3,5-Dioxopimelates as new synthetic building blocks. Cyclocondensation with 1,2-, 1,3- and 1,4-dinucleophiles

Article abstract of DOI:10.1016/j.tet.2012.05.119

Cyclocondensation reactions of 3,5-dioxopimelates, new and versatile synthetic building blocks, with hydrazines, urea, thiourea and phenylene-1,2-diamines allow for a convenient synthesis of various heterocycles containing two ester-substituted side-chains.

Full text of DOI:10.1016/j.tet.2012.05.119

Tetrahedron 68 (2012) 6456e6462
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
3,5-Dioxopimelates as new synthetic building blocks. Cyclocondensation
with 1,2-, 1,3- and 1,4-dinucleophiles
,
b
,
,
b
, ,
z
Franziska Bendrath a, Verena Specowius a, Dirk Michalik a y, Peter Langer a
*
a
€
€
Institut fur Chemie, Universitat Rostock,, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b
€
€
Leibniz-Institut fur Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclocondensation reactions of 3,5-dioxopimelates, new and versatile synthetic building blocks, with
hydrazines, urea, thiourea and phenylene-1,2-diamines allow for a convenient synthesis of various
heterocycles containing two ester-substituted side-chains.
Received 20 March 2012
Accepted 29 May 2012
Available online 6 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyclizations
Heterocycles
Tetracarbonyl compounds
Regioselectivity
1. Introduction
under the conditions of their formation. In fact, such reactions play
an important role in the biosynthesis of phenolic natural products
1,3-Dicarbonyl compounds represent important dielectrophilic
building blocks in organic chemistry. For example, pyrazoles are
available by cyclization of 1,3-diketones with hydrazines.1 Cyclo-
condensationswithurea2 andphenylene-1,2-diaminehavealsobeen
reported.3 The synthesis of 1,3,5-tricarbonyl compounds requires the
reaction of moisture and air sensitive 1,3-dicarbonyl dianions4 or 1,3-
bis(silyloxy)-1,3-butadienes5 with carboxylic acid derivatives.
Therefore, synthetic applications of 1,3,5-tricarbonyl compounds are
more rare. Examples include the cyclocondensation of methyl 3,5-
dioxohexanoate with methylhydrazine.6 In addition, the synthesis
of1,5-benzodiazepines bycyclization ofphenylene-1,2-diaminewith
heptane-2,4,6-triones7a and with perfluorinated 1,2,5-triketones
have been reported.7b 6-Chloro-3,5-dioxoalkanoates undergo base
mediated cyclizations to give 3(2H)furanones.8 3,5-Dioxoalkanoates
have been also used as building blocks during the synthesis of open-
chained fragments of natural products.9
via the polyketide pathway.10 Harris and co-workers reported the in
situ generation of polycarbonyl compounds based on the reaction of
1,3-dicarbonyl dianions or 1,3,5-tricarbonyl trianions with carbox-
ylic acid derivatives.11
In 2000, Jurczak and co-workers reported the first synthesis of
dimethyl 3,5-dioxopimelate, which represents a stable 1,3,5,7-
tetracarbonyl derivative, by reaction of ketene with malonyl dichlor-
ide.12 Due to the lower electrophilicity of ester compared to keto
groups, 3,5-dioxopimelates do not undergo intramolecular aldol re-
actions under the conditions of their formation. Recently, we have
reported a new and convenient synthesis of a broad range of 3,5-
dioxopimelates and a detailed analysis of their ketoeenol tautomer-
ism.13a,b We also reported the alkylation of the products.13c The syn-
thesis of various heterocycles by cyclocondensation of 1,3-diketones
with various dinucleophiles, such as hydrazines or thioureas, is
known for many years and is present in many textbooks related to
heterocyclic chemistry. However, similar cyclocondensations with
more complex tetracarbonyl compounds have, to the best of our
knowledge, not been reported to date. These reactions are more dif-
ficult to be carried out, because the tetracarbonyl compounds contain
more than two electrophilic sites and several side reactions are, in
principle, possible. Herein, we report, for the first time, a study related
to cyclocondensation reactions of 3,5-dioxopimelates. These re-
actions allow for the synthesis of various heterocycles containing
functionalized side-chains, which are not readily available by other
methods.
1,3,5,7-Tetracarbonyl compounds, such as 3,5,7-trioxoalkanoates
and 1,3,5,7-tetraketones, and their higher homologues are unstable
because they rapidly undergo intramolecular aldol condensations
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 49864112; e-mail
addresses: dirk.michalik@catalysis.de (D. Michalik), peter.langer@uni-rostock.de
(P. Langer).
y
Tel.: þ49 381 4986353
z
Tel.: þ49 381 4986410; fax: þ49 381 49864112.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.119

F. Bendrath et al. / Tetrahedron 68 (2012) 6456e6462
6457
2. Results and discussion
(6a) and urea (6b) afforded pyrimidinone 7a and pyrimidinethione
7b, respectively (Scheme 3). In the 1H NMR spectra of compounds
7a and 7b a broad NH signal with an intensity of one proton is
observed in the range of 14e15 ppm. In the 13C NMR spectra the
signals for both CCN atoms did not appear due to a fast proton
exchange. This indicates that both nitrogen atoms are involved in
the dynamic process. But, it cannot be confirmed, to what extent
the C]S and C]O groups are taking part in this process.
The reaction of 1,3-bis(silyloxy)-1,3-butadienes 1a,b with acid
chloride 2, following our recently reported procedure,13 afforded
the 3,5-dioxopimelates 3a,b in very good yields (Scheme 1).
Me3SiO OSiMe3
R1
OMe
O
O
O
O
1a,b
i
X
MeO
OMe
+
H2N NH2
X
R1
O
O
6a,b
O
N
NH O
i
MeO
Cl
3a (R = H): 83%)
3b (R = Me) (91%)
2
O
O
O
O
MeO
OMe
Scheme 1. Synthesis of 3,5-dioxopimelates 3a,b: (i) (1) CH2Cl2, TMSOTf, ꢀ78/22 ꢁC,
MeO
OMe
7a (X = S): 92%
7b (X = O): 93%
14 h; (2) NaHCO3.
3a
Scheme 3. Synthesis of 7a,b. Conditions: (i) EtOH, 22 ꢁC, 4 h.
2.1. Cyclization with hydrazines
Pyrazoles are of considerable pharmacological relevance.
Fomepizol is an antidote to ethyleneglycol by inhibition of alco-
holdehydrogenase (ADH).14 Fipronil is used as an insecticide in crop
protection.15 The reaction of 3,5-dioxopimelates 3a,b with hydra-
zines 4aee afforded the pyrazoles 5aef in 50e99% yields (Scheme
2, Table 1). The synthesis of 5a has been previously reported.16
While very good yields were obtained for products derived from
parent hydrazine and from aromatic hydrazines, moderate yields
were obtained for methylhydrazine. The cyclizations proceed via
the two keto groups of 3a,b, which are more electrophilic than the
ester groups. The products thus contain two ester-substituted side-
chains. The yields of the products derived from unsubstituted 3,5-
dioxopimelate 3a were generally slightly better than the yields of
the pyrazoles derived from 3b.
2.3. Cyclization with 1,2-diaminobenzenes
Benzodiazepines are of considerable pharmacological relevance.
For example, valium A und clobazam B are used in the clinic for the
treatment of psychological and neurological disorders, re-
spectively.19 The reaction of 3,5-dioxopimelates 3a,b with 1,2-
diaminobenzenes 8aej afforded heterocycles 9aet (Scheme 4,
Table 2). Most of the products were isolated in good to excellent
yields (50e99%).
R2
R3
R2 R3
H2N
NH2
i
8a-j
HN
NH
O
O
O
O
O
O
MeO
OMe
R1
9a-t
MeO
OMe
R1
3a,b
Scheme 4. Synthesis of 9aet. Conditions: (i) EtOH, 22 ꢁC, 12 h.
Scheme 2. Synthesis of pyrazoles 5aef. Conditions: (i) EtOH, 22 ꢁC, 4e12 h.
In general, benzodiazepines exclusively contain sp2 hybridized
carbon atoms and are completely conjugated. In contrast, de-
rivatives 9aet contain an sp3 hybridized carbon atom and two
exocyclic double bonds. The conjugation is interrupted. This might
be explained by the formation of two stable intramolecular hy-
drogen bonds in the 3-aminoacrylate substructures (Scheme 5). In
addition, it is known from more simple benzodiazepines of this
substitution pattern that they are not conjugated in order to min-
imize antiaromatic contributions. Protonation is known to lead to
a benzodiazepinium salt containing two electronically decoupled
Table 1
Synthesis of pyrazoles 5aef
5
R1
R2
5 (%)a
a
b
c
d
e
f
H
H
H
H
Me
Me
Me
H
Ph
Me
4-MeC6H4
Me
80
90
59
99
50
90
83
p
-systems, i.e., the benzene ring and the vinamidinium salt moiety.
