Elucidation of the reaction mechanism of ortho→α transmetalation reactions of alkyl aryl sulfone carbanions

Article abstract of DOI:10.1002/ejoc.201402171

The sulfonyl group, as an electron-accepting function, displays a strong acidifying effect on neighboring α-hydrogen atoms, leading to their deprotonation by bases. Recently, reversal of the metalation selectivity of α,γ-branched alkyl aryl sulfones was described, which instead undergo directed ortho-metalation with good regioselectivity, despite having a more acidic α-proton. Upon warming, a transmetalation to the α-carbanion proceeds; however, nothing is known about the course of this transmetalation. Here, a mechanistic study is presented that sheds light on the facility of the initial metalation and the subsequent transmetalation. Large kinetic isotope effects were observed for both the initial deprotonation and the ortho→α transmetalation, which strongly influence the initial metalation selectivity. The results of a kinetic investigation of the transmetalation and a crossover study indicate that a concerted intermolecular pathway, either from an aggregate or from a monomeric aryllithium, prevails. The potential involvement of a stepwise process via ortho,α-dilithium intermediates was investigated, but no hint of their involvement was found. Copyright

Full text of DOI:10.1002/ejoc.201402171

FULL PAPER
DOI: 10.1002/ejoc.201402171
Elucidation of the Reaction Mechanism of orthoǞα Transmetalation Reactions
of Alkyl Aryl Sulfone Carbanions
[a]
[a]
ˇ
Lucie Rehová and Ullrich Jahn*
Keywords: Reaction mechanisms / Transmetalation / Lithiation / Kinetics / Isotopic labeling
The sulfonyl group, as an electron-accepting function, dis-
plays a strong acidifying effect on neighboring α-hydrogen
atoms, leading to their deprotonation by bases. Recently, re-
versal of the metalation selectivity of α,γ-branched alkyl aryl
sulfones was described, which instead undergo directed or-
tho-metalation with good regioselectivity, despite having a
more acidic α-proton. Upon warming, a transmetalation to
the α-carbanion proceeds; however, nothing is known about
the course of this transmetalation. Here, a mechanistic study
is presented that sheds light on the facility of the initial met-
alation and the subsequent transmetalation. Large kinetic
isotope effects were observed for both the initial deproton-
ation and the orthoǞα transmetalation, which strongly influ-
ence the initial metalation selectivity. The results of a kinetic
investigation of the transmetalation and a crossover study
indicate that a concerted intermolecular pathway, either from
an aggregate or from a monomeric aryllithium, prevails. The
potential involvement of a stepwise process via ortho,α-di-
lithium intermediates was investigated, but no hint of their
involvement was found.
transmetalation to the thermodynamically more stable α-
sulfonyl carbanions III above –40 °C. The degree of
branching determined the metalation selectivity as well as
the onset of the transmetalation from II to III. In contrast,
α-branched sulfones lacking the additional γ-branching de-
protonated as usual in the α-position, leading directly to
III. The Gais group found a similar DoM/transmetalation
behavior for conformationally constrained sulfoximines.[5]
Introduction
Carbanions are widely used intermediates in organic
chemistry.[1] Their generation is especially facile when elec-
tron-accepting activating groups are present in the vicinity
of the envisaged site. Normally, the regioselectivity of the
deprotonation process can be easily predicted. If an alkyl
group has hydrogen atoms in an α-position to the electron-
accepting group, deprotonation takes place at this position
because of its much lower pKa value. If not, the activating
group can still act as a Lewis base, coordinating the coun-
terion of the base, especially for organolithium bases, and
direct the deprotonation in a more distant position accord-
ing to the complex-induced proximity effect (CIPE).[2] The
most common class of these processes constitute directed
ortho-metalations (DoM) at aryl units. Normally these two
basic metalation modes exclude each other.
The sulfone group is a commonly applied activating
group for the generation of carbanions and usually acts ac-
cording to the rules outlined above.[3] However, we recently
found a surprising reversal of the lithiation selectivity of
α,γ-branched alkyl aryl sulfones I,[4] in which selective DoM
at the aryl unit prevails, despite the presence of a consider-
ably more acidic α-proton (Scheme 1). The resulting aryl-
lithium intermediates II are stable at low temperature and
can react with a number of electrophiles, but they undergo
Scheme 1. Metalation selectivity dependence of sulfones I on the
substitution pattern.
Nothing is known about the mechanism of this trans-
metalation, but this is critical for the synthetic applicability
of II or III. Three pathways can be envisaged to account
for the transmetalation of branched aryllithiums V resulting
from sulfone IV to α-sulfonylalkyllithium IX (Scheme 2). It
may proceed in an intramolecular manner through a con-
certed process via a four-membered transition state VI. Al-
ternatively, two intermolecular pathways may be followed.
On one hand, a concerted proton transfer from an aggre-
gate[6] or two monomeric ortho-sulfonylphenyllithium units
V via a symmetrical transition state such as VII may occur.
[a] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic,
Flemingovo namesti 2, 16610 Prague, Czech Republic
E-mail: jahn@uochb.cas.cz
Homepage: http://www.uochb.cz/web/structure/616.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402171.
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Mechanism of orthoǞα Transmetalation Reactions
Scheme 2. Potential course of the transmetalation reaction of ortho-sulfonylphenyllithium V to α-sulfonylalkyllithium IX.
On the other hand, two consecutive proton transfers may mediates, are presented. Based on these results a plausible
first lead to an ortho,α-dilithium intermediate VIII and sub- mechanistic course of the transmetalation is suggested.
strate IV as the rate-limiting step, from which a second,
potentially fast proton transfer follows, leading to two units
of IX. Indeed, intermediates VIII were previously individu-
ally generated by Gais and colleagues by a reverse strategy
of initial α- and subsequent ortho-metalation.[5,7]
Results
Preparation of Starting Materials
To gain insight into reaction mechanisms, kinetic investi-
gations are often undertaken. Such investigations can dis-
tinguish between unimolecular vs. bimolecular pathways,
which is a situation given here with VI vs. VII and VIII/IV,
however not the latter two, because the same rate law may
apply to both. Another convenient strategy to determine
whether a reaction proceeds in an intra- or intermolecular
manner is crossover experiments. It can be hypothesized
that differentially deuterated precursors would be ideal re-
action partners for the given case, because it can be ex-
pected that the reaction rates are different, but the general
course should not change. Moreover, the products can be
directly and conveniently detected and identified by NMR
and mass spectrometry techniques. This necessitates the de-
termination of deuterium kinetic isotope effects (KIE).[8]
Especially during metalation reactions, large deuterium
KIEs may be observed, which influence their rate and selec-
tivity.[9]
2,6-Dimethylhept-4-yl phenyl sulfone (2) and pent-3-yl
phenyl sulfone (3) were prepared from commercially avail-
able methyl phenyl sulfone (1a) by deprotonation with
nBuLi in the presence of TMEDA and subsequent alkyl-
ation with isobutyl or ethyl iodide, respectively
(Scheme 3).[4b] The para-methyl-substituted sulfone 4 was
similarly prepared from 4-(methylsulfonyl)toluene (1b) by
deprotonation with nBuLi and alkylation with isobutyl
iodide.
Scheme 3. Preparation of α-branched aryl sulfones 2–4.
