Regiodivergent synthesis of 1- and 2-arylsulfonyl 1,3-dienes

Article abstract of DOI:10.1021/ol500259m

In the course of a study of the alkoxyallylation of allenic sulfones through the use of π-allylpalladium chemistry, we discovered an isomerization of allenic sulfones to arylsulfonyl 1,3-dienes. Under conditions of palladium catalysis in the presence of acids such as acetic acid, allenic sulfones are converted to 1-arylsulfonyl 1,3-dienes. On the other hand, nucleophilic catalysis using triphenylphosphine in the presence of a proton shuttle yields 2-arylsulfonyl 1,3-dienes. Thus, either regioisomer of the arylsulfonyl diene can be prepared at will based on changes in reaction conditions.

Full text of DOI:10.1021/ol500259m

Letter
pubs.acs.org/OrgLett
Regiodivergent Synthesis of 1- and 2‑Arylsulfonyl 1,3-Dienes
Carissa S. Hampton and Michael Harmata*
Department of Chemistry, University of MissouriColumbia, 601 South College Avenue, Columbia, Missouri 65211, United States
S
* Supporting Information
ABSTRACT: In the course of a study of the alkoxyallylation
of allenic sulfones through the use of π-allylpalladium
chemistry, we discovered an isomerization of allenic sulfones
to arylsulfonyl 1,3-dienes. Under conditions of palladium
catalysis in the presence of acids such as acetic acid, allenic sulfones are converted to 1-arylsulfonyl 1,3-dienes. On the other hand,
nucleophilic catalysis using triphenylphosphine in the presence of a proton shuttle yields 2-arylsulfonyl 1,3-dienes. Thus, either
regioisomer of the arylsulfonyl diene can be prepared at will based on changes in reaction conditions.
llenic sulfones are powerful reagents in organic synthesis.1
Scheme 2. Nucleophilic Catalysis of Allene Ester
Isomerization
AThey participate in many types of processes, including
cycloaddition and cyclization reactions.2 The sulfone group
serves to activate the allene as an electron-withdrawing group,
but it can be easily removed by various desulfonylation
methods.3
Table 1. Examination of Catalyst Variation for the Synthesis
of Diene 4a
We have an ongoing interest in the development of (4 + 3)-
cycloaddition reactions,4 including intramolecular cycloaddi-
tions of alkoxyallylic sulfones5 or (trimethylsilyl)methyl allylic
sulfones.6 In the former case, a key process in the synthesis of
the starting material is the addition of an alkoxide to an allenic
sulfone.7 We wondered whether we could perform such a
reaction coupled to an alkylation in order to facilitate the
synthesis of substrates for (4 + 3)-cycloaddition reactions. To
that end, we treated a mixture allenic sulfone 1a and allylic
carbonate 2 with Pd(PPh3)4 in anticipation of forming 3 via
alkoxide addition to the allene followed by alkylation with the
π-allyl palladium complex formed during the course of the
reaction.8
a
entry
catalyst
Pd2(dba)3
time
32 h
yield (%)
b
1
2
3
4
5
6
c
Pd(OAc)2
20 h
5
Pd(OAc)2/PPh3
Pd(PPh3)4
25 min
7 h
81
57
84
Pd(PPh3)4/AcOH
20 min
a
10 mol % of catalyst (and cocatalyst where appropriate) were used.
81% recovered 1a. 66% recovered 1a.
b
c
In the event, the reaction of 1a and 2 in the presence of 10
mol % of tetrakis(triphenylphosphine)palladium in refluxing
THF afforded not 3 but a 57% yield of 4a (Scheme 1). This
appeared to be a new reaction of allenic sulfones, which we
subsequently decided to pursue.
The formation of dienes through metal or nucleophilic
catalysis is well established in the rearrangement of alkynes
substituted with carbonyl groups.9
One of the few reported isomerizations of an allenic system
to a conjugated diene was demonstrated by Trost under
phosphine catalysis (Scheme 2).9c The paucity of literature on
allene isomerization is most likely due to the fact that alkynes
are generally easier to synthesize than allenes.10,11
Scheme 1. Attempted Formation of 3 via Nucleophilic
Addition/Allylation
We began our studies by examining a small selection of
catalysts using 1a as a substrate. The results are shown in Table
1. The use of palladium catalysts such as Pd(OAc)2 and
Pd2(dba)3 alone resulted in recovered starting material with
only trace amounts of isomerized product 4a being observed.
