N-Iodosuccinimide mediated regioselective heterocyclization of 3-cyclohex-2′-enyl-4-hydroxycoumarin

Article abstract of DOI:10.1016/S0040-4020(02)01024-4

A number of 3-cyclohex-2′-enyl-4-hydroxy[1]benzopyran-2-ones are regioselectively cyclized by treatment with N-iodosuccinimide in acetonitrile to afford 9′-iodo-2′-oxabicyclo[3,3,1]nonano[4′,3′-c][1] benzopyran-2-ones in excellent yield.

Full text of DOI:10.1016/S0040-4020(02)01024-4

Tetrahedron 58 (2002) 8501–8504
N-Iodosuccinimide mediated regioselective heterocyclization
of 3-cyclohex-20-enyl-4-hydroxycoumarin
*
K. C. Majumdar and S. Sarkar
Department of Chemistry, University of Kalyani, Kalyani 741 235, W. B., India
Received 29 May 2002; revised 24 July 2002; accepted 15 August 2002
Abstract—A number of 3-cyclohex-20-enyl-4-hydroxy[1]benzopyran-2-ones are regioselectively cyclized by treatment with N-iodo-
succinimide in acetonitrile to afford 90-iodo-20-oxabicyclo[3,3,1]nonano[40,30-c][1]benzopyran-2-ones in excellent yield. q 2002 Elsevier
Science Ltd. All rights reserved.
Coumarin1 and its derivatives2 are important due to their
physiological activity. The biological activity3,4 of 4-alkyl
and 3-alkyl coumarins has made their synthesis5 an
attractive target. We have reported the regioselective
synthesis of 3,4-fused pyrano- and furo coumarins.6 I0n
this context we attempted the cyclization of 3-(cyclohex-2 -
enyl)-4-hydroxycoumarin with pyridine hydrotribromide7
and failed to obtain any cyclized product. Our recent interest
in the reagent N-iodosuccinimide prompted us to undertake
a study on the use of this reagent for the regioselective
cyclization of 3-(cyclohex-20-enyl)-4-hydroxycoumarins.
Here we report the results.
1. Results and discussion
We had earlier attempted the cyclization of 3-(cyclohex-20-
enyl)-4-hydroxycoumarin with pyridine hydrotribromide
and observed exclusive formation of a tribromo derivative
(4) with no indication of cyclization (Scheme 2). Therefore,
we decided to treat substrates 3a–f with this reagent.
Substrate 3a when treated with N-iodosuccinimide in
acetonitrile at 0–58C for 1 h gave a crystalline white
The starting materials, 3-(cyclohex-20-enyl)-4-hydroxy-
coumarins (3a–f) for this study were prepared8 in
65–70% yield by refluxing 4-hydroxycoumarins (1a–f)
with 3-bromocyclohexene in acetone in the presence of
anhydrous potassium carbonate for 20 h (Scheme 1).
Scheme 2. Reagents: PyHBr3/CH2Cl2, 0–58c, 2 h (94%).
Scheme 1. Reagents: (i) acetone, K2CO3, reflux, 20 h.
Keywords: N-iodosuccinimide; regioselective cyclization; 4-hydroxycoumarin; bridged tricyclic heterocycle; 6-endo cyclization.
*
Corresponding author. Tel.: þ91-33-582-7521; fax: þ91-33-582-8282; e-mail: kcm@klyuniv.ernet.in
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01024-4

8502
K. C. Majumdar, S. Sarkar / Tetrahedron 58 (2002) 8501–8504
solid, mp 1408C in 85% yield. IR showed the absence of the
–OH absorption peak at 3300 cm21. Elemental analysis and
spectral data indicated this to be the bridged product 5a. The
1
high-field H NMR spectrum of the product showed three
lone protons: at d 4.44 assignable to proton Ha, at d 5.24
assignable to proton Hb, and at d 3.63 assignable to proton
Hc. The signal at d 4.44 due to Ha appeared as a ddd, J¼7.3,
4.9 and 10.0 Hz. The signal at d 5.24 due to Hb appeared as a
dd with coupling constants J¼6.9 and 7.3 Hz. The signal at
d 3.63 on careful expansion was found to be a dt with
coupling constants J¼6.9 and 7.1 Hz. From the splitting
pattern and the coupling constant values it is clear that Hb
and Hc are vicinal protons coupled to each other. This
clearly shows that the product has the bridged tricyclic
structure 5 instead of linearly fused structure 6 where Hb and
Hc would not be on adjacent carbons. Other substrates 3b–f
were treated similarly to give products 5b–f in 85–90%
yield (Scheme 3).
