Successive carbon-carbon bond formation by sequential generation of radical and anionic species with manganese and catalytic amounts of PbCl2 and Me3SiCl

Article abstract of DOI:10.1246/bcsj.76.347

Three-component coupling reactions of iodoalkanes, α,β-unsaturated nitriles (or esters), and carbonyl compounds are achieved in good to excellent yields with a moderate reducing system derived from manganese metal and a catalytic amount of PbCl₂ and Me₃SiCl. Although the role of PbCl2 is unclear, addition of a catalytic amount of the salt is essential for reducing the iodoalkane. The reaction proceeds with primary, secondary, and tertiary iodoalkanes. Both acrylonitrile and acrylic esters can be employed as activated olefins, while the reaction with an alkyl vinyl ketone gives a complex mixture. Ketones and aldehydes can be used as the third component and the diastereoselectivity of the anionic addition is approximately 1: 1-2: 1 ratio. By using the heterogenerative process, i.e., successive 1,4-addition by radical and anionic internal addition, cyclopropanation of electron- deficient olefins is achieved with chloroiodomethane, manganese, PbCl₂, Me₃SiCl, and DMAP.

Full text of DOI:10.1246/bcsj.76.347

c. Jpn.
© 2003 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 76, 347–353 (2003)
347
e Chemical
ciety of Ja-
n
e Chemical
ciety of Ja-
n
Successive Carbon–Carbon Bond Formation by Sequential Generation
of Radical and Anionic Species with Manganese and Catalytic Amounts
of PbCl2 and Me3SiCl
Heterogenerative Process with Mn, PbCl2, and Me3SiCl
K. Takai et al.
03
7
Kazuhiko Takai,* Takashi Ueda, Norihiko Ikeda, Takaya Ishiyama, and Hiroshi Matsushita
3
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima, Okayama 700-8530
(Received July 24, 2002)
SJA8
09-2673
202
Three-component coupling reactions of iodoalkanes, α,β-unsaturated nitriles (or esters), and carbonyl compounds
are achieved in good to excellent yields with a moderate reducing system derived from manganese metal and a catalytic
amount of PbCl2 and Me3SiCl. Although the role of PbCl2 is unclear, addition of a catalytic amount of the salt is essen-
tial for reducing the iodoalkane. The reaction proceeds with primary, secondary, and tertiary iodoalkanes. Both acry-
lonitrile and acrylic esters can be employed as activated olefins, while the reaction with an alkyl vinyl ketone gives a
complex mixture. Ketones and aldehydes can be used as the third component and the diastereoselectivity of the anionic
addition is approximately 1:1–2:1 ratio. By using the heterogenerative process, i.e., successive 1,4-addition by radical
and anionic internal addition, cyclopropanation of electron-deficient olefins is achieved with chloroiodomethane, manga-
nese, PbCl2, Me3SiCl, and DMAP.
02
02
0
Effectiveness is important for organic synthesis. The more
bonds that can be formed in a single step, the fewer the steps
that will be required in a synthetic scheme. Such expressions
as domino, tandem, and cascade are used for the sequential re-
actions in one-pot, and Wender classified the reactions into two
categories: homogenerative and heterogenerative processes.1
Because intermolecular sequential reactions cannot use the ad-
vantage of an entropy factor, which intramolecular reactions
have, it is difficult to perform intermolecular carbon–carbon
bond formation in a pair-selective manner using homogenera-
tive processes. In contrast, a heterogenerative process in
which two (or more) reactive species participate can discrimi-
nate the corresponding reaction-partners more easily, and is
usually employed for intermolecular cases. Carbanion and
radical chemistry represent integral parts of organic synthesis,
and the reactivities of the two intermediates are sometimes
complementary. Therefore, sequential utilization of the two
offers untapped potential for building more complex molecules
effectively (Scheme 1).2,3
Alkyl radicals are usually prepared either by chain methods,
homolytic cleavage of covalent bonds, or by nonchain methods
based on redox reactions. One of the latter accesses radicals
by reduction of alkyl halides (R–X) with reducing agents;
however, the method is not so popular because further reduc-
tion of the initial radicals (RO) leading to alkyl anions (R−)
normally proceeds faster than the first radical formation under
the reduction conditions.3 Although intramolecular radical cy-
clization before anionic reactions has been observed in several
cases,3a,4 there are few examples of the intermolecular version
due to the above restriction.5,6 Two requirements exist for a
suitable reducing agent to connect the two reactions: (1) The
initial radical (RO) is not easily reduced to R− and has suffi-
cient lifetime to undergo an intermolecular reaction. (2) The
final radical (RꢀO) is easily subjected by one-electron reduction
to Rꢀ−. Therefore, the desired reductant should be weak
enough to be able to discriminate between the two radicals RO
and RꢀO. With these considerations in mind, a novel manga-
nese-lead reducing agent was utilized, and the above concept
was realized as a three-component coupling reaction and cy-
clopropanation of electron deficient olefins.
Although manganese metal (Mn(Ⅱ)/Mn(0), E0 = −1.185)
has stronger reduction potential than zinc (Zn(Ⅱ)/Zn(0), E0 =
−0.762), its powder7 is less reactive toward organic com-
pounds than zinc powder due to a tight layer of manganese ox-
ide on its surface. Recently, it was found that such metal oxide
is effectively removed by treatment with Me3SiCl;8,9 and more-
over, the manganese metal is especially activated by addition
of a catalytic amount of PbCl2.8 We employed this activated
manganese in the following experiments.
