Uncatalyzed [4 + 2] cycloadditions of 3-nitrocoumarins with vinyl ethers in solventless conditions. A new entry to chromene derivatives

Article abstract of DOI:10.1021/jo0260185

The [4 + 2] cycloadditions of 3-nitrocoumarins 5 with electron-rich dienophiles (ethyl vinyl ether (8), 2,3-dihydrofuran (9), and 3,4-dihydro-2H-pyran (10)) were investigated in water, in neat conditions, and in organic solvents. The cycloadditions do not require the use of catalysts and are highly endo diastereoselective, and in water the cyclic nitronates 13, 18, and 23 are converted into chromene derivatives via hydrolysis, decarboxylation, and acetalation reactions. A one-pot procedure based on consecutive reactions in neat/water conditions allows 3-nitrocoumarins 5 to be used as building blocks for the synthesis of chromanols and tetrahydrofuro- and tetrahydropyranochromenes. For the first time, the hydrolysis of cyclic nitronates having the C-O bond of 1,2-oxazine ring as a part of an acetal was investigated.

Full text of DOI:10.1021/jo0260185

Un ca ta lyzed [4 + 2] Cycloa d d ition s of 3-Nitr ocou m a r in s w ith Vin yl
Eth er s in Solven tless Con d ition s. A New En tr y to Ch r om en e
Der iva tives
David Amantini, Francesco Fringuelli, and Ferdinando Pizzo*
Dipartimento di Chimica, Universita` di Perugia via Elce di Sotto 8, I-06123 Perugia, Italy
pizzo@unipg.it
Received J une 6, 2002
The [4 + 2] cycloadditions of 3-nitrocoumarins 5 with electron-rich dienophiles (ethyl vinyl ether
(8), 2,3-dihydrofuran (9), and 3,4-dihydro-2H-pyran (10)) were investigated in water, in neat
conditions, and in organic solvents. The cycloadditions do not require the use of catalysts and are
highly endo diastereoselective, and in water the cyclic nitronates 13, 18, and 23 are converted into
chromene derivatives via hydrolysis, decarboxylation, and acetalation reactions. A one-pot procedure
based on consecutive reactions in neat/water conditions allows 3-nitrocoumarins 5 to be used as
building blocks for the synthesis of chromanols and tetrahydrofuro- and tetrahydropyranochromenes.
For the first time, the hydrolysis of cyclic nitronates having the C-O bond of 1,2-oxazine ring as
a part of an acetal was investigated.
In tr od u ction
loids8g,j-m by opening the 1,2-oxazine ring using hydro-
lytic, reductive, and oxidative processes or by [3 + 2]
dipolar cycloaddition followed by reduction reactions.8
As a continuation of our investigations on organic
reactions performed in water,12 we recently reported12h
the synthesis of optically active nitronates 3 and 4 by [4
The [4 + 2] cycloaddition of R,â-unsaturated nitroal-
kenes1 has been investigated either with simple alkenes2
or with a variety of electron-rich olefins such as silyl enol
ethers,3 enamines,4 enolate anions,3b,5 silyl ketene
acetal,s3a,b,6 and allylsilanes.7 Important contributions
have been made by researchers from the Denmark
group.8
The reactions were usually carried out at low temper-
ature, in organic solvent, and in the presence of Lewis
acids. The resulting cycloadducts (1,2-oxazines N-oxide
or nitronates) were converted into a variety of compounds
such as nitroenamines,4 pyrrolidines,8a,d cycloalkyl-
amines,8b,c,e,f,h γ-diketones,3,4 γ-nitroketones,3,4 γ-keto
alcohols,9a N-oxy-â-lactams,10b â,γ-unsaturated R-hydroxy-
imino esters,11 and pyrrolizidine and indolizidine alka-
(8) For some recent papers, see: (a) Denmark, S. E.; Marcin, L. R.
J . Org. Chem. 1995, 60, 3221-3235. (b) Denmark, S. E.; Stolle, A.;
Dixon, J . A.; Guagnano, V. J . Am. Chem. Soc. 1995, 117, 2100-2101.
(c) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137-165.
(d) Denmark, S. E.; Hurd, A. R.; Sacha, H. J . J . Org. Chem. 1997, 62,
1668-1674. (e) Denmark, S. E.; Guagnano, V.; Dixon, J . A.; Stolle, A.
J . Org. Chem. 1997, 62, 4610-4628. (f) Denmark, S. E.; Dixon, J . A.
J . Org. Chem. 1997, 62, 7086-7087. (g) Denmark, S. E.; Hurd, A. R.
J . Org. Chem. 1998, 63, 3045-3050. (h) Denmark, S. E.; Dixon, J . A.
J . Org. Chem. 1998, 63, 6178-6195. (i) Denmark, S. E.; Seierstad, M.
J . Org. Chem. 1999, 64, 1610-1619. (j) Denmark, S. E.; Martinborough,
E. A. J . Am. Chem. Soc. 1999, 121, 3046-3056. (k) Denmark, S. E.;
Hurd, A. R. J . Org. Chem. 2000, 65, 2875-2886. (l) Denmark, S. E.;
Herbert, B. J . Org. Chem. 2000, 65, 2887-2896. (m) Denmark, S. E.;
Cottell, J . J . J . Org. Chem. 2001, 66, 4276-4284.
(9) (a) Denmark, S. E.; Cramer, C. J .; Sternberg, J . A. Helv. Chim.
Acta 1986, 69, 1971-1989. (b) Ba¨ckvall, J .-E.; Karlsson, U.; Chinchilla,
R. Tetrahedron Lett. 1991, 32, 5607-5610.
(10) (a) Uittenbogaard, R. M.; Seerden, J .-P. G.; Scheeren, H. W.
Tetrahedron 1997, 53, 11929-11936. (b) Kuster, G. J .; Kalmoua, F.;
de Gelder, R.; Scheeren, H. W. Chem. Commun. 1999, 855-856.
(11) Tohda, Y.; Yamawaki, N.; Matsui, H.; Kawashima, T.; Ariga,
M.; Mori, Y. Bull. Chem. Soc. J pn 1988, 61, 461-465.
(12) For some recent papers: (a) Brufola, G.; Fringuelli, F.; Pier-
matti, O.; Pizzo, F. Heterocycles 1996, 43, 1257-1266. (b) Ye, D.;
Fringuelli, F.; Piermatti, O.; Pizzo, F. J . Org. Chem. 1997, 62, 3748-
3750. (c) Fringuelli, F.; Piermatti, O.; Pizzo, F. In Organic Synthesis
in Water; Grieco, P. A., Ed.; Blackie Academic and Professional
Publishers: London, 1998; pp 223-249 and 250-261. (d) Fringuelli,
F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J . Org. Chem. 1999, 64, 6094-
6096. (e) Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2000, 311-314.
(f) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Eur. J . Org. Chem.
2001, 439-455. (g) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org. Chem.
