Zinc-mediated regiodiverse synthesis of vinyl bromide derivatives and their in situ palladium-catalysed cross-coupling reactions

Article abstract of DOI:10.1055/s-0033-1339616

The synthesis of vinyl bromide derivatives was realised by a zinc-mediated addition of a benzylic bromide to a terminal alkyne. The geometry of the C=C bond is dependent on the amount of zinc powder applied. When 5 mol% of Zn is used, the Z-configured vinyl bromide is generated while with 150 mol% the E-geometry is obtained predominantly. In a three-component one-pot reaction, the in situ generated vinyl bromides were reacted further in a palladium-catalysed Suzuki cross-coupling reaction utilizing aromatic boronic acids to obtain trisubstituted double bonds in good overall yields. The reactions were conducted on a 5-20 mmol scale to visualise that the reactions are also capable of generating larger amounts of products. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339616

3228▌
PRACTICAL SYNTHETIC PROCEDURES
pZraicnticcal-sMyntheetdiciparotceeddureRs egiodiverse Synthesis of Vinyl Bromide Derivatives and Their
in situ Palladium-Catalysed Cross-Coupling Reactions
Zinc-Mediated Regiodiverse Synthesis of Vinyl Bromides
Anne Miersch, Corinna Kohlmeyer, Gerhard Hilt*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: Hilt@chemie.uni-marburg.de
PSP
Received: 02.07.2013; Accepted after revision: 11.07.2013
Dedicated to Prof. Dr. Reinhard W. Hoffmann on the occasion of his 80th birthday.
Many thanks for the fruitful and entertaining discussions.
No260
Abstract: The synthesis of vinyl bromide derivatives was realised by a zinc-mediated addition of a benzylic bromide to a terminal alkyne.
The geometry of the C=C bond is dependent on the amount of zinc powder applied. When 5 mol% of Zn is used, the Z-configured vinyl
bromide is generated while with 150 mol% the E-geometry is obtained predominantly. In a three-component one-pot reaction, the in situ
generated vinyl bromides were reacted further in a palladium-catalysed Suzuki cross-coupling reaction utilizing aromatic boronic acids to
obtain trisubstituted double bonds in good overall yields. The reactions were conducted on a 5–20 mmol scale to visualise that the reactions
are also capable of generating larger amounts of products.
Key words: alkynes, cross coupling, palladium, vinyl bromides, zinc
S
Br
procedure 1
Zn powder
(150 mol%)
B(OH)2
Me
Me
CH2Cl2, r.t., 2 h
procedure 2
S
69%
(E/Z = 90:10)
Br
Pd(OAc)2
+
Ph3P, KOH
Me
THF, MeOH
40 °C, 16 h to 4 d
Zn powder
(5 mol%)
Br
S
CH2Cl2, r.t., 3 d
Me
Me
45%
(E/Z = 9:91)
Scheme 1 Zinc-mediated regiodiverse synthesis of vinyl bromide derivatives followed by a Suzuki cross-coupling reaction
The synthesis of double bonds has been a key issue in or- greatly on the amount of zinc powder added acting as ini-
ganic synthesis for a long time and many excellent exam- tiator for the transformation. The initial reaction condi-
ples are known to generate double bonds regio- and tions for the formation of the E-isomer 3 on a 1.0 mmol
stereoselectively.1 One general example for such a trans- scale were: alkyne 1 1.0 mmol, benzyl bromide 2
formation is the regioselective addition of organometallic 1.5 mmol, Zn powder 150 mol% in dichloromethane at
species to triple bonds to generate vinylic organometallic ambient temperature (Scheme 2). Utilizing this protocol,
intermediates, which can be utilised for a number of product 3 could be isolated in 95% yield and the ratio of
follow-up transformations.2 For the synthesis of vinyl bro- the stereoisomer 3 and 4 were in the range of E/Z = 87:13
mides such vinylic organometallic intermediates are gen- (Scheme 2). On the other hand, the Z-isomer 4 was gener-
erated in stoichiometric amounts and mostly have to be ated as the major stereoisomer (70%, E/Z = 7:93) when
quenched with bromine or other sources of the halide at- the reaction conditions were altered in the way that zinc
om.3
powder was applied in 5 mol% keeping the other reaction
conditions unchanged.
Recently, we reported a stereodiverse method for the syn-
thesis of vinyl bromide derivatives from an alkyne and a The rational for the change of stereoselectivity is believed
benzyl bromide addressing both double bond geometries to be HBr as the accompanying side-product formed from
(Scheme 1).4 The selectivity of the reactions depended 2 and zinc powder leading to the isomerisation of the in-
termediate. When an excess of 150 mmol% of zinc pow-
der is applied, the HBr is quenched and no isomerisation
can take place.
