Highly stereoselective synthesis of 2-methyl-1,3-dienes by palladium-catalyzed cross-coupling reaction with trimethylaluminum

Article abstract of DOI:10.1055/s-0033-1340477

Palladium-catalyzed cross-coupling reaction using tricyclohexylphosphine can be used to convert a range of 2-bromo-1,3-dienes efficiently and selectively to the corresponding methyl-branched conjugated dienes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340477

LETTER
▌531
letter
Highly Stereoselective Synthesis of 2-Methyl-1,3-dienes by Palladium-
Catalyzed Cross-Coupling Reaction with Trimethylaluminum
Pd-Catalyzed Cross-Coupling Reaction with Trimethylaluminum
Masahiro Miyazawa,* Risa Takehana, Takao Sanga, Aoi Hosomori, Hajime Yokoyama, Yoshiro Hirai
Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
Fax +81(76)4456614; E-mail: miyazawa@sci.u-toyama.ac.jp
Received: 13.10.2013; Accepted after revision: 25.11.2013
This work is dedicated to Dr. Masanori SAKAMOTO, Professor Emeritus of Meiji Pharmaceutical University, on the occasion of his
77th birthday (KIJU).
M
R3M
R3
Abstract: Palladium-catalyzed cross-coupling reaction using tricy-
clohexylphosphine can be used to convert a range of 2-bromo-1,3-
dienes efficiently and selectively to the corresponding methyl-
branched conjugated dienes.
R2
Br
Br
R1
R1
R1
R2
Br
R2
1
2
3
Scheme 1 Synthesis of alkyl-branched conjugated dienes
Key words: palladium catalyst, alkylation, isomerization, cross-
coupling, conjugated diene
We have also independently developed a stereoselective
coupling reaction of alkenyl halide 2 with trialkylalumi-
num reagents.5
Conjugated dienes are an important structural unit of bio-
logically active organic compounds, including carot-
enoids, antibiotics, and antitumor agents, and have been
synthesized by cross-coupling reaction of haloalkenes
with alkenyl metal compounds.1 However, stereoselective
construction of alkyl-branched conjugated dienes remains
an important problem. Differentiation of the two carbon–
halogen bonds of 1,1-dibromo-1-alkenes 1 in metal-cata-
lyzed reactions has been achieved in Suzuki coupling,
Stille coupling, and Negishi coupling (Scheme 1),2 but it
is remarkably difficult to introduce a second alkyl group
stereoselectively, because isomerization often occurs to
give regioisomers.3 Negishi and co-workers reported a
stereoselective coupling reaction of the alkenyl halide 2
with alkylzinc reagent using Pd(Pt-Bu3)2 catalyst.4
Here, we report a stereoselective construction of trisubsti-
tuted 1,3-butadiene via palladium-catalyzed alkylation of
2-bromo-1,3-butadiene with Me3Al. Initially, we exam-
ined the reaction of (E,E)-2-bromo-1,3-butadiene 4a–d
and trimethylaluminum in the presence of 5 mol% of
Pd(PPh3)4 in THF under reflux. Isomerization of the ole-
fin was observed when R1 was an alkyl group (Table 1,
entries 1 and 2). However, when the R1 was a phenyl moi-
ety, little isomerization was observed.
Next, we focused on the reaction of (1Z,3E)-2-bromo-1-
cyclohexyl-4-phenyl-1,3-butadiene (4e) with trimethyl-
aluminum in the presence of various ligands (Table 2). In-
deed, treatment of 4e with Me3Al (2 equiv) in the presence
of Pd2(dba)3CHCl3 (5 mol%) and PPh3 (20 mol%) in THF
under reflux afforded the methylated product 5e in 92%
Table 1 Palladium-Catalyzed Methylation of 2-Bromo-1,3-diene 4a–4d
Me3Al, PPh3,
Pd2(dba)3⋅CHCl3
Me
Br
Me
R1
R1
R2
+
R2
R2
THF, reflux
R1
R2
Ph
4
(E,E)-5
(Z,E)-5
Entry
Diene
R1
Me3Al (equiv) Time (h)
Yield (%)a
E,E/Z,Eb
1
2
3
4
4a
4b
4c
4d
n-C9H19
n-C9H19
Ph
2
4
2
2
5
19
3
39
95
48
90
32:68
36:64
95:5
CH2CH2OTBS
n-C7H15
Ph
Ph
3
>95:<5
a Isolated yield.
b Determined by GLC.
