Palladium-catalyzed cross-coupling of cyclopropylmethyl N-tosylhydrazones with aromatic bromides: An easy access to multisubstituted 1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2013.09.072

Direct synthesis of 1,1-disubstitued 1,3-butadienes has been efficiently realized from the cross-coupling of cyclopropylmethyl N-tosylhydrazones with aromatic bromides by means of PdCl₂(MeCN)₂ as catalyst. 1,1,4-Trisubstitued 1,3-but

Full text of DOI:10.1016/j.tetlet.2013.09.072

Tetrahedron Letters 54 (2013) 6485–6489
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed cross-coupling of cyclopropylmethyl
N-tosylhydrazones with aromatic bromides: an easy access
to multisubstituted 1,3-butadienes
⇑
Qin Yang, Huining Chai, Tingting Liu, Zhengkun Yu
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct synthesis of 1,1-disubstitued 1,3-butadienes has been efficiently realized from the cross-coupling
of cyclopropylmethyl N-tosylhydrazones with aromatic bromides by means of PdCl2(MeCN)2 as catalyst.
1,1,4-Trisubstitued 1,3-butadiene derivatives were obtained in up to 70% yields through a one-pot pro-
cedure catalyzed by Pd(OAc)2 in the presence of excessive amount of aromatic bromides. The present
methodology provides an easy and efficient route to multisubstituted 1,3-butadienes.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 21 August 2013
Accepted 17 September 2013
Available online 25 September 2013
Keywords:
Palladium
Cyclopropylmethyl
N-Tosylhydrazones
Aromatic bromides
1,3-Butadienes
Conjugate diene is a useful and fundamental structural motif in
a wide range of biologically active molecules and organic materi-
als.1 Molecules bearing diene groups are usually versatile building
blocks in numerous transformations such as Diels–Alder and cyclo-
addition reactions.2 Much attention has been paid to the develop-
ment of efficient synthetic protocols for the preparation of
conjugate dienes.3 The cross-coupling of two alkenyl species is
the most direct procedure, including that mediated by palladium4
and rhodium.5 Transition metal-catalyzed hydrovinylation of al-
kynes is a commendable protocol to stereoselectively prepare
1,3-dienes.6 Carbonyl alkenylation involving the Wittig reaction
or its variants has been applied for this purpose.7 Indirect transfor-
mations are also known for synthesizing 1,3-dienes.8 In(OTf)3-
mediated aryl-substituted cyclopropyl carbonyl compounds were
utilized to construct conjugate butadienes under sonication condi-
tions.8a Pd(PPh3)4-catalyzed isomerization of methylenecyclopro-
panes formed 1,3-dienes in up to 98% yields.8b In the above
mentioned literatures, the synthesis of conjugate dienes relies on
the substrates containing an alkenyl group.
Barluenga et al. found that N-tosylhydrazones derived from a,b-
unsaturated ketones can react with aryl halides to afford conjugate
dienes.11e Very recently, Wang and co-workers disclosed palla-
dium(0)-catalyzed cross-coupling of cyclopropylmethyl N-tosylhy-
drazones with aryl iodides, in which few aryl bromides were
employed as substrates, and they found that Pd(II) complexes could
not act as the effective catalysts for the same cross-coupling reac-
tions.11b To our delight, we surprisinglyfoundthat Pd(II) compounds
such as PdCl2(MeCN)2, PdCl2, and Pd(OAc)2 could catalyze the cross-
coupling of cyclopropylmethyl N-tosylhydrazones with aryl bro-
mides under modified conditions. Herein, we report Pd(II)-catalyzed
cross-coupling reactions of cyclopropylmethyl N-tosylhydrazones
with aryl bromides to form 1,1-disubstitued 1,3-butadienes as well
as 1,1,4-trisubstitued 1,3-butadienes in a one-pot fashion.
