Palladium-Catalyzed Allylic Alkylation of 2-Aryl-1,3-Dithianes, an Umpolung Synthesis of β,γ-Unsaturated Ketones

Article abstract of DOI:10.1002/adsc.201801035

Palladium-catalyzed allylic alkylation of 2-aryl-1,3-dithianes at room temperature is described. A variety of cyclic and acyclic electrophiles successfully coupled with in-situ generated 2-sodio-1,3-dithiane nucleophiles to afford the allylated products in good to excellent yields (25 examples). Deprotection of these products leads to valuable β,γ-unsaturated ketones. Direct synthesis of such β,γ-unsaturated ketones via a one-pot allylation-oxidation protocol is also presented. Investigation into the stereochemistry of the allylation reaction revealed that the 2-sodio-1,3-dithiane nucleophile behaves as a “soft” nucleophile, which underwent external attack on the π-allyl palladium complex to provide retention of stereochemistry (double inversion pathway). Additionally, the utility of this method was demonstrated through a sequential one-pot allylation-Heck cyclization to produce asterogynin derivatives, which are important bioactive compounds in medicinal chemistry. (Figure presented.).

Full text of DOI:10.1002/adsc.201801035

Title: Palladium-Catalyzed Allylic Alkylation of 2-Aryl-1,3-dithianes, an
Umpolung Synthesis of β,γ-Unsaturated Ketones
Authors: Nisalak Trongsiriwat, Minyan Li, Ana Pascual-Escudero, Baris
Yucel, and Patrick J. Walsh
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801035
Link to VoR: http://dx.doi.org/10.1002/adsc.201801035

10.1002/adsc.201801035
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Allylic Alkylation of 2-Aryl-1,3-dithianes,
an Umpolung Synthesis of β,γ-Unsaturated Ketones
Nisalak Trongsiriwat,a Minyan Li,a Ana Pascual-Escudero,b Baris Yucel,c and Patrick J.
Walsh*, a
aDepartment of Chemistry, University of Pennsylvania, 231 S. 34th St., Philadelphia, PA 19104, USA.
Email: pwalsh@sas.upenn.edu
bDpto. Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
cIstanbul Technical University, Science Faculty, Department of Chemistry, Maslak 34469, Istanbul, Turkey.
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))
Abstract. Palladium-catalyzed allylic alkylation of 2-aryl- Additionally, the utility of this method was
1,3-dithianes at room temperature is described. A variety of demonstrated through a sequential one-pot allylation-
cyclic and acyclic electrophiles successfully coupled with Heck cyclization to produce asterogynin derivatives,
in-situ generated 2-sodio-1,3-dithiane nucleophiles to which are important bioactive compounds in medicinal
afford the allylated products in good to excellent yields (25 chemistry.
examples). Deprotection of these products leads to valuable
β,γ-unsaturated ketones. Direct synthesis of such β,γ-
unsaturated ketones via a one-pot allylation-oxidation
protocol is also presented. Investigation into the
stereochemistry of the allylation reaction revealed that the
2-sodio-1,3-dithiane nucleophile behaves as a “soft”
nucleophile, which underwent external attack on the π-allyl
palladium complex to provide retention of stereochemistry
(double inversion pathway).
Keywords: Allylic Alkylation; Dithiane; Umpolung;
β,γ-Unsaturated Ketone; “soft” Nucleophile.
