1 Hz, 1
H of PhCH2O), 6.87–6.95 (2 H, m, 2 H of Ph), 7.06–7.20 (5 H, m, 5 H of Ph), 7.30–7.42 (6 H, m, 6 H of Ph), 7.43–
7.51 (2 H, m, 2 H of Ph), 7.68 (1 H, d, J = 14.3 Hz, NHCH=), 9.41 (1 H, br, NHCH=)
E-Isomer: 3.23 (1 H, dd, J = 3.0, 13.6 Hz, 1 H of PhCH2CH), 3.36 (1 H, dd, J = 5.7, 13.7 Hz, 1 H of PhCH2CH),
5.36 (2 H, s, PhCH2O), 9.87 (1 H, br s, NHCH=)
63/63¢c
DMSO-d6
Major E-Isomer: 1.44 (6 H, br s, 6 H of adamantyl), 1.60 (3 H, br d, J = 12.1 Hz, 3 H of adamantyl), 1.67 (3 H, br
d, J = 12.1 Hz, 3 H of adamantyl), 1.96 (3 H, br s, 3 H of adamantyl), 3.16–3.24 (2 H, m, CH2NHCH=), 3.98 (2 H,
s, 5-CH2), 4.33 (2 H, d, J = 6.0 Hz, CH2NHCO2Bn), 5.05 (2 H, s, PhCH2O), 7.26–7.40 (5 H, m, Ph), 7.43 (1 H, t,
J = 6.0 Hz, CH2NH), 7.82 (1 H, d, J = 14.7 Hz, NHCH=), 9.94 (1 H, dt, J = 6.9, 14.7 Hz, NHCH=)
Minor Z-Isomer: 3.92 (2 H, s, 5-CH2), 4.36 (2 H, d, J = 6.0 Hz, CH2NH), 7.46 (1 H, t, J = 6.0 Hz, CH2NH), 7.91 (1
H, d, J = 15.1 Hz, NHCH=), 9.54 (1 H, br, NHCH=)
64a
CDCl3
1.63 (9 H, s, t-Bu), 3.26 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.32 (1 H, dd, J = 5.3, 13.9 Hz, 1 H of
PhCH2CH), 4.41 (1 H, dd, J = 3.0, 4.9 Hz, PhCH2CH), 7.01–7.09 (2 H, m, 2 H of Ph), 7.13–7.24 (3 H, m, 3 H of
Ph), 7.47 (1 H, s, NHCH=), 12.27 (1 H, br s, NHCH=), 14.33 (1 H, br s, OH)
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2984
S. Pirc et al.
FEATURE ARTICLE
Table 4 1H NMR Data for Compounds 2¢c and 2c and Tetramic Acid Derivatives 3c, 4a–c, and 35/35¢–64/64¢ (continued)
Product
Solvent
CDCl3
1H NMR, d
64b
3.21 (1 H, dd, J = 3.0, 13.9 Hz, 1 H of PhCH2CH), 3.28 (1 H, dd, J = 5.3, 13.9 Hz, 1 H of PhCH2CH), 4.51 (1 H,
dd, J = 3.0, 5.3 Hz, PhCH2CH), 5.33 (1 H, d, J = 11.9 Hz, 1 H of PhCH2O), 5.39 (1 H, d, J = 11.9 Hz, 1 H of
PhCH2O), 6.84–6.91 (2 H, m, 2 H of Ph), 7.11–7.17 (3 H, m, 3 H of Ph), 7.36–7.49 (6 H, m, Ph, NHCH=), 12.27 (1
H, br s, NHCH=), 14.47 (1 H, br s, OH)
64/64¢c
DMSO-d6
Major E-Isomer: 4.10 (2 H, s, 5-CH2), 4.31 (2 H, d, J = 6.4 Hz, CH2NH), 5.05 (2 H, s, PhCH2O), 7.25–7.41 (5 H,
m, Ph), 7.46 (1 H, t, J = 6.4 Hz, CH2NH), 7.65 (1 H, s, NHCH=), 11.29 (1 H, br s, NHCH=), 14.01 (1 H, br s, OH)
Minor Z-Isomer: 7.79 (1 H, s, NHCH=)
Table 5 13C NMR Data for Compounds 2¢c, 2c, 3c, 4a–c, 35/35¢, 40/40¢a, 46/46¢b, 57/57¢c, 58/58¢b, 59/59¢b, 60/60¢a, 61/61¢b, 62/62¢b, and