Initially, the reaction of cyclopropylmethyl N-tosylhydrazone11b
(1a) and bromobenzene (2a) was chosen to screen the reaction
conditions (Table 1).12 The target product 3a was obtained in
69% yield by means of Pd(PPh3)4 as catalyst, Xphos as ligand, LiOt-
Bu as base, and dioxane as solvent (Table 1, entry 1), while a better
yield (75%) could be achieved in the case of using Pd(OAc)2 as cat-
alyst (Table 1, entry 2). This preliminary result encouraged us to
perform the reaction in the presence of various Pd(II) sources. It
was found that PdCl2 and Pd(PPh3)2Cl2 also effectively promoted
the reaction (Table 1, entries 3 and 4). Surprisingly, Pd(MeCN)2Cl2
remarkably improved the reaction efficiency, affording 3a in 81%
isolated yield (Table 1, entry 5). Both base and ligand effects were
obvious to affect the product yields (Table 1, entries 5–15), and
among the screened bases, that is, LiOtBu, Cs2CO3, K3PO4, KOtBu,
Recently, nonstabilized diazo precursors generated in situ from N-
tosylhydrazones have been employed as the nucleophilic coupling
partners for palladium-catalyzed cross-coupling to form a C@C
bond.9,10 In this aspect, electrophilic coupling partners, for example,
aryl halides, aryl triflates, aryl nonaflates have been used in palla-
dium-catalyzed cross-coupling reactions of N-tosylhydrazones.11
⇑
Corresponding author. Tel./fax: +86 411 8437 9227.
E-mail address: zkyu@dicp.ac.cn (Z. K. Yu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.072

6486
Q. Yang et al. / Tetrahedron Letters 54 (2013) 6485–6489
Table 1
and NaOtBu, LiOtBu behaved as the most effective base and KOtBu
did not work (Table 1, entries 5–9). Ligands Xantphos and PCy3
failed to facilitate the reaction, PPh3, dppf, dppb, and BINAP did
not efficiently acted as compared to Xphos ligand (Table 1, entries
5 and 10–15). Solvents also affected the formation of 3a (Table 1,
entries 5 and 16–19). Extending the reaction time slightly in-
creased the product yield (Table 1, entry 20), and increasing the
amount of N-tosylhydrazone 1a led to the desired product in 93%
isolated yield (Table 1, entry 21). Thus, the reaction conditions
were optimized to those for entry 21 in Table 1.
Palladium-catalyzed cross-coupling of N-tosylhydrazone (1a) with bromobenzene
(2a) to synthesize 1,1-disubstituted butadiene (3a)a
[Pd] (5 mol %)
NNHTs
Ph
ligand (10 mol %)
(1)
+
PhBr
Ph
base (2.2 equiv)
o
Ph
solvent, 90
C
1a
2a
3a
Entry
[Pd] source
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
PdCl2
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xantphos
PCy3
PPh3
dppf
dppp
BINAP
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
Cs2CO3
K3PO4
KOtBu
NaOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
NMP
69
75
79
71
To establish the generality of the protocol, the substrate scope
for aromatic bromides (2) was explored (Table 2). Electron-donat-
ing groups such as methyl and methoxy, and electron-withdrawing
substituents F, Cl, MeCO, and NO2 were tolerant in the aryl bromide
substrates, and the products of type 3 were obtained in 83–98%
yields. Only in the case of using 4-methoxyphenyl bromide, the
target product 3h was collected in a lower yield (51%). It should
be noted that (Z)/(E)-isomers of the products were obtained from
the reactions, and their molar ratios were close to 1:1 when a 4-
or 3-substituent was present in the aryl bromide substrates. How-
ever, a 2-methyl substituent remarkably altered the stereoselectiv-
ity of product 3d (Z/E = 92:8). The increased steric hindrance from
naphthyl resulted in Z/E = 92:8 in product 3j, revealing the (Z)-iso-
mer as the major product. As expected, when 1-bromo-4-chloro-
benzene was used as the substrate, the aryl bromide
functionality was preferentially transformed to product 3g and
the chloro moiety was tolerated. However, by means of Wang’s
catalytic system, the aryl chloro functionality could be coupled
with the N-tosylhydrazone at the same time,11b suggesting that
the present catalytic system can demonstrate a better substituent
tolerance. A heteroaryl also has impact on the stereochemistry of
the product, that is, 3k. The aryl dibromide, that is, 1,4-C6H4Br2,
Pd(PPh3)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
89 (81)c
22
43
trace
45
trace
trace
54
41
53
14
81
9
10
11
12
13
14
15
16
17
18
19
20d
21d,e
79
84
55
DME
DMF
Dioxane
Dioxane
90 (82)c
95 (93)c
a
Reaction conditions: 1a, 0.5 mmol; 2a, 0.5 mmol; [Pd], 0.025 mmol; ligand,
0.05 mmol; base, 1.1 mmol; solvent, 2 mL; 0.1 MPa N2, 1 h.
b
GC yield by using mesitylene as the internal standard.
Yield of the isolated product in parentheses.
2 h.
c
d
e
Compound 1a, 0.6 mmol.
