The cobalt-catalyzed cross-coupling reaction of alkyl halides with alkyl Grignard reagents: A new route to constructing quaternary carbon centers

Article abstract of DOI:10.1055/s-0033-1341152

The cross-coupling of alkyl (pseudo)halides with alkyl Grignard reagents is catalyzed efficiently by a cobalt(II) chloride-lithium iodide-1,3-diene catalytic system, which provides a new synthetic tool for constructing sp ³ carbon chains. This system is particularly useful for creating quaternary carbon centers via the use of tertiary alkyl Grignard reagents. Various functional groups including esters, amides and carbamates are well tolerated.

Full text of DOI:10.1055/s-0033-1341152

PRACTICAL SYNTHETIC PROCEDURES
▌1583
pTrahctiecalCsyonthbetaiclptr-ocCedaurtesalyzed Cross-Coupling Reaction of Alkyl Halides with Alkyl
Grignard Reagents: A New Route to Constructing Quaternary Carbon
Centers
Cobalt-Catalyzed Cross-Coupling Reactions
Takanori Iwasaki,a Hiroaki Takagawa,a Kanako Okamoto,a Surya Prakash Singh,b Hitoshi Kuniyasu,a
Nobuaki Kambe*a
a
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax +81(6)68797390; E-mail: kambe@chem.eng.osaka-u.ac.jp
b
Inorganic and Physical Chemistry Division, CSIR–Indian Institute of Chemical Technology,
PSP
Tarnaka, Hyderabad 500607, India
Received: 10.02.2014; Accepted after revision: 20.03.2014
No274
Abstract: The cross-coupling of alkyl (pseudo)halides with alkyl Grignard reagents is catalyzed efficiently by a cobalt(II) chloride–lithium
iodide–1,3-diene catalytic system, which provides a new synthetic tool for constructing sp3 carbon chains. This system is particularly useful
for creating quaternary carbon centers via the use of tertiary alkyl Grignard reagents. Various functional groups including esters, amides
and carbamates are well tolerated.
Key words: cobalt, cross-coupling, Grignard reagents, alkyl halides, quaternary carbon
procedure 1
CoCl2 (2 mol%), LiI (4 mol%)
O
O
isoprene (2 equiv)
+
Br
ClMg
2a (1.2 equiv)
THF, 50 °C, 5 h
EtO
EtO
4m
5m 78%
3e 82%
procedure 2
n-Oct–Br
CoCl2 (2 mol%), LiI (4 mol%)
isoprene (2 equiv)
ClMg
n-Oct
+
THF, 50 °C, 5 h
OMe
OMe
1a
procedure 3
2e (1.2 equiv)
CoCl2 (0.1 mol%), LiI (4 mol%)
isoprene (2 equiv)
n-Oct–Br
+
+
ClMg
2g (1.2 equiv)
n-Oct
THF, 50 °C, 24 h
1a (10 mmol)
3g 97%
procedure 4
CoCl2 (2 mol%), LiI (4 mol%)
isoprene (2 equiv)
n-Oct–Br
ClMg
2a (1.2 equiv)
n-Oct
3a 71% (6.0 g)
THF, 50 °C, 22 h
1a (50 mmol)
Scheme 1 General procedures for the cobalt-catalyzed cross-coupling reaction of alkyl halides with alkyl Grignard reagents (Procedures 1 and
2), a reaction using 0.1 mol% of catalyst (Procedure 3) and a large-scale reaction (Procedure 4)
ucts.2 Therefore, only a unique combination of copper cat-
Introduction
alysts and a tert-butylmagnesium halide (t-BuMgX)
Transition-metal-catalyzed alkyl–alkyl coupling reactions reagent have been reported as successful examples of al-
represent one of the simplest and most practical tech- kyl–alkyl cross-coupling reactions in which tertiary alkyl
niques for the construction of saturated hydrocarbon Grignard reagents are employed.3 During the course our
frameworks.1 The use of tertiary alkylmetal reagents in studies on transition-metal-catalyzed cross-couplings us-
cross-coupling would permit quaternary carbon centers to ing unsaturated hydrocarbon additives,3d,e,4 we found that
be produced, however, such attempts have often proved cobalt salts, with the aid of lithium iodide (LiI) and conju-
unsuccessful due to the facile β-hydrogen elimination gated diene additives such as 1,3-butadiene or isoprene,
and/or isomerization of tertiary alkylmetal intermediates catalyze successfully cross-coupling reactions of alkyl
resulting in the production of a mixture of coupling prod- (pseudo)halides with tertiary alkyl Grignard reagents giv-
ing rise to the formation of quaternary carbon centers,
where esters, amides, carbamates and acetal functional
groups were well tolerated.5–7 It was also possible to cou-
SYNTHESIS 2014, 46, 1583–1592
Advanced online publication: 14.05.2014
DOI: 10.1055/s-0033-1341152; Art ID: SS-2014-Z0096-PSP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
ple primary and secondary alkyl Grignard reagents with
alkyl halides using this catalyst system. The reactions

1584
T. Iwasaki et al.
PRACTICAL SYNTHETIC PROCEDURES
took place exclusively at the primary alkyl C–Br bonds,
even in the presence of C–Cl, secondary alkyl C–Br and
aromatic C–Br bonds. The reaction proceeded efficiently
using only 0.1 mol% of cobalt(II) chloride (CoCl2) and
could be easily scaled up to afford the expected product on
gram-scale. Herein, we report on the details of the proce-
dures employed in these cobalt-catalyzed alkyl–alkyl
cross-coupling reactions (Scheme 1).5
Table 1 Cross-Coupling of n-Octyl Bromide (1a) with Grignard
Reagentsa,b
Entry Grignard reagent
Product Yield (%)c
1d
2
84
92
MgCl
2a
3a
MgCl
3e
4e
2b
2c
3b
3c
91
MgCl
MgCl
Scope and Limitations
85 (82)
n-Octyl bromide (n-OctBr) (1a) reacted with tert-butyl-
magnesium chloride (t-BuMgCl), within five hours in tet-
rahydrofuran at 50 °C in the presence of cobalt(II)
chloride (2 mol%), lithium iodide (4 mol%) and 1,3-buta-
diene (2 equiv), to give the desired coupling product in
84% yield. The possible isomerized coupling product, n-
Oct–i-Bu, was not observed on GC analysis, and only
trace amounts of octane and octenes (1% or less) were
formed (Table 1, entry 1). The presence of lithium iodide
and a 1,3-diene were essential for achieving an efficient
coupling reaction. When lithium chloride (LiCl), lithium
bromide (LiBr), sodium iodide (NaI), potassium iodide
(KI) or magnesium iodide (MgI2) were used instead of
lithium iodide, the expected product was obtained, but in
lower yields (27%, 31%, 70%, 73% and 60%, respective-
ly). Interestingly, the combined use of cobalt(II) iodide
(CoI2) and lithium chloride gave the cross-coupling prod-
uct in 76% yield, being comparable to that found in the
case of Table 1, entry 1, employing cobalt(II) chloride and
lithium iodide. The use of isoprene as the 1,3-diene im-
proved the yield to 92% (Table 1, entry 2).
