Mechanistic Aspects of the Palladium-Catalyzed Isomerization of Allenic Sulfones to 1-Arylsulfonyl 1,3-Dienes

Article abstract of DOI:10.1021/acs.joc.6b00880

When an allenic sulfone is treated under palladium catalysis in the presence of a weak acid, isomerization to a 1-arylsulfonyl 1,3-diene occurs. Investigations of the mechanistic aspects of this isomerization were performed, leading to the mechanism proposed herein. Some further studies of reaction parameters are reported.

Full text of DOI:10.1021/acs.joc.6b00880

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Article
Mechanistic Aspects of the Palladium-Catalyzed
Isomerization of Allenic Sulfones to 1-Arylsulfonyl 1,3-Dienes
Carissa S. Hampton, and Michael Harmata
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00880 • Publication Date (Web): 29 Apr 2016
Downloaded from http://pubs.acs.org on May 1, 2016
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Mechanistic Aspects of the Palladium-Catalyzed Isomerization of
Allenic Sulfones to 1-Arylsulfonyl 1,3-Dienes
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Carissa S. Hampton and Michael Harmata*
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211
harmatam@missouri.edu
Abstract
When an allenic sulfone is treated under palladium catalysis in the presence of a weak
acid an isomerization to a 1-arylsulfonyl 1,3-diene occurs. Investigation of the
mechanistic aspects of this isomerization were performed leading to the mechanism
proposed herein. Some further studies of reaction parameters are reported.
ArO2S
ArO2S
[
Pd-H]
[Pd]
ArO2S
R2
R2
R2
R1
R1
R1
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Introduction
A group of compounds known as allenic sulfones are very versatile in organic
1
synthesis as a result of their ability to participate in many different types of reactions,
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including cycloaddition and cyclization reactions. An advantage of using an allenic
sulfone as compared to other allenic derivatives is that the sulfone moiety can be used as
a handle to control the chemistry desired and can be easily removed or modified once it
3
has served its purpose or can be used as a building block for other chemistries. The
electron-withdrawing nature of the sulfone group adjacent to the π-system and its ability
to stabilize an α-carbanion allows the α,β-unsaturated sulfone that is part and parcel of an
allenic sulfone to undergo conjugate addition at the β-carbon.
4
As an application of allenic sulfone chemistries in our group, we were interested
in generating an alkoxyallylic sulfone of the type 2 via a process shown in Scheme 1. In
the event, the reaction of 1 in the presence of tetrakis(triphenylphosphine)palladium(0)
led to an isomerization of the allenic sulfone to a 1-arylsulfonyl-1,3-diene 3. We recently
4
a
reported the initial discovery of this reaction.
Scheme 1. Attempted alkoxyalkylation of an allenic sulfone
O
Ts
Me
Me
O
OMe
OMe
Me
Ts
X
Pd(PPh3)4
Me
1
2
O
Ts
O
OMe
Pd(PPh ) (10 mol%)
THF, 0.03 M, reflux
7 h, 57%
3
4
3
Me
In 1988, the isomerization of acetylenic alkynones to conjugated (E,E)-dienones
was reported by the Trost group employing palladium catalysis, and by the Lu group
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using ruthenium catalysis. Soon after, Inoue and Imaizumi reported another ruthenium
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catalyst that was effective at catalyzing this reaction. Further study by Lu showed that
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IrH
5
[P(iPr)
3
]
2
was also an efficient catalyst. Each group proposed similar allenyl
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intermediates as part of the mechanism that were similar to those reported by Suzuki and
Moro-Oka in the isomerization of acetylenic silyl ethers to dienol silyl ethers by
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ruthenium hydride complexes.
In the mid 1990s, the isomerization of acetylenic phosphorus compounds was also
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reported to occur in a manner similar to that of carbonyl compounds. Later studies of
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11
both acetylenic carbonyl and phosphorus compounds showed that the reaction was
able to proceed under only phosphine catalysis (Scheme 2).
Scheme 2. Isomerization of acetylenic carbonyl and phosphorus compounds.
O
R3
Pd, Ir, or Ru catalyst
O
R3
R1
or PR3
R1
R2
R2
4
5
O
P
O
Pd catalyst
1
(
R )
P
2
(R1)2
R2
or PR3
R2
6
7
When simple phosphine catalysis is applied to allenic sulfones, a regioisomeric 2-
substituted diene is produced (Scheme 3); the mechanistic studies of this phosphine-
4
b
catalyzed reaction were recently reported. This comes as a result of the “chameleon”
nature of the sulfone group, which can behave either as an anionic stabilizing group or a
3
c, 3h, 6, 7, 12
leaving group.
