Recent Development in the Chemistry of Bicyclic 6-6 Systems
Containing One Bridgehead Nitrogen Atom and One Extra
Heteroatom and Their Benzologs.
István Hermecz
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
1
I. Introduction
II. Pyrido[1,2-b][1,2]oxazines, -[1,2]thiazines, -pyridazines and Their Benzologs
A. Structure
1. Theoretical Calculations
2. Experimental Structural Methods
B. Reactivity
1. Ring Opening
2. Oxidation
3. Reduction, Hydrogenation
4. Reactivity of the Ring Carbon Atom
5. Reactivity of Substituent Attached to a Ring Carbon Atom
6. Reactivity of Substituent Presents in a Side Chain
7. Ring Transformation
C. Synthesis
1. By Formation of One Bond α to the Bridgehead Nitrogen Atom [6+0(α)]
2. By Formation of One Bond γ to the Bridgehead Nitrogen Atom [6+0(γ)]
3. By Formation of Two Bond from [3+3] Atom Fragments
4. Ring Transformation
5. Miscellaneous
D. Applications and Important Compounds
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
2
III. Pyrido[1,2-c][1,3]oxazines, -[1,3]thiazines, -pyrimidines and Their Benzologs
A. Structure
1. Thermodynamic Aspects
2. Theoretical Calculations
3. Experimental Structural Methods
3. NMR Spectroscopy
4. Mass Spectrometry
5. X-Ray Investigations
C. Reactivity
1. Ring Opening
2. Oxidation
3. Hydrogenation, Reduction
4. Reactivity of the Ring Carbon Atom
5. Reactivity of the Ring Nitrogen Atom
6. Reactivity of Substituent Attached to a Ring Carbon Atom
7. Reactivity of Substituent Presents in a Side Chain
8. Ring Transformation
C. Synthesis
1. By Formation of One Bond α to the Bridgehead Nitrogen Atom [6+0(β)]
2. By Formation of One Bond γ to the Bridgehead Nitrogen Atom [6+0(γ)]
3. By Formation of Two Bond from [3+3] Atom Fragments
4. By Formation of Two Bond from [4+2] Atom Fragments
5. By Formation of Two Bond from [5+1] Atom Fragments
6. Ring Transformation
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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D. Applications and Important Compounds
References
I. Introduction
This chapter covers the primary chemical literature of the title bi- and tricyclic ring systems
cited in Chemical Abstracts Chemical Substance Indexes up to Volume 151 from Volume 144
between 2006 and 2009. Earlier literature data were systematically treated as primary subjects in
Comprehensive Heterocyclic Chemistry series <1996CHC-II(8)563, 2007CHC-III77>.
These ring systems occupy valuable parts of the chemical space for drug research, as most of
their derivatives have drug-like properties and their outstanding representatives play an
indispensable role in medicinal chemistry.
Me
Me
N
N
Me
N
N
N
HCl
MeO
N
N
Me
O
O
i
Actisomide
N
N
O
H
Ph
N
H
O
Me
N Pr2
MeO
Sunepirton
Trequinsin
O
Me
C
N
O
O
N
F
Me
3
Me
3
Me
Me
N
CO2H F
CO2H
O
(3S,R)-Ofloxacin
NH2 O
N
O
(3S)-(+)-Levofloxacin
N
F
Praziquantel
N
O
N
N
Me
N
N
S
N
CO2H
O
(S)-Pazufloxacin
N
F
CO2H
O
Rufloxacin
Figure 1. Outstanding representatives of ring systems which have been introduced into the
human and veterinary therapy
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
4
O
H
H
O
N
O
H
N
H
Hyperspine
NH
N
N
R
1
a) R = 1-methylpropyl
b) R = 2-methylpropyl
c) R = benzyl
Me
H
Myrioxazine A
OH
OH
N
N
O
MeO
O
H
N
OMe
NH
HO
H
Xylogranatinin
O
N
H
2
Figure 2. Representatives of the ring systems which were isolated
from different natural sources
8 9
N
1
O
5 4a 4
pyrido[1,2-b][1,2]oxazine
8 9
N
4a
5
1
S
4
pyrido[1,2-b][1,2]thiazine
8 9
N
5
4a
N
5
4a
N
9
9a
1
O
O
N
5 4a 4
6
5 4
pyrido[1,2-c][1,3]oxazine pyrido[2,1-c][1,4]oxazine
8
9
1
N
5
4a
9
S
9a
1
S
N
6
4
5
4
pyrido[1,2-c][1,3]thiazine pyrido[2,1-c][1,4]thiazine
H1
N
8 9 1
4
5
pyrido[1,2-b]pyridazine
8 9
8 9 1
N
4a
9 9a 1
N
NH
N
4
6
pyrido[1,2-c]pyrimidine
5
4
pyrido[1,2-a]pyrazine
H1
B
9
4
6
9a
1
PH
N
pyrido[2,1-f][2,1]azaborine
5
4
pyrido[1,2-a][1,4]azaphosphorine
Figure 3. Overview of the known bicyclic ring systems containing one bridgehead nitrogen
atom and one extra heteroatom with their numbering. The name of those ring systems which are
treated in this review are indicated italics.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
5
9
10
11
N
10
X
11
N
X
6
5
4
6
O
S
[1,2]oxazino[3,2-b]isoquinoline
N
pyridazino[1,6-b]isoquinoline
4
pyrido[1,2-b]cinnoline
1
11a 11b
X
N5
8
5
1
pyrido[1,2-b][1,2]benzoxazine
pyrido[1,2-b][1,2]benzothiazine
1
X
X
11a
X
10a N 11
4
7
7
1
11a 11b
4
N5
X6
6
8
O [1,2]oxazino[2,1-a]isoquinoline [1,2]oxazino[2,3-a]quinoline
[1,2]thiazino[2,3-a]quinoline
S
N pyridazino[6,1-a]isoquinoline pyridazino[1,6-a]quinoline pyrido[2,1-a]phthalazine
1
X
3
10 N 10a
2
4
X
N5
1
4
12a
X
7
6
9
8
pyrido[3,2,1-ij][2,1]benzoxazine [1,2]oxazino[3,2-j]quinoline
O
pyrido[3,2,1-ij]cinnoline
N
Figure 4. Overview of the known benzologs of pyrido[1,2-b][1,2]oxazine, -[1,2]thiazine, and
-pyridazine with their numbering. The name of those ring systems
which are treated in this review are indicated italics.
2
1
10
9
11
1
X
6
5
11a
X2
N
4
X3
11b N
10a
N
4
11
5
7
8
X
1
7
6
O
[1,3]oxazino[3,4-b]isoquinoline
[1,3]oxazino[4,3-a]isoquinoline [1,3]oxazino[3,4-a]quinoline
S
[1,3]thiazino[3,4-b]isoquinoline
[1,3]thiazino[4,3-a]isoquinoline
N
pyrimido[1,6-b]isoquinoline
pyrimido[6,1-a]isoquinoline
pyrimido[1,6-a]quinoline
2
1
11a
11b
N
X
4
1
10a
X
9
N
4
1
N
X5
7
12a
8
7
4
5
8
X
O pyrido[1,2-c][1,3]benzoxazine pyrido[3,2,1-ij][3,1]benzoxazine pyrido[2,1-j][3,1]benzoxazine
S pyrido[1,2-c][1,3]benzothiazine pyrido[3,2,1-ij][3,1]benzothiazine
N
pyrido[1,2-c]quinazoline
pyrido[3,2,1-ij]quinazoline
Figure 5. Overview of the known benzologs of pyrido[1,2-c][1,3]oxazine, -[1,3]thiazine, and
-[1,2-a]pyrimidine with their numbering. The name of those ring systems
which are treated in this review are indicated italics.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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2
X
1
10
11
11a
1
11a
11b N
X2
5
N
X
7
6
5
4
8
7
O
[1,4]oxazino[4,3-b]isoquinoline
[1,4]oxazino[3,4-a]isoquinoline
S
[1,4]thiazino[4,3-b]isoquinoline
[1,4]thiazino[3,4-a]isoquinoline
N
pyrazino[1,2-b]isoquinoline
pyrazino[2,1-a]isoquinoline
2
X3
1
10a
N
11
X
4
1X
1
11
4
N 11a
10a 10b
N
8
7
4
X5
7
6
7
O [1,4]oxazino[4,3-a]quinoline pyrido[2,1-c][1,4]benzoxazine
pyrido[1,2,3-de]-1,4-benzoxazine
S [1,4]thiazino[4,3-a]quinoline pyrido[2,1-c][1,4]benzothiazine pyrido[1,2,3-de]-1,4-benzothiazine
N
pyrazino[1,2-a]quinoline
pyrido[1,2-a]quinoxaline
pyrido[1,2,3-de]quinoxaline
Figure 6. Overview of the known benzologs of pyrido[2,1-c][1,4]oxazine, -[1,4]thiazine, and
-pyrazine with their numbering. The name of those ring systems
which are treated in this review are indicated italics.
This chapter is divided into three subsections to treat separately bicycles appeared on Figure
3 with their benzo derivatives (Figures 4-6), as their basic synthesis differs from each other.
Within each subsection structure, reactivity, synthesis and important compounds are discussed.