SYNTHESIS 2013, 45, 3228–3232
Advanced online publication: 15.08.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339616; Art ID: SS-2013-Z0450-PSP
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Zinc-Mediated Regiodiverse Synthesis of Vinyl Bromides
3229
For the synthesis of 4, 5 mol% of zinc powder were ap-
plied (Scheme 2). On a 10 mmol scale 4 could be generat-
ed in 69% yield (E/Z = 12:88). The yield only dropped
slightly to 62%, with remaining good E/Z selectivity of
11:89, when the reaction was performed on a 20 mmol
scale but the result is still acceptable yielding as much as
3.6 g of 4. The reduction of the excess of 2 from 1.5 to 1.2
equivalents led to a 56:44 mixture of 3 and 4 on a 10 mmol
scale, indicating that this process is only applicable for the
E-isomer. For other substrates the maximum scale of the
conversions were reduced to 10 mmol mostly for econom-
ic reasons. Nevertheless, three parameters were altered in
Br
procedure 1
Zn powder
(150 mol%)
Me
3
1
+
procedure 2
Br
Zn powder
(5 mol%)
Me
2
Br
Me
4
Scheme 2 Stereodiverse synthesis of the E-vinyl bromide 3 and the the substrate to evaluate the feasibility of the reaction
corresponding Z-isomer 4 by altering the amount of Zn powder
when modifications of 2 and 3 were applied (Scheme 3).
The use of 1-chloro-4-ethynylbenzene (5) under the reac-
tion conditions led to 6 in acceptable yield of 69% and a
good E/Z ratio of 89:11. More complex benzylic halides,
such as 7 could also be applied. For this dibromo deriva-
Starting from the initial reaction conditions and having
achieved good yields and selectivities, the scale for the
formation of 3 was increased successively (see Table 1).
tive only the benzylic halide reacts leaving the alkyl
At the beginning, we were expecting an exothermic reac-
bromide untouched. The application of (1,2-dibromoeth-
tion when applying 150 mol% zinc powder on a larger
scale, but until the end of this series of experiments, even-
tually ending with a 20 mmol scale reaction, the conver-
yl)benzene (7) generated 8 in 52% yield in a good E/Z ra-
tio of 87:13, but required a longer reaction time of
48 hours and warming to 40 °C. The reduced yield can be
sions led only to a moderate evolution of heat, which
attributed to an E1cB-type elimination of the in situ gen-
could be easily controlled with an ice bath, if necessary.
erated benzylic zinc organic species. Accordingly, the
The reduction of the excess zinc powder was not advis-
able. The in situ generated HBr, responsible for the isom-
erisation of the double bond geometry for the synthesis of
yield of 52% for the synthesis of 8 is quite remarkable. In
addition internal alkyne 9 could be used with more suc-
4, can only be efficiently quenched with the excess of zinc
powder applied. Also, the upscaling of the reaction for the
Br
Br
Br
Cl
synthesis of 3 utilizing 1.5 equivalents of 2 on a 10 mmol
scale led to an increasing amount of the Wurtz coupling
product from 2 resulting in an increasingly tedious work-
up. However, when the excess of 2 was reduced to 1.2
equivalents, the amount of accompanying Wurtz coupling
product was largely reduced. On a 10 mmol scale the de-
sired product 3 could be isolated in 81% yield and the E/Z
ratio was still in an acceptable range of 88:12. When the
scale was doubled to 20 mmol 3 was still obtained in 79%
with an E/Z ratio of 88:12. At this scope it was also possi-
ble to obtain 3 after distillative purification from the crude
product in 78% yield with E/Z = 86:14.
Zn powder
(150 mol%)
5
+
Br
69% (89:11)
Me
6
Me
2
Cl
Zn powder
(150 mol%)
1
+
Br
52% (87:13)
8
Br
Br
7
Table 1 Upscaling of the Synthesis of 3 and 4 According to Scheme 2
Me
Bu
Scale
Yield (%) 3 (E/Z)
Yield (%) 4 (E/Z)
Zn powder
(150 mol%)
9
+
Br
1 mmol
2 mmol
95 (87:13)
90 (86:14)
96 (88:12)
87 (86:14)
81 (88:12)a
79 (88:12)a
70 (7:93)
65 (9:91)
58 (9:91)
69 (12:88)
76 (56:44)a
62 (11:89)
75% (85:15)
Me
10
Me
2
Cl
5 mmol
Cl
10 mmol
10 mmola
20 mmol
Zn powder
(5 mol%)
5
+
Br
51% (5:95)
Br
Me
Me
11
2
a Reduced excess of 2 (1.2 equiv).
