Regioselective α-alkylation of ketones with alkyl chlorides and fluorides via highly nucleophilic magnesium enamides

Article abstract of DOI:10.1016/j.tet.2007.05.087

A magnesium enamide derived from N-2-(N′,N′-dimethylamino)ethyl imine reacts with primary and secondary alkyl chlorides and fluorides to give an α-alkylated ketone in good to excellent yields upon hydrolysis of the imine moiety. Reactions of the highly nucleophilic magnesium enamide derived from an unsymmetrical ketone take place regioselectively. In addition, the C-C bond formation is stereospecific: a substantial inversion of stereochemistry at the electrophilic carbon center (Walden inversion) was observed, proving its potential utility for the production of optically active compounds.

Full text of DOI:10.1016/j.tet.2007.05.087

Tetrahedron 63 (2007) 8440–8448
Regioselective a-alkylation of ketones with alkyl chlorides and
fluorides via highly nucleophilic magnesium enamides
Takuji Hatakeyama,a Shingo Ito,b Hiroaki Yamane,a Masaharu Nakamuraa, and
*
Eiichi Nakamurab,
*
aInternational Research Center for Elements Science, Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan
bDepartment of Chemistry, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 19 April 2007; accepted 22 May 2007
Available online 26 May 2007
Abstract—A magnesium enamide derived from N-2-(N0,N0-dimethylamino)ethyl imine reacts with primary and secondary alkyl chlorides
and fluorides to give an a-alkylated ketone in good to excellent yields upon hydrolysis of the imine moiety. Reactions of the highly nucleo-
philic magnesium enamide derived from an unsymmetrical ketone take place regioselectively. In addition, the C–C bond formation is ste-
reospecific: a substantial inversion of stereochemistry at the electrophilic carbon center (Walden inversion) was observed, proving its
potential utility for the production of optically active compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
NEt2
N
NEt2
MgBr
1. Introduction
O
(1)
MesMgBr
N
X
R*
R*
Alkylation of a ketone by nucleophilic substitution of an
alkyl halide with a metal enolate is a fundamental reaction
in organic chemistry.1 Significant advance was recorded in
the 1960’s through development of the chemistry of metal-
loenamines,2 lithium enolates,3 and enol silyl ethers.4 De-
spite such efforts, problems have remained unsolved since
then. For example, the scope of the alkyl halides to be
used for intermolecular ketone alkylation has been limited
largely to primary alkyl iodides and bromides, and benzylic
and allylic chlorides.5 Regioselectivity in the alkylation of
an unsymmetrical ketone is another problem, for example,
as we addressed in the 1970’s in the course of the fluoride
anion promoted reaction between silyl enol ethers and alkyl
halides.4b,c The regioselectivity of the deprotonation of an
unsymmetrical ketone is an additional, underlying issue
for the regioselectivity of the a-alkylation reaction.6 We
report here that a magnesium enamide bearing an internal
nitrogen coordination site significantly expands the scope
of the alkyl halides, allowing the use of alkyl chlorides
and fluorides as effective alkylating reagents (Scheme 1).7
The reaction often takes place regioselectively, and the the
SN2 substitution on the alkyl halide occurs largely with
Walden inversion.
(2) H3O+
X = Cl, F
Scheme 1. Alkylation of a magnesium enamide derived from N-2-(N0,N0-di-
methylamino)ethyl imine with an alkyl chloride or fluoride. Mes represents
a 2,4,6-trimethylphenyl group.
2. Results and discussion
2.1. Optimization of the enamide structure and the
metal cation
In our previous studies on the addition reaction of a zinc en-
amide with an olefin,8,9 we found that the nitrogen substitu-
ent on the metal enamide plays a key role for tuning the
reactivity and the thermal stability of the nucleophile.
Screening of a variety of combinations of the nitrogen sub-
stituent and the metal cation in the SN2 alkylation reaction
has been carried out (Chart 1 and Table 1). Thus the reaction
between chlorocycloheptane and a variety of metal en-
amides derived from a 3-pentanone in THF was studied
under various conditions as shown in Table 1. The deproto-
nation of the imine was achieved by treatment with 2,4,6-
trimethylphenylmagnesium bromide (MesMgBr) or in a
case with t-BuMgCl.
* Corresponding authors. Tel.: +81 774 38 3180; fax: +81 774 38 3186
(M.N.); tel./fax: +81 3 5841 4356 (E.N.); e-mail addresses: masaharu@
scl.kyoto-u.ac.jp; nakamura@chem.s.u-tokyo.ac.jp
We found that the magnesium enamide bearing a 2-(N,N-di-
ethylamino)ethyl group (entry 1; 1a) is the best reagent for
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.087

T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
8441
NEt2
OMe
NEt2
investigated the reaction with various alkyl chlorides to ex-
amine the scope of the method (Table 2). Entries 1–3 illus-
trate the viability of the use of secondary alkyl chlorides.
The reaction of 2-chloroheptane with 1a took place in 71%
yield to give the product 3, where we observed a 58:42
syn/anti diastereoselectivity as to the two secondary carbon
centers created by the reaction (entry 2). The acyclic chlo-
ride, (1-chloroethyl)benzene, reacted much faster to give
the product 5 in 85% yield with a 70:30 syn/anti selectivity
(entry 3). It is yet to be determined if the stereoselectivity is
of kinetic or thermodynamic origin.
NMe2
MgBr
R
MgBr
MgBr
MgX
M
N
N
N
N
N
1a (X = Br)
1b (X = Cl)
1c
1d
1e (R = c-Hex) 1g (M = Li)
1f (R = Ph)
1h (M = ZnCl)
1i (M = ZnBu)
Chart 1. Metal enamides examined for optimization.
Table 1. Screening of the nitrogen substituent and the metal cation
Certain functionalities can be tolerated under the reaction
conditions (entries 4–7). A tert-butyldimethylsilyloxy group
Cl
R
M
O
N
(1.2 mmol)
+
THF
45 °C, 24 h
60 °C, 12 h
2
cycloheptene
1a–1i
(1.0 mmol) then H3O+
Table 2. Alkylation of magnesium enamides with alkyl chlorides
NEt2
NEt2
MgBr
Entry
Metal
enamide
Product yielda (%)
Cycloheptene
Recovery of
c-C7H13Cl (mmol)
R3 Cl
MesMgBr
O
(1.1 equiv.)
(1.2 equiv.)
R3
2
N
N
R1
conditions
THF
THF
R1
R1
1
1a
1a
1b
1c
1d
1e
1e
1f
88
69
60
79
4
11
10
13
17
7
0.25
0.34
0.35
0.29
0.85
0.66
0.60
1.07
0.41
0.95
1.03
R2
2b
3
then H3O+
R2
R2
(1.0 equiv.)
4
Entrya Enamide
R3–Cl
Conditions Product yieldb (%)
5
6b
7
47
51
1
8
9
4
O
45 ꢀC, 24 h
60 ꢀC, 12 h
8
9
10
11
1
1a
1a
1g
1h
1i
23
21
3
44
4
3
Cl
Cl
2 (86)
O
a
Yields of 2 and cycloheptene, and recovery of the starting chlorocyclohep-
tane were determined by GC analysis with octane as an internal standard.
The reaction was carried out at 45 ꢀC for 24 h.
45 ꢀC, 24 h
C5H11
3 (71)
2
60 ꢀC, 12 h
b
C5H11
syn/anti = 58:42
the alkylation,10 and that it gives the desired secondary alkyl-
ated ketone 2 in 88% yield after reaction at 45 ꢀC and 60 ꢀC
and removal of the imine moiety by acidic workup. The re-
action accompanied the formation of cycloheptene in 11%
yield suggesting competitive dehydrohalogenation. Lower
temperature did not lead to completion of the reaction
(e.g., after 24 h at 45 ꢀC, 69% yield of 2, entry 2). The
same enamide possessing a MgCl counter cation (entry 3;
1b, prepared by imine deprotonation with t-BuMgCl) gave
the product in lower yield (60%).
