Bromine-Radical-Mediated Site-Selective Allylation of C(sp 3)-H Bonds

Article abstract of DOI:10.1055/s-0037-1610413

The C(sp ³)-H allylation of alkanes is investigated by using allyl bromides under radical reaction conditions. In many cases, methine C-H allylation preceded methylene and methyl C-H allylation with complete or a high degree of site selectivity

Full text of DOI:10.1055/s-0037-1610413

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
feature
A
en
M. Ueda et al.
Feature
Synthesis
Bromine-Radical-Mediated Site-Selective Allylation of C(sp3)–H
Bonds
Mitsuhiro Uedaa
Ayami Maedaa
CO2Et
CO2Et
+
Br
Kanako Hamaokaa
Mika Sasanoa
Takahide Fukuyamaa
Br
CO2Et
CO2Et
+
Br
Ilhyong Ryu*a,b
0
0
0
0-0
0
0
1-
7
7
1
5-4
7
2
7
up to 66% yield
16 examples
MeO
MeO
a Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka, 599-8531, Japan
b Department of Applied Chemistry, National Chiao Tung University,
Hsinchu 30010, Taiwan
ryu@c.s.osakafu-u.ac.jp
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Received: 12.10.2018
Accepted after revision: 26.11.2018
Published online: 07.01.2019
complete site selectivity was observed for the methine C–H
bond in the bromination of isooctane (Scheme 1).6b Russell
and Brown reported that methine selectivity with 2-methyl-
pentane drops to a level of 90% (Scheme 1),6c and it was rea-
soned that this decrease was due to the increased number
of methylene C–H bonds competing in the process.6d
DOI: 10.1055/s-0037-1610413; Art ID: ss-2018-z0686-fa
License terms:
Abstract The C(sp3)–H allylation of alkanes is investigated by using al-
lyl bromides under radical reaction conditions. In many cases, methine
C–H allylation preceded methylene and methyl C–H allylation with
complete or a high degree of site selectivity. The C–H allylation of allylic
compounds, such as allylbenzene, gives 1,5-dienes with the SH2′ reac-
tions of the allyl radicals occurring at the less hindered carbon.
SH2
Br2
R
H
+
R
Br
+
HBr
(1)
Key words C(sp3)–H allylation, bromine radicals, SH2 reaction, SH2′
reaction, site selectivity
100 (ref 6c)
100 (ref 6a)
90 (ref 6b)
+
+
Br
R
H
Site-selective alkyl C–H functionalization has become a
growing area of research,1 and useful catalytic methods
have appeared in recent years.2 SH2-type hydrogen abstrac-
tion has excellent potential for alkyl C–H functionalization,
and we and the Pavia group have jointly been engaged in
the development of C–H functionalization methods using
the decatungstate anion as a photocatalyst. Interestingly,
we found that both the polar and steric effects in the SH2
transition states strongly affect the site selectivity in C–H
functionalization of compounds possessing a polar func-
tionality, such as ketones, esters, nitriles, and pyridylal-
kanes.3,4 Radical bromination of saturated alkanes by mo-
lecular bromine has a long history, representing a textbook
radical reaction (Scheme 1, eq 1). The site selectivity is in
the order of methine C–H, methylene C–H, and methyl C–H,
which is regarded as a reflection of the bond-dissociation
energy of C–H bonds. We recently reported the results of
DFT calculations with respect to the transition states de-
rived from the hydrogen abstraction of C–H bonds by bro-
mine radical, which are illustrated in Scheme 1.5 In 1941,
Kharasch and co-workers reported methine selective C–H
bromination of 2-methylpropane (Scheme 1).6a Similarly
–30.8
–31.2
74.5
60.4
49.0
R
H Br
–29.4
CH3CH2
CH3CHCH3
CH3C(CH3)CH3
Br
H
R
Scheme 1 Bromine radical abstraction and site selectivity. Values are
given in kJ/mol calculated at the BH and HLYP/6-311++G(d,p)LanL2DZ-
dp(Br) levels.5
Although allylic bromides are found to act as useful al-
lylating reagents in a bromine-radical-mediated chain pro-
cess,7,8 the site-selective C–H allylation of saturated alkanes
has yet to be investigated.9,10 In this paper, we report our re-
sults on the C–H allylation of a variety of saturated alkanes
by allyl bromides under radical chain reaction conditions.
