Cycloaddition-Rearrangement Sequence of 2-Amido Substituted Furans as a Method of Synthesizing Hexahydroindolinones

Article abstract of DOI:10.1021/jo982061+

A convenient synthesis of various substituted hexahydroindolinones has been achieved by an intramolecular Diels-Alder cycloaddition (IMDAF) reaction of 2-amido substituted furans. The initially formed [4 + 2] cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation of the resulting zwitterion to give the rearranged ketone. The stereochemical outcome of the IMDAF cycloaddition has the sidearm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. The reaction rate and product yield were found to be markedly dependent upon the electronic properties of the alkenyl π-bond. 2-[2-(tert-Butoxycarbonylfuran-2-yl-amino)-ethyl]acrylic acid methyl ester was synthesized from 3-chlorocarbonyl-but-3-enoic acid methyl ester. Thermolysis of the carbomethoxy activated furanamide occurred at 80 °C to produce a rearranged hexahydroindolinone. When Me₃Al or (MeO)₃Al was used as a Lewis acid to promote the cycloaddition, a rearranged alcohol was obtained. The initially formed [4 + 2] cycloadduct undergoes ring opening in the presence of the Lewis acid, and the resulting aluminum intermediate delivers the substituent group from the same face as the neighboring oxygen to ultimately furnish a rearranged cis-alcohol. In contrast to this result, a mixture of diastereomeric methoxy alcohols was isolated when the IMDAF cycloaddition was carried out in methanol. The major isomer corresponds to the trans-diastereomer that results from trapping of the iminium ion from the less crowded face of the π-bond.

Full text of DOI:10.1021/jo982061+

J . Org. Chem. 1999, 64, 4617-4626
4617
Cycloa d d ition -Rea r r a n gem en t Sequ en ce of 2-Am id o Su bstitu ted
F u r a n s a s a Meth od of Syn th esizin g Hexa h yd r oin d olin on es
Albert Padwa,* Michael A. Brodney,† Kyosuke Satake, and Christopher S. Straub‡
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received October 13, 1998
A convenient synthesis of various substituted hexahydroindolinones has been achieved by an
intramolecular Diels-Alder cycloaddition (IMDAF) reaction of 2-amido substituted furans. The
initially formed [4 + 2] cycloadduct undergoes nitrogen-assisted ring opening followed by
deprotonation of the resulting zwitterion to give the rearranged ketone. The stereochemical outcome
of the IMDAF cycloaddition has the sidearm of the tethered alkenyl group oriented syn with respect
to the oxygen bridge. The reaction rate and product yield were found to be markedly dependent
upon the electronic properties of the alkenyl π-bond. 2-[2-(tert-Butoxycarbonylfuran-2-yl-amino)-
ethyl]acrylic acid methyl ester was synthesized from 3-chlorocarbonyl-but-3-enoic acid methyl ester.
Thermolysis of the carbomethoxy activated furanamide occurred at 80 °C to produce a rearranged
hexahydroindolinone. When Me3Al or (MeO)3Al was used as a Lewis acid to promote the
cycloaddition, a rearranged alcohol was obtained. The initially formed [4 + 2] cycloadduct undergoes
ring opening in the presence of the Lewis acid, and the resulting aluminum intermediate delivers
the substituent group from the same face as the neighboring oxygen to ultimately furnish a
rearranged cis-alcohol. In contrast to this result, a mixture of diastereomeric methoxy alcohols
was isolated when the IMDAF cycloaddition was carried out in methanol. The major isomer
corresponds to the trans-diastereomer that results from trapping of the iminium ion from the less
crowded face of the π-bond.
The hexahydroindolinone nucleus is a structural fea-
ture found in a wide variety of alkaloids,1 including the
strychnos,2 amaryllidaceae,3 and aspidosperma4 families.
These alkaloids possess diverse physiological properties5
as well as structural complexity and have attracted the
interest of many synthetic chemists.6 Strategies to pre-
pare the hexahydroindolinone skeleton include [4 + 2]
cycloadditions,7 sigmatropic rearrangements,8 Pummerer-
induced cyclizations,9 intramolecular condensation of
amines onto carbonyl compounds,10 1,3-dipolar cyclo-
additions,11 reaction of isocyanates with isocyanides,12
and transition metal mediated cyclization reactions.13
Despite the availability of many synthetic methods, there
still exists a need to develop more efficient procedures
than those currently in existence.
In our approach to the hexahydroindolinone core unit,
we chose to explore the ring opening reaction of an aza-
substituted oxabicyclo[2.2.1]heptene derivative.14 Oxabi-
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† Recipient of a Graduate Fellowship from the Organic Chemistry
Division of the American Chemical Society (1997-1998), sponsored
by Dupont Merck Pharmaceutical Co.
‡ Author to whom correspondence regarding X-ray crystallographic
determinations should be directed.
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10.1021/jo982061+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/03/1999

4618 J . Org. Chem., Vol. 64, No. 13, 1999
Padwa et al.
Sch em e 1
cyclic compounds are known to be valuable intermedi-
ates15 for the synthesis of a variety of molecules of
biological interest.16 A crucial transformation in many
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the cleavage of the oxygen bridge to produce functional-
ized cyclohexane or cycloheptane derivatives.17 To this
end, many groups have developed different solutions,
including â-eliminations of suitable derivatives,18 treat-
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functionalities, such as Cl or SO2Ph,20 fragmentation,21
and hydrolytic conditions.22 Our interest in the ring
opening of these oxabicyclic compounds was stimulated
by earlier studies in our laboratory dealing with the
Rh(II)-catalyzed reaction of diazoimides (e.g., 4).23 We
found that this reaction induces formation of an iso-
mu¨nchnone dipole (i.e., 5) by intramolecular cyclization
of the rhodium carbenoid onto the neighboring carbonyl
oxygen (Scheme 1). The resultant mesoionic ylide is
trapped by various alkenyl π-bonds to give cycloadducts
of type 6 in high yield.24 These uniquely functionalized
oxabicyclic cycloadducts contain a “masked” N-acyl-
iminium ion which can be released by treatment with a
Lewis acid. With an internal nucleophile incorporated on
Sch em e 2
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the tether, annulation of the original cycloadduct 6 allows
for the construction of complex azapolycyclic ring sys-
tems, such as 7.25
As an extension of this work, we undertook a study
dealing with the intramolecular Diels-Alder reaction
(IMDAF)26 of the related 2-amidofuran system (i.e., 8).
The initially formed [4 + 2] oxabicyclic adduct 11 was
found to undergo a related nitrogen-assisted ring open-
ing, and this was followed by a subsequent hydrogen shift
of the resulting zwitterion 12 to give the hexahydro-
indolinone ring system (Scheme 2).14 To better under-
stand the scope and stereoselectivity of this novel reac-
tion, we chose to explore the cycloaddition-ring opening
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123.

Cycloaddition-Rearrangement Sequence
J . Org. Chem., Vol. 64, No. 13, 1999 4619
Sch em e 3
sequence in greater detail. In this paper, we report the
results of our model studies that demonstrate that the
IMDAF cycloaddition of 2-amidofurans represents a
convenient method to synthesize hexahydroindolinones.
Resu lts a n d Discu ssion
We began our investigation of the intramolecular [4 +
2] aminofuran cycloaddition reaction by studying the
thermal behavior of N-alkenyl furanyl carbamates 8-10
that contain an unactivated π-bond on the tether. At-
tachment of the alkenyl group was accomplished by
treating the appropriate NH-carbamate with base fol-
lowed by the addition of either 4-bromo-2-methyl-1-
butene or 5-bromo-2-methyl-1-pentene. The IMDAF cy-
cloaddition was performed by heating a solution of the
carbamate in benzene in a sealed tube at 165-200 °C
for 14-36 h. In all three cases, the only products isolated
corresponded to the rearranged ketones 13-15 in 71, 90,
and 68% yield, respectively. The isolation of the hexahy-
droindolinone ring system from this reaction is in full
agreement with the proposed cycloaddition/ring opening/
rearrangement sequence outlined in Scheme 2.
Our previous studies dealing with the bimolecular [4
+ 2] cycloadditions of 2-amino substituted furans have
shown that the reaction rates and product yields are
markedly dependent upon the electronic properties of the
alkenyl group.27 Because electron-withdrawing substit-
uents on the π-bond exhibit a powerful influence on the
rate of HOMO-dienyl [4+2] cycloadditions,28 the synthe-
sis of a 2-carbomethoxy substituted olefinic carbamate,
such as 19 or 20, appeared to us to be a worthwhile goal.
In addition to facilitating the IMDAF cycloaddition by
modulation of the electronic properties of the π-bond, the
carbomethoxy group also provides a handle by which a
number of hexahydroindolinone derivatives may be pre-
pared and studied. As was pointed out earlier, the general
procedure used for the synthesis of N-alkenyl substituted
furanyl carbamates involves alkylation using a primary
bromide. Unfortunately, the alkylation method utilized
for the methyl-substituted alkenyl bromides was not
successful when applied to 4-bromo-2-carbomethoxy-1-
butene (18). Under a variety of conditions, the reaction
of the anion of carbamate 16 (or 17) with bromide 18
failed to produce the desired furan 19 (or 20). Apparently,
problems associated with both conjugate addition and
halide elimination became major drawbacks with this
approach.
