Practical access to spiroacetal enol ethers via nucleophilic dearomatization of 2-furylmethylenepalladium halides generated by Pd-catalyzed coupling of furfural tosylhydrazones with aryl halides

Article abstract of DOI:10.1039/c4cc01725k

Pd-catalyzed cross-coupling of furfural tosylhydrazones with aryl halides produces 2-furylmethylenepalladium halides, which can undergo intramolecular nucleophilic dearomatization to provide spiroacetal enol ethers. This is the first report on the formati

Full text of DOI:10.1039/c4cc01725k

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Biaolin Yin et al.
Practical access to spiroacetal enol ethers via nucleophilic
dearomatization of 2-furylmethylenepalladium halides generated by
Pd-catalyzed coupling of furfural tosylhydrazones with aryl halides

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Practical access to spiroacetal enol ethers via
nucleophilic dearomatization of 2-furylmethylene-
palladium halides generated by Pd-catalyzed
coupling of furfural tosylhydrazones with
aryl halides†
Cite this: Chem. Commun., 2014,
50, 8113
Received 7th March 2014,
Accepted 17th April 2014
DOI: 10.1039/c4cc01725k
Biaolin Yin,* Xiaoyu Zhang, Jianchao Liu, Xuehui Li and Huanfeng Jiang
www.rsc.org/chemcomm
Pd-catalyzed cross-coupling of furfural tosylhydrazones with aryl halides
produces 2-furylmethylenepalladium halides, which can undergo intra-
molecular nucleophilic dearomatization to provide spiroacetal enol ethers.
This is the first report on the formation of 2-furylmethylenepalladium
halides from stable furfural hydrazones instead of from 2-furylmethyl
halides, which are not readily accessible or are unstable.
The Pd-catalyzed cross-coupling of tosylhydrazones with aryl halides is
a very simple, powerful method to form C–C bonds using carbonyl
compounds as the nucleophilic components without the need for a
stoichiometric amount of an organometallic reagent.1 This reaction is
believed to occur via the mechanism outlined in Scheme 1. Oxidative
addition of the aryl halide to the Pd0 catalyst gives aryl Pd complex B,
which reacts with diazo compound A (generated in situ from tosyl-
hydrazone 1) to afford Pd carbene complex C. This complex can
undergo migratory insertion of the aryl group into the C–Pd bond to
give arylmethylenepalladium halide D (path a), which then either
undergoes b-hydrogen elimination to provide an olefin2 or is inter-
cepted by a nucleophile.3 This cross-coupling is an alternative to the
preparation of D via oxidative addition reactions between a Pd0
catalyst and arylmethyl halides 3 (path b), which are not readily
available or are unstable.4 The development of new coupling reactions
based on tosylhydrazones and exploration of their synthetic applica-
tions currently are attractive research topics.
Furan derivatives, such as furfurals, are readily available from
a renewable feedstock such as biomass.5 Furans demonstrate
the typical arene reactivity of heteroaromatic compounds,6 but
owing to the low aromaticity of the furan ring, they can also
behave as synthetic equivalents of alkenes, 1,3-dienes, alkynes,
1,4-diketones, and enol ethers.7,8 Thus, furans are attractive four-
carbon starting materials for various chemical transformations.
Because of the electron richness of the furan ring, 2-furylmethyl
Scheme 1 Formation and transformation of arylmethylenepalladium D.
halides are usually unstable and prone to oligomerization even
at room temperature. Accordingly, it is difficult to prepare and to
investigate the chemical properties of the exceedingly reactive
2-furylmethylenepalladium halides generated via oxidative addi-
tion of 2-furylmethyl halides to Pd0. On the basis of the pathway
shown in Scheme 1, we envisioned that coupling of 2-furfural
tosylhydrazone 4 with an aryl halide (Scheme 2) would produce
2-furylmethylenepalladium halide
5
or Z3-furylmethylene-
palladium halide 6 (via s–p isomerization of 5). Because the
structure of 6 is similar to that of other Z3-arylmethylene-
palladium halides, it could undergo intramolecular nucleophilic
dearomatization4d–g if a suitable nucleophile was tethered at
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, PR China. E-mail: blyin@scut.edu.cn;
Fax: +86 20 8711 3735
† Electronic supplementary information (ESI) available: Copies of 1H NMR and
13C NMR spectra of all the new compounds. See DOI: 10.1039/c4cc01725k
Scheme 2 Formation and dearomatization of 5.
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the 2-position of the furan ring (path c). As part of our ongoing solvents, such as DMF, DCE, THF, and 1,4-dioxane (entries 19–22).
studies on furan dearomatization9 and the use of furans as The optimal yield was obtained using Pd2(dba)3 as the catalyst,
building blocks,10 we report herein the dearomatizing transforma- L2 as the ligand, toluene as the solvent, and 90 1C as the
tions of 2-furylmethylenepalladium halides generated by Pd-catalyzed reaction temperature.
coupling of aryl halides with furfural tosylhydrazones 4, which
have a hydroxypropyl group tethered at the 2-position of the
furan ring, to prepare spiro dienyl ethers.11,12
First, the reaction of 4a with PhBr was employed as a model
