A novel cycloaddition reaction of α-diazo-γ-amido ketones catalyzed by rhodium(II) acetate. Scope and mechanistic details of the process

Article abstract of DOI:10.1021/jo952078h

α-Diazo ketones containing an amido group in the γ-position have been found to underdo a novel rhodium(II)-catalyzed cycloaddition reaction. Intramolecular cyclization of the keto carbenoid onto the oxygen atom of the amide group generates a carbonyl ylide dipole as a transient species. This highly stabilized dipole does not readily undergo 1,3-dipolar cycloaddition but ruther transfers a proton to produce a cyclic ketene N,O-acetal. The ketene acetale is unstable to moisture and upon standing is readily hydrolyzed to a γ-keto-δ-lactone and an amine. In the absence of any significant amount of water, the ketene N,O-acetal undergoes conjugate addition with the activated ?-bond of the dipolarophile to give a zwitterion intermediate. The anionic portion of the zwitterion adds to the neighboring carbonyl group. This is followed by epoxide ring formation with charge dissipation leading to an amido-substituted spiro cyclopentenyl epoxide. In certain cases a hydroxyl lactone was also isolated and its formation can be attributed to the competitive hydrolysis of the zwitterionic intermediate. The Rh(II)-catalyzed reaction of the diazo ketoamide derived from N-benzylpiperidone with DMAD afforded two different types of cyloadducts. In addition to the spiro cyclopentenyl epoxide, a product derived from trapping of the carbonyl ylide dipole was also obtained, thereby providing additional support for the proposed mechanism.

Full text of DOI:10.1021/jo952078h

J . Org. Chem. 1996, 61, 2283-2292
2283
A Novel Cycloa d d ition Rea ction of r-Dia zo-γ-a m id o Keton es
Ca ta lyzed by Rh od iu m (II) Aceta te. Scop e a n d Mech a n istic Deta ils
of th e P r ocess†
Albert Padwa,* Alan T. Price, and Lin Zhi
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received November 27, 1995X
R-Diazo ketones containing an amido group in the γ-position have been found to undergo a novel
rhodium(II)-catalyzed cycloaddition reaction. Intramolecular cyclization of the keto carbenoid onto
the oxygen atom of the amide group generates a carbonyl ylide dipole as a transient species. This
highly stabilized dipole does not readily undergo 1,3-dipolar cycloaddition but rather transfers a
proton to produce a cyclic ketene N,O-acetal. The ketene acetal is unstable to moisture and upon
standing is readily hydrolyzed to a γ-keto δ-lactone and an amine. In the absence of any significant
amount of water, the ketene N,O-acetal undergoes conjugate addition with the activated π-bond of
the dipolarophile to give a zwitterion intermediate. The anionic portion of the zwitterion adds to
the neighboring carbonyl group. This is followed by epoxide ring formation with charge dissipation
leading to an amido-substituted spiro cyclopentyl epoxide. In certain cases a hydroxy lactone was
also isolated and its formation can be attributed to the competitive hydrolysis of the zwitterionic
intermediate. The Rh(II)-catalyzed reaction of the diazo ketoamide derived from N-benzylpiperidone
with DMAD afforded two different types of cycloadducts. In addition to the spiro cyclopentyl epoxide,
a product derived from trapping of the carbonyl ylide dipole was also obtained, thereby providing
additional support for the proposed mechanism.
The development of methods that efficiently construct
polyazacyclic, multifunctional systems by tandem proc-
esses1-4 is of great interest in synthetic chemistry.
Sequential methods for synthesis are particularly attrac-
tive because complex products may be accessed in a
single, one-pot process from relatively simple precursors.5
Tandem cationic,6-10 anionic,11-18 radical,19-23 pericyclic24-28
and transition metal catalyzed processes29-36 have been
featured in the synthesis of important natural products
over the past two decades. Recent papers from these
laboratories have described a route to polycyclic ring
systems which involves the tandem cyclization-cycload-
dition of a transient rhodium carbenoid.37 As indicated
in Scheme 1, a cyclic carbonyl ylide intermediate (2) is
generated by treatment of a diazoalkanedione (1) with
rhodium(II) carboxylates. The success of the method
relies on intramolecular attack of the neighboring car-
bonyl oxygen at the rhodium carbenoid center to form
the 1,3-dipole which subsequently cycloadds across a
π-bond.
† This paper is dedicated to Professor Norman A. Lebel on the
occasion of his 65th birthday..
X Abstract published in Advance ACS Abstracts, March 15, 1996.
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0022-3263/96/1961-2283$12.00/0 © 1996 American Chemical Society

2284 J . Org. Chem., Vol. 61, No. 7, 1996
Padwa et al.
Sch em e 1
Sch em e 2
6 occurs via proton exchange with a small amount of
water that was present in the reaction mixture. 1,3-
Dipolar cycloaddition with DMAD provides cycloadduct
7, which undergoes a subsequent 1,3-alkoxy shift to
generate the tricyclic dihydropyrrolizine 8. The overall
reaction has been termed a “dipole cascade” since it
involves the interconversion of three distinct classes of
1,3-dipoles.39
Some of our more recent methodological achievements
in this area involve the use of diazo ketoamides.38 The
ensuing studies showed that the nature of the interacting
carbonyl group can significantly affect the course of the
tandem cycloaddition process. As a specific illustration,
1-acetyl-2-(1-diazoacetyl)pyrrolidine (4) was observed to
react with DMAD in the presence of a Rh(II) catalyst to
To further demonstrate the synthetic potential of the
amido cascade process, experiments involving a series of
related diazo ketoamides were carried out.41 In this
paper we present full details of our initial discovery and
development of a new class of bimolecular cycloaddition
of diazo ketoamides.41 This new tandem cycloaddition
process is generically outlined in Scheme 2. The reaction
takes place with both olefinic and acetylenic dipolaro-
philes to give spiro amido cyclopentyl epoxides of type
10 and occurs in several discrete stages. In order to
explore this novel process in more detail, several R-diazo-
γ′-amido ketones were synthesized and treated with a
rhodium(II) catalyst. The results of these studies are
reported herein.
give the rearranged cycloadduct 8.39,40 The mechanism
proposed to rationalize the formation of this novel product
involves generation of the expected carbonyl ylide dipole
5 by intramolecular cyclization of the keto carbenoid onto
the oxygen atom of the amide group. Isomerization of 5
to the thermodynamically more stable azomethine ylide
Resu lts a n d Discu ssion
The discovery of the dipole cascade process in our
laboratory39 which interconverts R-diazo ketones 11 to
azomethine ylides 13 via the intermediacy of carbonyl
ylides 12 prompted us to explore the generality of this
transformation using the related R-diazo keto amides 14
and/or 17. Mopac (PM3) calculations show that cyclic
(37) (a) Padwa, A.; Austin, D. J .; Hornbuckle, S. F.; Semones, M.
A.; Doyle, M. P.; Protopopova, M. N. J . Am. Chem. Soc. 1992, 114,
1874. (b) Padwa, A.; Austin, D. J .; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R. J . Am. Chem. Soc. 1993,
115, 8669. (c) Padwa, A.; Austin, D. J .; Hornbuckle, S. F.; Price, A. T.
Tetrahedron Lett. 1992, 33, 6427. (d) Padwa, A. Acc. Chem. Res. 1991,
24, 22. (e) Padwa, A.; Carter, S. P.; Nimmesgern, H. J . Org. Chem.
1986, 51, 1157. (f) Padwa, A.; Carter, S. P.; Nimmesgern, H.; Stull, P.
D. J . Am. Chem. Soc. 1988, 110, 2894. (g) Padwa, A.; Stull, P. D.
Tetrahedron Lett. 1987, 5407. (h) Padwa, A.; Fryxell, G. E.; Zhi,
L. J . Org. Chem. 1988, 53, 2877. (i) Padwa, A.; Fryxell, G. E.; Zhi, L.
J . Am. Chem. Soc. 1990, 112, 3100. (j) Padwa, A.; Chinn, R. L.;
Zhi, L. Tetrahedron Lett. 1989, 1491. (k) Padwa, A.; Hornbuckle, S.
F.; Fryxell, G. E.; Stull, P. D. J . Org. Chem. 1989, 54, 817. (l) Dean, D.
C.; Krumpe, K. E.; Padwa, A. J . Chem. Soc., Chem. Commun. 1989,
921. (m) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhi, L. Tetrahedron
Lett. 1989, 301. (n) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.;
Zhang, Z. J . J . Org. Chem. 1991, 56, 3271. (o) Padwa, A.; Sandanayaka,
V. P.; Curtis, E. A. J . Am. Chem. Soc. 1994, 116, 2667. (p) Curtis,
E. A.; Sandanayaka, V. P.; Padwa, A. Tetrahedron Lett. 1995, 36,
1989.
(38) (a) Padwa, A.; Hertzog, D. L.; Chinn, R. L. Tetrahedron Lett.
1989, 30, 4077. (b) Hertzog, D. L.; Austin, D. J .; Nadler, W. R.; Padwa,
A. Tetrahedron Lett. 1992, 33, 4731. (c) Padwa, A.; Hertzog, D. L.
Tetrahedron 1993, 49, 2589. (d) Padwa, A.; Osterhout, M. H.; Nadler,
W. R. Synthesis 1994, 123. (e) Padwa, A.; Hertzog, D. L.; Nadler, W.
R.; Osterhout, M. H.; Price, A. T. J . Org. Chem. 1994, 59, 1418. (f)
Padwa, A.; Marino, J . P.; Brown, D. S.; Elliott, M. C.; Moody, C. J .;
Mowlem, T. J . J . Org. Chem. 1994, 59, 2447. (g) Padwa, A.; Marino, J .
P.; Osterhout, M. H.; Price, A. T.; Semones, M. A. J . Org. Chem. 1994,
59, 5518. (h) Padwa, A.; Austin, D. J .; Price, A. T. Tetrahedron Lett.
1994, 7159. (i) Padwa, A.; Hertzog, D. L.; Nadler, W. R. J . Org. Chem.
1994, 59, 7072. (j) Padwa, A.; Marino, J . P.; Osterhout, M. H. J . Org.
Chem. 1995, 60, 2704. (k) Padwa, A.; Price, A. T. J . Org. Chem. 1995,
60, 6258.
azomethine ylides of type 13 are generally ca. 15 kcal/
mol lower in their heat of formation than the correspond-
ing carbonyl ylides 12. Some of this energy difference is
presumably responsible for the facility with which the
dipole reorganization occurs. Within this context, we
studied the rhodium(II)-catalyzed behavior of R-diazoketo
amide 14. In this case the carbonyl ylide dipole 15 was
trapped by dimethyl acetylenedicarboxylate (DMAD) to
(39) (a) Padwa, A.; Dean,. D. C.; Zhi, L. J . Am. Chem. Soc. 1992,
114, 593. (b) Padwa, A.; Dean, D. C.; Lin, Z. J . Am. Chem. Soc. 1989,
111, 6451.