Scheme 1. Sequential utilization of a radical and anionic
species.

348 Bull. Chem. Soc. Jpn., 76, No. 2 (2003)
Heterogenerative Process with Mn, PbCl2, and Me3SiCl
Table 1. Three-Component Coupling of Iodoalkanes, Electron-Deficient Olefins and Carbonyl Compoundsa)
Run
R1
R2
H
R3
H
W
R4
R5
Time/h
Yieldb)/%
d.r.c)
1
2
3
4
5
6
7
8
9
i-Pr
CN
–(CH2)5–
–(CH2)5–
0.5
0.5
1
0.5
0.5
1
6
0.5
6
86
—
Ph
Et
H
H
96
57/43
68/32
—
85d,e)
83
H
H
CO2Me
Ph
Et
Ph
Ph
Ph
H
H
H
H
H
81
41/59f)
51/49f)
77d,e)
68e)
67
g)
Me
H
H
H
H
H
Me
H
H
H
CN
CN
CN
CO2Me
CN
—
52/48
55/45
—
n-Pr
t-Bu
67e)
61e)
86
10
11
–(CH2)5–
4
0.5
Ph
H
59/41
a) Reaction was conducted on a 2.0 mmol scale. An iodoalkane (3.0 mol), a carbonyl compound (3.0 mol), Mn
(6.0 mol), PbCl2 (0.06 mol), and Me3SiCl (0.10 mol) were used per mol of an activated olefin. b) Isolated yields.
c) Diastereomer ratios were determined by isolation, GLPC or NMR. d) An aldehyde (1.2 mol) was used per mol
of an electron-deficient olefin. e) PbCl2 (0.3 mol) was used per mol of an olefin. f) anti/syn ratio. g) A mixture of
four isomers of undetermined structures.
Scheme 3.
Scheme 2.
Results and Discussion
Three-Component Coupling Reactions of Iodoalkanes,
Electron-Deficient Olefins, and Carbonyl Compounds.10
Treatment of the tertiary iodoalkane 1 with the activated man-
ganese metal in a mixed solvent of THF and DMF afforded
four compounds 2-5 (Scheme 2). The result suggests the for-
mation of an alkyl radical by reduction of the iodide with the
manganese system, as the dimer 2 could be produced by ho-
mocoupling of the radical 6, and 4 and 5 could be produced by
Scheme 4.
disproportionation of 6.
produced anionic species could be trapped with a carbonyl
compound under mild conditions (Scheme 4).12 Although the
role of PbCl2 is unclear, addition of a catalytic amount of the
salt was essential for reducing the iodoalkane. Addition of
Et2AlCl or anhydrous hydrochloric acid in place of Me3SiCl
was also effective in promoting the reaction.
The results of three-component coupling of iodoalkanes, ac-
tivated olefins, and carbonyl compounds are shown in Table 1.
Three mol of iodoalkanes and of carbonyl compounds were
In order to examine the nature of the manganese-generated
alkyl radicals, intermolecular 1,4-addition of the radicals to
α,β-unsaturated ester 7 under protic conditions was conducted,
and it was found that 1,4-adducts 8 were obtained in excellent
yields (Scheme 3).11 It is likely, therefore, that the second one-
electron reduction leading to an alkylmanganese compound is
slower than the first reduction with this manganese system.
When the reaction was conducted in an aprotic solvent, the

K. Takai et al.
Bull. Chem. Soc. Jpn., 76, No. 2 (2003) 349
Scheme 5.
Scheme 7. A Possible mechanism for the three-component
coupling.
products that are difficult to obtain with organocuprates in one-
pot reactions due to their complex nature.13
In 1978, Shono and Nishiguchi reported a similar three-
component coupling of iodoalkanes, α,β-unsaturated nitriles
(or esters), and carbonyl compounds using zinc metal.14 Al-
though the mechanism of the zinc-mediated coupling reaction
has not yet been clarified, the reaction could also be a similar
heterogenerative process of a radical and anionic species.
Scheme 6.
Cyclopropanation of Electron-Deficient Olefins.
Sim-
mons-Smith reaction, the carbenoid approach, is usually em-
ployed for cyclopropanation of olefinic double bonds;15,16
however, the reaction with electron-deficient olefins proceeds
slowly and sometimes results in recovery of the olefins.15b–d
The other pathway to cyclopropanation of electron-deficient
olefins is a sequential 1,4-addition-substitution reaction.17,18
We describe here a manganese-mediated cyclopropanation via
the latter approach, where an alkyl radical plays the key role
for the first 1,4-addition step.19
One-electron reduction of iodoalkanes with the activated
manganese metal proceeds smoothly to give the corresponding
alkyl radicals, which add to α,β-unsaturated esters in a 1,4-
fashion.10 Successive one-electron reduction affords ester eno-
lates, which add to carbonyl compounds to give aldol-type ad-
ducts.6 Thus, we examined intramolecular trapping of the
formed enolates with alkyl halides at the γ-position of the es-
ters, which will provide cyclopropyl compounds.
