Sulfur(IV)-mediated transformations: From ylide transfer to metal-free arylation of carbonyl compounds

Article abstract of DOI:10.1021/ja4017683

The development of a direct ylide transfer to carbonyl derivatives and of a sulfoxide-mediated arylation is presented from a unified perspective. Mechanistic studies (including density functional calculations) support a common reaction pathway and showcase how subtle changes in reactant properties can lead to disparate and seemingly unrelated reaction outcomes.

Full text of DOI:10.1021/ja4017683

Article
pubs.acs.org/JACS
Sulfur(IV)-Mediated Transformations: From Ylide Transfer to Metal-
Free Arylation of Carbonyl Compounds
Xueliang Huang,‡ Mahendra Patil,‡ Christophe Fares, Walter Thiel, and Nuno Maulide*
̀
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The development of a direct ylide transfer to
carbonyl derivatives and of a sulfoxide-mediated arylation is
presented from a unified perspective. Mechanistic studies
(including density functional calculations) support a common
reaction pathway and showcase how subtle changes in reactant
properties can lead to disparate and seemingly unrelated
reaction outcomes.
Scheme 2. Different Approaches to the α-Arylation of
Carbonyl Compounds
INTRODUCTION
■
α-Arylated carbonyl compounds are recurrent motifs and
subunits in organic molecules with interesting biological
activities (Scheme 1).1 Arguably, the most-studied approaches
Scheme 1. Selected Biologically Active Compounds Bearing
an α-Arylated Carbonyl Moiety
conditions.9 In their seminal studies toward the development of
this reagent, Martin and co-workers found that adding trans-
cyclohexane-1,2-diol 6a to a solution of 5 afforded epoxide 7 in
nearly quantitative yield (Scheme 3a). However, the reaction of
cis-cyclohexane-1,2-diol 6b with 5 gave cyclohexanone 8 and 2-
arylcyclohexanone 9, in 28% and 21% yields respectively
(Scheme 3b). Since the direct reaction of 8 with 5 was found
not to lead to 9, product 9 may have resulted from sigmatropic
rearrangement of hypothetical intermediate 10, itself generated
by two-fold ligand exchange followed by trans-elimination of
diphenylsulfoxide and alcohol (RFOH, Scheme 3b).9e
Inspired by this report, we speculated that a carbonyl
compound with a more favorable enol content (such as β-keto
ester 11a) might be amenable to form an intermediate 13 akin
to 10, eventually rearranging to α-arylated product 12 (Scheme
4).
for their synthesis thus far have relied on noble transition-
metal-catalyzed cross-coupling of enolates with aryl halides, aryl
pseudohalides, or more-reactive reagents.2 However, the high
cost of most noble transition metal complexes, the necessity of
careful exclusion of air and moisture during the reactions, and
the possibility of contamination of the end-products by trace
amounts of heavy metals represent potential drawbacks for
industrial and pharmaceutical applications and have stimulated
work toward the development of so-called “metal-free”
arylations. Useful transition-metal-free α-arylation processes3
typically entail stoichiometric reactions of enolate anions (or
equivalents thereof) with electrophilic aromatic derivatives of
Bi(V),4 Pb(IV),5 or I(III)6 or with benzynes7 as aryl donors
(Scheme 2), the preparation of some of which involves
multistep procedures. Although elegant organocatalytic ap-
proaches for the enantioselective α-arylation of carbonyl
compounds have been recently reported,8 the challenge of
developing transition-metal-free direct arylations of carbonyl
compounds remains alive within the synthetic community.
Martin’s sulfurane 5 is a highly efficient dehydrating reagent
for the direct conversion of alcohols to alkenes under mild
This simple yet conceptually appealing hypothesis led us to
perform the reaction depicted in Scheme 5. As shown, admixing
the β-keto ester 15a with Martin’s sulfurane 5 led to a single
product in essentially quantitative yield. To our surprise, this
was the sulfur ylide 16a (curiously, isomeric to the anticipated
α-arylated material 12, R1 = Me, R2 = Et).10
Received: February 22, 2013
© XXXX American Chemical Society
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Scheme 3. Reaction of Martin’s Sulfurane 5 with cis- and
trans-Cyclohexane-1,2-diol
Scheme 6. Diphenylsulfoxide-Mediated Arylation of 17a
synthetic utility of both procedures. In addition, NMR and
DFT mechanistic studies that shed light on the subtle yet
intricate connections between sulfur-mediated ylide transfer
and arylation are presented.
RESULTS AND DISCUSSION
■
Ylide Transfer to Carbonyl Compounds and Hetero-
aromatics. Sulfonium ylides have been extensively employed
in the preparation of small rings and the construcion of more-
complex structures.12 Nevertheless, standard methodology
available for preparation of sulfonium and sulfoxonium ylides
is still essentially the same that was introduced more than 40
years ago.13
During our preliminary investigations toward the direct α-
arylation of carbonyl compounds (vide supra), we found
Martin’s sulfurane 5 to be an excellent ylide-transfer agent.