We provide here a mechanistic study of the trans-
The deuterated sulfones intended for use in the determi-
metalation of ortho-sulfonylphenyllithium intermediates V nation of KIEs and crossover experiments were prepared
to the corresponding α-sulfonylalkyllithium compounds IX. by deprotonation of 2–4 and subsequent deuteration
Results of a kinetic investigation for the transmetalation re- (Scheme 4). ortho,orthoЈ-Dideuterated compound o,o-D2-2
action, studies aimed at the determination of deuterium was synthesized from sulfone 2 via ortho-deuterated o-D-2
KIEs, crossover experiments, and a study to determine by two consecutive deprotonations with nBuLi and subse-
whether dilithium intermediates VIII are competent inter- quent addition of deuterium oxide; the product was formed
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in 98% yield as a 92:8 mixture of o,o-D2-2 and monodeuter-
ated derivative o-D-2. It was, however, not possible to deu-
terate both positions in 100% yield without further deutera-
tion in the α-position. Deprotonation of o,o-D2-2 under
similar conditions with a slight excess of BuLi at –20 °C
and addition of D2O gave the trideuterated sulfone o,o,α-
D3-2 in very good yield and complete deuteration. α-Deu-
terated sulfones α-D-3 and α-D-4 were obtained by depro-
tonation/deuteration of 3 and 4, respectively, with complete
deuteration.
Scheme 4. Preparation of deuterated alkyl aryl sulfones.
Mechanistic Investigations on the Course of the
Transmetalation
Kinetics
Compound 2 served as the substrate for determination
of the kinetics of the transmetalation. It was deprotonated
by nBuLi in tetrahydrofuran (THF) in the presence of
N,N,NЈ,NЈ-tetramethylethylenediamine (TMEDA) at –50,
–45, –40, –35, and –30 °C (Figure 1, Supporting Infor-
mation Tables S3–7). The use of TMEDA proved to be ben-
eficial for obtaining optimal o-/α-selectivity.[4] After given
times, aliquots were taken, the reaction was quenched by
Figure 1. Kinetic trace of the transmetalation of o-Li-2 to α-Li-2
(for the raw data see the Supporting Information, Tables S3–7).
1
the addition of D2O, and the sample was analyzed by H
NMR and its mass balance was recorded, which proved to and α-D-2 reflects the ratio of organolithium intermediates
be quantitative. The ratio of deuterated compounds o-D-2 o-Li-2 and α-Li-2.
Figure 2. First-order plot for the transmetalation of monomeric ortho-sulfonylphenyllithium o-Li-2 to α-Li-2.
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Mechanism of orthoǞα Transmetalation Reactions
The obtained values fit best to first-order kinetics (Fig- mined by treatment with 0.9 equiv. of nBuLi in the presence
ure 2). The first-order rate constants of the transmetalation of TMEDA at –78 °C for 5 min (Scheme 5). Two samples
were calculated to k = 2.67ϫ10–4 s–1 at –50 °C, k = were taken at the same time and separately quenched with
3.85ϫ10–4 s–1 at –45 °C, k = 4.85ϫ10–4 s–1 at –40 °C, k = water and D2O, respectively, and analyzed by 1H NMR
1.02ϫ10–3 s–1 at –35 °C, and k = 2.28ϫ10–3 s–1 at –30 °C. spectroscopy. The intramolecular KIE was derived from the
An attempt to apply second-order kinetics resulted in a isotopic ratio of products o-D-2 and 2 after quenching with
more significant deviation from linearity (Figure S1). The water, as indicated by the increased integral of the ortho-H
integral method for determining the reaction order was also resonance, which amounted to a maximum of 2%. The ali-
used,[10] however, the calculated values of the rate constants quot of the reaction quenched by D2O revealed that lithi-
differed considerably. Because the sulfonyllithium interme- ation proceeded to an extent of 84%. This leads to a ortho-
diates o-Li-2 or α-Li-2 may occur aggregated in solu- D/H ratio of 82:2, from which an intramolecular KIE of
tion,[1g,6,7e,11] the kinetics were also calculated for dimers or kH/kD = 41 for the ortho-lithiation of o-D-2 can be derived.
tetramers of these intermediates, however, more satisfactory However, the error must be considered relatively large be-
results were not obtained. These results suggest that the cause of the small extent of ortho-H incorporation[9f] and
1
transmetalation may proceed either in an intramolecular the inherent integration error of H NMR spectroscopy.
manner via VI or as an aggregate via a transition state such
as VII (cf. Scheme 2).
To gain further insight into the reaction, the kinetics of
the transmetalation of o-Li-2 to α-Li-2 were determined at
–40 °C, at three different concentrations (Figure 3, Support-
ing Information, Table S8). The results clearly showed that
the rate of the transmetalation increased with increasing
Scheme 5. Determination of the intramolecular KIE for ortho-lithi-
ation of o-D-2.
concentration, which contradicts first-order kinetics, but is
more in line with second-order kinetics.
In trideuterated sulfone o,o,α-D3-2, the orthoǞα dedeu-
teration selectivity should be similar to that in 2, thus the
facility of the subsequent orthoǞα transmetalation may be
derived. When o,o,α-D3-2 was lithiated under standard con-
ditions and quenched with water at –78 °C, a mixture of
o,α-D2-2 and o,o-D2-2 was obtained in a 90:9 ratio (Table 1,
entry 1). The ortho-metalation selectivity of o,o,α-D3-2 was
thus slightly lower than that of 2, which amounted to a
ratio of 31:1 under identical conditions.[4b] The orthoǞα
transmetalation did not take place at temperatures below
–40 °C, as indicated by the almost constant hydrogen con-
tent in ortho- and α-positions of o,α-D2-2 and o,o-D2-2,
respectively (entries 2 and 3). The transmetalation started
to proceed at temperatures of –40 to 0 °C (entries 4 and 5),
thus at significantly higher temperature compared with that
of 2 (–50 °C, see above).[4b] Therefore an exact kinetic iso-
Figure 3. Dependence of the transmetalation rate on the concentra-
tion at –40 °C. The trace at c = 0.083 mol/L was taken from the
kinetic trace in Figure 1.
Table 1. DoM-transmetalation of trideuterated sulfone o,o,α-D3-2.
Kinetic Isotope Effects
We intended to use differentially deuterated sulfones in
a crossover study (see below). However, it first had to be
confirmed that deuterium KIEs operate with sufficiently
high values to avoid undesired orthoǞα deuterium transfer
and competitive dedeuteration by the base. Whereas KIEs
for DoM show typical values exceeding 19,[9e–9g] KIEs for
sulfones have so far not been determined. Therefore, met-
alation and transmetalation studies with differentially deu-
terated sulfones were performed.
Entry
T [°C]
t [min][a]
o,α-D2-2/o,o-D2-2 [%][b]
1
2
3
4
5
–78
–60
–40
–20
0
10
20
30
40
50
90:9[c]
92:8[c]
93:7
87:12
30:63
[a] Time refers to the start of the deprotonation. [b] Determined by
1H NMR spectroscopy. [c] Reaction run in duplicate with similar
The intramolecular kinetic isotope effect for the ortho-
lithiation of sulfone o-D-2 with 96% ortho-D was deter- results.