O
N
30 ꢀC, 24 h
3c
Ph
5 (85)
50 ꢀC, 12 h
Cl
Ph
4
syn/anti = 70:30
O
OSiMe2t-Bu
( )
OSiMe2t-Bu
(
50 ꢀC, 24 h
65 ꢀC, 12 h
4
1a
1a
4
)
4
Cl
Cl
6 (93)
O
OSiMe2t-Bu
(
OSiMe2t-Bu
(
50 ꢀC, 24 h
65 ꢀC, 12 h
)
5
2
)
2
7 (68)
NMe2
We found then that 3-(N,N-dimethylamino)propyl reagent 1c
is less nucleophilic than 1a and gives 2 in 79% yield and cy-
cloheptene (17%, entry 4). The reaction of 2-methoxyethyl
reagent 1d was sluggish and gave the alkylation product
only in 4% yield (entry 5). Metal enamides without any che-
lating side chain behave rather differently. The Stork’s origi-
nal imine, the N-cyclohexyl compound 1e (entry 6), gave 2 in
47% yield after 24 h at 45 ꢀC, and heating at 60 ꢀC did not im-
prove the yield very much (51%, entry 7). The N-phenyl com-
pound 1f (entry 8) was entirely unreactive and gave 2 in only
1% yield. The lithium variant 1g gave a 1:2 mixture of 2 and
cycloheptene (entry 9). The zinc enamides 1h and 1i are very
unreactive under the same conditions, (entries 10 and 11).
N
O
NMe2
6d
50 ꢀC, 36 h
(
)
2
Ph
(
)
Ph
O
2
Cl
9 (77)
8
50 ꢀC, 24 h
65 ꢀC, 12 h
N
7
1a
N
(
)
3
(
)
3
10 (80)e
Cl
a
The reaction was carried out in THF (ca. 0.8 M for enamide) on
1.0–2.2-mmol scale unless otherwise noted.
Isolated yield based on imine used.
b
c
d
The use of 1.5 equiv of alkyl chloride.
Enamide 8 (1.4 equiv for alkyl chloride) was prepared by using
t-BuMgCl. We used a hydrochloric acid salt of the aminoalkyl chloride
and used an excess t-BuMgCl to prepare in situ the free amine. Yield
was determined by GC analysis on the basis of the alkyl chloride.
Double alkylated product was also obtained in 8% yield.
2.2. Alkylation with alkyl chlorides
Having recognized the high nucleophilic reactivity of 1a,
possessing the 2-(N,N-diethylamino)ethyl group, we
e

8442
T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
survives the reaction to give the product 6 in 93% yield (en-
try 4). The success with the ethyl chloride bearing a nearby,
electron-withdrawing 2-siloxyethyl group shown in entry 5
provides an illustration of the very high nucleophilicity of
the zinc enamide. The neighboring amino function in the
chloride does not affect the reaction as shown in entry 6.
N-Indolyl group remained intact under the conditions to
give the product 10 in 80% yield (entry 7). The formation
of a double alkylated side product (albeit in 8% yield) was
observed only in this case.
The magnesium enamide 17 derived from a-tetralone also
gave the corresponding decylated product 18 in 73% yield
(entry 5). To our pleasant surprise, fluorocyclohexane, a sec-
ondary alkyl fluoride, also took part in the alkylation reac-
tion to give the product 19 in 69% yield (entry 6). The
reaction with the cyclic enamide 13 was slow requiring
80 ꢀC and gave the desired product 20 in 49% yield (entry 7).
2.4. Regioselective alkylation of unsymmetrical ketones
The regioselectivity of the reaction of unsymmetrical imines
was briefly examined (Tables 4–6). The magnesium enamide
prepared from 3-pentanone imine 21 reacted with 1-chloro-
decane to give an 85:15 mixture of 22a and 22b in 94% yield
(entry 1, Table 4). The reaction with 1-fluorodecane gave the
product with slightly higher selectivity (entry 2). The imine
deprotonation with alkylmagnesium bromide is known to
take place at the less hindered site,2 but the halide-depen-
dence of the regioselectivity indicates that the regioselectiv-
ity is not determined entirely in this imine deprotonation
stage. The reaction with chlorocycloheptane took place
slowly but very selectively to give the product 23a with
98% regioselectivity (entry 3). Similarly, the reaction with
fluorocyclohexane gave a 91:9 mixture of two regioisomers
24a and 24b in 41% yield (entry 4).
2.3. Alkylation with alkyl fluorides
We next investigated the alkylation with alkyl fluorides,
which are renowned for the low reactivity in nucleophilic
substitution reactions.5,11 The results summarized in Table
3 suggest that the fluorides are expectedly less reactive
than chlorides but still serve as viable alkylating reagents
under the present conditions. As shown in entries 1 and 2,
acyclic magnesium enamides 1a and 4 smoothly reacted with
1-fluorodecane at 65 ꢀC to give the products 11 and 12 in 87
and 97% yields, respectively. The reactions of cyclic sub-
strates 13 and 15 with 1-fluorodecane, which are slower
than those of acyclic substrates, gave the products 14 and
16 in 75 and 81% yields, respectively (entries 3 and 4).
The reaction of the magnesium enamide prepared from the
2-methylcyclohexanone imine 25 gave us information on
the regioselectivity of the a-alkylation as well as the dia-
stereoselectivity of the newly formed chiral center at C6
against the preexisting chiral center at C2. The regioselectiv-
ity was 99–100% for all cases shown in Table 5, but the
stereoselectivity was halide-dependent. The reactions with
1-chlorodecane and 1-fluorodecane gave 26 in 92 and 93%
yields, respectively (entries 1 and 2, Table 5), and the sec-
ondary chloride and fluoride gave lower yields (entries 3
and 4). While 1-chlorodecane gave a 1:1 mixture of cis
and trans isomers, other alkyl halides showed slightly im-
proved selectivity and gave a trans isomer as a major product
(72, 79, and 89% diastereoselectivities, respectively). The
Table 3. Alkylation of magnesium enamides with alkyl fluorides
NEt2
NEt2
MgBr
R3
F
MesMgBr
O
(1.1 equiv.)
(1.2 equiv.)
R3
N
N
R1
THF
65 °C, 36 h
THF
R1
R1
R2
then H3O+
R2
R2
(1.0 equiv.)
Entry
1
Enamide
R3–F
Product yielda (%)
O
C10H21
1a
4
F–C10H21
F–C10H21
F–C10H21
F–C10H21
F–C10H21
11 (87)
O
C10H21
2
3
4
5
6
12 (97)
Table 4. Regioselective alkylation of an unsymmetrical magnesium
enamide derived from 2-methyl-3-pentanone
O
N
(1)MesMgBr
NEt2
C10H21
(1.1 equiv.)
13
14 (75)
(2)
R–X
N
O
O
(1.2 equiv.)
R
N
O
R
+
C10H21
conditions
then H3O+
21
22a (R = C10H21
)
22b (R = C10H21)
15
16 (81)
(1.0 equiv.)
23a (R = c–C7H13
)
)
23b (R = c–C7H13
)
)
O
N
24a (R = c–C6H11
24b (R = c–C6H11
C10H21
Yielda (%) Regioselectivityb
17
Entry R–X
Conditions
18 (73)
1
2
Cl–C10H21
50 ꢀC, 24 h 94
65 ꢀC, 12 h
65 ꢀC, 36 h 90
22a/22b¼85:15
22a/22b¼91:9
O
1a
13
F–C10H21
F
F
19 (69)
3
4
65 ꢀC, 48 h 59
80 ꢀC, 48 h 41
23a/23b¼98:2
24a/24b¼91:9
O
Cl
7
20 (49)b
F
a
a
The isolated yield.
The reaction was carried out at 80 ꢀC for 40 h.
The isolated yield.
Regioselectivity was determined by GC or NMR analysis.
b
b

T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
8443
Table 5. Regioselective alkylation of an unsymmetrical magnesium en-
amide derived from 2-methylcyclohexanone
have not been synthetically useful alkylating agents. The
high yielding secondary alkylation now allows us to examine
this fundamental issue.