Treatment of a solution of 5 (in different solvents) with ethyl
acetoacetate 15a invariably led to the corresponding sulfonium
ylide in quantitative yields upon stirring at room temperature
for half an hour.14
Reaction Scope of the Ylide Transfer to Activated
Carbonyl Compounds. With optimal conditions in hand, the
reaction scope was examined by varying the electron-with-
drawing groups adjacent to the activated methylene. In the
event, a broad range of substrates were tolerated, and the ylide
products were obtained in good to excellent yields (Table 1).
Diverse keto esters reacted smoothly with 5 (entries 1−4, 11,
and 13). The phosphonate ester depicted in entry 11 also
undergoes ylide transfer in quantitative yield. The reactions of
acyclic and cyclic diketones bearing aromatic or aliphatic
substituents gave the corresponding ylides in good to
quantitative yields (entries 5−7, 12),and dimethyl malonate,
malononitrile,and Meldrum’s acid were viable substrates for this
reaction (entries 10, 14, and 15). It is interesting to note the
failure of acetophone (entry 18) in generating any ylide
product, for its α-cyano and α-bromo derivatives reacted well
(entries 16 and 17). These results suggest the existence of a
window of pKa values that defines reactivity toward ylide
formation by sulfurane 5. Given that the pKa value of
acetophenone is commonly estimated to be ca. 24.7
(DMSO),15 this can roughly be taken as an upper limit for
reactivity in the current transformation.
Scheme 4. Initial Design of a Transition-Metal-Free Process
for the α-Arylation of Carbonyl Compounds
Scheme 5. Direct Ylide Transfer to β-Keto Ester 15a
Phenylacetate derivatives reacted successfully with 5, leading
to the corresponding ylides in good isolated yields (entries 19
and 20). Unmodified ethyl (2-phenylacetate), for which pKa =
23.6 is tabulated,16 led to no ylide product. This is in agreement
with the aforementioned pKa-window hypothesis (result not
shown; compare with the use of the p-nitro derivative, entry
19) and further refines its upper border value.
This fortuitous observation paved the way for a series of
studies involving tetravalent sulfur(IV) compounds that
eventually led to a sulfoxide-mediated α-arylation of carbonyl
compounds (Scheme 6).11
Herein, we recount the development of these apparently
unrelated transformations from a unified perspective, along
with more-recent results that significantly extend the scope and
Reaction Scope of Heteroaromatics. Having delineated
an ylide transfer to carbonyl compounds, we looked for other
substrate classes that might be amenable to this transformation.
Indoles and pyrroles are important heterocycles that are often
found in natural products and drug candidates, and are
reportedly capable of binding to a variety of receptors with
high affinity.17 We hypothesized that the ylide-transfer ability of
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a
Table 1. Direct Ylide Transfer to Active Methylene
Compounds
Table 2. Direct Ylide Transfer to Indoles and Pyrroles
a
a
Yields refer to pure, isolated compounds. All reactions were run in
b
toluene using 1.5 equiv of 5 unless mentioned otherwise. 16% of the
4-sulfonium ylide 20o′ was also obtained (not shown), and the
structure of the major regioisomer (depicted) was confirmed by X-ray.
reaction. As might be expected, pyrrole 2-sulfonium ylide was
obtained as the exclusive regioisomer (entry 13). Other
derivatives bearing alkyl and carboxyl functionalities also
afforded the corresponding sulfonium ylides in good yields
(entries 14 and 15). Interestingly, the presence of an ester
substituent led to the production of small amounts of the 4-
sulfonium ylide isomer (entry 15), likely a result of that
substituent’s meta-directing ability.
Sulfoxide-Mediated α-Arylation of Carbonyl Com-
pounds. Having serendipitously uncovered the ylide-transfer
reaction, several lateral observations made during this study
prompted us to explore it further. For one, the use of a
substituted (cyclic) keto ester under various conditions resulted
in the formation of multiple products with rapid consumption
a
Yields refer to pure, isolated compounds. All reactions were run in
diethyl ether using 1.5 equiv of 5 unless mentioned otherwise.
b
c
Solvent was chloroform. Solvent was dichloromethane.
sulfurane 5 might be amenable to “Friedel−Crafts-like”
dearomatisation of indoles and pyrroles.
