Palladium-catalyzed cross-coupling reactions of electron-deficient alkenes with N-tosylhydrazones: Functional-group-controlled C-C bond construction

Article abstract of DOI:10.1002/chem.201202051

In the zone: A palladium-catalyzed cross-coupling reaction of electron-deficient alkenes with N-tosylhydrazones, which affords diverse C-C bonds resulting from the functional-group-controlled effect, is reported (see scheme). These cascade transformations present remarkable stereoselectivity and a high synthetic potential. The presence of water substantially promotes both reaction routes. Copyright

Full text of DOI:10.1002/chem.201202051

COMMUNICATION
DOI: 10.1002/chem.201202051
Palladium-Catalyzed Cross-Coupling Reactions of Electron-Deficient
Alkenes with N-Tosylhydrazones: Functional-Group-Controlled
À
C C Bond Construction
Huanfeng Jiang,* Wei Fu, and Huoji Chen[a]
Due to the versatility of the cyclopropane unit in organic
synthesis and the occurrence of a number of important cy-
clopropane-containing natural products and synthetic mate-
rials, the synthesis of cyclopropanes has drawn considerable
attention.[1] The most commonly used route is the transition-
metal-catalyzed decomposition of diazo compounds in the
presence of an alkene, in which a formal [2+1] cycloaddition
of metal–carbene complexes to alkenes proceeds rapidly[2]
and excellent stereoselectivity can be achieved in many
cases.[3] Nevertheless, in consideration of the stability and
Scheme 1. Initial studies of water concentration.
operability of diazo compounds without an electron-with-
drawing group, N-tosylhydrazones are readily prepared
from carbonyl compounds and are likely to have remarkable
synthetic potential as an in situ source of diazo com-
pounds.[4] This possibility extends the current methods for
the modification of carbonyl compounds.
After decades of development, palladium-catalyzed
carbon–carbon bond-forming reactions can be recognized as
one of the cornerstones in current organic synthetic chemis-
try.[5] The impressive selectivity, availability, and functional-
group tolerance illustrates the tremendous enabling ability
of these modern synthetic tools.[6] Moreover, sequential
transformations and multifarious coupling partners, ranging
from traditional organic reagents to organometallic reagents,
also promote the efficiency and application in total synthesis
of this type of reaction.[7]
Recently, great efforts have been made to develop Pd-cat-
alyzed carbene cross-coupling reactions based on N-tosylhy-
drazones due to these advantages.[8] With relation to our in-
terest in palladium chemistry,[9] we envisioned the possibility
of exploring a Pd-catalyzed, new, intermolecular cross-cou-
pling reaction between N-tosylhydrazones and functional-
ized terminal alkenes.
timal for reactions involving electron-deficient rather than
electron-rich alkenes.[10] Only a trace amount of the cyclo-
propane-containing product 3a was detected when an anhy-
drous solvent was used. After extensive screening of the re-
action conditions, the yield rose to about 30% when a hy-
drous solvent was used. This implied that the product yield
was dependent on the concentration of water in the reac-
tion. Initial studies elucidated that the electron-deficient ter-
minal alkenes could be effectively cyclopropanated by using
the Pd–carbene catalyst when 2.0 equivalents of water were
added.[11]
The investigation of different catalysts convinced us that
the palladium catalyst could not be neglected in this reac-
tion (Table 1, entry 1). A dramatic suppression effect caused
by extra ligands resulted in lower yields (Table 1, entries 2–
8). As a consequence, palladium acetate was chosen to cata-
lyze this cross-coupling reaction.
With the optimized reaction conditions, we then studied
the scope of this reaction by using various N-tosylhydra-
zones and acrylamides. As illustrated in Table 2, the cross-
Table 1. Investigation of the catalyst.[a]
At the outset of this investigation, we explored the Pd-
catalyzed reaction between N-tosylhydrazone (1a) and
acrylamide (2a; Scheme 1) because in comparison with Rh,
Ru, Co, and Cu metal–carbenes, Pd metal–carbenes are op-
Entry
Catalyst
Yield[b] [%]
1
2
3
4
5
6
7
8
–
0
Pd
PdCl2
Pd(OAc)2
[PdCl2A(PPh3)2]
[PdCl2A(CH3CN)2]
(dba)2]
(PPh3)4]
A
73 (68)
45
42
55
32
[c]
N
A
U
[a] Prof. Dr. H. F. Jiang, W. Fu, H. Chen
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (P.R. China)
Fax : (+86)20-8711-2906
A
U
[Pd
[Pd
U
35
50
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol),
a catalyst
E-mail: jianghf@scut.edu.cn
(10 mol%), H2O (2.0 equiv), and tBuOLi (3.0 equiv) in CH3CN (3 mL,
distilled) for 14 h under N2. [b] Determined by GC, number in parenthe-
ses is isolated yield. [c] PPh3 (25 mol%) was added.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202051.