5e
6
2d
2e
2f
3d
3e
3f
81 (80)
82 (80)
<1
MeO
MgCl
7
MgCl
8
9
2g
2h
3g
3h
93
MgCl
89 (83)
MgBr
10e
2i
3i
90 (86)
MgBr
MgCl
MgCl
11
2j
2k
2l
3j
92
77
12f
3k
Cross-couplings using various Grignard reagents were
performed under the optimized conditions with isoprene
as the additive (Table 1, entry 2), and the results are sum-
marized in Table 1. Acyclic tertiary alkyl Grignard re-
agents participated in the cross-coupling reaction, giving
good to excellent yields (Table 1, entries 3–6); however,
13
14
MeMgCl
3l
4
2m PhMgBr
3m
<1
a Reprinted (adapted) with permission from J. Am. Chem. Soc. 2013,
135, 9604. Copyright 2013 American Chemical Society.
b Reaction conditions: CoCl2 (2 mol%), LiI (4 mol%), isoprene (2
the desired product was not obtained when the adamantyl equiv), THF, 50 °C, 5 h.
c Yields were determined by GC. Yields of isolated products are in pa-
Grignard reagent was used (Table 1, entry 7). Primary and
secondary alkyl Grignard reagents also proved to be suit-
able coupling partners. For example, both acyclic and cy-
clic secondary alkyl Grignard reagents underwent
coupling with n-octyl bromide to furnish branched carbon
skeletons (Table 1, entries 8–10). No evidence for isomer-
ization of the alkyl groups of the alkyl Grignard reagents
was detected in any of the cases examined. Primary alkyl
Grignard reagents gave the corresponding coupling prod-
ucts in good yields (Table 1, entries 11 and 12), but meth-
ylmagnesium chloride (MeMgCl) and phenylmagnesium
bromide (PhMgBr) reacted sluggishly, due to difficulties
in generating the active catalytic species (Table 1, entries
13 and 14).5 The relative reactivity of n-, sec- and tert-
butyl Grignard reagents was estimated to be roughly
1:4:0.6, by competitive experiments.
rentheses.
d 1,3-Butadiene was used instead of isoprene.
e n-DecBr (1b) was used instead of n-OctBr.
f Reaction time was 20 h.
quantities of catalysts (a few mol% loading or higher) are
often required to achieve an efficient alkyl–alkyl coupling
reaction. We examined the efficiency of the present cata-
lyst system and a high turnover number (TON) of 970
could be achieved with a catalyst loading of only 0.1
mol% (Scheme 2). For example, when the reaction of 1a
with 2g was carried out on a 10 mmol scale with cobalt(II)
chloride (0.01 mmol) in the presence of lithium iodide
(0.4 mmol) and isoprene (20 mmol), the coupling reaction
proceeded smoothly, with a 68% yield of 3g being ob-
served after six hours; the reaction reached completion
within 24 hours to give 3g in 97% GC yield.
Due to the labile nature of the alkylmetal complexes aris-
ing mainly from β-hydrogen elimination, relatively larger
Synthesis 2014, 46, 1583–1592
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cobalt-Catalyzed Cross-Coupling Reactions
1585
Table 2 Cobalt-Catalyzed Cross-Coupling Reactionsa (continued)
CoCl2 (0.1 mol%)
LiI (4 mol%)
isoprene (2 equiv)
Entry Alkyl halide
Product
Yield
(%)b
n-Oct–Br
+
ClMg
THF, 50 °C
n-Oct
1a (10 mmol)
2g (12 mmol)
3g
68% (6 h)
97% (24 h)
I
t-Bu
69
(67)
N
O
N
O
12
13
14
4h
4i
5h
5i
Scheme 2 Coupling reaction using 0.1 mol% of the cobalt catalyst
The scope and limitations of the alkyl (pseudo)halides are
summarized in Table 2. An alkyl fluoride underwent cou-
pling with tert-butylmagnesium chloride to afford a mod-
erate 62% yield of the expected product (Table 2, entry 1).
The reaction of an alkyl chloride was sluggish and only
2% of the coupling product was obtained (Table 2, entry
2). However, an alkyl iodide and alkyl tosylate were
found to be suitable alkyl electrophiles (Table 2, entries 3
and 4). Alkenes, alkynes, trifluoromethyl, tert-butylsilyl
ethers and acetal functionalities were well tolerated (Ta-
ble 2, entries 6–10). An alkyl bromide having a hydroxy
group could be employed as the coupling partner by way
of in situ deprotonation with an excess of the Grignard re-
agent (Table 2, entry 11). Although carbonyl groups are
potentially labile toward Grignard reagents, the fact that
amides, carbamates and ester functional groups remained
intact demonstrates the usefulness of the present catalytic
system (Table 2, entries 12–19).
O
O
79
(73)
NEt2
NEt2
Br
t-Bu
O
O
81
(76)
N
N
4j
5j
Br
t-Bu
t-Bu
O
O
Br
Br
61
(60)
15
16
17
18
4k
4k
4l
5ka
5kg
5la
BocN
BocN
TsN
BocN
s-Bu
t-Bu
76
(74)
BocN
TsN
Br
58
(55)
s-Bu
Br
Table 2 Cobalt-Catalyzed Cross-Coupling Reactionsa
79
(74)
4l
5lg
TsN
O
TsN
O
Entry Alkyl halide
Product
Yield
(%)b
78
(72)
OEt
OEt
19
20
4m
4n
5m
1c 1c n-Oct–F
3a n-Oct–t-Bu
3a n-Oct–t-Bu
3a n-Oct–t-Bu
3a n-Oct–t-Bu
62
2
Br
t-Bu
t-Bu
2
3
4
1d n-Oct–Cl
1e n-Oct–I
S
S
Br
80
(78)
s-Bu
t-Bu
5n
5o
71
58
1f n-Oct–OTs
Br
t-Bu
21d 4o
75
Br
Br
t-Bu
Br
5
6
7
4a
4b
4c
5a
5b
5c
95
86
92
(88)
22
4p
5p
Cl
Cl
Br
Br
Br
Br
74
(71)
23e 4q
24e 4q
5qa
5qg
Br
Br
t-Bu
Br
t-Bu
88
(86)
s-Bu
s-Bu
86
71
Br
t-Bu
Br
Br
CF3
CF3
25
26
4r
4r
5rg
5rj
84
(80)
8
4d
5d
Br
Br
Br
Br
Br
t-Bu
n-Bu
94
80
(76)
9
4e TBSO
Br
5e TBSO
t-Bu
t-Bu
81f
(78)
Br
95
(91)
27
28
4s
4s
5sa
5sg
10
4f
5f
OTHP
OTHP
Br
Br
t-Bu
88f
(85)
Br
t-Bu
>99
(88)
11d 4g
5g
s-Bu
OH
OH
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1583–1592

1586
T. Iwasaki et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Cobalt-Catalyzed Cross-Coupling Reactionsa (continued)
sessing a phenyl or alkynyl substituent (benzyl and
propargyl bromides) were employed.
Entry Alkyl halide
Product
Yield
(%)b
The applicability of the present cobalt catalyst system to a
large-scale production was demonstrated by the gram-
scale (50 mmol) synthesis of 3a (Scheme 3). The reaction
of n-octyl bromide (9.7 g, 50 mmol) with tert-butylmag-
nesium chloride (60 mmol) in a modified procedure (see
procedure 4 for details) was complete within 22 hours,
and the resulting mixture was purified by distillation to
give analytically pure product 3a in 71% yield (6.0 g).
29
30
4s
4t
5sj
89f
n-Bu
i-Bu
Br
50g
(49)
Br
5td
n-Bu
68g
(66)
Br
Br
31
32
4t
4t
5th
5tn
Et
n-Oct
CoCl2 (2 mol%)
LiI (4 mol%)
isoprene (2 equiv)
71g
n-Oct–Br
+
THF, 50 °C, 22 h
ClMg
n-Oct
3a 71% (6.0 g)
1a (9.7 g, 50 mmol)
a Reprinted (adapted) with permission from J. Am. Chem. Soc. 2013,
135, 9604. Copyright 2013 American Chemical Society.
b Yield was determined by GC. Yields of isolated products are in pa-
rentheses.
2a (60 mmol)
Scheme 3 Gram-scale synthesis of 3a
c Reaction time was 24 h.
d Excess (2.5 equiv) of the Grignard reagent was used.
e Reaction time was 12 h.
Conclusion
f Only less than 1% of cyclized coupling product was formed.
g Ring-opened coupling product was formed in 2%, <1% and 3%
yields for entries 30, 31 and 32, respectively.
In summary, an efficient catalytic system for the cross-
coupling of alkyl halides with alkyl Grignard reagents us-
ing cobalt(II) chloride along with lithium iodide and 1,3-
dienes has been developed. Various polar functional
groups as well as 5-hexenyl and cyclopropylmethyl skel-
etons, which easily undergo radical rearrangement, were
well tolerated using the described system. Tertiary alkyl
Grignard reagents underwent efficient coupling with alkyl
halides to create quaternary carbon centers. The catalyst
loading could be reduced to 0.1 mol% without any loss of
yield and the reaction could be performed on large scale
(50 mmol). The present cross-coupling reaction does not
require toxic and expensive phosphine ligands, amines or
noble metals.