II. Pyrido[1,2-b][1,2]oxazines, -[1,2]thiazines, -pyridazines and Their
Benzologs
A. Structure
1. Theoretical Calculations
Partition coefficients of hexahydropyrido[1,2-b]pyridazines 31 were calculated by ACD
software to be 1.49 (R = CH2CH2tBu) and 1.09 (R = 4-FC6H5) <2008BML5002>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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N
3
R
N
O
H
N
OH
N
S
O
O O
S
N
Me
H
O
R = CH2CH2tBu
R = 4-F-PhCH2
On the basis of CoMFA and CoMSIA analysis three conformationally restricted selective D3
ligands, were successfully constructed and synthesized. One of them is cis-7H,9aH-7-{2-(2benzo[b]thienyl)carbonylamino]ethyl}-2-(2,3-dichlorophenyl)perhydropyrido[1,2-a]pyrazine
<2006BMC5898>.
2. Experimental Structural Methods
According to the 1H NMR investigations hydrazone 4 exists predominantly as E isomer,
while its pyrimidine analog 5 exhibits E-Z isomerism in CDCl3 ,2008TL5711>.
N+
N
H. . NH
O
N
S
O
N
O
.
H
. N N.
- .
O
H... NH
O
N
N
O
S
4
O
CDCl3
S
O
5
.H
N
O
The structure of 3,4-dihydropytidazino[1,6-b]isoquinolin-10-one 6 was determined by single
crystal X-ray experiment <2007SL3431>.
O
N
N
H Ph
Me
PhOC
Br
O
PhOC
N
N
H
6
Me
H Ph
7
CO2Me
CO2Me
N
N
H
CO2Me
CO2Me
8
The relative configurations of diastereomers of 5a-H epimers 7 and 8 were established by Xray crystallographic analysis <2008OL689>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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B. Reactivity
1. Ring Opening
When oxazine 9 was hydrogenated over PtO2 catalyst in the presence of CaCO3 and the
primarily formed perhydropyrido[1,2-b][1,2[oxazin-8-one 10 suffered an N-O cleavage to give
piperidin-2-one 11 <2009S6555>.
O
O
HN
O
Bu
H2, PtO2
O
N
O
Bu
NH
CaCO3, MeOH
MeO
Bu
88%
H
H
9
H
11
10
OH
2. Oxidation
Oxidation of 3,4-dihydro-10H-pyridazino[1,6-b]isoquinolin-10-ones 12 with DDQ afforded
the unsaturated 10H-derivatives 13 <2007S2208>.
O
R
O
N
N
Me
DDQ
, HPh
R1
N
N
Me
R1
57-61%
O
12
R
13
O
R = H; R1 = Cl, Br
1
R = Cl, Br; R = H
3. Reduction, Hydrogenation
Catalytic hydrogenation of 2-(2,4-difluorophenoxy)-5-{2-vinylphenyl and 2-[(1E)-prop-1enyl)phenyl]}-6H-pyrido[1,2-b]pyridazin-6-ones over Pd/C in EtOAc yielded 5-(2-ethyl- and 2propylphenyl) derivatives <2007USP(A)0129372>.
4. Reactivity of the Ring Carbon Atom
Reaction of 2-chloro-6H-pyrido[1,2-b]pyridazin-6-ones 14 with phenols, thiophenols, 2,4difluorobenzyl zinc bromide, biphen-2-ylboronic acid, 2,4-difluoroaniline, and NH4OH/NH4Cl
afforded
different
2-substituted
6H-pyrido[1,2-b]pyridazin-6-ones
15-20
(Scheme
1)
<2007USP(A)0129372>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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N
N
O
Ar
R = F, Cl
O
N
R
F
N
NH2
O
N
N
O
F
F
F
Ar
16
F 17
NMP
Cs2CO3
o
80-90 oC 90 C NH4Cl
phenols
16 h NH4OH
THF
1-2 h
2,4-difluorobenzylzinc bromide
Ar = 3-CO2Me,5-MeO-C6H3,
N
Cl
(Ph3P)4Pd(0)
2,6-F2-C6H3, 2-MeO-Ph,
N
80 oC, 0.5 h
2-F-Ph, 2-Cl-Ph
O
2,4-difluoroaniline
thiophenols
Ar
14
Pd(DBA), NaOBu
NaH
MePh
EtOH - MePh
THF
80 oC, 3 h
H
2M Na2CO3
10 min
N
N
(Ph3P)4Pd(0)
N
B(OH)2
90 oC, 1 h
N
S
N
O
F
F
F
F
O
R
F
N
N
20
F
F R = F, Cl
15
O
F
18
F
19
Scheme 1.
Treatment of pyrido[1,2-b][1,2]benzothiazine-2-carboxylate 21 with LiCl in DMSO at 130
o
C gave decarboxylated product 22 <2008TL5711>.
OH
OH O
OH
CO2Et
S
21 O
N
LiCl
DMSO, 130 oC, 3 h
O
S
22 O
N
O
5. Reactivity of Substituent Attached to a Ring Carbon Atom
Amino group of 2-amino-5-(2,4-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one was
reacted with (2-fluorophenyl)isocyanate, with 2,4-difluorobenzoyl chloride to give 2-[N2-(2fluorophenyl)ureido]
and
(2,4-difluorobenzoyl)amino
derivatives,
respectively
<2007USP(A)0129372>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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Condensation of 10-oxopyrido[1,2-b][1,2]benzothiazine-5,5-dioxide 22 with arylhydrazines
in boiling EtOH gave hydrazones 4 and 5 in 90-94% yield <2008TL5711>.
6. Reactivity of Substituent Presents in a Side Chain
Aromatic ester group presents in side chain attached to position 5 of pyrido[1,2-b]pyridazine
skeleton was hydrolyzed under basic conditions to carboxyl group which was converted to 5methyl-1,2,4-oxadiazol-2-yl group by treatment with ClCO2Et and NEt3, followed by with
H2NNH2 H2O then with MeC(OEt)3, and to carboxamide groups by treatment with ClCO2Et and
NEt3, followed by with primary and secondary amines <2007USP(A)0129372>.
Aromatic bromo atom presents in phenyl ring attached to position 5 of pyrido[1,2b]pyridazine skeleton was changed for 3-fluorophenyl and 5-pyrimidyl group by treatment with
boronic acids in the presence of (Ph3P)4Pd(0) and 2M Na2CO3 in a mixture of MePh and EtOH
at 90 oC for 16 h. Vinyl, (1E)-propen-1-yl and 2-furyl groups were introduced into phenyl group
attached to position 5 of pyrido[1,2-b]pyridazine skeleton by the treatment the appropriate bromo
derivative with tributyl(vinyl)tin, tributyl(1-propenyl)tin and tributyl(2-furyl)tin, respectively, in
the presence of (Ph3P)4Pd(0) in MePh at 80 oC for 1 h <2007USP(A)0129372>.
7. Ring Transformation
Heating of hydrazones 4 and 5 in PPA at 180 oC for 30 min afforded pentacyclic derivatives
23 <2008TL5711>.
X
N
H
HO
N
O
S
X = CH 78%
O
X=N
57%
23
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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C. Synthesis
1. By Formation of One Bond α to the Bridgehead Nitrogen Atom [6+0(α)]
Catalytic hydrogenation of oxazine 9 over Pd/C catalyst gave pyrido[1,2-b][1,2]oxazin-8-one
10, while hydrogenation over PtO2 afforded piperidone 11 <2009S655>.
Cyclization of 1-(6-chloropyridazin-3-yl)-1-aryl-but-3-yn-2-ones 24 in the presence of TBAF
gave 5-aryl-6H-pyrido[1,2-b]pyridazin-6-ones 25 <2007USA0129372>.
TMS
OH O
N
N
Cl
THF, 0 oC
O
Ar
N
TBAF
N
Cl
O
S
Ar
24
NH
O O
25
Cl
26
Treatment of benzothiazine 26 with NaOEt in the presence oh CuCO3 in DMF at 70 oC for 5
h
provided
tricyclic
pyrido[1,2-b][1,2]benzothiazine-5,5-dioxide
22
in
42%
yield
<2008TL5711>.
5. By Formation of One Bond γ to the Bridgehead Nitrogen Atom [6+0(γ)]
Reaction of 1-aminopiperidine-2-carboxylates 27 and (benzo[1,2,4]thiadiazin-3-yl)acetic
acid 28 in the presence of DDC, followed by the treatment with NaOEt afforded pyrido[1,2b]pyridazin-2-ones 2 <2008BML5002, 2008WOP08/073987>.
N
R HO2C
NH
+
CO2Et
27
N
H
N
N
O
R
N
DCC
R1
S
O
CH2Cl2
rt, 2 h
N
H
N
CO2Et
N
O
28
t
R
N
NaOEt
EtOH
OH
o
R1 25 C, 1 h
8-9%
60 oC, 4 h
S
O
O
H
N
N
O
R1
S
O
3
1
R = 4-F-PhCH2, Bu CH2CH2; R = NHSO2Me
6. By Formation of Two Bond from [3+3] Atom Fragments
6-Endo-trig cyclization of anion 29, formed from 3-methylpyridazine by LDA in THF at -78
o
C, with 3-propynoate provided 6H-pyrido[1,2-b]pyridazin-6-one 30 <2006TL5063>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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Me
Me
N
+
CO2Me
N
1) -78 oC
rt, 4 h
N
2) MeCN, 80 oC
H2-C
O
29
OH O
N
OEt
S
30
NH
31
O
O
Cyclocondenzation of [1,2]benzothiazine-3-ester 31 and ethyl 4-chlorobutyrate in the
presence of NaOEt and CuCO3 in a mixture of EtOH and DMF at 65 oC for 8 h gave pyrido[1,2b][1,2]benzothiazine 22 in 47% yield <2008TL5711>.