As a methylene radical-cation synthon, gem-dihalomethanes
were used. Treatment of 3-phenylpropyl acrylate (19) with di-
iodomethane, manganese, PbCl2, and Me3SiCl in THF pro-
duced the desired cyclopropanecarboxylic ester 20 in 3% yield
after being stirred for 24 h; The acrylate 19 was recovered in
88% yield (Table 2, run 1). Reactions with dibromo- and
dichloromethane did not proceed, either, and in each case, 19
was recovered in almost quantitative yields (runs 2 and 3). Ad-
dition of LiI to the reaction with dibromomethane resulted in
formation of 20 in 7% yield (run 4), which suggests that one of
the halogen should be an easily-reduced iodine atom. There-
fore, the ester 19 was treated with a combination of chloro-
iodomethane and the activated manganese, and cyclopropane-
carboxylic ester 20 was produced in 62% yield, along with 4-
chlorobutanoate 21, the 1,4-adduct in 16% yield (run 5). The
yield of the ester 20 was improved by addition of 0.15 equiv. of
4-(dimethylamino)pyridine (DMAP) as an activator of
used per mole of olefins. The reaction proceeded with prima-
ry, secondary, and tertiary iodoalkanes. In the case of primary
iodide, the amount of PbCl2 was increased from 1 to 5 mol%
of manganese to accelerate the reduction of the iodide (Table
1, runs 9 and 10). Both acrylonitrile and acrylic esters could
be employed as activated olefins, while the reaction with an
alkyl vinyl ketone gave a complex mixture. A substituent at
the β-position of the electron-deficient olefin decreased the re-
activity of the olefin, and the reaction also required 5 mol% of
PbCl2 (run 7). Ketones and aldehydes could be used as the
third component, and the diastereoselectivity of the anionic ad-
dition was approximately 1:1–2:1 ratio.
When 7-iodo-2-methyl-2-heptene (11) was used as an io-
doalkane, intramolecular radical cyclization occurred before
intermolecular addition to acrylonitrile (Scheme 5). No three-
component coupling product without the cyclization, however,
was detected.
Hydroxynitrile 13 was obtained in 50% yield in the case of
4-iodo-1-butene (Scheme 6), although no coupling product
was obtained from further cyclization. The result suggests that
the second one-electron reduction of radical 14 to a nitrile an-
ion 15 proceeds very quickly.
Consequently, the three-component coupling is realized by a
subtle balance of the reaction rates (Scheme 7). The reduction
rate of an alkyl radical 16 to an alkyl anion 17 is slower than
1,4-addition of the radical to an electron-deficient olefin.
However, one-electron transfer to the resulting radical 18 hav-
ing an electron-withdrawing group proceeds faster than addi-
tion to a different unsaturated bond. Sequential generation and
utilization of a radical and anionic species, therefore, are the
essential factors in the coupling reaction of iodoalkanes, α,β-
unsaturated nitriles (or esters), and ketones (or aldehydes), and
the protocol itself can provide a new access to similar coupling

350 Bull. Chem. Soc. Jpn., 76, No. 2 (2003)
Heterogenerative Process with Mn, PbCl2, and Me3SiCl
Table 2. Cyclopropanation of 3-Phenylpropyl Acrylate with Dihalomethane and Activated Manganesea)
Yield/%b)
Recov./%b)
Run
CH2X2
CH2I2
CH2Cl2
CH2Br2
Me3SiCl/equiv
Additive, equiv
Time/h
20
3
21
0
19
88
95
92
66
0
0
0
0
1
2
3
4
5
6
7
8
0.15
0.15
0.15
0.15
0.15
0.15
3.0
24
24
24
0
0
7
0
0
0
LiI, 3.0
DMAP, 0.15
DMAP, 3.0
24
CH2ClI
0.3
0.3
0.5
0.5
62
74
70
4
16
12
20
66
3.0
a) Reactions were conducted on a 1.0 mmol scale. Dihalomethane (3.0 mol), Mn (8.5 mol), and PbCl2 (0.085
mol) were employed per mol of the acrylate. b) Isolated yields.
Table 3. Cyclopropanation of Electron-Deficient Olefins
with Chloroiodomethane and Activated Manganesea)
Run
1
Time/h
0.3
Yield/%b)
61, 62c)
2
3
0.3
72
74, 81c)
33d)
Scheme 8. A Possible mechanism for cyclopropanation.
amide 23. It is worth noting that the protocol could also be ap-
plied to a vinyl sulfone with which the Simmons-Smith reac-
tion does not work well (run 5).15c The substituent at the β-po-
sition of α,β-unsaturated ester retarded the reaction consider-
ably, as is usually observed in 1,4-addition mediated by an
alkyl radical (run 3). In contrast to the Simmons-Smith reac-
tion, 2-methyl-5-phenyl-2-pentene, the trisubstituted olefin,
was recovered almost quantitatively (run 6).
A possible mechanism for the cyclopropanation is shown in
Scheme 8: 1) One-electron reduction of chloroiodomethane to
a chloromethyl radical by activated manganese metal with
PbCl2 and Me3SiCl; 2) 1,4-Addition of the radical to an elec-
tron-deficient olefin; 3) One-electron reduction of the resulting
radical having an electron-withdrawing group; 4) Anionic in-
tramolecular substitution leading to a cyclopropane compound.
Because of the mild reducing power of the activated manga-
nese metal, further reduction of chloromethyl radical to its an-
ion proceeds slower than 1,4-addition of the radical to an elec-
tron-deficient olefin.10,21 In contrast, the second one-electron
reduction proceeds smoothly due to the electron-withdrawing
group. Therefore, the cyclopropanation is also realized via
successive generation and utilization of a radical and anionic
species.
4
5
6
0.5
0.5
24
63, 67c)
59
0e)
a) Reactions were conducted on a 1.0 mmol scale.