2001, 66, 3554-3558. (h) Fringuelli, F.; Matteucci, M.; Piermatti, O.;
Pizzo, F.; Burla, M. C. J . Org. Chem. 2001, 66, 4661-4666. (i)
Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org. Chem. 2001, 66, 4719-
4722. (j) Amantini, D.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org.
Chem. 2001, 66, 6734-6737. (k) Amantini, D.; Fringuelli, F.; Pizzo,
F.; Vaccaro, L. J . Org. Chem. 2001, 66, 4463-4467.
* To whom correspondence should be addressed. Phone: +39 075
5855546. Fax: +39 075 5855560.
(1) The reaction of R,â-nitroalkenes as 4π components with electron-
rich olefins is mechanistically distinct involving Michael addition to
give betaine followed by collapse to form the nitronate, a formal [4 +
2] adduct: Denmark, S. E.; Dappen, M. S.; Cramer, C. J . J . Am. Chem.
Soc. 1986, 108, 1306-1307 and references therein.
(2) Denmark, S. E.; Cramer, C. J .; Sternberg, J . A. Tetrahedron Lett.
1986, 27, 3693-3696.
(3) (a) Miyashita, M.; Yanami, T.; Kumazawa, T.; Yoshikoshi, A. J .
Am. Chem. Soc. 1984, 106, 2149-2156. (b) Yoshikoshi, A.; Miyashita,
M. Acc. Chem. Res. 1985, 18, 284-290. (c) Seebach, D.; Lyapkalo, I.
M.; Dahinden, R. Helv. Chim. Acta 1999, 82, 1829-1842.
(4) (a) Nielsen, A. T.; Archibald, T. G. Tetrahedron 1970, 26, 3475-
3485. (b) Daneo, S.; Pitacco, G.; Risaliti, A.; Valentin, E. Tetrahedron
1982, 38, 1499-1503. (c) Varma, R. S.; Kabalka, G. W. Heterocycles
1986, 24, 2645-2677. (d) Felluga, F.; Nitti, P.; Pitacco, G.; Valentin,
E. Tetrahedron 1989, 45, 2099-2108.
(5) Nielsen, A. T.; Archibald, T. G. J . Org. Chem. 1969, 34, 1470-
1473.
(6) Miyashita, M.; Kumazawa, T.; Yoshikoshi, A. Chem. Lett. 1980,
1043-1044.
(7) Ochiai, M.; Arimoto, M.; Fujita, E. Tetrahedron Lett. 1981, 22,
1115-1118.
10.1021/jo0260185 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/13/2002
7238
J . Org. Chem. 2002, 67, 7238-7243

[4 + 2] Cycloadditions of 3-Nitrocoumarins
SCHEME 1
SCHEME 3
SCHEME 2
TABLE 1. [4 + 2] Cycloa d d ition s of 3-Nitr ocou m a r in
(5a ) w ith Eth yl Vin yl Eth er (EVE) (8) a t 20 °C
EVE (8)
(mol/equiv)
time
(h)
products
(%)
yielda
(%)
entry
medium
1
2
3
4
H2O (pH 8.3)
H2O (pH 4.5)
neat
neat + H2O
(pH 8.3)
CH2Cl2
MeCOMe
PhH
n-C6H14
EtOH
2
4
8
8
9
24
11 (56), 12 (44)
11 (56), 12 (44)
13
56
40
90
60
3
3-8b 11 (56), 12 (44)
5
6
7
8
9
4
4
4
4
4
1
2
6
6
1
13
13
13
80
80
80
+ 2] cycloadditions of (E)-2-aryl-1-cyano-1-nitroethenes
1 with the enantiopure vinyl ether 2. These reactions
occur in the heterogeneous phase, under mild conditions,
in good yield, and in a highly stereoselective way (Scheme
1).13
15c
97
a
b
Yield of isolated products. The first value refers to the
reaction carried out under neat conditions and the second to the
hydrolysis of 13. c 95:5 mixture of cis/trans streoisomers.
In an effort to carry out the synthesis of enantiopure
aryl-substituted 3-formylpropionic acids and succinic
acids from 1 (Scheme 1) by a one-pot procedure in
aqueous medium, the oxazines 3 and 4 were submitted
to hydrolysis and hydrolysis-oxidation reactions under
various pH conditions, but none of the desired products
were obtained.14 This outcome was attributed to side
reactions involving the intermediate hemiacetal (or the
aldehyde functionality), arising from the fission of 1,2-
oxazine-N-oxide ring. To circumvent this problem, we
planned to trap the aldehydic group by nucleophilic
intramolecular reaction in the aqueous medium. To
develop this idea, we chose 3-nitrocoumarins 5 for the
following reasons: besides having the required chemical
functionalities, they (i) allow chromene derivatives of
great interest to be prepared such as 3,4-dihydro-2H-1-
benzopyrans 6 and cis-fused tetrahydrofuro- and tetrahy-
dropyranochromenes 7 (Scheme 2), (ii) can be easily
prepared from o-hydroxybenzaldehydes and nitroaceto-
nitrile in aqueous medium by a one-pot procedure,12a and
(iii) have been rarely used as building blocks in organic
synthesis15 and never previously used to generate ni-
tronates. We wish to report the results of the [4 + 2]
cycloadditions of 3-nitrocoumarin (5a ) and some its
derivatives 5b-e with electron-rich alkenes 8-10 (Scheme
2) in water only, under neat conditions, and in organic
solvents and the hydrolysis reaction of the corresponding
nitronates.
Resu lts a n d Discu ssion
Nitrocoumarin 5a reacted with ethyl vinyl ether (8) (2
mol/equiv) in aqueous NaHCO3 (pH 8.3)16 under hetero-
geneous conditions at 20 °C giving after 9 h a mixture of
chromanols 11 and 12 in 56/44 ratio with 56% overall
yield (Scheme 3, Table 1, entry 1). At pH 4.5, the reaction
time was longer, the yield was lower, and 4 mol/equiv of
8 was necessary (Table 1, entry 2). Working under neat
conditions (Table 1, entry 3), the expected nitronate 13
was isolated in 90% yield as the sole reaction product,
(13) The cycloaddition reactions were totally enantioselective and
endo stereoselective. The trans adducts 4 which, in principle, are
derived from an exo-type addition, are the result of the epimerization
12h
at C-6 of kinetically favoured cis adduct 3.8c,
(14) The hydrolysis of cyclic nitronates gives good results when the
C-O bond of the 1,2-oxazine N-oxide ring is a part of a ketal and the
nucleophilic attack of water produces
a
secondary alcohol9 or
a
(15) Versleijen, J . P. G.; van Leusen, A. M.; Feringa, B. L. Tetra-
hedron Lett. 1999, 40, 5803-5806.
(16) The choice of pH is important for the success of the reaction
considering the stability of vinyl ethers 8-10 (basic pH) and of
3-nitrocoumarins 5 (acid pH).
ketone.4b,d Hydrolysis of cyclic nitronates that have the C-O bond of
the 1,2-oxazine ring as
a
part of an acetal was investigated in
dichloromethane.9b Methanolysis, in dry methanol, allows isolation of
the γ-nitro aldehyde protected as acetal.11
J . Org. Chem, Vol. 67, No. 21, 2002 7239

Amantini et al.
