A direct synthesis of symmetrical (E,E)-1,4-diaryl-1,3-butadienes by Wenkert arylation of thiophene

Article abstract of DOI:10.1002/adsc.201000350

The nickel-catalyzed coupling of thiophene with aryl Grignard reagents (Wenkert reaction) is accelerated by N-heterocyclic carbene or trialkylphosphane ligands, providing a general, scalable direct synthesis of symmetrical 1,4-diarylbutadienes.

Full text of DOI:10.1002/adsc.201000350

COMMUNICATIONS
DOI: 10.1002/adsc.201000350
A Direct Synthesis of Symmetrical (E,E)-1,4-Diaryl-1,3-buta-
dienes by Wenkert Arylation of Thiophene
Lukas Hintermann,a,* Marco Schmitz,b and Yun Chenb
a
Department Chemie, Technische Universitꢀt Mꢁnchen, Lichtenbergstr. 4, 85747 Garching, Germany
Fax : (+49)-(0)89-289-13669; phone (+49)-(0)89-289-13699; e-mail: lukas.hintermann@tum.de
Institut fꢁr Organische Chemie, RWTH Aachen University, 52074 Aachen, Germany
b
Received: May 5, 2010; Revised: July 28, 2010; Published online: September 14, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000350.
Abstract: The nickel-catalyzed coupling of thio-
phene with aryl Grignard reagents (Wenkert reac-
tion) is accelerated by N-heterocyclic carbene or
trialkylphosphane ligands, providing a general, scal-
able direct synthesis of symmetrical 1,4-diarylbuta-
dienes.
ic method. This is somewhat surprising, because trial-
kylphosphanes are not typical ligands in Wenkert re-
actions,[12] and NHC/nickel systems have not found
previous use in thioether cross-couplings at all, to the
best of our knowledge.
Our studies on the extension of the Wenkert aryla-
tion of thiophene set off with 2-tolylmagnesium bro-
mide as moderately bulky test nucleophile and nickel
catalysts at the 3 mol% level (Table 1). Standard cata-
lysts for Wenkert reactions[12] which contain triaryl- or
Keywords: alkenes; cross-coupling; homogeneous
catalysis; nickel; sulfur heterocycles
diarylphosphane ligands {NiCl
(CH2)nPPh2]} displayed low activity (entries 1, 6, 7).
However, the electron-rich trialkylphosphane (en-
2ACHTUNGTRENNUG(PPh3)2, NiCl2ACHTUNGTRENNUNG[Ph2P-
AHCTUNGTRENNUNG
Symmetrical 1,4-diaryl-1,3-butadienes are photo- tries 2–5, 8–10) and N-heterocyclic carbene (NHC) li-
active materials[1] and find use as starting materials in
Diels–Alder reactions,[2,3] photo- or thermocycliza-
tions,[4] or the McCormack reaction.[5] Their estab-
lished preparations (Scheme 1) by Wittig (A),[3,6]
Horner (A),[1b,4b] or via Perkin (A, B) reactions[7] dis-
play low atom-economy or yields, and ask for multi-
step syntheses of the precursor reagents. Catalytic
couplings of styryl-metals and/or halides (C, 1.),[8] or
of butadienyl-dimetals with aryl halides,[9] or of aryl
nucleophiles with 1,4-diiodobutadiene (C, 2.)[10] are
known, but since the coupling partners are expensive
or not readily available themselves, those routes are
limited to small-scale preparations.[10c] Thus, when we
recently wished to access a variety of symmetrical 1,4-
diaryl-1,4-butadienes, we concluded that a scalable
one-step synthesis for those was still elusive. Interest-
ingly, Wenkert and co-workers had elegantly obtained
1,4-diphenylbutadiene from thiophene (1) and phe-
nylmagnesium bromide in the presence of a nickel
catalyst.[11] Low activity and stereoselectivity appear
to have prevented applications, let alone a generaliza-
tion of this approach (C, 3.). We now find that suita-
ble ligands including trialkylphosphanes and N-
hetero
ACHTUNGTRENNUNGcyclic carbenes (NHC) turn the Wenkert aryla-
Scheme 1. Synthetic pathways to symmetrically substituted
tion of thiophene into a general and superior synthet- 1,4-diaryl-1,3-butadienes.
Adv. Synth. Catal. 2010, 352, 2411 – 2415
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2411

Lukas Hintermann et al.
