Studies in bicyclo[3.1.0]hexane methanolysis. Ring opening of activated cyclopropanes under acidic and basic conditions

Article abstract of DOI:10.1021/jo025909+

A bicyclo[3.1.0]hexane, with one cyclopropane carbon flanked by a ketone and an ester or an aldehyde, undergoes methanolysis with cleavage of one of the two activated cyclopropane bonds, depending on the reaction conditions. Acidic conditions yield primarily or exclusively a 4-methoxycyclohexane, while basic conditions yield a 3-methoxymethylcyclopentanone.

Full text of DOI:10.1021/jo025909+

SCHEME 1. Retr osyn th etic Ap p r oa ch to Op tica lly
Active P yr id on e 1
Stu d ies in Bicyclo[3.1.0]h exa n e
Meth a n olysis. Rin g Op en in g of Activa ted
Cyclop r op a n es u n d er Acid ic a n d Ba sic
Con d ition s
Yeon-Hee Lim, Kevin F. McGee, J r., and
Scott McN. Sieburth*
Department of Chemistry, 1901 N. 13th Street,
Temple University, Philadelphia, Pennsylvania 19122
sieburth@astro.temple.edu
Received May 6, 2002
Abst r a ct : A bicyclo[3.1.0]hexane, with one cyclopropane
carbon flanked by a ketone and an ester or an aldehyde,
undergoes methanolysis with cleavage of one of the two
activated cyclopropane bonds, depending on the reaction
conditions. Acidic conditions yield primarily or exclusively
a 4-methoxycyclohexane, while basic conditions yield a
3-methoxymethylcyclopentanone.
TABLE 1. Meth a n olysis of Bicyclo[3.1.0]h exa n e
Der iva tives
Cyclopropanes are key intermediates in many syn-
thetic strategies because of their ready availability and
high reactivity,1 and methods for asymmetric synthesis
of cyclopropanes have enhanced their importance.2 Among
the useful reactivities of cyclopropanes is ring opening
by nucleophiles when the cyclopropane is activated by
one or more electron-withdrawing groups.3 The stereo-
electronic predictability of this reaction and its selective
stereochemical result account for its utility in a broad
set of syntheses.4
As part of an ongoing investigation,5 we required
enantiomerically pure pyridone 1 and anticipated that
the retrosynthetic approach in Scheme 1 would generate
it expeditiously from cyclopropane 3. The attractive
attributes of this approach included carbonyls properly
positioned for a standard pyridone annulation6 and
stereochemistry derived from an asymmetric intramo-
lecular cyclopropanation of 4, which can be prepared in
* Phone: 215-204-7916. Fax: 215-204-1532.
(1) Carbocyclic Three- and Four-Membered Ring Compounds. In
Methods of Organic Chemistry (Houben-Weyl); de Meijere, A., Ed.;
Verlag: New York, 1997; Vols. E17a,b. Small Ring Compounds in
Organic Synthesis VI. In Topics in Current Chemistry; de Meijere, A.,
Ed.; Springer: New York, 2000; Vol. 207.
(2) Doyle, M. P. In Catalysis by Di- and Polynuclear Metal Cluster
Complexes; Adams, R. D., Cotton, F. A., Eds.; Wiley-VCH: New York,
1998; pp 249-282.
a
b
Cis:trans ratio ) 1.7:1. Cis:trans ratio ) 1.3:1.
two steps from acetoacetate. Despite ample precedent for
production of molecules such as 2 from 3, we report here
that the cyclopropane bond of 3 that is cleaved during
methanolysis is highly dependent on the reaction condi-
tions and the nature of the attached functional group.
Our studies began with methyl ester 5 and the use of
acidic conditions (Table 1, entry 1). Reflux of 5 in
methanol with catalytic p-toluenesulfonic acid gave not
one but two methanolysis products in nearly equal
quantities. These were readily identified as 6 and 7 by
(3) von Angerer, S. In Carbocyclic Three- and Four-Membered Ring
Compounds; de Meijere, A., Ed.; Methods of Organic Chemistry
(Houben-Weyl); Verlag: New York, 1997; Vol. E17c, pp 2041-2120.