(40) For a related report, see: Rodgers, J . D.; Caldwell, G. W.;
Gauthier, A. D. Tetrahedron Lett. 1992, 33, 3273.
(41) Padwa, A.; Zhi, L. J . Am. Chem. Soc. 1990, 112, 2037.

Rh(II)-Catalyzed Cycloaddition of R-Diazo-γ-amido Ketones
give cycloadduct 20 in 90% yield. No signs of any
J . Org. Chem., Vol. 61, No. 7, 1996 2285
zopyrrolidine pentanedione 22 also failed to give any
cycloadduct derived from an azomethine ylide intermedi-
ate (i.e., 24). Instead, the Rh(II)-catalyzed reaction of 22
in the presence of DMAD afforded the unusual rear-
rangement-cycloaddition product 25 as a 2:1 mixture of
diastereomers.43
material derived from azomethine ylide 16 could be
detected in the crude reaction mixture. The PM3 calcu-
lations42 indicate that the carbonyl ylide dipole derived
from 14 (i.e., 15) has a heat of formation (-69.6 kcal/
mol) that is 7.5 kcal less than that of the corresponding
azomethine ylide 16 (-62.1 kcal/mol). More than likely
the aromatic nature of the benzopyrylium oxide dipole
15 accounts for its enhanced stability relative to azome-
thine ylide 16 and its reluctance to undergo a proton
shift.
Similar results were obtained when diazo keto N-
phenyl-N-methylamide 26 was used. Treatment of this
compound with rhodium(II) acetate in the presence of
DMAD, methyl propiolate, or N-phenylmaleimide af-
forded cycloadducts 30 (60%), 31 (55%), and 32 (70%).
Analogous cycloadducts were also obtained when diazo
keto N,N-diethylamide (27), the related N,N-diphen-
ylamide (28), and N-phenyl-N-allylamide (29) were
used.
Subjection of the closely related R-diazo ketoamide 17
to the Rh(II)-catalyzed conditions was next carried out.
Our first expectation was that the initially formed
carbonyl ylide intermediate 18 would undergo proton
transfer to give the thermodynamically more stable
azomethine ylide dipole 19. Ampac calculations show
that carbonyl ylide 18 (R1 ) CH3) (-94.93 kcal) is 19
kcal less stable than azomethine ylide 19 (-113.95 kcal)
which fits the pattern previously encountered in the
dipole cascade process. We found, however, that treat-
ment of 17 with DMAD and a catalytic amount of
rhodium(II) acetate resulted in the isolation of the total-
ly unexpected cycloadduct 21 in 60% yield. The struc-
ture of 21 was assigned on the basis of its spectral
properties, in particular, the 1H-NMR spectrum which
showed the methyl groups as three distinct singlets at
3.19, 3.76 and 3.78, the epoxy hydrogens as doublets
at 3.06 (J ) 4.1 Hz) and 3.37, an AB pattern at 4.10
(J ) 17.1 Hz) and 4.23 (J ) 17.1 Hz), an ABX pattern
at 2.28 (dd, 1H, J ) 14.0 and 9.0 Hz), 2.45 (dd, 1H,
J ) 14.0 and 6.0 Hz), and 4.54 (dd, 1H, J ) 9.0 and 6.0
Hz) and a set of hydrogens attributable to the ethyl
group.
A clue to understanding the overall mechanistic details
of the process was gleaned from a study of the Rh(II)-
An additional attempt to induce the dipole cascade
rearrangement using the carbomethoxy-substituted dia-
(43) The formation of 25 as a 2:1 mixture of diastereomers might
involve racemization via structure 24 or possibly in the preparation
of R-diazo ketone 22.
(42) Calculations were performed with the Mopac program (QCPE
506) using the PM3 Hamiltonian.

2286 J . Org. Chem., Vol. 61, No. 7, 1996
Padwa et al.
catalyzed reaction of 1-diazo-5-(N-methyl-N-(p-nitro-
phenyl)amino)-2,5-pentanedione (36). When 36 was
treated with a catalytic quantity of rhodium(II) acetate
in the presence of DMAD, no trace of the spiro epoxy
cycloadduct was present in the crude reaction mixture.
Instead, the only compound isolated (87%) corresponded
to 6-(N-methyl-N-(p-nitrophenyl)amino)-2H-pyran-3(4H)-
one (37). This same structure was obtained when the
reaction was carried out in the absence of the trapping
agent. In sharp contrast to this result, the closely related
p-methoxy derivative 38 afforded the spiroepoxy cyclo-
adduct 39 (46%) and dimethyl (N-(p-methoxyphenyl)-
N-methylamino)maleate (40) (15%) and dihydro-2H-
pyran-2,5(3H)-dione (41) (15%) (vide infra). The cycload-
dition reaction of 38 and N-phenylmaleimide proceeded
in a similar manner, giving rise to the rearranged
cycloadduct 42 in 79% isolated yield. Once again, the
corresponding p-nitro derivative 36 afforded only pyra-
none 37 when N-phenylmaleimide was used as the
trapping agent.
Formation of the epoxy spiro cycloadducts can be
attributed to the initial generation of the expected
carbonyl ylide dipole 43 by intramolecular cyclization of
the keto carbenoid derived from the diazo ketoamide onto
the oxygen atom of the amido group. This highly
stabilized dipole does not readily undergo 1,3-dipolar
cycloaddition but rather transfers a proton to produce the
cyclic ketene N,O-acetal 44. The formation of 44 comes
as no real surprise since one of the characteristic reac-
tions of carbonyl ylides derived from the reaction of
R-diazoalkanes with ketones consists of an intramolecu-
lar proton transfer. The earliest example of this process
was reported by Kharasch and co-workers in 1953,45 and
many related cases have been recorded since that time.46-49
The overall reaction represents a new synthetic approach
to cyclic N,O-ketene acetals.
The unusual cycloadditions outlined here are envisaged
to involve nucleophilic addition of the cyclic ketene N,O-
acetal with the activated π-bond of the dipolarophile to
produce zwitterion 47. The anionic portion of 47 adds
to the adjacent carbonyl group, affording a new zwitte-
rionic intermediate (48). Under anhydrous conditions,
epoxide formation occurs with charge dissipation to
produce the observed rearranged cycloadduct (i.e., 31).
Indeed treatment of a pure sample of 44b (R1 ) Me; R2
) Ph) with an equivalent of methyl propiolate gave
cycloadduct 31 in 89% isolated yield. Similar results
were obtained using pyranone 44c (R1 ) R2 ) Ph) and
N-phenyl maleimide which afforded cycloadduct 34 in
85% yield. It is also of interest to note that the more
electron deficient nature of pyranone 37 (see also 44; R1
) Me; R2 ) p-NO2C6H4) changes its reactivity pattern
compared to the p-methoxy isomer derived from 38.
Thus, all attempts to induce a reaction between 37 and
DMAD or N-phenylmaleimide failed to give rise to a
spiroepoxy cycloadduct. This is presumably related to
the diminished involvement of the nitrogen lone pair of
electrons which no longer facilitates nucleophilic addition
to the electron-deficient dipolarophile.
A variety of reaction conditions were examined in order
to maximize the yield of the rearranged cycloadducts. We
found that the highest yields were obtained when the
solvent (benzene, CHCl3, or CH2Cl2) was rigorously dried.
Use of ordinary solvents routinely led to variable amounts
of the cycloadduct as well as lactone 41 together with
several other hydrolyzed products (vide infra). When the
reaction was carried out in the absence of a trapping
agent, cyclic ketene N,O-acetals of type 44 were isolated
in high yield. These compounds were readily hydrolyzed
on standing to give lactone 41 and the corresponding
amine 45. In fact, treatment of the initially formed
ketene N,O-acetals 44 with “wet” benzene in the presence
of DMAD (or methyl propiolate) afforded high yields of
lactone 41 as well as enamide 46 derived from conjugate
addition of the amine onto the activated acetylenic
π-bond.44
(45) Kharasch, M. S.; Rudy, T.; Nudenberg, W.; Buchi, G. J . Org.
Chem. 1953, 18, 1030.
(46) Lottes, A.; Landgrebe, J . A.; Larsen, K. Tetrahedron Lett. 1989,
30, 4089.
(47) Gutsche, C. D.; Hillman, M. J . Am. Chem. Soc. 1954, 76, 2236.
(48) Landgrebe, J . A.; Iranmanesh, H. J . Org. Chem. 1978, 43, 1244.
(49) Bien, S.; Gillon, A. Tetrahedron Lett. 1974, 3073.
(44) Dolfini, J . E. J . Org. Chem. 1965, 30, 1298. Stork, G.; Tomasz,
M. J . Am. Chem. Soc. 1964, 86, 471.

Rh(II)-Catalyzed Cycloaddition of R-Diazo-γ-amido Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2287
During our investigations of these reactions, we found
that the distribution of products obtained from any given
system was critically dependent upon the amount of
adventitious water present in the solvent. In certain
cases, an additional lactone (i.e., 49) could also be isolated
as a minor product from the cycloaddition reaction. For
example, in the Rh(II)-catalyzed reaction of diazo keto-
unequivocally established, but one reasonable possibility
is outlined below. Here it is proposed that the cyclic
ketene N,O-acetal undergoes stepwise 2 + 2 cycloaddi-
tion50 (via zwitterion 47) with methyl propiolate to give
50 which undergoes a subsequent 1,3-sigmatropic shift
to give the thermodynamically more stable isomer 51.
amides 26 and 27 with DMAD, lactone 49a (R3
)
CO2Me) was obtained in ca. 15% yield. The structure
assignment of 49a is based upon the following charac-
teristic spectral data: The correct molecular weight (256)
was obtained from the HRCI mass spectrum; the IR
(3460, 1740, and 1730 cm-1) and 13C-NMR spectra
indicate the presence of three carbonyl groups and two
vinylic carbons; the 1H-NMR spectrum shows absorptions
for two methoxy groups and the coupling patterns
expected for the remaining five protons (see Experimen-
tal Section). An analogous product (49b) was obtained
in 30% yield when methyl propiolate was used as the
trapping agent. The formation of these lactones can be
attributed to the hydrolysis of the zwitterionic intermedi-
ate 48, and their isolation provides convincing support
for the mechanism outlined in Scheme 3.