Scheme 3. Reagents: (i) NIS, CH3CN, 0–58C, 1 h.
A Dreiding model of compound 5a can be constructed by
1,3 fusion of the pyran ring in the half-chair conformation
with the cyclohexane ring in the chair conformation
(distorted) as shown in Fig. 1. However, the coupling
constant 10.0 Hz of Ha cannot be explained if the molecule
5a attains this conformation. The alternative model that can
be constructed, again by 1,3 fusion of the pyran ring in the
half-chair form with the cyclohexane ring in the boat
(distorted) form, is shown in Fig. 2. The coupling constant
J¼10.0 Hz can be explained if the molecule 5a attains this
conformation. It may be noted that [3.3.1] bicyclononane is
known to exist in the chair–boat conformation.9
Figure 1.
It is worths of note that the substrate 3-cyclohex-20-enyl-4-
hydroxycoumarin 3 did not react at all with N-bromosuc-
cinimide in acetonitrile at 0–58C and even at elevated
temperature no characterizable product was obtained.
The regioselective formation of the products may be easily
explained by the initial formation of an intermediate
iodonium ion 7a–f which may undergo a 6-endo cyclization
to give products 5a–f. The alternative pathway, a 5-exo
cyclization to give products 6a–f does not occur. In
conclusion all six substrates studied so far gave only the
bridged cyclic products by a 6-endo mode and the other
mode of cyclization was found to be totally absent. This is
therefore a regioselective method for the synthesis of
bridged 3,4-fused pyranocoumarin derivatives in excellent
yield (Scheme 4).
Figure 2.
Scheme 4. Reagents: (i) NIS, CH3CN, 0–58C, 1 h.

K. C. Majumdar, S. Sarkar / Tetrahedron 58 (2002) 8501–8504
8503
2. Experimental
830 cm21; lmax 218, 317 nm; dH (300 MHz, CDCl3) 1.55–
1.90 (m, 6H), 2.06 (s, 3H), 2.18 (s, 3H), 3.85–3.89 (m, 1H,
–CH–), 6.03–6.06 (m, 1H, vCH), 6.27–6.32 (m, 1H,
vCH), 7.19 (s, 1H), 7.58 (s, 1H); m/z 270 (Mþ).
Melting points were determined in a sulphuric acid bath and
are uncorrected. UV absorption spectra were recorded in
EtOH on a Hitachi 200-20 spectrophotometer (lmax in nm)
and IR spectra as KBr discs on a Perkin–Elmer 1330
2.1.5. 6-Tertiarybutyl-dimethyl-3-[20-cyclohexenyl]-4-
hydroxy-1-benzopyran-2(H)-one (3e). Yield: 65%, mp
1608C; [Found C 76.63; H 7.25. C19H22O3 requires C 76.51;
H 7.38%]; nmax 3300, 2920, 1710, 1470, 1280, 1105,
820 cm21; lmax 217, 310 nm; dH (300 MHz, CDCl3) 1.43 (s,
9H), 1.51–1.85 (m, 6H), 3.91–3.96 (m, 1H, –CH–), 5.90–
6.01 (m, 1H, vCH), 6.29–6.32 (m, 1H, vCH), 7.09 (d,
J¼9 Hz, 1H), 7.18 (d, J¼9 Hz, 1H), 7.33 (s, 1H); m/z 298
(Mþ).
1
apparatus (nmax in cm21). H NMR spectra were run in
CDCl3 with SiMe4 as internal standard on a Bruker
300 MHz instrument at the Indian Institute of Chemical
Biology, Kolkata (chemical shifts in d ppm). Elemental
analysis and mass spectra were recorded by RSIC (CDRI),
Lucknow. Silica gel (60–120 mesh) was used for
chromatographic separation. Extracts were dried over
anhydrous sodium sulphate.