4-MeC6H4
Ph
In the 1H NMR spectra of compounds 9aet, one or two signals in
g
a
the region of 10e11 ppm are displayed for NH with a total intensity
of 2H. Additionally, in the 1H and 13C NMR spectra of the Me
substituted compounds 9ket some signals appear as broadened or
doubled, which refer to a dynamic process. Therefore, we have
measured 9t in chloroform solution at different temperatures from
223 to 323 K. At 298 K two broad signals for CHMe and one broad
signal for CHMe were observed in the 300 MHz 1H NMR spectrum.
At lowering the temperature to 223 K, in the 1H NMR spectrum all
signals were doubled in the ratio of 1:0.6. Likewise, in the 13C NMR
Isolated yields.
2.2. Cyclization with urea and thiourea
Pyrimidines and pyrimidinethiones are also of considerable
pharmacological relevance. For example, propylthiouracil is used as
a thyreostatic.17 Trimethoprim is an antibiotic used for urinary tract
infections.18 The reaction of 3,5-dioxopimelates 3a,b with thiourea

6458
F. Bendrath et al. / Tetrahedron 68 (2012) 6456e6462
Table 2
Synthesis of 9aet
4. Experimental section
R1
R2
R3
9 (%)a
4.1. General
9
8
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
H
H
H
H
Me
Cl
C(O)C6H5
Me
Cl
Br
COOMe
CN
65
85
75
87
85
89
62
65
50
1H NMR spectra (250.13 and 300.13 MHz, respectively) and 13C
NMR spectra (62.9 and 75.5 MHz, respectively) of compounds 9aet
were recorded on Bruker spectrometers AVANCE 250 and AVANCE
300 in CDCl3 solution at 298 K. Compound 9t was measured at
temperatures from 223 to 323 K. The chemical shifts are referenced
to solvent signals (
d
1H¼7.26,
d
13C¼77.0).
4.2. Synthesis of pyrazoles 5aef, pyrimidinthione 7a and
pyrimidinone 7b
j
j
H
80
To a solution of dimethyl 3,5-dioxopimelate 31a,b (1.0 equiv) in
ethanol (15 mL/mmol) is added the hydrazine compound 4aee or
urea or thiourea 6a,b (1.1 equiv) at a temperature of 22 ꢁC. After
4e12 h of stirring the solvent is removed under reduced pressure
and after column chromatography on silica (heptane/ethylacetate)
the pure products 5aef, 7a,b are obtained.
k
l
m
g
h
i
Me
Me
Me
H
H
H
Br
COOMe
CN
82
59
65
n
j
Me
51
4.2.1. Dimethyl 2,20-(1H-pyrazole-3,5-diyl)diacetate (5a). Yield 102
mg, 80%, yellow solid, mp 138e140 ꢁC; 1H NMR (300.13 MHz,
o
p
q
r
s
t
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
H
H
H
H
Me
Cl
H
Me
Cl
C(O)C6H5
Me
Cl
99
20
65
30
70
62
CDCl3):
d
¼3.72 (s, 4H, CH2); 3.74 (s, 6H, OMe); 6.14 (s, 1H, CH); 6.95
(s, 1H, NH). 13C NMR (75.5 MHz, CDCl3):
d
¼32.6 (CH2); 52.1 (OMe);
104.8 (CH); 140.6 (br, Cq); 170.7 (C]O). IR (ATR, cmꢀ1):
~
n
¼ 3289ðwÞ; 3188 (w), 3131 (w), 3104 (w), 3031 (w), 2992 (w),
a
Isolated yields.
2952 (w), 2877 (w), 2794 (w), 1734 (br s), 1642 (s), 1586 (w), 1533
(m), 1463 (w), 1435 (w), 1417 (w), 1402 (w), 1369 (w), 1336 (w), 1316
(w), 1265 (w), 1198 (w), 1170 (w), 1030 (w), 1012 (w). MS (EI, 70 eV):
m/z (%)¼212 ([Mþ], 29), 180 (15), 154 (39), 153 (100), 152 (6), 121
(18), 93 (14), 84 (14). HRMS (EI, 70 eV): calcd for C9H12N2O4 ([Mþ])
212.07916, found 212.079032.
R2
R3
N
H
.
H
.
.
.
N
O
O
4.2.2. Dimethyl 2,20-(1-phenyl-1H-pyrazole-3,5-diyl)diacetate (5b).
Yield 156 mg, 90%, brown oil; 1H NMR (300.13 MHz, CDCl3):
d
¼3.66
MeO
OMe
H R1
(s, 3H, OMe); 3.69 (s, 2H, CH2); 3.73 (s, 3H, OMe); 3.75 (s, 2H, CH2);
6.40 (s, 1H, CH); 7.35e7.50 (m, 5H, Ph). 13C NMR (62.9 MHz, CDCl3):
Scheme 5. Intramolecular hydrogen bonds in 9aet.
d
¼32.1, 34.1 (CH2); 52.1, 52.3 (OMe); 107.7 (CH); 125.5, 128.3, 129.2
(CHPh); 136.3, 139.1, 145.9 (Cq); 169.6, 171.6 (C]O). IR (ATR, cmꢀ1):
spectrum (75 MHz) of 9t recorded at 298 K, all carbon atoms (ex-
cept C]O and MeO) gave doubled signals in the ratio of 1:0.6,
which coalescence at higher temperatures. Therefore, in the 13C
NMR spectrum recorded at 323 K only one set of signals was ob-
served for the carbon atoms. In the whole temperature range, the
~
n
¼ 3063ðwÞ; 2998 (w), 2952 (w), 2844 (w), 1734 (br s), 1597 (m),
1551 (m), 1502 (s), 1453 (w), 1435 (m), 1408 (w), 1387 (w), 1336 (w),
1256 (w), 1199 (w), 1161 (w), 1073 (w), 1040 (w), 1009 (w). MS (EI,
70 eV): m/z (%)¼288 ([Mþ], 64), 230 (38), 229 (100), 170 (11), 142
(4),169 (57),141 (10). HRMS (EI, 70 eV): calcd for C15H16N2O4 ([Mþ])
288.11046, found 288.110474.
signal for the NH protons at
d
¼10.63 remains nearly constant with
respect to position and intensity (for two H), which proves the
presence of the two intramolecular hydrogen bonds in all com-
pounds (Scheme 3). Therefore, the presence of two isomeric species
for 9ket, depending on the temperature, can not be explained by
tautomerism, but more likely by a change in the conformation of
the seven-membered ring system of the 1,4-diazepines.
4.2.3. Dimethyl 2,20-(1-methyl-1H-pyrazole-3,5-diyl)diacetate (5c).
Yield 66 mg, 59%, colourless oil; 1H NMR (250.13 MHz, CDCl3)
d
¼3.61 (s, 2H, CH2); 3.63 (s, 2H, CH2); 3.67 (s, 3H, Me); 3.69 (s, 3H,
Me); 3.75 (s, 3H, Me); 6.12 (s, 1H, CH). 13C NMR (62.9 MHz, CDCl3)
d
¼31.5, 34.0 (CH2); 36.3 (NMe); 51.9, 52.3 (OMe); 106.4 (CH); 135.6,
143.9 (CN); 169.2, 171.2 (C]O). IR (ATR, cmꢀ1):
¼ 3129ðwÞ; 2998
~
n
3. Conclusions
(w), 2953 (m), 2846 (w),1732 (s),1616 (w),1549 (m). MS (EI, 70 eV):
m/z¼226 (Mþ, 24), 225 (38), 193 (4), 168 (17), 167 (100), 108 (12).
Anal. Calcd for C10H14N2O4 (226.229): C, 53.09; H, 6.24; N, 12.38.
Found: C, 53.080; H, 6.153; N, 12,186.
We reported the first cyclocondensation reactions of 3,5-
dioxopimelates with 1,2-, 1,3-, and 1,4-dinucleophiles. With
regard to the dinucleophile, the reactions follow the pattern of
regioselectivity, which was earlier reported for reactions of simple
1,3-diketones. With regard to the 3,5-dioxopimelate, all cycliza-
tions regioselectively involve the two keto groups and not the (less
electrophilic) ester groups. Due to the polyfunctional character of
the 3,5-dioxopimelates and due to the regioselective character of
the cyclizations, the reactions reported herein allow for the syn-
thesis of a variety of functionalized heterocycles, which are not
readily available by other methods.
4.2.4. Dimethyl 2,20-(1-p-tolyl-1H-pyrazole-3,5-diyl)diacetate (5d).
Yield 145 mg, 99%, colourless liquid; 1H NMR (300.13 MHz, CDCl3)
d
¼2.39 (s, 3H, Me); 3.66 (s, 2H, CH2); 3.66 (s, 3H, OMe); 3.73 (s, 3H,
OMe); 3.74 (s, 2H, CH2); 6.39 (s, 1H, CH); 7.26 (m, 4H, Ar). 13C NMR
(75.5 MHz, CDCl3)
d
¼21.1 (Me); 32.1, 34.1 (CH2); 52.1, 52.4 (OMe);
107.5 (CH); 125.5, 129.8 (CHAr); 136.5, 136.5, 138.4, 145.6 (Cq); 169.6,
171.2 (C]O). IR (ATR, cmꢀ1):
¼ 3131ðwÞ; 2927 (w), 2952 (m),
~
n
2925 (w), 2846 (w), 1735 (s), 1613 (w), 1587 (w), 1549 (m), 1518 (s).