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coupling reaction proceeds smoothly with a wide range of
substrates to provide moderate to good yields. The cross-
coupling reaction of aromatic N-tosylhydrazones containing
electron-withdrawing or electron-donating groups gave the
desired products 3a–3 f (Table 2). The naphthyl N-tosylhy-
drazone was also a suitable substrate for this reaction (3g).
Heterocyclic N-tosylhydrazones, such as those based on
furan and benzofuran, also reacted smoothly with acryl-
AHCTUNGTREGaNNNU mide under similar conditions (3h and 3i). Notably, cyclic
N-tosylhydrazones performed well and gave the correspond-
ing products (3j–3l) in moderate yield. The steric hindrance
of N-benzyl-N-(tert-butyl)acrylamide implied that it would
not be a useable substrate; however, it reacted well with
substrates containing either electron-withdrawing or -donat-
ing groups to give the products 3m and 3n. Remarkably, the
formation of 3m was completely stereoselective, and the
structure was confirmed by X-ray diffraction (Scheme 2).
An acrylamide substrate containing a morpholine fragment
Table 2. Palladium-catalyzed cross-coupling of various N-tosylhydrazones
and acrylamides.[a]
Scheme 2. X-ray crystal structure of 3m.
was also found to be a reasonable coupling partner (3o and
3p). Encouraged by these initial findings, the a,b-unsaturat-
ed ketones were examined to provide a more extensive
scope of the electron-deficient terminal alkenes that suit this
strategy. The coupling reactions between N-tosylhydrazones
and the ketones proceeded effectively and a series of chain
products, shown in Table 3, were obtained. The reaction was
not significantly affected by the substituents on the aromatic
ring of the N-tosylhydrazones. Electron-donating and -with-
drawing groups were tolerated under the reaction conditions
(5a–5d). Naphthyl, cyclic, and heterocyclic N-tosylhydra-
zones also underwent smooth reactions to afford the corre-
sponding products (5e–5g) in good yields. The ketone sub-
strate containing a long aliphatic carbon chain was also a
good coupling partner (5h). The reactions of both alkyl- and
aryl-substituted N-tosylhydrazones were performed in a
highly stereoselective manner to produce compounds 5i and
5j; however, the reaction results were more complicated
when other aryl-substituted ketone substrates were treat-
ed.[11] In these cases, yields were low or only trace amounts
were obtained, and mixtures of chain and cyclopropane
product were detected.
To determine how water promotes this cross-coupling re-
action, two deuterium-labeling experiments were carried out
(Scheme 3). Under the optimized conditions, 2.0 equivalents
of D2O were added to the reaction instead of H2O (Sche-
me 3,a). Similarly, the deuterated substrate [D3]-1a was re-
acted with 2a (Scheme 3,b). The results suggest that the cy-
clopropane products might not directly originate from a
metallacyclobutane intermediate.[11]
The desired chain or cyclopropane product was not de-
tected when the N-tosylhydrazone derived from benzalde-
hyde (6a) was subjected to reactions with the functionalized
terminal alkenes (Scheme 4), indicating that the b-hydrogen
atoms may participate in the reaction processes. Although
[a] Reaction conditions:
(10 mol%), H2O (2.0 equiv), and tBuOLi (3.0 equiv) in CH3CN (3 mL,
distilled) for 14 h under N2. [b] Isolated yield.
1 (0.25 mmol), 2 (0.25 mmol), PdACHTNGUTREN(NGUN OAc)2
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Pd-Catalyzed Cross-Coupling Reactions of Electron-Deficient Alkenes
COMMUNICATION
Table 3. Palladium-catalyzed cross-coupling of various N-tosylhydrazones
and ketones.[a]
Scheme 3. Deuterium-labeling experiments.
Scheme 4. Control experiments.
Decomposition of the diazo compound, which is generat-
ed in situ from N-tosylhydrazone in the presence of base, by
a palladium catalyst leads to the palladium–carbene A.[4] Cy-
cloaddition of carbene A to an electron-deficient terminal
alkene affords a metallacyclobutane intermediate, B or C.
