Enantioconservative synthesis of polysubstituted pyrimido[4,5- b ]azepines

Article abstract of DOI:10.1055/s-0029-1218758

A three-step enantioconservative protocol was developed for the synthesis of polysubstituted pyrimido[4,5-b]azepines. First, 1,3-dimethyl-6-[N-(2- alkoxycarbonylalkyl)amino]uracils were synthesized by nucleophilic substitution of 6-chloro-1,3-dimethyluracil with amino acids. Subsequent acylation of the uracils by a mixture of acetic anhydride and cyanoacetic acid gave the corresponding 5-cyanoacetylated pyrimidines. In the final step, the pyrimidines were subjected to Dieckmann cyclization with a sodium alcoholate in the corresponding alcohol to afford the corresponding pyrimido[4,5-b]azepines. By using uracils of N-monosubstituted amino acids, cyclization was combined with ring opening of the pyrimidine ring system to afford polysubstituted azepines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218758

PAPER
2017
Enantioconservative Synthesis of Polysubstituted Pyrimido[4,5-b]azepines
Polysubstituted
P
r
yrimido
i
b
]a
t
zepine
t
s
a Gerig, Ulrich Girreser, Martin Schütt, Dieter Heber*
Christian Albrechts University of Kiel, 24118 Kiel, Germany
E-mail: dheber@pharmazie.uni-kiel.de
Received 3 January 2010; revised 15 March 2010
proach to the synthesis of pyrimido[4,5-b]azepines 5a–f
(Scheme 1).
Abstract: A three-step enantioconservative protocol was devel-
oped for the synthesis of polysubstituted pyrimido[4,5-b]azepines.
First,
1,3-dimethyl-6-[N-(2-alkoxycarbonylalkyl)amino]uracils
R2
were synthesized by nucleophilic substitution of 6-chloro-1,3-di-
methyluracil with amino acids. Subsequent acylation of the uracils
by a mixture of acetic anhydride and cyanoacetic acid gave the cor-
responding 5-cyanoacetylated pyrimidines. In the final step, the py-
rimidines were subjected to Dieckmann cyclization with a sodium
alcoholate in the corresponding alcohol to afford the corresponding
pyrimido[4,5-b]azepines. By using uracils of N-monosubstituted
amino acids, cyclization was combined with ring opening of the py-
rimidine ring system to afford polysubstituted azepines.
O
N
O
COOR3
HR1N
Me
O
Me
O
N
R2
2
NCCH2COOH
(MeCO)2O
N
DMF, reflux
COOR3
N
Cl
N
10 min, 100 °C
Me
3
Me
1
R1
O
43–83%
HO
O
O
N
CN
O
Me
O
CN
Me
Key words: ring closure, heterocycles, stereoselective synthesis,
pyrimidoazepines, nucleophilic substitutions
N
N
NaOR in ROH
r.t. or reflux
R1
N
O
N
N
R2
Me
Me
R1
COOR3
R2
Adenosine receptors (ARs) have emerged as important
targets for the synthesis of mono- and bicyclic annulated
pyrimidines.1 Important physiological processes are mod-
ulated by adenosine, especially when it acts at AR sub-
types A1 and A2A, which are ‘high-affinity subtypes’ that
are activated at low-nanomolar concentrations.2 Selective
antagonists of the AR subtype A1 have been proposed for
use as kidney-protective diuretics, in the treatment of con-
gestive heart failure,3 and in treatment of brain diseases
such as dementia.4 Antagonists that are selective towards
AR subtype A2A are very effective in the symptomatic
treatment of Parkinson’s disease, and they may exhibit
neuroprotective effects.5,6 Currently, the nonselective AR
antagonists theophylline and caffeine are the only AR an-
tagonists that are used as drugs.
5
4
48–79%
52–82%
Scheme 1 General three-step procedure for preparing pyrimi-
do[4,5-b]azepines 5
Table 1 Conversion of Amino Acid Esters 2 into Azepines 5 and
Related Compounds
Amino R1
acid
R2
R3 Yields (%)
3
4
5
6
–
–
–
–
–
–
7
–
–
–
–
–
–
2a
H
H
H
H
H
H
H
Et
45
65
52
27
51
75
79
82
52
82
80
82
75
rac-2b
rac-2c
(S)-2d
rac-2e
rac-2f
Me
i-Pr
Bn
Me 83
Et 55
Me 41
We found that the successful replacement of the xanthine
scaffold by substituted 1,3-dimethylpyrido[2,3-d]pyrimi-
dine-(1H,3H)-2,4-dione moieties could provide potent
and selective ligands for adenosine receptors.7 This suc-
cess in the development of novel AR antagonists prompt-
ed us to investigate seven-membered-ring annulated
pyrimidines, such as pyrimido[4,5-e]diazepines and py-
rimido[4,5-b]azepines.8
(CH2)2Ph Et
52
43
1-naphthyl- Et
methyl
rac-2g (CH2)4
rac-2h (CH2)3
Et
78
50
48
63
–
–
–
50
10
–
–
Me 47
Me 58
–
2i
Me
H
25
In applying a procedure for the preparation of pyrimi-
do[4,5-e]diazepines that is analogous to that used to pre-
pare benzodiazepines,9,10 we recently discovered an
unexpected sodium methoxide-catalyzed rearrangement
of 6-amino-5-aroyl-1,3-dimethyluracils to form novel
cinnamamides.11 Here we report the application of our ap-
6-Chloro-1,3-dimethyluracil (1) was obtained from N,N¢-
dimethylbarbituric acid and phosphoryl chloride by using
the procedure described by Pfleiderer.12 Treatment of
chlorouracil 1 with two equivalents of an amino acid ester
2 in N,N-dimethylformamide gave moderate yields of the
corresponding N-(6-pyrimidinyl)amino acid ester 3. Note,
however, that the nucleophilic substitution causes hydro-
lysis as well as aminolysis of the ester through formation
SYNTHESIS 2010, No. 12, pp 2017–2022
x
x.
x
x
.