Introduction
Although several methods have been reported for the
synthesis of β,γ-unsaturated ketones, only a few
procedures are practical. The acylation of olefins, for
example, is a potentially useful and common
procedure to access β,γ-unsaturated ketones, but α,β-
unsaturated ketone byproducts are nearly always
observed and usually very difficult to separate from
β,γ-Unsaturated ketones are important building
blocks for the synthesis of bioactive compounds used
in the pharmaceutical industry.[1] Some examples
include griseofulvin, isopinnatal, nidemone, and
trichostatin A (Figure 1). The synthesis of β,γ-
unsaturated ketones is challenging, however, due to
their facile isomerization to the thermodynamically
the desired products.[3]
A
variety of allylic
organometallics[4] have been used with acyl halides to
generate β,γ-unsaturated ketones in moderate to good
yields (Scheme 1, a). Unfortunately, these multi-step
procedures are time-consuming and complicated by
favored
α,β-unsaturated
ketones.[2]
OMe
O
OHC
H
OMe
O
O
O
O
MeO
OH
the need to synthesize and purify the intermediates,
H
Me
Me
Cl
O
5]
which limits their application.[4d,
In 2012,
Isopinnatal
Griseofulvin
Nagalakshmi and coworkers demonstrated that
copper nano particles could be employed as a
heterogeneous catalyst for the allylation of acid
chlorides; however, the scope of this reaction is
limited to linear allyl halides (Scheme 1, b).[6] Thus, it
is clear that new methods to prepare a wide range of
O
O
O
OH
O
OH
N
H
Me
Me2N
OMe
Nidomone
Trichostatin A
Figure 1. Examples of β,γ-unsaturated ketone motifs
in pharmaceuticals.
1
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
β,γ-unsaturated ketones in high yields are very
desirable.
Herein we report a room-temperature palladium-
catalyzed allylic alkylation of 1,3-dithianes to form
β,γ-unsaturated ketone equivalents in good to
excellent yields (Scheme 1, e) and a one-pot allylic
alkylation-deprotection to generate β,γ-unsaturated
ketones directly with yields up to 90%. To further
demonstrate the utility of this method, a sequential
dithiane initiated allylic substitution-Heck cyclization
to afford the core structure of asterogynin is
presented. Experiments to probe the stereochemistry
of the reaction point to a mechanism that involves
exo-attack of the metallated 1,3-dithiane on the π-
allyl palladium intermediate, indicating that the
metallated dithiane behaves as a “soft” nucleophile
(double inversion mechanism).
Retrosynthetic analysis of β,γ-unsaturated ketones
leads to two possible disconnections, the more
traditional acid chloride and allyl anion approach and
the less common allyl cation and the acyl anion
equivalent (Figure 2). Acyl anion equivalents can be
generated by a variety of methods, the most well
known of which is the use of 1,3-dithiane
nucleophiles.
The concept of umpolung synthesis, or dipole
inversion, was demonstrated by Corey and Seebach
in 1965 with the introduction of metallated
dithianes.[7] It was shown that 1,3-dithianes could be
deprotonated with strong bases, such as n-
butyllithium, and employed as acyl anion equivalents
with a variety of electrophiles. Following this
breakthrough, metallated 1,3-dithianes became well-
established reagents in organic synthesis and are
widely used in C–C bond formation.[8] Although the
reactivity of metallated 1,3-dithianes has been well-
developed over the years, it is surprising that only a
handful of publications have reported the use of 1,3-
dithianes in transition metal catalyzed reactions. In
our effort to develop deprotonative cross-coupling
processes (DCCP),[9] we became interested in the
coupling of 2-aryl-1,3-dithianes to aryl halides under
conditions where the dithianes are reversibly
deprotonated in the presence of base. Based on this
approach, we developed an arylation of dithianes and
demonstrated its application to the synthesis of
medicinally relevant benzophenone derivatives
(Scheme 1, c).[10] Schmink and coworkers
simultaneously reported very similar conditions for
this coupling reaction.[11] Since several of the
nucleophiles we employed in arylation reactions also
found utility in palladium and nickel catalyzed allylic
substitution reactions, we decided to investigate
metallated 1,3-dithianes in allylic alkylation reactions.
During our investigations, Liu, Zhang and coworkers
published an enantioselective allylic substitution (up
to 96% ee) with Boc activated (E)-1,3-diarylprop-2-
en-1-ols (Scheme 1, d).[12] There is little overlap
between their choices of electrophiles and the ones
presented herein.
a. Bindi
O
R'
O
In
R
Cl
Br
R"
R
DMF/H2O
24 oC
b. Nagalakshmi
O
O
Cu (nano particle)
THF, 24 oC
R
Cl
Br
R
c. Walsh and Schmink
Pd/NIXANTPHOS
base
Ar'Br
S
S
S
S
H
Ar
Ar'
Ar
After deprotection:
O
Ar
Ar'
d. Zhang
S
Ar
OBoc
Ar
S
S
H
Pd/L*
S
Ar
Ar
Ar
Ar
up to 96% ee
Ar
After deprotection:
Ar
Ar
O
or
Ar
Ar
Ar
e. This work
OBoc
Pd/SPhos
S
S
S
S
Ar
NaN(SiMe3)2 (2 equiv)
DME, 24 oC, 3 h
Ar
H
O
After deprotection:
Ar
Scheme 1. β,γ-Unsaturated ketone syntheses.
