Cyclopropyl building blocks for organic synthesis, part 100.[?] Advanced syntheses of cyclopropylideneacetates - Versatile multifunctional building blocks for organic synthesis

Article abstract of DOI:10.1002/adsc.200404025

A well reproducible and inexpensive preparation of the cyclopropylideneacetates 2-4 has been developed. The key intermediate 2-(1′-mesyloxycyclopropyl)acetic acid (8), produced either from methyl phenylacetate (1) or 3,3-dimethoxypropionate (5-Me) and 3,3-diethoxypropionate (5-Et) in a sequence of Kulinkovich reductive cyclopropanation, mesylation and oxidative cleavage or cleavage and oxidation, respectively, was either converted to the benzyl ester 11b, or chlorinated (brominated) via the in situ formed acid chloride. The α-chloro- 12a and α-bromo ester 12b were dehydromesylated by treatment with triethylamine to furnish methyl 2-chloro-2-cyclopropylideneacetate (3-Me) and the 2-bromo analogue 4-Me with an overall yield of 68% (65%, 68%) and 52% (49%, 51%) respectively, starting from 1 (5-Me, 5-Et). The parent benzyl cyclopropylideneacetate 2-Bn was obtained by dehydromesylation of 11b with potassium t-butoxide in t-butyl methyl ether with an overall yield of 60% (57%, 9%) from 1 (5-Me, 5-Et).

Full text of DOI:10.1002/adsc.200404025

FULL PAPERS
Cyclopropyl Building Blocks for Organic Synthesis, Part 100.[≥]
Advanced Syntheses of Cyclopropylideneacetates Versatile
Multifunctional Building Blocks for Organic Synthesis
Michael Limbach, Suryakanta Dalai, Armin de Meijere*
Institut f¸r Organische und Biomolekulare Chemie, Georg-August-Universit‰t Gˆttingen, Tammannstrasse 2,
37077 Gˆttingen, Germany
Fax: (þ49)-551-394-795, e-mail: ameijer1@gwdg.de
Received: January 27, 2004; Accepted: April 30, 2004
Dedicated to Dr. Joe P. Richmond on the occasion of his 60th birthday.
Abstract: A well reproducible and inexpensive prepa- triethylamine to furnish methyl 2-chloro-2-cyclopro-
ration of the cyclopropylideneacetates 2 4 has been pylideneacetate (3-Me) and the 2-bromo analogue
developed. The key intermediate 2-(1’-mesyloxycy- 4-Me with an overall yield of 68% (65%, 68%) and
clopropyl)acetic acid (8), produced either from meth- 52% (49%, 51%) respectively, starting from 1 (5-Me,
yl phenylacetate (1) or 3,3-dimethoxypropionate (5- 5-Et). The parent benzyl cyclopropylideneacetate 2-
Me) and 3,3-diethoxypropionate (5-Et) in a sequence Bn was obtained by dehydromesylation of 11b with
of Kulinkovich reductive cyclopropanation, mesyla- potassium t-butoxide in t-butyl methyl ether with an
tion and oxidative cleavage or cleavage and oxidation, overall yield of 60% (57%, 9%) from 1 (5-Me, 5-Et).
respectively, was either converted to the benzyl ester
11b, or chlorinated (brominated) via the in situ
formed acid chloride. The a-chloro- 12a and a-bromo Keywords: building blocks; molecular diversity; small
ester 12b were dehydromesylated by treatment with ring systems; synthetic methods; titanium
Introduction
surrogate do not really provide good yields of the prod-
ucts 2 and 4, respectively.
Acceptor-activated methylenecyclopropanes like alkyl
With the more recently developed conversion of car-
cyclopropylideneacetates (2),[1] 2-chloro-2-cyclopropy- boxylic acid esters to cyclopropanols, the so-called Ku-
lideneacetates (3)[2] and 2-bromo-2-cyclopropylidenea- linkovich reaction[9] in hand, it appeared feasible to em-
cetates (4)[3] are valuable building blocks for organic bark on a second-generation access to these reactive
synthesis.[4] Due to their enhanced reactivities and their methylenecyclopropanes 2 4 (Scheme 1).
multifunctionalities, they can be applied in a broad sense
towards elegant syntheses of spirocyclopropanated car-
bo-[5] and heterocycles,[6] various cyclopropyl group- Results and Discussion
containing amino acids[7] as well as potentially biologi-
cally active conformationally restricted peptide mim- Having the 2-(1’-mesyloxycyclopropyl)acetic acid (8) in
ics.[8]
mind as a key intermediate, the two precursors 1 and 5-R
Unfortunately, all of these building blocks so far have with masked carboxyl groups were considered.
not really been easily available. The known five-step
preparation of the chloro derivative 3, although reason-
ably productive and easily scalable, requires a halide-re-
sistant autoclave for the third step, and the overall atom
economy is rather poor. The previously developed syn-
thesis of the bromo derivative 4 and of the parent com-
pound 2 both start from cyclopropanone ethyl hemiace-
tal, the preparation of which requires the generation as
well as handling of finely dispersed sodium, and the Wit-
tig olefinations with the appropriately substituted tri-
phenylmethylenephosphoranes of the cyclopropanone propylideneacetates 2 4.