As depicted in Table 2, this reaction appears to be fairly
general. Indoles bearing a notable scope of substituents ranging
from electron-donating to electron-neutral and strong electron-
withdrawing were tolerated. The actual location of the
substituents on the indole system had only a negligible effect
on the efficiency of the transfer (entries 1−12). In addition,
pyrrole and its derivatives also performed competently in this
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of sulfurane 5. In addition, the relatively high cost of this
reagent stimulated a search for surrogates.18
Table 3. Direct Arylation of Carbonyl Compounds with
Diphenylsulfoxide
a
Inspired by prior reports,19 treatment of a mixture of ethyl
acetoacetate and diphenylsulfoxide with 2.0 equiv of triflic
anhydride led to the corresponding sulfonium ylide 16a in
moderate 51% isolated yield along with several additional,
highly polar compounds (Scheme 7a). However, and to our
Scheme 7. Different Reactivities of Substituted and
Unsubstituted β-Keto Esters
surprise, when ethyl 2-oxocyclohexanecarboxylate 17a was
exposed to similar conditions, the α-arylated keto ester 19aa
was isolated in 66% yield, and its structure was unambiguously
confirmed by single-crystal X-ray analysis (Scheme 7b; see
Scheme 6 for the X-ray structure).
Reaction Scope of Activated Carbonyl Compounds.
After optimizing conditions for what amounts to a “transition-
metal-free” arylation (see Supporting Information for details),
we sought to examine the scope of this transformation. As it
turned out, triflic anhydride was not always the best activating
agent (method A), and eventually TFAA (method B) was
found to be a more general solution in the majority of cases
(Table 3).
a
Method A: 1.5 equiv of Tf2O, 1.2 equiv of sulfoxide 18, CH2Cl2,
0.5M, 25 °C. Method B: 1.5 equiv of TFAA, 1.2 equiv of sulfoxide 18a,
MeCN, 0.5 M, 25 °C. Method B was applied in most cases unless
b
c
mentioned. Method A was employed. Based on recovered starting
d
material (34% of 17f was recovered). The reaction was run at 0 °C.
e
Combined yield with a d.r. of 9:1 (was determined by GC).
Scheme 8. Results Obtained Using Other Diarylsulfoxides as
Aryl Donors
In addition to six-membered cyclic β-keto esters, five-
membered substrates bearing different ester groups afforded
the corresponding arylated products in very good yields under
similar conditions (entries 1−6, and entry 14). When an acyclic
β-keto ester (entry 15) was employed, a slower reaction
resulted. This process also displayed high levels of diaster-
eoselectivity, as a keto ester derived from 4-tert-butylcyclohex-
anone generated the arylated counterpart in 75% yield with a
9:1 diastereomer ratio (entry 16). This interesting diaster-
eoselection (in favor of the axially disposed aryl stereoisomer)
is consistent with hypothetical C−C bond formation from a
pseudoaxial trajectory in a half-chair intermediate (vide infra).
Reaction Scope of Sulfoxides. After testing different
activated carbonyl compounds, we turned our attention to the
effects of different sulfoxide reagents. As shown in Scheme 8, by
employing sulfoxides with different electronic properties the
corresponding products could be obtained in moderate yields.
Scheme 8 also details the results of competition experiments
performed. As shown, the reaction of a slight excess of keto
ester 17a with equimolar amounts of an electron-rich (di-p-
tolylsulfoxide 18b) and an electron-poor (di-(p-chlorophenyl)-
sulfoxide 18c) sulfoxide afforded the tolylsulfanyl-arylated 19ab
as the only product of reaction.
Furthermore, the use of an unsymmetrical sulfoxide,
simultaneously bearing p-tolyl and p-chlorophenyl residues,
resulted in a highly regioselective transfer of the p-tolyl
fragment with less than 6% yields of the alternative products.
The strongly regioselective preference for transferring the most
electron-rich aromatic is a notable feature of this sulfoxide-
mediated arylation (vide infra).
Particularly enticing was the prospect of employing arylalkyl-
sulfoxides as donors, since these formally contain a single
equivalent of the aryl donor moiety. However, from the onset
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we were aware that sulfoxides bearing alkyl residues are prone
to the well-known Pummerer rearrangement, an internal redox
process that amounts to sulfoxide reduction with concomitant
α-oxidation.20 Nevertheless, we probed phenylmethylsulfoxide
under our optimized protocol and observed full conversion
within 2 h. Strikingly, arylated product 19ae was still obtained
as the major adduct of the reaction, together with traces of the
“normal” Pummerer product 20 detected in the reaction
mixture (Scheme 9a). This result is all the more noteworthy
Table 4. Scope of Arylalkylsulfoxides in the Arylation
Reaction
a
Scheme 9. Evaluation of Reactivity of Phenylmethylsulfoxide
taking into account that exposure of sulfoxide to the action of
TFAA almost instantaneously generates the trifluoroacetate 21
in very high yield (Scheme 9b). Importantly, mixing α-
acyloxysulfide 21 with the β-keto ester substrate 17a, under the
reaction conditions, leads only to a very slow reaction
producing 20. The obtention of product 19ae in detriment of
its isomer 20, from only 1.2 equiv of phenylmethylsulfoxide and
in spite of the rapid conversion of the latter into acetate in a
“background” process strongly suggests that the mechanism of
these arylations is fundamentally different from the classical
Pummerer reaction (vide infra).