Protection of the carboxylic acid group as an ortho ester
has proven to have advantages in a variety of synthe-
ses.30-32 Thus, we felt that mesylate 24 would be an
excellent synthetic equivalent to bromide 18, especially
since this substrate would not undergo conjugate addition
and/or elimination to carbomethoxy-1,3-butadiene. After
the typical Corey procedure was used,29 the known acid
chloride 2133 was converted into trioxabicyclooctane
(OBO) ortho ester 22 by esterification with 3-methyl-
oxetane-3-methanol followed by rearrangement using
boron trifluoride etherate (Scheme 3). LAH reduction of
22 gave alcohol 23, which was somewhat sensitive toward
acid and furnished ortho ester 25 when allowed to stand
under acidic conditions. More than likely, alcohol 23
reacts with the available acid to produce a ring-opened
tertiary allylic cation that is trapped by the neighboring
homoallylic alcohol to afford 25. In the absence of acid,
however, 23 was readily transformed into mesylate 24
in 93% yield. Treatment of 24 with the anion derived
from the NH-carbamate 16 or 17 furnished the OBO-
protected furans 26 and 27 in excellent yield. Methan-
olysis of the ortho ester group was carried out in
methanol with 0.1 equiv of pyridinium p-toluenesulfonate
(PPTS) followed by the addition of 1.1 equiv of potassium
carbonate.34 After these conditions were used, the desired
furanyl carbamates 19 and 20 were isolated in high yield.
In the case of the tert-butyl carbamate 26, addition of
potassium carbonate to the methanolic solution is neces-
sary, otherwise the intermediate 2,2-bis(hydroxymethyl)-
propyl ester was isolated from the reaction.30
To test the importance of dienophile activation, we
compared the rate of the IMDAF cycloadditions of
(30) Richardson, S. K.; J eganathan, A.; Watt, D. S. Tetrahedron Lett.
1987, 28, 2335.
(31) Corey, E. J .; Desai, M. C.; Engler, T. A. J . Am. Chem. Soc. 1985,
107, 4339.
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Spilling, C. D. J . Org. Chem. 1990, 55, 2409. Winkler, J . D.; Scott, R.
D.; Williard, P. G. J . Am. Chem. Soc. 1990, 112, 8971. Keinan, E.;
Sinha, S. C.; Singh, S. P. Tetrahedron, 1991, 47, 4631.
(33) Baker, B. R.; Schaub, R. E.; Williams, J . H. J . Org. Chem. 1952,
17, 116.
(34) Corey, E. J .; Shih, C.; Shih, N. Y.; Shimoji, K. Tetrahedron Lett.
1984, 25, 5013. J ones, R. C. F.; Schofield, J . J . Chem. Soc., Perkin
Trans. 1 1990, 375.
Of the alternate methods considered for the synthesis
of carbamate 19 or 20, the Corey method for carboxylic
acid protection seemed best suited for our purposes.29
(27) Padwa, A.; Kappe, C. O.; Cochran, J . E.; Snyder, J . P. J . Org.
Chem. 1997, 62, 2786. Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu,
T. J . Org. Chem. 1997, 62, 4088.
(28) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(29) Corey, E. J .; Raju, N. Tetrahedron Lett. 1983, 24, 5571. Corey,
E. J .; De, B. J . Am. Chem. Soc. 1984, 106, 2735.

4620 J . Org. Chem., Vol. 64, No. 13, 1999
Padwa et al.
Sch em e 4
a 1:3 mixture of the cis- and trans-methoxy alcohols 33
and 34 was obtained in 85% yield. The structure of the
trans alcohol 34 was based in part on the large coupling
constant (J ) 7.2 Hz) between the C4 and C5 hydrogens.
Further support for its assignment was obtained from a
single-crystal X-ray analysis of the 3,5-dibromo benzoate
ester.37 A similar distribution of alcohols was also ob-
served when benzyl alcohol was used as the solvent. In
this case, compounds 35 and 36 were produced as a 1:3
mixture in 80% overall yield. Control experiments dem-
onstrated that the two diastereomeric alcohols were not
interconverted on extended heating. Mechanistically,
these results can be explained in terms of a ring-opening
reaction of the [4 + 2] oxabicyclic adduct and subsequent
trapping of the zwitterionic intermediate (e.g., 12) with
the solvent from either the R- or â-face. The preferred
mode of attack takes place on the side opposite the
alcohol functionality that corresponds to the less-
congested face of the π-bond.
Intramolecular Diels-Alder reactions where the tether
connecting the diene and dienophile consists of three
carbon atoms have been extensively studied.38,39 How-
ever, this internal cycloaddition reaction is not as simple
as it might appear.40 In many cases, it is neither purely
kinetically controlled nor thermodynamically controlled.
Indeed, with certain systems, the reaction can be revers-
ible and is capable of giving a mixture of endo and exo
products.41 To account for the stereochemical results, it
becomes necessary to consider not only the relative
stabilities of the endo and exo products and the stabilizing
effect of FMO overlap on the transition state42 but also
the ability of the connecting chain to fold into the
required conformation necessary for the cycloaddition to
proceed. The stereochemical results that we have en-
countered with the IMDAF cycloaddition of 2-amidofuran
19 is consistent with that reported by others for related
furanyl systems possessing short tethers.43,44 The ring-
opened alcohols (i.e., 32-36) are derived from an IMDAF
furanamides 8, 26, and 19. The temperature and time
required for the reaction of 26 (165 °C) and yield of the
resulting hexahydroindolinone 30 were similar to that
encountered with the methyl-substituted systems (i.e.,
13). Incorporation of the carbomethoxy substituent on the
alkenyl π-bond, on the other hand, greatly facilitated the
cycloaddition (80 °C, 6 h) that afforded ketones 28 and
29 in 87% and 80% yield, respectively. This result is to
be expected since placement of an electron-withdrawing
substituent on the π-bond lowers the LUMO energy of
the dienophile and enhances the rate of the [4 + 2]
cycloaddition.28 Most interestingly, when a Lewis acid
such as Me2AlCl was used to promote the cycloaddition,35
it was possible to carry out the reaction at temperatures
as low as 25 °C. In this case, the only product isolated
(40%) corresponded to the rearranged alcohol 32. The
yield of 32 was significantly increased (82%) when a
trimethylaluminum/toluene solution was used to promote
the cycloaddition. We suspect that the initially formed
[4 + 2] cycloadduct undergoes a Lewis acid assisted ring
opening, and the resulting intermediate 31 delivers a
methyl group from the same face as the neighboring
oxygen to ultimately furnish the cis-alcohol 32 (Scheme
4).36
For comparison purposes, we have also carried out the
IMDAF cycloaddition of furanamide 19, using 2 equiv of
(MeO)3Al in benzene at 65 °C. Under these conditions,
cis-methoxy alcohol 33 was obtained as the major product
(80%) together with lesser quantities of ketone 28 (10%)
(Scheme 4). The structure and stereochemistry of 33 was
unequivocally established by a single-crystal X-ray analy-
sis of its 3,5-dibromo benzoate ester.37 Interestingly, when
the thermolysis of 19 was carried out in MeOH at 65 °C,
(38) Ciganek, E. Org. React. 1984, 32, 1. Fallis, A. G. Can. J . Chem.
1984, 62, 183.
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Chem. Soc. 1991, 113, 4241. Roush, W. R.; Gillis, H. R.; Ko, A. I. J .
Am. Chem. Soc. 1982, 104, 2269. Breiger, G.; Bennet, J . N. Chem. Rev.
1980, 80, 63. J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113,
224. J ung, M. E.; Truc, V. C. Tetrahedron Lett. 1989, 29, 6059. Sauer,
J .; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 779.
(40) J ung, M. Synlett 1990, 4, 186. J ung, M. E.; Gervay, J .
Tetrahedron Lett. 1988, 29, 2949. J ung, M. E.; Gervay, J . J . Am. Chem.
Soc. 1989, 111, 5469.
(41) Rogers, C. Synlett 1991, 5, 353. Houk, K. N.; Paddon-Row, M.
N.; Rondan, N. G.; Wu, Y.; Brown, F. K.; Spellmeyer, D. C.; Metz, J .
T.; Li, Y.; Loncharich, R. J . Science 1986, 231, 1108. Boeckman, R. K.,
J r.; Ko, S. S. J . Am. Chem. Soc. 1981, 46, 2273. Dewar, M. J . S.; Pierini,
A. B. J . Am. Chem. Soc. 1984, 106, 209.
(35) Fraile, J . M.; Garc´ıa, J . I.; Gracia, D.; Mayoral, J . A.; Pires, E.
J . Org. Chem. 1996, 61, 9479.
(36) The trans relationship between the carbomethoxy and hydroxyl
groups of 32 was assigned by comparison of its NMR properties with
those of related compounds whose structures were established by X-ray
crystallography.
(37) The authors have deposited atomic coordinates for the 3,5-
dibromobenzoate esters of alcohols 33 and 34 as well as compound 40
with the Cambridge Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, CB2 1EZ, U.K.
(42) Fukui, T. Angew. Chem., Int. Ed. Engl. 1982, 21, 801.
(43) Woo, S.; Keay, B. Tetrahedron: Asymmetry 1994, 5, 1411.
Rogers, C.; Keay, B. A. Tetrahedron Lett. 1991, 32, 6477. Rogers, C.;
Keay, B. A. Synlett 1991, 353. Rogers, C.; Keay, B. A. Can. J . Chem.
1992, 70, 2929.

Cycloaddition-Rearrangement Sequence
J . Org. Chem., Vol. 64, No. 13, 1999 4621
Sch em e 5
F igu r e 1. Exo transition state for IMDAF cycloaddition of
2-amidofuran 19.
cycloaddition where the sidearm of the tethered alkenyl
group is oriented syn (exo) with respect to the oxygen
bridge (Figure 1). Products resulting from an endo
sidearm transition state were neither detected nor iso-
lated. This result is not so surprising since, in these
mobile cycloaddition equilibria, the exo adducts are
expected to be thermodynamically more favored. We have
used the Still-Steliou model program to model energy
differences in the transition state for the IMDAF cyclo-
addition of 2-amidofuran 19. The transition-state geom-
etry was approximated by fixing the distance between
Sch em e 6
the reacting centers of the furan and alkene to be 3.0 (
1.0 Å. A Boltzmann distribution of the various conformers
of the fixed transition state was obtained from the
Bakmdl output. We assume that the relative energy
conformation of the starting furan and “approximated”
cycloadduct will parallel the activation energy of the
reaction. The calculations show that the energy difference
is ca. 10 kcal lower for the exo adduct, which is in accord
with the experimental findings.
