BF3·OEt2-Mediated 1,3-hydride shift followed by 6π electrocyclization: An efficient route for the synthesis of pyridopyrimidine, pyranoquinoline, and phenanthroline derivatives

Article abstract of DOI:10.1002/ejoc.201101065

The synthesis of pyridopyrimidine, pyranoquinoline, and phenanthroline derivatives can be easily and efficiently accomplished by the direct reaction of a 1-aminopenta-1,4-diene fragment, an aromatic aldehyde, and BF ₃·OEt₂ in the abs

Full text of DOI:10.1002/ejoc.201101065

FULL PAPER
DOI: 10.1002/ejoc.201101065
BF3·OEt2-Mediated 1,3-Hydride Shift Followed by 6π Electrocyclization: An
Efficient Route for the Synthesis of Pyridopyrimidine, Pyranoquinoline, and
Phenanthroline Derivatives
Krishna C. Majumdar,*[a,b] Sudipta Ponra,[a] and Raj Kumar Nandi[a]
Keywords: Imines / Rearrangement / Cyclization / Fused-ring systems / Nitrogen heterocycles
The synthesis of pyridopyrimidine, pyranoquinoline, and
phenanthroline derivatives can be easily and efficiently ac-
complished by the direct reaction of a 1-aminopenta-1,4-
diene fragment, an aromatic aldehyde, and BF3·OEt2 in the
absence of any metal catalyst. The notable features of this
procedure are mild reaction conditions, good to high yields,
and operational simplicity.
eases.[21–26] This makes the synthesis of pyridopyrimidine
and pyranoquinoline derivatives from easily accessible pre-
cursors interesting and significant.
Introduction
Among the small organic molecules, simple nitrogen-
containing heterocycles receive much attention in the litera-
ture as a consequence of their exciting biological properties
and role as pharmacophores of considerable historical im-
portance. Among these nitrogen-containing heterocycles,
the synthesis, reactions, and biological activities of pyridine-
containing molecules is an ever-expanding area of research
in heteroaromatic chemistry, and this structural motif ap-
pears in a large number of pharmaceutical agents and natu-
ral products.[1–8] Recently, the importance of pyridopyrim-
idine derivatives has increased dramatically because of their
biological and medicinal applications such as antibacteri-
als,[9] antiallergic,[10] CNS stimulants,[11] and inhibitors of
enzyme adenosine kinase (AK)[12] or dihydrofolatereductase
(DHFR).[13] Among the nitrogen heterocycles, quinoline
represents an important class of alkaloids and is often
found as structural framework in a large number of biolo-
gically active natural products and pharmaceuticals.[14]
Quinoline has also found applications in drug development.
Pyrano[3,2-f]quinolines, which contain both a quinoline
ring and pyran moiety, display unique biological activities,
such as psychotropic,[15] antiallergic,[16] anti-inflamma-
tory,[17] and estrogenic activities.[18] They are also used as
potential pharmaceuticals.[19] Helietidine, dutadrupine, and
geibalansine[20] are examples of natural products containing
pyranoquinoline as a core structure. 4,7-Phenanthroline de-
rivatives and their analogs exhibit high antibacterial activity
and are used for the treatment of gastrointestinal dis-
As a part of continuing efforts in our laboratory towards
the development of new protocols for the expeditious syn-
thesis of biologically relevant heterocyclic compounds,[27]
we became interested in exploring the possibility of de-
veloping newer methodologies for the synthesis of highly
bioactive pyridopyrimidine derivatives. A number of reports
in the literature for the synthesis of pyridopyrimidine deriv-
atives[28] usually require forcing conditions, long reaction
times, and complex synthetic pathways. We have previously
reported the synthesis of pyrido[3,2-d]pyrimidine deriva-
tives by the palladium-catalyzed intramolecular arylation of
pyrimidines[29] and the silver-catalyzed 6-endo-dig mode of
cycloisomerization from various N-propargylated heterocy-
clic compounds[30] that require harsh reaction conditions
and expensive metal catalysts. This prompted us to under-
take a study on the synthesis of these heterocycles by the
BF3·OEt2-mediated reaction of a 1-aminopenta-1,4-diene
fragment and aromatic aldehydes. Herein we report the re-
sults of our study.
Results and Discussion
The starting material, 6-allyl-5-amino-1,3-dimethyl-
pyrimidine-2,4-(1H,3H)-dione (1), for this study was pre-
pared according to our earlier published procedure.[31]
A
[a] Department of Chemistry, University of Kalyani,
Kalyani 741235, W.B., India
mixture of substrate 1 and 2a was heated in refluxing tolu-
ene in the presence of BF3·OEt2 for 12 h. Two products
were obtained, that is, 6-(4-chlorophenyl)-1,3,7-trimethyl-
pyrido[3,2-d]pyrimidine-2,4-(1H,3H)-dione (3a, 86%) along
with a small amount of 1,3,6-trimethylpyrrolo[3,2-d]pyrim-
idine-2,4-(1H,3H)-dione derivative 4 as a side product,
[b] Department of Chemical Sciences, Tezpur University,
Napaam, Tezpur 784028, Assam, India
Fax: +91-3712-267005
E-mail: kcm_ku@yahoo.co.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101065.