Scheme 1. Retrosynthetic considerations concerning cyclo-
760
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/adsc.200404025
Adv. Synth. Catal. 2004, 346, 760 766

Syntheses of Cyclopropylideneacetates
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Scheme 2. Preparation of 2-(1’-mesyloxycyclopropyl)acetic
acid (8) from methyl phenylacetate (1).
Scheme 4. Transformation of 8 to cyclopropylideneacetates
2 4. A: MeOH, cat. H2SO4, 208C , 12 h;B: BnOH, cat.
pTsOH, toluene, 608C , 6 h;C: SOC 2l, NCS, cat. conc. HCl,
1,2-DCE, 858C , 15 h;D: SOC 2l, NBS, cat. conc. HBr, 1,2-
DCE, 858C , 15 h.
trum was pure enough for further transformations, it
was directly treated with hydrogen chloride to cleave
the acetal and subsequently with hydrogen peroxide to
oxidize the aldehyde[15] to give the crystalline acid 8 in
74% yield (71% overall from 5-Me).
The analogous ethyl 3,3-diethoxypropionate (5-Et)
can be prepared on a large scale from ethyl vinyl ether,
tetrachloromethane and ethanol without the use of a
palladium catalyst.[16,17] The Kulinkovich reductive cy-
clopropanation of 5-Et under the established conditions
yielded the cyclopropanol 10-Et virtually quantitatively
(99%), even on a reasonably large scale (ca. 0.5 mol).
The cyclopropanol 10-Et was cleanly transformed under
DMAP-catalysis (5 mol %) in the presence of inexpen-
sive triethylamine as an HCl scavenger to the corre-
sponding mesylate, which could be deprotected and in
Scheme 3. Alternative preparation of 2-(1’-hydroxycyclopro-
pyl)acetic acid (8) from methyl acrylate (9) or ethyl 3,3-dieth-
oxypropionate (5-Et). A: 1) MsCl, Py, CH2Cl2, 208C , 15 h, 2)
cat. conc. HCl, H2O2, THF/H2O (2:1), 608C , 8 h;B: 1) MsCl,
cat. DMAP, NEt3, C HCl2, 208C, 4 h, 2) Oxone, THF/H2O
2
(1:2), 208C , 8 h.
The first one, methyl phenylacetate (1) was readily situ oxidized with 1.5 equivs. of oxone. With a single crys-
converted to 6[10] in 84% yield by treatment with 2.5 tallization from diethyl ether the pure acid 8 was ob-
equivalents of ethylmagnesium bromide in the presence tained as a colorless crystalline compound (73% over 3
of titanium tetraisopropoxide. The product 6 was pure steps).
enough for direct transformation to the more stable me-
The methyl ester 11a was obtained in 91% yield by
sylate 7,[11] which was obtained in 92% yield. Oxidative treatment of a solution of 8 in methanol with a catalytic
cleavage of the phenyl group with in situ generated amount of concentrated sulfuric acid, and was used with-
ruthenium tetroxide under conditions developed by out further purification. The corresponding benzyl ester
Sharpless et al.,[12] but with 7 equivalents of orthoperiod- 11b was prepared in 83% yield by refluxing 8 in benzyl
ic acid[13] as the cooxidant, led to 2-(1’-mesyloxycyclo- alcohol/toluene under Dean Stark conditions in the
propyl)acetic acid (8) in 96% yield (74% overall from presence of a catalytic amount of p-toluenesulfonic
1), after crystallization from diethyl ether (Scheme 2).
acid. Dehydromesylation of 11b could be achieved by
A more atom-economical route to the same precursor stirring it with potassium tert-butoxide in tert-butyl
8 turned out to be that starting from methyl 3,3-dime- methyl ether at 08Cfor 18 h to furnish benzyl cyclopro-
thoxypropionate (5-Me), which is commercially availa- pylideneacetate (2-Bn) as a viscous liquid in 97% yield
ble or easily prepared on a 200 mmol scale by Wacker (59% overall from 5-Me) after Kugelrohr distillation
oxidation of methyl acrylate (9).[14] Subsequent Kulin- (Scheme 4).
kovich reaction of 5-Me furnished the cyclopropanol
An attempted a-chlorination of 11a with sulfuryl
10-Me in 96% yield. The latter was converted under con- chloride in the presence of a catalytic amount of
ventional conditions into the corresponding mesylate AIBN at 708Cfailed. Instead, a significant amount of
(Scheme 3).
the elimination product, the methyl cyclopropylidenea-
As the mesylate of 10-Me could not easily be purified cetate corresponding to 2-Bn, was formed. Attempted
1
by crystallization, but according to its H NMR spec- bromination of the in situ generated acid chloride of 8
Adv. Synth. Catal. 2004, 346, 760 766
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761

Michael Limbach et al.
FULL PAPERS
given in ppm relative to resonances of solvent (1H: 7.26 ppm for
chloroform; 13C: 77.0 ppm for chloroform-d), coupling con-
stants Jare given in Hertz. Characterization of the multiplicity
of signals: s¼singlet, br s¼broad singlet, d¼doublet, t¼trip-
let, m¼multiplet. The multiplicities of signals were deter-
mined by the DEPT technique: DEPT: þ ¼primary or tertiary
(positive DEPT-signal), ¼secondary (negative DEPT-sig-
nal), Cquat ¼quaternary C-atoms. IR: Bruker IFS 66. MS: Finni-
gan MAT. Chromatography: Separations were carried out on
Merck Silica 60 (0.063 0.200 mm, 70 230 mesh ASTM).
