Radical-mediated cyclization reaction - Regioselective synthesis of pyrimidine- and coumarin-annulated [6,6]-fused oxygen heterocycles

Article abstract of DOI:10.1139/V08-087

The n-Bu₃SnH-AIBN mediated aryl radical cyclization of various 8-[(2-bromophenoxy)methyl]-1,3-dimethyl-2,3,4,6-tetrahydro-1H-pyrano[3,2-d] pyrimidine-2,4-diones and 1-[(2-bromophenoxy)methyl]-3,5-dihydropyrano[2,3-c] coumarins was investigated with the formation of [6,6]-fused oxygen heterocycles as a single regioisomer.

Full text of DOI:10.1139/V08-087

846
Radical-mediated cyclization reaction —
Regioselective synthesis of pyrimidine- and
coumarin-annulated [6,6]-fused oxygen
heterocycles
Krishna C. Majumdar, Pradip Debnath, and Pradip K. Maji
Abstract: The n-Bu3SnH-AIBN mediated aryl radical cyclization of various 8-[(2-bromophenoxy)methyl]-1,3-dimethyl-
2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-diones and 1-[(2-bromophenoxy)methyl]-3,5-dihydropyrano[2,3-
c]coumarins was investigated with the formation of [6,6]-fused oxygen heterocycles as a single regioisomer.
Key words: n-Bu3SnH-AIBN, aryl radical cyclization, 6-endo-trig, oxygen heterocycles, coumarin derivatives,
pyrimidine derivatives
Résumé : On a effectué une étude le la régiochimie de la cyclisation arylique radicalaire catalysée par le n-Bu3Sn-
AIBN de diverses 8-[2-bromophénoxy]méthyl-1,3-diméthyl-2,3,4,6-tétrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-diones et
de 1-[(2-bromophénoxy)méthyl]-3,5-dihydropyrano[2,3-c]coumarines qui conduit à la formation d’hétérocycles oxygénés
à fusion [6,6] sous la forme d’un seul régioisomère.
Mots-clés : n-Bu3Sn-AIBN, cyclisation arylique radicalaire, 6-endo-trig, hétérocycles oxygénés, dérivés de la
coumarine, dérivés de la pyrimidine.
[Traduit par la Rédaction] Majumdar et al. 854
Introduction
vored 5-exo cyclization is generally preferred over a 6-endo
cyclization in those systems having an alkenic bond at the 5-
position relative to the radical center. However, regio-
chemistry of the radical cyclization can be influenced, and
even reversed, to favor the formation of six-membered rings
by factors other than stereoelectronic control (11). The ex-
tensive investigations of the 5-hexenyl radical revealed that
there are three factors, namely the substitution pattern at C-
5, vinyl radical cyclization, and ring strain, that can direct 6-
endo cyclization over 5-exo cyclization (12). In this context,
we recently reported the synthesis of pyrone- and coumarin-
annulated [6,6]-fused sulfur and oxygen heterocycles, re-
spectively, based on the regioselective 6-endo-trig radical
cyclization, wherein a mixture of diastereoisomers was ob-
tained in some cases (13). More recently, we have shown
that n-Bu3SnH-mediated cyclization of sulfur and sulfone
precursors derived from coumarin afforded a mixture of
[6,6]-fused and (or) spiro heterocycles (14). All these previ-
ous investigations have influenced us to undertake a study of
the radical cyclization on o-bromoaryl enol ethers, using 8-
[(2-bromophenoxy]methyl]-1,3-dimethyl-2,3,4,6-tetrahydro-
1H-pyrano[3,2-d]pyrimidine-2,4-diones 5a–5f, and 1-[2-
bromophenoxy) methyl]-3,5-dihydropyrano[2,3-c]coumarin
5g–5l as the starting materials, with a view to synthesize the
Coumarin and its derivatives are important heterocyclic
compounds that are found in many natural products (1),
many of that exhibit remarkable physiological and biological
activities (2). Many compounds containing the coumarin
skeleton have shown antihelmintic, hypnotic, insecticidal,
anti-coagulant, and antifungal properties (3). Some pyrimi-
dine derivatives are active against cancer (4), viral disease
(5), and the AIDS virus (6). Several efforts have been made
to synthesize them. In the interest of synthesizing new
coumarin and pyrimidine ring systems of biological interest,
we previously reported the synthesis of several novel five-
and six-membered coumarin- and pyrimidine-annulated
heterocycles by the application of sigmatropic rearrange-
ments (7) and radical cyclization strategy (8).
In recent years, intramolecular aryl radical cyclization has
revolutionized the construction of various types of cyclic
compounds via carbon–carbon bond-forming processes (9).
In particular, the intramolecular addition of carbon-centered
radical intermediates to arene and aromatic heterocycles has
gained considerable prominence (10). It provides a mild and
often high-yielding route to condensed aromatic ring sys-
tems. It has been rationalized that a stereoelectronically fa-
Received 22 February 2008. Accepted 23 April 2008. Published on the NRC Research Press Web site at canjchem.nrc.ca on
11 July 2008.
K.C. Majumdar1, P. Debnath, and P.K. Maji. Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal,
India.
1Corresponding author (e-mail: kcm_ku@yahoo.co.in).
Can. J. Chem. 86: 846–854 (2008)
doi:10.1139/V08-087
© 2008 NRC Canada

Majumdar et al.
847
Scheme 1. Reagents and conditions: (i) K2CO3, NaI, acetone, re-
flux, 6–10 h; (ii) chlorobenzene, reflux, 3–5 h.
Scheme 2. Reagents and conditions: (i) Toluene (0.01 mol/L), n-
Bu3SnH, AIBN, reflux, 3.5 h.
Scheme 3.
polycyclic pyrimidine and coumarin derivatives, respec-
tively. Here, we report the results of our investigation.