64a
Product
2¢c
Solvent
d
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
26.9, 44.8, 49.6, 66.4, 87.4, 100.3, 107.8, 128.4, 128.6, 129.2, 137.9, 140.2, 157.4, 157.8, 164.8, 169.4, 188.6
27.0, 44.3, 44.7, 66.4, 90.7, 104.9, 128.56, 128.64, 129.2, 137.9, 157.3, 165.3, 170.4, 192.4
46.0, 49.1, 66.3, 94.7, 128.5, 128.6, 129.2, 137.9, 157.4, 169.2, 171.8, 177.5
2c
3c
4a
28.6 [(CH3)3COOC], 36.6 (PhCH2), 44.3 (NMe), 48.6 (NMe), 64.0 (5–C), 82.7 [(CH3)3COOC], 97.3 (3-C), 127.0
(1 C of Ph), 128.5 (2 C of Ph), 130.3 (2 C of Ph), 135.8 (1 C of Ph), 150.2 [(CH3)3COOC], 155.7 (3’–C), 157.3 (2-
C), 190.6 (4-C)
4b
CDCl3
36.3, 44.4, 48.7, 64.0, 68.1, 97.2, 127.0, 128.5, 128.7, 129.0, 130.3, 135.6, 136.2, 151.7, 156.0, 169.9, 190.3
44.7, 46.5, 48.8, 52.5, 66.3, 96.4, 128.5, 128.6, 129.2, 137.9, 156.6, 157.4, 169.7, 190.3
4c
DMSO-d6
35/35¢c
DMSO-d6 + Mixture of Isomers: 46.4, 52.7, 53.2, 66.4, 100.8, 119.6, 119.7, 127.6, 128.5, 128.7, 129.3, 130.6, 137.7, 138.9,
D2O
148.5, 148.7, 157.5, 169.0, 169.9, 170.1, 170.3, 191.2, 193.1
40/40¢a
CDCl3
Mixture of Isomers: 28.61, 28.62, 36.1, 36.4, 55.99, 56.01, 64.1, 65.1, 83.1, 83.4, 99.7, 100.8, 115.6, 119.5, 119.7,
127.3, 128.7, 130.1, 130.3, 131.2, 131.3, 135.3, 135.4, 146.3, 147.1, 150.1, 150.3, 158.9, 159.0, 167.4, 170.7, 193.2,
196.3
46/46¢b
57/57¢c
DMSO-d6
35.2, 35.8, 64.8, 68.2, 103.2, 127.7, 128.9, 129.0, 129.1, 130.3, 135.7, 136.6, 146.8, 151.6, 156.7
CDCl3
Mixture of Isomers: 14.5, 27.1, 28.1, 34.6, 36.7, 46.9, 52.3, 53.1, 63.4, 63.5, 63.9, 64.2, 67.3, 67.4, 99.5, 100.1,
128.4, 128.5, 128.9, 136.8, 154.9, 155.3, 156.9, 168.0, 168.1, 168.3, 169.4, 169.7, 170.7, 190.5, 193.6
58/58¢b
59/59¢b
CDCl3
CDCl3
Mixture of Isomers: 35.9, 36.1, 39.9, 40.1, 53.5, 63.9, 64.0, 64.2, 65.0, 68.2, 68.4, 99.0, 99.9, 127.11, 127.14, 128.2,
128.4, 128.5, 128.6, 128.7, 128.9, 128.99, 129.05, 129.5, 129.6, 130.1, 130.2, 134.5, 135.2, 151.8, 153.2, 154.0,
166.7, 169.3, 169.6, 169.9, 192.7, 196.0
Mixture of Isomers: 30.3, 36.0, 36.1, 53.5, 53.6, 62.6, 62.8, 64.0, 64.9, 68.2, 68.5, 98.6, 99.5, 107.9, 108.2, 112.2,
112.3, 118.3, 120.3, 122.9, 124.4, 124.6, 126.8, 126.9, 127.06, 127.15, 128.5, 128.6, 128.8, 128.97, 129.00, 129.1,
