Synthesis of 2,3-dihydrobenzofurans by Mn(OAc)3-based oxidative cycloaddition of 2-cyclohexenones with alkenes. Synthesis of (±)-conocarpan

Article abstract of DOI:10.1021/jo9708506

Oxidative cycloaddition of a 2-cyclohexenone or α-tetralone and an alkene with dried Mn(OAc)₃ in benzene at 80-140 °C provides a general route to dihydrobenzofurans 15 and dihydronaphthofurans 17. Although the yields are modest, this one-pot reaction provides simple access to these compounds, which have previously been prepared by multistep routes. Oxidative cycloaddition of 2-cyclohexenones with β-methylstyrenes provides a new route to benzofuranoid neolignans, which was applied to the synthesis of conocarpan (22). The formation of 2-acetoxyhexanedioic acids 27 and 47 from acetoxylation of 2-cyclohexenones in HOAc, but not in benzene, opens up a new class of Mn(OAc)₃ reactions and explains Watt and Demir's discovery that much higher yields of α'-acetoxy enones are obtained in benzene than in HOAc.

Full text of DOI:10.1021/jo9708506

6978
J . Org. Chem. 1997, 62, 6978-6984
Syn th esis of 2,3-Dih yd r oben zofu r a n s by Mn (OAc)3-Ba sed Oxid a tive
Cycloa d d ition of 2-Cycloh exen on es w ith Alk en es. Syn th esis of
(()-Con oca r p a n
Barry B. Snider,* Luning Han, and Chaoyu Xie
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02254-9110
Received May 13, 1997X
Oxidative cycloaddition of a 2-cyclohexenone or R-tetralone and an alkene with dried Mn(OAc)3 in
benzene at 80-140 °C provides a general route to dihydrobenzofurans 15 and dihydronaphthofurans
17. Although the yields are modest, this one-pot reaction provides simple access to these compounds,
which have previously been prepared by multistep routes. Oxidative cycloaddition of 2-cyclohex-
enones with â-methylstyrenes provides a new route to benzofuranoid neolignans, which was applied
to the synthesis of conocarpan (22). The formation of 2-acetoxyhexanedioic acids 27 and 47 from
acetoxylation of 2-cyclohexenones in HOAc, but not in benzene, opens up a new class of Mn(OAc)3
reactions and explains Watt and Demir’s discovery that much higher yields of R′-acetoxy enones
are obtained in benzene than in HOAc.
In 1976, Williams and Hunter reported that Mn-
Resu lts a n d Discu ssion
(OAc)3‚2H2O oxidation of enones in HOAc at reflux
affords 6-35% of R′-acetoxy enones.1,2 In a series of
papers initiated in 1984, Watt, Demir, and co-workers
reported that using Mn(OAc)3 dried over P2O5 in benzene
at reflux for 1 h to 2 d improves the yields of R′-
acetoxylation to 50-90%.3 These reactions proceed by
kinetic enolization of 2-cyclohexenone (1a ) to give
Mn(III) enolate 2a , which loses Mn(II) to give R′-keto
radical 3a , which is oxidized by a second equivalent of
Mn(OAc)3 to give R′-acetoxy enone 4a . No explanation
was provided for the vastly improved yields obtained in
benzene.
Oxid a tive Cycloa d d ition s in Ben zen e. To our
surprise, we found that oxidative addition of 2-cyclohex-
enones 1a -e with methylenecyclohexane (7a ) in benzene
at 80 °C for 3 d using Mn(OAc)3 dried over P2O5 in
vacuum as described by Watt affords 25-42% of dihy-
drobenzofurans 15a a -ea and 0-18% of 6-(1-cyclohex-
enylmethyl)-2-cyclohexenones 12a a -ea (the first letter
corresponds to the 2-cyclohexenone (1a -g) and the
second to the alkene 7a -c or 19a b). Grisan (15a a ), so
named because it contains the griseofulvin skeleton, has
been prepared twice by multistep routes5 and is now
available in a single step. No monomeric products are
formed from 1a and 1-octene under these reaction condi-
tions.
The following mechanistic scheme is consistent with
these results. Oxidation of cyclohexenone 1 will form R′-
keto radical 3. Addition of radical 3 to methylenecyclo-
hexane (7a ) will give radical 8, which is tertiary and is
therefore readily oxidized by Mn(OAc)3 to cation 11.2 Loss
of a proton from cation 11 will give 2-alkenyl-2-cyclo-
hexenone 12. Cyclization of 11 will give bicyclic cation
10. Loss of a proton from 10 will give tetrahydrobenzo-
furan 9 or a double bond position isomer. Electron-rich
double bonds are oxidized to radical cations by Mn-
(OAc)3.6 Therefore dienyl ether 9 should be oxidized to
cation radical 13, which should lose a proton to give
radical 14. Further oxidation will give a cation that will
lose a proton to give dihydrobenzofuran 15. We con-
firmed that tetrahydrobenzofurans are oxidized to dihy-
drobenzofurans 15 by Mn(OAc)3. Birch reduction7 of 2,3-
dihydro-3,3-dimethylbenzofuran (15a c)8 with Li in NH3,
EtOH, and ether provides >90% of 2,3,4,7-tetrahydro-
3,3-dimethylbenzofuran. Oxidation of the tetrahydroben-
zofuran with Mn(OAc)3 in benzene at 80 °C for 12 h
affords 15a c6 in good yield, thereby establishing that
We found that intramolecular trapping of the R′-keto
radicals obtained from cyclohexenones by suitably situ-
ated double bonds is much faster than acetoxylation,
affording good yields of bicyclic dienones in favorable
cases.4 For instance, oxidative cyclization of 5 with 5
equiv of Mn(OAc)3 and 1 equiv of Cu(OAc)2 in benzene
at reflux for 40 h affords 61% of 6 as a 3.4:1 E/Z mixture.
We therefore decided to examine the intermolecular
reactions of cyclohexenones and alkenes.
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) Williams, G. J .; Hunter, N. R. Can. J . Chem. 1976, 54, 3830.
(2) For reviews of Mn(OAc)3 as an oxidant, see: (a) Snider, B. B.
Chem. Rev. 1996, 96, 339. (b) Melikyan, G. G. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1997; Vol. 49, Chapter 3.
(3) (a) Dunlap, N. K.; Sabol, M. R.; Watt, D. S. Tetrahedron Lett.
1984, 25, 5839. (b) Demir, A. S.; J eganathan, A.; Watt, D. S. J . Org.
Chem. 1989, 54, 4020. (c) Demir, A. S.; J eganathan, A. Synthesis 1992,
235.
(5) (a) Antus, S.; Baitz-Ga´cs, E.; Snatzke, G.; Vas, J . Tetrahedron
1986, 42, 5637. (b) Kaufman, T. S.; Sindelar, R. D. J . Heterocycl. Chem.
1989, 26, 879.
(6) (a) Fristad, W. E.; Peterson, J . R.; Ernst, A. B.; Urbi, G. B.
Tetrahedron 1986, 42, 3429. (b) Vinogradov, M. G.; Todres, Z. V.; Il’ina,
G. P.; Rutavichus, A. I.; Kursanov, D. N.; Nikishin, G. I. Bull. Acad.
Sci. USSR 1976, 1278.
(7) Murai, A.; Sato, S.; Masamune, T. Bull. Chem. Soc. J pn. 1984,
57, 2286.
(8) Shulgin, A. T.; Baker, A. W. J . Org. Chem. 1963, 28, 2468.