F. Bendrath et al. / Tetrahedron 68 (2012) 6456e6462
6459
MS (EI, 70 eV): m/z¼302 (Mþ, 88); 243 (100), 183 (34), 169 (23), 91
(11). HRMS (ESI-TOF, 70 eV) calcd for C16H19N2O4 (303.13393,
[MþH]þ): 303.13429.
(m), 1623 (w), 1591 (s), 1504 (w). MS (EI, 70 eV): m/z¼240
(Mþ, 100), 209 (60), 182 (64), 177 (51), 150 (40), 44 (88). HRMS (EI,
70 eV) calcd for C10H12O5N2 (240.07407, Mþ): 240.074768.
4.2.5. Dimethyl 2,20-(1,4-dimethyl-1H-pyrazole-3,5-diyl)diacetate
4.3. Synthesis of benzo-1,5-diazepines 9aet
(5e). Yield 60 mg, 50%, yellow solid, mp 63e65 ꢁC; 1H NMR
(300.13 MHz, CDCl3):
2H, CH2); 3.68 (s, 3H, OMe); 3.69 (s, 3H, OMe); 3.77 (s, 3H, Me). 13
NMR (75.5 MHz, CDCl3):
d
¼1.94 (s, 3H, Me); 3.58 (s, 2H, CH2); 3.60 (s,
To an ethanolic solution (15 mL/mmol) of dimethyl 3,5-
dioxopimelates 31a,b (1.0 equiv) are added the diamines 8aej
(1.1 equiv) at 22 ꢁC. After 4e12 h of stirring the solid, product
compound can be separated and is washed with ethanol and dried.
In case of some remaining impurities, column chromatography on
silica (heptane/ethylacetate) is performed to afford the pure
product.
C
d
¼8.0 (Me); 30.3, 32.7 (CH2); 36.5 (NMe);
52.0, 52.3 (OMe); 113.9, 132.9, 142.6 (Cq); 169.3, 171.0 (C]O). IR
(ATR, cmꢀ1):
n
¼ 3442ðwÞ; 3003 (w), 2955 (w), 2867 (w), 2753
~
(w), 1721 (s), 1650 (w), 1622 (w), 1591 (w), 1576 (w), 1502 (w),
1470 (w), 1450 (w), 1435 (w), 1427 (w), 1408 (w), 1387 (m), 1340
(w), 1327 (m), 1307 (w), 1203 (br s), 1173 (w), 1147 (m), 1027 (w).
MS (EI, 70 eV): m/z (%)¼240 ([Mþ], 59), 182 (17), 181 (100), 180
(45), 122 (15), 121 (44). HRMS (ESI-TOF/MS): calcd for C11H17N2O4
([MþH]þ) 241.11828, found 241.11841.
4.3.1. (2Z,20Z)-Dimethyl 2,20-(1H-benzo[b][1,4]diazepine-2,4(3H,5H)-
diylidene)diacetate (9a). Yield 113 mg, 65%, white solid, mp
200e202 ꢁC; 1H NMR (250.13 MHz, CDCl3):
d
¼2.96 (br s, 2H, CH2);
3.69 (s, 6H, OMe); 4.74 (s, 2H, CH); 7.06 (m, 4H, Ar); 10.37 (br s, 2H,
NH). 13C NMR (62.9 MHz, CDCl3):
4.2.6. Dimethyl 2,20-(4-methyl-1-p-tolyl-1H-pyrazole-3,5-diyl)diace-
d
¼38.9 (CH2); 50.6 (OMe); 84.3
tate (5f). Yield 142 mg, yellow oil; 1H NMR (300.13 MHz, CDCl3):
(C-3); 122.6, 124.8 (CHAr); 131.1 (C-5); 157.1 (C-4); 170.7 (C]O). IR
(ATR, cmꢀ1):
¼ 3257ðwÞ; 3201 (w), 3037 (w), 3011 (w), 2995 (w),
~
n
d
¼2.02 (s, 3H, Me); 2.38 (s, 3H, Me); 3.61 (s, 2H, CH2); 3.66 (s, 3H,
OMe); 3.71 (s, 2H, CH2); 3.71 (s, 3H, OMe); 7.25 (m, 4H, Ar). 13C NMR
(75.5 MHz, CDCl3):
2948 (w), 2912 (w), 2831 (w), 1660 (w), 1645 (w), 1608 (br s), 1582
(w), 1502 (m), 1439 (m), 1372 (w), 1317 (m), 1271 (m), 1256 (w),
1234 (w), 1211 (w), 1186 (w), 1167 (m), 1145 (m), 1128 (w), 1040 (s).
MS (EI, 70 eV): m/z (%)¼288 ([Mþ], 80), 257 (19), 256 (100), 225
(19), 224 (86), 169 (22), 168 (33), 112 (13). HRMS (EI, 70 eV): calcd
for C15H16N2O4 ([Mþ]) 288.11046, found 288.111233. Anal. Calcd for
C15H16N2O4 (288.11): C, 62.49; H, 5.59; N, 9.72. Found: C, 62.434; H,
5.884; N, 9.533.
d
¼8.1 (Me); 21.3 (Me); 30.8, 32.8 (CH2); 52.0,
52.2 (OMe); 115.1 (Cq); 125.3, 129.6 (CHAr); 133.4, 136.8, 138.0, 144.5
(Cq); 169.3, 171.0 (C]O). IR (ATR, cmꢀ1):
n
¼ 3029ðwÞ; 2996 (w),
~
2952 (w), 2923 (w), 2864 (w), 2746 (w),1734 (s),1659 (w),1651 (w),
1640 (w), 1612 (w), 1589 (w), 1574 (w), 1518 (s), 1493 (w), 1434 (m),
1414 (w),1382 (m),1333 (w),1316 (w),1295 (w),1257 (m),1196 (w),
1159 (br s), 1121 (w), 1109 (w), 1084 (w), 1040 (w), 1005 (s). MS (EI,
70 eV): m/z (%)¼316 ([Mþ], 100), 315 (44), 257 (98), 225 (15), 197
(36), 183 (34), 91 (13). HRMS (EI, 70 eV): calcd for C17H20N2O4
([Mþ]) 316.14176, found 316.141499.
4.3.2. (2Z,20Z)-Dimethyl 2,20-(7-methyl-1H-benzo[b][1,4]diazepine-2,
4(3H,5H)-diylidene)diacetate (9b). Yield 128 mg, 85%, yellow solid,
mp 185 ꢁC; 1H NMR (250.13 MHz, CDCl3):
d
¼2.30 (s, 3H, Me); 2.95
4.2.7. Dimethyl 2,20-(3-methyl-1-phenyl-1H-pyrazole-3,5-diyl)diace-
(s, 2H, CH2); 3.68 (s, 3H, OMe); 3.69 (s, 3H, OMe); 4.72 (br s, 2H,
tate (5g). Yield 125 mg, 83%, yellow liquid; 1H NMR (300.13 MHz,
CH); 6.85e6.95 (m, 3H, Ar); 10.32 (br s, 2H, NH). 13C NMR
CDCl3)
(s, 2H, CH2); 3.73 (s, 3H, OMe); 7.35e7.48 (m, 5H, Ph). 13C NMR
(75.5 MHz, CDCl3)
d
¼2.03 (s, 3H, Me); 3.64 (s, 2H, CH2); 3.67 (s, 3H, OMe); 3.73
(62.9 MHz, CDCl3):
d
¼20.6 (Me); 38.9 (CH2); 50.6, 50.6 (OMe); 83.6,
84.1 (C-3,30); 122.5, 122.9, 125.7 (CHAr); 128.6 (C-5); 130.9 (C-10);
d¼8.1 (Me); 30.8, 32.8 (CH2); 52.0, 52.2 (OMe);
134.9 (C-8); 157.2, 157.3 (C-4,40); 170.7,170.8 (C]O). IR (ATR, cmꢀ1):
~
115.4 (Cq); 125.4, 127.9, 129.1 (CHPh); 133.4, 139.3, 144.8 (Cq); 169.6,
n
¼ 3270ðwÞ; 3205 (w), 3006 (w), 2947 (w), 2914 (w), 2855 (w),
170.9 (C]O). IR (ATR, cmꢀ1):
n
¼ 3061ðwÞ; 2996 (w), 2952 (m),
1742 (w), 1660 (w), 1652 (w), 1604 (br s), 1582 (w), 1515 (m), 1493
(m), 1428 (m), 1365 (w), 1319 (m), 1271 (m), 1239 (m), 1218 (m),
1189 (w), 1168 (w), 1150 (w), 1139 (w), 1042 (s), 1014 (w). MS (EI,
70 eV): m/z (%)¼302 ([Mþ], 74), 271 (18), 270 (100), 238 (89), 183
(19), 182 (30), 119 (12). HRMS (EI, 70 eV): calcd for C16H18N2O4
([Mþ]) 302.12611, found 302.126202.
