Cyclization-cycloaddition cascade of rhodium carbenoids using different carbonyl groups. Highlighting the position of interaction

Article abstract of DOI:10.1021/jo000378f

A series of 3-diazoalkanediones, when treated with a catalytic quantity of a rhodium(II) carboxylate, were found to afford oxabicyclic dipolar cycloadducts derived by the trapping of a carbonyl ylide intermediate. The reaction involves generation of the 1,3-dipole by intramolecular cyclization of the keto carbenoid onto the oxygen atom of the neighboring keto group. Both five- and six-ring carbonyl ylides are formed with the same efficiency. A study of the tandem cyclization-cycloaddition cascade of several α-diazo ketoesters was also carried out, and the cascade sequence proceeded in high yield. When the interacting keto carbonyl group was replaced by an imido group, the rhodium(II)-catalyzed reaction proceeded uneventfully. In contrast, α-diazo amidoesters do not undergo nitrogen extrusion on treatment with a Rh(II) catalyst. Instead, the diazo portion of the molecule undergoes 1,3-dipolar cycloaddition with various dipolarophiles to give substituted pyrazoles as the final products.

Full text of DOI:10.1021/jo000378f

J . Org. Chem. 2000, 65, 5223-5232
5223
Cycliza tion -Cycloa d d ition Ca sca d e of Rh od iu m Ca r ben oid s Usin g
Differ en t Ca r bon yl Gr ou p s. High ligh tin g th e P osition of
In ter a ction
Albert Padwa,* Zhijia J . Zhang, and Lin Zhi
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received March 15, 2000
A series of 3-diazoalkanediones, when treated with a catalytic quantity of a rhodium(II) carboxylate,
were found to afford oxabicyclic dipolar cycloadducts derived by the trapping of a carbonyl ylide
intermediate. The reaction involves generation of the 1,3-dipole by intramolecular cyclization of
the keto carbenoid onto the oxygen atom of the neighboring keto group. Both five- and six-ring
carbonyl ylides are formed with the same efficiency. A study of the tandem cyclization-cycloaddition
cascade of several R-diazo ketoesters was also carried out, and the cascade sequence proceeded in
high yield. When the interacting keto carbonyl group was replaced by an imido group, the
rhodium(II)-catalyzed reaction proceeded uneventfully. In contrast, R-diazo amidoesters do not
undergo nitrogen extrusion on treatment with a Rh(II) catalyst. Instead, the diazo portion of the
molecule undergoes 1,3-dipolar cycloaddition with various dipolarophiles to give substituted
pyrazoles as the final products.
Sch em e 1
The role of R-diazo carbonyl compounds in organic
synthesis is well established,1-14 and in recent years
much effort has been devoted to the study of the effect of
different transition-metal catalysts on these reactions.15-20
In earlier papers we described the formation of bridged
oxabicycloalkanes from the rhodium(II)-catalyzed reac-
tion of 1-diazoalkanediones.21 The reaction involves the
formation of a rhodium carbenoid intermediate and
subsequent transannular cyclization of the electrophilic
carbon onto the adjacent keto group to generate a cyclic
carbonyl ylide, followed by 1,3-dipolar cycloaddition
(Scheme 1).22
centers should be sufficiently close so that effective
overlap of the lone pair of electrons of the carbonyl group
with the metallocarbenoid can occur. Most of the studies
carried out involved five- and six-membered ring forma-
tion.21 The resulting cyclic dipole (i.e., 2) always contained
a carbonyl group within the ring. All of our attempts to
form carbonyl ylides from metal carbenoids that do not
possess an adjacent carbonyl group failed to produce the
dipole.23 We assumed that, by increasing the electrophilic
nature of the carbenoid intermediate, attack by the lone
pair of electrons on the tethered carbonyl group is
facilitated relative to other competitive pathways.
We24 and others25 have found that the intramolecular
trapping of carbonyl ylide dipoles with tethered alkenes
represents an effective method for the synthesis of a
The primary spatial requirement for carbonyl ylide
formation is that the distance between the two reacting
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10.1021/jo000378f CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/03/2000

5224 J . Org. Chem., Vol. 65, No. 17, 2000
Padwa et al.
Sch em e 2
satility in assembling different 3-diazoalkanediones,
involved a diazo transfer reaction.26 It is well-known that
direct diazo transfer to a ketone enolate is not a particu-
larly efficient reaction.27 Instead, generation of the diazo
group is usually achieved by a “deacylation diazo trans-
fer” strategy in which the ketone is first acylated and
then treated with a sulfonyl azide reagent such as
arylsulfonyl azide in the presence of base.27,28 Application
of this method to the preparation of a variety of diazo
carbonyl compounds is well documented in the liter-
ature.29-31 The starting material that we used for the
preparation of diazo ketones 11-14 corresponded to the
tricarbonyl compound 10, which in turn was prepared
by the Ni(II)-catalyzed reaction of various â-diketones
with vinyl ketones.32 Highly-resonance-stabilized carb-
anionic nucleophiles are known to undergo ready conju-
gate addition to R,â-unsaturated carbonyl compounds to
give 1,1,2-triacyl-substituted ethanes in high yield.33 It
is believed that carbonyl addition is a reversible process
and that the more stable product from conjugate addition
predominates under conditions of thermodynamic con-
trol.34 We tried various methods to effect the deacylation/
diazo transfer reaction, including the often-successful
combination of p-toluenesulfonyl azide and NaH in a
variety of solvents,35 but with only fair success. The use
of methanesulfonyl azide and triethylamine in acetoni-
trile,26 however, produced the desired 3-diazoalkanedione
in very good yield (Scheme 4).
Sch em e 3
variety of natural products. An interesting application
of this method is found as the central step of Dauben’s
synthesis of the tigliane ring system.25 Carbonyl ylide 5,
generated from the diazo carbonyl 4 in the presence of a
catalytic amount of rhodium(II) acetate, underwent in-
tramolecular addition with the olefin to form the C6,C9-
oxido bridged tigliane ring system 6 (Scheme 2). The two
new stereocenters at C-8 and C-9 were formed with the
correct configurations relative to C-14 and C-15 presented
by the natural tigliane compounds.
Of the many unexplored questions concerning the
factors that govern the formation of carbonyl ylides by
this method, one that is very easy to formulate focuses
upon the course of the reaction as a function of the
location of the diazo center. Because of the vast array of
pathways available to keto carbenoids and the demon-
strated susceptibility of these intermediates to both steric
and electronic effects, we felt that a systematic study of
the related 3-diazoalkanedione system (i.e., 7) would be
of some synthetic interest, as it could be used for the
construction of a variety of polyoxy bicyclic rings (Scheme
3). In this paper we detail our observations dealing with
the effect of diazo group location on the tandem cycliza-
tion-cycloaddition reaction.
Our investigations of the cascade reaction of this sys-
tem began with a study of the Rh(II)-catalyzed behavior
of 2-diazo-1,5-diphenyl-1,5-pentanedione (11). In this
particular case, commercially available 1,5-diphenyl-1,5-
pentanedione was treated with NaH in benzene at 0 °C,
and this was followed by reaction with ethyl formate.
The resulting formylated ketone was allowed to react
at room temperature with 2.0 equiv of methanesulfonyl
azide in acetonitrile containing 1 equiv of water and 2.0
equiv of triethylamine. Column chromatography on silica
gel furnished 11 as a yellow solid in 90% yield. Treatment
of 11 with dimethyl acetylenedicarboxylate (DMAD) in
the presence of Rh2OAc4 at 25 °C furnished cycloadduct
15 in 90% yield. A similar reaction of diazo ketones 12-
14 with DMAD in the presence of Rh2OAc4 afforded the
related cycloadducts 16-18 in 76%, 88%, and 78% yields,
(26) Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733. Regitz,
M.; Menz, F. Chem. Ber. 1968, 101, 2622. Regitz, M.; Maas, G. Diazo
Compounds, Properties and Synthesis; Academic Press: New York,
1986.
(27) Lombardo, L.; Mander, L. N. Synthesis 1980, 368. Evans, D.
A.; Britton, T. C. J . Am. Chem. Soc. 1987, 109, 6881, Hendrickson, J .
B.; Wolff, W. A. J . Org. Chem. 1968, 33, 3610.
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21, 15.
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Org. Chem. 1990, 55, 5, 1959.
Resu lts a n d Discu ssion
To investigate the scope of the Rh(II)-catalyzed cy-
clization-cycloaddition cascade of 3-diazoalkanediones
and the suitability of this reaction as a general synthetic
method, we needed an efficient synthesis of this system.
The approach we selected, which allowed for good ver-
(30) Taber, D. F.; Ruckle, R. E.; Hennessy, M. J . J . Org. Chem. 1986,
51, 4077. Taber, D. F.; Gleeve, D. M.; Herr, R. J .; Moody, K.; Hennessy,
M. J . J . Org. Chem. 1995, 60, 2283.
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M.; Shechter, H. Tetrahedron Lett. 1990, 31, 4987. Kumar, S. M. Synth.
Commun. 1991, 21, 2121.
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23, 312. Spino, C.; Deslongchamps, P. Tetrahedron Lett. 1990, 31, 3969.
(33) Duval, D.; Geribaldi, S. In The Chemistry of Enones, Patai, S.,
Rappoport, Z., Eds.; Wiley & Sons: New York, 1989; Part I, p 355.
(34) Schultz, A. G.; Yee, Y. K. J . Org. Chem. 1976, 41, 4004.
Luchetti, J .; Krief, A. Tetrahedron Lett. 1978, 2697.
(35) Askani, R.; Taber, D. F. In Comprehensive Organic Synthesis;
Winterfeldt, E., Ed.; Pergamon: Oxford, 1991; Vol. 6, p 103.
(24) Padwa, A.; Brodney, M. A.; Marino, J . P., J r.; Sheehan, S. M.
J . Org. Chem. 197, 62, 78. Padwa, A.; Price, A. T. J . Org. Chem. 1998,
63, 556. Padwa, A.; Precedo, L.; Semones, M. J . Org. Chem. 1999, 64,
4079.
(25) Dauben, W. G.; Dinges, J .; Smith, T. C. J . Org. Chem. 1993,
58, 7635.

Cyclization-Cycloaddition of Rhodium Carbenoids
J . Org. Chem., Vol. 65, No. 17, 2000 5225
Sch em e 4
Sch em e 6
OAc4-catalyzed reaction of R-diazo ketones 23 and 24
proceeded quite smoothly with DMAD and N-phenyl-
maleimide. With DMAD, cycloadducts 25 and 26 were
formed in 90% and 89% yields, respectively. When
N-phenylmaleimide was used as the trapping agent,
cycloadduct 27 was obtained in 90% yield as the exclusive
product. The stereochemical assignment of 27 (as well
as 19) was made on the basis of related reactions
encountered in our laboratory where the bimolecular
cycloaddition was found to occur endo with respect to the
carbonyl ylide dipole.40 The above results indicate that
intramolecular cyclization to generate six-ring carbonyl
ylide dipoles is just as efficient as the formation of five-
ring dipoles (Scheme 6).
