A General Procedure for the Synthesis of Pyrido-Condensed Heterocycles

Article abstract of DOI:10.1055/s-2003-42411

Reaction of 4-substituted isoxazolo[4,5-c]- and [5,4-b]pyridines with Mo(CO)₆ in refluxing methanol is an efficient and versatile procedure for the preparation of functionalized pyrido-condensed heterocycles containing from five to eight atoms in the ring.

Full text of DOI:10.1055/s-2003-42411

2518
PAPER
A General Procedure for the Synthesis of Pyrido-Condensed Heterocycles
S
ynthesis of Pyrid
o
o-Condensed
n
Heterocycle
a
s
to Donati, Serena Ferrini, Stefania Fusi, Fabio Ponticelli*
Department of Chemistry, University of Siena, via A. Moro, 53100 Siena, Italy
Fax +39(577)234278; E-mail: ponticelli@unisi.it
Received 2 July 2003; revised 6 August 2003
Cl
ZNH2
N
N
Z
Me
Me
N
Abstract: Reaction of 4-substituted isoxazolo[4,5-c]- and [5,4-
HZNH2
Me
N
Mo(CO)6
N
b]pyridines with Mo(CO)6 in refluxing methanol is an efficient and
versatile procedure for the preparation of functionalized pyrido-
condensed heterocycles containing from five to eight atoms in the
ring.
N
O
O
∆, MeOH
Cl
Cl
HO
Cl
1
2a-h
3b-g
Key words: condensed pyridines, molybdenum hexacarbonyl, ring
opening, rearrangements, benzodiazocines
Scheme 1
tion masked into the 1,2-oxazole system can be released
through ring opening at the level of N–O bond. This result
can be achieved both by catalytic hydrogenation4d,5 or by
reaction with Mo(CO)6 in methanol.6 We have chosen the
latter procedure, as an experimentally easier technique. In
addition, this reagent does not affect other functional
groups, such as halogens, double bonds or nitro groups,
etc. and it is not inhibited by sulfur derivatives.
Pyrido-condensed heterocycles are widely considered for
their interesting biological properties. Activity of pyrazol-
opyridines in renal insufficience, Parkinson, Alzheimer
and cerebrovascular disease was recently reported1a. Dif-
ferently substituted pyridopyrimidines were proposed as
antiallergics, analgesics, antidepressants, antiulcer agents,
enzyme inhibitors, etc.1b Pyridodiazepines activity in cen-
tral nervous system control is comparable to that of the
well-known benzo-condensed analogous;1c–g in addition,
some pyridodiazepine derivatives were considered as in-
termediates in the preparation of anti HIV-1 susbstanc-
es.1h The more frequently used synthetic approaches to the
title heterocyclic systems involve the cyclization of a se-
lectively substituted pyridine1,2a,b or the intramolecular
[4+2] cycloaddition with inverse electron demand of an
alkyne moiety into trifluoromethyl substituted 1,2,4-tria-
zines.2c However, the above procedures require the prep-
aration of different intermediates and the overall yields
are generally not very high. As a consequence, the search
for a common starting material, suitable for the access of
different pyrido-condensed heterocycles appears to be of
wide synthetic interest.
List of the heterocyclic systems obtained using this syn-
thetic strategy is reported in Table 1; the ketonic interme-
diates were usually not isolated, with the exception of the
isoxazolopyridines 2a,g,h which gave the acetylpyridines
4a,g,h (Figure 1). Prolonged reflux in xylene of the inter-
mediate 4g gave the benzopyridodiazocine 3g in good
yields. On the other hand, attempts to cyclize compound
4h led only to decomposition products.
The compounds 3e, 3g and 4h were fully characterized by
reaction with diazomethane to give the corresponding
methoxy derivative 5, 6 and 4i, respectively (Figure 1).
Single crystal X-ray diffractometric analysis of com-
pound 6 was also carried out (Figure 2).
Following our previous studies on the chemical and spec-
tral properties of 1,2- and 1,3-oxazolopyridines,3,4 in this
paper we consider the use of 4,6-dichloroisoxazolo[4,5-
c]pyridine 1 as a versatile building block for the synthesis
of heterocycles. In fact, the reactivity of the chlorine atom
in position 44a allows the siteselective introduction of a
number of nitrogen- and sulfur nucleophiles, eventually
carrying also a second electron rich atom, as reported in
Scheme 1 and Table 1.
Figure 1 Structures of compounds 4–6
The nucleophilic attack proceeds with very good yields;
the formation of disubstituted products is avoided by a
careful choice of the experimental conditions. After the
introduction of the suitable nucleophile, the ketonic func-
It is worth to note the puckering of eight-membered diaz-
ocine ring in this compound with consequent non-equiva-
lence of the two protons in position 11. Slow
conformational interconversion of these protons was ob-
served in dimethyl sulfoxide solution at room tempera-
ture. In fact, in the 1H NMR spectra of diazocine 3g and of
the corresponding methoxy derivative 6, the protons in 11
and 12 position resonate as an ABX system. DNMR anal-
SYNTHESIS 2003, No. 16, pp 2518–2524
x
x.
x
x
.
2
0
0
3
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42411; Art ID: P05603SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pyrido-Condensed Heterocycles
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Table 1 Preparation of pyrido-condensed heterocycles from [4,5-c]pyridines
Entry
Reagent HZNH2
Intermediate 2a–h
Product 3b–g
Yield (%)
a
a
–
–
NH2
H3C
N
N
O
Cl
b
c
66
65
H2N NH2
N
O
NH
HN NH2
H3C
H3C
NH
NH
N
N
Cl
Cl
O
CH3
N
CH3
N
N
O
NH2
H3C
N
H3C
N
O
Cl
Cl
d
e
35
41
NH
NH
N
HN
NH2
H2N
H2N
NH2
NH2
H3C
N
N
H3C
O
O
Cl
Cl
NH2
NH
NH
NH
N
H3C
N
H3C
N
O
Cl
O
Cl
f
67
46
S
N
S
NH2
SH NH2
H3C
N
N
H3C
O
N
H
O
Cl
g
H2N
H2N H2C
H2N
NH
NH
N
HN
H3C
N
H3C
N
O
Cl
O
Cl
a
h
–
–
H2N
NH2 NH2
HN
H3C
N
N
O
Cl
a The reaction gave the corresponding acetylpyridine 4a or 4h.