Figure 2. Retrosynthesis of β,γ-unsaturated ketones.
2
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
a. Microscale screening (10 micromol):
Cl2Pd(NCPh)2 10 mol %
OBoc
Results and Discussion
ligands 10–20 mol %
S
S
S
S
H
We carried out optimization studies using 2-phenyl-
1,3-dithiane 1a as the pronucleophile and tert-butyl
cyclohex-2-enyl carbonate 2a as an electrophilic
partner. Initially, we conducted the allylic alkylation
reaction using conditions similar to those employed
in our arylation of 2-aryl-1,3-dithianes and allylic
alkylation of diarylmethanes,[13] which are Pd(OAc)2
(10 mol %), van Leeuwen’s NIXANTPHOS[14] (20
mol %), NaN(SiMe3)2 (2 equiv), and DME solvent at
room temperature (Scheme 2). After 3 h the allylic
substitution product was afforded in 70% assay yield
(AY), as determined by 1H NMR of the crude
reaction mixture. We next examined palladium
Ph
Ph
MN(SiMe3)2 (2 equiv)
M = Li, Na
1a
1 equiv
2a
1.5 equiv
3aa
DME, 0.1 M, rt, 3 h
b. Lab-scale (0.1 mmol)
OBoc
Cl2Pd(NCPh)2 10 mol %
ligands 20 mol %
S
S
S
S
H
Ph
NaN(SiMe3)2 (2 equiv)
DME, 0.1 M, rt, 3 h
Ph
1a
1 equiv
2a
1.5 equiv
3aa
PCy2
MeO
OMe
PCy2
N
precursors
Pd(dba)2,
Cl2Pd(NCPh)2
and
[PdCl(C3H5)]2. Catalyst prepared from Cl2Pd(NCPh)2
showed the highest activity, affording product 3aa in
84% AY.
CataCXium PCy
94% AY
SPhos
92% AY
Scheme 3. Ligand identification in the allylic
substitution.
OBoc
Pd 10 mol %
NIXANTPHOS 20 mol %
NaN(SiMe3)2 (2 equiv)
DME, 0.1 M, rt, 3 h
S
S
S
S
H
With the optimized Pd/ligand combination, we next
studied the Pd-phosphine ratio. Decreasing the
palladium/ligand ratio from 10/20 mol % to 10/15
mol % did not impact the yield (Table 1, entry 1).
However, 10 mol % of each resulted in a drop in the
AY of 3aa to 83% yield (entry 2). We next examined
the impact of reducing the palladium and ligand
loading. Decreasing the palladium loading from 10 to
2.5 mol % with 3.75 mol % SPhos provided the
allylation product in 95% AY (entry 3). Further
decreasing catalyst loading to 1.0 mol % Pd and 1.5
mol% SPhos resulted in 60% AY (entry 4). Reaction
concentrations also impact the reaction outcome.
Reducing the concentration of 1a from 0.2 to 0.1 M
provided AY of 97%, whereas further reduction to
0.05 caused the assay yield to fall to 84% (entries 5–
6). Reducing the equivalents of the electrophile from
2 to 1.5 gave 96% AY, but further reduction to 1.2
equiv caused a decrease in AY to 84% (entries 7–8).
Heating the reaction mixture to 60 °C caused
increased decomposition of the electrophile 2a and
decreased the AY of 3aa to 87% (entry 9). The
optimized conditions in entry 7 were then used to
examine the scope of nucleophiles.
Ph
Ph
1a
1 equiv
2a
3aa
1.5 equiv
H
N
70% AY, Pd = Pd(OAc)2
50% AY, Pd = Pd(dba)2
O
84% AY, Pd = Cl2Pd(NCPh)2
60% AY, Pd = [PdCl(C3H5)]2
PPh2
PPh2
NIXANTPHOS
Scheme 2. Initial lab scale (0.1 mmol) optimization
using NIXANTPHOS as ligand with different Pd
sources.