2
0
1
0
Advanced online publication: 28.04.2010
DOI: 10.1055/s-0029-1218758; Art ID: T00110SS
© Georg Thieme Verlag Stuttgart · New York

2018
B. Gerig et al.
PAPER
of dimethylamine as a decomposition product of N,N- was deduced from a complete analysis of its one- and two-
dimethylformamide. The use of very pure and dry sol- dimensional NMR spectra, especially its 1H,13C-heteronu-
vents or ionic liquids13 minimized these side reactions. clear multiple bond coherence spectrum.
For example, in the case of the nucleophilic substitution
reaction with amino acid 2b, we obtained higher yields by
using butylmethylimidazolium bromide as the solvent.
We assume that the rearrangement to form 7 occurs by a
ring-opening/ring-closure sequence (Scheme 3).
Cyanoacetylation of the pyrimidines 3 by treatment with
CN
HO
O
O
a mixture of cyanoacetic acid and acetic anhydride gave
good yields of corresponding cyanoacetate esters 4. The
mechanism of this reaction involves formation of cy-
anoketene and electrophilic attack at the 5-position of the
pyrimidine ring.14,15 The cyano esters 4 readily underwent
Dieckmann cyclization in sodium alcoholate in a few min-
utes at room temperature. The reaction products were an-
alyzed by means of one- and two-dimensional NMR
spectroscopy. This cyclization procedure (Scheme 1)
could only be used in the case of derivatives of primary
amino acids.
CN
Me
MeOH
NaOMe
Me
O
Me
O
N
N
O
N
O
N
N
N
O
Me
Me
4i
Me
OMe
7 25%
Scheme 3 Formation of the pyrimido[4,5-d]azepine 7
In conclusion, we have developed a synthetic strategy for
the preparation of the new substituted pyrimido[4,5-
b]azepines 5, which have potential medicinal applica-
tions. The conceptually novel procedure involves only
three chemical operations: nucleophilic substitution of the
uracil 1 by an amino acid ester, cyanoacetylation, and
Dieckmann cyclisation.
To examine whether racemization occurred under the ba-
sic conditions of the reaction, the sequence was carried
out with commercially available methyl L-phenylalani-
nate [(S)-2d], as well as with the corresponding D-enan-
tiomer. Careful chromatography of the commercial
available amino acid esters (S)-2d on a chiral phase
[(R,R)-Whelk 01 column] and of the resulting enantiomer-
ic annulated azepines 5d (Chiralcel OD-R column) con-
firmed that only 3% of racemization occurred. The
azepine 5d was obtained in 94% ee.
1H (300 MHz) and 13C (75 MHz) NMR spectra of samples in CDCl3
or DMSO-d6 were recorded on a Bruker Avance III 300 MHz spec-
trometer. Signals are quoted in ppm as d shifts downfield from TMS
(d = 0.00 ppm), and coupling constants (J) are given in Hz. IR spec-
tra were recorded on a Perkin-Elmer 1600 PC FT-IR spectropho-
tometer by using KBr pellets. ESI mass spectra were recorded on a
Bruker Esquire LC with electrospray ionization. EI mass spectra
were recorded on a Hewlett Packard 5989 A mass spectrometer at
an ionization energy of 70 eV. HRMS (70 eV) were recorded on a
Finnigan MAT 8230 spectrometer at the Department of Organic
Initial attempts to perform the Dieckmann cyclization on
substrates 4g–i under the same experimental conditions
were disappointing. We therefore attempted the reaction
on the cyclic amino acid ester 4g by refluxing it for six
hours. It is well known in the literature16,17 that the pyrim- Chemistry of the Christian Albrechts University of Kiel. Elemental
analyses were performed at the Department of Inorganic Chemistry
idine scaffold in xanthines can be cleaved by heating in al-
of the Christian Albrechts University of Kiel using a CHNS analyz-
kaline solution. In an analogous manner, the Dieckmann
er (HEKAtech GmbH). Column chromatography and TLC were
performed on Merck silica gel 60 and GF 254, respectively. HPLC
analyses were carried out on a Merck-Hitachi System with an L-
5000 LC Controller, a 655AA-11 LC chromatograph, an AS-2000
autosampler, an L-4200 UV-vis detector, and a D-2500 Chromato-
Integrator, using a chiral stationary-phase column (CHIRALCEL
OD-R; 250 × 4.6 mm). Melting points were recorded on a Stuart
Scientific SMP03 melting point apparatus and are uncorrected. Un-
less otherwise stated, all chemicals were obtained from commercial
sources and were used as received.
cyclization products were formed after cleavage of the py-
rimidine moiety. It is likely that steric hindrance
(Scheme 2) prevents the formation of tricyclic pyrido[1,2-
a]pyrimido[5,4-f]azepines when the reaction is performed
at room temperature for a few minutes.
CN
HO
O
O
CN
EtOH
NaOEt
Me
O
Me
N
O
N
H
O
Uracils 3; General Procedure
N
N
HN
N
A mixture of 6-chloro-1,3-dimethyluracil (10 mmol, 1.74 g), amino
acid ester 2 (20 mmol), and Et3N (40 mmol, 4.04 g) in DMF (20
mL) was stirred at 156 °C, while the reaction was monitored by
TLC. When the reaction was complete, the solvent was evaporated,
crushed ice was added, and the mixture was extracted with CH2Cl2
(3 × 50 mL). The combined extracts were dried (Na2SO4), filtered,
and concentrated in vacuo to give a crude product that was purified
by column chromatography [silica gel, MeOH–CH2Cl2 (1:19)]. The
resulting product was used without further characterization.
Me
Me
EtOOC
4g
6a 50%
Scheme 2 Dieckmann cyclization of the cyclic amino acid deriva-
tive 4g
The use of sarcosine (2i) in the reaction sequence resulted
in an unexpected rearrangement when cyanoacetate was
refluxed for 90 minutes, and the pyrimido[4,5-d]azepine 7
was obtained in 25% yield. The structure of this product
Chloroacetyl Uracils 4; General Procedure
A mixture of uracil 3 (10 mmol), NCCH2CO2H (20 mmol), and
Ac2O (0.2 mol) was heated to 100 °C and maintained at this temper-
ature for 10 min.