Sch em e 3
A final area of study involves the Rh(II)-catalyzed
reaction of cyclic diazo ketoamides 53 and 58 derived
from the N-benzylpiperidinone ring system. Allylation
of N-benzyl-2-piperidone followed by ozonolysis allowed
access to the expected carboxylic acid which was easily
transformed by standard methodology to the desired
diazo ketoamide 53. The Rh(II)-catalyzed reaction of 53
in the presence of DMAD afforded a mixture of two
compounds whose structures were assigned as the spiro
epoxy adduct 55 (25%) and the ring-opened carbonyl ylide
derived cycloadduct 57 (53%). The formation of 57 is
envisaged to arise via dipolar cycloaddition of the initially
formed dipole 54 across DMAD to give 56 which is
subsequently converted to 57 on chromatographic work-
up. The lone pair of electrons on the amide nitrogen
undoubtedly assists in opening the oxy bridge generating
a transient iminium ion which reacts further with water
to give 57. In this case, the rate of the 1,4-proton transfer
has been sufficiently diminished to allow the bimolecular
dipolar cycloaddition to compete. This may be related
to the rigid nature of the cyclic system and the greater
difficulty in achieving the correct geometry for the
internal hydrogen shift. Cycloaddition would be expected
to take place exclusively from the carbonyl ylide dipole
if the R-position of the piperidone ring was blocked with
an alkyl group. Indeed, we found that the Rh(II)-
catalyzed reaction of diazo ketoamide 58 with DMAD
afforded only the carbonyl ylide derived product 61 in
good yield.
An interesting variation of the cycloaddition reaction
comes from a study of the Rh(II)-catalyzed reaction of
diazo ketoamide 27 with methyl propiolate. Exposure
of 27 to Rh2(OAc)4 in anhydrous benzene with methyl
propiolate over molecular sieves afforded a mixture of two
products. The major product corresponded to the spiro-
epoxy cycloadduct 33b (65%) whereas the minor compo-
nent was assigned as 8-carbomethoxy-7-(diethylamino)-
2-oxabicyclo[4.2.0]oct-7-en-4-one (51) (28%). Character-
In conclusion, we note the following points: (1) R-diazo
ketones containing an amido group in the γ-position
undergo a novel Rh(II)-catalyzed cycloaddition with ole-
finic and acetylenic dipolarophiles. (2) A mechanism
involving the initial formation of a carbonyl ylide dipole
followed by proton loss to form a cyclic ketene N,O-acetal
has been proposed. In the absence of any significant
amount of water, the ketene N,O-acetal undergoes con-
jugate addition with the activated π-bond of the dipo-
1
istic structural data for 51 (IR, H- and 13C-NMR) show
the presence of a keto and ester group. The six methyl-
ene protons on the pyranone backbone result from gemi-
nal and vicinal couplings (see Experimental Section). The
mechanism for this alternate cycloaddition has not been
(50) For some related
2 + 2 cycloadditions of enamines with
acetylenic esters, see: Menachery, M. D.; Carroll, P.; Cava, M. P.
Tetrahedron Lett. 1983, 24, 167. Lamm, B.; Aurell, C. J . Acta Chem.
Scand. 1982, B36, 435. Lamm, B.; Andersen, L.; Aurell, C. J .
Tetrahedron Lett. 1983, 24, 2413.

2288 J . Org. Chem., Vol. 61, No. 7, 1996
Padwa et al.
2:1 mixture of nitrogen invertomers. NMR (300 MHz, CDCI3)
major: δ 1.32 (t, 3H, J ) 7.1 Hz), 2.90 (s, 3H), 4.24 (q, 2H, J
) 7.1 Hz), 4.34 (s, 2H), 5.97 (s, 1H), and 7.31-7.66 (m, 4H);
13C NMR (75 MHz, CDCI3) δ 13.5, 37.3, 47.9, 55.6, 60.6, 126.7,
127.0, 128.5, 131.3, 135.1, 168.4, 170.8 and 185.9. Minor: δ
1.23 (t, 3H, J ) 7.2 Hz), 3.17 (s, 3H), 4.16 (q, 2H, J ) 7.1 Hz),
3.89 (s, 2H), 5.93 (s, 1H), and 7.31-7.66 (m, 4H); 13C-NMR
(75 MHz, CDCI3) δ 13.4, 33.2, 52.3, 55.4, 60.7, 126.4, 126.9,
131.3, 134.1, 135.2, 168.4, 170.7 and 186.1.
A mixture containing 300 mg (1.04 mmol) of 14 and 1.2
equiv of DMAD in 3 mL of benzene was allowed to react with
2 mg of rhodium(II) acetate. The reaction mixture was stirred
at rt for 30 min until no more N2 had evolved. Removal of
the solvent under reduced pressure followed by silica gel
chromatography afforded 5-(N-(carbethoxymethyl)-N-meth-
ylamino)-6,7-dicarbomethoxy-8,9-dihydro-9-oxa-5,8-epoxy-5H-
benzocycloheptene (20) (90%) as a clear oil: IR (neat) 1740,
1
1730, 1460, 1320, and 770 cm-1; H NMR (300 MHz, CDCI3)
δ 1.29 (t, 3H, J ) 7.1 Hz), 2.64 (s, 3H), 3.58 (s, 2H), 3.77 (s,
3H), 3.80 (s, 3H), 4.23 (q, 2H, J ) 7.1 Hz), 5.39 (s, 1H), 7.44-
7.58 (m, 3H), and 7.90 (d, 1H, J ) 7.0 Hz); 13C NMR (75 MHz,
CDCI3) δ 13.6, 37.1, 52.1, 52.2, 53.4, 60.2, 84.8, 106.5, 124.3,
126.4, 127.8, 129.3, 132.6, 135.4, 140.8, 150.3, 160.4, 162.5,
169.8, and 187.6. Anal. Calcd for C20H21NO8: C, 59.53; H, 5.25;
N, 3.47, found C, 59.39; H, 5.12; N, 3.26.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
5-(N-(Ca r b et h oxym et h yl)-N-m et h yla m in o)-1-d ia zop en -
ta n e-2,5-d ion e (17). A 2.0 g sample of 17 was prepared in
45% yield from 3.0 g (19.5 mmol) of sarcosine ethyl ester
hydrochloride and 2.0 g (20 mmol) of succinic anhydride using
the same procedure as described above: IR (neat) 2105, 1750,
1650, 1380, and 1210 cm-1
. The high-field NMR spectrum
showed that 17 exists as a 4:1 mixture of nitrogen invertomers.
1H NMR (300 MHz, CDCI3) major: δ 1.27 (t, 3H, J ) 7.1 Hz),
2.62-2.80 (m, 4H), 3.11 (s, 3H), 4.10 (s, 2H), 4.17 (q, 2H, J )
7.1 Hz), and 5.42 (brs, 1H); 13C NMR (75 MHz, CDCI3) δ 13.4,
27.1, 34.4, 35.7, 48.9, 54.0, 60.4, 168.6, 171.4 and 193.2.
Minor: δ 1.30 (t, 3H, J ) 7.1 Hz), 2.55-2.70 (m, 4H), 2.97 (s,
3H), 4.10 (s, 2H), 4.23 (q, 2H, J ) 7.1 Hz), and 5.42 (bs, 1H);
13C NMR (75 MHz, CDCI3) δ 13.4, 26.8, 34.3, 34.4, 50.8, 54.0,
61.0, 168.3, 171.2, and 193.2.
larophile to eventually give an amido cyclopentyl epoxide.
(3) The high efficiency of the process in conjunction with
the intriguing chemistry of the resulting cycloadducts
presents numerous synthetic possibilities which will be
reported on at a later date.
Exp er im en ta l Section
Treatment of 480 mg (2 mmol) of 17 and 250 mg (2 mmol)
of DMAD in 2 mL of CHCl3 with 2 mg of rhodium(II) acetate
afforded a mixture of three products which were separated by
silica gel chromatography. The minor component of the
mixture was identified as dimethyl 2-(N-(carbethoxymethyl)-
N-methylamino)maleate (46a ) (15%): IR (neat) 1750, 1705,
1595, 1215, 1165, and 1115 cm-1; 1H NMR (300 MHz, CDCI3)
δ 1.29 (t, 3H, J ) 7.1 Hz), 2.95 (s, 3H), 3.65 (s, 3H), 3.85 (s,
2H), 3.91 (s, 3H), 4.22 (q, 2H, J ) 7.1 Hz), and 4.69 (s, 1H);
13C NMR (75 MHz, CDCI3) δ 13.5, 38.6, 50.3, 52.4, 53.4, 60.9,
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.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
o-(N-(Ca r b et h oxym et h yl)-N-m et h ylca r b a m yl)-R-d ia zo-
a cetop h en on e (14). A mixture containing 3.07 g (20 mmol)
of sarcosine ethyl ester hydrochloride, 3.0 g (20 mmol) of
phthalic anhydride, and 2 mL of pyridine in 50 mL of THF
was stirred at rt for 10 h. The mixture was diluted with 20
mL of water, acidified to pH 5, and extracted with ethyl
acetate. The combined organic layer was washed with water,
dried over MgSO4, and concentrated under reduced pressure.
The resulting oil was identified as o-(N-(carbethoxymethyl)-
N-methylcarbamyl)benzoic acid whose NMR spectrum indi-
cates it to be a 2:1 mixture of nitrogen invertomers: 1H NMR
(90 MHz, CDCI3) major δ 1.10-1.35 (m, 3H), 2.85 (s, 3H),
4.00-4.35 (m, 2H), 4.35 (s, 2H), 7.30-8.25 (m, 4H), and 10.90
(s, 1H); minor δ 1.10-1.35 (m, 3H), 3.18 (s, 3H), 3.84 (s, 2H),
4.00-4.35 (m, 2H), 7.30-8.25 (m, 4H), and 10.90 (s, 1H).
The above acid was suspended in 200 mL of ether, and 1.7
mL of methyl chloroformate was added. The solution was
allowed to stir for 30 min at 25 °C, and then 1.4 mL of
triethylamine was added. After stirring for an additional 30
min, the reaction mixture was filtered and the filtrate was
allowed to react with 40 mmol of diazomethane in ether at 0
°C for 12 h. Removal of the solvent under reduced pressure
followed by silica gel chromatography of the residue gave 3.2
g (55%) of o-(N-carbethoxymethyl)-N-methylcarbamyl)-R-di-
azoacetophenone (14): IR (neat) 2110, 1750, 1650, 1365, and
1210 cm-1. The NMR spectrum indicates that 14 exists as a
86.3, 153.7, 165.0, 167.1, and 167.7. Anal. Calcd for C11H17
-
NO6: C, 54.94; H, 6.61; N, 5.40, found C, 54.83, H, 6.47, N,
5.29.
