Radical bromoallylation of alkynes leading to 1-bromo-1,4-dienes

Article abstract of DOI:10.1016/j.tet.2016.05.084

The full scope (30 examples) of the radical bromoallylation of alkynes using allyl bromides was studied. In this reaction, bromine radical adds to alkynes to form vinyl radicals, which then undergo an S_H2′ reaction with allyl bromides to produce good yields of 1-bromo-1,4-dienes with the liberation of a bromine radical, which creates a radical chain. The sp²-carbon–bromine bond of the product dienes was further functionalized via cross-coupling and carbonylation reactions.

Full text of DOI:10.1016/j.tet.2016.05.084

Tetrahedron xxx (2016) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical bromoallylation of alkynes leading to 1-bromo-1,4-dienes
*
Takashi Kippo, Kanako Hamaoka, Mitsuhiro Ueda, Takahide Fukuyama, Ilhyong Ryu
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The full scope (30 examples) of the radical bromoallylation of alkynes using allyl bromides was studied.
In this reaction, bromine radical adds to alkynes to form vinyl radicals, which then undergo an SH20
reaction with allyl bromides to produce good yields of 1-bromo-1,4-dienes with the liberation of a bro-
mine radical, which creates a radical chain. The sp2-carbonebromine bond of the product dienes was
further functionalized via cross-coupling and carbonylation reactions.
Received 19 April 2016
Received in revised form 20 May 2016
Accepted 31 May 2016
Available online xxx
Ó 2016 Published by Elsevier Ltd.
Keywords:
Radical reaction
Bromoallylation
Allyl bromides
Alkynes
Dienes
1. Introduction
with an electron-withdrawing group at the 2-position served as
excellent UMCT reagents11 and that alkynes need not be restricted
Radical-based allylation reactions,1 which use allyl-
heteroatoms, such as allyltins,2 allylsulfides,3 and allylsulfones,4
have found wide applications in organic synthesis, but relatively
little attention has been directed to the development of radical
allylation by allyl bromides. The original work dealing with the use
of allyl bromides in radical reactions dates to Kharasch’s report
published in 1949,5 in which 3-trichloromethylpropene was
formed via the addition/elimination sequence of bromotrichloro-
methane with an allyl bromide under photo-irradiation conditions.
In 1993, Singleton and co-workers reported a chain type of radical
allylation using allyl halides, but the procedure required the use of
hexabutylditin as a chain career.6 In 1999, Tanko and Sadeghipour
reported CeH allylation using allyl bromides and a radical initiator,
capitalized on the capability of bromine radicals to abstract hy-
drogen from cumene, isopropanol and the related compounds, in
which the resultant radicals undergo an SH20 reaction with allylic
bromides to give high yields of allylated products.7 Since bromine
radicals are capable of adding to CeC multiple bonds reversibly, we
initiated our research based on radical bromoallylation of un-
saturated compounds, which turned out to be quite useful in syn-
thesizing a variety of bromine-substituted dienes8e10 In our first
report, we described a radical bromoallylation of arylalkynes with
allyl and methallyl bromides, which led to 1-bromo-2-aryl-1,4-
dienes.8 Shortly after the report, we noticed that allyl bromides
to arylalkynes. In the present study, we disclose the full scope of the
bromoallylation chemistry of alkynes, which demonstrates that the
approach can be used to synthesize a variety of 1-bromo-
substituted 1,4-dienes.12 Since the 1,4-diene motif is frequently
found in a variety of biologically active compounds,13,14 and thus far
a variety of methods are available for the preparation,15 the present
method is unique because the vinyl-bromide moiety of prepared 1-
bromo-1,4-dienes can be functionalized further by cross-coupling
and carbonylation reactions that lead to a variety of 1-substituted
1,4-dienes (Scheme 1).
2. Results and discussion
Initially, we examined the reaction of phenylacetylene (1a) with
simple allyl bromide (2a) as a model (Table 1). Essentially, no re-
action took place when a mixture of 1a (1.0 mmol), 2a (2.0 mmol),
and V-65 (2,20-azobis(2,4-dimethylvaleronitrile), 20 mol %) as
a radical initiator, was treated at 60 ꢀC for 6 h without a solvent
(entry 1). However, the use of a large excess amount (58 equiv) of
2a gave 1-bromo-1,4-diene (3aa) in an 80% yield as a stereoiso-
meric mixture (E/Z¼23/77) (entry 2). The use of AIBN as a radical
initiator at 80 ꢀC was equally effective (entry 3). In these experi-
ments, a careful examination of NMR showed that no regioisomer
was formed. Since a large excess of 2a was necessary to compensate
for the modest reactivity of vinyl radicals towards 2a, which are
classified as nucleophilic radicals,16 we then examined ethyl 2-
(bromomethyl)acrylate (2b). The reaction of 1a with a twofold
* Corresponding author. Tel./fax: þ81 72 254 9695; e-mail address: ryu@
c.s.osakafu-u.ac.jp (I. Ryu).
http://dx.doi.org/10.1016/j.tet.2016.05.084
0040-4020/Ó 2016 Published by Elsevier Ltd.
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T. Kippo et al. / Tetrahedron xxx (2016) 1e9
Scheme 1. Concept: synthesis of substituted 1,4-dienes by radical bromoallylation of alkynes.
Table 1
(entries 17e23). In the reaction of an internal alkyne, 1-
phenylpropyne (1p), with 2b proceeded regioselectively to give
the bromoallylated product 3pb in a 57% yield, in which bromine
was incorporated into methyl-substituted carbon (entry 24).
Compared with arylalkynes, the reactivity of 1-octyne 1q toward
simple allyl bromide 2a was low. However, the reaction with 2b
took place smoothly to give 3qb in an 83% yield (entry 25). The
reaction of TBS-protected alkyne 1r with 2b gave the expected
bromo-substituted 1,4-diene 3rb and the desilylated product 3rb0
in 59 and 19% yields, respectively (entry 26). This desilylation re-
action was entirely suppressed by the addition of Na3PO4 as an HBr
scavenger, which gave 3rb in a 75% yield (entry 27). On the other
hand, the reaction of 1-ethynyl-1-cyclohexene (1s) with 2b was
sluggish, which gave a 34% yield of product 3sb with 43% of 1s
remained unreacted (entry 28). The reaction of cyclopropyl acety-
lene (1t) with 2b gave an 85% yield of 3tb, in which the cyclopropyl
group remained in the product (entry 29). No occurrence of the
Reaction conditions for the radical bromoallylation of phenylacetylene (1a) with 2a
and 2b
Entry Allyl bromide (equiv) Conditions
Product Yield (%)a EIZb
1
2a (2)
2a (58)
2a (58)
2b (2)
2b (2)
2b (4)
2b (4)
V-65 (20 mol %), 60 ꢀC
V-65 (20 mol %), 60 ꢀC
AIBN (20 mol %), 80 ꢀC
AIBN (20 mol %), 80 ꢀC
3aa
3aa
3aa
3ab
Trace
80d
80d
59
d
2c
3c
4
23/77
15/85
16/84
16/84
16/84
22/78
5
Solarbox (Xe, 350 W/m2) 3ab
Solarbox (Xe, 350 W/m2) 3ab
Solarbox (Xe, 350 W/m2) 3ab
63
6
71
7e
83d
a
NMR yield using CH2Br2 as an internal standard.
b
c
Determined by 1H NMR analysis of the crude reaction mixture.
ring-opening may be attributed to the
s-character of the vinyl
Without C6H6.
Isolated yield after column chromatography on SiO2.
12 h.
radical, which would not interact well with the adjacent cyclo-
propane ring.
d
e
The present alkyne-bromoallylation combines well with radical
cascades. The reaction of enyne 4 and 2b gave cyclopentane 5
bearing bromomethylene and 3-butenyl substituents in the adja-
cent carbons of the cyclopentane ring in a 76% yield (Scheme 2). The
product 5 would be formed through (i) addition of the bromine
radical to the alkyne terminus, (ii) 5-exo cyclization, (iii) an addition
excess of 2b delivered the expected bromoallylation product 3ab in
a 59% yield (entry 4). Photoirradiation conditions using a Solarbox
equipped with a xenon lamp slightly improved the yield (entry 5).
The use of a fourfold excess of 2b combined with a longer reaction
time (12 h) improved the yield of 3ab to 83% (entry 7). The differ-
ence in reactivity observed between 2b and 2a is understandable
considering the nucleophilic nature of vinyl radicals.
to allyl bromide 2b, and (iv)
b-fragmentation of the bromine
radical.
We employed both thermal and photo initiation for this study.
