Mechanistic Investigation of a Synthetic Route to Biaryls by the Sigmatropic Rearrangement of Arylsulfonium Species

Article abstract of DOI:10.1002/chem.202101735

A comprehensive mechanistic investigation was conducted on the coupling reaction of aryl sulfoxides with phenols by using trifluoroacetic anhydride to yield biaryls. NMR experiments revealed that our previously proposed mechanism, which consists of a cascade of an interrupted Pummerer reaction and a rate-determining [3,3] sigmatropic rearrangement, is reasonable. The electronic effects of the substrates were also evaluated to elucidate the nature of the rearrangement step. Based on experimental observations and theoretical calculations, we conclude that the rearrangement is highly asynchronous and stepwise rather than concerted when electron-rich phenols are employed for the reaction.

Full text of DOI:10.1002/chem.202101735

Accepted Article
Accepted Article
Title: Mechanistic Investigation of a Synthetic Route to Biaryls via the
Sigmatropic Rearrangement of Arylsulfonium Species
Authors: Tomoyuki Yanagi and Hideki Yorimitsu
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01/2020

10.1002/chem.202101735
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Mechanistic Investigation of a Synthetic Route to Biaryls via the
Sigmatropic Rearrangement of Arylsulfonium Species
Tomoyuki Yanagi[a] and Hideki Yorimitsu[a]*
[a]
T. Yanagi and Prof. Dr. Yorimitsu
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo-ku, Kyoto 606-8502
E-mail: yori@kuchem.kyoto-u.ac.jp
@yorimitsu_lab
Supporting information for this article is given via a link at the end of the document.
Abstract: A comprehensive mechanistic investigation was conducted
on the coupling reaction of aryl sulfoxides with phenols by means of
trifluoroacetic anhydride to yield biaryls. NMR experiments revealed
that our previously proposed mechanism, which consists of a cascade
of an interrupted Pummerer reaction and a rate-determining [3,3]
sigmatropic rearrangement, is reasonable. The electronic effects of
the substrates have also been evaluated to elucidate the nature of the
rearrangement step. Based on experimental observations and
theoretical calculations, we conclude that the rearrangement is highly
asynchronous and stepwise rather than concerted when electron-rich
phenols are employed for the reaction.
phenols[7] or N-sulfonylanilides[8] (Scheme 1B). This reaction is
thought to be initiated by the activation of the aryl sulfoxide by
trifluoroacetic anhydride (TFAA), followed by the assembly with
the nucleophilic coupling partner via an interrupted Pummerer
reaction.
A
subsequent sigmatropic rearrangement and
rearomatization would then furnish the desired biaryls. A similar
reaction mechanism has been proposed for the reactions shown
in Scheme 1A, based on experimental evidence and theoretical
calculations. Recently, Maulide has reported that this kind of
rearrangement is on the borderline between concerted and
stepwise mechanisms.[9] However, research focusing on the
nature of the charge-accelerated sigmatropic rearrangement of
arylsulfonium species remains limited.
Introduction
In the organic synthesis toolkit, [3,3] sigmatropic rearrangements
are some of the most powerful reactions for the formation of C–C
bonds, given that the well-defined six-membered transition state
(TS) of these reactions allows a highly regioselective formation of
the C–C bonds at remote sites. In particular, charge-accelerated
sigmatropic rearrangements that involve a charged atom in the
rearranging skeleton have attracted a great deal of attention, both
from a synthetic[1] and mechanistic perspective[2] due to the high
reactivity of these substrates relative to their electronically non-
biased counterparts.
Over the last decade, several [3,3] sigmatropic rearrangements
that involve a positively charged sulfur atom have emerged
(Scheme 1A).[3] These transformations exhibit some synthetically
useful characteristics: (1) The reaction temperature is typically
low (approximately ambient temperature), and (2) the precursors
for the rearrangement can usually be prepared in situ from stable
and readily available sulfoxides. Ever since those early reports on
the coupling of aryl sulfoxides with alkynes,[4a] allylsilanes,[4b] and
β-ketoesters,[4c] the ortho-selective C–H functionalizations of aryl
sulfoxides via sigmatropic rearrangements have been
investigated
actively,
and
many
variants,
including
propargylations[4d] and α-cyanomethylations[4e] have been
established.[5]
As part of our continuous interest in the [3,3] sigmatropic
rearrangement of such transient sulfonium species,[6] we have
reported the synthesis of biaryls from aryl sulfoxides and
1
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Scheme 1. Ortho-Selective C–H Functionalizations of Aryl Sulfoxides.