In the first investigation, we carried out the allylation of
isooctane (1a) with ethyl 2-(bromomethyl)acrylate (2a) us-
ing di-tert-butyl peroxide (DTBPO) as a radical initiator and
potassium carbonate as a HBr scavenger. When the reaction
mixture was heated at 130 °C for 24 hours, we were pleased
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

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M. Ueda et al.
Feature
Synthesis
to find that the envisaged methine-selective C–H allylation
of 1a proceeded to give the expected product, ethyl 4,4,6,6-
tetramethyl-2-methyleneheptanoate (3aa) (Scheme 2). In
this case, the yield of 3aa was moderate due to the isomeri-
zation of the initially formed 3aa into the internal olefin
product 4aa. A shorter reaction time of 8 hours suppressed
the isomerization and improved the isolated yield of 3aa to
55%. The use of excess amounts of alkane 1a was crucial to
obtain good yields of allylated products.11
due to the sterically congested methine C–H bonds, which
hamper access by the bromine radical.
We then examined four cycloalkanes, 1d, 1e, 1f, and 1g.
The reactions of cyclohexane (1d) with 2a and 2c took place
to afford the corresponding products 3da and 3dc in 59%
and 57% yields, respectively (Table 1, entries 8 and 9). The
reaction of cyclopentane (1e) with 2a gave allylated cyclo-
pentane 3ea in 41% yield (entry 10). The C–H allylation of
methylcyclohexane (1f) with 2a proceeds with a high de-
gree of site selectivity to give a mixture of methine C–H al-
lylated product 3fa and other regioisomers in an 84:16 ratio
(entry 11). The reaction of 1g with 2a gave an 86:14 mix-
ture of 3ga and other isomers in a 37% yield (entry 12).
The proposed reaction mechanism for the present bro-
mine-radical-mediated site-selective C–H allylation of al-
kanes is illustrated in Scheme 3 using the reaction of iso-
octane (1a) with 2a: (i) a tBuO radical is generated from
DTBPO by homolysis under heating, (ii) the tBuO radical ab-
stracts a hydrogen from alkane 1a to produce tertiary alkyl
radical A, (iii) the radical A adds to allylic bromide 2a to
form the radical intermediate B, which undergoes β-fission
to give the allylated alkane 3aa and a bromine radical, and
(iv) the liberated bromine radical abstracts a hydrogen site
selectively from another molecule of 1a to produce the car-
bon radical A, thereby sustaining the radical chain.
(t-BuO)2 (20 mol%)
K2CO3 (0.5 mmol)
CO2Et
+
Br
130 °C, time
1a (5 mL)
2a (0.5 mmol)
CO2Et
CO2Et
+
3aa
4aa
8 h
24 h
68 (55)%*
8 (5)%*
47%*
14%*
Scheme 2 Site-selective C–H allylation of isooctane. * NMR yields. Iso-
lated yields are in parentheses.
Encouraged by this result, we next examined the gener-
ality of the allylation of several structurally diverse alkanes
1 with allyl bromides 2 (Table 1). The reactions of isooctane
(1a) with [(3-bromoprop-1-en-2-yl)sulfonyl]benzene (2b)
and 2-(bromomethyl)acrylonitrile (2c) proceeded with
complete site selectivity to give the corresponding allylated
products 3ab and 3ac (Table 1, entries 1 and 2). The reac-
tion of 1a with (3-bromoprop-1-en-2-yl)benzene (2d) was
sluggish, giving product 3ad in a low yield via methine C–H
functionalization (entry 3). The C–H allylation of 3-methyl-
pentane (1b) with 2a gave a mixture of methine and meth-
ylene C–H allylated products 3ba and 5ba in a 92:8 ratio
(entry 4). The drop in the methine selectivity is due to the
increased number of methylene C–H bonds. The reactions
of 1b with 2b and 2c gave similar sets of products (entries 5
and 6). Interestingly the C–H allylation of 2,3-dimethylbu-
tane (1c) with 2a gave a 62:38 mixture of 5ca and 3ca in
31% total yield (entry 7). The low methine site selectivity is
CO2Et
Br
CO2Et
O
O
Br
2a
B
t-BuO
1a
CO2Et
Br
A
t-BuOH
3aa
HBr
1a
Scheme 3 Proposed radical chain mechanism
Biographical Sketches
Ilhyong Ryu received his Ph.D.