(4) For recent examples of syntheses employing bicyclo[3.1.0]hexane
cleavages, see: Aavula, B. R.; Cui, Q.; Mash, E. A. Tetrahedron:
Asymmetry 2000, 11, 4681-4686. Taber, D. F.; Kanai, K. J . Org. Chem.
1999, 64, 7983-7987. He, M.; Tanimori, S.; Nakayama, M. Biosci.
Biotechnol. Biochem. 1995, 59, 900-902. Tanimori, S.; Niki, T.; He,
M.; Nakayama, M. Heterocycles 1994, 38, 1533-1540. Shimizu, I.;
Ishikawa, T. Tetrahedron Lett. 1994, 35, 1905-1908.
1
NMR spectroscopy, particularly the H and DEPT spec-
tra. The expected chemical shifts of the methylene and
methine carbons were distinctive in the DEPT; the proton
(5) McGee, K. F., J r.; Al-Tel, T. H.; Sieburth, S. McN. Synthesis 2001,
1185-1196.
(6) Mariella, R. P. Org. Synth. 1963, C. V. 4, 210-212.
10.1021/jo025909+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/06/2002
J . Org. Chem. 2002, 67, 6535-6538
6535

NMR spectrum of 6 has a two-proton ABX pattern for
the methylene ether protons, whereas a single methine
ether proton is found in the 1H spectrum of 7. IR
spectroscopy was also supportive, with ketone absor-
bances at 1757 and 1717 cm-1 for 6 and 7, respectively.
Both 6 and 7 were single isomers. Compound 7 exists
primarily as the enol, partly on the basis of the pres-
the use of magnesium methoxide, entry 3. The use of this
base is simplifying, as methanol is usually dried by
heating to reflux over magnesium turnings. Following the
dissolution of magnesium metal in methanol at reflux,
addition of 5 directly to this mixture led to the most
favorable results. After a 30 min reaction time, the
starting 5 was fully consumed and the methanolysis
products were isolated in 84% yield, with a nearly 90%
selectivity for 6.
1
ence of a well-defined single proton at 12 ppm in the H
NMR spectrum. In contrast, cyclopentanone 6 is a ketone
with a methine doublet between the carbonyls clearly
visible in the H NMR spectrum. The coupling constant
for this doublet (10 Hz) does not allow for determination
of the stereochemistry, however, which is assumed to be
trans.
The selectivity of the ring opening by the alkoxides is
likely due to the need for both ketone and ester π-orbitals
to align with the breaking cyclopropane bond. Only one
cyclopropane bond can easily align with the ketone
π-bond. Nevertheless, the bond selectivity is not complete,
even under the basic cleavage conditions.
Stereoelectronics are expected to dominate in the bond
cleavage of activated cyclopropanes. For bicyclo[3.1.0]-
hexanes, we are only aware of two studies reporting
competitive cleavage of the central bond.8 Both cases
involve acidic conditions and a halogen nucleophile
(pyridinium halides and TMSBr), but the selectivities for
the internal bond cleavage are not as high as that
reported here. Tricyclic ring systems provide additional
examples of ring cleavage diversity.9 The role played by
conformation in the stereoelectronic bias for cyclopropane
bond cleavage can most clearly be found in the work of
Caine et al.10
1
While the mixture of 6 and 7 was understandable as a
balance of steric effects favoring 6 and carbocation
stability favoring 7, the formation of substantial amounts
of the latter was surprising. The overlap of cyclopro-
pane bonds with the ketone π-bonds would be expected
to strongly favor 6. To account for this outcome, we
reasoned that the ester of 5 is the strongest Lewis base
and that its conformational freedom might be the deter-
mining factor in the cyclopropane bond cleavage. We
therefore reduced ketoester 5 to keto aldehyde 8, antici-
pating that this would have two desirable effects: the
ketone would be the stronger Lewis base and would
thereby direct the methanolysis, and the product 9 would
be at the proper oxidation state for subsequent pyridone
annulation.