SCHEME 4
and analogous results were obtained by carrying out the
cycloaddition reaction under homogeneous conditions in
organic solvents with the exception of n-hexane where
no reaction occurred (Table 1, entry 5-8). The cyclo-
adduct 13 in water (pH 8.3, 20 °C, 8 h) gave a mixture of
11 and 12 in 60% yield and again in a 56/44 ratio. The
same result was obtained by in situ hydrolysis of 13
derived from the cycloaddition performed under neat
conditions (Table 1, entry 4). In ethanol, the reaction
between 5a and 8 was fast and gave the acetal 15 as the
main diastereoisomer (trans/cis ) 95/5), which in water
(pH 4.5, 80 °C, 2 h) produced the mixture of chromanols
11 and 12, again in 56/44 ratio. Oxidation of the mixture
of 11 and 12 with pyridinium chlorochromate at room
temperature gave 16 in 94% yield.
All these facts indicate that under neat conditions and
in organic solvent the cycloaddition reaction between 5a
and 8 is totally regioselective and endo-selective. It can
also be assumed that this occurs in water too, and
therefore, the mixture of chromanols 11 and 12 should
result from the hydrolysis of nitronate 13, which first
produces the intermediate 14, which then undergoes
decarboxylation and subsequent unstereoselective in-
tramolecular acetalation. The total endo diastereoselec-
tivity of the cycloaddition reaction between 5a and 8 can
be explained on the basis of strong secondary orbital
interactions between the oxygen of 8 and the nitrogen
atom of 5a present in the endo transition state; these
interactions are absent in the exo transition state.
We also decided to perform the cycloaddition reaction
of 5a with cyclic vinyl ethers such as dihydrofuran 9 and
dihydropyran 10. In these cases, the formation of a cyclic
hemiacetal intermediate was expected and the molecular
models indicated that a high diastereoselective tran-
shemiacetalation should occur. Furthermore, the process
is of synthetic interest because it allows cis-fused tet-
rahydrofuro- and tetrahydropyranobenzopyrans 7 to be
synthesized. These skeletons are present in natural
products of biological interest such as serrulatenol,17a,b
piscerythrol,17c and alboatrin,17d but their syntheses have
been scarcely investigated.17d,18
TABLE 2. [4 + 2] Cycloa d d ition s of 3-Nitr ocou m a r in
(5a ) w ith 2,3-Dih yd r ofu r a n (9)a a n d 3,4-Dih yd r o-2H-p yr a n
(10)b
vinyl
entry ether
T
(°C)
time
(h)
products yield
medium
(%)
(%)
1
2
9
9
H2O (pH 8.3)
H2O
30
1
17
100
67
30-80c 1-2c
19a (88),
20a (12)
18d
(pH 8.3; 4.5)c
CH2Cl2
3
4
5
6
7
8
9
9
9
9
9
9
9
9
30
30
30
30
30
30
1
1
1
8
1
0.25
46
47
24
MeCOMe
PhH
PhH
n-C6H14
neat
18d
18d
18d
100
18d
94
70
neat + H2O
(pH 4.5)
30-80c 0.25-2c 19a (98),
20a (2)
10
11
10 H2O (pH 8.3)
10 H2O (pH 4.5)
30
80
6
6
21 (80),
74
22 (20)
12
13
14
15
16
17
10 CH2Cl2
10 MeCOMe
10 PhH
10 n-C6H14
10 neat
40
56
80
70
80
80
6
6
6
6
23e
23e
23e
14
26
11
Nitrocoumarin 5a reacted with 9 in aqueous NaHCO3
at 30 °C for 1 h and gave quantitatively a mixture of
nitrohemiacetals 17 (Scheme 4, Table 2, entry 1). The
mixture, isolated and heated for 2 h at 80 °C in water at
pH 4.5, afforded cis-fused tetrahydrofuro[2,3-b]chromenes
19a and 20a in an 88/12 ratio with 67% overall yield
(Table 2, entry 2). In organic solvents (Table 2, entries
3-7), the reaction was slower and gave the endo ni-
tronate 18 (endo/exo ) 98/2). After 1 h, only 24-47% of
6
23e
21 (97),
22 (3)
96
60
10 neat + H2O
6-6c
(pH 4.5)
a
b
d
2
mol/equiv.
4
mol/equiv. c See text. Endo/exo ) 98/2.
e Endo/exo ) 97/3.
18 was produced in dichloromethane, acetone, and ben-
zene solution; in n-hexane, no product was observed and
a quantitative conversion of 5a in benzene required 8 h.
Under neat conditions, the reaction quantitatively af-
forded 18 in only 15 min (Table 2, entry 8). The nitronate
18 (endo/exo ) 98/2) in water (pH 4.5, 80 °C, 2 h) gave
19a and 20a (98/2, respectively) with 70% yield (Table
2, entry 9). The formation of 19a in aqueous medium from
5a and 9 can, once more, be explained by the following
sequential reactions: (i) [4 + 2] cycloaddition of these
reagents to give the nitronate 18, (ii) hydrolysis of the
1,2-oxazine ring of 18 to afford the nitrohemiacetal 17,
and (iii) hydrolysis of the lactone, decarboxylation, and
intramolecular acetalation to furnish the tetrahydro-
furochromene 19a .
(17) (a) Abell, A. D.; Horn, E.; J ones, G. P.; Snow, M. R.; Massy-
Westropp, R. A.; Riccio, R. Aust. J . Chem. 1985, 38, 1837-1845. (b)
Cowin, L. M.; Massy-Westropp, R. A. J . Nat. Prod. 1992, 55, 1790-
1794. (c) Tahara, S.; Moriyama, M.; Ingham, J . L.; Mizutani, J .
Phytochemistry 1993, 34, 303-315. (d) Graham, S. R.; Murphy, J . A.;
Kennedy, A. R. J . Chem. Soc., Perkin Trans. 1 1999, 3071-3073.
(18) (a) Yadav, J . S.; Subba Reddy, B. V.; Aruna, M.; Venugopal,
C.; Ramalingam, T.; Kiran Kumar, S.; Kunwar, A. C. J . Chem. Soc.,
Perkin Trans 1 2002, 165-171. (b) Yadav, J . S.; Subba Reddy, B. V.;
Madhuri, Ch.; Sabitha, G.; J agannadh, B.; Kiran Kumar, S.; Kunwar,
A. C. Tetrahedron Lett. 2001, 42, 6381-6384. (c) Diao, L.; Yang, C.;
Wan, P. J . Am. Chem. Soc. 1995, 117, 5369-5370. (d) Mellor, J . M.;
Mohammed, S. Tetrahedron 1993, 49, 7557-7566. (e) Chambers, J .