~
2923 (w), 2846 (w), 1733 (s), 1597 (m), 1502 (s). MS (GC/MS, 70 eV):
m/z¼302 (Mþ, 100), 301 (36), 243 (98), 211 (13), 183 (61), 77 (21).
HRMS (EI, 70 eV) calcd for C16H18O4N2 (302.12611, [M]þ):
302.125894.
4.2.8. Dimethyl 2,20-(2-thioxo-1,2-dihydropyrimidine-4,6-diyl)diace-
tate (7a). Yield 140 mg, 92%, yellow oil; 1H NMR (300.13 MHz,
4.3.3. (2Z,20Z)-Dimethyl 2,20-(7-chloro-1H-benzo[b][1,4]diazepine-2,
CDCl3):
d
¼3.37 (s, 4H, CH2); 3.74 (s, 6H, OMe); 5.74 (s,1H, CH); 14.80
4(3H,5H)-diylidene)diacetate (9c). Yield 121 mg, 75%, grey-white
(br s, 1H, NH). 13C NMR (62.9 MHz, CDCl3):
d
¼44.3 (CH2); 52.5
solid, mp 204 ꢁC; 1H NMR (250.13 MHz, CDCl3):
d
¼2.95 (s, 2H,
(OMe); 101.0 (CH); 167.6 (C]O); 185.8 (CS); (CN signal is not dis-
CH2); 3.69 (s, 6H, OMe); 4.76 (br s, 2H, CH); 6.94e7.05 (m, 3H, Ar);
played due to dynamical process). IR (ATR, cmꢀ1):
n
¼ 3366ðwÞ;
10.37 (br s, 2H, NH). 13C NMR (62.9 MHz, CDCl3):
d
¼38.8 (CH2); 50.7,
~
3268 (w), 3154 (w), 3091 (w), 3008 (w), 2956 (w), 2850 (w), 2682
(w), 2352 (w), 2108 (w), 1736 (br s), 1602 (br s), 1456 (w), 1436 (w),
1405 (w),1328 (w),1256 (w),1200 (w),1151 (w),1081 (w),1012 (w).
MS (EI, 70 eV): m/z (%)¼256 ([Mþ], 50), 241 (29), 240 (100), 225
(22), 224 (45), 212 (32), 198 (26), 184 (17), 171 (72), 153 (39), 143
(32), 111 (31), 69 (57). HRMS (ESI-TOF/MS): calcd for C10H11N2O4S
([MꢀH]ꢀ) 255.0445, found 255.04448.
50.7 (OMe); 84.9, 85.4 (C-3,30); 122.3, 123.6, 124.7 (CHAr); 129.7,
129.8 (C-5,8); 132.1 (C-10); 156.4,156.6 (C-4,40); 170.6,170.7 (C]O).
IR (ATR, cmꢀ1):
¼ 3269ðwÞ; 3210 (w), 3086 (w), 3056 (w), 3018
~
n
(w), 3002 (w), 2950 (w), 2904 (w), 2840 (w), 1672 (m), 1651 (w),
1620 (br s), 1615 (br s), 1579 (w), 1503 (m), 1485 (m), 1428 (s), 1359
(w), 1314 (m), 1282 (w), 1263 (w), 1239 (w), 1212 (m), 1174 (m), 1153
(m), 1133 (w), 1095 (m), 1041 (s). MS (EI, 70 eV): m/z (%)¼324 ([Mþ],
[
37Cl], 17), 322 ([Mþ], [35Cl], 56), 292 (30), 291 (18), 290 (100), 260
4.2.9. Dimethyl 2,20-(2-oxo-1,2-dihydropyrimidine-4,6-diyl)diacetate
(26), 258 (88), 202 (34), 129 (18). HRMS (EI, 70 eV): calcd for
(7b). Yield 111 mg, 93%; white solid; 1H NMR (250.13 MHz, CDCl3)
C15H15ClN2O4 ([Mþ], [35Cl]) 322.07149, found 322.071494.
d
¼3.34 (s, 4H, CH2); 3.71 (s, 6H, OMe); 5.71 (s, 1H, CH); 14.75 (br s,
1H, NH). 13C NMR (62.9 MHz, CDCl3)
d
¼44.2 (CH2); 52.4 (OMe);
4.3.4. (2Z,20Z)-Dimethyl 2,20-(7-benzoyl-1H-benzo-[b][1,4]diazepine-
100.9 (CH); 167.6 (C]O); 185.8 (NCO); (CN signal is not displayed
2,4(3H,5H)-diylidene)diacetate (9d). Yield 170 mg, 87%, orange solid,
due to dynamical process). IR (ATR, cmꢀ1):
n
¼ 3428ðmÞ; 3328 (m),
169e172 ꢁC; 1H NMR (300.13 MHz, CDCl3):
(s, 3H, OMe); 3.71 (s, 3H, OMe); 4.78 (s,1H, CH); 4.84 (s,1H, CH); 7.10
d
¼3.01 (s, 2H, CH2); 3.68
~
3251 (w), 3224 (w), 3108 (w), 2956 (w), 2849 (w), 1709 (m), 1673

6460
F. Bendrath et al. / Tetrahedron 68 (2012) 6456e6462
(d, 1H, 3J¼8.1 Hz, H-6); 7.46e7.62 (m, 5H, m-Ph, p-Ph, H-7,9);
7.74e7.77 (m, 2H, o-Ph); 10.41 (s,1H, NH); 10.55 (s,1H, NH). 13C NMR
mp 261 ꢁC; 1H NMR (300.13 MHz, CDCl3)
d
¼2.99 (s, 2H, CH2); 3.70
0
(s, 6H, OMe1,1 ); 3.90 (s, 3H, OMe); 4.77 (s, 1H, CH); 4.82 (s, 1H, CH);
3
3
4
(75.5 MHz, CDCl3):
d
¼38.9(CH2);50.7, 50.8(OMe);85.3, 86.4(C-3,30);
7.06 (d, J6,7¼8.1 Hz, 1H, H-6); 7.73 (dd, J6,7¼8.1 Hz, J7,9¼2.0 Hz,
1H, H-7); 7.76 (d, 4J7,9¼2.0 Hz, 1H, H-9); 10.45 (s, 1H, NH); 10.52 (s,
122.1, 124.7, 126.7 (CHAr); 128.4 (m-Ph); 129.8 (o-Ph); 130.6 (C-10);
132.4 (p-Ph); 133.7 (C-8); 134.8 (C-5); 137.5 (i-Ph); 156.0, 156.4 (C-
1H, NH). 13C NMR (62.9 MHz, CDCl3)
d
¼38.9 (CH2); 50.7, 50.8
4,4`); 170.6 (C]O); 194.8 (C]OPh). IR (ATR, cmꢀ1):
¼ 3248ðwÞ;
(OMe1,1 ); 52.2 (OMe); 85.2, 86.3 (C-3,3 ); 122.2, 124.2, 125.9 (CHAr);
0
0
~
n
3201 (w), 3076 (w), 3063 (w), 3030(w), 2998 (w), 2949(w), 2847 (w),
1742 (w), 1672 (w), 1650 (m), 1603 (w), 1574 (w), 1510 (w), 1495 (w),
1447 (w),1432 (m),1403 (w),1323 (m),1276 (w),1269 (w),1253 (w),
1233 (w), 1214 (m), 1189 (w), 1169 (m), 1153 (m), 1132 (w), 1075 (w),
1036 (s), 1010 (w). MS (EI, 70 eV): m/z (%)¼392 ([Mþ], 90), 361 (25),
360 (100), 328 (69), 195 (13), 105 (43). HRMS (ESI-TOF/MS): calcd for
C22H21N2O5 ([MþH]þ) 393.1445, found 393.1441.
126.3 (C-8); 130.6 (C-10); 135.0 (C-5); 156.0, 156.4 (C-4,40); 165.9
(C]OAr); 170.6, 170.6 (C]O). IR (ATR, cmꢀ1):
¼ 3407ðwÞ; 3259
~
n
(w), 3204 (w), 3086 (w), 2988 (w), 2949 (m), 2904 (w), 2845 (w),
1715 (s), 1662 (s), 1634 (m), 1613 (s), 1607 (w), 1579 (m), 1519 (m),
1511 (m), 1505 (m). MS (EI, 70 eV): m/z¼346 (Mþ, 85), 314 (100),
282 (81), 226 (20), 128 (25), 69 (28). HRMS (EI, 70 eV) calcd for
C15H15O4N729Br (366.02097, Mþ): 366.021437.