The ability to select for either a five- or six-membered
ring product from bicyclo[3.1.0]hexane should enhance
the value of these readily available cyclopropane inter-
mediates. Additional studies are in progress.
Treatment of keto aldehyde 8 with acidic methanol also
led to two products, entry 4, neither of which were
cyclopentanones! Each had a single methine ether proton
1
in their H NMR spectra and IR absorptions of 1716 and
Exp er im en ta l Section
1713 cm-1. Under these reaction conditions, the aldehyde
was simultaneously converted to an acetal, and it ap-
peared that the rate of acetal formation was competitive
with cyclopropane ring cleavage. To separate these two
processes, we converted aldehyde 8 to the acetal 12 using
trimethylorthoformate and then subjected this adduct to
acidic methanolysis conditions. Use of acetal 12 improved
the methanolysis yield, but again led only to a mixture
of cis and trans isomers of 10, entry 6. This selectivity is
inconsistent with involvement of the ketone in 12 and is
likely driven by a carbocation derived from the acetal.
The cis and trans isomers of 10, designated as 10a and
10b, are presumably kinetically derived isomers.
One additional attempt to bias the orbital alignment
of the free-rotating carbonyl was to condense 8 with
cyanoacetamide, entry 5. Condensation of acetamide with
the aldehyde and ketone before cyclopropane cleavage
would form an aza-analogue of the CC-1065 cyclopropane,
a structure known to open with methanol to give a
methoxymethyl-substituted cyclopentane in high yield.7
Unfortunately, this condensation/methanolysis combina-
tion gave tetrahydroquinolone 11 as the only identifiable
product.
2-Dia zo-3-oxo-6-h ep t en oic Acid Met h yl E st er (4, R )
m eth yl).11 To a solution of methyl 3-oxo-6-heptenoate12 (870 mg,
5.6 mmol) in acetonitrile (28 mL) was added triethylamine (1.01
mL, 7.3 mmol) followed by the addition of p-acetamidobenzene-
sulfonyl azide13 (1.74 g, 7.3 mmol). A white precipitate formed
within 5 min. After stirring for 2 h, the reaction mixture was
washed with saturated NH4Cl, and the aqueous layer was
extracted with ether. The combined organics were washed with
10% KOH, saturated NaHCO3, and saturated NaCl, dried over
anhydrous MgSO4, concentrated in vacuo to give 4 (993 mg, 98%)
as a clear liquid, and used without purification. 1H NMR
(CDCl3): δ 5.76 (ddt, J ) 17.1, 10.5, 6.0 Hz, 1H), 5.02-4.89 (m,
2H), 3.77 (s, 3H), 2.88 (t, J ) 6.0 Hz, 2H), 2.31 (dd, J ) 14.4, 6.6
Hz, 2H). 13C NMR (CDCl3): δ 191.8, 161.5, 136.7, 115.2, 52.0,
39.1, 28.0.
(8) Giacomini, E.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. J . Org.
Chem. 1980, 45, 519-522. Mash, E. A. J . Org. Chem. 1987, 52, 4142-
4143. See also: Rigby, J . H.; Senanayake, C. J . Org. Chem. 1988, 53,
440-443.
(9) Monti, S. A.; Bucheck, D. J .; Shepard, J . C. J . Org. Chem. 1969,
34, 3080-3084. Demuth, M.; Raghavan, P. R. Helv. Chim. Acta 1979,
62, 2338-2340. Miller, R. D.; McKean, D. R. J . Org. Chem. 1981, 46,
2412-2414. Demuth, M.; Mikhail, G. Tetrahedron 1983, 39, 991-997.
Imanishi, T.; Yamashita, M.; Matsui, M.; Tanaka, T.; Iwata, C. Chem.