As for the thermal initiation with V-65 (Method A), a cyano alkyl
radical was generated by the decomposition of V-65, and added to
the allyl bromide in an SH20 manner to form a bromine radical,
which initiated the reaction by addition to the CeC triple bond. In
the reaction of 1-octyne (1q) with 2b under photo-irradiation
conditions (Method B), we detected a small amount of the cou-
pling dimer 6 that was derived from 2b (Scheme 3). This suggested
that in the initiation step, a photo-induced homolysis of the CeBr
bond of 2b would take place to give allyl radical and bromine
radical, in which the former dimerizes17 and the latter acts as
a radical initiator via addition to the CeC triple bond. The addition
of 10 mol % of a 2,2,6,6-tetramethylpiperidine 1-oxyl free radical
(TEMPO) to the reaction completely suppressed the bromoallyla-
tion of 1q, and an allyl TEMPO 7 was isolated. These results support
the initiation mechanism based on the photo-induced homolysis of
2b to generate a bromine radical.
With the optimized conditions in hand, we then explored the
scope and limitations of the present bromoallylation reaction, using
various alkynes 1aet and allyl bromides 2aec, in which thermally
initiated conditions (Method A: V-65 (20 mol %), 60 ꢀC, 6 h) were
used for 2a and 2c, whereas photo-initiation conditions (Method B:
Solarbox (Xe, 350 W/m2), 12 h) were used for 2b (Table 2). The
reaction of arylacetylenes 1ae1m with allyl bromide (2a) (method
A) gave the corresponding products 3aae3ma in good yields (en-
tries 1e6, and 8e14). With the exception of 1-naphtylacetylene
(1k), which gave only an E-isomer (entry 12), Z-isomers were
preferred. The reaction of 1a with methallyl bromide (2c) gave 3ac
in a 95% yield (entry 7). The reaction of electron-deficient alkynes
such as ethyl propiolate (1n) and dimethyl acetylenedicarboxylate
(1o) with 2a gave the corresponding 1,4-dienes 3na and 3oa in 86
and 49% yields, respectively (entries 15 and 16).
The bromoallylation of arylacetylenes 1ae1m with ethyl 2-
(bromomethyl)acrylate (2b) under photo-irradiation conditions
(method B) worked quite well to give good yields of the
corresponding 1-bromo-2-aryl-4-ethoxycarbonyl-1,4-butadienes
A proposed mechanism for the bromoallylation of alkynes is
illustrated in Scheme 4. Irrespective of thermal/V-65 initiation or
photo-irradiation, bromine radicals are formed and add to the
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T. Kippo et al. / Tetrahedron xxx (2016) 1e9
3
Table 2
Bromoallylation of alkynes leading to 1-bromo-1,4-dienes
a Isolated yield after flash column chromatography on SiO2 and/or preparative HPLC using CHCl3 as an eluent. b The E/Z ratio was determined via 1H-NMR
analysis of the crude reaction mixture. c 18 h. d Na3PO4 (0.2 equiv).
alkyne terminus to give bromine-containing vinyl radical A. The
vinyl radical then reacts with 2 to produce radical intermediate B,
allylbromination are generally preferred. As we discussed in our
preliminary report, this can be explained by the less hindered site
attack of allyl bromide towards the vinyl radicals.8 An exception
was the case of 1-naphtylacetylene (1k), which gave E-isomer of
which undergoes
b-fission to give 1-bromo-1,4-diene 3 and a bro-
mine radical to sustain the radical chain.18 Products via trans-
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4
T. Kippo et al. / Tetrahedron xxx (2016) 1e9
Scheme 2. Cyclizative cascade bromoallylation.
Scheme 3. Radical initiation mechanism under photo-irradiation condition B.
3ka selectively. In this case, the approach of allyl bromide via
a similar alignment is difficult, since peri-hydrogen would shield
the vinyl radical. As the result, trans alignment of naphthyl ring and
bromine atom would be preferred probably in the transition state
where vinyl portion is free of conjugation with the naphthyl ring so
as to minimize the steric repulsion.
Since all the diene products 3 involve a vinyl bromide func-
tionality, further chemical transformations to prepare functional-
ized 1,4-dienes are feasible. Indeed, as we previously discussed in
our preliminary work,8 Pd-catalyzed formic acid reduction, the
Sonogashira reaction, and the SuzukieMiyaura coupling reaction
of product 3 all proceeded smoothly to give the corresponding
vinyl-substituted compounds. The Pd-catalyzed carbonylation of
1-bromo-1,4-diene 3ab also took place effectively under carbon
monoxide pressure (10 atm) to give
a
,
b
-unsaturated ester 8 in
a 93% yield.19 Also, 3ab underwent carbonylative SuzukieMiyaura
reaction to give
(Scheme 5).
a,b
-unsaturated ketone 9 in an 83% yield20
Scheme 4. Radical chain mechanism for the bromoallylation of 1p.
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T. Kippo et al. / Tetrahedron xxx (2016) 1e9
5
The mixture was stirred at 60 ꢀC for 6 h under argon atmosphere.
The reaction mixture was concentrated under reduced pressure.
The residue was purified by flash column chromatography on SiO2
using hexane to give the corresponding 1-bromo-2-phenyl-1,4-
pentadiene 3aa (179 mg, 80%).
Compound data: 3aa, 3ba, 3ca, 3da, 3ea, 3ac, 3ga, 3ha, 3ia, 3ja,
3ka, 3la, 3ma, 3na and 3oa have already been reported.8
4.2.2. Typical general procedure for bromoallylation of alkynes 1 with
2b (Method B). To a 4 mL screw capped test tube made by Pyrex
glass, ethynylbenzene 1a (1.0 mmol, 102 mg), ethyl 2-(bromo-
methyl)acrylate 2b (4.0 mmol, 772 mg) and benzene (1 mL) were
added. Then, this test tube was purged with argon and sealed. The
mixture was irradiated by Solarbox equipped 1500 W xenon lamp
(350 W/m2) with stirring for 12 h. The reaction mixture was con-
centrated under reduced pressure. The residue was purified by
flash column chromatography on SiO2 using hex/EtOAc (100/1) and
preparative HPLC (chloroform) to give the corresponding ethyl 5-
bromo-2-methylene-4-phenyl-4-pentenoate 3ab (245 mg, 83%).
Scheme 5. Carbonyl-functionalization of 1-bromo-1,4-diene 3ab.
3. Conclusions
We have demonstrated that radical bromoallylation has broad
applicability to a variety of substituted alkynes and allyl bromides,
and therefore, it is useful in the preparation of a wide range of 1-
bromo-substituted-1,4-dienes. The reaction proceeds either under
standard thermal initiation using typical diazo initiators such as V-
65 or simple irradiation from a xenon lamp with no radical initiator.
All these products have CeBr bonds that can be successfully sub-
jected to CeC bond formation reactions such as cross-coupling and
4.3. Characterization data
4.3.1. 1-Bromo-2-phenyl-1,4-pentadiene (3aa).8 Obtained as an E/Z
isomeric mixture in a 23/77 ratio (179 mg, 80%), as determined by
1H NMR analysis of the crude reaction mixture. The E- and Z-iso-
mers of 3aa were separated using a preparative HPLC. E/Z config-
uration was determined by NOESY analysis.
carbonylation with CO, serving as
a platform to access 1-
substituted-1,4-dienes. Since regiochemistry is opposite that of
the previously reported Kaneda’s Pd-catalyzed bromoallylation
reaction,21 both methods can be used in a complementary fashion.
4.3.2. 1-Bromo-2-(4-tolyl)-1,4-pentadiene (3ba).8 Obtained as an E/
Z isomeric mixture in a 16/84 ratio (190 mg, 80%), as determined by
1H NMR analysis of the crude reaction mixture. The E- and Z-iso-
mers of 3ba were separated using a preparative HPLC. E/Z config-
uration was determined by NOESY analysis.
4. Experimental
4.1. General information
4. 3. 3 . 1-Bro mo-2-(4-m ethoxyphenyl) -1, 4-pentadiene
(3ca).8 Obtained as an E/Z isomeric mixture in a 23/77 ratio
(177 mg, 70%), as determined by 1H NMR analysis of the crude re-
action mixture. The E- and Z-isomers of 3ca were separated using
a preparative HPLC. E/Z configuration was determined by NOESY
analysis.