Results and discussion
As radical precursors for our present study, we have pre-
pared
8-[(2-bromophenoxy)methyl]-1,3-dimethyl-2,3,4,6-
tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-diones (5a–5f)
and 1-[(2-bromophenoxy)methyl]-3,5-dihydropyrano[2,3-c]coumarins
(5g–5l), by the thermal rearrangement of 1,3-dimethyl 5-(4-
aryloxybut-2-ynyloxy) uracils (4a–4f) and 3-(4-aryloxybut-
2-ynyl)coumarins (4g–4l) in 81%–89% and 84%–90%
yields, respectively. The compounds 4a–4l were, in turn,
prepared by the classical alkylation of 1,3-dimethyl-5-
hydroxy uracil (1) or 3-hydroxycoumarin (2) with different
1-aryloxy-4-chlorobut-2-ynes (3a–3f) according to our ear-
lier published procedure (7) (Scheme 1).
one proton double triplet at δ 3.36 (J = 3.8 Hz and 11.7 Hz),
owing to ring-juncture protons. The stereochemistry of the
ring-juncture protons can be surmised from the molecular
model (Dreiding model), which showed a strain-free cis-
arrangement. Compared with the literature results (7,13), the
small coupling constant value (J = 3.8 Hz) of the ring junc-
ture protons of 6a also indicated the cis stereochemistry.
On the basis of this promising result, the tin hydride me-
diated cyclization of the precursors 5a–5f was conducted.
The results are summarized in Table 1. From Table 1 it is
observed that other substrates 5b–5f give exclusively the
[6,6] pyranopyran derivatives 6b–6f in 76%–89% yields. En-
couraged by the results of radical cyclization of pyrimidines,
we have investigated similar radical cyclization reactions of
substrates containing a coumarin moiety. Substrate 5g was
subjected to radical cyclization under the aforesaid reaction
conditions. Unfortunately, we were unable to obtain any
cyclized product because the starting material decomposed
under the reaction conditions. However, by changing the sol-
vent to benzene and lowering the reaction temperature to
75 °C, we eliminated the decomposition of the starting mate-
rial. It was observed that when the substrates 5g–5l were
treated with n-Bu3SnH (1.0 equiv) and AIBN in benzene,
cyclization proceeded affording the cyclized product 6g–6l
in 75%–90% yields (Table 1).
As our aim was to synthesize [6,6]-fused oxygen
heterocycles, we examined the scope of C–C bond formation
of compounds 5 by n-Bu3SnH–AIBN (azobis-isobutylnitrile)
mediated radical cyclization. Compound 5a, when heated
with n-Bu3SnH (1.1 equiv.) and AIBN (0.5 equiv.) in dry
1
benzene at 80 °C for 5 h, yielded a solid product. The H
NMR spectrum of the product revealed that the cyclization
did not occur. Only the halogen-reduced product was ob-
tained. However, by changing the solvent to toluene under
the same reaction conditions, we were able to obtain
regioselectivly the cyclized product 6a in 89% yield.
It has already been established that a very high level of
diastereoselectivity could be obtained when the concentra-
tion of the reactant is reduced from 0.1 to 0.01 mol/L (15).
These observations have been attributed to the reversibility
of the cyclization and the decreased availability of the tin
hydride. We then tried to carry out the cyclization reaction in
highly dilute conditions. The conditions for the n-Bu3SnH-
AIBN procedure were optimized for the six-membered
radical cyclizations of the substrates 5. Substrate 5a
(0.01 mol/L) was refluxed in degassed dry toluene under ni-
trogen atmosphere with n-Bu3SnH (1.0 equiv.) for 3.5 h. The
cyclization of 5a under dilute conditions gave 6a in 81%
The formation of the products 6 from 5 may be explained
by the generation of aryl radical 7, which may undergo ei-
ther a 5-exo trig or a 6-endo-trig cyclization at the double
bond of the pyran moiety as described in Scheme 3. A 6-
endo-trig cyclization of radical 7 may produce the intermedi-
ate radical 8 while a 5-exo-trig cyclization may give the
1
yield (Scheme 2). The high field H NMR (500 MHz in
CDCl3) spectrum of the compound 6a displayed one proton
double triplet at δ 3.28 (J = 3.8 Hz and 11.6 Hz) and another
© 2008 NRC Canada

848
Can. J. Chem. Vol. 86, 2008
Table 1. Tin hydride-mediated radical cyclization of compounds 5a–5l.
spirocyclic radical 9 (not isolated), followed by neophyl re-
arrangement (16) to radical intermediate 10. Abstraction of a
hydrogen from n-Bu3SnH by radical intermediate 7 may
give the [6,6]-fused cyclized products 6.
Conclusion
In conclusion, we have successfully extended the n-
Bu3SnH mediated radical cyclization reaction to the
regioselective synthesis of coumarin- and pyrimidine-
annulated [6,6]-fused heterocycles. The process is quite gen-
eral and regioselective and afforded the desired products in
good-to-excellent yields. The mildness of the reaction condi-
tions and high level of regioelectivity allow this radical
cyclization to serve as a powerful synthetic tool for the prep-
aration of complex aromatic heterocycles.
Aryl radical cyclization normally gives a high 5-exo : 6-
endo ratio indicating
a stronger preference for exo
cyclization than for alkyl radical cyclization. However, suit-
ably substituted 5-hexenyl radicals are known to undergo 6-
endo cyclization to give six-membered rings. It is interesting
to note that six-membered rings are formed regioselectively
in all cases we have studied at present. Earlier we had re-
ported the synthesis of the [6,6]pyranopyrans by sequential
Claisen rearrangement of the 4-aryloxy-2-ynyloxy deriva-
tives of uracil and coumarin (7). This radical cyclization pro-
tocol is found to give the polycyclic heterocycles in better
yields under mild conditions.
Experimental
Melting points were determined in an open capillary and
are uncorrected. IR spectra were recorded on
a
© 2008 NRC Canada

Majumdar et al.