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K. C. Majumdar, S. Ponra, R. K. Nandi
FULL PAPER
which is also potentially bioactive[32,33] (Scheme 1). Com- ene using BF3·OEt2 (40 mol-%) under refluxing conditions
pound 4 can also be obtained as a side product during the for 12 h provided the highest yield of the product (Table 1,
formation of the starting material from 5-(allylamino)-1,3- Entry 4). The optimized reaction conditions were then ap-
dimethylpyrimidine-2,4-(1H,3H)-dione by aza-Claisen re- plied to other substrates to examine the scope of this proto-
arrangement using BF3·OEt2 as a catalyst. The final prod- col to synthesize a range of pyridopyrimidine derivatives
1
ucts were characterized by H NMR and 13C NMR spec- (Table 2).
troscopy and mass spectrometry. The optimized reaction
Table 2. Scope of BF3·OEt2-mediated synthesis of substituted pyr-
idopyrimidine derivatives.
conditions were established by carrying out several experi-
ments by changing the nature and amount of the Lewis
acid catalyst used (Table 1). Among the various Lewis acid
catalysts screened, coinage metal-based catalysts like AuCl3,
AgSbF6, and CuI did not give satisfactory results (Table 1,
Entries 12, 16, 15). The reaction was also carried out in the
presence of AlCl3 and Yb(OTf)3 but these also did not give
results as satisfactory as those obtained with the use of
BF3·OEt2 (Table 1, Entries 13 and 14). On examining the
role of the solvents for improving the efficiency of this reac-
tion, we found that toluene gave better results than CH3CN,
CH2Cl2, THF, benzene, or xylene (Table 1, Entries 4–9).
The reaction did not proceed at all at room temperature
(Table 1, Entry 10). The yield of the product increased by
increasing the amount of catalyst (Table 1, Entry 1–4):
40 mol-% BF3·OEt2 gave an excellent yield, but the use of
greater amounts of catalyst resulted in the formation of side
products such as 4 (Table 1, Entry 11). Variation of the cat-
alyst and solvent showed that running the reaction in tolu-
Scheme 1. Reagent and conditions: (i) BF3·OEt2, toluene, reflux,
12 h.
Table 1. Screening of different catalysts and conditions in the for-
mation of pyridopyrimidine derivatives.
Entry
Catalyst
Conditions
% Yield 3a/4[f]
[a]
1
2
3
4
5
6
7
8
BF3·OEt2[b]
BF3·OEt2[c]
BF3·OEt2[d]
BF3·OEt2[d]
BF3·OEt2[d]
BF3·OEt2[d]
BF3·OEt2[d]
BF3·OEt2[d]
BF3·OEt2[d]
BF3·OEt2[e]
BF3·OEt2
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
CH3CN, reflux
CH2Cl2, reflux
THF, reflux
32:2
39:5
54:7
86:12
72:9
42:5
38:3
35:6
43:7
0:0
81:17
68:7
47:3
52:4
39:3
49:3
benzene, reflux
xylene, reflux
9
10
11
12
13
14
15
16
toluene, r.t., stirring
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
[d]
AuCl3
AlCl3
[d]
[d]
Yb(OTf)3
CuI[d]
[d]
AgSbF6
Various substituted benzaldehydes and heterocyclic alde-
hydes give desired products 3 uniformly in high yields. The
reaction is mostly unaffected by the substituents on the aro-
[a] 5 mol-% of catalyst. [b] 10 mol-% of catalyst. [c] 20 mol-% of
catalyst. [d] 40 mol-% of catalyst. [e] 50 mol-% of catalyst. [f] Iso-
lated yield.
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Synthesis of Pyridopyrimidine, Pyranoquinoline, and Phenanthroline Derivatives
matic ring of aldehydes 2a–j, as products 3a–j were ob- Table 3. BF3·OEt2-mediated synthesis of various pyranoquinoline
and phenanthroline derivatives.
tained in excellent yields of 76–86% (Table 2, Entries 1–10).
For heterocyclic aldehydes such as furfuraldehyde and thio-
phene aldehyde, desired products 3b and 3g were obtained
in 83 and 76% yield, respectively (Table 2, Entries 2 and 7).