Lewis acid [Ni(ClO4)2] catalyzed cycloaddition of 1-iminoquinolinium ylides 32 with
cyclopropanediesters 33 afforded diastereoselectively cis-1,2,3,4-tetrahydro-4aH-pyridazino[1,6a]quinoline-3,3-dicarboxylates 34. Somewhat lower conversion could be achieved by the
application of SC(OTf)3 and Mg(OCl4)2, while MgI2, Yb(OTf)3, Cu(OTf)2 and Cu(ClO4)2 gave
little or no conversion. The presence of water had a detrimental effect on the yield. Reaction in
the absence of 3Ǻ MS gave only 45% conversion, instead of 94% yield (R = H, R1 = Ph)
<2008OL689>.
R
R
R
H R1
N - EtO C
2
N+
O
CO2Et
+
32
R1
33
H
O
N
N
Ni(ClO4)2 H2O, (10 mol%)
O
H
3A MS, THF, rt, 16 H
H R1
CO2Et +
CO2Et
cis dr: 2.6-6.6 : 1
34
N
N
H
CO2Et
CO2Et
trans
t
R = H, CF3, OMe; R1 = H, vinyl, 4-R2-Ph; R2 = H, F, Bu, MeO, NO2
Similar reaction of N-benzoyl-2-iminoisoquinolinium ylide and cyclopropanediesters 33 (R1
= Ph) gave 1,2,3,4-tetrahydro-11bH-pyridazino[6,1-a]isoquinoline-1,1-dicarboxylate 35 with
high diastereoselectivity (dr > 20:1) <2008OL689>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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EtO2C
EtO2C
H
H
N
N
Ph
COPh
35
7. Ring Transformation
Heating hydrazones 36, obtained from the appropriate ketones and H2NNH2 H2O, in boiling
ethylene
glycol,
afforded
3,4-dihydro-10H-pyridazino[1,6-b]isoquinolin-10-ones
37
<2006SL3431, 2007RUS2130653, 2007S2208, 2008JAP209609>.
O
O
R
R
O
Me
R1
O H2N
36
N
, (CH2OH)2,
N
N
Me
R1
15-30 min
O
37
35-90%
Me
Me
25-69%
O
R
R1
O
R
NHNH2
O
Me
38
TsOH H2O, 
HPh, 10 min
N
Me
R1
O
39
Me
NH2
O
O
Me
Recyclization of hydrazides 38 was carried out by treatment with TsOH·H2O gave 3,4dihydro-10H-pyridazino[1,6-b]isoquinolin-10-ones 37 via tetrahydroisoquinolin-1-ones 39
<2006SL3431, 2007S2208>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
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8. Miscellaneous
Hydrogenation of 1,4-diketones 40 over PtO2, Pt (%5) and Pd/C (5%) catalysts afforded a
mixture
of
pyrrolo[1,2-a]quinoline-5-carboxylates
41,
[1,2]oxazino[2,3-a]quinoline-6-
carboxylates 42 and quinoline-4-carboxylate 43 <20006JHC1505>. When palladium catalyst
was applied 41 formed only a few percent.
R OH
R
NO2 O
O
R
H2
N
CO2Me
R = H, Me
41 CO2Me
H
N
Et
H +
H+
MeOH
40
O
N
42
CO2Me
PtO2 or 5% Pt (3 atm)
20-34%
36-53%
5% Pd/C (1 - 5 atm)
29-66%
3-4%
43
CO2Me
0%
4-37%
D. Applications and Important Compounds
Perhydropyrido[1,2-b][1,2]oxazine 10 was applied in the total synthesis of (-)-monomorine
I, an indolizidine alkaloid to control the stereoselectivity <2009S655>.
Hexahydropyrido[1,2-b]pyridazin-2-ones 3 and their lower homologs exhibited HCV NS5B
polymerase inhibitory activity and they may be applied in therapy to treat infections by hepatitis
C virus <2008BMC5002, 2008WOP08/073987>. 3,4-Dihydropyridazino[1,6-b]isoquinolin-10ones 37 are patented as electon-transfering agents in photoreceptors <2007RUP2310653,
2008JAP2008209609>.
III. Pyrido[1,2-c][1,3]oxazines, -[1,3]thiazines, -pyrimidines and
Their Benzologs
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
15
B. Structure
1. Thermodynamic Aspects
Diastereomers and optical isomers of hexahydropyrido[3,2,1-de]quinoxaline 44 were
separated by using silica gel flash column chromatography and preparative chiral HPLC
methods, respectively <2007JAP207131577>.
R
O
H
N
OMe
O
R
N
N
44
NH2
H
N
NH2
R = H, NO2
45
Diastereomers of nitro derivative of 45 (R = NO2) were separated on a silica gel column
chromatography, and enantiomers of cis-3H,7H derivative of 45 (R = H) were separated by
chiral HPLC <2006USA0004028>.
2. Theoretical Calculations
Actisomide was included in a set of drugs for in silico predictions of human drug clearance
using a different allometry methods <2008MI2, 2009JPS2472> and for in silico predictions of
volume of distribution using linear and nonlinear models <2009JMC4488>.
A new versatile 3D pharmacophore descriptor was developed, and perhydropyrido[1,2c]pyrimidines 46 and 47 were also used to built up this method <2008JCI797>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
16
O
N
S
N
N
N
O
O
O
H
H
O
NMe
O
N
N
N Ar1
N
NH
O
HN
t
CO2 Bu
5-HT1a,
46
5HT2a
HN
CO2tBu
47
α1-adrenergic
and
Ar
48
receptor
affinities
of
4-aryl-2-{4-[4-
(het)arylpiperazino]butyl}-2,3-dihydro-1H-, -2,3,5,6,7,8-hexahydro-1H- and -trans-4H,4aHperhydropyrido[1,2-c]pyrimidine1,3-diones 48 were analyzed by CoMFA methodology
<2006JJGM353>.
Chemical shifts of 13C CPMAS NMR spectra of 4-(4-fluorophenyl)-2-{4-[4-(3trifluoromethylphenyl)piperazino]butyl}-2,3-dihydro-1H-pyrido[1,2-c]pyrimidine1,3-dione and
its hydrochloride salt were unambiguously assigned by theoretical calculations at GIAO/DFT
(B3LYP/6-311+G**) level <2008JST325>.
3. NMR Spectroscopy
The temperature dependent 1H NMR measurements indicated that there is substantial double
character of C(10)-NMe2 bond
in 49. The barrier to rotation is about 18.5 kcal mol-1
<2008T8381>.
The structures of 4-aryl-2,3-dihydro-1H-pyrido[1,2-c]pyrimidine-1,3-diones hydrochlorides
50 were characterized by solid-state 13C CPMAS NMR spectroscopy <2008JST325>.
O
N
Me2N+
Me2N
N+
Cl-
N
O
Et
49
N
Cl-
N
HCl
N
N
N Ar
O
R = H, F;
Ar = 3-CF3-Ph, 2-pyridyl
2-pyrimidinyl;
50
Et
O
R
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
17
NOE measurement confirmed a cis-fused ring system of 4-methylperhydropyrido[1,2-a]pyrazin1-one N-oxide 51 with distorted conformation <2007TL1683>.
O
ON N
H
+
H
H
H
H
CH3
51
nOe enhancements
4. Mass Spectrometry
6-Methyl-3,4-dihydro-1H,6H-pyrido[1,2-c][1,3]oxazine-1,4-dione
was
identified
in
a
hemodialysate uremic sample by LC/MS/MS technique <2009RCM3194>.
9. X-Ray Investigations
Stereostructures of perhydropyrido[1,2-c][1,3]oxazines 52 and 53 <2006JOC8481,
2006TL923>, 3,4,4a,5-hexahydro-1H,8H-pyrido[1,2-c][1,3]oxazin-1-one 54 <2007EJO2015>,
1,11b-dihydro-2H,4H-pyrimido[6,1-a]isoquinolin-4-one 55 <2009OL1559>, and (+)-(3R,7R)-7amino-3-(4-methoxyphenyl)-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinazoline-1(2H)-one
<2006USA0004028>. The relative configuration of ethyl (1R*,2S*,11bS*)-1-benzyl-9,10dimethoxy-3-(4-methoxyphenyl)-4-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1a]isoquinolin-2-carboxylate was determined by X-ray crystallographic analysis <2009OL1559>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
18
t
O
N
O
O
O
N
Bu
N
O
H
H
OH
52
O
O
O
Br
H
PhH2CO H
53
H
54
OMe
EtO2C H
H
PhH2C
N
H
MeO
N
O
55
MeO
3,4,4a,5-Hexahydro-1H,8H-pyrido[1,2-c][1,3]oxazin-1-one adopts an unsymmetrical halfchair conformation with deviations of the C(2), C(3) and N(1), C(4) atoms, respectively, from
the main plain of the other ring atoms. The relative configurations of the asymmetric centers are
(2S*,4R*,8R*) <2007EJO2015>.