4.3.5. (2Z,20Z)-Dimethyl 2,20-(7,8-dimethyl-1H-benzo-[b][1,4]diazep-
4.3.9. (2Z,20Z)-Dimethyl 2,20-(7-cyano-1H-benzo[b][1,4]diazepine-2,
ine-2,4(3H,5H)-diylidene)diacetate (9e). Yield 134 mg, 85%, white
4(3H,5H)-diylidene)diacetate (9i). Light-brown solid, mp 209e
solid, mp 224e226 ꢁC; 1H NMR (300.13 MHz, CDCl3):
d
¼2.20 (s, 6H,
Me); 2.92 (s, 2H, CH2); 3.68 (s, 6H, OMe); 4.69 (s, 2H, CH); 6.81 (s, 2H,
Ar); 10.28 (br s, 2H, NH). 13C NMR (62.9 MHz, CDCl3):
210 ꢁC; 1H NMR (300.13 MHz, CDCl3)
d
¼2.99 (s, 2H, CH2); 3.70 (s,
3H, OMe); 3.70 (s, 3H, OMe); 4.81(s, 1H, CH); 4.85 (s, 1H, CH); 7.07
d
¼19.0 (Me);
(m, 1H), 7.30e7.34 (m, 2H), (Ar); 10.44 (s, 1H, NH); 10.55 (s, 1H, NH).
39.0 (CH2); 50.5 (OMe); 83.7 (C-3); 123.4 (C-6); 128.6 (C-5); 133.5(C-
13C NMR (75.5 MHz, CDCl3)
d
¼38.7 (CH2); 50.8, 50.9 (OMe); 86.3,
7); 157.3 (C-4); 170.8 (C]O). IR (ATR, cmꢀ1):
¼ 3268ðwÞ; 3203 (w),
87.2 (C-3,30); 107.6 (C-8); 118.0 (CN); 122.9, 126.2, 128.0 (CHAr);
~
n
2998 (w), 2951 (w), 2918 (w), 2863 (w), 1660 (s), 1621 (w), 1604 (s),
1581 (w),1515 (w),1500 (w),1449 (w),1430 (w),1375 (w),1328 (w),
1315 (w), 1286 (w), 1237 (s), 1237 (s), 1203 (w), 1187 (w), 1168 (w),
1150 (s), 1115 (m), 1036 (s), 1010 (w). MS (EI, 70 eV): m/z (%)¼316
([Mþ], 73), 285 (20), 284 (100), 253 (19), 252 (93), 237 (11),197 (21),
196 (34). HRMS (EI, 70 eV): calcd for C17H20N2O4 ([Mþ]) 316.14176,
found 316.142317. Anal. Calcd for C17H20N2O4 (316.35): C, 64.54; H,
6.37; N, 8.86. Found: C, 63.995; H, 6.279; N, 8.758.
131.3 (C-10); 135.0 (C-5); 155.3, 155.7 (C-4,40); 170.5 (C]O).IR (ATR,
cmꢀ1):
n
¼ 3260ðsÞ; 3204 (w), 3018 (w), 2951 (w), 2922 (w), 2851
~
(w), 2226 (m), 1738 (w), 1659 (m), 1614 (s), 1574 (s), 1514 (m). MS
(EI, 70 eV): m/z¼313 (Mþ, 57), 281 (100), 249 (89), 194 (27), 193
(50), 67 (6). HRMS (EI, 70 eV) calcd for C16H15O4N3 (313.10571, Mþ):
313.105712.
4.3.10. (2Z,20Z)-Dimethyl 2,20-(1H-naphtho[2,3-b][1,4]diazepine-2,4
(3H,5H)-diylidene)diacetate (9j). White solid, mp 245 ꢁC; 1H NMR
4.3.6. (2Z,20Z)-Dimethyl 2,20-(7,8-dichloro-1H-benzo[b][1,4]diazepi-
ne-2,4(3H,5H)-diylidene)diacetate (9f). Yield 158 mg, 89%, white
(300.13 MHz, CDCl3)
2H, CH); 7.40 (m, 2H), 7.49 (s, 2H), 7.70 (m, 2H), (Ar); 10.58 (s, 2H,
NH). 13C NMR (75.5 MHz, CDCl3)
d¼3.04 (s, 2H, CH2); 3.72 (s, 6H, OMe); 4.80 (s,
solid, mp 236e238 ꢁC; 1H NMR (300.13 MHz, CDCl3):
d
¼2.95 (s, 2H,
CH2); 3.69 (s, 6H, OMe); 4.78 (s, 2H, CH); 7.13 (s, 2H, Ar); 10.36 (s,
2H, NH). 13C NMR (62.9 MHz, CDCl3):
d
¼38.7 (CH2); 50.7 (OMe); 85.2 (C-
3); 119.3, 125.6, 126.7 (CHAr); 130.9, 131.0 (CAr); 157.1 (C-4); 170.6
(C]O). IR (ATR, cmꢀ1):
¼ 3274ðmÞ; 3205 (w), 3047 (w), 3013 (w),
~
n
d
¼38.7 (CH2); 50.8 (OMe);
85.9 (C-3); 123.6 (C-6); 127.8 (C-7); 130.7 (C-5); 156.0 (C-4); 170.6
2950 (m), 2836 (w), 1660 (m), 1653 (w), 1606 (s), 1518 (m). HRMS
(ESI-TOF, 70 eV) calcd for C19H19N2O2 (339.13393, [MþH]þ):
339.13346.
(C]O). IR (ATR, cmꢀ1):
¼ 3253ðwÞ; 3197 (w), 3115 (w), 3031 (w),
~
n
3001 (w), 2952 (w), 2907 (w), 2839 (w), 1661 (s), 1629 (w), 1608 (br
s), 1570 (w), 1502 (m), 1472 (w), 1430 (m), 1309 (m), 1283 (m), 1243
(m), 1217 (m), 1185 (w), 1168 (m), 1149 (w), 1140 (w), 1037 (s). MS
(EI, 70 eV): m/z (%)¼360 ([Mþ], [37Cl] [37Cl], 6), 358 ([Mþ], [37Cl]
4.3.11. (2Z,20Z)-Dimethyl 2,20-(7-bromo-3-methyl-1H-benzo[b][1,4]di-
azepine-2,4(3H,5H)-diylidene)diacetate (9k). Yield 157 mg, 87%, yel-
low solid, mp 195e198 ꢁC; 1H NMR (300.13 MHz, CDCl3):
[
35Cl], 36), 356 ([Mþ], [35Cl] [35Cl], 57), 326 (62), 324 (100), 294 (48),
292 (74), 236 (33), 69 (34). HRMS (EI, 70 eV): calcd for
C15H14Cl2N2O4 ([Mþ], [35Cl] [35Cl]) 256.03251, found 256.031827.
Anal. Calcd for C15H14Cl2N2O4 (357.19): C, 50.44; H, 3.95; N, 7.84.
Found: C, 49.985; H, 4.112; N, 7.986.
d
¼1.18e1.33 (br m, 3H, CHMe); 2.96 (br), 3.16 (br), (ratio 0.6:1, 1H,
CHMe); 3.69 (s, 3H, OMe); 3.70 (s, 3H, OMe); 4.74 (s, 1H, CH); 4.75 (s,
1H, CH); 6.90 (br d, 1H), 7.10e7.23 (br m, 2H), (Ar); 10.62 (s, 2H, NH).
13C NMR (75.5 MHz, CDCl3):
d¼12.6, 15.0 (CHMe); 36.4, 46.9 (CHMe);
50.7, 50.8 (OMe); 81.7, 82.3, 85.1, 85.5 (C-3,30); 116.2, 117.0 (C-8);
122.7, 123.7, 124.0, 125.1, 126.9, 127.7 (CHAr); 129.9,130.1 (C-5); 132.0,
132.3 (C-10); 159.5, 160.6 (C-4,40); 171.0, 171.1 (C]O). IR (ATR,
~
4.3.7. (2Z,20Z)-Dimethyl 2,20-(7-bromo-1H-benzo-[b][1,4]diazepine-2,
4(3H,5H)-diylidene)diacetate (9g). White solid, mp 221e222 ꢁC; 1H
NMR (300.13 MHz, CDCl3)
d
¼2.95 (s, 2H, CH2); 3.69 (s, 3H, OMe); 3.69
cmꢀ1):
n
¼ 3247ðwÞ; 3188 (w), 3120 (w), 3014 (w), 2986 (w), 2948
(s, 3H, OMe); 4.76 (br s, 2H, CH); 6.89 (d, 3J6,7¼8.4 Hz, 1H, H-6); 7.17
(dd, 3J6,7¼8.4 Hz, 4J7,9¼2.1 Hz,1H, H-7); 7.20 (d, 4J7,9¼2.1 Hz,1H, H-9);
(w), 2885 (w), 2841 (w), 1661 (s), 1624 (w), 1599 (br s), 1575 (w),
1503 (w), 1482 (w), 1451 (w), 1432 (m), 1377 (m), 1320 (w), 1273 (s),
1258 (w), 1214 (s), 1187 (w), 1162 (s), 1131 (w), 1083 (w), 1060 (w),
1015 (s). MS (EI, 70 eV): m/z (%)¼382 ([Mþ], [81Br]), 380 ([Mþ], [79Br],
34), 350 (43), 348 (43), 318 (24), 316 (25), 262 (17), 231 (100), 69
(22), 57 (50). HRMS (ESI-TOF/MS): calcd for C16H17BrN2NaO4
([MþNa]þ, [79Br]) 403.02639, found 403.02656. Anal. Calcd for
C16H17BrN2O4 (381.22): C, 50.41; H, 4.49; N, 7.35. Found: C, 49.982;
H, 4.824; N, 7.169.