An alkyl bromide carrying a thiophene ring underwent the
cross-coupling with sec-butylmagnesium chloride (s-
BuMgCl) to give the corresponding product in good yield
(Table 2, entry 20), but unfortunately, the similar reaction
with tert-butylmagnesium chloride resulted in the forma-
tion of a complex mixture, probably due to deprotonation
of the acidic α-proton of the thiophene ring. 1,4-Dibro-
mobutane (4o) underwent cross-coupling at both terminal
carbons to install two quaternary carbon centers (Table 2,
entry 21). When dihalogenated substrates having different
carbon–halogen bonds were employed using the present
catalytic system, the coupling reaction was chemoselec-
tive, taking place at the primary alkyl bromide moiety and
not at primary alkyl chloride, secondary alkyl bromide
and aromatic C–Br moieties (Table 2, entries 22–26).
Experimental Procedures
All reactions were performed under a nitrogen atmosphere using
standard Schlenk techniques. Anhydrous THF was purchased from
the Kanto Chemical Company and purified by SPS8 prior to use.
THF solutions of t-Bu (2a), s-Bu (2g), n-Bu (2j), i-Bu (2k), Me (2l),
Ph (2m), and n-Oct (2n) Grignard reagents were purchased from the
Kanto Chemical Company, Aldrich or TCI, and used after titration.
Other Grignard reagents were prepared by a standard procedure and
were used after titration. All catalytic reactions were performed
with highly pure CoCl2 (Aldrich, 99.999% purity) and LiI (Aldrich,
99.999% purity) to avoid contamination by other metals as impuri-
ties. 1-(2-Trifluoromethylphenyl)-5-bromopent-1-yne (4d) was
prepared by the reaction of the corresponding lithiated terminal al-
kyne with 1,3-dibromopropane. Tetrahydropyranyl (THP) and tert-
butyldimethylsilyl (TBS) ethers were prepared by standard protec-
tion procedures.9 N-(5-iodopentyl)piperidine-2-one (4h) was syn-
thesized by coupling piperidine-2-one with diiodopentane under
basic conditions (KOH) in THF. Amides 4i and 4j were prepared
from 6-bromohexanoyl bromide and the corresponding amines.
tert-Butoxycarbonyl (Boc) or tosyl (Ts)-protected bromoethylpi-
peridines 4k and 4l were synthesized via a protection and bromina-
tion sequence from hydroxyethylpiperidine. Thiophene derivative
4n was synthesized by deprotonation of thiophene with n-BuLi and
subsequent trapping with 1,3-dibromopropane. All other commer-
cially available reagents were used as received unless otherwise
stated. Yields were determined by GC using decane as an internal
standard. Yields in parentheses refer to analytically pure isolated
The reactions of 6-bromohex-1-ene (4s) with primary,
secondary and tertiary alkyl Grignard reagents afforded
the corresponding terminal olefins in 81–89% yields as
the sole coupling products (Table 2, entries 27–29), sug-
gesting that the free 6-hexenyl radical, which readily un-
dergoes 5-exo radical cyclization, was not generated in
this catalytic system. In addition, direct cross-coupling
products were obtained from (bromomethyl)cyclopro-
pane (4t), in moderate yields, without any detectable ring-
opened products (Table 2, entries 30–32). These results
indicate that no radical intermediates are generated from
alkyl halides in the present catalytic system. This is in
sharp contrast with previously reported cobalt-catalyzed
systems.6,7
Unfortunately, no coupling products were produced in the
case of secondary alkyl electrophiles. For example, less
than 20% yields of the coupled products were obtained,
even when highly reactive secondary alkyl bromides pos-
Synthesis 2014, 46, 1583–1592
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cobalt-Catalyzed Cross-Coupling Reactions
1587
compounds for which the obtained masses are provided in the ana-
lytical data sections. Flash column chromatography was carried out
using silica gel (60 mesh spherical) purchased from Kanto Chemi-
cal Company. GC was performed on a Shimadzu GC-2014 instru-
ment equipped with a GL Sciences InertCap 5 capillary column
(I.D. = 0.25 mm, length = 30 m, df = 0.25 μm) to determine the GC
yield. Gel permeation chromatography (GPC) was accomplished
using a Japan Analytical Industry Co. Ltd., Model LC-908 instru-
ment equipped with JAIGEL-1 and -2 columns with CHCl3 as the
eluent. Melting points were determined on a Stanford Research Sys-
tems OptiMelt MPA 100 with a glass capillary. IR spectra were ob-
Large-Scale Coupling of n-OctBr with t-BuMgCl; Procedure 4
(P4)
To a dry, nitrogen-flushed 300 mL three-necked flask, equipped
with a rubber septum and a magnetic stir bar, were added LiI (268
mg, 2 mmol), pentadecane (0.8 g as an internal standard) and THF
(40 mL) via a syringe and the solution was cooled to –78 °C using
a dry ice/EtOH bath. t-BuMgCl (2a) (58.0 mL, 1.03 M in THF, 60
mmol), isoprene (6.8 g, 100.0 mmol) and CoCl2 (25 mL, 0.04 M in
THF, 1 mmol) were added (see Note 1 above). The cold bath was
removed and the reaction mixture was stirred and warmed to r.t. (ca.
over 30 min), and then suspended in an oil bath and heated to 50 °C.
After reaching 50 °C, n-OctBr (1a) (9.66 g, 50 mmol) was added.
(Note: when n-OctBr was added at the beginning, as in P1–3, the
yield of the desired coupling product dropped to ca. 50% due to the
formation of unidentified side products, which may have been pro-
duced during the course of heating to 50 °C. The addition of alkyl
halides after the formation of the active catalytic species was found
to be effective in preventing side reactions in large-scale reactions,
see also Note 2 above). The reaction progress was monitored by
GC, which, after stirring for 22 h at 50 °C, indicated that the n-Oct-
Br had been consumed. The mixture was cooled to 0 °C in an ice
bath and carefully quenched with aq HCl (1 M) to give a clear bi-
layer solution. The product was extracted with Et2O (3 × 100 mL),
and the combined organic layer dried over Na2SO4, concentrated
and purified by distillation (bp 87 °C at 2.1 kPa) to give 2,2-dimeth-
yldecane (3a) as a colorless liquid (5.99 g, 71%).
tained using
a JASCO Corporation FT/IR-4200 instrument
equipped with ATR PRO450-S. H NMR (400 MHz), 13C NMR
(100 MHz) and 19F NMR (376 MHz) spectra were recorded at 20 °C
on a JEOL JNM-Alice 400. Chemical shifts are given in ppm and
spin-spin coupling constants, J, are given in Hz. Mass spectra were
acquired on a JEOL JMS-700 Mstation spectrometer. HRMS was
performed using the same spectrometer.
1
Coupling of Alkyl Halides with t-BuMgCl; Procedure 1 (P1)
An alkyl halide (1.0 mmol), decane (63 mg as an internal standard)
and LiI (5.3 mg, 0.04 mmol) were added to a dry, nitrogen-flushed
test tube equipped with a rubber septum and a magnetic stir bar.
THF (0.8 mL) was added and the solution was cooled to –78 °C us-
ing a dry ice/EtOH bath. t-BuMgCl (2a) (1.5 mL, 0.81 M in THF,
1.2 mmol) was added slowly followed by isoprene (136.2 mg, 2.0
mmol). To this mixture was added CoCl2 [2.6 mg, 0.02 mmol, as a
powder or as a THF solution (0.5 mL, 0.04 M)]. (Note 1: CoCl2
should be added after isoprene, otherwise the catalytic performance
decreases significantly). The cold bath was removed and the mix-
ture was warmed to r.t. (ca. over 10 min), and then heated for 5 h by
suspending the reaction vessel in an oil bath kept at 50 °C. (Note 2:
when the reaction mixture was heated at 30 °C during this stage, un-
identified side reactions occurred resulting in low yields of coupling
products). The resulting mixture was cooled to 0 °C in an ice bath
and the reaction was quenched with aq HCl (5 mL, 1 M). The prod-
uct was extracted with Et2O (3 × 20 mL). The combined organic
layer dried over Na2SO4, concentrated and analyzed by gas chroma-
tography to determine the GC yield. The residue was purified by sil-
ica gel column chromatography or by GPC.
2,2-Dimethyldecane (3a)
According to P1, n-OctBr (1a) (193 mg, 1.0 mmol) and t-BuMgCl
(2a) (0.81 M in THF, 1.2 mmol) were reacted under standard con-
ditions. See also P4 for a large-scale synthesis.