Cl
N
ysis was carried out on compound 3g, which gives an A2X
system at 117 °C, due to an interconversion barrier of 20.5
Kcal/mol at the coalescence temperature.
ZNH2
N
N
Z
Me
N
Me
HZNH2
Me
Mo(CO)6
N
O
O
∆, MeOH
HO
N
The above ring opening/ring closure strategy can be easily
extended to the isoxazolo[5,4-b]pyridine system. In this
case the 4-chloro derivative 7 was selected as starting ma-
terial, owing to the previously observed4c lack of site se-
lectivity towards nitrogen nucleophiles of the
corresponding dichloro derivative. The isoxazolo[5,4-
b]pyridines 8a–d were prepared by reacting with the ap-
propriate nucleophile (Scheme 2, Table 2).
7
8a-d
9a-d
Scheme 2
Reaction of 8a–d with Mo(CO)6 gave the corresponding
heteroaryl condensed pyridines 9a–d.
In conclusion, we observe that the above synthetic strate-
gy allows the preparation of heteroaryl-condensed py-
ridines containing from five to eight atoms into the new
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2520
D. Donati et al.
PAPER
recorded with a LCQ-DECA Thermo Finnigan instrument. TLC
was performed on precoated 5 × 20 silica gel 60 F254 plates (Mach-
erey-Nagel) with detection by UV light. Column chromatography
was carried out on Silica gel (E. Merck, 0.063–0.2 mm). Elemental
analyses were performed at the Department of Organic Chemistry,
University of Florence, Italy.
4-Substituted Isoxazolopyridines 2 and 8; General Procedure
To the ice-cooled nucleophile HZNH2 (10 mmol) was added 4,6-
dichloro-3-methylisoxazolo[4,5-c]- (1)4a or 4-chloro-3-methylisox-
azolo[5,4-b]pyridine (7)4c (1 mmol) in portions. In the case of am-
monia and hydrazine, a solution of the nucleophile in 1,4-dioxane
(2 mL) was used. The resulting mixture was heated to the disappear-
ance (TLC) of the starting 1 or 7. The solvent and the excess of nu-
cleophile were removed in vacuo and the residue was treated with
ice water to give compounds 2 or 8 as white solids, which were crys-
tallized from the suitable solvents as reported below.
Figure 2 X-ray crystal structure of 6
6-Chloro-3-methylisoxazolo[4,5-c]pyridin-4-ylamine (2a)
Yield: 70%; mp 241–242 °C (CHCl3–MeOH, 95:5).
IR (KBr): 3480, 3280, 3240, 3130, 1640 cm–1.
1H NMR (DMSO-d6): = 2.53 (s, 3 H, CH3), 5.20 (br s, 2 H, NH2,
exchangeable with D2O) 6.89 (s, 1 H, H-7), 7.12 (br s, 2 H, NH2, ex-
changeable with D2O).
13C NMR: = 11.2 (CH3), 94.1 (C-7), 103.2, 149.5, 154.1, 154.2,
170.6 (Cq).
ring. The resulting compounds contain functional groups
such as chloro- and hydroxy- substituents, opening access
to several further substituted molecules. For the synthesis
of pyridodiazocine a benzo-condensed system is required,
probably due to the more favorable orientation of acetyl
and amino groups in the ring opened intermediate, as a
consequence of a minor conformational freedom.
MS (APCI): m/z (%) = 184/186 (M + 1, 100/33), 167/169 (3/1),
157/159 (10/3).
Melting points were determined on a Kofler hot stage and were un-
corrected. Products yields are given for purified compounds. IR
spectra were obtained for KBr discs with a Perkin-Elmer 782 spec-
trophotometer. 1H and 13C NMR spectra were recorded on a Bruker
AC 200 spectrometer at 200 MHz and 50 MHz, respectively. Chem-
ical shifts are reported in ppm from internal TMS. All reagents were
of reagents grade and were used without purification. EI MS spectra
were recorded on a VG 70 250S instrument; APCI MS spectra were
Anal. Calcd for C7H6ClN3O: C, 45.79; H, 3.29; N, 22.89. Found: C,
45.85; H, 3.34; N, 23.01.
(6-Chloro-3-methylisoxazolo[4,5-c]pyridin-4-yl)hydrazine (2b)
Mp 198–200 (dec.) [Lit.4a mp 200–201 (dec.)].
MS (APCI): m/z (%) = 199/201 (M + 1, 100/33); 182/184 (9/3).
Table 2 Preparation of Pyrido-Condensed Heterocycles from [5,4-b] Pyridines
Entry
Reagent HZNH2
Intermediate
8a–d
Product 9a–d
Yield (%)
90
a
N
O
NH
HN NH2
H3C
H3C
N
N
O
H
N
b
65
CH3
N
CH3
N
N
O
NH2
H3C
N
H3C
O
N
N
H
c
55
75
NH
N
HN
NH2
H3C
N
H3C
O
N
O
N
H
d
NH2
NH
N
NH
N
H3C
H3C
N
O
N
O
H
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Synthesis of Pyrido-Condensed Heterocycles
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N-(6-Chloro-3-methylisoxazolo[4,5-c]pyridin-4-yl)acetamidine
(2c)
(2-Aminobenzyl)-(6-chloro-3-methylisoxazolo[4,5-c]pyridin-4-
yl)amine (2g)
Yield: 65%; mp 152–153 °C (EtOH).
Yield: 63%; mp 132–133 °C (EtOH–H2O).