Sch em e 5
In an effort to further extend the cyclization cascade
to other carbonyl-containing diazo substrates, we opted
to study the Rh(II)-catalyzed behavior of several R-diazo
ketoesters and amides. With this goal in mind, we first
examined the Rh2OAc4-catalyzed reaction of diazo keto-
esters 28-30. When the Rh(II)-induced reaction was
carried out in the presence of DMAD at room tempera-
ture, the cascade cycloadducts 31-33 were isolated in
91%, 73%, and 92% yield, respectively (Scheme 7).
Having established that R-diazo ketoesters can un-
dergo the tandem cascade, we decided to explore the
intramolecular reaction of a diazo ketoester which con-
tained a suitably positioned C-C double bond. To this
end, R-diazo ketoester 34 was prepared and treated with
Rh2OAc4 at 25 °C to furnish cycloadduct 35 in 80% yield
(Scheme 8). When DMAD was added to the reaction
mixture, it was possible to isolate the bimolecular adduct
36 in 85% yield. Apparently, the intramolecular cycload-
dition of the dipole to the unactivated π-bond is suf-
ficiently slow to allow the carbonyl ylide to react exclu-
sively with the more reactive acetylenic π-bond.
respectively. It was also possible to trap the five-ring
dipole with an electron-deficient olefin. Thus, the reaction
of diazo ketone 11 with Rh2OAc in the presence of
N-phenylmaleimide gave cycloadduct 19 as a crystalline
solid, mp 192-193 °C, in 89% yield. These results are
consistent with a mechanism in which the key step
involves intramolecular cyclization of the keto carbenoid
onto the oxygen atom of the neighboring carbonyl group
to give the resonance-stabilized five-membered carbonyl
ylide intermediate 8 (Scheme 3), which is trapped by the
added dipolarophile. An important point to note is that
ylide 8 is sufficiently long lived to undergo bimolecular
cycloaddition with DMAD to furnish the cascade adduct
(i.e., 15). In contrast to this result, the closely related
five-ring carbonyl ylide 21, obtained from the reaction
of 1-diazobutanedione 20 with Rh2OAc4, underwent rapid
intramolecular proton transfer to produce furanone 22
(Scheme 5). The expected cycloadduct 23 was not detected
in the reaction mixture. More than likely, the difference
between the two five-ring ylides is that the R-hydrogen
present in ylide 21 is doubly activated and undergoes an
internal proton transfer at a very fast rate, thereby
preventing the cycloaddition reaction.37
We attempted to carry out a related internal cycload-
dition using a system where the tethered alkenyl group
resided on the ester portion of the molecule. This led us
to study the cycloaddition chemistry of diazo ketoester
37. When the Rh(II)-catalyzed reaction of 37 was per-
(36) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang, Z. J . J . Org.
Chem. 1991, 56, 3271.
(37) Bien, S.; Gillon, A. Tetrahedron Lett. 1974, 3073. Bien, S.;
Gillon, A.; Kohen, S. J . Chem. Soc., Perkin Trans. 1 1976, 489.
(38) Kharasch, M. S.; Rudy, T.; Nudenberg, W.; Buchi, G. J . Org.
Chem. 1953, 18, 1030.
(39) Lottes, A.; Landgrebe, J . A.; Larsen, K. Tetrahedron Lett. 1989,
30, 4089.
(40) Padwa, A.; Fryxell, G. E.; Zhi, L. J . Am. Chem. Soc. 1990, 112,
3100.
Six-ring carbonyl ylides can also participate in these
tandem cyclization-cycloaddition reactions. The Rh2-

5226 J . Org. Chem., Vol. 65, No. 17, 2000
Padwa et al.
Sch em e 7
Sch em e 10
Sch em e 8
encountered showed that the amido group can signifi-
cantly alter the course of the tandem cycloaddition
process. Thus, R-diazo carbonyl compounds that possess
an amido group in the R-position (i.e., 40) were found to
undergo a rather novel rhodium(II)-catalyzed cycloaddi-
tion reaction (Scheme 10).43 The intramolecular cycliza-
tion of the keto carbenoid onto the oxygen atom of the
amide generated a push-pull carbonyl ylide dipole (41)
as a transient species. This highly stabilized dipole did
not undergo the 1,3-dipolar cycloaddition readily, but
instead underwent proton transfer to produce a cyclic
ketene N,O-acetal (42). The nucleophilic π-bond present
in 42 added to the activated π-bond of the dipolarophile
(AdB) to give a zwitterion intermediate (43). This step
is followed by epoxide ring formation with charge dis-
sipation, leading to the amido-substituted spirocyclopen-
tyl epoxide 44.
Sch em e 9
As a consequence of these earlier investigations, we
felt that it would be interesting to extend our studies to
include several R-diazo amides to more clearly define the
scope and generality of the amido carbenoid cascade.
Diazo ketoamide 45 was our first target, and this
compound was easily synthesized starting from N-(hy-
droxymethyl)phthalimide and 2,4-pentanedione (see the
Experimental Section). We were gratified to find that
treating a sample of 45 at 25 °C with DMAD and Rh2-
OAc4 furnished the cascade adduct 46 in 68% yield. Two
minor products were also isolated and were assigned as
the diazo dipolar cycloadducts 48 (21%) and 49 (7%).
When the reaction of 45 was carried out in the absence
of Rh2OAc4, the same two compounds were obtained, but
now in 68% and 22% yields, respectively (Scheme 11).
The formation of these substituted pyrazoles can best be
explained by a rapid 1,3-dipolar cycloaddition of the
starting R-diazo ketone across the activated acetylenic
π-bond to give the transient dipolar cycloadduct 47, which
undergoes a subsequent van Alphen-Hu¨ttel rearrange-
ment44 to furnish the observed products. The major pyr-
azole is that derived from a preferential 1,5-acetyl shift.45
We attempted to apply the intramolecular cyclization-
cycloaddition sequence to several closely related diazo
formed in the presence of DMAD, cycloadduct 38 was
obtained in 89% yield (Scheme 9). However, in the
absence of any trapping agent, no internal cycloadduct
could be detected. Instead, the only identifiable compound
obtained from this reaction (68%) corresponded to dihy-
drofuran 39. The formation of 39 is best rationalized by
a hydrogen shift of the initially produced dipole.38,39 More
than likely, the failure to trap the dipole is related to
conformational factors. It is well recognized that the
Z-conformers of esters are significantly more stable than
the corresponding E-conformers.41 In the Z-orientation,
intramolecular dipolar cycloaddition of the resulting car-
bonyl ylide cannot occur and instead the dipole collapses
by means of a proton transfer to give enol ether 39.
Our earlier studies in this general area have revealed
some unexpected results when a nitrogen atom was
incorporated at certain positions of the diazo keto skel-
eton.42 One of the more interesting examples that we
(42) Padwa, A.; Dean, D. C.; Zhi, L. J . Am. Chem. Soc. 1992, 114,
593. Padwa, A.; Dean, D. C.; Zhi, L. J . Am. Chem. Soc. 1989, 111, 6451.
(43) Padwa, A.; Price, A. T.; Zhi, L. J . Org. Chem. 1996, 61, 2283.
Padwa, A.; Zhi, L. J . Am. Chem. Soc. 1990, 112, 2037.
(44) Baumes, R.; Elguero, J .; J acquier, R.; Tarrago, G. Tetrahedron
Lett. 1973, 3781. Leigh, W. J .; Arnold, D. R. Can. J . Chem. 1979, 57,
1186.
(41) Wiberg, K. B.; Laidig, K. E. J . Am. Chem. Soc. 1988, 110, 1872.

Cyclization-Cycloaddition of Rhodium Carbenoids
J . Org. Chem., Vol. 65, No. 17, 2000 5227
Sch em e 11
Sch em e 13
One final point has to do with the rhodium(II)-
catalyzed reaction of 2-diazo-4-(methylphenylcarbamoyl)-
butyric acid methyl ester (57). All of our attempts to
obtain a cascade adduct derived from a carbonyl ylide
intermediate with this system failed. Several types of
dipolarophiles were examined, but only the standard
dipolar cycloadducts of the starting diazo compound with
the activated π-bonds were isolated (Scheme 13).
In conclusion, the model studies described in this paper
demonstrate that the rhodium(II)-catalyzed reaction of
3-diazoalkanediones occurs with high efficiency and
represents a useful approach toward the synthesis of
various oxabicyclo ring systems. Diazo ketoesters and
imides were found to undergo the rhodium(II)-catalyzed
cascade cycloaddition in high yield. In contrast, R-diazo
amidoesters are reluctant to form the key rhodium
carbenoid intermediate, and the major reaction involves
1,3-dipolar cycloaddition of the diazo portion of the
molecule with the added dipolarophile. We are continuing
to explore the scope, generality, and synthetic applica-
tions of the Rh(II) cascade reaction of other diazo carbonyl
substrates and will report additional findings at a later
date.
Sch em e 12
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 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.
amidoesters such as 50 and 51 with the hope that these
substrates would also undergo a reaction similar to that
encountered with diazo ketoamide 45 (i.e., 45 f 46).
Unfortunately, no cascade adduct derived from a carbonyl
ylide intermediate could be detected in the crude reaction
mixture. The only products obtained when DMAD was
used as the trapping dipolarophile corresponded to the
rearranged pyrazoles 53 and 54 (Scheme 12). A van
Alphen-Hu¨ttel rearrangement of the initially formed
dipolar cycloadduct 52 nicely rationalizes their formation.
A variety of experimental conditions using different
rhodium(II) catalysts in varying quantities were inves-
tigated, but in no case were we able to obtain a product
derived from the cyclization of a rhodium carbenoid inter-
mediate. It would appear as though the bimolecular 1,3-
dipolar cycloaddition of the diazo ester to the activated
alkyne proceeds at a much faster rate than the rhodium-
catalyzed loss of nitrogen from the starting diazo com-
pound. When N-phenylmaleimide was employed as the
trapping dipolarophile, dipolar cycloadducts 55 and 56
were isolated as the exclusive products and were obtained
in 70% and 83% isolated yielda, respectively.
2-Dia zo-1,5-d ip h en yl-1,5-p en ta n ed ion e (11). To a sus-
pension containing 1.0 g (25 mmol) of 60% NaH in 50 mL of
benzene at 0 °C was added two drops of anhydrous methanol
followed by 2.5 g (10 mmol) of 1,5-diphenyl-1,5-pentanedione
in 5 mL of benzene and 1.6 mL (25 mmol) of ethyl formate.