2.1. Preparation of 3-[20-cyclohexenyl]-4-hydroxy-1-
benzopyran-2(H)-one (3a–f)
2.1.6. 3-[20-Cyclohexenyl]-4-hydroxy-1-benzopyran-
2(H)-one (3f). Yield: 66%, mp 1088C Lit.8 mp 1108C.
A mixture of 4-hydroxycoumarin (0.02 mol), 3-bromo-
cyclohexene (0.03 mol) and anhydrous potassium carbonate
(3 g) was refluxed in acetone (150 mL) on a water bath for
20 h, cooled and filtered. The solvent was removed and the
residue was extracted with chloroform (3£50 mL). The
chloroform extract was washed with NaHCO3 solution
(10%, 2£50 mL) to remove the unreacted 4-hydroxy-
coumarin, water (50 mL), dried (Na2SO4) and solvent was
removed to give a highly viscous liquid. This was purified
by column chromatography over silica gel using pet-ether
(60–808C)/benzene (1:1) as eluent to give compound 3a–f.
2.2. Attempted procedure for the cyclization of 3a by
N-bromosuccinimide
N-bromosuccinimide (0.178 g, 1 mmol) was added to a dry
and distilled acetonitrile solution of the compound 3a
(1 mmol) at 0–58C. The reaction mixture was stirred for
several hours at 0–58C but no change was observed.
Decomposition was observed when the reaction mixture
was allowed to boil. No characterizable product was
obtained.
2.3. General procedure for the cyclization of compounds
3a–f by N-iodosuccinimide
2.1.1. 6-Methyl-3-[20-cyclohexenyl]-4-hydroxy-1-benzo-
pyran-2(H)-one (3a). Yield: 65%, mp 1188C; [Found C
75.15; H 6.33. C16H16O3 requires C 75.00; H 6.25%]; nmax
(KBr) 3350, 2920, 1700, 1490, 1280, 1105, 830 cm21; lmax
218, 313 nm; dH (300 MHz, CDCl3) 1.61–2.01 (m, 6H),
2.47 (s, 3H), 3.87–3.90 (m, 1H, –CH–), 6.03–6.06 (m, 1H,
vCH), 6.28–6.33 (m, 1H, vCH), 7.17 (s, 1H),7.37 (d, J¼
9 Hz, 1H), 7.71 (d, J¼9 Hz, 1H); m/z 256 (Mþ).
2.1.2. 8-Methyl-3-[20-cyclohexenyl]-4-hydroxy-1-benzo-
pyran-2(H)-one (3b). Yield: 67%, mp 1268C; [Found C
75.15; H 6.33. C16H16O3 requires C 75.00; H 6.25%]; nmax
(KBr) 3350, 2930, 1700, 1490, 1280, 1105, 830 cm21; lmax
210, 314 nm; dH (300 MHz, CDCl3) 1.65–1.98 (m, 6H),
2.55 (s, 3H), 3.85–3.89 (m, 1H, –CH–), 6.04–6.07 (m, 1H,
vCH), 6.29–6.33 (m, 1H, vCH), 7.13–7.18 (ddøt, J¼7.4,
8.1 Hz, 1H), 7.35 (d, J¼7.4 Hz, 1H), 7.61 (d, J¼8.1 Hz,
1H); m/z 256 (Mþ).
N-Iodosuccinimide (0.225 g, 1 mmol) was added to a dry
and distilled acetonitrile solution of the compounds 3a–f
(1 mmol) at 0–58C. The reaction mixture was then stirred
for 1 h at 0–58C. Stirring was continued for an additional
period of 30–45 min at rt. On completion of the reaction
(monitored by TLC) acetonitrile was removed from the
reaction mixture under reduced pressure. The residual mass
was then extracted with chloroform and the extract was
washed with 5% NaHSO3 solution (3£50 mL) and water
(3£50 mL) and dried (Na2SO4). The residual mass after
removal of the solvent was subjected to column chroma-
tography over silica gel using petroleum ether (60–808C)/
benzene (3:1) as eluent to give cyclization product 5a–f.