(4) Snider, B. B.; Kiselgof, E. Y. Tetrahedron 1996, 52, 6073.
S0022-3263(97)00850-5 CCC: $14.00 © 1997 American Chemical Society

Synthesis of 2,3-Dihydrobenzofurans
J . Org. Chem., Vol. 62, No. 20, 1997 6979
cycloaddition reactions of styrenes and quinone mono-
ketals, abnormal Claisen rearrangements of phenyl allyl
ethers, Lewis acid-catalyzed cycloadditions of benzo-
quinones with styrenes, oxidative cycloaddition of p-
methoxyphenols with electron-rich styrenes with PhI-
(OTFA)2, and Lewis acid-promoted reactions of styrenes
with N-(phenylsulfonyl)-1,4-benzoquinone monoimines.12,13
Oxidative cycloaddition of 2-cyclohexenone (1a ) with
â-methylstyrene (19a ) in benzene for 3 d at 80 °C affords
18% of the desired 2,3-dihydro-3-methyl-2-phenylbenzo-
furan (20a a )14 as a 93:7 trans/cis mixture and 2% of
cinnamyl acetate. The methyl group in the minor cis
isomer of 20a a is shielded by the phenyl group and
resonates at δ 0.81 as compared with δ 1.43 in the major
trans isomer of 20a a ; similarly, the methine proton in
the minor cis isomer of 20a a resonates at δ 5.81 as
compared with 5.16 in the major trans isomer of 20a a .14
tetrahydrobenzofurans are competent intermediates in
the formation of 15 from 1.
Remarkably, oxidative cycloaddition of Hagemann’s
ester (1d ) with 7a for 3 d affords 25% (50% based on
recovered 1d ) of 6-methyldihydrobenzofuran-5-carboxy-
late 15d a and 0% of alkenyl enone 12d a . The formation
of 15d a indicates that loss of the R′-proton occurs despite
the fact that the γ-proton is several orders of magnitude
more acidic due to the presence of the ester group (see
eq 1) and is lost exclusively in all other reactions of 1d .
The selective loss of the R′-proton from 1d provides clear
evidence that Mn(III) enolate 2d is formed by Mn(OAc)3-
assisted kinetic enolization rather than reaction of the
enol tautomer with Mn(OAc)3.
We were concerned about the scope of this reaction
with electron-rich â-methylstyrenes because anethole is
known to be oxidized to the radical cation by Mn(OAc)3.6a
Fortunately, oxidative cycloaddition of 2-cyclohexenone
(1a ) with anethole (19b) and 4 equiv of dried Mn(OAc)3
in benzene in a sealed tube at 140 °C for 2 d provides
The analogous oxidative cyclization of R-tetralone (16)
with an alkene should give dihydronaphthofuran 17. As
expected, reaction of R-tetralone (16) and methylene-
cyclohexane (7a ) in benzene with dried Mn(OAc)3 at 80
°C for 3 d yields the desired dihydronaphthofuran 17a
(45%) and alkenyltetralone 18a (18%) as the only prod-
ucts, indicating that R-tetralone behaves analogously to
cyclohexenones in these oxidative cycloadditions, provid-
ing a general route to dihydronaphthofurans.
(9) Hayashi, T.; Thomson, R. H. Phytochemistry 1975, 14, 1085.
Oxidative dimerization of p-(1E)-propenylphenol with FeCl3 affords
20% of conocarpan.
(10) Achenbach, H.; Gross, J .; Dominguez, X. A.; Cano, G.; Verde
Star, J .; Del Carmen Brussolo, L.; Mun˜oz, G.; Salgado, F.; Lo´pez, L.
Phytochemistry 1987, 26, 1159.
(11) Chauret, D. C.; Bernand, C. B.; Arnason, J . T.; Durst, T.;
Krishnamurty, H.; Sanchez-Vindas, P.; Moreno, N.; Roman, L. S.;
Poveda, L. J . Nat. Prod. 1996, 59, 152.
Syn t h esis of Dih yd r ob en zofu r a n Neolign a n s.
3-Methyl-2-aryldihydrobenzofuran neolignan natural prod-
ucts possess a wide variety of antibacterial, cytotoxic,
antiproliferative, immunosuppressive, and insecticidal
activities. For instance, conocarpan (22)9-11 is toxic to
the larvae of the European corn borer at 10 µg/mL.11
These neolignans have been prepared by acid-catalyzed
(12) Wang, S.; Gates, B. D.; Swenton, J . S. J . Org. Chem. 1991, 56,
1979 and references cited therein.
(13) Engler, T. A.; Chai, W. Tetrahedron Lett. 1996, 37, 6969 and
references cited therein.
(14) (a) Schmid, E.; Fra´ter, Gy.; Hansen, H.-J .; Schmid, H. Helv.
Chim. Acta 1972, 55, 1625. (b) Gregson, M.; Ollis, W. D.; Redman, B.
T.; Sutherland, I. O.; Dietrichs, H. H. J . Chem. Soc., Chem. Commun.
1968, 1394. (c) Bowden, B. F.; Ritchie, E.; Taylor, W. C. Aust. J . Chem.
1972, 25, 2659.

6980 J . Org. Chem., Vol. 62, No. 20, 1997
Snider et al.
31% of 2,3-dihydro-2-(4-methoxyphenyl)-3-methylbenzo-
furan (20a b) as a 49:1 trans/cis mixture, and only 4% of
the cinnamyl acetate, indicating that 2-cyclohexenone is
oxidized more rapidly than anethole under these condi-
tions.
We then turned our attention to the preparation of a
suitably substituted 2-cyclohexenone for conocarpan
synthesis. 4-Allyl-2-cyclohexenone (1f)15 gives a complex
mixture of products since addition can occur inter- or
intramolecularly to the allyl group.4 Alkylation of the
lithium enolate of 3-ethoxy-2-cyclohexenone with 1-chloro-
3-iodopropane in THF containing HMPA followed by
LAH reduction of the crude product and hydrolysis with
HCl provides 52% of 4-(3-chloropropyl)-2-cyclohexenone
(1g).15 Oxidative cycloaddition of 1g with anethole (19b)
in benzene at 110 °C for 1.5 d provides 25% of the desired
adduct 5-(3-chloropropyl)-2,3-dihydro-2-(4-methoxyphe-
nyl)-3-methylbenzofuran (20gb) as a 50:1 trans/cis mix-
ture, 32% of recovered 1g, and 31% of recovered anethole
as the only products. Elimination of HCl from 20gb with
potassium tert-butoxide in THF at reflux,16 followed by
evaporation of the THF and further heating to effect
conjugation of the double bond,17 yields 92% of 2,3-
dihydro-2-(4-methoxyphenyl)-3-methyl-5-((1E)-propenyl)-
benzofuran (21). Demethylation of 21 with LiPPh2 in
THF18 provides 84% of conocarpan (22) with spectral data
identical to those reported.9-11
Oxid a tive Cycloa d d ition s in Acetic Acid . Al-
though Watt and Demir obtained much higher yields of
R′-acetoxy enones with dried Mn(OAc)3 in benzene than
in acetic acid, the reactions are much slower in benzene.