Photoinduced reactions were carried out using a 4 mL screw
capped test tube made of Pyrex glass and a solar simulator equip-
ped with a 1500 W xenon lamp (CO.FO.ME.GRA, Milan, Italy,
SolarBox 1500e). 1H NMR spectra were recorded with JEOL ECP-500
(500 MHz) and JEOL ECS-400 (400 MHz) spectrometers in CDCl3
and are referenced at 7.26 ppm for solvent peak. 13C NMR spectra
were recorded with JEOL ECP-500 (125 MHz) and JEOL ECS-400
(100 MHz) spectrometers in CDCl3 and are referenced at
77.00 ppm for solvent peak. Chemical shifts are reported in parts
-
4.3.4. 1-Bromo-2-(4-ethoxycarbonylphenyl)-1,4-pentadiene (3da).8
Obtained as an E/Z isomeric mixture in a 35/65 ratio (275 mg,
93%), as determined by 1H NMR analysis of the crude reaction
mixture. The E- and Z-isomers of 3da were separated using a pre-
parative HPLC. E/Z configuration was determined by NOESY
analysis.
per million (d). Splitting patterns are indicated as follows: br, broad;
s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sex, sextet;
sep, septet; m, multiplet. Infrared spectra were obtained on a JASCO
FT/IR-4100 spectrometer; absorptions were reported in reciprocal
centimeters. Both conventional and high-resolution mass spectra
were recorded with a JEOL MS-700 spectrometer. Melting points
4.3.5. 1-Bromo-2-(4-acetylphenyl)-1,4-pentadiene (3ea).8 Obtained
as an E/Z isomeric mixture in a 27/73 ratio (249 mg, 94%), as de-
termined by 1H NMR analysis of the crude reaction mixture. The E-
and Z-isomers of 3ea were separated using a preparative HPLC. E/Z
configuration was determined by NOESY analysis.
€
were measured by BUCHI Melting Point B-540. The products were
purified by flash column chromatography on silica gel (Kanto
Chem. Co. Silica Gel 60N (spherical, neutral, 40e50 mm)) and/or
preparative HPLC (Japan Analytical Industry Co., Ltd., LC-908) with
GPC columns using distilled CHCl3 as an eluent. Benzene was
degassed by argon bubbling for 30 min before use. Compound 4
was synthesized by the reported procedure.22a Compound 6 is
known in literature.22b
4.3.6. 1-Bromo-2-(4-nitrophenyl)-1,4-pentadiene (3fa). Obtained as
an E/Z isomeric mixture in a 4/96 ratio (161 mg, 60%), as de-
termined by 1H NMR analysis of the crude reaction mixture. The E-
and Z-isomers of 3fa were separated using a preparative HPLC. Z
isomer; Light yellow oil; Rf¼0.23 (Hexane:Et2O¼30:1); 1H NMR
4.2. Experimental procedures
(500 MHz, CDCl3)
d
3.19 (dd, J¼6.9, 1.0 Hz, 2H), 5.04e5.14 (m, 2H),
5.73 (ddt, J¼16.9, 10.1, 6.9 Hz, 1H), 6.40 (s, 1H), 7.42e7.46 (m, 2H),
4.2.1. Typical general procedure for bromoallylation of alkynes 1 with
2a or 2c (Method A). To a 20 mL screw capped test tube, ethy-
nylbenzene 1a (1.0 mmol, 102 mg), 3-bromopropene 2a (5 mL), and
V-65 [2,20-azobis(2,4-dimethylvaleronitrile)] (0.2 mmol, 50 mg)
were added. Then, this test tube was purged with argon and sealed.
8.22e8.26 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
42.53, 105.57,
118.35, 123.55, 129.21, 133.33, 142.69, 146.11, 147.15; IR (neat): 3077,
1640, 1518 cmꢁ1; EIMS m/z (relative intensity) 267 ([M]þ, 39), 252
(7), 250 (7), 222 (6), 220 (6), 188 (49), 171 (12), 142 (100), 141 (98),
115 (51); HRMS (EI) m/z calcd for C11H10NO279Br [M]þ: 266.9895,
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6
T. Kippo et al. / Tetrahedron xxx (2016) 1e9
found: 266.9891.
E
isomer; Light yellow oil; Rf¼0.23
isomers of 3oa were separated by a flash column chromatography
(Hexane:Et2O¼30:1); 1H NMR (500 MHz, CDCl3)
d
3.47 (d, J¼6.0 Hz,
on silica gel (Hexane:Et2O¼10:1). E/Z configuration was de-
2H), 5.08e5.15 (m, 2H), 5.80 (ddt, J¼17.0, 10.1, 6.5 Hz, 1H), 6.71 (s,
termined by NOESY analysis.
1H), 7.48e7.52 (m, 2H), 8.17e8.22 (m, 2H); 13C NMR (125 MHz,
CDCl3)
d
37.39, 110.07, 117.24, 123.85, 127.17, 132.75, 141.80, 146.28,
4.3.17. Ethyl 5-bromo-2-methylene-4-phenyl-4-pentenoate
(3ab). Obtained as an E/Z isomeric mixture in a 22/78 ratio
(245 mg, 83%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.43 (Hexane:EtOAc¼10:1); Z
147.27; IR (neat): 3079, 1638, 1520 cmꢁ1; EIMS m/z (relative in-
tensity) 267 ([M]þ, 41), 252 (8), 250 (8), 222 (6), 220 (6), 188 (53),
171 (13), 142 (100), 141 (94), 115 (48); HRMS (EI) m/z calcd for
C
11H10NO279Br [M]þ: 266.9895, found: 266.9901. E/Z configuration
isomer; 1H NMR (400 MHz, CDCl3)
d
1.28 (t, J¼6.8 Hz, 3H), 3.45 (s,
was determined by NOESY analysis.
2H), 4.19 (q, J¼6.8 Hz, 2H), 5.50 (d, J¼1.2 Hz,1H), 6.20 (s,1H), 6.32 (s,
1H), 7.26e7.32 (m, 3H), 7.35e7.38 (m, 2H); 13C NMR (100 MHz,
4.3.7. 1-Bromo-4-methyl-2-phenyl-1,4-pentadiene (3ac).8 Obtained
as an E/Z isomeric mixture in a 10/90 ratio (225 mg, 95%), as de-
termined by 1H NMR analysis of the crude reaction mixture. The E-
and Z-isomers of 3ac were separated using a preparative HPLC.
CDCl3)
136.85, 138.79, 142.91, 166.30. E isomer; 1H NMR (400 MHz, CDCl3)
1.30 (t, J¼6.8 Hz, 3H), 3.71 (s, 2H), 4.21 (q, J¼6.8 Hz, 2H), 5.50e5.51
(m, 1H), 6.21 (s, 1H), 6.67 (s, 1H), 7.26e7.32 (m, 3H), 7.35e7.38 (m,
2H); 13C NMR (100 MHz, CDCl3)
14.09, 34.87, 60.78, 108.16, 125.47,
126.21, 127.98, 128.52, 135.67, 139.28, 142.43, 166.65; IR (neat):
d 14.09, 40.45, 60.78, 104.73, 127.31, 127.64, 128.07, 128.12,
d
d
4.3.8. 1-Bromo-2-(2-chlorophenyl)-1,4-pentadiene (3ga).8 Obtained
as an E/Z isomeric mixture in a 6/94 ratio (250 mg, 97%), as de-
termined by 1H NMR analysis of the crude reaction mixture. The E-
and Z-isomers of 3ga were separated using a preparative HPLC. E/Z
configuration was determined by NOESY analysis.
1716, 1443, 1142 cmꢁ1
; EIMS m/z (relative intensity) 249
([MꢁOEt]þ, 7), 215 (100), 187 (63), 169 (25), 141 (89), 115 (32), 102
(22), 91 (6), 71 (6); HRMS (EI) m/z calcd for C12H10O81Br [MꢁOEt]þ:
250.9895, found: 250.9893. E/Z configuration was determined by
NOESY analysis.
4.3.9. 1-Bromo-2-(3-chlorophenyl)-1,4-pentadiene (3ha).8
-
Obtained as an E/Z isomeric mixture in a 14/86 ratio (219 mg,
85%), as determined by 1H NMR analysis of the crude reaction
mixture. The E- and Z-isomers of 3ha were separated using a pre-
parative HPLC. E/Z configuration was determined by NOESY
analysis.
4.3.18. Ethyl 5-bromo-4-(4-methoxyphenyl)-2-methylene-4-
pentenoate (3cb). Obtained as an E/Z isomeric mixture in a 10/90
ratio (231 mg, 71%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.30 (Hexane:EtOAc¼10:1); Z
isomer; 1H NMR (400 MHz, CDCl3)
d
1.28 (t, J¼6.8 Hz, 3H), 3.43 (s,
2H), 3.81 (s, 3H), 4.19 (q, J¼6.8 Hz, 2H), 5.49 (s, 1H), 6.19 (s, 1H), 6.28
4.3.10. 1-Bromo-2-(4-chlorophenyl)-1,4-pentadiene (3ia).8
(s, 1H), 6.88e6.90 (m, 2H), 7.23e7.28 (m, 2H); 13C NMR (100 MHz,
-
Obtained as an E/Z isomeric mixture in a 18/82 ratio (207 mg,
81%), as determined by 1H NMR analysis of the crude reaction
mixture. The E- and Z-isomers of 3ia were separated using a pre-
parative HPLC. E/Z configuration was determined by NOESY
analysis.