The second minor component (18%) was assigned as 6,7-
dicarbomethoxy-5-hydroxy-3-oxabicyclo[3.2.1]oct-6-en-2-one
(49a ) (vide infra). The major product was a clear oil whose
structure was assigned as 6-(N-(carbethoxymethyl)-N-methyl)-
carbamyl)-4,5-dicarbomethoxy-1-oxaspiro[2.4]hept-4-ene (21)
(60%): 1H NMR (300 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.2 Hz),
2.28 (dd, 1H, J ) 14.0 and 9.0 Hz), 2.45 (dd, 1H, J ) 14.0 and
6.0 Hz), 3.06 (d, 1H, J ) 4.1 Hz), 3.19 (s, 3H), 3.37 (d, 1H, J
) 4.1 Hz), 3.76 (s,3H), 3.78 (s, 3H), 4.10 (d, 1H, J ) 17.1 Hz),
4.18 (q, 2H, J ) 7.2 Hz), 4.23 (d, 1H, J ) 17.1 Hz), and 4.54
(dd, 1H, J ) 9.0 and 6.0 Hz). Anal. Calcd for C16H21NO8: C,
54.07; H, 5.96; N, 3.94, found C, 53.85, H, 5.87; N, 3.71.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
5-(2′-Ca r bom eth -oxyp yr r olid in yl)-1-d ia zop en ta n e-2,5-d i-
on e (22). To 50 mL of a THF solution containing 3.33 g (20.1
mmol) of L-proline methyl ester hydrochloride was added a
suspension containing 0.80 g of NaH in 20 mL of THF. The
resulting mixture was stirred for 20 min at 25 °C and then
2.0 g (20 mmol) of succinic anhydride was added. The reaction
mixture was allowed to stir at rt overnight and was then
washed with dilute HCl and dried over MgSO4. Removal of
the solvent under reduced pressure left a colorless oil which

Rh(II)-Catalyzed Cycloaddition of R-Diazo-γ-amido Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2289
corresponded to 3-((2′-carbomethoxypyrrolidinyl)carbonyl)-
propanoic acid: 1H NMR (90 MHz, CDCI3) δ 1.80-2.50 (m,
4H), 2.70 (s, 4H), 3.55-3.70 (m, 2H), 3.73 (s, 3H), 4.55 (t, 1H,
J ) 5.4 Hz), and 9.68 (s, 1H).
1-oxaspiro[2.4]hept-4-ene (30): IR (neat) 1730, 1660, 1300,
1
1275, and 710 cm-1; H NMR (300 MHz, CDCI3) δ 2.02 (dd,
1H, J ) 14.4 and 9.1 Hz), 2.40 (dd, 1H, J ) 14.4 and 5.9 Hz),
3.00 (d, 1H, J ) 4.6 Hz), 3.29 (s, 3H), 3.33 (d, 1H, J ) 4.6 Hz),
3.75 (s, 3H), 3.78 (s, 3H), 4.11 (dd, 1H, J ) 9.1 and 5.9 Hz),
and 7.22-7.50 (m, 5H); 13C NMR (75 MHz, CDCI3) δ 33.6, 36.9,
45.8, 51.7, 52.5, 66.7, 126.8, 127.7, 129.4, 139.9, 142.5, 142.8,
162.4, 163.0, and 171.4. Anal. Calcd for C18H19NO6: C, 62.59;
H, 5.55; N, 4.06, found C, 62.51; H, 5.43; N, 3.96. The minor
fraction (15%) was identified as 6,7-dicarboxmethoxy-5-hy-
droxy-3-oxabicyclo[3.2.1]oct-6-en-2-one (49a ).
The reaction was also carried out in the absence of a
dipolarophile. To a sample containing 240 mg (1.04 mmol) of
26 in 3 mL of chloroform was added 2 mg of rhodium(II)
acetate. After stirring for 15 min, the crude NMR spectrum
showed the presence of 7-(methylphenylamino)-2H-pyran-
3(4H)-one (44b) (70%) which was isolated as an extremely
labile oil: IR (neat) 1750, 1610, 1510, 1135, and 715 cm-1; 1H
NMR (300 MHz, CDCI3) δ 3.01 (d, 2H, J ) 3.9 Hz), 3.15 (s,
3H), 4.30 (s, 2H), 4.46 (t, 1H, J ) 3.9 Hz), 6.94-7.05 (m, 2H),
and 7.24-7.32 (m, 3H); 13C NMR (75 MHz, CDCI3) δ 34.7, 38.6,
72.4, 80.2, 119.3, 121.4, 128.3, 146.1, 154.6 and 207.3. Anal.
Calcd for C12H13NO2: C, 70.90; H, 6.45; N, 6.89, found C, 70.74;
H, 6.43; N, 6.82.
An entirely different set of products was obtained if the
reaction of 26 was carried out with DMAD in the presence of
some water. To a mixture containing 346 mg (1.5 mmol) of
26, 1.2 equiv of DMAD, and 2.0 equiv of water in 3 mL of
benzene was added 2 mg of rhodium(II) acetate. After stirring
for 30 min at 25 °C, the mixture was concentrated to dryness
and the crude residue was subjected to silica gel chromatog-
raphy. The major fraction (45%) corresponded to dimethyl
2-(methylphenylamino)maleate (46b), mp 71-72 °C: IR (neat)
1750, 1700, 1580, and 1160 cm-1; 1H NMR (300 MHz, CDCI3)
δ 3.22 (s, 3H), 3.65 (s, 3H), 3.68 (s, 3H), 4.80 (s, 1H), and 7.18-
7.40 (m, 5H); 13C-NMR (75 MHz, CDCI3) 40.2, 50.3, 52.0, 87.5,
125.9, 126.8, 128.8, 143.9, 153.5, 164.7 and 167.2; Anal. Calcd
for C13H15NO4: C, 62.64; H, 6.07; N, 5.62, found C, 62.62, H,
6.09, N, 5.59.
Treatment of the above acid with methyl chloroformate/
triethylamine followed by diazomethane according to the
standard procedure gave 2.0 g (40%) of 5-(2′-carbomethoxy-
pyrrolidinyl)-1-diazopentane-2,5-dione (22) as a yellow oil: IR
(neat) 2110, 1750, 1645, 1440, and 1380 cm-1. The high-field
NMR spectrum indicated that 22 exists as a 4:1-mixture of
nitrogen invertomers. 1H NMR (300 MHz, CDCI3) major: δ
1.94-2.25 (m, 4H), 2.52-2.85 (m, 4H), 3.50-3.71 (m, 2H), 3.71
(s, 3H), 4.46 (dd, 1H, J ) 8.4 and 3.6 Hz), and 5.42 (s, 1H); 13
C
NMR (75 MHz, CDCI3) δ 24.0, 28.2, 28.5, 34.2, 46.2, 51.5, 54.0,
58.0, 169.6, 172.1 and 193.2. Minor: δ 1.86-2.25 (m, 4H),
2.52-2.85 (m, 4H), 3.50-3.71 (m, 2H), 3.77 (s, 3H), 4.54 (dd,
1H, J ) 9.5 and 2.6 Hz), and 5.42 (s, 1H); 13C NMR (75 MHz,
CDCI3) δ 21.9, 28.2, 30.7, 34.2, 45.7, 51.9, 54.0, 58.6, 169.8,
171.9, and 193.2.
Treatment of 260 mg (1.03 mmol) of 22 and 150 mg of
DMAD in 1 mL of CHCl3 with 2 mg of rhodium(II) acetate
afforded a mixture of several products. The first fraction
isolated (5%) was assigned as dimethyl (2′-carbomethoxy-
pyrrolidinyl)maleate: IR (oil) 1750, 1700, 1585, 1235, 1200,
1
and 1160 cm-1; H NMR (300 MHz, CDCI3) δ 1.97-2.17 (m,
3H), 2.17-2.33 (m, 1H), 3.26-3.40 (m, 1H), 3.40-3.55 (m, 1H),
3.63 (s, 3H), 3.74 (s, 3H), 3.89 (s, 3H), 4.17 (d, 1H, J ) 8.1
Hz), and 4.59 (s, 1H); 13C NMR (75 MHz, CDCI3) δ 22.5, 29.8,
47.9, 50.2, 51.9, 52.2, 60.3, 85.8, 150.7, 165.0, 167.2, and 171.6.
Anal. Calcd for C12H17NO6: C, 53.12; H, 6.32; N, 5.17, found
C, 53.04; H, 6.36; N, 5.01.
The second fraction (10%) was a pale yellow oil whose
structure was assigned as 6,7-dicarbomethoxy-5-hydroxy-3-
oxabicyclo[3.2.1]oct-6-en-2-one (49a ) on the basis of its spectral
data: IR (neat) 3460, 1740, 1730, 1275, 1145, and 1030 cm-1
;
1H NMR (300 MHz, CDCI3) δ 2.55 (d, 1H, J ) 10.9 Hz), 2.65
(ddd, 1H, J ) 10.9, 4.5, and 1.4 Hz), 3.69 (d, 1H, J ) 4.5 Hz),
3.82 (s, 3H), 3.88 (s, 3H), 4.33 (brs, 1H), 4.37 (d, 1H, J ) 10.8
Hz), and 4.45 (dd, 1H, J ) 10.8 and 1.4 Hz); 13C NMR (75 MHz,
CDCI3) δ 42.9, 45.8, 52.2, 52.3, 73.0, 77.2, 137.1, 144.9, 161.6,
163.3, and 165.1; HRMS calcd for C11H12O7 256.0583, found
256.0582. Anal. Calcd for C11H12O7: C, 51.55; H, 4.72, found
C, 51.32; H, 4.57.
The second fraction (40%) isolated from the column was a
clear oil whose structure was assigned as dihydro-2H-pyran-
2,5(3H)-dione (41): IR (neat) 1760, 1735, 1430, 1310, and 1150
1
cm-1; H NMR (300 MHz, CDCI3) δ 2.76 (t, 2H, J ) 7.2 Hz),
2.93 (t, 2H, J ) 7.2 Hz), and 4.69 (s, 2H); 13C NMR (75 MHz,
CDCI3) δ 27.0, 33.1, 72.4, 169.1, and 203.2. Anal. Calcd for
C5H6O3: C, 62.59; H, 5.55, found C, 62.51; H, 5.43. The last
fraction (10%) isolated corresponded to 6,7-dicarbomethoxy-
5-hydroxy-3-oxabicyclo[3.2.1]oct-6-en-2-one (49a ).
The third fraction (60%) was assigned as 6-trans-((2′-
carbomethoxypyrrolidinyl)carbonyl)-4,5-dicarbomethoxy-1-
oxaspiro[2.4]hept-4-ene (25) as a 2:1 mixture of two stereo-
isomers. 1H NMR (300 MHz, CDCI3) major: δ 1.92-2.30 (m,
5H), 2.44 (dd, 1H, J ) 14.2 and 4.4 Hz), 3.07 (d, 1H, J ) 4.4
Hz), 3.34 (d, 1H, J ) 4.4 Hz), 3.55-3.80 (m, 2H), 4.34 (t, 1H,
J ) 6.3 Hz), and 4.51 (dd, 1H, J ) 8.8 and 4.4 Hz). Anal.