Synthesis 2010, No. 12, 2017–2022 © Thieme Stuttgart · New York

PAPER
Polysubstituted Pyrimido[4,5-b]azepines
2019
Method A: The mixture was cooled to r.t. and the resulting white
crystals were filtered off, washed, and recrystallized from the spec-
ified solvent.
13C NMR (75 MHz, CDCl3): d = 14.8 (OCH2CH3), 18.4
[CH(CH3)2], 19.7 [CH(CH3)2], 29.0 (N3-CH3), 33.3 [CH(CH3)2],
34.5 (COCH2CN), 37.1 (N1-CH3), 62.8 (OCH2CH3), 66.2
(NHCHRCO2C2H5), 99.7 (C-5), 115.9 (CN), 151.4 (C-2), 162.2 (C-
4), 163.6 (C-6), 170.3 (CO2C2H5), 188.2 (COCH2CN).
MS (EI, 70 eV): m/z = 350 M+ (2), 310 (20), 277 (31), 236 (50), 208
(13), 156 (25), 129 (42), 110 (34), 82 (100), 55 (85), 41 (44).
Method B: Ac2O was removed under reduced pressure and the resi-
due was treated with crushed ice with vigorous stirring. The crystal-
line crude product that formed was filtered off and recrystallized
from the specified solvent.
Method C: Ac2O was removed under reduced pressure and the res-
idue was treated with crushed ice. The mixture was extracted with
CH2Cl2 (3 × 50 mL), and the combined extracts were dried
(Na2SO4) and concentrated to give a crude product that was crystal-
lized from the specified solvent.
ESI-MS: m/z = 351 [M + H]+, 373 [M + Na]+.
Anal. Calcd for C16H22N4O5 (350.58): C, 54.85; H, 6.33; N, 15.99.
Found: C, 54.53; H, 6.40; N, 15.60.
Methyl
N-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-yl]-l-phenylalaninate [(S)-4d]
Ethyl N-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]glycinate (4a)
Method A: White solid; yield: 3.91 g (51%); mp 152.3 °C (MeOH).
1H NMR (300 MHz, CDCl3): d = 3.21 (AB part of ABX-system,
3J = 10.0 Hz, 3J = 4.3 Hz, 2J = 14.0 Hz, 2 H, CH2Ar), 3.23 (s, 3 H,
N3-CH3), 3.26 (s, 3 H, N1-CH3), 3.82 (s, 3 H, OCH3), 4.21 (AB-sys-
tem, 2J = 19.6 Hz, 2 H, COCH2CN), 4.62 (X part of ABX-system,
3J = 9.5 Hz, 3J = 4.3 Hz, 1 H, CH), 7.25 (mc, 5 H, Ar-H), 11.32 (d,
3J = 9.4 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 28.2 (N3-CH3), 33.8 (COCH2CN),
36.2 (N1-CH3), 40.4 (CH2-Ar), 53.3 (OCH3), 61.2 (CH), 87.2 (C-5),
115.1 (CN), 127.0 (C-4¢), 128.7 (C-2¢, C-6¢), 129.4 (C-3¢, C-5¢),
135.8 (C-1¢), 153.0 (C-2), 161.1 (C-6), 163.7 (C-4), 171.9
(CO2CH3), 187.7 (COCH2CN).
Method A: White solid; yield: 4.0 g (65%); mp 160.8 °C (EtOH).
IR (KBr): 2986 (m, n, CH2), 2258 (w, n, CN) 1740 (s, n,
COOCH2CH3), 1652 (s, n, RNCONR), 1596 (m, d, NH), 1456 cm–
1 (m, d, CH2).
1H NMR (300 MHz, CDCl3): d = 1.31 (t, 3J = 7.1 Hz, 3 H,
OCH2CH3), 3.32 (s, 3 H, N3-CH3), 3.49 (s, 3 H, N1-CH3), 4.26 (mc,
6 H, NHCH2COOCH2CH3, COCH2CN, OCH2CH3), 11.64, (1 H,
NHCH2COOCH2CH3).
13C NMR (75 MHz, CDCl3): d = 14.0 (OCH2CH3), 28.3 (N3-CH3),
33.8 (COCH2CN), 35.3 (N1-CH3), 47.9 (NHCH2COOCH2CH3),
62.7 (OCH2CH3), 94.0 (C-5), 115.2 (CN), 150.7 (C-2), 161.5 (C-4),
162.5 (C-6), 167.6 (COOCH2CH3), 187.5 (CO).
MS (EI, 70 eV): m/z = 384 M+ (4), 344 (11), 293 (10), 284 (12), 233
(33), 208 (11), 162 (100), 131 (23), 91 (47), 82 (37), 42 (11).
ESI-MS: m/z = 385 [M + H]+.
MS (EI, 70 eV): m/z = 308 M+ (9), 268 (100), 235 (14), 208 (22),
194 (69), 82 (34), 69 (52), 42 (18).
ESI-MS: m/z = 309 [M + H]+, 331 [M + Na]+.
Anal. Calcd for C19H20N4O5 (384.40): C, 59.37; H, 5.24; N, 14.58.
Found: C, 59.68; H, 5.33; N, 14.53.
Anal. Calcd for C13H16N4O5 (308.30): C, 50.65; H, 5.23; N, 18.17.
Found: C, 50.59; H, 5.34; N, 18.07.
Ethyl 2-{[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]amino}-4-phenylbutanoate (4e)
Methyl
N-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-
Method A: White solid; yield: 6.0 g (75%); mp 116.9 °C (EtOH).
tetrahydropyrimidin-4-yl]alaninate (4b)
1H NMR (300 MHz, CDCl3): d = 1.28 (t, 3J = 7.13 Hz, 3 H,
OCH2CH3), 2.31 (mc, 2 H, CH2CH2-Ar), 2.81 (mc, 2 H, CH2CH2-
Ar), 3.21 (s, 3 H, N3-CH3), 3.31 (s, 3 H, N1-CH3), 4.24 (mc, 3 H, CH,
OCH2CH3), 4.31 (AB-system, JAB = 19.7 Hz, 2 H, COCH2CN),
7.21 (mc, 5 H, H-2¢¢, H-3¢¢, H-4¢¢, H-5¢¢, H-6¢¢), 11.59 (d, 3J = 8.52
Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.8 (OCH2CH3), 29.0 (N3-CH3),
32.2 (COCH2CN), 34.6 (CH2CH2-Ar), 35.6 (CH2CH2-Ar), 36.4
(N1-CH3), 59.1 (OCH2CH3), 63.1 (CH), 94.7 (C-5), 115.9 (CN),
127.5 (C-4¢), 129.1 (C-2¢, C-6¢), 129.5 (C-3¢, C-5¢), 139.6 (C-1¢),
151.2 (C-2), 162.2 (C-6), 163.1 (C-4), 170.9 (COOCH2CH3), 188.5
(COCH2CN).