Table 2
Synthesis of 1,1-disubstituted butadienes (3) from the reactions of N-tosylhydrazones (1a) with ArBr (2)a,b
PdCl (MeCN) (5 mol %)
2
2
NNHTs
Ar
Xphos (10 mol %)
(2)
+
ArBr
Ph
LiOtBu (2.2 equiv)
Ph
o
dioxane, 90 C, 2 h
1a
2
3
Ph
Ph
Ph
3c, 98%
(Z/E = 50:50)
Cl
Ph
Ph
3a, 93%
3b, 98%
(Z/E = 50:50)
F
3d, 97%
(Z/E = 92:8)
H3COC
MeO
Ph
3e, 93%
(Z/E = 60:40)
O2N
Ph
3g, 83%
(Z/E = 50:50)
Ph
3f, 89%
(Z/E = 52:48)
Ph
3h, 51%
(Z/E = 52:48)
Ph
Ph
S
Ph
Ph
Ph
3i, 95%
(Z/E = 53:47)
3j, 73%
(Z/E = 92:8)
3k, 88%
(Z/E = 77:23)
3l, 78c%
a
b
c
Reaction conditions: 1a, 0.6 mmol; 2, 0.5 mmol; PdCl2(MeCN)2, 0.025 mmol; Xphos, 0.05 mmol; LiOtBu, 1.1 mmol; dioxane, 2 mL; 0.1 MPa N2, 90 °C, 2 h.
Isolated yields based on 2. The Z/E ratios of 3 were determined by 1H NMR analysis.
0.25 mmol 1,4-C6H4Br2 was used. The Z/E ratio of 3l could not be determined by 1H NMR analysis.

Q. Yang et al. / Tetrahedron Letters 54 (2013) 6485–6489
6487
Table 3
Synthesis of 1,1-disubstituted butadienes (3) from the reactions of N-tosylhydrazones (1) with ArBr (2)a,b
PdCl (MeCN) (5 mol %)
2
2
NNHTs
Ar
Xphos (10 mol %)
(3)
+
ArBr
R
LiOtBu (2.2 equiv)
R
o
dioxane, 90 C, 2 h
1
2
3
Ph
Ph
Ph
Ph
MeO
tBu
3b, 90%
(Z/E = 50:50)
Ph
3m, 94%
(Z/E = 50:50)
Ph
3n, 86%
(Z/E = 96:4)
Ph
3e, 95%
(Z/E = 57:43)
Ph
Me
Cl
F
3f, 92%
(Z/E = 53:47)
3g, 97%
(Z/E = 50:50)
MeO
3o, 44%c
3j, 38%
(Z/E = 92:8)
F
3p, 54%
Cl
F
MeO
Cl
3q, 92%
3r, 88%
3s, 95%
3t, 87%
a
b
c
Reaction conditions: 1, 0.6 mmol; 2, 0.5 mmol; PdCl2(MeCN)2, 0.025 mmol; Xphos, 0.05 mmol; LiOtBu, 1.1 mmol; dioxane, 2 mL; 0.1 MPa N2, 90 °C, 2 h.
Isolated yields. The Z/E ratios of 3 were determined by 1H NMR analysis.
20 h.
reacted with 1a to form the corresponding bis(1,3-butadiene) 3l in
78% yield, featuring a skipped tetraene.
reaction underwent more efficiently by using of Pd(OAc)2 as cata-
lyst. LiOtBu base facilitated the transformation of 3a to 4a, whereas
other bases did not work very well for this step reaction. Ligands
and solvents also affected the formation of the intermediate spe-
cies 3a. Eventually, the conditions for the cross-coupling of 1a with
2a to form 4a were optimized to 5 mol % Pd(OAc)2 as catalyst,
10 mol % Xphos as ligand, and LiOtBu (4 equiv) as base, dioxane
as solvent, 100 °C for 18 h, and the reaction was carried out in a
10-mL sealed tube to yield 4a in 64% yield.13
Under the optimized reaction conditions, diverse reactions of
N-tosylhydrazones (1) with aryl bromides (2) were investigated
(Table 4). Both the electron-donating and -withdrawing substitu-
ents such as methyl, methoxy, chloro, and fluoro were tolerant.