Chloroiodo-methane (3.0 mol), Mn (8.5 mol), PbCl2
(0.085 mol), Me3SiCl (0.15 mol) and DMAP (0.15
mol) were employed per mol of an olefin. b) Isolated
yields. c) The amounts of Mn and PbCl2 were
increased to 18 and 0.18 mmol, respectively. d) anti/
syn = 13/1. e) Recovery: 97%.
Me3SiCl (run 6).20 Addition of 3 equiv of both Me3SiCl and
DMAP, however, resulted in formation of 21 (run 8), probably
due to smooth trapping of the formed enolate as a ketene silyl
acetal before workup.
The cyclopropanation with chloroiodomethane and activat-
ed manganese also proceeded with an α,β-unsaturated ketone
and an amide (Table 3, runs 1 and 4).16 The yield of 20 was
improved to 81% when the amount of manganese metal was
increased to 18 equiv of the ester 19; however, only slight im-
provements were observed in the case of the ketone 22 and
In summary, the mild reductant system, manganese metal
and a catalytic amount of PbCl2 and Me3SiCl, can discriminate

K. Takai et al.
Bull. Chem. Soc. Jpn., 76, No. 2 (2003) 351
7.3–7.5 (m, 5H); 13C NMR (CDCl3) δ 21.0, 22.9 (A), 23.0 (B),
25.9, 36.4, 36.5, 37.5 (B), 38.4 (A), 39.0 (B), 73.5 (A), 73.7 (B),
120.1, 126.0 (B), 126.3 (A), 128.3, 128.4, 140.0 (A), 140.6 (B).
between iodoalkanes, alkyl radicals, and radicals at the α posi-
tion of esters. In the presence of the manganese reductant, the
alkyl radical is so long-lived that it can undergo intermolecular
addition to an α,β-unsaturated ester. Rapid one-electron re-
duction of the formed radical at the α position of the ester re-
sults in a manganese enolate, which adds to a carbonyl com-
pound to afford a three-component coupling product. When
chloroiodomethane is used as the iodoalkane, an intramolecu-
lar reaction of the manganese enolate with a halogen at the 4
position occurs to give a cyclopropyl compound.
3-Hydroxy-2-isobutylpentanenitrile.14
Two diastereomers
were produced in a ratio of A/B = 68/32 and could not be separat-
ed by column chromatography on silica gel. bp 70 °C (bath temp,
0.5 Torr); IR (neat) 3447, 2962, 2937, 2875, 2241, 1467, 1370,
1
1114, 1061, 980 cm−1; H NMR (CDCl3) δ 0.90–1.10 (m, 9H),
1.25–1.50 (m, 1H), 1.50–1.95 (m, 5H), 2.60–2.82 (m, 1H), 3.49–
3.66 (m, 1H); 13C NMR (CDCl3) δ 9.94, 21.1 (B), 21.4 (A), 22.9
(A), 23.2 (B), 26.0 (A), 26.2 (B), 27.0 (B), 28.5 (A), 36.6 (B), 36.9
(A), 37.1 (B), 37.7 (A), 72.9 (A), 73.1 (B), 120.2 (A), 120.7 (B).
Methyl 2-(1-Hydroxycyclohexyl)-4-methylpentanoate. Bp
67 °C (bath temp, 0.08 Torr); IR (neat) 3500, 2935, 2868, 1717,
1438, 1367, 1197, 1169, 982, 665 cm−1; 1H NMR (CDCl3) δ 0.86
(d, J = 1.9 Hz, 3H), 0.91 (d, J = 2.1 Hz, 3H), 1.18–1.82 (m, 14H),
2.51 (dd, J = 11.8, 3.1 Hz, 1H), 3.69 (s, 3H); 13C NMR (CDCl3) δ
21.3, 21.6, 21.8, 23.6, 25.6, 26.5, 34.3, 35.5, 37.1, 51.2, 52.6,
71.6, 176.8. Anal. Calcd for C13H24O3: C, 68.38; H, 10.59%.
Found: C, 68.09; H, 10.88%.
Experimental
General. Unless otherwise noted, materials were obtained
from commercial suppliers and were used without further purifica-
tion. Manganese powder was purchased from either Rare Metallic
Co. (99% purity, –80 mesh) or Kojundo Chemical Laboratory
(99.9% purity, –50 mesh). PbCl2 (99.999% purity) was purchased
from Rare Metallic Co., Japan. Tetrahydrofuran (THF) was dis-
tilled from sodium/benzophenone just before use. N,N-Dimethyl-
formamide (DMF) was distilled from calcium hydride under re-
duced pressure with nitrogen bubbling. Distillations of small
amounts of products were performed with a Büchi Kugelrohr, and
boiling points are indicated by an air bath temperature without
correction. FT-IR spectra were obtained on a Bio-Rad FTS-7 or a
Nicolet Protégé 460 spectrometer. 1H and 13C NMR spectra were
determined with a Varian Gemini-200 or a JEOL JNM-LA400 in-
strument. Chemical shifts are expressed in ppm downfield from
internal tetramethylsilane using the δ scale. Low and high resolu-
tion of EI mass spectra were obtained with a capillary GC inter-
faced JEOL JMS-SX102A. Column chromatography was done
with silica gel (230–400 mesh).