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tope effect for the orthoǞα transmetalation could not be ated product o,o,α-D3-2 (major) and o,α-D2-2 (minor) on
determined, but it must be large. the other hand (entries 1 and 2). Trideuterated o,o,α-D3-2
ortho,orthoЈ-Dideuterated sulfone o,o-D2-2 (o,o-D2-2/o- thus results from competitive initial α-deprotonation of o,o-
D-2 92:8 mixture based on 185% ortho-D, 15% residual D2-2 to o,o-D2,α-Li-2 at –78 °C and subsequent deutera-
ortho-H by integration of the 1H NMR spectrum) was used tion. Minor amounts of dideuterated o,α-D2-2 must also be
to study the regioselectivity of the metalation (Table 2). Two generated by α-deprotonation, because the transmetalation
parallel metalation experiments were performed with the of o-D,o-Li-2 to o-D,α-Li-2 should not operate at this tem-
o,o-D2-2/o-D-2 mixture under the standard conditions at perature, as in the case of o-Li-2 to α-Li-2.[4b]
–78 °C. One of the setups was subsequently quenched with
Warming the reaction mixture to –20 °C during 15 min
D2O at given temperatures and times to determine the met- and quenching with D2O revealed a sharp increase of the
alation regioselectivity to o-D,o-Li-2 and/or o,o-D2,α-Li-2 ortho-proton integral to 59%, corresponding to a decreased
and the second with water to assess whether DoM to o- deuterium content of 141% at the ortho-position and an
D,o-Li-2 proceeded at all. Quenching the organolithium in- almost equal decrease of the proton integral at the α-posi-
termediates at –78 °C after 1 min or 5 min metalation time tion to 10% (= 90% deuteration) (entry 3). Thus, the trans-
with D2O and analyzing the mixture by 1H NMR spec- metalation of o-D,o-Li-2 to o-D,α-Li-2 took place on warm-
troscopy led to an essentially unchanged ortho-proton inte- ing, similar to that of o-Li-2 to α-Li-2 in the nondeuterated
gral of 15%, corresponding to 185% D compared to the series (see above).[4b]
starting mixture; however, the initially 100% integral of the
The setup quenched with water at –78 °C after 1 min or
α-proton decreased to 46 and 50%, respectively. This indi- 5 min confirmed that metalation of the o,o-D2-2/o-D-2 mix-
cates the formation of an almost 1:1 mixture consisting of ture was complete and it complements the deuteration re-
recovered o,o-D2-2 on one hand and the sum of trideuter- sult. The ortho-proton content is expected to be 100% if
Table 2. Metalation selectivity and transmetalation of dideuterated sulfone o,o-D2-2.[a]
Quench by:
D2O
H2O
Entry T [°C] t [min][b]
% ortho-D[c]
(o,o,α-D3-2 + o,α-D2-2 + o,o-D2-2)
% α-D
% ortho-H[d]
% α-H
(o,o,α-D3-2 + o,α-D2-2) (o,o-D2-2 + o-D-2) (o,o-D2-2 + o-D-2)
1
2
3
–78
–78
–20
1
5
15
185
188
141
46
50
90
63
69
64
97
96
93
[a] Reaction run in duplicate with very similar results. [b] Time refers to the start of the deprotonation. [c] Percent deuterium in the ortho-
1
position determined by integration of the residual ortho-H in the H NMR spectrum. Theoretically, o,o-D2-2 has two ortho-D = 200%.
[d] Percent ortho-H by integration of the 1H NMR spectrum; 100% = one ortho-H. The higher percentage of the ortho-hydrogen resonance
than expected is predominately because of the presence of monodeuterated o-D-2 in the starting material.
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Mechanism of orthoǞα Transmetalation Reactions
exclusive ortho-metalation of o,o-D2-2 followed by proton- competed to a significant extent. The α-D,o-Li-3/α-Li-3 ra-
ation occurred; the experimentally found ortho-proton con- tio of 3:7 did not change at –78 °C during 10 min, indicat-
tent of 63 and 69%, respectively, indicated that a little more ing that the orthoǞα transmetalation of α-D,o-Li-3 to o-
than 50% of ortho-metalation to o-D,o-Li-2 occurred (en- D,α-Li-3 does not take place at this temperature.
tries 1 and 2). The observed higher value of 63% protons
In summary, deuterated precursors o,o,α-D3-2, o,o-D2-2,
is accounted for by the presence of o-D-2 in the starting and α-D-3 provided valuable information about the met-
material o,o-D2-2, the ortho-proton content of which must alation selectivity, which changes significantly when
be added. No change was observed on warming, because hydrogen atoms in the ortho- as well as in the α-position
the transmetalation to o-D,α-Li-2 proceeds with exchange are substituted by deuterium. Although some kinetic iso-
of the α-hydrogen atom of o-D,o-Li-2 (entry 3). The proton tope effects could not be quantified due to the switch of
content in the α-position remained, as expected, close to metalation selectivity, they can be considered large at a
100%, indicating that no transmetalation with exchange of qualitative level. These facts did not allow the application
a deuterium atom occurred. These results showed that de- of o,o-D2-2, o,o,α-D3-2, and α-D-3 in crossover experi-
deuteration at the ortho-position of o,o-D2-2 leading to o- ments, because their rates of metalation and/or transmet-
D,o-Li-2 was significantly retarded compared with that of alation are not compatible with those of 2.
2, so that direct deprotonation at the α-position leading to
o,o-D2,α-Li-2 competed with a similar rate instead.
The orthoǞα transmetalation also has a large kinetic iso-
tope effect, which retards it significantly, based on the
Another potential crossover candidate was deuterated 3- transmetalation result of o,o,α-D3-2. This bodes well for the
pentylsulfone α-D-3. It may be expected that this substrate application of an α-deuterated substrate in the crossover
returns unchanged α-D-3 after the normally observed met- study, which is very similar to 2, but bears a remote substit-
alation to α-Li-3 and subsequent reaction with D2O, but uent at the aromatic ring. Therefore, the metalation/trans-
gives 3 by quenching with water, provided that no signifi- metalation behavior of p-tolyl sulfone 4 was studied under
cant isotope effect operates. In the event, lithiation of α-D-3 identical conditions to those for sulfone 2 (Table 4). The
at –78 °C and quenching with D2O gave in contrast ortho,α- initially formed ortho-sulfonylphenyllithium o-Li-4 trans-
dideuterated derivative o,α-D2-3 together with α-D-3 in a metallated to α-Li-4, as indicated by isolation of the deuter-
ratio of 3:7, which did not change significantly over 10 min ated compounds o-D-4 and/or α-D-4, but slightly slower
at –78 °C (Table 3, entries 1–3). Protonation provided α-D- than observed for 2.[4b]
3 and 3 in a 3:7 ratio. This clearly shows that dedeuteration
of α-D-3 at the α-position, generating α-Li-3, was retarded
Table 4. Deprotonation and transmetalation of p-tolyl sulfone 4.
compared with the α-deprotonation of 3[4b] to such an ex-
tent that DoM resulting in the formation of α-D,o-Li-3
Table 3. Metalation selectivity of α-deuterated sulfone α-D-3.
Entry
T [°C]
t [min][a]
Ratio o-D-4/α-D-4
1
2
3
4
5
–78
–60
–40
–20
0
10
20
30
40
50
99:1
9:1
4:1
1:4
1:11
[a] Time after start of the deprotonation.
Quench by:
Entry
D2O
H2O
t [min][a]
o,α-D2-3
α-D-3
α-D-3
3
[%][b]
[%][b]
[%][b]
[%][b]
Based on these results, α-deuterated p-tolyl sulfone α-D-4
can indeed serve as one of the components in the crossover
reaction because it has ortho-hydrogen atoms that are dis-
tinct from those of 2 (Scheme 6). However, its metalation
and transmetalation behavior had to be studied individu-
ally. DoM of α-D-4 under standard conditions, warming to
1
2
3
1
5
10
29
29
31
71
71
69
31
31
30
69
69
70
[a] Time refers to the start of the deprotonation. [b] Determined by
1H NMR spectroscopy.