Intermediate D would be produced from C by a b-hydrogen
elimination process (Scheme 5, route 1).[12] The second b-hy-
drogen elimination might be suppressed by a stronger coor-
dination effect resulting from resonance isomerization.[13]
Amide intermediates D then undergo an alkene insertion to
give cyclopropane structures.[14] A conceivable steric state
(E) may be responsible for the complete stereoselectivity of
the reaction. Considering the deuterium-labeling experi-
ments (Scheme 2), reductive elimination and protonolysis[15]
are expected to work together to finish the last procedure
and form compound F (Scheme 6).
[a] Reaction conditions:
(10 mol%), H2O (2.0 equiv), and tBuOLi (3.0 equiv) in CH3CN (3 mL,
distilled) for 14 h under N2. [b] Isolated yield. [c] No water was added.
[d] The E/Z selectivity was determined by H NMR spectroscopy.
1 (0.25 mmol), 4 (0.35 mmol), PdACHTNGUTREN(NGUN OAc)2
1
the desired cyclopropane products were not synthesized
when ketones were applied, this result would be helpful for
understanding the mechanism of this reaction system. A fea-
sible mechanism derived from the acquired results was con-
ceived (Scheme 5).
The weaker coordination effect of the ketone intermedi-
ates G is likely to make an alkene insertion unachievable,
instead leading to chain products H (Scheme 5, route 2).[16]
Probably, the water acts as an additional proton source and
ligand to restrain the b-hydro-
gen elimination process.[17]
In conclusion, we have un-
covered an alternative protocol
for the Pd-catalyzed intermo-
lecular cross-coupling reaction
of electron-deficient terminal
alkenes and N-tosylhydrazones.
Notably, the presence of water
substantially promotes both
cascade reaction routes, by
À
which diverse C C bonds
could be created as a result of
variations in the the electron-
withdrawing group of the al-
kenes. Further mechanistic
studies and the application of
this strategy to the selective
À
Scheme 5. Proposed reaction mechanism.
synthesis of C C bonds, de-
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H. F. Jiang et al.
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General procedure for the reaction of N-tosylhydrazone (1a) and N,N-di-
methylacrylamide (2a): PdACTHNUTRGNEU(GN OAc)2 (5.6 mg, 0.025 mmol), CH3CN (3 mL),
N-tosylhydrazone (72 mg, 0.25 mmol), N,N-dimethylacrylamide (25 mg,
0.25 mmol), water (9 mg, 0.5 mmol), and tBuOLi (60 mg, 0.75 mmol)
were added successively to a Schlenk tube. After stirring for 14 h at 908C
under a nitrogen atmosphere, the mixture was cooled to room tempera-
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were separated. The aqueous phase was extracted twice with ethyl ace-
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697 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.27–7.32 (m, 4H), 7.19–7.23
;
(m, 1H), 3.10 (s, 3H), 3.02 (s, 3H), 1.99 (dd, J=8.3, 6.0 Hz, 1H), 1.58
(dd, J=5.8, 4.9 Hz, 1H), 1.41 (s, 3H), 1.38 ppm (dd, J=8.4, 4.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=170.37, 145.80, 128.53, 126.12, 37.49,
35.63, 29.68, 27.59, 19.46, 19.09 ppm; HRMS (ESI): m/z calcd for
C13H17NO: 204.1383 [M+H+]; found: 204.1388.
Acknowledgements
We thank the National Natural Science Foundation of China (20932002
and 21172076), the National Basic Research Program of China (973 Pro-
gram) (2011CB808600), the Guangdong Natural Science Foundation
(10351064101000000), and the Fundamental Research Funds for the Cen-
tral Universities (2010ZP0003) for financial support.
Keywords: alkenes · domino reactions · cyclopropanes ·
electron-deficient compounds
palladium
·
N-tosylhydrazones
·
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Pd-Catalyzed Cross-Coupling Reactions of Electron-Deficient Alkenes
COMMUNICATION
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Received: June 9, 2012
Published online: && &&, 0000
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H. F. Jiang et al.
Cross-Coupling Reactions
H. F. Jiang,* W. Fu,
H. Chen ........................ &&&& — &&&&
Palladium-Catalyzed Cross-Coupling
Reactions of Electron-Deficient
Alkenes with N-Tosylhydrazones:
Functional-Group-Controlled
In the zone: A palladium-catalyzed
cross-coupling reaction of electron-
deficient alkenes with N-tosylhydra-
(see scheme). These cascade transfor-
mations present remarkable stereose-
lectivity and a high synthetic potential.
The presence of water substantially
promotes both reaction routes.
À
C C Bond Construction
À
zones, which affords diverse C C
bonds resulting from the functional-
group-controlled effect, is reported
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!