Scheme 3 Synthesis of E-configured vinyl bromides 6, 8, and 10 and
the Z-configured vinyl bromide 11
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3228–3232

3230
A. Miersch et al.
PRACTICAL SYNTHETIC PROCEDURES
cess yielding product 10 in 75% (E/Z = 85:15) with no
changes in the reaction conditions. The synthesis of the Z-
configured vinyl bromide 11 was realised utilizing the re-
action conditions applying only 5 mol% of zinc powder in
acceptable yield and with a good E/Z ratio of 5:95.
1
Zn powder
(5 mol%)
+
Br
Me
Br
Me
2
4
The vinyl bromides generated by the herein discussed pro-
tocol can be modified directly applying palladium-based
Suzuki cross-coupling conditions.5 Therefore, the forma-
tion of the intermediates was monitored by TLC and
GCMS analysis and after completion of the reaction, the
intermediates of type 3 were directly converted with bo-
ronic acids such as 12 and 13 to the corresponding trisub-
stituted alkene derivatives 14 and 15 (Scheme 4).
Pd(OAc)2
(HO)2B
S
12
45% (9:91)
S
Me
16
Br
Scheme 5 Zinc-mediated synthesis of Z-configured vinyl bromide 4
and its Suzuki cross-coupling with boronic acid 12
procedure 3
Zn powder
(150 mol%)
1
+
Me
Br
3
Nevertheless, only slight adaptions in the reaction proce-
dure are necessary during the scaling-up and it seems to be
possible to further enlarge the reaction scope due to its
mild and easy to handle reaction conditions.
Me
2
Pd(OAc)2
B(OH)2
Pd(OAc)2
(HO)2B
S
N
In summary, we have presented the multigram scale-up
for the zinc-mediated synthesis of vinyl bromides whereas
the stereoselectivity of the obtained double bond can be
directed with the amount of zinc applied. The presented
three-component sequence implying a Suzuki cross-
coupling with boronic acids enable the synthesis of high
functionalised alkenes in good yields and E/Z ratios.
12
13
OMe
OMe
N
69% (90:10)
S
74% (93:7)
Me
14
Me
15
All reactions were carried out under an argon atmosphere in heat-
gun-dried glassware. CH2Cl2 was distilled under N2 from P4O10 and
THF from Na. MeOH was distilled and dried over molecular sieves.
All solvents for chromatography were distilled. Commercially
available materials were used without further purification. Column
chromatography was performed on silica gel 60 (Merck 230–400
Scheme 4 Zinc-mediated synthesis of E-configured vinyl bromides
and their Suzuki cross-coupling with boronic acids
These three-component one-pot reactions were performed
on a 5 mmol scale and product 14 was obtained in 69%
yield as a mixture (E/Z = 90:10). The increased E/Z selec-
tivity can be rationalised by a slower rate of the Z-config-
ured intermediate in the Suzuki cross-coupling step based
on steric hindrance. A similar effect was observed for the
formation of 15, which was obtained in 74% yield as a
mixture (E/Z = 93:7).
1
mesh). H and 13C NMR: Bruker Avance-300. MS-EI: Hewlett
Packard 5973 Mass Selective Detector. HRMS-EI: Finnigan MAT
95. IR: Bruker Alpha P.
Procedure 1; E-Vinyl Bromides
In a Schlenk flask, the corresponding alkyne (1–20 mmol, 1.0
equiv) and bromoethylbenzene (1.2–1.5 equiv) were added via sy-
ringe and dissolved under an argon atmosphere in CH2Cl2 (1–
20 mL). Zn powder (150 mol%) was added and if necessary the re-
action temperature was controlled using an ice bath. The mixture
was stirred for 2 h at r.t. and filtered over silica gel (pentane–Et2O,
20:1). The solvent was removed and the residue was purified by col-
umn chromatography on silica gel (eluent as indicated) yielding the
E-vinyl bromides 3, 6, 8, and 10.
Similarly, the conversion of intermediate 4 in such a
three-component one-pot reaction utilizing the same bo-
ronic acid 12 as coupling partner led to the corresponding
product 16 (Scheme 5). On a 5 mmol scale the product
was obtained in an acceptable yield of 45%, with similar
E/Z ratio of 9:91 in favour of the desired Z-product. To
achieve this result, the reaction protocol had to be adjusted
to a longer reaction time of four days. The Suzuki cross-
coupling gave low yields, which was ascribed to the sig-
nificant amounts of accruing HBr generated in the first re-
action step eventually leading to proto-deboration of the
boronic acid. Unfortunately, the HBr could not be re-
moved efficiently by bubbling nitrogen through the solu-
tion to increase the yield of 16.