CDCl3)
130.78, 137.03, 142.25, 158.89, 166.36. E isomer; 1H NMR (400 MHz,
CDCl3)
1.30 (m, 3H), 3.68 (s, 2H), 3.80 (s, 3H), 4.20 (q, J¼6.8 Hz,
2H), 5.49 (s, 1H), 6.21 (s, 1H), 6.59 (s, 1H), 6.83e6.85 (m, 2H),
7.23e7.28 (m, 2H); 13C NMR (100 MHz, CDCl3)
14.09, 34.78, 55.16,
d 14.09, 40.36, 55.06, 60.76, 104.22, 113.40, 127.15, 129.43,
d
d
60.81, 106.48, 113.85, 125.36, 127.36, 131.65, 135.75, 141.74, 159.38,
166.69; IR (neat): 3073, 2981, 1715, 1509, 1249 cmꢁ1; EIMS m/z
(relative intensity) 324 ([M]þ, 6), 245 (100), 217 (18), 171 (40), 128
(19), 89 (10), 63 (3); HRMS (EI) m/z calcd for C15H17O379Br [M]þ:
324.0361, found: 324.0352. E/Z configuration was determined by
NOESY analysis.
-
4.3.11. 1-Bromo-2-(2,5-dimethoxyphenyl)-1,4-pentadiene (3ja).8
Obtained as an E/Z isomeric mixture in a 6/94 ratio (254 mg,
90%), as determined by 1H NMR analysis of the crude reaction
mixture. The E- and Z-isomers of 3ja were separated using a pre-
parative HPLC. E/Z configuration was determined by NOESY
analysis.
4.3.19. Ethyl 5-bromo-4-(4-ethoxycarbonylphenyl)-2-methylene-4-
pentenoate (3db). Obtained as an E/Z isomeric mixture in a 20/80
ratio (268 mg, 73%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.40 (Hexane:EtOAc¼10:1); Z
-
4.3.12. (E)-1-Bromo-2-(1-naphthyl)-1,4-pentadiene (3ka).8
Obtained as only E isomer (227 mg, 83%). E configuration was
determined by NOESY analysis.
isomer; 1H NMR (400 MHz, CDCl3)
d
1.28 (t, J¼6.8 Hz, 3H), 1.39 (t,
4.3.13. 1-Bromo-2-(2-naphthyl)-1,4-pentadiene (3la).8 Obtained as
an E/Z isomeric mixture in a 26/74 ratio (238 mg, 87%), as de-
termined by 1H NMR analysis of the crude reaction mixture. The E-
and Z-isomers of 3la were separated using a preparative HPLC. E/Z
configuration was determined by NOESY analysis.
J¼6.8 Hz, 3H), 3.45 (s, 2H), 4.19 (q, J¼6.8 Hz, 2H), 4.38 (q, J¼6.8, 2H),
5.48e5.49 (m, 1H), 6.19e6.20 (m, 1H), 6.37e6.38 (m, 1H), 7.33e7.35
(m, 2H), 8.04e8.06 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 14.11,
14.28, 40.33, 60.91, 60.94, 105.69, 127.59, 128.27, 129.44, 129.71,
136.56, 142.31, 143.48, 166.19. E isomer; 1H NMR (400 MHz, CDCl3)
d
1.30 (t, J¼7.2 Hz, 3H), 1.39 (t, J¼7.2 Hz, 3H), 3.73 (m, 2H), 4.22 (q,
4.3.14. 1-Bromo-2-thiophen-3-yl-1,4-pentadiene (3ma).8 Obtained
as an E/Z isomeric mixture in a 58/42 ratio (176 mg, 77%), as de-
termined by 1H NMR analysis of the crude reaction mixture. The E-
and Z-isomers of 3ma were separated using a preparative HPLC. E/Z
configuration was determined by NOESY analysis.
J¼7.2 Hz, 2H), 4.37 (q, J¼7.2 Hz, 2H), 5.48e5.49 (m, 1H), 6.21e6.22
(m,1H), 6.78 (s,1H), 7.36e7.38 (m, 2H), 7.98e8.00 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d 14.11, 14.28, 34.74, 60.91, 60.94, 110.09, 125.71,
126.17,129.82, 135.52, 141.85,143.48,166.05,166.53; IR (neat): 3417,
3074, 2981, 1714, 1275 cmꢁ1; EIMS m/z (relative intensity) 321
([MꢁOEt]þ, 8), 287 (100), 259 (39), 213 (21), 169 (13), 141 (26), 115
(12); HRMS (EI) m/z calcd for C15H14O379Br [MꢁOEt]þ: 321.0126,
found: 321.0125. E/Z configuration was determined by NOESY
analysis.
4.3.15. 1-Bromo-2-ethoxycarbonyl-1,4-pentadiene (3na).8 Obtained
as an E/Z isomeric mixture in a 26/74 ratio (188 mg, 86%), as de-
termined by 1H NMR analysis of the crude reaction mixture.
4.3.16. Dimethyl 2-allyl-3-bromofumarate (3oa).8 Obtained as an E/
Z isomeric mixture in a 34/66 ratio (132 mg, 49%), as determined by
1H NMR analysis of the crude reaction mixture. The E- and Z-
4.3.20. Ethyl 5-bromo-4-(2-chlorophenyl)-2-methylene-4-
pentenoate (3gb). Obtained as an E/Z isomeric mixture in a 7/
93 ratio (273 mg, 83%), as determined by 1H NMR analysis of the
Please cite this article in press as: Kippo, T.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.084

T. Kippo et al. / Tetrahedron xxx (2016) 1e9
7
crude reaction mixture. Colorless oil; Rf¼0.53 (Hexane:
126.93, 127.52, 136.85, 137.27, 138.12, 166.42. E isomer; 1H NMR
(400 MHz, CDCl3)
EtOAc¼10:1); Z isomer; 1H NMR (400 MHz, CDCl3)
d
1.28 (t,
d
1.30 (t, J¼6.8 Hz, 3H), 3.66e3.67 (m, 2H), 4.25
J¼7.2 Hz, 3H), 3.43 (s, 2H), 4.19 (q, J¼7.2 Hz, 2H), 5.46 (d,
J¼0.8 Hz, 1H), 6.19 (d, J¼0.8 Hz, 1H), 6.42 (t, J¼1.6 Hz, 1H),
7.04e7.09 (m, 1H), 7.18e7.28 (m, 2H), 7.39e7.43 (m, 1H); 13C
(q, J¼6.8, 2H), 5.49e5.50 (m, 1H), 6.22 (s, 1H), 6.80 (s, 1H), 7.13e7.14
(m, 1H), 7.17e7.18 (m, 1H), 7.27e7.31 (m, 1H); 13C NMR (100 MHz,
CDCl3)
d 14.10, 34.51, 60.91, 107.69, 121.47, 124.97, 125.21, 126.08,
NMR (100 MHz, CDCl3)
127.83, 128.90, 129.39, 130.24, 132.03, 136.21, 137.82, 141.72,
166.10. E isomer; 1H NMR (400 MHz, CDCl3)
3H), 3.71 (s, 2H), 4.10 (q, J¼7.2 Hz, 2H), 5.62 (d, J¼0.8 Hz, 1H),
6.14e6.16 (m, 1H), 6.36e6.37 (m, 1H), 7.04e7.09 (m, 1H),
7.18e7.28 (m, 2H), 7.39e7.43 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
14.04, 39.62, 60.71, 107.13, 126.49,
135.62, 137.17, 139.75, 166.76; IR (neat): 3106, 2980, 1714,
1140 cmꢁ1; EIMS m/z (relative intensity) 255 ([MꢁOEt]þ, 4), 221
(100), 193 (27), 147 (48), 108 (11), 103 (3); HRMS (EI) m/z calcd for
d
1.22 (t, J¼7.2 Hz,
C
10H8O79BrS [MꢁOEt]þ: 254.9479, found: 254.9476. E/Z configu-
ration was determined by NOESY analysis.
d
13.97, 35.74, 60.62, 109.57, 126.69, 129.01, 129.60, 130.63,
4.3.24. Ethyl 5-bromo-2-methylene-4-phenyl-4-hexenoate
(3pb). Obtained as an E/Z isomeric mixture in a 18/82 ratio
(176 mg, 57%), as determined by 1H NMR analysis of the crude re-
action mixture. Colorless oil; Rf¼0.43 (Hexane:EtOAc¼10:1); Z
132.31, 135.67, 138.39, 141.66, 166.34 (One carbon signal super-
posed that of Z isomer); IR (neat): 3070, 2981, 1717, 1630,
1143 cmꢁ1; EIMS m/z (relative intensity) 283 ([MꢁOEt]þ, 3), 251
(33), 249 (100), 221 (29), 175 (27), 141 (22), 139 (13), 115 (11), 83
(7), 75 (3); HRMS (EI) m/z calcd for C12H9O79Br35Cl [MꢁOEt]þ:
282.9525, found: 282.9529. E/Z configuration was determined by
NOESY analysis.
