Model Studies Directed toward the Total Synthesis of (±)-Ribasine. A Tandem Cyclization-Cycloaddition Route Leading to the Core Skeleton

Article abstract of DOI:10.1021/jo990136j

A series of α-diazo-β-(o-carbomethoxy)-substituted aryl ketones were prepared and employed as model systems for a synthetic approach toward the alkaloid ribasine. Six-membered ring carbonyl ylide dipoles were generated by treating the diazoketones with a rhodium(II) catalyst. The initially formed dipole was trapped using a variety of dipolarophiles including N-benzylidene methylamine. The Rh(II)-catalyzed behavior of ethyl 2-diazo-3-(2-formylphenyl)-3-oxo-propionate was also studied to probe the chemoselectivity of the reaction. The major products isolated are derived from bimolecular trapping of the carbonyl ylide dipole, as well as intramolecular C-H insertion of the rhodium carbenoid into the aldehydic hydrogen. Changing the catalyst from Rh(II) trifluoroacetate to Rh(II) acetate caused a significant alteration in product distribution. A study of the tandem cyclization-cycloaddition reaction of an o-allyl phenyl substituted diazoketone was also carried out. An unexpected low-temperature intramolecular dipolar cycloaddition of the diazo group across the neighboring π-bond first occurred, followed by nitrogen extrusion to give products derived from a 1,3-biradical intermediate. By subjecting the diazoketone to the Rh(II) catalyst at 110°C, it was possible to prepare the carbonyl ylide derived cycloadduct in high yield. This result provides good precedent for the future implementation of the cycloaddition strategy toward the synthesis of ribasine.

Full text of DOI:10.1021/jo990136j

J . Org. Chem. 1999, 64, 4079-4088
4079
Mod el Stu d ies Dir ected tow a r d th e Tota l Syn th esis of
(()-Riba sin e. A Ta n d em Cycliza tion -Cycloa d d ition Rou te Lea d in g
to th e Cor e Sk eleton
Albert Padwa,* Laura Precedo, and Mark A. Semones
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received J anuary 26, 1999
A series of R-diazo-â-(o-carbomethoxy)-substituted aryl ketones were prepared and employed as
model systems for a synthetic approach toward the alkaloid ribasine. Six-membered ring carbonyl
ylide dipoles were generated by treating the diazoketones with a rhodium(II) catalyst. The initially
formed dipole was trapped using a variety of dipolarophiles including N-benzylidene methylamine.
The Rh(II)-catalyzed behavior of ethyl 2-diazo-3-(2-formylphenyl)-3-oxo-propionate was also studied
to probe the chemoselectivity of the reaction. The major products isolated are derived from
bimolecular trapping of the carbonyl ylide dipole, as well as intramolecular C-H insertion of the
rhodium carbenoid into the aldehydic hydrogen. Changing the catalyst from Rh(II) trifluoroacetate
to Rh(II) acetate caused a significant alteration in product distribution. A study of the tandem
cyclization-cycloaddition reaction of an o-allyl phenyl substituted diazoketone was also carried
out. An unexpected low-temperature intramolecular dipolar cycloaddition of the diazo group across
the neighboring π-bond first occurred, followed by nitrogen extrusion to give products derived from
a 1,3-biradical intermediate. By subjecting the diazoketone to the Rh(II) catalyst at 110 °C, it was
possible to prepare the carbonyl ylide derived cycloadduct in high yield. This result provides good
precedent for the future implementation of the cycloaddition strategy toward the synthesis of
ribasine.
Sch em e 1
In tr od u ction
Ribasine (1), isolated from Fumariaceae plants in
1983,1 is the parent compound of a class of alkaloids that
contain an indanobenzazepine in their skeleton and are
biogenetically related to the isoquinoline alkaloid fam-
ily.2,3 Other members of this class are the hydroxy
ribasines himalayamine (2)4 and ribasidine (3),5 and the
N-demethyl congener norribasine (4).6 Although this
family of alkaloids is not known to possess any particular
medicinal activity, the presence of the reactive 8,14-
epoxy-indano[2,1-c][2]benzazepine ring may promote in-
teresting biological responses.7 Certainly, the structural
uniqueness of the skeletal framework makes these
compounds attractive targets for synthesis. Rather sur-
prisingly, construction of the ribasine alkaloids has
received little attention from synthetic organic chemists.8
To date, only the Dominguez group9 has described a
(1) Boente, J . M.; Castedo, L.; Cuadros, R.; Saa´, J . M.; Suau, R.;
Perales, A.; Mart´ınez-Ripoll, M.; Fayos, J . Tetrahedron Lett. 1983, 24,
2029.
(2) Rozwadowska, M. D. Heterocycles 1994, 39, 903.
(3) Manske, R. H. F. The Alkaloids; Academic Press: New York,
1971; Vol. 13, p 166. Ito, S. Natural Product Chemistry; Nakanishi,
K., Goto, T., Ito, S., Natori, S., Nozoe, S., Eds.; Academic Press: New
York, 1975; Vol. 2, pp 310-313.
(4) Allais, D. P.; Guineaudeau, H.; Freyer, A. J .; Shamma, M.;
Ganguli, N. C.; Talapatra, B.; Talapatra, S. K. Tetrahedron Lett. 1983,
24, 2445.
successful synthesis of ribasine by a stereocontrolled
addition of the 3,4-methylenedioxy-substituted R-lithium-
o-toluate (5) to 2-(9-phenylfluoren-9-yl)-amino-1-indanone
(6). The resulting lactone 7 was reduced and cyclized to
ultimately give ribasine 1 (Scheme 1).9
(5) Boente, J . M.; Campello, M. J .; Castedo, L.; Dominguez, D.; Saa´,
J . M.; Suau, R.; Vidal, M. Tetrahedron Lett. 1983, 24, 4481.
(6) Allais, D. P.; Guineaudeau, H. J . Nat. Prod. 1990, 53, 1280.
(7) Substituted phenyl benzazepines have generated considerable
interest as medicinal agents for the treatment of psychosis and as
specific ligands for serotonin and dopamine receptor subtypes; see:
Gentles, R. G.; Middlemiss, D.; Proctor, G. R.; Sneddon, A. H. J . Chem.
Soc., Perkin Trans. 1 1991, 6, 1423. Petterson, I.; Liljefors, T.; Bøgesø,
K. J . Med. Chem. 1990, 33, 2197. McCall, J . M. In Annual Reports in
Medicinal Chemistry; Academic Press: San Diego, CA, 1990; Vol. 25,
pp 1-50.
(8) For some earlier synthetic approaches, see: Paleo, M. R.;
Dom´ınguez, D.; Castedo, L. J . Org. Chem. 1993, 58, 2763. Paleo, M.
R.; Dom´ınguez, D.; Castedo, L. Tetrahedron Lett. 1993, 34, 2369. Allais,
D. P.; Guineaudeau, H. J . Nat. Prod. 1990, 53, 1280. Alonso, R.;
Castedo, L.; Dom´ınguez, D. J . Org. Chem. 1989, 54, 424. Alonso, R.;
Castedo, L.; Dom´ınguez, D. Tetrahedron Lett. 1986, 30, 3539. Ollero,
L.; Castedo, L.; Dominguez, D. Tetrahedron Lett. 1997, 32, 5723.
(9) Ollero, L.; Castedo, L.; Dominguez, D. Tetrahedron Lett. 1998,
39, 1413.
10.1021/jo990136j CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/29/1999

4080 J . Org. Chem., Vol. 64, No. 11, 1999
Padwa et al.
Sch em e 2
Sch em e 3
Unlike the above synthesis, which involves formation
of the C13-C14 bond by nucleophilic addition of an ortho-
substituted benzylic anion to a N-protected 2-amino-1-
indanone, our intention was to construct the indanobenz-
azepine skeleton in a single step by an intramolecular
cycloaddition reaction (vide infra). We have had a long-
standing interest in the tandem cyclization-cycloaddition
cascade of rhodium carbenoids as a method for the
synthesis of natural products.10,11 Our earlier explorations
in this area uncovered efficient intramolecular carbonyl
ylide cycloaddition reactions of diazo alkanediones such
as 8.12 The results arising from this earlier exploratory
work stimulated further synthetic investigations in our
group that utilized this process as the key N-heterocyclic
ring building step for the preparation of several different
classes of alkaloids.13 Our previous work also showed that
a variety of dipolarophiles could be used to trap the dipole
derived from cyclization of the rhodium carbenoid with
the neighboring carbonyl group.14 The high efficiency of
the tandem process as exemplified by the transformation
8 f 9 f 10 (Scheme 2) suggested that this method might
serve as the basis for a new strategy for the synthesis of
ribasine. As depicted in Scheme 3, preparation of ribasine
(1) based on this design relies on a rhodium(II)-catalyzed
cyclization of imino diazo keto aldehyde 12. We antici-
pated generating the carbonyl ylide dipole 11 from the
Rh(II)-catalyzed reaction of 12, and we hoped that this
intermediate would undergo intramolecular dipolar cyclo-
addition across the neighboring imine π-bond to produce
the indanobenzazepine skeleton found in ribasine. Al-
though the intramolecular cycloaddition reaction to
reaction of an appropriately substituted aryl diazoketone
(i.e., 12). To pursue this approach, we decided it was
necessary to first probe several issues related to the
following questions: (1) Is the rhodium carbenoid derived
from an R-diazo-â-aryl ketone comparable in behavior to
the more traditionally studied R-diazo-â-ketoester sys-
tem? (2) What is the propensity for carbonyl ylide dipoles
to cycloadd across CdN π-bonds? (3) Do aldehydic groups
undergo cyclization with rhodium carbenoids? (4) How
does the ligand group on the rhodium catalyst influence
the chemoselectivity of dipole formation? This final
question is a most important one because the carbonyl
and imino groups are equidistant from the carbenoid
center generated from diazoketone 12, and cyclization
could result in either a carbonyl or azomethine ylide
intermediate.
Our initial foray into this tandem cyclization-cyclo-
addition chemistry involved substrate 13, which con-
tained a carbomethoxy group in the ortho-position of the
aromatic ring. The tandem cascade was effected by
heating a solution of 13 and dimethyl acetylenedicar-
boxylate with rhodium(II) acetate at 80 °C in toluene.
Subsequent chromatography on silica gel afforded the
pure cycloadduct 14 in 91% yield. The Rh(II)-catalyzed
reaction of 13 in the absence of a trapping agent
furnished the 1:1 dimer 15 derived from head-to-tail
coupling of the transient carbonyl ylide dipole.