IR (KBr): 3390, 3200, 3110, 1630 cm–1.
IR (KBr): 3440, 3400, 3320, 3100, 1600 cm–1.
1H NMR (CDCl3): = 2.22 (s, 3 H, CH3), 2.71 (s, 3 H, CH3), 5.98
(br s, 1 H, NH, exchangeable with D2O), 7.04 (s, 1 H, H-7), 9.94 (br
s, 1 H, NH, exchangeable with D2O).
13C NMR (CDCl3): = 11.8 (3-CH3), 25.3 (CH3), 100.4 (C-7),
113.0, 147.6, 156.1, 157.8, 163.3, 169.7 (Cq).
1H NMR (DMSO-d6): = 2.48 (s, 3 H, CH3), 4.30 (br s, 2 H, NH2,
exchangeable with D2O), 4.62 (d, 2 H, J = 6.0 Hz, CH2), 5.16 (br, 1
H, NH, exchangeable with D2O), 6.54–7.22 (m, 4 H, C6H4), 6.71 (s,
1 H, H-7).
13C NMR (DMSO-d6): = 11.9 (3-CH3), 42.6 (CH2), 95.9 (C-7),
103.9 (C-3a), 116.3, 118.4, 122.6, 129.3, 130.7, 145.6 (C6H4),
150.3, 152.3, 152.7, 171.0 (C-7a).
MS (APCI): m/z (%) = 225/227 (M + 1, 100/33), 208/210 (10/3),
184/186 (7/2).
MS (EI): m/z (%) = 288/290 (M+, 29/9); 273/275 (24/8), 196 (8),
106 (100), 77 (18).
Anal. Calcd for C9H9ClN4O: C, 48.12; H, 4.04; N, 24.94. Found: C,
48.15; H, 3.93; N, 24.65.
Anal. Calcd for C14H13ClN4O: C, 58.24; H, 4.54; N, 19.40. Found:
C, 58.56; H, 4.44; N, 19.68.
N1-(6-Chloro-3-methylisoxazolo[4,5-c]pyridin-4-yl)ethane-1,2-
diamine (2d)
Yield: 54%; mp 141–142 °C (benzene).
N1-(6-Chloro-3-methylisoxazolo[4,5-c]pyridin-4-yl)propane-
1,3-diamine (2h)
Yield: 63%; mp 98–100 °C (benzene–cyclohexane).
IR (KBr): 3380, 3320, 3280, 1620 cm–1.
1H NMR: = 1.32 (br s, 2 H, NH2, exchangeable with D2O), 2.63
(s, 3 H, CH3), 2.99 (t, J = 5.4 Hz, 2 H, CH2NH2), 3.64 (q, J = 5.4
Hz, 2 H, CH2NH), 5.86 (br, 1 H, NH, exchangeable with D2O), 6.75
(s, 1 H, H-7).
13C NMR: = 11.8 (3-CH3), 40.5, 42.8 (2 CH2), 95.2 (C-7), 103.9,
150.6, 157.8, 163.9, 169.8 (Cq).
IR (KBr): 3400, 3100 cm–1.
1H NMR: = 1.51 (br s, 2 H, NH2, exchangeable with D2O), 1.76
(quint, J = 5.8 Hz, 2 H, CH2), 2.56 (s, 3 H, CH3), 2.98 (t, J = 5.8 Hz,
2 H, CH2NH2), 3.67 (dt, J = 5.8, 5.1 Hz, 2 H, CH2NH), 6.67 (s, 1 H,
H-7), 7.33 (s, 1 H, NH, exchangeable with D2O).
13C NMR: = 11.8 (3-CH3), 30.0 (CH2), 41.7 (CH2NH2), 42.3
(CH2NH), 94.4 (C-7), 150.6, 152.5, 153.1, 170.7 (C-7a).
MS (APCI): m/z (%) = 227/229 (M + 1, 100/33), 210/212 (29/10),
184/186 (6/2).
MS (EI): m/z (%) = 240/242 (M+, 27/9), 210/212 (47/15), 197/199
(100/30), 196/198 (62/23).
Anal. Calcd for C9H11ClN4O: C, 47.69; H, 4.89; N, 24.72. Found:
C, 47.39; H, 4.72; N, 24.49.
Anal. Calcd for C10H13ClN4O: C, 49.90; H, 5.44; N, 23.28. Found:
C, 50.00; H, 5.68; N, 23.22.
trans-N-(6-Chloro-3-methylisoxazolo[4,5-c]pyridin-4-yl)cyclo-
hexane-1,2-diamine (2e)
Yield: 55%; mp 92–93 °C (benzene–cyclohexane).
(3-Methylisoxazolo[5,4-b]pyridin-4-yl)hydrazine (8a)
Yield: 65%; mp 217 °C (EtOH).
IR (KBr): 3320, 3200, 1610 cm–1.
1H NMR (DMSO-d6): = 2.59 (s, 3 H, CH3), 4.58 (br s, 2 H, NH2,
exchangeable with D2O), 6.86 (d, 1 H, J = 6.0 Hz, H-7), 8.08 (d, 1
H, J = 6.0 Hz, H-6), 8.19 (br s, 1 H, NH, exchangeable with D2O).
IR (KBr): 3360, 3300, 3110, 1610 cm–1.
1H NMR: = 1.11–1.42 (m, 4 H, 2 CH2), 1.63–1.75 (m, 2 H, CH2),
1.83–2.08 (m, 2 H, CH2), 2.64 (s, 3 H, CH3), 2.63–2.78 (m, 1 H,
CH), 3.32 (br s, 2 H, NH2, exchangeable with D2O), 3.59–3.71 (m,
1 H, CH), 6.45 (br s, 1 H, NH, exchangeable with D2O), 6.97 (s, 1
H, H-7).
13C NMR (CDCl3): = 11.9 (3-CH3), 24.8, 25.2, 32.5, 36.5 (4 CH2),
55.9, 57.3 (CHNH2/CHNH), 95.5 (C-7), 104.1 (C-3a), 150.5, 152.8,
153.3, 170.9 (Cq).