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0 °C over 50 min and quenching with D2O furnished or- of 2 is not complete, remaining 2 will not mediate the trans-
tho,α-dideuterated sulfone o,α-D2-4 as the exclusive product metalation.
in 92% yield, thus confirming DoM. However, it did not
Table 5. Deprotonation of sulfone 2 by 0.5 equiv. nBuLi and its
prove that undesirable transmetalation was not interfering
transmetalation.
to some extent. Therefore, the mixture was quenched in
Entry
T [°C]
t [min][a]
o-D-2/α-D-2 o-D-2/α-D-2[b]
parallel with water at –20 °C after 30 min, which provided
1
2
3
4
5
–78
–60
–40
–20
0
10
20
30
40
50
42:1
19:1
2.3:1
1:34
1:37
31:1
22:1
2.7:1
1:46
1:46
95% α-D-4 and maximally 5% ortho-deuterated product o-
D-4, as determined by integration of the H NMR spectra.
1
These results clearly show that deprotonation of α-D-4 and
subsequent deuteration or protonation took place in the or-
tho-position and that the orthoǞα transmetalation indeed
proceeded only to a very small extent, which can be ex-
plained by the significant kinetic isotope effect of the trans-
metalation (cf. Table 1). These features allow application of
α-D-4 in the crossover study.
[a] Time after start of the deprotonation. [b] Values from ref.[4b]
Crossover Experiments
Based on these results, crossover experiments were per-
formed by subjecting a 2:1 mixture of sulfones 2 and α-D-
4 to DoM under the standard conditions (Table 6). Ali-
quots were taken at defined temperatures and times and
quenched with deuterium oxide and water separately at the
same time. The ratio of compounds o-D-2, α-D-2, o,α-D2-
4, and α-D-4 formed on deuteration showed that the initial
deprotonation took place at the ortho-positions of both 2
and α-D-4 (entry 1), generating both o-Li-2 and α-D,o-Li-4
selectively within experimental error based on the forma-
tion of o-D-2 and o,α-D2-4 as the strongly dominating
Table 6. Product distribution of the crossover experiment between
2 and α-D-4.
Scheme 6. Time- and temperature-dependent metalation of α-D-4
followed by deuteration or protonation.
Interfering Proton Transfer Equilibria between ortho-
Lithiated Sulfones and their Neutral Precursors
An important factor that may contribute to the trans-
metalation process is the ability of neutral protonated sulf-
ones to serve as proton donors toward the ortho-sulfonyl-
phenyllithium intermediates o-Li-2, for which the α-proton
with pKa values of 29–31 [dimethyl sulfoxide (DMSO)]
should be sufficiently acidic.[12] Unhindered compounds 3
and α-D-3 indeed proved to be proton (deuterium) donors
towards the ortho-sulfonylphenyllithium intermediate o-Li-
2 (see the Supporting Information, Tables S1 and S2). Thus,
complete deprotonation must be ensured with unhindered
sulfones to obtain mechanistically meaningful results. This
is, however, not true when neutral branched sulfones are
applied as proton source. When sulfone 2 was deprotonated
using only 0.5 equiv. nBuLi in the presence of TMEDA (cf.
Figure 1), the degree of deprotonation to o-Li-2 was clearly
only 50%, and the remainder of 2 could, in principle, serve
as a proton donor from the α-position and thus mediate the
transmetalation. This is, however, not the case (Table 5).
The ortho-sulfonylphenyllithium o-Li-2 remains stable at
–78 to –60 °C (entries 1 and 2) and transmetallated essen-
tially in an identical manner to that observed under the
previously reported stoichiometric lithiation and deuter-
ation conditions (entries 3–5).[4b] Thus 2, and probably also
related sulfone 4, are unreactive as proton donors toward
Quench by:
D2O
H2O
Entry
t
T
o-D-2/α-D-2/o,α-D2-4/α-D-4[b] 2/α-D-4/o-D-4[b]
[min][a] [°C]
1
2
3
10
20
50
–78
–30
–30
Ͼ95:Ͻ5:Ͼ45:Ͻ5
50:37:45:5
Ͻ5:95:32:18
Ͼ95:Ͼ45:Ͻ5
Ͼ95:Ͼ45:Ͻ5
Ͼ95:Ͼ45:Ͻ5
[a] Time refers to the start of the deprotonation. [b] Starting ratio
2/α-D-4, 2:1; compound ratio determined by integration of the H
1
o-Li-2 at low temperature and, thus, even though lithiation NMR spectra.
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Mechanism of orthoǞα Transmetalation Reactions
products in a 2:1 ratio. The mixture was placed in a bath
kept at –30 °C and another aliquot was quenched with D2O
after 10 min; this experiment revealed that o-Li-2 trans-
metallated, resulting in the detection of 50% of o-D-2 and
37% of α-D-2 (entry 2). Moreover 5% of α-D-4 was de-
tected, whereas the amount of o,α-D2-4 was reduced to
45%. After a further 30 min at –30 °C and deuteration, the
amount of o-D-2 became very small, whereas the amount
of α-D-2, with deuterium at the α-position was almost com-
plete, indicating almost complete orthoǞα transmetalation
(entry 3). At the same time, the content of α-deuterated, but
ortho-protonated α-D-4 increased to 18%, accompanied by
a parallel decrease of dideuterated o,α-D2-4 from 45 to
32%. This result can only be explained by a partial inter-
molecular proton transfer from the α-position of o-Li-2 to
α-D,o-Li-4.
Scheme 7. The potential involvement of dilithiated species o,α-Li2-
2 during transmetalation.
The product distribution of 2/α-D-4/o-D-4 on quenching
the reaction mixture with water was essentially identical
over time, revealing that the deuterium label in α-D-4 re-
mained in place. This showed that a potential lithium–deu-
terium transmetalation, which would be manifested by a
increase of the proton content in the α-positions of α-D-4,
did not take place to a significant extent. An experiment
using equimolar amounts of 2 and α-D-4 gave similar re-
sults (not shown).
A GC/+CI-MS evaluation of all samples quenched with
D2O of the crossover experiment revealed the presence of a
strongly predominating peak at m/z 270 for o-D-2/α-D-2.
The 32:18 ratio of o,α-D2-4/α-D-4 was also confirmed by a
2:1 ratio of peaks at m/z 285 and 284 in the GC/+CI-MS
spectra. In the mixture quenched with water after 50 min,
a peak at m/z 283, indicating the presence of non-deuterated
p-tolyl sulfone 4, was detected with only 4% intensity,
showing that metalation at the deuterated α-position of α-
D-4 or transmetalation to the deuterated α-position of α-
D,o-Li-4 occurred only to a negligible extent.
the event, however, the peak at m/z 270, corresponding to
the sum of singly deuterated o-D-2 and α-D-2 [M(o-D-2/α-
D-2)+H+], was strongly predominant in each sample. The
intensity of the peak at m/z 271, which should represent the
sum of the 13C isotope peak of o-D-2/α-D-2 and a potential
dideuterated compound, showed only the intensity required
for the 13C isotope peak and no further intensity gain, indi-
cating that o,α-Li2-2 was present under the transmetalation
conditions only to a very small extent, if at all. The intensity
of the peak at m/z 269 was accordingly also very small.
Similarly, no evidence for the presence of a dideuterated
compound o,α-D2-2 was found on analysis of the products
obtained in the crossover experiment (see above).