Therefore, to enable isomerization of the allenic sulfones to
occur in a manner similar to that of the carbonyl and phosphorus compounds, a
mechanism that does not involve the expulsion of a sulfinate group must be employed;
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this is where palladium comes into play. For the formation of 1-arylsulfonyl dienes, we
proposed a mechanism that involves palladium hydride chemistry to induce the double
bond isomerization of the allenes. Herein we detail the results of our study of the
mechanism of this isomerization and some further examination of reaction parameters.
Scheme 3. Regiodivergent reactions of allenic sulfones
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Ts
Ts
Me
Ts
Me
Pd(PPh ) , AcOH
PPh , phenol
3
4
3
THF, reflux
THF, reflux
Me
Me
3
1
8
Results and Discussion
Examination of Reaction Parameters
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a
As previously described, the best catalyst system found for the isomerization of
allenic
sulfones to 1-arylsulfonyl-1,3-dienes was mixture of
a
tetrakis(triphenylphosphine)palladium (0) (10 mol%) and acetic acid (10 mol%). The
scope of this reaction was examined with several allenic sulfones, whose dienyl products
along with their yields are shown in Figure 1.
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O2
S
O2
S
O2
S
Me
Me
Me
Me
9
, 75%
3, 84%
10, 77%
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Me
iPr
O2
S
O2
S
O2
S
Me
iPr
MeO
Me
iPr
Me
Me
Me
11, 84%
12, 81%
13, 78%
O2
O
2
S
O2
S
S
S
S
Me
1
4, 68%
15, 75%
16, 93%
Ts
Ts
Ts
Me
1
7, 74%
18, 97%
21, 88%
19, 45%
22, 70%
Ts
Ts
Ts
Me
Ph
Me
0, 63%
2
Figure 1. 1-Arylsulfonyl 1,3-dienes prepared via isomerization by palladium catalysis.
4
a
It was seen in our previous report that as the aryl ring of the sulfone became
more electron-deficient, the 1-substituted dienes were not the only products obtained.
Instead, increasing or complete formation of the regioisomeric 2-arylsulfonyl-1,3-dienes
was observed. In the case of the dimethyl-substituted allenes 23 and 24, the reaction
afforded only the 2-substituted dienes 27 and 29 in 56% and 61% yield, respectively
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(
Table 1, entries 4 and 6). Additionally, with allene 25, the reaction afforded a 54% yield
of an inseparable mixture of the expected product 30 as well as the corresponding 2-
arylsulfonyl 1,3-diene 31 in a 1:4 ratio (Table 1, entry 8). These outcomes are the result
of the nucleophilic reaction with triphenylphosphine taking precedence due to the
increased electrophilicity of the allene induced by the presence of an increasingly
electron-withdrawing sulfone. The triphenylphosphine required for this transformation to
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occur is liberated from Pd(PPh ) in solution and the nucleophilic attack on the allene
proceeds more quickly than the Pd-catalyzed process, leading to formation of the 2-
arylsulfonyl dienes. Based on our proposed mechanism of the formation for the 2-
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a
sulfonyldienes, we sought to correct this problem by modifying the reaction conditions
to circumvent the nucleophilic process and allow formation of the 1-arylsulfonyl-1,3-
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dienes. Since phosphine nucleophilicity is based on both electronic and steric effects,
we anticipated that a phosphine ligand with a larger cone angle than triphenylphosphine
would perform appropriately. It was shown in our study of the phosphine-catalyzed
reaction that a reaction did not proceed in the presence of sterically hindered phosphines
4
b
such as tricyclohexyphosphine and tris(o-tolyl)phosphine. Therefore, we chose to use
tricyclohexylphosphine in the reaction as its cone angle (170°) is considerably larger than
that of triphenylphosphine (145°), anticipating the nucleophilic catalysis would be shut
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down in favor of the organometallic process. Thus, treatment of 23 with 10 mol% of
palladium acetate and 20 mol% of tricyclohexylphosphine in refluxing THF for 3 hours
resulted only in the formation of 26 in 53% yield. Other examples with electron-
withdrawing aryl sulfones demonstrated the efficacy of this method (Table 1). In each
case, the 1-substituted dienes are the only products formed under the alternative reaction
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3 4
conditions (Condition A) whereas the previous results with Pd(PPh ) gave the 2-
substituted dienes or mixtures of dienes (Condition B). As we had previously shown that
2 3
the isomerization could be executed in the presence of Pd(OAc) /PPh as the catalyst
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4a
system, it is worthy to note that when 24 was treated with palladium acetate and
triphenylphosphine under the same reaction conditions, 29 was formed in 63% yield
(
Scheme 4). This demonstrates that ligand selection is important in directing the outcome
of the rearrangement reaction of certain allenic sulfones.
Table 1. Isomerization of electron-withdrawing allenic sulfones.