Stucture
of
4-(4-fluorophenyl)-2-{4-[4-(3-trifluoromethylphenyl)piperazino]butyl}-2,3-
dihydro-1H-pyrido[1,2-c]pyrimidine-1,3-dione was characterized by X-ray diffraction study
<2008JST325>. That of 6-oxopyrido[1,2-c]quinazolinium chloride 56 was established by X-ray
single-crystal diffraction <2008T8381>.
B. Reactivity
1. Ring Opening
Ring-opened products were obtained from 4-cyano-3-phenyl-3-trifluoromethyl-2,3-dihydro1H-pyrido[1,2-c]pyrimidin-1-one
<2005MI2>,
pyrido[1,2-c][1,3oxazin-1-ones
<2007EJC2015>,
3-methylene-3,4,4a,5-tetrahydro-1H,8Hperhydropyrido[1,2-c][1,3oxazines
<2006JOC8481, 2006OBC1587, 2006TL7923, 2009JA11707>, 10-(tert-butyl)-3-methylene3,4,4a,5-tetrahydro-3H-[1,3]oxazino[3,4-b]isoquinoline-1,10-dione
<2007EJO2015>
under
either acidic or basic conditions.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
19
Reduction of perhydropyrido[1,2-c][1,3oxazin-1-ones with Zn in AcOH yielded ring-opened
products <2006OBC1587>.
Reaction of 8-bromo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij][3,1]benzoxazine-1,3-dione
with methyl 3-amino-5-chlorobenzoate in NMP at 170 oC for 16 h gave N-(3.chloro-5methoxycarbonylphenyl)-5-bromo-1,2,3,4-tetrahydroquinoline-8-carboxamide
<2007WOP2007/028789>.
Me2N
49
HX
N+
Cl-
N
O
Me2N
- CO2
Et
X = MeO, HO, NMe2
N
Me2N
N Et + HCl when X = OH
N HN
O
57
X
56
Et
Pyrido[1,2-c]quinazolinium chloride 49 was stable when it was dissolved in MeOH, but ring
opened products 56 (X = NMe2) and 57 were obtained by treatment with HNMe2 at room
temperature in D2O and in H2O at 55 oC, respectively <2008T8381>. In MeOH the equilibrium
between 49 and 56 (R = OMe) favors tricyclic form. When volatiles were removed from D2O
solution of urea 56 (X = NMe2), it was converted back to the tricycle 49. In H2O carbamic acid
56 (X = OH) gradually losses CO2 to give 57 in 20% yield after 16 h.
H
N
Cl
58 O
H
Me
O
NH
Me
OH
Cl
59
Pyrido[2,1-j]-3,1-benzoxazin-6-one 58 could not be hydrolyzed to produce amino alcohol 59
<2006TL3815>.
2. Oxidation
Oxidation of 5-hydroxy-5-hydroxymethylperhydropyrido[1,2-c][1,3]oxazine derivative with
silica supported NaIO4 in CH2Cl2 at room temperature gave 8-oxo derivative <2006JOC8481,
2006TL7923>. That of 3-azidomethyl-5,6,7-tribenzyloxi-8-hydroxymethylperhydropyrido[1,2Hermecz I: Recent development in the chemistry…. 2010 January, February, March
20
c][1,3]oxazin-1-one with 2-iodoxybenzoic acid in DMSO afforded 8-aldehyde, which was
subsequently oxidized to 8-carboxyl derivative by the treatment with NaClO2 and NaPO4H2·H2O
in MeCN with 72% yield over two steps <2007CAR1813>.
Me
O
N
1) cat. OsO4,
H2O - dioxane, rt, 10 min
O
O
N
O
cat. PdCl2, CuCl, O2,
O
N
O
I 7:1 DMF - H2O, rt, 1 h
I 2) NaIO4, 75 min
H
61
O
H
3) RhCl(PPh3)3,
48% D, PhMe,
overnigth
I
H
86%
60
62
OsO4-Mediated dihydroxylation of 60 followed by an oxidative cleavage of the formed diol
with NaIO4 gave the aldehyde, which was decarbonylated with RhCl(PPh3)3 to yield 8-methyl
derivative 61 <2006OBC1587>. Wacker oxidation of 60 provided 8-(2-oxopropyl) derivative 62.
For some further example see Section III.B.6.
3. Hydrogenation, Reduction
Catalytic hydrogenation of (3S,4aS)-3-methyl-4,4a,7,8-tetrahydro-1H,3H-pyrido[1,2-c][1,3oxazin-1-one in MeOH over Pd/C (10%) afforded perhydro derivative <2009JA11707>.
Treatment of 5-oxoperhydropyrido[1,2-c][1,3]oxazine derivative with NaBH4 in MeOH
afforded trans-4aH,5H-5-hydroxy derivative <2006JOC8481, 2006TL7923>. Reduction of
trans-3H,4aH-4,4a,7,8-tetrahydro-1H,3H-pyrido[1,2-c][1,3]oxazin-1-one with LAH gave ring
opened 1-methyl-2-(2-phenyl-2-hydroxyethyl)-1,2,5,6-tetrahydropyridine <2008S1033>.
O
N
O
H
O
63
N
Li/NH3
o
Me Et2O, -55 C
70%
HO
H
64
O
O
N
+
Me
HO
 = 93/7
65
H
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
O
Me
21
Reduction of perhydropyrido[1,2-c][1,3]oxazin-6-one 63 with Li and NH3 in Et2O at -55 oC
gave a 93:7 diastereomeric mixture of 64 and 65 alcohols <2005OL5227>. Catalytic
hydrogenation of 5-benzyl-6,7-dihydroperhydropyrido[1,2-c][1,3]oxazine over 10% Pd/C in
EtOH for 9 h gave 5,6,7-trihydroxy derivative in 95% yield <2006JOC8481>. That of 3azidomethyl-5,6,7-tribenzyloxi-8-benzyloximethylperhydropyrido[1,2-c][1,3]oxazin-1-one over
Pearlman’s catalyst in aqueous MeOH in the present of a few drops of AcOH for 24 h afforded
3-aminomethyl-5,6,7-trihydroxy-8-hydroximethyl
<2007CAR1813>.
Similarly
c][1,3]oxazine-8-carboxylic
derivative
in
quantitative
yield
3-aminomethyl-5,6,7-trihydroxy-1-oxoperhydropyrido[1,2acid
and
3-methyl-5,6,7-trihydroxy-8-hydroxymethyl-
perhydropyrido[1,2-c][1,3]oxazin-1-one were obtained from 3-azidomethyl-5,6,7-tribenzyloxy1-oxoperhydropyrido[1,2-c][1,3]oxazine-8-carboxylic acid and 3-methylene-5,6,7-tribenzyloxy8-benzyloxymethylperhydropyrido[1,2-c][1,3]oxazin-1-one, respectively <2007CAR1813>.
7-Hydroxy- and 7-amino-3-aryl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin-1-ones
were prepared from 1,7-diones with NaBH4 in MeOH, and by treatment with NH4OAc in the
presence of NaBH3CN in a 1:1 mixture of CHCl3 and MeOH at 50 oC for 18 h, respectively
<2006USA0004028>. 7-Amino derivatives were also obtained from 7-hydroxyimino derivatives
by catalytic hydrogenation over Pd/C catalyst in a mixture of DMF and 2.5 M hydrogen chloride
methanol solution at 50 oC for 12 h.
Catalytic hydrogenation of 9-(3-substituted prop-1-enyl and prop-1-ynyl)-7-oxo-1H,3H,7H[1,3]oxazino[5,4,3-ij]quinoline-6-carboxylic acids and -6-carboxylates over Pd/C (10%) in a
solvent (CH2Cl2, a mixture of MeOH and CH2Cl2) for 5-65 h gave 9-(3-substituted propyl)
derivatives <2006WOP2006/050940, 2006WOP2006/050943, 2007WOP2007/054296>.
For some further example see Sections III.B.1. and 6.- 8.
4. Reactivity of Ring Carbon Atoms
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
22
O
N
O
O
Me
H
N
10% HCl
THF
O
66
92% H
O
Me
67
Conjugat addition of dipentylcuprate, prepared from pentylmagnesium bromide and CuI, to
3,4,4a,5-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-6-one 66 afforded nearly complete facial
selectivity
(>96%)
providing
8-pentylperhydro
pyrido[1,2-c][1,3]oxazin-6-one
67
<2005OL5227>.
Substitution reaction of 4-cyano-3-trichloromethyl-1H-pyrido[1,2-c]pyrimidin-1-one with
primary amines in boiling dioxane for 15 h gave 3-amino derivatives in
30-48% yields
<2005MI3>.
5. Reactivity of Ring Nitrogen Atom
Treatment of 6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-1H,3H-pyrido[1,2-c]pyrimidine1,3-dione with O-(2,4-dinitrophenyl)hydroxylamine in the presence of K2CO3 in a mixture of
THF and DMF at 80 oC for 2 h gave 2-amino derivative in 88% yield <2009TL785>.
4-Cyano-2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-1- and -3-ones were N-alkylated with MeI
in the presence of K2CO3 in DMF <2005MI2>. 4-Aryl-2,3-dihydro-1H-pyrido[1,2-c]pyrimidine1,3-diones were N(2)-alkylated with 1,4-dibromobutane in the presence of K2CO3 in boiling
acetone for 2 h in 57-95% yields <2006EJM125>.
