Study of the Rearrangements of Oxonium Ylides Generated from Ketals

Article abstract of DOI:10.1021/jo961896m

Intramolecular exposure of cyclic ketals to metal carbenoids generates a proposed oxonium ylide intermediate that subsequently rearranges to one of three general products. The product resulting from a 1,2-shift to the ketal carbon is favored by larger ketals that lack radical stabilizing groups. A bridged bicyclic structure is formed by competitive 1,2-shift to the exocyclic carbon of the ketal and is favored by smaller ketal ring sizes that possess radical-stabilizing groups. An alternative β-elimination pathway can also operate when neither of the 1,2-shift pathways are favored. The enol ether that is formed in this latter pathway rearranges easily to an isomeric dioxene.

Full text of DOI:10.1021/jo961896m

3902
J . Org. Chem. 1997, 62, 3902-3909
Stu d y of th e Rea r r a n gem en ts of Oxon iu m Ylid es Gen er a ted fr om
Keta ls
J ohn B. Brogan and Charles K. Zercher*
Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824
Cary B. Bauer and Robin D. Rogers1
Department of Chemistry, Northern Illinois University, DeKalb, Illinois 60115
Received October 8, 1996X
Intramolecular exposure of cyclic ketals to metal carbenoids generates a proposed oxonium ylide
intermediate that subsequently rearranges to one of three general products. The product resulting
from a 1,2-shift to the ketal carbon is favored by larger ketals that lack radical stabilizing groups.
A bridged bicyclic structure is formed by competitive 1,2-shift to the exocyclic carbon of the ketal
and is favored by smaller ketal ring sizes that possess radical-stabilizing groups. An alternative
â-elimination pathway can also operate when neither of the 1,2-shift pathways are favored. The
enol ether that is formed in this latter pathway rearranges easily to an isomeric dioxene.
In tr od u ction
While the application of phosphorus and sulfur ylides
to organic synthesis is quite common, the use of oxonium
ylides for synthetic transformations is encountered less
frequently. The reduced synthetic applicability of oxo-
nium ylides has been attributed to the inherent difficulty
in forming oxonium ylides via traditional methods such
as deprotonation of corresponding onium salts. Although
Olah demonstrated that dimethyloxonium methylide
could be generated by the deprotonation of the trimethyl-
oxonium salt,2 the tendency for trivalent oxygen to donate
alkyl groups before protons generally excluded the use
of strong base for synthetic applications.3 Gutsche
demonstrated in 1954 that generation of oxonium ylides
was possible through the decomposition of R-diazo car-
bonyls (Figure 1, reaction 1),4 yet this report appeared
to stimulate little new chemistry. The recent develop-
ment of chemoselective rhodium and copper catalysts has
renewed interest in oxonium ylides. Subsequent studies
have demonstrated that ylides derived from carbonyl and
ethereal oxygens can be used as intermediates in a wide
variety of subsequent transformations, including dipolar
cycloadditions, Steven’s 1,2-shifts, 2,3-sigmatropic re-
arrangements, and simple â-eliminations.5
F igu r e 1.
in the literature suggests that divergent reactivity is
possible from ketal-derived ylides. For example, Doyle
and co-workers have observed a 2,3-sigmatropic re-
arrangement of the oxonium ylide generated from the
dimethyl acetal of acrolein (Figure 1, reaction 2).6 This
reactivity complements the results of Gutsche and the
results of Roskamp and J ohnson (Figure 1, reaction 3),7
who demonstrated that ketal-derived oxonium ylides
decompose via 1,2-shift pathways.
Both the chemistry of carbonyl ylides and the chem-
istry of oxonium ylides derived from ethers have been
studied in some detail; however, ylides derived from
ketals have been largely ignored. Nevertheless, evidence
We initiated an investigation in order to clarify the
factors that influence ylide formation and reactivity
through the synthesis and catalytic decomposition of
various dioxolane substrates. In short, our initial study
addressed the competition between six-membered ring
bicyclic ylide formation and C-H insertion, competitive
ylide formation between diastereotopic oxygens, the
influence of copper(II) and rhodium(II) catalytic systems,
and the role substituents on the ketal play in determining
the subsequent reactivity of the resultant ylides.8 We
now report the details of our investigation, which suggest
that bicyclic ylide rearrangement is dominated by two
primary factors: ring-size of the intermediate bicyclic
ylide and the nature of substituents on the ketal.
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) Address questions about X-ray data to this author at the
following address: Department of Chemistry, The University of
Alabama, Box 870336, Tuscaloosa, AL 35487.
(2) Olah, G. A.; Doggweiler, H.; Felberg, J . D.; Frolich, S.; Grdina,
M. J .; Karpeles, R.; Keumi, T.; Inaba, S.; Ip, W. M.; Lammertsma, K.;
Salem, G.; Tabor, D. J . Am. Chem. Soc. 1984, 49, 2143.
(3) West, F. G.; Tester, R. W.; Eberlein, T. H. J . Org. Chem. 1992,
57, 3479.
(4) Gutsche, C. D.; Hillman, M. J . Am. Chem. Soc. 1954, 76i, 2236.
(5) (a) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885. (b) Pirrung,
M. C.; Werner, J . A. J . Am. Chem. Soc. 1986, 108, 6060. (c) Doyle, M.
P.; Tamblyn, W. H.; Bagheri, V. J . Org. Chem. 1981, 46, 5094. (d)
Moody, C. J .; Taylor, R. J . Tetrahedron Lett. 1988, 29, 6005. (e) Davies,
H. M. L.; Crisco, L. Van T. Tetrahedron Lett. 1987, 28, 371. (f) Doyle,
M. P.; Bagheri, V.; Harn, N. K. Tetrahedron Lett. 1988, 29, 5119. (g)
Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263. (h) Doyle, M.
P. Chem. Rev. 1986, 86, 919. (i) Clark, J . S. Tetrahedron Lett. 1992,
33, 6193. (j)Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. (k)
Oku, A.; Ohki, S.; Yoshida, T.; Kimura, K. Chem. Commun. 1996, 1077.
(6) Doyle, M. P.; Griffin, J . H.; Chinn, M. S.; van Leusen, D. J . Org.
Chem. 1984, 49, 1917.
(7) Roskamp, E. J .; J ohnson, C. R. J . Am. Chem. Soc. 1986, 108,
6062.
(8) Brogan, J . B.; Bauer, C. B.; Rogers, R. D.; Zercher, C. K.
Tetrahedron Lett. 1996, 29, 5053.
S0022-3263(96)01896-8 CCC: $14.00 © 1997 American Chemical Society

Oxonium Ylides Generated from Ketals
J . Org. Chem., Vol. 62, No. 12, 1997 3903
Sch em e 1a
Sch em e 3
tion of 5 into its crystalline semicarbazone derivative 6
provided a suitable substrate for X-ray analysis. It was
apparent from this X-ray structure that the proposed
intermediate ylide was formed through nucleophilic
attack of the least sterically hindered oxygen and that
1,2-shift to the exocyclic, allylic carbon occurred with
complete retention of configuration. The unusual feature
of this rearrangement was that the migration did not
involve the ketal carbon as observed in all previous
studies. Factors that influence competitive exocyclic and
endocyclic 1,2-shifts with cyclic ylides derived from ethers
have been reported;12 however, similar competition has
not been explored with ketal substrates. We undertook
the preparation and study of additional substrates that
would allow the determination of factors that control the
competitive rearrangements.
a
Key: (a) diol, (CH3O)3CH, p-TsOH; (b) (i) KOH/CH3OH; (ii)
H3O+; (c) carbonyldiimidazole; (ii) Mg2+(CH3O2CCH2CO2-)2; (d)
p-carboxybenzenesulfonazide, Et3N.
Sch em e 2
The generality of the exocyclic 1,2-shifts was confirmed
through preparation of the analogous diphenyl-substi-
tuted dioxolane 4b from (()-1,2-diphenyl-1,2-dihydroxy-
ethane. Exposure of 4b to Cu(hfacac)2 resulted in its
conversion to a single diastereomer in a 65% yield.