The use of Pd(PPh3)4 alone provided the isomerized product,
albeit in modest yield (57%). When triphenylphosphine was
Received: January 23, 2014
Published: February 3, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 2. Acid Effect on Product Formation
Table 4. Isomerization of Allenic Sulfones To Form 1-
a
Arylsulfonyl Dienes
a
entry
acid
pKa
time
4a
4a′
1
2
3
4
5
6
7
8
9
p-TolSO3H
CH3CO2H
−2.3
4.76
5 min
20 min
25 min
8 h
87
84
79
76
60
yield of
entry substrate
Ar
R1
R2
time
product 4 (%)
Me3CCO2H
4-nitrophenol
3-chlorophenol
2-naphthol
5.03
7.15
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
p-Tol
Me
Me
Me
Me
Me
Me
H
20 min
50 min
45 min
4.3 h
4a
4b
4c
4d
4e
4f
84
75
77
84
81
78
Ph
H
H
H
H
H
9.02
24 h
2-naphthyl
mesityl
trisyl
9.51
24 h
42
74
53
54
phenol
9.98
2 h
3.6 h
2,6-diphenylphenol
10.01
12.23
2.6 h
23 h
4-(MeO)
C6H4
35 min
b
BHT
a
b
7
8
1g
1h
2-Thienyl
Me
Me
H
H
2 h
4g
68
pKa in aqueous solution. BHT = 2,6-di-tert-butyl-4-methylphenol.
4-(CF3)
C6H4
20 min
b
b
Table 3. Catalyst Conditions for Isomerization of 1a to 4a′
9
1i
3,5-
Me
H
25 min
c
c
bis(CF3)
C6H3
10
11
12
13
14
1j
p-Tol
p-Tol
Ph
−(CH2)3−
−(CH2)4−
−(CH2)4−
−(CH2)4−
2.5 h
5 h
4j
4k
4l
4m
e
74
97
93
75
e
1k
1l
5 h
catalyst
yield of 1a
yield of 4a′
a
d
entry
system
time
(%)
(%)
1m
1n
2-thienyl
9 h
3,5-
bis(CF3)
C6H3
−
40 min
1
2
3
4
5
6
7
8
PPh3
22 h
5 h
50
CH2CH2-
C(Me)2C-
H2−
PPh3
AcOH
PhOH
31
70
54
PPh3
5.25 h
4 h
b
PPh3
BHT
15
16
17
18
1o
1p
1q
1r
p-Tol
p-Tol
p-Tol
p-Tol
H
H
H
H
Et
i-Pr
Ph
f
2 h
2 h
2 h
2 h
4o
4p
4q
4r
45
63
70
88
PhSO2Na
TsNa·H2O
32 h
36 h
20 h
20 h
35
b
BHT
60
AcOH
48
51
b
a
BHT
The reactions were conducted at a concentration of 0.1 M using 10
a
b
c
20 mol % of catalyst (and cocatalyst where appropriate) were used.
BHT = 2,6-di-tert-butyl-4-methylphenol.
mol % of catalyst and cocatalyst. 4h′ was isolated in a 56% yield. 4i′
b
d
was isolated in a 61% yield. Identical Rf values for 1m and 4m led to a
longer reaction time, as we were not certain when the reaction was
e
complete. The product was isolated as a 1:4 mixture (NMR) of
f
4n:4n′ in 54% yield. R2CH2− = cyclohexyl.
used in combination with Pd(OAc)2, the reaction proceeded
both relatively quickly and in high yield. This suggested that the
addition of acetic acid to the Pd(PPh3)4 catalyst would increase
the rate of the reaction. Indeed, as mentioned by Trost and
Schmidt in their acetylene isomerization work,9f the addition of
a weak acid to the reaction when a Pd(0) catalyst was used
greatly improved both the yield and reaction rate (Table 1,
entry 5).
To determine the effect of the acidity of cocatalysts on the
reaction, we varied the pKa of the acid used to accelerate the
reaction. Some of these results are shown in Table 2. The
reaction afforded 4a in the presence of p-toluenesulfonic acid
monohydrate in 87% yield, and we were able to demonstrate
that the reaction did not proceed in the absence of palladium;
i.e., it is not acid-catalyzed. Acids similar to acetic acid also
performed well (Table 2, entry 2).