In addition, our arylation reactions can be regarded as a new
Figure 1. 1H NMR study for the observation of transient intermediate 4a.
variant
of
the
benzidine
rearrangement,[10]
wherein
As a model reaction, we chose the coupling reaction of 2-
benzothienyl methyl sulfoxide (1) with phenol (2a) to yield 3a
(Figure 1). Treatment of a mixture of 1 and 2a (State A) with TFAA
at –80 °C in CD2Cl2 (State B) resulted in overall downfield shifts
hydrazobenzenes (ArNH–NHAr) are rearranged to 4,4′- or 2,2′-
diaminobiaryls under acidic conditions through [5,5] or [3,3]
sigmatropic rearrangements. The detailed mechanism of this
classical rearrangement step has long been discussed
controversially, and no generally accepted mechanism has been
established so far.[11] Therefore, the investigation of the nature of
the recent sulfur-based analogues is also of interest to gain a
better understanding of this series of benzidine-type
rearrangements.[12, 5b] Herein, we report a combined experimental
and theoretical mechanistic investigation into the synthesis of
biaryls via the sigmatropic rearrangement of arylsulfonium
species. Initially, we attempted to observe the key precursor for
the [3,3] sigmatropic rearrangement and to experimentally
determine the electronic effects in order to obtain the premise for
the subsequent theoretical study. The pathway of the cascade
reaction was then examined computationally to validate our
mechanistic hypothesis. Finally, the effects of the conformation of
the intermediate and of the substituents on the nature of the
rearrangement, especially its synchronicity and activation free
energy, were investigated.
1
in the H NMR spectrum.[13] In particular, the signals of C3–H in
the benzothienyl group and the methyl group on the sulfonium
center showed significant shifts, indicating the formation of the
proposed sulfonium intermediate 4a. At the same time, phenyl
trifluoroacetate (5) was formed by competitive acylation of part of
the phenol. As expected, 4a rearranged into biaryl product 3a
within 30 min when the mixture was allowed to warm to –60 °C
(State C), and accumulation of other intermediates was not
detected during the rearrangement. These results suggest that
the assembly of the two reaction components is quite facile, and
that the rearrangement can be considered as the rate-determining
step.
Substituent Effects on the Reaction
We performed competition reactions using electronically biased
phenols to evaluate the electronic effects on the transformation.
When phenol (2a) competed with p-cresol (2b; R = Me), electron-
rich 2b was preferentially converted into the coupling product 3b.
This trend was also observed in the competition between 2a and
electron-deficient p-(trifluoromethyl)phenol (2c; R = CF3), where
3a was obtained as the main product (65%).[14] We also tried to
observe the rearrangement precursors as in Figure 1, but could
not observe 4b, probably due to its high reactivity at –80 °C, while
Results and Discussion
1H NMR Study to Monitor the Reaction
We performed an in-situ NMR study to observe plausible
reaction intermediates and verify our working hypothesis.
2
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the conversion of 4c was slow even at –30 °C (Table S1). These
results indicate a correlation between the reaction activity of the
rearrangement precursor and the yield of the desired biaryl.
Electron-rich aryl groups on sulfoxides often enhance their
reactivity in the rearrangement step of similar reactions.[15] In our
reaction system, an m-methoxy group significantly promoted the
yield of the desired reaction product 7b compared to that of 7a
(Scheme 3).[7a] In contrast, m-trifluoromethyl and p-methoxy-
substituted sulfoxides 6c and 6d did not afford the desired biaryls
7c and 7d.[16] Low-temperature 1H NMR measurements revealed
an almost quantitative formation of the intermediates 11a,c-d.
However, elevation of the temperature (–30 °C or above) resulted
in decomposition of these intermediates (Table S1). Using 6b,
only biaryl product 7b was observed; 11b was not seen, not even
at –80 °C, probably due to its high reactivity. These results
indicate that the success of the overall transformation depends on
the competition between the rearrangement and side reactions.