Analysis of the 1H and 13C NMR spectra led to the
structural assignment of the bridged bicyclic compound
7 (Scheme 3). Since the coupling constant between the
two allylic methine protons in 5 (3J ) 8.5 Hz) was
consistent with the twist-boat conformation of its crystal
structure, the identification of a similar coupling constant
between the two benzylic methines in 7 (3J ) 9.1 Hz)
was suggestive of structure 7 in a similar twist-boat
conformation.
The unsubstituted dioxolane 4c was prepared through
a similar sequence of reactions, and its exposure to
Cu(hfacac)2 resulted in the formation of two compounds
(Scheme 4). The product 8 resulting from â-elimination
was generated in 57% yield, while a ring-fused product
9 was generated in an 18% yield.13 This latter product,
the result of an endocyclic 1,2-shift involving the ketal
carbon, is analogous to that observed in the earlier study
of J ohnson. The appearance of alternative reaction
pathways is not unexpected, since major variations in
product selectivity have been observed in previous ylide
studies.5k Although the ring-fused compound that was
formed is isomeric with and possesses a proton spin
system identical to the analogous bridged bicyclic struc-
ture, structural assignment by analysis of the NMR
spectra is possible. The difference in 13C chemical shifts
of the quaternary carbons (ketal, δ > 100 ppm; ether, δ
≈ 92 ppm) and the upfield shift of the methine proton in
the bridged bicyclic structure are characteristic of the two
ring systems.
Resu lts a n d Discu ssion
Our initial substrate was chosen for its potential to
undergo 1,2- and/or 2,3-shifts from an intermediate
oxonium ylide. The preparation of 4a (Scheme 1) was
initiated through the conversion of methyl levulinate (1)
to a mixture of ketals separable by chromatography. The
isomer 2a , derived from the d,l-diol, was saponified and
converted to the â-keto ester 3a according to the proce-
dure of Masamune.9 Diazo transfer was subsequently
effected with 4-carboxybenzenesulfonazide and triethyl-
amine.10 Upon exposure to catalytic Cu(hfacac)2 at
11
room temperature, compound 4a was converted to a
single compound 5 in 64% yield (Scheme 2). The com-
pound formed in this reaction was clearly the result of a
1,2-shift, yet connectivity within the ring system and the
stereochemical orientation of the vinyl groups could not
be determined from the spectroscopic data. Transforma-
(9) Brooks, D. W.; Lu, L. D.-D.; Masamune, S. Angew. Chem., Int.
Ed. Engl. 1979, 18, 72.
(10) Hendrickson, J . B.; Wolf, W. A. J . Org. Chem. 1968, 33, 3610.
(11) Both Rhodium and Copper catalysts effect this same rearrange-
ment; however, Cu(hfacac)2 has been found to be the most efficient
catalyst for the preparation of ylides from ketals (see ref 8). This
observation of catalyst efficiency has been made not only in regard to
intramolecular ylide formation but also with parallel studies on the
formation of ylides through intermolecular reactions. This result is
consistent with previous observations. (a) Clark, J . S.; Krowiak, S. K.;
Street, J . L. Tetrahedron Lett. 1993, 34, 4385. (b) West, F. G.; Naidu,
B. N.; Tester, R. W. J . Org. Chem. 1994, 59, 6892.
(12) (a) West, F. G.; Eberlein, T. H.; Tester, R. W. J . Chem. Soc.,
Perkin Trans. 1 1993, 2857. (b) Pirrung, M. C.; Brown, W. L.; Rege,
S.; Laughton, P. J . Am. Chem. Soc. 1991, 113, 8561.
(13) The stereochemical assignment of this ring-fused product is
consistent with that observed in two closely related systems. As
described later in the text, the assignment of cis-stereochemistry in
19 was made by X-ray analysis of a crystalline derivative. Roskamp
and J ohnson, in their study of oxonium ylide chemistry, reported a
cis-stereochemical relationship for a ring system that contained one
fewer carbon (see ref 7).

3904 J . Org. Chem., Vol. 62, No. 12, 1997
Brogan et al.
Sch em e 4
Sch em e 5a
The competitive relationship between the â-elimination
product 8 and the ring-fused product 9 merits some
discussion. While it has been difficult to completely
suppress formation of 8, the yield of the competitive ring-
fused compound 9 was optimized to 51% by dehydration
of the catalyst and employment of strictly anhydrous
conditions, thereby suggesting that water may act as a
base to promote the â-elimination reaction. When the
moisture-sensitive enol ether 8 was isolated and re-
exposed to catalytic Cu(hfacac)2, significant formation of
the ring-fused product 9 was observed. Although the
mechanistic details in the formation of 9 from 8 are not
known, it is clear that ring-fused products are not
necessarily formed through direct 1,2-shifts.
a
Key: (a) H2/Pd/C; (b) p-carboxysulfonylazide, Et3N; (c) cat.
Cu(hfacac)2.
Sch em e 6a
Although it is possible to isolate the â-elimination
product 8 by chromatography, the compound is quite
sensitive and rapidly isomerizes to dioxene 10 in the
presence of H2O. A reasonable mechanism for this
transformation is hydrolysis of the enol ether followed
by interconversion of two isomeric hemiacetals. Dehy-
dration of a hemiacetal produces dioxene 10 and regener-
ates water. This intriguing rearrangement provides a
potentially general route to functionalized dioxene de-
rivatives.
a
Key: (a) (i) KOH/CH3OH; (ii) H3O+; (b) (i) carbonyldiimidazole,
(ii) Mg2+(O2CCH2CO2CH3)2; (c) p-carboxybenzenesulfonazide, Et3N;
(d) cat. Cu(hfacac)2; (e) H2NHNCONH2.
In order to determine the influence of alkyl-substituted
dioxolanes in this chemistry, substrate 12 was prepared
by catalytic reduction of 3a followed by diazo transfer.
An authentic sample of a possible bridged bicyclic struc-
ture 13 was prepared by reduction of 5 (Scheme 5). When
diazo compound 12 was exposed to Cu(hfacac)2, no
evidence of the bridged bicyclic structure 13 was ob-
served. The presence of a â-elimination product 14 was
suggested by new olefinic proton resonances in the 1H
NMR spectrum. Although this moisture-sensitive com-
pound could not be fully characterized, its subsequent
rearrangement to dioxene product 15 provided further
confirmation that 14 was the product of â-elimination.
It is not at all clear why the ylide derived from the diethyl
dioxolane substrate 12 does not participate in a 1,2-shift
to provide the ring-fused product as was observed with
substrate 4c; however, the additional steric bulk of the
two ethyl groups must be considered as a possible factor.
While dioxolane substitution patterns clearly influence
the direction and efficiency of the 1,2-shifts, we were
interested in elucidating the effects of ring size on these
rearrangements. Preparation of the dioxane-containing
substrate 18 provided a vehicle for studying rearrange-
ments of the homologous bicyclic ylide. In contrast to
previous compounds, exposure of compound 18 to catalyst
resulted in quantitative conversion to the ring-fused
bicyclic structure 19 (Scheme 6). No â-elimination was
observed with either rigorously dried or hydrated cata-
lyst. The cis ring fusion of 19 was unambiguously
determined by X-ray analysis of its semicarbazone de-
rivative 20.
With a trend emerging whereby larger ketal ring size
facilitates endo 1,2-shifts and smaller cyclic ketals that
possess radical-stabilizing groups promote exocyclic shifts,
the benzodioxepin substrate 23 was prepared. This
larger bicyclic ylide should encounter little resistance to
transannular ring closure, while, at the same time, the
radical-stabilizing benzylic carbons should facilitate exo-
cyclic migration. Exposure of 23 to catalytic Cu(hfacac)2

Oxonium Ylides Generated from Ketals
J . Org. Chem., Vol. 62, No. 12, 1997 3905
Sch em e 7a
analogous 2,8-dioxabicyclo[3.2.1]octane core of Zaragozic
acid16 can also be approached in this fashion. Further
investigation into the remarkably facile generation of
these highly substituted bridged-bicyclic structures is
underway. These efforts include the further investiga-
tion of substituent effects, stereoelectronic considerations,
and the application of this methodology to natural
product synthesis.