NEt2
(1)MesMgBr
(1.1 equiv.)
N
(2)
O
O
R–X
As shown in Scheme 2, the reaction takes place with inver-
sion of stereochemistry at the electrophilic carbon atom.
Thus, (S)-(1-chloroethyl)benzene 33 (94.0% ee) reacted
with the magnesium enamide 32 at 30 ꢀC to give (S)-1,3-
diphenylbutan-1-one 34 in 64% yield with 89% ee . When
the reaction was carried out at more forcing conditions,
50 ꢀC, the enantioselectivity dropped to 85% ee (78% yield).
Because the starting benzylic halide 33 undergoes slow race-
mization under the reaction conditions, we consider that the
substitution occurs with a much higher level of inversion of
stereochemistry than observed.13 In the light of availability
of optically active alkyl chlorides,14 the present method
was proved to offer a new opportunity for asymmetric
C–C bond formation reactions.
R
(1.2 equiv.)
R
+
conditions
then H3O+
25
(1.0 equiv.)
26 (R = C10H21)
27 (R = c–C7H13
)
)
28 (R = c–C6H11
Entry R–X
Conditions Yielda (%) Diastereoselectivityb
1
2
Cl–C10H21
F–C10H21
50 ꢀC, 24 h 92
65 ꢀC, 12 h
65 ꢀC, 36 h 93
cis/trans¼50:50
cis/trans¼28:72
3
4
65 ꢀC, 48 h 52
80 ꢀC, 48 h 42
cis/trans¼21:79
cis/trans¼11:89
Cl
F
NEt2
a
The isolated yield.
Diastereoselectivity was determined by GC or NMR analysis.
b
MgCl
O
N
S
S
+
Ph
Ph
Cl
Ph
94% ee
33
conditions
THF
30 °C, 36 h
50 °C, 12 h
Ph
34
Table 6. Regioselective alkylation of an unsymmetrical magnesium en-
amide derived from b-tetralone
32
64% yield, 89% ee
78% yield, 85% ee
(1.2 equiv.)
(1.0 equiv.)
NEt2
Scheme 2. Stereoselective nucleophilic substitution of an optically active
alkyl chloride.
(1)MesMgBr
N
O
O
(1.05 equiv.)
R
R
(2)
R–X
(1.1 equiv.)
+
conditions
then H3O+
3. Conclusion
29
(1.0 equiv.)
30a (R = C10H21
)
30b (R = C10H21)
Through the present study, we have examined several issues
of general importance in the enolate and enamide alkylation
chemistry, and shown that the magnesio 2-aminoethyl-
enamide chemistry provides significant improvement over
the conventional chemistry of similar nature. The reaction
also provides new opportunities in synthetic chemistry, such
as utilization of secondary alkyl halides and alkyl fluorides
and the synthesis of optically active ketones by the use of op-
tically active secondary alkyl halides. With the availability
of optically active imines of the kind used in this study,15
we also expect that the present methodology will be useful
for the synthesis of optically active ketone derivatives in
general.
31a (R = c–C7H13) 31b (R = c–C7H13
)
Entry R–X
Conditions
Yielda (%) Regioselectivityb
1
2
Cl–C10H21
F–C10H21
50 ꢀC, 48 h 74
65 ꢀC, 48 h 89
30a/30b¼93:7
30a/30b>99:1
50 ꢀC, 24 h
65 ꢀC, 24 h
3
71
31a/31b¼99:1
Cl
a
Isolated yield.
Regioselectivity was determined by GC or NMR analysis.
b
trans selectivity has been considered to reflect the kinetic
preference of the reaction.12 The origin of the halide-depen-
dence is unclear at this time and can be due either to a kinetic
or a thermodynamic reason.
4. Experimental
4.1. General methods
The magnesium enamide prepared from b-tetralone imine
29 reacted regioselectively with 1-chlorodecane to give
a 93:7 mixture of 30a and 30b in 74% yield (Table 6, entry
1). As shown in entries 2 and 3, the reactions with 1-fluoro-
decane and chlorocycloheptane are slighly more regioselec-
tive and gave 30a and 31a with 99% selectivity.
All reactions dealing with air- or moisture- sensitive com-
pounds were carried out in a dry reaction vessel under posi-
tive pressure of argon. Analytical thin-layer chromatography
was performed on glass plates coated with 0.25 mm 230–
400 mesh silica gel containing a fluorescent indicator
(Merck, #1.05715.0009). Flash column chromatography
was performed on Kanto Silica gel 60 (spherical, neutral,
140–325 mesh) as described by Still et al.16 Proton nuclear
magnetic resonance (1H NMR) and carbon nuclear magnetic
resonance (13C NMR) spectra were recorded on JEOL ECX-
400 (400 MHz) or JEOL EX-270 (270.05 MHz) NMR spec-
trometers. Data are presented as: chemical shift, multiplicity
2.5. SN2 substitution of (S)-(1-chloroethyl)benzene
In any substitution reaction, the stereochemistry of the car-
bon atom where the substitution occurs is of general interest.
This issue has not been addressed properly in the enolate
chemistry however, since secondary (chiral) alkyl halides

8444
T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, quint¼quintet,
sext¼sextet, sept¼septet, m¼multiplet and/or multiplet res-
onances, br¼broad), coupling constant in hertz (Hz), and
signal area integration in natural numbers, assignment
(italic). IR spectra recorded on a React IR 1000 Reaction
Analysis System equipped with DuraSample IR (ASI Ap-
plied System) are reported in cmꢁ1. Characteristic IR
absorptions are reported in cmꢁ1. High-resolution mass
spectra are taken with EI (electron impact) method at
a JEOL GC-mate II. Diastereoselectivity (ds) and yield (by
using octane, decane, or undecane as an internal standard)
were determined for a crude product by GC analyses on a
Shimadzu GC-17A instrument equipped with an FID detec-
tor and a capillary column, HR-1 (Shinwa, 25 mꢂ0.25 mm
i.d., 0.25 mm film thickness). Enantioselectivity was deter-
mined by GC analyses on a Shimadzu GC-14B instrument
equipped with an FID detector and a capillary column,
g-DEX 225 (Supelco, 30 mꢂ0.25 mm i.d., 0.25 mm film
thickness), or by HPLC analyses on a JASCO CD-2095
Plus equipped with chiral column, CHIRALCEL OJ-H (Dai-
cel, 4.6ꢂ250 mm). Imines were prepared from correspond-
(0.192 g, 1.2 mmol) was added at room temperature. The re-
action was carried out at 65 ꢀC for 36 h. AcOH in H2O
(50 wt %, 1.0 mL) was added slowly at 0 ꢀC. The reaction
mixture was stirred at 50 ꢀC for 1 h and then cooled to
room temperature. The reaction mixture was neutralized
with saturated NaHCO3 aqueous solution. The aqueous layer
was extracted with Et2O five times. The combined organic
extracts were dried with Na2SO4. After the solvent was re-
moved in vacuo, the crude product was purified by chroma-
tography on silica gel (10 g, pentane and then 2% Et2O in
pentane) to obtain the title compound 12 (0.248 g, 97%
yield) as a colorless liquid. Rf¼0.62 (10% Et2O in pentane);
IR (neat) 2961, 2926, 2856, 1710 (C]O), 1459, 1378, 1123,
1
1031, 722; H NMR d 0.82–0.93 (m, 9H, C(CH2)2CH3,
CHCH2CH3, (CH2)9CH3), 1.15–1.32 (m, 16H, (CH2)8),
1.30–1.65 (m, 6H, CCH2CH2, CHCH2CH3, CHCH2CH2),
2.33–2.42 (m, 3H, CH2C(]O)CH); 13C NMR d 11.9, 13.8,
14.1, 16.9, 22.7, 24.6, 27.5, 29.3, 29.4, 29.6 (2C), 29.8, 31.4,
31.9, 44.2, 53.9, 215.0. Anal. Calcd for C17H34O C, 80.24;
H, 13.47. Found C, 80.16; H, 13.21.