The mixture was allowed to warm to rt and was stirred for an
additional 12 h, and then 2.4 g (19 mmol) of methanesulfonyl
azide and 1.2 mL of triethylamine were added. The mixture
was stirred for an additional 4 h, quenched with water, and
extracted with ether. The mixture was washed with 10%
NaOH and a brine solution, and the organic layer was dried
over anhydrous Na2SO4. After removal of the solvent, the
residue was chromatographed on silica gel to give 1.0 g (90%)
of 11 as a yellow solid: mp 52-53 °C; IR (neat) 2082, 1684,
1
1607, 1347, and 702 cm-1; H NMR (CDCl3, 300 MHz) δ 2.92
(t, 2H, J ) 6.1 Hz), 3.39 (t, 2H, J ) 6.1 Hz), and 7.36-7.98
(m, 10H); 13C NMR (CDCl3, 75 MHz) δ 19.6, 36.2, 67.1, 127.0,
127.9, 128.4, 128.5, 131.2, 133.3, 136.3, 137.4, and 199.1. Anal.
Calcd for C17H14N2O2: C, 73.37; H, 5.09; N, 10.07. Found: C,
73.32; H, 5.10; N, 9.96.
(45) Schless, P.; Stalder, H. Tetrahedron Lett. 1980, 1417.

5228 J . Org. Chem., Vol. 65, No. 17, 2000
Padwa et al.
Dim et h yl 1-P h en yl-4-b en zoyl-7-oxa b icyclo[2.2.1]-2-
h ep ten e-2,3-d ica r boxyla te (15). To a solution containing
0.16 g (0.6 mmol) of diazo ketone 11 in 3 mL of CH2Cl2 was
added 0.16 g (1.1 mmol) of DMAD in 2 mL of CH2Cl2 followed
by the addition of 2 mg of rhodium(II) acetate. The mixture
was stirred at rt for 30 min, and the solvent was removed
under reduced pressure. The residue was purified by silica gel
chromatography to give 0.23 g (90%) of 15 as a colorless oil:
To a solution containing 0.7 g (3.0 mmol) of the above
triketone in 8 mL of CH3CN were added 0.6 g (4.5 mmol) of
methanesulfonyl azide and 1.2 mL (18.7 mmol) of triethyl-
amine. The resulting solution was stirred for 5 h at rt, the
solvent was removed under reduced pressure, and the crude
residue was chromatographed on silica gel to give 0.23 g (36%)
of 13 as a labile yellow oil which was used in the next step
without further purification: IR (neat) 2082, 1684, 1636, and
1
1
IR (neat) 1725, 1688, 1440, and 1264 cm-1; H NMR (CDCl3,
693 cm-1; H NMR (CDCl3, 300 MHz) δ 2.19 (s, 3H), 2.72 (t,
300 MHz) δ 2.05 (ddd, 1H, J ) 12.1, 8.0, and 4.5 Hz), 2.25-
2.40 (m, 2H), 2.68 (ddd, 1H, J ) 12.4, 8.0, and 4.2 Hz), 3.64
(s, 3H), 3.65 (s, 3H), and 7.37-8.19 (m, 10H); 13C NMR (CDCl3,
75 MHz) δ 30.1, 30.4, 52.2, 52.3, 90.0, 93.5, 126.7, 128.2, 128.3,
128.8, 129.8, 133.4, 135.1, 135.5, 141.8, 146.8, 161.6, 163.5,
and 193.2. Anal. Calcd for C23H20O6: C, 70.39; H, 5.14.
Found: C, 70.26; H, 5.08.
1-P h en yl-4-ben zoyl-2,3-(N-p h en yl)d ica r boxylim id e-7-
oxa bicyclo[2.2.1]h ep ta n e (19). To a solution containing 0.3
g (1.1 mmol) of diazo ketone 11 in 8 mL of CH2Cl2 was added
0.37 g (2.2 mmol) of N-phenylmaleimide followed by the
addition of 2 mg of rhodium(II) acetate. The mixture was
stirred at rt for 1 h, the solvent was removed under reduced
pressure, and the crude residue was chromatographed on a
silica gel column to give 0.4 g (89%) of 19 as a white solid:
2H, J ) 6.0 Hz), 3.26 (t, 2H, J ) 6.0 Hz), and 7.47-7.95 (m,
5H).
Dim eth yl 1-P h en yl-4-a cetyl-7-oxa bicyclo[2.2.1]-2-h ep -
ten e-2,3-d ica r boxyla te (17). To a solution containing 0.12
g (0.6 mmol) of diazo ketone 13 in 2 mL of CH2Cl2 was added
0.16 g (1.1 mmol) of DMAD in 2 mL of CH2Cl2 followed by the
addition of 2 mg of rhodium(II) acetate. After the resulting
solution was stirred at 25 °C for 30 min, the solvent was
removed under reduced pressure and the crude residue was
purified by silica gel chromatography to give 0.16 g (88%) of
17 as a colorless oil: IR (neat) 1734, 1636, 1437, 1258, and
700 cm-1 1H NMR (CDCl3, 300 MHz) δ 1.87-1.98 (m, 1H),
;
2.16-2.36 (m, 3H), 2.38 (s, 3H), 3.59 (s, 3H), 3.80 (s, 3H), and
7.34-7.54 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 26.7, 29.4,
30.7, 52.1, 52.5, 92.3, 92.5, 126.9, 128.2, 128.8, 135.5, 141.6,
146.5, 162.1, 163.1, and 209.9. Anal. Calcd for C18H18O6: C,
65.43; H, 5.50. Found: C, 65.29; H, 5.41.
mp 192-193 °C; IR (neat) 1717, 1700, 1385, and 1190 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.07 (ddd, 1H, J ) 12.6, 9.2 and
4.0 Hz), 2.25-2.53 (m, 3H), 3.43 (d, 1H, J ) 7.1 Hz), 3.88 (d,
1H, J ) 7.1 Hz), 7.03 (dd, 2H, J ) 7.2 and 1.3 Hz), 7.22-7.53
(m, 10H), 7.57 (d, 1H, J ) 7.2 Hz), and 8.23 (d, 2H, J ) 7.5
Hz); 13C NMR (75 MHz, CDCl3) δ 35.3, 36.6, 43.3, 55.1, 91.6,
92.3, 125.1, 125.9, 128.2, 128.3, 128.8, 129.6, 131.4, 133.3,
1-P h en yl-2-d ia zo-1,5-h exa n ed ion e (14). A mixture con-
taining 6.9 g (32 mmol) of 4,4,4-trifluoro-1-phenyl-1,3-butane-
dione, 5.2 mL (64 mmol) of methyl vinyl ketone, and 0.25 g of
Ni(AcAc)2 in 10 mL of benzene was heated at 90 °C for 24 h.
The solvent was removed under reduced pressure, and the
crude residue was purified on a silica gel column to give 7.7 g
(85%) of 1-phenyl-2-trifluoroacetyl-1,5-hexanedione as a labile
yellow oil which was used in the next step without further
135.8, 136.6, 172.9, 173.5, and 196.6. Anal. Calcd for C27H21
-
NO4: C, 76.48; H, 5.00; N, 3.31. Found: C, 76.32; H, 5.07; N,
3.25.
purification: IR (neat) 1715, 1676, 1451, and 693 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 2.11 (s, 3H), 2.24 (t, 2H, J ) 6.6
Hz), 2.60 (t, 2H, J ) 6.6 Hz), 5.13 (t, 1H, J ) 6.6 Hz), and
7.42-8.10 (m, 5H).
To a solution containing 2.9 g (10 mmol) of the above
triketone in 10 mL of CH3CN were added 1.9 g (15 mmol) of
methanesulfonyl azide and 4.2 mL (30 mmol) of triethylamine.
The resulting solution was stirred at rt for 3 h, the solvent
was removed under reduced pressure, and the crude residue
was purified by silica gel chromatography to give 1.5 g (70%)
of 14 as a labile yellow oil which was used in the next step
without further purification: IR (neat) 2080, 1715, 1609, 1346,
and 704 cm-1; 1H NMR (CDCl3, 360 MHz) δ 2.17 (s, 3H), 2.71
(t, 2H, J ) 6.0 Hz), 2.83 (t, 2H, J ) 6.0 Hz), and 7.38-7.56
(m, 5H).
3-Dia zo-2,6-h ep ta n ed ion e (12). A mixture containing 1.7
g (10 mmol) of 3-acetyl-2,6-heptanedione,46 3.8 g (30 mmol) of
methanesulfonyl azide, and 4.3 mL (30 mmol) of triethylamine
in 5 mL of CH3CN was stirred at rt for 1.5 h. The solvent was
removed under reduced pressure, and the crude mixture was
chromatographed on a silica gel column to give 1.1 g (69%) of
12 as a labile yellow oil which was used in the next step
without further purification: IR (neat) 2079, 1709, 1630, 1360,
and 1161 cm-1; 1H NMR (CDCI3, 300 MHz) δ 2.11 (s, 3H), 2.16
(s, 3H), 2.49 (t, 2H, J ) 6.0 Hz), and 2.69 (t, 2H, J ) 6.0 Hz).
Dim eth yl 1-Meth yl-4-a cetyl-7-oxa bicyclo[2.2.1]h ep t-2-
en e-2,3-d ica r boxyla te (16). To a solution containing 0.2 g
(1.3 mmol) of R-diazo ketone 12 in 4 mL of heptane and 1 mL
of CH2Cl2 was added 0.38 g (2.6 mmol) of DMAD followed by
the addition of 2 mg of rhodium(II) acetate. The reaction
mixture was stirred for 5 h at rt, and the solvent was removed
under reduced pressure. The crude residue was purified by
silica gel chromatography to give 0.27 g (76%) of 16 as a
Dim et h yl 1-Met h yl-4-b en zoyl-7-oxa b icyclo[2.2.1]-2-
h ep ten e-2,3-d ica r boxyla te (18). To a solution containing 0.2
g (0.9 mmol) of diazo ketone 14 in 3 mL of CH2Cl2 was added
0.26 g (1.8 mmol) of DMAD in 2 mL of CH2Cl2 followed by the
addition of 2 mg of rhodium(II) acetate. After the resulting
solution was stirred at rt for 30 min, the solvent was removed
under reduced pressure and the crude residue was chromato-
graphed on a silica gel column to give 0.24 g (78%) of 18 as a
1
colorless oil: IR (neat) 1723, 1630, 1431, and 1253 cm-1; H
NMR (300 MHz, CDCl3) δ 1.70-1.90 (m, 5H), 2.08-2.18 (m,
2H), 2.28 (s, 3H), and 3.78 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 17.1, 26.2, 30.1, 32.5, 52.0, 52.3, 88.5, 92.6, 143.0, 143.9,
162.7, 162.8, and 203.3. Anal. Calcd for C13H16O6: C, 58.20;
H, 6.01. Found: C, 58.29; H, 6.11.
colorless oil: IR (neat) 1723, 1688, 1261, and 889 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 1.71-1.98 (m, 6H), 2.42-2.53 (m,
1H), 3.62 (s, 3H), 3.81 (s, 3H), and 7.36-8.05 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 17.4, 30.8, 32.2, 52.2, 52.3, 89.9, 92.4, 128.3,
129.7, 133.4, 134.9, 144.0, 144.1, 162.4, 163.4, and 193.7. Anal.