The dimensions of the columns are given as ™diameterꢀheight
of the silica column∫. TLC: Machery-Nagel, TLC plates Alu-
with a catalytic amount of chlorosulfonic acid and mo-
lecular bromine at 858Calso failed just like the first at-
tempts to halogenate 8 with NCS according to Wohl and
Ziegler, probably because of the poor solubility of 8 and
the acid chloride of 8 in tetrachloromethane. However,
1,2-dichloroethane (DCE) turned out to be a better sol-
vent for the starting material and thus upon chlorination
with NCS in DCE and subsequent treatment with meth-
anol the a-chloro ester 12a was obtained in 93% yield.
Under the same conditions, the acid chloride of 8 could
be transformed to the a-bromo ester 12b with NBS and a
catalytic amount of concentrated hydrobromic acid in
71% yield. Although 12a and 12b could be purified by
silica gel chromatography, they appeared not to be
very stable under these conditions. Therefore the crude
halogenated esters 12a and 12b were directly subjected
to dehydrohalogenation by treatment with triethyl-
amine in dichloromethane at 08C. The resulting 2-
chloro- (3-Me) and 2-bromocyclopropylideneacetates
4-Me could be purified by crystallization and chroma-
tography, respectively (Scheme 4).
¾
gram Sil G/UV254. Detection under UV light at 254 nm, devel-
opment with MOPS reagent (10% molybdophosphoric acid,
solution in ethanol). Melting points: apparatus according to
Dr. Tottoli (B¸chi); mps are uncorrected. Elemental analyses:
Mikroanalytisches Laboratorium des Instituts f¸r Organische
Chemie der Universit‰t Gˆttingen.
1-Benzylcyclopropanol (6)
To a solution of 15.0 g (99.9 mmol) of methyl phenylacetate in
100 mL of THF at 08Cwere added 5.70 mL (20.0 mmol) of ti-
tanium(IV) isopropoxide and slowly within 20 min 125 mL
(250 mmol) of ethylmagnesium bromide (2 M solution in di-
ethyl ether). The black solution was stirred for 40 min, the re-
action quenched by addition of 200 mL of 1 M sulfuric acid
at 08C, the aqueous phase was extracted with Et2O (3ꢀ
Conclusion
This new approach which furnishes methyl 2-chloro-2-
cyclopropylideneacetate (3-Me) and the 2-bromo ana-
logue 4-Me each in 6 simple steps (4 distinct operations) 200 mL), and the combined organic phases were dried over
MgSO4. Removal of volatiles under vacuum (water bath tem-
perature<308C!) afforded 6 as a slightly yellow liquid, which
was used in the next step without further purification; yield:
with an overall yield of 68 and 51% respectively, starting
from ethyl 3,3-diethoxypropionate (compared to 5 steps
with 18% overall yield and 3 steps with 13% overall
yield in thepast[18]), makes these valuablemultifunction-
al building blocks much more conveniently available
than previously. The parent benzyl cyclopropylidene-
acetate 2-Bn was accessible in 5 simple steps (4 distinct
operations) with an overall yield of 59% compared to
31% in 4 steps (including the generation and handling
of freshly prepared, finely dispersed sodium) according
to the best previously published protocol.
1
12.4 g (84%). H NMR (CDCl3, 250 MHz): d¼0.75 (m, 2H,
Cpr-CH2), 1.02 (m, 2H, Cpr-CH2), 3.24 (s, 2H, CH2Ph), 3.62
(br s, 1H, OH), 7.26 7.36 (m, 5H, aryl-H); 13C NMR (CDCl3,
62.9 MHz): d¼13.2 (ꢁ, 2C, Cpr-C), 44.1 (ꢁ, C HPh), 56.1
2
(Cquat, Cpr-C), 126.6 (Cquat, aryl-C), 128.5 (þ, 2C, aryl-C),
129.5 (þ, 2C, aryl-C), 138.6 (Cquat, Cipso). The additional exper-
imental data are identical to those reported in the literature.[10]
1-Benzylcyclopropyl Mesylate (7)
Experimental Section
To a solution of 14.8 g (99.9 mmol) of 6 in 300 mL of DCM at
08Cwere added 17.4 g (220 mmol) of pyridine and slowly with-
in 30 min 9.3 mL (120 mmol) of mesyl chloride. The solution
was stirred under rewarming to room temperature for 18 h, ex-
tracted with 1 N hydrochloric acid (2ꢀ50 mL), water (1ꢀ
50 mL) and brine (1ꢀ50 mL). Drying of the organic phase