(E)-(1-Bromobut-1-ene-1,3-diyl)dibenzene (3)
Reaction scale, 5 mmol: The product was prepared using phenyl-
acetylene (1; 511 mg, 5.0 mmol, 1.0 equiv), 1-bromoethylbenzene
(2; 1.39 g, 7.5 mmol, 1.5 equiv), and Zn powder (490 mg, 7.5 mmol,
150 mol%) in CH2Cl2 (5.0 mL). After column chromatography
(pentane–CH2Cl2, 200:1), product 3 was obtained as a colourless oil
(1.38 g, 4.79 mmol, 96%, E/Z = 88:12).
IR (film): 3059, 3027, 2966, 2926, 2869, 1601, 1491, 1444, 1373,
1015, 872, 764, 699, 543 cm–1.
Synthesis 2013, 45, 3228–3232
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Zinc-Mediated Regiodiverse Synthesis of Vinyl Bromides
3231
1H NMR (300 MHz, CDCl3): δ = 7.28–7.18 (m, 7 H), 7.16–7.12 (m,
1 H), 7.11–7.04 (m, 2 H), 6.27 (d, J = 10.7 Hz, 1 H), 3.43 (dq,
J = 10.7, 6.9 Hz, 1 H), 1.26 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 144.6, 138.5, 128.8, 128.7, 128.6,
128.3, 127.7, 126.8, 126.4, 119.8, 40.7, 22.0.
MS (EI): m/z (%) = 286 ([M+], 5), 207 (83), 191 (54), 129 (100),
105 (31), 77 (27).
HRMS (EI): m/z calcd for C20H23Br: 342.0983; found: 342.0977.
Procedure 2; Z-Vinyl Bromides
In a Schlenk flask, the corresponding alkyne (1–20 mmol,
1.0 equiv) and bromoethylbenzene 2 (1.5 equiv) were added via sy-
ringe and dissolved in CH2Cl2 (1–20 mL) under an argon atmo-
sphere. Zn powder (5 mol%) was added and if necessary the
reaction temperature was controlled using an ice bath. The mixture
was stirred for 48 h to 4 d at r.t. and filtered over silica gel (pen-
tane–Et2O, 20:1). The solvent was removed and the residue was pu-
rified by column chromatography on silica gel (eluent as indicated)
yielding the Z-vinyl bromides 4 and 11.
HRMS (EI): m/z calcd for C16H15Br: 286.0357; found: 286.0348.
(E)-1-(1-Bromo-3-phenylbut-1-enyl)-4-chlorobenzene (6)
Reaction scale, 10 mmol: The product was prepared using 1-chloro-
4-ethynylbenzene (5; 1.36 g, 10.0 mmol, 1.0 equiv), 1-bromoethyl-
benzene (2; 2.22 g, 12.0 mmol, 1.2 equiv), and Zn powder (981 mg,
15.0 mmol, 150 mol%) in CH2Cl2 (10.0 mL). After column chroma-
tography (pentane–CH2Cl2, 100:1), product 6 was obtained as a co-
lourless oil (2.22 g, 6.94 mmol, 69%, E/Z = 89:11).
(Z)-(1-Bromobut-1-ene-1,3-diyl)dibenzene (4)
Reaction scale, 10 mmol: The product was prepared using phenyl-
acetylene (1; 1.02 g, 10.0 mmol, 1.0 equiv), 1-bromoethylbenzene
(2; 2.78 g, 15.0 mmol, 1.5 equiv), and Zn powder (33 mg, 0.5 mmol,
5 mol%) in CH2Cl2 (10.0 mL) at r.t. and stirring for 3 d. After col-
umn chromatography (pentane–CH2Cl2, 100:1), product 4 was ob-
tained as a colourless oil (1.97 g, 6.87 mmol, 69%, E/Z = 12:88).
IR (film): 3028, 2968, 2927, 1596, 1487, 1450, 1257, 1090, 1012,
873, 823, 738, 697, 554 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.31–7.21 (m, 5 H), 7.20–7.14 (m,
2 H), 7.08 (d, J = 8.2 Hz, 2 H), 6.31 (d, J = 10.7 Hz, 1 H), 3.50–3.32
(m, 1 H), 1.28 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 144.5, 139.3, 137.3, 134.7, 130.3,
128.9, 128.7, 126.8, 126.7, 118.5, 41.0, 22.3.