ArO2S
ArO2S
ArO2S
Conditions
R2
or
R2
R1
THF, reflux, 0.1 M
R1
R1
R2
Condition A: Pd(OAc) (10 mol%), PCy (20 mol%)
2
3
Condition B: Pd(PPh ) (10 mol%), AcOH (10 mol%)
3 4
Yield
(%)
Entry
Substrate
Condition Time
Product
Ts
Ts
1
2
1
A
B
2.3 h
20 m
83
3
Me
Me
Me
Ts
1
84
53
3
Me
O2
S
O2
S
3
4
A
B
3 h
F3C
3
F C
2
3
Me
Me
Me
2
6
O2
S
23
20 m
56
F C
Me
3
27
O2
S
O2
S
F3C
F3C
5
6
A
B
3 h
83
61
2
4
F3C Me
Me
CF3
Me
28
O2
S
F3C
24
25 m
Me
CF3
29
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F3C
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Me Me
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F3C
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25
40 m
30:31
:4
CF3
1
Me Me
Scheme 4. Reaction of 24 with palladium acetate and triphenylphosphine.
O2
S
O2
S
F C
F C
3
3
Pd(OAc) (10 mol %)
2
PPh (20 mol %)
3
Me
CF3
2
4 F C Me
Me
THF, reflux, 63%
3
29
After initial demonstration of the isomerization of allenic sulfones to 1-
arylsulfonyl 1,3-dienes by palladium catalysis, further examination of the reaction
conditions to improve both the yield and efficiency of the reaction was pursued. The
4a
results obtained previously
showed in general that
a
combination of
tetrakis(triphenylphosphine)palladium(0) and acetic acid worked well for the palladium-
catalyzed reaction, and therefore, this catalyst system was used with 1 to study the
reaction parameters.
An examination of different solvents was performed first, and it was shown that
THF was a suitable choice, as it was the best solvent in the study, followed closely by
acetonitrile and toluene (Table 2, entries 2-3). Dimethyl carbonate and 1,3-dimethyl-
3,4,5,6-tetrahydro-2-pyrimidinone (DMPU) provided media in which the reaction was as
rapid, but the isolated yields were lower (Table 2, entries 4-5). Dimethylformamide
(
DMF) and t-butyl methyl ether (TBME) were also suitable, but not as efficient (Table 2,
entries 6-7). Dichloromethane was unsuitable as a solvent for the isomerization, leading
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to a 59% recovery of the starting material and no conversion to product (Table 2, entry
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).
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(a)
Table 2. Solvent effects on the palladium-catalyzed isomerization.
Ts
Ts
Me
Me
Pd(PPh ) , AcOH
3
4
solvent
1
3
Me
Entry
Solvent
THF
Temp (°C)
Time
20 min
20 min
25 min
20 min
25 min
1h 40min
8 h
Yield (%)
1
2
3
4
5
6
7
8
65
80
82
80
90
80
55
40
84
75
80
56
58
60
80
Toluene
MeCN
(
b)
DMPU
Dimethylcarbonate
(c)
DMF
(d)
TBME
(
e)
CH
2
Cl
2
25 h
(
a)
The reactions were conducted with 10 mol% catalyst and cocatalyst at 0.1 M
(
b)
(c)
concentration.
DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone
DMF =
(
d)
(e)
N,N-dimethylformamide TBME = t-butyl methyl ether 1 was recovered in 59% yield.
After determining that THF was the best solvent for this isomerization, the effect
of catalyst loading on the reaction time and yield was evaluated. The catalyst loading can
be lowered to 2.5 mol% with little decline in yield and relatively short reaction times
(
Table 3, entry 1). A concentration study to determine if the reaction proceeded better at
higher or lower concentrations was also performed. It was found that a slightly higher
yield was obtained in a more dilute reaction mixture (Table 4).
(
a)
Table 3. Effects of catalyst loading on the palladium-catalyzed isomerization.
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Ts
Ts
Me
Me
Pd(PPh ) , AcOH
3
4
THF, reflux
1
3
Me
Catalyst Loading
0
1
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8
9
0
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0
Entry
Temp (°C)
Time
Yield (%)
(
mol%)
1
2
3
2.5
5.0
65
65
65
25 min
25 min
20 min
83
88
84
10.0
(
a)
The reactions were conducted at 0.1 M concentration.
(a)
Table 4. Concentration effects on the palladium-catalyzed isomerization.
Ts
Ts
Me
Me
Pd(PPh ) , AcOH
3 4
THF, reflux
1
3
Me
Entry
Concentration (M)
Temp (°C)
Time
Yield (%)
1
2
3
4
0.025
0.05
0.10
0.15
65
65
65
65
20 min
20 min
20 min
25 min
88
81
84
86
(
a)
The reactions were conducted with 10 mol% catalyst and cocatalyst.