6. Reactivity of Substituent Attached to Ring Carbon Atom
Protodesilylation of 3,4,4a,5-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-6-one 68 in the
presence of 10% aqueous solution of HCl gave 7-unsubstituted derivative 69 <2005OL5227>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
23
O
TIPS
N
O
O
Me
H
N
10% HCl
THF
O
68
Heating
O
Me
97% H
69
4-cyano-1-(4-methylphenyl)-1-trifluoromethyl-2,3-dihydro-1H-pyrido[1,2-
c]pyrimidin-3-one in POCl3 for 6 h provided 3-chloro-1H-pyrido[1,2-c]pyrimidine in 89% yield
<2005MI2>.
Treatment of 5-benzyl-6,7-(dimethylmethylenedioxy)perhydropyrido[1,2-c][1,3]oxazine with
1N HCl in MeOH at ambient temperature for 4 h gave 5-benzyl-6,7-dihydro derivative
<2006TL7923>. Hydroxy derivatives of perhydropyrido[1,2-c][1,3]oxazines were O-benzylated
with BnBr in the presence of NaH and TBAI in boiling THF <2006JOC8481, 2006TL7923>. 5Hydroxy group of a perhydropyrido[1,2-c][1,3]oxazine was O-mesylated with MsCl in pyridine
at room temperature, and mesyloxy group was changed for an azido group by inversion by
treatment with LiN3 in DMF at 110 oC, and hydrogenation over Pd/C in MeOH yielded an 5amino
derivative
<2006JOC8481>.
The
dihydroxylation
of
5-
methyleneperhydroperhydropyrido[1,2-c][1,3]oxazine 70 using OsO4 in the presence of
K3Fe(CN)6 and K2CO3 produced 5-hydroxy-5-hydroxymethyl derivative 52 in 92% yield
<2006JOC8481, 2006TL7923>.
O
O
O OsO4, K3Fe(CN)6, K2CO3, py
N
t
O
H
70
N
O
O
BuOH-H2O (1:1), rt, 16 h
52
H
OH
OH
Epimeric mixture of 3-bromomethyl derivatives 71 undergoes rapid dehydrobromination
with KtBu to afford 3-methylene derivatives 72 <2007EJO2015>. Treatment of 3-iodomethyl5,6,7-tribenzyloxi-8-benzyloxymethylperhydropyrido[1,2-c][1,3]oxazin-1-one with Bu4NOH in
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
24
MeCN yielded 3-methylene derivative, which was converted to 8-acetoxymethyl-3-methyl5,6,7,8-tetrahydto-1H,4aH derivative by treatment with Ac2O in TFA <2007CAR1813>.
R1
R
R
R1
O
t
N
KO Bu, THF
O
Br
H
71
-25 to -20 oC
80-88%
R
R
O
N
O
R = H, R1 = Me, tBu;
R = -(CH=CH)2-, R1 = tBu
H
72
(+)-Hyperaspine, a ladybird alkaloid, was obtained in 50% yield from perhydropyrido[1,2c][1,3]oxazin-6-one 63 by reduction of 6-oxo group with Li/NH3, followed by the acylation of
the hydroxyl group of a 93:7 diastereomeric mixture of 64 and 65 alcohols with pyrrole-2carbonyl chloride in the presence of NEt3 <2005OL5227>.
Bromo atom of 2-(4-bromobutyl)-4-aryl-2,3-dihydro-1H-pyrido[1,2-c]pyrimidine-1,3-diones
was replaced by 4(het)arylpiperazino group by treatment with 1-(het)arylpiperazines in the
presence of K2CO3 and KI in boiling MeCN for 10-15 h <2006EJM125>.
4-Amino derivatives were prepared from 4-benzamido derivatives of 4,4a,5,6,7,8-hexahydro3H-pyrido[1,2-c]pyrimidin-3-ones and perhydropyrido[1,2-c]pyrimidine-1,3-diones by heating
in diluted H2SO4 solution under reflux for 45 min. <2007SL1905, 2009S2802>.
8-[(2-Hydroxyethyl)amino] derivatives was prepared from 2-(3-chlorophenyl)-8-fluoro2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazoline-1,3-dione with ethanolamine (6 equiv.) in
NMP at 200 oC for 2 h under microwave irradiation in 35% yield. Buchwald-Hartwick reaction
of 8-bromo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazoline-1,3-diones with 4-amino-1benzylpiperidine in the presence of NaOtBu, Pd2(dba)3 and a catalytic amount of BINAP in
PhMe at 80 oC for 2-16 h afforded 8-[(1-benzylpiperidin-4-yl)amino] derivatives in 20% yield
<2007WOP2007/028789>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
25
7-Hydroxyimino-3-(4-methoxyphenyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin1-one was prepared from 1,7-dione with HONH2·HCl in EtOH in the presence of pyridine at 80
o
C for 3 h <2006USA0004028>. 7-Amino-3-(4-methoxyphenyl)-2,3,6,7-tetrahydro-1H,5H-
pyrido[3,2,1-ij]quinazolin-1-one was reacted with 4-dimethylaminobenzaldehide in a mixture of
CHCl3 and MeOH containing HCl, followed by the treatment with NaBH3CN at 70 oC for 3 days
to give 7-(4-dimethylaminophenyl)amino derivative.
O
O
N
of
N
XCH2COR 74
S
S X = Cl; R = CMe , OEt, NHPh;
3
H2N
R
X = Br; R = 4-Br-Ph;
43-52%
75 O
CN
73
Reaction
N
NH
4-cyano-1-oxo-2,3-dihydro-1H-pyrido[1,2-c]pyrimidine-1-thione
73
with
halogeno ketones 74 afforded tricyclic derivatives 75 <2008MI1>.
NH2 O
NC
Cl
N
N N
NH
H2N
N
Ph
CO2Et
76
Cl
77
EtOH, , 4 h
H2NHN
NH2 O
HN
N
NH
Ph
CO2Et
58%
- H2
HN NH
HN
- NH3
N NH
O
N
Cl
H2N
NH
Ph
CO2Et
NH
Ph
CO2Et
H2NNH2 H2O
Cl
O
O
N
Cl
NH
Ph
CO2Et
Reaction of 8-amino-7-cyano-2,6-dihydro-1H-pyrido[1,2-c]pyrimidin-1-one 76 and H2NNH2
H2O afforded tricyclic derivative 77 <2008H(75)887>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
26
Reaction
of
2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-1H,3H-pyrido[1,2-
c]pyrimidine-1,3-dione with 3(R)-[(tert-butoxycarbonyl)amino]methylpyrrolidine in MeCN at 85
o
C for 24 h gave 6-{3(R)-[(tert-butoxycarbonyl)amino]methyl-1-pyrrolidinyl derivative in 83%
yield <2009TL785>.
1-Aryl-4-cyano-1-trifluoromethyl-2,3-dihydro-1H-pyrido[1,2-c]pyrimidine-3-thiones
were
prepared form the 3-oxo derivatives by using Lawesson’s reagent in boiling PhMe for 10 h in
64-67% yields. S-Alkylation of 1-aryl-4-cyano-1-trifluoromethyl-2,3-dihydro-1H-pyrido[1,2c]pyrimidine-3-thiones with benzyl bromides, ethyl 2-broroacetate, and 2-chloroacetamides in
the presence of K2CO3 in DMF at ambient temperature gave 3-[(substituted methyl)thio)]-1Hpyrido[1,2-c]pyrimidines in 51-87% yields <2007MI1>.
Heck and Sonogashira couplings of 9-iodo-7-oxo-1H,3H,7H-[1,3]oxazino[5,4,3-ij]quinoline6-carboxylic acids and -6-carboxylates with 3-substituted allyl and propargyl derivatives in the
presence of Pd(OAc)2 and NEt3 in boiling MeCN for 4.5 h <2007WOP2007/054296> and that
of Pd(PPh3)2Cl2, CuI and NEt3 in a solvent (EtOH, MeCN,) at 50-100 oC for 1-16 h, sometimes
under
microwave
irradiation
<2006WOP2006/050940,
2006WOP2006/050943,
2007WOP2007/054296>, respectively, gave 9-(3-substituted prop-1-enyl and prop-1-ynyl)
substituted derivatives. Reaction of 9-iodo-3,3-dimethyl-7-oxo-1H,3H,7H-[1,3]oxazino[5,4,3ij]quinoline-6-carboxylate with S-[2-(2-tert-butoxycarbonylaminoethoxy)ethyl thioacetate in the
presence of CuI, K2CO3 and ethylene glycol in EtOH in a sealed tube at 120 oC for 1 h under
microwave
irradiation
gave
9-[2-(2-tert-butoxycarbonylaminoethoxy)ethylthio
derivative
<2006WOP2006/050943>.
Hydrolysis of alkyl 7-oxo-1H,3H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxylates under
basic conditions afforded 6-carboxylic acids <2006WOP2006/50940, 2006WOP2006/05943,
2007WOP2007/054296>.
An
amide
derivatives
was
prepared
from
9-fluoro-10-(4-
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
27
methylpiperazin-1-yl)-8-methyl-1H,3H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxylic acid and
an amine in the presence of DCC and <2007WOP2007/042504>.
7. Reactivity of Substituent Presents in a Side Chain
3-(4-Piperidyl)indoles were N-alkylated with 4-aryl-2-(4-bromobutyl)-2,3-dihydro-1Hpyrido[1,2-c]pyrimidine1,3-diones in the presence of K2CO3 and a catalytic amount of KI in
boiling MeCN for 4-5 h in 50-90% yields <2009EJC1710>.