Method A: White solid; yield: 3.2 g (52%); mp 124.3 °C (MeOH).
IR (KBr): 2956 (w, n, CH2), 2260 (m, n, CN), 1716 (s, n, CO), 1652
(s, n, RNCONR), 1522 (m, d, NH), 1464 cm–1 (m, d, CH2).
1H NMR (300 MHz, CDCl3): d = 1.63 (d, 3J = 7.0 Hz, 3 H, CH3),
3.10 (s, 3 H, N3-CH3), 3.43 (s, 3 H, N3-CH3), 3.77 (s, 3 H, OCH3),
4.32 (AB-system, JAB = 19.5 Hz, 2 H, COCH2CN), 4.49 (dq,
3JCH/NH = 8.1 Hz, 3JCH/CH3¢ = 7.1, 1 H, CH), 11.43 (d, 3J = 8.1 Hz, 1
H, NH).
13C NMR (75 MHz, CDCl3): d = 20.1 (CH3), 29.0 (N3-CH3), 34.5
(CH2), 36.4 (N1-CH3), 53.9 (OCH3), 55.5 (CH), 95.0 (C-5), 115.8
(CN), 151.23 (C-2), 162.2 (C-4), 162.8 (C-6), 171.9 (COOCH3),
188.4 (CO).
MS (EI, 70 eV): m/z = 308 (6), 268 (6), 208 (27), 117 (13), 91 (100),
68 (11), 41 (16).
ESI-MS: m/z = 413 [M + H]+.
MS (EI, 70 eV): m/z = 308 M+ (5), 268 (68), 249 (27), 208 (100),
110 (44), 82 (61), 68 (32), 42 (36) cm–1.
ESI-MS: m/z = 309 [M + H]+, 331 [M + Na]+.
Anal. Calcd for C21H24N4O5 (412.45): C, 61.16; H, 5.87; N, 13.58.
Found: C, 61.35; H, 6.09; N, 13.94.
Anal. Calcd for C13H16N4O5 (308.30): C, 50.65; H, 5.23; N, 18.17.
Found: C, 50.44; H, 5.27; N, 18.04.
Ethyl N-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]-3-(1-naphthyl)alaninate (4f)
Ethyl N-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]valinate (4c)
Method C: White solid; yield: 3.5 g (43%); mp 114.2 °C (EtOH).
Method A: White solid; yield: 3.4 g; 52%; mp 124.3 °C (EtOH).
1H NMR (300 MHz, CDCl3): d = 1.34 (t, 3J = 7.20 Hz, 3 H,
OCH2CH3), 2.95 (s, 3 H, N3-CH3), 3.10 (s, 3 H, N1-CH3), 3.67 (AB-
part of the ABMX-system, JAX = 4.1 Hz, JBX = 10.1 Hz, JAB = 14.3
Hz, 2 H, CH2), 4.16 (AB-system, JAB = 19.75 Hz, 2 H, COCH2CN),
1H NMR (300 MHz, CDCl3): d = 1.04 [d, 3J = 6.8 Hz, 3 H,
CH(CH3)2], 1.08 [d, 3J = 6.9 Hz, 3 H, CH(CH3)2], 1.28 (t, 3J = 7.1
Hz, 3 H, OCH2CH3), 2.37 [mc, 1 H, CH(CH3)2], 3.30 (s, 3 H, N3-
CH3), 3.42 (s, 3 H, N1-CH3), 4.26 (mc, 5 H, NHCHRCO2CH3,
COCH2CN, OCH2CH3), 11.47 (d, 3J = 8.2 Hz, 1 H, NH).
3
4.26 (q, J = 7.1 Hz, 2 H, OCH2CH3,), 4.88 (dt, X-part of the
3
3
ABMX-system, JAX = 4.1 Hz, JBX = 3JXNH = 10.1 Hz, 1 H, CH),
7.29 (mc, 2 H, H-2¢, H-3¢), 7.53 (mc, 2 H, H-6¢, H-7¢), 7.68 (mc, 1 H,
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2020
B. Gerig et al.
PAPER
H-4¢), 7.84 (mc, 1 H, H-5¢), 7.98 (mc, 1 H, H-8¢), 11.41 (d, M-part of
the ABMX-system, 1 H, 3J = 9.9 Hz, NH).
1H NMR (300 MHz, CDCl3): d = 2.91 (s, 3 H, N-CH3), 3.27 (s, 3 H,
N3-CH3), 3.57 (s, 3 H, N1-CH3), 3.72 (s, 2 H, CH2), 3.76 (s, 3 H,
OCH3), 4.17 (s, 2 H, COCH2CN).
13C NMR (75 MHz, CDCl3): d = 28.5 (N3-CH3), 34.5 (COCH2CN),
34.8 (N1-CH3), 41.0 (N-CH3), 52.5 (OCH3), 54.4 (CH2), 100.8 (C-
5), 115.0 (CN), 151.6 (C-2), 162.3 (C-4), 163.3 (C-6), 169.5
(COOCH3), 185.3 (COCH2CN).
13C NMR (75 MHz, CDCl3): d = 14.1 (OCH2CH3), 27.9 (N3-CH3),
33.7 (COCH2CN), 35.9 (N1-CH3), 38.1 (CH2), 60.0 (CH), 62.7
(OCH2CH3), 94.6 (C-5), 115.2 (CN), 122.3 (C-8¢), 125.3 (C-3¢),
126.2 (C-6¢), 127.0 (C-7¢), 128.7 (2C, C-4¢, C-2¢), 129.2 (C-5¢),
131.0 (C-8a¢), 131.2 (C-1¢), 133.8 (C-4a¢), 149.9 (C-2), 162.3 (C-6),
162.3 (C-4), 169.5 (COOCH2CH3), 187.1 (CO).