After these studies with 1, attempts at combining some of the different reaction
conditions were examined and it was found that under a catalyst loading of 2.5 mol%, a
concentration of 0.05 M in THF the yield of 3 could be improved to 91% (Table 5, entry
2
). Although the reaction required one hour to complete, it is still a very reasonable
reaction time and produced excellent results. While these reaction conditions were ideal
for 1, it is likely that an increase in yield would be observed for other allenic sulfones as
well when treated under these conditions. Therefore, a few allenic sulfones were reacted
and the results are shown in Table 5. These reaction conditions were beneficial in the
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cases of allenes 10 and 12; the isomerization could be completed very rapidly
accompanied by an increase in yield (Table 5, entries 4 and 6) compared to the previous
reaction conditions (Table 5, entries 3 and 5). For diene 20, the starting allene and
product diene have identical Rf values, so ascertaining exactly when the reaction
completion occurred was fallible. However, the reaction was still complete within the 2
hour reaction time period and produced an almost identical yield of 65% (Table 5, entries
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
-8). It is reasonable that there may be some variation because these conditions were
optimized for a single allene example and there may be other factors that influence the
reaction for other allenes.
Table 5. Comparison of reaction conditions.
ArO2S
ArO2S
Conditions
THF, reflux
R2
R2
R1
R1
Condition A: Pd(PPh ) (10 mol%), AcOH (10 mol%), 0.1 M
3
4
Condition B: Pd(PPh ) (2.5 mol%), AcOH (2.5 mol%), 0.05 M
3
4
Entry Product Conditions Time Yield (%)
1
2
3
4
5
6
7
8
3
3
A
B
A
B
A
B
A
B
20 min
1 h
84
91
77
88
81
84
63
65
10
10
12
12
20
20
45 m
30 m
3.6 h
30 m
2 h
2 h
Mechanistic Studies
Transition metal catalysis offers a mild approach to the isomerization of alkynes
to cumulated and conjugated dienes. The literature describes the use of transition metal
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2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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3
4
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4
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5
5
6
hydrides to perform this function. Protonation of low-valent transition metals generates a
class of reagents that contain a M-H bond. This bond may function differently from
typical conjugate acids in that it may act as a hydridometal species rather than a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
16
protonated metal. (Eq 1) As observed in many metal protonation/metal hydride
complexes, umpolung of the hydrogen occurs during the transfer of the hydrogen from an
1
6
acetate as the base to the low-valent metal as the base. The mechanism proposed by the
Trost and Lu groups for the isomerization of alkynyl carbonyls suggested a hydridometal
species, which through a series of hydrometallations/β-hydride eliminations, presumably
5, 7, 12
through an allenyl intermediate, eventually led to an E,E-diene.
+
+
M: + H+
M+ -H
M-H
(Eq. 1)
On this basis and the data obtained initially, we proposed the mechanism shown
in Scheme 6 for the metal-catalyzed isomerization of allenic sulfones to dienes. Hence,
oxidative addition of a coordinatively unsaturated Pd(0) species 33 to acetic acid
produces the palladium hydride intermediate 34. This hydropalladates 1 to produce 35 or
3
6. Subsequent β-hydride elimination from 35 or the π-allyl palladium intermediate 37
affords 3 and regenerates 34 (Scheme 5).
Scheme 5. Proposed mechanism for the palladium-catalyzed isomerization.
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Pd(PPh3)4
Pd(PPh3)2 + 2 PPh3
3
2
3
3
HOAc
OAc
H
Ts
Ph P Pd PPh
3
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ts
H
H
3
4
Me
Me
H
1
Me
3
Ts
H
PdLn
H
Me
H
3
5
Ts
H
Ts
H
Me
Me
LnPd
LnPd
Me
Me
3
7
36
Deuterium Labeling
Mechanistic insights were pursued using deuterium labeling of an allenic sulfone
to demonstrate the migration of a deuterium atom via the isomerization process. This
seemed reasonable based on the allenic intermediates presented by others in the
5a, 12
isomerization of acetylenic compounds.
It was proposed that labeling the δ-carbons of an allene with deuterium and using
deuterated acetic acid to form a palladium deuteride species would enable a deuterium
atom to end up on the β-carbon of the diene (Scheme 6). This would result from
deuteropalladation of 38 followed by β-deuteride elimination.
Scheme 6. Proposed isomerization of deuterated allene 38.
Ts
Ts
D
D
Pd(PPh ) , AcOD-d
3
4
4
D
D
D
D
D
D
38
39
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
3 4
A few questions needed to be considered: 1) would a combination of Pd(PPh )
and AcOD-d
4
generate a palladium deuteride and would this be effective in
deuteropalladating an allenic sulfone?, 2) would it be possible for the α-position to be
exchanged by reversible hydropalladation/β-deuteride elimination?, 3) would deuterium
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
be incorporated into a non-deuterated diene after formation by exposure to AcOd-d
alone or to the Pd(PPh /AcOD-d reaction conditions?, and 4) would there be a kinetic
isotope effect for the rupture of a C-D bond versus a C-H bond in this process?