7
˚
ing ketones and amines using dry molecular sieves 4 A.
4.1.2.1. Synthesis of 4,5-dimethyldodecan-3-one17 (3).
The reaction was carried out according to the typical proce-
dure on a 1.0-mmol scale by using N0-(1-ethylpropylidene)-
N,N-diethyl-1,2-ethanediamine (0.184 g, 1.0 mmol) and
2-chloroheptane (0.162 g, 1.2 mmol). Conditions: 45 ꢀC,
24 h; 60 ꢀC, 12 h. The title compound 3 (0.131 g, 71% yield,
syn/anti¼58:42 determined by 1H NMR analysis) was
obtained as a colorless liquid after silica gel column chroma-
tography.
Mesitylmagnesium bromide (MesMgBr) was prepared from
bromomesitylene and magnesium (turnings) using a standard
method and titrated before use. FlorisilÒ (100–200 mesh)
was purchased from Yoneyama Yakuhin Kogyo Co., Ltd.
4.1.1. Typical procedure for alkylation in Table 1; synthe-
sis of 2-cycloheptylpentan-3-one (2). N0-(1-Ethylpropyl-
idene)-N,N-diethyl-1,2-ethanediamine (0.184 g, 1.0 mmol)
was added to mesitylmagnesium bromide (MesMgBr,
0.95 M in THF, 1.16 mL, 1.1 mmol) at room temperature.
The reaction mixture was stirred at 80 ꢀC for 1 h. After
the solvents were removed in vacuo, chlorocycloheptane
(0.159 g, 1.2 mmol) was added at room temperature. The
reaction was carried out at 45 ꢀC for 24 h and then at 60 ꢀC
for 12 h. AcOH in H2O (50 wt %, 1.0 mL) was added slowly
at 0 ꢀC. The reaction mixture was stirred at 50 ꢀC for 1 h and
then cooled to room temperature. The reaction mixture was
neutralized with saturated NaHCO3 aqueous solution. The
aqueous layer was extracted with Et2O five times. The com-
bined organic extracts were dried with Na2SO4. Gas chroma-
tography analysis was carried out (88% yield) by using
octane as an internal standard. After the solvent was removed
in vacuo, the crude product was purified by chromatography
on silica gel (10 g, pentane and then 2% Et2O in pentane) to
obtain the title compound 2 (0.157 g, 86% yield) as a color-
less liquid. Rf¼0.38 (10% Et2O in pentane); IR (neat) 2976,
2922, 2856, 1710 (C]O), 1459, 1378, 1104, 1019, 973, 803;
1H NMR d 1.00 (d, J¼6.9 Hz, 3H, CHCH3), 1.04 (t, J¼
7.2 Hz, 3H, CH2CH3), 1.13–1.33 (m, 2H, CHH(CH2)4CHH),
1.35–1.70 (m, 10H, CHH(CH2)4CHH), 1.79–1.88 (m, 1H,
CHCHCH3), 2.42–2.47 (m, 3H, CHCH3, CH2CH3); 13C
NMR d 7.8, 12.7, 26.6, 26.9, 28.1, 28.2, 30.0, 33.4, 34.7, 41.2,
52.4, 215.5. Anal. Calcd for C12H22O C, 79.06; H, 12.16.
Found C, 78.92; H, 11.92.
4.1.2.2. Synthesis of 3-ethyl-2-phenylheptan-4-one8c
(5). The reaction was carried out according to the typical
procedure on a 1.0-mmol scale by using N0-(1-propylbutyl-
idene)-N,N-diethyl-1,2-ethanediamine (0.212 g, 1.0 mmol)
and (1-chloroethyl)benzene (0.211 g, 1.5 mmol). Condi-
tions: 30 ꢀC, 12 h; 50 ꢀC, 3 h. The title compound 5
(0.186 g, 85% yield, syn/anti¼70:30 determined by 1H
NMR analysis) was obtained as a colorless liquid after silica
gel column chromatography. Rf¼0.50 (10% Et2O in pen-
tane); IR (neat) 3065 and 3030 (aromatic C–H), 2964,
2934, 2876, 1710 (C]O), 1494, 1455, 1378, 1270, 1127,
1
1027, 760, 698; syn-isomer: H NMR d 0.64 (t, J¼7.5 Hz,
3H, CH2CH2CH3), 0.81 (t, J¼7.5 Hz, 3H, CHCH2CH3),
1.25 (d, J¼6.9 Hz, 3H, CHCH3), 1.18–1.33 (m, 2H,
CH2CH2CH3), 1.58–1.73 (m, 2H, CHCH2CH3), 1.79–1.88
(m, 1H, CCHHCH2), 2.03–2.12 (m, 1H, CCHHCH2),
2.58–2.67 (m, 1H, CCHCH2), 2.87–2.97 (m, 1H, CHPh),
7.13–7.18 (m, 3H, CHCHCHCHCH), 7.23–7.27 (m, 2H,
CHCHCHCHCH); 13C NMR d 11.9, 13.5, 16.2, 18.8, 22.5,
41.7, 46.6, 60.8, 126.2, 127.4 (2C), 128.3 (2C), 145.4,
214.5; anti-isomer: 1H NMR d 0.70 (t, J¼7.5 Hz, 3H,
CH2CH2CH3), 0.93 (t, J¼7.5 Hz, 3H, CHCH2CH3), 1.16 (d,
J¼6.9 Hz, 3H, CHCH3), 1.25–1.45 (m, 2H, CH2CH2CH3),
1.57–1.66 (m, 2H, CHCH2CH3), 2.37–2.43 (m, 2H,
CCH2CH2), 2.58–2.67 (m, 1H, CCHCH2), 2.87–2.97 (m,
1H, CHPh), 7.17–7.31 (m, 5H, (CH)5); 13C NMR d 11.6,
13.8, 16.5, 20.4, 24.2, 42.1, 46.5, 60.3, 126.3, 127.4 (2C),
128.4 (2C), 145.1, 214.9.
4.1.2. Typical procedure for alkylation in Tables 2–5;
synthesis of 5-ethylpentadecan-4-one (12). N0-(1-Propyl-
butylidene)-N,N-diethyl-1,2-ethanediamine
(0.212 g,
1.0 mmol) was added to mesitylmagnesium bromide
(MesMgBr, 0.95 M in THF, 1.16 mL, 1.1 mmol) at room
temperature. After stirring at 80 ꢀC for 1 h, 1-fluorodecane
4.1.2.3. Synthesis of 8-tert-butyldimethylsilyloxy-4-
methyloctan-3-one18 (6). The reaction was carried out
according to the typical procedure on a 1.0-mmol scale

T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
8445
by using N0-(1-ethylpropylidene)-N,N-diethyl-1,2-ethanedi-
amine (0.184 g, 1.0 mmol) and tert-butyl-(4-chlorobutoxy)-
dimethylsilane (0.267 g, 1.2 mmol). Conditions: 50 ꢀC,
24 h; 65 ꢀC, 12 h. The title compound 6 (0.253 g, 93% yield)
was obtained as a colorless liquid after silica gel column
chromatography.
(d, J¼7.8 Hz, NCCCHCHCHCH); 13C NMR d 16.8 (2C),
28.0 (2C), 29.8 (2C), 44.5 (2C), 46.3 (2C), 101.0 (2C),
109.3 (2C), 119.2 (2C), 121.0 (2C), 121.4 (2C), 127.7
(2C), 128.5 (2C), 135.9 (2C), 216.9.
4.1.2.6. Synthesis of 2-decylcyclohexanone19 (14). The
reaction was carried out according to the typical procedure
on a 1.0-mmol scale by using N0-cyclohexylidene-N,N-di-
ethyl-1,2-ethanediamine (0.196 g, 1.0 mmol) and 1-fluoro-
decane (0.192 g, 1.2 mmol). Conditions: 65 ꢀC, 36 h. The
title compound 14 (0.178 g, 75% yield) was obtained as
a colorless liquid after silica gel column chromatography.
