Dehydrative Synthesis of Functionalized Skipped Dienes from Stabilized Phosphonium Ylides and Allylic Alcohols in Water

Article abstract of DOI:10.1002/adsc.201801266

A mild and extra activator-free dehydrative alkylation of stabilized phosphonium ylides with allylic alcohols in water is developed in the presence of [Pd(allyl)Cl]₂/dppf catalyst. A wide range of aryl, heteroaryl, alkyl and even allylic tertiary alcohols can readily react with stabilized phosphonium ylides with high regioselectivity for the efficient synthesis of functionalized skipped dienes in moderate to high yields. The role of water was investigated by means of a high-resolution mass spectrum and diffusion-ordered spectroscopy nuclear magnetic resonance, and the results revealed that water might play a crucial role in the formation of the π-allylpalladium complex via hydrogen bond. However, the present method is not suitable for water-sensitive phosphonium ylides. (Figure presented.).

Full text of DOI:10.1002/adsc.201801266

Title: Dehydrative Synthesis of Functionalized Skipped Dienes from
Stabilized Phosphonium Ylides and Allylic Alcohols in Water
Authors: Xiantao Ma, Jing Yu, Cuijie Han, Qiuju Zhou, Mengjuan Ren,
Lixin Li, and Lin Tang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801266
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10.1002/adsc.201801266
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Dehydrative Synthesis of Functionalized Skipped Dienes from
Stabilized Phosphonium Ylides and Allylic Alcohols in Water
Xiantao Ma,*a Jing Yu, a Cuijie Han, a Qiuju Zhou, b Mengjuan Ren, a Lixin Li a and Lin
Tang*a
a
College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang, Henan 464000, China.
E-mail: xiantaoma@126.com; lintang@xynu.edu.cn
Analysis & Testing Center, Xinyang Normal University, Xinyang, Henan 464000, China.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
alcohols, more easily-available, cheaper and stable,
Abstract: A mild and extra activator-free dehydrative
alkylation of stabilized phosphonium ylides with allylic have not been employed to streamline the synthesis
alcohols in water is developed in the presence of
of functionalized terminal skipped dienes.[9]
[Pd(allyl)Cl]2/dppf catalyst.
A wide range of aryl,
With our continuous interests in alcohol-based
alkylation[10] and aqueous media reactions,[11] herein,
heteroaryl, alkyl and even allylic tertiary alcohols can
readily react with stabilized phosphonium ylides with high
regioselectivity for the efficient synthesis of functionalized
skipped dienes in moderate to high yields. The role of
water was investigated by means of a high-resolution mass
spectrum and diffusion-ordered spectroscopy nuclear
magnetic resonance, and the results revealed that water
might play a crucial role in the formation of the л-
allylpalladium complex via hydrogen bond. However, the
present method is not suitable for water-sensitive
phosphonium ylides.
Keywords: Skipped dienes; Dehydrative synthesis; Allylic
alcohols; Water media; Hydrogen bond
Skipped dienes (also called 1,4-dienes) are important
motifs in natural products and biologically active
compounds showing unique antileukemia, antibiotic
and anticancer properties.[1] Therefore, much
attention has been paid for the synthesis of them.[2]
They are traditionally prepared by transition metal
(TM)-catalyzed
allylic
cross-couplings
of
alkenylmetal reagents with allylic partners under
harsh conditions (Scheme 1A).[3] Recently, TM-
catalyzed cross-couplings of simple alkenes[4] or dual
functionalization of alkynes[5] have been developed as
more preferable methods (Scheme 1B). However,
these methods are mainly restricted to the synthesis
of inner skipped dienes. To our best knowledge,
reports on the synthesis of functionalized terminal
skipped dienes are still rare.[6]
Phosphonium ylides are widely used in organic
synthesis.[7] The groups of You and Tian have
independently reported the allylic alkylation of
phosphonium ylides with allylic esters or amines for
the efficient synthesis of terminal functionalized
skipped dienes (Scheme 1C).[8] Possibly owing to the
poor leaving character of the hydroxy group, allylic
Scheme 1. Common methods for skipped diene synthesis
we wish to report a mild and activator-free
dehydrative
cross-couplings
of
stabilized
phosphonium ylides with allylic alcohols in water
media for the efficient synthesis of functionalized
terminal skipped dienes (Scheme 1D). The method
can also be applied to other common allylic
alkylating reagents such as allylic ethers and esters
under additive-free conditions.[12] Diffusion-ordered
spectroscopy nuclear magnetic resonance (DOSY
NMR) experiments suggested that hydrogen bond
might be formed between water and allylic alcohol.[13]
might be formed between water and allylic alcohol.[13]
1
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10.1002/adsc.201801266
Advanced Synthesis & Catalysis
Noteworthy, possibly owing to that water media is
under standard conditions, but by extra adding 10 mol%
TBAB, the target 4e could be obtained in a moderate
yield with specific α selectivity (run 5). On the other
hand, the method could be successfully applied to
aryl, heteroaryl, and alkyl ketone stabilized
phosphonium ylides, affording the target skipped
dienes 4f-l in high yields (runs 6-12).