Encouraged by these observations, we further explored other
alkyl aryl sufoxides as aryl donors. As demonstrated in Table 4,
increasing the length of the alkyl chain did not affect the
reaction efficiency (entries 1 and 2). The aryl moiety could also
be modified, and the corresponding arylated products were
isolated in moderate yields (entries 4−6).
Given the intrinsic nature of the “background” Pummerer
reaction of arylalkylsulfoxides, it was reasonable to assume that
the introduction of a tertiary alkyl residue in the sulfoxide might
shut this competitive process down and favor the arylation
pathway. To our surprise, when sulfoxide 18g bearing a tert-
butyl group was employed (Table 4, entry 3), only the
sulfenylated product 22 could be isolated from the reaction
mixture (Scheme 10). This is likely a consequence of loss of a
tert-butyl cation from the activated sulfoxide and concomitant
generation of phenylsulfanyl trifluoroacetate, an electrophilic
sulfenylating reagent.21
a
b
1.5 equiv of TFAA, 1.2 equiv of sulfoxide were employed. Yields
refer to pure, isolated products.
Scheme 10. Reaction of Keto Ester 17a with tert-
Butylphenylsulfoxide 18f
Scheme 11. Initial Attempt on Direct Arylation of
Cyclohexanone
Arylation of Simple Carbonyl Derivatives. The
challenge of transposing the α-arylation methodology described
in the preceding paragraphs to simple carbonyl derivatives such
as ketones and aldehydes is perhaps best expressed by the
recalcitrance of cyclohexanone, for which arylated product 9
was obtained in only 9% yield after 20 h at room temperature
(Scheme 11). Curiously, the main side product of this reaction
was diphenyl sulfide.22−24
In face of this setback, we probed a wide range of reaction
conditions and cyclohexanone derivatives, eventually finding
that a direct arylation of enol silanes under modified conditions
was possible.25 We then examined the potential of this novel
transformation (Table 5). Gratifyingly, the reaction of silyl enol
ethers bearing an α-disposed methyl group proceeded
smoothly, giving the corresponding products in high yield
(entry 2). Furthermore, the silylenol ether derived from
acetaldehyde was also a viable substrate, providing the
corresponding 2-arylacetaldehyde (entry 3). To the best of
our knowledge, this represents the first example of metal-free α-
arylation of simple aldehyde derivatives.26 The arylation of enol
silanes with two identical β,β-terminal substituents afforded the
desired arylated aldehydes (entries 4−6). The scope was
further extended to substrates carrying two different sub-
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coordinate (IRC) calculations were performed to verify the
transition state structures.30
Table 5. Arylation of Silyl Enol Ethers with
Diphenylsulfoxide
a
Empirical dispersion corrections for the B3LYP functional
were included using single-point B3LYP-D/6-31+G** energy
calculations.31 Gibbs free energies were in all cases computed
by adding to the single-point energies both zero-point
vibrational energies and thermal corrections (300 K) obtained
at the level of theory employed in the geometry optimization
(B3LYP/6-31+G** in the solvent phase). Relative free energies
are reported for all relevant stationary points at the following
two DFT levels: B3LYP-I, from solvent-phase geometry
optimizations [PCM/B3LYP/6-31+G**], and B3LYP-II, sol-
vent-phase dispersion-corrected single-point calculations at
solvent-phase optimized geometries [PCM/B3LYP-D/6-
31+G**//PCM/B3LYP/6-31+G**]. The relative free energies
are always given with respect to the separated reactants.
Comparison between the B3LYP-I and B3LYP-II results reveals
the effects of dispersion on the computed energies.
DFT Results for Ylide Transfer. The proposed mecha-
nistic pathway for ylide transfer to ethyl acetoacetate 15a in the
presence of Martin’s sulfurane 5 is shown in Scheme 12. The
Scheme 12. Proposed Mechanism for Ylide Transfer to
Substrate 15a
a
The reaction was run in 0.5 mmol scale, and the concentration was
b
0.5 M. Isolated yield after column chromatography.
reaction is expected to begin with proton abstraction from 15a
by the −OC(CF3)2Ph anion, formed reversibly upon solubiliza-
tion of sulfurane 5.32 The resulting enolate 35 can directly
attack the sulfonium ion 34 in an SN2 fashion, with
concomitant expulsion of −OC(CF3)2Ph, which acts as the
base for the final proton abstraction from the intermediate
sulfonium ion 36.