4
3
)
4
4
First, the dimethyl-substituted allene 1 was used to examine whether a palladium
deuteride could be formed and if it would deuteropalladate an allenic sulfone. The flaw
with this reaction is that, in theory, there is a palladium hydride produced by β-hydride
elimination for every hydro/deuteropalladation that occurs. This, therefore, can put limits
on how much deuterium can be incorporated into the product. At a minimum, this
reaction would show that deuterium incorporation into the product is possible, supporting
the proposal that a palladium hydride/deuteride is a key component of this reaction.
Therefore, 1 was treated with a 30 mol% loading of catalyst and one equivalent of
deuterated acetic acid. After consumption of the starting material, the remaining material
was purified by column chromatography. This reaction produced the protio product 3 and
the β-deutero product 40, as well as some of the α-deutero diene 41 (Scheme 7), which
resulted from reversible H/D exchange by deuteropalladation/β-hydride elimination.
Scheme 7. Incorporation of deuterium into 1.
Pd(PPh ) (30 mol %)
3
4
Ts
Ts
D
Ts
D
Ts
Me
Me
AcOD-d (1 equiv)
4
+
+
THF, reflux
Me
Me
Me
3
0 min, 83%
1
3
40
41
0
.66 : 0.14 : 0.20
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The ratio of products formed was determined by the following:
• Each signal was integrated as normal.
•
The doublet for the p-tolylsulfonyl group at 7.78 ppm was set to 2.00 protons as a
reference.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
•
The signal for the α proton of the diene appears at 6.31 ppm. The singlet signal
for the α proton of 40 overlaps with the right half of the doublet signal for the α
proton of 3 (Figure 2).
•
•
There is no skewing of the doublet signal and therefore, the area of the doublet
can be determined to be 0.66 protons, leaving the remaining integrated area to the
α-proton of 40 which is 0.14 protons (Figure 2).
As the the α proton of 3 integrates for 0.66 protons, the β-proton of 3 will also be
0
.66 protons.
Ts
D
H
Ts
H
Me
3
Me
40
ꢀ
Figure 2. α Proton signals for 3 and 40.
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
•
•
The signal for the β proton appears near 7.31 ppm, which is partially overlapped
with the second signal from the p-tolylsulfonyl aromatic protons.
The left half of the β proton’s doublet of 3 overlaps with the aromatic signal. The
right half of the β proton’s doublet of 3 overlaps with the β proton of 41 (Figure
3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
•
The right half of β-H of 3 should integrate to 0.33 protons, which leaves the
remainder of the integrated signal at 7.30 ppm (0.20 protons) to the β-H of 41.
Ts
H
D
Ts
H
41 Me
3
Me
CDCl3
ꢀ
Figure 3. β Proton signals of 3 and 41.
• Therefore, from the reaction the diene products are formed in a ratio of
.66:0.14:0.20 for 3:40:41.
0
Thus, this reaction also illustrated the ability of the α-position of the allenic sulfone to be
exchanged. A faster rate of hydropalladation than deuteropalladation would explain the
very small amount of deuterated products that were observed.
1
7
In 1973, Cruikshank and Davies reported isotope studies of the isomerization of
olefins homogeneously catalyzed by palladium and other metals. They discovered in the
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palladium-catalyzed reactions that the rate of disappearance of a terminal olefin was only
slightly different, but the formation of the isomerized product was significantly slowed
when the compound was deuterated. These data in combination illustrate an isotope
effect on the breaking of a carbon-deuterium bond versus a carbon-hydrogen bond in the
isomerization process. Since the disappearance of starting material is not hindered and
the formation of product is slowed, this points to only the second stage of isomerization,
breaking the C-D bond, as the cause. This is a clear example of a KIE for the
isomerization of unsaturated bonds.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cruikshank and Davies also note that when a mixture of d
are mixed and isomerized there is formation of both d and d products in addition to the
expected d and d products (Scheme 8).
Scheme 8. Deuterium transfer between alkenes.
0 2
and d isotopologues
1
3
0
2
17a
H H
D D
PdCl2
+
d , d , d , and d compounds
0 1 2 3
Ph
Ph
AcOD-d4
42
1.0 : 1.0
43
This indicates that a deuterium from a d
2
deuterated alkene has been transferred to
a d
0
molecule to generate the d
1
species, or to another d molecule to generate the d
2
3
17a
species (Scheme 9). It is by a method similar to this that the α-hydrogen of the allenic
sulfone can be exchanged for a deuterium atom (Scheme 10).
1
7a
Scheme 9. Mechanism for deuterium transfer between alkenes.
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1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Pd
D D
D D
Ph
Ph
44
Me
Pd-H
43
D D
D
D D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
Me
Ph
46
Me
Ph
Me
Pd
4
5
47 Pd-D
Pd-H
exchange with
47
Ph
48
Me
Pd-D
D
A
PhCH CH=CHCH
2
3
D
Ph
Me
Ph
Me
Pd
4
9
50 Pd-H
D D
Ph
exchange with
PhCD CH=CHCH
47
Me
2
3
5
1
Pd-D
D
B
D
D D
D D
Ph
Me
Ph
Me
Pd-H
Pd
5
2
53
Scheme 10. α-Proton exchange of an allenic sulfone.