Exp er im en ta l Section
Gen er a l Exp er im en ta l Meth od s. Tetrahydrofuran and
diethyl ether were distilled from benzophenone ketyl. Benzene
and was distilled from calcium hydride. The p-carboxyben-
zenesulfonazide,10 methyl levulinate,17 benzenedimethanol,18
and monomethyl malonate19 are known compounds. The
catalyst, Cu(hfacac)2, was obtained from Aldrich as the dihy-
drate. The catalyst was dried over H2SO4 in a vacuum
desiccator (0.1 Torr) for 3 days and transferred in a glovebag
under nitrogen atmosphere.20 All other materials were used
as received from commercial suppliers. Column chromatog-
raphy was performed on Baker 40 νm silica gel. Thin layer
chromatography (TLC) was carried out EM Science F254 glass
plates and visualized by UV and anisaldehyde stain. All
reactions were run in oven-dried glassware under nitrogen
atmosphere.
tr a n s-4,5-Dieth en yl-2-[2-(car boxym eth yl)eth yl]-2-m eth -
yl-1,3-d ioxola n e (2a ). A solution of methyl levulinate (1)
(2.38 g, 18.2 mmol), 1,5-hexadiene-3,4-diol (2.28 g, 20 mmol,
∼1:1 mixture of meso:dl), and trimethyl orthoformate (2.40 mL,
22 mmol) in dry benzene (30 mL) was charged with p-TsOH
(∼20 mg) and stirred for 2 h. The mixture was diluted with
Et2O, washed with saturated NaHCO3, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was chro-
matographed on silica (10% EtOAc in hexane, Rf 0.22) to yield
a mixture of diastereomers (3.72 g, 90%, ∼1:1 mixture of trans:
cis (the ratio of the two cis isomers was variable)). Further
chromatography on silica (5% EtOAc in hexane, Rf 0.18)
provided the desired trans isomer 2a (1.65 g, 40%) as a thick
oil: 1H NMR (360 MHz, CDCl3) δ 5.84-5.72 (m, 2H), 5.39-
5.22 (m, 4H), 4.13 (m, 1H), 4.02 (m, 1H), 3.7 (s, 3H), 2.48-
2.41 (m, 2H), 2.12-2.02 (m, 2H), 1.4 (s, 3H); 13C NMR (90 MHz,
CDCl3) δ 173.9, 134.2, 133.2, 119.02, 118.99, 109.67, 82.9, 82.1,
51.5, 34.8, 28.7, 25.4; IR (film) 3050-2850, 1750, 1450, 1350
cm-1; MS (CI, C2H6) 227, 195, 171, 139, 131, 99.
a
Key: (a) (i) KOH/CH3OH; (ii) H3O+; (b) (i) carbonyldiimidazole,
(ii) Mg2+(O2CCH2CO2CH3)2; (c) p-carboxybenzenesulfonazide, Et3N;
(d) cat. Cu(hfacac)2.
resulted in the formation of both 1,2-shift products 24
and 25 (Scheme 7). The major product 24, formed in
yields from 57 to 68%, was the result of an endocyclic
1,2-shift to the ketal carbon. The minor component 25,
an unstable bridged bicyclic skeleton resulting from an
exocyclic 1,2-shift to the benzylic position, was formed
in yields that ranged from trace amounts to 18% yield.
The factors that determined the efficiency in which 25
was formed in the reactions are not entirely understood;
however, it was abundantly clear that in every reaction
the ring-fused bicyclic skeleton 24 was formed with
greater efficiency. Therefore, the presence of benzylic
stabilization is not the dominant factor in determining
the fate of the intermediate oxonium ylide. The inti-
mately related factors of geometry and strain encoun-
tered in the 1,2-shift pathways appear to be important
factors in determining the fate of these oxonium ylides.
tr a n s-4,5-Dieth en yl-2-[4-(ca r boxym eth yl)-3-oxobu tyl]-
2-m eth yl-1,3-d ioxola n e (3a ). Ketal 2a (1.50 g, 6.6 mmol)
was treated with methanolic KOH (2 M, 30 mL) for 8 h,
acidified to pH 4.0 with saturated aqueous citric acid, and
extracted with diethyl ether (5 × 30 mL). The combined
organic extracts were carefully dried over anhydrous Na2SO4,
concentrated in vacuo, and dissolved in THF. Carbonyldi-
imidazole (1.15 g, 7.1 mmol) was added in small portions with
stirring, and acylimidazole formation was monitored by TLC.
In a separate flask, monomethyl malonate (1.20 g, 10.2 mmol)
was dissolved in THF (10 mL), treated with Bu2Mg (5.1 mL of
1.0 M in heptane, 5.1 mmol) at 0 °C, and warmed to room
temperature with stirring. The mixtures were combined and
Con clu sion
We have demonstrated that intramolecular ylide for-
mation and subsequent rearrangement is a facile process.
The efficiency and product selectivity of the rearrange-
ments appear to be influenced by two primary factors.
The first factor is the ring size of the bicyclic ylide, while
the second is the substitution pattern of the ketal. More
flexible bicyclic ylides (larger ring systems) rearrange via
1,2-shifts to the ketal carbon (endocyclic) far easier than
their analogues, which possess smaller ring ketals. This
could be due to conformational flexibility of the ring
system, stereoelectronic factors, or a combination of both.
However, it is clear that the presence of radical-stabiliz-
ing groups directly attached to the ketal oxygens promote
1,2-shifts to the stabilized exocyclic carbon.
(16) (a) Dawson, M. J .; Farthing, J . E.; Marshall, P. S.; Middleton,
R. F.; O’Neill, M. J .; Shuttleworth, A.; Stylli, C.; Tait, R. M.; Taylor,
P. M.; Wildman, H. G.; Buss, A. D.; Langley, D.; Hayes, M. V. J .
Antibiot. 1992, 45, 639. (b) Wilson, K. E.; Burk, R. M.; Biftu, T.; Ball,
R. G.; Hoogsteen, K. J . Org. Chem. 1992, 57, 7151. (c) Bergstrom, J .
D.; Kurtz, M. M.; Rew, D. J .; Amend, A. M.; Karkas, J . D.; Bostedor,
R. G.; Bansal, V. S.; Dufresne, C.; Van Middlesworth, F. L.; Hensens,
O. D.; Liesch, J . M.; Zink, D. L.; Wilson, K. E.; Onishi, J .; Milligan, J .
A.; Bills, G.; Kaplan, L.; Omstead, M. N.; J enkins, R. G.; Huang, L.;
Meinz, M. S.; Quinn, L; Burg, R. W.; Kong, Y. L.; Mochales, S.; Mojena,
M.; Martin, I.; Peleaz, F.; Deitz, M. T.; Alberts, A. W. Proc. Natl. Acad.
Sci. U.S.A. 1993, 90, 80.
(17) Schmid, G. H.; Weiler, L. S. J . Can J . Chem. 1965, 43, 1242.
(18) Oi, R.; Sharpless, K. B. Organic Syneses; Wiley: New York,
1973; Collect. Vol. V, p 1.
(19) Scheithauer, S.; Mayer, R. Chem. Ber. 1967, 100, 1413.
(20) Bertrand, J . A.; Kaplan, R. I. Inorg. Chem. 1965, 5, 489.
The highly functionalized 2,9-dioxabicyclo[3.3.1]nonane
skeleton is rapidly assembled utilizing this methodology.
This ring system, represented above in compounds 5 and
7, constitutes the core of the natural products streptolic
acid14 and tirandamycin.15 It appears likely that the
(14) Rinehart, K. L., J r.; Beck, J . R.; Epstein, W. E.; Spicer, L. D. J .
Am. Chem. Soc. 1963, 85, 4035.
(15) Meyer, C. E. J . Antibiot. 1971, 24, 558.