from Osaka University, Japan, in
1978. He was appointed as as-
sistant professor at Osaka Uni-
versity in 1988 and promoted to
associate professor in 1995. In
2000 he moved to Osaka Pre-
fecture University as a full pro-
fessor. Since 2016, he has held a
chair professorship at National
Chiao Tung University in Taiwan.
He has been the recipient of
many awards which include the
Chemical Society of Japan
Award for Creative Work (2004)
and the Society Award for Syn-
thetic Organic Chemistry, Japan
(2014). His current research in-
terests include new methodolo-
gies based on radical reactions
and green catalytic approaches.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

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M. Ueda et al.
Feature
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Table 1 Site Selectivity in the Br• Induced C–H Allylationa
(t-BuO)2 (20 mol%)
K2CO3 (0.5 mmol)
EWG
EWG
+
R–H
Br
R
130 °C, 8 h
1 (5 mL)
2 (0.5 mmol)
3
EWG
2a CO2Et
2b SO2Ph
2c CN
2d Ph
Entry
1
1
2
Products
Yield (%)b
2b
57
SO2Ph
1a
1a
3ab
3ac
3ad
2
3
4
2c
2d
2a
64
CN
1a
37
Ph
66
CO2Et
CO2Et
(92:8)c
+
+
1b
1b
3ba
3bb
5ba
5bb
5
6
7
2b
2c
2a
48
SO2Ph
SO2Ph
(83:17)c
1b
28
CN
CN
(91:9)c
+
+
3bc
3ca
5bc
5ca
31d
CO2Et
CO2Et
(38:62)c
1c
8
2a
2c
2a
59
57
41
CO2Et
1d
1d
3da
9
CN
3dc
3ea
10
CO2Et
1e
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

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M. Ueda et al.
Feature
Synthesis
Table 1 (continued)
Entry
11
1
2
Products
Yield (%)b
2a
2a
62
CO2Et
CO2Et
(84:16)c
CO2Et
+
1f
3fa
regioisomers
CO2Et
12
37
(86:14)c
+
1g
3ga
regioisomers
a Reaction conditions: 1 (5 mL), 2 (0.5 mmol), DTBPO (20 mol%), K2CO3 (0.5 mmol), 130 °C, 8 h.
b Yield of isolated products.
c Determined by 1H NMR analysis of the crude reaction mixture.
d Total yield of a mixture of 3ca and 5ca.
The bromine radical smoothly abstracts a hydrogen
from the allylic C–H bond of terminal alkenes, as we recent-
ly reported.12 We thought that the formation of allyl radi-
cals by bromine-radical-induced C–H bond cleavage would
be followed by allylation with allylic bromides at the least
substituted site to give 1,5-dienes. As summarized in
Scheme 4, both allylbenzene (1h) and p-allylanisole (1i) un-
dergo the envisaged hydrogen abstraction and SH2′ reaction
at their termini to give the corresponding dienes 3ha and
3ia in acceptable yields. In these reactions, 1,2-epoxybu-
tane was added as a HBr trap to significantly increase the
yield. 1-Hexen-3-ol is (1j) also participated in the allyl radi-
cal formation/allylation sequence. In the case of 1j, we ob-
tained the δ,ε-unsaturated ketone 3ja via enol–keto tau-
tomerization.
yl C–H bonds. These results are in good accordance with
previously investigated C–H brominations of alkanes. The
degree of the methine C–H preference is affected by both
increased numbers of competing C–H bonds and steric con-
gestion of the targeted methine C–H bond. In the case of al-
lylic compounds, C–C bond formation took place at the less
hindered site of the resulting allyl radical, which led to the
formation of 1,5-dienes.