IR (film): 3058, 3027, 2966, 2926, 2869, 1601, 1493, 1444, 1372,
1014, 870, 760, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.58 (d, J = 7.3 Hz, 2 H), 7.40–
7.27 (m, 8 H), 6.36 (d, J = 9.1 Hz, 1 H), 4.22–4.13 (m, 1 H), 1.53
(d, J = 7.0 Hz, 3 H).
MS (EI): m/z (%) = 322 ([M+], 9), 241 (100), 225 (36), 206 (27),
191 (31), 163 (28), 129 (42), 105 (27).
13C NMR (75 MHz, CDCl3): δ = 144.8, 138.7, 136.3, 128.7, 128.8,
128.4, 127.8, 127.2, 126.6, 124.4, 42.7, 20.8.
MS (EI): m/z (%) = 286 ([M+], 10), 207 (95), 191 (65), 129 (100),
HRMS (EI): m/z calcd for C16H14BrCl: 321.9947; found: 321.9959.
105 (22), 77 (22).
(E)-(1,4-Dibromobut-1-ene-1,3-diyl)dibenzene (8)
HRMS (EI): m/z calcd for C16H15Br: 286.0357; found: 286.0348.
Reaction scale, 10 mmol: The product was prepared using phenyl-
acetylene (1; 1.02 g, 10.0 mmol, 1.0 equiv), 1,2-dibromoethylben-
zene (7; 3.96 g, 15.0 mmol, 1.5 equiv), and Zn powder (981 mg,
15.0 mmol, 150 mol%) in CH2Cl2 (10.0 mL). The reaction mixture
was stirred at 40 °C for 48 h. After column chromatography (pen-
tane–CH2Cl2, 100:1), product 8 was obtained as a colourless oil
(1.90 g, 5.19 mmol, 52%, E/Z = 87:13).
(Z)-1-(1-Bromo-3-phenylbut-1-enyl)-4-chlorobenzene (11)
Reaction scale, 7.4 mmol: The product was prepared using 1-chlo-
ro-4-ethynylbenzene (5; 1.01 g, 7.4 mmol, 1.0 equiv), 1-bromoeth-
ylbenzene (2; 2.06 g, 11.0 mmol, 1.5 equiv), and Zn powder (24 mg,
0.37 mmol, 5 mol%) in CH2Cl2 (8.0 mL) at r.t. and stirring for 3 d.
After column chromatography (pentane–CH2Cl2, 200:1), product
11 was obtained as a colourless oil (1.20 g, 3.74 mmol, 51%,
E/Z = 5:95).
IR (film): 3058, 3026, 2957, 1597, 1489, 1446, 1258, 842, 761, 697,
544, 514 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.28 (m, 8 H), 7.15 (d,
J = 7.1 Hz, 2 H), 6.46 (d, J = 8.6 Hz, 1 H), 3.78–3.73 (m, 1 H), 3.56
(d, J = 7.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 140.7, 138.3, 129.0, 128.8, 128.7,
128.4, 128.3, 127.5, 127.2, 123.3, 48.5, 36.3.
IR (film): 3026, 2969, 2922, 1592, 1487, 1453, 1258, 1091, 1014,
873, 825, 738, 697, 553 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.53–7.43 (m, 2 H), 7.39–7.24 (m,
7 H), 6.31 (d, J = 9.1 Hz, 1 H), 4.17–4.06 (m, 1 H), 1.49 (dd, J = 7.0,
4.3 Hz, 3 H).
MS (EI): m/z (%) = 366 ([M+], 4), 271 (60), 205 (43), 191 (100),
128 (27), 103 (31), 77 (26).
13C NMR (75 MHz, CDCl3): δ = 144.2, 138.3, 136.7, 134.3, 128.9,
128.7, 128.3, 127.0, 126.5, 122.9, 42.6, 20.5.
MS (EI): m/z (%) = 322 ([M+], 10), 241 (100), 225 (51), 206 (25),
HRMS (EI): m/z calcd for C16H14Br2: 365.9442; found: 365.9446.
191 (33), 163 (26), 129 (27).
(E)-(1-Bromo-2-butylbut-1-ene-1,3-diyl)dibenzene (10)
Reaction scale, 10 mmol: The product was prepared using hex-1-
ynylbenzene (9; 1.58 g, 10.0 mmol, 1.0 equiv), 1-bromoethylben-
zene (2; 2,75 g, 15.0 mmol, 1.5 equiv), and Zn powder (981 mg,
15.0 mmol, 150 mol%) in CH2Cl2 (10.0 mL). After column chroma-
tography (pentane–CH2Cl2, 200:1), product 10 was obtained as a
colourless oil (2.57 g, 7.51 mmol, 75%, E/Z = 85:15).