ESI-MS: m/z = 309 [M + H]+, 639 [2M + Na]+.
MS (EI, 70 eV): m/z = 448 M+ (1), 307 (2), 226 (23), 153 (24), 141
(45), 82 (26), 55 (95), 41 (100).
Anal. Calcd for C13H16N4O5 (308.30): C, 50.65; H, 5.23; N, 18.17.
Found: C, 50.41; H, 5.19; N, 18.46.
Anal. Calcd for C24H24N4O5 (448.48): C, 64.28; H, 5.39; N, 12.49.
Found: C, 64.30; H, 5.51; N, 12.88.
Cyclization of 4; General Procedure
Method A: A mixture of cyanoacetate 4 (1 mmol) and Na (1 mmol)
in EtOH (or MeOH for methyl esters) was stirred at r.t. while the re-
action was monitored by TLC. When the reaction was complete, the
solvent was removed under reduced pressure and crushed ice was
added to the residue. The resulting solution was acidified with gla-
cial AcOH until a crude product formed. This was filtered off and
crystallized from the specified solvent.
Ethyl 1-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]piperidine-2-carboxylate (4g)
Method A: White solid; yield: 3.6 g (50%); mp 102.4 °C (EtOH).
IR (KBr): 2936 (m, n, CH2, CH3), 2200 (s, n, CN), 1736 (s, n,
COOCH2CH3), 1646 (s, n, RNCONR), 1474 (m, d, NH), 1430
cm–1 (m, d, CH2, CH3).
Method B: A soln of 4 (3.6 mmol) and NaOMe (45 mmol) in MeOH
(50 mL) was refluxed until the reaction was complete. The solvent
was evaporated, crushed ice was added to the residue, and the mix-
ture was acidified with glacial AcOH. The crude product was recov-
ered by filtration and crystallization from the specified solvent.
1H NMR (300 MHz, CDCl3): d = 1.20 (t, 3J = 7.1 Hz, 3 H,
OCH2CH3), 1.67 (mc, 4 H, piperidine-Ha-3, Ha-4, Ha,e-5), 1.92 (mc,
1 H, piperidine-He-4), 2.09 (mc, 1 H, piperidine-He-3), 3.15 (mc, 2
H, piperidine-N-Ha-6, He-6), 3.33 (s, 3 H, N3-CH3), 3.58 (s, 3 H, N1-
CH3), 3.78 (dd, J = 3.3 Hz, J = 9.4 Hz, 1 H, piperidine-N-H-2),
4.11 (AB-system, JAB = 19.6 Hz, 2 H, COCH2CN], 4.12 (mc, 2 H,
OCH2CH3).
3
3
5-Hydroxy-1,3-dimethyl-2,4,7-trioxo-2,3,4,7,8,9-hexahydro-
1H-pyrimido[4,5-b]azepine-6-carbonitrile (5a)
13C NMR (75 MHz, CDCl3): d = 14.0 (OCH2CH3), 22.5 (piperidine-
C-4), 24.3 (piperidine-C-5), 28.4 (N3-CH3), 29.5 (piperidine-C-3),
33.4 (N1-CH3), 34.1 (COCH2CN), 50.8 (piperidine-C-6), 60.9 (pip-
eridine-C-2), 61.6 (OCH2CH3), 104.6 (C-5), 114.7 (CN), 151.5 (C-
2), 161.8 (C-6), 162.8 (C-4), 171.4 (COOCH2CH3), 186.9
(COCH2CN).
MS (EI, 70 eV): m/z = 362 M+ (1), 322 (47), 289 (52), 248 (21), 191
(36), 156 (22), 149 (16), 110 (17), 82 (100), 55 (40), 41 (27).
ESI-MS: m/z = 363 [M + H]+, 747 [2M + Na]+.
Method A: White solid; yield: 0.35 g (82%); mp 281–282 °C
(EtOH–H2O).
IR (KBr): 3225 (m, n, OH), 2226 (s, n, CN) 1716 (s, n, CO), 1652
(s, n, RNCONR), 1596 (m, d, NH), 1480 cm–1 (m, d, CH2).
1H NMR (300 MHz, DMSO-d6): d = 3.29 (s, 3 H, N3-CH3), 3.44 (s,
3 H, N1-CH3), 3.81 (s, 2 H, CH2), 9.57 (s, 1 H, NH), 15.42 (s, 1 H,
OH).
13C NMR (75 MHz, DMSO-d6): d = 28.4 (N3-CH3), 31.0 (N1-CH3),
51.9 (CH2), 87.1 (C-4a), 89.3 (C-6), 116.5 (CN), 148.2 (C-2), 156.9
(C-9a), 167.3 (C-4), 176.6 (C-5), 183.7 (C-7).
Anal. Calcd for C17H22N4O5 (362.39): C, 56.35; H, 6.12; N, 15.48.
Found: C, 56.28; H, 6.17; N, 15.42.
MS (EI, 70 eV): m/z = 262 M+ (3), 218 (5), 164 (5), 82 (22), 57 (27),
Methyl
1-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-
44 (100).
tetrahydropyrimidin-4-yl]prolinate (4h)
ESI-MS: m/z = 263 [M + H]+, 524 [2M + H]+.
Method C: Pale yellow oil; yield: 3.21 g (48%).
Anal. Calcd for C11H10N4O4 (262.23): C, 50.38; H, 3.84; N, 21.37.
Found: C, 50.45; H, 3.94; N, 21.31.
1H NMR (300 MHz, CDCl3): d = 2.06 (mc, 3 H, pyrrolidine-Ha-3,
Ha,e-4), 2.60 (mc, 1 H, pyrrolidine-He-3), 3.22 (mc, 1 H, pyrrolidine-
Ha-5), 3.33 (s, 3 H, N3-CH3), 3.58 (s, 3 H, N1-CH3), 3.58 (mc, 1 H,
pyrrolidine-He-5), 3.70 (s, 3 H, OCH3), 4.14 (AB-system,
5-Hydroxy-1,3,8-trimethyl-2,4,7-trioxo-2,3,4,7,8,9-hexahydro-
1H-pyrimido[4,5-b]azepine-6-carbonitrile (5b)
3
3
Method A: White solid; yield: 144 mg (52%); mp 237.5 °C (EtOH).