130.1, 130.5, 135.2, 135.6, 135.9, 136.0, 136.7, 136.8, 151.4, 151.7, 153.4, 154.0, 167.0, 169.9, 170.1, 170.2, 192.5,
195.8
60/60¢a
61/61¢b
62/62¢b
64a
CDCl3
CDCl3
CDCl3
CDCl3
Mixture of Isomers: 14.50, 14.55, 28.59, 28.61, 34.8, 35.1, 36.1, 36.3, 46.2, 46.3, 61.7, 61.8, 63.9, 64.9, 82.8, 83.1,
98.5, 99.5, 127.07, 127.12, 128.50, 128.55, 130.1, 130.3, 135.55, 135.56, 150.1, 150.4, 154.6, 155.2, 167.5, 170.5,
170.7, 170.8, 192.8, 195.9
Mixture of Isomers: 35.3, 36.3, 36.5, 37.3, 64.3, 65.3, 68.7, 100.0, 100.9, 114.7, 127.4, 128.7, 128.8, 129.07, 129.12,
129.17, 129.23, 129.3, 130.06, 130.11, 135.0, 135.1, 135.3, 135.6, 150.8, 151.6, 154.2, 155.8, 166.8, 169.9, 192.7,
196.3
Mixture of Isomers: 36.1, 54.1, 54.2, 64.0, 64.9, 68.2, 68.3, 98.4, 99.3, 127.1, 127.2, 127.9, 128.0, 128.5, 128.6,
128.7, 128.76, 128.85, 128.9, 129.0, 129.1, 129.5, 129.6, 130.2, 130.3, 135.29, 135.34, 135.4, 135.5, 136.0, 136.1,
151.5, 151.9, 154.5, 155.4, 167.3, 170.3, 192.7, 195.7
28.8, 36.3, 63.2, 84.1, 95.2, 127.5, 128.8, 130.1, 134.5, 140.0, 150.4, 169.7, 192.5
Compounds 4a–c, 46a,b, 50c, and 64a,b were isolated in the minor isomers 35¢–45¢, 47¢–49¢, and 51¢–63¢. Attempt-
isomerically pure form, while the other coupling products ed chromatographic separations of isomeric compounds
35–45, 47–49, and 51–63 were isolated as the E/Z-mix- 35/35¢–64/64¢ failed, most probably due to fast isomerisa-
tures of the major isomers 35–45, 47–49, and 51–63 and tion around the exocyclic C(3)=C(3¢) double bond in so-
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2985
COCH2NHCOOBn
lution. Equilibration between the isomers 35/35¢–64/64¢ in
solution can be explained by involvement of tautomeric
structures 35¢¢–64¢¢, with a C(3)–C(3¢) single bond. In re-
lated (+)-camphor derived enaminone series, a free ener-
gy between the isomers, DG0296 = 4.9 kJ mol–1, was
recently measured (Scheme 3).8d As in related enami-
nones,6b,f,8d,e the ratio between the two isomers is solvent
dependent also in the case of compounds 35/35¢–64/64¢.
For example, (S)-5-benzyl-1-benzyloxycarbonyl-3-{[(4-
nitrophenyl)amino]methylidene}pyrrolidin-2,4-dione (37b)
precipitated from ethanol as a mixture of isomers in a ratio
of E:Z = 62:38 as determined by 1H NMR taken in CDCl3.