The computed transition states TS(15a→35) and TS(36→
16a) have geometries that are typical for an essentially collinear
proton transfer.33 Therefore only the transition state for
nucleophilic addition of the enolate 35 to the sulfonium ion 34
is shown in Figure 1. The optimized geometry of TS(35→36)
exhibits a very long incipient C···S bond (enolate−sulfonium
ion, 3.91 Å), with a CSO angle of 160°. The approach of 34 on
top of 35 (see Figure 1) is hindered by the two phenyl rings of
34, so that the two molecules are kept apart and interact only
weakly at TS(35→36). The low imaginary frequency of 28i
cm−1 also indicates a very feeble interaction between the
enolate and sulfonium ions at TS(35→36).34
stituents at the terminal position of the double bond (entries 7
and 8). It is noteworthy that these arylations provide aldehydes
with an all-carbon quaternary center in moderate to good
yields. However, when the enol ether derived from
acetophenone was subjected to the current system, no arylated
product was isolated (entry 9).
Mechanistic Theoretical Studies. We performed density
functional theory (DFT) calculations to gain more insight into
the mechanisms of ylide transfer and α-arylation. Ethyl
acetoacetate 15a and the cyclic β-keto ester 17a were taken
as model substrates for these two reactions, respectively.
Computational Methods. All stationary points were
optimized without any constraints in the solvent phase at the
B3LYP/6-31+G** level of theory.27 Solvation effects were
treated by the polarizable continuum model (PCM) with
acetonitrile as solvent (dielectric constant 36.64).28 All
calculations were performed with the Gaussian09 quantum
chemical programs.29 The optimized stationary points were
characterized as local minima or transition structures by
harmonic force constant analysis, and intrinsic reaction
The relative free energies computed at the B3LYP-I and
B3LYP-II levels are collected in Figure 2 for all relevant species
and transition states. At B3LYP-I, the initial complexation
between 15a and −OC(CF3)2Ph, which affords a suitable
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the formation of an activated intermediate such as 37.35 The
proposed mechanistic route for the arylation of 17a in the
presence of activated diphenylsulfoxide 18a is given in Scheme
13. The optimized transition state geometries are shown below
in Figure 3, and the free energy profiles obtained at the B3LYP-
I and B3LYP-II levels are presented in Figure 4.
Scheme 13. Proposed Mechanism for the Sulfoxide-
Mediated α-Arylation of β-Keto Ester 17a
Figure 1. Optimized geometry of the transition state for nucleophilic
attack TS(35→36) in the proposed mechanism for ylide transfer.
Relevant bond distances (Å) and angles (°) are given. For clarity, only
selected hydrogen atoms are shown.
As initial step of the reaction, we considered the generation
of an enolate through direct deprotonation of substrate 17a or
its enol tautomer by the anion −OSO2CF3 generated during
sulfoxide activation. However, compounding the large pKa gap
between both species (for 17a, pKa ≈ 14; for TfOH, pKa =
−15) is the fact that the barrier computed for this process is
prohibitively high (36.6 kcal/mol).36 IRC calculations indicate
that the anion −OSO2CF3 may not be able to retain the
abstracted proton but rather transfer it back to the carbonyl
oxygen of substrate 17a, thus effectively only assisting in keto−
enol tautomerization.37
Figure 2. Relative free energies (in kcal/mol) of intermediates and
transition states computed at the B3LYP-I and B3LYP-II levels for the
pathway shown in Scheme 12. Entries in parentheses such as (34+35)
denote complexes between the two moieties.
In a more likely scenario, the sulfonium ion 37 generated
through activation of sulfoxide 18a with triflic anhydride may
assist the deprotonation of substrate 17a. One may envision
that the cationic sulfur of 37 coordinates to the carbonyl
oxygen of 17a while the anion −OSO2CF3 is simultaneously
engaged in proton abstraction. The optimized geometry of the
transition state for this concerted process, TS(17a→38), is
depicted in Figure 3. Characteristic features are the lengths of
the breaking CH bond (1.32 Å), the forming OH bond (1.31
Å), and the coordinating SO bond (1.77 Å) as well as the large
Ph2S+···−OSO2CF3 distance (3.56 Å) between the separating
fragments. This reaction step generates an O-sulfenylated
enolate 38 which undergoes a formal sigmatropic rearrange-
ment (TS (38→39)) and subsequent proton loss TS(39→
19aa) to form the observed product. The optimized geometry
of transition state TS(38→39) exhibits a boat-like structure
with simultaneous cleavage of the O1···S bond and formation
of the C1···C2 bond (Figure 3). C−C bond formation takes
place between the central α-carbon atom (C1) of the enolate
system and the ortho-carbon atom (C2) of one of the phenyl
rings.
orientation of the −OC(CF3)2Ph anion for the subsequent
proton transfer, is endoergic by 7.5 kcal/mol. The proton
abstraction from 15a requires an additional energy of 7.2 kcal/
mol. The overall free energy barrier for this step is thus 14.7
kcal/mol, rendering it the rate-limiting step of the reaction. The
free energy barriers for the following two steps (relative to the
corresponding intermediates) are smaller: 6.0 kcal/mol for the
nucleophilic addition of enolate 35 to the sulfonium ion 34 via
TS(35→36), and 3.7 kcal/mol for the final proton abstraction
from intermediate 36 to furnish ylide 16a. The thermodynamic
stability of product 16a (ΔG = −32.5 kcal/mol) ensures
complete conversion of 15a to 16a.