In the reaction with 6a, 8–10 were observed as major byproducts.
Zwitterion 8 would be expected as the product of the electrophilic
substitution of the activated sulfoxide at the most electron-rich
position of 2-naphthol.[17] BINOL (9) and methyl phenyl sulfide
(10) may be formed via intermediate 11, as was reported in the
hypervalent-iodine-mediated oxidative functionalization of
phenols.[18] A similar reaction mode has also been used for biaryl
synthesis and the functionalization of phenols.[19]
Scheme 2. Substituent effects on the phenols; yields were determined by 1H
NMR spectroscopy.
Computational Investigation of the Pathway of the
Cascade Reaction
We then carried out DFT calculations using the coupling
reaction of 2-benzothienyl methyl sulfoxide (1a) with phenol (2a)
as a model reaction.
Scheme 3. Substituent effects of the aryl sulfoxides; yields were determined by
1H NMR spectroscopy.
3
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Figure 2. (A) Energy diagram for the overall reaction process; structures of the transition states (TSs) are drawn as ball-and-stick models; bond lengths are given in
Angstroms (Å); (B) IRC pathways from TS4b and TS4c.
4
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All geometry optimization and frequency calculations were
performed using the M06-2X functional[20] and 6-31+G(d,p) basis
set, unless noted otherwise. All structures were characterized by
frequency calculations to confirm their identity as either local
minima or first-order saddle points. Free energies at the optimized
structures were calculated at the same level of theory at 298.15
K. The effect of the solvent (dichloromethane) on the reaction was
evaluated using the solvation model based on density (SMD).[21]
The calculated energy profile is shown in Figure 2A. The reaction
begins with the nucleophilic addition of the oxygen atom of 1 to
TFAA to form adduct INT1. The subsequent elimination of the
trifluoroacetate anion results in the formation of ion pair INT2,
which recombines to give sulfurane INT2′. The assembly of INT2′
Figure 3. Potential energy surface around TS4b.
with phenol (2a) proceeds in
a concerted manner with
concomitant deprotonation of 2a by the trifluoroacetate anion to
provide INT3. The calculation results suggest that the formation
of INT3 is thermodynamically favorable and reversible, which is
consistent with the NMR studies.
To trace the structural changes during the rearrangement, we
performed a coordinate scan along the cleaving S–O bond and
the forming C–C bond of TS4b (Figure 3). The obtained potential
energy surface (PES) shows that the S–O-bond cleavage
precedes the C–C-bond formation in the early stage of the
rearrangement from INT3. The energetically nearly flat region
reached after the initial elongation of the S–O bond corresponds
to the hidden intermediate in Figure 2B, which can be regarded
as a π-complex of the benzothienyl and phenol moieties.
The C–C-bond-forming step from INT3 proceeds with cleavage
of the S–O bond, which indicates that this step is a concerted
sigmatropic rearrangement.[22] The boat-conformation TS (TS4b)
is more favorable than the sterically less hindered chair one
(TS4c; ΔΔG‡ = 2.4 kcal/mol).[23] Interestingly, the rearrangement
is also thermodynamically favorable (ΔG = –5.0 kcal/mol), even
though both aromatic rings lose their aromaticity during the
process. The subsequent rearomatization of the thionium moiety
of INT4 (TS5; ΔG‡ = 0.7 kcal/mol; ΔG = –25.0 kcal/mol) is quite
facile to afford INT5 irreversibly. Finally, tautomerization of the
dearomatized phenol moiety of INT5 with the aid of TFA (TS6;
ΔG‡ = 8.3 kcal/mol) results in the formation of the target biaryl 3a.
The rate-determining step of the overall transformation is the C–
C-bond-forming [3,3] sigmatropic rearrangement (INT3→TS4b;
ΔG‡ = 20.3 kcal/mol),[24] which means that the efficiency of this
step would strongly affect that of the overall process.