H
Ts
D
Ts
Ts
[Pd]
Me
[
Pd-D]
- [Pd-H]
D
Me
Me
Me
Me
Me
5
4
1
55
It was also necessary to confirm that any deuterium incorporated into the product
diene was a result of deuteropalladation of the allene and not an insertion of deuterium
after the product had already been formed. To that end, the non-deuterated diene 18 was
treated with one equivalent of deuterated acetic acid at reflux for 6 hours and there was
no incorporation of deuterium into the diene observed. Then, 18 was subjected to a
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3 4 4
mixture of Pd(PPh ) and AcOD-d at reflux for 6 hours (Scheme 11). There was also no
incorporation of deuterium in this case, suggesting that deuteropalladation only occurs in
the allene starting materials and not in the product dienes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 11. Subjection of 18 to deuterium conditions.
AcOD-d (1 equiv)
4
Ts
93% recovery
no D incorporation
THF, reflux, 6 h
Pd(PPh ) (10 mol %)
3 4
1
00% recovery
1
8
AcOD-d (1 equiv)
no D incorporation
4
THF, reflux, 6 h
In order to examine the isomerization proposed in Scheme 7, we prepared allene
3
8 by the steps outlined in Scheme 12. Cyclohexanone was refluxed with potassium
carbonate and deuterium oxide twice for 24 hours for α-exchange of the protons with
deuteriums. The labeled cyclohexanone 57 was then treated with ethynylmagnesium
chloride in THF at -78°C to afford the propargyl alcohol 58 in 51% yield. The sulfinate
ester 59 was prepared by treating p-toluenesulfonyl chloride and triethylamine with a
1
8
mixture of 58 and triphenylphosphine in dichloromethane. This ester then underwent a
1
8
[2,3]-sigmatropic rearrangement in the presence of silver hexafluoroantimonate to
produce 38 in 97% yield.
Scheme 12. Preparation of the tetra-deuterated allene 38.
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
HO
K CO
D
D
2
3
HCCMgCl
THF
D
D
D
D
D O
D
2
D
7
8%
5
1%
5
6
57
58
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
S
Ts
pTol
O
pTolSO Cl
AgSbF6
2
D
D
D
D
PPh , TEA
CH Cl
3
2
2
D
D
D
D
CH Cl
97%
2
2
59
38
4
After some experimentation with the deuterated allene 38 with AcOD-d and
palladium(0) in small scale reactions where an abundance of protons was observed in
positions expected to be deuterated, we reasoned that adventitious water may be having
an effect on the reaction and therefore, further experiments were performed with
glassware that had been refluxed with D
2
O and then dried overnight at 110 °C. When 38
was reacted with Pd(PPh /AcOD-d (Scheme 13) in the D
3
)
4
4
2
O-treated glassware, we were
able to improve the ratio of deuterated diene products.
Scheme 13. Isomerization of 38.
Ts
Pd(PPh3)
Ts
D
4
Ts
Ts
D
D
D
D
AcOD-d4
+
+
D
D
THF, reflux
D
D
D
D
D
7
7%
D
D
3
8
39
60
61
D
0
.39 : 0.33 : 0.09
To determine the ratio of dienes in the mixture, both manual and computer-
assisted integration techniques were used to determine the ratio of the dienes in the
1
overlapping signals in the H NMR (Figure 4). Using manual integration to select the
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area to be integrated for each signal, the following ratios were determined by an analysis
similar to that discussed for Scheme 8 and Figures 2-3.
•
•
Each signal was integrated as normal.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The doublet for the p-tolylsulfonyl group at 7.77 ppm was set to 2.00 protons as a
reference.ꢀ
7
.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3
ppm
1
Figure 4. H NMR overlapping peaks for reaction shown in Scheme 14.
• The signals for the α protons of the diene appear at 6.18 ppm. The singlet signal
for the α proton of 39 overlapped with the right half of the doublet signal for the α
proton of 59. This entire signal integrated for 0.74 protons.
• The signals for the β protons appear near 7.24 ppm. The singlet signal for the β
proton of 60 overlapped with the right half of the doublet signal for the β proton
of 39. This entire signal integrated for 0.40 protons.
•
In a separate integration, the peaks in question were integrated in two sections
each in order to determine the ratio of the compounds to one another.
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1
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1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
•
For the α proton signals, the singlet signal for 39 overlapped with the right half of
the doublet signal for the α proton of 59 (Figure 5). The area of the doublet of 59
was estimated to be 2.72 protons compared to the remaining integrated area for 39
equal to 2.86 protons.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ts
H
Ts
D
H
D
D
D
D
D
60
39
D
ꢀ
Figure 5. α Proton signals for 39 and 60.