Because 1.05–1.15 equiv. nBuLi was used for the depro-
tonation of sulfones to assure that the deprotonation pro-
ceeded to the highest possible extent, it may be assumed
that a quantity of up to 10% o,α-Li2-2 will be cogenerated
during deprotonation, which can, in principle, act as a cata-
lyst for the transmetalation (Scheme 8). More reactive o,α-
Proton Transfer Equilibria Among ortho- and α-Lithiated
Sulfones and the Potential Involvement of Discrete
Dilithium Species
The intermolecular proton transfer between o-Li-2 and
α-D,o-Li-4 observed in the crossover experiment leads to
the question: does the process proceed in a concerted man-
ner or stepwise with a discrete ortho,α-dilithiosulfone inter-
mediate (cf. Scheme 2). In the latter process the aryllithium
o-Li-2 acts as the base to abstract the α-proton of a second
molecule of o-Li-2, resulting in neutral 2 and dilithium spe-
cies o,α-Li2-2 in equilibrium (Scheme 7), which sub-
sequently undergo a thermodynamically favored proton
transfer to generate two molecules of α-Li-2.
To detect the involvement of a potential dilithium inter-
mediate o,α-Li2-2 during the transmetalation process, six of
the twelve samples that were quenched by D2O during the
kinetic run at –50 °C (see above) were investigated by GC/
+CI-MS. If present, a significant concentration of o,α-D2-2
resulting from o,α-Li2-2 should lead to a significant peak
Scheme 8. Potential action of o,α-Li2-2 as a catalyst during trans-
enhancement at m/z 271 and at m/z 269 for 2 [M + H]+. In metalation.
Eur. J. Org. Chem. 2014, 4610–4623
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
Table 7. Transmetalation of o-Li-4 to α-Li-4 in the presence of dilithium intermediate o,α-Li2-2.
Entry
T [°C]
t [min]
% ortho-D
(o-D-4)
% α-D
(α-D-4)
o-D-4/α-D-4
% ortho-D
(o,α-D2-2)
% α-D
(o,α-D2-2)
1
2
–40
–78
30[a]
5[b]
–
91
–
1
–
91:1
91
–
96
–
3
4
5
6
7
–78
–60
–40
–20
0
10[c]
20
30
40
50
89
87
77
12
9
1
5
17
85
89
89:1
17:1
4.5:1
1:7
93
91
89
93
87
96[d]
96[d]
96[d]
96[d]
96[d]
1:10
[a] Separate deprotonation of 2 with 2 equiv. nBuLi. [b] Separate deprotonation of 4 with 1 equiv. nBuLi. [c] Time 0 refers to mixing of
o,α-Li2-2 with o-Li-4 at –78 °C. [d] The α-H signals of o-D-4 and o,α-D2-2 are not distinguishable by 1H NMR spectroscopy. It is assumed
that the residual H-content of o,α-D2-2 is negligible and the decrease of the proton content is due to the transmetalation.
Li2-2 may promote proton transfer from the α-position of with D2O. Dilithium intermediate o,α-Li2-2 was stable up
o-Li-2, thus regenerating the catalyst o,α-Li2-2 and releasing to –60 °C, no proton transfer with 4 was observed and o,α-
unreactive α-Li-2. This cycle would operate until all o-Li-2 D2-2 was the sole observed product (entries 1–3). On fur-
is transformed.
ther warming, o,α-Li2-2 deprotonated 4 in the α-position
To obtain information about the feasibility of this giving α-D-2 and α-D-4 via α-Li-2 and α-Li-4, respectively.
mechanism, the dilithium species o,α-Li2-2 was individually The ortho-position of 4 was not deprotonated during the
generated (Table 7, entry 1) and subsequently added to a process. The results show that the rate of proton transfer
threefold excess of o-Li-4 generated from tolylsulfone 4 (en- from 4 to the dilithium intermediate o,α-Li2-2 was, in fact,
try 2). The mixture of o,α-Li2-2 and o-Li-4 remained stable somewhat slower than the transmetalation of o-Li-4 to α-
at –78 °C for 10 min, as determined by quenching aliquots Li-4 at a similar concentration (cf. Table 4).
by D2O and isolation of o-D-4 and o,α-D2-2, resulting from
deuteration of o-Li-4 and o,α-Li2-2, respectively (entry 3).
The mixture was subsequently warmed in the same time
and temperature regime as the individual transmetalation
Discussion
of o-Li-4 to α-Li-4 (entries 4–7, cf. Table 4). The rearrange-
The mechanism of the previously discovered reversal in
ment was not accelerated by added o,α-Li2-2, even though the lithiation selectivity of α,γ-branched sufones was investi-
it was present in a comparably very high concentration (cf. gated in the current study. Several points deserve comment.
Table 4). The dianion o,α-Li2-2 remained apparently un-
Both the ortho- and the α-deprotonation of sufones 2–4
changed during the whole transmetalation, since the D-con- and their deuterated analogues as well as the transmet-
tent of o,α-D2-2 only decreased to a small extent over time. alation of the resulting ortho-sulfonylphenyllithium inter-
The reverse experiment, in which the dianion from 4 was mediates display large kinetic isotope effects (Scheme 5,
added to a solution of o-Li-2 generated from 2, gave similar Tables 1, 2, and 3). The intramolecular KIE of monodeuter-
results (not shown). Thus, the small excess of nBuLi with ated sulfone was determined to be 41, which is in the typical
respect to the sulfone can be considered as insignificant for range for such processes. For all other metalation processes,
the course of the transmetalation.
an exact determination was not possible because the large
A final experiment, which addresses the facility of the rate difference of ortho-deprotonation and dedeuteration
subsequent intermolecular proton transfer between dilithi- leads to competitive α-deprotonation. This is reflected by
ated species o,α-Li2-2 and neutral sulfones 2 was performed the fact that ortho,orthoЈ-dideuterated sulfone o,o-D2-2 un-
(Table 8). Neutral sulfone 4 was added to a solution of o,α- dergoes ortho-dedeuteration and α-deprotonation competi-
Li2-2, generated by dilithiation at –78 °C,[5,7] and the reac- tively (Table 2). The reverse case, in which DoM competes
1
tion was monitored by H NMR analysis after quenching to a significant extent with α-dedeuteration, was found for
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Mechanism of orthoǞα Transmetalation Reactions
Table 8. Transmetalation reaction of the dilithium intermediate de-
rived from 2 with neutral 4.
The rates of the orthoǞα transmetalation reaction are
best described by first-order kinetics, but show a clear con-
centration dependence. These results suggest that the trans-
metalation does not proceed through an intramolecular
proton transfer as shown in VI, but that a bimolecular
course via aggregates VII or alternatively by two-step
mechanism via VIII and IV should be followed (cf.
Scheme 2). Unfortunately, nothing is known about the ag-
gregation behavior of ortho-lithiated aryl sulfones,[6] how-
ever α-sulfonyl carbanions form equilibria of monomers
and dimers of varying composition both in the solid state
and in solution.[1g,7e,11]
With the crossover experiment using 2 and α-D-4, it was
clearly demonstrated that the orthoǞα transmetalation
takes place at least partly as an intermolecular process
(Table 6). The lithiated species o-Li-2 and α-D,o-Li-4 are
stable at –78 °C, but undergo the transmetalation with dif-
ferent rates because of their differing kinetic isotope effects
at –30 °C (ref.[4b] vs. Scheme 6). An intermolecular proton
transfer from the α-position of o-Li-2 to α-D,o-Li-4 was
clearly established by the formation of significant amounts
of α-D-4 (Table 6). This result further decreases the likeli-
hood of an intramolecular transmetalation process via VI
(cf. Scheme 2).
Entry T [°C] t [min]
o,α-D2-2
(as% ortho-D)
α-D-4
(as% α-D)[c]
At this stage, two pathways for the intermolecular proton
transfer process from o-Li-2 to α-Li-2 remain (cf.