Since our intramolecular cyclizations generally proceeded
faster and in equally good yield in AcOH, we decided to
investigate dihydrobenzofuran formation in AcOH. Oxi-
dation of 2-cyclohexenone (1a ) as a 0.1-0.2 M solution
in HOAc containing 2 equiv of methylenecyclohexane (7a )
with 4 equiv of Mn(OAc)3‚2H2O at 80 °C for 1 d affords
25% of grisan (15a a ),5 2% of dihydrobenzofuran-3-yl
acetate 26a a , 4% of dihydrobenzofuran-7-yl acetate 33a a ,
and traces of 2-(1-cyclohexenylmethyl)-2-cyclohexenone
(38a a ). The yield of 15a a is much lower in acetic acid
than in benzene, no 12a a is formed, and minor products
26a a , 33a a , and 38a a , which are not formed at all in
benzene, are isolated in low yield, indicating that the
solvent profoundly influences the course of these radical
cyclizations.
23a b cyclizes to radical 24a b, which is then oxidized to
cation 25a b, which reacts to give the dihydrobenzofuran
as indicated above for the analogous cation 10. The
conversion of 23 to 25 is well-precedented in the oxidation
of secondary γ-carboxy radicals to lactones by Mn(OAc)3.2
The formation of 6-alkenyl-2-cyclohexenone 12 in much
greater yield in benzene than in HOAc is consistent with
exclusive oxidation of tertiary radical 8 to cation 11 in
benzene, while in HOAc radical 8 (23) mainly cyclizes to
radical 24 prior to oxidation. The failure to obtain
dihydrobenzofuran 15a b in benzene indicates that either
cyclization of radical 23a b to give radical 24a b or
oxidation of radical 24a b to provide cation 25a b does not
occur in benzene.
Similar oxidative cycloaddition of 2-cyclohexenone (1a )
with excess isobutene (7c) provides 22% of 2,3-dihydro-
2,2-dimethylbenzofuran (15a c),8 3% of 2,3-dihydro-2,2-
dimethylbenzofuran-3-yl acetate (26a c),19 6% of 2,3-
dihydro-2,2-dimethylbenzofuran-7-yl acetate (33a c), and
9% of 2-(2-methyl-2-propenyl)-2-cyclohexenone (38a c).
The structure of 33a c was confirmed by hydrolysis to the
phenol, which is identical to a commercially available
sample. Low yields of products are obtained from
1-octene and substituted 2-cyclohexenones 1b-e, and
from 2-cyclohexenone (1a ) and 1-methylcyclohexene.
Complex mixtures and polymer are obtained from 7a and
2-methylcyclopentenone, 3-methylcyclopentenone, mesit-
yl oxide, or 1-acetylcyclohexene, indicating the reaction
is synthetically useful only with 2-cyclohexenones that
lead to dihydrobenzofurans.
The formation of dihydrobenzofuran-3-yl acetate 26 is
easily accounted for by benzylic oxidation of dihydroben-
zofuran 15, which occurs in acetic acid, but not in
benzene. As expected, benzylic oxidation of 15a a with
Mn(OAc)3‚2H2O in HOAc at 80 °C for 18 h provides 99%
of 26a a . The mechanism outlined above for the oxidative
cycloaddition cannot account for the formation of minor,
but significant, amounts of dihydrobenzofuran-7-yl ac-
etate 33 or 2-alkenyl-2-cyclohexenone 38.
The lack of regioselectivity in the oxidative cycloaddi-
tion of 5-methylcyclohexenone (1e) with 7a in acetic acid
provides further evidence that the mechanism in acetic
acid is much more complicated than in benzene. We
obtained an unexpectedly complex mixture of products
containing 4% of dihydro-4-methylbenzofuran 15ea , 2%
of dihydro-4-methylbenzofuran-7-yl acetate 33ea , 3% of
38ea , along with 4% of dihydro-6-methylbenzofuran 40ea
(15ba ), which was obtained from 3-methylcyclohexenone
The successful oxidative cycloaddition of 1a with
1-octene (7b) in acetic acid, but not in benzene, provides
further evidence of significant solvent effects. Oxidation
of 2-cyclohexenone (1a ) with 1.5 equiv of 1-octene (7b)
and 4 equiv of Mn(OAc)3‚2H2O in AcOH at 80 °C for 1 d
affords 24% of 2,3-dihydrobenzofuran (15a b), 27% of
6-acetoxy-2-cyclohexenone (4a ), and a trace of dihy-
drobenzofuran-7-yl acetate (33a b) and 2-(2-octenyl)-2-
cyclohexenone (38a b). Acetoxy enone 4a is formed with
1-octene but not with the more nucleophilic methylene-
cyclohexane (7a ), which reacts with the electrophilic R′-
keto radical 3a more rapidly than 1-octene does.
Since secondary radicals cannot be oxidized to cations
by Mn(OAc)3, the successful oxidative cycloaddition with
1-octene in acetic acid indicates that secondary radical
(15) Stork, G.; Danheiser, R. L. J . Org. Chem. 1973, 38, 1775.
(16) Grethe, G.; Lee, H. T.; Mitt, T.; Uskokovic, M. Helv. Chim. Acta
1973, 56, 1485.
(17) Thach, L. N.; Hanh, D.-L.; Hiep, N. B.; Radhakrishna, A. S.;
Singh, B. B.; Loupy, A. Synth. Commun. 1993, 23, 1379 and references
cited therein.
(18) Ireland, R. E.; Walba, D. M. In Organic Syntheses; Noland, W.
E., Ed.; Wiley: New York, 1988; Collect. Vol. VI, pp 567-570.
(19) Hurd, C. D.; Dowbenko, R. J . Am. Chem. Soc. 1960, 82, 3662.

Synthesis of 2,3-Dihydrobenzofurans
J . Org. Chem., Vol. 62, No. 20, 1997 6981
(1b) in benzene, and 11% of dihydro-6-methylbenzofuran-
3-yl acetate 41ea . The formation of 40ea and 41ea from
1e indicates that addition of 7a to 1e is occurring at both
the R- and R′-positions. However, oxidation of 5-methyl-
2-cyclohexenone (1e) with Mn(OAc)3‚2H2O in HOAc gives
44% of 6-acetoxy-5-methyl-2-cyclohexenone (4e) as the
only organic soluble product, suggesting incorrectly that
enolization at the R′-carbon is the only reaction.
diastereomer 27a should have a single preferred confor-
mation with the larger CO2H and CH2CO2H substituents
extended and the smaller acetate and methyl groups
offset as shown in the left structure. The minor diaste-
reomer 27b is a mixture of two conformers so that the
two coupling constants are 8.1 and 5.5 Hz. The NMR
spectra of the diastereomers of dimethyl 4-(benzyloxy)-
2-acetoxyhexanedioate show similar differences.20 Simi-
larly, oxidation of 1a affords 22% of 4a and 21% of
2-acetoxyhexanedioic acid (47).
The formation of 27 suggests that 1e also reacts by
conjugate addition of acetate to give Mn(III) enolate 29.
Loss of Mn(II) will give R-keto radical 32, which can react
with Mn(OAc)3 to give 2,3-diacetoxycyclohexanone (30).
Further oxidation will give acetoxycyclohexanedione (31),
which will be oxidatively cleaved to give diacid 27.
Alternatively, elimination of an acetate from 30 will give
2-acetoxy-2-cyclohexenone 34, which could undergo con-
jugate addition of acetate and oxidation to give 3-acetoxy-
1,2-cyclohexanedione 31. The formation of diacid 27a as
the major diastereomer is consistent with this scheme
since conjugate addition of acetate to either 1e or 34
should occur predominantly by axial attack from the
R-face.