Calcd for C18H18O6: C, 65.43; H, 5.50. Found: C, 65.21; H,
5.37.
2-Dia zo-1,6-d ip h en yl-1,6-h exa n ed ion e (23). To a suspen-
sion containing 1.0 g (25 mmol) of 60% NaH in 50 mL of
benzene at 0 °C was added two drops of anhydrous methanol
followed by the addition of 2.7 g (10 mmol) of 1,6-diphenyl-
1,6-hexanedione in 5 mL of benzene, and 1.6 mL (25 mmol) of
methyl formate. The reaction mixture was allowed to warm
to rt and was stirred for 12 h, and then 2.3 g (18 mmol) of
methanesulfonyl azide was added. The mixture was stirred
for an additional 4 h and was then quenched with water. The
solution was extracted with ether and washed with 10% NaOH
and a brine solution. The organic layer was dried over
1-P h en yl-4-d ia zo-1,5-h exa n ed ion e (13). A mixture con-
taining 1.3 g (9.6 mmol) of phenyl vinyl ketone, 5 mL (48 mmol)
of 2,4-pentanedione, and 0.2 g of Ni(AcAc)2 in 10 mL of dry
benzene was heated at 90 °C for 20 h. The solvent was removed
under reduced pressure, and the crude residue was chromato-
graphed on silica gel to give 2.1 g (94%) of 1-phenyl-4-acetyl-
1,5-hexanedione as a pale yellow oil: IR (neat) 1684, 1597,
1
1449, and 690 cm-1; H NMR (CDCl3, 300 MHz) δ 2.16-2.28
(m, 7H), 2.68 (t, 1H, J ) 7.8 Hz), 2.97 (t, 1H, J ) 6.9 Hz), 3.06
(t, 1H, J ) 7.8 Hz), 3.79 (t, 1H, J ) 6.9 Hz), and 7.46-7.95
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ 21.7, 29.2, 35.4, 66.6,
127.7, 128.4, 133.0, 136.2, 190.9, and 204.0. Anal. Calcd for
C
14H16O3: C, 72.38; H, 6.95. Found: C, 72.25; H, 6.94.
(46) Nelson, J . H.; Howells, P. N.; DeLullo, G. C.; Landen, G. L.;
Henry, R. A. J . Org. Chem. 1980, 45, 1246.

Cyclization-Cycloaddition of Rhodium Carbenoids
J . Org. Chem., Vol. 65, No. 17, 2000 5229
anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The crude residue was purified by silica gel
chromatography to give two major products. The minor
component contained 1.3 g (57%) of 23 as a yellow solid: mp
73-74 °C; IR (neat) 2072, 1684, 1611, and 1346 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 2.05 (quint, 2H, J ) 7.2 Hz), 2.64 (t, 2H,
J ) 7.2 Hz), 3.10 (t, 2H, J ) 7.2 Hz), 7.37-7.58 (m, 8H), and
7.95 (d, 2H, J ) 7.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.6,
23.3, 37.1, 66.9, 127.0, 127.9, 128.4, 128.5, 131.3, 133.0, 136.6,
137.5, 189.4, and 199.1. Anal. Calcd for C18H16N2O2: C, 73.94;
H, 5.52; N, 9.59. Found: C, 73.81; H, 5.43; N, 9.46.
mmol) of 24 in 2 mL of CH2Cl2 was added 0.13 g (0.9 mmol) of
DMAD in 2 mL of CH2Cl2 followed by the addition of 2 mg of
rhodium(II) acetate. After the resultant solution was stirred
for 30 min at rt, the solvent was removed under reduced
pressure and the crude residue was chromatographed on a
silica gel column to give 0.15 g (89%) of 26 as a colorless oil:
1
IR (neat) 1725, 1648, 1438, and 1036 cm-1; H NMR (CDCl3,
300 MHz) δ 1.50 (s, 3H), 1.54-1.65 (m, 4H), 1.72-1.82 (m,
2H), 2.23 (s, 2H), 3.79 (s, 3H), and 3.80 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 17.6, 22.4, 23.9, 25.1, 29.1, 52.2, 52.4, 87.4,
92.2, 140.3, 140.7, 162.9, 163.1, and 205.0. Anal. Calcd for
Dim et h yl 1-P h en yl-5-b en zoyl-8-oxa b icyclo[3.2.1]-6-
octen e-6,7-d ica r boxyla te (25). To a solution containing 0.15
g (0.5 mmol) of diazo ketone 23 in 2 mL of CH2Cl2 was added
0.1 g (0.7 mmol) of DMAD in 2 mL of CH2Cl2 followed by the
addition of 2 mg of rhodium(II) acetate. After the resultant
solution was stirred at rt for 30 min, the solvent was removed
under reduced pressure and the crude residue was chromato-
graphed on a silica gel column to give 0.19 g (90%) of 25 as a
C
14H18O6: C, 59.55; H, 6.43. Found: C, 59.29; H, 6.37.
Eth yl 5-P h en yl-2-d ia zo-5-oxop en ta n oa te (28). A mix-
ture containing 1.2 g (9.1 mmol) of phenyl vinyl ketone, 5 mL
of ethyl acetoacetate, and 0.2 g of Ni(AcAc)2 in 10 mL of dry
benzene was heated at 90 °C for 20 h. The solvent was removed
under reduced pressure, and the crude residue was purified
by silica gel chromatography to give 2.1 g (90%) of ethyl
5-phenyl-2-acetyl-5-oxopentanoate as a colorless oil: IR (neat)
1
colorless oil: IR (neat) 1727, 1690, 1449, and 1262 cm-1; H
1740, 1717, 1686, 1150, and 691 cm-1; H NMR (CDCl3, 360
1
NMR (CDCl3, 300 MHz) δ 1.85-2.09 (m, 5H), 2.33 (dd, 1H, J
MHz) δ 1.26 (t, 3H, J ) 7.2 Hz), 2.22-2.32 (m, 5H), 3.05 (t,
2H, J ) 7.2 Hz), 3.63 (t, 1H, J ) 7.2 Hz), 4.17-4.26 (m, 2H),
and 7.44-7.95 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 22.0,
28.9, 35.4, 58.2, 61.3, 127.8, 128.4, 133.0, 136.4, 169.4, 198.7,
and 202.8. Anal. Calcd for C15H18O4: C, 68.67; H, 6.92.
Found: C, 68.52; H, 6.97.
To a solution containing 0.5 g (2.0 mmol) of the above
compound in 5 mL of CH3CN were added 0.5 g (4 mmol) of
methanesulfonyl azide and 0.8 mL (6 mmol) of triethylamine.
The resulting solution was stirred for 3 h at rt, the solvent
was removed under reduced pressure, and the crude residue
was purified by silica gel chromatography to give diazo
ketoester 28 (85%) as a yellow oil which was used in the next
step without further purification: IR (neat) 2095, 1684, 1371,
1175, and 691 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.25 (t, 3H,
J ) 7.2 Hz), 2.72 (t, 2H, J ) 6.3 Hz), 3.26 (t, 2H, J ) 6.3 Hz),
4.19 (q, 2H, J ) 7.2 Hz), and 7.43-7.94 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 14.4, 18.5, 36.6, 60.5, 127.9, 128.5, 133.2,
136.4, 167.4, and 178.7.
) 12.2 and 5.2 Hz), 3.69 (s, 3H), 3.73 (s, 3H), 7.31-7.49 (m,
7H), 7.56 (t, 1H, J ) 7.0 Hz), and 8.16 (d, 2H, J ) 7.4 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 17.8, 25.0, 27.6, 52.2, 52.4, 91.0, 92.1,
125.6, 128.1, 128.2, 129.9, 132.9, 135.1, 138.5, 138.9, 142.8,
162.2, 162.5, and 194.9. Anal. Calcd for C24H22O6: C, 70.91;
H, 5.46. Found: C, 70.84; H, 5.27.
1-P h en yl-5-ben zoyl-6,7-(N-p h en yl)d ica r boxylim id e-8-
oxa bicyclo[3.2.1]octa n e (27). To a solution of 0.1 g (0.4
mmol) of R-diazo ketone 23 in 4 mL of CH2Cl2 was added 0.1
g (0.6 mmol) of N-phenylmaleimide followed by the addition
of 2 mg of rhodium(II) acetate. The mixture was stirred at rt
for 1 h, and the solvent was removed under reduced pressure.
The crude residue was purified by silica gel chromatography
to give 0.15 g (90%) of 27 as a white solid: mp 178-179 °C;
IR (neat) 1717, 1698, 1383, and 1202 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.85-2.08 (m, 4H), 2.33 (dd, 1H, J ) 12.9 and 3.0
Hz), 2.44 (d, 1H, J ) 11.7 Hz), 3.60 (d, 1H, J ) 7.6 Hz), 3.90
(d, 1H, J ) 7.6 Hz), 6.79 (dd, 2H, J ) 8.0 and 2.2 Hz), 7.20-
7.58 (m, 11H), and 8.10 (d, 2H, J ) 7.3 Hz); 13C NMR (75 MHz,
CDCl3) δ 17.8, 32.8, 36.0, 52.9, 54.3, 88.1, 90.5, 124.9, 125.8,
127.8, 127.9, 128.1, 128.3, 128.8, 129.7, 131.3, 132.5, 136.3,
139.5, 173.3, 173.6, and 198.8. Anal. Calcd for C28H23NO4: C,
76.87; H, 5.30; N, 3.20. Found: C, 76.69; H, 5.33; N, 3.23.
3-Dia zo-2,7-octa n ed ion e (24). To a solution containing 3.0
g (30 mmol) of 2,4-pentanedione in 30 mL of THF was slowly
added 30 mL of a 1 M THF solution of potassium tert-butoxide
followed by the addition of 3.2 g (15 mmol) of 5-iodo-2-
pentanone. The resulting solution was heated at reflux for 20
h. To this mixture was added a 1 N HCl solution, the mixture
was extracted with ether and washed with water, and the
organic layer was dried over anhydrous MgSO4. The solvent
was removed under reduced pressure, and the crude residue
was chromatographed on a silica gel column to give 1.5 g (54%)
of 3-acetyl-2,7-octanedione as a colorless oil (bp 95 °C (0.2
mmHg)): IR (neat) 1717, 1420, 1360, and 1160 cm-1; 1H NMR
(CDCl3, 360 MHz) δ 1.42-1.52 (m, 2H), 1.75-1.85 (m, 2H),
2.10 (s, 3H), 2.15 (s, 6H), 2.44 (t, 2H, J ) 7.2 Hz), and 3.59 (t,
2H, J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.0, 26.9, 28.1,
29.4, 42.5, 67.9, 203.5, and 207.5; Anal. Calcd for C10H16O3:
C, 65.19; H, 8.75. Found: C, 65.26; H, 8.80.
