Synthesis of cyclopropanes via iodine-magnesium exchange between 3-iodomethyl-1-oxacyclopentanes and organomagnesium reagents

Article abstract of DOI:10.1016/j.tet.2003.11.038

Iodine-magnesium exchange occurs upon treatment of 3-iodomethyl-1- oxacyclopentanes with alkyl Grignard reagents or trialkylmagnesate. The resulting organomagnesium compounds undergo intramolecular nucleophilic substitution in ether to afford cyclopropane skeletons in a stereoselective manner.

Full text of DOI:10.1016/j.tet.2003.11.038

Tetrahedron 60 (2004) 973–978
Synthesis of cyclopropanes via iodine–magnesium
exchange between 3-iodomethyl-1-oxacyclopentanes
and organomagnesium reagents
*
Takashi Tsuji, Tomoaki Nakamura, Hideki Yorimitsu, Hiroshi Shinokubo and Koichiro Oshima
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku, Katsura, Nishikyo-ku,
Kyoto 615-8510, Japan
Received 6 October 2003; accepted 12 November 2003
Abstract—Iodine–magnesium exchange occurs upon treatment of 3-iodomethyl-1-oxacyclopentanes with alkyl Grignard reagents or
trialkylmagnesate. The resulting organomagnesium compounds undergo intramolecular nucleophilic substitution in ether to afford
cyclopropane skeletons in a stereoselective manner.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
metal exchanges with metal reagents other than organo-
lithium to form cyclopropanes.3
Cyclopropane rings are highly strained entities and hence
attracts much attention. They are not only structurally
challenging targets but also found in a wide variety of
naturally occurring useful compounds. While many
methodologies are available to construct three-membered
rings, synthesis of cyclopropanes still gains in importance.1
Ring closure of alkyl halide having a leaving group at the
third position via halogen–lithium exchange is promising.2
On the other hand, there are a limited number of halogen–
Iodine–magnesium exchange between Grignard reagents
and organic iodides is a convenient method to prepare new
organomagnesium compounds.4 Aryl and vinyl iodides5 and
alkyl iodides bearing another electronegative groups such as
CF3I, RCHI2, and ROCH2I6 are usually the choice of
precursors. In general, the exchange reaction using alkyl
iodides is much less widely used because the exchange is
complicated by the possible occurrence of Wultz-type
Scheme 1.
Keywords: Cyclopropanes; Iodine–magnesium exchange; Ate complex.
*
Corresponding author. Tel.: þ81-75-383-2437; fax: þ81-75-383-2438; e-mail address: oshima@fm1.kuic.kyoto-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.038

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T. Tsuji et al. / Tetrahedron 60 (2004) 973–978
coupling in an ethereal solvent and the fact that complete
conversion to product is not achieved.4c,7 Here we report
iodine–magnesium exchange of 3-iodomethyl-1-oxacyclo-
pentane derivatives. Following intramolecular nucleophilic
substitution led to the construction of cyclopropane with
concomitant opening of the oxacyclopentane ring.
Table 1. Formation of cyclopropanes from iodomethyl-substituted
oxacyclopentanes
Substrate Mg reagent
Product
Yield (%)
2b
3c
3d
n-Bu3MgLi
i-PrMgBr
i-PrMgBr
i-PrMgBr
73a
2. Results and discussion
The starting compounds 2a and 2b were readily prepared
by iodoetherification of vinyl ether with allylic alcohol and
N-iodosuccinimide and subsequent triethylborane-induced
atom transfer radical cyclization (Scheme 1).8 b-Iodo-
methyl-g-lactones 3c–3e were prepared by Jones oxidation
of the corresponding cyclic acetals 2c–2e. Radical cycliza-
tion of 1a, 1b and 1d, which have R3¼n-C5H11 and R4¼H,
proceeded with exclusive trans selectivity in regard to the
pentyl and iodomethyl groups, as is often observed in
radical cyclization.9
69
79
60
Iodo acetal 2a (0.50 mmol) was added to an ethereal
solution of isopropylmagnesium bromide (2.0 mmol,
4 equiv.) at 0 8C under argon (Scheme 2). The reaction
mixture was stirred for 10 h at 25 8C. Usual workup
followed by silica gel column purification afforded 4a in
73% yield. The alcohol 4a has four stereogenic centers. To
simplify the assignment of the stereochemistry, 4a was
subjected to Jones oxidation to provide ketone 5a in 90%
yield. Ketone 5a consisted of two isomers in a ratio of
71/29. On the other hand, Jones oxidation of 2a furnished
lactone 3a in a ratio of 70/30. These facts are informative to
consider the reaction mechanism (vide infra).