The steric hindrance from 2-methyl or naphthyl is evident, leading
to 4c and 4e in relatively poor yields (32% and 26%). It seems that
such a steric effect lessened the reaction efficiency for both the
cross-coupling of 1 with 2 and the subsequent Heck reaction of
intermediate 3 with 2 in the reaction sequence. In other cases,
the trisubstituted 1,3-diene products were obtained in moderate
to good yields (33–70%). 1,1,4-Trisubstitued 1,3-dienes are usually
synthesized from the reactions of alkenyl halides, alkenes, or 1,3-
dienes with aryl halides.3 To the best of our knowledge, a one-
pot process has not been established in this area.
Next, the scope of substrates N-tosylhydrazones (1) was inves-
tigated (Table 3). A relatively broad range of N-tosylhydrazone
derivatives smoothly underwent the cross-coupling to produce
the target products 3 in 87–97% yields. The substituent effect from
those electron-donating or -withdrawing groups on the aryl moie-
ties of N-tosylhydrazones (1) did not exhibit obvious impact on
their reactivity. However, the alkyl N-tosylhydrazone only showed
a moderate reactivity, yielding the target product (E)-3o in 44%
yield over a period of 20 h. 2-Methyl substituent remarkably in-
creased the stereoselectivity of product 3n (Z/E = 96:4). The bulky
naphthyl N-tosylhydrazone did not exhibit a high reactivity either,
producing 3j and 3p in 38% and 54% yields, respectively. When
both the two substrates bear the same aryl moieties, the resultant
products, that is, 3a and 3p–t, only exhibit one configuration. It is
noteworthy that products of type 3 can be efficiently prepared
through both the procedures described in equations 2 and 3 by
altering the aryl functionalities in 1 and 2.
Heck-type reaction is usually applied for the preparation of
substituted alkenes in the presence of a base under palladium
catalysis. We envisioned that 3 generated in situ could further re-
act with aryl bromides under suitable conditions, affording the cor-
responding trisubstituted 1,3-diene derivatives. We tested the
reaction of 1a with PhBr (2a) by increasing the loadings of PhBr
and LiOtBu each to at least two equivalents under the stated con-
ditions as shown in Tables 2 and 3. To our delight, the desired
product, that is, 4a, was formed in 55% yield at 100 °C within
18 h. After screening the palladium catalysts, we found that the
A plausible mechanism for the formation of 1,3-diene (3) is
proposed as depicted in Scheme 1. Palladium(II) complex A is gen-
erated from the oxidative addition of aryl bromide (2) to the in-situ
formed Pd(0) species. The diazo compound A’ generated in situ
from the decomposition of N-tosylhydrazone (1) reacts with A to
produce palladium-carbene species B. A migratory insertion of

6488
Q. Yang et al. / Tetrahedron Letters 54 (2013) 6485–6489
Table 4
the aryl moiety originated from 2 occurs to afford alkyl palla-
One-pot synthesis of 1,1,4-trisubstituted 1,3-butadienes (4)a,b
dium(II) species C.11b b-Carbon–Pd elimination proceeds to form
intermediate D which subsequently undergoes b-hydride elimina-
tion to form the target product 3.8b
Pd(OAc)2 (5 mol %)
NNHTs
Ar'
Xphos (10 mol %)
Ar'
In summary, we have disclosed an efficient protocol to synthe-
size 1,3-butadienes from the direct cross-coupling of cyclopro-
pylmethyl N-tosylhydrazones with aryl bromides. 1,1-
Disubstituted 1,3-butadienes can be obtained in up to 98% yields
by using PdCl2(MeCN)2 as catalyst. By altering the conditions and
using Pd(OAc)2 as catalyst 1,1,4-trisubstituted 1,3-butadienes were
also prepared in moderate yields. The present methodology pro-
vides a direct route to multisubstituted conjugate butadienes.
(4)
+
2 Ar'Br
Ar
LiOtBu (4 equiv)
Ar
dioxane, 100 oC, 18 h
1
2
4
Ph
Ph
Ph
Ph
Ph
4a, 64%
4b, 57%
(Z,E/E,E = 51:49)
4c, 32%
(Z,E/E,E = 90:10)
Acknowledgment
Cl
Ph
We are grateful to the National Natural Science Foundation of
China (21272232) for support of this research.
Cl
Ph
Ph
Supplementary data
Ph
4d, 53%c
4e, 26%
(Z,E/E,E = 84:16)
4f, 68%
(Z,E/E,E = 53:47)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.09.
072.
OMe
Ph
MeO
Ph
References and notes
Cl
1. (a) Erb, W.; Zhu, J. P. Nat. Prod. Rep. 2013, 30, 161; (b) Biermann, U.;
Bornscheuer, U.; Meier, M. A. R.; Metzger, J. O.; Schäfer, H. J. Angew. Chem., Int.