D.; Crawford, J .; Williams, H. W. R.; Dufresne, C.; Scheigetz, J .;
Bernstein, M. A.; Lau, C. K. Can. J . Chem. 1992, 70, 1717-1732. (f)
Cremins, P. J .; Hayes, R.; Wallace, T. W. Tetrahedron 1991, 47, 9431-
9438. (g) Krause, M.; Hoffmann, H. M. R. Synlett 1990, 485-486.
7240 J . Org. Chem., Vol. 67, No. 21, 2002

[4 + 2] Cycloadditions of 3-Nitrocoumarins
TABLE 3. Syn th esis of Tetr a h yd r ofu r och r om en es by a
On e-P ot Con secu tive P r ocess P er for m ed u n d er Nea t
Con d ition s F ollow ed by Tr ea tm en t w ith Wa ter
tons H4 and H3 [J (H4-H3â) ) 4.8 Hz; J (H4-H3R) ) 4.8
Hz] and H2 and H3 [J (H2-H3â) ) 2.7 Hz; J (H2-H3R) )
2.7 Hz] are typical of an equatorial-axial and equato-
rial-equatorial relationship. Protons H4 and H2 are
therefore cis and in equatorial position. The axial position
of CH2NO2 and OH substituents is probably favored by
a hydrogen bond between the proton of the hydroxy group
and one of the oxygen of the nitro group. No NOE effect
was also observed on the proton H2 of 12 from the
saturation of H4 which excludes, also for this compound,
a cis diaxial relationship between H4 and H2. The
coupling constant values of H4 with H3 protons [J (H4-
DHFa
timeb
(h)
products
(%)
yieldc
(%)
entry coumarin (mol/equiv)
1
2
3
4
5
5a
5b
5c
5d
5e
2
10
10
10
4
0.25 19a (98), 20a (2)
70
57
37
44
32
3
24
10
19b (97), 20b (3)
19c (95), 20c (5)
19d (96), 20a (4)
19e (99), 20e (1)
0.5
a
b
Dihydrofuran 9. Reaction time of cycloaddition carried out
under neat conditions at 30 °C. The transformation of the nitronate
was performed by adding water at pH 4.5 to the crude reaction
mixture and heating at 80 °C for 2 h. c Overall isolated yield of
main reaction product.
H
3R) ) 8.9 Hz; J (H4-H3â) ) 5.5 Hz] and H2 with H3 [
J (H2-H3R ) 4.8 Hz; J (H2-H3â) ) 2.7 Hz] are typical of
axial-axial, axial-equatorial, and equatorial-equatorial
relationships, respectively. The protons H4 and H2 are
trans to each other in axial and equatorial positions,
respectively.
The saturation of H2 proton frequency of 13 gives NOE
effects on protons H10b and H1R, and the saturation of H10b
frequency gives a NOE effect on proton H1R. Protons H10b
and H2 are therefore in axial positions. This is also
supported by vicinal coupling constant values of H10b, H1
and H2; J (H10b-H1R) ) 12.1 Hz and J (H10b-H1â) ) 6.4
Hz are typical of an axial-axial and axial-equatorial
relationship of H10b, H1â, and H1R protons. The values of
J (H2-H1â ) 7.3 Hz and J (H2-H1R) ) 4.1 Hz lead to the
same conclusion for the H2, H1â, and H1R protons.
The optimum protocol to prepare 19a by a one-pot
procedure involves carrying out the cycloaddition under
neat conditions and then adding water in situ prior to
workup. This one-pot multistep consecutive process,
performed in neat conditions and in water, was used to
synthesize substituted tetrahydrofurochromenes 19b-
e. The results are reported in Table 3. The processes are
highly endo diastereoselective and occur with satisfactory
overall yields considering that five main sequential
reactions are involved. The same one-pot processes
carried out exclusively in water at pH 8.3 required less
excess of 9 (2-4 mol/equiv) and a comparable cyclo-
addition reaction time, but were less diastereoselective
(19/20 ) ca. 90/10) and gave lower yields (by ca. 10%)
than those reported in Table 3.
Con clu sion s
Nitrocoumarins 5 are valuable building blocks for
synthesizing chromene derivatives such as chromanols
and tetrahydrofuro- and tetrahydropyranochromenes by
a one-pot innovative procedure carried out exclusively in
water or by a consecutive process performed in neat/
water conditions. The nitronates arising from [4 + 2]
cycloadditions of 3-nitrocoumarins with electron-rich
olefins were obtained in a highly endo-selective way
without using catalysts. They were then converted into
chromene derivatives via hydrolysis, decarboxylation,
and transacetalation reactions. The hydrolysis of cyclic
nitronates having the C-O bond of the 1,2-oxazine ring
as a part of an acetal was investigated for the first time
in water only.
The reactions performed in water occurred in the
heterogeneous phase and allowed better results to be
obtained than when they are carried out in homogeneous
organic solution. The high acid/base reactivity of water,
which is sometimes considered to be an unfavorable
chemical property because it interferes with the desired
reaction, is fundamental for the success of chromene
derivative synthesis from 3-nitrocoumarins by a one-pot
process. The utility of water in developing environmen-
tally benign chemical processes and its unexpected
potential as a reaction medium on reaction rates and
product selectivity encourage us to continue these stud-
ies.
Analogous results were obtained by using 2,3-dihydro-
pyran 10. The reaction of 5a with 10 works in aqueous
medium at pH 4.5 (Table 2, compare entries 10 and 11).
Under these conditions and at 80 °C, tetrahydropyrano-
chromenes 21 and 22 (80/20 ratio) were isolated in 74%
overall yield. In organic solvents at reflux (Table 2,
entries 12-15) discouraging results were obtained: long
reaction times were required and a low yield of cyclo-
adduct 23 were observed. This is probably ascribable to
10 being less stable in organic medium than in water.
Working under neat conditions, the nitronate 23 (endo/
exo ) 97/3) was isolated in excellent yield (Table 2, entry
16) and converted in situ with water at pH 4.5 into 21
(97%) and 22 (3%) in 60% overall yield (Table 2, entry
17).19
Str u ctu r e of Com p ou n d s. Compounds 13, 16, 18, 19,
21, and 23 were isolated as pure compounds, while
attempts to separate the diastereoisomers 11 and 12 were
unsuccessful and the structures of these two compounds
were assigned by using enriched mixtures. The configu-
rations of all the compounds were assigned on the basis
1
of H NMR coupling constant values and NOE experi-
ments. Characterization data for all of the compounds
are reported in the Experimental Section and in the
Supporting Information. The data recorded for 11, 12,
and 13 are briefly discussed as an example.
The saturation of H4 proton frequency of 11 does not
give an NOE effect on proton H2 (and vice versa)
excluding a cis diaxial relationship between these two
hydrogens. The vicinal coupling constant values of pro-
Exp er im en ta l Section
Reagents were purchased and used without further purifi-
1
cation. H and 13C NMR spectra were recorded at 400 or 200
MHz for proton and at 100.6 or 50.3 MHz for carbon nuclei in
CDCl3, CD3COCD3, or in CD3SOCD3. GC-MS analyses were
carried out at 70 eV. GC analyses were performed with an
SPB-5 fused silica capillary column (30 m, 0.25 mm diameter)
(19) The two series of experiments 2, 8, 9 and 11, 16, 17 of Table 2
seem to indicate that the cycloadditions of 5a with 9 and 10 are more
diastereoselective when carried out under neat conditions than when
they are performed in water.