HO
HO
O
N
O
I
H
78
The Sharpless asymmetric dihydroxylation (AD-mix-α) of epimeric mixture of 8-allylperhydropyrido[1,2-c][1,3-oxazin-1-one 60 in a mixture of tBuOH and H2O at 0 oC for 17 h gave
a diasteromeric mixture of dihydroxy derivative 78 in 90% yield <2006OBC1587>.
An oxo group presents in a side chain of perhydro-1H-pyrido[1,2-c][1,3-oxazin-1-one was
converted into an cyclic acetal group by treatment with ethyleneglycol in the presence of pTsOH·H2O in refluxing PhH <2006OBC1587>.
Iodo atom of a 3-iodomethylperhydropyrido[1,2-c][1,3]oxazin-1-one was changed for azido
group with NaN3 in the present of Bu4I in CH2Cl2. Treatment of 3-azidomethyl-5,6,7tribenzyloxi-8-benzyloxymethylperhydropyrido[1,2-c][1,3]oxazin-1-one with a mixture of Ac2O
and TFA at ambient temperature for 9 h gave 8-acetoxymethyl derivative, which was
deacetylated to 8-hydroxymethyl derivative under Zemplén conditions by treatment with
catalytic amount of Na in MeOH <2007CAR1813>.
Amino group, presents in a side chain of 7-oxo-1H,3H,7H-[1,3]oxazino[5,4,3-ij]quinoline-3carboxylic acids, was acylated with carbonyl(imidazol-1-yl) derivatives in DMF by dropwise
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
28
addition of DBU solution in DMF at room temperature. Reaction of the amino group of 9-(3aminopropyl)-3,3-dimethyl-1H,3H,7H-[1,3]oxazino[5,4,3-ij]quinoline-3-carboxylic acid and an
aldehyde in MeOH in the presence of NaOAc, followed by the treatment of the formed Schiff
base with NaBH3CN and AcOH gave N-alkylated product. This secondary amin was Nmethylated with a mixture of 37% H2CO aqueous solution and HCO2H in CHCl3 at 60 oC
Methanolysis of an acetoxy group, presents in a side chain of 7-oxo-1H,3H,7H[1,3]oxazino[5,4,3-ij]quinoline-6-carboxylic acids stirring in MeOH at 50 oC overnight yielded
hydroxyl derivatives <2006WOP2006/050943>.
A carbonate moiety, presents in a side chain of 7-oxo-1H,3H,7H-[1,3]oxazino[5,4,3ij]quinoline skeleton, was hydrolysed under basic condition to yield a 1,3-dihydroxy derivative
<2007WOP2007/054296>. Ester and pivaloyloxy groups, present in a side chain of 1,2,3,5,6,7hexahydropyrido[3,2,1-ij]quinazolin-1-ones, were hydrolyzed to carboxyl and hydroxyl groups,
respectively
under
basic
benzyloxycarbonylamino
conditions
<2007JP2007131577>.
<2007JP2007131577>
and
Phtalimido,
tert-butoxycarbonylamino
and
groups
<2006WOP2006/050490, 2006WOP2006/050943>, present in a side chain of pyrido[3,2,1ij]quinazolin-1-ones, were converted to an amino group by treatment with H2NNH2·H2O in
boiling EtOH for 45 min, by catalytic hydrogenation over Pd/C in MeOH, by treatment with
TFA in CH2Cl2 , respectively.
Reaction of an amino group, presents in a side chain of 7-oxo-1H,7H-[1,3]oxazino[5,4,3ij]quinoline-3-carboxylic acids, with ethylene derivatives in the presence of NEt3 in DMSO at 50
o
C yielded (2-substituted ethyl)amino additional products <2006WOP2006/050940
For some further example see Sections III.B.4.
8. Ring Transformation
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
29
Methanolysis of 8-acetoxymethyl-5,6,7,8-tetrahydro-1H,4aH-pyrido[1,2-a]pyrimidin-1-one
79 under Zemplén condition in MeOH with catalytic amount of Na yielded 8-hydroxymethyl
derivative 80, which underwent ring transformation by intramolecular attack of the hydroxyl
group on the carbonyl group to give oxazino[3,4-a]pyridinone 81 in 70% yield
<2007CAR1813>.
AcO
BnO
N
BnO
BnO
HO
O
H
Me
79
H
BnO
BnO
O
O
N
BnO
BnO
H
80
N
O
Me
O
BnO
BnO
O
O
H
Me
81
Ring opening and ring closure reaction of 1H-pyrido[1,2-c]pyrimidin-1-one 82 with H2NNH2
H2O afforded triazin-5-one 83 <2005MI3>. That of 1H-pyrido[1,2-c]pyrimidin-3-ones 84 (X =
O) and 1H-pyrido[1,2-a]pyrimidin-3-ones 84 (X = S) with bromomethyl aryl ketones gave
oxazolidine and thioxazolidine derivatives 85 (X = O, S) <2005MI2, 2007MI1>. Thioxazolidine
derivatives 85 (X = S, R = OEt) were also obtained from ethyl 2-[(4-cyano-1-aryl-1trifluoromethyl-1H-pyrido[1,2-c]pyrimidin-3-yl)thio]acetates in DMF at 80-90 oC for 18 h
<2007MI1>.
Heating
3-(aminocarbonylmethylthio)-4-cyano-1-(4-methylphenyl)-1-
trifluoromethyl-1H-pyrido[1,2-c]pyrimidine in the presence of K2CO3 in DMF at 80-90 oC for 28
h gave (Z)-2-[cyano-(2-pyridyl)methylene]-1,3-tiazolidin-4-one in 67% yield <2007MI1>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
30
O
N
O
H2NNH2 H2O
N
DMF, 1 h
CCl3
82
NH
83
N
NH
X
CN
84
CN
O
CF3
Br
NH
N
H
68%
CN
Ar
N
Ar CF3
N HN
R
K2CO3, DMF,
60-65 oC, 8 h 13-72%
X = O, S
R
X
CN
85
O
2,3,5,6,7,8-Hexahydro-1H-pyrimido[5,6,1-jk][1,4]benzdiazepine-1,8-one 87 was obtained in
6% yield when NaN3 was gradually added to a solution of 2,3,5,6-tetrahydro-1H,7Hpyrido[3,2,1-ij]quinazoline-1,7-dione 86 in MeSO3H at 0 oC, then the green reaction mixture was
stirred at ambient temperature for 1 h <2006USA0004028>.
OMe
OMe
H
N
O
O
N
NaN3, MeSO3H
o
0 C
86
H
N
N
rt, 1 h
NH
O
O
87
C. Synthesis
1. By Formation of One Bond α to the Bridgehead Nitrogen Atom [6+0(β)]
Photocyclization
of
the
epimeric
mixture
of
trimethylsilyloxazine
88
gave
5-
methylperhydropyrido[1,2-c][1,3]oxazine 89 <2006JOC8481, 2006TL7923>. If the reaction was
carried out in the presence of 1,4-dicyanonaphthalene (DCN) 5-methylene derivative 90 was the
product <2006JOC8481>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
31
O
O
N
O
h, 450 W lamp
MeCN : 2-PrOH (3:1)
4h
O
N
TMS
DCN, h, 450 W lamp
88
MeCN : 2-PrOH (3:1)
4h
O
O
O
N
O
O
H
Me 60%
89
H
60%
90
Perhydropyrido[1,2-c][1,3]oxazin-1-one 92 was obtained from 1-(tert-butoxycarbonyl)-2-(2hydroxyethyl)piperidine 91 with MsCl in the presence of NEt3, followed by heating in boiling
MeCN in the presence of K2CO3 <2006JOC8481>.
1) MsCl, NEt3
CO2tBu
o
N
OH CH2Cl2, 0 C, 10 min
HO
2) K2CO3, , MeCN, 6 h
HO
91
H
OCH2Ph
O
HO
HO
89%
92
N
O
H
OCH2Ph
Heating of 6-(4-chloro-3-hydroxybutyl)-2,4-dimethoxy-5-methylpyrimidine in methanol
saturated with gaseous NH3 at 60 oC overnight gave 7-hydroxy-3-methoxy-4-methyl-5,6,7,8tetrahydro-1H-pyrido[1,2-c]pyrimidin-1-one in 72% yield <2005MI1>.
Heating a well-mixed mixture of 1-(2-hydroxyethyl)-2-ethoxycarbonyl-6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline and solid NaOMe at 130 oC for 45 min followed by extraction of
the reaction mixture with EtOAc provided 9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4H[1,3]oxazino[4,3-a]isoquinolin-4-one in 52% yield <2009T8021>.
EtO2C
PhH2C
MeO
MeO
N
OMe
N
CF3CO2H
O
93
CH2Cl2, rt, 1.5 h
67%
EtO2C
PhH2C
N
H
MeO
N
O
MeO
OMe
94
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
32
Pyrimidinone
93
was
converted
into
1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-
a]isoquinolin-4-one 94 by a Pictet-Spengler reaction under a strong acidic conditions
<2009OL1559>.