Several types of dipolarophiles were examined so as
to establish the scope and generality of the process
(Scheme 4). The cycloaddition proceeded readily across
the carbonyl group of benzaldehyde affording the ex-
pected cycloadduct 16 as a 2:1 mixture of endo (16a ) and
exo (16b) isomers in 90% overall yield. The regiochem-
istry observed can be readily rationalized in terms of
maximum overlap of the dipole HOMO-dipolarophile
LUMO, as is generally the case with carbonyl ylide
cycloadditions.16 When Manders reagent17 was used as
the trapping agent, cycloadduct 17 was obtained in 97%
construct a seven-membered ring was precedented,15
a
comparable addition across a CdN double bond had not
yet been examined when our synthesis was initiated.
The details of our studies include (1) probing the cyclo
addition approach described above, (2) uncovering an
interesting ligand effect of the metal, and (3) successfully
executing a concise transannular cyclization-cycloaddi-
tion strategy on a model system are discussed in detail
below.
Resu lts a n d Discu ssion
The strategy delineated in Scheme 3 for the synthesis
of ribasine relies on a tandem cyclization-cycloaddition
(10) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(11) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J . Org. Chem.
1997, 62, 1317.
(12) Padwa, A.; Carter, S. P.; Nimmesgern, H. J . Org. Chem. 1986,
51, 1157. Padwa, A.; Carter, S. P.; Nimmesgern, H.; Stull, P. D. J .
Am. Chem. Soc. 1988, 110, 2894.
(13) Padwa, A.; Harring, S. R.; Semones, M. A. J . Org. Chem. 1998,
63, 44. Padwa, A.; Price, A. T. J . Org. Chem. 1998, 63, 556. Padwa,
A.; Brodney, M. A.; Marino, J . P., J r.; Sheehan, S. M. J . Org. Chem.
1997, 62, 78.
(14) Padwa, A.; Fryxell, G. E.; Zhi, L. J . Am. Chem. Soc. 1990, 112,
3100.
(15) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhi, L. Tetrahedron
Lett. 1989, 24, 301. Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang,
Z. J . J . Org. Chem. 1991, 56, 3271.
(16) Houk, K. N.; Sims, J .; Duke, R. E.; Strozier, R. W.; George, J .
K. J . Am. Chem. Soc. 1973, 95, 7287.
(17) Mander, L. N.; Sethi, P. Tetrahedron Lett. 1983, 5425.

Tandem Cyclization-Cycloaddition
J . Org. Chem., Vol. 64, No. 11, 1999 4081
Sch em e 4
Sch em e 5
this reactive dipole collapses to generate the thermody-
namically more stable isobenzofuran 22. Carrying out the
above reaction in the presence of DMAD afforded cyclo-
adduct 23 in 93% yield. It should be noted that all of our
attempts to isolate the putative isobenzofuran 22 in the
absence of a trapping agent failed to give any character-
izable product.
The ease of ring closure as a function of ring size
generally increases on going from three- to five-mem-
bered rings and then decreases rapidly.21 This literature
observation would tend to suggest that five-membered
ring carbonyl ylide formation should occur at a faster rate
than six-membered ring formation. Indeed, this was
borne out by an examination of the rhodium(II) acetate
catalyzed behavior of the dicarbomethoxy-substituted
diazoketone 24. Treatment of 24 with Rh2(OAc)4 at 110
°C in the presence of DMAD afforded a 4:1-mixture of
cycloadducts 27 and 28 in 85% yield. The major product
is derived from trapping of the five-membered ring
carbonyl ylide 25, and its structure was unequivocally
established by a single-crystal X-ray structure analysis.19
Interestingly, changing the ligand on the rhodium(II)
catalyst caused a significant change in product distribu-
tion. Reaction of 24 with Rh2(tfa)4 and DMAD afforded a
2:1 mixture of the five- and six-membered ring cyclo-
adducts (27 and 28) (Scheme 6). Catalysis by rhodium(II)
caprolactam (Rh2(cap)4), however, significantly dimin-
ished the yield of the six-membered ring dipole adduct
28 to 5%, and 27 was isolated in 78% yield. Site
selectivity in Rh(II)-catalyzed diazocarbonyl reactions are
often influenced by the nature of the bridging ligands.22-24
In the above example, the variation in product distribu-
tion presumably reflects both entropic effects and differ-
ences in electrophilicity between the various rhodium
carbenoids involved in the cyclization-cycloaddition
reaction.23-25
yield as a single regioisomer, also consistent with FMO
theory.18 Because we were most interested in evaluating
the feasibility of cycloaddition of the dipole across a CdN
π-bond, we undertook a study of the rhodium(II)-
catalyzed reaction of 13 with both N-benzylidene ben-
zenesulfonamide and methylamine. In both cases, a
mixture of endo (major) and exo (minor) cycloadducts
were obtained. The diastereomers were separated for full
characterization, and the endo isomer (80%), in the case
of cycloadduct 18, was unequivocally established by an
X-ray crystallographic study.19 The assignment of the
stereochemistry of the related cycloadduct 19a was based
on comparison of NMR signals with those of the endo
isomer 18a . The results indicate that the endo arrange-
ment in the transition state is slightly favored over its
exo counterpart, perhaps as a consequence of symmetry-
controlled HOMO-LUMO interactions.18,20 The effect of
the catalyst on the ratio of stereoisomers was briefly
addressed, but the specific catalyst used with this system
did not have a pronounced effect on the distribution of
isomers. Several aspects of the above chemistry are
notable. The tandem cyclization-cycloaddition reactions
can be carried out under very mild conditions. This is a
clear testimony to the efficiency of the method. In
addition, the yields are generally quite high.
When rhodium(II) acetate is used as the catalyst, the
product distribution encountered amounts to an energy
difference of approximately 0.8 kcal/mol at 25 °C. The
chemoselectivity encountered is quite similar to that of
intramolecular nucleophilic substitution reactions,21 with
Decomposition of the isomeric diazo ketoester 20 also
occurred readily in the presence of a catalytic amount of
rhodium(II) acetate, producing in this case the five-
membered ring dipole 21 (Scheme 5). More than likely,
(18) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(19) The authors have deposited coordinates for structures 18a , 27,
and 35 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(21) Liebman, J . F.; Greenberg, A. Chem. Rev. 1976, 76, 311.
(22) Cotton, F. A.; Walton, R. A. Multiple Bonds Between Metal
Atoms; Wiley: New York, 1982; Chapter 7.
(23) Padwa, A.; Austin, D. J . Angew. Chem., Int. Ed. Engl. 1994,
33, 1797.
(24) Doyle, M. P.; Forbes, D. C.; Protopopova, M. N.; Stanley, S. A.;
Vasbinder, M. M.; Xavier, K. R. J . Org. Chem. 1997, 62, 7210.
(25) Ye, T.; McKervey, A. Chem. Rev. 1994, 94, 1091.
(20) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, 1984.

4082 J . Org. Chem., Vol. 64, No. 11, 1999
Padwa et al.
Sch em e 6
Sch em e 7
catalyzed reaction produces a mixture of both the six-
membered ring dipole 31 as well and as the C-H
aldehydic insertion product 33.26 Dione 33 exists in rapid
equilibrium with its enol tautomer 34, which in turn
undergoes rapid bimolecular cycloaddition with the car-
bonyl ylide present in solution. Indenone 34 is much more
reactive toward dipolar cycloaddition than is DMAD;
dimer 35 is the exclusive product formed even when a
3-molar excess of DMAD was present.
Having established the feasibility of the cyclization
reaction to occur with an aldehydic group in the ortho-
position of the aromatic ring, we next initiated an
intramolecular study of the cycloaddition reaction using
but-3-enyl diazophenyl benzoate 36. The internal trap-
ping of a carbonyl ylide dipole with a tethered alkene
could prove to be a very effective method for the synthesis
of a variety of novel oxypolycyclic ring systems. Diazo-
ketone 36 was easily synthesized starting from benz-
alphthalide and 3-buten-1-ol. Heating a sample of 36 in
toluene at 110 °C in the presence of Rh2(OAc)4 furnished
cycloadduct 37 in 96% yield. In this case, cycloaddition
of the dipole readily occurs across the unactivated alkenyl
π-bond attached to the ester portion of the molecule.
Little difference in the yield of 37 was noted using a
variety of ligands on the rhodium(II) metal.
five-membered ring formation proceeding at the faster
rate. This conclusion assumes that the rate of dipolar
cycloaddition is approximately the same with both dipoles
and that the rate of cyclization to produce the carbonyl
ylides would differ. The observed cyclization-cycloaddi-
tion profile is clearly related to entropic considerations.
The entropy of activation associated with six-membered
ring formation is simply more negative than that with
the shorter tether. In contrast to the rhodium(II)-
catalyzed cycloaddition reaction, heating a sample of 24
in toluene at 110 °C afforded isochromanone 29 in 87%
yield. Similar results were obtained upon photolysis of
24 in benzene using a Pyrex filter. The formation of this
product can be attributed to an extrusion of nitrogen
followed by a Wolff rearrangement of the resulting
carbene. The initially formed ketene undergoes a subse-
quent electrocyclic ring closure to furnish isochromanone
29.
Because an ester carbonyl group in the ortho-position
is capable of promoting dipole formation, we decided to
explore whether an aldehydic group in the same location
would undergo a related reaction. To this end, diazo
ketoester 30 was synthesized and subjected to the
tandem cyclization-cycloaddition sequence. We were
gratified to find that the Rh2(tfa)4-catalyzed reaction of
30 in the presence of DMAD afforded cycloadduct 32 in
82% yield. This product is derived by trapping of the
expected six-membered ring dipole 31 with DMAD
(Scheme 7). Most surprisingly, when Rh2(OAc)4 was used
as the catalyst, there were no signs of cycloadduct 32 in
the crude reaction mixture. Instead, the only product
formed (63%) corresponded to the unusual dimer 35. The
structure of this compound was verified by a single-
crystal X-ray analysis.19 What is so remarkable about this
result is the degree of chemoselectivity that can be
achieved by simply changing the dirhodium(II) ligand
from trifluoracetate to acetate. The more electrophilic
ligand on the rhodium metal apparently promotes ex-
clusive dipole formation. We believe that the Rh2(OAc)4-
At this point of our studies, we decided to apply the
intramolecular cyclization-cycloaddition sequence to the
o-allyl substituted diazo ketoester 40. We envisaged that
internal cycloaddition of the six-membered ring dipole
across the tethered π-bond of this model system would
establish the viability of our planned approach toward
the indanobenzazepine skeleton of ribasine. Keto ester
38 was treated with azidotris(diethylamino)phosphonium
bromide (39)27 at -78 °C and the solution was allowed
to warm to -10 °C over a period of several hours. The
electrophilic azide salt 39 is an ideal reagent to use for
(26) For a related ligand effect, see: Padwa, A.; Austin, D. J .; Price,
A. T.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N.; Winchester,
W. R.; Tran, A. J . Am. Chem. Soc. 1993, 115, 8669.
(27) McGuiness, M.; Shechter, H. Tetrahedron Lett. 1990, 31, 4987.