Ed. 2011, 50, 3854; (c) Trisuwan, K.; Rukachaisirikul, V.; Sukpondma, Y.;
Preedanon, S.; Phongpaichit, S.; Rungjindamai, N.; Sakayaroj, J. J. Nat. Prod.
2008, 71, 1323.
2. (a) Dzhemilev, U. M.; Tolstikov, G. A.; Khusnutdinov, R. I. Russ. J. Org. Chem.
2009, 45, 957; (b) Welker, M. E. Tetrahedron 2008, 64, 11529; For selected
examples, see: (c) Patel, R. M.; Argade, N. P. Org. Lett. 2013, 15, 14; (d) Bouillon,
J.-P.; Mykhaylychenko, S.; Melissen, S.; Martinez, A.; Harakat, D.; Shermolovich,
Y. G. Tetrahedron 2012, 68, 8663.
MeO
4i, 67%
4g, 61%c
4h, 70%
Cl
F
Cl
F
3. (a) Shang, X. J.; Liu, Z. Q. Chem. Soc. Rev. 2013, 42, 3253; Wang, G. W.; Mohan, S.;
Negishi, E.-i. Proc. Natl. Acad. Sci. 2011, 108, 11344.
Cl
4. (a) Delcamp, J. H.; Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2013, 135,
8460; (b) Zheng, C. W.; Wang, D.; Stahl, S. S. J. Am. Chem. Soc. 2012, 134, 16496;
(c) Zhang, Y. X.; Cui, Z. L.; Li, Z. J.; Liu, Z.-Q. Org. Lett. 1838, 2012, 14; (d)
Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 592; (e) Yu, H.
F.; Jin, W. W.; Sun, C. L.; Chen, J. P.; Du, W. M.; He, S. B.; Yu, Z. K. Angew. Chem.,
Int. Ed. 2010, 49, 5792.
5. Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F. Chem.-Eur. J. 2011, 17, 7167.
6. (a) Saito, N.; Saito, K.; Shiro, M.; Sato, Y. Org. Lett. 2011, 13, 2718; (b) Shibata, Y.;
Hirano, M.; Tanaka, K. Org. Lett. 2008, 10, 2829; (c) Nakao, Y.; Yada, A.; Ebata, S.;
Hiyama, T. J. Am. Chem. Soc. 2007, 129, 2428.
F
4j, 33%
4k, 62%
a
Reaction conditions: compound 1, 0.5 mmol; 2, 1.5 mmol; Pd(OAc)2,
0.025 mmol; Xphos, 0.05 mmol; LiOtBu, 2.0 mmol; dioxane, 2 mL; 0.1 MPa N2, 18 h.
The reactions were performed in a 10-mL sealed tube.
Isolated yields. The Z,E/E,E ratios of 4 were determined by 1H NMR analysis.
b
The Z,E/E,E ratios were not successfully determined by 1H NMR analysis.
c
7. (a) Cui, H.; Li, Y.; Zhang, S. L. Org. Biomol. Chem. 2012, 10, 2862; (b) Dong, D.-J.;
Li, H.-H.; Tian, S.-K. J. Am. Chem. Soc. 2010, 132, 5018; (c) Zhou, R.; Wang, C. Z.;
Song, H. B.; He, Z. J. Org. Lett. 2010, 12, 976.
8. (a) Ranu, B. C.; Banerjee, S. Eur. J. Org. Chem. 2006, 3012; (b) Shi, M.; Wang, B.-
Y.; Huang, J.-W. J. Org. Chem. 2005, 70, 5606.
N2
NNHTs
LiOtBu
Ar
1
Ar
A'
Ar'
Br
9. (a) Xiao, Q.; Zhang, Y.; Wang, J. B. Acc. Chem. Res. 2013, 46, 236; (b) Shao, Z. H.;
Zhang, H. B. Chem. Soc. Rev. 2012, 41, 560; (c) Barluenga, J.; Valdés, C. Angew.
Chem., Int. Ed. 2011, 50, 7486.
LnPd
Ar'Br
A
Pd(II)
10. (a) Chen, H. J.; Huang, L.; Fu, W.; Liu, X. H.; Jiang, H. F. Chem.-Eur. J. 2012, 18,
N2
ˇ
10497; (b) Barluenga, J.; Quinones, N.; Cabal, M.-P.; Aznar, F.; Valdés, C. Angew.