J
AB = 19.4 Hz, 2 H, COCH2CN], 4.27 (dd, J = 6.1, J = 8.3, 1 H,
pyrrolidine-H-2).
IR (KBr): 2956 (w, n, CH2), 2260 (m, n, CN), 1716 (s, n, CO), 1652
(s, n, RNCONR), 1522 (m, d, NH), 1464 cm–1 (m, d, CH2).
13C NMR (75 MHz, CDCl3): d = 25.5 (pyrrolidine-C-4), 28.5 (N3-
CH3), 30.4 (pyrrolidine-C-3), 34.4 (COCH2CN), 35.1 (N1-CH3),
52.5 (OCH3), 52.8 (pyrrolidine-C-5), 63.0 (pyrrolidine-C-2), 100.7
(C-5), 115.1 (CN), 151.6 (C-2), 160.1 (C-4), 162.5 (C-6), 172.8
(COOCH3), 185.4 (COCH2CN).
MS (EI, 70 eV): m/z = 334 M+ (1), 294 (42), 275 (24), 234 (23), 207
(11), 177 (24), 149 (24), 82 (100), 68 (86), 41 (90).
3
1H NMR (300 MHz, DMSO-d6): d = 1.36 (d, J = 7.0 Hz, 3 H,
CH3), 3.26 (s, 3 H, N3-CH3), 3.43 (s, 3 H, N1-CH3), 3.82 (q, 3J = 7.0
Hz, 1 H, CH), 8.63 (br s, 1 H, NH), 15.54 (br s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 18.1 (CH3), 28.3 (N3-CH3),
31.2 (N1-CH3), 56.1 (C-8), 87.8 (C-4a), 88.7 (C-6), 116.7 (CN),
148.4 (C-2), 155.5 (C-9a), 167.2 (C-4), 175.8 (C-5), 188.4 (C-7).
MS (EI, 70 eV): m/z = 276 M+ (1), 82 (17), 44 (100).
ESI-MS: m/z = 277 [M + H]+, 299 [M + Na]+.
ESI-MS: m/z = 335 [M + H]+.
HRMS (EI): m/z = M+ calcd for C15H18N4O5: 334.12772; found:
334.12780.
HRMS (EI): m/z = M+ calcd for C12H12N4O4: 276.08585; found:
276.08568.
Methyl
N-[5-(Cyanoacetyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-yl]-N-methylglycinate (4i)
Anal. Calcd for C12H12N4O4 (276.25): C, 52.17; H, 4.38; N, 20.28.
Found: C, 51.88; H, 4.46; N, 19.92.
Method B: White solid; yield: 3.9 g (63%); mp 102.4 °C (MeOH).
Synthesis 2010, No. 12, 2017–2022 © Thieme Stuttgart · New York

PAPER
Polysubstituted Pyrimido[4,5-b]azepines
2021
5-Hydroxy-8-isopropyl-1,3-dimethyl-2,4,7-trioxo-2,3,4,7,8,9-
hexahydro-1H-pyrimido[4,5-b]azepine-6-carbonitrile (5c)
Anal. Calcd for C19H18N4O4 (366.38): C, 62.29; H, 4.95; N, 15.29.
Found: C, 62.01; H, 5.01; N, 15.21.
Method A: White solid; yield: 250 mg (82%); mp 268.2 °C (EtOH).
5-Hydroxy-1,3-dimethyl-8-(1-naphthylmethyl)-2,4,7-trioxo-
2,3,4,7,8,9-hexahydro-1H-pyrimido[4,5-b]azepine-6-carboni-
trile (5f)
IR (KBr): 3236 (m, n, OH), 2222 (w, n, CN), 1712 (s, n, CO), 1636
(s, n, RNCONR), 1574 (m, d, NH), 1360 cm–1 (m, d, OH).
Method A: White solid; yield: 302 mg (75%); mp 291.2 °C (diox-
ane).
3
1H NMR (300 MHz, DMSO-d6): d = 0.84 [d, J = 6.1 Hz, 3 H,
3
CH(CH3)2], 0.86 [d, J = 6.1 Hz, 3 H, CH(CH3)2], 1.99 [mc, 1 H,
CH(CH3)2], 3.25 (s, 3 H, N3-CH3), 3.45 (mc, 4 H, N1-CH3, CH), 8.88
1H NMR (300 MHz, DMSO-d6): d = 3.04 (s, 3 H, N1-CH3), 3.24 (s,
3 H, N3-CH3), 3.52 [zAB (1056 Hz), AB-part of the ABX-system,
JAX = 4.6 Hz, JBX = 9.9 Hz, JAB = 14.7 Hz, C = 36.42 Hz, n0d = 0.24
ppm (71 Hz), na = 3.64 ppm (1092 Hz), nb = 3.40 ppm (1020 Hz), 2
H, CH2], 4.19 (X-part of ABX-system, dd, 3J = 4.6 Hz, 3J = 9.9 Hz,
1 H, CH), 7.43 (mc, 2 H, H-2¢, H-3¢), 7.55 (mc, 2 H, H-6¢, H-7¢), 7.84
(d, 3J = 7.3 Hz, 1 H, H-4¢), 7.94 (d, 3J = 7.2 Hz, 1 H, H-5¢), 8.06 (d,
3J = 7.9 Hz, 1 H, H-8¢), 8.54 (br s, 1 H, NH), 15.91 (br s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 28.5 (N3-CH3), 30.7 (CH2),
30.9 (N1-CH3), 61.6 (CH), 88.2 (C-4a), 89.0 (C-6), 116.7 (CN),
123.2 (C-8¢), 125.3 (C-3¢), 125.7 (C-6¢), 126.3 (C-7¢), 127.5 (C-4¢),
127.6 (C-2¢), 128.7 (C-5¢), 131.2 (C-8a¢), 132.5 (C-1¢), 133.5 (C-
4a¢), 148.2 (C-2), 154.7 (C-9a), 167.1 (C-4), 175.6 (C-5), 185.2 (C-
7).