The B3LYP-II relative free energies (Figure 2) differ from
the B3LYP-I values by the inclusion of dispersion corrections,
which tend to stabilize more compact structures. The relative
free energies in Figure 2 refer to the separated reactants (15a
and 5), one of which (5) is strongly favored by the dispersion
corrections, and therefore the B3LYP-II values for the other
species in Figure 2 are consistently higher those from B3LYP-I.
As a result, the free energies of the transition states (involving
fragments of 5) rise by 4−9 kcal/mol, but the overall
mechanistic scenario remains the same.
The relevant distances for O1···S (breaking bond) and
C1···C2 (forming bond) are 2.85 and 2.49 Å, respectively.
Inspection of the frontier molecular orbitals reveals an
unexpected electronic structure for TS(38→39). The highest
occupied molecular orbital (HOMO) shows a distinct orbital
DFT Results for Arylation. It is well established that the
treatment of a sulfoxide with TFAA (or Tf2O) should lead to
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Figure 4. Relative free energies (in kcal/mol) of intermediates and
transition states computed at the B3LYP-I and B3LYP-II levels for the
pathway shown in Scheme 13. Entries in parentheses such as (17a
+37) denote complexes between the two moieties.
The B3LYP-II relative free energies (Figure 4) differ from
the B3LYP-I values by the inclusion of dispersion corrections,
which generally tend to favor compact structures. Since the
separated reactants, 17a+18a+Tf2O, are taken as reference
system in Figure 4, it is clear that the relative free energies for
the other species will generally be lower for B3LYP-II than for
B3LYP-I (typically by about 10 kcal/mol). The overall
mechanistic scenario, however, remains the same. The
transition state TS(17a→38) continues to be the highest
point on the free energy profile (now at 6.7 kcal/mol), and the
computed barriers are even smaller than in the B3LYP-I case,
since the dispersion corrections stabilize the transition states
more than the less compact intermediates. It should be
emphasized that the B3LYP-II values come from single-point
calculations (without geometry reoptimization) and may thus
be expected to underestimate the actual barriers.
Finally, we have studied the reaction between 17a and the
unsymmetrically substituted sulfoxide 18d (cf. Scheme 8)
bearing one electron-rich (4-Me) and one electron-poor (4-Cl)
aryl ring, focusing on the two distinct transition states for the
internal nucleophilic addition step (i.e., corresponding to
TS(17a→38) in Figures 3 and 4). In accord with the
experimental results, we find that the arylation process clearly
favors the electron-rich over the electron-poor aryl ring, with
the difference in the computed free energies of the two
transition states amounting to 3.7 (3.2) kcal/mol at the B3LYP-
I (B3LYP-II) level. Arylation involves the formation of a C−C
bond between the substrate (C1) and one of the sulfoxide aryl
rings (C2), see Figure 3. According to natural bond orbital
analysis for the two transition states, C1 has a small positive
charge, while C2 carries a substantial negative charge that is
larger when C2 resides in the electron-rich (4-Me) rather than
the electron-poor (4-Cl) aryl ring. In the former case, the
electrostatic interaction between C1 and C2 is therefore
stronger, which contributes to the observed preference for
arylation.
Figure 3. Optimized geometries of the transition states for the
conversions 17a→38, 38→39, and 39→19aa. Selected distances are
given in Å.
disconnection at the C(ipso)−C(ortho) bond of the reacting
phenyl ring, and none of the occupied orbitals has a closed loop
of interacting atomic orbitals along the six-membered ring that
contains the breaking and forming bonds. By contrast, the
lowest unoccupied molecular orbital (LUMO) is mainly located
at the C(ipso)−C(ortho) bond of the reacting phenyl ring and
has a shape that allows its participation in the formation of the
new σ-bond. This MO analysis thus suggests that the
conversion 38→39 should best be described as an intra-
molecular nucleophilic addition rather than a sigmatropic
rearrangement.38−42 The transition state TS(39→19aa) for the
final proton abstraction has the expected structure (Figure 3):
the O···H···C2 moiety is essentially linear, the breaking C2···H
bond is stretched (1.31 Å), and the forming O···H bond is still
rather long (1.39 Å), indicating an early transition state.