•
For the β proton signals, the singlet signal for 60 overlapped with the right half of
the doublet signal for the β proton of 59 (Figure 6). The area of the doublet of 59
was estimated to be 2.00 compared to the remaining integrated area for 60 equal
to 0.73 protons.
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Ts
H
Ts
H
D
D
D
D
D
D
D
6
0
61
CDCl
3
10
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59
60
Figure 6. β Proton signals for 60 and 61.
A summary for this method gives a ratio of
•
α-39 = 2.86
α-59 = 2.72
β-59 = 2.00
β-60 = 0.73
= 1.43
= 1.36
= 1.00
= 0.365
à
The second method of integration allowed the instrument software to deconvolute the
overlapping signals from one another. The integrations can be seen in Tables 6-7.
Table 6. Computer-assisted analysis of the α-proton peaks.
%
chisq
Lor.
Fit
Frequency
Width
ppm
0.00386
0.00772
0.00465
Intensity
Area
8.140
Peak
ppm
6.199
6.176
6.169
Hz
3100.26
3088.82
3085.41
Hz
1.929
3.860
2.325
STD:
STD:
STD:
0.847
1.167
0.892
100.00
22.441 100.00
10.329 100.00
α-157
α-150
α-157
Table 7. Computer-assisted analysis of the β-proton peaks.
%Lor.
Area
Fit
Frequency
Width
Intensity
Peak
chisq
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2
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ppm
7.258
7.236
7.228
Hz
3629.88
3619.17
3614.77
ppm
0.00404
0.00737
0.00386
Hz
2.023
3.687
1.932
STD:
STD:
STD:
0.897
0.228
0.964
9.044
4.184
9.283
100.00
100.00
100.00
β-157
β-158
β-157
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0
•
•
The total integrated area of the α-proton of 59 was 18.469 protons compared to
the α-proton of 39 which was 22.441 protons.
The total integrated area of the β-proton of 59 was 18.327 protons compared to
the β-proton of 60 which was 4.184 protons.
• A summary for this method gives a ratio of
α-39 = 22.441
α-59 = 18.469
β-59 = 18.327
β-60 = 4.184
= 1.22
= 1.01
= 1.00
= 0.228
à
Next, the integrated areas on the original NMR (Figure 4) were used to calculate how
much of each peak is due to each proton:
!!ꢀꢁ
!.!
!!ꢀꢁ
!.!"
!.!!"
!.!!"
=
à 0.326
=
à 0.074
!
.!"
!.!!"
!
!ꢀꢁ
!.!"
!.!"
!!ꢀꢁ
!.!"
!.!!
!.!"
=
à 0.335
=
à 0.405
!
.!"
The α-59 and β-59 correspond to the same molecule, and they are averaged together to
approximate the ratio of compounds in the mixture (Figure 7).
Ts
Ts
D
Ts
D
D
D
D
D
D
D
D
D
D
6
0
61
39
60 : 61 : 39 = 0.33 : 0.07 : 0.41 = 0.81
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Figure 7. Ratio of dienes determined by H NMR integration.
The sum of the ratios of these compounds does not equal 1.0, and therefore there
must be another compound that makes up the remainder of the product mixture, but yet
does not contribute to the vinylic hydrogens being examined. This compound is proposed
to be the pentadeuterated species 62 (Figure 8). This pentadeuterated compound 62
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60
1
would be difficult to detect by H NMR because there is no separate signal by which to
identify it apart from the other diene isotopologues. The only discernable differences in
1
the H NMR spectra are in the vinylic region where the pentadeuterated species would
13
not contribute; in the C NMR, the deuterated carbon signals of 62 are the same as the
other deuterated carbon signals present for 39 and 61 in the product mixture.
Ts
D
D
D
D
D
6
2
Figure 8. Pentadeuterated diene 62.
After showing that there was a significant amount of protons in the diene product
mixture above, it was necessary to accurately determine the extent of deuteration of the
1
starting material 38. Initial examination of the H NMR of 38 appeared clean with an
1
absence of a peak where the compounds should be deuterated (by comparing to the H
NMR of the nondeuterated 18) though integration of the same region indicated an
2
integration of ~0.12 protons. A H NMR also showed this position to be the only
deuterated position in the molecule (Figure 9).
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Figure 9. H NMR vs. H NMR comparison of 38.
To further determine the extent of deuteration of the starting allene and the ratio
of diene isotopologues in the product mixture, electronspray ionization mass
spectrometry (ESI-MS) was taken of both the deuterated allene 38 and the deuterated
diene product mixture. It is then necessary to determine how well the experimental results
aligned.