(br s, 1 H, NH), 15.85 (br s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 18.6 [(CH(CH3)2], 19.4
[CH(CH3)2], 25.7 [CH(CH3)2], 28.4 (N3-CH3), 31.2 (N1-CH3), 67.8
(C-8), 87.5 (C-4a), 88.2 (C-6), 116.6 (CN), 148.4 (C-2), 154.1 (C-
9a), 167.0 (C-4), 175.2 (C-5), 185.0 (C-7).
MS (EI, 70 eV): m/z = 259 (10), 246 (7), 221 (5), 138 (5), 82 (20),
55 (25), 44 (100).
ESI-MS: m/z = 305 [M + H]+, 609 [2M + H]+.
Anal. Calcd for C14H16N4O4 (304.31): C, 55.26; H, 5.30; N, 18.41.
Found: C, 55.31; H, 5.43; N, 18.36.
(8S)-5-Hydroxy-1,3-dimethyl-8-(2-methylphenyl)-2,4,7-trioxo-
2,3,4,7,8,9-hexahydro-1H-pyrimido[4,5-b]azepine-6-carboni-
trile [(S)-5d]
MS (EI, 70 eV): m/z = 402 M+ (1), 141 (8), 57 (26), 44 (100).
ESI-MS: m/z = 403 [M + H]+, 805 [2M + H]+.
Method A: White solid; yield: 282 mg (80%); mp 252.8 °C (diox-
ane); [a]D20 +113.9 (c 1.00, DMF).
Anal. Calcd for C22H18N4O4 (402.41): C, 65.67; H, 4.51; N, 13.92.
Found: C, 65.88; H, 4.59; N, 14.05.
HPLC: CHIRALCEL OD-R column, aq K2HPO4 buffer (pH 2)–
MeCN (3:2); injection volume: 10.0 mL of 5d and its R-enantiomer;
flow rate: 0.6 mL/min; UV detection: 254 nm; S-enantiomer
tR = 13.54 min; R-enantiomer tR = 14.88 min.
9-Cyano-8-hydroxy-N-methyl-6-(methylamino)-10-oxo-
1,2,3,4,10,10a-hexahydropyrido[1,2-a]azepine-7-carboxamide
(6a)
1H NMR (300 MHz, CDCl3): d = 3.09 (AB part of ABX-system,
3J = 10.4 Hz, 3J = 5.1 Hz, 2J = 14.2 Hz, 2 H, CH2Ar), 3.09 (s, 3 H,
N3-CH3), 3.24 (s, 3 H, N1-CH3), 4.02 (X part of ABX-system, 3J =
10.2 Hz, 3J = 5.1 Hz, 1 H, CH), 7.24 (mc, 5 H, Ar-H), 8.56 (br s, 1
H, NH), 15.74 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 28.8 (N3-CH3), 31.1 (N1-CH3), 33.4
(CH2-Ar), 62.3 (CH), 88.5 (C-4a), 89.1 (C-6), 117.0 (CN), 127.0
(C-4¢), 128.7 (C-2¢, C-6¢), 129.4 (C-3¢, C-5¢), 136.9 (C-1¢), 148.6 (C-
2), 155.2 (C-9a), 167.2 (C-4), 175.8 (C-5), 185.4 (C-7).
Method A: White solid; yield: 146 mg (50%); mp 291.2 °C (diox-
ane).
1H NMR (300 MHz, DMSO-d6): d = 1.63 (mc, 4 H, Ha-1, Ha-2, Ha,e-
3), 2.11 (mc, 1 H, He-2), 2.73 (mc, 5 H, He-1, Ha-4, HNCH3), 2.89
(mc, 1 H, He-4), 3.31 (s, 3 H, H3CNHCO), 3.86 (mc, 1 H, H-10a),
7.78 (br s, 1 H, NH), 8.02 (br s, 1 H, NH), 15.86 (br s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 19.1 (C-2), 21.9 (C-3), 23.2 (C-
1), 25.8 (HNCH3), 32.3 (H3CNHCO), 44.5 (C-4), 58.9 (C-10a),
79.3 (C-9), 84.8 (C-7), 119.0 (CN), 162.6 (H3CNHCO), 170.8 (C-
6), 177.2 (C-8), 187.0 (C-10).
MS (EI, 70 eV): m/z = 259 (2), 111 (11), 91 (20), 83 (32), 55 (100),
43 (80).
ESI-MS: m/z = 353 [M + H]+.
MS (EI, 70 eV): m/z = 223 (70), 193 (61), 137 (28), 84 (100), 58
(63), 41 (45).
ESI-MS: m/z = 291 [M + H]+, 581 [M + M]+.
HRMS (EI): m/z = M+ calcd for C14H18N4O3: 290.13788; found:
Anal. Calcd for C18H16N4O4 (352.35): C, 61.36; H, 4.58; N, 15.90.
Found: C, 61.27; H, 4.61; N, 15.98.
5-Hydroxy-1,3-dimethyl-2,4,7-trioxo-8-(2-phenylethyl)-
2,3,4,7,8,9-hexahydro-1H-pyrimido[4,5-b]azepine-6-carboni-
trile (5e)
290.13793.
8-Cyano-7-hydroxy-N-methyl-5-(methylamino)-9-oxo-2,3,9,9a-
tetrahydro-1H-pyrrolo[1,2-a]azepine-6-carboxamide (6b)
Method A: White solid; yield: 300 mg (82%); mp 230.5 °C (diox-
ane).
Method A: White solid; yield: 28 mg (10%); mp 240.1 °C (diox-
ane).
1H NMR (300 MHz, DMSO-d6): d = 2.07 (mc, 2 H, CH2CH2-Ar),
2.61 (mc, 2 H, CH2CH2-Ar), 3.25 (s, 3 H, N3-CH3), 3.38 (s, 3 H, N1-
CH3), 3.78 (t, 3J = 7.3 Hz, 1 H, CH), 7.22 (mc, 5 H, Ar-H), 8.74 (br
s, 1 H, NH), 15.76 (br s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 28.4 (N3-CH3), 28.9 (CH2CH2-
Ar), 31.2 (N1-CH3), 31.3 (CH2CH2-Ar), 60.5 (CH), 87.8 (C-4a),
88.5 (C-6), 116.7 (CN), 125.9 (C-4¢), 128.2 (C-2¢, C-6¢), 128.2 (C-
3¢, C-5¢), 140.7 (C-1¢), 148.3 (C-2), 155.1 (C-9a), 167.1 (C-4), 175.7
(C-5), 185.1 (C-7).