Tandem Cyclization-Cycloaddition
J . Org. Chem., Vol. 64, No. 11, 1999 4083
Wolff rearrangement.32 The transient ketene that is first
formed undergoes a subsequent intramolecular [2 + 2]
cycloaddition across the tethered π-bond to furnish the
observed product.33
Sch em e 8
The myriad of products encountered in the thermal
reaction of diazo ketoester 40 could be significantly
suppressed by adding Rh2(OAc)4 to a hexane solution of
40 and rapidly heating the mixture to 80 °C. In this way,
the internal dipolar cycloaddition reaction of the diazo
group across the alkenyl π-bond can be minimized. The
reaction of 40 under these conditions provides the desired
cycloadduct 46 in 65% yield, together with lesser quanti-
ties of 42 and 43 (20% total). Various conditions were
investigated so as to maximize the yield of 46. Best
results were obtained by heating a sample of 40 in
toluene at 110 °C in the presence of Rh2(tfa)4. With this
catalyst system, the ratio of 46 to 43/42 is g10:1, and
the bicyclic adduct could be isolated in 87% yield. A
similar tandem cyclization-cycloaddition sequence was
used with the closely related diazoketo diester 47, which
afforded the analogous cycloadduct 48 in 68% yield.
low-temperature diazo transfer reactions because the
insoluble byproducts can be easily removed by filtration.28
We found that formation of the desired diazoketone 40
occurred, but over a period of time, it slowly underwent
intramolecular dipolar cycloaddition29 across the neigh-
boring π-bond at -10 °C to furnish indenopyrazole 41
(Scheme 8). Stirring a sample of 41 in CHCl3 at 25 °C
resulted in extrusion of nitrogen and formation of a 1:1
mixture of cyclopropane 42 and indene 43 in 80% overall
yield.30
In some of the experiments, the diazo transfer-
nitrogen extrusion sequence (i.e., 38 f 40 f 42 + 43)
was also accompanied by an additional product (ca. 10%)
whose structure was eventually identified as cyclo-
butanone 44. This same ketone could be prepared in
yields as high as 80% by irradiating a sample of diazo
ketoester 40 with a Pyrex filter sleeve. Longer irradiation
times led to the formation of indene 45 which results from
a Norrish type I induced loss of ketene from cyclo-
butanone 44.31 The formation of cyclobutanone 44 can
The next task in our projected synthesis of ribasine
by this cycloaddition approach would involve using a
N-methyl imine or its equivalent in place of the meth-
ylene π-bond. It seemed reasonable to first evaluate the
possibility of using a cyano functionality as the trapping
dipolarophile because we had already shown that a
carbonyl ylide dipole can cycloadd across a nitrile group
in a bimolecular process (i.e., 13 f 17). Toward this end,
cyano ketoester 49 was prepared and treated under the
low-temperature diazo transfer conditions previously
utilized to prepare 40. We found, however, that treating
49 with azidotris(diethylamino)phosphonium bromide
(39) and base gave only the product (i.e., 50) derived from
diazo transfer R to the cyano functionality. When this
compound was allowed to stand at room temperature for
75 min, triazole 53 was obtained in 92% isolated yield.
The formation of this compound apparently results by
attack of the enol tautomer (i.e., 51) onto the nitrile
functionality followed by a subsequent cyclization at the
be explained in terms of a photochemical (and/or thermal)
(28) Regitz, M. Synthesis 1972, 351. Regitz, M.; Mass, G. Diazo
Compounds: Properties and Synthesis; Academic Press: Orlando, FL,
1986; Chapter 13.
(29) Sturm, H.; Ongania, K. H.; Daly, J . J .; Klo¨tzer, W. Chem. Ber.
1981, 114, 190.
(30) Regitz, M.; Heydt, H. Diazoalkanes in 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York, 1984; Vol.
1, pp 393-558.
(31) Yates, P. Pure Appl. Chem. 1968, 16, 93. Morton, D. R.; Lee-
Ruff, E.; Southam, R. M.; Turro, N. J . J . Am. Chem. Soc. 1970, 92,
4349.
(32) Wentrup, C. Adv. Heterocycl. Chem. 1981, 28, 231. Gassman,
P. G.; Williams, F. J .; Seter, J . J . Am. Chem. Soc. 1968, 90, 6983. Wolff,
L. Liebigs Ann. Chem. 1902, 325, 129.
(33) Snider, B. B. Chem. Rev. 1988, 88, 793. Hyatt, J . A.; Raynolds,
P. W. Org. React. 1994, 45, 159.

4084 J . Org. Chem., Vol. 64, No. 11, 1999
Padwa et al.
for 10 min gave the head-to-tail dimer 15 (87% yield) as a white
powder: mp 245-246 °C; IR (KBr) 1704, 1597, 1282, and 1061
Sch em e 9
1
cm-1; H NMR (300 MHz, CDCl3) δ 3.44 (s, 3H), 6.57 (d, 1H,
J ) 7.8 Hz), 7.11 (dt, 1H, J ) 7.8 and 1.0 Hz), 7.21-7.24 (m,
3H), 7.32 (dt, 1H, J ) 7.8 and 1.0 Hz), 7.80-7.82 (m, 2H), and
8.05 (dd, 1H, J ) 7.8 and 1.0 Hz); 13C NMR (75 MHz, CDCl3)
δ 51.7, 85.1, 100.8, 126.7, 126.9, 127.0, 127.4, 127.8, 129.1,
132.2, 133.0, 134.9, 136.8, and 190.4. Anal. Calcd for
C
32H24O6: C, 76.18; H, 4.79. Found: C, 76.21; H, 4.83.
1-Meth oxy-9,10-diph en yl-11,12-dioxa-tr icyclo[7.2.1](2,7)-
d od eca -2,4,6-tr ien -8-on e (16). The rhodium(II) acetate cata-
lyzed reaction of 39 µL (0.4 mmol) of benzaldehyde and 0.1 g
(0.4 mmol) of diazoketone 13 in 3 mL of toluene at 110 °C for
15 min gave a 2:1 mixture of the endo (16a , 60%) and exo (16b,
30%) cycloadducts. Silica gel chromatography furnished the
endo isomer 16a as a white solid: mp 49-50 °C; IR (neat)
1
1707, 1604, 1452, 1292, 1220, and 1071 cm-1; H NMR (300
MHz, CDCl3) δ 3.85 (s, 3H), 5.21 (s, 1H), 6.87 (d, 2H, J ) 7.4
Hz), 7.17-7.26 (m, 3H), 7.38-7.45 (m, 3H), 7.52 (t, 1H, J )
7.4 Hz), 7.58-7.60 (m, 2H), 7.69 (t, 1H, J ) 7.7 Hz), 7.80 (d,
1H, J ) 7.7 Hz), and 7.95 (d, 1H, J ) 7.7 Hz); 13C NMR (75
MHz, CDCl3) δ 49.7, 85.0, 91.2, 117.5, 122.2, 126.3, 127.1,
127.5, 127.9, 128.2, 128.3, 129.0, 129.4, 130.8, 133.7, 133.8,
134.1, 143.5, and 191.0. Anal. Calcd for C23H18O4: C, 77.09;
H, 5.09. Found: C, 77.35; H, 5.30.
The second fraction contained the exo isomer 16b as a white
diazonium site. The product derived from this cyclization
(i.e., 52) undergoes an in situ oxidation to produce the
thermodynamically more robust triazole 53 (Scheme 9).
In conclusion, the model studies described in this paper
demonstrate that the tandem cyclization-cycloaddition
sequence of ortho-substituted diazo ketoesters represents
a useful approach toward the synthesis of the oxabicyclo-
[3.2.1]octane ring system found in ribasine. In particular,
the results obtained with the rhodium(II)-catalyzed reac-
tion of diazo ketoesters 40 and 47 provide good precedent
for the future implementation of the strategy toward the
synthesis of this alkaloid. Remaining challenges include
replacement of the o-carboalkoxy functionality with an
aldehydic carbonyl group, as well as the incorporation
of an imino group at the ortho-position of the second
aromatic ring. Further studies along these lines will be
reported in due course.
o
crystalline solid: mp 169-170 C; IR (KBr) 1702, 1601, 1455,
1290, 1228, and 1073 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.92
(s, 3H), 5.14 (s, 1H), 7.09-7.17 (m, 8H), 7.22 (dd, 2H, J ) 7.5
and 1.5 Hz), 7.53 (dt, 1H, J ) 7.5 and 0.9 Hz), 7.68 (dt, 1H, J
) 7.5 and 0.9 Hz), 7.75 (d, 1H, J ) 7.5 Hz), and 8.08 (d, 1H,
J ) 7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 50.6, 81.2, 90.5,
117.7, 122.8, 127.1, 127.3, 127.5, 128.0, 128.1, 128.4, 129.2,
129.5, 133.1, 134.5, 136.1, 142.1, and 192.0. Anal. Calcd for
C
23H18O4: C, 77.09; H, 5.06. Found: C, 77.00; H, 5.10.
Eth yl 1-Meth oxy-8-oxo-9-p h en yl-12-oxa -11-a za -tr icy-
clo[7.2.1](2,7)-dodeca-2,4,6,10-tetr aen e-10-car boxylate (17).
The rhodium(II) acetate catalyzed reaction of 0.2 g (0.5 mmol)
of diazoketone 13 with 61 µL (0.6 mmol) of ethyl cyanoformate
in 5 mL of toluene at 110 °C for 30 min gave cycloadduct 17
(97%) as a pale yellow oil: IR (neat) 1735, 1718, 1640, 1276,
and 1059 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H, J )
7.2 Hz), 3.82 (s, 3H), 4.24 (m, 2H), 7.40-7.59 (m, 5H), 7.67
(dd, 1H, J ) 7.5 and 0.9 Hz), 7.83 (dd, 2H, J ) 8.1 and 1.5
Hz), and 7.96 (dd, 1H, J ) 7.5 and 1.5 Hz); 13C NMR (75 MHz,
CDCl3) δ 13.7, 51.4, 62.7, 95.9, 120.9, 123.0, 126.6, 126.9, 127.3,
127.8, 127.9, 128.2, 128.4, 131.1, 140.9, 161.1, 168.8, and 185.2.