3906 J . Org. Chem., Vol. 62, No. 12, 1997
Brogan et al.
stirred for 24 h, diluted with diethyl ether (20 mL), washed
with aqueous NH4Cl and NaHCO3, and concentrated. The
residue was chromatographed on silica (20% EtOAc in hexane,
Rf 0.20) to yield 3a (1.1 g, 62%): 1H NMR (360 MHz, CDCl3)
δ 5.83-5.72 (m, 2H), 5.39-5.22 (m, 4H), 4.11 (m, 1H), 4.00
(m, 1H), 3.7 (s, 3H), 3.5 (s, 2H), 2.71-2.65 (m, 2H), 2.10-2.03
(m, 2H), 1.4 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 202.2, 167.6,
134.2, 133.2, 119.2, 118.9, 109.7, 82.9, 82.2, 52.3, 48.9, 37.7,
33.6, 25.5; IR (film) 3000-2800, 1775, 1725 cm-1; MS (CI, CH4)
269, 231, 173, 155, 139, 97; HRMS (CI, CH4) ([M + H]+) calcd
for C14H21O5 269.1389, found 269.1390.
× 10 mL). The combined ether extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue
was flushed through a plug of silica with 5% EtOAc in hexanes
and concentrated to yield 4b (22 mg, 98%) as an oil: 1H NMR
(360 MHz, CDCl3) δ 7.37-7.20 (m, 10H), 4.75 (s, 2H), 3.85 (s,
3H), 3.34-3.13 (m, 2H), 2.37-3.32 (m, 2H), 1.7 (s, 3H); 13C
NMR (90 MHz, CDCl3) δ 192.2, 161.7, 137.0, 136.2, 128.4,
128.2, 127.0, 126.6, 110.1, 85.9, 85.3, 75.9, 52.2, 35.2, 34.3, 25.6;
IR (film) 3000, 2200(s), 1750, 1700, 1500 cm-1; MS (CI, NH3)
395, 301, 239, 220, 199, 180, 167, 98, 48; HRMS (MH+) calcd
for C22H23N2O5 395.1607, found 395.1607.
2-[2-(Car boxym eth yl)eth yl]-2-m eth yl-1,3-dioxolan e (2c).
A solution of methyl levulinate (1) (3.48 g, 26.7 mmol), ethylene
glycol (1.86 g, 30.0 mmol), and trimethyl orthoformate (3.18
mL, 30.0 mmol) in dry benzene (30 mL) was charged with
p-TsOH (∼20 mg) and stirred for 2 h. The mixture was diluted
with diethyl ether, washed with saturated NaHCO3, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue
was distilled at reduced pressure to yield 2c (4.65 g, 69%): bp
tr a n s-4,5-Diet h en yl-2-[4-(ca r b oxym et h yl)-4-d ia zo-3-
oxobu tyl]-2-m eth yl-1,3-d ioxola n e (4a ). A solution of 3a
(563 mg, 2.1 mmol) and Et3N (0.64 mL, 4.95 mmol) in CH3CN
(5 mL) was charged with 4-carboxybenzenesulfonazide (545
mg, 2.4 mmol) at room temperature and stirred for 2.5 h. The
reaction mixture was poured into saturated aqueous NaHCO3
(30 mL) and extracted with diethyl ether (3 × 10 mL). The
combined ether washes were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was chromatographed on
silica (20% EtOAc in hexane, Rf 0.21) to yield 4a (598 mg, 97%)
as a bright yellow oil: 1H NMR (360 MHz, CDCl3) δ 5.88-
5.72 (m, 2H), 5.39.5.21 (m, 4H), 4.12-4.02 (m, 2H), 3.8 (s, 3H),
3.10-2.90 (m, 2H), 2.12-2.02 (m, 2H), 1.5 (s, 2H); 13C NMR
(90 MHz, CDCl3) δ 192.2, 161.7, 134.3, 133.6, 119.0, 118.8,
110.0, 82.9, 82.2, 75.7, 52.1, 34.9, 34.0, 25.5; IR (film) 3000-
2800, 2200 (s), 1750, 1650 cm-1; MS (CI, NH3) 295, 279, 199,
154, 139, 124, 113, 99, 799, 55; HRMS (MH+) calcd for
C14H19N2O5 295.1294, found 295.1283.
2-[2-(Ca r b oxym e t h yl)e t h yl]-2-m e t h yl-t r a n s-4,5-d i-
p h en yl-1,3-d ioxola n e (2b). A solution of methyl levulinate
(1) (156 mg, 1.20 mmol), 1,2-diphenyl-1,2-ethane diol (242 mg,
1.13 mmol), and trimethyl orthoformate (0.15 mL, 1.4 mmol)
in dry benzene (5 mL) was charged with p-TsOH (∼5 mg) and
stirred for 6 h. The mixture was diluted with diethyl ether,
washed with saturated NaHCO3, dried over anhydrous Na2SO4,
and concentrated in vacuo. The residue was chromatographed
on silica (5% EtOAc in hexane, Rf 0.22) to yield 2b as an oil
(346 mg, 94%): 1H NMR (360 MHz, CDCl3) δ 7.40-7.21 (m,
10H), 4.83-4.74 (m, 2H), 3.7 (s, 3H), 2.74-2.66 (m, 2H), 2.41-
2.34 (m, 2H), 1.7 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 173.7,
136.8, 136.0, 128.4, 128.3, 128.2,128.1, 126.7, 126.5, 109.7,
85.9, 85.0, 51.5, 35.1, 28.9, 25.4; IR (film) 3200, 3000, 1750
cm-1; MS (CI, C2H6) 355, 327, 249, 221, 197, 131, 99.
2-[4-(Ca r boxym eth yl)-3-oxobu tyl]-2-m eth yl-tr a n s-4,5-
d ip h en yl-1,3-d ioxola n e (3b). Ketal 2b (60 mg, 0.18 mmol)
was treated with methanolic KOH (2 M, 3 mL) for 8 h, acidified
to pH 4.0 with saturated aqueous citric acid, and extracted
with diethyl ether (5 × 30 mL). The combined organic
washings were carefully dried over anhydrous Na2SO4, con-
centrated in vacuo, and dissolved in tetrahydrofuran. Car-
bonyldiimidazole (50 mg, 0.31 mmol) was added in small
portions. In a separate flask, monomethyl malonate (128 mg,
1.10 mmol) was dissolved in THF (5 mL), treated with Bu2Mg
(1.0 M in heptane, 0.55 mmol) at 0 °C, and warmed to room
temperature with stirring. The mixtures were combined and
stirred further for 24 h, diluted with diethyl ether (20 mL),
washed successively with aqueous NH4Cl, NaHCO3, and brine,
and concentrated in vacuo. The residue was chromatographed
on silica (5% EtOAc in hexane, Rf 0.21) to yield an oil that
was identified as compound 3b (51 mg, 77%): 1H NMR (360
MHz, CDCl3) δ 7.47-7.18 (m, 10H), 4.80 (d, J ) 14 Hz, 1H),
4.69 (d, J ) 14 Hz, 1H), 3.75 (s, 3H), 3.55 (s, 2H), 2.92-2.85
(m, 2H), 2.33-2.26 (m, 2H), 1.7 (s, 3H); 13C NMR (90 MHz,
CDCl3) δ 202.1, 167.6, 136.8, 136.0, 128.6, 128.5, 128.3, 126.8,
126.6, 109.8, 85.9, 85.2, 52.4, 49.0, 38.0, 33.9, 25.5; IR (film)
3200, 1750, 1700 cm-1; MS (CI, NH3) 369, 344, 330, 214, 190,
173, 156; HRMS (CI, NH3) ([M + NH4]) calcd for C22H28NO5
386.1971, found 386.1971.
1
60 °C (0.5 mm) (lit.21 bp (103 °C, 9 mm); H NMR (360 MHz,
CDCl3) δ 3.91-3.82 (m, 4H), 3.62 (s, 3H), 2.38-3.32 (m, 2H),
2.01-1.95 (m, 2H), 1.25 (s, 3H); 13C NMR (90 MHz, CDCl3) δ
173.9, 109.2, 64.7, 51.5, 33.9, 28.7, 23.9; IR (film) 3000, 2900,
1750, 1700, 1450 cm-1; MS (CI, C2H6) (MH+) 175, 159, 143,
119, 99, 73.