Yield: 94% (determined by GC using decane as an internal stan-
dard).
IR (Zn/Se-ATR, neat): 2951, 2924, 2855, 1465, 1364, 954, 890, 762
cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.85 (s, 9 H), 0.88 (t, J = 6.4 Hz,
3 H), 1.16 (br s, 2 H), 1.27 (br s, 12 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 24.6, 29.38, 29.42,
29.7, 30.3, 30.7, 31.9, 44.3.
Coupling of n-OctBr with Alkyl Grignard Reagents; Procedure
2 (P2)
3,3-Dimethyltridecane (3b)
According to P2, n-DecBr (1b) (221 mg, 1.0 mmol) and 2-methyl-
2-butylmagnesium chloride (2b) (0.60 M in THF, 1.2 mmol) were
reacted under standard conditions.
n-OctBr (1a) (193 mg, 1.0 mmol), decane (63 mg as an internal
standard) and LiI (5.3 mg, 0.04 mmol) were added to a dry, nitro-
gen-flushed test tube equipped with a rubber septum and a magnetic
stir bar. THF (0.8 mL) was added and the solution was cooled to
–78 °C using a dry ice/EtOH bath. The appropriate Grignard reagent
(in THF, 1.2 mmol) was added slowly followed by the addition of
isoprene (136.2 mg, 2.0 mmol). To this mixture was added CoCl2
[2.6 mg, 0.02 mmol, as powder or as a THF solution (0.5 mL, 0.04
M)] (see Note 1 above). The process was continued and the reaction
mixture was worked up following procedure 1 (P1) as described
above.
Yield: 91% (determined by GC using decane as an internal stan-
dard).
5,5-Dimethylpentadecane (3c)
According to P2, n-DecBr (1b) (221 mg, 1.0 mmol) and 2-methyl-
2-hexylmagnesium chloride (2c) (0.65 M in THF, 1.2 mmol) were
reacted under standard conditions. After aqueous work-up, purifica-
tion by GPC (with CHCl3 as the eluent) afforded the title compound.
Yield: 173 mg (82%); colorless oil.
IR (Zn/Se-ATR, neat): 2956, 2925, 2855, 1469, 949 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.74 (s, 6 H), 0.81 (t, J = 6.9 Hz,
3 H), 0.82 (t, J = 7.4 Hz, 3 H), 1.08–1.19 (br m, 24 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 14.2, 22.7, 23.7, 24.0, 26.3,
27.3, 29.4, 29.68, 29.74, 29.76, 30.7, 31.9, 32.5, 41.8, 42.0.
MS (EI): m/z (%) = 240 (57) [M]+, 225 (11), 183 (14), 168 (7), 141
(8).
Coupling of n-OctBr with s-BuMgCl Using 0.1 mol% of CoCl2;
Procedure 3 (P3)
In a glove box, LiI (53.5 mg, 0.4 mmol) was added to a 100 mL test
tube equipped with a rubber septum and a magnetic stir bar. The test
tube was removed from the glove box and THF (1.0 mL), n-OctBr
(1a) (1.94 g, 10.0 mmol) and decane (0.35 g as an internal standard)
were added. The solution was cooled to –78 °C using a dry
ice/EtOH bath. s-BuMgCl (2g) (18.5 mL, 0.65 M in THF, 12.0
mmol) was added slowly followed by isoprene (2.0 mL, 20.0 mmol)
and CoCl2 (powdered, 1.3 mg, 0.01 mmol) (see Note 1 above). The
cold bath was removed and the mixture was stirred, warmed to r.t.
(ca. over 10 min), and then heated at 50 °C by suspending in a pre-
heated oil bath (see Note 2 above). The progress of the reaction was
monitored by GC. The product yield reached 68% and 97% after 6
h and 24 h, respectively.
HRMS (EI): m/z [M]+ calcd for C17H36: 240.2817; found: 240.2816.
2,5,5-Trimethylpentadecane (3d)
According to P2, n-DecBr (1b) (221 mg, 1.0 mmol) and 2,5-dimeth-
yl-2-hexylmagnesium chloride (2d) (0.65 M in THF, 1.2 mmol)
were reacted under standard conditions. After aqueous work-up, pu-
© Georg Thieme Verlag Stuttgart · New York
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1588
T. Iwasaki et al.
PRACTICAL SYNTHETIC PROCEDURES
rification by GPC (with CHCl3 as the eluent) afforded the title com-
pound.
under standard conditions. After aqueous work-up, purification by
GPC (with CHCl3 as the eluent) afforded the title compound.
Yield: 181 mg (80%); pale yellow oil.
Yield: 205 mg (86%); colorless oil.
IR (Zn/Se-ATR, neat): 2955, 2925, 2854, 1469, 948 cm–1.
IR (Zn/Se-ATR, neat): 2922, 2852, 1461, 952, 762 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.73–0.83 (br m, 15 H), 0.98–1.19
1H NMR (400 MHz, CDCl3): δ = 0.81 (t, J = 6.4 Hz, 3 H), 1.02–1.61
(br m, 22 H), 1.36 (m, 1 H).
(br m, 31 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 22.8, 24.0, 27.3, 28.8,
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 26.6, 27.5, 28.6, 29.4,
29.4, 29.67, 29.73, 29.8, 30.9, 31.9, 32.4, 33.1, 39.5, 41.9.
29.67, 29.71, 29.8, 30.0, 31.9, 34.7, 38.3, 39.3.
MS (CI): m/z (%) = 253 (51) [M – H]+, 238 (15), 197 (18), 183 (31),
MS (EI): m/z (%) = 290 (49) [M]+, 275 (18), 261 (7), 233 (11), 219
169 (9), 155 (8), 141 (6).
(5).
HRMS (CI): m/z [M – H]+ calcd for C18H37: 253.2895; found:
HRMS (EI): m/z [M]+ calcd for C17H34: 238.2660; found: 238.2660.
253.2893.
Dodecane (3j)
According to P2, n-OctBr (1a) (193 mg, 1.0 mmol) and n-BuMgCl
(2j) (1.0 M in THF, 1.2 mmol) were reacted under standard condi-
tions.
1-(3,3-Dimethylundecyl)-4-methoxybenzene (3e)
According to P2, n-OctBr (1a) (193 mg, 1.0 mmol) and 4-(4-meth-
oxyphenyl)-2-methyl-2-butylmagnesium chloride (2e) (0.70 M in
THF, 1.2 mmol) were reacted under standard conditions. After
aqueous work-up, purification by GPC (with CHCl3 as the eluent)
afforded the title compound.
Yield: 92% (determined by GC using decane as an internal stan-
dard).
2-Methylundecane (3k)
Yield: 232 mg (80%); colorless oil.
According to P2, n-OctBr (1a) (193 mg, 1.0 mmol) and i-BuMgCl
(2k) (1.9 M in THF, 1.2 mmol) were reacted under standard condi-
tions for 20 h.
IR (Zn/Se-ATR, neat): 2954, 2926, 2855, 1512, 1467, 1247, 1177,
1041, 822 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 3 H), 0.90 (s,
6 H), 1.20–1.35 (br m, 14 H), 1.44 (t, J = 8.7 Hz, 2 H), 2.47 (t, J =
8.7 Hz, 2 H), 3.78 (s, 3 H), 6.82 (d, J = 8.2 Hz, 2 H), 7.09 (d, J = 8.2
Hz, 2 H).
Yield: 77% (determined by GC using decane as an internal stan-
dard).
(3,3-Dimethylbutyl)benzene (5a)
According to P1, (2-bromoethyl)benzene (4a) (185 mg, 1.0 mmol)
and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were reacted under
standard conditions.
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 24.0, 27.3, 29.4, 29.7,
29.8, 30.6, 31.9, 32.8, 41.9, 44.5, 55.2, 113.7, 129.1, 135.7, 157.5.
MS (EI): m/z (%) = 290 (32) [M]+, 275 (20), 261 (8), 249 (7), 233
(13), 219 (6).
Yield: 95% (determined by GC using decane as an internal stan-
dard).
HRMS (EI): m/z [M]+ calcd for C20H34O: 290.2609; found:
290.2608.
8,8-Dimethylnon-1-ene (5b)
According to P1, 7-bromohept-1-ene (4b) (177 mg, 1.0 mmol) and
t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were reacted under stan-
dard conditions.