J . Org. Chem, Vol. 67, No. 21, 2002 7241

Amantini et al.
using an “on column” injector system and a FID detector with
hydrogen as the carrier gas. IR spectra were recorded with a
FT-IR instrument, using CHCl3 as solvent. Column chroma-
tographies were carried out on silica gel 230-400 mesh. The
pH values of the reactions were controlled using a pH-meter
apparatus with a combined refillable pH electrode. Melting
points are uncorrected. 3-Nitrocoumarins 5a -e20 and chro-
manone 1621 are known compounds, but short analytical data
were reported for 5b-e and 16. 3-Nitrocoumarins 5a -e were
prepared by a one-pot procedure in water as previously
described.12a
4.73 (dd, J ) 9.3, 12.7 Hz, 1H), 5.02 (dd, J ) 5.9, 12.8 Hz,
1H), 5.74 (t, J ) 2.7 Hz, 1H), 6.80-7.30 (m, 4H); 13C NMR
(50.3 MHz, CDCl3) δ C 151.3, 119.8, CH 129.1, 128.8, 121.6,
117.7, 91.5, 30.9, CH2 80.5, 28.9.
tr a n s-4-(Nitr om eth yl)ch r om a n -2-ol (12): characterized
in an enriched mixture; 1H NMR (200 MHz, CDCl3 + D2O)
δ1.90-2.25 (m, 2H), 3.89 (dddd, J ) 5.1 Hz, J ) 5.5, 8.9, 9.3
Hz, 1H), 4.51 (dd, J ) 9.3 Hz, J ) 12.4, 1H), 4.84 (dd, J ) 5.1
Hz, J ) 12.4 Hz, 1H), 5.65 (dd, J ) 2.7 Hz, J ) 4.8 Hz, 1H),
6.80-7.30 (m, 4H); 13C NMR (50.3 MHz, CDCl3) δ C 151.8,
119.9, CH 129.0, 126.7, 119.8, 117.8, 90.7, 30.0, CH2 79.9, 31.1.
6-Hyd r oxy-3-n itr ocou m a r in (5b): 84% yield; brown solid;
mp ) 219-221 °C (ethanol) (lit.20a mp ) 215-218 °C); 1H NMR
(200 MHz, CDCl3) δ 7.29-7.39 (m, 3H), 8.93 (s, 1H), 9.02-
9.15 (bs, OH); 13C NMR (50.3 MHz, CD3COCD3) δ C 154.5,
152.0, 148.5, 135.8, 117.2, CH 142.0, 124.0, 117.5, 114.4; IR
(CHCl3) cm-1 3686 (s), 3448 (b), 3018 (m), 1755 (m), 1600 (s).
Anal. Calcd for C9H5NO5: C, 52.19; H, 2.43; N, 6.76. Found:
C, 52.23; H, 2.38; N, 6.75.
tr a n s-4-(2,2-Dieth oxyeth yl)-3-n itr och r om a n -2-on e (15).
Ethyl vinyl ether (8) (0.576 g, 8 mmol) was added dropwise to
a solution of 3-nitrocoumarin (5a ) (0.382 g, 2 mmol) in ethanol
(10 mL) at 20 °C and the reaction mixture left under stirring
at this temperature for 1 h. The orange alcoholic solution was
evaporated under reduced pressure, and the residual oil was
chromatographed on silica gel (acetic acid/ethyl acetate/
petroleum ether ) 15/15/70) to give 0.590 g (97% yield) of 15
(95/5 trans/cis diastereoisomeric mixture) as a yellow oil (Table
1, entry 9): 1H NMR (200 MHz, CD3COCD3) δ 1.10 (t, J ) 7.0
Hz, 3H), 1.20 (t, J ) 7.0 Hz, 3H), 1.89-2.17 (m, 2H), 3.29-
3.77 (m, 4H), 4.16 (td, J ) 3.7, 7.0 Hz, 1H), 4.60 (t, J ) 5.1
Hz, 1H), 6.04 (d, J ) 3.7 Hz, 1H), 7.12-7.30 (m, 2H), 7.35-
7.45 (m, 2H); 13C NMR (50.3 MHz, CD3COCD3) δ C 158.2,
149.9, 121.6, CH 129.6, 128.7, 125.6, 117.0, 100.7, 85.5, 32.6,
CH2 61.8, 61.6, 35.7, CH3 14.8, 14.7; IR (CHCl3) cm-1 2981
(m), 1784 (s), 1563 (s), 1488 (m), 1460 (m), 1371 (m), 1249 (m),
1177 (s), 1123 (m), 1062 (s). Anal. Calcd for C15H19NO6: C,
58.25; H, 6.19; N, 4.53. Found: C, 58.37; H, 6.10; N, 4.59.
4-(Nitr om eth yl)ch r om a n -2-on e (16). To a suspension of
pyridine chlorochromate (0.648 g, 3 mmol) in dichloromethane
(6 mL), left under stirring at room temperature for 5 min, was
added a dichloromethane solution (3 mL) of chromanols 11 and
12 (0.314 g, 1.5 mmol) rapidly at room temperature, and the
reaction was stirred for 30 h. The black reaction mixture was
filtered, and the solid was washed twice with ethyl acetate.
The organic layers were collected, dried (Na2SO4), evaporated
under reduced pressure, and the residue purified by column
chromatography on silica gel (ethyl acetate/petroleum ether
) 10/90) to give 0.292 g (94%) of chromanone 16 as slightly
yellow oil: 1H NMR (200 MHz, CD3COCD3) δ 2.93 (dd, J )
4.2, 16.7 Hz, 1H), 3.18 (dd, J ) 6.5, 16.7 Hz, 1H), 3.97-4.10
(m, 1H), 4.85 (abx system, 2H), 7.04-7.27 (m, 2H), 7.33-7.43
(m, 2H); 13C NMR (50.3 MHz, CD3COCD3) δ C 166.0, 151.8,
121.5, CH 129.7, 128.1, 124.7, 117.1, 33.5, CH2 77.8, 31.2; IR
(CHCl3) cm-1 3029 (w), 1776 (s), 1550 (s), 1490 (m), 1458 (m),
1162 (m). Anal. Calcd for C10H9NO4: C, 57.97; H, 4.38; N, 6.76.
Found: C, 57.83; H, 4.48; N, 6.69.