13C NMR (DMSO-d6): = 13.0 (3-CH3), 97.3 (C-5), 100.1 (C-3a),
150.6, 153.8, 154.5, 171.4 (C-7a).
MS (APCI): m/z (%) = 165 (M + 1, 100), 163 (5), 150 (7), 136 (8).
Anal. Calcd for C7H8N4O: C, 51.21; H, 4.91; N, 34.13. Found: C,
51.48; H, 4.56; N, 33.82.
MS (EI, 20 eV): m/z (%) = 280 (M+, 4); 256 (4), 184 (10), 97 (100).
Anal. Calcd for C13H17ClN4O: C, 55.61; H, 6.10; N, 19.96. Found:
C, 55.32; H, 6.12; N, 19.55.
N-(3-Methylisoxazolo[5,4-b]pyridin-4-yl)acetamidine (8b)
Yield: 85%; mp 174–176 °C (benzene).
2-(6-Chloro-3-methylisoxazolo[4,5-c]pyridin-4-ylsulfanyl)eth-
ylamine (2f)
Yield: 85%; mp 80–81 °C (sublimed in vacuo).
IR (KBr): 3300, 3100–2000, 1590 cm–1.
1H NMR (CDCl3): = 1.49 (br s, 2 H, NH2, exchangeable with
D2O), 2.71 (s, 3 H, CH3), 3.05 (t, 2 H, J = 5.7 Hz, CH2NH2/CH2S),
3.42 (t, 2 H, J = 5.7 Hz, CH2S/CH2NH2), 7.13 (s, 1 H, H-7).
13C NMR: = 12.2 (3-CH3), 33.6 (SCH2), 41.4 (CH2NH2), 101.5
(C-7), 116.8, 150.1, 154.2, 156.1, 168.4 (Cq).
IR (KBr): 3420, 3305, 3170, 1650 cm–1.
1H NMR (CDCl3–DMSO-d6): = 1.98 (s, 3 H, CH3), 2.40 (s, 3 H,
3-CH3), 6.12 (br s, 2 H, NH2, exchangeable with D2O), 6.58 (s, 1 H,
H-5), 8.19 (d, 1 H, J = 5.4 Hz, H-6).
MS (APCI): m/z (%) = 191 (M + 1, 100), 176 (23), 150 (5).
Anal. Calcd for C9H10N4O: C, 56.83; H, 5.30; N, 29.46. Found: C,
56.57; H, 5.36; N, 29.79.
N1-(3-Methylisoxazolo[5,4-b]pyridin-4-yl)ethane-1,2-diamine
MS (APCI): m/z (%) = 244/246 (M + 1, 100/33), 227/229 (36/12),
(8c)
200/202 (3/1).
Yield: 76%; mp 123–125 °C (benzene).
Anal. Calcd for C9H10ClN3OS: C, 44.35; H, 4.14; N, 17.24. Found:
C, 44.39; H, 4.00; N, 16.97.
IR (KBr): 3350, 3300, 3240, 1610 cm–1.
1H NMR (CDCl3): = 1.44 (br s, 2 H, NH2, exchangeable with
D2O), 2.63 (s, 3 H, CH3), 3.12 (m, 2 H, CH2NH2), 3.30 (m, CH2NH),
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D. Donati et al.
PAPER
5.73 (br s, 1 H, NH, exchangeable with D2O), 6.26 (d, 1 H, J = 5.7
Hz, H-5), 8.14 (d, 1 H, J = 5.7 Hz, H-6).
13C NMR (DMSO-d6): = 25.0, 25.2 (2 C, 2 CH3), 111.6 (Cq),
112.0 (C-6), 145.9, 156.7, 166.9, 170.3, 175.4 (Cq).
13C NMR (CDCl3): = 13.0 (CH3), 39.9, 44.0 (CH2NH2 and
CH2NH), 99.9 (C-5), 151.7 (C-5).
MS (EI): m/z (%) = 209/211 (M+, 100/33), 181/183 (15/5), 168/170
(7/2), 133 (8).
MS (APCI): m/z (%) = 193 (M + 1, 100), 162 (8), 150 (4), 135 (4).
Anal. Calcd for C9H8ClN3O: C, 51.56; H, 3.85; N, 20.04. Found: C,
51.81; H, 3.77; N, 20.35.
Anal. Calcd for C9H12N4O: C, 56.24; H, 6.29; N, 29.15. Found: C,
56.29; H, 6.25; N, 29.24.
8-Chloro-5-methyl-1,2,3,9-tetrahydropyrido[2,3-e][1,4]diaz-
epin-6-one (3d)
Yield: 35%; mp 193–195 °C (dec.) (MeOH).
IR (KBr): 3250, 3200–2200, 1640 cm–1.
trans-N-(3-Methylisoxazolo[5,4-b]pyridin-4-yl)cyclohexane-
1,2-diamine (8d)
Yield: 60%; mp 213–215 °C (as hydrochloride).
IR (free base, KBr): 3360, 3270, 1615 cm–1.
1H NMR (DMSO-d6): = 2.56 (s, 3 H, CH3), 3.42, 3.54 (2 m, 4 H,
2- and 3-CH2), 5.50 (s, 1 H, H-7), 7.51 (br t, 1 H, J = 3.2 Hz, NH,
exchangeable with D2O), 10.51 (br s, 1 H, NH/OH, exchangeable
with D2O).
13C NMR (DMSO-d6): = 25.7 (CH3), 46.9, 47.2 (C-2 and C-3),
100.6 (Cq), 105.2 (C-7), 154.1, 159.9, 175.2, 179.6 (Cq).