3-Methylundecane (3g)
According to P2, n-OctBr (1a) (193 mg, 1.0 mmol) and s-BuMgCl
(2g) (0.76 M in THF, 1.2 mmol) were reacted under standard con-
ditions.
Yield: 86% (determined by GC using decane as an internal stan-
dard).
Yield: 93% (determined by GC using decane as an internal stan-
dard).
12,12-Dimethyltridec-1-ene (5c)
According to P1, 11-bromoundec-1-ene (4c) (233 mg, 1.0 mmol)
and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were reacted under
standard conditions. After aqueous work-up, purification by GPC
(with CHCl3 as the eluent) afforded the title compound.
See also P3 for the reaction using 0.1 mol% of CoCl2. Yields were
determined by GC analysis (using decane as an internal standard) to
be 68% and 97% after 6 h and 24 h, respectively.
5-Ethyltridecane (3h)
Yield: 181 mg (86%); colorless oil.
According to P2, n-OctBr (1a) (193 mg, 1.0 mmol) and 3-heptyl-
magnesium bromide (2h) (1.0 M in THF, 1.2 mmol) were reacted
under standard conditions. After aqueous work-up, purification by
GPC (with CHCl3 as the eluent) afforded the title compound.
IR (Zn/Se-ATR, neat): 2926, 2855, 1468, 1364, 990, 909 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (s, 9 H), 1.14–1.39 (br m, 16
H), 2.04 (m, 2 H), 4.93 (d, J = 10.5 Hz, 1 H), 4.99 (d, J = 17.4 Hz,
1 H), 5.81 (ddt, J = 17.0, 10.1, 6.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.6, 29.0, 29.2, 29.4, 29.5, 29.6,
29.7, 30.3, 30.6, 33.8, 44.3, 114.1, 139.3.
MS (EI): m/z (%) = 210 (18) [M]+, 195 (16), 180 (13), 153 (53), 139
(15).
HRMS (EI): m/z [M]+ calcd for C15H30: 210.2348; found: 210.2345.
Yield: 177 mg (83%); colorless oil.
IR (Zn/Se-ATR, neat): 2958, 2924, 2856, 1467, 953 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.81–0.91 (br m, 9 H), 1.16–1.34
(br d, 23 H).
13C NMR (100 MHz, CDCl3): δ = 10.9, 14.1, 14.2, 22.7, 23.2, 25.9,
26.7, 29.0, 29.4, 29.7, 30.2, 31.9, 32.9, 33.2, 38.8.
MS (EI): m/z (%) = 212 (46) [M]+, 197 (11), 185 (26), 147 (15), 133
(9).
1-(6,6-Dimethylhept-1-yn-1-yl)-2-(trifluoromethyl)benzene
(5d)
According to P1, 1-(2-trifluoromethylphenyl)-5-bromopent-1-yne
(4d) (291 mg, 1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2
mmol) were reacted under standard conditions. After aqueous
work-up, purification by GPC (with CHCl3 as the eluent) afforded
the title compound.
HRMS (EI): m/z [M]+ calcd for C15H32: 212.2504; found: 212.2499.
Decylcycloheptane (3i)
According to P2, n-DecBr (1b) (221 mg, 1.0 mmol) and cyclohep-
tylmagnesium bromide (2i) (1.0 M in THF, 1.2 mmol) were reacted
Yield: 215 mg (80%); orange oil.
Synthesis 2014, 46, 1583–1592
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cobalt-Catalyzed Cross-Coupling Reactions
1589
IR (Zn/Se-ATR, neat): 2954, 1491, 1451, 1318, 1160, 1138, 1113,
1063, 1034, 765 cm–1.
13C NMR (100 MHz, CDCl3): δ = 24.5, 25.7, 29.4, 29.6, 29.7, 30.2,
30.6, 32.7, 44.2, 63.0.
1H NMR (400 MHz, CDCl3): δ = 0.91 (s, 9 H), 1.35 (m, 2 H), 1.58
(m, 2 H), 2.42 (t, J = 6.9 Hz, 2 H), 7.34 (t, J = 7.3 Hz, 1 H), 7.44 (t,
J = 7.3 Hz, 1 H), 7.52 (d, J = 7.3 Hz, 1 H), 7.61 (d, J = 7.3 Hz, 1 H).
MS (CI): m/z (%) = 227 (31) [M–H]+, 211 (100), 171 (6), 155 (13),
141 (14), 127 (16), 113 (14).
HRMS (CI): m/z [M–H]+ calcd for C15H31O: 227.2375; found:
227.2373.
13C NMR (100 MHz, CDCl3): δ = 20.4, 23.7, 29.3, 30.2, 43.3, 76.7,
96.8, 122.3, 125.0, 125.6, 127.1, 131.2, 131.3, 133.9.
19F NMR (376 MHz, CDCl3): δ = –62.4.
MS (EI): m/z (%) = 268 (27) [M]+, 253 (21), 211 (46), 202 (10), 197
(8), 187 (21).
HRMS (EI): m/z [M]+ calcd for C16H19F3: 268.1439; found:
268.1437.
N-(6,6-Dimethylheptyl)piperidin-2-one (5h)
According to P1, N-(5-iodopentyl)piperidin-2-one (4h) (295 mg,
1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were re-
acted under standard conditions. After aqueous work-up, purifica-
tion by flash column chromatography (hexane–EtOAc, 20:1)
afforded the title compound.
Yield: 151 mg (67%); yellow oil.
1-[(tert-Butyldimethylsilyl)oxy]-4,4-dimethylpentane (5e)
According to P1, 1-bromo-3-[(tert-butyldimethylsilyl)oxy]propane
(4e) (253 mg, 1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2
mmol) were reacted under standard conditions. After aqueous
work-up, purification by GPC (with CHCl3 as the eluent) afforded
the title compound.
IR (Zn/Se-ATR, neat): 2933, 2861, 1644, 1494, 1468, 1448, 1418,
1353, 1329, 1301, 1176, 972 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (s, 9 H), 1.17–1.28 (br m, 6
H), 1.54 (m, 2 H), 1.73–1.85 (br m, 4 H), 2.37 (t, J = 6.4 Hz, 2 H),
3.27 (t, J = 6.2 Hz, 2 H), 3.34 (t, J = 7.8 Hz, 2 H).
Yield: 174 mg (76%); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 21.4, 23.2, 24.3, 27.1, 27.8, 29.3,
30.2, 32.3, 44.1, 47.2, 47.8, 169.5.
MS (EI): m/z (%) = 225 (16) [M]+, 220 (15), 205 (7), 167 (59), 153
IR (Zn/Se-ATR, neat): 2953, 2893, 2858, 1471, 1253, 1100, 1006,
940, 834, 814, 773 cm–1.
(18), 139 (8).
1H NMR (400 MHz, CDCl3): δ = 0.10 (s, 6 H), 0.92 (s, 9 H), 0.94
(s, 9 H), 1.21 (m, 2 H), 1.53 (m, 2 H), 3.62 (t, J = 6.8 Hz, 2 H).
HRMS (EI): m/z [M]+ calcd for C14H27NO: 225.2093; found:
225.2091.
13C NMR (100 MHz, CDCl3): δ = –5.2, 18.4, 26.0, 28.2, 29.4, 30.0,
39.9, 64.2.
N,N-Diethyl-7,7-dimethyloctanamide (5i)
MS (EI): m/z (%) = 230 (11) [M]+, 215 (42), 200 (36), 185 (35), 173
(84), 170 (19), 158 (9), 116 (21).
HRMS (EI): m/z [M]+ calcd for C13H30OSi: 230.2066; found:
230.2066.
According to P1, 6-bromo-N,N-diethylhexanamide (4i) (250 mg,
1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were re-
acted under standard conditions. After aqueous work-up, purifica-
tion by flash column chromatography (hexane–EtOAc, 20:1)
afforded the title compound.
2-[(5,5-Dimethylhexyl)oxy]tetrahydro-2H-pyran (5f)
Yield: 167 mg (73%); yellow oil.
According to P1, 2-(4-bromobutoxy)tetrahydro-2H-pyran (4f) (237
mg, 1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were
reacted under standard conditions. After aqueous work-up, purifica-
tion by GPC (with CHCl3 as the eluent) afforded the title compound.