4.1.2.4. Synthesis of 6-tert-butyldimethylsilyloxy-4-
methylhexan-3-one (7). The reaction was carried out
according to the typical procedure on a 1.0-mmol scale by
using
N0-(1-ethylpropylidene)-N,N-diethyl-1,2-ethanedi-
amine (0.184 g, 1.0 mmol) and tert-butyl-(2-chloroethoxy)-
dimethylsilane (0.238 g, 1.2 mmol). Conditions: 50 ꢀC,
24 h; 65 ꢀC, 12 h. The title compound 7 (0.131 g, 68% yield)
was obtained as a colorless liquid after silica gel column
chromatography. Rf¼0.35 (10% Et2O in pentane); IR
(neat) 2957, 2934, 2860, 1714 (C]O), 1463, 1254, 1096,
4.1.2.7. Synthesis of 2-decylcycloheptanone (16). The
reaction was carried out according to the typical procedure
on a 1.0-mmol scale by using N0-cycloheptylidene-N,N-
diethyl-1,2-ethanediamine (0.210 g, 1.0 mmol) and 1-
fluorodecane (0.192 g, 1.2 mmol). Conditions: 65 ꢀC, 36 h.
The title compound 16 (0.205 g, 81% yield) was obtained
as a colorless liquid after silica gel column chromato-
graphy. Rf¼0.15 (5% EtOAc in hexane); IR (neat) 2922,
2853, 1702 (C]O), 1455, 934, 733; 1H NMR d 0.88
(t, J¼6.6 Hz, 3H, CH3), 1.15–1.95 (m, 26H, (CH2)9CH3,
1
899, 834, 776; H NMR d 0.03 (s, 6H, Si(CH3)2), 0.88 (s,
9H, C(CH3)3), 1.04 (t, J¼7.2 Hz, 3H, CH2CH3), 1.08 (d,
J¼7.4 Hz, 3H, CHCH3), 1.46–1.54 (m, 1H, CHCHH),
1.87–1.94 (m, 1H, CHCHH), 2.45–2.53 (m, 2H, CCH2),
2.69–2.78 (m, 1H, CCH), 3.59 (t, J¼7.2 Hz, 2H, CH2OSi);
13C NMR d ꢁ5.5 (2C), 7.8, 16.5, 18.2, 25.9 (3C), 34.3, 35.8,
42.4, 60.7, 215.1. Anal. Calcd for C13H28O2Si C, 63.87; H,
11.55. Found C, 64.04; H, 11.35.
C(]O)CH2CH2CH2CH2CH2),
2.34–2.58
(m,
3H,
CH2C(]O)CH); 13C NMR d 14.2, 22.7, 24.7, 27.3, 28.5,
29.4, 29.6, 29.7 (3C), 29.8, 31.3, 31.9, 32.5, 42.7, 52.4,
216.4.
4.1.2.5. Synthesis of 7-(1H-indol-1-yl)-4-methylhep-
tan-3-one (10). The reaction was carried out according to
the typical procedure on a 1.0-mmol scale by using N0-(1-
ethylpropylidene)-N,N-diethyl-1,2-ethanediamine (0.184 g,
1.0 mmol) and 1-(3-chloropropyl)-1H-indole (0.231 g,
1.2 mmol). Conditions: 50 ꢀC, 24 h; 65 ꢀC, 12 h. The title
compound 10 (0.193 g, 80% yield) was obtained as a pale
yellow liquid after silica gel column chromatography.
Rf¼0.13 (5% EtOAc in hexane); IR (neat) 2971, 2936,
4.1.2.8. Synthesis of 2-decyl-1-tetralone (18). The reac-
tion was carried out according to the typical procedure on
a 1.0-mmol scale by using N0-(3,4-dihydronaphthalen-
1(2H)-ylidene)-N,N-diethyl-1,2-ethanediamine
(0.244 g,
1.0 mmol) and 1-fluorodecane (0.192 g, 1.2 mmol). Condi-
tions: 65 ꢀC, 36 h. The title compound 18 (0.209 g, 73%
yield) was obtained as a colorless liquid after silica gel col-
umn chromatography. Rf¼0.69 (10% EtOAc in hexane); IR
(neat) 2922, 2853, 1683 (C]O), 1601, 1455, 1357, 1288,
1
2875, 1707 (C]O), 1461, 1313, 738; H NMR d 0.99 (t,
J¼7.1 Hz, 3H, CH2CH3), 1.03 (d, J¼7.1 Hz, 1H, CHCH3),
1.21–1.41 (m, 1H, C(]O)CHCHH), 1.57–1.87 (m, 3H,
NCH2CH2, C(]O)CHCHH), 2.18–2.54 (m, 3H, CH3CH2,
CH3CH), 4.09 (dt, J¼2.7, 6.9 Hz, 2H, CH2N), 6.48 (d,
J¼3.0 Hz, 1H, NCHCH), 7.06 (d, J¼3.0 Hz, 1H, NCH),
7.09 (t, J¼7.6 Hz, 1H, NCCHCHCH), 7.20 (t, J¼7.6 Hz,
1H, NCCHCH), 7.31 (d, J¼8.1 Hz, 1H, NCCH), 7.62 (d, J¼
7.8 Hz, 1H, NCCCH); 13C NMR d 7.8, 16.8, 28.0, 30.2, 34.3,
45.6, 46.3, 101.0, 109.2, 119.1, 120.9, 121.3, 127.6, 128.5,
135.7, 214.5. The double alkylated product, 1,9-di(1H-
indol-1-yl)-4,6-dimethylnonan-5-one was also obtained in
8% yield (0.030 g) as a 6:4 mixture of diastereomers.
Rf¼0.07 (5% EtOAc in hexane); the major diastereomer:
1H NMR d 0.95 (t, J¼6.5 Hz, 6H, CH3), 1.10–1.81 (m,
8H, NCH2CH2CH2), 2.34–2.55 (m, 2H, C(]O)CH), 3.92–
4.16 (m, 4H, NCH2), 6.46 (d, J¼3.0 Hz, NCHCH), 7.01
(d, J¼3.2 Hz, NCH), 7.08 (t, J¼7.8 Hz, NCCCHCHCH),
7.19 (t, J¼7.8 Hz, NCCHCH), 7.28 (d, J¼7.6 Hz, NCCH),
7.61 (d, J¼7.8 Hz, NCCCHCHCHCH); 13C NMR d 16.5
(2C), 27.8 (2C), 29.9 (2C), 44.5 (2C), 46.2 (2C), 101.0 (2C),
109.3 (2C), 119.2 (2C), 121.0 (2C), 121.4 (2C), 127.7 (2C),
1
1221, 909, 740; H NMR d 0.88 (t, J¼6.6 Hz, 3H, CH3),
1.20–1.60 (m, 17H, CHH(CH2)8CH3), 1.80–2.02 (m, 2H,
C(]O)CHCHH, C(]O)CCCH2CHH), 2.16–2.31 (dq,
J¼4.9, 13.5 Hz, 1H, C(]O)CCCH2CHH), 2.39–2.54 (m,
1H, C(]O)CCCHH), 2.93–3.03 (m, 2H, C(]O)CH,
C(]O)CCCHH), 7.22 (d, J¼7.8 Hz, 1H, CH2CCH), 7.29
(t, J¼7.8 Hz, 1H, C(]O)CCHCH), 7.44 (td, J¼1.4,
7.2 Hz, 1H, C(]O)CHCHCH), 8.01 (dd, J¼1.4, 8.4 Hz,
1H, C(]O)CCH); 13C NMR d 14.2, 22.8, 27.1, 28.3, 28.4,
29.4, 29.5, 29.7, 29.7 (2C), 29.9, 32.0, 47.5, 126.4, 127.4,
128.5, 132.5, 132.9, 143.8, 200.3.