isomer; 1H NMR (400 MHz, CDCl3)
d
1.27 (t, J¼7.2 Hz, 3H), 2.48 (s,
3H), 3.45 (s, 2H), 4.17 (q, J¼7.2 Hz, 2H), 5.46e5.47 (m, 1H), 6.17 (s,
1H), 7.11e7.15 (m, 2H), 7.22e7.33 (m, 3H); 13C NMR (100 MHz,
CDCl3)
128.45, 136.31, 136.37, 142.70, 166.58. E isomer; 1H NMR (400 MHz,
CDCl3)
1.24 (t, J¼7.2 Hz, 3H), 2.26 (s, 3H), 3.63 (s, 2H), 4.12 (q,
J¼7.2 Hz, 2H), 5.57e5.59 (m, 1H), 6.18e6.19 (m, 1H), 7.11e7.15 (m,
2H), 7.22e7.33 (m, 3H); 13C NMR (100 MHz, CDCl3)
14.09, 26.74,
d 14.12, 25.86, 37.07, 60.80, 120.71, 126.12, 127.01, 127.89,
4.3.21. Ethyl 5-bromo-4-(3-chlorophenyl)-2-methylene-4-
pentenoate (3hb). Obtained as an E/Z isomeric mixture in a 13/87
ratio (264 mg, 80%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.47 (Hexane:EtOAc¼10:1); Z
d
d
40.81, 60.67, 122.81, 125.55, 127.17, 128.20, 128.41, 136.27, 136.95,
139.74, 166.79; IR (neat): 2981, 1714, 1140 cmꢁ1; EIMS m/z (relative
intensity) 263 ([MꢁOEt]þ, 2), 229 (100), 183 (18), 155 (49), 115 (22),
77 (4); HRMS (EI) m/z calcd for C13H12O79Br [MꢁOEt]þ: 263.0072,
found: 263.0069. E/Z configuration was determined by NOESY
analysis.
isomer; 1H NMR (400 MHz, CDCl3)
d
1.29 (t, J¼6.8 Hz, 3H), 3.42 (s,
2H), 4.20 (q, J¼6.8 Hz, 2H), 5.51 (d, J¼1.6 Hz, 1H), 6.22 (s, 1H), 6.34
(s, 1H), 7.11e7.22 (m, 1H), 7.24e7.32 (m, 3H); 13C NMR (100 MHz,
CDCl3)
129.46, 133.95, 136.58, 140.62, 141.78, 166.16. E isomer; 1H NMR
(400 MHz, CDCl3)
d 14.10, 40.34, 60.90, 105.70, 126.47, 127.58, 127.82, 128.23,
d
1.30 (t, J¼7.2 Hz, 3H), 3.68 (s, 2H), 4.22 (q,
J¼7.2 Hz, 2H), 5.49 (d, J¼1.2 Hz, 1H), 6.22 (s, 1H), 6.70 (s, 1H),
4.3.25. Ethyl 4-bromomethylene-2-methylene-decanoate (3qb).
Obtained as an E/Z isomeric mixture in a 93/7 ratio (252 mg, 83%),
as determined by 1H NMR analysis of the crude reaction mixture.
Colorless oil; Rf¼0.47 (Hexane:EtOAc¼10:1); Z isomer; 1H NMR
7.11e7.22 (m, 1H), 7.24e7.32 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
14.10, 34.80, 60.90, 109.43, 124.44, 125.68, 126.39, 128.05, 129.78,
134.45, 135.44, 141.09, 141.39, 166.50; IR (neat): 3070, 2981, 1714,
1142 cmꢁ1; EIMS m/z (relative intensity) 283 ([MꢁOEt]þ, 3), 251
(35), 249 (100), 221 (42), 175 (25), 141 (17), 115 (7), 70 (4); HRMS
(EI) m/z calcd for C12H9O79Br35Cl [MꢁOEt]þ: 282.9525, found:
282.9527. E/Z configuration was determined by NOESY analysis.
(400 MHz, CDCl3)
d
0.87 (t, J¼6.8 Hz, 3H), 1.38e1.44 (m, 11H),
2.05e2.08 (m, 2H), 3.24 (s, 2H), 4.23 (q, J¼6.8 Hz, 2H), 5.53 (d,
J¼1.2 Hz, 1H), 6.09 (s, 1H), 6.23e6.24 (m, 1H); 13C NMR (100 MHz,
CDCl3)
d 27.54, 28.79, 34.33, 35.89, 60.76, 103.78, 125.31, 136.07,
142.66, 166.86 (Some carbon signals superposed that of E isomer). E
4.3.22. Ethyl 5-bromo-4-(4-chlorophenyl)-2-methylene-4-
pentenoate (3ib). Obtained as an E/Z isomeric mixture in a 13/87
ratio (270 mg, 82%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.53 (Hexane:EtOAc¼10:1); Z
isomer; 1H NMR (400 MHz, CDCl3)
d
0.89 (t, J¼6.4 Hz, 3H),
1.25e1.33 (m,11H), 2.16e2.20 (m, 2H), 3.10 (s, 2H), 4.20 (q, J¼6.4 Hz,
2H), 5.55 (d, J¼1.2 Hz, 1H), 5.94 (s, 1H), 6.25 (s, 1H); 13C NMR
(100 MHz, CDCl3)
d 13.99, 14.09, 22.52, 26.83, 29.03, 31.55, 32.49,
isomer; 1H NMR (400 MHz, CDCl3)
d
1.28 (t, J¼6.8 Hz, 3H), 3.42 (s,
37.69, 60.76, 103.66, 126.63, 137.58, 142.66, 166.46; IR (neat): 3076,
2928, 2858, 1719, 1142 cmꢁ1; EIMS m/z (relative intensity) 257
([MꢁOEt]þ, 1), 223 (100), 195 (92), 177 (18), 149 (39), 93 (25), 79
(23), 67 (13); HRMS (EI) m/z calcd for C12H18O79Br [MꢁOEt]þ:
257.0541, found: 257.0543. E/Z configuration was determined by
NOESY analysis.
2H), 4.19 (q, J¼6.8 Hz, 2H), 5.48e5.49 (m, 1H), 6.20e6.21 (m, 1H),
6.33e6.34 (m, 1H), 7.20e7.23 (m, 2H), 7.32e7.35 (m, 2H); 13C NMR
(100 MHz, CDCl3)
129.51, 133.36, 136.56, 137.03, 141.75, 166.00. E isomer; 1H NMR
(400 MHz, CDCl3)
d 13.99, 40.21, 60.73, 105.30, 127.33, 128.25,
d
1.32 (t, J¼7.2 Hz, 3H), 3.67e3.68 (m, 2H), 4.21 (q,
J¼7.2 Hz, 2H), 5.48e5.49 (m, 1H), 6.20e6.21 (m, 1H), 6.67 (s, 1H),
7.20e7.24 (m, 2H), 7.29e7.35 (m, 2H); 13C NMR (100 MHz, CDCl3)
4.3.26. Ethyl 4-bromomethylene-6-(tert-butyldimethylsilyl)oxy-2-
methylene-hexanoate (3rb). Obtained as an E/Z isomeric mixture
in a 91/9 ratio (283 mg, 75%), as determined by 1H NMR analysis of
d
13.99, 34.65, 60.78, 108.61, 125.48, 127.42, 128.57, 133.74, 135.43,
137.54, 141.29, 166.34; IR (neat): 3073, 2981, 1714, 1141 cmꢁ1; EIMS
m/z (relative intensity) 283 ([MꢁOEt]þ, 9), 251 (82), 249 (100), 221
(79), 203 (22), 175 (66), 141 (41), 115 (19), 70 (8); HRMS (EI) m/z
calcd for C12H9O79Br35Cl [MꢁOEt]þ: 282.9525, found: 282.9522. E/Z
configuration was determined by NOESY analysis.
the
crude
reaction
mixture.