IR (Zn/Se-ATR, neat): 2934, 2866, 1648, 1465, 1428, 1363, 1260,
1143, 1081, 946 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (s, 9 H), 1.11 (t, J = 7.4 Hz,
3 H), 1.17 (t, J = 7.4 Hz, 3 H), 1.17–1.28 (m, 6 H), 1.65 (m, 2 H),
2.28 (t, J = 7.8 Hz, 2 H), 3.30 (q, J = 7.4 Hz, 2 H), 3.37 (q, J = 7.4
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 13.1, 14.4, 24.4, 25.5, 29.4, 30.2,
30.4, 33.1, 40.0, 41.9, 44.0, 172.3.
MS (EI): m/z (%) = 227 (18) [M]+, 212 (14), 198 (10), 170 (62), 169
(7), 155 (11).
Yield: 196 mg (91%); colorless oil.
IR (Zn/Se-ATR, neat): 2941, 2868, 1475, 1137, 1120, 1078, 1036,
988, 906, 870, 816 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.87 (s, 9 H), 1.17–1.23 (m, 2 H),
1.27–1.37 (m, 2 H), 1.49–1.62 (m, 5 H), 1.67–1.77 (m, 1 H), 1.79–
1.87 (m, 1 H), 3.39 (dd, J = 16.5, 6.8 Hz, 1 H), 3.47–3.54 (m, 1 H),
3.75 (dd, J = 16.5, 6.8 Hz, 1 H), 3.84–3.93 (m, 1 H), 4.58 (t, J = 7.3
Hz, 2 H).
HRMS (EI): m/z [M]+ calcd for C14H29NO: 227.2249; found:
227.2242.
13C NMR (100 MHz, CDCl3): δ = 19.7, 21.2, 25.5, 29.4, 30.3, 30.6,
30.8, 44.0, 62.3, 67.7, 98.8.
MS (CI): m/z (%) = 215 (21) [M + H]+, 200 (15), 158 (71), 144 (10),
130 (6).
HRMS (CI): m/z [M + H]+ calcd for C13H27O2: 215.2011; found:
215.2015.
N-(7,7-Dimethyloctanoyl)morpholine (5j)
According to P1, N-(6-bromohexanoyl)morpholine (4j) (264 mg,
1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were re-
acted under standard conditions. After aqueous work-up, purifica-
tion by flash column chromatography (hexane–EtOAc, 15:1)
afforded the title compound.
12,12-Dimethyltridecan-1-ol (5g)
Yield: 183 mg (76%); pale yellow oil.
According to P1, 11-bromoundecan-1-ol (4g) (251 mg, 1.0 mmol)
and t-BuMgCl (2a) (1.04 M in THF, 2.5 mmol) were reacted under
standard conditions. After aqueous work-up, purification by flash
column chromatography (hexane then Et2O) afforded the title com-
pound.
IR (Zn/Se-ATR, neat): 2953, 2860, 1651, 1461, 1430, 1272, 1242,
1119, 1035, 962, 851 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (s, 9 H), 1.16–1.30 (br m, 6
H), 1.66 (m, 2 H), 2.31 (t, J = 7.8 Hz, 2 H), 3.46–3.76 (br m, 8 H).
Yield: 201 mg (88%); colorless oil.
13C NMR (100 MHz, CDCl3): δ = 24.3, 25.3, 29.4, 30.2, 30.4, 33.1,
41.8, 44.0, 46.0, 66.7, 66.9, 171.9.
MS (EI): m/z (%) = 241 (20) [M]+, 226 (13), 184 (65), 170 (9), 155
(9).
IR (Zn/Se-ATR, neat): 3400, 2925, 2854, 1466, 1363, 1056 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (s, 9 H), 1.14–1.31 (m, 18 H),
1.57 (quin, J = 7.2 Hz, 2 H), 3.64 (t, J = 7.2 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York
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1590
T. Iwasaki et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS (EI): m/z [M]+ calcd for C14H27NO2: 241.2042; found:
241.2041.
tion by flash column chromatography (hexane–EtOAc, 10:1)
afforded the title compound.
Yield: 240 mg (74%); white solid; mp 88–89 °C.
1-tert-Butoxycarbonyl-4-(3,3-dimethylbutyl)piperidine (5ka)
According to P1, 4-(2-bromoethyl)-1-(tert-butoxycarbonyl)piperi-
dine (4k) (292 mg, 1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF,
1.2 mmol) were reacted under standard conditions. After aqueous
work-up, purification by flash column chromatography (hexane–
EtOAc, 10:1) afforded the title compound.
IR (Zn/Se-ATR, neat): 2925, 2851, 1336, 1166, 1089, 1043, 927,
917, 809, 726, 650, 607 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.81 (d, J = 6.4 Hz, 3 H), 0.82 (t,
J = 6.9 Hz, 3 H), 1.01–1.29 (m, 10 H), 1.70 (d, J = 11.4 Hz, 2 H),
2.19 (t, J = 9.2 Hz, 2 H), 2.43 (s, 3 H), 3.75 (d, J = 11.4 Hz, 2 H),
7.31 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 8.7 Hz, 2 H).
Yield: 162 mg (60%); pale yellow oil.
13C NMR (100 MHz, CDCl3): δ = 11.3, 19.1, 21.5, 29.4, 31.5, 31.7,
33.4, 34.4, 35.5, 46.6, 127.7, 129.5, 133.2, 142.3.
IR (Zn/Se-ATR, neat): 2926, 2855, 1698, 1475, 1422, 1365, 1279,
1250, 1232, 1163, 1116, 965, 869 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (s, 9 H), 1.06–1.28 (br m, 7
H), 1.45 (s, 9 H), 1.65 (m, 2 H), 2.66 (m, 2 H), 4.06 (m, 2 H).
MS (EI): m/z (%) = 323 (28) [M]+, 308 (13), 294 (11), 293 (6), 266
(11), 238 (9), 232 (10).
13C NMR (100 MHz, CDCl3): δ = 28.5, 29.3, 30.1, 31.3, 32.3, 36.8,
41.0, 79.1, 154.9.
HRMS (EI): m/z [M]+ calcd for C18H29NO2S: 323.1919; found:
323.1915.
MS (EI): m/z (%) = 269 (9) [M]+, 254 (35), 239 (19), 224 (8), 212
(81), 197 (8), 196 (6), 182 (7), 155 (17).
HRMS (EI): m/z [M]+ calcd for C16H31NO2: 269.2355; found:
269.2356.
Ethyl 7,7-Dimethyloctanoate (5m)
According to P1, ethyl 6-bromohexanoate (4m) (223 mg, 1.0 mmol)
and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were reacted under
standard conditions. After aqueous work-up, purification by flash
column chromatography (hexane–EtOAc, 10:1) afforded the title
compound.
1-tert-Butoxycarbonyl-4-(3-methylpentyl)piperidine (5kg)
According to P1, 4-(2-bromoethyl)-1-(tert-butoxycarbonyl)piperi-
dine (4k) (292 mg, 1.0 mmol) and s-BuMgCl (2g) (0.76 M in THF,
1.2 mmol) were reacted under standard conditions. After aqueous
work-up, purification by flash column chromatography (hexane–
EtOAc, 10:1) afforded the title compound.
Yield: 145 mg (72%); colorless oil.
IR (Zn/Se-ATR, neat): 2952, 2865, 1739, 1468, 1382, 1365, 1241,
1182, 1127, 1084, 1036, 935 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86 (s, 9 H), 1.13–1.17 (m, 2 H),
1.23–1.28 (m, 7 H), 1.63 (quin, J = 7.3 Hz, 2 H), 2.29 (t, J = 7.3 Hz,
2 H), 4.12 (q, J = 6.9 Hz, 2 H).
Yield: 200 mg (74%); pale yellow oil.
IR (Zn/Se-ATR, neat): 2962, 2924, 2852, 1698, 1455, 1422, 1365,
1278, 1246, 1175, 1155, 964 cm–1.
13C NMR (100 MHz, CDCl3): δ = 14.2, 24.2, 25.0, 29.4, 30.1, 30.2,
1H NMR (400 MHz, CDCl3): δ = 0.79 (m, 6 H), 0.97–1.27 (br m, 10
H), 1.38 (s, 9 H), 1.58 (m, 2 H), 2.59 (m, 2 H), 3.99 (m, 2 H).