Computationally Revealed Substituent Effects
The rearrangement is highly affected by the electronic nature of
the phenol. When an electron-withdrawing trifluoromethyl group
is placed at the para-position of phenol 2c, the process becomes
more synchronous (Figure S19). In contrast, the “hidden
intermediate” is no longer hidden when an electron-donating
group is introduced at the para-position of phenol 2b (Figure
4).[26,27] In this case, the rearrangement proceeds sequentially via
S–O-bond cleavage and C–C-bond formation. The transient
intermediate INT4′Me is an open-shell species, with negligible
singlet biradical character (y0 = 0.01) based on the Yamaguchi
scheme.[28] Viewed from the perspective of charge distribution,
the electron density of the cresol moiety (O part = green)
significantly decreases during the S–O-bond cleavage to reach a
minimum at INT4′Me and then begins to increase again as the C–
C-bond formation proceeds.
Conformation Effects on Synchronicity
In the TSs TS4b and TS4c, both the cleaving S–O bond and the
forming C–C bond of the boat TS (TS4b) are much longer than
those of the chair TS (TS4c), indicating that TS4b is the more
dissociative TS.[2] Indeed, the Wiberg bond index (WBI) of the S–
O bond of TS4b is only 0.07 whereas that of the forming C–C
bond has not been well developed (WBI: 0.22). The asynchronous
character of the favorable boat TS was also supported by intrinsic
reaction coordinate (IRC) calculations (Figure 2B).
The energy diagrams of the rearrangement from both the boat
and chair conformations have no energy minima along the IRC,
albeit that the former has a nearly flat region before TS4b. The
RMS gradient shows a small dip around the flat region, which
suggests the existence of a “hidden intermediate”.[2e, 25]
Based on the negligible diradical character and charge
distribution, INT4′Me can thus be considered to consist of a
predominant contribution from a canonical structure of a complex
of 2-benzothienyl methyl sulfide and a phenoxonium cation.
5
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Figure 5. Valence-bond diagram of the rearrangement process. [a] Activation
free energy for the rearrangement step(s); all values are given in kcal/mol.
Considering the above, the rearrangements, and especially the
rearrangements involving electron-neutral or -rich phenol
moieties, can be regarded as consisting of two elementary steps:
(1) oxidation of the phenol moiety with S–O-bond cleavage to form
a π-complex composed of the aryl sulfide and the phenoxonium;
(2) intramolecular nucleophilic addition of the aryl group on the
sulfur atom to form the phenoxonium moiety, rather than a
conjugate addition of the intramolecular phenoxide moiety to the
arylsulfonium species of INT3. This mechanistic scenario is
consistent with the high reactivity observed for m-methoxyphenyl
methyl sulfoxide (6b; Scheme 3), whose ortho-position should be
the most nucleophilic among the four sulfoxides (6a-d). When the
aryl group on the sulfur atom is not sufficiently nucleophilic, as e.g.
in the case of 6a, the electrophilic 2-naphthol moiety would be
trapped by an external nucleophile, i.e., 2-naphthol, to give BINOL
(cf. 11→9 in Scheme 3).[19] The activation free energies for the
rearrangement steps were estimated to be 20.4, 19.8, 21.7, and
25.5 kcal/mol for R = H, m-OMe, p-OMe, and m-CF3, respectively,
which qualitatively reproduces the observed trend of the
reactivity.[31]
Figure 4. Stepwise rearrangement with p-cresol, calculated at the UM06-2X/6-
31+G(d,p) level of theory using the SMD (dichloromethane).
Notably, a similar π-complex, i.e., Dewar’s complex, has been
proposed
as
the
intermediate
of
such
benzidine
rearrangements,[10,11] and some computational studies have
suggested the existence of such π-complexes for benzidine-
rearrangement-type transformations.[12] Moreover, Maulide has
proposed that the [3,3] rearrangements of some kinds of
aryl(enol)sulfonium species proceed in a stepwise manner, and
that the nature of the intermediate can be represented by a π-
complex of an aryl sulfide and an enol cation.[9]
In addition to the bond-reorganization mode, the electronic
nature of the phenol affects the activation free energy. The
rearrangements with electron-rich phenols show more
IBO Analysis
asynchronous character with lower calculated energies (ΔG‡
=
In addition, we performed the intrinsic bond orbital (IBO) analysis
developed by Knizia[32] along the IRC of the rearrangement of the
sulfonium intermediate derived from phenyl methyl sulfoxide and
phenol (2a) (Figure 6). This analysis is able to associate quantum
chemistry with the classical curly arrows that are commonly used
for the interpretation of reaction mechanisms in organic chemistry.