1H NMR (free base, CDCl3): = 1.15–1.52 (m, 6 H, 2 CH2 and
NH2), 1.75–1.90 (m, 2 H, CH2), 1.94–2.09 and 2.21–2.33 (m, 2 H,
CH2), 2.63 (s, 3 H, CH3), 2.64 (br td, 1 H, CHNH2), 3.15 (m, 1 H,
CHNH), 5.17 (br d, 1 H, NH, exchangeable with D2O), 6.38 (d, 1 H,
J = 5.8 Hz, H-5), 8.13 (d, 1 H, J = 5.8 Hz, H-6).
13C NMR (free base, CDCl3): = 13.24 (3-CH3), 24.72, 24.91,
32.06, 36.09 (4 CH2), 55.76, 59.24 (CH2NH2/CH2NH), 100.42 (C-
5), 151.73 (C-6).
MS (EI): m/z (%) = 211/213 (M+, 75/23), 210/212 (26/15), 196/198
(6/2), 183/185 (100/31), 181 (24), 169 (11), 168 (10), 148 (23), 147
(24).
MS (APCI): m/z (%) = 247 (M + 1, 100), 230 (4), 216 (4), 150 (6).
Anal. Calcd for C9H10ClN3O: C, 51.07; H, 4.76; N, 19.85. Found:
C, 50.77; H, 4.82; N, 19.54.
Anal. Calcd for C13H18N4O·HCl: C, 55.22; H, 6.77; N, 19.81.
Found: C, 54.91; H, 6.89; N, 20.05.
R*,R*-2-Chloro-5-methyl-1,6a,7,8,9,10,10a,11-octahydroben-
zo[b]pyrido[2,3-e][1,4]diazepin-4-one (3e)
Mp >300 °C (dec.) (MeOH).
IR (KBr): 3400, 3230, 3000–2300, 1625 cm–1.
1H NMR (DMSO-d6): = 1.15–1.40, 1.43–1.80, 2.04–2.22 (3 br m,
8 H, 4 CH2) 2.54 (s, 3 H, CH3), 3.27–3.52 (m, 2 H, 2 CHN) 5.63 (s,
1 H, 3-H), 6.69 (br s, 1 H, NH, exchangeable with D2O), 10.24 (br
s, 1 H, NH/OH, exchangeable with D2O).
13C NMR (DMSO-d6): = 22.5, 23.2 (2 CH2), 24.3 (CH3), 30.1,
33.8 (2 CH2), 59.1, 62.6 (2 NCH), 101.9 (C-3) 105.9, 153.8, 156.3,
158.5, 162.5 (Cq).
Reaction of 4-Substituted Isoxazolopyridines 2a–h and 8a–d
with Mo(CO)6; General Procedure
Isoxazolopyridine 2 or 8 (1 mmol) and Mo(CO)6 (1 mmol) in
MeOH (30 mL) were refluxed till the disappearance of the starting
material (TLC). The black inorganic material was filtered off,
washed with MeOH, and the combined solvents were evaporated to
give a solid, which was chromatographed with CHCl3–MeOH (9:1)
through a short column in order to completely remove the inorganic
materials.
3-Acetyl-2-amino-6-chloro-1H-pyridin-4-one (4a)
Yield: 65%; mp 203–205 (MeOH).
MS (EI): m/z (%) = 265/267 (M+, 100/33), 250/252 (23/8), 237/239
IR (KBr): 3390, 3250, 3130-2350, 1635 cm–1.
(18/6) 222/225 (43/15), 196/198 (53/18).
1H NMR (CDCl3): = 2.67 (s, 3 H, CH3), 5.42 (br s, 2 H, NH2, ex-
changeable with D2O), 6.33 (s, 1 H, H-5), 10.45 (br s, 1 H, NH/OH,
exchangeable with D2O).
2-Chloro-5-methyl-7,8-dihydro-1H-9-thia-1,6-diazabenzocy-
clohepten-4-one (3f)
Mp >300 °C (dec.) (MeOH).
Anal. Calcd for C7H7ClN2O2: C, 45.06; H, 3.78; N, 15.01. Found:
C, 44.90; H, 3.56; N, 14.82.
IR (KBr): 3250, 3100–2000, 1625 cm–1.
1H NMR (DMSO-d6): = 2.32 (s, 3 H, CH3), 3.41–3.64 (m, 4 H, 7-
and 8-CH2), 6.69 (s, 1 H, H-3), 10.64 (br s, 1 H, NH/OH, exchange-
able with D2O).
6-Chloro-3-methyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one
(3b)
Mp >300 °C (MeOH).
13C NMR (DMSO-d6): = 24.8 (CH3), 31.8 (C-8), 48.0 (C-7), 110.2
IR (KBr): 3300–2300, 1625, 1590 cm–1.
(Cq), 112.1 (C-3), 150.5, 154.1, 167.3, 171.0 (Cq)
MS (EI): m/z (%) = 228/230 (M+, 55/18), 213/215 (12/4), 200/198
(100/33).
1H NMR (DMSO-d6): = 2.52 (s, 3 H, CH3), 6.45 (s, 1 H, H-5),
11.94, 13.08 (br s, 2 H, NH and NH/OH, both exchangeable with
D2O).
Anal. Calcd for C9H9ClN2OS: C, 47.27; H, 3.97; N, 12.25. Found:
C, 46.99; H, 4.20; N, 12.55.
13C NMR (DMSO-d6): = 15.8 (CH3), 100.7 (C-5), 103.9, 150.1,
153.9, 161.6, 170.5 (Cq).
3-Acetyl-2-(2-aminobenzylamino)-6-chloro-1H-pyridin-4-one
(4g)
Yield: 62%; mp 145–147 °C (CHCl3).
Anal. Calcd for C7H6ClN3O: C, 45.79; H, 3.29; N, 22.89. Found: C,
45.63; H, 3.47; N, 22.91.
IR (KBr): 3360, 3240, 3100, 3000–2200, 1630 cm–1.