over MgSO4, removal of the solvent under vacuum and crystal-
lization from Pent/Et2O (2:1, Rf ¼0.5, MOPS) afforded 7 as a
General Remarks
All reagents were used as purchased from commercial suppli-
ers without further purification. All reactions in non-aqueous
solvents were carried out using standard Schlenk techniques
under an atmosphere of dry nitrogen. Solvents were purified
and dried according to conventional methods prior to use; di-
ethyl ether (Et2O), 1,2-dimethoxyethane (DME) and tetrahy-
drofuran (THF) were freshly distilled from sodium/benzophe-
none. Solvents are abbreviated as follows: DCM¼dichlorome-
thane, DCE¼1,2-dichloroethane, MeCN¼acetonitrile, Py¼
pyridine, MTBE¼tert-butyl methyl ether, EtOAc¼ethyl ace-
tate, MeOH¼methanol, BnOH¼benzyl alcohol, Pent ¼pen-
tane. 1H and 13CNMR spectra were recorded at ambient tem-
perature on a Bruker AM 250 instrument. Chemical shifts d are
˜
colorless solid; yield: 20.7 g (92%); mp 79 818C; IR (film): n¼
3089, 3063, 3035, 3022, 2943, 2926, 1602, 1498, 1453, 1436, 1423,
1333, 1245, 1173, 974, 942, 921 cmꢁ1 1H NMR (CDCl3,
;
250 MHz): d¼0.83 (m, 2H, Cpr-CH2), 1.33 (m, 2H, Cpr-
CH2), 2.88 (s, 3H, CH3), 3.26 (s, 2H, CH2Ph), 7.26 7.34 (m,
5H, aryl-H); 13CNMR (CDCl 3, 62.9 MHz): d¼11.2 (ꢁ, 2C ,
Cpr-C), 39.7 (þ, C H), 41.2 (ꢁ, C HPh), 66.2 (Cquat, Cpr-C),
3
2
126.8 (Cquat, aryl-C), 128.4 (þ, 2C, aryl-C), 129.4 (þ, 2C ,
aryl-C), 136.7 (Cquat, Cipso); MS (EI, 70 eV): m/z (%)¼226 (1)
762
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Syntheses of Cyclopropylideneacetates
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[Mþ], 130 (48), 91 (100), 65 (10); anal. calcd. for C11H14O3S
(226.3): C58.38, H 6.24; found: C58.09, H 5.97.
7.2 Hz, 1H, CH); 13C NMR (CDCl3, 62.9 MHz): d¼9.7 (þ,
2C, CH3), 12.3 (ꢁ, 2C, Cpr-C), 40.8 (ꢁ, C H), 53.1 (Cquat
,
2
Cpr-C), 61.7 (ꢁ, 2C , OC H), 102.9 (þ, CH); MS (EI, 70 eV):
2
m/z (%)¼129 (6), 128 (10), 103 (49), 83 (92), 75 (48), 55 (63),
47 (100); anal. calcd. for C9H18O3 (174.2): C62.04, H 10.41;
found: C61.79, H 10.38.
Methyl 3,3-Dimethoxypropionate (5-Me)
To a suspension of 837 mg (4.72 mmol) of palladium(II) chlor-
ide in 50 mL of DME were added 19.8 g (200 mmol) of cop-
per(I) chloride. At 208Ca solution of 17.2 g (200 mmol) of
acrylic acid methyl ester in 64.1 g (2.00 mol) of MeOH was add-
ed, the flask was flooded with oxygen and the mixture was heat-
ed at 508Cfor 48 h under an atmosphere of oxygen (balloon).
After cooling to room temperature, 50 mL of Et2O were added,
the precipitate was filtered off, washed with Et2O, and the vol-
atiles were removed under vacuum (408Cwater bath). Distil-
lation of the residue under reduced pressure (10 mbar, bp
57 608C) afforded 5-Me as a colorless liquid; yield: 21.7 g
2-(1’-Mesyloxycyclopropyl)acetic Acid (8)
Method A: To a solution of 14.8 g (101 mmol) of 10-Me in
200 mL of DCM were added 19.2 mL (243 mmol) of pyridine
and slowly within 30 min 13.9 mL (180 mmol) of mesyl chlor-
ide. The solution was stirred for 18 h at 208C, extracted with
1 N HC l (2ꢀ50 mL), water (1ꢀ50 mL) and saturated aqueous
NaHCO3 solution (1ꢀ50 mL). Drying over MgSO4 and eva-
poration of the solvent yielded the raw mesylate as a dark
oil, which was dissolved in 30 mL of THF/H2O (2:1). To this
solution were added at 08C5 mL of concentrated aqueous
HCl, and it was stirred at this temperature for 30 min. At
1
3
(73%); H NMR (CDCl3, 250 MHz): d¼2.62 (d, J¼7.1 Hz,
2H, CH2), 3.22 (s, 6H, 2OCH3), 3,64 (s, 3H, OCH3), 4.68 (t,
3J¼7.1 Hz, 1H, CH); 13C NMR (CDCl3, 62.9 MHz): d¼38.6
(ꢁ, C H), 51.7 (þ, OC H), 53.4 (þ, 2C , OC H), 101.2 (þ,
2
3
3
¼
CH), 170.2 (Cquat, C O). The additional experimental data
are identical to those reported in literature.[15]
208Cwere added 23.5 g (206 mmol) of 30% aqueous H O2,
2
and the light yellow solution was heated at 608Cfor 8 h. Ex-
traction of the mixture with DCM (3ꢀ100 mL), drying of the