In all of the above examples, products were derived
from an oxabicyclic intermediate that either undergoes
deprotonation or reacts with an external nucleophile. In
the next phase of our study, we investigated the effect of
placing an alkyl or aryl group at the 5-position of the
furan ring since it was not at all clear what would happen
on blocking the deprotonation reaction. One possibility
would involve a [1,2]-alkyl or aryl shift proceeding from
the zwitterionic intermediate 41 (Scheme 5). We found,
however, that the reaction pathway changed quite dra-
matically by replacing the hydrogen atom with a sub-
stituent group in the 5-position of the furan ring. Thus,
when furans 37 and 38 were subjected to the IMDAF
cycloaddition in benzene, tetrahydro-2H-indoles 39 and
40 were isolated in 89% and 82% yield, respectively. No
signs of a rearranged hexahydroindolinone (i.e., 42) could
be detected in the crude reaction mixture by NMR
analysis. In the case of 40, its stereochemistry was
established from a single-crystal X-ray analysis that
clearly fixes the syn relationship of the methyl and aryl
groups. The isolation of a single diastereomer from this
reaction is consistent with the exo-mode of cycloaddition.
In contrast to this result, when the IMDAF cycloaddition
of 37 was carried out in methanol, the expected ring-
opened methoxy alcohol 43 was isolated as a 2:1 mixture
of diastereomers in 76% yield. Formation of the tetrahy-
dro-2H-indole ring system from the benzene thermolysis
suggests that fragmentation of the t-Boc group to give
isobutylene and CO2 proceeds at a faster rate than either
an alkyl or aryl group shift. Interestingly, when 39 was
treated with methyl iodide followed by an aqueous
workup, azabicyclo[3.2.2]nonanone 45 was obtained in
90% yield. This novel sequence of reactions, whereby
furan 37 is transformed into 45 in 81% overall yield, can
be rationalized by the hydrolysis of the iminium ion
derived from the methylation step followed by an intra-
molecular Michael addition across the resulting cyclo-
hexenone intermediate 44 (Scheme 6).
(44) De Clercq, P. J .; Van Royen, L. A. Synth. Commun. 1979, 9,
771. Van Royen, L. A.; Mijngheer, R.; De Clercq, P. J . Bull. Soc. Chim.
Belg. 1984, 93, 1019. Fischer, K.; Hunig, S. J . Org. Chem. 1987, 52,
564.

4622 J . Org. Chem., Vol. 64, No. 13, 1999
Padwa et al.
NMR (CDCl3, 400 MHz) δ 1.28 (t, 3H, J ) 7.2 Hz), 4.21 (q,
2H, J ) 7.2 Hz), 6.06 (s, 1H), 6.33 (dd, 1H, J ) 3.2 and 2.0
Hz), 7.06 (s, 1H), and 7.14 (s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 14.6, 62.0, 95.4, 111.5, 136.4, 145.2, and 153.1. HRMS Calcd
for C7H9NO3: 155.0582. Found: 155.0577.
In conclusion, this paper describes a versatile new
approach toward hexahydroindolinones that contain
various substitution patterns. The synthetic procedure
described herein involves an intramolecular Diels-Alder
reaction of 2-amidofurans containing a tethered alkenyl
group on the nitrogen atom. The initially formed [4 + 2]
cycloadduct undergoes a nitrogen-assisted ring opening
followed by a subsequent deprotonation of the resulting
zwitterionic intermediate to give the rearranged ketone.
The ability to carry out the domino cascade with Lewis
acid catalysts at room temperature makes this reaction
even more useful for the synthesis of complex nitrogen-
containing natural products. Further applications of this
cycloaddition approach toward several alkaloids are in
progress and will be reported in due course.
To solution containing containing 2.3 g (15 mmol) of car-
bamate 17, 2.1 g (53 mmol) of powdered sodium hydroxide,
4.2 g (30 mmol) of potassium carbonate, 1.0 g (3.0 mmol) of
tetrabutylammonium hydrogen sulfate in 250 mL of benzene
was heated at reflux for 30 min, and then 4.5 g (30.2 mmol) of
4-bromo-2-methyl-1-butene in 10 mL of benzene was added
dropwise to the solution. The mixture was heated for an
additional 5 h, quenched with 200 mL of H2O, and extracted
with CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The solvent
was removed under reduced pressure, and the residue was
purified by silica gel chromatography to give 2.4 g (71%) of 9
as a colorless oil: IR (neat) 2982, 1723, 1652, 1616, and 1452
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.22 (t, 3H, J ) 6.8 Hz),
Exp er im en ta l Section
1.72 (s, 3H), 2.26 (t, 2H, J ) 6.8 Hz), 3.70 (t, 2H, J ) 6.8 Hz),
4.16 (q, 2H, J ) 6.8 Hz), 4.69 (d, 1H, J ) 0.8 Hz), 4.76 (s, 1H),
6.03 (brs, 1H), 6.35 (dd, 1H, J ) 3.2 and 2.4 Hz), and 7.19 (d,
1H, J ) 0.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.6, 22.6, 36.7,
47.6, 62.3, 102.6, 111.1, 112.1, 138.7, 142.6, 148.0, and 155.0.
Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found:
C, 64.71; H, 7.73; N, 6.12.
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using an ethyl
acetate/hexane mixture as the eluent unless, specified other-
wise. All solids were recrystallized from ethyl acetate/hexane
for analytical data.
Eth yl 3a -Meth yl-5-oxo-2,3,3a ,4,5,6-h exa h yd r oin d ol-1-
ca r boxyla te (14). A 0.8 g (3.4 mmol) sample of carbamate 9
in 10 mL benzene in a sealed tube was heated at 165 °C for
14 h. The solution was concentrated under reduced pressure
after cooling to room temperature, and the residue was purified
by flash silica gel chromatography to give 0.7 g (90%) of ketone
14 as a white solid: mp 48-49 °C; IR (KBr) 2974, 1716, 1665,
and 1464 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.06 (s, 3H), 1.30
(t, 3H, J ) 6.8 Hz), 1.79-1.83 (m, 2H), 2.45 (d, 1H, J ) 14.2
Hz), 2.54 (d, 1H, J ) 14.2 Hz), 2.94 (s, 1H), 2.95 (d, 1H, J )
1.2 Hz), 3.61 (q, 1H, J ) 9.6 Hz), 3.83 (m, 1H), 4.19 (q, 2H, J
) 6.8 Hz), and 5.99 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ
14.8, 23.7, 36.7, 37.6, 43.1, 46.6, 52.8, 61.6, 97.9, 144.4, 153.4,
and 210.1. Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N,
6.27. Found: C, 64.44; H, 7.68; N, 6.18.
Eth yl N-(4-Meth yl-p en t-4-en yl)-N-(2-fu r yl)ca r ba m a te
(10). To a solution containing 5.0 g (32 mmol) of carbamate
17 and 300 mL of a 4:1 DMF/THF mixture at room temper-
ature was added 21 g (64 mmol) of cesium carbonate. The
reaction mixture was stirred at room temperature for 45 min
and then charged with 10.5 g (64 mmol) of 5-bromo-2-methyl-
pent-1-ene.46 The mixture was heated at 70 °C for 6 h,
quenched with 50 mL of H2O, and extracted with ether. The
combined organic layers were dried over MgSO4 and concen-
trated under reduced pressure. The residue was subjected to
flash silica gel chromatography to give 7.0 g (91%) of 10 as a
clear oil: IR (neat) 2980, 1731, 1616, and 1506 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.23 (t, 3H, J ) 6.8 Hz), 1.69 (s, 3H), 1.71-
1.75 (m, 2H), 2.01 (t, 2H, J ) 7.6 Hz), 3.57 (t, 2H, J ) 7.6 Hz),
4.16 (q, 2H, J ) 6.8 Hz), 4.65-4.69 (m, 2H), 6.03 (brs, 1H),
6.34-6.35 (m, 1H), and 7.18-7.19 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 14.6, 22.5, 26.5, 34.8, 49.0, 62.3, 102.1, 110.4,
111.1, 138.7, 145.0, 148.2, and 155.2. Anal. Calcd for
ter t-Bu tyl N-(3-Meth yl-3-bu ten yl)-N-(2-fu r yl)ca r ba m -
a te (8). A 2.3 g (13 mmol) sample of furan-2-ylcarbamic acid
tert-butyl ester (16),27 4.0 g (13 mmol) of tetrabutylammonium
bromide, and 4.0 g (28 mmol) of 4-bromo-2-methyl-1-butene45
in 100 mL of CH2Cl2 at 0 °C was treated dropwise with a 50%
aqueous NaOH solution. The mixture was heated at reflux for
15 h, cooled to room temperature, and diluted with water, and
the aqueous phase was extracted with CH2Cl2. The combined
organic phase was washed with 3 N HCl, water, and brine
and was dried over sodium sulfate. The solvent was removed
under reduced pressure, and the residue was purified by silica
gel chromatography to give 2.5 g (79%) of 8 as a colorless oil:
1
IR (neat) 3403, 2975, 2925, and 1716 cm-1; H NMR (CDCl3,
400 MHz) δ 1.45 (s, 9H), 1.74 (s, 3H), 2.27 (t, 2H, J ) 7.2 Hz),
3.67 (dd, 2H, J ) 9.2 and 6.0 Hz), 4.71 (s, 1H), 4.76 (s, 1H),
6.33 (brs, 1H), 7.14 (t, 1H, J ) 1.2 Hz), and 7.18 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 22.2, 28.0, 36.6, 46.9, 80.7, 100.9,
110.7, 111.8, 137.8, 142.3, 148.3, and 153.5. Anal. Calcd for
C
14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.93; H,
8.38; N, 5.60.