theoretically
disadvantageous
to
dehydrative
reactions, the activator-free dehydrative couplings of
allylic alcohols in water are much rare.[14-16]
Table 1. Optimization of the reaction conditions[a]
Table 2. Dehydrative synthesis of functionalized
skipped dienes from stabilized phosphonium ylides
and α-unbranched allylic alcohols in water [a]
run
1
[Pd]
[Pd(allyl)Cl]2
Pd(OAc)2
PdCl2
Pd(dba)2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
ligand
dppf
dppf
dppf
dppf
dppb
binap
dppf
dppf
dppf
dppf
dppf
dppf
solvent
H2O
H2O
H2O
H2O
4a/%[b]
92
78
trace
8
45
trace
65
64
60
45
2[c]
3 [c]
4 [c]
5
H2O
H2O
6
7
8
9
MeOH
EtOH
i-PrOH
(CH2OH)2
HFIP
H2O
10
11
trace
80
12[d]
[a]
Unless otherwise noted, the mixture of 1a (0.36 mmol),
2a (0.3 mmol), Pd catalyst (2.5 mol%), ligand (5 mol%) in
a solvent (0.5 mL) was sealed under N2 in a Schlenk tube,
heated at 60 oC for 10 h, then HCHO (37% v/v in water, 3
equiv.) was added and stirred at rt for another 6 h and
]
[b
monitored by TLC and/or GC-MS.
isolated yield based
on 2a. [c] 5 mol% Pd catalyst was used. [d] under air.
A mixture of cinnamyl alcohol 1a and phosphonium
ylide 2a in water under a nitrogen atmosphere was
heated at 60 oC for 10 h in the presence of
[Pd(allyl)Cl]2 (2.5 mol %) and dppf (5 mol), to our
delight, a new phosphonium ylide 3a was detected
[a] Unless otherwise noted, see run 1 of Table 1 for reaction
conditions. Isolated yields of 4 were based on 2. [b]10 mol%
TBAB was added. [c] 70 oC
Table 3. Dehydrative synthesis of functionalized
skipped dienes from stabilized phosphonium ylides
and α-branched terminal allylic alcohols in water [a]
(Table
1,
run
1).[17]
Then
a
one-pot
allylation/olefination was conducted, affording a
skipped diene 4a in a total isolated yield of 92% (run
1). Then other palladium catalysts were screened, but
only low to moderate yields were obtained (runs 2-4).
The ligands were also investigated, but dppf is still
the best one (runs 5-6). Other protic solvents that
were widely used as good hydrogen bond donors,[18]
were also investigated, but the target 4a were
obtained only in low to moderate yields, showing that
water is an indispensable solvent for the reaction
(runs 7-11). Surprisingly, the reaction under air could
also give the target 4a in 80% isolated yield (run 12).
Various α-unbranched allylic alcohols and
phosphonium ylides were then tested to extend the
scope of the method. [19] As shown in table 2, as the
model reaction, both electron-rich and -deficient
cinnamyl alcohols including the sterically bulkier
ortho-substituted ones reacted effectively with
phosphonium
ylide
2a
via
a
one-pot
allylation/olefination sequence, affording high yields
of the desired product 4a-d (table 2, runs 1-4). [20] The
reaction of alkyl substituted allylic alcohols, such as
(E)-hex-2-en-1-ol could not give the desired products
[a]
Unless otherwise noted, see run 1 of Table 1 for
reaction conditions. Isolated yields of 4 were based on 2a.
[b]
10 mol% TBAB was added. [c] 80 oC. [d] E/Z = 92/8GC
2
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10.1002/adsc.201801266
Advanced Synthesis & Catalysis
Then α-branched terminal allylic alcohols were also
investigated. As shown in table 3, aryl, heteroaryl,
alkyl and even allylic tertiary alcohols reacted
smoothly with phosphonium ylide 2a, specifically
affording the target terminal skipped dienes in
moderate to high yields with exclusive γ selectivity
(table 3, runs 1-9).
The one-pot allylation/olefination sequence was then
extended to ester-stabilized phosphonium ylides, but
no desired skipped dienes could be obtained under
standard conditions. Instead, an ester 6a was obtained
in 30% isolated yield (eq. 1A), Likewise, only trace
amount of nitrile 6b was obtained in the reaction of
nitrile-stabilized phosphonium ylides (eq. 1B), which
is quite different from the literature reports.[8]
Interestingly, the ester 6a could also be obtained in
30% isolated yield in the absence of formaldehyde
(eq. 1C), revealing that 6a might be generated from
the hydrolysis of phosphonium ylide intermediates 7a
(vide infra),[21] suggesting that this new method is not
suitable for water-sensitive phosphonium ylides.
Based on these control experiments and the literature
[8-9,22-24]
reports,
a possible reaction mechanism was
depicted in scheme 2. [Pd] (0), an active catalyst, is in
situ generated from [Pd] (II) and phosphine ligand.