Reaction of R-keto radical 32 with 7a will lead to
tertiary radical 36, which will be oxidized to give cation
37. Loss of a proton and elimination of the â-acetoxy
group will give 2-alkenyl-2-cyclohexenone 38ea . Cycliza-
tion of radical 36 and oxidation will give cation 39, which
will lose a proton and HOAc to give a tetrahydrobenzo-
furan that will be oxidized to dihydro-6-methylbenzo-
furan 40ea . Dihydro-4-methylbenzofuran-7-yl acetate
33ea can be formed by R′-enolization of 34 to give radical
35, which should react with 7a to give 33ea analogously
to the conversion of 3 to 15 discussed above. The
formation of dihydrobenzofuran-7-yl acetate 33 from
2-cyclohexenone (1a ) and 5-methyl-2-cyclohexenone (1e),
but not from 3-substituted 2-cyclohexenones 1b-d , is
consistent with this mechanism. (These reactions are
described in the Supporting Information.) The substitu-
ent on the â-carbon of enones 1b-d should retard
conjugate addition of acetate so that enolization from the
R′-carbon is the exclusive reaction.
We had observed a single instance of conjugate addi-
tion of acetate in our study of oxidative cyclizations of
alkenyl cyclohexenones.4 6-(4-Pentenyl)-2-cyclohexenone
(42) affords 24% of 10-acetoxybicyclo[5.3.1]undec-3-en-
11-one (44) as the major product. The 6-alkyl substituent
slows down enolization at the R′-position so that conju-
gate addition of acetate becomes the major pathway.
We investigated the oxidation of 1,2-cyclohexanedione
(45) with Mn(OAc)3 as a model for proposed intermediate
The crucial observation entailed examination of the
aqueous layer from the workup of the oxidation of 1e.
Acidification and extraction with EtOAc yields 20% of a
4:1 mixture of 2-acetoxy-4-methylhexanedioic acids (27a
and 27b), which was treated with diazomethane to give
a 4:1 mixture of dimethyl 2-acetoxy-4-methylhexanedio-
ates (28a and 28b). The stereochemical assignment
follows from the absorption of CHOAc, which occurs as
a dd, J ) 10.5, 3.5 Hz, in the major isomer and a dd, J )
8.1, 5.5 Hz, in the minor isomer. The more disparate
coupling constants of the major diastereomer isomer
indicate that it exists in one conformation to a greater
extent than the minor diastereomer does. The major
(20) Suemune, H.; Matsuno, K.; Uchida, M.; Sakai, K. Tetrahedron:
Asymmetry 1992, 3, 297.

6982 J . Org. Chem., Vol. 62, No. 20, 1997
Snider et al.
The formation of naphthoquinone 50 was not expected.
We established the structure of the analogue obtained
from isobutene by comparison of the 1H and 13C NMR
spectral data with literature data.23,24 These naphtho-
quinones are readily available by [3 + 2] photoaddition
of 2-hydroxy-1,4-naphthoquinone (lawsone, 49) with
alkynes or with alkenes followed by air oxidation.23 We
thought that R-tetralone 16 might be oxidized by Mn-
(OAc)3‚2H2O to give 49, which could undergo oxidative
cycloaddition with alkenes to give 50. As expected,
oxidative cycloaddition of 49 with 7a and 4 equiv of
Mn(OAc)3‚2H2O in HOAc at 80 °C for 15 h affords 95%
of 50. Oxidative cycloaddition of lawsone with alkenes
thus provides an alternative to the photochemical route
developed by Suginome.23 Oxidative cycloaddition of
â-tetralone with 7a in acetic acid provides 20% of 50 as
the only isolable product, suggesting that â-tetralone is
also oxidized to lawsone by Mn(OAc)3‚2H2O.
34. As expected, oxidation of 45 with Mn(OAc)3‚2H2O
in HOAc at 80 °C for 1 h affords 27% of 2,6-diacetoxy-
2-cyclohexenone (46), which is analogous to 31, and 40%
of 2-acetoxyhexanedioic acid (47). Nikishin and co-
workers reported a similar oxidation of 45 with CuCl2
and H2O2 that affords 2-chlorohexanedioic acid.21 Reac-
tion of 45 with Ac2O in HOAc provides 2-acetoxy-2-
cyclohexenone (48). Oxidation of 48 and 7a with
Mn(OAc)3‚2H2O in HOAc at 80 °C for 20 h provides 11%
of dihydrobenzofuran-7-yl acetate 33a a , indicating that
2-acetoxy-2-cyclohexenones 34 and 48 are competent
intermediates for the formation of 33a .
Con clu sion . Oxidative cycloaddition of a 2-cyclohex-
enone or R-tetralone and an alkene with dried Mn(OAc)3
in benzene at 80-140 °C provides a general route to
dihydrobenzofurans 15 and dihydronaphthofurans 17.
Although the yields are modest, this one-step reaction
provides simple access to these compounds, which have
previously been prepared by multistep routes. Oxidative
cycloaddition of 2-cyclohexenones with â-methylstyrenes
provides a new route to benzofuranoid neolignans, which
was applied to the synthesis of conocarpan (22). The
formation of 2-acetoxyhexanedioic acids 27 and 47 from
acetoxylation of 2-cyclohexenones in HOAc, but not in
benzene, opens up a new class of Mn(OAc)3 reactions and
explains Watt and Demir’s discovery that much higher
yields of R′-acetoxyenones are obtained in benzene than
in HOAc.
The formation of 2-acetoxyhexanedioic acids as signifi-
cant products from the oxidation of 2-cyclohexenones with
Mn(OAc)3‚2H2O in HOAc explains the modest yields of
6-acetoxy-2-cyclohexenones 4 obtained by Williams and
Hunter in acetic acid.1 Higher yields of 4 were obtained
by Watt and Demir in benzene because conjugate addi-
tion of acetate does not occur in this solvent and no
hexanedioic acids are formed.
There are several advantages to carrying out these
oxidative cycloadditions in benzene and one benefit to
carrying them out in acetic acid. Conjugate addition of
acetic acid does not occur in benzene so that no material
is converted to diacid, and regioisomers and dihydroben-
zofuran-7-yl acetate 33 are not obtained. Benzylic oxida-
tion does not occur as readily in benzene, so that
overoxidized products such as dihydrobenzofuran-3-yl
acetates 26 and 41 are not obtained. On the other hand,
terminal alkenes can be used in acetic acid but not in
benzene since secondary radical 23a b cyclizes to afford
24a b which is then oxidized to provide 25a b only in
acetic acid.
Oxidative cycloaddition of R-tetralone (16) with 7a and
6 equiv of Mn(OAc)3‚2H2O in HOAc at 80 °C for 15 h
affords 19% of 2-acetoxy-R-tetralone, 24% of the naph-
thofuranone derived from oxidation of 17, 15% of alk-
enyltetralone 18, and 19% of naphthoquinone 50. Simi-
lar products are obtained in comparable yields from
isobutene. Dihydronaphthofuran 17 is formed and un-
dergoes rapid benzylic oxidation to give the naphtho-
furanone since the naphthalene ring is more readily
oxidized than a benzene ring.22
Exp er im en ta l Section
Gen er a l P r oced u r es. NMR spectra were recorded at 300
MHz in CDCl3. Chemical shifts are reported in δ (ppm) and
coupling constants in hertz. IR spectra are reported in cm-1
.