Since Rychnovsky reported that phenol was a good cocatalyst
for the phosphine-catalyzed isomerization of alkynones,12 we
tried phenol as the cocatalyst in our palladium-catalyzed
isomerization. Instead of 4a, we isolated a new product,
identified as the 2-arylsulfonyl diene 4a′ (Table 2, entry 7). As a
result, we began studying the effects of phenols on the product
formation as well (Table 2, entries 4−9). The results seem to
show that at a pKa of ∼9.0−9.5 (aqueous pKa values) there is a
change in product formation and consequently a change in the
mechanism of the process.
Mechanistic considerations led us to realize that palladium
was not necessary for the formation of 4a′, and several
experiments were conducted to examine this idea. The results
are summarized in Table 3. Triphenylphosphine alone in
refluxing THF consumed 1a to the extent of 50%, but no diene
of any type was produced (Table 3, entry 1). Triphenylphos-
phine and acetic acid afforded a low yield of 4a′ (Table 3, entry
2). As expected, the presence of phenol or BHT in conjunction
with triphenylphosphine resulted in good yields of 4a′, with
phenol being superior (Table 3, entries 3 and 4). We
hypothesized that during the course of the reaction arylsulfinate
ions were being produced and were actually responsible for the
formation of 4a′.13 Interestingly, when sodium benzenesulfinate
was used as a catalyst, only a low yield of starting material could
be isolated from the reaction (Table 3, entry 5). However,
when sodium p-toluenesulfinate hydrate in combination with
BHT was used as the catalyst, diene 4a′ was obtained in 60%
yield (Table 3, entry 6). Neither acetic acid alone nor BHT
alone afforded any diene product (Table 3, entries 7 and 8).
With this information in hand, we set out to explore the
scope and limitations of both the palladium-catalyzed and
phosphine-catalyzed isomerizations. The results are summar-
ized in Tables 4 and 5.
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Organic Letters
Letter
a
group were not expected to be too dramatic. Thus, the p-
methoxybenzenesulfonyl system reacted essentially in the same
fashion as the simple phenyl system (Table 4, entry 6).
Interestingly, the thiophene-2-yl system required more time to
go to completion but still delivered a good yield of diene
(Table 4, entry 7). As the aryl ring became more electron-
deficient, the reaction began to change course. For the
dimethyl-substituted allenes 1h and 1i, the reaction afforded
only 4h′ in 56% yield and 4i′ in 61% yield, respectively (Table
4, entries 8 and 9). With the allene 1n, the reaction afforded a
54% yield of an inseparable mixture of the expected product 4n
as well as 4n′ in a 1:4 ratio (Table 4, entry 14). Since
Pd(PPh3)4 liberates free PPh3 in solution,14 it is likely that in
these latter cases the increased electrophilicity of the allene
dominates the reaction and nucleophilic attack on the allene
proceeds more quickly than the Pd-catalyzed process, leading
to increasing or complete formation of the 2-arylsulfonyl
dienes. Finally, we have conducted a brief study of the effect of
varying substitution on the allene on the process. Five and six-
membered rings led to dienes uneventfully and in good yield
(Table 4, entries 10−12).
Table 5. Formation of 2-Arylsulfonyl Dienes
entry
substrate
time
product
yield of 4′ (%)
1
1a
1b
1c
1d
1e
1f
5.25 h
8.5 h
4 h
4a′
4b′
4c′
4d′
b
70
42
79
52
b
2
3
4
6 h
5
16 h
6
2.75 h
35 min
15 min
45 min
30 min
2 h
4f′
4g′
4h′
4i′
4j′
4k′
4l′
64
71
68
63
57
7
1g
1h
1i
8
9
10
11
12
13
1j
c
1k
1l
40
c
4 h
d
c
1m
9 h
4m′
52
a
The reactions were conducted at a concentration of 0.1 M using 20
mol % of catalyst and cocatalyst. 41% of 1e was recovered. Expected
product as well as a byproduct from 1,4-addition of phenol to the
b
c
γ-Monosubstituted allenes also isomerized readily to the
corresponding 1-arylsulfonyl dienes in fair yield (Table 4,
entries 15−18).
d
allenic sulfone were observed. Identical Rf values for 1m and 4m′ led
to longer reaction time as we were not certain when the reaction was
complete.
