Hydroxyl group-assisted palladium-catalyzed lactonization of homoallylic alcohols

Article abstract of DOI:10.1002/cctc.201300903

A convenient and highly efficient synthesis of α-methylene-γ- lactones through the palladium(II)-catalyzed lactonization of homoallylic alcohols with alkynamides has been reported. The hydroxyl group in the terminal olefins cooperates with the amide in alkynamides to promote the cyclization by suppressing the β-H elimination. This process provides a route to construct naturally occurring biologically multifunctional α-methylene-γ- lactones. The time has come to.i?lactonize: α-Methylene- γ-lactones are synthesized through the Pd^II-catalyzed lactonization of homoallylic alcohols with alkynamides. The hydroxyl group in the terminal olefins cooperates with the amide in alkynamides to promote the cyclization by suppressing the β-H elimination. This provides a route towards naturally occurring biologically multifunctional α-methylene- γ-lactones. Copyright

Full text of DOI:10.1002/cctc.201300903

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DOI: 10.1002/cctc.201300903
Hydroxyl Group-Assisted Palladium-Catalyzed
Lactonization of Homoallylic Alcohols
Liangbin Huang,[a] Qian Wang,[a] Wanqing Wu,[a] and Huanfeng Jiang*[a, b]
A convenient and highly efficient synthesis of a-methylene-g-
lactones through the palladium(II)-catalyzed lactonization of
homoallylic alcohols with alkynamides has been reported. The
hydroxyl group in the terminal olefins cooperates with the
amide in alkynamides to promote the cyclization by suppress-
ing the b-H elimination. This process provides a route to con-
struct naturally occurring biologically multifunctional a-methyl-
ene-g-lactones.
Introduction
The development of transition-
metal-mediated transformations
to construct carbon–carbon and
carbon–hetero bonds in a con-
venient and concise manner
continue to attract tremendous
attention.[1] Of numerous exam-
ples, the nucleopalladation of
carbon–carbon multiple bonds
has been broadly used to syn-
thesize various functional mole-
cules.[2] And the nucleopallada-
tion of alkynes, that is, Kaneda
reaction,[3,4] provides an eco-
nomical and supplementary ap-
proach to construct vinylpalladi-
um intermediates, which are
formed through the oxidative
addition of vinyl–X (X=halide or trifluoromethanesulfonate) to
Pd0 or through the transmetalation of vinylmetallic reagents to
the PdII center.[5] Classically, the alkenes used to capture the vi-
nylpalladium intermediates are restricted to activated olefins,
such as styrene or a,b-unsaturated carbonyls [Eq. (1)].[4b–d]
if the alkenes without a significant electronic difference at the
two olefinic sites are used as substrates.[6–8] Our group report-
ed the oxidative cross-coupling reaction between alkynes and
allylic alcohols to synthesize b-alkenyl ketones through selec-
tive b-H elimination.[4a] By means of the chelate effect, we envi-
sioned that coordinating groups in appropriately remote sites
could play the bidentate role to suppress the b-H elimination.[9]
Because of our persistent attention on the Pd-catalyzed al-
kynes–alkenes cross-coupling reaction,[4,10] we herein report
the hydroxyl group-assisted lactonization of homoallylic alco-
hols [Eq. (2)].[11,12]
R1 =Ar, Alkyl; R2 =Alkoxyl, Alkyl, Ar; R3 =electron-withdrawing
group, Ar; R4 =Ar, Alkyl
One of the main challenges in this type of reaction is the
highly selective b-H elimination on the alkyl–Pd intermediate I
[a] L. Huang, Q. Wang, Dr. W. Wu, Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (P.R. China)
The a-methylene-g-lactone skeleton is an important moiety
in natural products and demonstrates potential biological ac-
tivities, such as andrographolide and some sesquiterpene lac-
tones.[13] And it constitutes approximately 10% of the >30000
known natural products.[14e] Examples of hydroxyl group-con-
taining biologically active a-methylene-g-lactones, such as
paeonilactone B, parthenolide, and hispitolide A (their func-
tions include pain relief, anti-inflammatory, anticancer, and an-
tiviral activities), are shown in Figure 1.[14] Thus, it is important
Fax: (+86)20-87112906
E-mail: jianghf@scut.edu.cn
[b] Prof. Dr. H. Jiang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (P.R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300903.
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Table 1. Optimization of reaction conditions.[a]
Entry
Pd catalyst
Additive/oxidant
Solvent
Yield[b] [%]
Figure 1. Examples for hydroxyl group-containing biologically active a-meth-
ylene-g-lactones.