Table 1. Screening of conditions for the Ni-catalyzed Wenkert arylation of thiophene with 2-tolylmagnesium bromide.[a]
COMMUNICATIONS
Entry
Catalyst
[mol%]
T [8C]
Solvent[b]
2 after 12 h [%][c]
2 after 36 h [%][c]
total
E,E:E,Z:Z,Z
total
E,E:E,Z:Z,Z
1
NiCl
NiCl
NiCl
N
3
3
3
3
3
3
3
80
80
80
80
80
100
100
80
80
80
80
80
80
80
80
80
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Et2O
THF
THF
THF
THF
Et2O
Et2O
40
42
59
47
46
37
12
38
93
55
73
80
67
29
4
43:16:41
77:11:12
62:15:23
88:9:3
88:10:2
41:15:44
68:12:20
75:11:14
19:20:61
10:7:83
65:16:19
33:22:45
56:22:22
86:9:5
28:35:37
33:33:34
43
62
82
72
72
41
15
56
90
71
75
89
77
42
6
54:14:32
82:10:8
73:13:14
89:9:2
2
3[d]
4
NiCl2[P
5
6
7
8
NiCl
NiCl
NiCl
92:7:1
50:13:37
75:11:14
82:10:8
38:26:36
16:8:76
90:9:1
40:21:39
68:20:12
90:9:1
Ni
NiCl
NiCl2[P
T
3+7.5
3
3
3+7.5
3+6
3+7.5
3 + 75
3+6
3+6
9
10
11
12[d]
13
14
15
16
Ni
Ni
Ni
Ni
Ni
Ni
U
86:8:6
33:32:35
5
6
[a]
Reaction conditions: thiophene (1.26 mmol), 2-TolMgBr (3 mmol, 2.38 equiv.; 2 molLꢀ1 in THF or Et2O), toluene (2 mL),
catalyst, internal standard dodecane (100 mL).
Co-solvent from the Grignard reagent.
Yields and product ratios determined by GC/FID against internal standard.
Reaction diluted with additional toluene (10 mL). Abbreviations: Cy=cyclohexyl; Tol=tolyl; dppe/dppp=Ph2P-
[b]
[c]
[d]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
gands (entries 11–16) provided high catalytic activity
and yields of up to 90% of diene isomers 2.
Concluding from Table 1, favorable reaction condi-
tions are defined by use of trialkylphosphane ligands
Electronic ligand effects are critical (compare en- with either THF or Et2O as co-solvent, or carbene li-
tries 1, 6, 7 vs. 2–5), but steric ligand effects are not gands and THF as co-solvent.[14] These conditions
pronounced (compare the trialkylphosphane series, were tested with a range of Grignard reagents
entries 2–5). The isomer composition was ligand-de- (Table 2). The butadiene isomer fraction was isolated
pendent, with preference for either (E,E)- or (Z,Z)-, as a stereoisomer mixture and quantified after 20 h of
but not (E,Z)-2 as the major product. From the time- reaction time to identify the most active catalysts, ir-
dependency of the isomer ratio it is clear that isomeri- respective of isomer selectivity (Table 2, column
zation from (Z,Z)- via (E,Z)- to (E,E)-2 occurs under “mix”).[15] Next, the most promising catalyst/cosolvent
the reaction conditions; however, the isomerization is combination was applied in the synthesis of the
relatively slow, thus the high (E,E)-selectivity of cer- (E,E)-isomer [Table 2, column (E,E)]. The proportion
tain entries after 12 h appears to be intrinsic rather of (E,E)-isomer in the crude product was increased
than a consequence of isomerization. While Wenkert either by applying extended reaction times or by per-
reactions require apolar bulk solvents,[11] the stereose- forming an iodine-catalyzed photoisomerization on
lectivity of the reaction also depends on the etheral the initial crude product isomer mixture. A range of
co-solvent introduced with the Grignard reagent: (E,E)-1,4-diaryl-1,3-butadienes were prepared by the
THF generally favors the (E,E)-2 isomer, whereas the new methodology, some for the first time, in fair to
combinations of phosphane ligands and Et2O as co- high yields (Table 2). Phenyl or ortho- and para-sub-
solvent show a marked initial selectivity for (Z,Z)-2 stituted aryl nucleophiles often gave yields in excess
(entries 9, 10). The combination of NHC ligands and of 60%. meta-Substituted aryl reagents were saliently
Et2O as co-solvent is inefficient (entries 15, 16).[13] In lower yielding (entries 5, 7, 15). The reaction was suc-
general, higher conversions were achieved by diluting cessful with annelated aromatic Grignard reagents
the reaction mixture with additional toluene (en- (13, 14, 16). The use of thiophene and aryl Grignard
tries 3, 12).
reagents allows for a simple upscaling of the reaction.