2-[4-(Ca r b oxym e t h yl)-3-oxob u t yl]-2-m e t h yl-1,3-d i-
oxola n e (3c). Ketal 2c (1.01 g, 5.9 mmol) was treated with
methanolic KOH (2 M, 30 mL) for 8 h, acidified to pH 4.0 with
saturated citric acid, and extracted with diethyl ether (5 × 30
mL). The combined organic extracts were carefully dried over
anhydrous Na2SO4, concentrated in vacuo, and dissolved in
THF. Carbonyldiimidazole (1.08 g, 6.7 mmol) was added in
small portions with stirring. In a separate flask, monomethyl
malonate (0.859 g, 7.3 mmol) was dissolved in THF (10 mL),
treated with Bu2Mg (1.0 M in heptane, 3.63 mmol) at 0 °C,
and stirred while warming to room temperature. The mixtures
were combined and stirred for 24 h, diluted with diethyl ether
(20 mL), successively washed with saturated aqueous NH4Cl,
NaHCO3, and brine, and concentrated in vacuo. The residue
was chromatographed on silica (25% EtOAc in hexane, Rf 0.18)
to yield 3c (907 mg, 71%): 1H NMR (360 MHz, CDCl3) δ 3.96-
3.87 (m, 4H), 3.72 (s, 3H), 3.48 (s, 2H), 2.62-2.59 (m, 2H),
2.03-1.98 (m, 2H), 1.31 (s, 3H); 13C NMR (90 MHz, CDCl3) δ
202.2, 167.7, 109.1, 64.8, 52.3, 48.9, 37.6, 32.7, 24.0; IR (film)
3000, 2900, 1750, 1700 cm-1; MS (CI, CH4) 217, 201, 185, 155,
141, 99; HRMS (CI, CH4) ([M + H]+) calcd for C10H17O5
217.1076, found 217.1083.
2-[4-(Ca r b oxym et h yl)-4-d ia zo-3-oxob u t yl]-2-m et h yl-
1,3-d ioxola n e (4c). A solution of 3c (235 mg, 1.1 mmol) and
Et3N (0.33 mL, 2.4 mmol) in CH3CN (5 mL) was stirred with
4-carboxybenzenesulfonazide (271 mg, 1.2 mmol) at room
temperature for 2.5 h. The reaction mixture was poured into
saturated aqueous NaHCO3 (15 mL) and extracted with
diethyl ether (3 × 10 mL). The combined ether extracts were
dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica (25% EtOAc in hexane,
Rf 0.21) to yield 4c (223 mg, 84%) as a bright yellow oil: 1H
NMR (360 MHz, CDCl3) δ 3.96 (s, 4H), 3.83 (s, 3H), 3.00-
2.94 (m, 2H), 2.09-2.03 (m, 2H), 1.38 (s, 3H); 13C NMR (90
MHz, CDCl3) δ 192.3, 161.8, 109.3, 75.7, 64.8, 52.1, 35.0, 33.0,
24.1; IR (film) 3000, 2900, 2200(s), 1750, 1700, 1500 cm-1; MS
(CI, C2H6) (MH+) 243, 183, 139, 113, 87.
(()-(1S,3S,4S,5S)-5-(Ca r b oxym et h yl)-3,4-d iet h en yl-1-
m eth yl-6-oxo-2,9-d ioxa bicyclo[3.3.1]n on a n e (5). A stirred
solution of diazo compound 4a (94 mg, 0.32 mmol) in dry
benzene was charged with Cu(hfacac)2 (∼20 mg) and heated
at 80 °C for 4 h. The reaction mixture was poured into
saturated aqueous NaHCO3 (30 mL) and extracted with
diethyl ether (3 × 10 mL). The combined ether washes were
dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica (20% EtOAc in hexane,
Rf 0.19) to yield 5 (55.3 mg, 65%) as a pale yellow oil: 1H NMR
(360 MHz, CDCl3) δ 5.77-5.53 (m, 2H), 5.17-5.06 (m, 4H),
2-[4-(Ca r b oxym et h yl)-4-d ia zo-3-oxob u t yl]-2-m et h yl-
tr a n s-4,5-d ip h en yl-1,3-d ioxola n e (4b). A solution of com-
pound 3b (21 mg, 0.06 mmol) and Et3N (0.03 mL, 0.36 mmol)
in CH3CN (2 mL) was charged with 4-carboxybenzenesulfon-
azide (41 mg, 0.18 mmol) at room temperature and stirred for
2.5 h. The reaction mixture was poured into saturated
aqueous NaHCO3 (5 mL) and extracted with diethyl ether (3
(21) Bornowski, H.; Feistkorn, V.; Schwarz, H.; Levsen, K.; Schmitz,
P. Z. Naturforsch., B: Anorg. Chem., Org. Chem. 1977, 32B, 664.

Oxonium Ylides Generated from Ketals
J . Org. Chem., Vol. 62, No. 12, 1997 3907
3.89 (m, 1H), 3.64 (s, 3H), 3.40 (m, 1H), 2.63 (m, 1H), 2.49-
2.41 (m, 2H), 2.16 (m, 1H), 1.50 (s, 3H); 13C NMR (90 MHz,
CDCl3) δ 205.5, 165.3, 134.5, 132.4, 120.5, 116.8, 101.4, 87.1,
73.2, 56.5, 52.8, 37.2, 33.2, 21.3; IR (film) 3000-2800, 1750,
1700 cm-1; MS (EI) 266, 210, 152, 139, 99; HRMS (EI) M+ calcd
for C14H18O5 266.1154, found 266.1159.
Sem ica r ba zon e of Com p ou n d 5 (6). A solution of
semicarbazide‚HCl (111 mg, 1.0 mmol) and NaOAc (91 mg,
1.1 mmol) in H2O (5 mL) was added to compound 5 (223 mg,
8.4 mmol) dissolved in 95% EtOH (3 mL). Additional EtOH
was added until the solution became homogeneous, and the
mixture was heated on a steam bath for 1 h. Semicarbazone
6 formed as a white precipitate upon cooling (135 mg, 49%),
mp > 225 °C dec. Crystals suitable for X-ray analysis24 were
obtained by slow crystallization from CCl4: 1H NMR (360 MHz,
CDCl3) δ 9.0 (s, 1H), 6.0 (br s, 2H), 5.89-5.70 (m, 2H), 5.21-
5.11 (m, 4H), 3.97 (m, 1H), 3.70 (s, 3H), 3.30 (m, 1H), 2.87 (m,
1H), 2.29-2.12 (m, 2H), 2.02 (m, 1H), 1.51 (s, 3H); 13C NMR
(90 MHz, CDCl3) δ 168.1, 158.1, 148.5, 135.3, 133.9, 119.4,
116.6, 100.6, 82.6, 73.6, 56.7, 52.7, 34.4, 22.5, 19.0.
(()-(1S,3S,4S,5S)-5-(Ca r b oxym et h yl)-1-m et h yl-6-oxo-
3,4-d ip h en yl-2,9-d ioxa bicyclo[3.3.1]n on a n e (7). A stirred
solution of diazo compound 4b (61 mg, 0.15 mmol) in dry
benzene was charged with Cu(hfacac)2 (∼5 mg) and heated at
80 °C for 4 h. The reaction mixture was poured into saturated
aqueous NaHCO3 (10 mL) and extracted with diethyl ether (3
× 10 mL). The combined ether extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue
was chromatographed on silica (20% EtOAc in hexane, Rf 0.19)
to yield an oil identified as 7 (37 mg, 65%): 1H NMR (360 MHz,
CDCl3) δ 7.34-7.07 (m, 10H), 4.82 (d, 1H, J ) 9.1 Hz), 4.28
(d, 1H, J ) 9.1 Hz), 3.30 (s, 3H), 2.87 (m, 1H), 2.70-2.60 (m,
2H), 2.37 (m, 1H), 1.75 (s, 3H); 13C NMR (90 MHz, CDCl3) δ
206.4, 165.3, 138.6, 137.5, 128.7, 128.5, 128.4, 128.2, 127.6,
127.0, 102.1, 88.9, 77.7, 60.0, 52.5, 37.7, 33.4, 21.6; IR (film)
3000, 1750, 1700, 1500 cm-1; MS (CI, NH3) 367, 260, 231, 202,
189, 121, 101; HRMS (CI, NH3) ([M + H]+) calcd for C22H23O5
367.1545, found 367.1546.