HRMS (EI): m/z calcd for C16H14BrCl: 321.9947; found: 321.9959.
Procedure 3; Trisubstituted Alkenes 14–16
For the synthesis of trisubstituted alkenes 14–16, the corresponding
vinyl bromides were prepared in situ as before on a 5 mmol scale
(procedure 1 or 2). After complete conversion of the starting mate-
rial THF (5.0 mL), MeOH (5.0 mL), KOH (561 mg, 10 mmol, 2.0
equiv), Ph3P (52 mg, 0.2 mmol, 4 mol%), Pd(OAc)2 (22 mg, 0.1
mmol, 2 mol%), and the corresponding boronic acid (6.5 mmol, 1.3
equiv) were added. The reaction mixture was stirred at 40 °C until
complete conversion was detected and filtered over silica gel (pen-
tane–Et2O, 1:1). The solvent was removed and the residue was pu-
rified by column chromatography on silica gel (eluent as indicated),
yielding the products 14–16.
IR (film): 3060, 3027, 2958, 2871, 1601, 1494, 1452, 1374, 1101,
1027, 840, 761, 699, 549 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.41–7.39 (m, 4 H), 7.36–7.28 (m,
3 H), 7.24–7.14 (m, 3 H), 3.92 (q, J = 7.2 Hz, 1 H), 2.24–2.01 (m, 2
H), 1.40 (d, J = 7.2 Hz, 3 H), 1.34–1.17 (m, 2 H), 1.16–1.03 (m, 2
H), 0.84 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 145.1, 142.9, 141.5, 129.0, 128.5,
128.1, 127.9, 127.4, 126.3, 119.4, 41.9, 32.5, 30.6, 23.2, 17.5, 13.7.
MS (EI): m/z (%) = 342 ([M+], 10), 263 (100), 219 (16), 205 (68),
143 (24), 115 (33), 105 (70).
(E)-2-(1,3-Diphenylbut-1-enyl)thiophene (14)
The intermediate was prepared in situ using phenylacetylene (1; 510
mg, 5.0 mmol, 1.0 equiv), 1-bromoethylbenzene (2; 1.11 g, 6.0
mmol, 1.2 equiv), and Zn powder (489 mg, 7.5 mmol, 150 mol%)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3228–3232

3232
A. Miersch et al.
PRACTICAL SYNTHETIC PROCEDURES
in CH2Cl2 (5.0 mL) (procedure 1). After complete conversion, pro-
cedure 3 was realised using 2-thiopheneboronic acid (12; 832 mg,
6.5 mmol, 1.3 equiv); reaction time 16 h. After column chromatog-
raphy (pentane–CH2Cl2, 100:1), product 14 was obtained as a co-
lourless oil (1.03 g, 3.55 mmol, 71%, E/Z = 90:10).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
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References
IR (film): 3024, 2963, 1598, 1491, 1491, 1446, 1349, 1230, 1016,
912, 869, 829, 768, 692, 548 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.49–7.36 (m, 3 H), 7.36–7.27 (m,
4 H), 7.24–7.17 (m, 3 H), 7.14 (d, J = 5.1 Hz, 1 H), 6.88 (dd,
J = 5.1, 3.6 Hz, 1 H), 6.58 (d, J = 3.6 Hz, 1 H), 6.27 (d, J = 10.2 Hz,
1 H), 3.50 (dq, J = 10.5, 6.9 Hz, 1 H), 1.38 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 147.0, 145.8, 139.1, 134.5, 132.8,
128.5, 128.3, 127.5, 127.2, 126.9, 126.0, 125.3, 123.9, 39.0, 22.1.
MS (EI): m/z (%) = 290 ([M+], 100), 275 (72), 241 (16), 191 (39),
171 (20), 129 (19), 91 (18), 77 (9).
(1) For key references, see: (a) Negishi, E.-I.; Huang, Z.; Wang,
G. W.; Mohan, S.; Wang, C. Acc. Chem. Res. 2008, 41,
1474. (b) Mori, M. Eur. J. Org. Chem. 2007, 4981.
(2) (a) Nozaki, K.; Yamashita, M.; Okuno, Y. Eur. J. Org.
Chem. 2011, 3951. (b) Negishi, E.-I.; Xu, S.; Lee, C.-T.;
Rao, H. Adv. Synth. Catal. 2011, 353, 2981. (c) Negishi, E.-
I.; Wang, G.; Rao, H.; Xu, Z. J. Org. Chem. 2010, 75, 3151.