849
Table 1 (concluded).
Note: Reagent conditions: n-Bu3SnH, AIBN, toluene, reflux, 3–4 h; n-Bu3SnH, AIBN, benzene,
75 °C, 3–4 h.
PerkinElmer L 120-000A spectrometer (νmax in cm–1) on
5-({4-[(2-Bromo-6-methylphenyl)oxy]but-2-ynyl}oxy)-1,3-
1
KBr disks. H NMR (300 MHz, 400 MHz, and 500 MHz)
dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4a)
Yield 91%; colorless solid; mp 161–163 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2923, 1707, 1648. 1H NMR
(400 MHz, CDCl3) δH: 2.56 (s, 3H, ArCH3), 3.61 (s, 6H,
-NCH3), 4.94 (s, 2H, -OCH2), 4.99 (s, 2H, -OCH2), 7.51 (m,
3H), 7.76 (s, 1H, C6H). MS m/z: 392, 394 (M+). Anal. calcd.
for C17H17N2O4Br: C 51.92, H 4.36, N 12; found: C 52.06,
H 4.31, N 7.14.
and 13C NMR (125.7 MHz) spectra were recorded on a
Bruker DPX-300, Varian-400 FT–NMR, Bruker DPX-500
and spectrometer in CDCl3 (chemical shift in δ) with TMS
as internal standard. Silica gel [(60–120 mesh),
Spectrochem, India] was used for chromatographic separa-
tion. Petroleum ether refers to the fraction boiling between
60 and 80 °C.
5-({4-[(2-Bromo-4,6-dimethylphenyl)oxy]but-2-ynyl}oxy)-
1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4b):
Yield 90%; colorless solid; mp 122–123 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2982, 1706, 1642. 1H NMR
General procedure for the preparation of compounds
4a–4l
The compounds 4a–4l were synthesized according to the
earlier published procedure (7).
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850
Can. J. Chem. Vol. 86, 2008
(400 MHz, CDCl3) δH: 2.24 (s, 3H, ArCH3), 2.27 (s, 3H,
ArCH3), 3.34 (s, 3H, -NCH3), 3.35 (s, 3H, -NCH3), 4.65 (s,
2H, -OCH2), 4.73 (s, 2H, -OCH2), 6.90 (s, 1H), 7.01 (s, 1H),
7.17 (s, 1H, C6H). MS m/z: 406, 408 (M+). Anal. calcd. for
C18H19N2O4Br: C 53.08, H 4.70, N 6.88; found: C 53.24, H
4.76, N 6.91.
3-({4-[(2-Bromo-4,6-dimethylphenyl)oxy]but-2-ynyl}oxy)-
2H-chromen-2-one (4h)
Yield: 79%; colorless solid; mp 133–134 °C (dichloro-
methane–hexane). IR (KBr, cm–1): 2928, 1730, 1621. 1H
NMR (500 MHz, CDCl3) δH: 2.19 (s, 3H), 2.26 (s, 3H), 4.71
(s, 2H), 4.86 (s, 2H), 6.84 (s, 1H), 7.00–7.10 (m, 2H), 7.27–
7.44 (m, 4H). MS m/z: 412, 414 (M+). Anal. calcd. for
C21H17BrO4: C 61.03, H 4.15; found: C 60.17, H 4.10.
5-({4-[(2-Bromo-4-methylphenyl)oxy]but-2-ynyl}oxy)-1,3-
dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4c)
3-({4-[(2-Bromo-4-methylphenyl)oxy]but-2-ynyl}oxy)-2H-
chromen-2-one (4i)
Yield 93%; colorless solid; mp 155–157 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2948, 1700, 1642. 1H NMR
(400 MHz, CDCl3) δH: 2.27 (s, 3H, ArCH3), 3.22 (s, 3H,
-NCH3), 3.36 (s, 3H, -NCH3), 4.73 (s, 2H, -OCH2), 4.76 (s,
2H, -OCH2), 7.08 (s, 1H, C6H), 7.24–7.29 (m, 3H). MS m/z:
392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C 51.92, H
4.36, N 7.12; found: C 51.85, H 4.41, N 7.10.
Yield: 69%; colorless solid; mp 107–109 °C (dichloro-
methane–hexane). IR (KBr, cm–1): 2916, 1731, 1632. 1H
NMR (400 MHz, CDCl3) δH : 2.20 (s, 3H), 4.78 (s, 2H),
4.86 (s, 2H), 7.04 (s, 1H), 7.21–7.44 (m, 7H). MS m/z: 398,
400 (M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79;
found: C 60.40, H 3.85.
3-({4-[(1-Bromonaphthalene-2-yl)oxy]but-2-ynyl}oxy)-2H-
chromen-2-one (4j)
5-({4-[(1-Bromonaphthalene-2-yl)oxy]but-2-ynyl}oxy)-1,3-
dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4d)
Yield: 77%; colorless solid; mp 103–105 °C (dichloro-
methane–hexane). IR (KBr, cm–1): 2916, 1730, 1627. 1H
NMR (400 MHz, CDCl3) δH: 4.83 (s, 2H), 4.93 (s, 2H), 6.84
(s, 1H), 7.04–7.14 (m, 10H). MS m/z: 434, 436 (M+). Anal.
calcd. for C23H15BrO4: C 63.47, H 3.47; found: C 63.79, H
3.51.
Yield 87%; colorless solid; mp 118–120 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2979, 1701, 1638. 1H NMR
(400 MHz, CDCl3) δH: 3.05 (s, 3H, -NCH3), 3.29 (s, 3H,
-NCH3), 4.72 (s, 2H, -OCH2), 4.93 (s, 2H, -OCH2), 6.80 (s,
1H, C6H), 7.30 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H),
7.56 (t, J = 7.6 Hz, 1H), 7.76 (m, 2H), 8.20 (d, J = 8.5 Hz,
1H). MS m/z: 428, 430 (M+). Anal. calcd. for C20H17N2O4Br:
C 55.96, H 3.99, N 6.53; found: C 56.26, H 4.05, N 6.62.