ter t-Bu t yl 3a -Met h yl-5-oxo-2,3,3a ,4,5,6-h exa h yd r oin -
d ol-1-ca r boxyla te (13). A 2.2 g (8.7 mmol) sample of car-
bamate 8 in 10 mL of benzene in a sealed tube was heated at
165 °C for 14 h. The solution was concentrated under reduced
pressure after cooling to room temperature, and the residue
was purified by flash silica gel chromatography to give 1.5 g
(71%) of ketone 13 as a white solid: mp 112-113 °C; IR (KBr)
3402, 2961, 1709, and 1388 cm-1 1H NMR (DMSO-d6, 400
;
MHz) δ 0.94 (s, 3H), 1.42 (s, 9H), 1.72 (m, 2H), 2.35 (d, 1H, J
) 14.6 Hz), 2.49 (d, 1H, J ) 14.6 Hz), 2.63 (dd, 1H, J ) 14.6
and 2.8 Hz), 2.89 (dd, 1H, J ) 14.6 and 4.8 Hz), 3.51 (m, 1H),
3.66 (m, 1H), and 5.78 (brs, 1H); 13C NMR (DMSO-d6, 100
MHz) δ 22.8, 27.7, 35.2, 36.7, 42.5, 46.1, 51.6, 79.6, 96.4, 143.7,
151.5, and 208.3. Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42;
N, 5.57. Found: C, 66.99; H, 8.38; N, 5.49.
C
13H19O3N: C, 65.80; H, 8.07; N, 5.90. Found: C, 66.05; H,
8.04; N, 5.67.
E t h yl 4a -Met h yl-6-oxo-3,4,4a ,5,6,7-h exa h yd r o-(2H )-
qu in olin e-1-ca r boxy-la te (15). A solution of 1.2 g (5 mmol)
of furan 10 in 13 mL of benzene was heated in a sealed tube
at 200 °C for 36 h. The solution was concentrated under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 0.8 g (68%) of 15 as a clear oil: IR
(KBr) 2932, 1716, 1467, 1410, and 1168 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.05 (s, 3H), 1.20 (t, 3H, J ) 7.2 Hz), 1.52-1.59
(m, 1H), 1.61-1.67 (m, 2H), 1.71-1.79 (m, 1H), 2.31 (dd, 1H,
J ) 13.6 and 1.6 Hz), 2.56 (d, 1H, J ) 13.6 Hz), 2.85-2.89 (m,
1H), 2.91 (d, 1H, J ) 3.2 Hz), 3.05 (dd, 1H, J ) 21.8 and 3.6
Eth yl N-(3-Meth yl-3-bu ten yl)-N-(2-fu r yl)ca r ba m a te (9).
A solution containing 19.0 g (142 mmol) of 2-furyl azide in 250
mL of ethanol was heated at reflux for 12 h. The solution was
concentrated under reduced pressure, and the residue was
purified by flash silica gel chromatography to give 17.6 g (80%)
of furan-2-ylcarbamic acid ethyl ester (17) as a white solid:
1
mp 27-28 °C; IR (neat) 3288, 1723, 1531, and 1260 cm-1; H
(45) Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M. A.;
Blackwell, C. M.; Anderson, L. G. J . Am. Chem. Soc. 1992, 114, 7375.
(46) Snider, B. B.; Walner, M. Tetrahedron 1989, 45, 3171.

Cycloaddition-Rearrangement Sequence
J . Org. Chem., Vol. 64, No. 13, 1999 4623
Hz), 4.10 (dq, 2H, J ) 7.2 and 0.8 Hz), 4.22-4.27 (m, 1H),
and 5.50 (t, 1H, J ) 3.6 Hz); 13C NMR (CDCl3, 100 MHz) δ
14.7, 21.5, 24.2, 39.3, 39.5, 39.6, 46.6, 54.0, 61.7, 116.9, 140.5,
155.7, and 208.3. HRMS Calcd for C13H19NO3: 237.1365.
Found: 237.1365.
δ 0.83 (s, 3H), 2.62 (t, 2H, J ) 7.2 Hz), 2.98 (s, 3H), 3.95 (s,
6H), 4.36 (t, 2H, J ) 6.8 Hz), 5.14 (s, 1H), and 5.58 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 14.6, 30.6, 31.7, 37.7, 69.1, 73.0,
107.0, 117.7, and 139.4. HRMS Calcd for C10H16SO5 (M -
CH2O): 248.0718. Found: 248.0725.
2-Meth ylen esu ccin ic Acid 4-Meth yl Ester 1-(2-Meth yl-
oxeta n -2-yl-m eth yl) Ester . To a solution containing 48 g (470
mmol) of 3-methyl-3-oxetanemethanol and 500 mL of CH2Cl2
at 0 °C was added 41 g (517 mmol) of pyridine. The mixture
was allowed to stir at 0 °C for 20 min, and then 70 g (430
mmol) of 3-chlorocarbonyl-but-3-enoic acid methyl ester (21)33
was added over a 30 min period. The reaction mixture was
allowed to stir at 0 °C for 4 h and was then quenched with
300 mL of H2O and extracted with CH2Cl2. The combined
organic extracts were dried over MgSO4 and concentrated
under reduced pressure. The crude residue was purified by
flash silica gel chromatography to give 71 g (77%) of the above
ester as a colorless oil: IR (neat) 2954, 1737, 1637, 1324, and
ter t-Bu tyl N-[3-(4-Meth yl-2,6,7-tr ioxa bicyclo[2.2.2]oct-
1-yl)-3-bu ten yl]-N-(2-fu r yl)ca r ba m a te (26). A solution con-
taining 1.0 g (5.5 mmol) of carbamate 16, 0.8 g (19 mmol) of
sodium hydroxide, 1.5 g (11 mmol) of potassium carbonate,
and 0.4 g (1.3 mmol) of tetrabutylammonium hydrogen sulfate
in 60 mL of benzene was heated at reflux for 20 min, and then
1.5 g (5.5 mmol) of mesylate 24 in 10 mL of benzene was added
dropwise to the solution. The mixture was heated for 2 h,
quenched with 100 mL of H2O, and extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 1.7 g (84%) of
26 as a white solid: mp 68-69 °C; IR (neat) 2975, 1702, 1616,
1403, 1360, and 1154 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.80
(s, 3H), 1.44 (s, 9H), 2.44 (t, 2H, J ) 7.6 Hz), 3.66-3.71 (m,
2H), 3.92 (s, 6H), 5.02 (s, 1H), 5.49 (s, 1H), 6.01 (brs, 1H), 6.31
(t, 1H, J ) 2.0 Hz), and 7.16 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ 14.6, 28.4, 30.5, 30.7, 48.6, 73.0, 81.1, 100.9, 111.0,
115.3, 138.1, 142.1, 148.8, 153.9, and 161.3. Anal. Calcd for
1
969 cm-1; H NMR (CDCl3, 400 MHz) δ 1.31 (s, 3H), 3.32 (s,
2H), 3.66 (s, 3H), 4.21 (s, 2H), 4.35 (d, 2H, J ) 6 Hz), 4.49 (d,
2H, J ) 6 Hz), 5.71 (s, 1H), and 6.34 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 21.2, 21.3, 37.7, 39.3, 52.2, 69.4, 79.5, 129.3, 133.6,
166.1, and 171.2. Anal. Calcd for C11H16O5: C, 57.89; H, 7.07.
Found: C, 57.70; H, 6.99.
3-(4-Meth yl-2,6,7-tr ioxabicyclo[2.2.2]oct-1-yl)-bu t-3-en o-
ic Acid Meth yl Ester (22). To a solution containing 32 g (138
mmol) of the above oxetane in 500 mL of CH2Cl2 at -10 °C
was added 4.9 g (105 mmol) of boron trifluoride diethyl
etherate. The reaction mixture was allowed to stir at -10 °C
for 15 h and was quenched at 0 °C with 14 g (138 mmol) of
triethylamine. The solution was concentrated under reduced
pressure, and the crude residue was purified by flash silica
gel chromatography to give 29 g (91%) of 22 as a white solid:
C19H27NO6: C, 62.45; H, 7.45; N, 3.83. Found: C, 62.18; H,
7.61; N, 3.73.
2-[2-(ter t-Bu toxycar bon yl-fu r an -2-yl-am in o)eth yl]acr yl-
ic Acid Meth yl Ester (19). To a solution containing 1.5 g
(4.1 mmol) of carbamate 26, 35 mL of methanol, and 0.5 mL
of H2O at room temperature was added 0.1 g (0.4 mmol) of
pyridinium p-toluenesulfonate. The mixture was stirred at
room temperature for 2 h, and to this solution was added 0.15
g (1.1 mmol) of potassium carbonate and the mixture was
stirred for an additional 2 h at room temperature. The solution
was quenched with H2O, extracted with ethyl acetate, dried
over MgSO4, and concentrated under reduced pressure. The
crude residue was purified by flash silica gel chromatography
to give 0.98 g (85%) of 19 as a colorless oil: IR (neat) 2975,
1716, 1609, 1531, 1445, and 1303 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.42 (s, 9H), 2.56 (t, 2H, J ) 6.8 Hz), 3.73 (s, 3H), 3.72
(t, 2H, J ) 6.8 Hz), 5.60 (d, 1H, J ) 1.2 Hz), 5.99 (brs, 1H),
6.19 (s, 1H), 6.32 (d, 1H, J ) 2.0 Hz), and 7.15 (d, 1H, J ) 1.2
Hz); 13C NMR (CDCl3, 100 MHz) δ 28.3, 31.8, 47.7, 52.0, 81.4,
101.2, 111.1, 127.3, 137.4, 138.1, 148.6, 153.9, and 167.3.