Calcd for C17H21NO8: C, 55.57; H, 5.76; N, 3.81, found C, 55.39;
H, 5.66; N, 3.64. All attempts to separate the two diastereo-
mers failed.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
1-Dia zo-5-(m eth ylp h en yla m in o)p en ta n e-2,5-d ion e (26). A
solution containing 2.0 g (20 mmol) of succinic anhydride and
2.15 g (20 mmol) of N-methylaniline in 50 mL of THF was
stirred at rt for 4 h. Removal of the solvent under reduced
pressure left 3.5 g (85%) of N-methyl-N-phenylsuccinimic acid,
mp 83-84 °C: 1H NMR (90 MHz, CDCI3) δ 2.36 (t, 2H, J )
6.0 Hz), 2.63 (t, 2H, J ) 6.0 Hz), 3.31 (s, 3H), 7.20-7.55 (m,
5H), and 10.91 (s, 1H). The above acid was treated with
methyl chloroformate/triethylamine and diazomethane in the
standard manner to give 1-diazo-5-(methylphenylamino)pen-
tane-2,5-dione (26) in 73% yield as a yellow oil: IR (neat) 2110,
1670, 1655, 1380, and 710 cm-1; NMR (300 MHz, CDCI3) δ
2.40 (t, 2H, J ) 6.4 Hz), 2.61 (brs, 2H), 3.25 (s, 3H), 5.34 (brs,
1H), and 7.20-7.48 (m, 5H); 13C NMR (75 MHz, CDCI3) δ 28.4,
34.9, 36.7, 53.9, 126.7, 127.2, 129.2, 143.1, 170.8, and 193.2.
To a mixture containing 465 mg (2.01 mmol) of 26 and 1.2
equiv of DMAD in 3 mL of benzene was added 2 mg of
rhodium(II) acetate. After stirring for 10 min at rt, the solvent
was removed under reduced pressure and the residue was
subjected to silica gel chromatography. The major fraction
(60%) isolated was a clear oil whose structure was assigned
as 4,5-dicarbomethoxy-6-trans-(N-methyl-N-phenylcarbamyl)-
The rhodium(II)-catalyzed reaction of a 460 mg (1.99 mmol)
sample of 26 was also carried out in the presence of 1.2 equiv
of methyl propiolate in 2 mL of CH2Cl2 at 25 °C for 1 h. Two
major products were isolated by silica gel chromatography. The
first fraction (25%) corresponded to 4-carbomethoxy-6-trans-
(N-m et h yl-N-ph en ylca r ba m yl)-1-oxa spir o[2.4]h ept -4-en e
1
(31): IR (oil) 1735, 1665, 1510, 1395, and 715 cm-1; H NMR
(300 MHz, CDCI3) δ 1.94 (dd, 1H, J ) 14.4 and 8.4 Hz), 2.67
(dd, 1H, J ) 14.4 and 5.4 Hz), 2.96 (d, 1H, J ) 5.1 Hz), 3.30
(s, 3H), 3.69 (s, 3H), 3.78 (d, 1H, J ) 5.1 Hz), 3.87 (ddd, 1H, J
) 8.4, 5.4, and 2.3 Hz), 6.90 (d, 1H, J ) 2.3 Hz), 7.23 (d, 2H,
J ) 7.5 Hz), and 7.40-7.55 (m, 3H); 13C NMR (75 MHz, CDCI3)
δ 34.9, 37.3, 44.8, 51.0, 51.5, 65.6, 126.7, 127.9, 129.6, 134.0,
142.6, 148.4, 162.1, and 171.2. Anal. Calcd for C16H17NO4:
C, 66.87; H, 5.97; N, 4.88, found C, 66.71; H, 5.83; N, 4.92.
Cycloadduct 31 was obtained in 89% isolated yield by heating
a sample of pyranone 44b with methyl propiolate in anhydrous
benzene at 40 °C for 3 h.
The second fraction (30%) isolated from the column was
assigned as 6-carbomethoxy-5-hydroxy-3-oxabicyclo[3.2.1]oct-
6-en-2-one (49b): IR (oil) 3500, 1760, 1735, 1290, 1170, and
1070 cm-1; 1H NMR (300 MHz, CDCI3) δ 2.50 (d, 2H, J ) 5.5
Hz), 3.41 (dd, 1H, J ) 5.5 and 3.6 Hz), 2.82 (s, 3H), 4.20 (d,
1H, J ) 10.5 Hz), 4.33 (d, 1H, J ) 10.5 Hz), 4.39 (bs, 1H), and
7.00 (d, 1H, J ) 3.6 Hz); 13C NMR (75 MHz, CDCI3) δ 42.6,
45.1, 51.7, 73.5, 75.4, 139.1, 141.9, 163.7, and 165.6. Anal.
Calcd for C9H10O5: C, 54.53; H, 5.09, found C, 54.36; H, 5.12.
A third fraction (10%) was also isolated from the silica gel

2290 J . Org. Chem., Vol. 61, No. 7, 1996
Padwa et al.
column and was identified as methyl 3-(methylphenylamino)-
4.5 and 4.4 Hz), 3.67 (s, 3H), 3.70-3.95 (m, 2H), 4.00 (d, 1H,
J ) 17.6 Hz), 4.15 (d, 1H, J ) 17.6 Hz), and 4.85 (d, 1H, J )
4.4 Hz); 13C NMR (75 MHz, CDCI3) δ 12.9, 13.6, 27.2, 28.6,
40.0, 40.4, 43.5, 49.9, 68.1, 89.5, 157.2, 162.5 and 209.8. Anal.
Calcd for C13H19NO4: C, 61.63; H, 7.56; N, 5.53, found C, 61.54;
H, 7.39; N, 5.29.
The third fraction (10%) was identified as 6-carbomethoxy-
5-hydroxy-3-oxabicyclo[3.2.1]oct-6-en-2-one (49b), and the last
fraction (35%) was a clear oil whose structure was assigned
as 4-carbomethoxy-6-(N,N-diethylcarbamyl)-1-oxaspiro[2.4]-
hept-4-ene (33b): 1H NMR (300 MHz, CDCI3) δ 1.13 (t, 3H, J
) 7.1 Hz), 1.24 (t, 3H, J ) 7.1 Hz), 2.24 (dd, 1H, J ) 14.3 and
8.5 Hz), 2.69 (dd, 1H, J ) 14.3 and 5.3 Hz), 3.00 (d, 1H, J )
5.0 Hz), 3.40 (q, 4H, J ) 7.1 Hz), 3.72 (s, 3H), 3.82 (d, 1H, J )
5.0 Hz), 4.10 (ddd, 1H, J ) 8.5, 5.3, and 2.7 Hz), and 7.03 (d,
1H, J ) 2.7 Hz). Anal. Calcd for C13H19NO4: C, 61.63; H,
7.56; N, 5.53, found C, 61.42; H, 7.39; N, 5.50.
2-propenoate51 (46c): IR (oil) 1710, 1630, 1600, 1510, and 1140
1
cm-1; H-NMR (300 MHz, CDCI3) δ 3.23 (s, 3H), 3.70 (s, 3H),
4.92 (d, 1H, J ) 13.2 Hz), 7.12 (d, 3H, J ) 7.5 Hz), 7.34 (d,
2H, J ) 7.5 Hz), and 7.93 (d, 1H, J ) 13.2 Hz).
The rhodium(II) acetate catalyzed reaction of 460 mg (1.99
mmol) of 26 with 350 mg of N-phenylmaleimide was carried
out in 2 mL of CHCl3 and afforded 6-trans-(N-methyl-N-
phenylcarbamyl)-4,5-trans-((N-phenylimino)dicarbonyl)-1-ox-
aspiro[2.4]-heptane (32) in 70% yield; mp 194-195 °C; IR
(KBr) 1715, 1650, 1600, 1500, and 720 cm-1 1H NMR (300
;
MHz, CDCI3) δ 1.70 (dd, 1H, J ) 14.4 and 7.1 Hz), 2.76 (dd,
1H, J ) 14.4 and 11.4 Hz), 2.90 (d, 1H, J ) 8.8 Hz), 2.95 (d,
1H, J ) 4.1 Hz), 3.21 (dd, 1H, J ) 9.7 and 8.8 Hz), 3.30 (s,
3H), 3.43 (d, 1H, J ) 4.1 Hz), 3.45 (ddd, 1H, J ) 11.4, 9.7, and
7.1 Hz), and 7.28-7.55 (m, 10H); 13C NMR (75 MHz, CDCI3)
δ 34.9, 37.3, 43.6, 45.9, 47.1, 50.7, 64.6, 125.9, 126.9, 127.9,
128.1, 128.6, 129.4, 131.1, 142.8, 169.3, 173.6, and 175.1. Anal.
Calcd for C22H20N2O4: C, 70.20; H, 5.36; N, 7.44, found C,
70.28; H, 5.38; N, 7.41.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
1-Dia zo-5-(N,N-d ip h en yla m in o)-2,5-p en t a n ed ion e (28).
Treatment of 2.7 g (10 mmol) of 4-(N,N-diphenylamino)-4-
oxobutanoic acid54 with 0.8 mL (10 mmol) of methyl chloro-
formate and 1.4 mL of triethylamine followed by 20 mmol of
diazomethane in ether according to the standard procedure
gave 2.1 g (74%) of R-diazo ketoamide 28 as a yellow crystalline
solid, mp 128-129 °C: IR (neat) 2100, 1668, 1640, 1490, and
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
1-Diazo-5-(dieth ylam in o)pen tan e-2,5-dion e (27). A sample
of 27 was prepared in 44% yield starting from 3.5 g (20.2 mmol)
of N,N-diethylsuccinamic acid using the standard procedure
described above: IR (oil) 2110, 1790, 1640, 1380, 1145, and
1
705 cm-1; H NMR (300 MHz, CDCl3) δ 2.57 (t, 2H, J ) 5.8
1
1100 cm-1; H NMR (300 MHz, CDCI3) δ 1.09 (t, 3H, J ) 7.4
Hz), 2.66 (t, 2H, J ) 5.8 Hz), 5.31 (s, 1H), and 7.31 (brs, 10H).
Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33, found
C, 69.73; H, 5.18; N, 14.24.
Hz), 1.20 (t, 3H, J ) 7.4 Hz), 2.68 (brs, 4H), 3.34 (q, 2H, J )
7.4 Hz), 3.36 (q, 2H, J ) 7.4 Hz), and 5.41 (brs, 1H); 13C NMR
(75 MHz, CDCI3) δ 12.3, 13.4, 27.0, 34.7, 39.5, 41.1, 53.9, 169.6,
and 193.6.