Both electron-donating and electron-withdrawing groups
on the aromatic ring of the aldehyde give the desired deriva-
tives in high yields. However, in case of substrates with NO2
substitution on the aromatic ring of the aldehyde (i.e., 2m,
2n), the exclusive formation of pyrrolo[3,2-d]pyrimidine[20]
derivative 4 (83 and 81% yield, respectively) was observed,
and this product was also the side product in other cases
(Scheme 2).
Scheme 2. Synthesis of pyrrolo[3,2-d]pyrimidine derivatives.
This methodology has also been applied for the synthesis
of bioactive pyranoquinoline and phenanthroline deriva-
tives 6a–d in 75–83% yield (Table 3). Phenanthroline deriv-
ative 6e has also been synthesized from the reaction of 5b
and aldehyde 2a under the same conditions as those stated
earlier. Compounds 5a and 5b can be prepared according
to our previously published procedure.[34] Interestingly, sub-
strate 1 reacts with aliphatic aldehydes such as formalde-
hyde (2o) to give 1,3,5,7-trimethyl-5,6,7,8-tetrahydropyr-
ido[3,2-d]pyrimidine-2,4-(1H,3H)-dione (7) in 82% yield
under the same reaction conditions (Scheme 3).
It is observed from the examples described earlier that
various pyridopyrimidine, pyranoquinoline, and phen-
anthroline derivatives can easily be synthesized by the
Scheme 3. Synthesis of 1,3,5,7-tetramethyl-5,6,7,8-tetrahydropyr-
ido[3,2-d]pyrimidine-2,4-(1H,3H)-dione.
application of this methodology. A survey of the literature
reveals that several methods have been developed for the
synthesis of quinolines,[35] pyranoquinolines,[27b,30] and pyr-
idopyrimidines,[28] but this present methodology is simple,
facile, and novel for the construction of these derivatives
from a 1-aminopenta-1,4-diene fragment and aldehydes.
The formation of the pyridine ring may be rationalized
by the initial BF3-catalyzed formation of imine A from the
reaction of the 1-aminopenta-1,4-diene fragment and 2
through a simple condensation reaction (Scheme 4). The
electron-dense olefin can then attack the nucleophilic nitro-
gen to form intermediate B, which under acid catalysis re-
arranges to isomer D via intermediate C obtained through
1,3-H shift. Intermediate D undergoes cyclization through
a simple 6π electrocyclization process to form intermediate
is unfavorable when R = NO2C6H4 due to the strong elec-
tron-withdrawing properties of the NO2 group. This might
be the reason why nitrobenzaldehydes fail to give the final
product. So, the formation of compounds 4 is rationalized
by the participation of the lone pair of electrons on the
nitrogen atom (intermediate G) that attack the double bond
coordinated by the Lewis acid. Removal of the acid may
give intermediate I, which may then isomerize to give prod-
ucts 4.
Conclusions
In conclusion, we have developed an efficient, rapid, and
E, which can undergo further rearrangement and aromati- high-yielding procedure for the construction of potentially
zation to give the desired products. Formation of D from C bioactive pyridopyrimidine, pyranoquinoline, and phen-
Eur. J. Org. Chem. 2011, 6909–6915
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K. C. Majumdar, S. Ponra, R. K. Nandi
FULL PAPER
Scheme 4. The proposed mechanism for the synthesis of quinoline derivatives and product 4.
3.53 (s, 3 H, NCH3), 3.63 (s, 3 H, NCH3), 7.41 (d, J = 8.0 Hz, 2
H, ArH), 7.49 (d, J = 8.4 Hz, 2 H, ArH), 7.51 (s, 1 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.1 (CH3), 29.0, 30.6, 123.8,
128.5, 130.0, 130.7, 134.6, 136.7, 137.3, 137.7, 150.7, 153.9,
160.4 ppm. HRMS (ESI): calcd. for C16H14ClN3O2 [M + Na]+
338.0672; found 338.0691.
anthroline derivatives from easily available starting materi-
als. This method is simple, easy to handle, and does not
require a transition-metal catalyst. This methodology will
be readily applicable to the synthesis of various substituted
quinoline derivatives and heterocyclic systems.
6-(Furan-2-yl)-1,3,7-trimethylpyrido[3,2-d]pyrimidine-2,4-(1H,3H)-
dione (3b): Using the general procedure, 1 (200 mg, 1.02 mmol), 2b
(98 mg, 1.02 mmol), and BF3·OEt2 (57.9 mg, 0.05 mL, 0.408 mmol)
gave 3b (230.7 mg) as a grayish solid. Yield: 83%. M.p. 222–224 °C.