SYNLETT 2014, 25, 0531–0534
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DOI: 10.1055/s-0033-1340477; Art ID: ST-2013-U0962-L
© Georg Thieme Verlag Stuttgart · New York

532
M. Miyazawa et al.
LETTER
yield as a diastereomeric mixture [(E,E)-5e/(Z,E)-5e = clusively afforded the retention product.4 In our case,
67:33; Table 2, entry 1]. The reaction rate and stereoselec- Pd(Pt-Bu3)2 afforded the retention product (E,E)-5e as the
tivity of the reaction products decreased as the amount of major isomer, but the stereoselectivity was only 89% (Ta-
triphenylphosphine was increased (Table 2, entries 1 and ble 2, entry 10). The reactions using tri(2-furyl)phosphine
2). The reaction using bidentate DPPE showed no stere- and triphenylarsine were not completed, because the cata-
oselectivity (entry 3). Although 2,2′-bis(diphenylphosph- lysts were easily deactivated (Table 2, entries 11 and 12).
anyl)-1,1′-biphenyl (DPBP)6 afforded the retention
Next, we focused on screening of solvent conditions (Ta-
ble 3). The reaction using diethyl ether and hexane did not
afford the cross-coupling product, because the catalyst
hardly dissolved in these solvents (Table 3, entries 2 and
product (E,E)-5e as the major isomer (94% selectivity),
the catalyst was easily deactivated7 (Table 2, entry 4). The
use of a very bulky ligand such as tri-o-tolylphosphine or
tricyclohexylphosphine, furnished the cross-coupling
3). The reaction using toluene and dichloromethane af-
product in good yield with retention of stereochemistry
forded 5e in moderate yield and the catalyst was easily de-
(Table 2, entries 5 and 6). Although the isomerization
activated (Table 3, entries 4 and 5).
product was not observed using triphenylphosphite, the
reaction was not completed, because the catalyst was eas-
ily deactivated (Table 2, entry 8). Negishi and co-workers
reported that PdCl2(DPEphos) was the best catalyst for al-
kylation of 2-bromo-1,3-diene by Me2Zn with inversion
of configuration.3 In our case, PdCl2(DPEphos) also af-
forded the inversion product (Z,E)-5e as a major isomer,
but the stereoselectivity was only 87% (Table 2, entry 9).
On the other hand, Negishi reported that Pd(Pt-Bu3)2 ex-
Table 3 Screening of Solvent Conditions for Palladium-Catalyzed
Methylation of 2-Bromo-1,3-diene 4e
Me
Me3Al (2 equiv)
Ph
Pd2(dba)3⋅CHCl3
(E,E)-5e
Br
(0.05 equiv)
+
Ph
Cy3P (0.2 equiv)
solvent
Me
4e
Ph
Table 2 Optimization of Palladium-Catalyzed Methylation of 2-Bro-
mo-1,3-diene 4e
Me
(Z,E)-5e
Me3Al (2 equiv)
Ph
Pd2(dba)3⋅CHCl3
E,E/Z,Ea
(E,E)-5e
Entry Solvent
Temp
(°C)
Time
(h)
Yield
(%)a
Br
(0.05 equiv)
+
Ph
ligand
THF, reflux
Me
4e
1
2
3
4
5
6
7
THF
reflux
reflux
reflux
60
3
95
–
>95:<5
–
Ph
Et2O
–
hexane
toluene
CH2Cl2
dioxane
dioxane
–
–
–
(Z,E)-5e
4.5
5
54
46
87
12
94:6
89:11
>95:<5
72:28
Entry Ligand
Time (h) Yield (%)a E,E/Z,Ea
reflux
60
1
1
2
Ph3P (0.2 equiv)
1.5
4
92
90
81
32
81
95
87
69
65
77
39
29
67:33
26:74
53:47
94:6
27
4
Ph3P (0.4 equiv)
a Determined by GLC analysis.
3
dppe (0.1 equiv)
14
4
dpbp (0.1 equiv)
2
The reaction using 1,4-dioxane at 60 °C afforded 5e in
87% yield and excellent stereoselectivity, but the catalyst
was rapidly deactivated (Table 3, entry 6). At 27 °C, the
cross-coupling reaction of 4e afforded 5e in only 12%
yield and low stereoselectivity (Table 3, entry 7).
5
o-tolyl3P (0.2 equiv)
Cy3P (0.2 equiv)
0.5
3
95:5
6
>95:<5
88:12
>95:<5
13:87
89:11
81:19
85:15
7
n-Bu3P (0.32 equiv)
(PhO)3P (0.3 equiv)
DPEphos (0.1 equiv)b
t-Bu3P (0.2 equiv)c
(2-furyl)3P (0.2 equiv)
Ph3As (0.2 equiv)
13
8
3
3
3
2
1
A plausible mechanism of the olefin isomerization is
shown in Scheme 2. There are two plausible mechanisms
for the olefin isomerization. The first one is the π–σ–π re-
arrangement mechanism via alkylidene-π-allyl palladium
species 9 (path a). The alkylidene-π-allyl palladium spe-
cies 9, which were prepared from 2-bromo-1,3-dienes
have been previously reported.6,8 Although the π–σ–π re-
arrangement product should be (Z,Z)-diene 11, the isom-
erization products were (Z,E)-diene 15. At least, 15 was
not formed via π-σ-π rearrangement mechanism. The oth-
9
10
11
12
a Determined by GLC analysis.
b Amount of PdCl2(DPEphos) used was 0.1 equiv.
c Amount of Pd(Pt-Bu3)2 used was 0.1 equiv.
Synlett 2014, 25, 531–534
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pd-Catalyzed Cross-Coupling Reaction with Trimethylaluminum
533
er mechanism involves the isomerization mechanism via
palladoene intermediate 12 (path b). In the case of alkyla-
tion of 2-bromo-1,3-butadiene with Me2Zn in the pres-
ence of palladium catalyst, Negishi and co-workers
proposed that the isomerization proceeded through 2-pal-
lado-3-ene 12 with the loss of bromide ion via coordina-
tion of the 3-olefin.9 In such a cross-coupling reaction, the
transmetallation step (6 → 7 or 13 → 14) is almost always
the rate-determining step. If transmetallation between pal-
ladium complex and Me3Al is easy (6 → 7), the retention
product would be produced stereoselectively. However,
formation of the retention product decreases with increas-
ing amount of phosphine ligand. The reason is probably
that phosphine ligands, which are good σ-donors and in-
crease the electron density of the palladium, suppress the
transmetallation step. On the other hand, σ-donation of
phosphite is lower than that of phosphine, so phosphite li-
gand facilitates the transmetallation step. When sterically
bulky phosphine ligands such as tri-o-tolylphosphine or
tricyclohexylphosphine were used, isomerization was
hardly observed. Bulky ligands probably retard the intra-
molecular coordination of 3-olefin with palladium, there-
by blocking the formation of 2-pallado-3-ene 12.
Table 4 Palladium-Catalyzed Methylation of 2-Bromo-1,3-dienes
4a–4d
Me
R1
Me3Al (2 equiv)
Pd2(dba)3⋅CHCl3 (0.05 equiv)
Cy3P (0.2 equiv)
R2
Br
(E,E)-5
R1
+
R2
Me
THF, reflux, 3 h
4
R2
R1
(Z,E)-5
Entry
Diene
R1
R2
Ph
Yield E,E/Z,Eb
(%)a
1
2
3
4
5
6
4a
4b
4e
4c
4f
n-C9H19
n-C9H19
Cy
57
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
CH2CH2OTBS 99
Ph
95
93
93
79
Ph
n-C7H15
Cy
Ph
4d
Ph
Ph
a Isolated yield.
b Determined by GLC.
R2
Me
PdMeLn
Me
R1
R1
On the other hand, the reaction of dienyl bromide 4e with
triethylaluminum under the same conditions afforded the
ethylated product 16 as the sole product in 88% yield
(Scheme 3). Thus, ethylation also proceeded stereoselec-
tively with retention of configuration.
R2
R2
R1
8
7
11
Me3Al
Me3Al
R2
LnBrPd
PdBrLn
Br
Et3Al (2 equiv)
Pd2(dba)3⋅CHCl3
(0.05 equiv)
PdLn
R1
R1
R2
2
R1
R2
4
1
3
10
Br
Et
4
Cy3P (0.2 equiv)
6
Ph
Ph
path a
path b
THF, reflux, 3 h
4e
16
E,E/Z,E = >95:<5
Br–
Br–
+PdLn
PdLn
Scheme 3 Palladium-catalyzed ethylation of 2-bromo-1,3-diene 4e
R1
R1
R2
R2
+
In conclusion, we have demonstrated a novel and efficient
preparation of geometrically pure methyl-branched conju-
gated dienes from 2-bromo-1,3-dienes with Me3Al re-
agent by palladium-catalyzed cross-coupling reaction
using tricyclohexylphosphine ligand. This system is as
useful as methylation with Me2Zn reagent in the presence
of Pd catalyst containing t-Bu3P, since tricyclohexylphos-
phine has advantages over t-Bu3P in terms of stability and
ease of use. Further investigations into synthetic applica-
tions of this reaction are under way.