When this CDCl3 solution of 37b was allowed to stand at
r.t. for 24 h, the ratio between the isomers changed to
E:Z = 44:56 (Scheme 3).
COCH2NHCOOBn
N
2
C
2
C
N
O
O
4
4
3
3
C
C
H
O
HN
O
3'
3'
Ph
H
NH
35'c
35c
Ph
Boc
Ph
2
C
N
O
4
3
C
HN
O
3'
H
55a
COOMe
Boc
N
Boc
N
Ph
Ph
2
C
2
O
O
C
EtOOC
4
4
3
3
C
C
R2
N
R2
N
HN
3'
O
H
O
3'
NH
60'a
H
O
R1
O
R1
60a
EtOOC
H
R3HN
35/35'–64/64'
O
O
Boc
N
Boc
N
NHR3
E-isomer
H
Ph
Ph
2
O
2
C
Z-isomer
O
C
4
4
3
3
C
C
H
H
O
O
R2
N
3'
3'
HN OH
NMe2
O
R1
64a
4a
3JC,H [Hz]
(E) or (Z)
Compound
N
OH
C(2)-H(3') C(4)-H(3')
R3
H
(E)
(E)
(Z)
(Z)
(Z)
(E)
(E)
2 (cis)
3 (cis)
9 (trans)
9 (trans)
9 (trans)
3 (cis)
7 (trans)
7 (trans)
3 (cis)
3 (cis)
3 (cis)
7 (trans)
7 (trans)
4a
35c (major isomer)
35'c (minor isomer)
55a (major isomer)
60a (major isomer)
60'a (minor isomer)
64a
35''–64''
Scheme 3
3 (cis)
Configurations around the exocyclic C=C double bond in
compounds 4a, 35c, 35¢c, 55a, 60a, 60¢a, and 64a were
determined by HMBC spectroscopy on the basis of long-
range coupling constants (3JC,H) between the methylidene
proton [H–C(3¢)] and the carbonyl carbon atoms [O=C(2)
and O=C(4)], measured from the antiphase splitting of
cross peaks in the HMBC spectrum. Generally, the mag-
nitude of coupling constant, 3JC,H, for nuclei with cis-con-
figuration around the C=C double bond are smaller (2–6
Hz) than that for trans-oriented nuclei (8–12 Hz).6–8,10,11
In compounds 4a, 35c, 60¢a, and 64a, the magnitudes of
Figure 2 Determination of configuration around the exocyclic
C(3)=C(3¢) double bond by HMBC spectroscopy
3
coupling constants, JC(2),H(3¢) = 2–3 Hz (cis) and
3JC(4),H(3¢) = 6–7 Hz (trans) showed the E-configuration
around the exocyclic C=C double bond. In the same
manner, the Z-configuration in compounds 35¢c, 55a and
60a was determined on the basis of coupling constants,
3JC-(2),H(3¢) = 9 Hz (trans) and JC-(4),H(3¢) = 3 Hz (cis)
3
(Figure 2).
Structures of compounds 4a and 35c were determined by
X-Ray diffraction (Figures 3 and 4). The C(3)–C(4) (ca.
1.39 Å) and C(3)–C(3¢) (ca. 1.42 Å) bond lengths in com-
pounds 4a and 35a indicate a partial bond character,
which support tautomeric equilibrium in solution accord-
ing to structural investigations of 3-acyltetramic acids re-
ported by Steyn and co-workers (Figures 3, 4).12
Figure 3 ORTEP view of compound 4a
The configurations around the exocyclic C=C double
bond in compounds 35–64 were correlated with chemical
shifts d for H–C(3¢) and H–N–C(3¢) and with magnitudes
of the vicinal coupling constants 3JH(3¢),NH. Within each set
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2986
S. Pirc et al.
FEATURE ARTICLE
CHN-analyses. This could be explained by trimerisation
of cyano compounds 61a–c into the corresponding 1,3,5-
triazine derivatives.13 Appearance of fragments, corre-
sponding to MH+, M2H+, and M3H+, in the FAB mass
spectrum of compound 61a, could be in agreement with
the trimeric structure. However, the absence of a typical
1,3,5-triazine carbon signal at ca. 170 ppm13 and the pres-
ence of typical C≡N peak at 114.7 ppm in 13C NMR spec-
trum of 61a support the proposed monomeric structures of
61a–c.