In search of a more efficient catalyst, we then
screened 42 diverse mono-dentate (20 mol %) and
bidentate (10 mol %) phosphine ligands and 2 bases,
Li and NaN(SiMe)2, using microscale (10 μmol)
high-throughput experiments (HTE) (see Supporting
Information for details). The results revealed that the
most promising hits were CataCXium PCy[15] and
SPhos.[16] Employing the two top hits on laboratory
scale (0.1 mmol) led to product 3aa in 94%
(CataCXium PCy) and 92% (SPhos) AY, respectively.
We chose to continue with SPhos, because it is more
economical.
Table 1. Optimization of allylic alkylation of 1a.[a],[b]
3
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
Pd
OBoc
In order to be useful, reactions must be scalable. To
examine the scalability of our substitution, the
allylation of 2-thiophen-1,3-dithiane with 2a was
examined on 4.9 mmol scale (1.0 g), providing the
corresponding product 3ia in 69% yield (0.96 g).
NIXANTPHOS
S
S
S
S
H
Ph
NaN(SiMe3)2
DME
Ph
1a
1 equiv
2a
1.5 equiv
3aa
Entry
X/Y
(mol %)
10/15
10/10
2.5/3.75
1/1.5
2.5/3.75
2.5/3.75
2.5/3.75 1:1.5
2.5/3.75 1:1.2
1a:2
a
T
oC
rt
rt
rt
rt
rt
rt
rt
rt
Conc.
AY
(%)
95
84
95
60
97
84
96
84
87
Table 2. Scope of nucleophiles in allylic alkylation
with 2a.[a],[b]
(M)
0.2
0.2
0.2
0.2
0.1
0.05
0.1
0.1
0.1
Cl2Pd(NCPh)2 2.5 mol %
SPhos 3.75 mol %
OBoc
1
2
3
4
5
6
7
8
9
1:2
1:2
1:2
1:2
1:2
1:2
S
S
S
S
H
Ar
NaN(SiMe3)2 (2 equiv)
DME, rt, 3 h
Ar
1a-i
2a
3aa–ia
1 equiv
S
1.5 equiv
S
S
S
S
S
MeO
2.5/3.75 1:1.5 60
3aa, 95%
3ba, 74%
3ca, 77%
[a]Reactions conducted on 0.1 mmol scale. [b]Assay yields
(AY) determined by H NMR spectroscopy of the crude
reaction mixture.
S
S
S
S
1
S
S
OMe
F
F
Scope of Nucleophiles in the Palladium-Catalyzed
Allylic Alkylation Reaction.
3da, 83%
3ea, 99%
3fa, 90%
S
S
S
S
S
S
Having identified the optimal conditions, we explored
allylic alkylation with tert-butyl cyclohex-2-en-1-yl
S
carbonate 2a and
a
variety of 1,3-dithiane
CF3
3ga, 89%
3ha, 70%
3ia, 71%
pronucleophiles. The parent 2-phenyl-1,3-dithiane
furnished the product 3aa in 95% isolated yield.
Pronucleophiles with electron donating groups are
less acidic and more challenging to deprotonate.
Nonetheless, both 2-(4-tolyl)-1,3-dithiane and 2-(4-
methoxyphenyl)-1,3-dithiane gave the corresponding
products, 3ba and 3ca in 74 and 77% yields,
[c]
(0.96 g, 69%)
[a]Reactions conducted on 0.1 mmol scale. [b]Isolated yields
after chromatographic purification. [c]4.9 mmol 2a.
Scope of Electrophiles in the Palladium-Catalyzed
Allylic Alkylation reaction.
Under optimal conditions, the scope of allylic
carbonate derived electrophiles reacting with 2-
phenyl-1,3-dithiane 1a was examined (Table 3).