(d) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107,
4698. (e) Negishi, E.-I.; Tan, Z. Angew. Chem. Int. Ed. 2006,
45, 762. (f) Zhou, C. X.; Larock, R. C. J. Org. Chem. 2005,
70, 3765. (g) Mori, M.; Sato, Y.; Takimoto, M.; Shimizu, K.
Org. Lett. 2005, 7, 195. (h) Kamei, T.; Itami, K.; Yoshida, Y.
Adv. Synth. Catal. 2004, 346, 1824. (i) Fallis, A. G.;
Forgione, P. Tetrahedron 2001, 57, 5899. (j) Li, M.-M.;
Zhang, Q.; Yue, H.-L.; Ma, L.; Ji, J.-X. Tetrahedron Lett.
2012, 53, 317. (k) Murakami, K.; Yorimitsu, H.; Oshima, K.
Chem. Eur. J. 2010, 16, 7688. (l) Biswas, S.; Maiti, S.; Jana,
U. Eur. J. Org. Chem. 2009, 2354. (m) Li, H.-H.; Jin, Y.-H.;
Wang, J.-Q.; Tian, S.-K. Org. Biomol. Chem. 2009, 16,
3219. (n) Liu, Z.; Wang Zhao, J. Y.; Zhou, B. Adv. Synth.
Catal. 2009, 351, 371.
HRMS (EI): m/z calcd for C20H18S: 220.1129; found: 290.1127.
(E)-5-(1,3-Diphenylbut-1-enyl)-2-methoxypyridine (15)
The intermediate was prepared in situ using phenylacetylene (1; 510
mg, 5.0 mmol, 1.0 equiv), 1-bromoethylbenzene (2; 1.11 g, 6.0
mmol, 1.2 equiv), and Zn powder (489 mg, 7.5 mmol, 150 mol%)
in CH2Cl2 (5.0 mL) (procedure 1). After complete conversion, pro-
cedure 3 was realised using 6-methoxypyridine-3-boronic acid (13;
995 mg, 6.5 mmol, 1.3 equiv); reaction time 16 h. After column
chromatography (pentane–EtOAc, 50:1), product 15 was obtained
as a colourless oil (1.17 g, 3.70 mmol, 74%, E/Z = 93:7).
(3) For the synthesis of alkenyl halides, see: (a) Spaggiari, A.;
Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. J. Org. Chem.
2007, 72, 2216. (b) Barluenga, J.; Palomas, D.; Rubio, E.;
González, J. M. Org. Lett. 2007, 9, 2823. (c) Lee, S. I.;
Hwang, G. S.; Ryu, D. H. Synlett 2007, 59. (d) Yadav, J. S.;
Reddy, B. V. S.; Gupta, M. K.; Pandey, S. K. J. Mol. Catal.
A: Chem. 2007, 264, 309. (e) Durandetti, M.; Périchon, J.
Synthesis 2004, 3079. (f) Pawluć, P.; Hreczycho, G.;
Szudkowska, J.; Kubicki, M.; Marciniec, B. Org. Lett.
2009, 11, 3390. (g) Kamei, K.; Maeda, N.; Tatsuoka, T.
Tetrahedron Lett. 2005, 46, 229. (h) Yadav, J. S.; Reddy, B.
V. S.; Gupta, M. K.; Eeshwaraiah, B. Synthesis 2005, 57.
(i) Blum, J.; Gelman, D.; Baidossi, W.; Shakh, E.;
IR (film): 3023, 2966, 1599, 1491, 1451, 1381, 1348, 1285, 1251,
1127, 1024, 830, 766, 700, 627 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.98 (dd, J = 2.5, 0.6 Hz, 1 H),
7.45 (dd, J = 8.7, 2.5 Hz, 1 H), 7.42–7.35 (m, 2 H), 7.33–7.27 (m, 3
H), 7.25–7.14 (m, 5 H), 6.63 (dd, J = 8.7, 0.7 Hz, 1 H), 6.14 (d,
J = 10.3 Hz, 1 H), 3.91 (s, 3 H), 3.61 (dq, J = 10.4, 6.9 Hz, 1 H),
1.39 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.2, 146.1, 145.5, 139.4, 137.3,
137.0, 133.5, 131.5, 129.6, 128.5, 128.4, 127.3, 126.9, 126.1, 110.1,
53.4, 39.2, 22.4.
MS (EI): m/z (%) = 315 ([M+], 60), 300 (100), 284 (7), 238 (7), 222
(18), 191 (9), 165 (8), 91 (11), 77 (5).
Rosenfeld, A.; Wassermann, B. C.; Frick, M.; Heymer, B.;
Schutte, S.; Wernik, S.; Schumann, H. J. Org. Chem. 1997,
62, 8681. (j) Sun, J. W.; Kozmin, S. A. J. Am. Chem. Soc.