Melting points were determined on a Kofler micro hot stage. The 1H
NMR spectra were obtained on a Bruker Avance DPX 300 at 300
Figure 4 ORTEP view of compound 35c
1
MHz for H and 75.5 MHz for 13C nucleus, using DMSO-d6 and
CDCl3 with TMS as the internal standard, as solvents. Mass spectra
were recorded on an AutoSpecQ spectrometer, IR spectra on a Per-
kin-Elmer Spectrum BX FTIR spectrophotometer. Microanalyses
were performed on a Perkin-Elmer CHN Analyser 2400. Column
chromatography (CC) was performed on silica gel (Fluka, silica gel
60, 0.04–0.06 mm) and on aluminium oxide (Fluka, type 507 C neu-
tral, 0.05–0.15 mm, pH 7.0 0.5). The Z/E-ratios of isomers were
determined by 1H NMR spectroscopy.
of isomeric compounds 35/35¢–64/64¢, the signal for H–
C(3¢) of the Z-isomer appeared at lower field (7.51–8.90
ppm) than the signal for H–C(3¢) of the E-isomer (7.36–
8.81 ppm) with typical chemical shift difference,
Dd = 0.1–0.2 ppm. On the other hand, within each set of
isomers 35/35¢–64/64¢, the signal for H–N–C(3¢) of the E-
isomer appeared at lower field (9.65–12.34 ppm) than the
signal for H–N–C(3¢) of the Z-isomer (9.29–11.81 ppm)
with a typical chemical shift difference, Dd = 0.1–0.4
ppm. In addition to this, the magnitude of the vicinal cou-
pling constant,3JH(3¢),NH, was larger in the case of the Z-iso-
mers (3JH(3¢),NH = 12.8–15.1 Hz) than in the case of the E-
isomers (3JH(3¢),NH = 10.2–14.7 Hz). In the 1H NMR spec-
tra of isomeric mixtures 35/35¢–37/37¢c, 39/39¢c, 40/40¢c,
42/42¢c, 46a, 48/48¢c, 53/53¢c, and 64/64¢c, a very small
coupling constant, 3JH(3¢),NH = ~0 Hz was observed for both
isomers (Table 2). Typical example of differentiation be-
tween the E-isomer 40a and the Z-isomer 40¢a on the basis
of chemical shifts for protons H–C(3¢) and H–N–C(3¢)
and coupling constants,3JH(3¢),NH, is depicted in Figure 5.
Boc-L-phenylalanine (1a), Z-L-phenylalanine (1b), N-(glycyl)gly-
cine, Meldrum’s acid, 4-dimethylaminopyridine (DMAP), N,N’-di-
cyclohexylcarbodiimide (DCC), N,N-dimethylformamide dimethyl
acetal (DMFDMA), and amines 5–34 are commercially available
(Sigma-Aldrich). N-[N-(Benzyloxycarbonyl)glycyl]glycine (1c)
was prepared from N-(glycyl)glycine according to the general pro-
cedure for the preparation of N-benzyloxycarbonyl protected amino
acids.14 (S)-5-Benzyl-1-tert-butoxycarbonyl-4-hydroxy-2,5-dihy-
dropyrrol-2-one (3a)9a and (S)-5-benzyl-1-benzyloxycarbonyl-4-
hydroxy-2,5-dihydropyrrol-2-one (3b)9b were prepared according
to the literature procedures.