We chose three important orbitals, i.e., the aromatic π-bonds in
the phenoxy moiety (blue) and sulfonium moiety (green) and the
S–O σ-bond (red) (Figure 6). In the early stage of the
rearrangement, the orbital in the phenoxy moiety (blue) is
converted into the C–O π-orbital with concomitant conversion of
the S–O σ-bond (red) into a lone pair on the sulfide (A→B).
Subsequently, the C–C π-orbital in the sulfonium moiety (green)
forms the C–C bond between the two aryl fragments (B→C→D).
Importantly, the mechanistic scenario based on the IBO analysis
is consistent with the discussion above.
24.8, 20.3, and 19.1 kcal/mol for R = CF3, H, and Me,
respectively).[29] This tendency is qualitatively consistent with our
experimental results (Scheme 2).
For a qualitative interpretation of the trend, a valence-bond
diagram was employed.[30] As shown in Figure 5, the relative
energies of three species, namely, the initial state, the putative π-
complex, and the product state, can be expected to determine the
nature of the process. When an electron-withdrawing
trifluoromethyl group is placed at the phenol moiety (cf. reaction
with 2c), the corresponding π-complex should be relatively
destabilized due to the partial cationic character of the phenol
moiety. This would lead to the direct intersection of the PESs of
the initial and product states, resulting in a relatively synchronous
rearrangement with a high activation barrier. In contrast, the PES
of the π-complex can intersect with both of those of the initial and
product states at lower energies when R = Me (2b) due to the
stabilization ability of the cation, leading to a more asynchronous
but energetically favorable process.
6
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[3]
For recent reviews, see: a) X. Huang, S. Klimczyk, N. Maulide, Synthesis
2012, 44, 175-180; b) A. P. Pulis, D. J. Procter, Angew. Chem., Int. Ed.
2016, 55, 9842-9860; Angew. Chem. 2016, 128, 9996-10014; c) T.
Yanagi, K. Nogi, H. Yorimitsu, Tetrahedron Lett. 2018, 59, 2951-2959; d)
D. Kaiser, I. Klose, R. Oost, J. Neuhaus, N. Maulide, Chem. Rev. 2019,
119, 8701-8780; e) L. Zhang, M. Hu, B. Peng, Synlett 2019, 30, 2203-
2208.
[4]
For selected examples, see: a) A. B. Cuenca, S. Montserrat, K. M.
Hossain, G. Mancha, A. Lledós, M. Medio-Simón, G. Ujaque, G. Asensio,
Org. Lett. 2009, 11, 4906-4909; b) A. J. Eberhart, J. E. Imbriglio, D. J.
Procter, Org. Lett. 2011, 13, 5882-5885; c) X. Huang, M. Patil, C. Farès,
W. Thiel, N. Maulide, J. Am. Chem. Soc. 2013, 135, 7312-7323; d) A. J.
Eberhart, D. J. Procter, Angew. Chem., Int. Ed. 2013, 52, 4008-4011;
Angew. Chem. 2013, 125, 4100-4103; e) L. Shang, Y. Chang, F. Luo, J.-
N. He, X. Huang, L. Zhang, L. Kong, K. Li, B. Peng, J. Am. Chem. Soc.
2017, 139, 4211-4217.
Figure 6. Intrinsic bond orbital (IBO) analysis along the IRC of the [3,3]
sigmatropic rearrangement, calculated at the RM06-2X/def2-TZVP//RM06-
2X/6-31+G(d,p) level of theory.
[5]
Parallel strands of chemistry using hypervalent iodanes have also been
investigated actively; for selected examples, see: a) Y. Wu, S. Bouvet, S.
Izquierdo, A. Shafir, Angew. Chem., Int. Ed. 2019, 58, 2617-2621; Angew.
Chem. 2019, 131, 2643-2647; b) M. Hori, J.-D. Guo, T. Yanagi, K. Nogi,
T. Sasamori, H. Yorimitsu, Angew. Chem., Int. Ed. 2018, 57, 4663-4667;
Angew. Chem. 2018, 130, 4753-4757; c) J. Tian, F. Luo, Q. Zhang, Y.
Liang, D. Li, Y. Zhan, L. Kong, Z.-X. Wang, B. Peng, J. Am. Chem. Soc.