7-Hyd r oxy-3-n itr ocou m a r in (5c): 92% yield; yellow solid;
mp ) 270-273 °C (ethanol/ethyl acetate/petroleum ether 3/3.5/
1
3.5); H NMR (200 MHz, CD3COCD3) δ 6.85 (bd, J ) 2.3 Hz,
1H), 7.02 (dd, J ) 2.3, 8.7 Hz, 1H), 7.88 (d, J ) 8.6 Hz, 1H),
9.01 (s, 1H), 10.22-10.42 (bs, OH); 13C NMR (50.3 MHz, CD3-
COCD3) δ C 166.0, 165.9, 158.4, 152.8, 110.3, CH, 144.1, 133.9,
115.6, 103.0; IR (CHCl3) cm-1 3124 (b), 1755 (m), 1605 (s), 1317
(m). Anal. Calcd for C9H5NO5: C, 52.19; H, 2.43; N, 6.76.
Found: C, 52.31; H, 2.39; N, 6.69.
8-Hyd r oxy-3-n itr ocou m a r in (5d ): 86% yield; brown solid;
mp ) 234-236 °C (ethyl acetate/petroleum ether 6/4); 1H NMR
(200 MHz, CD3COCD3) δ 7.28-7.40 (m, 2H), 7.46 (dd, J ) 2.8,
6.8 Hz, 1H), 8.99 (s, 1H), 9.28-9.52 (bs, OH); 13C NMR (50.3
MHz, CD3COCD3) δ C 152.0, 144.9, 143.5, 135.8, 117.9, CH
143.1, 126.1, 122.3, 121.9; IR (CHCl3) cm-1 3619 (m), 3440 (b),
2976 (s), 1753 (w), 1608 (w), 1241 (m), 1046 (s). Anal. Calcd
for C9H5NO5: C, 52.19; H, 2.43; N, 6.76. Found: C, 52.01; H,
2.51; N, 6.65.
6-Ch lor o-3-n itr ocou m a r in (5e): 93% yield; yellow solid;
mp ) 179-180 °C (ethyl acetate/petroleum ether 5/5) (lit.20b
mp ) 176-177 °C); 1H NMR (200 MHz, CD3COCD3) δ 7.53
(bd, J ) 8.9 Hz, 1H), 7.87 (dd, J ) 2.6, 8.9 Hz, 1H), 8.09 (bd,
J ) 2.6 Hz, 1H), 9.02 (s, 1H); 13C NMR (50.3 MHz, CD3COCD3)
δ C 153.9, 152.1, 137.0, 130.6, 118.7, CH, 141.6, 135.8, 130.5,
119.1; IR (CHCl3) cm-1 3457 (b), 2976 (s), 1768 (s), 1605 (m),
1563 (m), 1046 (s); MS m/z (relative intensity) 225 (M+, 55),
125 (38), 123 (100). Anal. Calcd for C9H4ClNO4: C, 47.92; H,
1.79; N, 6.21. Found C, 47.99; H, 1.74; N, 6.28.
On e-P ot Syn th esis of Ch r om a n ols 11 a n d 12 in Wa ter .
3-Nitrocoumarin (5a ) (0.382 g, 2 mmol) and NaHCO3 (0.420
g, 5 mmol) were added with stirring to 10 mL of distilled water
at 20 °C. The heterogeneous reaction mixture was stirred for
5 min, and ethyl vinyl ether (8) (0.288 g, 4 mmol) was added
dropwise in 5 min. After 45 min, the reaction mixture became
homogeneous. The reaction was monitored by TLC (ethyl
acetate/petroleum ether 3/7), and after 9 h it was cooled in an
ice bath. The pH value of the reaction medium was 8.3, which
was then adjusted to pH 4.0 by adding a cold 50% H2SO4
aqueous solution, and the resulting mixture was extracted with
ethyl acetate. The combined organic layers were dried (Na2-
SO4), evaporated under reduced pressure, and purified by
column chromatography on silica gel (ethyl acetate/petroleum
ether ) 15/85) to give 0.234 g (56% yield) of a diastereoisomeric
mixture of chromanols 11/12 as a slightly yellow oil in 56/44
ratio (Table 1, entry 1).
Syn th esis of Nitr on a tes 13, 18, a n d 23 u n d er Nea t
Con dition s. Typical P r ocedu r e. 3-Nitrocoumarin (5a) (0.382
g, 2 mmol) and the suitable vinyl ether (for mol/equiv see
Tables 1 and 2) were mixed in a 5 mL flask thermostated at
the temperature indicated in Tables 1 and 2. The heteroge-
neous reaction mixture was stirred for the appropriate time
(Tables 1 and 2), and the resulting white solid was recrystal-
lized to give the cycloadduct.
cis-2-Eth oxy-1,10b-dih ydr o-2H,5H-ch r om en o[3,4-c][1,2]-
oxa zin -5-on e 4-oxid e (13): yield 90% (Table 1, entry 3); white
1
solid; mp ) 104-106 °C (diethyl ether); H NMR (200 MHz,
CD3COCD3) δ 1.23 (t, J ) 7.2 Hz, 3H), 2.13 (ddd, J ) 4.1, 12.1,
13.5 Hz, 1H), 3.16 (ddd, J ) 6.4, 7.3, 13.6 Hz, 1H), 3.68 (dq, J
) 7.1, 9.5 Hz, 1H), 4.07 (dq, J ) 7.1, 9.5 Hz, 1H), 4.22 (dd, J
) 6.4, 12.1 Hz, 1H), 5.65 (dd, J ) 4.1, 7.4 Hz, 1H), 7.03-7.48
(m, 4H); 13C NMR (50.3 MHz, CD3COCD3) δ C 153.1, 148.8,
119.0, 115.3, CH 129.3, 127.0, 125.0, 117.3, 104.5, 33.4, CH2
65.6, 38.8, CH3 14.5. Anal. Calcd for C13H13NO5: C, 59.31; H,
4.98; N, 5.32. Found: C, 59.43; H, 4.98; N, 5.39.
cis-4-(Nitr om eth yl)ch r om a n -2-ol (11): characterized in
an enriched mixture; 1H NMR (200 MHz, CDCl3 + D2O) δ
1.90-2.25 (m, 2H), 3.73 (dddd, J ) 4.8, 4.8, 5.9, 9.3 Hz, 1H),
(20) (a) Perrella, F. W.; Chen, S.-F.; Behrens, D. L.; Kaltenbach, R.
F., III; Seitz, S. P. J . Med. Chem. 1994, 37, 2232-2237. (b) Dauzonne,
D.; Royer, R. Synthesis 1983, 836-837.
(21) Bojilova, A.; Kostadinova, T.; Ivanov, C. Synth. Commun. 1989,
19, 2963-2975.