Oxid a tive Cycloa d d ition of 2-Cycloh exen on e (1a ) w ith
Meth ylen ecycloh exa n e (7a ) in Ben zen e. A solution of 1a
(107 mg, 1.11 mmol), 7a (213 mg, 2.22 mmol), and Mn(OAc)3
(1.03 g, 4.44 mmol) in 10 mL of benzene was refluxed at 80 °C
for 3 d. Saturated NaHSO3 solution was added and the
mixture was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with saturated NaCl solution,
dried (Na2SO4), and concentrated in vacuo to provide 191 mg
of crude product, which was purified by flash chromatography
on silica gel (50:1 hexane/EtOAc, then 10:1 hexane/EtOAc) to
yield 88 mg (42%) of 15a a , followed by 37 mg (18%) of 12a a .
The data for 12a a : 1H NMR 6.93 (dddd, 1, J ) 10.1, 5.3,
4.4, 0.7), 5.99 (ddd, 1, J ) 10.1, 2.1, 2.0), 5.43 (br s, 1), 2.56
(br d, 1, J ) 15), 2.47-2.30 (m, 3), 2.10-1.87 (m, 5), 1.71-
1.50 (m, 6); 13C NMR 201.8, 149.7, 134.9, 129.4, 123.6, 44.2,
37.6, 27.8, 26.7, 25.3, 24.7, 22.9, 22.4; IR (neat) 1715, 1673,
1443, 1219.
(22) Ross, S. D.; Finkelstein, M.; Rudd, E. J . Anodic Oxidation;
Academic Press: New York, 1975; Chapters 5 and 12.
(23) Kobayashi, K.; Shimizu, H.; Sasaki, A.; Suginome, H. J . Org.
Chem. 1993, 58, 4614.
(24) Ferreira, C. A. C.; Ferreira, V. F.; Pinto, A. V.; Lopes, R. S. C.;
Pinto, M. C. R.; Da Silva, A. J . R. An. Acad. Brasil. Cienc. 1987, 59, 5;
Chem. Abstr. 1988, 108, 221435w.
(21) Starostin, E. K.; Mazupchick, A. A.; Ignatenko, A. V.; Nikishin,
G. I. Synthesis 1992, 917.

Synthesis of 2,3-Dihydrobenzofurans
J . Org. Chem., Vol. 62, No. 20, 1997 6983
The data for 15a a : 1H NMR 7.12 (br d, 1, J ) 7.4), 7.09 (br
dd, 1, J ) 8.0, 7.4), 6.79 (br dd, 1, J ) 7.4, 7.4), 6.74 (br d, 1,
J ) 8.0), 2.96 (s, 2), 1.85-1.40 (m, 10); 13C NMR 158.9, 127.8,
126.8, 125.1, 119.7, 109.5, 88.4, 41.0, 37.2 (2 C), 25.2, 23.1 (2
C); IR (neat) 1597, 1481, 1240, 747. The data are identical to
those previously reported.5
Oxid a tive Cycloa d d ition of 3-Meth yl-2-cycloh exen on e
(1b) w ith 7a in Ben zen e. A solution of 1b (101 mg, 0.92
mmol), 7a (176 mg, 1.84 mmol), and Mn(OAc)3 (852 mg, 3.67
mmol) in 10 mL of benzene was refluxed at 80 °C for 3 d.
Normal workup and flash chromatography on silica gel (50:1
hexane/EtOAc, 10:1 hexane/EtOAc, then 3:1 hexane/EtOAc)
gave 58 mg (31%) of 15ba , followed by 22 mg (12%) of 6-(1-
cyclohexenylmethyl)-3-methyl-2-cyclohexenone (12ba ) and 23
mg (23%) of recovered 1b.
1.51 (m, 10); 13C NMR 158.5, 134.9, 127.7, 125.6, 120.7, 106.7,
88.1, 39.9, 37.3, 25.2, 23.1, 18.8; IR (neat) 1614, 1599, 1460,
1275, 1023, 932, 767.
Oxid a tive Cycloa d d ition of 16 w ith 7a in Ben zen e. A
solution of 16 (100 mg, 0.68 mmol), 7a (132 mg, 1.36 mmol),
and Mn(OAc)3 (636 mg, 2.72 mmol) in 10 mL of benzene was
refluxed at 80 °C for 3 d. Normal workup and flash chroma-
tography on silica gel (50:1 hexane/EtOAc, then 15:1 hexane/
EtOAc) gave 74 mg (45%) of spiro[cyclohexane-1,2′(3′H)-
naphtho[1,2-b]furan] (17), followed by 29 mg (18%) of 18 and
26 mg (26%) of recovered 16.
The data for 17: 1H NMR 7.97 (m, 1), 7.77 (m, 1), 7.39 (m,
2), 7.32 (d, 1, J ) 8.2), 7.28 (d, 1, J ) 8.2), 3.12 (s, 2), 1.97-
1.48 (m, 10); 13C NMR 154.2, 133.9, 127.8, 125.3, 124.8, 123.3,
121.7, 120.8, 119.3, 119.2, 89.3, 41.9, 37.4, 25.3, 23.0; IR (neat)
3056, 1944, 1814, 1684, 1581, 1516, 1445, 1378.
The data for 12ba : 1H NMR 5.85 (br dd, 1, J ) 2.7, 1.3),
5.42 (br s, 1), 2.54 (br d, 1, J ) 14.9), 2.38-2.24 (m, 3), 2.09-
1.82 (m, 5), 1.95 (s, 3), 1.68-1.49 (m, 6); 13C NMR 201.7, 161.5,
135.2, 126.2, 123.4, 43.1, 37.7, 29.8, 27.8, 26.6, 25.3, 24.1, 22.9,
22.4; IR (neat) 1669, 1638, 1438, 1379, 1210.
The data for 18: 1H NMR 8.03 (d, 1, J ) 7.8), 7.46 (dd, 1, J
) 7.8, 7.6), 7.30 (dd, 1, J ) 7.6, 7.5), 7.24 (d, 1, J ) 7.5), 5.47
(s, 1), 3.00-2.93 (m, 2), 2.72-2.58 (m, 2), 2.22-1.47 (m, 11);
13C NMR 200.4, 144.1, 135.1, 133.1, 132.5, 128.7, 127.5, 126.5,
123.7, 45.2, 38.0, 28.1, 27.9, 27.4, 25.3, 23.0, 22.5; IR (neat)
1682, 1600, 741.
Oxid a tive Cycloa d d ition of 1a w ith â-Meth ylstyr en e
(19a ) in Ben zen e. A solution of 1a (105 mg, 1.10 mmol), 19a
(143 mg, 1.21 mmol), and Mn(OAc)3 (1.02 g, 4.40 mmol) in 10
mL of benzene was refluxed at 80 °C for 3 d. Normal workup
and flash chromatography on silica gel (50:1 hexane/EtOAc,
then 15:1 hexane/EtOAc) gave 69 mg (42%) of unreacted 19a ,
followed by 46 mg (18%) of a 93:7 mixture of trans-2,3-dihydro-
3-methyl-2-phenylbenzofuran (20a a ) and the cis isomer, and
2% of cinnamyl acetate.
The data for 15ba : 1H NMR 7.00 (d, 1, J ) 7.5), 6.61 (d, 1,
J ) 7.5), 6.58 (s, 1), 2.92 (s, 2), 2.29 (s, 3), 1.80-1.47 (m, 10);
13C NMR 159.0, 137.9, 124.7, 123.8, 120.4, 110.2, 88.6, 40.7,
37.2, 25.2, 23.1, 21.5; IR (neat) 1622, 1590, 1499, 1448, 1275,
1250, 1032, 946, 796.