Anal. Calcd for C20H17NO5: C, 68.36; H, 4.88; N, 3.99. Found:
C, 68.19; H, 4.93; N, 3.90.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in oven-dried glassware under
an atmosphere of dry nitrogen. 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
otherwise.
11-Ben zen esu lfon yl-1-m eth oxy-9,10-d ip h en yl-12-oxa -
11-a za t r icyclo-[7.2.1](2,7)-d od eca -2,4,6-t r ien -8-on e (18).
The rhodium(II) acetate catalyzed reaction of 0.15 g (0.5 mmol)
of diazoketone 13 and 0.1 g (0.5 mmol) of N-benzylidene-
benzenesulfonamide in 5 mL of toluene at 110 °C for 30 min
gave an 8:1 mixture of endo (18a ) (80%) and exo (18b) (10%)
cycloadducts. Recrystallization of the crude reaction mixture
from ether afforded crystals of the endo cycloadduct 18a : mp
6,7-Dica r bom eth oxy-5,8-d ih yd r o-5,8-ep oxy-5-m eth oxy-
9-oxo-8-p h en yl-9H -b en zocycloh ep t en e (14). The rho-
dium(II) acetate catalyzed reaction of 0.03 g (0.1 mmol) of
R-diazoketone 1334 and 0.2 mL of dimethyl acetylenedicar-
boxylate (DMAD) in 2 mL of toluene at 80 °C for 40 min gave
cycloadduct 14 as a white solid (91%): mp 135-136 °C; IR
178-179 °C; IR (KBr) 1707, 1602, 1220, and 1155 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 3.82 (s, 3H), 5.04 (s, 1H), 6.59 (d,
2H, J ) 7.8 Hz), 6.96 (t, 2H, J ) 7.8 Hz), 7.10-7.18 (m, 4H),
7.23 (d, 2H, J ) 7.4 Hz), 7.33 (s, 5H), 7.55 (t, 1H, J ) 7.8 Hz),
7.76 (t, 1H, J ) 7.8 Hz), 7.87 (d, 1H, J ) 7.8 Hz), and 7.98 (d,
1H, J ) 7.4 Hz); 13C NMR (75 MHz, CDCl3) δ 52.6, 70.9, 87.9,
110.9, 122.5, 125.9, 127.2, 127.4, 127.5, 127.7, 127.8, 128.2,
128.4, 128.5, 129.3, 129.6, 130.1, 131.6, 132.1, 134.3, 141.0,
143.7, and 190.2. Anal. Calcd for C29H23NO5S: C, 70.00; H,
4.66; N, 2.81. Found: C, 69.97; H, 4.70; N, 2.72.
1
(KBr) 1725, 1649, 1593, 1432, and 1258 cm-1; H NMR (300
MHz, CDCl3) δ 3.71 (s, 3H), 3.72 (s, 3H), 3.76 (s, 3H), 7.40-
7.58 (m, 6H), 7.71 (d, 2H, J ) 7.5 Hz), and 7.99 (d, 1H, J )
7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 52.5, 52.6, 52.7, 91.5,
108.8, 122.5, 126.6, 126.7, 128.1, 128.6, 128.9, 129.9, 132.7,
133.3, 142.0, 142.5, 147.3, 161.2, 163.0, and 187.1. Anal. Calcd
for C22H18O7: C, 67.01; H, 4.60. Found: C, 66.94; H, 4.63.
5,6,7,12,13,14-H exa h yd r o-5,12-d im et h oxy-7,14-d ioxo-
6,13-d i p h e n y l-5,13:6,12-d i e p o x y d i b e n z o [a ,f]c y c lo -
d ecen e (15). The rhodium(II) acetate catalyzed reaction of 0.1
g (0.4 mmol) of R-diazoketone 13 in 50 mL of toluene at 80 °C
Silica gel chromatography of the mother liquor afforded the
exo cycloadduct 18b as a white solid: mp 195-196 °C; IR (KBr)
1704, 1600, 1448, and 1171 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.78 (s, 3H), 4.83 (s, 1H), 7.04-7.24 (m, 12H), 7.33 (t, 2H, J
) 8.0 Hz), 7.49 (dt, 1H, J ) 7.5 and 1.2 Hz), 7.64 (d, 1H, J )
8.0 Hz), 7.73 (dt, 1H, J ) 7.5 and 1.2 Hz), 7.78 (d, 1H, J ) 7.5
Hz), and 7.99 (d, 1H, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3)
δ 51.6, 66.4, 90.1, 110.2, 125.2, 127.2, 127.4, 127.5, 127.6, 128.0,
(34) Regitz, M. Chem. Ber. 1965, 98, 1210.

Tandem Cyclization-Cycloaddition
J . Org. Chem., Vol. 64, No. 11, 1999 4085
128.1, 128.4, 128.5, 129.6, 127.7, 132.7, 132.9, 136.1, 142.9,
and 192.2. Anal. Calcd for C29H23NO5S: C, 70.00; H, 4.66; N,
2.81. Found: C, 69.89; H, 4.66; N, 2.78.
3 mL of toluene at 110 °C for 40 min gave 23 in 93% yield as
a white solid: mp 124-125 °C; IR (KBr) 1726, 1689, 1457,
and 1257 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.64 (s, 3H), 3.70
(s, 3H), 3.72 (s, 3H), 7.00-7.11 (m, 2H), 7.35 (t, 2H, J ) 7.5
Hz), 7.42-7.55 (m, 3H), and 8.06 (d, 2H, J ) 7.5 Hz); 13C NMR
(75 MHz, CDCl3) δ 52.5, 55.3, 89.2, 115.4, 120.7, 122.3, 126.7,
126.8, 128.4, 130.2, 133.8, 134.4, 143.0, 146.3, 147.8, 155.2,
162.3, 162.8, and 191.3. Anal. Calcd for C22H18O7: C, 67.00;
H, 4.60. Found: C, 66.83; H, 4.68.
Dim eth yl 1-Meth oxy-8-(2-m eth oxyca r bon yl-ben zoyl)-
11-oxa -t r icyclo-[6.2.1](2,7)u n d eca -2,4,6,9-t et r a en e-9,10-
d ica r boxyla te (27). To a solution containing 0.06 g (0.9 mmol)
of potassium methoxide in 2 mL of dry CH3CN at 0 °C under
N2 was added a solution of 0.16 g (0.8 mmol) of tosyl azide
and 0.2 g (0.7 mmol) of 3-(2-carbomethoxybenzylidene)phtha-
lide36 in 8 mL of CH3CN. The mixture was stirred at 25 °C for
3 h, filtered through a pad of Celite with ether, and concen-
trated under reduced pressure. The residue was dissolved in
CH2Cl2 and washed with a 10% NaOH solution followed by a
pH 7 phosphate buffer, and dried over Na2SO4. The solvent
was removed under reduced pressure, and the residue was
subjected to flash silica gel chromatography to give 0.11 g
(45%) of methyl 2-[1-diazo-2-oxo-2-(2-carbomethoxyphenyl)-
ethyl] benzoate (24) as a labile oil which was immediately used
in the next step to minimize decomposition: IR (neat) 2093,
1722, 1631, and 1285 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.89
(s, 3H), 3.92 (s, 3H), and 7.23-8.04 (m, 8H); 13C NMR (75 MHz,
CDCl3) δ 52.3, 52.4, 73.1, 127.1, 128.1, 128.5, 129.0, 129.4,
129.6, 130.3, 130.4, 131.1, 132.2, 132.4, 140.3, 166.3, 166.4,
and 189.1.
1-Meth oxy-11-m eth yl-9,10-d ip h en yl-12-oxa -11-a za -tr i-
cyclo[7.2.1](2,7)-d od eca -2,4,6-t r ien -8-on e (19). The rho-
dium(II) acetate catalyzed reaction of 0.2 g (0.6 mmol) of
diazoketone 13 with 150 µL (1.2 mmol) of N-benzylidene
methyl-amine in 5 mL of toluene at 110 °C for 30 min gave a
2:1 mixture of endo (19a ) (60%) and exo (19b ) (30%) cyclo-
adducts. Silica gel chromatography of the mixture afforded a
pure sample of the endo isomer 19a as a colorless oil: IR (neat)
1703, 1599, 1449, and 1263 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.17 (s, 3H), 3.68 (s, 3H), 4.65 (s, 1H), 6.74 (d, 2H, J ) 6.9
Hz), 7.18-7.27 (m, 5H), 7.31 (dd, 2H, J ) 4.5 and 1.5 Hz),
7.42-7.45 (m, 2H), 7.62 (d, 2H, J ) 4.5 Hz), and 8.01 (d, 1H,
J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 30.7, 49.9, 73.9, 90.3,
110.6, 122.7, 126.1, 127.4, 127.6, 127.8, 128.2, 128.3, 128.4,
130.0, 131.3, 133.2, 133.9, 136.1, 146.0, and 192.4. Anal. Calcd
for C24H21NO3: C, 77.61; H, 5.70; N, 3.77. Found: C, 77.45;
H, 5.61; N, 3.56.
The second fraction isolated from the column contained the
exo isomer 19b as a white solid: mp 138-139 °C; IR (KBr)
1699, 1599, 1448, and 1065 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.04 (s, 3H), 3.69 (s, 1H), 3.83 (s, 3H), 7.04-7.10 (m, 7H),
7.23-7.25 (m, 3H), 7.49 (dt, J ) 7.1 and 2.0 Hz), 7.63-7.66
(m, 2H), and 8.14 (d, 1H, J ) 8.1 Hz); 13C NMR (75 MHz,
CDCl3) δ 33.7, 49.3, 71.5, 88.1, 110.9, 124.5, 126.7, 126.9, 127.3,
127.5, 127.6, 127.7, 127.8, 128.7, 128.8, 129.4, 133.7, 138.3,
140.9, and 192.1. Anal. Calcd for C24H21NO3: C, 77.61; H, 5.70;
N, 3.77. Found: C, 77.50; H, 5.65; N, 3.72.
Meth yl 2-(2-Oxo-2-p h en yleth yl)ben zoa te. A procedure
similar to that used by McKillop35 was employed to synthesize
2-(2-oxo-2-phenyl)ethyl benzoic acid. To a solution containing
20 g (120 mmol) of 1-benzoyl acetone, 2.5 g (12 mmol) of
2-bromobenzoic acid, and 0.1 g (0.7 mmol) of cuprous bromide
in 20 mL of benzene under nitrogen was added 1.2 g (30 mmol)
of NaH (60%) in 10 mL of benzene. The reaction mixture was
heated at reflux for 3 h, cooled to 25 °C, and poured into 50
mL of water. The solution was allowed to stand for 15 min
and was filtered through a pad of Celite. The filtrate was
extracted with ether, and the aqueous layer was acidified to
pH 3 with concentrated HCl. The white solid that formed was
washed with 10 mL of water, dried, and dissolved in 20 mL of
THF.