Pharm. Bull. 1989, 37, 3114-3116. Fernandez-Mateos, A.; Alonso, J .
J . P.; Gonzalez, R. R. Tetrahedron 1999, 55, 847-860.
(10) Caine, D.; Boucugnani, A. A.; Chu, C.-Y.; Graham, S. L.; Troy
L. Smith, J . Tetrahedron Lett. 1978, 2667-2670.
The use of basic conditions proved to be much more
selective for the desired 6. Treatment of ester 5 with
sodium methoxide led to a rapid ring opening, entry 2;
however, the yield for this transformation was modest.
In an effort to employ milder conditions, we turned to
(11) Taber, D. F.; Amedio, J . C., J r.; Sherrill, R. G. J . Org. Chem.
1986, 51, 3382-3384.
(12) Deslongchamps, P.; Rowan, D. D.; Pothier, N.; Saunders, J . K.
Can. J . Chem. 1981, 59, 1122-1131. Hayes, T. K.; Villani, R.; Weinreb,
S. M. J . Am. Chem. Soc. 1988, 110, 5533-5543. Snider, B. B.; Patricia,
J . J . J . Org. Chem. 1989, 54, 38-46.
(7) Boger, D. L.; Garbaccio, R. M.; J in, Q. J . Org. Chem. 1997, 62,
8875-8891.
(13) Baum, J . S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709-1716.
6536 J . Org. Chem., Vol. 67, No. 18, 2002

2-Oxo-bicyclo[3.1.0]h exan e-1-car boxylic Acid Meth yl Es-
ter (5).14 To a -15 °C solution of 4 (663 mg, 3.64 mmol) in
methylene chloride (2 mL) was added Rh2(AcO)4 (6.43 mg,
0.15 mmol), and the green reaction mixture was allowed to
stir overnight. The solution was concentrated in vacuo and
purified over silica gel (1:1 ethyl acetate/hexanes) to yield 5
(550 mg, 98%) as a tan oil. Rf ) 0.5 (1:1 ethyl acetate/hex-
anes). 1H NMR (CDCl3): δ 3.70 (s, 3H), 2.59-2.53 (m, 1H),
2.39-2.11 (m, 3H), 2.03-1.93 (m, 2H), 1.36 (t, J ) 5.1 Hz, 1H).
13C NMR (CDCl3): δ 206.9, 168.8, 52.2, 37.5, 33.5, 33.0, 22.2,
20.8.
1-Hyd r oxym eth yl-bicyclo[3.1.0]h exa n -2-ol. To a -20 °C
suspension of LiAlH4 (2.29 g, 57.2 mmol) in ether (102 mL)
was added dropwise a solution of 5 (2.205 g, 14.3 mmol) in
ether (3 mL). After 3 h, the reaction was brought to room
temperature for 1 h. Ethyl acetate (2 mL) was carefully added,
followed by water (2 mL), 15% NaOH (2 mL), and then water (3
mL). The mixture was filtered and the residue washed with
ether. The combined organic phases were washed with water
and brine solution, dried over anhydrous MgSO4, and concen-
trated in vacuo. Flash chromatography (1:19 methanol/methyl-
ene chloride) gave the title compound (1.68 g, 92%) as a clear
liquid. Rf ) 0.2 (2:98 methanol/methylene chloride). 1H NMR
(CDCl3): δ 4.48 (t, J ) 8.3 Hz, 1H), 3.76 (d, J ) 11.4 Hz, 1H),
3.50 (d, J ) 11.4 Hz, 1H), 3.47 (bs, 2H), 1.85 (m, 1H), 1.69 (m,
2H), 1.14 (m, 2H), 0.80 (t, J ) 4.6 Hz, 1H), 0.39 (dd, J ) 7.9, 5.3
Hz, 1H). 13C NMR (CDCl3): δ 75.8, 66.8, 33.6, 28.7, 23.7, 20.8,
8.64.