1
2
3
4
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
Pd(CH3CN)2Cl2
–
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
LiCl/1 atm O2
LiCl/4 atm O2
LiCl/8 atm O2
LiCl/8 atm O2
LiCl/8 atm O2
LiCl/CuCl2·2H2O
LiCl/CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuBr2
CH3CN
CH3CN
CH3CN
HOAc
<5
12
34
–
17
to design and synthesize multifunctional a-methylene-g-lac-
5
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
HOAc
tones.
6[c]
7[d]
8[e]
9[e]
10[e]
11[e]
12[e]
13[e]
14[e]
37
67
83 (80)
92 (90)
88
n.d.
18
Results and Discussion
The coupling reaction between 3-phenylpropiolamide (1a) and
homoallylic alcohol (2a) was chosen as a model reaction for
optimization studies (Table 1). We initially examined the feasi-
bility of this model reaction with oxygen as the oxidant, which
was previously established for the alkenes–alkynes coupling re-
action.[4c–e,9a,d–e] The reaction of 1a with 1.2 equiv. of 2a per-
formed in CH3CN at room temperature in the presence of
5 mol% of PdCl2 and 8 equiv. of LiCl gave the desired product
3a in 34% yield with the increase in oxygen pressure to 8 atm
(1 atm=101.3 kPa; entries 1–3).[15] Thus, the screening of the
solvent for this transformation revealed that acetonitrile was
the most suitable solvent (entries 4 and 5). Further investiga-
tion revealed that CuCl2·2H2O significantly increases
the yield of the desired product (entries 6–8). The
use of 5 mol% of Pd(OAc)2 slightly increases the
yield of the product (entries 9 and 10). The blank ex-
periment showed that no a-methylene-g-lactone ap-
peared in the absence of the Pd catalyst (entry 11).
Inspired by the result of the transformation initiated
by chloropalladation, we investigated similar trans-
formations with bromonium ion and acetoxyl group
as nucleophiles to initiate the trans-selective Kaneda
reaction of 1a.[4a,e] Unfortunately, those nucleophiles
were not compatible with this transformation (en-
tries 12–14).
Cu(OAc)2
Cu(OAc)2
n.d.
n.d.
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Pd catalyst
(5 mol%), additive (4 mmol) in the solvent (0.5 mL) at RT for 12 h;
[b] Yield was determined from GC analysis with dodecane as the internal
standard and the number in parentheses was isolated yield. [c] LiCl
(4 mmol) and CuCl2·2H2O (0.5 mmol); [d] LiCl (4 mmol) and CuCl2·2H2O
(1 mmol); [e] Cu salt (1.5 mmol).
We began our study with the homoallylic alcohol
with dual function as regulating group and substrate
and tested the Pd-catalyzed lactonization. Notably,
the alkenes without the hydroxyl group yielded only
the b-H elimination product (see below for details),
which indicated that the absence of the chelate
effect disfavored the cycloaddition. As shown in
Scheme 1, this reaction could be applied to various
alkynamides. A series of para-substituted 3-phenyl-
propiolamides, with either electron-donating (3b) or
electron-withdrawing groups (3e and h), could be
converted to the corresponding a-methylene-g-lac-
tones in good to excellent yields. The electron-do-
nating group decreased the activity of nucleopalla-
Scheme 1. Substrate scope of alkynamides for the Pd-catalyzed lactonization of homoal-
lylic alcohols. The reactions were performed at RT and by using homoallylic alcohol
(0.6 mmol), alkynamide (0.5 mmol), Pd(OAc)2 (5 mol%), CuCl2·2H2O (1.5 mmol), and ace-
tonitrile (0.5 mL) for 12 h. dr=Diastereomeric ratio.
dation by making the CÀC triple bond more elec-
tron-rich. Halo substituents, such as Cl and Br, were
well tolerated, which provided the possibility for fur-
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ther functionalization (3c and d).
In contrast to the para- and
meta-substituted
alkynamides,
the ortho-substituted material
could not be converted to the
products (3 f and g). With use of
but-2-ynamide and oct-2-yna-
mide in this transformation, the
corresponding products could
be obtained in good yields (3i
and j). 3-Methylbut-3-en-1-ol
and hept-1-en-4-ol were both
suitable for this transformation
(3k and l).