Thin-layer chromatography (TLC) was performed on Merck precoated
plates (silica gel 60 F254, Art 5715, 0.25 nm). The products were puri-
fied by flash chromatography on silica gel [Kanto Chem. Co. Silica Gel
60N (spherical, neutral, 40–50 μm)]; if necessary, they were further
purified using recycling preparative HPLC (Japan Analytical Industry
Co. Ltd., LC-918) equipped with GPC columns (JAIGEL-1H + JAIGEL-
2H) with CHCl3 as the eluent. Infrared spectra were recorded on a JAS-
CO FT/IR-4100 spectrophotometer and are reported as wavenumbers
(cm–1). 1H NMR spectra were recorded using JEOL ECS400 (400 MHz),
JEOL ECP500 (500 MHz) and Varian MR400 (400 MHz) spectrometers
and referenced to the solvent peak at 7.26 ppm for CHCl3. 13C NMR
spectra were recorded using JEOL JNM-ECS400 (100 MHz) and Varian
MR400 (100 MHz) spectrometers and referenced to the solvent peak
at 77.16 ppm for CHCl3. Splitting patterns are indicated as follows: br,
broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High-
resolution mass spectrometry (HRMS) was performed using a JEOL
MS700 spectrometer and ESI-QTOF (compact-NPC, Bruker). Analyti-
cal data for compounds 3ca,13 3da,14 3ea,15 and 5ca16 have already
been reported.
In summary, the C–H allylation of saturated alkanes
with allyl bromides proceeds with good to excellent prefer-
ence for the methine C–H bonds over methylene and meth-
(t-BuO)2
(20 mol%)
1,2-epoxybutane
(1.5 mmol)
CO2Et
+
2a
120 °C, 16 h
R
R
55%
59%
3ha
3ia
1h (R = H) (10 mmol)
1i (R = MeO)
(1 mmol)
O
CO2Et
OH
Ethyl 4,4,6,6-Tetramethyl-2-methyleneheptanoate (3aa); Typical
Procedure
+
2a
120 °C, 10 h
Isooctane (1a) (5 mL, 30 mmol), ethyl 2-(bromomethyl)acrylate (2a)
(96.5 mg, 0.5 mmol), potassium carbonate (69.1 mg, 0.5 mmol), and
di-tert-butyl peroxide (DTBPO) (14.6 mg, 0.1 mmol) were added to a
50 mL screw-capped pressure-resistant test tube; this test tube was
then purged with argon and sealed. The mixture was stirred at 130 °C
for 8 h and then filtered with Et2O through a short plug of Celite. The
filtrate was concentrated under reduced pressure and the residue was
purified by flash column chromatography on silica gel (hexane/EtOAc,
100:1) and by preparative HPLC (chloroform) to give product 3aa. A
small amount of isomerized product 4aa was also obtained.
36%
1j
3ja
CO2Et
OH
OH
Br
SH2
Br
– Br
SH2'
Scheme 4 C–H allylation of allylic C–H bonds
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M. Ueda et al.
Feature
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Yield: 58.5 mg (55%); yellow oil; Rf = 0.33 (hexane/EtOAc, 20:1).
IR (neat): 2953, 1720, 1626 cm–1
HRMS (ESI): m/z [M + Na]+ calcd for C17H26Na: 253.1927; found:
253.0922.
.
1H NMR (400 MHz, CDCl3): δ = 0.93 (s, 6 H), 0.99 (s, 9 H), 1.28–1.32
(m, 5 H), 2.35 (s, 2 H), 4.20 (q, J = 7.2 Hz, 2 H), 5.43 (s, 1 H), 6.16 (d, J =
2.0 Hz, 1 H).
Ethyl 4-Ethyl-4-methyl-2-methylenehexanoate (3ba)
Yield: 65.4 mg (66%); colorless oil; Rf = 0.40 (hexane/EtOAc, 20:1).
IR (neat): 2965, 2938, 1720, 1176 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 14.42, 27.87, 32.22, 32.43, 36.01,
1H NMR (500 MHz, CDCl3): δ = 0.73 (s, 3 H), 0.80 (t, J = 7.5 Hz, 6 H),
1.22 (m, 4 H), 1.29 (t, J = 8.5 Hz, 3 H), 2.28 (s, 2 H), 4.19 (q, J = 7.0 Hz, 2
H), 5.42 (s, 1 H), 6.15 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 8.10, 14.30, 23.46, 30.49, 36.51, 39.84,
60.75, 126.79, 139.25, 168.67.