Colorless
oil;
Rf¼0.50
(Hexane:EtOAc¼10:1); Z isomer; 1H NMR (400 MHz, CDCl3)
d
0.03
(s, 6H), 0.87 (s, 9H), 1.30 (m, 3H), 2.29 (t, J¼6.4 Hz, 2H), 3.26 (s, 2H),
3.66 (t, J¼6.4 Hz, 2H), 4.20 (m, 2H), 5.56 (s, 1H), 6.17 (s, 1H), 6.26 (s,
1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.42, 25.83, 34.71, 38.95, 61.09,
4.3.23. Ethyl 5-bromo-2-methylene-4-(3-thiophenyl)-4-pentenoate
(3mb). Obtained as an E/Z isomeric mixture in a 24/76 ratio
(220 mg, 73%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.43 (Hexane:EtOAc¼10:1); Z
105.65, 125.52, 135.92, 139.54, 166.87 (One carbon signal super-
posed that of E isomer). E isomer; 1H NMR (400 MHz, CDCl3)
d
0.06
(s, 6H), 0.89 (s, 9H), 1.30 (t, J¼6.8 Hz, 3H), 2.44 (t, J¼6.8 Hz, 2H), 3.16
(s, 2H), 3.71 (t, J¼6.8 Hz, 2H), 4.20 (q, J¼6.8 Hz, 2H), 5.56 (s,1H), 6.03
isomer; 1H NMR (400 MHz, CDCl3)
d
1.29 (t, J¼6.8 Hz, 3H),
(s, 1H), 6.26 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢁ5.37, 14.14, 18.25,
3.46e3.47 (m, 2H), 4.20 (q, J¼6.8, 2H), 5.52e5.53 (m, 1H), 6.22 (s,
25.90, 35.98, 38.81, 60.71, 60.82, 105.36, 126.81, 137.45, 139.95,
1H), 6.30 (s, 1H), 7.27e7.31 (m, 2H), 7.48 (dd, J¼2.8, 1.2 Hz, 1H); 13
C
166.47; IR (neat): 2955, 2929, 1720, 1255, 1096 cmꢁ1; EIMS m/z
t
NMR (100 MHz, CDCl3)
d
14.10, 40.01, 60.85, 104.41, 124.43, 124.70,
(relative intensity) 319 ([Mꢁ Bu]þ, 96), 275 (19), 273 (19), 139 (11),
Please cite this article in press as: Kippo, T.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.084

8
T. Kippo et al. / Tetrahedron xxx (2016) 1e9
137 (11), 91 (10), 75 (12), 73 (11); HRMS (EI) m/z calcd for
C
ration was determined by NOESY analysis.
(193 mg, 1.0 mmol) and benzene (1.0 mL) were added. Then, this
test tube was purged with argon and sealed. The mixture was ir-
radiated by Solarbox equipped 1500 W xenon lamp (350 W/m2)
with stirring for 12 h. The reaction mixture was concentrated under
reduced pressure. The residue was purified by flash column chro-
matography on SiO2 and preparative HPLC (chloroform) to give the
corresponding product 5 (173 mg, 76%, E isomer only).
12H2081BrO3Si [Mꢁ Bu]þ: 321.0345, found: 321.0342. E/Z configu-
t
4.3.27. Ethyl 4-bromomethylene-6-hydroxy-2-methylene-hexanoate
(3rb0). Obtained as an E/Z isomeric mixture in a 96/4 ratio (50 mg,
19%), as determined by 1H NMR analysis of the crude reaction
mixture. Colorless oil; Rf¼0.18 (Hexane:EtOAc¼5:1); Z isomer; 1H
NMR (400 MHz, CDCl3)
d
1.32e1.33 (m, 3H), 1.69 (br s, 1H), 2.36 (t,
4.4.1. (E)-Diethyl 3-(bromomethylene)-4-(4-(ethoxycarbonyl)-2-
methyl-4-penten-2-yl)cyclopentane-1,1-dicarboxylate (5). Colorless
oil; Rf¼0.21 (Hexane:EtOAc¼10:1); 1H NMR (400 MHz, CDCl3)
J¼6.4 Hz, 2H), 3.29 (s, 2H), 3.70 (t, J¼6.4 Hz, 2H), 4.24e4.28 (m, 2H),
5.59e5.60 (m, 1H), 6.22 (s, 1H), 6.27 (s, 1H); 13C NMR (100 MHz,
CDCl3)
d
14.10, 34.39, 38.87, 60.13, 61.01, 105.94, 125.90, 135.92,
1.30 (t,
d
0.82 (s, 3H), 0.83 (s, 3H), 1.22e1.33 (m, 9H), 2.08 (dd, J¼12.4,
139.25, 166.91. E isomer; 1H NMR (400 MHz, CDCl3)
d
8.4 Hz, 1H), 2.29 (d, J¼13.2 Hz, 1H), 2.37 (d, J¼12.4 Hz, 1H),
2.58e2.74 (m, 3H), 3.28e3.36 (m,1H), 4.12e4.28 (m, 6H), 5.47e5.50
(m, 1H), 6.09 (m, 1H), 6.21e6.24 (m, 1H); 13C NMR (100 MHz, CDCl3)
J¼6.8 Hz, 3H), 1.69 (br s, 1H), 2.52 (t, J¼6.4 Hz, 2H), 3.16 (s, 2H), 3.80
(t, J¼6.4 Hz, 2H), 4.21 (q, J¼6.8 Hz, 2H), 5.62e5.63 (m, 1H), 6.06 (s,
1H), 6.29 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
14.10, 36.21, 38.49,
d 13.97, 14.09, 23.64, 24.09, 36.00, 37.17, 39.62, 42.34, 52.42, 57.92,
60.36, 61.12, 105.65, 127.51, 137.20, 139.90, 166.65; IR (neat): 3418,
2980,1714, 1147 cmꢁ1; EIMS m/z (relative intensity) 217 ([MꢁOEt]þ,
3),183 (100),153 (54),137 (43),125 (34), 79 (32), 77 (28); HRMS (EI)
m/z calcd for C8H1079BrO2 [MꢁOEt]þ: 216.9864, found: 216.9862. E/
Z configuration was determined by NOESY analysis.
60.73, 61.55, 61.63, 101.46, 127.76, 137.94, 145.71, 167.92, 170.90,
170.97; IR (neat): 2979, 2938, 2906, 2874, 1732, 1627, 1302,
1249 cmꢁ1; EIMS m/z (relative intensity) 458 ([M]þ, 1), 413
([MꢁOEt]þ, 3), 379 (33), 347 (17), 345 (17), 333 (50), 305 (25), 273
(37), 271 (38), 259 (53), 155 (100), 109 (77), 81 (50); HRMS (EI) m/z
calcd for C19H26BrO5 [MꢁOEt]þ: 413.0964, found: 413.0976.
4.3.28. Ethyl 5-bromo-4-(1-cyclohexenyl)-2-methylene-4-
pentenoate (3sb). Obtained as an E/Z isomeric mixture in a 24/76
ratio (102 mg, 34%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.48 (Hexane:EtOAc¼10:1); Z
4.5. Experimental procedure for the formation of ethyl 2-
(2,2,6,6-tetramethyl-1-piperidinyloxymethyl)acrylate (7)
isomer; 1H NMR (400 MHz, CDCl3)
d
1.29 (t, J¼6.8 Hz, 3H),
To a 4 mL screw capped test tube made by Pyrex glass, 1-octyne
1q (0.5 mmol, 55 mg), ethyl 2-(bromomethyl)acrylate 2b
(2.0 mmol, 386 mg), TEMPO (0.05 mmol, 8 mg) and benzene
(0.5 mL) were added. Then, this test tube was purged with argon
and sealed. The mixture was irradiated by Solarbox equipped
1500 W xenon lamp (350 W/m2) with stirring for 12 h. The reaction
mixture was concentrated under reduced pressure. The residue was
purified by flash column chromatography on SiO2 (Hexane/
EtOAc¼1:0 to 100:1) and preparative HPLC (chloroform) to give
ethyl 2-(2,2,6,6-tetramethyl-1-piperidinyloxymethyl)acrylate (7).
1.52e1.68 (m, 4H), 2.01e2.09 (m, 4H), 3.15 (s, 2H), 4.20 (q, J¼6.8 Hz,
2H), 5.52e5.56 (m, 2H), 5.96 (s, 1H), 6.21e6.22 (m, 1H); 13C NMR
(100 MHz, CDCl3)
102.30, 126.83, 127.03, 135.69, 137.30, 145.35, 166.55; E isomer; 1H
NMR (400 MHz, CDCl3)
d 14.14, 21.89, 22.53, 24.96, 26.83, 38.64, 60.74,
d
1.33 (t, J¼6.8 Hz, 3H), 1.52e1.68 (m, 4H),
2.12e2.14 (m, 4H), 3.30e3.45 (m, 2H), 4.24 (q, J¼6.8 Hz, 2H),
5.38e5.40 (m, 1H), 5.79e5.81 (m, 1H), 6.18e6.20 (m, 1H), 6.43 (s,
1H); 13C NMR (100 MHz, CDCl3)
d 14.14, 21.84, 22.60, 25.80, 25.97,
32.43, 60.80, 106.37, 124.64, 134.30, 136.24, 143.13, 166.94 (One
carbon signal superposed that of Z isomer); IR (neat): 3031, 2930,
1715, 1138 cmꢁ1; EIMS m/z (relative intensity) 253 ([MꢁOEt]þ, 3),
219 (100), 191 (9), 145 (25), 91 (9), 83 (5), 67 (3); HRMS (EI) m/z
calcd for C12H1479BrO [MꢁOEt]þ: 253.0228, found: 253.0225. E/Z
configuration was determined by NOESY analysis.