HRMS Calcd for C15H21NO5: 295.1420. Found: 295.1419.
When the above reaction was carried out without the
addition of potassium carbonate, the only product isolated
(100%) corresponded to 2-[2-(tert-butoxy-carbonyl-furan-2-yl-
amino)ethyl]acrylic acid 3-hydroxy-2-hydroxymethyl propyl
ester, which was obtained as a clear oil: IR (neat) 3490, 2967,
1725, 1613, and 1502 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.84
(s, 3H), 1.38 (s, 9H), 2.54 (t, 2H, J ) 6.8 Hz), 3.46 (bs, 2H),
3.52 (m, 4H), 3.70 (t, 2H, J ) 6.8 Hz), 4.19 (s, 2H), 5.61 (s,
1H), 5.95 (brs, 1H), 6.19 (s, 1H), 6.31 (s, 1H), and 7.15 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 17.1, 28.2, 32.0, 40.9, 47.6, 66.9,
67.2, 77.5, 81.6, 101.6, 111.1, 127.9, 137.2, 138.3, 148.3, 154.1,
and 167.3. Further treatment of this ester under the above
conditions gave furanyl carbamate 19.
mp 80-81 °C; IR (neat) 2961, 2868, 1751, 1445, and 1189 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 0.81 (s, 3H), 3.15 (s, 2H), 3.68
(s, 3H), 3.94 (s, 6H), 5.20 (s, 1H), and 5.65 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 14.6, 30.6, 37.3, 52.5, 68.9, 73.2, 106.8,
118.0, 137.8, and 171.9. Anal. Calcd for C11H16O5: C, 57.89;
H, 7.07. Found: C, 57.82; H, 7.02.
3-(4-Meth yl-2,6,7-tr ioxa bicyclo[2.2.2]oct-1-yl)-bu t-3-en -
1-ol (23). To a suspension of 9.7 g (256 mmol) of lithium
aluminum hydride in ether at 0 °C was slowly added 39 g (170
mmol) of ester 22. The reaction mixture was allowed to stir at
0 °C for 4 h and was slowly quenched at 0 °C with 5 mL of
H2O. The aluminum complex was broken up by the addition
of 5 mL of a 50% NaOH solution followed by 2.5 mL of H2O.
The organic layer was dried over sodium sulfate, and the
mixture was filtered and concentrated under reduced pressure
to provide 31 g (90%) of 23 as a colorless oil: IR (neat) 3487,
2876, 1652, 1467, and 1147 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 0.82 (s, 3H), 2.37 (brs, 1H), 2.44 (t, 2H, J ) 5.6 Hz), 3.72 (t,
2H, J ) 5.2 Hz), 3.95 (s, 6H), 5.10 (d, 1H, J ) 1.2 Hz), and
5.55 (d, 1H, J ) 1.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.6,
30.5, 35.3, 62.1, 73.0, 107.1, 117.3, 141.7. Anal. Calcd for
C
10H16O4: C, 59.98; H, 8.05. Found: C, 59.84; H, 7.94.
If alcohol 23 was allowed to stand for a period of time in
CDCl3 that contained a trace of DCl, it was slowly converted
into 8-methyl-4-methylene-1,6,10-trioxaspiro[4.5]-dec-8-yl-
methanol (25) in 85% yield: 1H NMR (CDCl3, 400 MHz) δ 0.73
(s, 3H), 2.63-2.65 (m, 2H), 3.30 (s, 1H), 3.62-3.65 (m, 2H),
3.77 (s, 2H), 3.98-3.94 (m, 4H), 5.13 (m, 1H), and 5.34 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ 17.1, 29.9, 34.4, 64.6, 64.8,
66.9, 67.9, 109.9, 115.3, and 145.7.
Meth a n esu lfon ic Acid 3-(4-Meth yl-2,6,7-tr ioxa bicyclo-
[2.2.2]oct-1-yl)-bu t-3-en yl Ester (24). To a 6.0 g (30 mmol)
sample of alcohol 23 in 100 mL of CH2Cl2 was added a mixture
of 3.3 g (33 mmol) of triethylamine in 200 mL of CH2Cl2 at 0
°C. To this solution was added 3.8 g (33 mmol) of methane-
sulfonyl chloride dropwise over a 10 min period. The reaction
mixture was allowed to stir at 0 °C for 6 h and was then
quenched at 0 °C with 150 mL of H2O and extracted with ether.
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure to give 7.72 g (93%) of
mesylate 24 as a white solid: mp 50-51 °C; IR (neat) 2947,
2876, 1716, 1628, and 1474 cm-1; 1H NMR (CDCl3, 400 MHz)
5-Oxo-2,3,5,6-t et r a h yd r o-4H-in d ole-1,3a -d ica r b oxylic
Acid N-ter t-Bu tyl Ester 3a -Meth yl Ester (28). A solution
of 0.1 g (0.3 mmol) of furan 19 in 10 mL of benzene was heated
at 80 °C for 6 h in a sealed tube. The solution was concentrated
under reduced pressure, and the residue was subjected to to
flash silica gel chromatography to give 0.09 g (87%) of 28 as a
yellow solid: mp 78-79 °C; IR (KBr) 2982, 1729, 1705, 1665,
and 1474 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H),
;
1.74-1.83 (m, 1H), 2.30 (d, 1H, J ) 16.0 Hz), 2.46-2.50 (m,
1H), 2.88 (d, 1H, J ) 15.6 Hz), 2.91 (dd, 1H, J ) 20.0 and 5.6
Hz), 3.06 (dd, 1H, J ) 20.0 and 2.0 Hz), 3.67 (s, 3H), 3.75-
3.85 (m, 2H), and 5.57-6.21 (brs, 1H); 13C NMR (CDCl3, 100
MHz) δ 28.5, 29.9, 32.8, 36.9, 48.2, 52.9, 70.8, 81.2, 101.8,
138.5, 152.7, 172.8, and 207.3. Anal. Calcd for C15H21NO5: C,
61.00; H, 7.17; N, 4.74. Found: C, 60.73; H, 7.24; N, 4.35.
ter t-Bu tyl 3a -(4-Meth yl-2,6,7-tr ioxa bicyclic[2.2.2]oct-
1-yl)-5-oxo-2,3,3a ,-4,5,6-h exah ydr oin dol-1-car boxylate (30).

4624 J . Org. Chem., Vol. 64, No. 13, 1999
Padwa et al.
A 0.3 g (0.7 mmol) sample of carbamate 26 in 10 mL of benzene
in a sealed tube was heated at 165 °C for 14 h. The solution
was concentrated under reduced pressure after cooling to room
temperature, and the residue was purified by flash silica gel
chromatography to give 0.17 g (70%) of ketone 30 as a white
solid: mp 217-218 °C; IR (KBr) 1726, 1694, 1664, 1392, and
1176 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.74 (s, 3H), 1.50 (s,
9H), 1.54-1.63 (m, 1H), 2.03 (d, 1H, J ) 16.0 Hz), 2.41 (dd,
1H, J ) 12.8 and 7.2 Hz), 2.73 (dd, 1H, J ) 22.4 and 5.6 Hz),
2.94 (d, 1H, J ) 16.0 Hz), 3.09 (d, 1H, J ) 22.4 Hz), 3.53-
3.58 (m, 1H), 3.62-3.67 (m, 1H), 3.81 (s, 6H), and 6.27 (brs,
1H); 13C NMR (CDCl3, 100 MHz) δ 14.6, 28.7, 30.6, 31.9, 37.8,
48.1, 48.2, 52.5, 72.8, 80.3, 102.8, 112.0, 139.4, 152.9, and
209.8. Anal. Calcd for C19H27NO6: C, 62.45; H, 7.45; N, 3.83.
Found: C, 62.22; H, 7.40; N, 3.83.
138.4, 153.3, 172.7, and 207.1. HRMS Calcd for C13H17NO5:
267.1107. Found: 267.1104.
5-Hyd r oxy-6-m eth yl-2,3,5,6-tetr a h yd r o-4H-in d ole-1,3a -
d ica r boxylic Acid N-ter t-Bu tyl Ester 3a -Meth yl Ester
(32). To a solution of 0.25 g (0.9 mmol) of furan 19 in 20 mL
of benzene was added 1.7 mL (1.7 mmol) of a 1.0 M solution
of dimethylaluminum chloride in hexane dropwise over a 5
min period. The reaction mixture was allowed to stir for 30
min at room temperature and was then quenched with 2 mL
of H2O and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.1 g (40%) of 32 as a colorless oil: IR
(neat) 2975, 1716, 1374, and 1168 cm-1; 1H NMR (CDCl3, 400
MHz) δ 0.98 (d, 3H, J ) 6.8 Hz), 1.23-1.34 (m, 1H), 1.49 (s,
9H), 1.58 (t, 1H, J ) 12.0 Hz), 1.71-1.79 (m, 1H), 2.25 (dd,
1H, J ) 12.6 and 6.2 Hz), 2.39 (dd, 1H, J ) 12.4 and 3.6 Hz),
2.64 (brs, 1H), 3.42 (dt, 1H, J ) 11.0 and 6.0 Hz), 3.58-3.63
(m, 1H), 3.69 (s, 3H), 3.96-4.01 (m, 1H), and 5.99 (brs, 1H);
13C NMR (CDCl3, 100 MHz) δ 15.3, 28.3, 28.6, 34.5, 36.6, 46.6,
52.9, 68.0, 80.5, 81.6, 111.4, 137.0, 152.6, and 174.8. HRMS
Calcd for C16H25NO5: 311.1733. Found: 311.1732.