2,3-Dim eth yl 4-Eth yl 1-P h en yl-7-oxa bicyclo[2.2.1]-2-
h ep ten e-2,3,4-tr ica r boxyla te (31). To a solution containing
0.14 g (0.6 mmol) of diazo ketoester 28 in 3 mL of CH2Cl2 was
added 0.17 g (1.2 mmol) of DMAD in 2 mL of CH2Cl2 followed
by the addition of 2 mg of rhodium(II) acetate. After the
resulting solution was stirred at rt for 30 min, the solvent was
removed under reduced pressure and the crude residue was
purified by silica gel chromatography to give 0.19 g (91%) of
31 as a clear oil: IR (neat) 1746, 1640, 1437, 1265, and 700
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.31 (t, 3H, J ) 7.2 Hz),
1.99 (dt, 1H, J ) 9.9 and 3.3 Hz), 2.21 (dt, 1H, J ) 9.9 and 3.3
Hz), 2.35 (dt, 1H, J ) 10.2 and 3.3 Hz), 2.47 (dt, 1H, J ) 10.2
and 3.3 Hz), 3.56 (s, 3H), 3.77 (s, 3H), 4.23-4.41 (m, 2H), and
7.30-7.50 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 30.5,
30.7, 52.1, 52.3, 61.9, 87.9, 92.5, 126.9, 128.1, 128.7, 135.2,
141.0, 146.4, 162.2, 163.1, and 167.0. Anal. Calcd for C19H20O7:
C, 63.35; H, 5.60. Found: C, 63.42; H, 5.73.
Eth yl 2-Dia zo-5-a cetylp en ta n oa te (29). To a solution
containing 2.1 g (9.8 mmol) of ethyl 2,5-diacetylpentanoate47
in 20 mL of CH3CN were added 1.8 g (14 mmol) of methane-
sulfonyl azide and 4 mL (29 mmol) of triethylamine. The
resulting solution was stirred for 10 h at rt, the solvent was
removed under reduced pressure, and the crude residue was
washed with 5% NaOH and extracted with ether. The organic
layer was dried over anhydrous Na2SO4, and the solvent was
removed under reduced pressure. The crude residue was
purified by silica gel chromatography to give 1.8 g (66%) of 29
as a yellow oil which was used in the next step without further
To a solution containing 1.0 g (5.4 mmol) of this triketone
in 10 mL of CH3CN were added 1.0 g (7.8 mmol) of methane-
sulfonyl azide and 2.3 mL (16.5 mmol) of triethylamine. The
resulting solution was stirred at rt for 3 h, the solvent was
removed under reduced pressure, and the crude residue was
chromatographed on a silica gel column to give 0.7 g (78%) of
24 as a yellow oil which was used in the next step without
further purification: IR (neat) 2074, 1715, 1636, 1420, and
1
purification: IR (neat) 2083, 1686, 1371, and 1159 cm-1; H
NMR (CDCl3, 360 MHz) δ 1.26 (t, 3H, J ) 7.2 Hz), 1.78 (quint,
2H, J ) 7.2 Hz), 2.14 (s, 3H), 2.31 (t, 2H, J ) 7.2 Hz), 2.49 (t,
2H, J ) 7.2 Hz), and 4.20 (q, 2H, J ) 7.2 Hz); 13C NMR (CDCl3,
75 MHz) δ 14.4, 21.7, 22.6, 29.8, 42.0, 60.6, 167.3, and 207.7.
1
1157 cm-1; H NMR (CDCl3, 300 MHz) δ 1.68-1.82 (m, 2H),
2.11 (s, 3H), 2.20 (s, 3H), 2.31 (t, 2H, J ) 7.2 Hz), and 2.46 (t,
2H, J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 20.7, 24.8, 29.4,
41.6, 67.8, 190.5, and 203.6.
Dim eth yl 1-Meth yl-5-acetyl-8-oxabicyclo[3.2.1]-6-octen e-
6,7-d ica r boxyla te (26). To a solution containing 0.1 g (0.6
(47) J ager, H.; Keymer, R. Arch. Pharm. Ber. Dtsch. Pharm. Ges.
1960, 293, 896.

5230 J . Org. Chem., Vol. 65, No. 17, 2000
Padwa et al.
6,7-Dim eth yl 5-Eth yl 1-Meth yl-8-oxa bicyclo[3.2.1]-6-
octen e-5,6,7-tr ica r boxyla te (32). To a solution containing
0.1 g (0.5 mmol) of diazo ketoester 29 in 2 mL of CH2Cl2 was
added 0.15 g (1.0 mmol) of DMAD in 2 mL of CH2Cl2 followed
by the addition of 2 mg of rhodium(II) acetate. After the
resultant solutionw as stirred for 30 min at rt, the solvent was
removed under reduced pressure and the crude residue was
chromatographed on a silica gel column to give 0.12 g (73%)
of 32 as a colorless oil: IR (neat) 1725, 1653, 1380, 1296, and
the organic layer was dried over MgSO4. The solvent was
removed under reduced pressure, and the crude residue was
chromatographed on a silica gel column to give 3.4 g (90%) of
1-(2-allylphenyl)-2-propen-1-ol as a colorless oil: IR (neat)
3334, 1638, and 1451 cm-1; 1H NMR (CDCI3, 300 MHz) δ 1.90
(s, 1H), 3.48 (d, 2H, J ) 6.1 Hz), 4.95-5.50 (m, 5H), 5.90-
6.15 (m, 2H), and 7.10-7.50 (m, 4H); 13C NMR (CDCI3, 75
MHz) δ 36.4, 70.9, 114.6, 115.7, 126.5, 127.5, 129.6, 136.8,
137.2, 139.6, and 140.2. Anal. Calcd for C12H14O: C, 82.72; H,
8.10. Found: C, 82.69; H, 8.13.
1
1038 cm-1; H NMR (CDCl3, 300 MHz) δ 1.22 (t, 3H, J ) 7.2
Hz), 1.45 (s, 3H), 1.55-1.85 (m, 6H), 3.75 (s, 6H), and 4.18
(dq, 2H, J ) 7.2 and 1.5 Hz); 13C NMR (CDCl3, 75 MHz) δ
13.9, 17.6, 22.4, 25.4, 29.0, 52.2, 52.3, 61.7, 87.3, 88.2, 139.4,
140.6, 162.9, 163.3, and 168.3; HRMS calcd for C15H20O7
312.1209, found 312.1204.
To a solution containing 2.7 g (15.5 mmol) of the above
alcohol in 50 mL of CH2CI2 was slowly added 6.5 g (30 mmol)
of pyridinium chlorochromate at 0 °C. After the resulting
solution was stirred for 2 h, 100 mL of ether was added and
the mixture was passed through a short pad of silica gel. The
solvent was removed under reduced pressure, and the crude
residue was chromatographed on a silica gel column to give
1.2 g (45%) of o-allylphenyl vinyl ketone as a colorless liquid:
Eth yl 2-Dia zo-3-[2-(r-tetr a lon yl)]p r op ion a te (30). A
mixture containing 0.8 g (5.1 mmol) of 2-methylene-R-tetra-
lone,48 1.3 g (10 mmol) of ethyl acetoacetate, and 0.1 g of Ni-
(AcAc)2 in 5 mL of dry benzene was heated at 90 °C for 20 h.
The solvent was removed under reduced pressure, and the
crude residue was purified by silica gel chromatography to give
1.4 g (88%) of ethyl 2-acetyl-3-[2-(R-tetralonyl)]propionate as
a colorless oil which was used in the next step without further
IR (neat) 1661, 1402, and 1231 cm-1 1H NMR (CDCI3, 300
;
MHz) δ 3.51 (d, 2H, J ) 6.3 Hz), 4.95-5.10 (m, 2H), 5.85-
6.20 (m, 3H), 6.75 (dd, 1H, J ) 17.4 and 10.2 Hz), and 7.20-
7.45 (m, 4H); 13C NMR (CDCI3, 75 MHz) δ 37.2, 115.8, 125.6,
128.2, 130.4, 130.6, 131.2, 136.5, 136.8, 137.7, 138.9, and 196.3.
Anal. Calcd for C12H12O: C, 83.68; H, 7.03. Found: C, 83.51;
H, 6.92.
1
purification: IR (neat) 1740, 1715, 1682, and 1360 cm-1; H
NMR (CDCl3, 360 MHz) δ 1.27 (t, 3H, J ) 7.2 Hz), 1.90-2.15
(m, 2H), 2.18-2.28 (m, 1H), 2.33-2.40 (m, 4H), 2.45-2.55 (m,
1H), 2.95-3.05 (m, 2H), 3.88-3.99 (m, 1H), 4.19 (q, 2H, J )
7.2 Hz), 7.21-7.30 (m, 2H), and 7.46 (t, 1H, J ) 7.2 Hz), and
7.90-7.95 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 28.2,
28.6, 28.9, 29.5, 44.9, 56.9, 61.2, 126.5, 127.1, 127.7, 128.6,
132.2, 143.6, 169.4, 199.5 and 202.9.
A mixture containing 1.3 g (7.6 mmol) of the above ketone,
5 mL of methyl acetoacetate, and 0.2 g of Ni(AcAc)2 was heated
at 90 °C for 20 h. The solvent was removed under reduced
pressure, and the crude residue was chromotographed on a
silica gel column to give 1.8 g (83%) of methyl 2-acetyl-5-oxo-
5-(o-allylphenyl)pentanoate as a colorless oil: IR (neat) 1744,
1717, 1688, and 1360 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.20-
2.30 (m, 5H), 2.93 (d, 2H, J ) 7.2 Hz), 3.58-3.65 (m, 3H), 3.73
(s, 3H), 4.90-5.05 (m, 2H), 5.86-6.02 (m, 1H), 7.22-7.30 (m,
To a solution containing 0.6 g (2 mmol) of the above
compound in 8 mL of CH3CN were added 0.5 g (4 mmol) of
methanesulfonyl azide and 0.8 mL (6 mmol) of triethylamine.
The resulting solution was stirred at rt for 6 h, the solvent
was removed under reduced pressure, and the crude residue
was chromatographed on silica gel to give 0.4 g (72%) of 30 as
a yellow oil which was used in the next step without further
2H), 7.40 (t, 1H, J ) 7.5 Hz), and 7.56 (d, 1H, J ) 7.5 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 22.1, 28.9, 37.6, 38.4, 52.2, 57.9,
115.5, 126.0, 128.0, 131.0, 131.2, 137.2, 137.8, 139.2, 169.8,
202.6, and 203.0. Anal. Calcd for C17H20O4: C, 70.82; H, 6.99.
Found: C, 70.72; H, 7.06.