7-Chloro-2,4-dimethyl-8H-pyrido[2,3-d]pyrimidin-5-one (3c)
1H NMR (DMSO-d6): = 2.51 (s, 3 H, CH3), 3.43 (br s, 3 H, NH2
and NH/OH, exchangeable with D2O), 4.49 (d, 2 H, J = 5.6 Hz,
CH2), 6.36 (s, 1 H, H-5), 6.79–7.19 (m, 4 H, C6H4), 9.64 (t, 1 H,
J = 5.6 Hz, NHCH2, exchangeable with D2O).
Mp >300 °C (EtOH).
IR (KBr): 3200–2100, 1640 cm–1.
1H NMR (DMSO-d6): = 2.61 (s, 3 H, CH3), 2.89 (s, 3 H, CH3),
4.21 (br s, 1 H, NH, exchangeable with D2O), 6.38 (s, 1 H, H-6).
Synthesis 2003, No. 16, 2518–2524 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrido-Condensed Heterocycles
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13C NMR (DMSO-d6): = 33.7 (CH3), 40.1 (CH2), 99.6, 101.7 (C-
5 and C-3), 115.2, 116.5, 122.4, 127.9, 129.1, 145.7 (aryl), 153.0,
158.9, 169.3 (C-2, C-4 and C-6), 198.7 (C=O).
5-Methyl-1,2,3,7-tetrahydropyrido[4,3-e][1,4]diazepin-6-one
(9c)
Mp 305–307 °C (dec.) (MeOH).
MS (EI): m/z (%) = 291/293 (M+, 22/7), 273/275 (12/4), 121 (10),
IR (KBr): 3260, 3110, 3100–2300, 1630 cm–1.
106 (100), 77 (14).
1H NMR (CDCl3–DMSO-d6): = 2.32 (s, 3 H, CH3), 3.46, 3.75 (2
m, 4 H, 2- and 3-CH2), 5.54 (d, 1 H, J = 7.2 Hz, 9-H), 6.56 (br s, 1
H, NH, exchangeable with D2O), 6.79 (d, 1 H, J = 7.2 Hz, 8-H),
10.38 (br s, 1 H, NH/OH, exchangeable with D2O).
Anal. Calcd for C14H14ClN3O2: C, 57.64; H, 4.84; N, 14.40. Found:
C, 57.44; H, 4.88; N, 14.11.
2-Chloro-5-methyl-11,12-dihydro-1H-1,6,12-triazadiben-
zo[a,e]cycloocten-4-one (3g)
Obtained by refluxing compound 4g in xylene for 12 h; mp 256–
257 °C (CHCl3).
13C NMR (CDCl3 + DMSO-d6): = 25.8 (CH3), 48.5, 49.2 (C-2, C-
3), 99.4 (C-9), 101.1 (Cq), 132.9 (C-8), 153.9, 162.6, 170.0 (Cq).
MS (APCI): m/z (%) = 178 (M + 1, 100), 161 (18), 149 (5).
IR (KBr): 3280, 3180–2100, 1640, 1580 cm–1.
Anal. Calcd for C9H11N3O: C, 61.00; H, 6.26; N, 23.71. Found: C,
61.27; H, 6.42; N, 23.54.
1H NMR (DMSO-d6): = 2.43 (s, 3 H, CH3), 3.86, 4.14 (ABX, 2 H,
J = 14.2, 8.1, 6.1 Hz, 11-CH2), 6.04 (s, 1 H, H-3), 6.77 (br dd, 1 H,
J = 8.1, 6.1 Hz, NHCH2, exchangeable with D2O), 6.84–7.26 (m, 4
H, C6H4), 10.94 (br s, NH/OH, exchangeable with D2O).
13C NMR (DMSO-d6): = 27.3 (CH3), 45.6 (C-11), 101.5 (C-3),
119.8, 124.2, 128.4, 129.4 (aryl CH), 125.3, 149.0, 152.1, 157.1,
163.4, 168.4 (Cq).
(R*,R*)-11-Methyl-2,5,5a,6,7,8,9,9a-octahydrobenzo[b]pyri-
do[4,3-e][1,4]diazepin-1-one (9d)
Mp 335 °C (dec.) (C6H6).
IR (KBr): 3290, 3150, 3100, 1660, 1610 cm–1.
1H NMR (CDCl3 –DMSO-d6): = 1.08–1.31 (m, 4 H, 2 CH2), 1.41–
1.74 (m, 2 H, CH2), 1.85–2.12 (m, 2 H, 2 CH), 2.26 (s, 3 H, CH3),
3.15–3.41 (m, 2 H, 2 NCH), 5.68 (d, 1 H, J = 7.2 Hz, 4-H), 5.89 (s,
1 H, NH, exchangeable with D2O), 6.82 (d, 1 H, J = 7.2 Hz, 3-H),
10.38 (br, 1 H, NH, exchangeable with D2O).
13C NMR (CDCl3 + DMSO-d6): = 22.1, 22.7 (2 CH2), 24.8 (CH3),
32.3, 34.2, (2 CH2), 59.3, 62.2 (2 NCH), 99.7 (C-4), 101.2 (Cq),
133.3 (C-3), 152.9, 161.6, 167.6 (Cq).
MS (EI): m/z (%) = 273/275 (M+, 100/33), 258/260 (30/10), 2451/
247 (26/9), 235 (13) 233 (22), 232 (39), 231(65).
Anal. Calcd for C14H12ClN3O: C, 61.43; H, 4.42; N, 15.35. Found:
C, 61.22; H, 4.30; N, 15.10.
3-Acetyl-2-(3-aminopropylamino)-6-chloro-1H-pyridin-4-one
(4h)
Yield: 75%; mp >300 °C (MeOH).
IR (KBr): 3200–2100, 1590, 1570 cm–1.