To a solution of 30 mmol of diazomethane in ether at 0 °C
was added the above solution, and the mixture was warmed
to 25 °C, stirred overnight, and concentrated under reduced
pressure. The resultant residue was recrystallized from ether-
hexane to give 0.55 g of methyl 2-(2-oxo-2-phenylethyl) ben-
zoate as a white solid: mp 93-94 °C; IR (KBr) 1710, 1682,
1596, 1267, and 1082 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.75
(s, 3H), 4.73 (s, 2H), 7.24-7.61 (m, 6H), and 8.05-8.08 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 44.8, 51.8, 127.1, 128.1,
128.5, 129.5, 131.0, 132.3, 132.5, 132.9, 136.8, 137.0, 167.3,
and 197.1. Anal. Calcd for C16H14O3: C, 75.58; H, 5.55.
Found: C, 75.52; H, 5.57.
The rhodium(II) acetate catalyzed reaction of 0.05 g (0.2
mmol) of R-diazoketone 24 with 24 µL (0.2 mmol) of DMAD in
2 mL of toluene at 110 °C for 1.5 h followed by removal of the
solvent afforded a clear oil which was subjected to silica gel
chromatography. The major fraction isolated (68%) corre-
sponded to cycloadduct 27 and was obtained as a white solid:
mp 160-161 °C; IR (KBr) 1729, 1654, 1436, and 1290 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.53 (s, 3H), 3.59 (s, 3H), 3.73
(s, 3H), 3.82 (s, 3H), 7.12-7.14 (m, 2H), 7.40-7.43 (m, 1H),
7.49-7.60 (m, 4H), and 7.92 (dd, 1H, J ) 7.1 and 1.5 Hz); 13
C
NMR (75 MHz, CDCl3) δ 52.4, 52.5, 52.7, 55.1, 90.2, 114.5,
120.7, 120.8, 126.7, 126.9, 128.1, 129.4, 130.2, 130.9, 132.3,
137.7, 142.9, 144.0, 147.4, 156.7, 161.9, 162.9, 166.7, and 197.4.
Anal. Calcd for C24H20O9: C, 63.70; H, 4.46. Found: C, 63.58;
H, 4.39.
The minor fraction isolated from the column contained
cycloadduct 6-dicarbomethoxy-5,8-dihydro-5,8-epoxy-5-meth-
oxy-9-oxo-8-(2-carbomethoxyphenyl)-9H-benzocycloheptene (28)
(17%) as a white solid: mp 149-150 °C; IR (neat) 1729, 1653,
1437, and 1254; 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 3H),
3.82 (s, 3H), 3.94 (s, 3H), 4.06 (s, 3H), 7.49-7.77 (m, 4H), 7.91
(m, 1H), and 8.15-8.22 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
52.6, 52.7, 52.7, 52.8, 88.4, 113.9, 123.2, 123.6, 128.3, 128.9,
129.0, 130.1, 131.0, 132.3, 133.8, 142.0, 142.6, 153.1, 164.7,
164.9, 166.6, and 181.3. Anal. Calcd for C24H20O9: C, 63.70;
H, 4.46. Found: C, 63.51; H, 4.42.
Dim eth yl 1-Ben zoyl-8-m eth oxy-11-oxa -tr icyclo[6.2.1]-
(2,7)u n d eca -2,4,6,9-tetr a en e-9,10-d ica r boxyla te (23). A
suspension containing 0.01 g (0.5 mmol) of NaH in 2 mL of
THF was cooled to -78 °C under N2 and treated with a
solution containing 0.19 g (0.5 mmol) of azidotris(diethyl-
amino)phosphonium bromide30 and 0.1 g (0.4 mmol) of the
above ester in 1 mL of THF. The resulting solution was stirred
at -78 °C for 10 min and was allowed to warm to 0 °C over a
2 h period. The solution was concentrated under reduced
pressure, and the residue was subjected to flash silica gel
chromatography to give 0.06 g (51%) of R-diazoketone 20 as a
labile orange oil which was immediately used in the next step
to minimize decomposition: IR (neat) 2070, 1723, 1626, and
Meth yl 2-(1-Meth oxy-3-oxo-3H-isoch r om en -4-yl)-ben -
zoa te (29). Heating a 0.05 g (0.2 mmol) sample of R-diazo-
ketone 24 at 110 °C in toluene for 12 h followed by silica gel
chromatography afforded isochromanone 29 (87%) as a pale
yellow oil: IR (neat) 1743, 1727, 1647, 1290, and 1256 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.63 (s, 3H), 3.87 (s, 3H), 6.85
(d, 1H, J ) 8.1 Hz), 7.26-7.32 (m, 2H), 7.46-7.51 (m, 2H),
7.60 (dt, 1H, J ) 7.5 and 1.2 Hz), 8.04 (dd, 1H, J ) 7.5 and
1.2 Hz), and 8.24 (d, 1H, J ) 7.5 Hz); 13C NMR (75 MHz,
CDCl3) δ 51.9, 56.5, 96.1, 117.0, 123.0, 125.1, 128.1, 129.8,
130.8, 131.7, 132.2, 132.8, 133.0, 134.9, 140.9, 153.1, 161.0,
and 167.0; HRMS calcd for C18H14O5 310.0841, found 310.0840.
1
Eth yl 2-Diazo-3-(2-for m yl-ph en yl)-3-oxo-pr opion ate (30).
A solution of LDA was prepared by the addition of 4.0 mL (6.7
mmol) of a 1.6 M solution of n-BuLi in hexane to 0.9 mL (6.7
1255 cm-1; H NMR (300 MHz, CDCl3) δ 3.84 (s, 3H), 7.31-
7.46 (m, 5H), 7.49-7.56 (m, 3H), and 8.02 (d, 1H, J ) 7.8 Hz).
The rhodium(II) acetate catalyzed reaction of 0.06 g (0.2
mmol) of R-diazoketone 20 with 32 µL (0.3 mmol) of DMAD in
(36) Letsinger, R. L.; Oftendahl, E. N.; Nazy, J . R. J . Am. Chem.
Soc. 1965, 87, 742.
(35) Bruggink, A.; McKillop, A. Tetrahedron 1975, 2607.

4086 J . Org. Chem., Vol. 64, No. 11, 1999
Padwa et al.
mmol) of diisopropylamine in 10 mL of THF at 0 °C. This
solution was added dropwise to a mixture containing 0.9 g (7.6
mmol) of ethyl diazoacetate and 1.1 g (6.1 mmol) of 2-dimethoxy-
methylbenzaldehyde37 in 30 mL of THF at -78 °C. After 2 h
of stirring at -78 °C, the solution was transferred to an ice
bath and was quenched by the addition of 5 mL of a pH 7
phosphate buffer solution. The reaction mixture was extracted
with CH2Cl2, and the organic extracts were washed with water
and brine, dried over Na2SO4, and concentrated under reduced
pressure to give ethyl 2-diazo-3-(2-dimethoxymethylphenyl)-
3-hydroxy-propionate as a yellow oil: IR (neat) 3440, 2097,
1685, 1371, and 1107 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.29
(t, 3H, J ) 7.1 Hz), 3.33 (s, 6H), 4.27 (q, 2H, J ) 7.1 Hz), 5.44
(s, 1H), 6.23 (s, 1H), 7.34 (dt, 1H, J ) 7.5 and 1.2 Hz), 7.41
(dt, 1H, J ) 7.5 and 1.2 Hz), 7.56 (d, 1H, J ) 7.5 Hz), and
7.65 (d, 1H, J ) 7.5 Hz). This compound was used directly in
the next step without further purification.
A 3.1 g (12.1 mmol) sample of BaMnO4 was added to a
solution of the above ester in 60 mL of CH2Cl2, and the mixture
was heated at reflux for 44 h. After cooling to room temper-
ature, the mixture was filtered through a plug of Celite and
was concentrated under reduced pressure to give ethyl 2-diazo-
3-(2-dimethoxymethylphenyl)-3-oxo-propionate as a yellow
oil: IR (neat) 2143, 1726, 1693, 1269, and 1108 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.15 (t, 3H, J ) 7.2 Hz), 3.27 (s, 6H), 4.15
(q, 2H, J ) 7.2 Hz), 5.64 (s, 1H), 7.24 (d, 1H, J ) 7.7 Hz), 7.37
(t, 1H, J ) 7.7 Hz), 7.44 (dt, 1H, J ) 7.7 and 0.9 Hz), and 7.61
(d, 1H, J ) 7.7 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 52.5,
61.2, 100.2, 126.4, 126.8, 127.7, 129.5, 135.5, 137.3, 160.5, and
188.4. This compound was used in the next step without
further purification.
93.1, 123.7, 127.0, 127.4, 128.0, 129.3, 129.6, 130.8, 133.3,
134.6, 135.9, 139.7, 151.9, 163.5, 165.8, 185.6, and 193.6. Anal.
Calcd for C24H20O8: C, 66.06; H, 4.62. Found: C, 65.91; H,
4.56.
6,7-Dica r bom eth oxy-5,8-d ih yd r o-5,8-ep oxy-5-m eth oxy-
9-oxo-8-p h en yl-9H-ben zocycloh ep ten e (37). To a solution
containing 0.1 g (0.3 mmol) of 60% NaH in 10 mL of ether at
0 °C under N2 was added 0.2 g (0.3 mmol) of 3-buten-1-ol. The
reaction mixture was stirred at 0 °C for 15 min, and the ether
was removed under reduced pressure. The resulting salt was
suspended in 5 mL of CH3CN and cooled to 0 °C under N2. To
this suspension was added a mixture of 0.5 g (2.5 mmol) of
tosyl azide and 0.5 g (2.2 mmol) of benzalphthalide in 5 mL of
CH3CN. The reaction mixture was allowed to warm to room
temperature and was stirred for 2 h. An additional 0.5 g (2.5
mmol) of tosyl azide was added, followed by 0.3 g (0.3 mmol)
of sodium salt of 3-buten-1-ol in 5 mL of CH3CN at 0 °C. The
reaction mixture was stirred overnight at 25 °C, the solution
was filtered through Celite with ether, and the solvent was
removed under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 0.3 g (42%) of but-
3-enyl 2-(2-diazophenylacetyl) benzoate (36) as a bright orange
oil: IR (neat) 2076, 1720, 1636, 1596, and 1283 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.35-2.42 (m, 2H), 4.29 (t, 2H, J ) 6.7
Hz), 5.05 (dd, 1H, J ) 9.8 and 1.2 Hz), 5.04 (dd, 1H, J ) 17.0
and 1.2 Hz), 5.67-5.80 (m, 1H), 7.21 (t, 1H, J ) 7.5 Hz), 7.30-
7.60 (m, 7H), and 7.99 (d, 1H, J ) 7.5 Hz); 13C NMR (75 MHz,
CDCl3) δ 32.7, 61.3, 64.6, 117.3, 125.3, 125.5, 126.8, 127.0,
128.6, 128.9, 129.8, 130.6, 132.6, 133.7, 140.5, 165.6, and 189.2.