3-({4-[(2-Bromophenyl)oxy]but-2-ynyl}oxy)-2H-chromen-
2-one (4k)
Yield: 78%; colorless solid; mp 128–130 °C (dichloro-
methane–hexane). IR (KBr, cm–1): 2917, 1734, 1617. 1H
NMR (400 MHz, CDCl3) δH: 4.73 (s, 2H), 4.85 (s, 2H), 6.94
(s, 1H), 7.14–7.44 (m, 8H). MS m/z: 384, 386 (M+). Anal.
calcd. for C19H13BrO4: C 59.24, H 3.40; found: C 59.36, H
3.37.
5-({4-[(2-Bromophenyl)oxy]but-2-ynyl}oxy)-1,3-dimethyl-
1,2,3,4-tetrahydropyrimidine-2,4-dione (4e)
Yield 96%; colorless solid; mp 104–106 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2979, 1705, 1639. 1H NMR
(400 MHz, CDCl3) δH: 3.32 (s, 3H, -NCH3), 3.35 (s, 3H,
-NCH3), 4.72 (s, 2H, -OCH2), 4.80 (s, 2H, -OCH2), 6.86–
6.99 (m, 2H), 7.06 (s, 1H, C6H), 7.47 (d, J = 8.0 Hz, 1H),
7.53 (d, J = 7.8 Hz, 1H). MS m/z:378, 380 (M+). Anal.
calcd. for C16H15N2O4Br: C 50.68, H 3.99, N 7.39; found: C
50.58, H 4.02, N 7.37.
3-({4-[(2-Bromo-3-methylphenyl)oxy]but-2-ynyl}oxy)-2H-
chromen-2-one (4l)
Yield: 80%; colorless solid; mp 163–165 °C (dichloro-
methane–hexane). IR (KBr, cm–1): 2919, 1739, 1629. 1H
NMR (400 MHz, CDCl3) δH: 2.31 (s, 3H), 4.77 (s, 2H), 4.86
(s, 2H), 6.84 (s, 1H), 7.03–7.43 (m, 7H). MS m/z: 398, 400
(M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79; found:
C 60.03, H 3.88.
5-({4-[(2-Bromo-3-methylphenyl)oxy]but-2-ynyl}oxy)-1,3-
dimethyl–1,2,3,4-tetrahydropyrimidine-2,4-dione (4f)
Yield 88%; colorless solid; mp 110–111 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2950, 1707, 1661. 1H NMR
(400 MHz, CDCl3) δH: 2.40 (s, 3H, ArCH3), 3.20 (s, 3H,
-NCH3), 3.32 (s, 3H, -NCH3), 4.72 (s, 2H, -OCH2), 4.78 (s,
2H, -OCH2), 6.77–6.84 (m, 1H), 6.92 (s, 1H, C6H), 7.08–
7.12 (m, 1H), 7.35–7.43 (m, 1H). MS m/z: 392, 394 (M+).
Anal. calcd. for C17H17N2O4Br: C 51.92, H 4.36, N 7.12;
found: C 52.16, H 4.37, N 7.23.
General procedure for the preparation of compounds
5a–5l.
The compounds 5a–l were synthesized according to the
earlier published procedure (7).
8-{[(2-Bromo-6-methylphenyl)oxy]methyl}-1,3-dimethyl-
2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione
(5a)
3-({4-[(2-Bromo-6-methylphenyl)oxy]but-2-ynyl}oxy)-2H-
chromen-2-one (4g)
Yield 89%; colorless solid; mp 139–141 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2957, 1696, 1648. 1H NMR
Yield: 81%; colorless solid; mp 148–149 °C (dichloro-
methane–hexane). IR (KBr, cm–1): 2920, 1732, 1629. 1H
NMR (400 MHz, CDCl3) δH: 2.27 (s, 3H), 4.71 (s, 2H), 4.85
(s, 2H), 6.97 (s, 1H), 7.18–7.43 (m, 7H). MS m/z: 398, 400
(M+). Anal. calcd. for C20H15BrO4: C 60.17, H 3.79; found:
C 60.38, H 3.86.
(400 MHz, CDCl ) H: 2.23 (s, 3H, ArCH3), 3.40 (s, 3H,
δ
3
-NCH3), 3.54 (s, 3H, -NCH3), 4.58 (d, J = 4.8 Hz, 2H,
-OCH2), 4.71 (s, 2H, -OCH2), 6.30 (t, J = 4.8 Hz, 1H), 7.25–
754 (m, 3H). MS m/z: 392, 394 (M+). Anal. calcd. for
C17H17N2O4Br: C 51.92, H 4.36, N 7.12; found: C 52.09, H
4.45, N 7.09.
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Majumdar et al.
851
8-{[(2-Bromo-4,6-dimethylphenyl)oxy]methyl}-1,3-
dimethyl-2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-
2,4-dione (5b)
1-[(2-Bromo-6-methylphenyl)oxy]-3,5-dihydropyrano[2,3-
c]chromen-5-one (5g)
Yield: 85%; colorless solid; mp 166–168 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2920, 1729,
Yield 83%; colorless solid; mp 175–177 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2942, 1698, 1651. 1H NMR
(400 MHz, CDCl3) δH: 2.21 (s, 3H, ArCH3), 2.28 (s, 3H,
ArCH3), 3.39 (s, 3H, -NCH3), 3.52 (s, 3H, -NCH3), 4.58 (d,
J = 4.8 Hz, 2H, -OCH2), 4.69 (s, 2H, -OCH2), 6.33 (t, J =
4.8 Hz, 1H), 6.92 (s, 1H), 7.20 (s, 1H). MS m/z: 406, 408
(M+). Anal. calcd. for C18H19N2O4Br: C 53.08, H 4.70, N
6.88; found: C 53.36, H 4.54, N 6.93.