Experimental Section
General Methods: Melting points were determined in open capillar-
ies. IR spectra were run for KBr discs with a Perkin–Elmer 120–
000A apparatus, and NMR spectra were determined for solutions
in CDCl3 with TMS as an internal standard with Bruker DPX-300
and Bruker DPX-400 instruments. 13C NMR spectra were deter-
mined for solutions in CDCl3 with a Bruker DPX-400 spectrome-
ter. CHN analyses were recorded with a 2400 series II CHN ana-
lyzer by Perkin–Elmer. Mass spectra were recorded with a QTOF
Micro instrument. Silica gel (60–120 mesh and 230–400 mesh) was
used for chromatographic separation. Silica gel-G [E-Mark (India)]
was used for TLC. Petroleum ether refers to the fraction between
60 and 80 °C.
IR (KBr): ν = 3114, 1712, 1667 cm–1. 1H NMR (400 MHz, CDCl ):
˜
3
δ = 2.71 (s, 3 H, -CH3), 3.53 (s, 3 H, NCH3), 3.61 (s, 3 H, NCH3),
6.56 (t, J = 1.6 Hz, 1 H, ArH), 7.12 (d, J = 3.2 Hz, 1 H, ArH),
7.40 (s, 1 H, ArH), 7.59 (s, 1 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.5 (CH3), 28.9, 30.6, 111.7, 112.2, 124.3, 129.6,
135.9, 136.7, 143.5, 144.5, 150.6, 152.6, 160.2 ppm. HRMS (ESI):
calcd. for C14H13N3O3 [M + Na]+ 294.0885; found 294.0836.
6-(4-Methoxyphenyl)-1,3,7-trimethylpyrido[3,2-d]pyrimidine-2,4-
(1H,3H)-dione (3c): Using the general procedure, 1 (200 mg,
1.02 mmol), 2c (139.5 mg, 1.02 mmol), and BF3·OEt2 (57.9 mg,
0.05 mL, 0.408 mmol) gave 3c (268 mg) as a white powder. Yield:
General Procedure for the Preparation of Compounds 3a–j: A mix-
ture of 6-allyl-5-amino-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione
(1, 1.0 equiv.) and aromatic aldehyde 2a–j (1.0 equiv.) was stirred
in toluene (5 mL) at room temperature for 10 min. After the ad-
dition of BF3·OEt2 (40 mol-%, mol-% calculated relative to 1) the
reaction mixture was heated at reflux for 12 h. After completion of
the reaction as monitored by TLC, the reaction mixture was cooled
and diluted with a saturated NaHCO3 solution (50 mL). This was
extracted with ethyl acetate (3ϫ25 mL). The combined organic ex-
tract was washed with brine (50 mL) and dried (Na2SO4). The sol-
vent was distilled off. The resulting crude product was purified by
column chromatography over silica gel (230–400 mesh, petroleum
ether/ethyl acetate) and recrystallized (CH3CN) to give compounds
3a–j.
84%. M.p. 250–252 °C IR (KBr): ν = 2841, 1704, 1662 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 2.52 (s, 3 H, CH3), 3.54 (s, 3 H,
NCH3), 3.63 (s, 3 H, NCH3), 3.86 (s, 3 H, OCH3), 6.97 (d, J =
8.8 Hz, 2 H, ArH), 7.46 (s, 1 H, ArH), 7.51 (dd, J = 2, 8.8 Hz, 2
H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3 (CH3), 28.9,
30.6, 55.4, 113.6, 114.2, 123.7, 128.3, 129.7, 130.6, 131.4, 136.3,
137.8, 150.8, 154.9, 159.8, 160.6 ppm. HRMS (ESI): calcd. for
C17H17N3O3 [M + H]+ 312.1328; found 312.1343.
1,3,7-Trimethyl-6-p-tolylpyrido[3,2-d]pyrimidine-2,4-(1H,3H)-dione
(3d): Using the general procedure, 1 (200 mg, 1.02 mmol), 2d
(122.4 mg, 1.02 mmol), and BF3·OEt2 (57.9 mg, 0.05 mL,
0.408 mmol) gave 3d (245 mg) as a white powder. Yield: 81%. M.p.
218–220 °C. IR (KBr): ν = 2919, 1710, 1665 cm–1 1H NMR
.
˜
6-(4-Chlorophenyl)-1,3,7-trimethylpyrido[3,2-d]pyrimidine-2,4-
(400 MHz, CDCl3): δ = 2.40 (s, 3 H, CH3), 2.51 (s, 3 H, CH3), 3.54
(1H,3H)-dione (3a): Using the general procedure, 1 (200 mg, (s, 3 H, NCH3), 3.63 (s, 3 H, NCH3), 7.24 (d, J = 7.2 Hz, 2 H,
1.02 mmol), 2a (143.3 mg, 1.02 mmol), and BF3·OEt2 (57.9 mg,
0.05 mL, 0.408 mmol) gave compound 3a (280.8 mg) as a white
ArH), 7.45 (m, 3 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 21.3 (CH3), 21.3 (CH3), 29.0, 30.6, 123.6, 128.9, 129.2, 129.8,
136.0, 136.4, 137.9, 138.3, 150.8, 155.4, 160.6 ppm. HRMS (ESI):
powder. Yield: 86%. M.p. 228–230 °C. IR (KBr): ν = 2951, 1707,
˜
1
1663 cm–1. H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H, CH3), calcd. for C17H17N3O2 [M + H]+ 296.1406; found 296.1393.