Scheme 2). It may occur by concerted proton transfer of
two monomeric aryllithium units via a transition state sim-
ilar to VII. Alternatively, a dimeric aggregate may also ac-
count for the process. Both pathways display concentration
1
2
3
4
5
6
–40
–78
–60
–40
–20
0
30[a]
10[b]
20
30
40
90
87
85
75
53
20
–
1
1
9
26
69
50
[a] Separate deprotonation of sulfone 2 with 2 equiv. nBuLi. dependence, but involve only the concentration of one spe-
[b] Time 0 refers to mixing of o,α-Li2-2 with 4 at –78 °C. [c] The α-
cies.
resonances of o,α-D2-2, α-D-2 and α-D-4 cannot be distinguished.
However, an alternative stepwise mechanism may, in
Because the α-D content of α-D-2 and o,α-D2-2 does not change,
principle, also account for product formation, in which li-
the decrease of the α-H integral corresponds to the increase of the
thiated sulfone o-Li-2 deprotonates a second o-Li-2 inter-
mediate, resulting in free 2 and ortho,α-sulfonyl dilithium
intermediate o,α-Li2-2 (Scheme 7). Several results exclude
the dilithium intermediate from the mechanistic options.
α-D content of α-D-4.
α-D-3, although the rate difference was not large enough First, the transmetalation proceeds in the presence of a
to induce high metalation selectivity. However the resulting large excess of free sulfone 2, which prevents the formation
ortho-lithiated species remained stable at low temperature of o,α-Li2-2, with the same rate (Table 5).
(Table 3). The orthoǞα transmetalation proceeds with or-
Second, if o,α-Li2-2 was present in significant concentra-
tho,orthoЈ,α-trideuterated substrate o,o,α-D3-2, but much tions it should be detectable by mass spectrometry. How-
slower and at considerably higher temperature than that of ever, dideuterated compounds were not detected by GC/
sulfone 2 (Table 1).
+CI-MS monitoring of the D2O quenched product mix-
Free sulfones show a diverse behavior toward metalated tures of several transmetalation reactions. These results do
sulfones and in transmetalation processes. Sterically rela- not support the double proton transfer pathway via o,α-Li2-
tively unhindered sulfones, such as 3, or its deuterated de- 2, however, it also does not exclude it conclusively.
rivative α-D-3 protonate or deuterate o-Li-2 fast and with-
Third, the potential action of o,α-Li2-2 as a catalyst is
out a significant energy barrier at –78 °C (Tables S1–S2). not supported by the results, because the transmetalation
This reflects the thermodynamic acidity difference. In con- process is not influenced with respect to its time and tem-
trast, once deprotonated, o-Li-2 displays a significant bar- perature profile, even in the presence of large amounts of
rier to proton transfer from sterically hindered γ-branched dilithiated species (Scheme 8, Table 7). Thus, o,α-Li2-2 is
sulfones at low temperature, and it remains stable up to not competent to accelerate the orthoǞα transmetalation;
–40 °C even in the presence of large amounts of 2 (Table 5). it would be at maximum an innocent bystander in case it is
These results show that the sulfone structure has an impor- generated. It was also shown that the subsequently manda-
tant influence on their application as substrates for proton tory proton transfer from o,α-Li2-2 to 4 is even somewhat
transfers.
slower than the transmetalation of 2 or 4 (see Table 8 vs.
Eur. J. Org. Chem. 2014, 4610–4623
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L. Rehová, U. Jahn
FULL PAPER
Tables 4 and 5). Based on these results, the involvement of
dilithium intermediates in the transmetalation process can
be considered unlikely.
Thus, based on the experimental evidence, it is most
likely that the orthoǞα transmetalation of α,γ-branched
sulfones, such as 2 or 4, proceeds through an intermolecular
concerted process either via transition state 5 or from a sim-
ilar dimeric aggregate (Scheme 9).
Experimental Section
For general information see the Supporting Information. Com-
pounds 2–4 are known compounds that have been characterized
previously.[13] Dialkylated sulfones 2 and 3 were prepared according
to a reported procedure.[4b]
2,6-Dimethylhept-4-yl 4-Methylphenyl Sulfone (4):[13] nBuLi (1.6 m
in hexane, 6.56 mL, 10.5 mmol) was added dropwise to a stirred
solution of 4-(methylsulfonyl)toluene (1.7 g, 10 mmol) and
TMEDA (3 mL, 19.5 mmol) in anhydrous THF (50 mL) at –78 °C
under a nitrogen atmosphere. After stirring for 10 min, isobutyl
iodide (1.03 mL, 10.5 mmol) was added dropwise at –78 °C. After
stirring for 10 min, the reaction mixture was warmed to 0 °C during
1 h. The reaction mixture was cooled to –78 °C and TMEDA
(3 mL, 19.5 mmol) and nBuLi (1.6 m in hexane, 6.56 mL,
10.5 mmol) were added dropwise. After 5 min, isobutyl iodide
(1.03 mL, 10.5 mmol) was added, the solution was stirred at –78 °C
for 30 min, warmed to 0 °C during 1 h and stirred until the reaction
was complete, as indicated by TLC. The reaction mixture was
quenched with a saturated NH4Cl solution, the layers were sepa-
rated and the aqueous layer was extracted with diethyl ether (3ϫ
50 mL). The combined organic extracts were washed with brine,
dried with MgSO4, filtered, and the solvents evaporated. Purifica-
tion by column chromatography (EtOAc/hexane, 1:40 to 1:10) gave
4 (2.23 g, 79%) as a colorless solid. The analytical data were consis-
tent with reported data.[13]
Scheme 9. Mechanistic proposal for the orthoǞα-transmetalation
of lithiated 2.
Conclusions
The previously described surprising reversal of the de-
protonation selectivity of α,γ-branched alkyl phenyl sulf-
ones bearing α-hydrogen atoms toward DoM is based on
the limited steric accessibility of the α-hydrogen atoms by
organolithium bases and the parallel operation of the com-
plex-induced proximity effect. Here, the mechanism of the
transmetalation of the resulting ortho-sulfonylphenyllithium
to the thermodynamic α-sulfonyl carbanions was studied in
detail. Significant kinetic isotope effects were observed for
both the initial deprotonation and the orthoǞα trans-
metalation. Although not studied in detail here, deuterated
precursors may be used to steer the metalation selectivity.
The kinetics of the transmetalation were determined. A bet-
ter fit to first-order kinetics was found, but a contrasting
concentration dependence of the rate was observed. The
study of proton transfer equilibria between the different or-
tho-sulfonylaryllithium intermediates showed that the trans-
metalation is fast with unhindered free sulfones, but does
not proceed with more hindered α,γ-branched sulfones such
as 2 or 4 at low temperature. Crossover experiments pro-
vided conclusive evidence that the transmetalation takes an
intermolecular course. Two possibilities of such an intermo-
lecular process were investigated. A stepwise procedure via
dilithiated intermediates was discarded because the individ-
ually generated dilithium species did not influence the
course of the transmetalation reactions. Thus, it is most
likely that the transmetalation proceeds by an intermo-
lecular concerted or aggregate-based process, which has a
high enough activation barrier that both the ortho-sulfonyl-
aryllithium as well as the α-sulfonylalkyllithium intermedi-
ates can be reliably applied as synthetic intermediates. The
processes described here may also be observed in other
ortho-Deuteration of Sulfones 2, o-D-2 and α-Deuteration of 3. Ge-
neral Procedure: nBuLi (1.6 m in hexane, 0.75 mL, 1.15 mmol, or
0.82 mL, 1.3 mmol) was added dropwise to a stirred solution of
sulfone 2, o-D-2, or 3 (1 mmol) and TMEDA (0.3 mL, 1.95 mmol)
in anhydrous THF (5 mL) at –78 °C under a nitrogen atmosphere.