to optimize the reaction conditions (Table 1). Using Pd(PPh3)4
as the catalyst and LiOtBu as the base, reaction in toluene at
90 1C for 2 h afforded 7a in 31% yield as an inseparable Z/E
mixture (Z/E = 4/1, entry 1). The stereochemistry of 7a was
Next, we investigated the substrate scope of the transformation
unambiguously established by 2D-NMR spectroscopy (see the by reacting 4a with various aryl bromides under the optimized
NOESY spectrum of 7a in the ESI†). The Z-isomers demon- conditions (Table 2). The substituent on the phenyl ring clearly
influenced the reaction outcome. When R was electron-donating,
the reaction gave the desired products (7a–7g) in moderate to
good yields. Electron-withdrawing groups generally led to lower
yields of the corresponding products (7h–7l). When R was a
strated the NOEs between the olefinic protons of an enol ether
and an endo-cyclic double bond. To improve the yield of 7a, we
screened various Pd catalysts, ligands, bases, and solvents.
Pd2(dba)3 showed superior catalytic activity (entry 5), affording
7a in 52% yield (entry 5). Among the ligands examined, 2,4-dinitro group, none of the desired product (7l) was detected,
tricyclohexyl phosphine L2 gave the highest yield of 7a (74%, implying that the electron-rich phenyl ring favored the for-
entry 8). Other bases, including KOtBu, NaOtBu, NaH, and mation of 6 and thus led to a higher yield of 7. 2-Naphthyl
K2CO3 did not improve the yield (entries 15–18), nor did other bromide and 2-thienyl bromide gave 7m and naturally occur-
ring 7n,13 respectively, in good yields. The stereochemistry of
7b–7n was assigned as shown in Table 2 in analogy with 7a, with
Z-isomer as the major or exclusive one. Nitrogen-containing aryl
bromides, such as 2-pyridyl bromide, 2-quinolyl bromide, and
Table 1 Optimization of reaction conditions for coupling of 4a with
PhBra,b
2-pyrimidyl bromide, also afforded the desired products (7o–7q),
but in low yields, perhaps because of the electron-poor nature
of the nitrogen-containing rings. Notably, 7o was produced as
exclusive E-isomer based on the NOESY spectrum (see ESI†).
The stereochemistry of 7p and 7q was assigned as the exclusive
Conditions
Entry
Catalyst
Ligand
Base
Yieldc [%]
Table 2 Substrate scope of reaction of 4aa
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(MeCN)2Cl2
Pd(OAc)2
—
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
KOtBu
NaOtBu
NaH
31
PPh3
PPh3
—
PPh3
BINAP
L1
L2
L3
L4
dppp
dppf
dppe
L5
L2
L2
L2
L2
L2
L2
40
NDd
18
Pd(PPh3)2Cl2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
52
22
17
74
32
25
Trace
18
Trace
NDd
7
9
10
11
12
13
14
15
16
17
18
19e
20f
21g
22h
28
Trace
Trace
ND
28
45
ND
K2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
L2
L2
a
Reaction conditions: 4a (1.0 equiv.), PhBr (1.2 equiv.), Pd (5.0 mol%),
b
ligand (10 mol%), base (3.5 equiv.), 90 1C for 2 h. The solvent was
toluene unless stated otherwise. All reactions were performed at a
0.3 mmol scale. Yield determined by 1H NMR analysis with mesitylene
c
a
as an internal standard. The products were Z/E mixtures (approximately
All reactions were performed at a 0.3 mmol scale; percentages are
4/1), as indicated by 1H NMR analysis of the crude product. Not isolated yields; ratios of Z/E isomers were determined by 1H NMR
d
e
f
g
analysis of the isolated product mixtures (the Z/E isomers are insepar-
able by flash chromatography).
detected. DMF was the solvent. DCE was the solvent. THF was
h
the solvent. 1,4-Dioxane was the solvent.
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To rationalize the stereoselectivities obtained, we proposed
stereochemical models A, B and C (Scheme 3). For 7a–7n, model A
was preferred due to the absence of interaction between the
phenyl group and the ligand (model A vs. model B). While for
7o–7q, these reactions exclusively proceeded through model C due
to the chelation between the nitrogen atom and palladium.
In summary, we have developed a simple, practical Pd-catalyzed
coupling of furfural hydrazones with aryl halides, which proceeds via
2-furylmethylenepalladium halide intermediates to provide efficient
access to spiroacetal enol ethers. This is the first report on the
formation of 2-furylmethylenepalladium halides from stable furfural
hydrazones instead of from unstable 2-furylmethyl halides. The
2-furylmethylenepalladium halides can undergo intramolecular
nucleophilic dearomatization, and thus this protocol greatly expands
the synthetic applications of furan derivatives, which can be
obtained sustainably. Further exploration of the reaction scope,
especially the variation of the dearomatizing aryl rings and nucleo-
philes, is currently underway in our laboratory, with the goal of
synthesizing bioactive and natural products via this route.
This work was supported by the National Natural Science
Foundation of China (Nos 21072062, 21272078 and 21336002),
the Fundamental Research Funds for the Central Universities
(2014ZG0027), the Natural Science Foundation of Guangdong
Province, China (10351064101000000), and the Program for
New Century Excellent Talents in Universities (NCET-12-0189).
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