Eth yl-N-[3-(4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]oct-1-yl)-
3-bu ten yl]-N-(2-fu r yl)ca r ba m a te (27). To a solution con-
taining 2.5 g (16 mmol) of carbamate 17 and 250 mL of a 4:1
DMF/THF mixture at room temperature was added 5.3 g (16.4
mmol) of cesium carbonate. The reaction mixture was stirred
at room temperature for 45 min and was then allowed to react
with 7.7 g (27 mmol) of mesylate 24. The mixture was heated
at 70 °C for 8 h and quenched with 100 mL of H2O and
extracted with ether. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. The
resulting residue was subjected to flash silica gel chromatog-
raphy to give 3.2 g (70%) of 27 as a colorless oil: IR (neat)
2954, 1716, 1616, 1502, 1296, and 1196 cm-1; 1H NMR (CDCl3,
400 MHz) δ 0.81 (s, 3H), 1.24 (t, 3H, J ) 7.2 Hz), 2.46 (t, 2H,
J ) 8.0 Hz), 3.72-3.76 (m, 2H), 3.94 (s, 6H), 4.17 (q, 2H, J )
7.2 Hz), 5.03 (d, 1H, J ) 0.8 Hz), 5.50 (s, 1H), 6.05 (brs, 1H),
6.34-6.35 (m, 1H), and 7.19 (d, 1H, J ) 1.2 Hz); 13C NMR
(CDCl3, 100 MHz) δ 15.5, 31.1, 31.3, 49.5, 63.0, 73.5, 73.8,
103.2, 108.1, 111.9, 116.1, 139.4, 142.9, 149.5, 155.9. Anal.
Calcd for C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C,
60.40; H, 6.80; N, 4.09.
To a solution of 0.2 g (0.5 mmol) of furan 19 in 10 mL of
benzene was added 0.3 mL (0.6 mmol) of a 2.0 M solution of
trimethylaluminum in toluene dropwise over a 5 min period.
The reaction mixture was allowed to stir for 2 h at room
temperature and was concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography
to give 0.1 g (82%) of 32.
5-Hydr oxy-6-m eth oxy-2,3,5,6-tetr ah ydr o-4H-in dole-1,3a -
d ica r boxylic Acid N-ter t-Bu tyl Ester 3a -Meth yl Ester (33
a n d 34). A solution of 0.2 g (0.7 mmol) of furan 19 in 10 mL
of MeOH was heated to reflux for 4 h. The solvent was removed
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 0.05 g (22%) of cis-alcohol
33 and 0.14 g (64%) of trans-alcohol 34. The minor cis-isomer
33 was isolated as a colorless oil: IR (KBr) 3499, 2974, 1730,
2-[2-E t h oxyca r b on yl-fu r a n -2-yl-a m in o)et h yl]a cr ylic
Acid Eth yl Ester (20). To a solution containing 2.7 g (8 mmol)
of the above carbamate 27, 35 mL of methanol, and 5 mL of
H2O at room temperature was added 0.2 g (0.8 mmol) of
pyridinium p-toluenesulfonate. The reaction mixture was
stirred at room temperature for 1 h and was concentrated
under reduced pressure. The residue was diluted with ethyl
acetate and washed with water, and the organic layer was
dried over MgSO4. The solvent was removed under reduced
pressure, and the crude oil was taken up in 35 mL of methanol.
To this solution was added 0.3 g (1.8 mmol) of potassium
carbonate, and the mixture was allowed to stir at room
temperature for 3 h. The solution was quenched with H2O and
extracted with ethyl acetate, and the organic layer was dried
over MgSO4 and concentrated under reduced pressure. The
crude residue was purified by flash silica gel chromatography
to give 1.5 g (71%) of 20 as a colorless oil: IR (neat) 2947,
1730, 1616, 1445, 1410, and 1139 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.21-1.25 (m, 3H), 2.59 (t, 2H, J ) 6.8 Hz), 3.74 (s,
3H), 3.77 (t, 2H, J ) 6.8 Hz), 4.15 (q, 2H, J ) 6.8 Hz), 5.60 (s,
1H), 6.03 (brs, 1H), 6.20 (d, 1H, J ) 0.8 Hz), 6.34-6.36 (m,
1H), and 7.19 (d, 1H, J ) 0.8 Hz); 13C NMR (CDCl3, 100 MHz)
δ 14.6, 31.7, 48.1, 52.1, 62.4, 102.5, 111.2, 127.4, 137.3, 138.8,
148.1, 155.2, and 167.3. HRMS Calcd for C13H17NO5: 267.1107.
Found: 267.1099.
1478, and 1392 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.50 (s,
;
9H), 1.59 (t, 1H, J ) 12.4 Hz), 1.75-1.83 (m, 1H), 2.27 (dd,
1H, J ) 12.4 and 5.2 Hz), 2.43 (dd, 1H, J ) 12.0 and 3.6 Hz),
2.84 (d, 1H, J ) 9.6 Hz), 3.36-3.45 (m, 1H), 3.46 (s, 3H), 3.63-
3.67 (m, 1H), 3.69 (s, 3H), 3.71-3.76 (m, 1H), 3.83 (t, 1H, J )
4.6 Hz), and 6.40 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 28.5,
34.1, 38.9, 46.9, 52.9, 53.3, 56.6, 68.9, 80.8, 83.5, 103.1, 141.0,
152.2, and 174.0. Anal. Calcd for C16H25NO6: C, 58.70; H, 7.70;
N, 4.28. Found: C, 58.65; H, 7.81; N, 4.22.
The major trans-isomer 34 was obtained as a colorless oil:
IR (KBr) 3449, 2974, 1716, 1471, and 1385 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.48 (s, 9H), 1.61 (t, 1H, J ) 12.4 Hz),
1.69-1.78 (m, 1H), 2.21 (dd, 1H, J ) 12.2 and 5.6 Hz), 2.55
(dd, 1H, J ) 12.4 and 4.0 Hz), 2.81 (s, 1H), 3.37 (s, 3H), 3.42
(dt, 1H, J ) 11.6 and 6.0 Hz), 3.64 (dd, 1H, J ) 11.2 and 8.8
Hz), 3.68 (s, 3H), 3.75-3.81 (m, 1H), 3.91 (dd, 1H, J ) 7.0
and 3.4 Hz), and 6.19 (brs,1H); 13C NMR (CDCl3, 100 MHz) δ
28.5, 34.1, 38.9, 46.9, 52.9, 53.3, 56.0, 68.9, 80.8, 83.5, 103.1,
141.0, 152.2, and 174.0. HRMS Calcd for C16H25NO6: 327.1682.
Found: 327.1679.
The cis-isomer 33 was obtained as the exclusive stereoiso-
mer by carrying out the reaction of furan 19 in the presence
of aluminum methoxide in benzene. To a solution of 0.15 g
(0.5 mmol) of 19 in 10 mL of benzene was added 0.32 g (2.0
mmol) of aluminum methoxide. The mixture was heated at
65 °C for 6 h under an argon atmoshere, and the solvent was
removed under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 33 in 80% yield
together with lesser quantities of ketone 28 (10%).
cis-5-(3,5-Dib r om ob en zoyloxy)-6-m et h oxy-2,3,5,6-t et -
r a h yd r o-4H-in d ole-1,3a -d ica r boxylic Acid N-ter t-Bu tyl
Ester 3a -Meth yl Ester . To a solution of 0.6 g (1.8 mmol) of
cis-alcohol 33 in 40 mL of CH2Cl2 at room temperature was
added 0.5 g (2.0 mmol) of 1,3-dicyclohexylcarbodiimide, 0.7 g
(2.4 mmol) of 3,5-dibromobenzoic acid, and 0.05 g (0.5 mmol)
of 4-(dimethylamino)pyridine. The reaction mixture was al-
lowed to stir at room temperature for 4 h, and then the
suspension was taken up in ether and filtered. The solvent
5-Oxo-2,3,5,6-t et r a h yd r o-4H-in d ole-1,3a -d ica r b oxylic
Acid 1-Eth yl Ester 3a -Meth yl Ester (29). A solution of 0.15
g (0.6 mmol) of furan 20 in 12 mL of benzene was heated in a
sealed tube. The solution was concentrated under reduced
pressure, and the residue was subjected to flash silica gel
chromatography to give 0.11 g (80%) of 29 as a clear oil: IR
(neat) 2975, 1723, 1666, 1403, and 1324 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.28 (t, 3H, J ) 6.8 Hz), 1.74-1.84 (m, 1H), 2.29
(d, 1H, J ) 16.0 Hz), 2.50 (dd, 1H, J ) 12.6 and 5.8 Hz), 2.89
(d, 1H, J ) 16 Hz), 2.93 (d, 1H, J ) 5.6 Hz), 3.05 (dd, 1H, J )
20.0 and 2.8 Hz), 3.65 (s, 3H), 3.78-3.83 (m, 2H), 4.18 (q, 2H,
J ) 6.8 Hz), and 5.79-6.23 (brs, 1H); 13C NMR (CDCl3, 100
MHz) δ 14.7, 32.9, 36.8, 47.9, 48.1, 52.7, 53.0, 61.7, 102.2,

Cycloaddition-Rearrangement Sequence
J . Org. Chem., Vol. 64, No. 13, 1999 4625
was then removed under reduced pressure, and the residue
was purified by silica gel chromatography to give 0.9 g (83%)
of the 3,5-dibromobenzoate ester of 33 as a white solid suitable
for an X-ray crystal analysis: mp 153-154 °C; IR (KBr) 1725,
1558, 1390, and 1269 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.50
(s, 9H), 1.81-1.90 (m, 1H), 2.07 (t, 1H, J ) 12.4 Hz), 2.31 (dd,
1H, J ) 12.4 and 6.0 Hz), 2.51 (dd, 1H, J ) 12.0 and 3.2 Hz),
3.40 (s, 3H), 3.46 (dt, 1H, J ) 11.2 and 6.0 Hz), 3.68 (dd, 1H,
J ) 10.0 and 9.2 Hz), 3.80 (s, 3H), 4.17 (t, 1H, J ) 11.2 Hz),
5.12 (dt, 1H, J ) 12.8 and 3.6 Hz), 6.35 (brs, 1H), 7.84 (t, 1H,
J ) 1.6 Hz), and 8.08 (d, 2H, J ) 1.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 28.5, 33.9, 46.7, 53.2, 53.6, 58.6, 60.5, 72.0, 73.1,
81.0, 103.7, 123.2, 131.6, 133.4, 138.6, 141.4, 152.3, 163.7, and
173.6. Anal. Calcd for C23H27NO7Br2: C, 46.88; H, 4.62; N, 2.38.
Found: C, 46.96; H, 4.65; N, 2.35.