4.5.1. Ethyl 2-(2,2,6,6-tetramethyl-1-piperidinyloxymethyl)acrylate
(7). Colorless oil; Rf¼0.50 (Hexane:EtOAc¼10:1); 1H NMR
(400 MHz, CDCl3)
d
1.12 (s, 6H), 1.17 (s, 6H), 1.30 (t, J¼7.2 Hz, 3H),
1.30e1.35 (m, 1H), 1.43e1.66 (m, 5H), 4.21 (q, J¼7.2 Hz, 2H), 4.49 (s,
2H), 5.88e5.90 (m, 1H), 6.26e6.29 (m, 1H); 13C NMR (100 MHz,
4.3.29. Ethyl 5-bromo-4-cyclopropyl-2-methylene-4-pentenoate
(3tb). Obtained as an E/Z isomeric mixture in a 12/88 ratio
(220 mg, 85%), as determined by 1H NMR analysis of the crude
reaction mixture. Colorless oil; Rf¼0.50 (Hexane:EtOAc¼10:1); Z
CDCl3) d 14.18, 17.06, 20.22, 32.74, 39.62, 59.91, 60.60, 74.58, 125.06,
137.15, 165.95; IR (neat): 2977, 2932, 1727, 1472, 1060 cmꢁ1; EIMS
m/z (relative intensity) 269 ([M]þ, 3), 156 (100), 123 (14), 114 (4), 83
(6), 69 (9); HRMS (EI) m/z calcd for C14H24NO3 [MꢁMe]þ: 254.1756,
found: 254.1765.
isomer; 1H NMR (400 MHz, CDCl3)
d 0.56e0.60 (m, 2H), 0.74e0.79
(m, 2H), 1.30 (t, J¼6.8 Hz, 3H), 1.93e1.99 (m, 1H), 2.72e2.74 (m, 2H),
4.20 (q, J¼6.8 Hz, 2H), 5.57e5.58 (m, 1H), 5.94e5.95 (m, 1H),
6.25e6.26 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
5.20, 14.07, 14.31,
4.6. Experimental procedure for Pd-catalyzed carbonylation
33.23, 60.79, 104.23, 126.57, 137.64, 141.74, 166.41. E isomer; 1H
NMR (400 MHz, CDCl3) 0.43e0.47 (m, 2H), 0.62e0.67 (m, 2H),1.32
reaction leading to
a,b
-unsaturated ester 819
d
(t, J¼6.8 Hz, 3H), 1.36e1.48 (m, 1H), 3.18e3.20 (m, 2H), 4.23 (q,
Ethyl 5-bromo-2-methylene-4-phenyl-4-pentenoate
3ab
J¼6.8 Hz, 2H), 5.57e5.58 (m, 1H), 6.09 (s, 1H), 6.25e6.26 (m, 1H);
(87 mg, E/Z¼2/98, 0.30 mmol), PdCl2(PPh3)2 (6.3 mg, 0.009 mmol,
3.0 mol %), PPh3 (4.7 mg, 0.018 mmol, 6.0 mol %), diisopropyle-
thylamine (49 mg, 0.36 mmol, 1.2 equiv), dry THF (0.6 mL) and dry
MeOH (0.6 mL) were placed in a 30 mL stainless steel autoclave.
The autoclave was closed, purged three times with 10 atm of
carbon monoxide, pressured with 10 atm of carbon monoxide, and
then heated at 100 ꢀC for 3.5 h. After the reaction excess carbon
monoxide was discharged at room temperature. The reaction
mixture poured into NH4Cl aq solution. The aqueous phase was
extracted with Et2O, and the combined organic layers were
washed with brine, dried over anhydrous magnesium sulfate, and
filtered. The filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography on SiO2
13C NMR (100 MHz, CDCl3)
d 5.30, 14.10, 16.45, 34.13, 60.76, 103.19,
125.29, 136.18, 143.28, 166.81; IR (neat): 3086, 2982, 1715,
1145 cmꢁ1; EIMS m/z (relative intensity) 213 ([MꢁOEt]þ, 1), 179
(100),151 (31),105 (52), 79 (19), 77 (14), 63 (2); HRMS (EI) m/z calcd
for C9H1079BrO [MꢁOEt]þ: 212.9915, found: 212.9916. E/Z configu-
ration was determined by NOESY analysis.
4.4. Experimental procedure for radical cascade reaction of
enyne malonate (4) with 2b
To a 4 mL screw capped test tube made by Pyrex glass, enyne
malonate 4 (126 mg, 0.5 mmol), ethyl 2-(bromomethyl)acrylate 2b
Please cite this article in press as: Kippo, T.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.084

T. Kippo et al. / Tetrahedron xxx (2016) 1e9
9
L.; Quiclet-Sire, B.; Zard, S. Z. Acc. Chem. Res. 2015, 48, 1237e1253 For selected
examples, see: (d) Saito, I.; Ikehira, H.; Matsuura, H. T. Tetrahedron Lett. 1985, 26,
1993e1994; (e) Chatgilialoglu, C.; Ballestri, M.; Vecchi, D.; Curran, D. P. Tetra-
hedron Lett. 1996, 37, 6383e6386; (f) Chatgilialoglu, C.; Ferreri, C.; Ballestri, M.;
Curran, D. P. Tetrahedron Lett. 1996, 37, 6387e6390; (g) Rouquet, G.; Robert, F.;
(Hexane:EtOAc¼25:1) to give 6-ethyl 1-methyl-5-methylene-3-
phenyl-2-hexenedioate 8 (77 mg, 93%, E/Z¼1/99).
4.6.1. (Z)-6-Ethyl 1-methyl-5-methylene-3-phenyl-2-hexenedioate
ꢀ
(8). Light yellow oil; Rf¼0.19 (Hexane:EtOAc¼10:1); 1H NMR
Mereau, R.; Castet, F.; Landais, Y. Chem.dEur. J. 2011, 17, 13904e13911.
2. (a) Kosugi, M.; Kurino, K.; Takayama, K.; Migita, T. J. Organomet. Chem. 1973, 56,
C11eC13; (b) Grignon, J.; Pereyre, M. J. Organomet. Chem. 1973, 61, C33eC35; (c)
Grignon, J.; Servens, C.; Pereyre, M. J. Organomet. Chem. 1975, 96, 225e235; (d)
Migita, T.; Nagai, K.; Kosugi, M. Bull. Chem. Soc. Jpn. 1983, 56, 2480e2484; (e) Keck,
G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829e5831; (f) Keck, G. E.; Enholm, E.
J.; Kachensky, D. F. Tetrahedron Lett. 1984, 25, 1867e1870; (g) Keck, G. E.; Ka-
chensky, D. F.; Enholm, E. J. J. Org. Chem. 1985, 50, 4317e4325; (h) Mizuno, K.;
Ikeda, S.; Toda, S.; Otsuji, Y. J. Am. Chem. Soc. 1988, 110, 1288e1290; (i) Ryu, I.;
Yamazaki, H.; Kusano, K.; Ogawa, A.; Sonoda, N. J. Am. Chem. Soc. 1991, 113,
8558e8560; (j) Ryu, I.; Yamazaki, H.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am.
Chem. Soc. 1993, 115, 1187e1189; (k) Sibi, M. P.; Chandramouli, S. V. Tetrahedron
Lett. 1997, 38, 8929e8932; (l) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32,
163e171; (m) Uenoyama, Y.; Fukuyama, T.; Ryu, I. Synlett 2006, 2342e2344.
3. (a) Keck, G. E.; Byers, H. J. J. Org. Chem. 1985, 50, 5442e5444; (b) Yanagisawa, A.;
Noritake, Y.; Yamamoto, H. Chem. Lett. 1988, 1899e1902 For a review on thiyl
(400 MHz, CDCl3)
d
1.29 (t, J¼6.8 Hz, 3H), 3.44 (t, J¼0.8 Hz, 2H), 3.54
(s, 3H), 4.20 (q, J¼6.8 Hz, 2H), 5.55 (q, J¼1.6 Hz, 1H), 5.88 (t,
J¼1.2 Hz, 1H), 6.28 (d, J¼0.8 Hz, 1H), 7.16e7.22 (m, 2H), 7.27e7.38
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 14.06, 42.07, 50.98, 60.87,
118.01, 127.16, 127.78, 128.20, 136.56, 139.45, 156.59, 166.06, 166.18;
IR (neat): 2984, 2950, 1716, 1633, 1223, 1166 cmꢁ1; EIMS m/z (rel-
ative intensity); 274 ([M]þ, 8), 242 (22), 228 (58), 201 (22), 185 (25),
170 (18), 169 (72), 168 (19), 142 (28), 141 (100), 115 (27); HRMS (EI)
m/z calcd for C16H18O4 [M]þ: 274.1205, found: 274.1206. Z config-
uration was determined by NOESY analysis.