1-[N-(Benzyloxycarbonyl)glycyl]-4-hydroxy-2,5-dihydropyr-
rol-2-one (3c)
A solution of DCC (2.65 g, 12.9 mmol) in anhyd CH2Cl2 (15 mL)
was slowly added to a stirred cold (0 °C) solution of 1c (3 g, 11.3
mmol), Meldrum’s acid (1.79 g, 12.4 mmol), and DMAP (2.07 g,
16.9 mmol) in anhyd CH2Cl2. Upon addition of DCC, the mixture
was stirred at r.t. for 24 h, filtered, and the precipitate was washed
with CH2Cl2 (2 × 10 mL). The filtrate was poured into cold (0 °C)
EtOAc (100 mL), scratched with a glass stick, and the precipitate
was collected by filtration to give 4-(dimethylamino)pyridinium 2-
{[N-(benzyloxycarbonyl)glycyl]amino}-1-(2,2-dimethyl-4,6-di-
oxo-1,3-dioxan-5-ylidene)ethanolate (2¢c) in 93% yield. The salt
2¢c was then dissolved in CH2Cl2 (100 mL), the solution was
washed with 1 M aq NaHSO4 (100 mL) and brine (100 mL), dried
(Na2SO4), filtered, and the filtrate was evaporated in vacuo to give
2c in quantitative yield. Compound 2c (3.31 g, 8.4 mmol) was dis-
solved in EtOAc (100 mL), the solution was refluxed for 30 min,
cooled, and evaporated in vacuo to give 3c. Experimental, analyti-
cal, and spectral data for compounds 2¢c, 2c, and 3c are given in
Tables 2–5.
(3E,5S)-5-Benzyl-1-(tert-butoxycarbonyl)-3-[(dimethylami-
no)methylidene]pyrrolidine-2,4-dione (4a)
A mixture of 3a (1.45 g, 5 mmol), anhyd toluene (15 mL), and
DMFDMA (0.8 mL, 5.5 mmol) was stirred at 80–90 °C for 45 min,
cooled, and evaporated in vacuo. The residue was purified by CC
(Al2O3, EtOAc). Fractions containing product were combined and
evaporated in vacuo to give 4a. Experimental, analytical, and spec-
tral data for compound 4a are given in Tables 2–5.
Figure 5 Partial 1H NMR spectrum of a mixture of isomers 40/40¢a
IR spectra of compounds 61a–c, obtained from 4a–c and
aminoacetonitrile (31), exhibit no typical C≡N vibration
(~2230 cm–1), although these compounds gave correct
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of N-Substituted 3-Aminomethylidenetetramic Acids
2987
(3E,5S)-5-Benzyl-1-(benzyloxycarbonyl)-3-[(dimethylami-
no)methylidene]pyrrolidine-2,4-dione (4b)
Table 6 Crystal Data for Compounds 4a and 35c
Compound
Formula
Mr
4a
35c
A mixture of 3b (3.25 g, 10.1 mmol), anh CH2Cl2 (50 mL), and DM-
FDMA (2.4 mL, 16 mmol) was stirred under reflux for 3 h, cooled,
and evaporated in vacuo. The residue was purified by CC (silica gel,
CHCl3–MeOH, 40:1). Fractions containing product were combined
and evaporated in vacuo to give 4b. Experimental, analytical, and
spectral data for compound 4b are given in Tables 2–5.
C19H24N2O4
344.411
C21H19N3O5
393.399
monoclinic
P21/c
System
Sp. Group
a (Å)
orthorhombic
P212121
(3E)-1-[N-(Benzyloxycarbonyl)glycyl]-3-[(dimethylamino)me-
thylidene]pyrrolidine-2,4-dione (4c)
9.758(1)
17.364(2)
22.031(3)
21.1556(4)
11.3544(2)
7.9603(1)
91.2968(8)
1911.65(6)
4
A mixture of 3c (2.75 g, 9.5 mmol), anhyd CH2Cl2 (50 mL) and
DMFDMA (1.6 mL, 11 mmol) was stirred under reflux for 30 min,
cooled, and evaporated in vacuo. The residue was dissolved in
CH2Cl2 (100 mL), silica gel (5 g) was added, the mixture was stirred
at r.t. for 2 h, filtered, and the filtrate was evaporated in vacuo to
give 4c. Experimental, analytical, and spectral data for compound
4c are given in Tables 2–5.