The reaction of 450 mg (1.53 mmol) of R-diazo ketoamide
28 in 5 mL of CHCl3 with 2 mg of rhodium(II) acetate at rt for
30 min afforded 6-(N,N-diphenyl-amino)-2H-pyran-3(4H)-one
The reaction between 400 mg (2.03 mmol) of 27 and 1.2
molar equiv of DMAD in 3 mL of CHCl3 was carried out in
the presence of 2 mg of rhodium(II) acetate. Standard workup
afforded three products. The major fraction (70%) was a clear
oil whose structure corresponded to 4,5-dicarbomethoxy-6-
trans-(N,N-diethylcarbamyl)-1-oxaspiro[2.4]hept-4-ene (33a ):
1
(44c) in 71% yield; H NMR (300 MHz, CDCl3) δ 2.98 (d, 2H,
J ) 3.4 Hz), 4.33 (s, 2H), 4.58 (t, 1H, J ) 3.4 Hz), and 7.05-
7.45 (m, 10H). This compound was quite labile to moisture
and it was not possible to obtain an analytically pure sample.
Instead, treatment of 44c with 300 mg of N-phenyl maleimide
afforded 6-trans-((N,N-diphenylamino)carbonyl)-4,5-trans-((N-
phenylimino)dicarbonyl)-1-oxaspiro[2.4]-heptane (34) in 85%
yield as a clear oil: IR (neat) 1710, 1662, 1491, 1384, and 706
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.78 (dd, 1H, J ) 14.6 and
6.9 Hz), 2.79 (dd, 1H, J ) 14.6 and 10.8 Hz), 2.94 (d, 1H, J )
8.0 Hz), 2.96 (d, 1H, J ) 3.9 Hz), 3.30 (dd, 1H, J ) 10.6 and
8.0 Hz), 3.43 (d, 1H, J ) 3.9 Hz), 3.65 (ddd, 1H, J ) 10.8, 10.6,
and 6.9 Hz), and 7.25-7.60 (m, 15H); 13C NMR (75 MHz,
CDCl3) δ 34.9, 44.1, 46.1, 47.0, 50.8, 64.6, 126.1, 126.3, 128.1,
128.2, 128.3, 128.5, 128.6, 129.5, 131.1, 141.8, 141.9, 169.5,
173.6, and 175.0. Anal. Calcd for C27H22N2O4: C, 73.95; H,
5.06; N, 6.39, found C, 73.78; H, 5.11; N, 6.17.
IR (neat) 1730, 1640, 1440, 1300, 1270, and 1230 cm-1 1H
;
NMR (300 MHz, CDCI3) δ 1.11 (t, 3H, J ) 7.1 Hz), 1.25 (t,
3H, J ) 7.1 Hz), 2.36 (dd, 1H, J ) 14.2 and 5.4 Hz), 2.41 (dd,
1H, J ) 14.2 and 8.4 Hz), 3.05 (d, 1H, J ) 4.6 Hz), 3.35 (dq,
1H, J ) 14.2 and 7.1 Hz), 3.38 (q, 2H, J ) 7.1 Hz), 3.39 (d,
1H, J ) 4.6 Hz), 3.49 (dq, 1H, J ) 14.2 and 7.1 Hz), 3.76 (s,
3H), 3.78 (s, 3H), and 4.40 (dd, 1H, J ) 8.4 and 5.4 Hz); 13C
NMR (75 MHz, CDCI3) δ 12.3, 14.0, 33.6, 40.0, 41.8, 44.9, 51.6,
51.7, 52.7, 67.0, 140.2, 142.1, 162.7, 162.9, and 170.4. Anal.
Calcd for C15H21NO6: C, 57.85; H, 6.80; N, 4.50, found C, 57.79;
H, 6.87; N, 4.47.
The second product (15%) isolated from the column was
identified as lactone 49a , and the third fraction (10%) was
identified as dimethyl (diethylamino)maleate52 (46d ): IR (oil)
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
5-(N-Allyl-N-ph en ylam in o)-1-diazo-2,5-pen tan edion e (29).
A solution containing 1.0 g (10 mmol) of succinic anhydride
and 1.35 g (10.1 mmol) of N-allylaniline in 20 mL of THF was
allowed to stir at rt for 1 h. Standard workup afforded 4-(N-
allyl-N-phenyl-amino)-4-oxobutanoic acid as a clear oil (90%):
1
1750, 1700, 1580, 1165, and 1135 cm-1; H NMR (300 MHz,
CDCI3) δ 1.18 (t, 6H, J ) 7.1 Hz), 3.18 (q, 4H, J ) 7.1 Hz),
3.63 (s, 3H), 3.93 (s, 3H), and 4.61 (s, 1H); 13C NMR (75 MHz,
CDCI3) δ 12.1, 12.2, 44.3, 44.4, 50.0, 52.2, 82.2, 153.1, 165.5,
and 167.7.
1
IR (neat) 1736, 1718, 1660, 1600, and 708 cm-1; H NMR (90
The reaction between 400 mg (2.03 mmol) of 27 and 180
mg of methyl propiolate in 2 mL of chloroform with 2 mg of
rhodium(II) acetate produced a mixture of four products. The
first fraction (10%) corresponded to methyl 3-(diethylamino)-
2-propenoate53 (46e): IR (oil) 1690, 1610, 1195, 1155, 1115
MHz, CDCl3) δ 2.35 (t, 2H, J ) 6.0 Hz), 2.64 (t, 2H, J ) 6.0
Hz), 4.31 (d, 2H, J ) 6.2 Hz), 4.95-5.23 (m, 2H), 5.70-6.08
(m, 1H), 7.15-7.52 (m, 5H), and 9.90 (brs, 1H). This material
was converted to R-diazo ketoamide 29 by the standard
procedure in 74% yield: IR (neat) 2113, 1670, 1502, and 716
1
cm-1; H NMR (300 MHz, CDCI3) δ 1.16 (t, 6H, J ) 7.1 Hz),
1
cm-1; H NMR (300 MHz, CDCl3) δ 2.38 (t, 2H, J ) 6.3 Hz),
3.19 (q, 4H, J ) 7.1 Hz), 3.66 (s, 3H), 4.57 (d, 1H, J ) 13.1
Hz), and 7.44 (d, 1H, J ) 13.1 Hz); 13C NMR (75 MHz, CDCI3)
δ 29.1, 49.8, 82.3, 150.4, and 169.7.
2.60 (t, 2H, J ) 6.3 Hz), 4.28 (d, 2H, J ) 6.0 Hz), 5.07 (d, 1H,
J ) 17.1 Hz), 5.10 (d, 1H, J ) 9.5 Hz), 5.32 (s, 1H), 5.84 (ddt,
1H, J ) 17.1, 9.5, and 6.0 Hz), 7.21 (d, 2H, J ) 7.5 Hz), and
7.29-7.46 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 28.6, 34.8,
51.6, 53.9, 117.1, 127.4, 127.7, 129.0, 132.4, 141.5, 170.4, and
193.2.
The second fraction (15%) was a clear oil whose structure
was assigned as 8-carbomethoxy-7-(diethylamino)-2-oxabicyclo-
[4.2.0]oct-7-en-4-one (51): IR (oil) 1735, 1690, 1620, 1200, 1140,
1125, and 1080 cm-1; 1H NMR (300 MHz, CDCI3) δ 1.18 (brs,
6H), 2.70 (dd, 1H, J ) 14.9 and 6.3 Hz), 2.91 (dd, 1H, J ) 14.9
and 4.5 Hz), 3.15 (q, 2H, J ) 6.7 Hz), 3.35 (ddd, 1H, J ) 6.3,
Treatment of 260 mg (1.01 mmol) of 29 with 2 mg of
rhodium(II) acetate in 3 mL of CHCl3 in the presence of 200
mg (1.04 mmol) of N-phenylmaleimide afforded 6-trans-(N-
allyl-N-phenylcarbamyl)-4,5-trans-((N-phenylimino)dicarbonyl)-
1-oxaspiro[2.4]heptane (58%) (35): mp 127-128 °C; IR (neat)
(51) Bozell, J . J .; Hegedus, L. S. J . Org. Chem. 1981, 46, 2561.
(52) Kandeel, K. A.; Vernon, J . M. J . Chem. Soc., Perkin Trans. I
1987, 2023.
(53) Burgi, von D.; Sterchi, A.; Neuenschwander, M. Helv. Chim.
Acta 1977, 60, 2195.
(54) Vejdelek. Z;. Rajsner, M.; Olabac, A.; Ryska, M.; Holubek, J .;
Svatek, E.; Protiva, M. Collect. Czech. Chem. Commun. 1980, 45, 3593.

Rh(II)-Catalyzed Cycloaddition of R-Diazo-γ-amido Ketones
1726, 1660, 1508, 1395, and 720 cm-1 1H NMR (300 MHz,
J . Org. Chem., Vol. 61, No. 7, 1996 2291
;
) 14.4 and 9.2 Hz), 2.37 (dd, 1H, J ) 14.4 and 5.0 Hz), 2.99
(d, 1H, J ) 4.5 Hz), 3.25 (s, 3H), 3.33 (d, 1H, J ) 4.5 Hz), 3.75
(s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 4.14 (dd, 1H, J ) 9.2 and 5.0
CDCl3) δ 1.70 (dd, 1H, J ) 14.4 and 6.8 Hz), 2.75 (dd, 1H, J )
14.4 and 11.2 Hz), 2.91 (d, 1H, J ) 8.2 Hz), 2.94 (d, 1H, J )
4.0 Hz), 3.22 (dd, 1H, J ) 10.0, and 8.2 Hz), 3.39 (ddd, 1H, J
) 11.2, 10.0 and 6.8 Hz), 3.44 (d, 1H, J ) 4.0 Hz), 4.27 (dd,
1H, J ) 14.7 and 6.7 Hz) 4.37 (dd, 1H, J ) 14.7 and 6.0 Hz),
5.05 (d, 1H, J ) 16.9 Hz), 5.10 (d, 1H, J ) 9.8 Hz), 5.92 (dddd,
1H, J ) 16.9, 9.8, 6.7, and 6.0 Hz), and 7.29-7.53 (m, 10H);
13C NMR (75 MHz, CDCl3) δ 35.0, 43.8, 46.1, 47.1, 50.8, 52.3,
64.6, 117.5, 126.0, 127.9, 128.0, 128.2, 128.6, 129.2, 131.1,
132.3, 141.1, 169.0, 173.6, and 174.9. Anal. Calcd for
C24H22N2O4: C, 71.63; H, 5.51; N, 6.96, found C, 71.70; H, 5.52;
N, 6.96.