General Procedure for Three-Component Addition Reac-
tions. To a mixture of manganese powder (0.66 g, 12 mmol) and
PbCl2 (34 mg, 0.12 mmol) in THF (8 mL) was added Me3SiCl (26
µL, 0.20 mmol) at 25 °C, and the mixture was stirred at 25 °C for
30 min. A solution of an electron-deficient olefin (2.0 mmol) and
a carbonyl compound (6.0 mmol) in DMF (2 mL) was added to
the suspension, and then a solution of an iodoalkane (6.0 mmol) in
DMF (2 mL) was added slowly to the mixture at 25 °C, producing
an exothermic reaction (ca. 40 °C). After being stirred at 25 °C
for an appropriate time as described in Table 1, the reaction was
quenched by addition of a few drops of water. The mixture was
filtered with Celite using ether (50 mL) as an eluent. Organic ex-
tracts were washed with water and dried over MgSO4 and then
concentrated. Purification of the crude product by column chro-
matography on silica gel gave the desired coupling product.
2-(1-Hydroxycyclohexyl)-4-methylpentanenitrile (10).14
anti-Methyl 2-(1-Hydroxy-1-phenylmethyl)-4-methylpen-
tanoate. Mp 69–71 °C (hexane); IR (nujol) 3470, 2953, 2854,
1737, 1453, 1378, 1158, 1046, 767, 704, 665 cm−1 1H NMR
;
(CDCl3) δ 0.80 (d, J = 2.7 Hz, 3H), 0.83 (d, J = 2.8 Hz, 3H), 1.03
(ddd, J = 13.5, 8.9, 4.3 Hz, 1H), 1.35–1.75 (m, 2H), 2.73 (d, J =
5.6 Hz, 1H), 2.79–2.94 (m, 1H), 3.69 (s, 3H), 4.75 (dd, J = 7.8,
2.2 Hz, 1H), 7.20–7.40 (m, 5H); 13C NMR (CDCl3) δ 21.4, 23.2,
26.0, 38.5, 51.2, 75.9, 126.4, 127.9, 128.5, 142.1, 176.0. Anal.
Calcd for C14H20O3: C, 71.16; H, 8.53%. Found: C, 71.00; H,
8.76%.
syn-Methyl
tanoate. Bp 72 °C (bath temp, 0.08 Torr); IR (neat) 3455, 2956,
2871, 1734, 1437, 1367, 1247, 1195, 1167, 1044, 771, 701 cm−1
2-(1-Hydroxy-1-phenylmethyl)-4-methylpen-
;
1H NMR (CDCl3) δ 0.79 (d, J = 6.1 Hz, 3H), 0.85 (d, J = 6.3 Hz,
3H), 1.25–1.50 (m, 2H), 1.55–1.80 (m, 1H), 2.75–2.86 (m, 2H),
3.59 (s, 3H), 4.93 (dd, J = 5.4, 2.7 Hz, 1H), 7.20–7.38 (m, 5H);
13C NMR (CDCl3) δ 21.3, 23.4, 26.3, 36.1, 51.3, 51.5, 74.5, 126.0,
127.6, 128.2, 141.5, 175.5. Anal. Calcd for C14H20O3: C, 71.16;
H, 8.53%. Found: C, 71.13; H, 8.48%.
anti-Methyl 3-Hydroxy-2-isobutylpentanoate.
Bp 48 °C
(bath temp, 0.12 Torr); IR (neat) 3430, 2959, 2874, 1737, 1466,
1439, 1369, 1197, 1169, 1108, 981, 666 cm−1; 1H NMR (CDCl3)
δ 0.85–0.94 (m, 6H), 0.96 (t, J = 7.8 Hz, 3H), 1.25–1.80 (m, 5H),
2.33 (d, J = 4.6 Hz, 1H), 2.56 (dt, J = 10.9, 3.8 Hz, 1H), 3.62–
3.77 (m, 4H); 13C NMR (CDCl3) δ 10.2, 21.6, 23.4, 26.4, 27.1,
35.9, 48.7, 51.6, 73.8, 176.2. Anal. Calcd for C10H20O3: C, 63.80;
H, 10.71%. Found: C, 63.51; H, 10.98%.
syn-Methyl 3-Hydroxy-2-isobutylpentanoate.
Bp 46 °C
Mp 55–56 °C; bp 92 °C (bath temp, 0.10 Torr); IR (nujol) 3457,
(bath temp, 0.13 Torr); IR (neat) 3450, 2958, 2873, 1710, 1471,
2955, 2245, 1444, 1163, 1140, 985, 908, 845 cm−1
;
1H NMR
1438, 1369, 1197, 1169, 1124, 976 cm−1; H NMR (CDCl3) δ
1
(CDCl3) δ 0.92 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H),
1.15–1.93 (m, 14H), 2.59 (dd, J = 12.0, 4.4 Hz, 1H); 13C NMR
(CDCl3) δ 20.8, 21.2, 21.3, 23.4, 25.2, 26.3, 34.5, 34.7, 42.5, 71.5,
120.7.
0.87 (d, J = 4.5 Hz, 3H), 0.91 (d, J = 4.6 Hz, 3H), 0.96 (t, J = 7.3
Hz, 3H), 1.22–1.77 (m, 5H), 2.44 (d, J = 8.1 Hz, 1H), 2.55 (dt, J
= 9.8, 5.0 Hz, 1H), 3.44–3.62 (m, 1H), 3.69 (s, 3H); 13C NMR
(CDCl3) δ 10.0, 21.9, 23.0, 26.2, 28.6, 38.7, 48.5, 51.5, 74.1,
176.3. Anal. Calcd for C10H20O3: C, 63.80; H, 10.71%. Found:
C, 63.55; H, 10.95%.