The results for the phosphine-catalyzed reactions are
summarized in Table 5. In the phosphine/phenol-catalyzed
reaction, electron-withdrawing groups on the aromatic ring of
the sulfonyl functional groups led to rapid isomerization to the
corresponding 2-substituted sulfonyl diene, possibly due to the
better leaving group ability of the sulfinate anions involved
(Table 5, entries 8 and 9). Allenes bearing relatively electron-
rich groups such as the thiophene or the p-methoxyphenyl
rearrange at reaction rates that are qualitatively rather fast as
well, perhaps due to increased nucleophilicity of the sulfinate
anions involved (Table 5, entries 6 and 7). Compounds with
sulfonyl groups with weakly electron-rich substituents (Table 5,
entries 1, 3, and 4) were followed by compounds such as the
phenylsulfonyl-substituted 1b, which took the longest time to
react among those allenes whose sulfonyl substituents were not
sterically encumbering (Table 5, entries 2 and 5).
For the palladium-catalyzed process, we used a 10 mol %
loading of Pd(PPh3)4 along with an equimolar amount (with
respect to Pd) of AcOH. The reactions were conducted in
refluxing THF at a concentration of 0.1 M with respect to the
substrate and were monitored by TLC at regular intervals. We
first examined the effect of the aryl group associated with the
sulfone functional group on the course of the reaction. For
simple, unhindered groups such as phenyl, p-methylphenyl, and
2-naphthyl, the reaction was complete in less than 1 h and
furnished the corresponding 1-arylsulfonyl-substituted dienes in
very good yields (Table 4, entries 1−3). As the size of the aryl
group increased to mesityl and trisyl, the reaction proceeded
more slowly but still afforded excellent yields of products
(Table 4, entries 4 and 5). Electronic effects based on the aryl
Scheme 3. Mechanistic Proposals for the Formation of 1- and 2-Arylsulfonyldienes from Allenes
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Organic Letters
Letter
(7) Denmark, S. E.; Harmata, M. A.; White, K. S. J. Org. Chem. 1987,
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The data obtained thus far in conjunction with mechanistic
hypotheses put forth in the literature on related processes
suggest a mechanism for the formation of 1-arylsulfonyl dienes
such as 4a as depicted in Scheme 3, box A. Thus, oxidative
addition of a coordinatively unsaturated Pd(0) species (8) to
acetic acid produces the palladium hydride intermediate 9. This
hydropalladates 1a to produce 10 or 11. Subsequent β-hydride
elimination from 10 or the π-allylpalladium intermediate 12
affords 4a and regenerates 9.
The formation of 4a′ appears to be more complex. We
postulate that nucleophilic addition of triphenylphosphine to 1a
produces 13, which deprotonates phenol to produce 14
(Scheme 3, box B). The resultant phosphonium salt is
deprotonated by the resulting phenoxide, eliminating a sulfinate
anion and affording the phosphonium salt 15. This step is
actually critical in generating the small amounts of sulfinate ion
necessary to produce 4a′. Thus, nucleophilic addition of
arylsulfinate anion to 1a produces 16 and once again phenol
serves as a proton shuttle, ultimately regenerating sulfinate
anion and producing 4a′. Efforts to lend support to these
mechanistic proposals are underway.
Castle, S. L. Tetrahedron 2005, 61, 10377. (d) Backvall, J.-E.;
̈
Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 1998, 98, 2291.
(12) Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59, 2659.
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Clavijo, E.; Carmona, A. T.; Reissig, H.-U.; Moreno-Vargas, A. J.;
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K. J. Org. Lett. 2012, 14, 3024.
In summary, we have developed methods for the selective
conversion of readily accessible arylsulfonyl allenes15 to either
1-arylsulfonyl- or 2-arylsulfonyl dienes. Further studies of these
isomerization processes, their scope and mechanism, and the
application of the products to synthetic problems are underway,
and results will be reported in due course.
(14) Tolman, C. A.; Seidel, W. C.; Gerlach, D. H. J. Am. Chem. Soc.
1972, 94, 2669.
(15) (a) Harmata, M.; Cai, Z.; Huang, C.; Brummond, K. M.; Wen,
B. Org. Synth. 2011, 88, 309. (b) Harmata, M.; Huang, C. Adv. Synth.
Catal. 2008, 350, 972.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and copies of 1H and 13C NMR spectra for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: harmatam@missouri.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a grant from the National Science
Foundation and the Department of Chemistry at the University
of MissouriColumbia. We thank Mr. Rama Rao Tata
(MissouriColumbia) for supplying some of the allenes
used in this study.
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