2.3.1. 6-Methyl-90-iodo-20-oxabicyclo[3,3,1]nonano[40,30-c]-
[1]benzopyran-2-one (5a). Yield 90%; mp 1408C; [Found
C 50.38; H 3.89 C16H15IO3 requires C 50.26; H 3.92%];
nmax (KBr) 2900, 1705, 1390, 1250, 1090, 800 cm21; lmax
222, 293 nm; dH (300 MHz, CDCl3) 1.33–1.39 (m, 1H),
1.57–1.66 (m, 1H), 1.83–1.96 (m, 3H), 2.07–2.17 (m, 1H),
2.42 (s, 3H), 3.63 (dtøq, J¼6.9, 7.1 Hz, Hc), 4.44 (ddd,
J¼10.0, 7.3, 4.9 Hz, Ha), 5.24 (dd, J¼6.9, 7.3 Hz, Hb), 7.24
(d, J¼8.5 Hz, 1H), 7.35–7.39 (dd, J¼8.5, 1 Hz, 1H); 7.48
(d, J¼1 Hz, 1H); m/z 382 (Mþ).
2.3.2. 8-Methyl-90-iodo-20-oxabicyclo[3,3,1]nonano[40,30-c]-
[1]benzopyran-2-one (5b). Yield 85%, mp 1368C; [Found
C 50.43; H 4.11. C16H15IO3 requires C 50.26; H 3.92%];
nmax (KBr) 2900, 1705, 1390, 1250, 1090, 800 cm21; lmax
222, 293 nm; dH (300 MHz, CDCl3) 1.32–1.39 (m, 1H),
1.58–1.66 (m, 1H), 1.81–1.95 (m, 3H), 2.01–2.08 (m, 1H),
2.1.3. 5,8-Dimethyl-3-[20-cyclohexenyl]-4-hydroxy-1-
benzopyran-2(H)-one (3c). Yield: 70%, mp 1488C;
[Found C 75.47; H 6.79. C17H18O3 requires C 75.56; H
6.67%]; nmax (KBr) 3300, 2920, 1705, 1490, 1280, 1100,
830 cm21; lmax 217, 310 nm; dH (300 MHz, CDCl3) 1.56–
1.87 (m, 6H), 2.09 (s, 3H), 2.21 (s, 3H), 3.84–3.87 (m, 1H,
–CH–), 6.03–6.07 (m, 1H, vCH), 6.29–6.33 (m, 1H,
vCH), 7.22 (d, J¼9 Hz, 1H), 7.55 (d, J¼9 Hz, 1H); m/z 270
(Mþ).
2.1.4. 6,8-Dimethyl-3-[20-cyclohexenyl]-4-hydroxy-1-
benzopyran-2(H)-one (3d). Yield: 70%, mp 1548C;
[Found C 75.72; H 6.53. C17H18O3 requires C 75.56; H
6.67%]; nmax (KBr) 3300, 2920, 1700, 1490, 1280, 1100,

8504
K. C. Majumdar, S. Sarkar / Tetrahedron 58 (2002) 8501–8504
2.47 (s, 3H), 3.63 (dtøq, J¼6.9, 7.1 Hz, Hc), 4.47 (ddd, J¼
10.04, 7.3, 4.9 Hz, Ha), 5.24 (dd, J¼6.9, 7.3 Hz, Hb), 7.16–
7.21 (ddøt, J¼7.1, 7.7 Hz, 1H), 7.40 (d, J¼7.1 Hz, 1H),
7.53 (d, J¼7.7 Hz, 1H); m/z 382 (Mþ).