(()-(1S ,6S )-6-(Ca r b oxym e t h yl)-1-m e t h yl-7-oxo-2,5-
d ioxa bicyclo[4.3.0]n on a n e (9) (Op tim ized ).22 A flame
dried round-bottom flask was equipped with a stir bar and
cooled in a glovebag under a nitrogen atmosphere. A solution
of diazo compound 4c (129 mg, 0.535 mmol) in dry benzene
was added via syringe. The solution was charged with
Cu(hfacac)2 (∼10 mg) and heated at 80 °C for 12 h. The
reaction mixture was poured into saturated aqueous NaHCO3
(30 mL) and extracted with Et2O (3 × 10 mL). The combined
ether extracts were dried over anhydrous Na2SO4 and con-
centrated in vacuo. The residue was chromatographed on
silica (5% EtOAc in hexane with 1% Et3N, Rf 0.17) to yield 9
(57.5 mg, 50%) as a pale yellow oil: 1H NMR (360 MHz, CDCl3)
δ 3.92 (m, 1H), 3.79 (s, 3H), 3.75-3.61 (m, 2H), 3.48 (m, 1H),
2.59-2.50 (m, 2H), 2.27 (m, 1H), 2.04 (m, 1H), 1.43 (s, 3H);
13C NMR (90 MHz, CDCl3) δ 212.0, 166.5, 87.1, 77.8, 62.4, 59.5,
53.0, 34.2, 32.0, 17.2; IR (film) 3000, 2800, 1800, 1700, 1550
cm-1; MS (EI) 214, 182, 155, 139, 127, 113, 99; HRMS (EI)
(M+) calcd for C10H14O5 214.0841, found 214.0842.
2800, 1700, 1650, 1100 cm-1; MS (EI) 214, 183, 171, 155, 139,
99; HRMS (EI) M+ calcd for C10H14O5 214.0841, found 214.0839.
tr a n s-4,5-Dieth yl-2-[4-(ca r boxym eth yl)-3-oxobu tyl]-2-
m et h yl-1,3-d ioxola n e (11). A solution of 5 (225 mg, 0.86
mmol) in anhydrous methanol (5 mL) was charged with 10%
palladium on carbon (10 mg), equipped with a balloon filled
with H2 gas, and stirred for 12 h and monitored periodically
by TLC. The reaction mixture was filtered through a plug of
silica and concentrated in vacuo. The residue was purified
by chromatography on silica (20% EtOAc in hexane) to yield
11 (145 mg, 64%) as an oil: 1H NMR (360 MHz, CDCl3) δ 3.65
(s, 3H), 3.53 (m, 1H), 3.41 (s, 2H), 3.38 (m, 1H), 2.69-2.52 (m,
2H), 1.95-1.90 (m, 2H), 1.52-1.41 (m, 4H), 1.28 (s, 3H), 0.95-
0.89 (m, 6H); 13C NMR (90 MHz, CDCl3) δ 201.4, 178.0, 107.2,
81.7, 80.7, 51.3, 47.8, 36.8, 32.8, 25.2, 24.8, 24.4, 9.4, 9.2; IR
(film) 3600 (br), 3050-2800, 1750, 1700, 1650 cm-1; MS (CI)
273, 257, 173, 155, 143, 129; HRMS (CI,CH4) ([M + H]+) calcd
for C14H25O5 273.1702, found 273.1698.
t r a n s-4,5-D ie t h y l-2-[4-(c a r b o x y m e t h y l)-4-d ia zo -3-
oxobu tyl]-2-m eth yl-1,3-d ioxola n e (12). A solution of 11
(245 mg, 0.9 mmol) and Et3N (0.3 mL, 2.4 mmol) in CH3CN (5
mL) was charged with 4-carboxybenzenesulfonazide (273 mg,
1.2 mmol) at room temperature and stirred for 2.5 h. The
reaction mixture was poured into saturated aqueous NaHCO3
(15 mL) and extracted with diethyl ether (3 × 10 mL). The
combined ether extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was chromatographed
on silica (20% EtOAc in hexane, Rf 0.21) to yield 12 (229 mg,
85%) as a bright yellow oil: 1H NMR (360 MHz, CDCl3) δ 3.80
(s, 3H), 3.58-3.45 (m, 2H), 3.02-2.81 (m, 2H), 2.02-1.95 (m,
2H), 1.57-1.45 (m, 4H), 1.32 (s, 3H), 0.99-0.91 (m, 6H); 13C
NMR (90 MHz, CDCl3) δ 192.4, 161.7, 108.4, 82.5, 81.6, 75.6,
52.1, 35.0, 34.2, 26.1, 25.8, 25.5, 10.3, 10.1; IR (film) 3000-
2800, 2200(s), 1750, 1650 cm-1; MS (CI, NH3) 299, 289, 273,
257, 245,199, 189, 173, 155, 143, 99, 55; HRMS (MH+) calcd
for C14H23N2O5 299.1607, found 299.1599.
(()-(1S,3S,4S,5S)-5-(Car boxym eth yl)-3,4-dieth yl-1-m eth -
yl-6-oxo-2,9-d ioxa bicyclo[3.3.1]n on a n e (13). A solution of
5 (50 mg, 0.19 mmol) in anhydrous methanol (5 mL) was
charged with 10% palladium on carbon (∼15 mg), equipped
with a balloon filled with H2 gas, and stirred for 12 h. The
reaction mixture was filtered through a plug of silica and
concentrated in vacuo. The residue was purified by chroma-
tography on silica (20% EtOAc in hexane) to yield compound
13 (26 mg, 50%) as an oil: 1H NMR (360 MHz, CDCl3) δ 3.78
(s, 3H), 3.33 (m, 1H), 2.74 (m, 1H), 2.64 (m, 1H), 2.50-2.42
(m, 2H), 2.16 (m, 1H), 1.61-1.38 (m, 7H), 0.95-0.90 (m, 6H);
13C NMR (90 MHz, CDCl3) δ 206.4, 166.6, 101.1, 87.8, 74.3,
52.9, 51.4, 37.5, 33.1, 28.4, 21.4, 20.8, 11.5, 10.3; IR (film) 3000,
2900, 1750, 1725 cm-1; MS (EI) 270, 215, 194, 185, 172, 141,
99; HRMS (EI) M+ calcd for C14H22O5 270.1467, found 270.1466.
2-(Ca r b oxym et h yl)-tr a n s-5,6-d iet h yl-3-(3-oxob u t yl)-
d ioxen e (15). A stirred solution of compound 12 (52 mg, 0.17
mmol) in dry benzene was charged with Cu(hfacac)2 (∼10 mg),
heated at 80 °C, and monitored by TLC until the starting
material was consumed. The reaction mixture was poured into
saturated NaHCO3 (10 mL) and extracted with diethyl ether
(3 × 10 mL). The combined ether extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue
was chromatographed on silica (20% EtOAc in hexane with
1% Et3N) to yield an acid-sensitive compound (14, 17 mg, 36%).
This compound isomerized quantitatively to dioxene 15 in
CDCl3: 1H NMR (360 MHz, CDCl3) δ 3.80 (s, 3H), 3.68 (m,
1H), 3.56 (m, 1H), 3.00-2.93 (m, 2H), 2.71-2.64 (m, 2H), 2.19
(s, 3H), 1.72-1.53 (m, 4H), 1.10-0.98 (m, 6H); 13C NMR (90
MHz, CDCl3) δ 207.2, 164.3, 148.5, 123.8, 78.3, 75.7, 51.5, 41.2,
29.7, 25.6, 23.9, 23.4, 9.4, 9.1; IR (film) 3000, 2900, 1750, 1700
cm-1; MS (EI) 270, 239, 227, 195, 169, 145; HRMS (EI) M+
calcd for C14H22O5 270.1467, found 270.1474.
2-(Car boxym eth yl)-3-(3-oxobu tyl)dioxen e (10). A stirred
solution of compound 4c (146 mg, 0.60 mmol) in dry benzene
was charged with Cu(hfacac)2 (∼20 mg), heated at 80 °C, and
monitored by TLC until the starting material was consumed.