Homoallylic alcohols are versa-
tile synthetic intermediates, as
exemplified by their application
toward natural product synthe-
sis.[16] Various derivatives can be
obtained with stoichiometric
metals (e.g., Mn, Mg, Zn, Sn, In,
and Cr) under Barbier-type con-
ditions.[17] Thus, we used alde-
hyde (0.7 mmol), 2 equiv. of Zn,
and 1.2 equiv. of allyl bromide in
3 mL of the THF/NH4Cl solvent
Scheme 2. Substrate scope of the lactonization of homoallylic alcohols with alkynamides. The reactions were per-
formed at RT by using aldehyde (0.7 mmol), allyl bromide (1.2 equiv.), Zn (2 equiv.), and THF/NH4Cl (1:3 v/v, 3 mL)
for 12 h. The crude products were extracted with ethyl ether. The terminal alkynamide (0.5 mmol), Pd(OAc)2
(5 mol%), CuCl2·2H2O (1.5 mmol, and acetonitrile (0.5 mL) were added overnight at RT. [a] Cinnamic aldehyde was
used as the substrate.
(1:3 v/v) at room temperature for 12 h to afford homoallylic al-
cohols. Upon the completion of the reaction, crude products,
extracted with ethyl ether, were subjected to the Pd-catalyzed
lactonization of homoallylic alcohols with alkynamides without
further purification (Scheme 2). First, a series of homoallylic
secondary alcohols were examined in the reaction system. The
functional group compatibility of homoallylic alcohols was ex-
cellent, which provided the possibility for further functionaliza-
tion. For example, methoxyl, halogen, and ester groups were
tolerated in this transformation (4e–h). Both electron-donating
and electron-withdrawing group substituted 1-phenylbut-3-en-
1-ols could be transformed to the devised a-methylene-g-lac-
tones in good yields (4c and d). The aliphatic aldehyde was
also applicable to this system (3l). With use of cinnamic alde-
hyde as the substrate (4i), the dehydrated product was ob-
tained instead of the desired product.
underwent the transformation in good yield (4t). Notably, the
alkyl halide and aryl halide were both tolerant in this reaction
(4q and t).
The transformations using cyclic ketones as substrates af-
forded the corresponding a-methylene-g-lactone products,
even though in various yields (Scheme 4). In contrast to cyclo-
butanone and cyclooctanone, the yields of the corresponding
products were much higher than those of cyclohexanone and
cycloheptanone used as substrates. It could be due to the ring
tension. Furthermore, dihydro-2H-pyran-4(3H)-one and 1,4-
dioxaspiro[4.5]decan-8-one led to the formation of the desired
products 4y and z only in moderate yields. Finally, the isolated
yield for the reaction of 2-adamantanone was 74%. The struc-
ture of 4bc was confirmed by X-ray crystallographic analysis
(see the Supporting Information for details).
To further confirm that the chelate effect of the hydroxyl
group towards the PdII center was crucial for the Pd-catalyzed
lactonization of olefins, a comparative experiment was per-
formed [Eq. (3)].[18]
Subsequently, the scope of the reaction was expanded to
a range of homoallylic tertiary alcohols. Similarly, homoallylic
tertiary alcohols were easily synthesized through the combina-
tion of allyl–MgBr and ketone at 08C and directly subjected to
the next step of the reaction after extraction with ethyl ether
(Scheme 3). Aliphatic ketones could be
As expected, but-3-enylbenzene (A=H), without a coordinat-
ing group, was transformed to the b-H elimination product 4a’
converted to the desired products in high
yields (Scheme 3, 4j and k). With the ex-
tension of the reaction scale to 3 mmol
scale, the isolated yield of 4j was 71%.
Dibenzylketone was also a suitable sub-
strate (4l). A series of benzophenones
could be converted to the corresponding
a-methylene-g-lactones in good to excel-
lent yields (4m–s). b-Chloro ketone also
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reactions. Thus, we used 2a and
ethyl 3-phenylpropiolate and re-
acted each of them with the ho-
moallylic alcohol under 1 atm
CO under the standard reaction
conditions [Eqs. (4) and (5)]. The
a-methylene-g-lactone 3a was
obtained without a decrease in
the yield [Eq. (4)]. CO-insertion
product 5a was isolated in 53%
yield in the reaction of 3-phenyl-
propiolate and homoallylic alco-
hol under 1 atm CO.[19] The
amide in the alkynamide acceler-
ated the formation of the
C(sp3)ÀO bond.[20] And the
C(sp3)ÀO bond formation was
faster than the insertion of CO
to the alkyl–PdII intermediate IV
[Eq. (5)].