After stirring for 10 min, D2O (0.5 mL) was added. The reaction
mixture was warmed to room temperature and diluted with water
(2 mL). The layers were separated and the aqueous layer was ex-
tracted with diethyl ether (3ϫ 10 mL). The combined organic ex-
tracts were washed with brine, dried with MgSO4, filtered, and the
solvents evaporated. Purification by column chromatography
(EtOAc/hexane, 1:20) gave deuterated sulfones o-D-2, o,o-D2-2, or
α-D-3.
2,6-Dimethylhept-4-yl 2-Deuteriophenyl Sulfone (o-D-2): Yield
266 mg (98%); 96% ortho-D; colorless crystals; m.p. 48–49 °C; Rf
= 0.47 (EtOAc/hexane, 1:5). IR: ν = 2968, 2933, 2879, 1472, 1444,
˜
1439, 1374, 1316, 1300, 1154, 1128, 1085, 914, 784, 760, 733 cm–1.
MS (ESI+): m/z (%) = 270 (100) [M + H+], 144 [ArSO2H + H+].
HRMS (CI+): m/z calcd. for C15H24D2O2S+ [M + H+] 270.1638;
found 270.1632. 1H NMR (400 MHz, CDCl3): δ = 0.73 (d, J =
6.2 Hz, 6 H), 0.82 (d, J = 6.2 Hz, 6 H), 1.24 (m, 2 H), 1.64 (m, 4
H), 2.96 (m, 1 H), 7.50 (m, 2 H), 7.58 (m, 1 H), 7.81 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 22.0 (q), 23.0 (q), 25.7 (d), 38.7
(t), 61.1 (d), 129.0 (d), 129.1 (d), 133.6 (d), 138.0 (s) ppm.
2,6-Dimethylhept-4-yl 2,6-Dideuteriophenyl Sulfone (o,o-D2-2):
Yield 265 mg (98%); 92% ortho-D; colorless crystals; m.p. 48–
49 °C. R = 0.46 (EtOAc/hexane, 1:5). IR: ν = 3063, 2958, 2935,
˜
f
1573, 1432, 1387, 1369, 1314, 1296, 1213, 1152, 771 cm–1. MS
(ESI+): m/z (%) = 563 (20) [2M + Na+], 293 (100) [M + Na+].
HRMS (ESI+): m/z calcd. for C15H23D2O2S+ [M + H+] 271.1695;
found 271.1697. 1H NMR (400 MHz, CDCl3): δ = 0.72 (d, J =
6.1 Hz, 6 H), 0.81 (d, J = 6.2 Hz, 6 H), 1.21 (m, 2 H), 1.60 (m, 4
H), 2.93 (m, 1 H), 7.48 (m, 2 H), 7.58 (m, 1 H), 7.80 (m, 8%
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.9 (q), 22.9 (q), 25.6
compound classes such as phosphine oxides, sulfides, or (d), 38.6 (t), 61.0 (d), 128.9 (d), 133.5 (d), 137.9 (s) ppm.
sulfoxides. Such processes are being investigated in these
laboratories and results will be reported in due course.
(4-Deuterio-2,6-dimethylhept-4-yl) 2,6-Dideuteriophenyl Sulfone
(o,o,α-D3-2): nBuLi (1.6 m in hexane, 2.7 mL, 4.3 mmol) was added
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Mechanism of orthoǞα Transmetalation Reactions
dropwise to a stirred solution of sulfone o,o-D2-2 (992 mg,
3.7 mmol) and TMEDA (1 mL, 6.5 mmol) in anhydrous THF
(4 mL) at –20 °C under a nitrogen atmosphere. After stirring for
10 min, D2O (0.5 mL) was added and the reaction mixture was
warmed to room temperature. The layers were separated and the
aqueous layer was extracted with diethyl ether (3ϫ 20 mL). The
combined organic extracts were washed with brine, dried with
MgSO4, filtered, and the solvents evaporated. Purification by short
column chromatography (EtOAc/hexane, 1:20) gave o,o,α-D3-2
(901 mg, 90%; 96% ortho-D, 100% α-D) as colorless crystals; m.p.
was repeated. The raw data are listed in Tables S3–7. For genera-
tion of Figure 1, the individual data points were transformed from
real percentage of deuterated o-D-2/α-D-2 to ideal 100% deutera-
tion degree; e.g., isolated o-D-2/α-D-2 with a 95% deuteration de-
gree, ratio 9.6:1, which corresponds to 86% o-D-2 and 9% α-D-2
was transformed to 100% D content at a 9.6:1 ratio = 90.5% o-D-
2 and 9.5% α-D-2. The values in the tables are the average values
calculated from at least three kinetic measurements at every tem-
perature.
Determination of the Intramolecular Kinetic Isotope Effect at o-D-
2: See Scheme 5. nBuLi (1.6 m in hexane, 62 μL, 0.1 mmol) was
added dropwise to a stirred solution of sulfone o-D-2 (30 mg,
0.11 mmol) and TMEDA (0.03 mL, 0.2 mmol) in anhydrous THF
(1 mL) at –78 °C under a nitrogen atmosphere. After stirring for
5 min, a sample was removed by using a syringe and quenched with
H2O, and a second sample with D2O (0.5 mL). The products were
extracted with diethyl ether (2 mL) and the organic extracts were
dried with MgSO4, filtered, evaporated, and the residue was ana-
48–49 °C; R = 0.48 (EtOAc/hexane, 1:5). IR: ν = 2967, 2941, 2879,
˜
f
1473, 1437, 1312, 1299, 1154, 1114, 838, 760, 724 cm–1. MS (ESI+):
m/z (%) = 565 (20) [2M + Na+], 294 (100) [M + Na+]. HRMS
(ESI+): m/z calcd. for C15H21D3O2SNa+ [M + Na+] 294.1578;
found 294.1579. 1H NMR (400 MHz, CDCl3): δ = 0.76 (d, J =
6.1 Hz, 6 H), 0.85 (d, J = 6.3 Hz, 6 H), 1.26 (m, 2 H), 1.66 (m, 4
H), 7.53 (m, 2 H), 7.61 (m, 1 H), 7.85 (m, 4% H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.1 (q), 23.0 (q), 25.7 (d), 38.7 (t), 129.0
(d), 133.6 (d), 138.1 (s) ppm.
1
lyzed by H NMR spectroscopy.
3-Deuteriopent-3-yl Phenyl Sulfone (α-D-3): Yield 210 mg (99%);
100% D; colorless crystals; m.p. 47–48 °C; Rf = 0.57 (EtOAc/hex-
Transmetalation of 4 and Deuterated Compounds o,o-D2-2, o,o,α-
D3-2, α-D-3 and α-D-4. General Procedure: See Tables 1, 2, 3, and 4,
Scheme 6. TMEDA (0.15 mL, 1 mmol) and nBuLi (1.6 m in hexane,
0.344 mL, 0.55 mmol) were added to a stirred solution of sulfone
4 or o,o-D2-2, o,o,α-D3-2, α-D-3, or α-D-4 (0.5 mmol) in anhydrous
THF (3–5 mL) at –78 °C. After the given time (Tables 1, 2, 3, and
4) an aliquot of the solution was removed by using a syringe and
added to a capped vial containing a few drops of D2O or H2O. The
volume of the sample corresponded to the total volume divided by
the number of samples taken. The product was extracted with di-
ethyl ether (2 mL) and the organic extract was dried with MgSO4,
filtered, evaporated, and the residue was analyzed by 1H NMR
spectroscopy. The procedure was repeated as described in the
tables.
ane, 1:5). IR: ν = 2980, 2949, 2890, 1467, 1451, 1305, 1158, 1140,
˜
1084, 736, 726, 694, 612 cm–1. MS (ESI+): m/z (%) = 236 (100) [M
+ Na+]. HRMS (ESI+): m/z calcd. for C11H15DO2SNa+ [M + Na+]
1
236.0826; found 236.0825. H NMR (400 MHz, CDCl3): δ = 1.00
(t, J = 7.5 Hz, 6 H), 1.69 (dq, J = 7.5, 15.1 Hz, 2 H), 1.87 (dq, J
= 7.5, 15.1 Hz, 2 H), 7.26 (m, 2 H), 7.62 (m, 1 H), 7.89 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.3 (q), 20.4 (t), 66.8
[s (d, J = 20.7 Hz)], 128.9 (d), 129.3 (d), 133.6 (d), 138.6 (s) ppm.