The reaction mixture was poured into saturated aqueous
NaHCO3 (30 mL) and extracted with diethyl ether (3 × 10 mL).
The combined ether extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo to provide 128 mg of an
oil. A portion (77 mg) of this residue was chromatographed
on silica (5% EtOAc in hexane with 1% Et3N, Rf 0.18) to yield
9 (14 mg, 18%) and the acid-sensitive 8 (44 mg, 57%), which
isomerized quantitatively in chloroform to generate dioxene
10: 1H NMR (360 MHz, CDCl3) δ 4.16-4.12 (m, 2H) 4.09-
4.06 (m, 2H), 3.80 (s, 3H), 2.96-2.91 (m, 2H), 2.71-2.67 (m,
2H), 2.17 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 207.2, 164.0,
150.0, 125.5, 65.2, 63.2, 51.8, 41.1, 30.0, 25.7; IR (film) 3000,
2-[2-(Ca r boxym eth yl)eth yl]-2-m eth yl-1,3-d ioxa n e (16).
A solution of methyl levulinate (1) (3.13 g, 24.0 mmol), 1,3-
propanediol (2.28 g, 30.0 mmol), and trimethyl orthoformate
(3.25 mL, 30.0 mmol) in dry benzene (50 mL) was charged with
p-TsOH (∼20 mg) and stirred for 12 h. The mixture was
diluted with diethyl ether, washed with saturated NaHCO3,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
(22) The catalyst that was used had been rigorously dried.

3908 J . Org. Chem., Vol. 62, No. 12, 1997
Brogan et al.
residue was distilled at reduced pressure to yield 16 (1.9 g,
42%) as an oil: bp 75 °C, 0.5 mm; 1H NMR (360 MHz, CDCl3)
δ 3.85-3.79 (m, 4H), 3.64 (m, 3H), 2.45-2.40 (m, 2H), 2.03-
1.98 (m, 2H), 1.75 (m, 1H), 1.52 (m, 1H), 1.38 (s, 3H); 13C NMR
(90 MHz, CDCl3) δ 174.8, 98.5, 60.1, 51.9, 34.0, 28.7, 25.7, 21.0;
IR (film) 3000, 2800, 1750 (br), 1450 cm-1; MS (CI, C2H6) ([M
+ H]+) 189, 171, 145, 119, 99, 87, 83.
3-[2-(Ca r boxym eth yl)eth yl]-3-m eth yl-1,5-d ih yd r o-3H-
2,4-ben zod ioxep in (21). A stirred solution of benzene-
dimethanol (1.13 g, 8.2 mmol), trimethyl orthoformate (1.3 mL,
12 mmol), and p-TsOH (30 mg) in benzene (250 mL) was
distilled until the volume was reduced to 50 mL, at which time
methyl levulinate (1) (1.02 g, 7.80 mmol) was added. The
reaction was stirred at room temperature for 12 h and poured
into saturated NaHCO3. The solution was extracted with
ether (3 × 30 mL), dried over Na2SO4, and concentrated in
vacuo. The residue was chromatographed on silica (10%
EtOAc in hexane; Rf 0.18) to yield ketal 21 (995 mg, 51%): 1H
NMR (360 MHz, CDCl3) δ 7.22-7.02 (m, 4H), 4.85 (s, 4H), 3.71
(s, 3H), 2.51-2.43 (m, 2H), 2.20-2.15 (m, 2H), 1.45 (s, 3H);
13C NMR (90 MHz, CDCl3) δ 173.7, 138.0, 126.7, 126.1, 103.1,
64.8, 51.7, 31.3, 29.6, 20.8; IR (film) 3200, 3000, 1750, 1725,
1450 cm-1; MS (CI, C2H6) 251, 219, 149, 131, 99.
3-[4-(Car boxym eth yl)-3-oxobu tyl]-3-m eth yl-1,5-dih ydr o-
3H-2,4-ben zod ioxep in (22). Ketal 21 (635 mg, 2.7 mmol)
was treated with methanolic KOH (2 M, 30 mL) for 8 h,
acidified to pH 4.0 with saturated aqueous citric acid, and
extracted with diethyl ether (5 × 30 mL). The combined
organic extracts were carefully dried over anhydrous Na2SO4,
concentrated in vacuo, and dissolved in tetrahydrofuran.
Carbonyldiimidazole (438 mg, 2.7 mmol) was added in small
portions. In a separate flask, monomethyl malonate (515 mg,
4.4 mmol) was stirred in THF (10 mL), treated with Bu2Mg
(1.0 M in heptane, 2.2 mmol) at 0 °C, and allowed to warm to
room temperature. The two solutions were combined and
stirred for an additional 24 h, diluted with diethyl ether (20
mL), successively washed with aqueous NH4Cl, aqueous
NaHCO3, and brine, and finally concentrated in vacuo. The
residue was chromatographed on silica (20% EtOAc in hexane;
Rf 0.21) to yield 22 (543 mg, 69%): 1H NMR (360 MHz, CDCl3)
δ 7.20-7.14 (m, 4H), 4.82 (s, 4H), 3.75 (s, 3H), 3.50 (s, 2H),
2.73-2.67 (m, 2H), 2.19-2.12 (m, 2H), 1.45 (s, 3H); 13C NMR
(90 MHz, CDCl3) δ 201.9, 167.6, 137.9, 126.7, 126.1, 103.1,
64.7, 52.2, 49.1, 38.2, 29.9, 21.0; IR (film) 3200, 2950, 1800,
1750, 1250 cm-1; MS (CI, NH3) 293, 283, 275, 261, 243, 196,
173; HRMS (CI, NH3) ([M + H]+) calcd for C16H21O5 293.1389,
found 293.1380.
3-[4-(Ca r b oxym et h yl)-4-d ia zo-3-oxob u t yl]-3-m et h yl-
1,5-d ih yd r o-3H-2,4-ben zod ioxep in (23). A room-tempera-
ture solution of 22 (499 mg, 1.7 mmol) and Et3N (0.67 mL, 5.0
mmol) in CH3CN (10 mL) was charged with 4-carboxyben-
zenesulfonyl azide (467 mg, 2.0 mmol) and stirred for 2.5 h.
The reaction mixture was poured into saturated aqueous
NaHCO3 (15 mL) and extracted with diethyl ether (3 × 10 mL).
The combined ether washes were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was chromatographed
on silica (20% EtOAc in hexane, Rf 0.22) to yield 23 (492 mg,
91%): 1H NMR (360 MHz, CDCl3) δ 7.20-7.00 (m, 4H), 4.92-
4.86 (m, 4H), 3.85 (s, 3H), 3.06-2.99 (m, 2H), 2.22-2.18 (m,
2H), 1.49 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 192.0, 161.6,
138.0, 126.6, 126.0, 103.3, 75.8, 64.8, 52.1, 35.5, 30.5, 21.0; IR
(film) 3000, 2900, 2200(s), 1750, 1650 cm-1; MS (CI, NH3) 319,
273, 241, 219, 259, 199, 163, 119, 99; HRMS (MH+) calcd for
C16H19N2O5 319.1294, found 319.1296.
Tr icyclic Rin g-F u sed Com p ou n d 24. A stirred solution
of diazo compound 23 (72 mg, 0.24 mmol) in dry benzene was
charged with Cu(hfacac)2 (∼10 mg) and heated at 80 °C for 4
h. The cooled reaction mixture was charged with p-TsOH (20
mg) and H2O (1 mL) and heated for 4 h.23 The reaction
mixture was poured into saturated aqueous NaHCO3 (30 mL)
and extracted with diethyl ether (3 × 10 mL). The combined
ether extracts were dried over anhydrous Na2SO4 and con-
centrated in vacuo. The residue was chromatographed on
silica (10% EtOAc in hexane, Rf 0.22) to yield 24 (39 mg, 56%)
and 25 (13 mg, 19%): 1H NMR (360 MHz, CDCl3) δ 7.22-
2-[4-(Ca r b oxym e t h yl)-3-oxob u t yl]-2-m e t h yl-1,3-d i-
oxa n e (17). Ketal 16 (1.60 g, 8.5 mmol) was treated with
methanolic KOH (2 M, 50 mL) for 8 h, acidified to pH 4.0 with
saturated aqueous citric acid, and extracted with diethyl ether
(5 × 30 mL). The combined organic extracts were dried over
anhydrous Na2SO4, concentrated in vacuo, and dissolved in
tetrahydrofuran. Carbonyldiimidazole (1.76 g, 11 mmol) was
added in small portions while the solution was stirred. In a
separate flask, monomethyl malonate (1.12 g, 9.5 mmol) was
stirred in THF (10 mL), treated with Bu2Mg (1.0 M heptane,
4.75 mmol) at 0 °C, and allowed to warm to room temperature.