2-(1-Hydroxy-1-phenylmethyl)-4-methylpentanenitrile.14
Two diastereomers were produced in a ratio of A/B = 57/43 and
could not be separated by column chromatography on silica gel.
Bp 112 °C (bath temp, 0.08 Torr); IR (neat) 3450, 3064, 3032,
2-(1-Hydroxy-1-phenylmethyl)-3,4-dimethylpentaneni-
trile.14 Four diastereomers were produced with undefined struc-
tures; they could not be separated by column chromatography on
silica gel. bp 114 °C (bath temp, 0.08 Torr); IR (neat) 3448, 2965,
1
2958, 2872, 2243, 1456, 1389, 1043, 762, 702 cm−1; H NMR
(CDCl3) δ 0.86–0.97 (m, 6H), 1.10–2.00 (m, 3H), 2.34 (d, J = 3.3
Hz, 1H(A)), 2.42 (d, J = 3.7 Hz, 1H(B)), 2.89 (dt, J = 11.2, 5.2
Hz, 1H(B)), 3.02 (dt, J = 11.1, 4.8 Hz, 1H(A)), 4.7–4.85 (m, 1H),
2877, 2243, 1458, 1388, 1267, 1053, 738, 701, 665 cm−1
;
1H NMR (CDCl3) δ 0.75–1.30 (m, 9H), 1.55–2.20 (m, 3H), 2.95–

352 Bull. Chem. Soc. Jpn., 76, No. 2 (2003)
Heterogenerative Process with Mn, PbCl2, and Me3SiCl
3.10, 4.75–5.03 (m, 1H), 7.20–7.55 (m, 5H); 13C NMR (CDCl3) δ
11.2, 11.8, 12.8, 13.3, 15.2, 15.6, 18.8, 19.5, 20.2, 20.3, 21.4,
21.5, 29.2, 29.6, 31.1, 31.7, 36.5, 36.8, 37.2, 37.7, 43.9, 44.1,
45.4, 46.7, 70.7, 71.7, 72.3, 73.1, 118.8, 119.3, 119.6, 125.6,
126.2, 126.5, 126.8, 126.9, 128.3, 128.4, 128.6, 128.7, 128.8,
139.8, 140.3, 140.9, 141.3.
2-(1-Hydroxy-1-phenylmethyl)-6-heptenenitrile (13). Two
diastereomers were produced in a ratio of 56/44; they could not be
separated by column chromatography. bp 124 °C (bath temp, 0.06
Torr); IR (neat) 3447, 3066, 2928, 2864, 2243, 1640, 1456, 1048,
995, 915, 764, 702 cm−1; 1H NMR (CDCl3) δ 1.40–1.80 (m, 4H),
1.98–2.12 (m, 2H), 2.42 (d, J = 2.7 Hz, 1H(A)), 2.51 (d, J = 3.3
Hz, 1H(B)), 2.78–3.02 (m, 1H), 4.76 (dd, J = 6.1, 3.6 Hz, 1H(B)),
4.81 (dd, J = 6.3, 3.1 Hz, 1H(A)), 4.90–5.07 (m, 2H), 5.62–5.88
(m, 1H), 7.30–7.48 (m, 5H); 13C NMR (CDCl3) δ 26.2, 27.4, 28.4,
32.9, 33.0, 40.3, 40.9, 73.7, 74.0, 115.3, 115.3, 120.0, 126.1,
126.4, 128.7, 128.8, 137.5, 137.6, 140.0, 140.3; EI MS m/z (%)
215 (M+, 8), 198 (4), 167 (4), 147 (25), 108 (95), 107 (95), 105
(80), 79 (100), 77 (98). HRMS (EI) m/z calcd for (M+)
C14H17NO: 215.1310, found 215.1320.
Typical Procedure for 3-Phenylpropyl Cyclopropanecar-
boxylate (20). To a suspension of manganese powder (0.47 g,
8.5 mmol),6 PbCl2 (24 mg, 0.085 mmol),6 and DMAP (18 mg,
0.15 mmol) in THF (6 mL) was added Me3SiCl (0.019 mL, 0.15
mmol), and the mixture was stirred at 25 °C for 30 min. A solu-
tion of 3-phenylpropyl acrylate (0.19 g, 1.0 mmol) in DMF (1.5
mL) and a solution of chloroiodomethane (0.53 g, 3.0 mmol) in
DMF (1.5 mL) were successively added to the mixture. After be-
ing stirred at 25 °C for 15 min, the resulting mixture was poured
into an NH4Cl solution (10 mL) and the mixture was extracted
with ether (3 × 10 mL). The organic extracts were washed with
brine, dried over anhydrous MgSO4 and concentrated. Purifica-
tion by column chromatography on silica gel (ethyl acetate–hex-
ane, 1:30–1:50) afforded cycropropanecarboxylic ester 20 in 74%
yield (0.15 g) and 1,4-adduct 21 in 12% yield (29 mg).