Oxid a tive Cycloa d d ition of 3-Eth oxy-2-cycloh exen on e
(1c) w ith 7b in Ben zen e. A solution of 1c (115 mg, 0.82
mmol), 7a (158 mg, 1.64 mmol), and Mn(OAc)3 (762 mg, 3.38
mmol) in 10 mL of benzene was refluxed at 80 °C for 3 d.
Normal workup and flash chromatography on silica gel (50:1
hexane/EtOAc, 15:1 hexane/EtOAc, then 1:1 hexane/EtOAc)
gave 74 mg (39%) of 6-ethoxyspiro[benzofuran-2(3H),1′-cyclo-
hexane] (15ca ), followed by 4 mg (2%) of 6-(1-cyclohexenyl-
methyl)-3-ethoxy-2-cyclohexenone (12ca ), and 50 mg (43%) of
recovered 1c.
The data for 20a a : 1H NMR 7.45-7.30 (m, 5), 7.19 (br d, 1,
J ) 7.4), 7.15 (br dd, 1, J ) 8.0, 7.4), 6.92 (br dd, 1, J ) 7.4,
7.4), 6.87 (br d, 1, J ) 8.0), 5.16 (d, 1, J ) 8.7), 3.44 (dq, 1, J
) 8.7, 6.8), 1.43 (d, 3, J ) 6.8); 13C NMR 159.2, 140.9, 131.9,
128.6 (2 C), 128.24, 128.18, 126.0 (2 C), 123.6, 120.8, 109.5,
92.4, 45.6, 18.1; IR (neat) 1597, 1478, 1432, 750.
The data for 12ca : 1H NMR 7.54 (d, 1, J ) 8.6), 6.60 (dd, 1,
J ) 2.2, 8.6), 6.51 (d, 1, J ) 2.2), 4.10 (q, 2, J ) 7.0), 1.81-
1.55 (m, 10), 1.45 (t, 3, J ) 7.0); 13C NMR 201.8, 173.6, 167.6,
125.7, 113.0, 111.8, 96.6, 90.6, 64.2, 31.7, 24.6, 21.7, 14.5; IR
(neat) 1709, 1613, 1447, 1292, 1179, 1097.
Partial data for the cis isomer: 1H NMR 5.81 (d, 1, J ) 8.8),
3.70 (m, 1), 0.81 (d, 3, J ) 7.2).
Oxid a tive Cycloa d d ition of 1a w ith An eth ole (19b) in
Ben zen e. A solution of 1a (96 mg, 1.00 mmol), anethole (150
mg, 1.01 mmol), Mn(OAc)3 (928 mg, 4.00 mmol), and 8 mL of
benzene was stirred in a sealed tube at 140 °C for 2 d. Normal
workup and flash chromatography on silica gel (50:1 hexane/
EtOAc, then 10:1 hexane/EtOAc) gave 55 mg (37%) of recov-
ered trans-anethole, followed by 73 mg (31%) of a 50:1 mixture
of trans-2,3-dihydro-2-(4-methoxyphenyl)-3-methylbenzofuran
(20a b ) and the cis isomer, and 8 mg (4%) of 3-(4-methoxy-
phenyl)-2(E)-propenyl acetate.
The data for 15ca : 1H NMR 6.97 (br d, 1, J ) 8.5), 6.35
(dd, 1, J ) 8.5, 2.0), 6.34 (d, 1, J ) 2), 3.97 (q, 2, J ) 7.0), 2.89
(s, 2), 1.86-1.45 (m, 10), 1.37 (t, 3, J ) 7.0); 13C NMR 160.3,
160.0, 125.4, 118.9, 106.4, 97.0, 89.8, 63.9, 40.7, 37.5, 25.5, 23.4,
15.2; IR (neat) 1621, 1495, 1446, 1294, 1168, 1038, 969, 926.
Oxid a tive Cycloa d d ition of Eth yl 2-Meth yl-4-oxo-2-
cycloh exen eca r boxyla te (1d ) w ith 7a in Ben zen e.
A
solution of 1d (121 mg, 0.66 mmol), 7a (128 mg, 1.33 mmol),
and Mn(OAc)3 (617 mg, 2.66 mmol) in 10 mL of benzene was
refluxed at 80 °C for 3 d. Normal workup and flash chroma-
tography on silica gel (25:1 hexane/EtOAc, then 3:1 hexane/
EtOAc) gave 34 mg (25%) of ethyl 6-methylspiro[benzofuran-
2(3H),1′-cyclohexane]-5-carboxylate (15d a ), followed by 62 mg
(51%) of recovered 1c.
The data for 20a b: 1H NMR 7.35 (d, 2, J ) 8.7), 7.16 (dd,
1, J ) 6.9, 6.1), 7.13 (d, 1, J ) 6.9), 6.90 (d, 2, J ) 8.7), 6.88-
6.94 (m, 1), 6.84 (d, 1, J ) 8.3), 5.09 (d, 1, J ) 8.9), 3.79 (s, 3),
3.43 (dq, 1, J ) 8.9, 6.8), 1.39 (d, 3, J ) 6.8); 13C NMR 160.0,
159.5, 133.1, 132.4, 128.6, 128.0, 124.0, 121.0, 114.4, 109.8,
92.7, 55.7, 45.7, 18.2; IR (neat) 1614, 1514, 1478, 1376, 1249.
Partial data for the cis isomer: 1H NMR 5.75 (d, 1, J ) 8.7),
0.82 (d, 3, J ) 8.3).
P r ep a r a t ion of 4-(3-Ch lor op r op yl)-2-cycloh exen on e
(1g).15 To a solution of diisopropylamine (0.9 mL, 7.00 mmol)
in 5 mL of dry THF at 0 °C under N2 was added n-butyllithium
solution (2.5 M in hexane, 2.5 mL, 6.25 mmol). After 15 min
at 0 °C, the solution was cooled to -78 °C, and 3-ethoxy-2-
cyclohexenone (712 mg, 5.08 mmol) in 2.5 mL of THF was
added dropwise over 30 min. The solution was warmed to -40
°C, and HMPA (1.25 g, 6.98 mmol) in THF and then 1-chloro-
3-iodopropane (1.43 g, 7.01 mmol) were added. The mixture
was warmed to rt over 1.5 h and then stirred at rt for
additional 2 h. Saturated NH4Cl solution was added, and the
mixture was extracted with hexane (2 × 10 mL). The
combined organic layers were washed with saturated NaCl
solution, dried (Na2SO4), and concentrated to provide 1.3 g of
crude product.
The data for 15d a : 1H NMR 7.77 (s, 1), 6.59 (s, 1), 4.30 (q,
2, J ) 7.1), 2.93 (s, 2), 2.56 (s, 3), 1.85-1.70 (m, 4), 1.70-1.60
(m, 2), 1.60-1.45 (m, 4), 1.37 (t, 3, J ) 7.1); 13C NMR 167.4,
162.1, 142.4, 128.0, 124.4, 121.2, 112.4, 90.2, 60.1, 40.3, 37.1,
25.1, 23.0, 22.5, 14.4; IR (neat) 1712, 1621, 1583, 1494, 1257.
Oxid a tive Cycloa d d ition 5-Meth yl-2-cycloh exen on e
(1e) w ith 7a in Ben zen e. A solution of 1e (92 mg, 0.84
mmol), 7a (160 mg, 1.66 mmol), and Mn(OAc)3 (770 mg, 3.32
mmol) in 10 mL of benzene was refluxed at 80 °C for 3 d.