3a ,11c-cis-11b,11c-cis-1,2,11b,11c-Tetr a h yd r o-3a H,6H-
ch r om en o[3,4-c]fu r o[3,2-e][1,2]oxa zin -6-on e 5-oxid e (18):
yield 94% (Table 2, entry 8); white solid; mp ) 153-154 °C
(dry acetone); 1H NMR (200 MHz, CDCl3) δ 1.76 (m, 1H), 1.99
7242 J . Org. Chem., Vol. 67, No. 21, 2002

[4 + 2] Cycloadditions of 3-Nitrocoumarins
(m, 1H), 3.65 (dddd, J ) 4.8, 5.3, 7.1, 10.2 Hz, 1H), 3.85-4.16
(m, 2H), 4.46 (d, J ) 4.8 Hz, 1H), 6.16 (d, J ) 7.1 Hz, 1H),
7.05-7.40 (m, 4H); 13C NMR (50.3 MHz, CD3COCD3) δ C 153.1,
151.1, 119.6, 115.1, CH 130.1, 128.8, 125.8, 117.7, 110.6, 47.2,
38.3, CH2 69.7, 26.8. Anal. Calcd for C13H11NO5: C, 59.77; H,
4.24; N, 5.36. Found: C, 59.87; H, 4.29; N, 5.39.
m/z (relative intensity) 251 (M+, 43), 203 (43), 191 (53), 176
(100), 123 (90). Anal. Calcd for C12H13NO5: C, 57.37; H, 5.22;
N, 5.58. Found: C, 57.33; H, 5.20; N, 5.61.
3a ,4-tr a n s-3a ,9a -cis-4-(Nitr om eth yl)-2,3,3a ,9a -tetr a h y-
d r o-4H-fu r o[2,3-b]ch r om en -8-ol (19d ): eluted with ethyl
acetate/petroleum ether ) 5/5; colorless and thick oil; 1H NMR
(200 MHz, CD3COCD3) δ 1.42-1.63 (m, 1H), 2.08-2.22 (m,
1H), 2.75-2.89 (m, 1H), 3.70 (td, J ) 1.8, 7.7 Hz, 1H), 3.75-
3.84 (m, 2H), 4.70 (dd, J ) 7.6, 12.8 Hz, 1H), 4.84 (dd, J )
7.9, 12.8 Hz, 1H), 5.83 (d, J ) 5.4 Hz, 1H), 6.63-6.71 (m, 1H),
6.73-6.82 (m, 2H), 7.69 (bs, OH); 13C NMR (50.3 MHz, CD3-
COCD3) δ C 146.1, 140.6, 121.4, CH 121.9, 120.1, 115.6, 100.5,
40.8, 37.2, CH2 78.9, 67.4, 28.3; IR (CHCl3) cm-1 3540 (b), 3025
(w), 2982 (w), 1553 (s), 1482 (s), 1377 (m), 1222 (m), 1053 (m),
972 (m); MS m/z (relative intensity) 251 (M+, 66), 203 (48),
176 (100), 175 (45), 147 (38), 123 (49), 107 (45), 77 (42). Anal.
Calcd for C12H13NO5: C, 57.37; H, 5.22; N, 5.58. Found: C,
57.31; H, 5.30; N, 5.55.
4a ,12c -ci s-12b ,12c -ci s-2,3,12b ,12c -T e t r a h y d r o -1H ,
4a H ,7H -ch r om en o[3,4-c]p yr a n o[3,2-e][1,2]oxa zin -7-on e
6-oxid e (23): yield 96% (Table 2, entry 16); white solid; mp )
1
119-120 °C (dry acetone); H NMR (200 MHz, CD3SOCD3) δ
1.06-1.28 (m, 1H), 1.36-1.52 (m, 1H), 1.54-1.79 (m, 2H),
2.94-3.09 (m, 1H), 3.66 (td, J ) 3.4, 11.3 Hz, 1H), 3.68-3.84
(m, 1H), 4.68 (d, J ) 4.0 Hz, 1H), 6.09 (d, J ) 3.8 Hz, 1H),
7.07 (dd, J ) 1.3, 8.0 Hz, 1H), 7.17-7.27 (m, 1H), 7.28-7.40
(m, 1H), 7.47 (bd, J ) 7.5 Hz, 1H); 13C NMR (50.3 MHz, CD3-
SOCD3) δ C 153.6, 149.7, 117.7, 109.4, CH 129.0, 127.2, 124.8,
116.6, 102.9, 36.7, 31.1, CH2 61.5, 22.8, 18.5. Anal. Calcd for
C
14H13NO5: C, 61.09; H, 4.76; N, 5.09. Found: C, 61.14; H,
4.68; N, 5.15.
3a ,4-tr a n s-3a ,9a -cis-6-Ch lor o-4-(n itr om eth yl)-2,3,3a ,9a -
tetr a h yd r o-4H-fu r o[2,3-b]ch r om en e (19e): eluted with eth-
yl acetate/petroleum ether ) 5/5; white solid; mp ) 137-139
°C (ethyl acetate/petroleum ether 4/6); 1H NMR (200 MHz,
CD3COCD3) δ 1.45-1.67 (m, 1H), 2.11-2.28 (m, 1H), 2.80-
2.93 (m, 1H), 3.79 (td, J ) 1.8, 7.7 Hz, 1H), 3.80-3.88 (m, 2H),
4.77 (dd, J ) 7.4, 13.1 Hz, 1H), 4.90 (dd, J ) 7.8, 13.1 Hz,
1H), 5.82 (d, J ) 5.2 Hz, 1H), 6.84 (d, J ) 8.3 Hz, 1H), 7.19-
7.31 (m, 2H); 13C NMR (50.3 MHz, CD3COCD3) δ C 152.8,
126.2, 123.0, CH 130.1, 129.9, 119.6, 100.8, 40.9, 37.3, CH2
79.2, 67.9, 28.7; IR (CHCl3) cm-1 2975 (m), 1553 (s), 1479 (m),
1372 (m), 1219 (m), 1038 (m), 880 (m); MS m/z (relative
intensity) 271 (M+ + 2, 12), 269 (M+, 34), 221 (44), 196 (35),
194 (100), 193 (34), 141 (44). Anal. Calcd for C12H12ClNO4: C,
53.44; H, 4.49; N, 5.19. Found: C, 53.31; H, 4.45; N, 5.15.
On e-P ot Syn t h esis of 4a ,5-tr a n s-4a ,10a -cis-5-(Nit r o-
m eth yl)-3,4,4a ,10a -tetr a h yd r o-2H,5H-p yr a n o[2,3-b]ch r o-
m en e (21). Nitrocoumarin 5a (0.382 g, 2 mmol) and dihydro-
pyran 10 (0.672 g, 8 mmol) were mixed in a 25 mL flask
thermostated at 80 °C and equipped with a magnetic stirrer
and a condenser. The heterogeneous reaction mixture was
stirred for 6 h; 20 mL of distilled water was then added, and
the resulting pH value was 4.5. The reaction mixture was
stirred at this temperature for an additional 6 h. The cooled
reaction mixture was saturated with NaCl and extracted with
ethyl acetate. The combined organic layers were dried (Na2-
SO4), evaporated under reduced pressure, and purified by
column chromatography on silica gel (ethyl acetate/petroleum
ether ) 20/80) to give 0.299 g (60% yield) of a 97/3 diastereo-
isomeric mixture of 21 and 22. 21: white solid; mp ) 117-
118 °C (diethyl ether/petroleum ether 2/8); 1H NMR (200 MHz,
CDCl3 ) δ 1.45-1.95 (m, 4H), 2.09 (m, 1H), 3.44 (ddd, J ) 1.6,
7.3, 8.6 Hz, 1H), 3.76 (m, 1H), 3.97 (dt, J ) 2.6, 11.6 Hz, 1H),
4.44-4.65 (abx system, 2H), 5.44 (d, J ) 2.5 Hz, 1H), 6.87-
7.30 (m, 4H); 13C NMR (50.3 MHz, CDCl3) δ C 153.1, 117.0,
CH 129.3, 129.3, 121.4, 117.3, 93.0, 40.3, 34.1, CH2 79.8, 60.8,
24.5, 23.3; IR (CHCl3) cm-1 3145 (m), 1578 (m), 1550 (s), 1477
(m), 1365 (m), 1218 (m), 1042 (m), 974 (m); MS m/z (relative
intensity) 249 (M+, 23), 201 (339), 172 (100), 145 (72), 131 (69),
107 (79), 91 (68). Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07;
N, 5.62. Found: C, 62.55; H, 6.09; N, 5.59.