b (Å)
c (Å)
b (°)
Vol. (Å3)
Za
3732.9(8)
8
Coupling of Enaminones 4a–c with Primary Amines 5–34;
N(3¢)-Substituted 3-Aminomethylidenetetramic Acid Deriva-
tives 35–64; General Procedure
Dx (mg/m3)
m (mm–1)
Appearance
1.226
0.0863
1.367
Method A: Amine hydrochloride 5–34 (0.5 mmol) or amine 5–34
(0.5 mmol) and 37% aq HCl (2 drops) were added to a solution of 4
(0.5 mmol) in EtOH (3 mL) and the mixture was stirred at 20–60 °C
for 1–48 h. Volatile components were evaporated in vacuo and the
residue was purified by CC (silica gel, EtOAc–hexanes). Fractions
containing the product were combined and evaporated in vacuo to
give 35–64. Experimental, analytical, and spectral data for com-
pounds 35–64 are given in Tables 2–5.
0.0993
prismatic yellow
crystal
pale green plate
Dimensions (mm)
0.44 × 0.34 × 0.33
0.30 × 0.25 × 0.025
a Z: Multiplicity of the space group.
Method B: Amine hydrochloride 5–34 (0.5 mmol) or amine 5–34
(0.5 mmol) and 37% aq HCl (2 drops) were added to a solution of 4
(0.5 mmol) in EtOH (3 mL) and the mixture was stirred at r.t. for 1–
48 h. The precipitate was collected by filtration and washed with
cold EtOH and Et2O to give 35–64. Experimental, analytical, and
spectral data for compounds 35–64 are given in Tables 2–5.
in the Laboratory of Inorganic Chemistry, Faculty of Chemistry and
chemical Technology, University of Ljubljana, Slovenia. We ack-
nowledge with thanks the financial contribution of the Ministry of
Science and technology, Republic of Slovenia through grant Packet
X-2000 and PS-511-102, which thus made the purchase of the ap-
paratus possible.
X-ray Structure Analysis
Single crystal data were collected at r.t. on an Enraf-Nonius CAD4
(for 4a) and on a Nonius Kappa CCD (for 35c) diffractometer using
graphite monochromatic Mo-Ka radiation. Structures were solved
by direct methods using SIR92.15 We employed full-matrix least-
squares refinements on F magnitudes with anisotropic displacement
factors for all non-hydrogen atoms. All hydrogen atoms of both
compounds were located from difference Fourier maps. The param-
eters of hydrogen atoms were not refined. In the final cycle of the
refinement we used 2013 and 2610 reflections (included were those
less-than reflections for which FC was greater than FO) and 453 and
319 parameters for 4a and 35c, respectively. The final R and Rw
were 0.037 and 0.045 for 4a and 0.051 and 0.055 for 35c, respec-
tively. The Xtal3.416 system of crystallographic programs was used
for the structure refinement and interpretation. ORTEPII17 was used
to produce molecular graphics. The asymmetric units with atom-
numbering scheme are shown in Figures 3 and 4 for 4a and 35c, re-
spectively. Crystal data for 4a and 35c are given in Table 6.18
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Acknowledgment
The financial support from the Ministry of Education, Science, and
Sport (project numbers: PS-0502-0103, P1-0179, and J1-6689),
Slovenia, is gratefully acknowledged. We acknowledge with thanks
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Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York

2988
S. Pirc et al.
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both compounds have been deposited with the Cambridge
Crystallographic Data Centre as supplementary material
with the deposition numbers: CCDC 272155 & 272156,
respectively. These data can be obtained, free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html.
Synthesis 2005, No. 17, 2969–2988 © Thieme Stuttgart · New York