combined organic phases over MgSO4, evaporation of the sol-
vent and recrystallization of the residue from Et2O/Pent af-
forded 8 as colorless crystals; yield: 14.6 g (74%); mp 96
1-(2,2-Dimethoxyethyl)cyclopropanol (10-Me)
To a solution of 10.4 g (70.5 mmol) of 5-Me in 200 mL of Et2O
were added 4.00 mL (13.6 mmol) of titanium(IV) isopropox-
ide at 08Cand slowly 88 mL (176 mmol) of EtMgBr (2 M sol-
ution in Et2O). The deep black solution was stirred at 258Cfor
18 h, the reaction quenched by slow addition of 15 mL of water
at 08C, and the mixture stirred until the precipitate was com-
plete. Filtration of the precipitate over MgSO4 and removal
of the solvent under vacuum afforded 10-Me as a slightly yel-
˜
988C; IR (film): n¼3032, 1710, 1424, 1408, 1331, 1265, 1230,
1
1184, 1155, 942, 907 cmꢁ1; H NMR (CDCl3, 250 MHz): d¼
0.93 (m, 2H, Cpr-CH2), 1.42 (m, 2H, Cpr-CH2), 2.91 (s, 2H,
CH2), 3.05 (s, 3H, CH3), 10.85 11.23 (br s, 1H, CO2H);
13C NMR (CDCl3, 62.9 MHz): d¼12.0 (ꢁ, 2C, Cpr-C), 39.7
(þ, C H), 40.9 (ꢁ, C H), 61.6 (Cquat, Cpr-C), 175.9 (Cquat
,
3
2
C O); MS (DCI, 70 eV): m/z (%)¼406 (3) [2M þNH4þ],
212 (100) [Mþ þNH4þ]; anal. calcd. for C6H10O5S (194.2): C
37.11, H 5.19; found: C37.39, H 4.96.
þ
¼
˜
low liquid; yield: 9.88 g (96%); IR (film): n¼3420, 2938, 2835,
1717, 1700, 1457, 1387, 1192, 1122, 1053 cmꢁ1
;
1H NMR
Method B: To a solution of 68.7 g (394 mmol) of 10-Et in
700 mL of DCM were added 65.5 mL (474 mmol) of triethyl-
amine, 2.40 g (19.8 mmol) of DMAP and slowly within
30 min 49.6 g (435 mmol) of mesyl chloride. The solution was
stirred for 4 h at 208C, extracted with 1 N HCl (1ꢀ200 mL)
and water (1ꢀ200 mL). Drying over Na2SO4 and evaporation
of the solvent yielded the raw mesylate as a brown oil, which
was dissolved in 1.00 L of THF/H2O (1:2). To this solution
were added 350 g (570 mmol) of oxone at 08Cand the suspen-
sion was stirred at 208Cfor 8 h. Water (500 ml) was added and
the aqueous phase was extracted with EtOAc (3ꢀ500 mL).
Drying over MgSO4, evaporation of the solvent and recrystal-
lization of the residue from Et2O afforded 8 as colorless crys-
tals; yield: 57.0 g (74%).
Method C: To a solution of 10.0 g (44.2 mmol) of 7 in a ter-
nary system of 50 mL of tetrachloromethane, 50 mL of aceto-
nitrile and 75 mL of water were added 90.0 g (314 mmol) of or-
thoperiodic acid and 274 mg of RuO2 ¥H2O. The originally col-
orless mixture, which immediately turned yellow upon addi-
tion of the catalyst, was vigorously stirred at 408Cfor 22 h.
(CDCl3, 250 MHz): d¼0.46 (m, 2H, Cpr-CH2), 0.75 (m, 2H,
3
Cpr-CH2), 1.84 (d, J¼7.2 Hz, 2H, CH2), 3.39 (s, 6H, 2 CH3),
3
3.45 (br s, 1H, OH), 4.63 (t, J¼7.2 Hz, 1H, CH); 13CNMR
(CDCl3, 62.9 MHz): d¼12.5 (ꢁ, 2C, Cpr-C), 39.8 (ꢁ, C H),
2
52.9 (Cquat, Cpr-C), 53.1 (þ, 2C , OC H), 104.6 (þ, C H); MS
(DCI, 70 eV): m/z (%)¼146 (20) [Mþ3], 75 (100), 58 (60), 43
(41); anal. calcd. for C7H14O3 (146.2): C57.51, H 9.65; found:
C57.42, H 9.62.
1-(2,2-Diethoxyethyl)cyclopropanol (10-Et)
To a solutionof95.0 g (499 mmol)of5-Etin1.00 L ofTHF/Et2O
(1:1) was added 28.4 mL (99 mmol) of titanium(IV) isoprop-
oxide at 08Cand 520 mL (1.25 mol) of EtMgBr (2.4 M solution
in Et2O) over 60 min. The deep black solution was stirred at
208Cfor 18 h, the reaction quenched by slow addition of
100 mL of water at 08Cand 500 mL of Et 2O, and the mixture
stirred until the precipitate was complete. Filtration of the pre-
cipitate over MgSO4 and then over Celite and removal of the
solvent under vacuum afforded 10-Et as a slightly yellow li-
At 08C , 10 mL of EtO were added, the aqueous solution was
2
˜
quid; yield: 85.9 g (99%); IR (film): n¼3420, 2938, 2835,
stirred for 10 min and extracted with EE (3ꢀ100 mL). Extrac-
tion of the combined organic phases with saturated brine (1ꢀ
50 mL), drying over MgSO4, evaporation of the solvent and re-
crystallization from Et2O afforded 8 as a colorless solid; yield:
8.18 g (96%).