10.36 (br s, 2H, NH). 13C NMR (75.5 MHz, CDCl3)
d¼38.7 (CH2); 50.7,
50.7 (OMe); 85.0, 85.5 (C-3,30); 117.0 (C-8); 123.8,125.2,127.6 (CHAr);
130.3 (C-5); 132.3 (C-10); 156.4,156.5 (C-4,40); 170.6,170.7 (C]O). IR
(ATR, cmꢀ1):
¼ 3260ðwÞ; 3203 (w), 3089 (w), 2999 (w), 2947 (m),
~
n
2842(w),1672 (m),1650 (m),1614 (s),1594 (w),1579(w),1504 (s). MS
(EI, 70 eV): m/z¼368 (Mþ, 81Br, 58), 366 (Mþ, 79Br, 58), 336 (81Br,100),
334 (79Br, 99), 304 (81Br, 71), 302 (79Br, 71), 248 (81Br, 31), 246 (79Br,
30), 168 (20). HRMS (EI, 70 eV) calcd for C15H15O4N729Br (366.02097,
Mþ): 366.021437; calcd for C15H15O4N821Br (368.01892, Mþ):
368.019265. Anal. Calcd for C15H15BrN2O4 (367.195): C, 49.06; H, 4.12;
N, 7.63. Found: C, 48.575; H, 4.189; N, 7.74.
4.3.12. (2Z,20Z)-Dimethyl 2,20-(3-methyl-7-methoxycarbonyl-1H-ben-
zo[b][1,4]diazepine-2,4-(3H,5H)-diylidene)diacetate (9l). Yield 107
mg, 59%, yellow solid, mp 208e209 ꢁC; 1H NMR (300.13 MHz,
CDCl3):
d
¼1.17e1.33 (br m, 3H, CHMe); 2.99 (br), 3.31 (br), (ratio
4.3.8. (2Z,20Z)-Dimethyl 2,20-(7-(methoxycarbonyl)-1H-benzo[b][1,4]
diazepine-2,4(3H,5H)-diylidene)diacetate (9h). Light-brown solid,
0.6:1, 1H, CHMe); 3.70 (s, 6H, OMe1,1 ); 3.89 (s, 3H, OMe); 4.75 (s,1H,
CH); 4.80 (s, 1H, CH); 7.07 (br, 1H), 7.68e7.77 (br, 2H), (Ar); 10.70
0

F. Bendrath et al. / Tetrahedron 68 (2012) 6456e6462
6461
(s, 1H, NH); 10.76 (s, 1H, NH). 13C NMR (75.5 MHz, CDCl3):
d
¼12.7,
HRMS (EI, 70 eV) calcd for
302.125515. Anal. Calcd for C16H18N2O4 (302.325): C, 63.57; H,
6.00. Found: C, 63.28; H, 6.16.
C
16H18O4N2 (302.12611, [M]þ):
0
15.2 (CHMe); 36.5, 46.9 (CHMe); 50.7, 50.8 (OMe1,1 ); 52.1 (OMe);
81.8, 83.2, 85.1, 86.4 (C-3,30); 121.2, 122.0, 123.2, 124.1, 125.5, 126.0
(CHAr); 125.6, 126.2 (C-8); 130.2, 130.5 (C-10); 134.5, 134.8 (C-5);
159.0, 159.5, 160.1, 160.6 (C-4,40); 166.0 (C]OAr); 171.0, 171.0 (C]O).
~
4.3.16. (2Z,20Z)-Dimethyl 2,20-(3,7-dimethyl-1H-benzo-[b][1,4]diaze-
IR (ATR, cmꢀ1):
n
¼ 3242ðwÞ; 3186 (w), 3120 (w), 3072 (w), 2992
pine-2,4(3H,5H)-diylidene)diacetate (9p). White solid, mp 178 ꢁC;
(w), 2948 (w), 2842 (w), 1720 (s), 1660 (m), 1625 (w), 1599 (br s),
1579 (w), 1514 (w), 1490 (w), 1455 (w), 1433 (s), 1393 (m), 1340 (m),
1276 (s), 1249 (w), 1209 (s), 1187 (w), 1161 (m), 1104 (w), 1062 (w),
1016 (w). MS (EI, 70 eV): m/z (%)¼360 ([Mþ], 100), 329 (27), 228
(97), 301 (15), 296 (51), 269 (24), 241 (30), 240 (30), 148 (11). HRMS
(ESI-TOF/MS): calcd for C18H20N2NaO6 ([MþNa]þ) 383.12136, found
383.12204. Anal. Calcd for C18H20N2O6 (360.36): C, 59.99; H, 5.59; N,
7.77. Found: C, 59.772; H, 5.998; N, 7.401.
1H NMR (300.13 MHz, CDCl3)
3H, Me); 2.94 (br q, J¼6.6 Hz), 3.18 (br q, J¼6.6 Hz) (ratio 0.6:1, 1H,
CHMe); 3.68 (s, 3H, OMe); 3.69 (s, 3H, OMe); 4.69 (s, 1H), 4.70 (s,
1H), (CH); 6.81e6.96 (m, 3H, Ar); 10.58 (br s, 2H, NH). 13C NMR
d
¼1.17e1.31 (br m, 3H, CHMe); 2.30 (s,
(75.5 MHz, CDCl3)
d
¼12.6, 14.7 (CHMe); 20.6, 20.6 (Me); 36.5, 47.1
(CHMe); 50.6, 50.6 (OMe); 80.4, 80.9, 83.8, 84.3 (C-3,30); 121.4,
121.9, 122.4, 122.8, 125.0, 125.7 (CHAr); 128.2, 128.5 (C-10); 130.4,
130.8 (C-5); 134.1, 132.9 (C-8); 160.1, 161.2 (C-4,40); 171.1 (C]O). IR
~
(ATR, cmꢀ1):
n
¼ 3248ðmÞ; 3192 (m), 3017 (w), 2986 (w), 2946 (m),
4.3.13. (2Z,20Z)-Dimethyl 2,20-(7-cyano-3-methyl-1H-benzo[b][1,4]di-
azepine-2,4(3H,5H)-diylidene)diacetate (9m). Yield 106 mg, 65%,
white solid, mp 197e199 ꢁC; 1H NMR (300.13 MHz, CDCl3):
2917 (w), 2838 (w), 1660 (s), 1626 (m), 1596 (s), 1582 (w), 1515 (m).
MS (EI, 70 eV): m/z¼316 (Mþ, 100), 284 (98), 252 (79), 225 (42), 196
(45), 126 (14). HRMS (EI, 70 eV) calcd for C17H20O4N2 (316.14176,
[M]þ): 316.141626.
d
¼1.20e1.33 (br m, 3H, CHMe); 3.08 (br, 1H, CHMe); 3.70 (s, 3H,
OMe); 3.70 (s, 3H, OMe); 4.79 (s, 1H, CH); 4.84 (s, 1H, CH); 7.06
(br d, 1H), 7.30 (br s, 2H), (Ar); 10.70 (s, 1H, NH); 10.80 (s, 1H,
4.3.17. (2Z,20Z)-Dimethyl 2,20-(7-chloro-3-methyl-1H-benzo[b][1,4]di-
NH). 13C NMR (75.5 MHz, CDCl3):
d
¼12.7, 15.3 (CHMe); 36.4, 46.9
azepine-2,4(3H,5H)-diylidene)diacetate (9q). White solid, mp
(CHMe); 50.9, 50.9 (OMe); 83.1, 84.2, 86.2, 87.2 (C-3,30); 107.3 (C-
8); 118.1 (CN); 121.9, 122.7, 125.2, 126.1, 127.5, 128.5 (CHAr); 131.5
(C-10); 134.8 (C-5); 158.6, 159.6 (C-4,40); 170.9 (C]O). IR (ATR,
~
195e196 ꢁC; 1H NMR (300.13 MHz, CDCl3)
d¼1.18e1.31 (br m, 3H,
CHMe); 2.96 (br), 3.15 (br), (ratio 0.6:1, 1H, CHMe); 3.69 (s, 3H,
OMe); 3.69 (s, 3H, OMe); 4.73 (s, 1H), 4.75 (s, 1H), (CH); 6.92e7.07
cmꢀ1):
n
¼ 3246ðwÞ; 3190 (w), 3120 (w), 3082 (w), 3013 (w),
(m, 3H, Ar); 10.62 (br s, 2H, NH). 13C NMR (75.5 MHz, CDCl3)
d¼12.6,
2983 (w), 2955 (w), 2923 (w), 2850 (w), 2232 (w), 2223 (m), 1745
(br m), 1680 (w), 1657 (br m), 1623 (w), 1596 (br s), 1570 (w), 1513
(w), 1496 (w), 1485 (w), 1448 (w), 1433 (w), 1428 (w), 1388 (w),
1376 (w), 1330 (w), 1273 (br s), 1219 (br s), 1184 (w), 1171 (w),
1157 (w), 1142 (w), 1116 (w), 1063 (w), 1013 (br, s). MS (EI, 70 eV):
m/z (%)¼327 (Mþ, 83), 295 (100), 268 (13), 264 (17), 263 (63), 236
(29), 208 (37), 207 (42), 84 (47). HRMS (EI, 70 eV): calcd for
C17H17N2O4 ([Mþ]) 327.12136, found 327.121290. Anal. Calcd for
C17H17N3O4 (327.33): C, 62.38; H, 5.23; N, 12.84. Found: C, 62.228;
H, 6.060.