2412
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2411 – 2415

A Direct Synthesis of Symmetrical (E,E)-1,4-Diaryl-1,3-butadienes
Table 2. Synthesis of 1,4-diaryl-1,3-butadienes from thio-
ACHTUNGTRENNUNG
phene.[a]
Entry
ArMgX
Ligand
Solvent
Yield [%][b]
mix
E,E
1
2
PhMgCl
PhMgCl
IMes
IPr
THF
THF
70
68
61[c]
3
PCy3
IMes
Et2O
THF
62
4
5
6
90
74[c]
24[c]
62[c]
IMes
PCy3
THF
THF
32
29
Scheme 2. Proposed reaction mechanism, see text.
IMes
IPr
THF
THF
73
73
In the case of (E,E)-di-1-naphthyl-1,3-butadiene, a
0.25-molar scale reaction was performed and the
product obtained with only a slight reduction in yield
(entry 13).
PCy3
PBu3
THF
Et2O
28
19
7
19
71
The role of both thiolate and sulfide as leaving
groups in this cross-coupling reaction is notable.
Based on experimental observations and literature
precedents, we propose the following mechanism
(Scheme 2) via metallacyclic intermediates to explain
both the absence of monoarylated intermediates,[11]
and the stereoselectivity for either (Z,Z)- or (E,E)-
isomeric products seen in our study (Table 1).
PBu3
PBu3
THF
Et2O
76
37
8
9
IPr
IMes
PCy3
THF
THF
Et2O
72
98
94
-
75[c]
–
IPr
PBu3
THF
THF
70
51
62[c]
–
10
11
12
ꢀ
Insertion of Ni(0) into a C S bond of thiophene
(1!A),[16,17] transmetallation to B and reductive elim-
ination will generate a h4-Ni(0)-diene-thiolate, meso-
meric to metallacycle C, which undergoes 1,4-elimina-
tion of magnesium sulfide to butadienyl-nickel species
D.[18]
PCy3
IMes
THF
THF
65
49
54
–
PBu3
PCy3
Et2O
56
43
Et2O
Et2O
85
–
64
Alternatively, dissociation from C and stereoisome-
rization of open-chain species E produces F. Depend-
ing on the configuration of the butadienyl-nickel(II)
intermediate (D or F), either (Z,Z)- or (E,E)-diene is
eventually formed. Spectator ligands at nickel will
affect the relative rates to D and F, and polar co-sol-
vents will favor dissociation to E, increasing the
amount of (E,E)-diene.
13
14
57[d]
PCy3
Et2O
–
46
IMes
IMes
THF
THF
–
–
56
15
(76)[e]
In conclusion, we have shown that trialkylphos-
phane and NHC complexes of nickel are superior cat-
alysts in the Wenkert arylation of thiophene with aryl
Grignard reagents. A direct and scalable synthesis of
(E,E)-1,4-diaryl-1,3-butadienes is thus available.
16
IMes
THF
–
49
[a]
Reaction conditions: thiophene (1 equiv.), 3 mol% NiCl2
ACHTUNGTRENNUNG(PR3)2 or 3 mol% NiCAHTUNGTREN(NUGN acac)2 +7.5 mol% NHC·HCl,
ArMgX (2.3 equiv.), toluene (5 mLmmolꢀ1).
The term “mix” refers to the yield of butadiene stereo-
isomer mixture, at a 2-mmol scale, 808C, 20 h; “E,E”
refers to yield of (E,E)-isomer at a 10-mmol scale, 808C,
36 h.
[b]
Experimental Section
[c]
[d]
[e]
ACHTUNGTRENN(UNG E,E)-1,4-Dimesityl-1,3-butadiene
Yield after iodine isomerization, see text.
0.25-molar scale.
To a Schlenk vessel containing NiCl2[PACHTUGNTREN(UNNG n-Bu3)]2 (0.160 g,
Yield of 1,4-diarylbutane after hydrogenation of the
0.30 mmol, 3 mol%) under argon, dry toluene (50 mL) was
diene isomer mixture.[15]
Adv. Synth. Catal. 2010, 352, 2411 – 2415
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2413

Lukas Hintermann et al.