12
9
PdMeLn
Me
Me3Al
PdBrLn
R2
R2
R2
R1
R1
R1
13
14
15
Scheme 2 Plausible mechanism for the olefin isomerization
To extend the range applicability of the reaction, various
dienyl bromides were subjected to reaction with trimeth-
ylaluminum under the optimal conditions.10 As shown in
Table 4, the reaction of dienyl bromides bearing a phenyl
group and/or an alkyl group proceeded smoothly to pro-
vide the corresponding methyl adducts in good yield with
high regioselectivity.
Acknowledgment
This work was financially supported by the Grant-in-Aid for Scien-
tific Research on Priority Areas (C) from the Ministry of Education,
Science, Sports, and Culture.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 531–534

534
M. Miyazawa et al.
LETTER
a solution of (1Z,3E)-2-bromo-1-cyclohexyl-4-phenyl-1,3-
butadiene (4e; 146 mg, 0.501 mmol) in THF (10 mL). After
stirring at r.t. for 5 min, Me3Al (1.05 M hexane solution, 1.0
mL, 1.0 mmol) was added to the solution and the mixture
was refluxed for 3 h. The reaction mixture was allowed to
cool to r.t. and quenched with diluted cold HCl. The aqueous
layer was extracted with Et2O (3 ×). The combined organic
layers were washed with aq sat. NaHCO3 solution and brine,
dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatog-
raphy using hexane as eluent to afford the title compound
[107 mg, 95%, (E,E)-5e/(Z,E)-5e >95:<5]. (1E,3E)-1-
Cyclohexyl-2-methyl-4-phenylbuta-1,3-diene (E,E-5e):
1H NMR (600 MHz, CDCl3): δ = 7.37–7.42 (m, 2 H), 7.27–
7.32 (m, 2 H), 7.16–7.20 (m, 1 H), 6.78 (dd, J = 16.1, 0.7 Hz,
1 H), 6.45 (d, J = 16.1 Hz, 1 H), 5.48 (d, J = 9.2 Hz, 1 H),
2.36 (dtt, J = 9.1, 11.1, 3.7 Hz, 1 H), 1.88 (d, J = 1.1 Hz, 3
H), 1.73 (dquint, J = 13.4, 3.4 Hz, 2 H), 1.63–1.71 (m, 3 H),
1.31 (tq, J = 3.3, 12.7 Hz, 2 H), 1.20 (tq, J = 3.3, 12.5 Hz, 1
H), 1.11 (dq, J = 3.0, 12.2 Hz, 2 H). 13C (75 MHz, CDCl3): δ
= 140.30, 138.03, 134.29, 131.92, 128.50 (2 × C), 126.76,
126.10 (2 × C), 125.62, 37.40, 33.02 (2 × C), 26.03, 25.92 (2
× C), 12.56. IR (neat): 3079, 3058, 3026, 2924, 2849, 1629,
1598, 1494, 1447, 958, 746, 691 cm–1. MS (EI): m/z = 226
(64%). HRMS (EI): m/z [M+] calcd for C17H22: 226.1722;
found: 226.1731. (1E,3Z)-1-Cyclohexyl-2-methyl-4-
phenylbuta-1,3-diene (Z,E-5e): 1H NMR (600 MHz,
CDCl3): δ = 7.43–7.49 (m, 2 H), 7.31–7.37 (m, 2 H), 7.19–
7.24 (m, 1 H), 7.19 (d, J = 16.1 Hz, 1 H), 6.54 (d, J = 16.1
Hz, 1 H), 5.31 (d, J = 9.5 Hz, 1 H), 2.54 (dtt, J = 9.2, 11.1,
3.7 Hz, 1 H), 1.92 (d, J = 1.1 Hz, 3 H), 1.74 (dquint, J = 13.6,
3.4 Hz, 2 H), 1.65–1.71 (m, 3 H), 1.34 (tq, J = 3.3, 12.7 Hz,
2 H), 1.19 (tq, J = 3.5, 12.7 Hz, 1 H), 1.10 (dq, J = 3.0, 12.3
Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 138.51, 138.10,
130.06, 128.56 (2 × C), 128.10, 127.12, 126.37, 126.35 (2 ×
C), 36.52, 33.53 (2 × C), 26.01, 25.93 (2 × C), 20.60. IR
(neat): 3080, 3058, 3036, 3024, 2923, 2849, 1632, 1597,
1494, 1446, 957, 747, 691 cm–1. MS (EI): m/z = 226 (83%).
HRMS (EI): m/z [M+] calcd for C17H22: 226.1722; found:
226.1742.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
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(10) Typical Procedure for the Synthesis of (E,E)-5e: A
mixture of Pd2(dba)3CHCl3 (26 mg, 0.025 mmol) and PCy3
(28 mg, 0.100 mmol) was dissolved in THF (5 mL) under a
nitrogen atmosphere. To the resultant red solution was added
Synlett 2014, 25, 531–534
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