On the basis of the above re-
sults, a possible mechanism for
the hydroxyl group-assisted Pd-
catalyzed lactonization of homo-
allylic alcohols with alkynamides
is proposed (Scheme 5). This re-
action was initiated by the halo-
Scheme 3. Scope of tertiary homoallylic alcohols for Pd-catalyzed lactonization reactions. Reaction conditions:
T=08C, ketone (0.7 mmol), allyl–MgBr (1.2 equiv.), and THF (2 mL), t=3 h. The crude products were extracted
with ethyl ether. Alkynamide (0.5 mmol), Pd(OAc)2 (5 mol%), CuCl2·2H2O (0.25 g), and acetonitrile (0.5 mL) were
added overnight at RT. [a] Ketone (5 mmol) and alkynamide (3 mmol) were used.
and a trace of the lactonization product could be de-
tected. As mentioned above, with use of the homoal-
lylic alcohol as the substrate, the corresponding a-
methylene-g-lactone 4a could be isolated in 78%
yield. And it clearly demonstrated that the chelate
effect of the hydroxyl group could completely sup-
press the b-H elimination.
On the basis of our previous studies on the halo-
palladation of alkynoates,[4] we believed that alkyna-
mides also play a key role in those difunctionalization
palladation of alkynamides, which afforded vinylpalla-
dium intermediate VI. Subsequently, intermediate VI
was captured by the alkene via migratory insertion to
produce intermediate VII. If the alkene did not con-
tain a coordinating group (but-3-enylbenzene, A=H),
intermediate VII would undergo b-H elimination. The
amide of the alkynamide cooperated with the hy-
droxyl group in the olefin to chelate Pd. The coordi-
native saturation of the metal center represents an
established strategy to suppress b-H elimination.[9,21]
With the coordinating groups in the homoallylic site,
the five- to six-membered ring palladacycle inter-
mediate VII transformed to intermediate VIII by iso-
merization, followed by C(sp3)ÀO bond formation to
give five-membered ring based lactones. Finally, the
PdII active species was regenerated through the oxi-
Scheme 4. Scope of tertiary homoallylic alcohols for Pd-catalyzed lactonization reactions.
See the caption of Scheme 3 for the reaction conditions.
dation of Cu2+
.
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separated by using column chromatography to obtain the pure
products 3a–l and 4a–bc.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (20932002, 21172076, and 21202046), the National Basic
Research Program of China (973 Program; 2011CB808600), the
Guangdong Natural Science Foundation (10351064101000000
and S2012040007088), and the Fundamental Research Funds for
the Central Universities (2014ZP0004 and 2014ZZ0046) for finan-
cial support.
Keywords: alkenes · CÀO bond formation · lactonization ·
palladium · elimination
Scheme 5. Possible reaction mechanism.
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Conclusions
We have reported a mild and efficient PdII-catalyzed lactoniza-
tion of homoallylic alcohols with alkynamides assisted by the
synergistic effects of the two coupling partners. The hydroxyl
group in olefins plays dual roles not only as a helping hand to
stabilize the metal center through the chelate effect but also
as a key fragment in organic molecules. This new strategy is
applied to construct a bioactive a-methylene-g-lactone skele-
ton that contains multifunctionalized groups that is further
converted synthetically. We believe that this new and conven-
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remote group-assisted difunctionalization of alkenes in Pd
chemistry.
Experimental Section
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General
All reactions were performed in 10 mL tubes. TLC was performed
with commercially prepared 100–400 mesh silica gel plates
(GF254), and visualization was effected at 254 nm. All reagents
were purchased as reagent grade and used without further purifi-
1
cation. The H NMR spectra were recorded at 400 MHz with TMS as
an internal standard, and the 13C NMR spectra were recorded at
100 MHz with CDCl3 by using a BRUKER DRX-400 spectrometer .
The chemical shifts were referenced to signals at 7.24 and
77.0 ppm, respectively. The IR spectra were obtained either as KBr
pellets or as liquid films between two KBr pellets by using a Bruker
Vector 22 spectrometer.
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Typical method for the synthesis of a-methylene-g-lactone
First, a mixture of the alkynamide (0.5 mmol), homoallylic alcohol
(0.6 mmol), Pd(OAc)2 (5 mol%), CuCl2·2H2O (0.25 g), and CH3CN
(0.5 mL) was added to a dried Schlenk tube, and the solution was
stirred at RT for the desired reaction time. Then, the mixture was
stirred at RT for 12 h. Upon the completion of the reaction, the re-
action mixture was washed with saturated aqueous NaCl solution
(2ꢁ10 mL) and then extracted with EtOAc (2ꢁ10 mL). Finally, the
organic layers were combined, dried over anhydrous MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was
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Received: October 22, 2013
Published online on January 16, 2014
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