1H NMR (DMSO-d6): = 1.80 (qint, 2 H, J = 5.9 Hz, CH2), 2.51 (s,
3 H, CH3), 2.78 (t, 2 H, J = 5.9 Hz, CH2NH2), 3.40 (q, 2 H, J = 5.9
Hz, CH2NH), 4.06 (br s, 2 H, NH2, exchangeable with D2O) 5.69 (s,
1 H, CH), 9.85 (br t, 1 H, J = 5.9 Hz, NH, exchangeable with D2O).
13C NMR (DMSO-d6): = 27.9 (CH2), 32.8 (CH3), 36.5 (2 CH2)
104.9 (Cq) 106.5 (CH), 151.6, 161.3, 179.2, (Cq), 198.2 (C=O).
MS (EI): m/z (%) = 231 (M+, 100), 216 (19), 202 (20), 188 (71), 162
(100), 148 (25).
Anal. Calcd for C13H17N3O: C, 67.51; H, 7.41; N, 18.17. Found: C,
67.47; H, 7.62; N, 18.44.
Reaction of Pyridones 3e,g and 4h with Diazomethane; General
Procedure
To a suspension of 3e,g or 4h (0.1 mmol) in MeOH (5 mL) was add-
ed ethereal diazomethane (0.4 mmol). After 12 h, the solvents were
removed and the residue was column chromatographed with Et2O
as eluent to give the corresponding methoxypyridines.
MS (EI): m/z (%) = 243/245 (M+, 32/11), 225 (35), 213 (42), 211
(38), 196 (90), 187 (82), 185 (100), 183 (80), 171 (52), 169 (43).
Anal. Calcd for C10H14ClN3O2: C, 49.29; H, 5.79; N, 17.24. Found:
C, 48.99; H, 5.66; N, 17.35.
(R*,R*)-2-Chloro-4-methoxy-5-methyl-7,8,9,10,10a,11-hexahy-
dro-6aH-benzo[b]pyrido[2,3-e][1,4]diazepine (5)
Yield: 85%; mp 162–164 °C (sublimed at 100 °C/ 0.2 mmHg).
IR (KBr): 3380, 3280, 1640, 1630 cm–1.
3-Methyl-1,5-dihydro-pyrazolo[4,3-c]pyridin-4-one (9a)
Identical (mp and IR spectrum) with an authentic sample.7
1H NMR (CDCl3): = 1.20–1.70, 1.72–1.89, 2.10–2.25 (3 m, 8 H,
4 CH2), 2.28 (s, 3 H, CH3) 3.19, 3.53 (2 td, J = 10.6, 4.0 Hz, 2 CH),
3.86 (s, 3 H, OCH3), 4.36 (br s, 1 H, NH, exchangeable with D2O),
6.34 (s, 1 H, H-3).
13C NMR (CDCl3): = 23.8, 24.1, (2 CH2) 26.8, (CH3), 33.5, 36.2,
(2 CH2), 55.9, (OCH3), 61.4, 65.7 (2 CH), 98.5 (C-3), 104.8, 151.6,
156.3, 165.8, 166.5 (Cq).
MS (EI): m/z (%) = 279/291 (M+, 91/30), 264/266 (48/16), 250/252
(12/4), 236/238 (66/32), 222 (31, 210 (100), 196 (63), 183 (10), 181
(12).
2,4-Dimethyl-6H-pyrido[4,3-d]pyrimidin-5-one (9b)
Mp 270–273 °C (CHCl3).
IR (KBr): 3150, 3100–2100, 1650 cm–1.
1H NMR (CDCl3 + DMSO-d6): = 2.20 (s, 3 H, CH3), 2.48 (s, 3 H,
CH3), 5.94 (d, 1 H, J = 7.2 Hz, 8-H), 6.91 (br d, 1 H, 7-H), 10.89
(br, 1 H, NH, exchangeable with D2O).
13C NMR (CDCl3 + DMSO-d6): = 24.3, 24.9 (2 CH3), 103.6 (C-
8), 114.2 (Cq), 134.1 (C-7), 159.1, 161.2, 167.3, 169.9 (Cq).
MS (EI): m/z (%) = 175 (M+, 100), 160 (12), 147 (32), 134 (11), 106
(24).
Anal. Calcd for C14H18ClN3O: C, 60.10; H, 6.49; N, 15.02. Found:
C, 60.37; H, 6.44; N, 15.35.
Anal. Calcd for C9H9N3O: C, 61.70; H, 5.18; N, 23.99. Found: C,
61.47; H, 5.42; N, 23.64.
2-Chloro-4-methoxy-5-methyl-11,12-dihydro-1,6,12-triaza-
dibenzo[a,e]cyclooctene (6)
Yield: 88%; mp 235–236 °C (dec.) (Et2O).
IR (KBr): 3300, 1645, 1570 cm–1.
1H NMR (CDCl3): = 2.50 (s, 3 H, CH3), 3.79 (s, 3 H, OCH3), 3.92,
4,41 (ABX, 2 H, J = 14.2, 8.0, 6.1 Hz, 11-CH2), 5.04 (br m, 1 H,
Synthesis 2003, No. 16, 2518–2524 © Thieme Stuttgart · New York

2524
D. Donati et al.
PAPER
NHCH2, exchangeable with D2O), 6.16 (s, 1 H, H-3), 6.92–7.29 (m,
4 H, C6H4).
References
(1) (a) Maemoto, T.; Finlayson, K.; Olverman, H. J.; Akahane,
A.; Horton, R. W.; Butcher, S. P. Br. J. Pharmacol. 1997,
122, 1202. (b) Lunt, E.; Newton, C. G. In Comprehensive
Heterocyclic Chemistry, Vol. 3; Katritzki, A. R.; Rees, C.
W.; Boulton, A. J.; McKillop, A., Eds.; Pergamon: Oxford,
1984, 199. (c) Radinov, R.; Hainova, M.; Simova, E.;
Tyutyulkova, N.; Gorantcheva, J. Arch. Pharm. (Weinheim,
Ger.) 1987, 320, 704. (d) Deutsche Gold und Silber-
Scheideanstsalt vorm. Roessler, French Patent 2162482,
1973; Chem. Abstr. 1974, 80, 3561. (e) Carboni, S.; Da
Settimo, A.; Bertini, D.; Ferrarini, P. L.; Livi, O.; Tonetti, I.