MS (EI, 70 eV): m/z = 366 M+(1), 104 (12), 91 (53), 65 (16), 44
(100).
HRMS (EI): m/z = M+ calcd for C19H18N4O4: 366.13281; found:
366.13264.
1H NMR (300 MHz, DMSO-d6): d = 1.77 (mc, 2 H, pyrrolidine-Ha-
1, -Ha-2), 2.01 (mc, 1 H, pyrrolidine-He-2), 2.58 (mc, 1 H, He-1),
2.73 (mc, 3 H, HNCH3,), 3.32 (s, 3 H, CONHCH3), 3.34 (m, 1 H,
Ha-3), 3.48 (mc, 1 H, He-3), 3.99 (d, 1 H, H-9a), 7.42 (br s, 1 H, NH),
7.92 (br s, 1 H, NH), 15.55 (br s, 1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 23.3 (C-2), 24.6 (C-1), 25.7
(CONHCH3), 32.3 (NHCH3), 48.0 (C-3), 64.3 (C-9a), 81.0 (C-8),
84.3 (C-6), 119.4 (CN), 158.1 (C-5), 170.1 (CONHCH3), 175.6 (C-
7), 184.7 (C-9).
MS (EI, 70 eV): m/z = 241 (38), 168 (33), 155 (4), 140 (35), 111
(44), 82 (100), 55 (98).
ESI-MS: m/z = 277 [M + H]+, 553 [2M + H]+.
Synthesis 2010, No. 12, 2017–2022 © Thieme Stuttgart · New York

2022
B. Gerig et al.
PAPER
(2) Müller, C. E.; Sandoval-Ramirez, J. Eur. J. Pharm. Sci.
HRMS (EI): m/z = M+ calcd for C13H16N4O3: 276.12225; found:
276.12224.
2000, 10, 259.
(3) Vallon, V.; Miracle, C.; Thomson, S. Eur. J. Heart Failure
2008, 10, 176.
5-Hydroxy-1,3,7-trimethyl-2,4,8-trioxo-2,3,4,7,8,9-hexahydro-
1H-pyrimido[4,5-d]azepine-6-carbonitrile (7)
(4) Maemoto, T.; Tada, M.; Mihara, T.; Ueyama, N.; Matsuoka,
H.; Harada, K.; Yamaji, T.; Shirakawa, K.; Kuroda, S.;
Akahane, A.; Iwashita, A.; Matsuoka, N.; Mutoh, S.
J. Pharmacol. Sci. (Tokyo, Jpn.) 2004, 96, 42.
(5) Xu, K.; Bastia, E.; Schwarzschild, M. Pharmacol. Ther.
2005, 105, 267.
Method B: Pale yellow solid; yield: 69 mg (25%); mp 251.9 °C (di-
oxane).
1H NMR (300 MHz, DMSO-d6): d = 2.54 (s, 3 H, N-CH3), 3.23 (s,
3 H, N3-CH3), 3.68 (s, 3 H, N1-CH3), 5.00 (br s, 2 H, CH2), 13.44 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 27.5 (N3-CH3), 34.9 (N1-CH3),
36.3 (N-CH3), 66.3 (C-9), 84.0 (C-4a), 93.0 (C-6), 114.2 (CN),
140.2 (C-9a), 151.1 (C-2), 162.6 (C-5), 164.8 (C-8), 165.4 (C-4).
ESI-MS: m/z = 277 [M + H]+, 553 [2M + H]+.
HRMS (EI): m/z = M+ calcd for C12H12N4O4: 276.08585; found:
(6) Hockemeyer, J.; Burbiel, J. C.; Müller, C. E. J. Org. Chem.
2004, 69, 3308.
(7) Bulicz, J.; Bertarelli, D. C. G.; Baumert, D.; Fülle, F.;
Müller, C. E.; Heber, D. Bioorg. Med. Chem. 2006, 14, 2837.
(8) Gerig, B. PhD Thesis; Christian Albrechts University of
Kiel: Germany, 2008.
(9) Senda, S.; Hirota, K. Chem. Pharm. Bull. 1974, 22, 2921.
(10) Sternbach, L. H.; Reeder, E.; Keller, O.; Metlesics, W.
J. Org. Chem. 1961, 26, 4488.
276.08584.
Anal. Calcd for C12H12N4O4 (276.25): C, 52.17; H, 4.38; N, 20.28.
Found: C, 50.42; H, 4.49; N, 20.15.
(11) Gerig, B.; Girreser, U.; Näther, C.; Heber, D. Z. Naturforsch.
B: J. Chem. Sci. 2009, 64, 662.
(12) Pfleiderer, W.; Schündehütte, K.-H. Justus Liebigs Ann.
Chem. 1958, 612, 158.
Acknowledgment
(13) Weingärtner, H. Angew. Chem. Int. Ed. 2008, 47, 654.
(14) Kappe, T.; Stelzel, H. P.; Ziegler, E. Monatsh. Chem. 1983,
114, 953.
The authors are grateful to Mr Schade and Mr Wichmann for their
excellent assistance with HPLC and mass spectrometry.
(15) Slätt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760.
(16) Brown, R. D.; Duffin, H. C.; Maynard, J. C.; Ridd, J. H.
J. Chem. Soc. 1953, 3937.
References
(1) Kieć-Kononowicz, K.; Drabczyńska, A.; Pękala, E.;
Michalak, B.; Müller, C. E.; Schumacher, B.; Karolak-
Wojciechwska, J.; Duddeck, H.; Rockitt, S.; Wartchow, R.
Pure Appl. Chem. 2001, 73, 1411.
(17) Kala, H.; Moldenhauer, H.; Wolff, K. Pharmazie 1959, 14,
519.
Synthesis 2010, No. 12, 2017–2022 © Thieme Stuttgart · New York