The reaction of 260 mg (1.01 mmol) of 29 in 3 mL of CHCl3
with 2 mg of rhodium(II) acetate in the absence of a dipolaro-
phile afforded 6-(N-allyl-N-phenylamino)-2H-pyran-3(4H)-one
(44d ) in 72% yield as a labile oil: 1H NMR (300 MHz, CDCl3)
δ 2.99 (d, 2H, J ) 3.8 Hz), 4.19 (d, 2H, J ) 5.0 Hz), 4.31 (s,
2H), 4.58 (t, 1H, J ) 3.8 Hz), 5.16 (d, 1H, J ) 10.4 Hz), 5.24
(d, 1H, J ) 17.5 Hz), 5.89 (ddt, 1H, J ) 17.5, 10.4, and 5.0
Hz), 6.96 (d, 2H, J ) 8.4 Hz), and 7.18-7.31 (m, 3H). All
attempts to obtain an analytically pure sample of 44d failed
as it was rapidly converted to dihydropyrandione 41.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
1-Dia zo-5-(N-Met h yl-N-(p -n it r op h en yl)a m in o)-2,5-p en -
ta n ed ion e (36). R-Diazo ketoamide 36 was prepared in 51%
yield from 3.1 g (20.4 mmol) of N-methyl-4-nitroaniline and
2.1 g (21 mmol) of succinic anhydride followed by condensation
with diazomethane as described above: IR (oil) 2105, 1665,
1517, and 1342 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.53 (brs,
2H), 2.69 (brs, 2H), 3.35 (s, 3H), 5.36 (s, 1H), 7.49 (d, 2H, J )
8.7 Hz), and 8.29 (d, 2H, J ) 8.7 Hz); 13C NMR (75 MHz,
CDCl3) δ 28.3, 34.6, 36.7, 54.1, 124.4, 127.1, 145.7, 148.8, 170.5,
and 192.8.
Hz), 6.94 (d, 2H, J ) 8.4 Hz), and 7.17 (d, 2H, J ) 8.4 Hz); 13
C
NMR (75 MHz, CDCl3) δ 33.5, 37.0, 45.7, 51.7, 52.4, 54.9, 66.7,
114.4, 127.9, 135.5, 140.1, 142.3, 158.5, 162.5, 163.0, and 171.7.
Anal. Calcd for C19H21NO7: C, 60.78; H, 5.64; N, 3.73, found
C, 60.53; H, 5.45; N, 3.47.
The major product (46%) isolated from the rhodium(II)-
catalyzed cycloaddition reaction of 38 with N-phenylmaleimide
in dry CHCl3 was identified as 4,5-trans-((N-phenylimino)-
dicabonyl)-6-trans-(N-(p-methoxyphenyl)-N-methylamino)-1-
oxaspiro[2.4]heptane (42): mp 165-166 °C; IR (KBr) 1721,
1640, 1509, and 1188 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.68
(dd, 1H, J ) 14.5 and 6.9 Hz), 2.75 (dd, 1H, J ) 14.5 and 11.5
Hz), 2.91 (d, 1H, J ) 8.2 Hz), 2.96 (d, 1H, J ) 4.0 Hz), 3.21
(dd, 1H, J ) 9.6, and 8.2 Hz), 3.27 (s, 3H), 3.44 (d, 1H, J ) 4.0
Hz), 3.47 (ddd, 1H, J ) 11.5, 9.6 and 6.9 Hz), 3.85 (s, 3H),
6.96 (d, 2H, J ) 8.7 Hz), and 7.30-7.52 (m, 7H); 13C NMR (75
MHz, CDCl3) δ 34.8, 37.4, 43.6, 45.9, 47.0, 50.8, 54.9, 64.6,
114.4, 125.9, 128.0, 128.1, 128.5, 131.1, 135.5, 158.7, 169.5,
173.6, and 175.1. Anal. Calcd for C23H22N2O5: C, 67.97; H,
5.46; N, 6.89, found C, 67.86; H, 5.43; N, 6.85.
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
N-Ben zyl-3-(3′-d ia zo-2′-oxop r op yl)-2-p ip er id on e (53). To
a solution containing 5.6 mL of diisopropylamine (44.4 mmol)
and 27.7 mL of a 1.6 M n-butyllithium solution in hexane (44.4
mmol) at -78 °C in 150 mL of THF was added 7.0 g (37 mmol)
of N-benzyl-2-piperidone.55 The mixture was allowed to stir
for 3 h and was then slowly warmed to 10 °C. The solution
was recooled to -78 °C, and 14.2 mL (111.0 mmol) of allyl
bromide was added. The solution was stirred at -78 °C for 2
h and was warmed to rt, and the reaction was quenched by
the addition of a saturated NH4Cl solution. The mixture was
extracted with ether, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica
gel chromatography to give 7.04 g (84%) of N-benzyl-3-allyl-
2-piperidone (52a ) as an amber oil: IR (neat) 2900, 1615, and
Treatment of a sample of 36 with 2 mg of rhodium(II)
acetate afforded 6-(N-methyl-N-p-nitrophenyl)amino-2H-py-
ran-3(4H)-one (37) in 87% yield as a pale yellow oil; 1H NMR
(300 MHz, CDCl3) δ 3.08 (d, 2H, J ) 3.4 Hz), 3.25 (s, 3H),
4.43 (s, 2H), 4.95 (t, 1H, J ) 3.4 Hz), 6.88 (d, 2H, J ) 9.3 Hz),
and 8.13 (d, 2H, J ) 9.3 Hz). Anal. Calcd for C12H12N2O4: C,
58.05; H, 4.88; N, 11.29, found C, 57.97; H, 4.96; N, 11.04. This
material was unreactive with DMAD and N-phenylmaleimide
and failed to produce a cycloadduct. Over a period of time, it
slowly decomposed to give dihydro-2H-pyran-2,5(3H)-dione
(41) and N-methyl-4-nitroaniline.
1475 cm-1; H NMR (CDCl3, 300 MHz) δ 1.40-1.95 (m, 4H),
1
2.25-2.50 (m, 2H), 2.65-2.80 (m, 1H), 3.17 (dd, 2H, J ) 5.0
and 2.0 Hz), 4.60 (dd, 2H, J ) 14.6 and 4.2 Hz), 5.00-5.25 (m,
2H), 5.70-5.95 (m, 1H), and 7.10-7.45 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 21.6, 26.0, 36.5, 41.3, 47.5, 50.3, 116.8,
127.2, 127.9, 128.5, 136.4, 137.4, and 171.9.
A solution containing 8.5 g (37.1 mmol) of the above
compound in 100 mL CH2Cl2 at -78 °C was ozonized until a
light blue color persisted. The mixture was flushed with
oxygen to remove the excess ozone. The ozonide was warmed
to 0 °C, and 14.0 mL (37.1 mmol) of J ones reagent was slowly
added to the mixture. The solution was allowed to stir for 1
h, filtered to remove the chromium salts, and concentrated
under reduced pressure. The residue was taken up in 50 mL
of 1 N NaOH, washed twice with ether, and acidified to pH 2.
The mixture was extracted with ether, dried over Na2SO4, and
concentrated under reduced pressure to give 5.1 g (56%) of
N-benzyl-2-piperidone ethanoic acid as a clear oil: IR (neat)
3419, 1717, and 1625 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.60-
2.05 (m, 4H), 2.20-2.65 (m 1H), 3.26 (dd, 2H, J ) 8.4 and 4.1
Hz), 2.75-2.90 (m, 2H), 4.60 (d, 1H, J ) 14.6 Hz) 4.66 (d, 1H
J ) 14.6 Hz), and 7.05-7.45 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 22.0, 27.4, 37.4, 38.2, 47.5, 50.7, 127.6, 128.0, 128.7,
136.4, 172.8, and 175.7.
To a solution containing 1.5 g (6.1 mmol) of the above acid
and 687 mg (7.3 mmol) of methyl chloroformate in 100 mL of
ether was added 613 mg (6.06 mmol) of triethylamine. The
resulting white suspension was stirred at rt for 1 h. The
precipitated triethylamine hydrochloride was removed by
filtration, and the colorless filtrate was immediately added to
40 mmol of freshly prepared diazomethane in ether at 0 °C.
The mixture was allowed to warm to rt overnight, and the
excess diazomethane was removed under reduced pressure.
The resulting yellow oil was purified by silica gel chromatog-
raphy to give 600 mg (37%) of N-benzyl-3-(3′-diazo-2′-oxopro-
P r ep a r a tion a n d Rh od iu m (II)-Ca ta lyzed Rea ction of
1-Diazo-5-(N-(p-m eth oxyph en yl)-N-m eth ylam in o)-2,5-pen -
ta n ed ion e (38). R-Diazo ketoamide 38 was prepared in 73%
yield from 2.8 g (20.4 mmol) of N-methyl-p-anisidine and 2.1
g (21 mmol) of succinic anhydride followed by condensation
with diazomethane as described above and was isolated as a
yellow solid: mp 87-88 °C; IR (neat) 2112, 1740, 1647, 1515,
1
and 850 cm-1; H NMR (300 MHz, CDCl3) δ 2.38 (t, 2H, J )
7.4 Hz), 2.59 (t, 2H, J ) 7.4 Hz), 3.22 (s, 3H), 3.83 (s, 3H),
5.34 (s, 1H), 6.92 (d, 2H, J ) 8.6 Hz), and 7.15 (d, 2H, J ) 8.6
Hz); 13C NMR (75 MHz, CDCl3) δ 28.3, 35.0, 36.8, 53.9, 54.8,
114.3, 127.8, 135.8, 158.3, 171.2, and 193.3. Anal. Calcd for
C13H15N3O3: C, 59.76; H, 5.79; N, 16.08, found C, 59.80; H,
5.82; N, 15.98.
The reaction of 270 mg (1.03 mmol) of 38 with 2 mg of
rhodium(II) acetate at rt in 3 mL of CHCl3 for 30 min in the
presence of DMAD afforded three products. The first frac-
tion (15% yield) isolated from the silica gel column was
assigned as dimethyl (N-(p-methoxyphenyl)-N-methylamino)-
maleate (40): mp 106-107 °C; IR (KBr) 1736, 1686, 1562, and
1
790 cm-1; H NMR (300 MHz, CDCl3) δ 3.14 (s, 3H), 3.60 (s,
3H), 3.64 (s, 3H), 3.76 (s, 3H), 4.70 (s, 1H), 6.82 (d, 2H, J )
9.0 Hz), and 7.09 (d, 2H, J ) 9.0 Hz). Anal. Calcd for C14H17
-
NO5: C, 60.19; H, 6.14; N, 5.02, found C, 59.84; H, 5.88; N,
4.97.