Most elements appear in nature as isotopic mixtures. These isotopes are
responsible for the peaks in a mass spectrum appearing as an isotopic cluster, i.e. mass
peaks that are one, two, three, etc. mass units higher than the nominal mass, due to their
statistical distribution. Therefore, given the relative natural abundances of isotopes we
can calculate the theoretical relative intensities of peaks corresponding to
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isotopologues. This comparison of ESI-MS and H NMR data was used qualitatively to
1
ascertain whether the isotopologue mixtures that were seen in the H NMR of the diene
product mixture corresponded with the ratios present in the starting material 38 for the
reaction.
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60
In order to calculate theoretical intensities of isotopic clusters, the relative natural
1
12
13
abundances of isotopes that are relevant are as follows: H = 0.99985, C = 0.989, C =
1
6
32
33
34
0
.011, O = 0.9976, S = 0.9502, S = 0.0075, S = 0.0421.
The theoretical relative intensities of an isotopic cluster can be calculated by the
formula shown in Equation 2.
!
! #!!
!"! #!"!
!"! #!"!
!"! #!"!
!"! #!"!
ꢀ ꢀ = (ꢀ )
∙ (ꢀ
)
∙ (ꢀ
)
∙ (ꢀ
)
∙ (ꢀ
)
∙ #
ꢀ
(Eq. 2)
!"! !"
where
ꢀ = mass unit
ꢀ
ꢀ = probabililty of the mass unit
ꢀ!"!
= relative abundance of C, etc.
13
13
13
#
C = number of C atoms in the molecule, etc.
ꢀ is a permutation for how many different ways there are to insert
!"! !"
#
13
#
C atoms into the molecule.
To calculate the theoretical relative intensities of the isotopic peaks accompanying the
molecular ion peak of the allenes or dienes, we consider its molecular formula of C15
S. There are 15 carbon atoms; what is the probability of any number of carbon-13
atoms (0-15) being present in this molecule? These calculations were repeated for each
H
18-
n
n 2
D O
3
2
33
34
isotope of sulfur ( S, S, and S). The probabilities for each mass unit can be summed
to yield a total probability. From here the percent theoretical relative abundances for an
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18-n n 2
isotopic cluster can be calculated. For compounds with the formula C15H D O S (n =
2
-5), the percent theoretical relative abundances are shown in Table 8.
Table 8. Theoretical relative abundances of isotope clusters.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
1
2
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4
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9
0
1
2
3
4
5
6
7
8
9
0
Relative
Mass
264
Abundance (%)
100.0000
17.4728
7.1602
C
15
C
15
C
15
C
15
H
16
H
15
H
14
H
13
D
2
D
3
D
4
D
5
O
2
O
2
O
2
O
2
S
S
S
S
2
2
2
2
65
66
67
68
1.1353
0.1682
265
100.0000
17.4728
7.1602
1.1353
0.1682
100.0000
17.4728
7.1602
1.1353
0.1682
100.0000
17.4753
7.1746
1.1377
0.1686
2
2
2
2
66
67
68
69
266
2
2
2
2
67
68
69
70
267
2
2
2
2
68
69
70
71
Some of the peaks to be analyzed in the spectrum would correspond to multiple
isotopologues as demonstrated in Table 9. Given the experimental intensities of each
mass peak and using the theoretical isotopic cluster ratios we can extract the final ratios
of the isotopologues in the mixture.
Table 9. Isotopologue contributions to mass ion peaks.
Mass Peak
d
2
d
3
d
4
d
5
2
2
2
268
269
65
66
67
n
n+1
n+2
n+3
n
n+1
n+2
n+3
n
n+1
n+2
n
n+1
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n+3
n+2
n+3
Allene 38 was treated under isomerization conditions as shown in Scheme 14. It
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1
can clearly be seen in the H NMR data in Figure 4 above and the mass spectrometry data
below of the product mixture that there is a mixture of isotopologues, which contains at
5 4 3 2
least d , d , d , and d compounds (Figure 10). Given the experimental peak intensities
and using theoretical isotopic cluster ratios we can extract the final ratio of the
isotopologues in the mixture. After normalization, it was determined that the dienes are in
a ratio of 0.0410 : 0.3417 : 0.4959 : 0.1214 of d
2
:d
3
:d
4
:d
5
4
dienes. The two d isomers can
1
be separated by using the integration and ratio obtained by H NMR to give a final ratio
of 0.0410 : 0.3417 : 0.4236 : 0.0723 : 0.1214 of 63/64 : 60 : 39 : 61 : 62.
Scheme 14. Diene products from isomerization of allene 38.
Ts
Ts
Ts
D
H
D
+
+
H
D
D
D
D
D
D
63
64
0.0410
60
Ts
0.3417
Pd(PPh3)4
d3
d2
D
D
AcOD-d4
D
D
THF, reflux
Ts
D
Ts
Ts
D
D
D
D
D
3
8
+
+
D
D
D
D
D
D
39
61
62
0.4236
0.0723
0.1214
d4
d5
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