45.56, 55.40, 60.63, 127.17, 139.17, 168.59.
EIMS: m/z (%) = 226 [M+] (2), 181 [M+ – OEt] (7), 155 (29), 114 (100),
113 (28), 109 (28), 86 (21), 57 (97).
HRMS (EI): m/z [M – OEt]+ calcd for C12H21O: 181.1587; found:
181.1589.
HRMS (ESI): m/z [M + Na]+ calcd for C12H22O2Na: 221.1512; found:
221.1513.
Ethyl (Z)-2,4,4,6,6-Pentamethylhept-2-enoate (4aa)
Yield: 5.66 mg (5%); yellow oil; Rf = 0.33 (hexane/EtOAc, 20:1).
[(4-Ethyl-4-methylhex-1-en-2-yl)sulfonyl]benzene (3bb)
IR (neat): 2955, 2903, 1710, 1247 cm–1
.
Yield: 63.9 mg (48%); orange oil; Rf = 0.20 (hexane/EtOAc, 20:1).
1H NMR (400 MHz, CDCl3): δ = 0.95 (s, 9 H), 1.22 (s, 6 H), 1.28 (t, J =
7.5 Hz, 3 H), 1.53 (s, 2 H), 1.95 (s, 3 H), 4.18 (q, J = 7.5 Hz, 2 H), 6.86 (s,
1 H).
13C NMR (100 MHz, CDCl3): δ = 13.37, 14.43, 30.62, 31.83, 32.28,
37.95, 56.70, 60.64, 125.11, 151.90, 169.54.
IR (neat): 2965, 2938, 1305, 1148 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.74 (t, J = 6.4 Hz, 6 H), 0.78 (s, 3 H),
1.23 (q, J = 7.2 Hz, 4 H), 2.17 (s, 2 H), 5.85 (s, 1 H), 6.49 (s, 1 H), 7.54 (t,
J = 7.2 Hz, 2 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 8.03, 24.02, 30.82, 36.54, 36.83,
126.23, 128.49, 129.21, 133.42, 139.40, 148.73.
HRMS (ESI): m/z [M + Na]+ calcd for C14H26O2Na: 249.1825; found:
249.1825.
EIMS: m/z (%) = 237 [M+ – C2H5] (5), 182 (100), 142 (26), 125 [M+
–
SO2Ph] (61), 95 (29), 85 (41), 83 (23), 78 (21), 77 (23).
[(4,4,6,6-Tetramethylhept-1-en-2-yl)sulfonyl]benzene (3ab)
Yield: 83.9 mg (57%); yellow oil; Rf = 0.15 (hexane/EtOAc, 30:1).
HRMS (EI): m/z [M – C2H5]+ calcd for C13H17O2S: 237.0944; found:
237.0946.
IR (neat): 2956, 1446, 1365, 1151 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.93 (s, 9 H), 0.99 (s, 6 H), 1.25 (s, 2 H),
2.28 (s, 2 H), 5.90 (s, 1 H), 6.49 (s, 1 H), 7.52 (t, J = 7.2 Hz, 2 H), 7.60 (t,
J = 7.2 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 2 H).
4-Ethyl-4-methyl-2-methylenehexanenitrile (3bc)
Yield: 21.2 mg (28%); colorless oil; Rf = 0.50 (hexane/EtOAc, 10:1).
IR (neat): 2924, 2852, 1719, 1178 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 28.70, 32.07, 32.33, 36.23, 42.44,
1H NMR (400 MHz, CDCl3): δ = 0.83 (t, J = 6.0 Hz, 6 H), 0.89 (s, 3 H),
1.28–1.33 (m, 4 H), 2.15 (s, 2 H), 5.67 (d, J = 1.0 Hz, 1 H), 5.96 (d, J = 1.0
Hz, 1 H).
55.03, 126.76, 128.50, 129.22, 133.42, 139.51, 148.98.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O2NaS: 317.1546; found:
317.1554.