COMMUNICATIONS
added, followed by thiophene (0.80 mL, 10.0 mmol) and me-
sityl-magnesium bromide (2M in THF; 11.5 mL,
23.0 mmol). The reaction mixture was heated to 808C with
stirring. After 36 h, the reaction mixture, which had turned
into a thick suspension, was cooled, diluted with 2–4 vol-
umes of toluene, and quenched by careful addition of an
equal volume of saturated aqueous NH4Cl. [Caution: Work-
up must be carried out in a well-ventilated hood, because H2S
is released upon hydrolysis.] The organic phase was washed
with equal volumes of aqueous HCl (2.4 molLꢀ1), aqueous
NaOH (2 molLꢀ1), and water. After drying (MgSO4), the so-
lution was filtered and evaporated. Chromatographic purifi-
cation (SiO2/hexanes) of the crude gave the product as a col-
orless solid; yield: 2.062 g (71%)
Nakao, Y. Kobayashi, M. Sakai, N. Uchino, Y. Sakaki-
bara, K. Takagi, Bull. Chem. Soc. Jpn. 1993, 66, 2446;
f) J. P. Parrish, Y. C. Jung, R. J. Floyd, K. W. Jung, Tet-
rahedron Lett. 2002, 43, 7899; g) Y. Yamamoto, Synlett
2007, 1913; h) K. Itami, Y. Ushiogi, T. Nokami, Y.
Ohashi, J. Yoshida, Org. Lett. 2004, 6, 3695; i) Y. Nishi-
bayashi, C. S. Cho, K. Ohe, S. Uemura, J. Organomet.
Chem. 1996, 526, 335; j) N. Kamigata, J. Ozaki, M. Ko-
bayashi, J. Org. Chem. 1985, 50, 5045.
[9] a) R. S. Coleman, M. C. Walczak, Org. Lett. 2005, 7,
2289; b) S. E. Denmark, S. A. Tymonko, J. Am. Chem.
Soc. 2005, 127, 8004.
[10] a) I. G. Trostyanskaya, D. Y. Titskiy, E. A. Anufrieva,
A. A. Borisenko, M. A. Kazankova, I. P. Beletskaya,
Russ. Chem. Bull. Int. Ed. 2001, 50, 2095; b) F. Babudri,
G. M. Farinoli, F. Naso, R. Ragni, G. Spina, Synthesis
2007, 3088; c) for example, the latter procedure asks
for using 300 mol% of Ag2CO3 as base.
See the Supporting Information for full experimental de-
1
tails, characterization of products and copies of product H
and 13C NMR spectra.
[11] a) E. Wenkert, M. H. Leftin, E. L. Michelotti, J. Chem.
Soc. Chem. Commun. 1984, 617; b) E. Wenkert, T. W.
Ferreira, E. L. Michelotti, J. Chem. Soc. Chem.
Commun. 1979, 637; c) M. Tiecco, M. Tingoli, E. Wen-
kert, J. Org. Chem. 1985, 50, 3828.
Acknowledgements
We thank DFG for funding, and Prof. C. Bolm, RWTH
Aachen University, for support.
[12] Wenkert reactions more commonly use cyclic enol
ethers as electrophiles: a) J.-P. Ducoux, P. Le Mꢃnez, N.
Kunesch, G. Kunesch, E. Wenkert, Tetrahedron 1992,
48, 6403; b) E. Wenkert, E. L. Michelotti, C. S. Swin-
dell, J. Am. Chem. Soc. 1979, 101, 2246; c) E. Wenkert,
T. W. Ferreira, Organometallics 1982, 1, 1670; d) E.
Wenkert, E. L. Michelotti, C. S. Swindell, M. Tingoli, J.
Org. Chem. 1984, 49, 4894; e) E. Wenkert, V. F. Ferre-
ira, E. L. Michelotti, M. Tingoli, J. Org. Chem. 1985,
50, 719; f) J.-P. Ducoux, P. Le Mꢃnez, N. Kunesch, G.
Kunesch, E. Wenkert, Tetrahedron Lett. 1990, 31, 2595;
g) S. Wadman, R. Whitby, C. Yeates, P. Kocienski, K.
Copper, J. Chem. Soc. Chem. Commun. 1987, 241;
h) R. Whitby, C. Yeates, P. Kocienski, G. Costello, J.
Chem. Soc. Chem. Commun. 1987, 429; i) P. Kocienski,
N. J. Dixon, S. Wadman, Tetrahedron Lett. 1988, 29,
2353; j) P. Kocienski, S. Wadman, J. Org. Chem. 1989,
54, 1215.
References
[1] a) S. Abraham, V. A. Mallia, K. V. Ratheesh, N. Tam-
aoki, S. Das, J. Am. Chem. Soc. 2006, 128, 7692;
b) A. K. Singh, M. Darshi, S. Kanvah, J. Phys. Chem. A
2000, 104, 464; c) D. R. Kanis, M. A. Ratner, T. J.