2-Oxo-bicyclo[3.1.0]h exa n e-1-ca r ba ld eh yd e (8). To a -78
°C solution of oxalyl chloride (860.7 µL, 9.86 mmol) in meth-
ylene chloride (25 mL) was added over 10 min a solution of
DMSO (1.4 mL, 19.7 mmol) in methylene chloride (1 mL), and
the mixture was stirred for an additional 10 min. A solution
of 1-hydroxymethyl-bicyclo[3.1.0]hexan-2-ol (632.3 mg, 4.93
mmol) in DMSO (3 mL) was added. After the mixture was stirred
for 25 min, triethylamine was added dropwise. After an ad-
ditional 15 min at -78 °C, the mixture was warmed to room
temperature. Following addition of water, the organic phase was
washed successively with 1% HCl and 5% NaHCO3. The aqueous
phase was extracted with methylene chloride. The combined
organics were dried over anhydrous MgSO4, concentrated in
vacuo, and purified by flash chromatography (2:98 methanol/
methylene chloride) to give 8 (441.8 mg, 72%). Rf ) 0.13
(1:5 ethyl acetate/hexane). 1H NMR (CDCl3): δ 10.1 (s, 1H), 2.70
(m, 1H), 2.26-2.21 (m, 3H), 2.04-2.01 (m, 2H), 1.60 (t, J ) 10
Hz, 1H). 13C NMR (CDCl3): δ 215.7, 197.1, 169.8, 35.1, 33.8,
27.2, 21.9.
1659, 1618, 1443, 1281, 1206, 736 cm-1. MS (DCI) m/z (%): 187
(M + H, 60), 155 (100). Exact mass calcd for C9H14O4: 186.0892.
Found: 186.0888.
2-Dim eth oxym eth yl-4-m eth oxy-cycloh exan on es (10a an d
10b). Following a procedure identical to that described for 6 and
7 from 5 with p-toluenesulfonic acid, aldehyde 8 (73.2 mg, 0.58
mmol) gave a mixture that was purified by flash chromatog-
raphy (1:3 ethyl acetate/hexane) to give 10a (47.6 mg) and 10b
(28.5 mg). Compound 10a : Rf ) 0.2 (1:3 ethyl acetate/hexane).
1H NMR (CDCl3): δ 4.79 (d, J ) 6 Hz, 1H), 3.52 (m, 1H), 3.35
(s, 3H), 3.34 (s, 3H), 3.33 (s, 3H), 2.58 (m, 1H), 2.39 (m, 1H),
2.23 (m, 2H), 2.10 (m, 1H), 1.69-1.74 (m, 2H). 13C NMR
(CDCl3): δ 211.7, 104.1, 56.9, 55.8, 48.8, 38.6, 32.2, 31.7, 30.6,
30.3. ΙR (KBr mull): 2930, 1716, 1456, 1374, 1104, 1070 cm-1
.
MS (DCI) m/z (%): 187 (M + H, 50), 155 (100), 99 (55). MS (CI+)
m/z (%): 202.1 (M), 171.1 (M - OCH3, 100). Exact mass calcd
for C10H18O4: 202.1204. Found: 202.1210. Compound 10b: Rf
) 0.5 (1:5 ethyl acetate/hexane). 1H NMR (CDCl3): δ 4.7 (d, J
) 4 Hz, 1H), 3.68 (bs, 1H), 3.37 (s, 3H), 3.35 (s, 3H), 3.33 (s,
3H), 3.25 (m, 1H), 2.88 (m, 1H), 2.52 (m, 1H), 2.26 (m, 1H), 2.19-
2.11 (m, 2H), 1.70 (m, 1H). 13C NMR (CDCl3): δ 206.0, 105.1,
56.5, 52.5, 39.6, 33.1, 32.7, 30.1, 28.2, 26.5. ΙR (KBr mull): 2933,
1713, 1268, 1071, 737 cm-1. MS (CI+) m/z (%): 202.1 (M), 171.1
(M - OCH3, 100). Exact mass calcd for C10H18O4: 202.1204.
Found: 202.1209.