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Synthesis of Pyridopyrimidine, Pyranoquinoline, and Phenanthroline Derivatives
6-(5-Chloro-2-methoxyphenyl)-1,3,7-trimethylpyrido[3,2-d]pyrim-
idine-2,4-(1H,3H)-dione (3e): Using the general procedure, 1
6-(2-Methoxyphenyl)-1,3,7-trimethylpyrido[3,2-d]pyrimidine-2,4-
(1H,3H)-dione (3j): Using the general procedure, 1 (200 mg,
( 20 0 mg , 1 . 02 mm o l ) , 2 e ( 1 7 3 . 9 m g , 1 . 0 2 m mo l ) , a n d 1.02 mmol), 2j (139.5 mg, 1.02 mmol), and BF3·OEt2(57.9 mg,
BF3·OEt2(57.9 mg, 0.05 mL, 0.408 mmol) gave 3e (280 mg) as a 0.05 mL, 0.408 mmol) gave 3j (264.7 mg) as a white powder. Yield:
1
white powder. Yield: 79%. M.p. 240–242 °C. IR (KBr): ν = 2835,
83%. M.p. 240–242 °C. IR (KBr): ν = 2833, 1708, 1659 cm–1. H
˜
˜
1704, 1667 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.31 (s, 3 H,
CH3), 3.53 (s, 3 H, NCH3), 3.63 (s, 3 H, NCH3), 3.72 (s, 3 H,
OCH3), 6.85 (d, J = 8.8 Hz, 1 H, ArH), 7.29 (d, J = 2.8 Hz, 1 H,
NMR (400 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 3.53 (s, 3 H,
NCH3), 3.64 (s, 3 H, NCH3), 3.74 (s, 3 H, OCH3), 6.93 (d, J =
8.4 Hz, 1 H, ArH), 7.05 (t, J = 7.6 Hz, 1 H, ArH), 7.31 (dd, J =
ArH), 7.32 (dd, J = 2.4, 8.8 Hz, 1 H, ArH), 7.46 (s, 1 H, ArH) 1.6, 7.2 Hz, 1 H, ArH), 7.39 (td, J = 1.6, 9.6 Hz, 1 H, ArH) 7.44
ppm. 13C NMR (100 MHz, CDCl3): δ = 19.7 (CH3), 29.0, 30.6, (s, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.8 (CH3),
55.8, 111.9, 122.6, 125.9, 129.7, 129.8, 130.9, 137.1, 139.9, 150.8,
152.3, 155.5, 160.5 ppm. HRMS (ESI): calcd. for C17H16ClN3O3
[M + H]+ 346.0938; found 346.0953.
28.9, 30.6, 55.4, 110.6, 120.9, 122.5, 128.3, 129.5, 130.0, 130.9,
136.9, 140.0, 150.8, 153.9, 156.7, 160.7 ppm. HRMS (ESI): calcd.
for C17H17N3O3 [M + H]+ 312.1328; found 312.1341.
6-(3-Chlorophenyl)-1,3,7-trimethylpyrido[3,2-d]pyrimidine-2,4-
(1H,3H)-dione (3f): Using the general procedure, 1 (200 mg,
1.02 mmol), 2f (143.3 mg, 1.02 mmol), and BF3·OEt2(57.9 mg,
1,3,5,7-Tetramethyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2,4-
(1H,3H)-dione (7): Using the general procedure, 1 (200 mg,
1.02 mmol), 2o (61.2 mg, 2.04 mmol), and BF3·OEt2(57.9 mg,
0.05 mL, 0.408 mmol) gave 3f (267.7 mg) as a white powder. Yield: 0.05 mL, 0.408 mmol) gave 7 (187.5 mg) as a white powder. Yield:
1
1
82%. M.p. 232–234 °C. IR (KBr): ν = 2954, 1707, 1663 cm–1. H 82%. M.p. 240–242 °C. IR (KBr): ν = 2951, 1684, 1637 cm–1. H
˜
˜
NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H, CH3), 3.54 (s, 3 H,
NCH3), 3.64 (s, 3 H, NCH3), 7.36–7.41 (m, 3 H, ArH), 7.49 (s, 1
H, ArH) 7.55 (s, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 21.0 (CH3), 29.0, 30.7, 123.8, 127.4, 128.6, 129.4, 129.5, 129.9,
134.2, 136.8, 137.9, 140.5, 150.7, 153.7, 160.4 ppm. HRMS (ESI):
calcd. for C16H14ClN3O2 [M + H]+ 316.0859; found 316.0847.