13C NMR (100 MHz, CDCl3): δ = 7.99, 23.71, 30.60, 36.66, 43.45,
120.09 120.49, 133.93.
4,4,6,6-Tetramethyl-2-methyleneheptanenitrile (3ac)
Yield: 57.4 mg (64%); yellow oil; Rf = 0.45 (hexane/EtOAc, 30:1).
EIMS: m/z (%) = 152 [M+ + H] (43), 149 (19), 121 (11), 118 (23), 85
(96), 83 (100), 57 (51).
HRMS (ESI): m/z [M + Na]+ calcd for C10H17NNa: 174.1253; found:
174.1254.
IR (neat): 2953, 2902, 2221, 1473, 1367 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.01 (s, 9 H), 1.07 (s, 6 H), 1.33 (s, 2 H),
.
2.21 (s, 2 H), 5.67 (s, 1 H), 5.98 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.24, 32.15, 32.45, 36.12, 49.58,
54.69, 120.30, 120.59, 134.28.
EIMS: m/z (%) = 180 [M+] (32), 124 (31), 113 [M+ – C4H4N] (20), 127
(29), 57 (100).
2-(Cyclohexylmethyl)acrylonitrile (3dc)
Yield: 42.5 mg (57%); yellow oil; Rf = 0.40 (hexane/EtOAc, 20:1).
IR (neat): 2924, 2852, 2222, 1449, 940 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.86–0.96 (m, 2 H), 1.08–1.34 (m, 4 H),
1.51–1.78 (m, 5 H), 2.14 (d, J = 9.0 Hz, 2 H), 5.66 (d, J = 1.5 Hz, 1 H),
5.86 (s, 1 H).
HRMS (EI): m/z [M + H]+ calcd for C12H22N: 180.1747; found:
180.1744.
13C NMR (100 MHz, CDCl3): δ = 26.07, 26.36, 32.72, 36.14, 42.61,
(4,4,6,6-Tetramethylhept-1-en-2-yl)benzene (3ad)
119.07, 131.32.
Yield: 42.6 mg (37%); colorless oil; Rf = 0.75 (hexane).
HRMS (ESI): m/z [M + Na]+ calcd for C10H15NNa: 172.1097; found:
172.1095.
IR (neat): 2951, 2871, 1471, 1365 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.83 (s, 6 H), 0.95 (s, 9 H), 1.25 (s, 2 H),
2.53 (s, 2 H), 5.01 (s, 1 H), 5.23 (s, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 7.29 (t,
J = 7.6 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 29.02, 32.26, 32.44, 36.40, 50.11,
56.02, 117.10, 126.75, 126.99, 128.22, 144.34, 147.72.
Ethyl 2-[(1-Methylcyclohexyl)methyl]acrylate (3fa)
Yield: 65.2 mg (62%); colorless oil; Rf = 0.40 (hexane/EtOAc, 20:1).
IR (neat): 2925, 2851, 1719, 1153 cm–1
.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

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M. Ueda et al.
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1H NMR (400 MHz, CDCl3): δ = 0.82 (s, 3 H), 1.23–1.25 (m, 4 H), 1.28
(t, J = 7.6 Hz, 3 H), 1.39–1.50 (m, 6 H), 2.31 (s, 2 H), 4.17 (q, J = 7.2 Hz,
2 H), 5.43 (d, J = 1.2 Hz, 1 H), 6.16 (d, J = 1.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.33, 22.18, 24.27, 26.50, 34.01,
37.56, 43.49, 60.76, 127.05, 138.76, 168.62.
EIMS: m/z (%) = 211 [M+ + H] (59), 182 (100), 169 (59), 116 (24), 115
(67), 101 (30), 97 (100), 55 (51).
HRMS (EI): m/z [M + H]+ calcd for C13H23O2: 211.1693; found:
211.1613.
Ethyl 2-Methylene-6-oxononanoate (3ja)
Yield: 76.4 mg (36%); colorless oil; Rf = 0.25 (hexane/EtOAc, 20:1).