1
purification: IR (neat) 2095, 1684, 1601, and 1178 cm-1; H
A mixture containing 0.8 g (2.9 mmol) of the above com-
pound, 0.7 g (5.6 mmol) of methanesulfonyl azide, and 1.1 mL
(8 mmol) of triethylamine in 6 mL of CH3CN was stirred at rt
for 2 h. The solvent was removed under reduced pressure, and
the crude residue was chromatographed on a silica gel column
to give 34 (63%) as a yellow oil which was used in the next
step without further purification: IR (neat) 2091, 1696, 1437,
NMR (CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 7.2 Hz), 1.85-2.00
(m, 1H), 2.20-2.30 (m, 1H), 2.55-2.65 (m, 1H), 2.70-2.80 (m,
2H), 2.95-3.15 (m, 2H), 4.19 (q, 2H, J ) 7.2 Hz), 7.24 (d, 1H,
J ) 7.8 Hz), 7.28 (t, 1H, J ) 7.8 Hz), 7.45 (t, 1H, J ) 7.8 Hz),
and 7.99 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 75 MHz) δ
14.3, 24.5, 28.6, 28.9, 47.0, 54.6, 60.5, 126.4, 127.1, 128.6, 132.2,
133.3, 143.8, 167.6, and 199.3.
2-Eth yl 3,4-Dim eth yl 2,4a -ep oxy-1,9,10,10a -tetr a h yd r o-
p h en a n th r en e-2,3,4-tr ica r boxyla te (33). To a solution con-
taining 0.24 g (0.9 mmol) of diazo ketoester 30 in 3 mL of
CH2Cl2 was added 0.25 g (1.8 mmol) of DMAD in 2 mL of CH2-
Cl2 followed by the addition of 2 mg of rhodium(II) acetate.
After the resulting solution was stirred at rt for 30 min, the
solvent was removed under reduced pressure and the crude
residue was chromatographed on a silica gel column to give
0.32 g (92%) of 33 as a colorless oil: IR (neat) 1750, 1638, 1240,
and 1130 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.30 (t, 3H, J )
7.2 Hz), 1.60-1.75 (m, 1H), 1.98-2.08 (m, 1H), 2.12-2.20 (m,
1H), 2.23-2.35 (m, 2H), 2.80-2.90 (m, 2H), 3.60 (s, 3H), 3.81
(s, 3H), 4.20-4.40 (m, 2H), and 7.10-7.40 (m, 4H); 13C NMR
(CDCl3, 75 MHz) δ 13.9, 27.9, 29.5, 37.6, 39.7, 52.1, 52.3, 61.8,
88.1, 90.2, 126.3, 128.4, 128.9, 129.4, 130.1, 139.3, 142.8, 146.4,
162.2. 162.3, and 167.0. Anal. Calcd for C21H22O7: C, 65.28;
H, 5.74. Found: C, 65.48; H, 5.87.
1333, and 1111 cm-1 1H NMR (CDCI3, 360 MHz) δ 2.70 (t,
;
2H, J ) 6.5 Hz), 3.17 (t, 2H, J ) 6.5 Hz), 3.62 (d, 2H, J ) 6.5
Hz), 3.75 (s, 3H), 4.95-5.04 (m, 2H), 5.80-6.00 (m, 1H), 7.25-
7.35 (m, 2H), 7.42 (t, 1H, J ) 7.5 Hz), and 7.76 (d, 1H, J ) 7.5
Hz); 13C NMR (CDCI3, 75 MHz) δ 18.6, 37.8, 39.5, 51.7, 115.5,
126.1, 128.3, 131.2, 131.5, 137.2, 137.6, 139.5, 167.7, and 202.9.
Meth yl 2,4a -Ep oxy-3,4,9,9a -tetr a h yd r o-1H-flu or en e-2-
ca r boxyla te (35). To a solution containing 0.24 g (0.9 mmol)
of diazo ketoester 34 in 10 mL of CH2CI2 was added 2 mg of
rhodium(II) acetate. After the resulting solution was stirred
for 5 h at rt, the solvent was removed under reduced pressure
and the crude residue was chromatographed on a silica gel
column to give 0.17 g (80%) of 35 as a white solid: mp 97-98
°C; IR (neat) 1738, 1269, and 1105 cm-1; 1H NMR (CDCI3, 300
MHz) δ 1.85-1.95 (m, 1H), 2.00-2.08 (m, 1H), 2.10-2.25 (m,
2H), 2.33-2.43 (m, 2H), 2.70-2.80 (m, 2H), 3.05-3.18 (m, 1H),
3.78 (s, 3H), 7.20-7.30 (m, 3H), and 7.44 (d, 1H, J ) 7.2 Hz);
13C NMR (CDCI3, 75 MHz) δ 30.5, 33.5, 38.2, 43.3, 48.8, 52.1,
86.9, 96.8, 124.3, 125.0, 126.3, 129.7, 136.9, 147.0, and 171.8.
Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.70;
H, 6.56.
Meth yl 2-Dia zo-5-oxo-5-(2-a llylp h en yl)p en ta n oa te (34).
To a mixture containing 1.8 mL (10 mmol) of tetravinyltin in
30 mL of ether was slowly added 28 mL of 1.4 M methyllithium
at 0 °C. After being stirred for 30 min, the resulting solution
was cannulated into a solution containing 3.2 g (22 mmol) of
o-allylbenzaldehyde49 in 40 mL of ether at 0 °C. After being
stirred for 2 h at rt, the mixture was poured into a 1.0 N HCl
solution. The aqueous phase was extracted with ether, and
Tr im eth yl 4-(o-Allylp h en yl)-7-oxa bicyclo[2.2.1]-2-h ep -
ten e-1,2,3-tr ica r boxyla te (36). To a mixture containing 0.3
g (1.1 mmol) of diazo ketoester 34 in 5 mL of CH2Cl2 was added
0.33 g (2.3 mmol) of DMAD followed by the addition of 2 mg
of rhodium(II) acetate. After the resulting solution was stirred
for 1 h at rt, the solvent was removed under reduced pressure
and the crude residue was chromatographed on a silica gel
column to give 0.36 g (85%) of 36 as a clear oil: IR (neat) 1752,
(48) Gras, J . L. Tetrahedron Lett. 1978, 2111.
(49) Kampmeier, J . A.; Harris, S. H.; Mergelsberg, I. J . Org. Chem.
1984, 49, 621.

Cyclization-Cycloaddition of Rhodium Carbenoids
J . Org. Chem., Vol. 65, No. 17, 2000 5231
1640, 1437, and 1263 cm-1; 1H NMR (CDCI3, 300 MHz) δ 1.90-
2.00 (m, 1H), 2.18-2.28 (m, 1H), 2.36-2.46 (m, 1H), 2.54-
2.64 (m, 1H), 3.40-3.68 (m, 5H), 3.80 (s, 3H), 3.86 (s, 3H),
4.98-5.08 (m, 2H), 5.84-5.98 (m, 1H), 7.20-7.35 (m, 3H), and
7.43 (d, 1H, J ) 7.2 Hz); 13C NMR (CDCI3, 75 MHz) δ 29.7,
31.3, 37.6, 52.1, 52.5, 52.7, 88.3, 92.5, 115.6, 125.7, 128.4, 129.1,
130.6, 132.2, 137.9, 139.5, 140.8, 146.6, 162.1, 162.9 and 167.6.
Anal. Calcd for C21H22O7: C, 65.27; H, 5.73. Found: C, 65.26;
H, 5.63.
N-(2-Dia zo-3-oxobu tyl)p h th a lim id e (45). To a solution
containing 8.9 g (50 mmol) of N-(hydroxymethyl)phthalimide
and 10 mL of 2,4-pentanedione was slowly added 30 mL of
98% H2SO4 at 0 °C. The resulting mixture was stirred at 50
°C for 6 h and then poured into ice-water. The solid was
filtered and rinsed with a small amount of water and ether to
give 11.6 g (84%) of N-(2-acetyl-3-oxobutyl)phthalimide: mp
129-130 °C; IR (CHCI3) 1771, 1715, 1396, and 1346 cm-1; 1H
NMR (CDCI3, 300 MHz) δ 2.35 (s, 7H), 4.56 (s, 2H), and 7.68-
7.85 (m, 4H); 13C NMR (CDCI3, 75 MHz) δ 23.5, 36.3, 105.8,
Allyl 2-Dia zo-3-[2-(r-tetr a lon yl]p r op ion a te (37). A mix-
ture containing 1.8 g (11.5 mmol) of 2-methylene-R-tetralone,
1.4 g (10 mmol) of allyl acetoactate, and 0.2 g of Ni(AcAc)2 in
10 mL of benzene was heated at 90 °C for 40 h. The solvent
was removed under reduced pressure, and the crude residue
was purified by silica gel chromatography to give 2.5 g (84%)
of allyl 2-acetyl-3-[2-(R-tetralonyl)]propionate as a colorless
123.2, 131.7, 134.1, 168.1, and 193.4. Anal. Calcd for C14H13
-
NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.93; H, 5.02; N,
5.39.
A mixture containing 0.77 g (3 mmol) of the above phthal-
imide, 0.6 g (4.5 mmol) of methanesulfonyl azide, and 1.3 mL
(9 mmol) of triethylamine was stirred at rt for 3 h. The solvent
was removed under reduced pressure, and the crude residue
was chromatographed on a silica gel column to give 0.65 g
(90%) of 45 as a yellow solid: mp 112-113 °C; IR (neat) 2103,
1713, 1626, and 1315 cm-1; 1H NMR (CDCI3, 300 MHz) δ 2.21
(s, 3H), 4.66 (s, 2H), 7.73 (s, 2H), and 7.85 (s, 2H); 13C NMR
(CDCI3, 75 MHz) δ 25.0, 32.5, 66.5, 123.4, 131.7, 134.1, 167.6,
and 189.0. Anal. Calcd for C12H9N3O3: C, 59.26; H, 3.73.
Found: C, 59.18; H, 3.69.
oil: IR (neat) 1717, 1682, 1360, and 1221 cm-1 1H NMR
;
(CDCI3, 360 MHz) δ 1.85-2.15 (m, 2H), 2.18-2.28 (m, 1H),
2.30-2.40 (m, 4H), 2.44-2.54 (m, 1H), 2.95-3.05 (m, 2H),
3.90-4.05 (m, 1H), 4.61 (d, 2H, J ) 5.7 Hz), 5.20-5.37 (m,
2H), 5.80-5.95 (m, 1H), 7.20-7.45 (m, 3H), and 7.90-8.00 (m,
1H); 13C NMR (CDCI3, 75 MHz) δ 28.1, 28.5, 28.8, 29.5, 44.6,
56.7, 65.6, 118.7, 126.3, 126.9, 127.0, 128.5, 131.3, 133.1, 143.5,
168.9, 199.3, and 202.6. Anal. Calcd for C18H20O4: C, 71.98;
H, 6.71. Found: C, 72.07; H, 6.75.