The mixtures were combined and stirred for 24 h, diluted with
diethyl ether (20 mL), successively washed with aqueous
NH4Cl, aqueous NaHCO3, and brine, and finally concentrated
in vacuo. The residue was chromatographed on silica (20%
EtOAc in hexane; Rf 0.19) to yield 17 (1.2 g, 61%): 1H NMR
(360 MHz, acetone-d6) δ 3.94-3.86 (m, 2H), 3.79-3.74 (m, 2H),
3.65 (m, 3H), 3.52 (s, 2H), 2.67-2.63 (m, 2H), 1.92-1.87 (m,
2H), 1.72 (m, 1H), 1.58 (m, 1H), 1.33 (s, 3H); 13C NMR (90
MHz, acetone-d6) δ 207.6, 172.9, 103.2, 64.5, 56.4, 53.8, 41.9,
38.2, 30.6, 24.9; IR (film) 3000, 2800, 1800, 1750 cm-1; MS
(CI, NH3) 231, 215, 199, 189, 173, 155, 101; HRMS (CI, NH3)
([M + H]+) calcd for C11H19O5 231.1231, found 231.1232.
2-[4-(Ca r b oxym et h yl)-4-d ia zo-3-oxob u t yl]-2-m et h yl-
1,3-d ioxa n e (18). A solution of 17 (740 mg, 3.2 mmol) and
Et3N (1.0 mL, 7.2 mmol) in CH3CN (10 mL) was charged with
4-carboxybenzenesulfonazide (953 mg, 4.2 mmol) at room
temperature and stirred for 2.5 h. The reaction mixture was
poured into saturated aqueous NaHCO3 (15 mL) and extracted
with diethyl ether (3 × 10 mL). The combined ether extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was chromatographed on silica (20% EtOAc in
hexane, Rf 0.21) to yield 18 (714 mg, 87%) as a bright yellow
oil: 1H NMR (360 MHz, CDCl3) δ 3.81-3.69 (m, 7H), 2.86-
2.81 (m, 2H), 1.93-1.88 (m, 2H), 1.62 (m, 1H), 1.43 (m, 1H),
1.27 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 192.1, 161.3, 98.0,
75.2, 59.3, 51.8, 34.1, 32.1, 25.0, 20.6; IR (film) 3000, 2900,
2200(s), 1750, 1650, 1450 cm-1; MS (CI, NH3) 257, 229, 216,
199, 117, 101, 94, 83, 64; HRMS (MH+) calcd for C11H19N2O5
257.1137, found 257.1135.
(()-(1S ,7S )-7-(Ca r b oxym e t h yl)-1-m e t h yl-8-oxo-2,6-
d ioxa bicyclo[5.3.0]d eca n e (19). A stirred solution of com-
pound 18 (252 mg, 0.98 mmol) in dry benzene was charged
with Cu(hfacac)2 (∼20 mg) and heated at 80 °C for 4 h. The
reaction mixture was poured into saturated aqueous NaHCO3
(30 mL) and extracted with diethyl ether (3 × 10 mL). The
combined ether washes were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was chromatographed on
silica (20% EtOAc in hexane, Rf 0.19) to yield 19 (217 mg, 97%)
as a pale yellow oil: 1H NMR (360 MHz, CDCl3) δ 4.05 (m,
1H), 3.95-3.82 (m, 2H), 3.76 (s, 3H), 3.75 (m, 1H), 2.62-2.45
(m, 2H), 2.25-1.96 (m, 4H), 1.45 (s, 3H); 13C NMR (90 MHz,
CDCl3) δ 212.1, 168.2, 91.9, 85.8, 64.7, 61.3, 52.8, 34.6, 34.0,
32.6, 19.2; IR (film) 3050, 2900, 1800, 1775, 1750 cm-1; MS
(EI) 228, 196, 169, 152, 140, 127, 119, 99; HRMS (EI) M+ calcd
for C11H16O5 228.0998, found 228.1007.
Sem ica r ba zon e of 19 (20). To a solution of semicarbazide‚
HCl and NaOAc in H2O (5 mL) was added compound 19
dissolved in 95% EtOH (3 mL). Additional EtOH was added
until the solution became homogeneous, and the mixture was
heated on a steam bath for 0.5 h. Semicarbazone 20 was
formed as a white precipitate upon cooling. Crystals suitable
for X-ray analysis24 were obtained by slow crystallization from
CCl4: mp > 225 °C dec; 1H NMR (360 MHz, CDCl3) δ 8.50 (s,
1H), 6.0 (br s, 1H), 5.2 (br s, 1H), 3.92-3.80 (m, 3H), 3.70-
3.61 (m, 4H), 2.58-2.40 (m, 2H), 2.10-1.89 (m, 4H), 1.30 (s,
3H); 13C NMR (90 MHz, CDCl3) δ 170.7, 157.6, 91.6, 86.4, 63.1,
60.6, 52.7, 35.9, 32.1, 25.4, 18.4.
(23) The bicyclic structure of 25 was easily destroyed by acidic
hydrolysis. Small amounts of 25 could be isolated by a nonacidic
workup followed by careful chromatography on silica.
(24) The author has deposited atomic coordinates for 6 and 20 with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Oxonium Ylides Generated from Ketals
J . Org. Chem., Vol. 62, No. 12, 1997 3909
7.02 (m, 4H), 5.39 (d, 1H, J ) 13.9 Hz), 5.05 (d, 1H, J ) 13.5
Hz), 4.88 (d, 1H, J ) 13.5 Hz), 4.70 (d, 1H, J ) 13.9 Hz), 3.78
(s, 3H), 2.64-2.50 (m, 2H), 2.26-2.20 (m, 2H), 1.55 (s, 3H);
13C NMR (90 MHz, CDCl3) δ 212.0, 169.0, 136.8, 135.8, 128.5,
127.9, 127.5, 127.1, 90.3, 83.2, 71.3, 68.0, 52.7, 36.4, 34.8, 20.8;
IR (film) 3000, 2800, 1800, 1700 cm-1; MS (CI, NH3) 291, 273,
119, 104, 78; HRMS (CI, NH3) ([M + H]+) calcd for C16H19O5
291.1232, found 291.1236.
Ack n ow led gm en t. We would like to acknowledge
the University of New Hampshire for financial support
in the form of a Biomedical Research Support Grant (2
S07 RR07108-20).
Su p p or tin g In for m a tion Ava ila ble: 1H spectra of 2a -
c, 3a -c, 4a -c, and 5-24 and 13C NMR spectra of 2a -c, 3a -
c, 4a -c, 5-13, and 15-24 (57 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.
Br id ged tr icyclic com p ou n d 25: 1H NMR (360 MHz,
CDCl3) δ 7.25-7.03 (m, 4H), 5.35 (d, 1H, J ) 15 Hz), 4.6 (d,
1H, J ) 15 Hz), 4.1 (d, 1H, J ) 16.8 Hz), 3.2 (d, 1H, J ) 16.8
Hz), 3.85 (s, 3H), 3.2 (d, 1H, J ) 16.8 Hz), 2.1-2.2 (m, 2H),
1.8-1.9 (m, 2H), 1.75 (s, 3H); 13C NMR (90 MHz, CDCl3) δ
168.3, 137.7, 133.9, 130.7, 127.1, 126.8, 126.2, 109.8, 89.7, 66.9,
52.9, 36.8, 35.5, 32.1, 18.4; MS (EI) 290, 220, 203, 143, 128,
73, 43.
J O961896M