2.3.3. 5,8-Dimethyl-90-iodo-20-oxabicyclo[3,3,1]nonano-
[40,30-c][1]benzopyran-2-one (5c). Yield 88%, mp 1488C;
(Found C 51.79; H 4.44; C17H17IO3 requires C 51.51;
H 4.29%); nmax (KBr) 2900, 1700, 1420, 1230, 1090,
820 cm21; lmax 219, 292 nm; dH (300 MHz, CDCl3) 1.25–
1.33 (m, 1H), 1.58–1.65 (m, 1H), 1.79–1.91 (m, 3H), 2.04–
2.11 (m, 1H), 2.44 (s, 3H), 2.47 (s, 3H), 3.61 (dtøq, J¼6.9,
7.1 Hz, Hc), 4.36 (ddd, J¼10.0, 7.3, 4.9 Hz, Ha), 5.21 (dd,
J¼6.9, 7.3 Hz, Hb), 6.94 (d, J¼7.5 Hz, 1H), 7.25 (d, J¼
7.5 Hz, 1H); m/z 396 (Mþ).
7.54–7.60 (ddøt, J¼7.70, 8.2 Hz, 2H), 7.70 (d, J¼8.2 Hz,
1H); m/z 368 (Mþ).
Acknowledgements
We thank the CSIR (New Delhi) for financial assistance.
One of us (S. S.) is thankful to CSIR (New Delhi) for a
Junior Research Fellowship.
References
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2.3.4. 6,8-Dimethyl-90-iodo-20-oxabicyclo[3,3,1]nonano-
[40,30-c][1]benzopyran-2-one (5d). Yield 86%, mp 1538C;
[Found C 51.63; H 4.38. C17H17IO3 requires C 51.51; H
4.29%]; nmax (KBr) 2900, 1700, 1420, 1230, 1090,
820 cm21; lmax 220, 292 nm; dH (300 MHz, CDCl3)
1.26–1.33 (m, 1H), 1.56–1.63 (m, 1H), 1.79–1.92 (m,
3H), 2.01–2.19 (m, 1H), 2.41 (s, 3H), 2.43 (s, 3H), 3.63
(dtøq, J¼6.9, 7.1 Hz, Hc), 4.38 (ddd, J¼10.0, 7.3, 4.9 Hz,
Ha), 5.24 (dd, J¼6.9, 7.3 Hz, Hb), 6.99 (s, 1H), 7.39 (s, 1H);
m/z 396 (Mþ).
3. Deana, A. A.; Stokker, G. E.; Schultz, E. M.; Smith, R. L.;
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2.3.5. 6-Tertiarybutyl-90-iodo-20-oxabicyclo[3,3,1]-
nonano[40,30-c][1]benzopyran-2-one (5e). Yield 85%, mp
1308C; [Found C 53.65; H 4.87. C19H21O3 requires C 53.77;
H 4.95%]; nmax (KBr) 2905, 1705, 1390, 1250, 1080,
800 cm21; lmax 222, 295 nm; dH (300 MHz, CDCl3) 1.25–
1.36 (m, 1H), 1.59–1.63 (m, 1H), 1.70–1.92 (m, 3H), 2.01–
2.13 (m, 1H), 1.44 (s, 9H), 3.61 (dtøq, J¼6.9, 7.1 Hz, Hc),
4.54 (ddd, J¼10.0, 7.3, 4.9 Hz, Ha), 5.24 (dd, J¼6.9, 7.3 Hz,
Hb), 7.27 (d, J¼10.0 Hz, 1H), 7.35 (d, J¼10.0 Hz, 1H), 7.63
(s, 1H); m/z 424 (Mþ).
6. Majumdar, K. C.; Khan, A. T.; De, R. N. Synth. Commun. 1988,
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2.3.6. 90-Iodo-20-oxabicyclo[3,3,1]nonano[40,30-c][1]benzo-
pyran-2-one (5f). Yield 85%, mp 928C; [Found C 49.11; H
3.73. C15H13IO3 requires C 48.91; H 3.53%]; nmax (KBr)
2900, 1700, 1420, 1250, 1090, 800 cm21; lmax 219,
293 nm; dH (300 MHz, CDCl3) 1.38–1.44 (m, 1H), 1.54–
1.69 (m, 1H), 1.82–1.95 (m, 3H), 2.07–2.15 (m, 1H), 3.63
(dtøq, J¼6.9, 7.1 Hz, Hc), 4.28 (ddd, J¼10.0, 7.3, 4.9 Hz,
Ha), 5.25 (dd, J¼6.9, 7.3 Hz, Hb), 7.30 (d, J¼7.70 Hz, 1H),