Cyclopentenyl and cycloheptenyl electrophiles
reacted to provide the desired products 3ab and 3ac
in 97 and 87% yields, respectively. The reaction of
the 7-membered ring substrate was slower and
required a longer reaction time (16 h). In the case of
linear allylic carbonate derivatives, CataCXium PCy
performed better than SPhos under the optimized
conditions. The parent allyl OBoc and 2-Me allyl
OBoc delivered 3ad and 3ae in 87 and 88% yields
after 3 h, respectively. Longer reaction times (16 h)
were needed for unsymmetrical η3-allyl groups. It is
known that π-allyl palladium complexes often react
respectively.
Pronucleophiles
with
electron
withdrawing groups underwent substitution to give
excellent yields. Thus, 2-(3-methoxyphenyl)-, 2-(4-
fluorophenyl)-, 2-(3-fluorophenyl)-, and 2-(3-
trifluoromethylphenyl)-1,3-dithianes underwent Pd
catalyzed allylation with 2a to afford 3da, 3ea, 3fa
and 3ga in 83, 99, 90 and 89% yields, respectively. A
sterically hindered substrate 2-(1-napthalyl)-1,3-
dithiane reacted to afford 3ha[29] in 70% yield;
however, 2-(2-tolyl)-1,3-dithiane did not perform
well under the established reaction conditions, giving
only 8% yield. The heterocyclic substrate 2-(3-
thiophenyl)-1,3-dithiane reacted to provide 3ia in
71% yield, but 2-(3-furyl)-1,3-dithiane was not an
effective pronucleophile in this reaction.
4
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
with carbon nucleophiles at the less substituted end of
the π-allyl.[17] For Boc-protected prenyl alcohol 2f,
however, the branched isomer 3af’ was slightly
favored (linear:branched 1:1.7, 86% yield). The
allylation with Boc-protected cinnamyl alcohol 2h
slightly favored the linear product 3ah (80%) with
linear:branched ratio of 2.2:1. Surprisingly the
allylation with geranyl alcohol 2g gave only linear
product 3ag in moderate yield (69%).
nucleophiles undergo attack on the metal center of
the π-allyl palladium complex followed by reductive
elimination. This reaction pathway proceeds by a
single inversion in the allylic substitution. In contrast,
“soft” nucleophiles directly attack the π-allyl,
providing net retention of stereochemistry (via double
inversion).
To determine which of these two pathways was
operative in our allylic substitution, 2-phenyl-1,3-
dithiane (pKa = 31[19]) was coupled with cis-
disubstituted stereoprobe 2j to generate the
substitution product in 92% yield as a single
Table 3. Scope of electrophiles in allylic alkylation
with 1a.[a],[b]
1
diastereomer (Scheme 4). Analysis of the H NMR
OBoc
Cl2Pd(NCPh)2 2.5 mol %
S
S
H
S
S
SPhos 3.75 mol %
NaN(SiMe3)2 (2 equiv)
DME, 24 oC, 3 h
spectrum of 3aj indicated that the structure was
consistent with the cis-isomer. This result reveals that
2-phenyl-1,3-dithiane behaves as a “soft” nucleophile.
This result is consistent with our prior work using
diphenylmethane pronucleophiles,[17e, 20] and supports
our hypothesis that soft nucleophiles should be
classified as those with pronucleophile pKa's up to at
least 32.
R
n
Ph
R
n
1a
2a-2h
3aa–3ah
1 equiv
1.5 equiv
S
S
S
S
S
S
3ab, 97%
3ac, 87%[c]
3ad, 87%[d]
S
S
S
S
S
S
H
Cl2Pd(NCPh)2 2.5 mol %
SPhos 3.75 mol %
Ph
OTBDMS
S
S
1a
3ae, 88%[d]
3ag, 69%[e]
Ph
NaN(SiMe3)2 (2 equiv)
OTBDMS
DME, 0.1 M, rt, 10 h
BocO
3aj, 92%
single disatereomer
S
S
S
S
S
Ph
2j
3ah and 3ah’, 82%[e]
(L:B=2.2:1)
3af and 3af’, 90%[e]
(L:B=1:1.7)
Scheme 4. Stereoprobe study indicating that the
allylic substitution reaction proceeds via the double
inversion or soft nucleophile pathway.
S
S
S
Ph
[a]Reactions conducted on 0.1 mmol scale. [b]Isolated yield
after chromatographic purification. [c]16 h. [d]3.75 mol% of
CataCXium PCy. [e]3.75 mol% of CataCXium PCy, 16 h,
Development of a sequential one-pot umpolung
synthesis of β, γ-unsaturated ketones.