Normal workup and flash chromatography on silica gel (50:1
hexane/EtOAc, then 15:1 hexane/EtOAc) gave 70 mg (41%) of
15ea , followed by 18 mg (9%) of 6-(1-cyclohexenylmethyl)-5-
methyl-2-cyclohexenone (12ea ) as a 3:2 trans/cis mixture and
3 mg (3%) of recovered 1e.
The data for 12ea : 1H NMR 6.80 (m,1), 5.96 (br d, J ) 10.0),
5.46 (br s, 0.6 × 1), 5.41 (br s, 0.4 × 1), 2.60-1.80 (m, 10),
1.70-1.50 (m, 4), 1.05 (d, 0.6 × 3, J ) 6.9), 0.92 (d, 0.4 × 3, J
) 6.9); 13C NMR (202.1, 202.0), (147.3, 146.9), (135.1, 134.9),
(129.2, 128.4), (123.7, 123.3), (51.4, 49.5), (38.1, 37.3), (33.7,
33.3), (31.5, 31.1), (27.97, 27.90), (25.3, 25.3), (22.92, 22.88),
(22.43, 22.37), (19.8, 14.2).
The above product in 10 mL of dry THF was added dropwise
to lithium aluminum hydride solution (1.0 M in THF, 4.6 mL,
4.60 mmol) under N2 at 0 °C. The mixture was warmed to rt
and then held at rt for 1 h. Water (0.1 mL, then 5 mL) and
then 2 N HCl solution (to adjust the pH to 2) were added. After
The data for 15ea : 1H NMR 7.00 (dd, 1, J ) 7.6. 7.6), 6.62
(d, 1, J ) 7.6), 6.58 (d, 1, J ) 7.6), 2.87 (s, 2), 2.21 (s, 3), 1.86-

6984 J . Org. Chem., Vol. 62, No. 20, 1997
Snider et al.
20 min of stirring, the solution was extracted with CH2Cl2 (3
× 20 mL). The combined organic layers were washed with
saturated NaHCO3 solution and NaCl solution and dried (Na2-
SO4). Evaporation followed by flash chromatography on silica
gel gave 454 mg (52%) of 1g: 1H NMR 6.86 (ddd, 1, J ) 10.2,
2.7, 1.4), 5.99 (ddd, 1, J ) 10.2, 2.4, 0.7), 3.59 (dd, 2, J ) 6.5,
6.5), 2.57-2.32 (m, 3), 2.19-2.10 (m, 1), 1.94-1.85 (m, 2),
1.79-1.52 (m, 3); 13C NMR 199.2, 154.0, 129.0, 44.5, 36.6, 35.2,
31.5, 29.6, 28.2; IR (neat) 1678.
Oxid a tive Cycloa d d ition 1g w ith 19b in Ben zen e. A
solution of 1g (96 mg, 0.56 mmol), trans-anethole (83 mg, 0.56
mmol), Mn(OAc)3 (518 mg, 2.23 mmol), and 5 mL of benzene
was stirred at 110 °C for 1.5 d. Normal workup and flash
chromatography on silica gel (50:1 hexane/EtOAc) gave 26 mg
(31%) of recovered anethole, followed by 43 mg (24.5%) of 5-(3-
chloropropyl)-2,3-dihydro-2-(4-methoxyphenyl)-3-methylbenzo-
furan (20gb) as a 50:1 trans/cis mixture and 31 mg (32%) of
recovered 1g.
The data for 20gb: 1H NMR 7.35 (dt, 2, J ) 8.6, 1.9), 6.96
(d, 1, J ) 7.8), 6.96 (s, 1), 6.91 (dt, 2, J ) 8.6, 1.9), 6.76 (d, 1,
J ) 7.8), 5.08 (d, 1, J ) 9.2), 3.81 (s, 3), 3.54 (dd, 2, J ) 6.5,
6.5), 3.40 (dq, 1, J ) 9.2, 6.8), 2.73 (dd, 2, J ) 7.5, 7.5), 2.06
(dddd, 2, J ) 6.5, 6.5, 7.5, 7.5), 1.38 (d, 3, J ) 6.8); 13C NMR
160.0, 157.9, 133.4, 133.0, 132.6, 128.5, 128.0, 124.0, 114.3,
109.5, 92.9, 55.7, 45.7, 44.7, 34.9, 32.6, 18.0; IR (neat) 1613,
1515, 1487, 1242.
P r ep a r a tion of tr a n s-2,3-Dih yd r o-2-(4-m eth oxyp h en -
yl)-3-m eth yl-5-(1(E)-p r op en yl)ben zofu r a n (21). A solution
of 20gb (16 mg, 0.051 mmol) in 2 mL of dry THF and 1.0 M
KO-t-Bu in THF (0.12 mL) was refluxed at 67 °C for 4 h. After
the THF evaporated, the viscous residue was stirred at 70 °C
for an additional 3 h. NaOH solution (1 N, 3 mL) was added,
and the solution was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated. Purification of the residue by chro-
matography on silica gel (50:1 hexane/EtOAc) gave 13 mg
(92%) of 21: 1H NMR 7.35 (dt, 2, J ) 8.7, 2.0), 7.14 (s, 1), 7.12
(d, 1, J ) 8.1), 6.91 (dt, 2, J ) 8.7, 2.0), 6.76 (d, 1, J ) 8.1),
6.36 (dd, 1, J ) 15.7, 1.5), 6.09 (dq, 1, J ) 15.7, 6.6), 5.09 (d,
1, J ) 8.8), 3.81 (s, 3), 3.40 (dq, 1, J ) 8.8, 6.8), 1.86 (dd, 3, J
) 6.6, 1.6), 1.39 (d, 3, J ) 6.8); 13C NMR 159.6, 158.3, 132.6,
132.4, 131.2, 130.7, 127.6, 126.3, 123.0, 120.7, 114.0, 109.3,
92.6, 55.3, 45.2, 18.4, 17.8; IR (neat) 1612, 1515, 1486, 1241.
Syn th esis of Con oca r p a n (22). n-Butyllithium (2.5 M in
hexane, 0.06 mL, 0.15 mmol) was added dropwise to a solution
of diphenylphosphine (0.02 mL, 0.12 mmol) in THF (0.2 mL)
under N2 at 0 °C. The solution was stirred at 0 °C for 30 min,
and 21 (10 mg, 0.035 mmol) in 0.1 mL of THF was added. The
mixture was warmed to rt and stirred at rt for 4 h. NaOH
solution (2 N, 5 mL) was added, and the solution was extracted
with hexane (3 × 3 mL) which was dried (MgSO4), and
concentrated. Flash chromatography of the residue on silica
gel (50:1 hexane/EtOAc) gave 0.6 mg (6%) of recovered 21. The
basic aqueous layer was cooled in an ice bath and acidified by
4 N HCl solution to pH ) 3-4. The cloudy solution was
extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were washed with saturated NaCl solution, dried (Na2-
SO4), and concentrated. Flash chromatography of the residue
on silica gel provided 7.8 mg (84%) of 22: 1H NMR 7.30 (dt, 2,
J ) 8.6, 2.0), 7.14 (s, 1), 7.12 (d, 1, J ) 8.3), 6.83 (dt, 2, J )
8.6, 2.0), 6.76 (d, 1, J ) 8.3), 6.37 (dd, 1, J ) 15.7, 1.6), 6.09
(dq, 1, J ) 15.7, 6.6), 5.09 (d, 1, J ) 8.8), 4.95 (s, 1, OH), 3.39
(dq, 1, J ) 8.8, 6.8), 1.86 (dd, 3, J ) 6.6, 1.6), 1.39 (d, 3, J )
6.8); 13C NMR 158.2, 155.6, 132.9, 132.3, 131.2, 130.7, 127.9,
126.3, 123.0, 120.7, 115.4, 109.3, 92.6, 45.2, 18.4, 17.8; IR (neat)
3394 (OH), 1613, 1605, 1516, 1486, 1239.