2-(1-Hydroxy-1-phenylmethyl)-2,4-dimethylpentaneni-
trile.14 Two diastereomers were produced in a ratio of 52/48;
they could not be separated by column chromatography. bp 117
°C (bath temp, 0.07 Torr); IR (neat) 3458, 2959, 2873, 2238,
1
1458, 1389, 1267, 1172, 1167, 1056, 768, 703 cm−1; H NMR
(CDCl3) δ 0.92–1.14 (m, 6H), 1.15–1.55 (m, 1H), 1.19 and 1.40
(s, 3H), 1.75–2.00 (m, 2H), 2.30 and 2.38 (d, J = 3.4 Hz, 1H),
4.56 and 4.59 (d, J = 3.5 Hz, 1H), 7.30–7.50 (m, 5H); 13C NMR
(CDCl3) δ 20.2, 20.5, 23.2, 23.3, 24.3, 24.5, 24.9, 25.0, 42.0, 42.4,
43.4, 44.2, 78.0, 78.7, 123.3, 123.4, 127.5, 128.1, 128.5, 128.5,
138.9, 139.0.
2-(1-Hydroxy-1-phenylmethyl)hexanenitrile. Two diastere-
omers were produced in a ratio of 55/45; they could not be sepa-
rated by column chromatography. bp 75 °C (bath temp, 0.07
Torr); IR (neat) 3446, 2958, 2931, 2871, 2250, 1663, 1456, 1388,
1
1098, 1057, 762, 703 cm−1; H NMR (CDCl3) δ 0.80–1.96 (m,
3H), 1.20–1.70 (m, 6H), 2.20 and 2.31 (d, J = 3.4 Hz, 1H), 2.75–
3.00 (m, 1H), 4.74–4.88 (m, 1H), 7.30–7.50 (m, 5H); 13C NMR
(CDCl3) δ 13.6, 13.7, 22.0, 22.1, 27.5, 28.5, 29.1, 29.1, 40.3, 40.9,
73.4, 73.7, 120.1. 120.2, 126.1, 126.4, 128.4, 128.5, 128.5, 128.6,
140.0, 140.4. Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N,
6.89%. Found: C, 76.92; H, 8.59; N, 6.85%.
Methyl 2-(1-Hydroxycyclohexyl)hexanoate. Bp 72 °C (bath
temp, 0.07 Torr); IR (neat) 3510, 2934, 2861, 1710, 1435, 1356,
1195, 1170, 982, 926, 852, 665 cm−1; 1H NMR (CDCl3) δ 0.88 (t,
J = 7.0 Hz, 3H), 1.10–1.85 (m, 16H), 2.41 (dd, J = 10.9, 4.2 Hz,
1H), 2.72 (s, 1H), 3.71 (s, 3H); 13C NMR (CDCl3) δ 13.6, 21.4,
21.6, 22.4, 25.5, 25.9, 29.9, 34.3, 36.8, 51.0, 54.7, 71.3, 176.5.
Anal. Calcd for C13H24O3: C, 68.38; H, 10.59%. Found: C, 68.09;
H, 10.92%.
2-(1-Hydroxy-1-phenylmethyl)-4,4-dimethylpentanenitrile.
Two diastereomers were produced in a ratio of A/B = 59/41; they
could not be separated by column chromatography. mp 68–70 °C
(ether–hexane); IR (nujol) 3381, 2951, 2853, 2244, 1453, 1378,
1289, 1232, 1084, 1066, 1041, 767, 713 cm−1; 1H NMR (CDCl3)
δ 0.92 and 0.94 (s, 9H), 1.21–1.78 (m, 2H), 2.27 (d, J = 3.6 Hz,
1H(A)), 2.36 (d, J = 3.6 Hz, 1H(B)), 2.82 (ddd, J = 10.5, 6.1, 2.3
Hz, 1H(B)), 2.92 (ddd, J = 9.1, 5.1, 4.0 Hz, 1H(A)), 4.76 (dd, J =
5.9, 3.5 Hz, 1H(B)), 4.81 (dd, J = 5.8, 3.6 Hz, 1H(A)), 7.30–7.47
(m, 5H); 13C NMR (CDCl3) δ 29.0, 29.1, 30.3, 30.3, 35.5 (A),
36.2 (B), 41.1 (A), 42.3 (B), 74.2 (A), 74.7 (B), 121.5 (B), 121.7
(A), 126.3, 126.4, 128.4, 128.5, 139.7 (A), 140.1 (B). Anal. Cal-
cd for C14H19NO: C, 77.34; H, 8.81; N, 6.45%. Found: C, 77.63;
H, 8.92; N, 6.47%.
4-Cyclopentyl-2-(1-hydroxy-1-phenylmethyl)-4-methylpen-
tanenitrile (12). Two diastereomers were produced in a ratio of
52/48; they could not be separated by column chromatography.
bp 138 °C (bath temp, 0.08 Torr); IR (neat) 3442, 2956, 2868,
2242, 1453, 1390, 1369, 1058, 763, 716, 702, 666 cm−1; 1H NMR
(CDCl3) δ 0.81, 0.84, 0.87, and 0.88 (s, 6H), 1.00–2.00 (m, 11H),
2.20–2.38 (m, 1H), 2.78–2.98 (m, 1H), 4.67–4.84 (m, 1H), 7.30–
7.48 (m, 5H); 13C NMR (CDCl3) δ 23.9, 24.1, 25.6, 26.6, 26.7,
34.5, 34.6, 34.9, 35.8, 38.8, 40.3, 49.0, 49.0, 74.5, 75.2, 121.6,
121.8, 126.3, 126.4, 128.4, 128.5, 139.8, 140.2. Anal. Calcd for
C18H25NO: C, 79.66; H, 9.28; N, 5.16%. Found: C, 79.37; H,
9.53; N, 4.97%.