1
ratio of linear:branched (L:B) determined by H NMR of
purified reaction products.
Conversion of the dithiane product to the
corresponding ketone can be challenging.[21] With our
allylic substitution products, great care must be
exercised to avoid the facile isomerization of the
alkene into conjugation with the carbonyl group
during deprotection. An attractive oxidative approach
employs iodine in the conversion of 1,3-dithianes to
the corresponding carbonyl compounds.[22] A key
advantage of using iodine to remove the dithiane is
that it avoids heavy metal reagents, such as
mercury,[23] silver,[24] thallium,[25] and cerium,[26]
some of which are toxic. In 2008, Barik and
Probing the stereochemistry of the allylic
substitution.
In Tsuji-Trost allylic alkylation reactions, the
nucleophiles are divided into two classes based on the
pKa of the pronucleophile: (1) “hard” or unstabilized
nucleophiles from pronucleophiles with pKa values >
25 and (2) “soft” or stabilized nucleophiles from
pronucleophiles with pKa’s < 25.[18] The difference
between these two species is the nature of attack by
the nucleophile on the π-allyl intermediate. The “hard”
5
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
conditions were developed based on Barik’s conditions.
[d]Allylation product isolated and purified before oxidation
(16 h reaction time).
coworkers disclosed an effective protocol for 1,3-
dithiane deprotection using a combination of iodine
and hydrogen peroxide in the presence of SDS
(sodium dodecyl sulfate, proposed to stabilize
reactive intermediates).[27] Based on these conditions,
we developed a one-pot allylation-deprotection that
could be conducted without isolation or purification
of the intermediate dithiane. We found that hydrogen
peroxide was not necessary when the deprotection
was carried out over a longer reaction time (12 h)
under air. Thus, after the allylic alkylation step was
completed, as judged by TLC, the crude reaction
mixture was evaporated to dryness and I2 was added
in a catalytic amount (2 mol %) in THF. A solution of
SDS in water was then added to the flask, and the
resulting reaction mixture was stirred at rt for 12–16
h. Using the 2-(4-tolyl)-1,3-dithiane 1b, 2-(2-
fluorophenyl)-1,3-dithiane 1f, and 2-(3-thiophenyl)-
1,3-dithiane 1i, the corresponding β,γ-unsaturated
ketones were isolated directly from a single reaction
flask in 90 (4ba), 83 (4fa), and 55% yields (4ia), over
the two steps (Table 4). The yield of the β,γ-
unsaturated ketone 4ia could be improved to 72% by
isolating and purifying dithiane 3ia prior to
submission to the oxidative deprotection conditions.
Using the two-step method, allylated products with
five, six and seven membered ring 3ab, 3aa and 3ac
underwent deprotection to afford the corresponding
β,γ-unsaturated ketones 4ab, 4aa and 4ac in 71%,
80% and 52% yields respectively.
Development of a sequential allylation-Heck
cyclization.
Asterogynin derivatives are important bioactive
compounds in medicinal chemistry. To further
demonstrate the synthetic value of our method, we
were interested in pursuing the synthesis of
asterogynin derivatives via a tandem allylation-Heck
cyclization. Considering the differences between
allylic alkylation and Heck cyclization, we explored
the reaction conditions separately. Based on the Heck
reaction literature,[28] we started investigating the
cyclization of the allylated product 3jb with the
combination of Cl2Pd(NCPh)2 or Pd(OAc)2, PPh3,
and carbonate bases in DME or acetonitrile at 60 or
80 °C, but under these conditions the cyclization
product was either not detected or only traces were
formed (Table 5, entries 1–5). We next studied
different temperatures and found that 5 mol%
Pd(OAc)2, 15 mol % PPh3, and 5 equiv of NEt3 in
acetonitrile at 80 oC were the most promising
conditions, which afforded 4jb in 75% yield (Table 5,
entry 7). Based on this result, we began examining a
sequential allylation-Heck cyclization of 1j with
different electrophiles (Scheme 5). After completion
of the allylation (as determined by TLC), the catalyst
was removed from the crude reaction mixture by
filtration through a pad of silica. The reaction mixture
was dried under vacuum, dissolved in MeCN and
transferred to a separate vial containing a premixed
solution of Pd(OAc)2 and PPh3 in MeCN and NEt3.