14.9 (CHMe); 36.4, 46.8 (CHMe); 50.7, 50.7 (OMe); 81.7, 82.2, 84.9,
85.5 (C-3,30); 121.1, 122.2, 122.4, 123.5, 124.0, 124.5 (CHAr); 128.9,
129.4, 129.6 (C-5,8); 131.6, 132.0 (C-10); 159.5, 160.5, 160.7 (C-4,40);
~
170.9, 171.0 (C]O). IR (ATR, cmꢀ1):
n
¼ 3246ðwÞ; 3191 (w), 3119
(w), 3015 (w), 2983 (w), 2949 (m), 2842 (w),1661 (s),1622 (w),1598
(s), 1576 (w), 1501 (m). MS (EI, 70 eV): m/z¼338 (Mþ, 37Cl, 31), 336
(Mþ, 35Cl, 93), 306 (37Cl, 35), 304 (35Cl, 100), 274 (22), 272 (76), 245
(23), 216 (39), 136 (14). HRMS (EI, 70 eV) calcd for C16H17O4N325Cl
(336.08714, [M]þ): 336.087080; calcd for C16H17O4N327Cl (338.08419,
[M]þ): 333.084983. Anal. Calcd for C16H17ClN2O4 (336.770): C, 57.06;
H, 5.09; N, 8.32. Found: C, 57.122; H, 5.331; N, 8.050.
4.3.14. (2Z,20Z)-Dimethyl 2,20-(3-methyl-1H-naphtho[2,3-b][1,4]dia-
zepine-2,4(3H,5H)-diylidene)diacetate (9n). Yield 90 mg, 51%, yel-
low solid, mp 227e228 ꢁC; 1H NMR (300.13 MHz, CDCl3):
4.3.18. (2Z,20Z)-Dimethyl 2,20-(7-benzoyl-3-methyl-1H-benzo[b][1,4]
diazepine-2,4(3H,5H)-diylidene)diacetate (9r). Brown solid, mp
d
¼1.19e1.35 (br m, 3H, CHMe); 3.01 (br), 3.33 (br), (ratio 0.6:1, 1H,
187 ꢁC; 1H NMR (300.13 MHz, CDCl3)
d¼1.22e1.35 (br m, 3H,
CHMe); 3.72 (s, 6H, OMe); 4.79 (s, 2H, CH); 7.39 (br, 2H), 7.47 (br,
CHMe); 3.01 (br s), 3.22 (br s), (ratio 0.6:1, 1H, CHMe); 3.70 (s, 3H,
OMe); 3.71 (s, 3H, OMe); 4.76 (s, 1H), 4.83 (s, 1H), (CH); 7.10 (br, 1H,
H-6); 7.46e7.62 (m, 5H, H-7,9, m-Ph, p-Ph); 7.75e7.79 (m, 2H, o-
Ph); 10.68 (s, 1H, NH); 10.81 (s, 1H, NH). 13C NMR (75.5 MHz, CDCl3)
2H), 7.70 (br, 2H), (Ar); 10.84 (s, 2H, NH). 13C NMR (75.5 MHz,
CDCl3):
d
¼12.7, 15.4 (CHMe); 36.1, 46.9 (CHMe); 50.7 (OMe); 81.8,
85.2 (C-3); 117.9, 119.3 (C-6); 125.7, 126.6 (br), (CHAr); 130.5 (br, C-
5); 131.0 (CAr); 160.1, 161.3 (C-4); 171.0 (C]O). IR (ATR, cmꢀ1):
n
¼
d
¼12.7, 15.2 (CHMe); 36.5, 47.0 (CHMe); 50.7, 50.8 (OMe); 82.0,
~
3255ðwÞ; 3189 (w), 3120 (w), 3050 (w), 3019 (w), 2987 (w), 2948
(w), 2833 (w), 1662 (br s), 1605 (m), 1591 (w), 1537 (w), 1518 (w),
1490 (m), 1468 (w), 1436 (w), 1422 (w), 1380 (s), 1315 (w), 1291 (s),
1248 (w), 1233 (w), 1188 (m), 1158 (s), 1120 (w), 1091 (w), 1063 (w),
1016 (br s). MS (EI, 70 eV): m/z (%)¼352 ([Mþ], 100), 321 (21), 320
(89), 288 (51), 261 (22), 232 (37), 219 (17), 208 (11), 180 (10), 78
(30), 63 (35). HRMS (EI, 70 eV): calcd for C20H20N2O4 ([Mþ])
352.14176, found 352.141511.
83.3, 85.3, 86.6 (C-3,30); 121.0, 122.0, 123.6, 124.7, 126.2, 126.8
(CHAr); 128.4, 129.7 (o-Ph, m-Ph); 130.1, 130.4 (C-10); 132.3 (p-Ph);
133.0, 133.7 (C-8); 134.4, 134.7 (C-5); 137.5 (i-Ph); 159.0, 159.3,
160.1, 160.5 (C-4,40); 171.0 (C]O); 194.8 (C]OPh). IR (ATR, cmꢀ1):
~
n
¼ 3247ðwÞ; 3191 (w), 3119 (w), 2991 (w), 2948 (w), 2844 (w),
1652 (s), 1622 (m), 1593 (s), 1572 (w), 1514 (w). MS (EI, 70 eV): m/
z¼406 (Mþ, 100), 374 (88), 242 (45), 287 (17), 105 (59), 77 (17).
HRMS (EI, 70 eV) calcd for C23H22O5N2 (406.15232, [M]þ):
406.152380.
4.3.15. (2Z,20Z)-Dimethyl 2,20-(3-methyl-1H-benzo[b][1,4]diazepine-
2,4(3H,5H)-diylidene)diacetate (9o). Brown solid, mp 156e158 ꢁC;
4.3.19. (2Z,20Z)-Dimethyl 2,20-(3,7,8-trimethyl-1H-benzo-[b][1,4]dia-
1H NMR (300.13 MHz, CDCl3)
d
¼1.16e1.32 (br, 3H, CHMe); 2.96
zepine-2,4(3H,5H)-diylidene)diacetate (9s). White solid, mp 224 ꢁC;
(br), 3.19 (br), (1H, CHMe); 3.69 (s, 6H, OMe); 4.72 (s, 2H, CH);
1H NMR (300.13 MHz, CDCl3)
d
¼1.17e1.31 (br m, 3H, CHMe); 2.21 (s,
6.99e7.09 (br m, 4H, Ar); 10.62 (s, 2H, NH). 13C NMR (75.5 MHz,
6H, Me); 2.95 (br), 3.18 (br), (ratio 0.6:1, 1H, CHMe); 3.69 (s, 6H,
CDCl3)
d
¼12.6, 14.8 (CHMe); 36.4, 47.0 (CHMe); 50.6 (OMe); 81.0,
OMe); 4.68 (s, 2H, CH); 6.83 (br, 2H, Ar); 10.58 (br s, 2H, NH). 13C
84.4 (C-3); 116.8, 120.3, 122.5, 124.8 (CHAr); 130.6, 131.0 (CAr);
NMR (75.5 MHz, CDCl3)
(CHMe); 50.5 (OMe); 80.3, 83.7 (C-3); 122.4, 123.3 (CHAr); 128.1,
d
¼12.6, 14.6 (CHMe); 19.0 (Me); 36.5, 47.0
160.0, 161.2 (C-4); 171.1 (C]O). IR (ATR, cmꢀ1):
n
¼ 3383ðwÞ; 3361
~
(w), 3248 (m), 3192 (m), 2983 (w), 2947 (m), 2834 (w), 1738 (w),
1659 (s), 1618 (w), 1591 (s), 1581 (s), 1501 (s). MS (EI, 70 eV): m/
z¼302 (Mþ, 94), 270 (100), 238 (58), 211 (40), 183 (43), 182 (45).