2020, 142, 6884-6890. Reviews: d) A. Shafir, Tetrahedron Lett. 2016, 57,
2673-2682; e) W. W. Chen, A. B. Cuenca, A. Shafir, Angew. Chem., Int.
Ed. 2020, 59, 16294-16309; Angew. Chem. 2020, 132, 16434-16449.
For recent reviews, see: a) H. Yorimitsu, Chem. Rec. 2017, 17, 1156-
1167; b) H. Yorimitsu, J. Synth. Org. Chem. Jpn. 2013, 71, 341-354.
Selected examples: c) S. Yoshida, H. Yorimitsu, K. Oshima, Org. Lett.
2009, 11, 2185-2188; d) T. Kobatake, S. Yoshida, H. Yorimitsu, K.
Oshima, Angew. Chem., Int. Ed. 2010, 49, 2340-2343; Angew. Chem.
2010, 122, 2390-2393; e) T. Kobatake, D. Fujino, S. Yoshida, H.
Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2010, 132, 11838-11840.
a) T. Yanagi, S. Otsuka, Y. Kasuga, K. Fujimoto, K. Murakami, K. Nogi,
H. Yorimitsu, A. Osuka, J. Am. Chem. Soc. 2016, 138, 14582-14585. b)
K. Okamoto, M. Hori, T. Yanagi, K. Murakami, H Yorimitsu, Angew.
Chem., Int. Ed. 2018, 57, 14230-14234; Angew. Chem. 2018, 130,
14426-14430. Procter has reported a conceptually similar reaction using
benzothiophene S-oxide as a substrate; for details, see: c) H. J. Shrives,
J. A. Fernández-Salas, C. Hedtke, A. P. Pulis, D. J. Procter, Nat.
Commun. 2017, 8, 14801.
Conclusions
We conducted a mechanistic investigation focusing on the
overall reaction mechanism for our coupling reaction of aryl
sulfoxides with phenols, including the nature of the rearrangement.
The experimental study confirmed the formation of an S–O-
tethered intermediate via an interrupted Pummerer reaction and
a subsequent rearrangement, as well as electronic effects on the
[6]
transformation.
Theoretical
calculations
supported
the
experimental observations and revealed a highly asynchronous,
sometimes completely stepwise, nature of the rearrangement on
the basis of the structures, charge distribution, and IBO analysis
around the various transition states.
[7]
Acknowledgements
This work was financially supported by JSPS KAKENHI grant
JP19H00895 and by JST CREST grant JPMJCR19R4. H.Y.
thanks the Mitsubishi Foundation for financial support. T.Y.
thanks the JSPS for a Predoctoral Fellowship. Computation time
was provided by the SuperComputer System at the Institute for
Chemical Research (ICR) of Kyoto University.
[8]
[9]
a) T. Yanagi, K. Nogi, H. Yorimitsu, Chem.-Eur. J. 2020, 26, 783-787; b)
A. Yoshida, K. Okamoto, T. Yanagi, K. Nogi, H. Yorimitsu, Tetrahedron
2020, 76, 131232.
B. Maryasin, D. Kaldre, R. Galaverna, I. Klose, S. Ruider, M. Drescher,
H. Kählig, L. González, M. N. Eberlin, I. D. Jurberg, N. Maulide, Chem.
Sci. 2018, 9, 4124-4131.
[10] For a relevant review, see: D. V. Banthorpe, E. D. Hughes, C. Ingold, J.
Chem. Soc. 1964, 2864-2901.
Keywords: sigmatropic rearrangement • aryl sulfoxide • phenol •
[11] For recent computational studies, see: a) S. Yamabe, H. Nakata, S.
Yamazaki, Org. Biomol. Chem. 2009, 7, 4631-4640; b) G. Ghigo, S.
Osella, A. Maranzana, G. Tonachini, Eur. J. Org. Chem. 2011, 2326-
2333; c) G. Ghigo, A. Maranzana, G. Tonachini, Tetrahedron 2012, 68,
2161-2165.
DFT calculation • mechanistic study
[1]
[2]
For relevant reviews, see: a) R. P. Lutz, Chem. Rev. 1984, 84, 205-247;
b) L. A. Paquette, Angew. Chem., Int. Ed. Engl. 1990, 29, 609-626;
Angew. Chem. 1990, 102, 642-660; c) U. Nubbemeyer, Top. Curr. Chem.