2. By Formation of One Bond α to the Bridgehead Nitrogen Atom [6+0(γ)]
Bromocyclocarbamation reaction of 2-allyl-1-(tert-butoxycarbonyl)tetrahydropyridine 95
gave inseparable mixture of 3-epimer of 96 and 97. When a bulky R1 substituent (tBu) was
present in 95 a good level of diastereoselectivity was observed <207EJO2015>. Reaction of 2,6diallyl-tetrahydropyridine 98 with Boc2O in boiling THF, followed by bromocyclocarbamation
reaction with NBS, than treatment of the reaction mixture with KOtBu yielded a mixture of 5and 7-bromo-3-methylene-tetrahydro-1H-pyrido[1,2-c][1,3]oxazin-1-ones 99 and 100.
R1
R
R
R1
O
t
N
O Bu
R
NBS, CHCl3
, 1 h
N
R
O
O
Br
R
H
O
N
+
Br
R
H
R1
O
H
96
95
97
96 : 97
1
R = H, R = Me
1
: 1
92%
4
: 1
91%
R = -(CH=CH)2-, R = Bu 4.8 : 1
88%
t
R = H, R1 = Bu
1
t
O
H
Br
NH
1) Boc2O, THF, , 1-2 h
N
O
2) NBS, CHCl3, , 1 h,
3) KOtBu, THF, -20 oC, 5 min
98
Br
O
H
H
Br

N
O
H
99
100
Iodocyclocarbamation reaction of trans-2,6-diallyl-1-(methoxycarbonyl)-perhydropyridine
with I2 in CH2Cl2 overnight provided an 3-epimeric mixture of trans-4aH,8H-3-iodomethyl-8allylperhydropyrido[1,2-c][1,3]oxazin-1-one in 98% yield <2006OBC1587>. That of 2-allyl-1-
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
33
benzyloxycarbonylpiperidina
101
gave
cis-3H,4aH-3-iodomethylperhydropyrido[1,2-
c][1,3]oxazin-1-one 102 <2007CAR1813>.
BnO
BnO
BnO
N
CO2CH2Ph
BnO
I2, CHCl3
o
0 C, 3 h
BnO
BnO
H
101
N
O
I
BnO
92%
O
BnO
H
102
Bromocyclocarbamation reaction of 1-allyl-2-[(R)-menthyloxycarbonyl] derivatives of
Reisert compound 103 was accompanied by BrOMe addition to the C(3)-C(4) double bond to
give 2-bromomethyl-[1,3]oxazino[4,3-a]isoquinoline-4-ones 104 either under condition A with
Br2 or under condition B using pyridinium tribromides <2008JHC1651>.
Br
R
R
O
NC
N
O
NC
O-(R)-Menthyl
Condition A: Br2, CH2Cl2-MeOH
N
Condition B: Py·HBr3, CH2Cl2-MeOH
103
R = H, Condition A, 35%
R = Me, Condition B, 66%
O
OMe
104
Br
Treatment of methoxymethoxy derivatives 105 and 107 with iodotrimethylsilane gave
perhydropyrido[1,2-c][1,3]oxazin-1-ones 106 and 108, respectively in moderate yields
<2006OBC1587>. Better yields could be achieved when alcohol 109 was treated either with
iodotrimethylsilane or with Corey’s reagent PrSLi, prepared from PrSH and BuLi.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
34
O
O
N
O
CO2Me
TMSI
N
O
o
H
MOMO
105
MeCN, 0 C, 2 h
50%
O
H
97%
106
TMSI
MeCN,
0 oC, 2 h
O
O
N
PrSLi
THF, rt, 5 d
O
CO2Me
TMSI
N
MeCN, 0 oC, 2 h
H
MOMO
N
O
CO2Me
H
HO
109
90%
H
48%
108
107
[1,3]Oxazin-2-ones 110 and 112 underwent ring-closing methathesis on treatment with the
Grubb’s first-generation and second-generation catalysts to yield tetrahydro-1H,3H-pyrido[1,2c][1,3]oxazin-1-ones 111 <2008S1033> and 113 <209JA11707>, respectively.
O
N
O
(Cy3P)2Cl2Ru=CHPh
O
Ph
H
CH2Cl2, rt, 3 h
N
82%
H
110
Mes N N Mes
Cl
Ru
Cl
PCy3Ph
O
N
O
O
Ph
111
O
N
O
o
H
Me
PhMe, 65 C, 3 h
112
80%
H
Me
113
The first representative 114 of pyrido[2,1-j]-3,1-benzoxazine ring system was synthesized by
the ring-closing methathesis of perhydro-3,1-benzoxazine 115 in the presence of the second
generation of Grubb’s catalyst <2006TL3815>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
35
H
Cl
N
Me
O
MesN NMes
Cl
Ph
Ru
Cl PCy
H
Me
O
3
N
o
PhH, 65 C,
86%
114 O
Cl
115 O
3. By Formation of Two Bond from [3+3] Atom Fragments
Cyclocondenzation of 2-pyridylacetonitrile and ethoxycarbonyl isothiocyanate in MeCN
gave
4-cyano-1-oxo-2,3-dihydro-1H-pyrido[1,2-c]pyrimidine-1-thione
in
18%
yield
<2008MI1>.
6-Endo-trig cyclization of anion, formed from 4-methylpyrimidine by LDA in THF at -78 oC,
with
3-propynoate
provided
8-methyl-6H-pyrido[2,1-c]pyrimidin-6-one
in
47%
yield
<2006TL5063>.
NC
CN
HN
Ar
O
NH O
NC
N
Ph
CO2Et
EtOH, , 3 H
N
Ar
NH O
NC
NH
Ph
CO2Et
N
Ar
NH
Ph
CO2Et
H H
Ar = Ph, 4-Cl-Ph, 4-MeO-Ph
75-80%
piperidine (cat)
O
NC
+
Ar
NH2 O
CN
HN
H3C
NC
N
Ph
CO2Et
116
N
Ar
117
NH
Ph
CO2Et
HC(OMe)3
, 4 h
CO2Et
N
O
N
H
Ph
Ph
Ph
HN
CO2Et
OEt
N
O
N
O
N
H
HN
Ph
CO2Et
CO2Et
N
O
N
O
Ph
CO2Et
72%
N
H
118
N
O
N
Ph
CO2Et
Scheme 2.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
36
Reaction of pyrimidin-2(1H)-one 116 and arylmethylenemalononitrile in the presence of
catalytic amount of piperidine gave 1,2-dihydro-6H-pyrido[1,2-c]pyrimidin-1-ones 117
<2008H(75)887>. The proposed reaction mechanism is depicted on Scheme 2. Heating 116 in
boiling HC(OMe)3 yielded 1H-pyrido[1,2-c]pyrimidin-1-one 118.
Reaction of N,C-dianion, formed from perhydro-3,1-benzoxacine 119 with BuLi, and 1,3propanediol di-p-tosylate afforded 6H-pyrido[2,1-j]-3,1-benzoxacin-6-one 120 with high
diastereoselectivity <2007OL2155>.
Ph
O
N S
Ph
O
N S
Me
HN
119
H
O
O
o
o
Me 1) BuLi, THF, -50 C to -10 C
2) TsO-(CH2)3-OTs, -50 oC to rt
Me
H
Me
N
59% (conv. 72%), de > 98%
120
H
O
O
4. By Formation of Two Bond from [4+2] Atom Fragments
Reaction of 2-allylpiperidine 121 with N,N-di(tert-butoxycarbonyl)thiourea in the presence
of HgCl2 yielded an epimeric mixtures of 3-(chloromercuriomethyl)perhydropyrido[1,2c]pyrimidine
122
and
2-chloromercuriomethylperhydrofuro[3,2-b]pyridine
123
<2007CAR1813>.
BnO
BnO
BnO
NH
N,N'-di-Boc-thiourea, HgCl2 BnO
NEt3, DMF, 0 oC, 24 h
BnO
BnO
H
121
BnO
25% BnO
BocN
BnO
NBoc
N
NBoc
H
122
+
HgCl
NHBoc
N
HgCl
O
BnO
23% OBn
123
5. By Formation of Two Bond from [5+1] Atom Fragments
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
37
O
TIPS
N
O
O
CH2Br2, K2CO3
TIPS
Me 10% DMSO/THF
Aliquat 336
82%
H
NH OH
O
Me
H
COCl2
TIPS
base
N
O
Me
H
124
125
O
126
Treatment of tetrahydropyridin-4-one 124 with CH2Br2 and COCl2 in the presence of a base
afforded tetrahydro-1H,3H-pyrido[1,2-c][1,3]oxazin-6-one 125 and -1,6-dione 126, respectively
<2005OL5227>.