Dim eth yl 3-Acetyl-3,10b-ep oxy-3,4,6,10b-tetr a h yd r o-
p yr id o[2,1-a ]isooxin d ole-1,2-d ica r boxyla te (46). To a so-
lution containing 0.18 g (0.7 mmol) of diazo imide 45 in 3 mL
of CH2Cl2 and 2 mL of pentane was added 0.2 g (1.4 mmol) of
DMAD followed by the addition of 2 mg of rhodium(II) acetate.
The resulting mixture was stirred at rt for 5 h, and the solvent
was removed under reduced pressure. The crude residue was
chromatographed on silica gel to give 0.18 g (68%) of 46 as a
A mixture containing 0.5 g (1.7 mmol) of the above com-
pound, 0.4 g (3.3 mmol) of methanesulfonyl azide, and 0.7 mL
(5.0 mmol) of triethylamine in 4 mL of CH3CN was stirred at
rt for 5 h. The solvent was removed under reduced pressure,
and the crude residue was purified by silica gel chromatog-
raphy to give allyl 3-[2-(R-tetralonyl]propionate (90%) as a
yellow oil which was used in the next step without further
1
colorless oil: IR (neat) 1721, 1675, 1231, and 1138 cm-1; H
1
purification: IR (neat) 2093, 1686, 1456, and 1124 cm-1; H
NMR (360 MHz, CDCl3) δ 2.32 (s, 3H), 3.36 (d, 1H, J ) 10.1
Hz), 3.66 (s, 3H), 3.75 (d, 1H, J ) 10.1 Hz), 3.87 (s, 3H), and
7.60-7.90 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 26.3, 45.0,
52.5, 52.9, 96.8, 102.7, 124.5, 125.1, 131.9, 132.6, 135.1, 135.6,
139.5, 146.1, 160.5, 161.6, 169.9, and 199.3. Anal. Calcd for
NMR (CDCI3, 300 MHz) δ 1.90-2.05 (m, 1H), 2.22-2.35 (m,
1H), 2.56-2.68 (m, 1H), 2.70-2.90 (m, 2H), 2.95-3.15 (m, 2H),
4.65 (d, 2H, J ) 5.7 Hz), 5.20-5.40 (m, 2H), 5.80-6.00 (m,
1H), 7.20-7.38 (m, 2H), 7.46 (d, 1H, J ) 7.5 Hz), and 7.99 (d,
1H, J ) 7.5 Hz); 13C NMR (CDCI3, 75 MHz) δ 24.5, 28.7, 28.9,
47.0, 65.0, 117.7, 126.5, 127.1, 128.6, 132.1, 132.2, 133.3, 143.8,
167.2, and 199.2.
C
18H15NO7: C, 60.49; H, 4.23; N, 3.92. Found: C, 60.37; H,
3.98; N, 3.81.
N -Ac e t y l-3,4-d ic a r b o m e t h o x y -5-p h t h a lim id y lp y r -
a zole (48). In addition to compound 46, two additional
compounds (48 and 49) were also isolated from the above silica
gel chromatography. These same two compounds were also
formed by stirring a 0.2 g (0.8 mmol) sample of diazo ketone
45 and 0.2 g (1.4 mmol) of DMAD in 5 mL of benzene at rt.
The solvent was removed under reduced pressure, and the
crude residue was subjected to silica gel chromatography. The
major fraction contained 0.26 g (67%) of 48 as a white solid,
2-Allyl 3,4-Dim eth yl 2,4a -ep oxy-1,9,10,10a -tetr a h yd r o-
p h en a n th r en e-2,3,4-tr ica r boxyla te (38). To a solution con-
taining 0.21 g (0.8 mmol) of diazo ketoester 37 in 2 mL of
CH2CI2 was added 0.21 g (1.5 mmol) of DMAD in 2 mL of CH2-
CI2 followed by the addition of 2 mg of rhodium(II) acetate.
After the resulting solution was stirred at rt for 2 h, the solvent
was removed under reduced pressure and the crude residue
was chromatographed on a silica gel column to give 0.27 g
(89%) of 38 as a colorless oil: IR (neat) 1746, 1435, 1238, and
mp 138-139 °C; IR (CHCI3) 1721, 1398, 1315, and 1169 cm-1
;
1
1128 cm-1; H NMR (CDCI3, 300 MHz) δ 1.60-1.72 (m, 1H),
1H NMR (CDCI3, 300 MHz) δ 2.71 (s, 3H), 3.56 (s, 3H), 3.84
(s, 3H), 5.36 (s, 2H), and 7.60-7.80 (m, 4H); 13C NMR (CDCI3,
75 MHz) δ 23.4, 33.5, 52.4, 52.7, 118.1, 123.3, 131.5, 134.1,
141.8, 144.2, 161.2, 162.2, 167.0, 167.2, and 171.5. Anal. Calcd
for C18H15N3O7: C, 56.11; H, 3.87; N, 10.90. Found: C, 56.04;
H, 3.86; N, 10.75.
1.98-2.08 (m, 2H), 2.23-2.35 (m, 2H), 2.75-2.90 (m, 2H), 3.58
(s, 3H), 3.78 (s, 3H), 4.65-4.80 (m, 2H), 5.22-5.40 (m, 2H),
5.85-6.00 (m, 1H), 7.10-7.25 (m, 3H), and 7.36 (d, 1H, J )
7.8 Hz); 13C NMR (CDCI3, 75 MHz) δ 27.9, 29.5, 37.6, 39.7,
52.1, 52.4, 66.4, 88.1, 90.3, 119.1, 126.4, 128.5, 129.0, 129.4,
130.2, 131.3, 139.3, 142.6, 146.6, 162.2, 163.4, and 166.8. Anal.
Calcd for C22H22O7: C, 66.31; H, 5.57. Found: C, 66.23; H,
5.61.
The minor product isolated from the chromatographic
separation contained 0.09 g (22%) of N-phthalimidyl-3-acetyl-
4,5-dicarbomethoxypyrazole (49) as a white solid: mp 175-
176 °C; IR (CHCI3) 1713, 1395, 1377, and 1109 cm-1; 1H NMR
(CDCI3, 300 MHz) δ 2.41 (s, 3H), 3.83 (s, 3H), 3.93 (s, 3H),
5.11 (s, 2H), and 7.65-7.85 (m, 4H); 13C NMR (CDCI3, 75 MHz)
δ 21.6, 35.4, 52.3, 53.5, 113.5, 123.4, 132.0, 134.1, 138.8, 150.5,
160.7, 161.4, 167.6, 168.7 and 196.2. Anal. Calcd for
Allyl 2,3,4,5-Tetr a h yd r on a p h th o[1,2-b]fu r a n -2-ca r box-
yla te (39). To a solution containing 0.23 g (0.8 mmol) of diazo
ketoester 37 in 10 mL of CH2Cl2 was added 2 mg of rhodium-
(II) acetate. After the resulting solution was stirred for 3 h at
rt, the solvent was removed under reduced pressure and the
crude residue was chromatographed on a silica gel column to
give 0.16 g (68%) of 39 as a clear oil: IR (neat) 1740, 1194,
C
18H15N3O7: C, 56.11; H, 3.87; N, 10.90. Found: C, 56.10; H,
3.92; N, 10.96.
1065, and 1032 cm-1 1H NMR (CDCI3, 360 MHz) δ 2.39 (t,
;
Eth yl 2-Diazo-3-(N-ben zoyl-N-m eth ylam in o)pr opan oate
(50). To a suspension containing 0.2 g of sodium hydride (60%
in mineral oil) in 6 mL of benzene at 0 °C was added one drop
of anhydrous ethanol, followed by the dropwise addition of 0.5
g of methyl 3-(N-benzoyl-N-methyl)aminopropanoate50 and 0.4
2H, J ) 7.9 Hz), 2.90-3.00 (m, 3H), 3.10-3.20 (m, 1H), 4.70
(d, 2H, J ) 5.8 Hz), 5.16 (dd, 1H, J ) 10.8 and 6.8 Hz), 5.26
(dd, 1H, J ) 10.1 and 1.1 Hz), 5.36 (dd, 1H, J ) 16.9 and 1.1
Hz), 5.88-6.00 (m, 1H), and 7.10-7.35 (m, 4H); 13C NMR
(CDCI3, 75 MHz) δ 21.9, 28.4, 37.4, 65.7, 77.9, 107.8, 118.6,
120.4, 126.3, 127.1, 127.3, 127.6, 131.6, 135.8, 150.1 and 171.5.
Anal. Calcd for C16H16O3: C, 74.97; H, 6.30. Found: C, 74.72;
H, 6.18.
(50) Thomas, W. B.; McElvain, S. M. J . Am. Chem. Soc. 1932, 54,
3295.

5232 J . Org. Chem., Vol. 65, No. 17, 2000
Padwa et al.
g of ethyl formate. The reaction was allowed to warm to 25 °C
and was stirred for 12 h followed by the addition of 0.5 g of
mesyl azide. The mixture was stirred for 4 h and was quenched
with water. The organic layer was separated, washed with a
10% NaOH solution, and dried over Na2SO4. Removal of the
solvent under reduced pressure and chromatography of the
residue gave 50 (85%) as a yellow oil which was used in the
next step without further purification: IR (neat) 2100, 1695,
1335, 1175, and 1120 cm-1; NMR (CDCl3, 300 MHz) δ 1.29 (t,
3H, J ) 7.0 Hz), 3.08 (s, 3H), 4.25 (q, 2H, J ) 7.0 Hz), 4.42 (s,
2H), and 7.42 (s, 5H); 13C NMR (CDCl3, 75 MHz) δ 13.8, 37.4,
37.5, 43.0, 60.4, 126.6, 127.7, 129.3, 134.8, 166.5, and 171.9.
1-Ca r b oet h oxy-3,4-d ica r b om et h oxy-5-(N-b en zoyl-N-
m eth yl)a m in om eth ylp yr a zole (53). To 5 mL of a benzene
solution containing 0.3 g of DMAD and 2 mg of rhodium(II)
acetate at 80 °C was added dropwise a solution containing 0.2
g of diazo amide 50 in 1 mL of benzene over a 30 min period.
The mixture was heated at reflux for an additional 30 min
and was then concentrated under reduced pressure. Silica gel
chromatography of the crude oil afforded 53 as a clear oil in
90% yield: IR (neat) 1735, 1660, 1255, and 1073 cm-1; NMR
(CDCl3, 300 MHz) δ 1.34 (t, 3H, J ) 7.2 Hz), 3.05 (s, 3H), 3.93
(s, 3H), 3.94 (s, 3H), 4.34 (q, 2H, J ) 7.2 Hz), 6.15 (brs, 2H),
and 7.36-7.53 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 13.2, 51.9,
52.2, 52.3, 52.5, 61.8, 114.8, 120.7, 126.7, 127.8, 129.6, 134.2,
139.6, 157.1, 160.1, 162.5 and 171.7. Anal. Calcd for
2-Diazo-4-(m eth ylph en ylcar bam oyl)bu tyr ic Acid Meth -
yl Ester (57). A solution containing 3.5 g of glutaric anhydride
and 4.0 g of N-methylaniline in 50 mL of THF was allowed to
stir at 25 °C for 3 h and was then concentrated under reduced
pressure to give 4-(methylphenylcarbamoyl)butyric acid in 90%
yield: mp 97-98 °C. To a solution of this acid in 100 mL of
methanol at -15 °C was slowly added 4.0 g of thionyl chloride.