The reaction mixture was then stirred for 16 h at 80
oC. The cyclopentenyl electrophile 2b reacted to
afford the allylation-Heck cyclization product 4jb in
67% yield over the two steps, and the acyclic allylic
carbonate 2d yielded the isolated product 4jd in 75%
yield. In the case of the cyclohexenyl electrophile 2a,
the cyclization was more challenging. With this
substrate, the reaction was conducted in DMF, and
the temperature had to be increased to 120 °C. Under
these conditions, the product 4ja was isolated in 71%
yield (Scheme 5) with cis isomer confirmed by the
crystal structure of 4jb (Figure 3, obtained by slow
evaporation of THF to give colorless crystal; CCDC
number is 1854101). The structure crystalized in the
orthorhombic space group Pca21 which showed that
Table 4. Sequential one-pot synthesis of β,γ-
unsaturated ketones (4ba and 4fa).[a],[b],[c] and two step
procedure (4ia, 4aa, 4ab, 4ac).[d]
[a]Reactions conducted on 0.1 mmol scale. [b]Isolated yield
after chromatographic purification. [c]The oxidation
6
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
24 oC for 36 h. Heck cyclization: Pd(OAc)2 5 mol %, PPh3
15 mol %, NEt3 (5 equiv) in MeCN at 120 °C for 16 h.
two hydrogen atoms on C8 and C12 are cis to each
other.
Finally, we conducted a one-pot allylation-Heck
cyclization-deprotection process using dithiane 1j and
the cyclopentenyl-OBoc 2b (Scheme 6, see
Supporting Information for experimental details). The
ketone derivative 5jb was isolated in 52% overall
yield over three steps.
Table 5. Optimization of Heck cyclization of 3jb.[a]
Pd source 5 mol %
PPh3 15 mol %
S
S
S
S
H
H
base (5 equiv)
solvent, temp, 16 h
Br
3jb
4jb
Entry
Pd
Base
Sol.
T
AY
(%)
0
0
0
trace
12
30
75
O
1) Allylic substitution
2) Heck reaction
3) Deprotection
S
S
H
OBoc
H
H
(oC)
60
60
60
60
80
60
80
1
2
3
4
5
6
7
Cl2Pd(NCPh)2
Cl2Pd(NCPh)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ag2CO3
Na2CO3
Ag2CO3
Na2CO3
Na2CO3
NEt3
DME
DME
DME
DME
MeCN
DME
MeCN
Br
1j
1 equiv
2b
1.5 equiv
5jb
52% yield
Scheme 6. A one-pot synthesis of 5jb.[a],[b]
[a]Reactions conducted on 0.1 mmol scale. [b]Isolated yield
after chromatographic purification. Allylation:
Cl2Pd(NCPh)2 5 mol %, dppe 7.5 mol %, NaN(SiMe3)2 (2
equiv) in DME at 24 oC for 36 h. Heck cyclization:
Pd(OAc)2 5 mol %, PPh3 15 mol %, NEt3 (5 equiv) in
MeCN at 120 °C for 16 h. Deprotection: SDS (0.2 equiv),
I2 (0.05 equiv) in THF:H2O (3:1) at 24 °C for 16 h.
Pd(OAc)2
Pd(OAc)2
NEt3
[a]Assay yields (AY) determined by 1H NMR spectroscopy
of the crude reaction mixtures.
Conclusion
In summary, we have developed the palladium-
catalyzed allylic alkylation of 2-aryl-1,3-dithiane
derivatives for umpolung synthesis of variously
substituted β,γ-unsaturated ketone derivatives. This
protocol is easily applicable to various substitution
patterns of the 2-aryl-1,3-dithianes and allylic
electrophiles (including cyclic derivatives). In
addition, allylated dithianes can be effectively
transformed in the same reaction flask to the
corresponding β,γ-unsaturated ketone derivatives in
good yields. Importantly, our conditions successfully
avoid isomerization of the β,γ-unsaturated ketone
products. We also have employed this method in a
sequential synthesis of asterogynin derivatives.