IR (neat): 2874, 1715, 1462 cm–1
1H NMR (400 MHz, CDCl3): δ = 0.89–0.93 (t, J = 7.2 Hz, 3 H), 1.28 (t, J =
7.6 Hz, 3 H), 1.58–1.64 (m, 2 H), 1.76 (q, J = 7.6 Hz, 2 H), 2.30 (t, J = 8.0
Hz, 2 H), 2.36–2.44 (m, 4 H), 4.20 (q, J = 6.8 Hz, 2 H), 5.54 (s, 1 H), 6.16
(s, 1 H).
.
13C NMR (100 MHz, CDCl3): δ = 13.42, 13.88, 16.94, 22.06, 30.57,
39.33, 44.38, 60.35, 124.70, 139.88, 166.77, 210.64.
EIMS: m/z (%) = 212 [M+] (2), 167 (35), 166 (54), 138 (59), 123 (65), 99
(53), 95 (78), 71 (100).
Ethyl 2-[(1-Methylcyclopentyl)methyl]acrylate (3ga)
Yield: 36.3 mg (37%); colorless oil; Rf = 0.50 (hexane/EtOAc, 10:1).
HRMS (EI): m/z [M]+ calcd for C12H20O3: 212.1412; found: 212.1415.
IR (neat): 2954, 2871, 1719, 1161 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.89 (s, 3 H), 1.24–1.32 (m, 5 H), 1.38–
1.45 (m, 2 H), 1.61–1.65 (m, 4 H), 2.38 (s, 2 H), 4.20 (q, J = 7.0 Hz, 2 H),
5.51 (s, 1 H), 6.15 (d, J = 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.33, 23.97, 25.62, 38.87, 42.31,
43.10, 60.78, 126.72, 139.65, 168.54.
Funding Information
This work was supported by Grants-in-Aid for Scientific Research (A)
(no. 26248031) from JSPS and Scientific Research on Innovative Areas
2707 Middle Molecular Strategy (no. 15H05850) from MEXT.
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HRMS (ESI): m/z [M + Na]+ calcd for C12H20O2Na: 219.1356; found:
219.1356.
Acknowledgment
Ethyl (E)-2-Methylene-6-phenylhex-5-enoate (3ha); Typical Proce-
dure
We thank Kazuya Kamikawa for collecting additional spectral data.
Allylbenzene (1h) (1181.8 mg, 10.0 mmol), ethyl 2-(bromomethyl)ac-
rylate (2a) (193.0 mg, 1.0 mmol), 1,2-epoxybutane (144.2 mg, 1.5
mmol), and di-tert-butyl peroxide (DTBPO) (29.2 mg, 0.2 mmol) were
added to a 5 mL screw-capped test tube; this test tube was then
purged with argon and sealed. The mixture was stirred at 120 °C for
16 h and then concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (hexane/EtOAc,
100:1) and by preparative HPLC (chloroform) to give product 3ha.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610413.
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References
Yield: 126.7 mg (55%); colorless oil; Rf = 0.50 (hexane/EtOAc, 20:1).
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1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H), 2.40 (q, J = 6.8
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Ethyl (E)-6-(4-Methoxyphenyl)-2-methylenehex-5-enoate (3ia)
Yield: 153.6 mg (59%); colorless oil; Rf = 0.50 (hexane/EtOAc, 20:1).
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H), 2.37 (q, J = 6.8
Hz, 2 H), 2.48 (t, J = 7.6 Hz, 2 H), 3.80 (s, 3 H), 4.21 (q, J = 6.8 Hz, 2 H),
5.56 (s, 1 H), 6.04–6.07 (m, 1 H), 6.18 (s, 1 H), 6.34 (d, J = 15.6 Hz, 1 H),
6.82–6.84 (m, 2 H), 7.20–7.27 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.12, 31.79 (two overlapping sig-
nals), 55.14, 60.53, 113.78, 124.83, 126.96, 127.26, 129.78, 130.35,
140.09, 158.63, 167.08.
IR (neat): 2933, 1714, 1607, 1509, 1176, 1138 cm–1
.
EIMS: m/z (%) = 260 [M+] (9), 148 (11), 147 (100), 121 (10), 115 (12),
91 (21).
HRMS (EI): m/z [M]+ calcd for C16H20O3: 260.1412; found: 260.1411.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G