4-Deuterio-2,6-dimethylhept-4-yl 4-Methylphenyl Sulfone (α-D-4):
nBuLi (1.6 m in hexane, 2.7 mL, 4.3 mmol) was added dropwise to
a stirred solution of sulfone 4 (1.04 g, 3.7 mmol) and TMEDA
(1 mL, 6.5 mmol) in anhydrous THF (4 mL) at –20 °C under a ni-
trogen atmosphere. After stirring for 10 min, D2O (0.5 mL) was
added and the reaction mixture was warmed to room temperature.
The layers were separated and the aqueous layer was extracted with
diethyl ether (3ϫ 20 mL). The combined organic extracts were
washed with brine, dried with MgSO4, filtered, and the solvents
evaporated. Purification by short column chromatography (EtOAc/
hexane, 1:20) gave α-D-4 (1.04 g, 99%; 100% D) as colorless crys-
ortho- to α-Transmetalation of 2 Using 0.5 equiv. of Base and Deu-
teration: See Table 5. TMEDA (0.07 mL, 0.5 mmol) and nBuLi
(1.6 m in hexane, 156 μL, 0.25 mmol) were added to a stirred solu-
tion of sulfone 2 (134 mg, 0.5 mmol) in THF (5 mL) at –78 °C. The
further procedure was identical to the general procedure for the
transmetalation of deuterated compounds.
Crossover Reaction of 2 and α-D-4: See Table 6. TMEDA (0.15 mL,
1 mmol) and nBuLi (1.6 m in hexane, 0.363 mL, 0.58 mmol) were
added to a stirred solution of sulfone 2 (86 mg, 0.33 mmol) and α-
D-4 (45 mg, 0.165 mmol) in anhydrous THF (3 mL) at –78 °C. Af-
ter 10 min, an aliquot of the solution was removed by using a sy-
ringe and added to a capped vial containing a few drops of D2O
or H2O. The sample volume corresponded to the total volume di-
vided by the number of samples taken. The product was extracted
with diethyl ether (2 mL) and the organic extract was dried with
tals; m.p. 77–78 °C; R = 0.76 (EtOAc/hexane, 1:5). IR: ν = 2967,
˜
f
2939, 2878, 1600, 1472, 1391, 1374, 1315, 1303, 1291, 1144, 1135,
1089, 822, 731, 722, 696 cm–1. MS (CI+): m/z (%) = 284 (80) [M +
H+], 185 (40) [M – H2C=C(CH3)2 – iPr + H+], 157 (100)
[CH3C5H4SO2H2+]. HRMS (EI): m/z calcd. for C16H25DO2S+ [M+]
1
283.1716; found 283.1715. H NMR (400 MHz, CDCl3): δ = 0.74
(d, J = 6.2 Hz, 6 H), 0.82 (d, J = 6.3 Hz, 6 H), 1.22 (m, 2 H), 1.64
(m, 4 H), 2.39 (s, 3 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.68 (d, J =
8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6 (q), 22.0
(q), 22.9 (q), 25.6 (d), 38.6 (t), 129.0 (d), 129.6 (d), 135.0 (s), 144.3
(s) ppm.
1
MgSO4, filtered, evaporated, and the residue was analyzed by H
NMR spectroscopy.
ortho- to α-Transmetalation of o-Li-4 in the Presence of o,α-Li2-2:
See Table 7. The two deprotonations were performed in separate
flasks. nBuLi (1.6 m in hexane, 0.164 mL, 0.26 mmol) was added
dropwise to a stirred solution of sulfone 2 (34 mg, 0.13 mmol) and
TMEDA (0.1 mL, 0.65 mmol) in anhydrous THF (1 mL) at –40 °C
under a nitrogen atmosphere. The reaction mixture was stirred at
this temperature for 30 min and cooled to –78 °C. In the meantime,
nBuLi (1.6 m in hexane, 0.247 mL, 0.39 mmol) was added dropwise
to a stirred solution of sulfone 4 (106 mg, 0.38 mmol) and TMEDA
(0.1 mL, 0.65 mmol) in anhydrous THF (3 mL) at –78 °C under a
nitrogen atmosphere in another flask. The reaction mixture con-
taining o,α-Li2-2 was added by cannula to the flask containing or-
Kinetic Study of the Transmetalation of 2: TMEDA (0.3 mL,
2 mmol) and nBuLi (1.6 m in hexane, 0.72 mL, 1.15 mmol) were
added to a stirred solution of sulfone 2 (268 mg, 1 mmol) in anhy-
drous THF (12 mL) at the given temperature. After the given time
(Supporting Information, Tables S3–7), an aliquot of the solution
was removed by using a syringe and added to a capped dry vial
containing a few drops of D2O. The volume of the sample corre-
sponded to the total volume divided by the number of taken sam-
ples. The product was extracted with diethyl ether (2 mL) and the
organic extract was dried with MgSO4, filtered, evaporated, and
the residue was analyzed by 1H NMR spectroscopy. The procedure
Eur. J. Org. Chem. 2014, 4610–4623
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4621

ˇ
L. Rehová, U. Jahn
FULL PAPER
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dried with MgSO4, filtered, and the solvents evaporated. The re-
maining reaction mixture was placed in a bath at –60 °C and kept
for 10 min. Another sample (1 mL) was removed and deuterated as
described above. The procedure was repeated at –40, –20, and 0 °C.
The mass balance was determined to be quantitative for each mix-
1
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ˇ
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THF (3 mL) at –40 °C. After 30 min, 0.5 mL of the solution was
taken by using a syringe and added to a dry capped vial containing
a few drops of D2O. The product was extracted with diethyl ether
(2 mL) and the organic extract was dried with MgSO4, filtered, and
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added to a dry capped vial containing a few drops of D2O. The
product was extracted with diethyl ether (2 mL) and the organic
extract was dried with MgSO4, filtered, and the solvents evapo-
rated. The remaining reaction mixture was placed in a bath at
–60 °C and kept for 10 min. Another sample (0.5 mL) was removed
and deuterated as described above. The procedure was repeated at
–40, –20, and 0 °C. The mass balance was determined to be quanti-
tative for each mixture and the product mixtures were analyzed by
1H NMR spectroscopy.
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, analytical data for all compounds,
1
raw data of kinetic and crossover measurements, and copies of H
and 13C NMR spectra of all new compounds.
Acknowledgments
This work was generously supported by the Grant Agency of the
Czech Republic (P207/11/1598) and the Institute of Organic Chem-
istry and Biochemistry of the Academy of Sciences of the Czech
Republic (RVO: 61388963).
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Received: March 1, 2014
Published Online: June 3, 2014
Eur. J. Org. Chem. 2014, 4610–4623
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4623