Marks, Chem. Rev. 1994, 94, 195.
[2] J. E. Rainbolt, G. P. Miller, J. Org. Chem. 2007, 72,
3020.
[3] R. N. McDonald, T. W. Campbell, J. Org. Chem. 1959,
24, 1969.
[4] a) R. J. Hayward, A. C. Hopkinson, C. C. Leznoff, Tet-
rahedron 1972, 28, 439; b) J. Liu, N. L. Wendt, K. J.
Boarman, Org. Lett. 2005, 7, 1007; c) M. Mꢁller, J. Pe-
tersen, R. Strohmaier, C. Gꢁnther, N. Karl, K. Mꢁllen,
Angew. Chem. 1996, 108, 947; Angew. Chem. Int. Ed.
Engl. 1996, 35, 886.
[5] a) F. Guillen, M. Rivard, M. Toffano, J.-Y. Legros, J.-C.
Daran, J.-C. Fiaud, Tetrahedron 2002, 58, 5895;
b) J. I. G. Cadogan, R. J. Scott, R. D. Gee, I. Gosney, J.
Chem. Soc. Perkin Trans. 1 1974, 1694; c) L. Hinter-
mann, M. Schmitz, Adv. Synth. Catal. 2008, 350, 1469.
[6] R. N. McDonald, T. W. Campbell, Org. Synth. Coll.
Vol. V 1973, 499.
[7] a) S. Israelashvili, Y. Gottlieb, M. Imber, A. Habas, J.
Org. Chem. 1951, 16, 1519; b) Y. Hirshberg, E. Berg-
mann, F. Bergmann, J. Am. Chem. Soc. 1950, 72, 5120;
c) B. B. Corson, Org. Synth. Coll. Vol. II 1943, 229;
d) R. Kuhn, A. Winterstein, Helv. Chim. Acta 1928, 11,
87.
[8] a) G. Cahiez, A. Moyeux, J. Buendia, C. Duplais, J.
Am. Chem. Soc. 2007, 129, 13788; b) N. Kamigata, J.
Ozaki, M. Kobayashi, Chem. Lett. 1985, 705; c) F. Ber-
thiol, H. Doucet, M. Santelli, Synlett 2003, 841; d) C.
Cannes, S. Condon, M. Durandetti, J. Pꢃrichon, J.-Y.
Nꢃdꢃlec, J. Org. Chem. 2000, 65, 4575; e) K. Sasaki, K.
[13] This was also the case with preformed NiCl2ACHTUNGTRENNUNG(NHC)2
complex as the catalyst; for the latter, see: a) K. Matsu-
bara, K. Ueno, Y. Shibata, Organometallics 2006, 25,
3422; b) W. A. Herrmann, G. Gerstberger, M. Spiegler,
Organometallics 1997, 16, 2209.
[14] The use of carbene ligands in nickel-catalyzed cross-
couplings of thioethers is unprecedented, to our knowl-
edge. For typical protocols, see: a) Y. Baba, A. Toshi-
mitsu, S. Matsubara, Synlett 2008, 2061; b) S. Kane-
mura, A. Kondoh, H. Yorimitsu, K. Oshima, Synthesis
2008, 2659; c) A. Sabarre, J. Love, Org. Lett. 2008, 10,
3941; d) F. Babudri, V. Fiandanese, L. Mazzone, F.
Naso, Tetrahedron Lett. 1994, 35, 8847; e) V. Fianda-
nese, G. Marchese, G. Mascolo, F. Naso, L. Ronzini,
Tetrahedron Lett. 1988, 29, 3705; f) T.-Y. Luh, Z.-J. Ni,
Synthesis 1990, 89.
[15] See the Supporting Information for additional screen-
ing results.
[16] D. A. Vicic, W. D. Jones, J. Am. Chem. Soc. 1999, 121,
7606.
2414
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2411 – 2415

A Direct Synthesis of Symmetrical (E,E)-1,4-Diaryl-1,3-butadienes
[17] For a related mechanism in the nickel-catalyzed desul-
furization of benzothiophene with Grignard reagents: J.
Torres-Nieto, A. Arꢃvalo, J. J. Garcꢄa, Organometallics
2007, 26, 2228.
[18] For a similar elimination of a 2-alkoxy-zirconacyclo-
pentene to a butadienyl-zirconium species, see: N.
Chinkov, S. Majumdar, I. Marek, J. Am. Chem. Soc.
2003, 125, 13258.
Adv. Synth. Catal. 2010, 352, 2411 – 2415
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2415