(15a b), followed by 1 mg (1%) of a 1:1 mixture of 2,3-dihydro-
2-hexylbenzofuran-7-yl acetate (33a b) and 2-(2-octenyl)-2-
cyclohexenone (38a b ), and 21 mg (27%) of 6-acetoxy-2-
cyclohexen-1-one (4a ).25
The data for 15a b: 1H NMR 7.14 (br d, 1, J ) 7.3), 7.09 (br
dd, 1, J ) 8.0, 7.4), 6.81 (br dd, 1, J ) 7.4, 7.3), 6.76 (br d, 1,
J ) 8.0), 4.76 (m, 1), 3.26 (dd, 1, J ) 15.4, 9.0), 2.85 (dd, 1, J
) 15.4, 7.9), 1.85-1.25 (m, 10), 0.89 (t, 3, J ) 6.7); 13C NMR
159.6, 127.9, 127.0, 124.9, 120.0, 109.2, 83.4, 36.1, 35.5, 31.8,
29.2, 25.4, 22.6, 14.1; IR (neat) 1599, 1482, 1233, 749.
Oxid a tion of 5-Meth yl-2-cycloh exen on e (1e). A solution
of 1e (93 mg, 0.85 mmol) and Mn(OAc)3‚2H2O (679 mg, 2.54
mmol) in 8 mL of HOAc was stirred at 80 °C for 5 h. Workup
as described above for the oxidation of 1a and 7b in HOAc
provided 63 mg (44%) of 6-acetoxy-5-methyl-2-cyclohexenone
(4e) as a 1:1 trans/cis mixture in the organic layer and 39 mg
(20%) of a 4:1 mixture of 27a and 28b (2-acetoxy-4-methyl-
hexanedioic acid) in the water layer. Flash chromatography
of 4e gave 5 mg of pure trans-4e followed by a mixture of
isomers.
The data for trans-4e: 1H NMR 6.95 (ddd, 1, J ) 10.1, 6.1,
2.0), 6.06 (dd, 1, J ) 10.1, 2.0), 5.11 (d, 1, J ) 12.7), 2.58 (ddd,
1, J ) 18, 6.2, 3.1), 2.51-2.26 (m, 2), 1.55 (s, 3), 1.11 (d, 3, J
) 6.1); 13C NMR 193.8, 170.4, 149.1, 128.3, 79.1, 35.7, 34.4,
20.8, 19.1.
The data for cis-4e: 1H NMR 6.85 (dddd, 1, J ) 10.0, 5.4,
2.7, 1.2), 6.05 (ddd, 1, J ) 10.0, 2.7, 2.7), 5.51 (d, 1, J ) 3.8),
2.80 (dddd, 1, J ) 19.2, 5.4, 2.7, 2.7), 2.63-2.52 (m, 1), 2.36
(br d, 1, J ) 19.2); 13C NMR 193.8, 170.4, 147.5, 128.3, 79.1,
33.6, 33.0, 21.1, 13.2.
The data for 27a : 1H NMR 9.60-9.00 (br s, 2, OH), 5.08
(dd, 1, J ) 10.4, 3.4), 2.39 (dd, 1, J ) 15.3, 6.3), 2.30 (dd, 1, J
) 15.3, 7.2), 2.22-2.00 (m, 1), 2.09 (s, 3), 1.97 (ddd, 1, J )
14.2, 10.4, 4.2), 1.79 (ddd, 1, J ) 14.2, 9.5, 3.4), 1.04 (d, 3, J )
6.4); 13C NMR 179.5, 175.9, 170.8, 70.0, 41.4, 37.1, 26.7, 20.8,
18.9; IR (neat) 3471, 1726, 1377, 1232, 1075, 937.
Partial data for 27b: 1H NMR 5.06 (dd, 1, J ) 8.1, 5.5),
1.06 (d, 3, J ) 6.5).
Ester ifica tion of 27. A solution of diazomethane in ether
was added to 27 (39 mg, 0.20 mmol). The mixture was stirred
and evaporated to provide 43 mg (99%) of a 4:1 mixture of 28a
and 28b.
The data for 28a : 1H NMR 5.06 (dd, 1, J ) 10.5, 3.5), 3.75
(s, 3), 3.68 (s, 3), 2.34 (dd, 1, J ) 14.8, 6.2), 2.23 (dd, 1, J )
14.8, 7.4), 2.16-2.06 (m, 1), 2.15 (s, 3), 1.92 (ddd, 1, J ) 14.2,
10.5, 4.3), 1.71 (ddd, 1, J ) 14.2, 9.4, 3.4), 1.00 (d, 3, J ) 6.5);
13C NMR 172.7, 170.8, 170.5, 70.3, 52.3, 51.5, 41.5, 37.4, 26.8,
20.6, 18.8; IR (neat) 1732, 1438, 1373, 1224, 1082, 1009.
Partial data for 28b: 1H NMR 5.03 (dd, 1, J ) 8.1, 5.5),
3.75 (s, 3), 3.67 (s, 3), 1.02 (d, 3, J ) 6.7).
Oxid a tive Cycloa d d ition of 2-Hyd r oxy-1,4-n a p h th o-
qu in on e (49) w ith 7a in HOAc. Mn(OAc)3‚2H2O (890 mg,
3.32 mmol), 49 (144 mg, 0.83 mmol), and 7a (180 mg, 1.87
mmol) were stirred in 8 mL of HOAc at 80 °C for 15 h. Normal
1
workup gave 137 mg (95%) of 50: mp 189-200 °C; H NMR
8.09-8.05 (m, 2), 7.75-7.63 (m, 2), 2.96 (s, 2), 1.89-1.49 (m,
10); 13C NMR 182.7, 178.4, 159.2, 134.0, 133.1, 132.8, 131.6,
126.2, 125.9, 123.3, 94.2, 38.0, 37.0, 24.7, 22.7; IR (KBr) 1682,
1639, 1622, 1593.
Ack n ow led gm en t. Financial assistance provided by
the National Institutes of Health is gratefully acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for other oxidative cycloadditions in HOAc, and 1H
and 13C NMR spectra for new compounds (64 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Oxid a tive Cycloa d d ition of 2-Cycloh exen on e (1a ) w ith
1-Octen e (7b) in HOAc. A solution of 1a (48 mg, 0.50 mmol),
7b (84 mg, 0.75 mmol), and Mn(OAc)3‚2H2O (536 mg, 2.00
mmol) in 5 mL of HOAc was stirred under N2 at 80 °C for 16
h. Water (20 mL) and saturated NaHSO3 solution (10 mL)
were added, and the mixture was extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were washed with
saturated NaHCO3 solution, dried (Na2SO4), and concentrated
in vacuo to provide 138 mg of crude product, which was
purified by flash chromatography on silica gel (20:1 hexane/
EtOAc) to yield 25 mg (24%) of 2,3-dihydro-2-hexylbenzofuran
J O9708506
(25) Rubottom, G. M.; Gruber, J . M. J . Org. Chem. 1978, 43, 1599.