NMR (400 MHz, CDCl3): δ = 1.07 (d, J = 5.2 Hz, 3 H, CH3),
2.03–2.05 (m, 2 H, CH2), 2.54–2.64 (m, 2 H, CH2), 2.76 (s, 3 H,
NCH3), 2.91 (d, J = 12.8 Hz, 1 H, CH), 3.37 (s, 6 H, NCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 18.6 (CH3), 21.9, 28.2, 30.6,
33.5, 41.2, 57.7, 122.7, 137.9, 151.2, 160.2 ppm. MS: m/z = 246.13
[M + Na]+. C11H17N3O2 (223.27): calcd. C 59.17, H 7.67, N 18.82;
found C 59.39, H 7.58, N 18.71.
1,3,7-Trimethyl-6-(thiophen-2-yl)pyrido[3,2-d]pyrimidine-2,4-
(1H,3H)-dione (3g): Using the general procedure, 1 (200 mg, 8-(4-Methoxyphenyl)-9-methyl-3H-pyrano[3,2-f]quinolin-3-one (6a):
1.02 mmol), 2g (114.2 mg, 1.02 mmol), and BF3·OEt2(57.9 mg,
Using the general procedure, 5a (200 mg, 0.995 mmol), 2c
(135.3 mg, 0.995 mmol), and BF3·OEt2 (56.5 mg, 0.05 mL,
0.05 mL, 0.408 mmol) gave 3g (223.7 mg) as a white powder. Yield:
1
76%. M.p. 221–223 °C. IR (KBr): ν = 2952, 1710, 1666 cm–1. H 0.398 mmol) gave 6a (261.8 mg) as a white powder. Yield: 83%.
˜
1
NMR (400 MHz, CDCl3): δ = 2.72 (s, 3 H, CH3), 3.53 (s, 3 H,
M.p. 226–228 °C. IR (KBr): ν = 2917, 2849, 1726 cm–1. H NMR
˜
NCH3), 3.62 (s, 3 H, NCH3), 7.13 (t, J = 3.6 Hz, 1 H, ArH), 7.43 (400 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 3.89 (s, 3 H, OCH3),
(s, 1 H, ArH), 7.45 (dd, J = 0.8, 5.2 Hz, 1 H, ArH), 7.52 (d, J = 6.61 (d, J = 9.6 Hz, 1 H, ArH), 7.04 (d, J = 8.8 Hz, 2 H, ArH),
3.6 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.2
(CH3), 28.9, 30.6, 124.3, 127.6, 128.2, 129.5, 135.9, 136.6, 143.0,
148.1, 150.6, 160.1 ppm. HRMS (ESI): calcd. for C14H13N3O2S [M
+ H]+ 288.0781; found 288.0801.
7.58 (d, J = 8.8 Hz, 2 H, ArH), 7.62 (d, J = 9.2 Hz, 1 H, ArH),
8.25 (d, J = 8.8 Hz, 1 H, ArH), 8.37 (s, 1 H, ArH), 8.44 (d, J =
10 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3
(CH3), 55.4, 112.0, 113.9, 116.0, 119.7, 123.13, 130.4, 130.8, 131.4,
132.4, 134.3, 138.5, 143.8, 153.5, 159.9, 159.9, 160.7 ppm. HRMS
(ESI): calcd. for C20H15NO3 [M + H]+ 318.1136; found 318.1184.
6-(2,5-Dimethoxyphenyl)-1,3,7-trimethylpyrido[3,2-d]pyrimidine-2,4-
(1H,3H)-dione (3h): Using the general procedure, 1 (200 mg,
1.02 mmol), 2h (169.3 mg, 1.02 mmol), and BF3·OEt2(57.9 mg,
9-Methyl-8-(thiophen-2-yl)-3H-pyrano[3,2-f]quinolin-3-one (6b):
Using the general procedure, 5a (200 mg, 0.995 mmol), 2g
0.05 mL, 0.408 mmol) gave 3h (280 mg) as a white powder. Yield:
1
80%. M.p. 194–196 °C. IR (KBr): ν = 2941, 1704, 1663 cm–1. H (111.4 mg, 0.995 mmol), and BF3·OEt2 (56.5 mg, 0.05 mL,
˜
NMR (400 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 3.53 (s, 3 H,
NCH3), 3.62 (s, 3 H, NCH3), 3.72 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 6.50 (d, J = 2.0 Hz, 1 H, ArH), 6.57 (dd, J = 2, 8 Hz, 1
0.398 mmol) gave 6b (236.1 mg) as a white powder. Yield: 81%.