The diazoketone was immediately used in the next step to
minimize decomposition.
The rhodium(II) acetate catalyzed reaction of 0.04 g (0.1
mmol) of diazoketone 36 in 25 mL of toluene at 110 °C for 10
min gave the internal cycloadduct 37 in 96% yield as a white
solid: mp 141-142 °C; IR (KBr) 1696, 1602, 1444, 1272, 1194,
To a suspension of 14 g of silica gel in 80 mL of CH2Cl2 was
added 2.8 mL of 10% HCl with vigorous stirring. A solution of
the above ester in 20 mL of CH2Cl2 was added dropwise to
the silica gel suspension, the reaction mixture was stirred at
25 °C for 3 h, and then 0.8 g of solid NaHCO3 was added to
the mixture. After 5 min of stirring, the solid phase was
separated, and the solution was concentrated under reduced
pressure. The resulting residue was subjected to flash silica
gel chromatography to give 0.9 g (53% yield) of ethyl 2-diazo-
3-(2-formylphenyl)-3-oxo-propionate (30) as a yellow solid: mp
1
and 1039 cm-1; H NMR (300 MHz, CDCl3) δ 1.85-1.96 (m,
1H), 2.31 (dd, 1H, J ) 12.8 and 4.0 Hz), 2.32-2.44 (m, 1H),
2.71 (dd, 1H, J ) 12.8 and 8.7 Hz), 2.75-2.84 (m, 1H), 4.40
(ddd, 1H, J ) 15.5, 7.2, and 1.9 Hz), 4.53 (ddd, 1H, J ) 15.5,
7.5, and 1.5 Hz), 7.29-7.66 (m, 9H), and 7.96 (d, 1H, J ) 7.5
Hz); 13C NMR (75 MHz, CDCl3) δ 33.4, 40.5, 48.3, 71.5, 91.0,
113.9, 121.7, 126.1, 127.7, 127.9, 128.7, 130.0, 133.9, 138.8,
144.8, and 195.5. Anal. Calcd for C19H16O3: C, 78.07; H, 5.52.
Found: C, 78.15; H, 5.56.
58-59 °C; IR (neat) 2147, 1717, 1698, 1320, and 1126 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.13 (t, 3H, J ) 7.1 Hz), 4.09 (q,
2H, J ) 7.1 Hz), 7.34 (dd, 1H, J ) 7.0 and 1.8 Hz), 7.63 (m,
2H), 7.87 (dd, 1H, J ) 7.0 and 1.8 Hz), and 9.99 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 14.0, 61.4, 127.1, 130.2, 131.4, 133.6,
133.7, 139.6, 160.5, 190.8, and 190.9. Anal. Calcd for
3-(2-Allylben zylid en e)p h th a lid e. A procedure similar to
that used by Weiss38 was employed to synthesize 3-(2-bromo-
benzylidene)phthalide. In a three-necked, 50 mL round-bottom
flask equipped with a thermometer and two glass stoppers was
placed 2.0 g (13.5 mmol) of phthalic anhydride, 3.4 g (16 mmol)
of 2-bromophenyl-acetic acid, and 0.05 g (0.6 mmol) of anhy-
drous NaOAc. The reaction mixture was heated for 2 h at 220
°C and cooled to room temperature, and the solid was
recrystallized from CH2Cl2-ether to give 2.2 g (55%) of 3-(2-
bromobenzylidene)phthalide as light yellow crystals:39 mp
C
12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C, 58.36; H,
4.15; N, 11.33.
9-Eth yl-10,11-dim eth yl-8-oxo-12-oxa-tr icyclo[7.2.1](2,7)-
d od eca -2,4,6,10-tetr a en e-9,10,11-tr ica r boxyla te (32). The
rhodium(II) trifluoroacetate catalyzed reaction of 0.06 g (0.3
mmol) of R-diazoketone 30 with 38 µL (0.3 mmol) of DMAD in
5 mL of CH2Cl2 at 40 °C for 40 min followed by silica gel
chromatography afforded cycloadduct 32 (82%) as a white
solid: mp 121-122 °C; IR (KBr) 1743, 1723, 1710, 1651, 1602,
and 1284 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J )
7.1 Hz), 3.77 (s, 3H), 3.86 (s, 3H), 4.37 (m, 2H), 5.92 (s, 1H),
7.30 (dd, 1H, J ) 7.2 and 1.2 Hz), 7.49 (m, 2H), and 8.01 (dd,
1H, J ) 7.2 and 1.5 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9,
52.8, 52.8, 62.9, 82.9, 96.5, 123.8, 126.7, 129.1, 129.7, 134.0,
141.2, 141.5, 142.9, 160.7, 162.9, 163.1, and 183.2. Anal. Calcd
for C18H16O8: C, 60.01; H, 4.48. Found: C, 60.11; H, 4.49.
153-154 °C; IR (KBr) 1785, 1475, and 1075 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 6.88 (s, 1H), 7.15 (t, 1H, J ) 7.7 Hz), 7.38
(t, 1H, J ) 7.7 Hz), 7.58 (t, 1H, J ) 7.7 Hz), 7.62 (d, 1H, J )
7.7 Hz), 7.75 (t, 1H, J ) 7.7 Hz), 7.86 (d, 1H, J ) 7.7 Hz), 7.95
(d, 1H, J ) 7.7 Hz), and 8.29 (d, 1H, J ) 7.7 Hz); 13C NMR (75
MHz, CDCl3) δ 104.9, 120.2, 123.4, 124.6, 125.5, 127.7, 129.4,
130.2, 131.8, 132.5, 132.9, 134.6, 140.3, 145.7, and 166.7.
A solution containing 2.0 g (6.6 mmol) of the above phtha-
lide, 2.2 mL (7 mmol) of allyltributyltin, and 0.07 g (0.07 mmol)
of tetrakis(triphenylphosphine)palladium(0) in 7 mL of ben-
zene was heated at 100 °C in a sealed tube for 2 h. The mixture
was cooled to room temperature, diluted with ether, and
poured into a 10% aqueous KF solution. The aqueous mixture
was extracted with ether, dried over MgSO4, and concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography to give 1.2 g (69%) of 3-(2-allylben-
zylidene)phthalide as white needles: mp 89-90 °C; IR (KBr)
The same reaction was repeated using rhodium(II) acetate,
which furnished 4b,5,6,11,11a,12-hexahydro-5,11a-dicarbo-
ethoxy-4b-hydroxy-6,12-dioxo-dibenz[a,f]-azulene (35) (63%) as
a white solid: mp 188-189 °C; IR (KBr) 3400, 1750, 1721,
1603, and 1277 cm-1 1H NMR (300 MHz, CDCl3) δ 1.15 (t,
;
3H, J ) 7.2 Hz), 1.22 (t, 3H, J ) 7.2 Hz), 4.08 (m, 4H), 5.12 (s,
1H), 5.90 (s, 1H), 7.44-7.61 (m, 4H), 7.74 (d, 1H, J ) 7.0 Hz),
7.76 (d, 1H, J ) 7.5 Hz), and 8.07 (t, 2H, J ) 8.5 Hz); 13C
NMR (75 MHz, CDCl3) δ 13.8, 13.9, 62.0, 63.0, 74.8, 79.8, 87.5,
(38) Weiss, R. Org. Synth. Coll. Vol. 2 1943, 61.
(39) Krasnec, L., J r.; Solca´niova´, P. Hernciar. Collect. Czech. Chem.
Commun. 1980, 45, 1589.
(37) Meegalla, S. K.; Rodrigo, R. J . Org. Chem. 1991, 56, 1882.

Tandem Cyclization-Cycloaddition
J . Org. Chem., Vol. 64, No. 11, 1999 4087
1
1784, 1770, 1657, 1637, and 1264 cm-1; H NMR (300 MHz,
CDCl3) δ 3.55 (d, 2H, J ) 6.0 Hz), 5.04 (dd, 1H, J ) 16.8 and
1.1 Hz), 5.11 (dd, 1H, J ) 10.5 and 1.1 Hz), 6.01 (ddt, 1H, J )
16.8, 10.5 and 6.0 Hz), 6.67 (s, 1H), 7.28 (m, 3H), 7.55 (t, 1H,
J ) 7.5 Hz), 7.70 (d, 1H, J ) 7.5 Hz), 7.76 (d, 1H, J ) 7.5 Hz),
7.93 (d, 1H, J ) 7.5 Hz), and 8.16 (d, 1H, J ) 7.5 Hz); 13C
NMR (75 MHz, CDCl3) δ 38.2, 103.9, 104.9, 116.2, 119.8, 123.5,
125.5, 127.0, 128.6, 129.9, 130.9, 131.5, 134.4, 136.8, 140.6,
144.8, and 167.1. Anal. Calcd for C18H14O2: C, 82.42; H, 5.38.
Found: C, 82.21; H, 5.39.
Eth yl 2-(2-Meth yl-3H-in den e-1-car bon yl)-ben zoate (43).
The second fraction isolated from the above chromatographic
separation contained indene 43 (40%) as a colorless oil: IR
1
(neat) 1720, 1671, 1596, and 1280 cm-1; H NMR (300 MHz,
CDCl3) δ 1.07 (t, 3H, J ) 7.1 Hz), 1.86 (s, 3H), 3.51 (s, 2H),
4.04 (q, 2H, J ) 7.1 Hz), 7.17 (t, 1H, J ) 7.2 Hz), 7.25 (t, 1H,
J ) 7.2 Hz), 7.37 (d, 1H, J ) 7.2 Hz), 7.46 (d, 1H, J ) 7.2 Hz),
7.57 (m, 2H), 7.67 (d, 1H, J ) 7.2 Hz), and 7.92 (d, 1H, J )
7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 13.7, 16.4, 45.1, 61.6,
121.8, 123.0, 124.8, 126.6, 127.4, 129.8, 130.0, 130.1, 130.4,
137.3, 140.7, 143.0, 143.2, 155.9, 166.9, and 194.3; HRMS calcd
for C20H18O3 306.1256, found, 306.1269.