1-Dim eth oxym eth yl-bicyclo[3.1.0]h exa n -2-on e (12). To a
solution of keto aldehyde 8 (87 mg, 0.708 mmol) in methanol
(1.5 mL) was added trimethyl orthoformate (116 mg, 1.06 mmol)
and p-toluenesulfonic acid (14 mg, 0.071 mmol) at room tem-
perature. After 30 min, the mixture was poured into a mixture
of saturated NaHCO3 and ether. The organic phase was washed
with saturated NaCl, dried MgSO4, and concentrated in vacuo.
Purification by flash chromatography (1:199 methanol/methyl-
ene chloride) gave 12 (88 mg, 73%) as a colorless oil. Rf ) 0.6
(1:99 methanol/methylene chloride). 1H NMR (CDCl3): δ 4.85
(s, 1H), 3.33 (s, 3H), 3.28 (s, 3H), 2.18 (m, 1H), 2.07 (m, 2H),
2.03 (m, 1H), 1.89 (m, 1H), 1.37 (m, 1H), 0.90 (t, J ) 9 Hz, 1H).
13C NMR (CDCl3): δ 206.7, 56.8, 55.8, 52.2, 37.5, 33.5, 33.0, 22.2,
20.8.
2-Dim eth oxym eth yl-4-m eth oxy-cycloh exan on es (10a an d
10b). Following a procedure identical to that described for 6 and
7, acetal 12 (99.2 mg, 0.58 mmol) gave a mixture that was
purified by flash chromatography (1:3 ethyl acetate/hexane) to
give 10a (52.0 mg) and 10b (41.6 mg).
6-Meth oxy-2-oxo-1,2,5,6,7,8-h exa h yd r o-qu in olin e-3-ca r -
bon itr ile (11). To a solution of 8 (52 mg, 0.42 mmol) in meth-
anol (4 mL) was added cyanoacetamide (38 mg, 0.45 mmol), a
mixture of acetic acid and piperidine in methanol (180 µL, 0.18
mmol), and p-toluenesulfonic acid (79.7 mg, 0.42 mmol). The
mixture was heated to reflux for 3 h. The resulting red wine
mixture was cooled to 0 °C, and glacial acetic acid was added
until the solution was pH 5.5. The reaction mixture was diluted
with methylene chloride and water. The organic phase was
washed with saturated NaCl, dried over MgSO4, concentrated
in vacuo, and purified by flash chromatography (1:19 meth-
anol/methylene chloride) to give 11 (22 mg, 23%). Rf ) 0.5
(1:19 methanol/methylene chloride). 1H NMR (CDCl3): δ 13.5
(bs, N-1H), 7.64 (s, 1H), 3.71 (m, 1H), 3.39 (s, 3H), 2.91 (m,
1H), 2.80 (m, 1H), 2.76 (d, J ) 3.6 Hz, 1H), 2.66-2.61 (m,
1H), 2.08 (m, 1H), 1.94 (m, 1H). 13C NMR (CDCl3): δ 162.7,
150.8, 150.3, 116.1, 113.1, 101.8, 73.4, 56.4, 31.7, 24.9, 24.2. ΙR
(KBr mull): 3853, 3649, 2922, 2831, 2226, 1652, 1265, 1095,
736 cm-1. MS (FAB+) m/z (%): 205 (M + H, 100), 154.2 (35).
Exact mass calcd for C11H13N2O2 (M + H): 205.0977. Found:
205.077.