1
M.p. 236–238 °C. IR (KBr): ν = 2922, 2853, 1691 cm–1. H NMR
˜
(400 MHz, CDCl3): δ = 2.82 (s, 3 H, CH3), 6.60 (d, J = 10 Hz, 1
H, ArH) 7.25 (d, J = 8.4 Hz, 2 H, ArH), 7.43 (s, 1 H, ArH) ppm. H, ArH), 7.19 (t, J = 4.8 Hz, 1 H, ArH), 7.51 (d, J = 5.2 Hz, 1 H,
13C NMR (100 MHz, CDCl3): δ = 20.0 (CH3), 29.0, 30.6, 55.4,
55.5, 98.4, 104.7, 121.4, 122.5, 129.6, 131.7, 136.7, 140.3, 150.9,
153.8, 157.8, 160.7, 161.4 ppm. HRMS (ESI): calcd. for
C18H19N3O4 [M + Na]+ 364.1273; found 364.1264.
ArH), 7.61 (d, J = 9.2 Hz, 1 H, ArH), 7.65 (d, J = 3.2 Hz, 1 H,
ArH), 8.21 (d, J = 9.2 Hz, 1 H, ArH), 8.33 (s, 1 H, ArH), 8.40 (d,
J = 9.6 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
22.4 (CH3), 116.2, 120.1, 127.9, 128.2, 128.8, 130.2, 131.6, 134.0,
138.3, 153.5, 160.6 ppm. HRMS (ESI): calcd. for C17H11NO2S [M
+ H]+ 294.0547; found 294.0583.
6-(5-tert-Butyl-2-methoxyphenyl)-1,3,7-trimethylpyrido[3,2-d]-
pyrimidine-2,4-(1H,3H)-dione (3i): Using the general procedure, 1
( 20 0 mg , 1 . 02 mm o l ) , 2 i ( 1 9 6 . 9 m g , 1 . 0 2 m m o l ) , a n d
BF3·OEt2(57.9 mg, 0.05 mL, 0.408 mmol) gave 3i (313.2 mg) as a
8-(2-Chlorophenyl)-9-methyl-3H-pyrano[3,2-f]quinolin-3-one (6c):
Using the general procedure, 5a (200 mg, 0.995 mmol), 2k
(139.8 mg.0.995 mmol), and BF3·OEt2 (56.5 mg, 0.05 mL,
0.398 mmol) gave 6c (240 mg) as a white powder. Yield: 75%. M.p.
white powder. Yield: 83%. M.p. 234–236 °C. IR (KBr): ν = 2959,
˜
1712, 1667 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.30 [s, 9 H,
C(CH3)3], 2.30 (s, 3 H, CH3), 3.54 (s, 3 H, NCH3), 3.64 (s, 3 H, 206–208 °C. IR (KBr): ν = 2920, 2851, 1717 cm–1 1H NMR
.
˜
NCH3), 3.71 (s, 3 H, OCH3), 6.85 (d, J = 8.8 Hz, 1 H, ArH), 7.25
(s, 1 H. ArH), 7.37 (dd, J = 2.4, 8.8 Hz, 1 H, ArH), 7.44 (s, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.1 (CH3), 29.0,
30.6, 31.5, 34.2, 55.5, 110.3, 122.4, 126.7, 127.7, 129.5, 136.8, 140.1,
143.5, 150.9, 154.6, 160.7 ppm. HRMS (ESI): calcd. for
C21H25N3O3 [M + H]+ 368.1953; found 368.1969.
(400 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 6.63 (d, J = 9.6 Hz, 1
H, ArH), 7.42 (m, 3 H, ArH), 7.52 (m, 1 H, ArH), 7.66 (d, J =
9.2 Hz, 1 H, ArH), 8.26 (d, J = 9.2 Hz, 1 H, ArH), 8.42 (s, 1 H,
ArH), 8.46 (d, J = 10 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.7 (CH3), 112.2, 116.2, 119.9, 123.9, 127.3, 129.7,
130.0, 130.1, 132.4, 132.6, 134.3, 138.4, 139.0, 143.4, 153.8, 158.8,
Eur. J. Org. Chem. 2011, 6909–6915
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6913

K. C. Majumdar, S. Ponra, R. K. Nandi
FULL PAPER
160.6 ppm. HRMS (ESI): calcd. for C19H12ClNO2 [M + H]+
322.0625; found 322.0629.
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P198350h].