3e
a
Overall yield after Jones oxidation (83% for cyclopropane formation and
88% for oxidation).
corresponding alcohol 4d was obtained in 30% yield, in
addition to remaining starting material (27% yield).
Oxidation of 4b–4d proceeded in more than 85% yield.
Other substrates were subjected to the transformation
(Table 1). Treatment of 2b with tributylmagnesate afforded
7 in good yield after Jones oxidation. Exclusive formation of
the trans isomer was deduced by analysis of the coupling
constants of the protons on cyclopropane ring,13 which
indicates the stereospecificity of the reaction. Lactones
3c–3e also participated in the reaction to provide 2-cyclo-
propylisobutyric acids. However, treatment of lactone 11
with isopropyl Grignard reagent did not afford the expected
product, instead giving diol 13 (Scheme 3). Formation of the
enolate of 11 followed by intramolecular nucleophilic
substitution gave bicyclic 12. Addition of the Grignard
reagent to 12 afforded 13.
Scheme 2.
Use of three equimolar amounts of isopropyl Grignard
reagent resulted in lower yield (58%). An increasing amount
of the Grignard reagent (6 equiv.) did not improve the yield
of 4a (75%). It is worth noting that the reaction did not
afford 4a in THF at all, and reduced product 6 was obtained
instead as a sole product.10 t-Butyllithium was less effective
to give 4d in 26% yield, in addition to 38% yield of 6.
We assume the reaction mechanism as shown in Scheme 4.
Iodine–magnesium exchange occurs upon treatment of
3-iodomethyl-1-oxacyclopentane 2 or 3 with a Grignard
reagent. The resulting organomagnesium species 14 or 15
undergoes intramolecular nucleophilic substitution in ether
to afford the cyclopropane skeleton. However, in THF as
aforementioned, no cyclopropanes were obtained. This fact
implies that the coordination of 14 or 15 to Lewis acidic
magnesium species in the substitution step would play a
critical role.
Other magnesium reagents effected similar reactions.
Reaction with cyclohexyl Grignard reagent furnished the
corresponding alcohol 4b in 68% yield. Use of primary
Grignard reagents such as n-BuMgBr resulted in the
recovery of the starting material. Instead, tributylmagnesate
n-Bu3MgLi, prepared from n-BuMgBr and 2 equiv. of
n-BuLi,11 was suitable to yield the butylated product 4c
(72%).12 t-BuMgBr worked less efficiently, and the
To confirm the stereochemistry of the cyclopropanation

T. Tsuji et al. / Tetrahedron 60 (2004) 973–978
975
Scheme 3.
Scheme 4.
step, we prepared optically pure lactone (3S,4R)-3d from
(R)-1-octen-3-ol (Scheme 5). Upon treatment of (3S,4R)-3d
with isopropyl Grignard reagent, carboxylic acid 9 was
obtained as a single enantiomer (Fig. 1). We assume that its
absolute stereochemistry would be (3R,4R) and that the
cyclopropanation would proceed with inversion of
configuration.
oxacyclopentanes and organomagnesium reagents in ether
led to the formation of cyclopropane skeleton. The present
reaction probably constructs 1,1,2,2-tetrasubstituted cyclo-
propane, starting from a proper 3-iodomethyl-1-oxacyclo-
pentane derivative. Synthesis of 1,1,2,2,3-penta- or
1,1,2,2,3,3-hexasubstituted cyclopropane through the
present method seems difficult because the synthesis
requires halogen–magnesium exchange of secondary or
tertiary alkyl halide at the initial stage. Although lacking
functional group compatiblitity because of the use of
organomagnesium reagents, this method can construct
highly complex stereodefined cyclopropanes from simple
starting materials, vinyl ether, allylic alcohol, and Grignard
reagent, in a few steps.