Chem., Int. Ed. 2011, 50, 2350; (c) Zhou, L.; Ye, F.; Ma, J. C.; Zhang, Y.; Wang, J. B.
Angew. Chem., Int. Ed. 2011, 50, 3510; (d) Chen, Z.-S.; Duan, X.-H.; Wu, L.-Y.; Ali,
S.; Ji, K.-G.; Zhou, P.-X.; Liu, X.-Y.; Liang, Y.-M. Chem.-Eur. J. 2011, 17, 6918; (e)
Brachet, E.; Hamze, A.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Org. Lett. 2010, 12,
4042; (f) Barluenga, J.; Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Chem.-Eur. J.
2010, 16, 12801; (g) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. B. Chem.
Commun. 2010, 1724; (h) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. B. Org.
Lett. 2009, 11, 4732; (i) Barluenga, J.; Escribano, M.; Moriel, P.; Aznar, F.; Valdés,
C. Chem.-Eur. J. 2009, 15, 13291; (j) Barluenga, J.; Tomás-Gamasa, M.; Moriel, P.;
Aznar, F.; Valdés, C. Chem.-Eur. J. 2008, 14, 4792.
Br
Pd
Ar'
LnPd(0)
Ar'
Ar
B
Ar
3
LiBr + tBuOH
Ar'
Ar
BrPd
11. (a) Florentino, L.; Aznar, F.; Valdés, C. Org. Lett. 2012, 14, 2323; (b) Zhou, L.; Ye,
F.; Zhang, Y.; Wang, J. B. Org. Lett. 2012, 14, 922; (c) Barluenga, J.; Florentino, L.;
Aznar, F.; Valdés, C. Org. Lett. 2011, 13, 510; (d) Barluenga, J.; Escribano, M.;
Aznar, F.; Valdés, C. Angew. Chem., Int. Ed. 2010, 49, 6856; (e) Barluenga, J.;
Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Adv. Synth. Catal. 2010, 352, 3235; (f)
Tréguier, B.; Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. Tetrahedron Lett.
2009, 50, 6549; (g) Barluenga, J.; Moriel, P.; Valdés, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 5587.
PdBr
LiOtBu
C
Ar'
Ar
D
Scheme 1. Proposed mechanism.

Q. Yang et al. / Tetrahedron Letters 54 (2013) 6485–6489
6489
12. A general procedure for the direct synthesis of 1,1-disubstituted-1,3-butadienes (3)
from the cross-coupling reactions of N-tosylhydrazones (1) with aryl bromides
(2)—synthesis of 3a: under nitrogen atmosphere, cyclopropylmethyl N-
tosylhydrazone (1a, 189 mg, 0.6 mmol), PdCl2(MeCN)2 (6.5 mg, 0.025 mmol),
13. A general procedure for the direct synthesis of 1,1,3-trisubstituted-1,3-butadienes
(4)—synthesis of 4a: under nitrogen atmosphere, cyclopropylmethyl N-
tosylhydrazone (1a, 157 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol),
Xphos (23.8 mg, 0.05 mmol), lithium t-butoxide (160 mg, 2 mmol), and
2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl
(Xphos)
(23.8 mg,
dioxane (2 mL) were successively added to a 10-mL sealed tube with
0.05 mmol), lithium t-butoxide (88 mg, 1.1 mmol), and dioxane (2 mL) were
successively added to a 10-mL Schlenck flask with stirring. After the mixture
was stirred for one minute, phenyl bromide (2a, 78.5 mg, 0.5 mmol) was
added. The resultant mixture was stirred at 90 °C for 2 h. After cooled to
ambient temperature, the reaction mixture was filtered through a short pad of
celite and rinsed with 20 mL CH2Cl2. The combined filtrate was concentrated
under reduced pressure and the resulting residue was purified by flash column
chromatography on silica gel (eluent: petroleum ether (60–90 °C)) to afford
product 3a (96 mg, 93%) as a colorless oil.
stirring. After the resultant mixture was stirred for one minute, phenyl
bromide (2a, 236 mg, 1.5 mmol) was added. The reaction mixture was stirred
at 100 °C for 18 h. After cooled to ambient temperature, the resultant mixture
was filtered through a short pad of celite and rinsed with 20 mL CH2Cl2. The
combined filtrate was concentrated under reduced pressure and the resulting
residue was purified by flash column chromatography on silica gel (eluent:
petroleum ether (60–90 °C)) to afford product 4a (90 mg, 64%) as a colorless
oil.