1717, 1700, 1457, 1387, 1192, 1122, 1053 cmꢁ1
;
1H NMR
(CDCl3, 250 MHz): d¼0.42 (m, 2H, Cpr-CH2), 0.73 (m, 2H,
Cpr-CH2), 1.21 (t, 3J¼7.3 Hz, 6H, 2 CH3), 1.85 (d, 3J¼7.2 Hz,
2H, CH2), 3.42 3.78 (m, 5H, 2 CH2 þOH), 4.77 (t, 3J¼
Adv. Synth. Catal. 2004, 346, 760 766
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Michael Limbach et al.
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¼
C O). The additional experimental data are identical to those
Methyl 2-(1’-Mesyloxycyclopropyl)acetate (11a)
reported in literature.[1]
To a solution of 2.20 g (11.3 mmol) of 8 in 100 mL of methanol
were added ten drops of concentrated sulfuric acid, and the sol-
ution was stirred at 208Cfor 18 h. The solvent was removed un-
der vacuum, the residue dissolved in 50 mL of EtOAc, and the
solution neutralized with 20 mL of saturated NaHCO3 solu-
tion. The aqueous phase was extracted with EtOAc (3ꢀ
50 mL), drying of the combined organic phases over Na2SO4
and removal of the solvent under vacuum afforded 11a as a
slightly yellow oil; yield: 2.15 g (91%); (Et2O, Rf ¼0.66,
Methyl 2-Bromo-(1-methanesulfonyloxy-
cyclopropyl)acetate (12b)
To a solution of 4.00 g (20.6 mmol) of 8 in 50 mL of DCE were
added 1.82 mL (25.0 mmol) of thionyl chloride, and the solu-
tion was heated under reflux for 30 min. At ambient tempera-
ture were added 4.44 g (25.0 mmol) of NBS and 4 drops of con-
centrated aqueous HBr, and the solution was heated under re-
flux at 908Cfor 8 h. MeOH(50 mL) was added at20 8C, and the
solution was stirred for an additional 1 h. The solvents were re-
moved under vacuum, the residue suspended in tetrachloro-
methane, and the mixture filtered. Removal of the solvent
and chromatographic purification of the residue on 40 g of sili-
ca gel (column, 3ꢀ20 cm, Pent/Et2O¼3:1; Rf ¼0.19) afforded
˜
MOPS). IR (film): n¼3023, 2956, 1739, 1439, 1352, 1175,
1
1031, 942, 908, 824 cmꢁ1; H NMR (CDCl3, 250 MHz): d¼
0.86 (m, 2H, Cpr-CH2), 1.35 (m, 2H, Cpr-CH2), 2.83 (s, 2H,
CH2), 3.00 (s, 3H, CH3), 3.70 (s, 3H, OCH3); 13CNMR
(CDCl3, 62.9 MHz): d¼12.0 (ꢁ, 2C, Cpr-C), 39.6 (þ, C H),
3
40.8 (ꢁ, C H), 51.9 (þ, OC H), 62.0 (Cquat, Cpr-C), 170.2
2
3
þ
¼
(Cquat, C O); MS (DCI, 70 eV): m/z (%)¼209 (8) [M þH],
129 (100), 101 (55), 97 (82), 81 (34), 79 (30), 59 (92), 55 (60),
42 (32); anal. calcd. for C7H12O5S (208.2): C40.38, H 5.81;
found: C40.46, H 5.61.
˜
12b as a slightly yellow liquid; yield: 4.24 g (71%); IR (film): n¼
3031, 2944, 1423, 1366, 1168 cmꢁ1
;
1H NMR (CDCl3,
250 MHz): d¼0.82 (m, 2H, Cpr-CH2), 1.21 (m, 2H, Cpr-
CH2), 3.08 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.85 (s, 1H, Br-
CH); 13C NMR (CDCl3, 62.9 MHz): d¼11.2 (ꢁ, 2C, Cpr-C),
40.4 (þ, C H), 52.5 (þ, OC H), 62.3 (Cquat, Cpr-C), 63.2 (þ,
Benzyl 2-(1’-Mesyloxycyclopropyl)acetate (11b)
3
3
¼
Br-CH), 171.2 (Cquat, C O); MS (EI, 70 eV): m/z (%)¼288/
286 (3/4) [Mþ], 209 (63) [Mþ ꢁBr], 207 (19), 129 (100), 79
(28), 56 (75); anal. calcd. for C7H11BrO5S (287.1): C29.28, H
3.86; found: C29.17, H 3.83.