2005, 127, 13512. (k) Gao, F.; Hoveyda, A. H. J. Am. Chem.
Soc. 2010, 132, 10961. (l) Kuang, C.; Yang, Q.; Senboku,
H.; Tokuda, M. Synthesis 2005, 1319. (m) Ye, C.; Shreeve,
J. M. J. Org. Chem. 2004, 69, 8561. (n) Nakajima, R.;
Delas, C.; Takayama, Y.; Sato, F. Angew. Chem. Int. Ed.
2002, 41, 3023. (o) Li, W.; Li, J.; Wan, Z.-K.; Wu, J.;
Massefski, W. Org. Lett. 2007, 9, 4607. (p) Jennings, M. P.;
Cork, E. A.; Ramachandran, P. V. J. Org. Chem. 2000, 65,
8763. (q) Takahashi, T.; Sun, W. H.; Xi, C. J.; Ubayama, H.;
Xi, Z. F. Tetrahedron 1998, 54, 715. (r) Stüdemann, T.;
Ibrahim-Ouali, M.; Knochel, P. Tetrahedron 1998, 54, 1299.
(s) Wang, C.; Tobrman, T.; Xu, Z.; Negishi, E.-i. Org. Lett.
2009, 11, 4092. (t) Takahashi, T.; Kondakov, D. Y.; Xi, Z.
F.; Suzuki, N. J. Am. Chem. Soc. 1995, 117, 5871.
HRMS (EI): m/z calcd for C22H21NO: 315.1623; found: 315.1624.
(Z)-2-(1,3-Diphenylbut-1-enyl)thiophene (16)
The intermediate was prepared in situ using phenylacetylene (1; 510
mg, 5.0 mmol, 1.0 equiv), 1-bromoethylbenzene (2; 1.39 g, 7.5
mmol, 1.5 equiv), and Zn powder (16 mg, 0.25 mmol, 5 mol%) in
CH2Cl2 (5.0 mL) (procedure 2). After complete conversion (3 d),
procedure 3 was realised using 2-thiopheneboronic acid (12; 832
mg, 6.5 mmol, 1.3 equiv); reaction time 4 d. After column chroma-
tography (pentane–CH2Cl2, 100:1), product 16 was obtained as a
colourless oil (653 mg, 2.25 mmol, 45%, E/Z = 9:91).
IR (film): 3023, 2963, 1596, 1491, 1490, 1439, 1349, 1233, 1016,
912, 869, 825, 767, 695, 549 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.28 (m, 2 H), 7.28–7.21 (m,
7 H), 7.21–7.13 (m, 2 H), 7.02 (dd, J = 5.1, 3.5 Hz, 1 H), 6.89 (dd,
J = 3.5, 1.2 Hz, 1 H), 6.16 (d, J = 10.3 Hz, 1 H), 3.90 (dq, J = 10.3,
6.9 Hz, 1 H), 1.41 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 145.9, 142.7, 141.2, 137.1, 133.3,
128.6, 128.1, 127.8, 127.5, 127.4, 127.1, 126.8, 126.2, 125.7, 39.5,
22.4.
(4) Miersch, A.; Hilt, G. Chem. Eur. J. 2012, 18, 9798.
(5) (a) Monteiro, A. L.; Nunes, C. M.; Steffens, D. Synlett 2007,
103. (b) Kirchhoff, J. H.; Netherton, M. R.; Hill, I. D.; Fu, G.
C. J. Am. Chem. Soc. 2002, 124, 13662. (c) Song, C.; Ma,
Y.; Chai, Q.; Ma, C.; Jiang, W.; Andrus, M. B. Tetrahedron
2005, 61, 7438. (d) Lu, G.-P.; Voigtritter, K. R.; Cai, C.;
Lipshutz, B. H. J. Org. Chem. 2012, 77, 3700. (e) Yamada,
Y. M. A.; Takeda, K.; Takashashi, H.; Ikegami, S. J. Org.
Chem. 2003, 68, 7733. (f) Alacid, E.; Nájera, C. J. Org.
Chem. 2009, 74, 2321. (g) Liron, F.; Fosse, C.; Pernolet, A.;
Roulland, E. J. Org. Chem. 2007, 72, 2220.
MS (EI): m/z (%) = 290 ([M+], 100), 275 (74), 241 (16), 191 (47),
171 (26), 129 (15), 91 (24), 77 (15).
HRMS (EI): m/z calcd for C20H18S: 220.1129; found: 290.1127.
Synthesis 2013, 45, 3228–3232
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