1
1608. H NMR (500 MHz, CDCl3) δH: 2.29 (s, 3H), 4.80 (d,
J = 4.2 Hz, 2H), 4.98 (s, 2H), 6.27 (t, J = 4.3 Hz, 1H), 7.21–
7.64 (m, 7H). MS m/z: 398, 400 (M+). Anal. calcd. for
C20H15BrO4: C 60.17, H 3.79; found: C 60.01, H 3.84.
1-[(2-Bromo-4,6-dimethylphenyl)oxy]-3,5-
dihydropyrano[2,3-c]chromen-5-one (5h)
Yield: 90%; colorless solid; mp 145–147 °C (dichloro-
8-{[(2-Bromo-4-methylphenyl)oxy]methyl}-1,3-dimethyl-
2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione
(5c)
methane – petroleum ether). IR (KBr, cm–1): 2923, 1725,
1
1608. H NMR (500 MHz, CDCl3) δH: 2.26 (s, 3H), 2.32 (s,
3H), 4.76 (d, J = 4.1 Hz, 2H), 4.99 (s, 2H), 6.23 (t, J =
4.1 Hz, 1H), 7.28–7.53 (m, 6H). MS m/z: 412, 414 (M+).
Anal. calcd. for C21H17BrO4: C 61.03, H 4.15; found: C
61.32, H 4.24.
Yield 81%; colorless solid; mp 105–108 °C (acetonitrile–
methanol). IR (KBr, cm–1): 3001, 2940, 1693, 1654. 1H
NMR (400 MHz, CDCl3) δH: 2.26 (s, 3H, ArCH3), 3.39 (s,
3H, -NCH3), 3.48 (s, 3H, -NCH3), 4.57 (d, J = 4.8 Hz, 2H,
-OCH2), 4.83 (s, 2H, -OCH2), 6.26 (t, J = 4.8 Hz, 1H), 6.72
(d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H).
MS m/z: 392, 394 (M+). Anal. calcd. for C17H17N2O4Br: C
51.92, H 4.36, N 7.12; found: C 52.11, H 4.39, N 7.19.
1-[(2-Bromo-4-methylphenyl)oxy]-3,5-dihydropyrano[2,3-
c]chromen-5-one (5i)
Yield: 86%; colorless solid; mp 153–154 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2931, 1723,
1
1611. H NMR (500 MHz, CDCl3) δH: 2.30 (s, 3H), 4.78 (d,
8-{[(1-Bromonaphthlene-2-yl)oxy]methyl}-1,3-dimethyl-
2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione
(5d)
J = 4.3 Hz, 2H), 4.95 (s, 2H), 6.25 (t, J = 4.0 Hz, 1H), 7.21
(s, 1H), 7.26–7.52 (m, 5H), 8.07 (d, J = 7.9 Hz, 1H). MS
m/z: 398, 400 (M+). Anal. calcd. for C20H15BrO4: C 60.17. H
3.79; found: C 60.27, H 3.83.
Yield 86%; colorless solid; mp 115–117 °C (acetonitrile–
methanol). IR (KBr, cm–1): 3009, 1697, 1654. 1H NMR
(500 MHz, CDCl3) δH: 3.40 (s, 3H, -NCH3), 3.55 (s, 3H,
-NCH3), 4.59 (d, J = 4.9 Hz, 2H, -OCH2), 5.02 (s, 2H,
-OCH2), 6.32 (t, J = 4.9 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H),
7.43 (t, J = 8.5 Hz, 1H), 7.57 (t, J = 8.3 Hz, 1H), 7.77 (m,
2H), 8.20 (d, J = 8.5 Hz, 1H). MS m/z: 428, 430 (M+). Anal.
calcd. for C20H17N2O4Br: C 55.96, H 3.99, N 6.53; found: C
55.87, H 4.03, N 6.59.
1-{(1-Bromonaphthalen-2-yl)oxy}-3,5-dihydropyrano[2,3-
c]chromen-5-one (5j)
Yield: 86%; colorless solid; mp 190–192 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2864, 1721,
1
1605. H NMR (500 MHz, CDCl3) δH: 4.79 (d, J = 4.6 Hz,
2H), 5.14 (s, 2H), 6.36 (t, J = 4.5 Hz, 1H), 7.22 (d, J =
8.9 Hz, 1H), 7.25–7.28 (m, 1H), 7.36 (dd, J = 1.2, 8.2 Hz,
1H), 7.39–7.60 (m, 3H), 7.79–7.82 (m, 2H), 7.88 (dd, J =
1.0, 8.0 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H). MS m/z: 434, 436
(M+). Anal. calcd. for C23H15BrO4: C 63.47, H 3.47; found:
C 63.54, H 3.50.
8-{[(2-Bromophenyl)oxy]methyl}-1,3-dimethyl-2,3,4,6-
tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione (5e)
Yield 85%; colorless solid; mp 133–135 °C (acetonitrile–
methanol). IR (KBr, cm–1): 2929, 1704, 1656. 1H NMR
(400 MHz, CDCl3) δH: 3.40 (s, 3H, -NCH3), 3.56 (s, 3H,
-NCH3), 4.59 (d, J = 4.8 Hz, 2H, -OCH2), 4.82 (s, 2H,
-OCH2), 6.38 (t, J = 4.8 Hz, 1H), 6.90 (t, J = 8.0 Hz, 2H),
7.51 (d, J = 8.0 Hz, 2H). MS m/z: 378, 380 (M+). Anal.
calcd. for C16H15N2O4Br: C 50.68, H 3.99, N 7.39; found: C
50.95, H 3.92, N 7.41.