To a solution of 4.45 g (22.91 mmol) of 8 in 150 mL of toluene
were added 2.00 g (10.5 mmol) of p-toluenesulfonic acid hy-
drate and 10.0 g (92.5 mmol) of benzyl alcohol. The solution
was heated under reflux in a Dean Stark apparatus for 6 h, di-
luted with 100 mL of DCM, extracted with saturated aqueous
NaHCO3 solution (2ꢀ50 mL) and dried over MgSO4. Remov-
al of the volatiles under vacuum and chromatographic purifica-
tion of the residue on 150 g of silica gel (column, 3ꢀ25 cm,
Pent/Et2O¼1:1; Rf ¼0.36, MOPS) afforded 11b as a colorless
Methyl 2-Bromo-2-cyclopropylideneacetate (4-Me)
To a solution of 4.48 g (15.6 mmol) of 12b in 50 mL of DCM
kept at 08Cwere added 1.72 mL (12.4 mmol) of triethylamine,
and the solution was stirred at this temperature for 4 h. DCM
(100 mL) and 1 N aqueous HCl (10 mL) were added. Separa-
tion of the phases, drying of the organic phase over MgSO4
and removal of the solvent under vacuum afforded 4-Me as a
˜
liquid; yield: 5.41 g (83%); IR (film): n¼3033, 2941, 1739, 1456,
1
1353, 1175, 940, 907 cmꢁ1; H NMR (CDCl3, 250 MHz): d¼
0.96 (m, 2H, Cpr-CH2), 1.44 (m, 2H, Cpr-CH2), 2.45 (s, 2H,
CH2), 2.94 (s, 3H, CH3), 5.18 (s, 2H, CH2Ph), 7.28 7.39 (m,
5H, aryl-H); 13C NMR (CDCl3, 62.9 MHz): d¼12.1 (ꢁ, 2C ,
Cpr-C), 39.6 (þ, C H), 41.1 (ꢁ, C H), 62.0 (Cquat, Cpr-C),
1
slightly yellow liquid; yield: 2.92 g (98%); H NMR (CDCl3,
3
2
250 MHz): d¼1.39 (m, 2H, Cpr-CH2), 1.76 (m, 2H, Cpr-
66.7 (ꢁ, C HPh), 128.27 (þ, 2C, aryl-C), 128.33 (þ, aryl-C),
2
CH2), 3.82 (s, 3H, CH3); 13C NMR (CDCl3, 62.9 MHz): d¼
¼
128.5 (þ, 2 C, aryl-C), 135.6 (Cquat, Cipso), 169.9 (Cquat, C O);
MS (EI, 70 eV): m/z (%)¼284 (2) [Mþ], 205 (4), 97 (10), 91
(100); anal. calcd. for C13H16O5S (284.3):C54.92, H 5.67; found:
C54.83, H 5.66.
7.0 (ꢁ, Cpr-C), 12.1 (ꢁ, Cpr-C), 53.2 (þ, C H), 103.7 (Cquat
,
3
¼
Cpr-C), 143.6 (Cquat, Br-C), 162.6 (Cquat, C O). The additional
experimental data are identical to those reported in litera-
ture.[3]
Benzyl Cyclopropylideneacetate (2-Bn)
Methyl 2-Chloro-(1-methanesulfonyloxy-
cyclopropyl)acetate (12a)
To a solution of 4.30 g (15.1 mmol) of 11b in 100 mL of MTBE
were added at 08Cin small portions 2.04 g (18.1 mmol) of t-
BuOK, the solution was stirred at this temperature for 18 h
and then diluted with 100 mL of Et2O. The organic phase was
extracted with 50 mL of water, dried over MgSO4, and the sol-
vents were evaporated. Column chromatography on 150 g of
silica gel (column, 3ꢀ25 cm, Et2O/PE¼1:9, Rf ¼0.45;
MOPS) afforded 2-Bn as a colorless oil; yield: 2.76 g (97%);
1H NMR (CDCl3, 250 MHz): d¼1.24 (m, 2H, Cpr-CH2), 1.46
(m, 2H, Cpr-CH2), 5.20 (s, 2H, CH2Ph), 6.32 (m, 1H, CH),
7.28 7.42 (m, 5H, aryl-H); 13C NMR (CDCl3, 62.9 MHz): d¼
To a solution of 14.0 g (72.1 mmol) of 8 in 450 mL of DCE were
added 6.52 mL (89.9 mmol) of thionyl chloride, and the solu-
tion was heated under reflux for 60 min. At room temperature
were added 14.4 g (108 mmol) of NCS and 15 drops of concen-
trated aqueous HCl, and the solution was heated under reflux
at 908Cfor 12 h. At 20 8C, MeOH (50 mL) was added, and the
solution stirred at this temperature for an additional 1 h. The
solvent was removed under vacuum, the residue suspended
in cold (08C) tetrachloromethane, and the mixture was fil-
tered. Removal of the solvent afforded 12a as a yellow oil,
2.0 (ꢁ, Cpr-C), 4.6 (ꢁ, Cpr-C), 65.7 (ꢁ, C HPh), 110.9
2
(CH), 127.8 (þ, 2C, aryl-C), 128.3 (þ, aryl-C), 128.6 (þ, 2C , which was used in the next step without further purification;
aryl-C), 136.4 (Cquat, Cipso), 145.2 (Cquat, Cpr-C), 165.5 (Cquat
,
yield: 16.3 g (93%). An analytical sample was purified on
764
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 760 766

Syntheses of Cyclopropylideneacetates
FULL PAPERS
100 g of silica gel (column, 4ꢀ20 cm, Pent/Et2O¼3:1; Rf ¼
1989 2000; b) Benzyl: N. F. Osborne, J. Chem. Soc. Per-
kin Trans. 1 1982, 1435 1439; c) Ref.[3a]
[4] A. de Meijere, S. I. Kozhushkov, L. P. Hadjiarapoglou,
Topics Curr. Chem. 2000, 207, 149 227.