4.1.2.9. Synthesis of 2,4-dimethyl-3-tetradodecanone
(22a) and 4,4-dimethyl-3-tetradodecanone (22b). The re-
action was carried out according to the typical procedure
on a 1.0-mmol scale by using N0-(1-isopropylpropylidene)-
N,N-diethyl-1,2-ethanediamine 21 (0.198 g, 1.0 mmol) and
1-fluorodecane (0.192 g, 1.2 mmol). Conditions: 65 ꢀC;
36 h. The title compounds (0.216 g, 90% yield, 22a/
22b¼91:9 determined by 1H NMR analysis) were obtained
as a colorless liquid after silica gel column chromatography.
Rf¼0.31 (3% Et2O in pentane); IR (neat) 2964, 2926, 2856,
1714 (C]O), 1463, 1382, 1015, 722. Anal. Calcd for
C16H32O C, 79.93; H, 13.42. Found C, 79.77; H, 13.35;
2,4-dimethyl-3-tetradodecanone: 1H NMR d 0.88 (t, J¼
7.2 Hz, 3H, CH2CH3), 1.00–1.11 (m, 9H, CH(CH3)2,
1
128.5 (2C), 135.9 (2C), 217.0; the minor diastereomer: H
NMR d 0.95 (t, J¼6.5 Hz, 6H, CH3), 1.10–1.81 (m, 8H,
NCH2CH2CH2), 2.34–2.55 (m, 2H, C(]O)CH), 3.92–4.16
(m, 4H, NCH2), 6.47 (d, J¼3.0 Hz, NCHCH), 7.04 (d, J¼
3.2 Hz, NCH), 7.08 (t, J¼7.8 Hz, NCCCHCHCH), 7.18 (t,
J¼7.8 Hz, NCCHCH), 7.30 (d, J¼8.1 Hz, NCCH), 7.61

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T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
CHCH3), 1.32–1.43 (m, 18H, (CH2)9), 2.63–2.77 (m, 2H,
CHC(]O)CH); 13C NMR d 14.1, 16.8, 18.2, 18.4, 22.7,
27.5, 29.4, 29.5, 29.6 (2C), 29.7, 31.9, 33.2, 39.6, 44.6,
218.7.
temperature for 0.5 h and then neutralized with saturated
NaHCO3 aqueous solution. The aqueous layer was extracted
with pentane five times. The combined organic extracts were
dried over Na2SO4. After the solvents were removed in va-
cuo, the crude product was purified by chromatography on
silica gel (12 g, pentane and then 2% Et2O in pentane) to ob-
tain the title compound 20 (0.089 g, 49% yield) as a colorless
liquid.
The reaction was carried out according to the typical
procedure on a 1.0-mmol scale by using N0-(1-isopropyl-
propylidene)-N,N-diethyl-1,2-ethanediamine 21 (0.198 g,
1.0 mmol) and 1-chlorodecane (0.212 g, 1.2 mmol). Condi-
tions: 50 ꢀC, 24 h; 65 ꢀC, 12 h. The title compound (0.226 g,
94% yield, 22a/22b¼85:15, determined by 1H NMR analy-
sis) was obtained as a colorless liquid after silica gel column
chromatography.
4.1.3.1. Synthesis of 2-cyclohexylpentan-3-one21 (19).
The reaction was carried out according to the typical proce-
dure on a 1.0-mmol scale by using N0-(1-ethylpropylidene)-
N,N-diethyl-1,2-ethanediamine (0.184 g, 1.0 mmol) and
fluorocyclohexane (0.122 g, 1.2 mmol). Conditions: 65 ꢀC,
36 h. The title compound 19 (0.116 g, 69% yield) was
obtained as a colorless liquid after silica gel column chroma-
tography.
4.1.2.10. Synthesis of 2-decyl-5-methylcyclohexanone
(26). The reaction was carried out according to the typical
procedure on a 1.0-mmol scale by using N0-(2-methylcyclo-
hexylidene)-N,N-diethyl-1,2-ethanediamine 25 (0.210 g,
1.0 mmol) and 1-fluorodecane (0.192 g, 1.2 mmol). Condi-
tions: 65 ꢀC, 36 h. The title compound 26 (0.235 g, 93%
4.1.3.2. Synthesis of 2-cycloheptyl-4-methyl-3-pent-
anone (23a) and 2-cycloheptyl-2-methyl-3-pentanone
(23b). The reaction was carried out according to the typical
procedure on a 1.0-mmol scale by using N0-(1-isopropyl-
propylidene)-N,N-diethyl-1,2-ethanediamine 21 (0.198 g,
1.0 mmol) and chlorocycloheptane (0.159 g, 1.2 mmol).
Conditions: 65 ꢀC, 48 h. The title compounds (0.116 g,
59% yield, 23a/23b¼98:2 determined by 1H NMR analysis)
were obtained as a colorless liquid after silica gel column
chromatography; IR (neat) 2918, 2854, 1708 (C]O),
1460, 1381, 1098, 1015, 1000, 801; 2-Cycloheptyl-4-methyl-
1
yield, cis/trans¼28:72 determined by H NMR analysis)
was obtained as a colorless liquid after silica gel column
chromatography. Rf¼0.47 (trans isomer), 0.65 (cis isomer)
(10% Et2O in pentane); IR (neat) 2922, 2853, 1714
(C]O), 1455, 1378, 1127, 984, 857, 722. Anal. Calcd for
C17H32O C, 80.88; H, 12.78. Found C, 80.76; H, 12.96; trans
isomer: 1H NMR d 0.88 (t, J¼6.9 Hz, 3H, CH2CH3), 1.00 (d,
J¼6.3 Hz, 3H, CHCH3), 1.08–1.18 (m, 1H, CHCHH(CH2)8),
1.18–1.40 (m, 18H, CHCHHCH2CHHCH), (CH2)8CH3),
1.65–1.86 (m, 3H, CHCH2CH2CH2CH, CHH(CH2)8CH3),
2.18–2.18 (m, 2H, CHCHHCH2CHHCH), 2.19–2.28
(m, 1H, CH(CH2)9), 2.34–2.44 (m, 1H, CHCH3); 13C
NMR d 14.1, 14.5, 22.7, 25.6, 27.3, 29.1, 29.3, 29.5, 29.6
(2C), 29.9, 31.9, 35.2, 37.5, 45.6, 50.8, 214.4; cis
isomer: 1H NMR d 0.88 (t, J¼6.9 Hz, 3H, CH2CH3),
1.05 (d, J¼6.3 Hz, 3H, CHCH3), 1.10–1.20 (m, 1H,
CHH(CH2)8CH3), 1.18–1.33 (m, 16H, (CH2)8CH3), 1.33–
1.48 (m, 2H, CHCHHCH2CHHCH), 1.64–1.88 (m, 4H,
CH3CHCH2CH2CHHCH, CHH(CH2)8CH3), 1.94–2.02 (m,
1H, CH(CH3)CHH), 2.37–2.44 (m, 1H, CH(CH2)9), 2.49–
2.57 (m, 1H, CHCH3); 13C NMR d 14.1, 15.3, 20.5, 22.7,
27.3, 29.3, 29.5, 29.6 (3C), 30.9, 31.9, 32.4, 35.6, 42.2,
49.5, 217.0.
1
3-pentanone (major): H NMR d 0.92 (d, J¼7.5 Hz, 3H,
CHCHCH3), 0.98 (d, J¼7.2 Hz, 3H, CH3CHCH3), 1.00 (d,
J¼7.5 Hz, 3H, CH3CHCH3), 1.04–1.60 (m, 12H, (CH2)6),
1.70–1.79 (m, 1H, CH2CH), 2.57 (quint, J¼7.8 Hz, 1H,
CHCHCH3), 2.72 (sept, J¼7.8 Hz, 1H, CH3CHCH3); 13C
NMR d 13.0, 18.0, 18.8, 26.5, 26.9, 28.1, 28.2, 30.0, 33.5,
39.8, 41.0, 50.7, 218.5. Anal. Calcd for C13H24O C, 79.53;
H, 12.32. Found C, 79.41; H, 12.50.