According to the relative free energies computed at the
B3LYP-I level (Figure 4), the initial association of 17a and 37 is
endoergic by 9.2 kcal/mol, largely because of the entropic
penalty for complexation. The subsequent generation of
intermediate 38 requires another 8.5 kcal/mol of activation,
and the transition state TS(17a→38) is the highest point on
the free energy profile (17.7 kcal/mol). The following two steps
are rather facile, with free energy barriers (relative to the
preceding intermediate) of 10.1 kcal/mol for the rearrangement
via TS(38→39) and 5.1 kcal/mol for the final proton transfer
via TS(39→19aa). Both the overall and the individual barriers
are fairly small so that the overall 17a→38→39→19aa
conversion is predicted to proceed smoothly. The overall free
energy of reaction is −32.0 kcal/mol, indicative of a large
thermodynamic driving force for this α-arylation reaction.
Procter and co-workers reported a conceptually related
nucleophilic allylation of activated sulfoxides by allyl silanes,42
which may proceed through a similar mechanistic rationale.
Comment on Differences between the Computed
Pathways. One key distinction is the proton affinity of the
anions that are initially generated (Schemes 12a and 13a).
Judging from the gas-phase B3LYP values, the proton affinity of
−OC(CF3)2Ph is about 40 kcal/mol higher than that of
−OSO2CF3. Hence, −OC(CF3)2Ph is able to deprotonate
H
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Article
substrate 15a and form the corresponding enolate 35.
Nucleophilic attack of 35 at the sulfonium ion 34 yields the
C-sulfenylated intermediate 36, which is more stable than the
alternative O-sulfenylated intermediate by 19.0 kcal/mol
(B3LYP-I, thermodynamic control) and is then easily
deprotonated to give the ylide product 16a (see Scheme 12
completed (cf. leftmost peak in Figure 5). This species was
characterized by low-temperature (−20 °C) NMR correlation
experiments. The quaternary carbon at position C6 (see
Scheme 14 for numbering) with a chemical shift of 63.8 ppm
Scheme 14. NMR Assignment of Late-Stage Intermediate J
and Plausible Mechanism for Its Reversible Formation
−
and Figure 2). By contrast, the weaker base OSO2CF3 is not
able to deprotonate substrate 17a. The only viable pathway that
we have found involves deprotonation with assistance of the
sulfonium ion 37 and formation of the O-sulfenylated
intermediate 38. The latter may, in principle, undergo a 1,3-
sulfur migration to the C1-sulfenylated intermediate, which is
more stable than 38 by 15.6 kcal/mol (B3LYP-I) but obviously
cannot lead to ylide formation as it lacks a C1−H bond.
Moreover, the barrier for the 1,3-sulfur migration is estimated
(B3LYP-I) to be about 5 kcal/mol higher than that for the
competing rearrangement (38→39), all of which are factors
conspiring to favor the arylation pathway (see Scheme 13 and
Figure 4).
correlates through 3-bond coupling to an aromatic proton
(H12), implying that the bond to the ortho-position is already
formed. This is therefore a late-stage intermediate, and the
attached carbon is fully aromatic as revealed by six aromatic
carbon shifts in the benzene ring, two of which are substituted.
However, this species distinguishes itself from the actual
product by the following observations: (a) chemical shifts in
the aromatic rings suggest a positive charge at the sulfur, and
(b) C1 has a peculiar 13C chemical shift of 115.4 ppm which
surprisingly presents a very weak coupling correlation to the
free phenyl ring (H17). This information can only be reconciled
with a structure where sulfur is covalently attached to the
cyclohexane ring through C1. From a mechanistic standpoint, it
would appear that J and the short-lived, dearomatized
intermediate 39 (Scheme 13) are related through a
straightforward bond reorganization as shown in Scheme 14.
Taken together, the kinetic NMR data can be fit to the
reaction model shown in Figure 6, which closely resembles that
NMR Investigation. An NMR kinetic and mechanistic
study was also undertaken on the arylation reaction. Figure 5
Figure 5. Time evolution of the carbon methylene region of the ethyl
ester group of 17 during the arylation process.
shows the time evolution of the 13C signal intensity of the
methylene group in the keto ester (17a),45 the enol ester (17a-
enol), and the product (19aa) in the reaction depicted in
Scheme 6. Interestingly, a stable intermediate species (J) can
also be detected. It becomes apparent from inspection of Figure
5 that the enol curve declines more sharply than the
corresponding keto curve. The keto and enol forms are in
exchange (k1, k−1 ≪ 100 s−1) at room temperature with keto
formation being about 3 times as fast as the reverse enol
Figure 6. Kinetic profile for the direct arylation reaction.
formation ([enol]/[keto] = k− /k1 = 0.77/0.23 = 3.3). One can
1
thus conclude that it is the keto form that reacts with the
activated sulfoxide since that form will tend to accumulate
upstream to the rate-limiting step. This is in agreement with the
model proposed in Scheme 13.