[5] a) L. Hadjiarapoglou, I. Klein, D. Spitzner, A. de Mei-
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Kˆrbe, M. Noltemeyer, A. de Meijere, Eur. J. Org.
Chem. 2001, 2283 2292; c) Ref.[3a]; d) K. H. Ang, S.
Br‰se, A. G. Steinig, F. E. Meyer, A. Llebaria, K. Voigt,
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˜
0.16). IR (film): n¼3045, 2830, 1717, 1456, 1424, 1408, 1329,
1
1175, 987, 935, 882 cmꢁ1; H NMR (CDCl3, 250 MHz): d¼
0.84 (m, 2H, Cpr-CH2), 1.33 (m, 2H, Cpr-CH2), 3.01 (s, 3H,
CH3), 3.77 (s, 3H, OCH3), 4.58 (s, 1H, Cl-CH); 13CNMR
(CDCl3, 62.9 MHz): d¼10.0 (ꢁ, 2C, Cpr-C), 39.3 (þ, C H),
3
52.0 (þ, OC H), 62.0 (Cquat, Cpr-C), 63.2 (þ, Cl-CH), 170.8
3
þ
¼
(Cquat, C O); MS (DCI, 70 eV): m/z (%)¼244/242 (2/7) [M
], 207 (63) [Mþ ꢁCl], 129 (100), 99 (35), 97 (28); anal. calcd.
for C7H11ClO5S (242.7): C34.65, H 4.57; found: C34.60, H 4.56.
Methyl 2-Chloro-2-cyclopropylideneacetate (3-Me)
[6] a) M. W. Nˆtzel, M. Tamm, T. Labahn, M. Noltemeyer,
M. Es-Sayed, A. de Meijere, J. Org. Chem. 2000, 65,
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de Meijere, Org. Lett. 2002, 4, 839 841; c) A. de Meijere,
I. D. Kuchuk, V. V. Sokolov, T. Labahn, K. Rauch, M. Es-
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ni, A. Goti, A. Brandi, Tetrahedron 1993, 49, 9867 9876;
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839 842.
To a solution of 8.96 g (36.9 mmol) of 12a in 150 mL of DCM
kept at 08Cwere added 7.68 mL (55.2 mmol) of triethylamine,
and the solution was stirred at this temperature for 8 h. DCM
(100 mL) and aqueous 1 N HCl (3ꢀ10 mL) were added and
the phases were separated. Drying of the organic phase over
MgSO4 and removal of the solvent under vacuum afforded 3-
Me as colorless crystals; yield: 5.35 g (99%); 1H NMR
(CDCl3, 250 MHz): d¼1.41 1.50 (m, 2H, Cpr-CH2), 1.66
1.75 (m, 2H, Cpr-CH2), 3.83 (s, 3H, CH3); 13C NMR (CDCl3,
62.9 MHz): d¼5.5 (ꢁ, Cpr-C), 9.7 (ꢁ, Cpr-C), 52.9 (þ,
CH3), 114.7 (Cquat, Cpr-C), 139.1 (Cquat, Cl-C), 162.7 (Cquat
,
¼
C O). The additional experimental data are identical to those
reported in literature.[18]
[7] a) A. Rulev, J. Maddaluno, Eur. J. Org. Chem. 2001, 2569
2576; b) M. Tamm, M. Thutewohl, C. B. Ricker, N. T.
Bes, A. de Meijere, Eur. J. Org. Chem. 1999, 2017
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Wessjohann, G. McGaffin, A. de Meijere, Synthesis 1989,
359 363; e) Ref.[1f]
Acknowledgements
This work was supported by the Fonds der Chemischen Indus-
trie. We are grateful to Celanese and Bayer CropScience AG
for generous gifts of chemicals. M. L. is indebted to the German
Merit Foundation (Studienstiftung des deutschen Volkes) for a
student (2000 2002) and a doctoral fellowship (2002 2004).
The authors are grateful to Dr. B. Knieriem, Gˆttingen, for his
careful reading of the final manuscript.
[8] V. N. Belov, C. Funke, T. Labahn, M. Es-Sayed, A. de -
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A. I. Savchenko, T. S. Pritytskaya, J. Org. Chem. USSR
(Engl. Transl.) 1991, 27, 250 253; Zh. Org. Khim. 1991,
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T. Hatajima, H. Takahashi, Tetrahedron Lett. 1989, 30,
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;
1
[11] The H NMR spectrum disclosed the presence of only
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upon treatment of the cyclopropanol 6 with acid or base
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[2] a) Methyl: T. Liese, G. Splettstˆsser, A. de Meijere, An-
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766
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 760 766