1-[(2-Bromophenyl)oxy]-3,5-dihydropyrano[2,3-c]chromen-
5-one (5k)
Yield: 88%; colorless solid; mp 140–141 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2907, 1724,
1
1610. H NMR (500 MHz, CDCl3) δH: 4.81 (d, J = 4.1 Hz,
2H), 4.92 (s, 2H), 6.31 (t, J = 4.2 Hz, 1H), 7.20–7.71 (m,
8H). MS m/z: 384, 386 (M+). Anal. calcd. for C19H13BrO4: C
59.24, H 3.40; found: C 59.41, H 3.51.
8-{[(2-Bromo-3-methylphenyl)oxy]methyl}-1,3-dimethyl-
2,3,4,6-tetrahydro-1H-pyrano[3,2-d]pyrimidine-2,4-dione
(5f)
Yield 81%; colorless solid; mp 101–104 °C (acetonitrile–
methanol). IR (KBr, cm–1): 3012, 2953, 1697, 1654. 1H
NMR (400 MHz, CDCl3) δH: 2.40 (s, 3H, ArCH3) 3.39 (s,
3H, -NCH3), 3.47 (s, 3H, -NCH3), 4.58 (d, J = 4.8 Hz, 2H,
-OCH2), 4.85 (s, 2H, -OCH2), 6.30 (t, J = 4.8 Hz, 1H), 6.68
(d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 7.16 (t, J =
8.0 Hz, 1H, ArH). MS m/z: 392, 394 (M+). Anal. calcd. for
C17H17N2O4Br: C 51.92, H 4.36, N 7.12; found: C 51.99, H
4.38, N 7.23.
1-[(2-Bromo-3-methylphenyl)oxy]-3,5-dihydropyrano[2,3-
c]chromen-5-one (5l)
Yield: 84%; colorless solid; mp 169–171 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2909, 1720,
1
1620. H NMR (400 MHz, CDCl3) δH: 2.30 (s, 3H), 4.76 (d,
J = 4.2 Hz, 2H), 4.93 (s, 2H), 6.27 (t, J = 4.1 Hz, 1H), 7.18–
7.69 (m, 7H). MS m/z: 398, 400 (M+). Anal. calcd. for
C20H15BrO4: C 60.17, H 3.79; found: C 60.30, H 3.72.
© 2008 NRC Canada

852
Can. J. Chem. Vol. 86, 2008
General procedure for the radical cyclization of
compounds 5
2,4-Dimethyl-1,2,3,4,4b,5,12c,13-octahydro-
benzo[5′,6′]chromeno[3′,4′:4,5] pyroano[3,2-d]pyrimidine-
1,3-dione (6d)
A
suspension of the compounds 5 (0.30 mmol,
Yield: 76%; colorless solid; mp 156–157 °C (acetonitrile–
methanol). IR (KBr, cm–1): 1654, 1631. 1H NMR (500 MHz,
CDCl3) δH: 3.35 (dt, J = 3.8, 11.0 Hz, 1H), 3.44 (s, 3H, -
NCH3), 3.54 (s, 3H, -NCH3), 3.88 (dt, J = 3.9, 11.4 Hz, 1H),
4.00 (t, J = 11.4 Hz, 1H), 4.16 (t, J = 11.3 Hz, 1H), 4.57
(dd, J = 2.4, 11.6 Hz, 1H), 4.86 (dd, J = 3.2, 11.8 Hz, 1H),
7.06 (d, J = 8.9 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.54 (t, J
= 8.2 Hz, 1H), 7.71 (t, J = 8.9 Hz, 1H), 7.80 (d, J = 8.1 Hz,
1H), 7.90 (d, J = 8.5 Hz, 1H). MS m/z: 350 (M+). Anal.
calcd. for C20H18N2O4: C 68.56, H 5.18, N 8.00; found: C
68.73, H 5.22, N 8.13.
0.01mol/L), n-Bu3SnH (0.08 mL, 0.30 mmol), and AIBN
(25 mg) in dry degassed toluene (for 5a–f) or benzene (for
5g–l) were heated for 3–4 h under N2. After the completion
of the reaction the solvent was removed under reduced pres-
sure. The residue was dissolved in CH2Cl2 (15 mL) and
stirred with 10% aqueous KF solution (10 mL) for 1 h. The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined CH2Cl2 extract was washed with water (2 ×
20 mL) and then brine solution (1 × 20 mL), and was dried
(Na2SO4). The solvent was removed and the residual mass
was subjected to column chromatography over silica gel us-
ing petroleum ether – ethyl acetate as eluant to give 6a–l.
Compounds 6a–f were recrystallized from acetonitrile–
methanol mixture and compounds 6g–l were recrystalized
from dichloromethane – petroleum ether (60–80 °C).
2,4-Dimethyl-1,2,3,4,4b,5,10b,11-octahydro-
chromeno[3′,4′:4,5]pyrano[3,2-d]pyrimidine-1,3-dione (6e)
Yield: 89%; colorless solid; mp 200-202 °C (acetonitrile–
methanol). IR (KBr, cm–1): 1651, 1623. 1H NMR (300 MHz,
CDCl3) δH: 3.17–3.36 (m, 2H), 3.41 (s, 3H, -NCH3), 3.51 (s,
3H, -NCH3), 4.00 (dt, J = 4.1, 11.1Hz, 2H), 4.47–4.50 (m,
2H), 6.89–7.36 (m, 4H). MS m/z: 300 (M+). Anal. calcd. for
C16H16N2O4: C 63.99, H 5.37, N 9.33; found: C 64.08, H
5.45, N 9.49.