34.4, 44.0, 60.1, 174.0.
MS (EI): m/z (%) = 200 (21) [M]+, 185 (14), 171 (11), 170 (7), 155
13C NMR (100 MHz, CDCl3): δ = 11.3, 19.2, 28.5, 29.4, 32.2, 33.5,
33.9, 34.5, 36.3, 79.1, 154.9.
(4), 143 (51), 114 (3).
HRMS (EI): m/z [M]+ calcd for C12H24O2: 200.1776; found:
MS (EI): m/z (%) = 269 (15) [M]+, 254 (10), 240 (12), 239 (8), 212
200.1773.
(14), 197 (10), 196 (9), 182 (6), 155 (10).
HRMS (EI): m/z [M]+ calcd for C16H31NO2: 269.2355; found:
269.2352.
2-(4-Methylhexyl)thiophene (5n)
According to P1, 2-(3-bromopropyl)thiophene (4n) (205 mg, 1.0
mmol) and s-BuMgCl (2g) (0.76 M in THF, 1.2 mmol) were reacted
under standard conditions. After aqueous work-up, purification by
flash column chromatography (hexane) afforded the title com-
pound.
4-(3,3-Dimethylbutyl)-1-tosylpiperidine (5la)
According to P1, 4-(2-bromoethyl)-1-tosylpiperidine (4l) (346 mg,
1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were re-
acted under standard conditions. After aqueous work-up, purifica-
tion by flash column chromatography (hexane–EtOAc, 10:1)
afforded the title compound.
Yield: 146 mg (78%); colorless oil.
IR (Zn/Se-ATR, neat): 2959, 2930, 2872, 1461, 1440, 1377, 850,
819, 688 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.8 Hz, 3 H), 0.86 (d,
J = 5.7 Hz, 3 H), 1.10–1.22 (m, 2 H), 1.29–1.42 (m, 3 H), 1.60–1.75
(m, 2 H), 2.80 (t, J = 7.3 Hz, 2 H), 6.78 (d, J = 2.8 Hz, 1 H), 6.91
(dd, J = 4.8, 2.8 Hz, 1 H), 7.10 (d, J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.4, 19.1, 29.4, 30.2, 34.2, 36.0,
122.7, 123.9, 126.6, 145.9.
MS (EI): m/z (%) = 182 (36) [M]+, 111 (12), 98 (40), 97 (100).
HRMS (EI): m/z [M]+ calcd for C11H18S: 182.1129; found:
Yield: 178 mg (55%); white solid; mp 143–144 °C.
IR (Zn/Se-ATR, neat): 2945, 2844, 1336, 1160, 1093, 1046, 928,
919, 811, 727, 651, 608 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.83 (s, 9 H), 1.07–1.32 (br m, 7
H), 1.71 (m, 2 H), 2.19 (m, 2 H), 2.43 (s, 3 H), 3.75 (m, 2 H), 7.31
(d, J = 7.8 Hz, 2 H), 7.64 (d, J = 7.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 29.3, 30.1, 30.9, 31.6, 36.0,
41.0, 46.6, 127.7, 129.5, 133.2, 143.3.
MS (EI): m/z (%) = 323 (12) [M]+, 308 (12), 293 (9), 266 (46), 238
182.1130.
(11), 232 (9).
2,2,7,7-Tetramethyloctane (5o)
HRMS (EI): m/z [M]+ calcd for C18H29NO2S: 323.1919; found:
323.1921.
According to P1, 1,4-dibromobutane (4o) (217 mg, 1.0 mmol) and
t-BuMgCl (2a) (0.81 M in THF, 2.5 mmol) were reacted under stan-
dard conditions.
4-(3-Methylpentyl)-1-tosylpiperidine (5lg)
Yield: 75% (determined by GC using decane as an internal stan-
dard).
According to P1, 4-(2-bromoethyl)-1-tosylpiperidine (4l) (346 mg,
1.0 mmol) and s-BuMgCl (2g) (0.76 M in THF, 1.2 mmol) were re-
acted under standard conditions. After aqueous work-up, purifica-
Synthesis 2014, 46, 1583–1592
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cobalt-Catalyzed Cross-Coupling Reactions
7,7-Dimethyloct-1-ene (5sa)
1591
1-Chloro-8,8-dimethylnonane (5p)
According to P1, 1-bromo-7-chloroheptane (4p) (214 mg, 1.0
mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were reacted
under standard conditions. After aqueous work-up, purification by
GPC (with CHCl3 as the eluent) afforded the title compound.
According to P1, 6-bromohex-1-ene (4s) (163 mg, 1.0 mmol) and t-
BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were reacted under stan-
dard conditions. After aqueous work-up, purification by GPC (with
CHCl3 as the eluent) afforded the title compound.
Yield: 168 mg (88%); pale yellow oil.
Yield: 110 mg (78%); pale yellow oil.
IR (Zn/Se-ATR, neat): 2953, 2931, 2860, 1469, 1393, 1363, 951,
761, 727 cm–1.
IR (Zn/Se-ATR, neat): 2954, 2931, 2864, 1641, 1474, 1364, 990,
969, 910 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.84 (s, 9 H), 1.14–1.30 (br m, 8
H), 1.40 (m, 2 H), 1.75 (quin, J = 6.9 Hz, 2 H), 3.51 (t, J = 6.9 Hz,
2 H).
1H NMR (400 MHz, CDCl3): δ = 0.79 (s, 9 H), 1.15–1.37 (br m, 6
H), 2.06 (q, J = 6.8 Hz, 2 H), 4.93 (d, J = 9.2 Hz, 1 H), 4.99 (d, J =
17.0 Hz, 1 H), 5.82 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.4, 26.9, 29.0, 29.4, 30.4, 32.7,
13C NMR (100 MHz, CDCl3): δ = 24.1, 29.4, 29.9, 30.3, 33.9, 44.1,
44.2, 45.2.
114.1, 139.2.
MS (EI): m/z (%) = 192 (4) [M(37Cl)]+, 190 (11) [M(35Cl)]+, 177 (3),
175 (9), 135 (13), 133 (41).
HRMS (EI): m/z [M]+ calcd for C11H2335Cl: 190.1488; found:
190.1489.
HRMS (EI): m/z [M]+ calcd for C11H2337Cl: 192.1459; found:
192.1459.
MS (EI): m/z (%) = 140 (19) [M]+, 125 (12), 110 (5), 83 (53).
HRMS (EI): m/z [M]+ calcd for C10H20: 140.1565; found: 140.1561.
7-Methylnon-1-ene (5sg)
According to P1, 6-bromohex-1-ene (4s) (163 mg, 1.0 mmol) and s-
BuMgCl (2g) (0.76 M in THF, 1.2 mmol) were reacted under stan-
dard conditions. After aqueous work-up, purification by GPC (with
CHCl3 as the eluent) afforded the title compound.
6-Bromo-2,2-dimethylheptane (5qa)
According to P1, 1,4-dibromopentane (4q) (230 mg, 1.0 mmol) and
t-BuMgCl (2a) (0.81 M in THF, 1.2 mmol) were reacted under stan-
dard conditions. After aqueous work-up, purification by GPC (with
CHCl3 as the eluent) afforded the title compound.
Yield: 120 mg (85%); pale yellow oil.
IR (Zn/Se-ATR, neat): 2961, 2927, 2857, 1641, 1463, 1378, 991,
910 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.77 (d, J = 6.4 Hz, 3 H), 0.78 (t,
J = 7.4 Hz, 3 H), 1.01–1.07 (br m, 2 H), 1.22–1.29 (br m, 7 H), 1.97
(m, 2 H), 4.88 (dt, J = 10.1, 1.4 Hz, 1 H), 4.92 (dd, J = 17.2, 1.4 Hz,
1 H), 5.74 (ddt, J = 17.2, 10.1, 6.9 Hz, 1 H).
Yield: 147 mg (71%); pale yellow oil.
IR (Zn/Se-ATR, neat): 2953, 2867, 1474, 1393, 1379, 1364, 1247,
1211, 961, 738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.81 (s, 9 H), 1.10 (m, 2 H), 1.35
(m, 2 H), 1.63–1.76 (br m, 5 H), 1.64 (d, J = 6.7 Hz, 3 H), 4.08 (m,
1 H).
13C NMR (100 MHz, CDCl3): δ = 22.9, 26.5, 29.4, 30.3, 42.0, 43.4,
52.0.