Allylated o-bromo phenyl substituted dithiane
derivatives can undergo Heck-type cyclization by a
simple synthetic operation to give oligo cyclic
ketones in good overall yields. Moreover, we have
presented the first stereochemical investigation of Pd-
catalyzed allylic substitution of 2-aryl-1,3-dithianes.
The result of this study showed that deprotonated 2-
phenyl-1,3-dithiane behaves as a “soft” nucleophile,
which undergoes external attack on the π-allyl
palladium complex under our reaction conditions.
Figure 3.The structure of 4jb with 50% thermal
ellipsoids.
OBoc
S
S
H
H
OBoc
2a
S
S
H
H
S
S
H
4ja, 71%[c]
2b
OBoc
Br
2d
S
S
4jb, 67%
1j
4jd, 75%
Scheme
5.
Sequential
Allylation-Heck
cyclizations.[a],[b]
[a]Reactions conducted on 0.1 mmol scale. [b]Isolated yield
after chromatographic purification. [c]Heck cyclization
conducted in DMF at 120 C. Allylation: Cl2Pd(NCPh)2 5
o
mol %, dppe 7.5 mol %, NaN(SiMe3)2 (2 equiv) in DME at
7
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
Experimental Section
the reaction mixture was quenched with 3 drops of
H2O, diluted with 3 mL of ethyl acetate, and filtered
over a pad of silica. The pad was rinsed with 6 mL
ethyl acetate (2×3), and the solution was concentrated.
The crude material was loaded onto a silica gel
column and purified by flash chromatography with
2% ethyl acetate in hexanes.
General Methods All reactions were performed
under nitrogen using oven-dried glassware and
standard Schlenk or vacuum line techniques. Air- and
moisture-sensitive solutions were handled under
nitrogen and transferred via syringe. Anhydrous
DME and Acetonitrile were purchased from Sigma-
Aldrich and used as solvents without further
purification. Unless otherwise stated, reagents were
commercially available and used as purchased
without further purification. Chemicals were obtained
from Sigma-Aldrich, Acros, TCI America or Matrix
Scientific. TLC was performed with Merck TLC
Silicagel60 F254 plates and detection was under UV
light at 220 nm. Silica gel (230–400 mesh, Silicycle)
was used for flash chromatography. The 1H NMR and
13C{1H} NMR spectra were obtained using a Bruker
AM-500 Fourier-transform NMR spectrometer at 500
and 125 MHz, respectively. Chemical shifts are
reported in units of parts per million (ppm) downfield
from tetramethylsilane (TMS), and all coupling
constants are reported in hertz. The infrared spectra
were obtained with KBr plates using a Perkin-Elmer
Spectrum 100 Series FTIR spectrometer. High
resolution mass spectrometry (HRMS) data were
obtained on a Waters LC-TOF mass spectrometer
(model LCT-XE Premier) using chemical ionization
(CI) or electrospray ionization (ESI) in positive or
negative mode, depending on the analyte. Melting
points were determined on a Unimelt Thomas-
Hoover melting point apparatus.
Acknowledgements
P. J. W. thanks the National Science Foundation (CHE-
1464744) for financial support. A. P.-E. thanks MINECO,
Spain, for predoctoral and mobility fellowships. We thank
Dr. Patrick J. Carroll and Brian Manor for crystallography
and X-ray data.
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9
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10.1002/adsc.201801035
Advanced Synthesis & Catalysis
Palladium-Catalyzed Allylic Alkylation of 2-
Aryl-1,3-dithianes, an Umpolung Synthesis of
β,γ-Unsaturated Ketones
OBoc
S
S
Cl2Pd(NCPh)2/SPhos
Ar
S
S
H
NaN(SiMe3)2
n
Ar
R
DME, 24 oC, 3 h
n
R
Adv. Synth. Catal. Year, Volume, Page – Page
n=0,1,2
pKa up to 31
up to 99% yield
“Soft” nucleophiles
Nisalak Trongsiriwat,a Minyan Li,a Ana Pascual-
Escudero,b Baris Yucel,c and Patrick J. Walsh*, a
10
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