128.6 (C-5); 132.8, 133.6 (C-7); 160.2, 161.3 (C-4); 171.2 (C]O). IR
(ATR, cmꢀ1):
n
¼ 3245ðmÞ; 3187 (m), 3015 (w), 2986 (w), 2949 (m),
~
2916 (w), 2882 (w), 2859 (w), 1659 (s), 1622 (m), 1597 (s), 1591 (w),

6462
F. Bendrath et al. / Tetrahedron 68 (2012) 6456e6462
1514 (m). MS (EI, 70 eV): m/z¼330 (Mþ, 93), 298 (100), 266 (66),
251 (10), 239 (27), 210 (36). HRMS (ESI, 70 eV) calcd for C18H23O4N2
(331.16523, [MþH]þ): 331.16529. Anal. Calcd for C18H22N2O4
(330.378): C, 65.44; H, 6.71; N, 8.48. Found: C, 65.483; H, 6.922; N,
8.493.
4. Reviews of dianions: (a) Kaiser, E. M.; Petty, J. D.; Knutson, P. L. A. Synthesis
1977, 509; (b) Thompson, C. M.; Green, D. Tetrahedron 1991, 47, 4223; (c)
Thompson, C. M. Dianion Chemistry in Organic Synthesis; CRC: Boca Raton, FL,
1994; (d) Langer, P.; Freiberg, W. Chem. Rev. 2004, 104, 4125.
5. (a) Rahn, T.; Nguyen, V. T. H.; Dang, T. H. T.; Ahmed, Z.; Lalk, M.; Fischer, C.;
Spannenberg, A.; Langer, P. J. Org. Chem. 2007, 72, 1957; (b) Rahn, T.; Dang, T. H.
T.; Spannenberg, A.; Fischer, C.; Langer, P. Org. Biomol. Chem. 2008, 6, 3366; (c)
€
Rahn, T.; Appel, B.; Baumann, W.; Jiao, H.; Fischer, C.; Borner, A.; Langer, P. Org.
4.3.20. (2Z,20Z)-Dimethyl 2,20-(7,8-dichloro-3-methyl-1H-benzo[b][1,
Biomol. Chem. 2009, 7, 1931.
6. (a) Vicentini, C. B.; Manfrini, M.; Mozzanti, M.; Manferdine, M.; Morelli, C. F.;
4]diazepine-2,4(3H,5H)-diylidene)diacetate (9t). Brown solid, mp
€
Veronese, C. Heterocycles 2000, 53, 1285; See also: (b) Friedmann, H.; Hansel,
228e229 ꢁC; 1H NMR (300.13 MHz, CDCl3)
d
¼1.18e1.35 (br, 3H,
W. Arch. Pharm. (Weinheim) 1983, 316, 726.
CHMe); 2.97 (br), 3.15 (br), (1H, CHMe); 3.70 (s, 6H, OMe); 4.76 (s,
7. (a) Furuhashi, A.; Aoki, K.; Sugimoto, M. Bull. Chem. Soc. Jpn. 1979, 52, 2157; (b)
Yachevskii, D. S.; Chizhov, D. L.; Kodess, M. I.; Pashkevich, K. I. Monatsh. Chem.
2004, 135, 23.
2H, CH); 7.13 (s, 2H, Ar); 10.63 (s, 2H, NH). 13C NMR (75.5 MHz,
CDCl3)
d
¼12.5, 15.2 (CHMe); 36.4, 46.7 (CHMe); 50.8 (OMe); 82.7,
8. Yamaguchi, M.; Shibato, K. Tetrahedron 1988, 44, 4767.
86.0 (C-3); 122.5, 123.5 (CHAr); 127.0, 127.8 (C-7); 130.4, 130.6 (C-5);
9. (a) Barrett, A. G. M.; Carr, R. A. E.; Finch, M. A. W.; Florent, J.-C.; Richardson, G.;
Walshe, N. D. A. J. Org. Chem. 1986, 51, 4254; (b) Barrett, A. G. M.; Morris, T. M.;
Barton, D. H. R. J. Chem. Soc., Perkin Trans. 1 1980, 2272; for 5-aryl-3,5-dioxo-
pentanoates, see for example: (c) Narasimhan, N. S.; Ammanamanchi, R. K. J.
Org. Chem. 1983, 48, 3945; (d) Douglas, C. J.; Sklenicka, H. M.; Shen, H. C.;
159.1, 160.2 (C-4); 171.0 (C]O). IR (ATR, cmꢀ1):
¼ 3246ðwÞ; 3189
~
n
(w), 3116 (w), 2991 (w), 2949 (m), 2837 (w),1660 (s),1621 (w),1598
(s), 1569 (m), 1503 (m). MS (EI, 70 eV): m/z¼374 (Mþ, 37Cl37Cl, 9),
372 (Mþ, 35Cl37Cl, 50), 370 (Mþ, 35Cl35Cl, 79), 342 (37Cl37Cl, 12), 340
€
Mathias, D. S.; Degen, S. J.; Golding, G. M.; Morgan, C. D.; Shih, R. A.; Muller, K.
L.; Seurer, L. M.; Johnson, E. W.; Hsung, R. P. Tetrahedron 1999, 55, 13683.
(
35Cl37Cl, 66), 338 (35Cl35Cl, 100), 310 (37Cl37Cl, 10), 308 (35Cl37Cl,
10. Poly(b-oxo)carboxylic acids (polyketides) occur in a variety of natural products
44), 306 (35Cl35Cl, 66), 250 (37), 231 (25). HRMS (ESI, 70 eV) calcd
and are of great pharmacological relevance: (a) Staunton, J.; Weissman, K. J. Nat.
35
Cl2O4N2 (371.05599, Mþ): 371.05652; calcd for
Prod. Rep. 2001, 18, 380; (b) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. Rev.
for C16
H
16
€
C16
H
Cl2O4N2 (373.05335, Mþ): 373.05362. Anal. Calcd for
37
2005, 34, 677; (c) Rompp-Lexikon Naturstoffe; Fugmann, B., Ed.; Georg Thieme:
16
Stuttgart, New York, NY, 1997.
C16H16Cl2N2O4 (371.215): C, 51.77; H, 4.34; N, 7.55. Found: C, 51.588;
H, 4.525; N, 7.527.
11. For a review, see: (a) Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33, 2159; see
also: (b) Murray, T. P.; Harris, T. M. J. Am. Chem. Soc. 1972, 94, 8253; (c) Harris, C.
M.; Roberson, J. S.; Harris, T. M. J. Am. Chem. Soc. 1976, 98, 5380; (d) Harris, T. M.;
Hay, J. V. J. Am. Chem. Soc. 1977, 99, 1631; (e) Hubbard, J. S.; Harris, T. M. Tet-
rahedron Lett. 1978, 47, 4601; (f) Sandifer, R. M.; Bhattacharya, A. K.; Harris, T. M.
J. Org. Chem. 1981, 46, 2260; (g) Gilbreath, S. G.; Harris, C. M.; Harris, T. M. J. Am.
Chem. Soc. 1988, 110, 6172; (h) Harris, T. M.; Boatman, S.; Hauser, C. R. J. Am.
Chem. Soc. 1965, 87, 3186.
Acknowledgements
Financial support from the State of Mecklenburg-Vorpommern
is gratefully acknowledged.
12. Kiegiel, J.; Jozwik, J.; Wozniak, K.; Jurczak, J. Tetrahedron Lett. 2000, 41, 4959.
13. (a) Reim, S.; Michalik, D.; Weisz, K.; Xiao, Z.; Langer, P. Org. Biomol. Chem. 2008,
6, 3079; (b) Erfle, S.; Reim, S.; Michalik, D.; Jiao, H.; Langer, P. Eur. J. Org. Chem.
2011, 4367; (c) Erfle, S.; Rahn, T.; Bendrath, F.; Baumann, W.; Michalik, D.; Jiao,
Supplementary data
€
H.; Spannenberg, A.; Borner, A.; Langer, P. Tetrahedron 2011, 67, 8780.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi:10.1016/j.tet.2012.05.119.
14. (a) Bestic, M.; Blackford, M.; Reed, M. J. Clin. Pharmacol. 2009, 49, 130; (b)
Martens, F. Pharmakotherapie; Springer: Hamburg, 2010; p 507.
15. (a) Ebert, T. A.; Taylor, R. A.; Downer, R. A.; Hall, F. R. Pestic. Sci. 1999, 55, 793; (b)
Krieger, R. I. Handbook of Pesticide Toxicology: Principles, 2. Aufl.; Academic: San
Diego, CA, 2001; 344ff.
References and notes
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1. For recent applications, see: (a) Anandarajagopal, K.; Anbu Jeba Sunilson, J.;
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ima, Y.; Nagpal, Y.; Kumar, R.; Weigand, W.; Mehta, K. S. Phosphorus, Sulfur, and
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21, 3478.