[4]
[5]
8-(4-Bromophenyl)-9-methyl-3H-pyrano[3,2-f]quinolin-3-one (6d):
Using the general procedure, 5a (200 mg, 0.995 mmol), 2l (184 mg,
0.995 mmol), and BF3·OEt2 (56.5 mg, 0.05 mL, 0.398 mmol) gave
[6]
[7]
6d (287.7 mg) as a white powder. Yield: 81%. M.p. 264–266 °C. IR
1
(KBr): ν = 2923, 1753, 1741 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 2.57 (s, 3 H, CH3), 6.62 (d, J = 10.0 Hz, 1 H, ArH), 7.50 (d, J
= 8.4 Hz, 2 H, ArH), 7.64 (d, J = 8.4 Hz, 3 H, ArH), 8.24 (d, J =
9.6 Hz, 1 H, ArH), 8.40 (s, 1 H, ArH), 8.43 (d, J = 9.6 Hz, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.0 (CH3), 77.2,
112.1, 116.3, 120.1, 123.1, 123.4, 130.6, 131.0, 131.7, 134.3, 138.3,
138.9, 143.7, 153.7, 159.0, 160.5 ppm. MS: m/z = 365.93
[M + H]+, 367.92 [M + H + 2]+. C19H12BrNO2 (366.21): calcd. C
62.32, H 3.30, N 3.82; found C 62.18, H 3.39, N 3.94.
[8]
C. J. Shishoo, K. S. Jain, J. Heterocycl. Chem. 1992, 29, 883–
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[11]
8-(4-Chlorophenyl)-4,9-dimethyl-4,7-phenanthrolin-3(4H)-one (6e):
Using the general procedure, 5b (200 mg, 0.934 mmol), 2a
(131.3 mg, 0.934 mmol), and BF3·OEt2 (53.02 mg, 0.048 mL,
0.373 mmol) gave 6e (262.6 mg) as a white powder. Yield: 84%.
[12]
[13]
[14]
M.p. 246–248 °C. IR (KBr): ν = 2918, 1658 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 2.57 (s, 3 H, CH3), 3.90 (s, 3 H, NCH3),
6.93 (d, J = 9.6 Hz, 1 H, ArH), 7.48 (m, 2 H, ArH), 7.58 (d, J =
8.4 Hz, 2 H, ArH), 7.79 (d, J = 9.6 Hz, 1 H, ArH), 8.26 (d, J =
9.2 Hz, 1 H, ArH), 8.49 (s, 1 H, ArH), 8.52 (m, 1 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.1 (CH3), 30.3, 77.2, 113.6,
117.7, 121.4, 128.7, 130.4, 130.8, 131.2, 133.0, 133.2, 134.6, 138.6,
139.1, 142.6, 158.2 ppm. HRMS (ESI): calcd. for C20H15ClN2O [M
+ H]+ 335.0938; found 335.0946.
[15]
[16]
[17]
[18]
1,3,6-Trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (4):
The general procedure was used with 1 (200 mg, 1.02 mmol) and
3-nitrobenzaldehyde or 4-nitrobenzaldehyde (154 mg, 1.02 mmol).
The mixture was stirred in toluene at room temperature for 10 min.
After the addition of BF3·OEt2 (57.9 mg, 0.05 mL, 0.408 mmol),
the reaction mixture was heated at reflux for 12 h. After completion
of the reaction as monitored by TLC, the reaction mixture was
cooled and diluted with a saturated NaHCO3 solution (50 mL).
This was extracted with ethyl acetate (3ϫ25 mL). The combined
organic extract was washed with brine (50 mL) and dried
(Na2SO4). The solvent was distilled off. The resulting crude product
was purified by column chromatography over silica gel (230–
400 mesh; petroleum ether/ethyl acetate, 80:20) to give 4 as a color-
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
less solid.[20] M.p. 268–270 °C. IR (KBr):
ν = 2929, 1694,
˜
1637 cm–1. H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3),
3.47 (s, 6 H, NCH3), 5.74 (s, 1 H, ArH), 11.42 (s, 1 H, NH) ppm.
13C NMR (100 MHz, CDCl3): δ = 13.5 (CH3), 27.9, 32.1, 93.7,
109.3, 136.8, 139.3, 151.7, 155.7 ppm.
1
S. Ordzhoni kidze, FRG Patent 1232156, 1967 [Chem. Abstr.
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Patent 1382542, 1964 [Chem. Abstr. 1965, 63, 7912a].
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2578; b) K. C. Majumdar, S. Ponra, D. Ghosh, A. Taher, Syn-
lett 2011, 104–110; c) K. C. Majumdar, S. Ponra, D. Ghosh,
Synthesis 2011, 1132–1136.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
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(New Delhi) and the Department of Science and Technology (DST)
(New Delhi) for financial assistance. S. P and R. K. N are grateful
to CSIR (New Delhi) for their Research Fellowships. We also thank
the DST (New Delhi) for providing the NMR spectrometer
(400 MHz), CHN analyzer, and FTIR spectrophotometer.
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6914
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6909–6915

Synthesis of Pyridopyrimidine, Pyranoquinoline, and Phenanthroline Derivatives
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Published Online: September 28, 2011
Eur. J. Org. Chem. 2011, 6909–6915
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6915