3-Phenylpropyl Cyclopropanecarboxylate (20):
Bp 80 °C
(bath temp, 0.11 Torr); IR (neat) 3026, 2955, 2928, 2857, 1727,
1497, 1454, 1403, 1372, 1267, 1200, 1175, 1077, 1030, 745, 700
cm−1; 1H NMR (CDCl3) δ 0.84–0.88 (m, 2H), 0.97–1.02 (m, 2H),
1.58–1.65 (m, 1H), 1.93–2.00 (m, 2H), 2.70 (t, J = 7.3 Hz, 2H),
4.10 (t, J = 6.6 Hz, 2H), 7.12–7.35 (m, 5H); 13C NMR (CDCl3) δ
8.3, 12.9, 30.3, 32.2, 63.8, 126.0, 128.4, 128.4, 141.3, 174.9.
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90%. Found: C, 76.30;
H, 8.06%.
3-Phenylpropyl 4-Chlorobutanoate (21).
temp, 0.47 Torr); IR (neat) 3027, 2958, 2862, 1735, 1497, 1454,
1315, 1299, 1242, 1209, 1176, 1147, 1019, 747, 700 cm−1
Bp 95 °C (bath
;
1H NMR (CDCl3) δ 1.94–2.01 (m, 2H), 2.05–2.13 (m, 2H), 2.50
(t, J = 7.2 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H), 3.61 (t, J = 6.3 Hz,
2H), 4.12 (t, J = 6.6 Hz, 2H), 7.16–7.32 (m, 5H); 13C NMR
(CDCl3) δ 27.7, 30.2, 31.2, 32.2, 44.1, 64.0, 126.0, 128.4, 141.1,
172.7. Anal. Calcd for C13H17ClO2: C, 64.86; H, 7.12%. Found:
C, 64.58; H, 7.06%.
1-Cyclopropyl-3-phenyl-1-propanone.22
temp, 0.20 Torr); IR (neat) 3027, 3008, 2950, 2929, 1698, 1497,
Bp 80 °C (bath
1453, 1388, 1100, 1086, 1073, 1032, 1012, 750, 700, 666 cm−1
;
1H NMR (CDCl3) δ 0.83–0.89 (m, 2H), 1.00–1.04 (m, 2H), 1.88–
1.95 (m, 1H), 2.86–2.95 (m, 4H), 7.15–7.33 (m, 5H); 13C NMR
(CDCl3) δ 10.7, 20.5, 29.9, 45.0, 126.0, 128.3, 128.4, 141.2,
210.0.
3-Phenylpropyl 2-Methylcyclopropanecarboxylate. Bp 85
°C (bath temp, 0.40 Torr); IR (neat) 3027, 2957, 2870, 1725,
1497, 1454, 1411, 1376, 1323, 1265, 1182, 1167, 1077, 1032,
746, 700, 666 cm−1; 1H NMR (CDCl3) δ 0.71–0.76 (m, 1H), 1.18
(d, J = 6.0 Hz, 3H), 1.20–1.25 (m, 1H), 1.38–1.49 (m, 2H), 1.99–
2.06 (m, 2H), 2.76 (t, J = 7.8 Hz, 2H), 4.14 (t, J = 6.6 Hz, 2H),
7.24–7.40 (m, 5H); 13C NMR (CDCl3) δ 16.7, 17.2, 17.9, 21.3,
30.3, 32.2, 63.7, 126.0, 128.4, 128.4, 141.3, 174.5. Anal. Calcd

K. Takai et al.
Bull. Chem. Soc. Jpn., 76, No. 2 (2003) 353
for C14H18O2: C, 77.03; H, 8.31%. Found: C, 76.79; H, 8.40%.
N-Benzyl-N-methylcyclopropanecarboxamide. Bp 125 °C
(bath temp, 0.17 Torr); IR (neat) 3479, 3029, 2927, 2636, 1495,
1453, 1417, 1357, 1281, 1219, 1207, 1120, 1088, 1030, 881, 733,
700 cm−1; 1H NMR (CDCl3) δ 0.72–0.82 (m, 2H), 1.01–1.07 (m,
2H), 1.70–1.82 (m, 1H), 2.97 and 3.08 (s, 3H), 4.61 and 4.72 (s,
2H), 7.22–7.39 (m, 5H); 13C NMR (CDCl3) δ 7.6 and 7.7, 11.2
and 11.3, 34.4 and 34.8, 51.2, 53.3, 126.4, 127.2 and 127.5, 128.0,
128.5 and 128.8, 137.1 and 137.6, 173.6 and 173.9. Anal. Calcd
for C12H15NO: C, 76.16; H, 7.99%. Found: C, 75.91; H, 8.11%.
Cyclopropyl Phenyl Sulfone.23 Bp 130 °C (bath temp, 0.5
Torr); IR (neat) 3058, 1447, 1317, 1291, 1149, 1090, 886, 763,
732, 691 cm−1; 1H NMR (CDCl3) δ 1.00–1.06 (m, 2H), 1.33–1.38
(m, 2H), 2.43–2.50 (m, 1H), 7.54–7.58 (m, 2H), 7.62–7.66 (m,
1H), 7.88–7.92 (m, 1H); 13C NMR (CDCl3) δ 6.0, 32.9, 127.5,
129.2, 133.3, 140.7.
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the Promotion of Science and from the Ministry of Education,
Science and Culture is gratefully acknowledged.
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K. Takai, T. Ueda, T. Hayashi, and T. Moriwake, Tetrahe-