13C NMR (100 MHz, CDCl3): δ = 11.4, 19.2, 26.6, 29.3, 29.5, 33.9,
34.3, 36.4, 114.1, 139.2.
MS (EI): m/z (%) = 140 (39) [M]+, 125 (8), 111 (19).
HRMS (EI): m/z [M]+ calcd for C10H20: 140.1565; found: 140.1561.
MS (EI): m/z (%) = 208 (16) [M(81Br)]+, 206 (17) [M(79Br)]+, 193
Dec-1-ene (5sj)
According to P1, 6-bromohex-1-ene (4s) (163 mg, 1.0 mmol) and
n-BuMgCl (2j) (1.0 M in THF, 1.2 mmol) were reacted under stan-
dard conditions.
(11), 191 (12), 178 (5), 176 (5), 151 (49), 149 (52).
HRMS (EI): m/z [M]+ calcd for C9H1979Br: 206.0670; found:
206.0670.
HRMS (EI): m/z [M]+ calcd for C9H1981Br: 208.0650; found:
208.0649.
Yield: 89% (determined by GC using decane as an internal stan-
dard).
(2,2,5-Trimethylhexyl)cyclopropane (5td)
2-Bromo-6-methyloctane (5qg)
According to P1, (bromomethyl)cyclopropane (4t) (135 mg, 1.0
mmol) and 2,5-dimethyl-2-hexylmagnesium chloride (2d) (0.65 M
in THF, 1.2 mmol) were reacted under standard conditions. After
aqueous work-up, purification by GPC (with CHCl3 as the eluent)
afforded the title compound.
According to P1, 1,4-dibromopentane (4q) (264 mg, 1.0 mmol) and
s-BuMgCl (2g) (0.76 M in THF, 1.2 mmol) were reacted under stan-
dard conditions.
Yield: 86% (determined by GC using decane as an internal stan-
dard).
Yield: 83 mg (49%); pale yellow oil.
IR (Zn/Se-ATR, neat): 2955, 2928, 2871, 1469, 1385, 1366, 1016,
974, 822 cm–1.
1H NMR (400 MHz, CDCl3): δ = –0.01 (m, 2 H), 0.42 (m, 2 H), 0.63
1-Bromo-4-(3-methylpentyl)benzene (5rg)
According to P1, 1-bromo-4-(2-bromoethyl)benzene (4r) (230 mg,
1.0 mmol) and s-BuMgCl (2g) (0.76 M in THF, 1.2 mmol) were re-
acted under standard conditions.
(m, 1 H), 0.89 (m, 12 H), 1.22 (m, 6 H), 1.44 (m, 1 H).
Yield: 71% (determined by GC using decane as an internal stan-
dard).
13C NMR (100 MHz, CDCl3): δ = 4.7, 6.5, 22.8, 27.5, 28.9, 33.1,
33.9, 39.9, 46.9.
1-Bromo-4-hexylbenzene (5rj)
MS (EI): m/z (%) = 168 (28) [M]+, 153 (16), 125 (20), 97 (9).
HRMS (EI): m/z [M]+ calcd for C12H24: 168.1878; found: 168.1873.
According to P1, 1-bromo-4-(2-bromoethyl)benzene (4r) (230 mg,
1.0 mmol) and n-BuMgCl (2j) (1.0 M in THF, 1.2 mmol) were re-
acted under standard conditions.
(2-Ethylhexyl)cyclopropane (5th)
According to P1, (bromomethyl)cyclopropane (4t) (135 mg, 1.0
mmol) and 3-heptylmagnesium bromide (2h) (1.0 M in THF, 1.2
mmol) were reacted under standard conditions. After aqueous
work-up, purification by GPC (with CHCl3 as the eluent) afforded
the title compound.
Yield: 94% (determined by GC using decane as an internal stan-
dard).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1583–1592

1592
T. Iwasaki et al.
PRACTICAL SYNTHETIC PROCEDURES
Yield: 101 mg (66%); colorless oil.
Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646. (e) Terao, J.;
Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew.
Chem. Int. Ed. 2007, 46, 2086. (f) Cahiez, G.; Gager, O.;
Buendia, J. Synlett 2010, 299. (g) Yang, C.-T.; Zhang, Z.-Q.;
Liang, J.; Liu, J.-H.; Lu, X.-Y.; Chen, H.-H.; Liu, L. J. Am.
Chem. Soc. 2012, 134, 11124. (h) Ren, P.; Stern, L.-A.; Hu,
X. L. Angew. Chem. Int. Ed. 2012, 51, 9110.
IR (Zn/Se-ATR, neat): 2959, 2925, 2860, 1463, 1042, 1015, 942,
821 cm–1.
1H NMR (400 MHz, CDCl3): δ = –0.01 (m, 2 H), 0.40 (m, 2 H), 0.67
(m, 1 H), 0.85 (t, J = 6.9 Hz, 3 H), 0.90 (t, J = 7.3 Hz, 3 H), 1.14–
1.36 (br m, 11 H).
13C NMR (100 MHz, CDCl3): δ = 4.6, 4.7, 8.8, 10.9, 14.2, 23.2,
25.9, 29.0, 32.8, 38.5, 39.9.
(4) (a) Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79,
663. (b) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41,
1545. (c) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222. (d) Terao, J.;
Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Lett. 2003, 32,
890. (e) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.;
Kambe, N. Angew. Chem. Int. Ed. 2004, 43, 6180. (f) Terao,
J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Commun.
2007, 825. (g) Singh, S. P.; Terao, J.; Kambe, N.
MS (EI): m/z (%) = 154 (39) [M]+, 125 (20), 111 (9), 97 (11).
HRMS (EI): m/z [M]+ calcd for C11H22: 154.1721; found: 154.1721.
Nonylcyclopropane (5tn)
According to P1, (bromomethyl)cyclopropane (4t) (135 mg, 1.0
mmol) and n-octylmagnesium chloride (2n) (1.8 M in THF, 1.2
mmol) were reacted under standard conditions.
Tetrahedron Lett. 2009, 50, 5644. (h) Singh, S. P.; Iwasaki,
T.; Terao, J.; Kambe, N. Tetrahedron Lett. 2011, 52, 774.
(i) Iwasaki, T.; Tsumura, A.; Omori, T.; Kuniyasu, H.;
Terao, J.; Kambe, N. Chem. Lett. 2011, 40, 1024. (j) Shen,
R.; Iwasaki, T.; Terao, J.; Kambe, N. Chem. Commun. 2012,
48, 9313. (k) Iwasaki, T.; Higashikawa, K.; Reddy, V. P.;
Ho, W. W. S.; Fujimoto, Y.; Fukase, K.; Terao, J.; Kuniyasu,
H.; Kambe, N. Chem. Eur. J. 2013, 19, 2956. (l) For the
alkylation of 2-methylthiobenzothiazoles, see: Ghaderi, A.;
Iwasaki, T.; Fukuoka, A.; Terao, J.; Kambe, N. Chem. Eur.
J. 2013, 19, 2951.
Yield: 71% (determined by GC using decane as an internal stan-
dard).
Acknowledgment
This work was partly supported by a Grant-in-Aid for Scientific Re-
search (S) (20225004) and (A) (25248025), a Grant-in-Aid for Sci-
entific Research on Innovative Areas ‘Organic Synthesis Based on
Reaction Integration’ (2015) and ‘Molecular Activation Directed
toward Straightforward Synthesis’ (2204), and a Grant-in-Aid for
Young Scientists (B) (22750094) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. T.I. thanks the
NOVARTIS Foundation (Japan), the General Sekiyu Foundation
and the Itoh Chubee Foundation.
(5) Iwasaki, T.; Takagawa, H.; Singh, S. P.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2013, 135, 9604.
(6) For reviews on Co-catalyzed C–C bond forming reactions,
see: (a) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004,
2081. (b) Yorimitsu, H.; Oshima, K. Pure Appl. Chem.
2006, 78, 441. (c) Gosmini, C.; Bégouin, J.-M.; Moncomble,
A. Chem. Commun. 2008, 3221. (d) Cahiez, G.; Moyeux, A.
Chem. Rev. 2010, 110, 1435.
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Synthesis 2014, 46, 1583–1592
© Georg Thieme Verlag Stuttgart · New York