2,4,7-Trimethyl-1,2,3,4,4b,5,10b,11-octahydrochro-
meno[3′,4′:4,5]pyrano[3,2-d]pyrimidine-1,3-dione (6a)
Yield: 81%; colorless solid; mp 171–172 °C (acetonitrile–
methanol). IR (KBr, cm–1): 1655, 1633. 1H NMR (500 MHz,
CDCl3) δH: 2.20 (s, 3H, ArCH3), 3.24 (dt, J = 3.8, 11.6 Hz,
1H), 3.36 (dt, J = 3.8, 11.7 Hz, 1H), 3.41 (s, 3H, -NCH3),
3.52 (s, 3H, -NCH3), 3.90 (t, J = 11.2 Hz, 1H), 4.00 (t, J =
11.3 Hz 1H), 4.46 (ddd, J = 1.8, 4.3, 11.6 Hz, 1H), 4.53
(ddd, J = 1.3, 4.3, 11.6 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H),
7.00 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H). MS m/z:
314 (M+). Anal. calcd. for C17H18N2O4: C 64.96, H 5.77, N
8.91; found: C 65.18, H 5.85, N 8.99.
2,4,10-Trimethyl-1,2,3,4,4b,5,10b,11-
octahydrochromeno[3′,4′:4,5]pyroano[3,2-d]pyrimidine-
1,3-dione (6f)
Yield: 81%; colorless solid; mp 144–146 °C (acetonitrile–
methanol). IR (KBr, cm–1): 1667, 1624. 1H NMR (500 MHz,
CDCl3) δH: 2.35 (s, 3H, ArCH3), 3.24 (dt, J = 4.1, 11.1 Hz,
2H), 3.41(s, 3H, -NCH3), 3.50 (s, 3H, -NCH3), 3.88 (t, J =
11.5 Hz, 1H), 4.01 (t, J = 11.3 Hz 1H), 4.49 (dd, J = 4.3,
11.6 Hz, 1H), 4.56 (dd, J = 1.8, 11.6 Hz, 1H), 6.74–7.14 (m,
3H). MS m/z: 314 (M+). Anal. calcd. for C17H18N2O4: C
64.96, H 5.77, N 8.91; found: C 65.01, H 5.89, N 8.98.
2,4,7,9-Tetramethyl-1,2,3,4,4b,5,10b,11-
octahydrochromeno[3′,4′:4,5]pyrano[3,2-d]pyrimidine-1,3-
dione (6b)
Yield: 86%; colorless solid; mp 190–192 °C (acetonitrile–
methanol). IR (KBr, cm–1): 1657, 1633. 1H NMR (500 MHz,
CDCl3) δH: 2.21 (s, 3H, ArCH3), 2.32 (s, 3H, ArCH3), 3.23
(dt, J = 4.4, 11.6 Hz, 2H), 3.41 (s, 3H, -NCH3), 3.51 (s,
3H, -NCH3), 3.90 (t, J = 11.2 Hz, 1H), 3.93 (t, J = 11.4 Hz,
1H), 4.47 (ddd, J = 1.3, 4.1, 11.3 Hz, 1H), 4.55 (ddd, J =
1.8, 4.1, 11.4 Hz, 1H), 6.79 (s, 1H), 6.89 (s, 1H). 13C NMR
(75.5MHz, CDCl3): δC 16.2, 20.8, 28.9, 31.3, 31.8, 32.9,
65.7, 67.7, 117.7, 126.7, 127.4, 127.9, 130.7, 131.5, 132.2,
150.8, 151.1, 158.7. MS m/z: 328 (M+). Anal. calcd. for
C18H20N2O4: C 65.84. H 6.14, N 8.53; found: C 66.02, H
6.11, N 8.56.
9-Methyl-6c,7,12b,13-tetrahydro-1H-
chromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6g)
Yield: 75%; colorless solid; mp 124–125 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2919, 1731,
1623. 1H NMR (500 MHz, CDCl3) δH: 2.23 (s, 3H), 3.34 (dt,
J = 4.4, 10.4 Hz, 1H), 3.56 (dt, J = 4.0, 11.0 Hz, 1H), 3.97
(t, J = 11.5 Hz, 1H), 4.18 (t, J = 11.6 Hz, 1H), 4.61 (dd, J =
4.5, 12.6 Hz, 1H), 4.74 (dd, J = 2.0, 11.6 Hz, 1H), 6.84–7.10
(m, 3H), 7.33–7.71 (m, 4H). MS m/z: 320 (M+). Anal. calcd.
for C20H16O4: C 74.99, H 5.03; found: C 75.23, H 5.18.
2,4,9-Trimethyl-1,2,3,4,4b,5,10b,11-
octahydrochromeno[3′,4′:4,5]pyrano[3,2-d]pyrimidine-
1,3-dione (6c)
9,11-Dimethyl-6c,7,12b,13-tetrahydro-1H-
chromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6h)
Yield: 82%; colorless solid; mp 181–183 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2921, 1737,
Yield: 85%; colorless solid; mp 130–132 °C (acetonitrile–
methanol). IR (KBr, cm–1): 1651, 1627. 1H NMR (500 MHz,
CDCl3) δH: 2.29 (s, 3H, ArCH3), 3.30 (dt, J = 4.4, 11.7 Hz,
2H), 3.41(s, 3H, -NCH3), 3.50 (s, 3H, -NCH3), 3.91 (t, J =
11.2 Hz, 2H), 4.44 (ddd, J = 1.7, 4.5, 11.3 Hz, 2H), 6.78 (d,
J = 8.2 Hz, 1H), 6.95 (s, 1H), 7.01 (t, J = 8.1 Hz, 1H). MS
m/z: 314 (M+). Anal. calcd. for C17H18N2O4: C 64.96, H
5.77, N 8.91; found: C 65.19, H 5.79, N 8.88.
1
1623. H NMR (500 MHz, CDCl3) δH: 2.20 (s, 3H), 2.28 (s,
3H), 3.33 (dt, J = 4.2, 10.2 Hz, 1H), 3.57 (dt, J = 4.1,
11.3 Hz, 1H), 3.93 (t, J = 11.3 Hz, 1H), 4.16 (t, J = 11.7 Hz,
1H), 4.60 (dd, J = 4.3, 11.5 Hz, 1H), 4.71 (dd, J = 2.6,
11.5 Hz, 1H), 6.84 (s, 1H), 6.91 (s, 1H), 7.33–7.70 (m, 4H).
MS m/z: 334 (M+). Anal. calcd. for C21H18O4: C 75.43, H
5.43; found: C 75.50, H 5.38.