Farmaco Ed. Sci. 1975, 237. (f) Carboni, S.; Da Settimo,
A.; Bertini, D.; Ferrarini, P. L.; Livi, O.; Tonetti, I. Farmaco
Ed. Sci. 1976, 322. (g) Walser, A.; Fryer, R. I. In The
Chemistry of Heterocyclic Compounds, Vol. 50; Fryer, R. I.,
Ed.; Wiley: New York, 1991, 947–1052. (h) Ho, W.; Kukla,
M. J.; Breshin, H. J.; Ludovici, D. W.; Grous, P. P.;
Diamond, C. J.; Miranda, M.; Rodgers, J. D.; Ho, C. J.; De
Clerq, E.; Pauwels, R.; Andries, K.; Janssen, M. A. C.;
Janssen, P. A. J. J. Med. Chem. 1995, 38, 794.
MS (EI): m/z (%) = 287/289 (M+, 100/33), 286/288 (16/19), 272/
274 (43/14), 259/261(35/12), 258/260 (22/7), 246/248 (42/14), 246/
248 (45/13), 245/247 (78/26).
Anal. Calcd for C15H14ClN3O: C, 62.61; H, 4.90; N, 14.60. Found:
C, 62.58; H, 4.95; N, 14.34.
1-[2-(3-Aminopropylamino)-6-chloro-4-methoxypyridin-3-
yl]ethanone (4i)
Yield: 85%; mp 166–169 °C (dec.) (MeOH).
IR (KBr): 3500–2600, 1635, 1590, 1570 cm–1.
1H NMR (CD3OD): = 1.97 (quint, 2 H, J = 6.2 Hz, CH2), 2.53 (s,
3 H, CH3), 2.98 (t, 2 H, J = 6.2 Hz, CH2NH2), 3.58 (t, 2 H, J = 6.2
Hz, CH2NH), 3.96 (s, 3 H, OCH3), 6.43 (s, 1 H, CH).
13C NMR (CD3OD): = 28.9 (CH2), 34.1 (CH3), 38.4, 38.5 (2 CH2),
57.1 (OCH3), 97.2 (CH), 103.7, 155.6, 160.8, 171.3, (Cq), 201.1
(C=O).
MS (APCI): m/z (%) = 258/260 (M + 1, 100/33) 241/243 (48/16),
213/215 (23/7), 195/197 (9/3).
(2) (a) Dorgan, R. J.; Parrick, J.; Hardy, C. R. J. Chem. Soc.,
Perkin Trans. 1 1980, 938. (b) Thompson, M. D. J.
Heterocycl. Chem. 1986, 23, 1545. (c) John, R.; Seitz, G.
Chem. Ber. 1990, 123, 133.
Anal. Calcd for C11H16ClN3O2: C, 51.26; H, 6.26; N, 16.30. Found:
C, 50.85; H, 5.94; N, 16.47.
Crystal Data and Structure Refinement of Compound 6
Crystal data: C15H14ClN3O, Mw = 287.74, triclinic, Space group P-
1, Z = 2, a = 8.408(1), b = 8.764(1), c = 10.649(1)
(3) (a) Donati, D.; Fusi, S.; Ponticelli, F. Tetrahedron Lett.
2002, 43, 9527. (b) Giorgi, G. L.; Ponticelli, F.; Czira, G.;
Vékèy, K. J. Am. Soc. Mass Spectrom. 1995, 6, 962.
(c) Donati, D.; Fusi, S.; Ponticelli, F. Eur. J. Org. Chem.
2002, 4211.
(4) (a) Adembri, G.; Ponticelli, F.; Tedeschi, P. J. Chem. Soc.,
Perkin Trans. 1 1975, 2190. (b) Adembri, G.; Camparini,
A.; Ponticelli, F.; Tedeschi, P. J. Heterocycl. Chem. 1979,
16, 49. (c) Camparini, A.; Ponticelli, F.; Tedeschi, P. J.
Heterocycl. Chem. 1977, 14, 435. (d) Adembri, G.;
Camparini, A.; Ponticelli, F.; Tedeschi, P. Tetrahedron Lett.
1982, 23, 4375.
Å
=
78.240(10), = 68.180(20), = 77.960(10)°, V = 705.53(17) Å3,
Dc = 1.355 gcm–3, F(000) = 3000, Mo-K radiation = 0.71073.
Intensity data were collected with a Siemens P4 four circle diffrac-
tometer. 2479 reflections were measured, 1709 were observed with
I>2s(I), psi-scan absorption correction was applied. The structure
was solved by direct methods using SHELXL-97.8 Anisotropic tem-
perature factors were used for non-hydrogen atoms. The positions
of hydrogen atoms were found by difference Fourier map and re-
2
fined isotropically. Final R1 = 0.043 wR2 = 0.1047, w–1 = [ 2(Fo )
+ (0.0420P)2 + 0.1447P ] where P = (Fo2 + 2Fc2)/3.
(5) Denzel, T.; Hohn, H. Arch. Pharm. (Weinheim, Ger.) 1973,
306, 746.
(6) Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin Trans. 1
1985, 1401.
Acknowledgment
(7) Donati, D.; Fusi, S.; Ponticelli, F. Heterocycles 1988, 27,
1899.
The authors wish to thank the University of Siena (quota Progetti
2002) for funding and the ‘Centro di Analisi e Determinazioni
Strutturali’ of the University of Siena for MS spectra and X-ray data
collection.
(8) (a) Sheldrick, G. M. SHELXL-97. Program for the
Refinement of Crystal Structure; University of Gottingen:
Germany, 1997. (b) Crystallographic data (excluding
structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-204629. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: (internat.)
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk]
Synthesis 2003, No. 16, 2518–2524 © Thieme Stuttgart · New York