On e-P ot Syn th esis of Tetr a h yd r o-4H-fu r o[2,3-b]ch r o-
m en es (19a -e). Typ ica l P r oced u r e. A mixture of nitrocou-
marin (5a -e) (2 mmol) and dihydrofuran 9 (for mol/equiv see
Table 3) was stirred at 30 °C for the appropriate time (Table
3). Distilled water (20 mL) was then added, and the resulting
pH value was 4.5. The mixture was then warmed at 80 °C,
stirred at this temperature for 2 h, cooled to room temperature,
saturated with NaCl, and extracted with ethyl acetate. The
combined organic layers were dried (Na2SO4), evaporated
under reduced pressure, and purified by column chromatog-
raphy on silica gel to give diastereoisomeric mixtures of 19a -
e/20a -e (yields in Table 3).
3a ,4-tr a n s-3a ,9a -cis-4-(Nitr om eth yl)-2,3,3a ,9a -tetr a h y-
dr o-4H-fu r o[2,3-b]ch r om en e (19a): eluted with ethyl acetate/
petroleum ether ) 1/9; white solid; mp ) 88-90 °C (diethyl
ether/petroleum ether ) 8/2); 1H NMR (200 MHz, CDCl3) δ
1.63 (m, 1H), 2.14 (m, 1H), 2.74 (ddd, J ) 1.8, 5.5, 9.6 Hz,
1H), 3.69 (ddd, J ) 1.8, 7.1, 8.7 Hz, 1H), 3.89 (m, 2H), 4.48-
4.67 (abx system, 2H), 5.80 (d, J ) 5.4 Hz, 1H), 6.90-7.30 (m,
4 H); 13C NMR (50.3 MHz, CDCl3) δ C 152.9, 119.5, CH 129.7,
129.3, 122.0, 117.7, 99.7, 40.3, 37.3, CH2 78.8, 67.4, 28.2; IR
(CHCl3) cm-1 3025 (w), 1588 (m), 1552 (s), 1488 (m), 1377 (m),
1219 (m), 1044 (m), 978 (m); MS m/z (relative intensity) 235
(M+, 12), 187 (37), 160 (100), 131 (55), 115 (35), 107 (77), 91
(83). Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95.
Found: C, 61.20; H, 5.49; N, 5.99.
3a ,4-tr a n s-3a ,9a -cis-4-(Nitr om eth yl)-2,3,3a ,9a -tetr a h y-
d r o-4H-fu r o[2,3-b]ch r om en -6-ol (19b): eluted with ethyl
acetate/petroleum ether ) 3/7; pale yellow and thick oil; H
1
NMR (200 MHz, CD3COCD3) δ 1.40-1.65 (m, 1H), 2.08-2.23
(m, 1H), 2.73-2.88 (m, 1H), 3.61 (td, J ) 1.8, 7.8 Hz, 1H),
3.68-3.78 (m, 2H), 4.68 (dd, J ) 8.0, 12.7 Hz, 1H), 4.83 (dd, J
) 7.5, 12.7 Hz, 1H), 5.73 (d, J ) 5.8 Hz, 1H), 6.62-6.73 (m,
3H), 8.09 (bs, OH); 13C NMR (50.3 MHz, CD3COCD3) δ C 151.4,
145.4, 121.9, CH 117.8, 115.6, 115.4, 100.0, 40.1, 37.3, CH2
78.0, 66.6, 27.9; IR (CHCl3) cm-1 3321 (b), 3024 (m), 1554 (s),
1499 (s), 1376 (m), 1213 (s), 1042 (m), 982 (m); MS m/z (relative
intensity) 251 (M+, 60), 203 (50), 176 (100), 147 (40), 123 (47),
107 (53). Anal. Calcd for C12H13NO5: C, 57.37; H, 5.22; N, 5.58.
Found: C, 57.44; H, 5.30; N, 5.52.
3a ,4-tr a n s-3a ,9a -cis-4-(Nitr om eth yl)-2,3,3a ,9a -tetr a h y-
d r o-4H-fu r o[2,3-b]ch r om en -7-ol (19c): eluted with ethyl
acetate/petroleum ether ) 5/5; white solid; mp ) 212-213 °C
(ethyl acetate/petroleum ether 5/5); 1H NMR (200 MHz, CD3-
COCD3) δ 1.32-1.63 (m, 1H), 2.00-2.20 (m, 1H), 2.63-2.78
(m, 1H), 3.68 (td, J ) 1.4, 7.6 Hz, 1H), 3.78 (dd, J ) 5.8, 8.6
Hz, 2H), 4.61 (dd, J ) 7.6, 12.6 Hz, 1H), 4.75 (dd, J ) 7.8,
12.6 Hz, 1H), 5.71 (d, J ) 5.2 Hz, 1H), 6.28 (d, J ) 2.3 Hz,
1H), 6.38 (dd, J ) 2.4, 8.2 Hz, 1H), 6.94 (d, J ) 8.2 Hz, 1H),
8.36 (bs, OH); 13C NMR (50.3 MHz, CD3COCD3) δ C 158.8,
154.5, 111.3, CH 130.7, 109.5, 104.4, 100.1, 40.8, 36.9, CH2
79.7, 67.4, 28.4; IR (CHCl3) cm-1 3249 (b), 2930 (m), 1623 (m),
1553 (s), 1510 (m), 1465 (m), 1377 (m), 1159 (m), 993 (m); MS
Ack n ow led gm en t. The Ministero dell’Istruzione
dell’Universita` e della Ricerca (MIUR), the Consiglio
Nazionale delle Ricerche (CNR), and the Universita`
degli Studi di Perugia are thanked for financial support.
Su p p or tin g In for m a tion Ava ila ble: Analytical data with
1H and 13C NMR peak assignments and NOE interactions of
compounds 11-13, 15, 16, 18, 19a -e, 21, and 23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0260185
J . Org. Chem, Vol. 67, No. 21, 2002 7243