tr a n s-5-(3,5-Dib r om ob en zoyloxy)-6-m et h oxy-2,3,5,6-
tetr a h yd r o-4H-in d ole-1,3a -d ica r boxylic Acid N-ter t-Bu -
tyl Ester 3a -Meth yl Ester . To a solution of 0.3 g (1.0 mmol)
of trans-alcohol 34 in 10 mL of CH2Cl2 at room temperature
was added 0.2 g (1.1 mmol) of 1,3-dicyclohexylcarbodiimide,
0.3 g (1.1 mmol) of 3,5-dibromobenzoic acid, and 0.02 g (0.1
mmol) of 4-(dimethylamino)pyridine. The reaction mixture was
allowed to stir at room temperature for 45 min, and the
suspension was taken up in ether and filtered. The solvent
was removed under reduced pressure, and the residue was
purified by silica gel chromatography to give 0.5 g (84%) of
the 3,5-dibromobenzoate ester of 34 as a white solid suitable
for an X-ray crystal analysis: mp 146-147 °C; IR (KBr) 1726,
1710, 1665, 1560, and 1480 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.52 (s, 9H), 1.71-1.80 (m, 2H), 2.31 (dd, 1H, J ) 12.2 and
5.6 Hz), 2.74 (dd, 1H, J ) 12.2 and 4.4 Hz), 3.34 (s, 3H), 3.53
(dt, 1H, J ) 11.4 and 5.6 Hz), 3.71 (t, 1H, J ) 10.4 Hz), 3.80
(s, 3H), 4.36 (dd, 1H, J ) 7.0 and 3.6 Hz), 4.35 (ddd, 1H, J )
12.0, 6.8 and 4.8 Hz), 6.24 (brs, 1H), 7.84 (t, 1H, J ) 1.6 Hz),
and 8.08 (d, 2H, J ) 1.6 Hz); 13C NMR (CDCl3, 100 MHz) δ
28.6, 34.1, 37.1, 47.2, 53.2, 54.8, 60.8, 72.2, 79.0, 81.5, 103.7,
123.2, 126.2, 131.6, 138.5, 141.8, 152.3, 163.5, and 173.2. Anal.
Calcd for C23H27NO7Br2: C, 46.88; H, 4.62; N, 2.38. Found:
C, 47.16; H, 4.73; N, 2.17.
6-Ben zyloxy 5-Hyd r oxy-2,3,5,6-tetr a h yd r o-4H-in d ole-
1,3a -d ica r boxylic Acid N-ter t-Bu t yl E st er 3a -Met h yl
Ester (35 a n d 36). A solution of 1.0 g (3.4 mmol) of furan 19
in 20 mL of benzyl alcohol was heated at 70 °C for 4 h. The
solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography to give 0.3 g
(20%) of cis-alcohol 35 and 0.8 g (60%) of trans-alcohol 36. The
cis-isomer 35 was obtained as a colorless oil: IR (neat) 3530,
1730, 1709, 1666, and 1388 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.50 (s, 9H), 1.67 (t, 1H, J ) 12.4 Hz), 1.76-1.84 (m, 1H),
2.27 (dd, 1H, J ) 12.4 and 6.0 Hz), 2.43 (dd, 1H, J ) 12.0 and
3.6 Hz), 2.82 (brs, 1H), 3.41 (dt, 1H, J ) 11.4 and 6.0 Hz),
3.66-3.67 (m, 1H), 3.69 (s, 3H), 3.74-3.80 (m, 1H), 4.12 (m,
1H), 4.48-4.54 (m, 1H), 4.70-4.79 (m, 1H), 6.44 (brs, 1H), and
7.27-7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 28.5, 33.8,
36.9, 46.6, 52.9, 66.7, 71.6, 73.0, 77.5, 81.1, 103.4, 128.1, 128.2,
collected by filtration, washed with 50 mL of H2O, and dried
under reduced pressure to give 3.1 g (87%) of tert-butyl N-[2-
(5-methylfuryl)]carbamate as a white solid: mp 76-77 °C; IR
(KBr) 3331, 1550, and 1709 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.49 (s, 9H), 2.21 (s, 3H), 5.90 (brs, 2H), and 6.42 (brs, 1H);
13C NMR (CDCl3, 100 MHz) δ 13.3, 28.2, 81.0, 97.4, 106.7,
143.1, 146.2, and 152.4. HRMS Calcd for C10H15NO3: 197.1052.
Found 197.1056.
ter t-Bu tyl N-[3-(2-Meth ylbu ten yl)]-N-[2-(5-m eth ylfu r -
yl)]ca r ba m a te (37). A solution containing 3.7 g (19 mmol) of
the above furanyl carbamate, 2.6 g (65 mmol) of powdered
sodium hydroxide, 5.2 g (38 mmol) of potassium carbonate,
and 0.6 g (1.8 mmol) of tetrabutylammonium hydrogen sulfate
in 50 mL of benzene was heated at reflux for 30 min, and then
4.2 g (28 mmol) of 2-methyl-4-bromobutene in 25 mL of
benzene was added dropwise to the solution. The mixture was
heated for an additional 4 h, quenched with 50 mL of H2O,
and extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography
to give 3.5 g (70%) of 37 as a colorless oil: IR (neat) 3075,
1709, 1623, and 1573 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.44
(s, 9H), 1.73 (s, 3H), 2.24 (s, 3H), 2.26 (t, 2H, J ) 7.2 Hz), 3.62
(t, 2H, J ) 7.2 Hz), 4.70 (s, 1H), 4.75 (s, 1H), 5.86 (brs, 1H),
and 5.90 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.6, 22.4,
28.1, 36.6, 47.4, 80.7, 102.6, 106.4, 111.7, 142.7, 146.5, 147.7,
and 154.1. HRMS Calcd for C15H23NO3: 265.1678. Found:
265.1686.
3a ,5-Dim et h yl-5-h yd r oxy-3,3a ,4,5-t et r a h yd r o-2H -in -
d ole (39). A solution of 0.3 g (1.2 mmol) of furan 37 in 12 mL
of benzene was heated in a sealed tube at 190 °C for 12 h.
The solution was concentrated under reduced pressure, and
the residue was subjected to flash silica gel chromatography
to give 0.18 g (89%) of 39 as a colorless solid: mp 82-83 °C;
1
IR (KBr) 3300, 2961, 1795, and 1630 cm-1; H NMR (CDCl3,
400 MHz) δ 1.06 (s, 3H), 1.42 (s, 3H), 1.56 (m, 1H), 1.78 (m,
1H), 1.82 (d, 1H, J ) 13.2 Hz), 2.22 (d, 1H, J ) 13.2 Hz), 3.69
(m, 1H), 3.88 (m, 2H), 6.10 (d, 1H, J ) 4.0 Hz), and 6.15 (d,
1H, J ) 4.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 21.8, 29.0, 40.3,
47.9, 51.7, 57.5, 69.6, 120.8, 146.9, and 177.3. HRMS Calcd
for C10H15NO: 165.1154. Found: 165.1160.
ter t-Bu tyl N-[2-(5-p-Nitr op h en ylfu r yl)]ca r ba m a te. A
solution of 3.0 g (13 mmol) of 5-(p-nitrophenyl)furan-2-car-
boxylic acid, 3.9 g (14 mol) of diphenylphosphoryl azide, and
1.5 g (15 mmol) of triethylamine in 50 mL of tert-butyl alcohol
was heated at reflux for 16 h. The reaction mixture was cooled
to room temperature and poured into 300 mL of saturated
sodium bicarbonate. The resulting mixture was extracted with
ether and washed with brine, and the combined organic layers
were dried over anhydrous magnesium sulfate. The solvent
was removed under reduced pressure, and the residue was
purified by flash silica gel chromatography to give 3.4 g (86%)
of tert-butyl N-[2-(5-p-nitrophenylfuryl)]carbamate as a yellow
solid: mp 147-148 °C; IR (KBr) 3409, 1706, 1557, 1331, and
1161 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.53 (s, 9H), 6.22 (brs,
1H), 6.84 (d, 1H, J ) 3.6 Hz), 7.10 (brs, 1H), 7.59 (d, 2H, J )
9.2 Hz), and 8.17 (d, 2H, J ) 9.2 Hz); 13C NMR (CDCl3, 100
MHz) δ 28.1, 82.0, 96.1, 111.6, 122.6, 124.3, 136.1, 144.3, 145.5,
147.7, and 150.9. Anal. Calcd for C15H16N2O5: C, 59.21; H,
5.30; N, 9.21. Found: C, 59.01; H, 5.31; N, 9.00.