3. Conclusion
Iodine–magnesium exchange between 3-iodomethyl-1-
4. Experimental
4.1. General
1H NMR (300 MHz) and 13C NMR (75.3 MHz) spectra
were taken on a Varian GEMINI 300 spectrometer in CDCl3
as a solvent, and chemical shifts were given in d value with
tetramethylsilane as an internal standard IR spectra were
Scheme 5.
Figure 1. Chromatograms of racemic 9 and optically pure 9 derived from (3S,4R)-3d.

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T. Tsuji et al. / Tetrahedron 60 (2004) 973–978
determined on a JASCO IR-810 spectrometer. TLC
analyses were performed on commercial glass plates
bearing a 0.25-mm layer of Merck Silica gel 60F254. Silica
gel (Wakogel 200 mesh) was used for column chroma-
tography. Elemental analyses were carried out at the
Elemental Analysis Center of Kyoto University. The optical
purity of 9 was established by chiral HPLC analysis
(CHIRALCELw AS-H column 4.6 mm£250 mm Daisel
Chemical Industries, Hexane/2-propanol/trifluoroacetic
acid¼100/1/0.1 eluent, 1.0 mL/min, 25 8C, and RI detector).
layer to transfer the carboxylate into the aqueous layer.
After removal of the organic layer, 1 M HCl was then added
to the aqueous solution until the solution became acidic.
Extraction with ethyl acetate (20 mL£3) and concentration
afforded colorless oil. Purification on silica gel with hexane/
ethyl acetate¼3/1 as an eluent yielded carboxylic acid
8 (0.044 g, 0.34 mmol) in 69% yield.
4.5. Characterization data
Spectral data for 8 was found in the literature.14
Unless otherwise noted, materials obtained from commer-
cial suppliers were used without further purification. Ether
was purified over slices of sodium. THF was distilled from
sodium benzophenone ketyl. Dichloromethane was stored
over molecular sieves 3A. (R)-1-Octen-3-ol was purchased
from Tokyo Kasei Kogyo Co.
4.5.1. 2-Ethoxy-4-iodomethyl-3-methyl-5-pentyltetra-
hydrofuran (2a, diastereomer ratio is 55/18/15/12). IR
(neat) 2930, 2860, 1458, 1377, 1188, 1084, 1051, 962 cm21
;
1H NMR (CDCl3) For the most abundant isomer: d 0.89 (t,
J¼6.6 Hz, 3H), 0.95 (d, J¼7.2 Hz, 3H), 1.18 (t, J¼7.2 Hz,
3H), 1.23–1.60 (m, 8H), 2.31–2.40 (m, 1H), 2.57–2.68 (m,
1H), 2.99 (t, J¼10.5 Hz, 1H), 3.16–3.21 (m, 1H), 3.25–
3.45 (m, 1H), 3.62–3.77 (m, 2H), 4.71 (s, 1H); 13C NMR
(CDCl3) For the most abundant isomer: d 2.58, 10.82, 14.12,
15.28, 22.68, 26.07, 31.87, 36.81, 43.60, 48.87, 62.21,
82.34, 108.33. Found: C, 46.13; H, 7.40%. Calcd for
C13H25IO2: C, 45.89; H, 7.41%.
4.2. Preparation of iodo compounds 2 and 11
Iodo acetal 1 was prepared by treatment of an equimolar
mixture of the corresponding vinyl ether and allylic alcohol
with an equal amount of N-iodosuccinimide in dichloro-
methane at 0 8C for 2 h. Preparation of 1a–d was efficient
(more than 90% yield). However, preparation of 1e resulted
in a lower yield (15%, not optimized).
4.5.2. 4-Iodomethyl-2-methoxy-3,3-dimethyl-5-pentyl-
tetrahydrofuran (2b, single isomer). IR (neat) 1468,
1
Preparation of 2a is representative. Iodo acetal 1a (10.2 g,
30.0 mmol) was dissolved in hexane (25 mL). The solution
was flushed with argon in a toy balloon. A solution of
triethylborane in hexane (1.0 M, 6.0 mL, 6.0 mmol) was
added to iodo acetal. After being stirred for 2 h at ambient
temperature, the reaction mixture was evaporated. Silica gel
column purification (hexane/ethyl acetate¼20/1) provided
2a (9.31 g, 27.4 mmol) in 91% yield. The diastereomer ratio
of 2a was determined by 1H NMR spectra to be 55/18/15/12.