4.1.3.3. Synthesis of 2-cyclohexyl-4-methyl-3-penta-
none (24a) and 2-cyclohexyl-2-methyl-3-pentanone
(24b). The reaction was carried out according to the typical
procedure on a 1.0-mmol scale by using N0-(1-isopropyl-
propylidene)-N,N-diethyl-1,2-ethanediamine 21 (0.198 g,
1.0 mmol). Conditions: 80 ꢀC, 48 h. The title compounds
(0.074 g, 41% yield, 24a/24b¼91:9 determined by 1H
NMR analysis) were obtained as a colorless liquid after
silica gel column chromatography.
The reaction was carried out according to the typical
procedure on a 1.0-mmol scale by using N0-(2-methylcyclo-
hexylidene)-N,N-diethyl-1,2-ethanediamine 25 (0.210 g,
1.0 mmol) and 1-chlorodecane (0.212 g, 1.2 mmol). Condi-
tions: 50 ꢀC, 24 h; 65 ꢀC, 12 h. The title compound 26
(0.233 g, 92% yield, cis/trans¼50:50 determined by 1H
NMR analysis) was obtained as a colorless liquid after silica
gel column chromatography.
4.1.3.4. Synthesis of 2-cycloheptyl-6-methylcyclohexa-
none (27). The reaction was carried out according to the
typical procedure on a 1.0-mmol scale by using N0-(2-
methylcyclohexylidene)-N,N-diethyl-1,2-ethanediamine 25
(0.210 g, 1.0 mmol), MesMgBr (1.18 M in THF, 1.69 mL,
2.0 mmol), and chlorocycloheptane (0.159 g, 1.2 mmol).
Conditions: 65 ꢀC, 48 h. The title compound 27 (0.104 g,
4.1.3. Typical procedure for alkylation in Tables 2–6;
synthesis of 2-cyclohexylcyclohexanone20 (20). To N0-
cyclohexylidene-N,N-diethyl-1,2-ethanediamine (0.196 g,
1.0 mmol) was added mesitylmagnesium bromide
(MesMgBr, 1.18 M in THF, 0.932 mL, 1.1 mmol) at room
temperature. The reaction mixture was stirred at 80 ꢀC for
1 h. Fluorocyclohexane (0.122 g, 1.2 mmol) was added at
room temperature. The reaction was carried out at 80 ꢀC
for 40 h. AcOH in H2O (10 wt %, 2.0 mL) was added slowly
at 0 ꢀC. The reaction mixture was stirred at room
1
52% yield, cis/trans¼21:79 determined by H, 13C NMR
analyses) was obtained as a colorless liquid after silica gel
column chromatography; IR (neat) 2918, 2852, 1705
(C]O), 1451, 1375, 1123, 992, 855; trans isomer: 1H
NMR d 1.01 (d, J¼6.6 Hz, 3H, CH3), 1.08–1.89 (m, 16H,
CHCHHCH2CHHCH, (CH2)6), 1.92–2.05 (m, 3H,
CHCHHCH2CHHCH, CCHCH), 2.14 (dt, J¼4.6, 9.2 Hz,
1H, CCHCH), 2.47 (dquint, J¼6.5, 10.5 Hz, 1H, CH3CH);

T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
8447
13C NMR d 15.1, 20.6, 26.1, 26.4, 28.2, 28.6, 29.3, 31.0,
32.2, 36.1, 37.8, 42.6, 56.3, 216.9. Anal. Calcd for
C14H24O C, 80.71; H, 11.61. Found C, 80.75; H, 11.78.
13C NMR d 25.8, 26.0, 27.6, 27.9, 28.2, 32.1, 32.5, 37.1,
41.8, 61.9, 126.4, 126.7, 127.9, 129.8, 136.6, 137.0, 212.9.
Anal. Calcd for C17H22O C, 84.25; H, 9.15. Found C,
84.22; H, 9.22.
4.1.3.5. Synthesis of 2-cyclohexyl-6-methylcyclohexa-
none (28). The reaction was carried out according to the
typical procedure on a 1.0-mmol scale by using N0-(2-
methylcyclohexylidene)-N,N-diethyl-1,2-ethanediamine 25
(0.210 g, 1.0 mmol). Conditions: 80 ꢀC, 48 h. The title com-
pound 28 (0.082 g, 42% yield, cis/trans¼11:89 determined
4.1.4. Synthesis of 4-dimethylamino-2-methyl-1-phenyl-
butan-1-one (9). N0-(1-Phenylpropylidene)-N,N-diethyl-
1,2-ethanediamine (0.629 g, 3.08 mmol) was added to
t-BuMgCl (2.12 M in THF, 1.44 mL, 3.08 mmol) at
ꢁ78 ꢀC. The mixture was stirred at 0 ꢀC for 1 h, and then
warmed to room temperature. The reaction mixture was
transferred to the alkyl chloride, prepared from t-BuMgCl
(2.12 M in THF, 1.04 mL, 2.2 mmol) and 2-dimethylamino-
ethylchloride hydrochloride (0.317 g, 2.2 mmol) in THF
(1.0 mL), via cannula at room temperature and rinsed with
THF (0.5 mL) twice. The reaction mixture was heated at
50 ꢀC for 36 h. AcOH in H2O (50 wt %, 2.0 mL) was added
slowly at 0 ꢀC. The reaction mixture was stirred at 50 ꢀC for
1 h and then cooled to room temperature. H2O (8.0 mL) was
added and the aqueous layer was washed with pentane three
times to remove propiophenone. To the aqueous layer was
added 3 N NaOH until pH >12. The aqueous layer was
extracted with Et2O five times. The combined extracts
were filtered with a pad of Na2SO4 by using Et2O as an
eluent. Gas chromatography analysis was carried out (77%
yield) by using undecane as an internal standard. The solvent
was removed in vacuo. The title compound 9 (0.310 g, 69%
yield) was obtained as a colorless liquid after Kugelrohr
distillation; bp 140 ꢀC/5 mmHg. Rf¼0.17 (100% MeOH);
IR (neat) 3065 (aromatic C–H), 2968, 2941, 2860, 2818,
2768, 1679 (C]O), 1598, 1579, 1447, 1370, 1220, 1177,
1
by H, 13C NMR analyses22) was obtained as a colorless
liquid after silica gel column chromatography; IR (neat)
2923, 2852, 1705 (C]O), 1449, 1376, 1123, 864; trans
isomer: H NMR d 0.74–1.41 (m, 8H, CHH(CH2)3CHH),
1
1.00 (d, 3H, J¼6.6 Hz, CH3), 1.55–1.91 (m, 7H,
CHH(CH2)3CHH, CHCHHCH2CHHCH, CCHCH), 1.98–
2.11 (m, 3H, CHCHHCH2CHHCH, CCHCH), 2.47 (dquint,
J¼6.5, 11.0 Hz, 1H, CH3CH); 13C NMR d 14.8, 20.7, 26.2
(2C), 28.9 (2C), 30.3, 31.2, 36.3, 36.5, 42.5, 56.7, 216.7.
Anal. Calcd for C13H22O C, 80.35; H, 11.41. Found C,
80.08; H, 11.15.
4.1.3.6. Synthesis of 1-decyl-2-tetralone (30a) and 3-
decyl-2-tetralone (30b). The reaction was carried out
according to the typical procedure on a 1.0-mmol scale by
using N0-(3,4-dihydronaphthalen-2(2H)-ylidene)-N,N-di-
ethyl-1,2-ethanediamine 29 (0.244 g, 1.0 mmol), MesMgBr
(1.18 M in THF, 0.889 mL, 1.05 mmol), and 1-chlorodecane
(0.194 g, 1.1 mmol). Conditions: 50 ꢀC, 48 h. The title
compounds (0.212 g, 74% yield, 30a/30b¼93:7 determined
1
by H NMR analysis) were obtained as a colorless liquid
1
after silica gel column chromatography; IR (neat) 3019
(aromatic C–H), 2922, 2852, 1709 (C]O), 1457, 1207,
1039, 754; 1-decyl-2-tetralone (major): H NMR d 0.87
1042, 973, 795, 703; H NMR d 1.21 (d, J¼6.9 Hz, 3H,
CHCH3), 1.54–1.61 (m, 1H, CHCHH), 1.99–2.06 (m, 1H,
CHCHH), 2.17 (s, 6H, N(CH3)2), 2.22–2.39 (m, 2H,
NCH2), 3.57 (sext, J¼6.9 Hz, 1H, CHCH3), 7.46 (br
t, J¼7.5 Hz, 2H, CH(CH)3CH), 7.55 (br t, J¼7.5 Hz,
1H, (CH)2CH(CH)2), 7.97 (br d, J¼7.5 Hz, 2H,
CHCHCHCHCH); 13C NMR d 17.5, 31.6, 38.6, 45.4 (2C),
57.4, 128.2 (2C), 128.5 (2C), 132.7, 136.8, 204.2. Anal.