128.7, 138.3, 142.4, 152.5, and 174.0. HRMS Calcd for C22H29
NO6: 403.1995. Found: 403.2003.
-
The trans-isomer 36 was isolated as a colorless oil: IR (neat)
3480, 1730, 1709, 1666, and 1388 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.51 (s, 9H), 1.62 (t, 1H, J ) 12.4 Hz), 1.71-1.81 (m,
1H), 2.23 (dd, 1H, J ) 12.6 and 6.0 Hz), 2.42 (brs, 1H), 2.58
(dd, 1H, J ) 12.4 and 4.0 Hz), 3.46 (dt, 1H, J ) 11.6 and 6.0
Hz), 3.65-3.69 (m, 1H), 3.70 (s, 3H), 3.85-3.90 (m, 1H), 4.12
(dd, 1H, J ) 7.4 and 3.2 Hz), 4.51 (d, 1H, J ) 11.2 Hz), 4.73
(m, 1H), 6.31 (brs, 1H), and 7.31-7.37 (m, 5H); 13C NMR
(CDCl3, 100 MHz) δ 28.5, 34.2, 38.9, 47.0, 52.9, 69.3, 69.9, 77.4,
80.9, 81.9, 103.5, 127.8, 128.1, 128.6, 138.8, 141.1, 152.3, and
174.0. HRMS Calcd for C22H29NO6: 403.1995. Found: 403.1988.
ter t-Bu tyl N-[2-(5-Meth ylfu r yl)]ca r ba m a te. A solution
of 2.3 g (18 mmol) of 5-methylfuran-2-carboxylic acid, 5.8 g
(21 mmol) of diphenylphosphoryl azide, and 2.2 g (22 mmol)
of triethylamine in 25 mL of tert-butyl alcohol was heated at
reflux for 15 h. The reaction mixture was cooled to room
temperature and poured into 250 mL of a saturated sodium
bicarbonate solution at 0 °C. The resultant percipitate was
ter t-Bu tyl N-[3-(2-Meth ylbu ten yl)]-N-[2-(5-p-n itr oph en -
ylfu r yl)] Ca r ba m a te (38). A solution containing 0.9 g (2.5
mmol) of the above furanyl carbamate, 0.5 g (13 mmol) of
powered sodium hydroxide, 2.0 g (15 mmol) of potassium
carbonate, and 0.1 g (0.3 mmol) of tetrabutylammonium
hydrogen sulfate in 30 mL of benzene was heated at reflux
for 30 min, and then 0.7 g (5 mmol) of 2-methyl-4-bromobutene
in 10 mL of benzene was added dropwise to the solution. The
mixture was heated for an additional 12 h, quenched with 50
mL of H2O, and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.7 g (57%) of 38 as an orange solid: mp
74-75 °C; IR (KBr) 2976, 1709, 1559, 1337, and 1165 cm-1
1H NMR (CDCl3, 400 MHz) δ 1.50 (s, 9H), 1.78 (s, 3H), 2.36 (t,
;

4626 J . Org. Chem., Vol. 64, No. 13, 1999
Padwa et al.
2H, J ) 8.0 Hz), 3.84 (t, 2H, J ) 8.0 Hz), 4.74 (s, 1H), 4.81 (s,
1H), 6.05 (brs, 1H), 6.86 (d, 1H, J ) 3.6 Hz), 7.68 (d, 2H, J )
8.0 Hz), and 8.22 (d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3, 100
MHz) δ 22.4, 28.2, 36.9, 46.5, 81.9, 102.1, 111.0, 112.4, 122.9,
124.4, 136.3, 142.3, 145.8, 146.0, 150.3, and 152.7. Anal. Calcd
for C20H24N2O5: C, 64.50; H, 6.50; N, 7.52. Found: C, 64.54;
H, 6.55; N, 7.39.
δ 1.11 (s, 3H), 1.38 (s, 3H), 1.46 (bs, 10H), 1.49 (d, 1H, J )
12.0 Hz), 1.58 (dd, 1H, J ) 12.0 and 6.0 Hz), 1.67 (dd, 1H, J
) 12.0 and 3.0 Hz), 1.95 (dd, 1H, J ) 12.0 and 6.0 Hz), 2.06
(d, 1H, J ) 12.0 Hz), 3.34 (s, 3H), 3.40-3.60 (m, 2H), and 6.40
(bs, 1H); 13C NMR (CDCl3, 100 MHz) δ 16.3, 21.8, 28.4, 33.9,
36.1, 49.5, 50.8, 55.8, 80.7, 83.9, 84.9, 102.0, 141.0, and 154.1.
HRMS Calcd for C16H27NO4: 298.2018. Found: 298.2012.
5-Hyd r oxy-3a -m eth yl-5-p-n itr op h en yl-3,3a ,4,5-tetr a h y-
d r o-2H-in d ole (40). A solution of 0.3 g (0.8 mmol) of furan
38 in 15 mL of benzene was heated in a sealed tube at 180 °C
for 16 h. The solution was concentrated under reduced pres-
sure, and the residue was subjected to flash silica gel chro-
matography to give 0.18 g (82%) of 40 as a colorless solid: mp
8-Hyd r oxy-2,5,8-tr im eth yl-2-a za bicyclo[3.2.2]n on a n -6-
on e (45). To a solution of 0.02 g (0.14 mmol) of tetrahydro-
2H-indole 39 in 10 mL of CH2Cl2 was added 0.02 g (0.15 mmol)
of iodomethane, and the reaction was stirred for 12 h. The
solution was concentrated under reduced pressure, and to the
residue was added 1 mL of H2O and 0.5 g (3.1 mmol) of K2CO3.
The aqueous layer was extracted with ether, and the combined
organic layers were dried over MgSO4 and subjected to flash
silica gel chromatography to give 0.02 g (90%) of 45 as a white
209-210 °C; IR (KBr) 3197, 1640, 1517, and 1342 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 0.61 (s, 3H), 1.70 (m, 1H), 1.75 (brs,
1H), 1.76 (m, 1H), 2.25 (d, 1H, J ) 13.6 Hz), 2.76 (d, 1H, J )
13.6 Hz), 3.73 (m, 1H), 3.95 (m, 1H), 6.50 (d, 1H, J ) 10.4
Hz), 7.63 (d, 1H, J ) 10.4 Hz), 7.74 (d, 2H, J ) 6.8 Hz), and
8.23 (d, 2H, J ) 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 21.0,
40.5, 47.6, 52.5, 57.9, 73.3, 123.6, 125.0, 127.7, 142.3, 147.4,
153.2, and 176.3. HRMS (M + H) Calcd for C15H17N2O3:
273.1239. Found: 273.1235.
5-Hydr oxy-6-m eth oxy-3a ,5-dim eth yl-2,3,3a ,4,5,6-h exah y-
d r oin d ole-1-ca r boxylic Acid ter t-Bu tyl Ester (43). A solu-
tion of 0.2 g (0.6 mmol) of furan 37 in 5 mL of methyl alcohol
was heated to 140 °C for 17 h. The solvent was removed under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give a 2:1 diastereomeric mixture of
43 in 76% yield. Extensive shaving of the front and tail
fractions eventually gave samples of each diastereomer. The
major isomer was obtained as a colorless oil: IR (neat) 3420,
2975, 2819, 1709, and 1545 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.04 (s, 3H), 1.35 (s, 3H), 1.37 (d, 1H, J ) 12 Hz), 1.46 (bs,
10H), 1.58 (m, 1H), 1.66 (d, 1H, J ) 12.0 Hz), 1.98 (dd, 1H, J
) 12.0 and 6.8 Hz), 2.16 (dd, 1H, J ) 12.8 and 3.6 Hz), 3.34
(s, 3H), 3.48 (m, 1H), 3.62-3.69 (m, 1H), and 6.30 (bs, 1H);
13C NMR (CDCl3, 100 MHz) δ 16.4, 21.0, 28.4, 31.5, 36.9, 44.8,
48.5, 58.1, 79.9, 83.3, 85.0, 103.1, 140.8, and 153.9. HRMS
Calcd for C16H27NO4: 298.2018. Found: 298.2026.
solid: mp 110-111ïC; IR (KBr) 3281, 2925, and 1710 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 0.97 (s, 3H), 1.27 (s, 3H), 1.47
(dq, 1H, J ) 13.6 and 2.0 Hz), 1.61 (dd, 1H, J ) 14.0 Hz), 1.96
(d, 1H, J ) 14.0 Hz), 2.14 (td, 1H, J ) 14.0 (t) and 4.8 (d) Hz),
2.31 (t, 1H, J ) 4.8 Hz), 2.38 (d, 1H, J ) 4.8 Hz), 2.42 (s, 3H),
2.61 (dd, 1H, J ) 17.0 and 2.5 Hz), 2.72-2.78 (m, 2H), and
3.46 (s, 1H, exchanged with D2O); 13C NMR (CDCl3, 100 MHz)
δ 23.4, 30.1, 33.3, 36.7, 45.8, 46.8, 49.8, 50.3, 66.9, 67.3, and
213.4. HRMS Calcd for C11H19NO2: 197.1416. Found: 197.1416.
Ack n ow led gm en t. We gratefully acknowledge the
National Institute of Health for generous support of this
work. Use of high-field NMR spectrometers used in
these studies was made possible through equipment
grants from the NIH and NSF.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for new compounds lacking analyses together
with ORTEP drawings for the 3,5-dibromo-benzoate esters of
alcohols 33 and 34 as well as compound 40. This material is
available free of charge via the Internet at http://pubs.acs.org.
The minor diastereomer was isolated as a colorless oil: IR
(neat) 3446, 2969, and 1702 cm-1; 1H NMR (CDCl3, 400 MHz)
J O982061+