© 2008 NRC Canada

Majumdar et al.
853
11-Methyl-6c,7,12b,13-tetrahydro-1H-
References
chromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6i)
Yield: 76%; colorless solid; mp 141–144 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2930, 1735,
1624. 1H NMR (500 MHz, CDCl3) δH: 2.31 (s, 3H), 3.34 (dt,
J = 4.4, 10.7 Hz, 1H), 3.59 (dt, J = 4.0, 11.0 Hz, 1H), 3.94
(t, J = 11.3 Hz, 1H), 4.17 (t, J = 11.7 Hz, 1H), 4.61 (dd, J =
4.1, 11.6 Hz, 1H), 4.67 (dd, J = 2.6, 12.6 Hz, 1H), 6.82 (d,
J = 8.2 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H),
7.33–7.46 (m, 3H), 7.65 (d, J = 7.7 Hz, 1H). MS m/z: 320
(M+). Anal. calcd. for C20H16O4: C 74.99, H 5.03; found: C
75.12, H 5.09.
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4c,5,12c,13-Tetrahydro-7H-benzo[f]chromeno[4′,3′:5,6]py-
rano[4,3-c]chromen-7-one (6j)
Yield: 90%; colorless solid; mp 201–202 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2916, 1727,
1
1620. H NMR (500 MHz, CDCl3) δH: 3.69 (dt, J = 4.2,
11.3 Hz, 1H), 3.95 (dt, J = 4.1, 11.4 Hz, 1H), 4.20 (t, J =
11.5 Hz, 1H), 4.24 (t, J = 11.5 Hz, 1H), 4.77 (dd, J = 3.7,
11.6 Hz, 1H), 5.00 (dd, J = 3.0, 12.0 Hz, 1H), 7.10 (d, J =
8.1 Hz, 1H), 7.35–7.59 (m, 5H), 7.68 (d, J = 7.7 Hz, 1H),
7.72 (d, J = 6.7 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.95 (d,
J = 8.5 Hz, 1H). MS m/z: 356 (M+). Anal. calcd. for
C23H16O4: C 77.52, H 4.53; found: C 77.76, H 4.63.
6c,7,12b,13-Tetrahydro-1H-chromeno[3′,4′:4,5]pyrano[2,3-
c]chromen-1-one (6k)
Yield: 86%; colorless solid; mp 176–177 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2919, 1725,
1
1621. H NMR (500 MHz, CDCl3) δH: 3.38–3.43 (m, 1H),
3.61–3.65 (m, 1H), 3.98 (t, J = 11.4 Hz, 1H), 4.19 (t, J =
11.8 Hz, 1H), 4.62 (dd, J = 4.5, 11.6 Hz, 1H), 4.68 (dd, J =
2.8. 11.6 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.98 (t, J =
7.3 Hz, 1H), 7.21–7.46 (m, 5H), 7.65(d, J = 7.8 Hz, 1H). 13
C
9. (a) B. Giese. In Radicals in organic synthesis: Formation of
Carbon–Carbon Bonds. Pergamon, Oxford. 1986; (b) In Radi-
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Rev. 96, 289 (1996); (d) C.P. Jasperse, D.P. Curran, and T.L.
Fevig. Chem Rev. 91, 1237 (1991); (e) K.C. Majumdar and
P.K. Basu. Heterocycles, 57, 2413 (2002); (f) W.R. Bowman,
A.J. Fletcher, and G.B.S. Pots. J. Chem. Soc. Perkin Trans. 1,
2747 (2002); (g) K.C. Majumdar, P.K. Basu, and P.P.
Mukhopadhyay. Tetrahedron, 60, 6239 (2004); (h) D.P.
Curran. Synthesis, 417 (1988).
NMR (125 MHz, CDCl3) δc: 30.0, 31.6, 66.0, 68.6, 117.6,
117.8, 118.9, 119.5, 120.9, 121.9, 122.4, 125.4, 129.2,
129.5, 130.4, 140.5, 149.8, 155.3, 156.9. MS: m/z = 306
(M+). Anal. calcd. for C19H14O4: C 74.50, H 4.61; found: C
74.81, H 4.72.
12-Methyl-6c,7,12b,13-tetrahydro-1H-
chromeno[3′,4′:4,5]pyrano[2,3-c]chromen-1-one (6l)
Yield: 85%; colorless solid; mp 143–145 °C (dichloro-
methane – petroleum ether). IR (KBr, cm–1): 2917, 1735,
10. (a) V. Snieckus. Bull. Soc. Chim. Fr. 67 (1988); (b) D.C.
1
1619. H NMR (300 MHz, CDCl3) δH: 2.23 (s, 3H), 3.38–
Harrowven.
Tetrahedron
Lett.
34,
5653
(1993);
3.41 (m, 1H), 3.61–3.65 (m, 1H), 3.96 (t, J = 10.9 Hz, 1H),
4.17 (t, J = 11.2 Hz, 1H), 4.62 (dd, J = 3.9, 11.4 Hz, 1H),
4.74 (dd, J = 2.5, 11.2 Hz, 1H), 6.90–7.70 (m, 7H). MS m/z:
320 (M+). Anal. calcd. for C20H16O4: C 74.99, H 5.03;
found: C 74.85, H, 5.07.
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Acknowledgements
We thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, and the Department of Science
and Technology (DST), New Delhi, for financial assistance.
PKM and PD are thankful to the University Grants Commis-
sion (UGC), New Delhi, and CSIR for their respective fel-
lowships.
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© 2008 NRC Canada