2005, 244, 149-213.
[12] For recent examples of the synthesis of biaryls via [3,3] or [5,5]
sigmatropic rearrangements of hydrazobenzenes and analogues that
possess other heteroatom–heteroatom linkers such as N–O bonds, see:
a) G.-Q. Li, H. Gao, C. Keene, M. Devonas, D. H. Ess, L. Kürti, J. Am.
Chem. Soc. 2013, 135, 7414-7417; b) C. K. De, F. Pesciaioli, B. List,
Angew. Chem., Int. Ed. 2013, 52, 9293-9295; Angew. Chem. 2013, 125,
9463-9465; c) H. Gao, D. H. Ess, M. Yousufuddin, L. Kürti, J. Am. Chem.
Soc. 2013, 135, 7086-7089; d) L. Guo, F. Liu, L. Wang, H. Yuan, L. Feng,
L. Kürti, H. Gao, Org. Lett. 2019, 21, 2894-2898.
For selected examples, see: a) J. J. Gajewski, Acc. Chem. Res. 1997,
30, 219-225; b) F. Haeffner, K. N. Houk, Y. R. Reddy, L. A. Paquette, J.
Am. Chem. Soc. 1999, 121, 11800-11884; c) K. A. Black, S. Wilsey, K.
N. Houk, J. Am. Chem. Soc. 2003, 125, 6715-6724; d) M. Kirsten, J.
Rehbein, M. Hiersemann, T. Strassner, J. Org. Chem. 2007, 72, 4001-
4011; e) D. V. Vidhani, J. W. Cran, M. E. Krafft, M. Manoharan, I. V.
Alabugin, J. Org. Chem. 2013, 78, 2059-2073; f) I. Chogii, P. Das, J. S.
Fell, K. A. Scott, M. N. Crawford, K. N. Houk, J. T. Njardarson, J. Am.
Chem. Soc. 2017, 139, 13141-13146; g) A. A. Ott, M. H. Packard, M. A.
Ortuño, A. Johnson, V. P. Suding, C. J. Cramer, Joseph J. Topczewski,
J. Org. Chem. 2018, 83, 8214-8224; h) S. R. Hare, A. Li, D. J. Tantillo,
Chem. Sci. 2018, 9, 8937-8945.
[13] As 4 is very sensitive to moisture, an excess of TFAA was used not only
as an activator, but also as a dehydrating agent.
[14] The formation of the rearrangement of precursor 4 might be the
selectivity-determining step. However, this possibility was ruled out,
because the addition of 2a to pre-formed 4c resulted in the preferential
7
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10.1002/chem.202101735
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formation of 3a. For further details, see the Supporting Information
(Scheme S1).
indicate preferential formation of the rearranged product compared to the
other byproducts.
[15] For diaryl sulfoxides that possess two different aryl groups, it has been
reported that rearrangements occur preferentially with the more electron-
rich aromatic ring; for selected examples, see: a) J. A. Fernández-Salas,
A. J. Eberhart, D. J. Procter, J. Am. Chem. Soc. 2016, 138, 790-793; b)
B. Peng, X. Huang, L.-G. Xie, N. Maulide, Angew. Chem., Int. Ed. 2014,
53, 8718-8721; Angew. Chem. 2014, 126, 8862-8866. See also refs. 4a-
b.
[32] a) G. Knizia, J. Chem. Theory. Comput. 2013, 9, 4834-4843; b) G. Knizia,
J. E. M. N. Klein, Angew. Chem., Int. Ed. 2015, 54, 5518-5522; Angew.
Chem. 2015, 127, 5609-5613.
[16] A strong electron-donating group such as a methoxy group at the para-
position on the aryl group may not promote the desired rearrangement
because it can potentially neither assist the C–C-bond formation nor
stabilize the resulting thionium cation via a resonance effect (for details,
see: Computationally Revealed Substituents Effects in the main text).
Furthermore, such groups at the para-position are known to promote
aromatic Pummerer-type reactions that lead to the formation of several
byproducts.
[17] D. Chen, Q. Feng, Y. Yang, X.-M. Cai, F. Wang, S. Huang, Chem. Sci.
2017, 8, 1601-1606.