Calcd for C13H19NO C, 76.06; H, 9.33; N, 6.82. Found C,
75.99; H, 9.39; N, 6.77.
1
(t, J¼6.6 Hz, 3H, CH3), 1.17–1.27 (m, 16H, (CH2)8),
1.80–1.83 (m, 2H, CH2CH), 2.50 (ddd, J¼6.6, 9.9,
17.4 Hz, 1H, C(]O)CH2CHH), 2.65 (ddd, J¼5.4, 6.0,
17.4 Hz, 1H, C(]O)CH2CHH), 2.99 (ddd, J¼5.4, 6.6,
15.6 Hz, 1H, C(]O)CHHCH2), 3.18 (ddd, J¼6.0, 9.9,
15.6 Hz, 1H, C(]O)CHHCH2), 3.38 (t, J¼6.9 Hz, 1H,
CCH), 7.09–7.33 (m, 4H, (CH)4); 13C NMR d 14.0, 22.6,
26.9, 27.8, 29.2, 29.3, 29.5 (3C), 31.8, 32.2, 37.5, 54.0,
126.6, 126.7, 127.8, 128.1, 136.3, 137.6, 212.8. Anal. Calcd
for C20H30O C, 83.86; H, 10.56. Found C, 83.31; H, 10.50.
4.1.5. Synthesis of (3S)-1,3-diphenylbutan-1-one23 (34).
The starting alkyl halide, (1S)-(1-chloroethyl)benzene 33,
was prepared according to the literature procedure24 from
(1R)-1-phenylethanol in 46% yield. The enantiomeric
excess of the chloride was determined as 94.0% by GC
analysis.
4.1.3.7. Synthesis of 1-cycloheptyl-2-tetralone (31a)
and 3-cycloheptyl-2-tetralone (31b). The reaction was car-
ried out according to the typical procedure on a 0.45-mmol
scale by using N0-(3,4-dihydronaphthalen-2(2H)-ylidene)-
N,N-diethyl-1,2-ethanediamine 29 (0.110 g, 0.45 mmol),
MesMgBr (1.18 M in THF, 0.400 mL, 0.47 mmol), and
chlorocycloheptane (0.066 g, 0.50 mmol). Conditions:
50 ꢀC, 24 h; 65 ꢀC, 24 h. The title compounds (0.071 g,
71% yield, 31a/31b¼99:1 determined by 1H NMR analysis)
were obtained as a colorless liquid after silica gel column
chromatography; IR (neat) 3019 (aromatic C–H), 2923,
2852, 1708 (C]O), 1457, 1220, 1178, 970, 739; 1-cyclo-
N0-(1-Phenylethylidene)-N,N-diethyl-1,2-ethanediamine
(0.131 g, 0.6 mmol) was added to t-BuMgCl (2.06 M in
THF, 0.29 mL, 0.6 mmol) at ꢁ78 ꢀC. The mixture was
stirred at 0 ꢀC for 1 h, and then warmed to room temperature.
After 1 h, (1S)-(1-chloroethyl)benzene 33 (0.070 g,
0.5 mmol, 94% ee) was added at room temperature. The re-
action mixture was stirred at 30 ꢀC for 36 h. AcOH in H2O
(50 wt %, 0.5 mL) was added slowly at 0 ꢀC. The reaction
mixture was stirred at 50 ꢀC for 1 h and then cooled to
room temperature. The reaction mixture was neutralized
with saturated NaHCO3 aqueous solution. The aqueous layer
was extracted with Et2O five times. The combined organic
extracts were dried with Na2SO4. After the solvents were re-
moved in vacuo, the crude product was chromatographed on
1
heptyl-2-tetralone (major): H NMR d 1.22–1.84 (m, 12H,
(CH2)6), 2.12–2.21 (m, 1H, CH2CH), 2.52 (ddd, J¼6.9,
11.4, 11.8 Hz, 1H, C(]O)CH2CHH), 2.75 (ddd, J¼2.7,
6.3, 18.3 Hz, 1H, C(]O)CH2CHH), 2.96 (ddd, J¼2.7,
6.9, 15.9 Hz, 1H, C(]O)CHH), 3.26 (d, J¼8.1 Hz, 1H,
CCH), 3.38 (ddd, J¼6.3, 11.4, 15.9 Hz, 1H, C(]O)CHH);

8448
T. Hatakeyama et al. / Tetrahedron 63 (2007) 8440–8448
5. (a) Hirano, K.; Fujita, K.; Yorimitsu, H.; Shinokubo, H.;
Oshima, K. Tetrahedron Lett. 2004, 45, 2555–2557; (b) Ooi,
T.; Uraguchi, D.; Kagoshima, N.; Maruoka, K. Tetrahedron
Lett. 1997, 38, 5679–5682.
6. See also the stereochemical control of lithium enolate: (a)
Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 491,
495; (b) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am.
Chem. Soc. 1991, 113, 9571–9574 and Ref. 3.
silica gel (5 g, pentane and then 3% Et2O in pentane) to ob-
tain the title compound 34 (0.072 g, 64% yield, 89% ee) as
a colorless liquid. The enantiomeric excess of the compound
was determined by HPLC analysis (CHIRALCEL OJ-H,
Daicel, 4.6ꢂ250 mm; column temperature, 15 ꢀC; eluent,
hexane/i-PrOH¼99:1; flow rate, 0.3 mL/min; detector,
254 nm (UV)). Peaks at the retention times of 49.3 and
63.8 min; [a]2D6 +12.43 (c 0.58, CCl4). The starting alkyl
chloride was recovered (30% 1H NMR yield, 81% ee). Sim-
ilarly, the reaction at 50 ꢀC for 12 h gave 34 in 78% yield
with 85% ee (0.088 g).
7. Preliminary communication: Hatakeyama, T.; Ito, S.;
Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127,
14192–14193.
8. (a) Paterson, I. Tetrahedron Lett. 1979, 1519–1520; (b) Reetz,
€
€
M. T.; Huttenhain, S. H.; Walz, P.; Lowe, U. Tetrahedron Lett.
1979, 4971–4974; (c) Reetz, M. T.; Walz, P.; H€ubner, F.;
Acknowledgements
€
Huttenhain, S. H.; Heimbach, H.; Schwellnus, K. Chem. Ber.
1984, 117, 322–335.
We thank the Ministry of Education, Culture, Sports, Sci-
ence, and Technology of Japan for financial supports,
9. Nakamura, M.; Hatakeyama, T.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 11820–11825.
a
Grant-in-Aid for Scientific Research (S, E.N.,
10. Some other dialkyl amino derivatives gave comparable results:
dimethylamino (87%), piperidyl (88%), pyrrolidyl (72%), and
morpholyl (82%).
11. Begum, S. A.; Terao, J.; Kambe, N. Chem. Lett. 2007, 36,
196–197.
18105004), a Grant-in-Aid for Scientific Research on Prior-
ity Areas ‘Synergistic Effects for Creation of Functional
Molecules’ from MEXT (M.N., 18064006), and a Grant-
in-Aid for Young Scientists from JSPS (T.H., 19750077).
ꢀ
12. (a) Farrall, M. J.; Frechet, J. M. J. Am. Chem. Soc. 1978, 90,
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