O
F
N
COCl2
CN
Cl
MeO
128
F
N
KOtBu Cl
CH2Cl2
MeO
o
-78 C
rt
NH2
F
1) CDI, DBU
N2, 2 h rt, CH2Cl2
O
2) TFA-CH2Cl2 (10% w/w)
N
Cl
NH
O
MeO
127
130
93%
O
F
N HN
Cl
Im
O
MeO
129
While reaction of 2-[(aminocarbonyl)cyclopropylmethyl]pyridine 127 with COCl2 in the
presence of KOtBu led to the dehydration of the carbamoyl function of 127 to give nitrile 128,
instead of the bicyclic derivative 130, reaction applying CDI and DBU provided the desired
bicycle 130 formed in 20% yield, detected by HPLC <2009TL785>. When the cooled reaction
mixture was quenched by drop-wise addition of a solution of TFA in CH2Cl2 the isolated yield
was increased up to 93%. It was suggested that acid (TFA) simply activate the
carbonylimidazole (COim) leaving group of the reaction intermediate 129, driving cyclization. In
the absence of acid the intermediate was hydrolyzed back to the starting material 127.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
38
Reaction of 5-bromo-1,2,3,4-tetrahydroquinoline-8-carboxylic acid with COCl2 in THF at
room
temperature
for
16
h
gave
8-bromo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-
ij][3,1]benzoxazine-1,3-dione in 80% yield <2007WOP2007/028789>. Reaction of methyl 5fluoro-1,2,3,4-tetrahydroquinoline-8-carboxylate and (3-Cl-Ph)NCO in PhMe at 90 oC for 20 h
afforded 2-(3-chlorophenyl)-8-fluoro-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazoline-1,3dione in 35% yield. 8-Bromo-2-aryl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazoline-1,3diones were also prepared in the reaction of N-aryl-5-bromo-1,2,3,4-tetrahydroquinoline-8carboxamides and ClCO2Ph in boiling 1,2-dichloroethane for 30 min.
Reaction of 8-hydroxymethyl-4-oxo-1,4-dihydroquinoline-3-carboxylates 131 with 1,1diethoxyethane, 2,2-dimethoxypropane and ClCH2I yielded 7-oxo-1H,3H,7H-[1,3]oxazino[5,4,3ij]quinoline-6-carboxylates
132
<2006WOP2006/050940,
2006WOP206/050943,
2007WOP2007/054296>.
OH
H
N
I
MeCH(OMe)2and MeC(OEt)2Me
pTsOH H2O, MS(3Å), NMP, 80 oC, 1.5-7 h
CO2R
131
O
Reaction
of
R2
R1
O
ClCH2I, DMF,
K2CO3, 100 oC, 17 h
N
I
R = Me, Et
R1 = H, Me
R2 = H, Me
CO2R
132
4-amino-1,2,3,4-tetrahydroquinoline-8-carboxamide
O
and
2H-chromene-3-
carbaldehydes in MeOH in the presence of pTsOH·H2O at room temperature for 20 min than
heating for 2 h afforded racemic mixtures of cis-3H,7H- and trans-3H,7H-3-substituted 7-amino1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinazolin-1-ones, which were separated by flash column
chromatography <2007JP2007131577>. Similar reactions of 4-oxo-1,2,3,4-tetrahydroquinoline8-carboxamide
and
aromatic
aldehydes
gave
3-aryl-1,2,3,5,6,7-hexahydropyrido[3,2,1-
ij]quinazolin-1,7-ones <2006USA0004028>.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
39
Pyrido[1,2-c]quinazolinium chloride 49 was obtained in 81% yield, when 2-[2(ethylamino)phenyl]-4-dimethylaminopyridine was reacted with COCl2 in the presence of
polymer-supported diisopropylamine in CHCl3 at ambient temperature for 0.5 h <2008T8381>.
Reaction of 1-(2-hydroxyethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with 36%
H2CO solution in MeOH at room temperature provided 9,10-dimethoxy-1,6,7,11b-tetrahydro2H,4H-[1,3]oxazino[4,3-a]isoquinoline in 82% yield <2009T8021>.
6. Miscellaneous
Solvent-free three-component Biginelli reactions of 2-phenyl-1,3-oxazol-5-one, D-xylose/Dglucose and (thio)ureas 133 in the presence of Ce2(SO4)3 salt (10%)
under microwave
irradiation produced perhydropyrido[1,2-c]pyrimidines 134 and 135 with >94% trans
diastereoselectivity (Scheme 3). In the absence of Ce3+ salt no reaction occurred, and without
microwave irradiation using conventional heating at 90 oC yields were significantly lower (3951%) even for longer reaction times (3-5 h). If shorter reaction periods (4-7 min) was applied
addition products 136 could be isolated, which then were converted to pyrido[1,2-c]pyrimidines
134 (X = O, R = H) and 135 (X = S, R = Ph) <2007SL1905>.
w, 90 oC, 4-7 min, - H2O
X = O, R = H, n = 3
X
HO
HO
N
N
R
CHO
(CHOH)3
CH2OH
D-xylose
o
O MW, 90 C,
H
8-12 min,
OH NHCOPh
- H2O
134 74-82%
CH2OH
n(HOHC)
H
N
X
H
H
N
O NHR
O
Ph
136
MW, 90 oC,
4-6 min,
X
N
O +
H2N
w, 90 oC, 4-7 min, - H2O
X = S, R = Ph, n = 4
CHO
(CHOH)4
CH2OH
D-glucose
o
NHR MW, 90 C,
9-13 min,
133
- H2O
X = O, S; R = H, Et, Ph, 2-Me-Ph
Ph
O
HO
HO
X
N
N
R
HO
O
H
NHCOPh
OH
78-89% 135
Scheme 3.
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
40
Similar reactions using K-10 clay and amidines 137, instead of (thio)ureas, afforded
4,4a,5,6,7,8-hexahydro-3H-pyrido[1,2-c]pyrimidin-3-ones 138 and 139 with >95% trans
diastereoselectivity (Scheme 4). When other catalyst (CeCl3·7H2O, CeCl3·7H2O/NaI, silica gel,
neutral and acidic alumina), than K-10 clay, was applied the yield was lower. Applying shorter
reaction period addition products 140 could be also isolated and then cyclized <2009S2802>.
CH2OH
(HOHC)n
NH Me
H
H
N
O NH
O
Ph
140
w, K-10, 85 oC, 5-7 min,
n = 3, - H2O
HO
HO
N
N
CHO
(CHOH)4
CH2OH
D-glucose
4-6 min,
R
N
MW, 85 oC,
O
H
10-12 min,
OH NHCOPh
K-10
79-92% 138
- H2O
n = 4, - H2O
MW, 85 oC,
CHO
(CHOH)3
CH2OH
D-xylose
R
w, K-10, 85 oC, 5-7 min,
Ph
O
O
+
H2N
HO
R
HO
N
N
o
MW, 85 C,
10-12 min,
K-10
- H2O
NH
137
HO
O
H
OH NHCOPh
82-91% 139
R = H, Me, Ph, 4-NO2-Ph, 4-NH2-Ph, NH2
Scheme 4
Enantiomers of racemic cis-3H,7H- and trans-3H,7H-3-substituted 7-amino-1,2,3,5,6,7hexahydropyrido[3,2,1-ij]quinazolin-1-ones were separated by using chiral preparative HPLC
method <2006USA0004028, 2007JP2007131577>.
Me
EtO
NH
OEt
HN
MeO
S
141
EtO
NH
(CO2H)2
R
N
H2O, rt, 24 h
MeO
Me
Me
R
53%
cis:trans = 4:3
142
S
85% H3PO4
, 1.5 h
22%
NH
OEt
HN
S
143
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
41
Thiourea 141 was cyclized into a 4:3 cis-trans mixture of tricyclic compound 142 (R = OMe)
on the action of saturated aqueous solution of (CO2H)2 at room temperature, while thiourea 143
could be cyclized only in refluxing 85% H3PO4 <2006ROC1269>.
D. Applications and Important Compounds
O
N
N
N
N Ar1
O
Ar
The
affinities
of
144
4-aryl-2-{4-[4-(het)arylpiperazino]butyl}-2,3-dihydro-1H-pyrido[1,2-
c]pyrimidine1,3-diones 144 for 5-HT1a, 5HT2a and α1-adrenergic receptors were evaluated in
vitro
<2006EJM125>.
4-Aryl-2-{4-[4-(1H-indol-3-yl)piperidin-1-yl]butyl}-2,3-dihydro-1H-
pyrido[1,2-c]pyrimidine1,3-diones exhibit both selective 5-HT reuptake inhibitory and
presynaptic 5-HT1a receptor blocking activities <2009EJM1710>.
Trequinsin, a selective PDE3 inhibitor <2007CTM221>, significantly augmented glucosedependent insulin secretion in both INS(832/13) cell and rat islets <2008MI3>. 9,10-Dimethoxy2-[(2,4,6-trimethylphenyl)imino]-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro- and 9,10dimethoxy-2-(2,6-diisopropylphenoxy)-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-4-ones
are
long-acting PDE3/4 inhibitors exhibiting a both range both bronchoprotective and antiinflammatory activities <2006JEP840>.
Perhydropyrido[1,2-c][1,3]oxazin-1-ones were applied in the total synthesis of different
alkaloids [(-)-porantheridine, (-)-2-epi-porantheridine, (+)-epi-dihydropinidine, (-)-solenopsin A,
precoccinelline] to control the stereochemistry <2006OBC1587>. Sedamine <2008S1033> and
(+)-allosedridine alkaloids <2009JA11707> were synthesized through pyrido[1,2-c][1,3]oxazin1-one derivatives. trans-4aH,8H-3-Methylene-8-methyl-3,4,4a,5-tetrahydro-1H,8H-pyrido[1,2-
Hermecz I: Recent development in the chemistry…. 2010 January, February, March
42
c][1,3]oxazin-1-one was used in the synthesis of the (±)-6-epipinidinone alkaloid
<2007EJO2015>.
O
N C
N
HN
F
N
MeO
N
O
145
MeO
6,7-Dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one 145 did not blocked nicotinic acid
adenosine dinucleotide phosphate signaling <2009NCB220>.
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