Then the activation of OH group in allylic alcohol 1
by water via a hydrogen bond, followed by the
cleavage of C-O bond gives π-allyl palladium 10.[17]
Then a nucleophilic attack of phosphonium ylide 2 to
π-allyl palladium 10, followed by a proton transfer of
phosphonium salt 11 gives a new phosphonium ylide
3 and byproduct water,[17] meanwhile regenerates the
active Pd (0) to continue the catalytic cycle. Finally, a
one-pot Wittig reaction of phosphonium ylide 3 with
formaldehyde affords the target skipped dienes 4.
Control experiments with other common allylic
alkylating reagents, such as (E)-(3-ethoxyprop-1-en-
1-yl)benzene 8a and cinnamyl acetate 8b were also
investigated under standard conditions, interestingly,
both reactions could give the desired product 4a in
high yields under additive-free conditions (eq. 2).
Scheme 2. The possible reaction mechanism
In conclusion, we developed a mild and extra
activator-free dehydrative alkylation of stabilized
phosphonium ylides with allylic alcohols in water for
the efficient synthesis of functionalized terminal
skipped dienes. The method can also be applied to
other common allylic alkylating reagent such as
allylic ethers and esters under additive-free
conditions. DOSY NMR experiments and other
studies suggested that hydrogen bond might be
formed between water and allylic alcohol, and water
might play a crucial role in the formation of the л-
allylpalladium complex via hydrogen bond. The
asymmetric synthesis using this novel method is
under way.
ESI-high resolution mass spectrum (ESI-HRMS)
analysis of the reaction mixture of cinnamyl alcohol
1a and phosphonium ylide 2a were carried out to
probe the possible mechanism.[17] According to the
high-resolution mass data, it can be concluded that
[Pd(CH2CH=CHPh)(dppf)]+ may be the key
intermediate,[17] suggesting that the C-O bond of the
allylic alcohol is cleaved and an л-allylpalladium
complex is formed during the reaction. Different
from Len’s report,[22] water may not serve as ligands
of Pd species in our reactions.
The interaction of a water molecule with allylic
alcohols was investigated by means of DOSY
NMR.[23] The results revealed that hydrogen bond
might be formed between water and allylic alcohol.
Likely, other protic solvents such as methanol and
HFIP were also investigated, showing that the
interaction between water and allylic alcohol is much
stronger than that between other two molecules and
allylic alcohol.[17] Therefore, the reactions in water
media are more efficient than that in other protic
solvents.
Experimental Section
A mixture of allylic alcohol 1 (0.36 mmol), phosphonium
ylide 2 (0.30 mmol), [Pd(ally)Cl]2 (2.8 mg, 2.5 mol%), and
dppf (8.3 mg, 5 mol%) in water (0.50 mL) was heated
o
under nitrogen at 60 C for 10 h. After cooling down to
room temperature, formalin (37% in water, w/w, 0.068 mL,
0.90 mmol) was added, and the resulting mixture was
stirred for 6 h. Then the solvent was evaporated and the
residue was purified by silica gel chromatography, eluting
with ethyl acetate/petroleum ether (0/100~1/5), to give
compound 4.
Acknowledgements
3
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10.1002/adsc.201801266
Advanced Synthesis & Catalysis
We thank the Key Scientific Research Project of Henan Province
(19B150018 18A150049, 17A150049), Key Scientific and
Technological Project of Henan Province (182400410166), the
Nanhu Scholars Program for Young Scholars of XYNU and
Young Core Instructor Program of XYNU (2018GGJS—05).
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Weinheim, Germany, 2004; pp 1−17; b) Y. Ju, In
Modern Organic Reactions; Y.-F. Hu, G.-Q. Lin, Eds.;
Chemical Industry Press: Beijing, China, 2008; Vol. 3,
pp 413−460 (in Chinese); c) Y. Gu, S.-K. Tian, Top.
Curr. Chem. 2012, 327, 197.
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4
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10.1002/adsc.201801266
Advanced Synthesis & Catalysis
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formed, see SI for details.
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[19] Other aldehydes such as benzaldehyde was employed
in the second olefination step, however, only trace
amount of the desired 1,4-diene product was observed.
[20] As to β- substituted cinnamyl alcohols, such as (E)-2-
methyl-3-phenylprop-2-en-1-ol, only trace amount of
target product was observed.
[24] T. Kitanosono, K. Masuda, P. Xu, S. Kobayashi,
Chem. Rev. 2018, 118, 679.
[21] Possibly owing to that ester-stabilized phosphonium
ylide intermediate (7a) is not stable enough under
reaction conditions, it will be hydrolyzed to give the
target 6a.
5
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10.1002/adsc.201801266
Advanced Synthesis & Catalysis
COMMUNICATION
Dehydrative Synthesis of Functionalized
Skipped Dienes from Stabilized Phosphonium
Ylides and Allylic Alcohols in Water
Adv. Synth. Catal. Year, Volume, Page – Page
X. Ma,* J. Yu, C. Han, Q. Zhou, M. Ren, L. Li, L.
Tang*
6
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