2-Met h oxym et h yl-5-oxo-cyclop en t a n eca r b oxylic Acid
Meth yl Ester (6) a n d 2-Hyd r oxy-5-m eth oxy-cycloh ex-1-
en eca r boxylic Acid Meth yl Ester (7). To a room temperature
solution of sodium methoxide, prepared from sodium (290 mg,
12.1 mmol) and methanol (11 mL), was added 5 (233 mg, 1.51
mmol) in methanol (1 mL). After 30 min, the reaction mixture
was poured into saturated NH4Cl and the aqueous phase was
extracted with ether. The combined organic phases were washed
with saturated NaCl, dried over MgSO4, filtered, concentrated,
2-Met h oxym et h yl-5-oxo-cyclop en t a n eca r b oxylic Acid
Meth yl Ester (6) a n d 2-Hyd r oxy-5-m eth oxy-cycloh ex-1-
en eca r boxylic Acid Meth yl Ester (7). To a solution of 5 (110.4
mg, 0.716 mmol) in methanol (10 mL) was added p-toluene-
sulfonic acid (133 mg, 0.716 mmol), and the mixture was heated
to reflux for 5 h. After cooling to room temperature, the mixture
was concentrated on a rotary evaporator and diluted with ethyl
acetate and water, and the resulting aqueous phase was
extracted with ether. The combined organic phases were dried
over anhydrous MgSO4, concentrated, and purified by flash
chromatography (1:5 ethyl acetate/hexane) to give 6 (49.3 mg)
and 7 (54.1 mg). Com p ou n d 6: Rf ) 0.2 (1:5 ethyl acetate/
1
hexane). H NMR (CDCl3): δ 3.69 (s, 3H), 3.38 (m, 2H), 3.27 (s,
3H), 3.05-3.03 (d, J ) 10.0 Hz, 1H), 2.81 (m, 1H), 2.35 (m, 1H),
2.27 (m, 1H), 2.09 (m, 1H), 1.65 (m, 1H). 13C NMR (CDCl3): δ
211.7, 169.8, 74.5, 59.4, 58.5, 52.8, 41.5, 38.0, 24.2. ΙR (KBr
mull): 2953, 2881, 2360, 1757, 1729, 1437, 1114 cm-1. MS (DCI)
m/z (%): 187 (M + H, 50), 155 (100), 99 (55). Exact mass calcd
for C9H15O4 (M + H): 187.0970. Found: 187.0968. Com p ou n d
1
7: Rf ) 0.5 (1:5 ethyl acetate/hexane). H NMR (CDCl3): δ 12.0
(s, 1H), 3.75 (s, 3H), 3.50 (m, 1H), 3.36 (s, 3H), 2.50 (dd, J ) 4.7,
1.0 Hz, 1H), 2.35 (m, 1H), 2.23 (m, 1H), 2.18 (m, 1H), 1.79 (m,
1H), 1.76 (m, 1H). 13C NMR (CDCl3): δ 206.0, 170.8, 94.9, 74.5,
56.5, 52.5, 28.2, 26.5, 26.3. ΙR (KBr mull): 2951, 1746, 1717,
(14) Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J . Am. Chem.
Soc. 1989, 111, 6443-6444.
J . Org. Chem, Vol. 67, No. 18, 2002 6537

and purified by flash chromatography (1:5 ethyl acetate/hexane)
to give 6 (112 mg, 40%) and 7 (13 mg, 4.6%).
ethyl acetate/hexanes) to give 6 (1.09 g, 75%) and 7 (122 mg,
8.4%).
2-Met h oxym et h yl-5-oxo-cyclop en t a n eca r b oxylic Acid
Meth yl Ester (6) a n d 2-Hyd r oxy-5-m eth oxy-cycloh ex-1-
en eca r boxylic Acid Meth yl Ester (7). Mg turnings (1.90 g,
0.078 g atom) in methanol (56 mL) were heated to reflux for 1
h, and the resulting white suspension was cooled to room
temperature. Ketone 5 (1.2 g, 7.8 mmol) in methanol (3 mL) was
added dropwise. After 30 min, 10% HCl was added and the
aqueous phase was extracted with ether. The combined organic
phases were washed with saturated NaCl, dried over MgSO4,
filtered, concentrated, and purified by flash chromatography (1:5
Ack n ow led gm en t. Support of the National Insti-
tutes of Health is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Proton NMR spectra
for all new products. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O025909+
6538 J . Org. Chem., Vol. 67, No. 18, 2002