Eth yl 2-[(2-Allylp h en yl)a cetyl]-ben zoa te (38). To a solu-
tion containing 0.7 g (2.7 mmol) of the above compound in 15
mL of absolute ethanol was added 0.3 mL concentrated sulfuric
acid and the mixture was heated at 55 °C for 12 h. The solution
was poured into a pH 7 phosphate buffer, extracted with ether,
dried over MgSO4, and concentrated under reduced pressure.
The residue was subjected to silica gel chromatography. The
major fraction isolated from the column contained 0.4 g (48%)
Eth yl 2-(2-Oxo-1,2,7,7a -tetr a h yd r ocyclobu t[a ]in d en -
2a -yl)-ben zoa te (44). In addition to the above two com-
pounds, a small amount (8%) of cyclobutanone 44 was also
isolated from the chromatograhic column as a clear oil: IR
1
(neat) 1773, 1715, 1259, and 1072 cm-1; H NMR (300 MHz,
CDCl3) δ 1.30 (t, 3H, J ) 7.1 Hz), 2.75 (dd, 1H, J ) 17.5 and
5.2 Hz), 3.03 (d, 1H, J ) 16.5 Hz), 3.38 (ddd, 1H, J ) 9.0, 7.0
and 5.2 Hz), 3.52 (dd, 1H, J ) 16.5 and 7.0 Hz), 3.56 (dd, 1H,
J ) 17.5 and 9.0 Hz), 4.23 (m, 2H), 7.10 (dt, 1H, J ) 7.5 and
0.9 Hz), 7.30 (m, 6H), and 7.76 (dd, 1H, J ) 7.5 and 1.6 Hz);
13C NMR (75 MHz, CDCl3) δ 14.1, 37.8, 38.6, 51.1, 61.2, 83.9,
125.8, 126.6, 127.1, 127.4, 128.4, 129.4, 130.0, 131.0, 131.3,
138.7, 141.3, 144.3, 168.7, and 205.1. Anal. Calcd for
of 38 as a clear oil: IR (neat) 1715, 1638, 1596, and 1279 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J ) 7.2 Hz), 3.37 (d,
2H, J ) 6.3 Hz), 4.18 (s, 2H), 4.36 (q, 2H, J ) 7.2 Hz), 4.94
(dd, 1H, J ) 17.1 and 1.5 Hz), 5.03 (dd, 1H, J ) 10.4 and 1.5
Hz), 5.90 (ddt, 1H, J ) 17.1, 10.4 and 6.3 Hz), 7.19 (m, 5H),
7.48 (m, 2H), and 7.92 (dd, 1H, J ) 6.7 and 2.4 Hz); 13C NMR
(75 MHz, CDCl3) δ 14.1, 37.4, 46.8, 61.6, 115.8, 126.5, 126.6,
127.4, 128.6, 129.6, 129.8, 130.9, 131.9, 132.4, 136.8, 142.9,
166.5, and 202.8. Anal. Calcd for C20H20O3: C, 77.90; H, 6.54.
Found: C, 77.97; H, 6.56.
C
20H18O3: C, 78.41; H, 5.92. Found: C, 78.13; H, 5.91.
Cyclobutanone 44 could also be obtained in higher yield by
carrying out an irradiation of a solution of 0.09 g (0.3 mmol)
of 40 in 200 mL of CH2Cl2 at -10 °C with a 450-W Hanovia
lamp equipped with a Pyrex glass filter sleeve for 1 h under
argon. Removal of the solvent under reduced pressure followed
by silica gel chromatography of the residue gave 44 in 80%
yield.
Eth yl 2-(1H-In d en -3-yl)-ben zoa te (45). A solution con-
taining 0.06 g (0.2 mmol) of cyclobutanone 44 in 100 mL of
CH2Cl2 at 25 °C was irradiated with a 450-W Hanovia lamp
equipped with a Pyrex glass filter sleeve for 3 h under argon.
The solvent was removed under reduced pressure, and the
residue was subjected to silica gel chromatography to give the
known indene 4540 as a clear oil in 78% yield: IR (neat) 1713,
1598, 1288, and 1128 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.82
(t, 3H, J ) 7.0 Hz), 3.52 (d, 2H, J ) 1.9 Hz), 3.96 (q, 2H, J )
7.0 Hz), 6.46 (t, 1H, J ) 1.9 Hz), 7.07 (m, 1H), 7.20 (m, 2H),
7.50 (m, 4H), and 7.95 (dd, 1H, J ) 7.5 and 1.5 Hz); 13C NMR
(75 MHz, CDCl3) δ 13.2, 38.1, 60.8, 119.5, 123.7, 124.5, 126.0,
127.5, 130.0, 130.2, 130.6, 130.9, 131.7, 136.4, 143.2, 145.2,
145.5, and 168.0.
E t h yl 2-(3a ,4-Dih yd r o-3H -in d en o[1,2-c]p yr a zole-8b-
ca r bon yl)-ben zoa te (41). A suspension containing 0.08 g (1.9
mmol) of NaH (60%) in 5 mL of THF was washed with hexane,
cooled to -78 °C under nitrogen, and treated with a solution
containing 0.77 g (2.1 mmol) of azidotris(diethylamino)phos-
phonium bromide (39)27 and 0.48 g (1.6 mmol) of 38 in 4 mL
of THF. The solution was stirred at -78 °C for 10 min and
then at -10 °C for 2 h. Removal of the solvent under reduced
pressure afforded ethyl 2-[(2-allylphenyl)-diazo-acetyl]-ben-
zoate (40) as an orange oil (71%), which was immediately used
in the next step to minimize decomposition; IR (neat) 2079,
1716, 1282, and 1084 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.36
(t, 3H, J ) 7.0 Hz), 3.47 (d, 2H, J ) 6.3 Hz), 4.36 (q, 2H, J )
7.0 Hz), 5.06 (d, 1H, J ) 17.0 Hz), 5.10 (d, 1H, J ) 9.6 Hz),
5.95 (m, 1H), 7.00-7.60 (m, 6H), 7.68 (t, 1H, J ) 7.8 Hz), and
7.97 (d, 1H, J ) 7.8 Hz).
When a hexane solution of R-diazoketone 40 was allowed
to stand at -10 °C for 4 days, it slowly underwent intramo-
lecular 1,3-dipolar cycloaddition to give indenopyrazole 41
(55%) as a white solid: mp 83-84 °C; IR (KBr) 1705, 1654,
1282, and 1081 cm-1; 1H NMR (300 MHz, C6D6) δ 0.76 (t, 3H,
J ) 7.2 Hz), 2.16 (d, 1H, J ) 16.5 Hz), 3.23 (dd, 1H, J ) 16.5
and 8.2 Hz), 3.37 (ddd, 1H, J ) 9.8, 8.2 and 6.2 Hz), 3.55 (dd,
1H, J ) 18.1 and 6.2 Hz), 3.72 (m, 2H), 4.76 (dd, 1H, J ) 18.1
and 9.8 Hz), 6.78-6.98 (m, 5H), 7.24 (d, 1H, J ) 7.5 Hz), 7.32
(t, 1H, J ) 8.0 Hz), and 7.71 (d, 1H, J ) 7.5 Hz); 13C NMR (75
MHz, CDCl3) δ 14.0, 37.9, 38.7, 61.7, 77.3, 86.0, 117.4, 125.0,
125.7, 127.0, 128.6, 129.2, 120.4, 129.7, 132.9, 138.4, 141.8,
166.0, and 203.2.
Eth yl 2-(6,6a -Dih yd r o-1H-cyclop r op [a ]in d en e-1a -ca r -
bon yl)-ben zoa te (42). A solution containing 0.1 g (0.3 mmol)
of 41 in 1.0 mL of chloroform was allowed to stand at 25 °C
for 2 days. Removal of the solvent under reduced pressure
afforded a clear oil, which was subjected to flash silica gel
chromatography. Cyclopropane 42 was obtained (40%) as a
clear oil: IR (neat) 1717, 1674, 1277, and 1259 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.87 (dd, 1H, J ) 5.6 and 4.2 Hz), 1.21 (t,
3H, J ) 7.2 Hz), 2.17 (dd, 1H, J ) 8.6 and 4.2 Hz), 2.58 (ddd,
1H, J ) 8.6, 6.8 and 5.6 Hz), 2.96 (d, 1H, J ) 16.9 Hz), 3.35
(dd, 1H, J ) 16.9 and 6.8 Hz), 4.21 (m, 2H), 7.04 (m, 5H), 7.44
(dt, 1H, J ) 7.5 and 1.1 Hz), 7.51 (dt, 1H, J ) 7.5 and 1.1 Hz),
and 7.91 (d, 1H, J ) 8.4 Hz); 13C NMR (75 MHz, CDCl3) δ
14.0, 27.9, 33.3, 34.4, 45.7, 61.5, 104.9, 125.3, 126.1, 126.2,
126.8, 129.1, 129.2, 129.8, 132.1, 142.0, 142.2, 142.6, 165.9,
and 204.2. Anal. Calcd for C20H18O3: C, 78.41; H, 5.92.
Found: C, 77.84; H, 5.88.
4b,10-Ep oxy-10-eth oxy-4b,5,10,11,11a ,12-h exa h yd r o-5-
oxo-d iben z-[a ,g]a zu len e (46). A mixture containing 0.1 g
diazoketone 40 and 0.02 g of rhodium(II) acetate in 80 mL of
hexane was rapidly heated at 80 °C for 30 min. Removal of
the solvent followed by silica gel chromatography afforded
cycloadduct 46 (65%) together with a 1:1 mixture of 42 and
43 in 20% yield. Repetition of the experiment using rho-
dium(II) trifluoroacetate in toluene at 110 °C for 30 min gave
cycloadduct 46 as a crystalline solid in 87% yield: mp 142-
1
143 °C; IR (neat) 1696, 1600, 1454, 1174, and 1006 cm-1; H
NMR (300 MHz, CDCl3) δ 1.25 (t, 3H, J ) 7.0 Hz), 2.29 (dd,
1H, J ) 12.2 and 6.4 Hz), 2.52 (dd, 1H, J ) 12.2 and 9.0 Hz),
2.94 (m, 1H), 3.06 (dd, 1H, J ) 16.6 and 5.8 Hz), 3.44 (dd, 1H,
J ) 16.6 and 9.5 Hz), 3.70 (m, 2H), 7.24-7.52 (m, 6H), 7.64 (t,
1H, J ) 7.5 Hz), and 8.09 (d, 1H, J ) 7.5 Hz);13C NMR (75
MHz, CDCl3) δ 15.4, 39.1, 43.2, 44.2, 60.6, 98.5, 109.7, 123.5,
124.9, 126.9, 127.0, 127.4, 128.6, 130.1, 130.7, 133.9, 136.5,
145.9, 146.1, and 194.1. Anal. Calcd for C20H18O3: C, 78.41;
H, 5.92. Found: C, 78.53; H, 5.96.