1369, 1188, 1099, 1020, 978 cm21; H NMR (CDCl3): d
0.90 (t, J¼6.6 Hz, 3H), 0.91 (s, 3H), 1.09 (s, 3H), 1.26–1.40
(m, 5H), 1.50–1.60 (m, 2H), 1.78–1.90 (m, 1H), 2.22 (ddd,
J¼6.0, 8.4, 8.4 Hz, 1H), 3.05 (dd, J¼8.4, 10.2 Hz, 1H), 3.20
(dd, J¼6.0, 10.2 Hz, 1H), 3.30 (s, 3H), 3.70 (dt, J¼2.7,
8.4 Hz, 1H), 4.31 (s, 1H); 13C NMR (CDCl3): d 1.48, 14.04,
20.18, 21.43, 22.61, 26.09, 31.75, 37.82, 47.28, 52.84,
54.28, 85.50, 111.59. Found: C, 45.88; H, 7.12%. Calcd for
C13H25IO: C, 45.89; H, 7.41%.
Iodo compound 11 was prepared according to the
literature.8
4.5.3. 4-Iodomethyl-3,3-dimethyldihydrofuran-2(3H)-
one (3c). IR (neat) 1757, 1342, 1196, 1115, 1097,
1
1013 cm21; H NMR (CDCl3): d 1.10 (s, 3H), 1.30 (s,
4.3. Synthesis of cyclopropanes 4 from cyclic acetals 2
3H), 2.66 (dddd, J¼4.8, 7.2, 9.3, 11.1 Hz, 1H), 3.04 (dd,
J¼9.9, 11.1 Hz, 1H), 3.24 (dd, J¼4.8, 9.9 Hz, 1H), 3.87 (dd,
J¼9.6, 9.6 Hz, 1H), 4.49 (dd, J¼7.2, 9.6 Hz, 1H); 13C NMR
(CDCl3): d 20.21, 18.03, 23.90, 43.16, 48.67, 71.01,
181.37. Found: C, 33.09; H, 4.39%. Calcd for C7H11IO2:
C, 33.09; H, 4.36%.
Iodo acetal 2a (0.170 g, 0.500 mmol) in ether (2 mL) was
added to an ethereal solution of isopropylmagnesium
bromide (1.0 M ether solution, 4 equiv., 2.0 mL,
2.0 mmol) at 0 8C under argon. The reaction mixture was
stirred at ambient temperature for 10 h. The mixture
was poured into a saturated NH4Cl solution. The product
was then extracted with ethyl acetate (20 mL£3). The
combined organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was chromatographed
on silica gel (hexane/ethyl acetate¼20/1) to furnish alcohol
4a (0.077 g, 0.36 mmol) in 73% yield.
4.5.4. 4-Iodomethyl-3,3-dimethyl-5-pentyldihydrofuran-
2(3H)-one (3d). IR (neat) 2932, 2860, 1771, 1466, 1389,
1
1223, 1148, 1117, 1007, 934 cm21; H NMR (CDCl3): d
0.90 (t, J¼6.9 Hz, 3H), 1.16 (s, 3H), 1.26–1.50 (m, 5H),
1.37 (s, 3H), 1.50–1.70 (m, 2H), 1.87–2.00 (m, 1H),
2.28 (ddd, J¼7.2, 7.2, 9.3 Hz, 1H), 3.12 (d, J¼7.2 Hz, 1H),
3.13 (d, J¼7.2 Hz, 1H), 4.00 (dt, J¼3.0, 9.3 Hz, 1H);
13C NMR (CDCl3): d 22.16, 14.08, 18.56, 22.55, 25.15,
25.42, 31.54, 34.52, 43.93, 52.94, 82.43, 180.68. Found:
C, 44.57; H, 6.65%. Calcd for C12H21IO2: C, 44.46; H,
6.53%.
4.4. Reaction of b-iodomethyl-g-lactones 3
Under argon, iodo lactone 3c (0.170 g, 0.500 mmol) in ether
(2 mL) was added to isopropylmagnesium bromide (1.0 M
ether solution, 2 equiv., 1.0 mL, 1.0 mmol) at 0 8C. The
reaction mixture was stirred at ambient temperature for
10 h. The mixture was poured into 1 M HCl solution. The
product was extracted with ether (10 mL£3). Sodium
hydroxide (2 M, 5 mL) was added to the combined organic
4.5.5. 4-Iodomethyl-3,3,5,5-tetramethyldihydrofuran-
2(3H)-one (3e). IR (neat) 2341, 1757, 1462, 1377, 1286,
1
1099, 1065, 941 cm21; H NMR (CDCl3): d 1.22 (s, 3H),
1.37 (s, 3H), 1.38 (s, 3H), 1.58 (s, 3H), 2.48 (dd, J¼7.5,

T. Tsuji et al. / Tetrahedron 60 (2004) 973–978
977
8.1 Hz, 1H), 3.13 (dd, J¼8.1, 10.5 Hz, 1H), 3.21 (dd, J¼7.5,
10.5 Hz, 1H); 13C NMR (CDCl3): d 22.78, 20.32, 22.77,
27.23, 30.28, 44.11, 56.37, 84.19, 180.17. Found: C, 38.26;
H, 5.37%. Calcd for C9H15IO2: C, 38.32; H, 5.36%.
3H), 1.08 (d, J¼6.9 Hz, 3H), 1.11 (s, 9H), 1.18–1.40
(m, 8H), 2.24 (dq, J¼9.3, 6.9 Hz, 1H); 13C NMR (CDCl3)
For major isomer d 12.20, 14.20, 18.06, 19.02, 22.76, 22.93,
26.02, 29.33, 31.80, 34.15, 44.00, 44.10, 206.09. Found:
C, 80.08; H, 12.58%. Calcd for C15H28O: C, 80.29; H,
12.58%.
4.5.6. 2-Methyl-4-(2-pentylcyclopropyl)-3-pentanone
(5a, diastereomer ratio is 71/29). IR (neat) 2964, 2926,
2874, 2855, 1713, 1468, 1381, 1350, 1092, 1016 cm21; 1H
NMR (CDCl3) For major isomer: d 0.19–0.32 (m, 1H),
0.34–0.40 (m, 1H), 0.43–0.67 (m, 2H), 0.88 (t, J¼6.6 Hz,
3H), 1.06 (d, J¼6.9 Hz, 6H), 1.13 (d, J¼6.9 Hz, 3H), 1.05–
1.14 (m, 2H), 1.20–1.40 (m, 6H), 1.92 (dq, J¼9.3, 6.9 Hz,
1H), 2.77 (qq, J¼6.9, 6.9 Hz, 1H), for minor isomer, d
0.19–0.32 (m, 1H), 0.34–0.40 (m, 1H), 0.43–0.67 (m, 2H),
0.86 (t, J¼7.2 Hz, 3H), 1.07 (d, J¼6.9 Hz, 6H), 1.09 (d,
J¼6.9 Hz, 3H), 1.05–1.14 (m, 2H), 1.20–1.40 (m, 6H),
1.95 (dq, J¼9.3, 6.9 Hz, 1H), 2.77 (qq, J¼6.9, 6.9 Hz, 1H);
13C NMR (CDCl3) For major isomer: d 12.14, 14.18, 16.68,
18.19, 18.21, 18.71, 22.11, 22.74, 29.29, 31.77, 34.08,
39.36, 49.25, 217.62. Found: C, 79.88; H, 12.76%. Calcd for
C14H26O: C, 79.94; H, 12.46%.
4.5.10. 2-Methyl-2-(2-pentylcyclopropyl)-3-heptanone
(7). IR (neat) 2959, 2928, 2856, 1709, 1468, 1364,
1
1042 cm21; H NMR (CDCl3): d 0.17 (ddd, J¼5.1, 5.1,
8.7 Hz, 1H), 0.44 (ddd, J¼5.1, 5.1, 8.7 Hz, 1H), 0.58 (ddd,
J¼5.1, 5.1, 8.7 Hz, 1H), 0.63–0.71 (m, 1H), 0.88 (t, J¼
6.9 Hz, 3H), 0.90 (s, 3H), 0.91 (t, J¼7.5 Hz, 3H), 0.97 (s,
3H), 1.15–1.40 (m, 10H), 1.49–1.59 (m, 2H), 2.54 (t,
J¼7.2 Hz, 2H); 13C NMR (CDCl3) d 8.21, 13.96, 14.05,
14.81, 21.69, 22.47, 22.55, 22.64, 26.00, 26.45, 29.20,
31.72, 34.28, 36.95, 46.18, 215.57. Found: C, 80.32; H,
12.82%. Calcd for C16H30O: C, 80.61; H, 12.68%.
4.5.11. 2-Methyl-2-(2-pentylcyclopropyl)propionic acid
(9). IR (neat) 2924, 2856, 2569, 1703, 1474, 1412, 1296,
1155, 943 cm21; 1H NMR (CDCl3): d 0.17 (ddd, J¼5.1, 5.1,
8.7 Hz, 1H), 0.47 (ddd, J¼5.1, 5.1, 8.7 Hz, 1H), 0.62–0.74
(m, 1H), 0.77 (ddd, J¼5.1, 5.1, 8.7 Hz, 1H), 0.87 (t, J¼
6.6 Hz, 3H), 1.05 (s, 3H), 1.07 (s, 3H), 1.20–1.40 (m, 8H),
11.20 (bs, 1H); 13C NMR (CDCl3) d 8.23, 14.18, 14.83,
22.77, 22.91, 23.30, 27.23, 29.25, 31.76, 34.29, 41.21,
184.53. Found: C, 72.89; H, 11.03%. Calcd for C12H22O2:
C, 72.68; H, 11.18%.
4.5.7. 1-Cyclohexyl-2-(2-pentylcyclopropyl)-1-propa-
none (5b, diastereomer ratio is 72/28). IR (neat) 2928,
1
2855, 1709, 1450, 1373, 993 cm21; H NMR (CDCl3) For
major isomer: d 0.24–0.31 (m, 1H), 0.36–0.39 (m, 1H),
0.45–0.60 (m, 2H), 0.88 (t, J¼6.6 Hz, 3H), 1.12 (d, J¼
6.9 Hz, 3H), 1.06–1.15 (m, 1H), 1.17–1.45 (m, 12H),
1.60–1.70 (m, 1H), 1.70–1.84 (m, 4H), 1.90 (dq, J¼9.6,
6.9 Hz, 1H), 2.49 (m, 1H), for minor isomer, d 0.24–0.31
(m, 1H), 0.36–0.39 (m, 1H), 0.45–0.60 (m, 2H), 0.88 (t,
J¼6.6 Hz, 3H), 1.07 (d, J¼6.6 Hz, 3H), 1.06–1.15 (m, 1H),
1.17–1.45 (m, 12H), 1.60–1.70 (m, 1H), 1.70–1.84 (m,
4H), 1.90 (dq, J¼9.6, 6.9 Hz, 1H), 2.49 (m, 1H); 13C NMR
(CDCl3) d 12.08, 14.18, 16.64, 18.17, 22.00, 22.74, 25.73,
25.94, 28.32, 28.87, 29.30, 31.77, 33.98, 34.08, 49.34,
49.64, 216.92. Found: C, 81.25; H, 11.95%. Calcd for
C17H30O: C, 81.54; H, 12.08%.
4.5.12. 2-(2,2-Dimethylcyclopropyl)-2-methylpropionic
acid (10). IR (neat) 2874, 2571, 1703, 1458, 1412, 1379,
1294, 1175, 1028, 941, 827 cm21; 1H NMR (CDCl3): d 0.42
(d, J¼8.4 Hz, 2H), 0.78 (t, J¼8.4 Hz, 1H), 1.04 (s, 3H), 1.11
(s, 3H), 1.17 (s, 3H), 1.30 (s, 3H), 11.74 (bs, 1H); 13C NMR
(CDCl3) d 16.51, 16.80, 19.86, 24.79, 27.52, 29.21, 33.43,
41.33, 184.77. Found: C, 68.99; H, 10.11%. Calcd for
C9H16O2: C, 69.19; H, 10.32%.
4.5.8. 2-(2-Pentylcyclopropyl)-3-heptanone (5c, dia-
stereomer ratio is 71/29). IR (neat) 2959, 2928, 2856,
1713, 1458, 1373, 1259, 1030 cm21; 1H NMR (CDCl3): For
major isomer d 0.23–0.35 (m, 1H), 0.38–0.43 (m, 1H),
0.46–0.55 (m, 2H), 0.88 (t, J¼8.1 Hz, 3H), 0.90 (t, J¼
7.5 Hz, 3H), 1.13 (d, J¼6.9 Hz, 3H), 1.22–1.40 (m, 10H),
1.49–1.59 (m, 2H), 1.69–1.80 (m, 1H), 2.38–2.57 (m, 2H),
for minor isomer, d 0.23–0.35 (m, 1H), 0.38–0.43 (m, 1H),
0.46–0.55 (m, 2H), 0.88 (t, J¼8.1 Hz, 3H), 0.90 (t, J¼
7.5 Hz, 3H), 1.09 (d, J¼6.9 Hz, 3H), 1.22–1.40 (m, 10H),
1.49–1.59 (m, 2H), 1.69–1.80 (m, 1H), 2.38–2.57 (m, 2H);
13C NMR (CDCl3) For major isomer d 12.23, 14.01, 14.18,
16.23, 18.38, 22.20, 22.49, 22.74, 25.80, 29.29, 31.76,
34.08, 40.87, 51.13, 214.01. HRMS (m/z) Found: 224.2149.
Calcd for C15H28O: 224.2140.
4.5.13. 3-(2-Hydroxymethylcyclopropyl)-2,4-dimethyl-3-
pentanol (13). IR (neat) 3285, 2966, 2878, 1470, 1385,
1
1367, 1238, 1005, 899 cm21; H NMR (CDCl3): d 0.64–
0.72 (m, 2H), 0.72–0.84 (m, 1H), 0.94–1.02 (m, 1H),
0.99 (d, J¼6.9 Hz, 6H), 1.00 (d, J¼6.9 Hz, 6H), 1.92 (qq,
J¼6.9, 6.9 Hz, 1H), 1.98 (qq, J¼6.9, 6.9 Hz, 1H), 2.33 (bs,
2H), 3.86 (dd, J¼5.1, 11.4 Hz, 1H), 3.95 (dd, J¼5.1,
11.4 Hz, 1H); 13C NMR (CDCl3) d 4.42, 17.39, 17.70,
17.87, 17.98, 18.32, 20.20, 36.12, 36.79, 61.34, 76.73.
Found: C, 71.16; H, 11.96%. Calcd for C11H22O2: C, 70.92;
H, 11.90%.
Acknowledgements
4.5.9. 2,2-Dimethyl-4-(2-pentylcyclopropyl)-3-pentanone
(5d, diastereomer ratio is 72/28). IR (neat) 2964, 2926,
This work was supported by Grants-in-Aid for Scientific
Research (Nos. 12305058 and 10208208) and COE research
from the Ministry of Education, Culture, Sports, Science
and Technology, Government of Japan. Drs. Kawashima,
Nakao, and Kurahashi of Professor Hiyama’s group at
Kyoto University are acknowledged for helping HPLC
analysis. We thank Daicel Chemical Industries, Ltd for
determining the optical purity of 9.
1
2855, 1705, 1477, 1466, 1367, 1049, 991 cm21; H NMR
(CDCl3) For major isomer: d 0.16–0.29 (m, 2H), 0.41–0.55
(m, 1H), 0.65–0.78 (m, 1H), 0.87 (t, J¼6.9 Hz, 3H), 1.10 (s,
9H), 1.12 (d, J¼6.6 Hz, 3H), 1.18–1.40 (m, 8H), 2.24 (dq,
J¼9.3, 6.9 Hz, 1H), for minor isomer, d 0.16–0.29 (m, 2H),
0.41–0.55 (m, 1H), 0.65–0.78 (m, 1H), 0.87 (t, J¼6.9 Hz,

978
T. Tsuji et al. / Tetrahedron 60 (2004) 973–978
´
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