[18] a) L. Kürti, P. Herczegh, J. Visy, M. Simonyi, S. Antus, A. Pelter, J. Chem.
Soc., Perkin Trans. 1 1999, 379-380; b) K. Morimoto, K. Sakamoto, T.
Ohshika, T. Dohi, Y. Kita, Angew. Chem., Int. Ed. 2016, 55, 3652-3656;
Angew. Chem. 2016, 128, 3716-3720.
[19] a) K. Higuchi, T. Tago, Y. Kokubo, M. Ito, M. Tayu, S. Sugiyama, T.
Kawasaki, Org. Chem. Front. 2018, 5, 3219-3225; b) Z. He, A. P. Pulis,
D. J. Procter, Angew. Chem., Int. Ed. 2019, 58, 7813-7817; Angew.
Chem. 2019, 131, 7895-7899; c) Z. He, G. J. P. Perry, D. J. Procter,
Chem. Sci. 2020, 11, 2001-2005.
[20] Y. Zhao, D. Truhlar, Theor. Chem. Acc. 2008, 120, 215−241.
[21] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113,
6378-6396.
[22] We think that the rearrangement is
a pericyclic rather than a
pseudopericyclic reaction based on its orbital connectivity and the
geometrical features of the structure. For further details, see the
Supporting Information (Figure S18).
[23] The pair of aromatic rings in the TS might be stabilized by π-π
interactions. However, a quantitative evaluation is difficult because the
effects of the underdeveloped C–C bond in TS4b on the stacked
structure would be non-negligible.
[24] Considering that the reaction proceeded at –60 °C, the experimental
activation barrier may be by
a few kcal/mol lower than the
computationally obtained values (20 kcal/mol). However, the potential
error can be expected to be insufficient to change the rate-determining
step of the overall transformation.
[25] a) E. Kraka, D. Cremer, Acc. Chem. Res. 2010, 43, 591-601; b) H. S.
Rzepa, C. Wentrup, J. Org. Chem. 2013, 78, 7565-7574.
[26] Substituents on either aryl sulfoxides or phenols did not have a significant
effect on the interplanar distance between the two aromatic rings in the
transition state. For further details, see the Supporting Information
(Figures S21 and S22).
[27] Preliminary investigations have revealed that the reaction of
benzothienyl methyl sulfoxide 1a with methanesulfanilide proceeds
through a concerted but asynchronous rearrangement similar to that with
phenol.
[28] K. Yamaguchi, Chem. Phys. Lett. 1975, 33, 330-335.
[29] The rearrangement from the methyl or trifluoromethyl-substituted
intermediate (derived from 1 with 2b or 2c) also favors the boat
conformation, as in the case with 2a. For details, see the Supporting
Information (Figure S20).
[30] a) S. Shaik, A. Shurki, Angew. Chem., Int. Ed. 1999, 38, 586-625; Angew.
Chem., Int. Ed. 1999, 111, 616-657; b) D. Usharani, W. Lai, C. Li, H.
Chen, D. Danovich, S. Shaik, Chem. Soc. Rev. 2014, 43, 4968-4988; c)
E. E. Kwan, Y. Zeng, H. A. Besser, E. N. Jacobsen, Nat. Chem. 2018,
10, 917-923; d) D. E. Ortega, R. Ormazábal-Toledo, R. Contreras, R. A.
Matute, Org. Biomol. Chem. 2019, 17, 9874-9882; e) K. Yasui, M.
Kamitani, H. Fujimoto, M. Tobisu, Bull. Chem. Soc. Jpn. 2020, 93, 1424-
1429.
[31] In principle, ΔG‡ does not correspond to the product yields. However,
ΔG‡ could be an indicator of product yields because a lower ΔG‡ would
8
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Entry for the Table of Contents
Experimental and computational investigations revealed that, depending on the structure and electronic features of the substrates in
the coupling reaction of aryl sulfoxides with phenols, the reaction pathway of the rate-determining [3,3] sigmatropic rearrangements of
the interrupted Pummerer intermediates can vary due to changes in energy synchronicity. As an extreme case, when an electron-rich
phenol is involved, the rearrangement is no longer concerted, but instead stepwise via a π-complex of the corresponding aryl sulfide
and phenoxonium cation.
9
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