Meth yl 2-[2-[2-(2-Meth oxycar bon ylallyl)ph en yl]acetyl]-
ben zoa t e. To a solution containing 0.9 g (3 mmol) of 3-(2-
bromobenzylidene)phthalide and 1.8 g (4.5 mmol) of 2-(car-
bomethoxy)allyl tributyltin41 in 4 mL of toluene was added 0.02
g (0.03 mmol) of bis(tri-o-tolylphosphine) palladium(II) chlo-
(40) Miettinen, T. Acta Chem. Scand. B 1978, 32, 613.
(41) Baldwin, J . E.; Adlington, R. M.; Birch, D. J .; Crawford, J . A.;
Sweeney, J . B. J . Chem. Soc., Chem. Commun. 1986, 1339.

4088 J . Org. Chem., Vol. 64, No. 11, 1999
Padwa et al.
ride,42 and the mixture was heated for 1 h at reflux under an
argon atmosphere. The solvent was removed under reduced
pressure, and the residue was subjected to flash silica gel
chromatography to give 0.5 g (52%) of 3-[2-(2-methyl-allyl)-
benzylidene]-3H-isobenzofuranone as a white solid: mp 105-
106 °C; 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 3H), 3.80 (s, 2H),
5.28 (s, 1H), 6.25 (s, 1H), 6.58 (s, 1H), 7.20-7.37 (m, 3H), 7.55
(dt, 1H, J ) 7.0 and 1.1 Hz), 7.69-7.77 (m, 2H), 7.93 (d, 1H,
J ) 7.6 Hz), and 8.18 (d, 1H, J ) 7.6 Hz).
To a solution containing 0.5 g (1.5 mmol) of the above
compound in 8 mL of methanol was added 0.15 mL of
concentrated sulfuric acid, and the mixture was heated at 60
°C for 12 h. The solution was poured into a pH 7 phosphate
buffer and extracted with ether. The combined organic extracts
were dried over MgSO4 and concentrated under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy to give 0.25 g (48%) of methyl 2-[2-[2-(2-methoxycar-
bonylallyl)-phenyl]acetyl] benzoate: IR (neat) 1720, 1715,
1640, 1598, and 1280 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.62
(s, 2H), 3.73 (s, 3H), 3.88 (s, 3H), 4.15 (s, 2H), 5.22 (s, 1H),
6.18 (s, 1H), 7.13-7.56 (m, 7H), and 7.91 (dd, 1H, J ) 7.1 and
1.5 Hz); 13C NMR (75 MHz, CDCl3) δ 34.9, 46.7, 51.8, 52.5,
126.3, 126.5, 126.8, 127.4, 128.2, 129.6, 129.9, 130.3, 131.1,
132.1, 132.6, 137.3, 139.3, 143.0, 166.9, 167.3, and 202.7. Anal.
Calcd for C21H20O5: C, 71.56; H, 5.72. Found: C, 71.38; H,
5.66.
Hz), and 8.05 (d, 1H, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3)
δ 22.4, 101.7, 117.4, 120.2, 123.7, 125.7, 128.1, 128.8, 128.9,
129.3, 130.5, 131.3, 131.4, 134.7, 139.8, 146.2, and 166.6. Anal.
Calcd for C17H11NO2: C, 78.15; H, 4.24; N, 5.36. Found: C,
78.13; H, 4.26; N, 5.19.
Meth yl 2-[2-[2-(Cya n om eth yl)p h en yl]a cetyl]-ben zoa te
(49). To a solution containing 0.4 g (1.5 mmol) of the above
compound in 70 mL of methanol was added 5 drops of
concentrated sulfuric acid, and the reaction mixture was
heated at reflux for 12 h. The solution was poured into a pH
7 phosphate buffer and extracted with ether. The combined
organic extracts were dried over MgSO4 and concentrated
under reduced pressure. Recrystallization of the residue gave
0.26 g (58%) of methyl 2-[2-[2-(cyanomethyl)phenyl]acetyl]
benzoate: mp 126-127 °C; IR (KBr) 2250, 1715, 1693, 1458,
1287, and 1115 cm-1 1H NMR (300 MHz, CDCl3) δ 3.82 (s,
;
2H), 3.83 (s, 3H), 4.15 (s, 2H), 7.11 (d, 1H, J ) 6.5 Hz), 7.17-
7.28 (m, 3H), 7.39-7.54 (m, 3H), and 7.98 (d, 1H, J ) 7.5 Hz);
13C NMR (75 MHz, CDCl3) δ 21.7, 47.3, 52.7, 118.0, 126.2,
127.8, 128.3, 129.1, 129.8, 130.0, 130.1, 131.6, 132.1, 132.5,
143.1, 166.6, and 202.2. Anal. Calcd for C18H15NO3: C, 73.71;
H, 5.15; N, 4.77. Found: C, 73.54; H, 5.24; N, 4.61.
Meth yl 2-(In d en o[1,2,3]tr ia zole-8-ca r bon yl)-ben zoa te
(53). A suspension containing 0.009 g (0.4 mmol) of NaH in 2
mL of THF was cooled to -78 °C under nitrogen and treated
with 0.15 g (0.4 mmol) of azidotris(diethylamino)phosphonium
bromide27 in 2 mL of THF. After the mixture stirred for 10
min, 0.09 g (0.3 mmol) of cyano ester 50 in 2 mL of THF was
added, and the reaction mixture was stirred at -78 °C for 10
min and then at -25 °C for 2 h. The crude R-diazo nitrile was
filtered through a plug of silica gel using ether as the eluent
to give methyl 2-[2-[2-(cyanodiazo-methyl)phenyl]acetyl] ben-
zoate (50) as an orange oil: IR (neat) 2244, 2086, 1717, 1623,
and 1282 cm-1. This diazo compound rapidly decomposed and
was used immediately in the next step without further
purification.
11a -C a r b o m e t h o x y -4b ,10-e p o x y -4b ,5,10,11,11a ,12-
h exah ydr o-10-m eth oxy-5-oxo-diben z[a ,g]azu len e (48). The
above compound was subjected to the diazo transfer conditions
using azidotris(diethylamino)phosphonium bromide (39) as the
diazo transfer agent. No attempts were made to isolate or
characterize diazo ketoester 47. Instead, the crude mixture
was subjected to the rhodium(II) acetate thermal conditions,
and the crude residue was subjected to silica gel chromatog-
raphy to give 48 as a white solid (68%): mp 136-137 °C; IR
1
(neat) 1733, 1702, 1600, and 1263 cm-1; H NMR (300 MHz,
A 0.1 g sample of 50 in 8 mL of toluene was stirred at 25 °C
for 75 min. The solution was concentrated under reduced
pressure, and the residue was recrystallized from CH2Cl2-
hexane to give 53 (92%) as a yellow solid: mp 184-185 °C; IR
CDCl3) δ 2.53 (d, 1H, J ) 12.7 Hz), 3.04 (d, 1H, J ) 12.7 Hz),
3.27 (s, 3H), 3.30 (d, 1H, J ) 16.5 Hz), 3.38 (s, 3H), 3.71 (d,
1H, J ) 16.5 Hz), 7.19-7.46 (m, 6H), 7.60 (t, 1H, J ) 7.5 Hz),
and 7.97 (t, 1H, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 44.6,
47.4, 52.5, 52.7, 62.0, 100.4, 109.8, 123.6, 124.5, 126.8, 127.1,
127.2, 128.9, 130.4, 131.9, 134.0, 135.9, 144.5, 145.1, 172.8,
and 191.4. Anal. Calcd for C21H18O5: C, 71.98; H, 5.18.
Found: C, 71.84; H, 5.03.
[2-(3-Oxo-3H-isoben zofu r a n -1-ylid en e-m eth yl)p h en yl]-
a ceton itr ile. A solution containing 1.0 g (3.3 mmol) of 3-(2-
bromobenzylidene)phthalide, 0.12 g (0.5 mmol) of palladium
acetate, 1.26 g (3.8 mmol) of cyanomethyltributyltin,43 and 0.33
g (1.1 mmol) of tri-o-tolylphosphine in 60 mL of toluene under
an argon atmosphere was heated at reflux for 12 h. The solvent
was removed under reduced pressure, and the residue was
filtered and recrystallized from CH2Cl2-ether to give 0.6 g
(71%) of [2-(3-oxo-3H-isobenzofuran-1-ylidene-methyl)phenyl]-
acetonitrile: mp 180-181 °C; IR (KBr) 2246, 1785, 1764, 1659,
and 982 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 2H), 6.45
(s, 1H), 7.27 (t, 1H, J ) 7.5 Hz), 7.34-7.39 (m, 2H), 7.54 (t,
1H, J ) 7.5 Hz), 7.78 (d, 1H, J ) 7.5 Hz), 7.88 (d, 1H, J ) 7.5
1
(KBr) 1705, 1690, 1299, and 1225 cm-1; H NMR (300 MHz,
CDCl3) δ 3.55 (s, 3H), 7.64 (dt, 1H, J ) 7.8 and 1.4 Hz), 7.69-
7.79 (m, 2H), 8.04 (d, 1H, J ) 7.8 Hz), 8.15-8.26 (m, 2H), 8.38
(d, 1H, J ) 7.8 Hz), and 9.18 (d, 1H, J ) 8.2 Hz); 13C NMR (75
MHz, CDCl3) δ 52.5, 113.9, 124.1, 124.3, 127.4, 127.7, 128.9,
129.3, 129.8, 130.6, 133.0, 134.5, 135.6, 139.9, 141.6, 154.6,
166.6, and 196.3. Anal. Calcd for C18H11N3O3: C, 68.14; H,
3.49; N, 13.24. Found: C, 68.04; H, 3.45; N, 13.02.
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health for generous support of
this work. Use of high-field NMR spectrometers 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 and 13C NMR
spectra for new compounds lacking elemental analyses and
ORTEP drawings for structures 18a , 27, and 35 (5 pages). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(42) Zhang, H. X.; Guibe´, F.; Balavoine, G. J . Org. Chem. 1990, 55,
1857.
(43) Nair, V.; Turner, G. A.; Buenger, G. S.; Chamberlaine, S. D. J .
Org. Chem. 1988, 53, 3051.
J O990136J