The second fraction (15%) was identified as dihydro-2H-
pyran-2,5(3H)-dione (41). The major fraction (49%) was a clear
oil whose structure was assigned as 6-trans-((N-(p-methoxy-
phenyl)-N-methylamino)carbonyl)-4,5-dicarbomethoxy-1-
oxaspiro[2.4]hept-4-ene (39): IR (neat) 1720, 1655, 1492, 1437,
1
and 1130 cm-1; H NMR (300 MHz, CDCl3) δ 2.01 (dd, 1H, J
(55) Magee, D. I.; Ramaseshan, M. Synlett 1994, 9, 743.

2292 J . Org. Chem., Vol. 61, No. 7, 1996
Padwa et al.
pyl)-2-piperidone (53) as a viscous yellow oil: IR (neat) 2944,
to stir at 0 °C for 1 h, and the reaction was quenched by the
addition of H2O. The mixture was extracted with ether,
washed with concentrated NaCl, and dried over MgSO4. The
solution was concentrated under reduced pressure, and the
residue was purified by silica gel chromatography to give 97
mg (48%) of N-benzyl-3-(carbomethoxymethyl)-3-methyl-2-
piperidone as a colorless oil: IR (neat) 2940, 1734, and 1635
1
2118, 1822, and 1737 cm-1; H NMR (CDCl3 , MHz) δ 1.60-
2.15 (m, 4H), 2.60 (dd, 1H, J )15.1 and 6.7 Hz), 2.80-3.05
(m, 2H), 3.23 (dd, 2H, J ) 8.9 and 5.0 Hz), 4.47 (d, 1H, J )
14.6 Hz), 4.67 (d, 1H, J ) 14.6 Hz), 5.32 (brs, 1H), and 7.20-
7.45 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 22.4, 27.2, 39.0,
42.5, 47.3, 50.4, 54.9, 127.3, 127.9, 128.6, 137.2, 171.5, and
193.5.
cm-1 1H NMR (CDCl3, 300 MHz) δ 1.31 (s, 3H), 1.60-2.05
;
(m, 3H), 2.10 (td, 1H, J ) 12.7 and 3.5 Hz), 2.34 (d, 1H, J )
16.4 Hz), 3.10 (d, 1H, J ) 16.4 Hz), 3.15-3.50 (m, 2H), 3.63
(s, 3H), 4.65 (bs, 2H) and 7.30 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 19.6, 26.6, 33.0, 40.2, 44.1, 47.6, 50.5, 51.3, 127.1,
128.0, 128.5, 137.5, 172.1, and 174.4.
To a 68 mg (0.25 mmol) sample of 53 in 5 mL of CH2Cl2
were added 42 mg (0.30 mmol) of dimethyl acetylenedicar-
boxylate and 2 mg of rhodium(II) acetate. The mixture was
allowed to stir at rt for 1 h and was then concentrated under
reduced pressure. The residue was subjected to flash chro-
matography on silica gel to give 24 mg (25%) of 10-benzyl-4,5-
dicarbomethoxy-11-oxo-1-oxa-10-azadispiro[2.2.5.1]dodec-4-
To a 300 mg (1.09 mmol) sample of the above ester in 10
mL of ether was added 165 mg (1.31 mmol) of potassium
trimethylsilanolate, and the mixture was heated at reflux for
12 h. The solution was cooled to 0 °C, and 0.16 mL (1.54 mmol)
of methyl chloroformate was added. The resulting white
suspension was allowed to warm to rt over a period of 4 h.
The precipitate was filtered, and the filtrate was quickly added
to 20 mmol of freshly prepared diazo-methane at 0 °C. The
solution was allowed to warm to rt over a period of 12 h, and
the excess diazomethane and ether were removed under
reduced pressure. The mixture was purified by silica gel
chromatography to give 192 mg (63%) of N-benzyl-3-(3′-diazo-
2′-oxopropyl)-3-methyl-2-piperidone (58) as a bright yellow
ene (55) as a colorless oil: IR (neat) 1714, 1626, and 1573 cm-1
;
NMR (CDCl3, 300 MHz) δ 1.76-2.00 (m, 4H), 2.03 (d, 1H, J )
14.1Hz), 2.49 (td, 1H, J ) 12.7 and 4.4 Hz), 2.84 (d, 1H, J )
14.1 Hz), 3.00 (d, 1H, J ) 4.4 Hz), 3.32 (d, 1H, J ) 4.4 Hz),
3.38 (dd, 2H, J ) 11.8 and 5.1 Hz), 3.71 (s, 3H), 3.77 (s, 3H),
4.43 (d, 1H, J ) 14.6 Hz), 4.75 (d, 1H, J ) 14.6 Hz), and 7.20-
7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 20.6, 33.5, 43.2,
47.6, 50.9, 51.9, 52.3, 52.4, 55.3, 66.1, 127.4, 128.6, 128.6, 136.9,
142.3, 145.2, 163.0, 163.8, and 171.2; HRMS calcd for C21H23
NO6 385.1526, found 385.1525.
-
The second fraction isolated from the column contained 53
mg (53%) of a yellow oil whose structure was assigned as
N-benzyl-7,9a-dihydroxy-8,9-dicarbomethoxy-6-oxo-1-azabicyclo-
[4.5]undec-8-ene (57): IR (neat) 2952, 1740, 1692, and 1572
cm-1; NMR (CDCl3, 300 MHz) δ 1.20-1.75 (m, 5H), 2.45 (dd,
1H, J ) 17.4 and 13.0 Hz), 2.62-2.81 (m, 2H), 3.13 (dd, 2H, J
)7.3 and 6.8 Hz), 3.61 (s, 3H), 3.92 (s, 3H), 4.32 (s, 1H), 4.57
(d, 1H, J ) 17.8 Hz), 4.70 (d, 1H, J ) 17.8 Hz), and 7.20-7.40
(m 5H); 13C NMR (CDCl3, 75 MHz) δ 23.8, 26.8, 37.1, 39.3,
49.8, 50.8, 53.1, 54.0, 72.9, 85.3, 127.3, 127.9, 128.9, 135.4,
oil: IR (neat) 2099, 1699, and 1627 cm-1
;
1H NMR (CDCl3,
300 MHz) δ 1.28 (s, 3H), 1.50-1.95 (m, 3H), 2.00-2.35 (m,
2H), 3.10-3.25 (m, 2H), 3.32 (td, 1H, J ) 11.6 and 4.6 Hz),
4.49 (d, 1H, J ) 14.7 Hz), 4.63 (d, 1H, J ) 14.7 Hz), 5.26 (brs,
1H), and 7.20-7.45 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 19.6,
27.1, 32.8, 41.2, 47.8, 50.6, 55.3, 60.3, 127.2, 127.9, 128.5, 137.4,
174.4, and 193.3.
To a solution containing 27 mg (0.10 mmol) of the 58 and
17.5 µL (0.20 mmol) of dimethyl acetylenedicarboxylate in 10
mL of CH2Cl2 was added 5 mg of rhodium(II) acetate. Im-
mediate nitrogen evolution was observed, and the solution was
allowed to stir for an additional 2 h. The mixture was
concentrated under reduced pressure to give (41%) of N-benzyl-
7,9a-dihydroxy-8,9-dicarbomethoxy-6-oxo-1-azabicyclo[4.5]undec-
8-ene (61): IR (neat) 3548, 1734, 1686, and 1565 cm-1; NMR
(CDCl3, 300 MHz) δ 1.24 (s, 3H), 1.40-1.60 (m, 4H), 2.48 (d,
1H, J ) 16.5 Hz), 2.67 (d, 1H, J ) 16.5 Hz), 3.00-3.20 (m,
2H), 3.62 (s, 3H), 3.92 (s, 3H), 4.30 (s, 2H), 4.66 (s, 1H), 4.69
(s, 2H), and 7.20-7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
23.3, 26.9, 34.9, 40.8, 45.8, 49.8, 50.9, 53.1, 54.0, 72.4, 85.4,
127.3, 127.9, 128.9, 135.3, 154.3, 166.1, 168.0, 172.6, and
203.31; HRMS calcd for C22H27NO7 417.1785, found 417.1782.
154.3, 166.1, 168.0, 171.3, and 203.2; HRMS calcd for C21H25
NO7 403.1632, found 403.1631.
-
P r ep a r a tion a n d Rh od iu m -Ca ta lyzed Decom p osition
of N-Ben zyl-3-(3′-d ia zo-2′-oxop r op yl)-3-m eth yl-2-p ip er i-
d on e (58). To a solution containing 2.93 g (14.6 mmol) of
N-benzyl-3-methyl-2-pipiridone in 50 mL THF at -78 °C was
added 12 mL of 1.6 M n-butyllithium in hexane (16.1 mmol).
The solution was warmed to 0 °C over a period of 4 h while
stirring and then cooled to -78 °C. A 5.3 g (43.8 mmol) sample
of allyl bromide was added, and the solution was allowed to
warm to rt over 12 h. The reaction was quenched by the
addition of a saturated NH4Cl solution, and the solution was
extracted with ether, washed with a saturated NaCl solution,
and dried over MgSO4. The mixture was concentrated under
reduced pressure and purified by silica gel chromatography
to give 1.65 g (47%) of 3-allyl-1-benzyl-3-methyl-2-piperidone
Ack n ow led gm en t. We gratefully acknowledge sup-
port of this work by the National Institutes of Health
(CA-26751). Use of the high-field NMR spectrometer
used in these studies was made possible through equip-
ment grants from the NIH and NSF.
(52b) as a pale yellow oil: IR (neat) 2920, 1620, and 1490 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.25 (s, 3H), 1.50-1.65 (m, 1H),
1.70-1.95 (m, 3H), 2.24 (dd, 1H, J ) 13.6 and 8.1 Hz), 2.57
(dd, 1H, J ) 13.6 and 6.7 Hz), 3.17 (t, 2H, J ) 5.4 Hz), 4.50
(d, 1H, J ) 14.6 Hz), 4.63 (d, 1H, J ) 14.6 Hz), 5.05-5.10 (m,
2H), 5.75 (m, 1H), and 7.20-7.45 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 19.4, 25.9, 32.5, 41.6, 44.4, 47.8, 50.4, 118.0, 127.2,
127.9, 128.5, 134.6, 137.6, and 175.0.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
new compounds lacking analyses (3 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
A solution containing 0.15 g (0.74 mmol) of the above
compound, 20 mL of methanol, and 3.75 mL of a 0.5 N
methanolic NaOH solution at -78 °C was ozonized for 35
min.56 A stream of oxygen was bubbled through the solution
so as to remove the excess ozone. The solution was allowed
J O952078H
(56) Marshall, J . A.; Garofalo, A. W. J . Org. Chem. 1993, 58, 3675.