ꢀ
ꢁ
radical in organic synthesis, see: (c) Denes, F.; Pichowicz, M.; Povie, G.; Renaud,
4.7. Experimental procedure for Pd-catalyzed carbonylation
P. Chem. Rev. 2014, 114, 2587e2693.
reaction leading to a,b
-unsaturated ketone 920
4. (a) Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem., Int. Ed. 1998, 37,
2864e2866; (b) Blakskjaer, P.; Pedersen, L.; Skrydstrup, T. J. Chem. Soc., Perkin
Trans. 1 2001, 910e916.
To a 20 mL test tube, ethyl 5-bromo-2-methylene-4-phenyl-4-
pentenoate 3ab (59 mg, 0.2 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol,
5 mol %), NaBPh4 (69 mg, 0.2 mmol), dry toluene (2 mL) were added.
The test tube was purged three times with 1 atm of carbon mon-
oxide then heated at 90 ꢀC for 24 h. The reaction mixture poured into
NH4Cl aq solution. The aqueous phase was extracted with EtOAc, and
the combined organic layers were washed with brine, dried over
anhydrous MgSO4, and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by flash column chro-
matography on silica gel (Hexane:EtOAc¼25:1) to give ethyl 2-
methylene-6-oxo-4,6-diphenyl-4-hexenoate 9 (53 mg, 83%).
5. (a) Kharasch, M. S.; Sage, M. J. Org. Chem. 1949, 14, 79e83; (b) Kharasch, M. S.;
Buchi, G. J. Org. Chem. 1949, 14, 84e90; (c) Breuilles, P.; Uguen, D. Tetrahedron
Lett. 1990, 31, 357e360.
€
6. (a) Huval, C. C.; Singleton, D. A. Tetrahedron Lett.1993, 34, 3041e3042; (b) Heinrich,
M. R.; Blank, O.; Ullrich, D.; Kirschstein, M. J. Org. Chem. 2007, 72, 9609e9616; (c)
Jasch, H.; Landais, Y.; Heinrich, M. R. Chem.dEur. J. 2013, 19, 8411e8416.
7. (a) Tanko, J. M.; Sadeghipour, M. Angew. Chem., Int. Ed. 1999, 38, 159e161; (b)
Struss, J. A.; Sadeghipour, M.; Tanko, J. M. Tetrahedron Lett. 2009, 50, 2119e2120.
8. For our preliminary report, see: Kippo, T.; Fukuyama, T.; Ryu, I. Org. Lett. 2010,
12, 4006e4009.
9. (a) Kippo, T.; Fukuyama, T.; Ryu, I. Org. Lett. 2011, 13, 3864e3867; (b) Kippo, T.;
Hamaoka, K.; Ryu, I. J. Am. Chem. Soc. 2013, 135, 632e635; (c) Kippo, T.; Ryu, I.
Chem. Commun. 2014, 5993e5996.
10. For a radical vinylation, see: Kippo, T.; Kimura, Y.; Maeda, A.; Matsubara, H.;
Fukuyama, T.; Ryu, I. Org. Chem. Front. 2014, 1, 755e758.
11. (a) Curran, D. P.; Xu, J.; Lazzarini, E. J. Am. Chem. Soc. 1995, 117, 6603e6604; (b)
Curran, D. P.; Xu, J.; Lazzarini, E. J. Chem. Soc., Perkin Trans. 1 1995, 3049e3059.
12. For free radical-mediated addition of perfuluoroallyl iodide to alkynes to give iodo-
1,4-dienes, see:Liu, S.Q.;Wang, S.W.;Qing, F. L.J. Fluorine Chem. 2005,126, 771e778.
13. Jie, M. S. F. L. K.; Pasha, M. K.; Syed-Rahmatullah, M. S. K. Nat. Prod. Rep. 1997, 14,
163e189.
14. (a) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T. J. Am. Chem. Soc. 1991, 113,
3173e3174; (b) Wilson, M. C.; Nam, S.-J.; Gulder, T. A. M.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W.; Moore, B. S. J. Am. Chem. Soc. 2011, 133, 1971e1977; (c)
Connor, D. T.; Greenough, R. C.; Strandtmann, M. J. Org. Chem. 1977, 42,
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4.7.1. Ethyl 2-methylene-6-oxo-4,6-diphenyl-4-hexenoate
(9). Obtained as an E/Z isomeric mixture in a 17/83 ratio, as de-
termined by 1H NMR analysis of the crude reaction mixture. Col-
orless oil; Rf¼0.40 (Hexane:EtOAc¼10:1); Z isomer; 1H NMR
(400 MHz, CDCl3)
d
1.32 (t, J¼7.2 Hz, 3H), 3.58 (s, 2H), 4.25 (q,
J¼7.2 Hz, 2H), 5.65 (q, J¼1.2 Hz, 1H), 6.33 (d, J¼0.8 Hz, 1H), 6.60 (t,
J¼1.6 Hz, 1H), 7.15e7.25 (m, 4H), 7.29e7.60 (m, 4H), 7.75e7.82 (m,
2H); 13C NMR (100 MHz, CDCl3)
d 14.14, 41.44, 61.02, 125.31, 127.89,
128.03, 128.20, 128.78, 132.58, 137.17, 137.56, 137.76, 139.48, 152.52,
166.53, 193.71. E isomer; 1H NMR (400 MHz, CDCl3)
d
1.27 (t,
15. (a) Miller, A.; Moore, M. Tetrahedron Lett. 1980, 577e580; (b) Camps, F.; Coll, J.;
J¼7.2 Hz, 3H), 4.12 (m, 2H), 4.19 (q, J¼7.2 Hz, 2H), 5.50 (q, J¼1.2 Hz,
1H), 6.19 (q, J¼1.6 Hz, 1H), 7.15e7.25 (m, 4H), 7.29e7.60 (m, 5H),
ꢀ
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ꢀ
Camps, F.; Moreto, J. M. Tetrahedron 1993, 49, 1283e1296; (d) Kosugi, M.; Sa-
7.98e8.02 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 14.21, 33.02, 60.86,
kaya, T.; Ogawa, S.; Migita, T. Bull. Chem. Soc. Jpn. 1993, 66, 3058e3061; (e)
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Macromol. Symp. 2002, 182, 1e14.
124.10, 126.84, 154.74, 166.81, 190.88 (Some carbon signals super-
posed that of Z isomer); IR (neat): 3060, 2980, 1715, 1666,
1237 cmꢁ1; EIMS m/z (relative intensity); 320 ([M]þ, 7), 319 (7), 274
(93), 247 (25), 215 (38), 169 (100), 141 (38), 105 (89), 77 (37); HRMS
(EI) m/z calcd for C21H20O3 [M]þ: 320.1412 found: 320.1418.
Acknowledgements
This work is financially supported by a Grant-in-Aid for Scien-
tific Research (A) from Japan Society for the Promotion of Science
(JP26248031)
17. Alternatively, 1,5-hexadiene 6 can be formed by the reaction of the allyl radical
with 2b.
18. A similar mechanism was proposed in radical addition of allyl compounds to
phenyl-acetylene; see: (a) Harvey, I. W.; Phillips, E. D.; Whitham, G. H. Tetra-
hedron 1997, 53, 6493e6508; (b) Miura, K.; Saito, H.; Nakagawa, T.; Hondo, T.;
Tateiwa, J.; Sonoda, M.; Hosomi, A. J. Org. Chem. 1998, 63, 5740e5741.
19. Silveira, P. B.; Monteiro, A. L. J. Mol. Catal. A: Chem. 2006, 247, 1e6.
Supplementary data
€
ꢀ
€
ꢀ
ꢀ
20. Skoda-Foldes, R.; Szekvolgyi, Z.; Kollar, L.; Berente, Z.; Horvath, J.; Tuba, Z.
Tetrahedron 2000, 56, 3415e3418.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.05.084.
21. (a) Kaneda, K.; Kawamoto, F.; Fujiwara, Y.; Imanaka, T.; Teranishi, S. Tetrahedron
Lett. 1974, 1067e1070; (b) Kaneda, K.; Kobayashi, H.; Fujiwara, Y.; Imanaka, T.;
Teranishi, S. Tetrahedron Lett. 1975, 2833e2836; (c) Kaneda, K.; Uchiyama, T.;
Fujiwara, Y.; Imanaka, T.; Teranishi, S. J. Org. Chem. 1979, 44, 55e63; (d) Im-
anaka, T.; Kimura, T.; Kaneda, K.; Teranishi, S. J. Mol. Catal. 1980, 9, 103e113.
References and notes
~
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Please cite this article in press as: Kippo, T.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.084