The resulting mixture was allowed to warm to 25 °C and was
stirred for 4 h. Concentration of the solution under reduced
pressure followed by silica gel chromatography gave 6.0 g
(95%) of 4-(methylphenylcarbamoyl)butyric acid methyl es-
ter: NMR (CDCl3, 90 MHz) δ 1.96 (sept, 2H, J ) 6.0 Hz), 2.16
(t, 2H, J ) 6.0 Hz), 2.31 (t, 2H, J ) 6.0 Hz), 3.32 (s, 3H), 3.64
(s, 3H), and 7.18-7.50 (m, 5H). This compound was converted
to 57 in 73% yield by the standard diazo transfer method: IR
(neat) 2091, 1690, 1437, and 1115 cm-1; NMR (CDCl3, 300
MHz) δ 2.30 (t, 2H, J ) 6.3 Hz), 2.54 (t, 2H, J ) 6.3 Hz), 3.27
(s, 3H), 3.70 (s, 3H), 7.17 (d, 2H, J ) 7.2 Hz), 7.37 (t, 1H, J )
7.2 Hz) and 7.42 (t, 2H, J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz)
δ 19.7, 32.3, 37.2, 51.6, 127.1, 127.8, 129.8, 143.5, and 171.4.
Diazo amidoester 57 was used in the next step without further
purification.
5-(3′-(N-Meth yl-N-p h en yla m in o-3′-oxo)p r op yl-1,4,5-tr i-
ca r bom eth oxyp yr a zole (58). To 5 mL of a benzene solution
containing 0.25 g of DMAD and 2 mg of rhodium(II) acetate
at 80 °C was slowly added 0.4 g of diazoamide 57 in 2 mL of
benzene. The mixture was heated at reflux for 30 min and was
then concentrated under reduced pressure and chromato-
graphed on silica gel to give 58 in 89% yield; mp 119-120 °C;
IR (neat) 1773, 1738, 1659, 1224, and 1061 cm-1; NMR (CDCl3,
300 MHz) δ 2.44 (t, 2H, J ) 7.4 Hz), 3.25 (s, 3H), 3.53 (t, 2H,
J ) 7.4 Hz), 3.85 (s, 3H), 3.92 (s, 3H), 3.92 (s, 3H), 4.05 (s,
3H), 7.13 (d, 2H, J ) 7.5 Hz), and 7.24-7.50 (m, 3H); 13C NMR
(CDCl3, 75 MHz) δ 22.0, 32.5, 37.2, 52.1, 52.7, 55.3, 115.3,
127.1, 127.7, 129.6, 143.5, 145.7, 149.4, 151.2, 161.7, 161.9,
and 170.5. Anal. Calcd for C19H21N3O7: C, 56.57; H, 5.25; N,
10.41. Found: C, 56.47; H, 5.23; N, 10.37.
C
19H21N3O7: C, 56.56; H, 5.25; N, 10.42. Found: C, 56.41; H,
5.06; N, 10.25.
3-(N-Ben zoyl-N-m et h yla m in o)m et h yl-3-ca r b oet h oxy-
4,6-dioxo-5-ph en yl-3a,4,6,6a-tetr ah ydr opyr r olo[3,4-d]pyr -
a zole (55). Treatment of a 0.1 g sample of diazo amide 50
with N-phenylmaleimide according to the procedure outlined
above afforded 55 in 70% yield after silica gel chromatogra-
phy: IR (neat) 1725, 1636, 1499, 1385 and 1198 cm-1; NMR
(CDCl3, 300 MHz) δ 1.17 (t, 3H, J ) 7.0 Hz), 2.91 (s, 3H), 3.99
(d, 1H, J ) 14.5 Hz), 4.05-4.40 (m, 3H), 5.10 (d, 1H, J ) 14.5
Hz), 6.02 (d, 1H, J ) 8.3 Hz), and 7.10-7.55 (m, 10H); 13C
NMR (CDCl3, 75 MHz) δ 13.1, 40.5, 43.9, 51.3, 52.9, 62.6, 95.4,
102.7, 125.7, 126.2, 128.0, 128.5, 128.6, 129.7, 130.3, 134.3,
166.8, 171.7 and 173.0. Anal. Calcd for C23H22N4O5: C, 63.57;
H, 5.11; N, 12.90. Found: C, 63.32; H, 5.06; N, 12.64.
Met h yl 2-Dia zo-3-(2′-oxo-1′-p yr r olid in yl)p r op a n oa t e
(51). Following the procedure outlined above, a sample of diazo
amide 51 was prepared from 2.0 g of methyl 3-(2′-oxo-1′-
pyrrolidinyl)propanoate51 by the diazo transfer method in 80%
yield and was used in the next step without further purifica-
tion: IR (neat) 2100, 1696, 1308, and 1130 cm-1; NMR (CDCl3,
300 MHz) δ 2.05 (tt, 2H, J ) 8.0 and 7.1 Hz), 2.38 (t, 2H, J )
8.0 Hz), 3.47 (t, 2H, J ) 7.1 Hz), 3.78 (s, 3H), and 4.23 (s, 2H);
13C NMR (CDCl3, 75 MHz) δ 17.8, 30.4, 37.8, 47.0, 51.9, 166.8
and 175.8.
3-Ca r bom eth oxy-4,6-d ioxo-3-(3′-(N-m eth yl-N-p h en yl)-
am in o-3′-oxo)pr opyl-5-ph en yl-3a,4,6,6a-tetr ah ydr opyr r olo-
[3,4-d ]p yr a zole (59). Heating a mixture of diazo amide 57
and N-phenylmaleimide in benzene at 80 °C with rhodium-
(II) acetate afforded pyrazole 59 in 81% yield as a white solid:
mp 155-156 °C; IR (neat) 1770, 1720, 1646, 1385, and 1195
cm-1; NMR (CDCl3, 300 MHz) δ 2.21-2.42 (m, 3H), 2.42-2.61
(m, 1H), 3.24 (s, 3H), 3.35 (d, 1H, J ) 8.2 Hz), 3.58 (s, 3H),
6.00 (d, 1H, J ) 8.2 Hz), and 7.10-7.58 (m, 10H); 13C NMR
(CDCl3, 75 MHz) δ 28.7, 31.5, 37.4, 46.2, 53.1, 95.0, 102.6,
126.2, 127.1, 128.0, 129.0, 129.2, 129.9, 130.9, 143.4, 166.5,
167.5, 171.1, and 172.4. Anal. Calcd for C23H22N4O5: C, 63.58;
H, 5.10; N, 12.90. Found: C, 63.55; H, 5.11; N, 12.78.
5-(2′-Oxo-1′-pyr r olidin yl)m eth yl-1,3,4-tr icar bom eth oxy-
p yr a zole (54). A mixture containing 0.3 g of diazo amide 51,
1.2 equiv of DMAD, and 2 mg of rhodium(II) acetate was
allowed to stir at rt for 4 h. The crude reaction mixture was
subjected to silica gel chromatography. The major product
(87%) obtained was a clear oil and was assigned as structure
54 on the basis of its spectral properties: NMR (CDCl3, 300
MHz) δ 2.03 (tt, 2H, J ) 8.0 and 7.2 Hz), 2.39 (t, 2H, J ) 8.0
Hz), 3.45 (t, 2H, J ) 8.0 Hz), 3.93 (s, 3H), 3.94 (s, 3H), 3.96 (s,
3H) and 6.02 (s, 2H). Anal. Calcd for C14H17N3O7: C, 49.54;
H, 5.05; N, 12.39. Found: C, 49.27; H, 4.83; N, 12.17.
3-Ca r b om et h oxy-4,6-d ioxo-3-(2′-oxo-1′-p yr r olid in yl)-
m eth yl-5-p h en yl-3a ,4,6,6a -tetr a h yd r op yr r olo[3,4-d ]p yr -
a zole (56). The reaction of a 0.1 g sample of diazo amide 51
with N-phenylmaleimide according to the procedure outlined
above afforded 56 as a clear oil in 83% yield: NMR (CDCl3,
300 MHz) δ 1.95-2.45 (m, 4H), 3.30-3.45 (m, 2H), 3.74 (s,
3H), 3.80 (d, 1H, J ) 15.0 Hz), 4.05 (d, 1H, J ) 8.4 Hz), 4.58
(d, 1H, J ) 15.0 Hz), 5.91 (d, 1H, J ) 8.4 Hz), and 7.35-7.58
(m, 5H). Anal. Calcd for C18H18N4O5: C, 58.36; H, 4.90; N,
15.13. Found: C, 58.14; H, 4.76; N, 15.27.
1,5-Dica r b om e t h oxy-4,5-d ih yd r o-5-(3′-(N -m e t h yl-N -
ph en yl)am in o-3′-oxo)pr opylpyr azole (60). Heating a sample
of diazo amide 57 with methyl acrylate in refluxing benzene
afforded pyrazole 60 in 65% yield as a white solid: mp 125-
126 °C; IR (neat) 1720, 1701, 1655, 1260, and 1121 cm-1; NMR
(CDCl3, 300 MHz) δ 2.02-2.17 (m, 3H), 2.17-2.34 (m, 1H),
2.68 (d, 1H, J ) 17.8 Hz), 3.25 (s, 3H), 3.35 (d, 1H, J ) 17.8
Hz), 3.68 (s, 3H), 3.81 (s, 3H), 6.80 (s, 1H), 7.17 (d, 2H, J )
7.5 Hz), 7.37 (t, 1H, J ) 7.5 Hz), and 7.43 (t, 2H, J ) 7.5 Hz);
13C NMR (CDCl3, 75 MHz) δ 28.9, 32.4, 37.3, 39.2, 52.0, 52.8,
72.4, 127.1, 128.0, 129.8, 141.5, 143.5, 162.2, 171.1 and 173.5.
Anal. Calcd for C17H21N3O5: C, 58.78; H, 6.09; N, 12.10.
Found: C, 58.51; H, 6.09; N, 12.15.
Ack n ow led gm en t. We gratefully acknowledge the
National Science Foundation (Grant CHE-9806331) for
generous support of this work.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectrum
for compound 32. This material is available free of charge via
the Internet at http://pubs.acs.org.
(51) Gribble, G. W. J . Org. Chem. 1970, 35, 1944.
J O000378F