Of particular interest is the detection of an intermediate
species (J) that forms early during the reaction, reaches a
maximum after 4−5 h and declines to zero when the reaction is
of Scheme 13. The slow tautomeric interconversion between
the keto (17a) and enol (17a-enol) forms is driven by the rate
constants k1 and k−1. In comparison, the encounter of 17a with
the activated sulfoxide 37 to form an invisible intermediate 38/
39 is slower and represents the rate determining step. This
intermediate, or group of rapidly interconverting intermediates,
are invisible to NMR and cannot be further characterized by
I
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Article
this method. However, two seemingly competing isomerization
reactions (with similar rates) take place from this intermediate,
one leading to a relatively stable five-membered ring (J), the
other leading to the end product (19aa).
In an attempt to identify similar intermediates and kinetic
curves in the slower reaction starting from the acyclic β-keto
ester 17m and forming the α-arylated carbonyl compound
19ma, a side-product 40 was fortuitously encountered (Scheme
15). The structure of 40, isomeric with 19ma and
depending on both structural factors and counteranion basicity.
In-depth mechanistic insight has been acquired by NMR
structural and kinetic analysis as well as DFT calculations,
highlighting inter alia an intriguing role for sulfonium ions as
mediators for deprotonation and allowing the identification of
hidden pathways that interconnect ylide transfer and carbonyl
arylation. The transformations reported herein should find
growing synthetic utility among the community.
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 15. Interception of an “Interrupted Ylide-Transfer”
Intermediate 40
Optimized Cartesian coordinates (B3LYP-I) and total energies
(B3LYP-I, B3LYP-II) of all computed stationary points, plots of
relevant frontier molecular orbitals, complete ref 29, and
experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
maulide@mpi-muelheim.mpg.de
■
corresponding to ca. 20% of the converted material, was
assigned by NMR. The low-field shifted 13C signals in the ortho-
and para-positions of the aromatic rings in agreement with a
positively charged sulfur center, while the quaternary 13C of
84.1 ppm reveals the location of sulfur at the α-position. The
structure of 40 is suggestive of an “interrupted ylide-transfer”
process.46
Author Contributions
‡X.H. and M.P. contributed equally.
Notes
The authors declare no competing financial interest.
Summary of the Mechanistic Findings. Our combined
mechanistic analysis highlights a clear analogy between the
ylide-transfer and arylation processes, both proceeding through
very similar cationic electrophilic S(IV) species. It would thus
appear that the basicity of the counteranion (a trifluoromethy-
lated alkoxide versus triflate) accompanying the S(IV) species is
crucial. On one hand, high basicity leads to deprotonation of
the dicarbonyl substrates. On the other hand, the lower basicity
of triflate and its inability to mediate direct proton abstraction
mandates the adoption of a different mechanistic route, where
the S(IV) electrophile serves as an interesting “organic Lewis
acid”47 to enable deprotonation (by triflate).
The conjugate base of the dicarbonyl substrate appears to
have a preference for C−S bond formation, ultimately leading
to an energetically favored ylide-transfer process. Conversely,
the S(IV)-assisted deprotonation intrinsically generates an O−S
bound intermediate, from which the sequence of events
eventually leading to arylation is energetically downhill. The
detection of minor amounts of C−S bound species even in
cases where arylation is ultimately favored, consistent with the
observation of low yields of ylide transfer on unsubstituted
active methylene compounds (cf. Scheme 7a), suggests that
pathways may exist for migration of sulfur from O to C but that
their efficiency is, in any case, lower than that of the main
reaction manifolds observed.48
ACKNOWLEDGMENTS
We are grateful to the Max-Planck-Society, the Max-Planck-
■
Institut fur Kohlenforschung, the Deutsche Forschungsgemein-
̈
schaft (Grant MA 4861/4-1), and the Fonds der Chemischen
Industrie (Sachkostenzuschuss to N.M.) for generous support
of our research programs.
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■
In summary, we have developed an ensemble of sulfur(IV)-
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1998, 120, 841.
(44) For similar rationale on the mechanism, see: Cuenca, A. B.;
́
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Montserrat, S.; Hossain, K. M.; Mancha, G.; Lledοs, A.; Medio-Simοn,
M.; Ujaque, G.; Asensio, G. Org. Lett. 2009, 11, 4906.
(45) We chose the methylene 13C signals for the NMR kinetic
experiment because they are particularly well resolved in a relatively
low-crowded region and are expected to have very similar relaxation
properties, so that their intensities can be directly compared.
(46) For details concerning assignment of structure 40 from the
reaction mixture, see the Supporting Information.
(47) Garcia, P. G.; Lay, F.; Garcia, P. G.; Rabalakos, C.; List, B.
Angew. Chem., Int. Ed. 2009, 48, 4363.
(48) 1,3-Sulfur migration in an O-sulfenylated enolate intermediate
may be a competing pathway. In the case of substrate 15a, the free
energy barrier from B3LYP-I calculations for this migration is 5 kcal/
mol higher than that for the sigmatropic rearrangement.
L
dx.doi.org/10.1021/ja4017683 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX