Catalyst-Controlled Regiodivergence in Rearrangements of Indole-Based Onium Ylides

Article abstract of DOI:10.1021/jacs.1c00283

We have developed catalyst-controlled regiodivergent rearrangements of onium-ylides derived from indole substrates. Oxonium ylides formed in situ from substituted indoles selectively undergo [2,3]- and [1,2]-rearrangements in the presence of a rhodium and a copper catalyst, respectively. The combined experimental and density functional theory (DFT) computational studies indicate divergent mechanistic pathways involving a metal-free ylide in the rhodium catalyzed reaction favoring [2,3]-rearrangement, and a metal-coordinated ion-pair in the copper catalyzed [1,2]-rearrangement that recombines in the solvent-cage. The application of our methodology was demonstrated in the first total synthesis of the indole alkaloid (±)-sorazolon B, which enabled the stereochemical reassignment of the natural product. Further functional group transformations of the rearrangement products to generate valuable synthetic intermediates were also demonstrated.

Full text of DOI:10.1021/jacs.1c00283

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Article
Catalyst-Controlled Regiodivergence in Rearrangements of Indole-
Based Onium Ylides
Vaishnavi N. Nair, Volga Kojasoy, Croix J. Laconsay, Wang Yeuk Kong, Dean J. Tantillo,*
and Uttam K. Tambar*
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ABSTRACT: We have developed catalyst-controlled regiodiver-
gent rearrangements of onium-ylides derived from indole
substrates. Oxonium ylides formed in situ from substituted indoles
selectively undergo [2,3]- and [1,2]-rearrangements in the
presence of a rhodium and a copper catalyst, respectively. The
combined experimental and density functional theory (DFT)
computational studies indicate divergent mechanistic pathways
involving a metal-free ylide in the rhodium catalyzed reaction
favoring [2,3]-rearrangement, and a metal-coordinated ion-pair in
the copper catalyzed [1,2]-rearrangement that recombines in the
solvent-cage. The application of our methodology was demon-
strated in the first total synthesis of the indole alkaloid
( )-sorazolon B, which enabled the stereochemical reassignment
of the natural product. Further functional group transformations of the rearrangement products to generate valuable synthetic
intermediates were also demonstrated.
rearrangements of oxonium systems (X = OR) are not known,
presumably because of side reactions through nonylide
pathways such as C−H insertion and cyclopropanation that
compete with facile ylide formation.9 Also, the examples for the
[1,2]-rearrangement of oxonium ylides in the literature are
generally limited to cyclic ylides.4b−k Catalytic methods for the
selective formation of either [1,2]- or [2,3]-rearrangement
products of aromatic systems from the same starting materials
would provide a valuable new strategy for the synthesis of
complex molecules.
Herein, we report the first catalyst-controlled regiodivergent
aromatic rearrangements of indole-based oxonium ylides
(Scheme 1B). With the proper choice of catalyst system, we
can selectively generate the [1,2]- or [2,3]-rearrangement
product. As our initial target for the rearrangements, we chose
the indole-scaffold because of its prevalence in many natural
products and medicinally valuable compounds.10 In addition to
exploring the scope of this reaction, we also performed DFT
calculations to examine mechanisms and the origins of catalyst-
controlled regiodivergence. Finally, to showcase the utility of
INTRODUCTION
■
Molecular rearrangements are arguably some of the most
effective reactions for the generation of new carbon−carbon
bonds in the synthesis of complex molecules.1 In recent years,
advances in catalytic onium ylide rearrangements have paved
the way for catalyst control of rearrangements that are
traditionally unselective.2,3 In this context, catalytic generation
of onium ylides from diazocarbonyl compounds has served as a
versatile platform for selective rearrangements (Scheme 1A).
Despite many reports of catalytic onium ylide rearrangements
of aliphatic systems,4,5 only a few examples of analogous
aromatic rearrangements are known which are limited to
sulfonium (X = SR) and ammonium (X = NR2) ylides.6 The
challenge of developing this class of rearrangements is partially
due to the energetic penalty associated with disruption of
aromaticity in the sigmatropic [2,3]-rearrangement (Scheme
1A).7 A pioneering study on catalytic thia-Sommelet-Hauser
rearrangement was reported by Wang and co-workers in
2008.6c In recent years, examples of controlled [1,2]- and
[2,3]-rearrangements of ylides in aromatic systems have
appeared in the literature.8 Pan and co-workers reported
rearrangements of sulfonium ylides where the selectivity for
[1,2]- vs [2,3]-rearrangement is controlled by the solvent and
substrate.8a Another report from Koenigs and co-workers
shows a solvent controlled approach in rearrangements of
sulfonium ylides formed from donor/acceptor carbenes.8b
Alternatively, catalytic ylide-formation and aromatic [2,3]-
Received: January 9, 2021
Published: June 14, 2021
https://doi.org/10.1021/jacs.1c00283
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a
Scheme 1. Catalyst Control of Regioselectivity in Onium
Ylide Rearrangements
Table 1. Optimization of [1,2]- and [2,3]-Rearrangements
b
c
Conversion
(%)
Yield
(%)
Entry
Catalyst
PdCI2
AgOTf
Ph3PAuCI
Cu(OTf)·
benzene
Solvent
3a:4a
1
2
3
4
CH2CI2
CH2CI2
CH2CI2
CH2CI2
<5
<5
<5
5
<5
<5
<5
5
82:18
5
6
7
8
CuCI
CuCI2
CuOAc/NaBArF
[Cu(MeCN)4]
PF6
Cu(hfacac)2
Cu(hfacac)2
Rh2(OAc)4
Rh2(cap)4
Rh2(TFA)4
Rh2(TPA)4
Rh2(oct)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
CH2CI2
CH2CI2
CH2CI2
CH2CI2
5
8
26
42
5
7
18
38
71:29
75:25
76:24
86:14
d
d
9
10
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
DCE
67
>95
55
<5
30
56
44
92
41
51
20
52
78
42
92:8
>95:5
<5:95
e
d
d
11
12
13
14
15
<5
<5
23
33
26
36
33
16
32:68
10:90
<5:95
<5:95
<5:95
<5:95
e
16
17
18
19
CHCI3
toluene
our method, we demonstrated the conversion of rearrange-
ment products into the indole alkaloid sorazolon B and several
valuable building blocks for drug discovery.
a
Reaction conditions: indole 1a (0.16 mmol), benzyl diazoester 2a
(1.2 equiv, added using syringe pump as 0.2 M solution in solvent at a
rate of 2 mL/h), copper catalyst (5 mol %) or rhodium catalyst (2
RESULTS AND DISCUSSION
b
c
■
mol %). Conversion of 1a. NMR yield using 1,3,5-trimethox-
d
e
Development of Regiodivergent Rearrangements.
Our initial investigations began with the screening of various
catalysts that are generally applied in carbene chemistry,11
using 3-(methoxymethyl)-1-tosyl-1H-indole (1a) and benzyl
diazoester (2a) as substrates (Table 1). While we did not
observe any reactivity in the presence of palladium, silver, or
gold catalysts (entries 1−3), CuOTf·benzene (5 mol %)
afforded a mixture of [1,2]- and [2,3]-rearrangement products
3a and 4a (82:18 rr), respectively, in low yield (entry 4).
Moreover, we were pleased to note that indoline 4a bearing an
exomethylene moiety (presumably from the [2,3]-rearrange-
ment) was formed with excellent diastereoselectivity (>20:1
dr). Moving forward with this initial result that gave 3a as the
major product, we began optimizing the [1,2]-rearrangement
of the oxonium ylides by screening additional copper sources.
Other copper catalysts such as CuCl, CuCl2, and CuOAc/
NaBArF gave similar or slightly improved yields, but relatively
lower regioselectivities (entry 5−7). We were delighted to see
an improved yield (38%) as well as regioselectivity (86:14 rr)
with [Cu(MeCN)4]PF6 as catalyst (entry 8). The use of
Cu(hfacac)2 to perform the rearrangement further enhanced
the yield (52%) and regioselectivity (92:8 rr) (entry 9). An
examination of the conversion of the starting materials under
these conditions revealed that the yield was limited by the
incomplete consumption of indole 1a, whereas the diazoester
2a was completely consumed to give the desired products
along with minor amounts of dibenzyl fumarate and dibenzyl
ybenzene as internal standard. Isolated yield. 2.4 equiv of 2a was
used.
maleate as the side products resulting from homodimerization.
Increasing the amount of benzyl diazoester 2a to 2.4 equiv
resulted in >95% conversion of 1a to provide the [1,2]-
rearrangement product 3a in 78% yield and >95:5 rr (entry
10).
Alternatively, when Rh2(OAc)4 (2 mol %) was used as the
catalyst, we observed a switch in the regioselectivity that gave
the [2,3]-rearrangement product 4a as the major product
(>95:5 rr) in 42% yield and >20:1 dr (entry 11). The
screening of several other dirhodium carboxylate catalysts
commonly used in metal-carbene transformations, such as
Rh2(cap)4, Rh2(TFA)4, Rh2(TPA)4, and Rh2(oct)4,12 failed to
improve the yield for the reaction (entries 12−15). Similar to
the copper-catalyzed [1,2]-rearrangement, an incomplete
consumption of indole 1a (55%) was identified as the reason
for the moderate yields. However, increasing the amount of
diazoester 2a to 2.4 equiv diminished the yield of the [2,3]-
rearrangement product 4a to 26% (entry 16). We speculate
that the reason for the lower yield with excess diazoester might
be the propensity of the exomethylene group in 4a to undergo
cyclopropanation with excess highly reactive rhodium-carbene
(see SI for details). We also examined other indole substrates
besides methyl ether 1a for optimization studies. While ethyl
ether underwent the [2,3]-rearrangement, other alkyl and
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Table 2. Products Generated by Regiodivergent [1,2]- and [2,3]-Rearrangements
a
rsm = recovered starting material 1.
arylethers such as isopropyl and phenyl ethers did not give any
conversion under the [2,3]-rearrangement conditions (see SI
for details). Other N-protecting groups such as Me, Boc, and
Ac were also screened during optimization for [2,3]-rearrange-
ment, but most of these substrates did not show significant
product formation (see SI for details). Further screening of
different solvents also did not provide improvement in the
yield (entries 17−19). As a result, the conditions with
Rh2(OAc)4 (2 mol %) in CH2Cl2 at 23 °C were identified
as optimal for the catalytic ylide-formation/aromatic [2,3]-
rearrangement (entry 11).
catalyzed ylide-formation/[2,3]-rearrangement in hand (en-
tries 10 and 11, Table 1), we next explored reaction scope
(Table 2).
Indole substrates with a broad range of substituents at
various positions on the heteroaromatic ring (3a−3p) worked
efficiently under the [1,2]-rearrangement conditions. Electron-
rich 5-and 6-substituted indole substrates provided high yields
and excellent regioselectivities (3b−3e). Substitution at the 2-
position generated the desired [1,2]-rearrangement product 3f,
albeit in slightly lower yield, but nonetheless gave excellent
regioselectivity (>95:5 rr). Several electron-withdrawing
substituents on the indole ring, including fluoro, bromo,
trifluoromethyl, and ester groups (3g−3m), provided good
yields and high regioselectivities. The reaction also progressed
Substrate Scope of Regiodivergent Rearrangements.
With the optimized reaction conditions for both the copper-
catalyzed ylide-formation/[1,2]-rearrangement and rhodium-
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Figure 1. Computed (PWPB95-D3(BJ)/def2-QZVPP//IEFPCM(CH2Cl2)-B3LYP/6-31G(d), SDD) relative free energies (kcal/mol, italics) for
minima and TSSs involved in the Rh-promoted reaction of 1a and 2a.
smoothly to generate dihalogenated product 3n in 51% yield
and >95:5 rr. In addition, other alkyl and aryl diazoesters were
shown to be competent in generating [1,2]-rearrangement
products in moderate to good yields (3o and 3p).
were performed using density functional theory at the
PWPB95-D3(BJ)/def2-QZVPP//IEFPCM(CH2Cl2)-B3LYP/
6-31G(d), SDD level (see SI for details).15 The robustness of
our chosen level of theory was evaluated through a series of
tests with other functionals and basis sets (see SI for details);
while there is some variation in predicted relative energies,
these variations do not affect our mechanistic conclusions. 3-
(Methoxymethyl)-1-tosyl-1H-indole 1a was selected as the
model substrate.
For the rhodium-catalyzed ylide-formation/[2,3]-rearrange-
ment, we first examined the structure of the metal-bound
oxonium ylide (Figure 1). Formation of the carbon-bound
ylide 5 is predicted to be exergonic by 9.2 kcal/mol, whereas
formation of the oxygen-bound ylide 6 is endergonic by 7.0
kcal/mol.
Our proposed pathway for a concerted [2,3]-rearrangement
process is summarized in Figure 1. Dissociation of Rh2(OAc)4
prior to rearrangement generates free oxonium ylide 7. Early
dissociation of rhodium(II) complexes from ylides has been
reported for other diazocarbonyl-mediated reactions.4a,16 The
most probable pathway to the product involves a metal-free
[2,3]-rearrangement of oxonium ylide 7, which leads to the
observed product 4a with the experimentally observed relative
stereochemistry.17 As expected, we were not able to find a
transition state structure for the symmetry-forbidden metal-
free [1,2]-rearrangement of oxonium ylide 7.18 The relative
Next, we explored the scope of the rhodium-catalyzed ylide-
formation/[2,3]-rearrangement to provide various substituted
indolines (4) that would be difficult to access in high selectivity
by conventional methods.13 Several electron-deficient indole
rings with different substitution patterns underwent selective
aromatic [2,3]-rearrangement to generate indolines (4b−4f) in
moderate yields and with excellent regioselectivities. Electron-
donating substituents on the indole ring led to comparatively
lower isolated yields of the products (4g and 4h); however, the
[2,3]-rearrangement proceeded with excellent regioselectiv-
ity.14 The rearrangement products were generally stable to
rearomatization, presumably because of the electron-with-
drawing tosyl protecting group similar to other known
indolines.13b,c Notably, the [2,3]-rearrangement of all the
substrates exhibited high diastereoselectivity (>20:1 dr). The
relative stereochemistry of the major anti-diastereomer of
product 4e was confirmed by X-ray crystallography, and the
relative stereochemistry of the major diastereomer of all other
2-substituted indolines was assigned by analogy.
Mechanistic Studies. To gain insight into the divergent
mechanisms of the catalyst controlled ylide-formation/
rearrangement reactions, a series of computational studies
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Figure 2. (A) Computed (PWPB95-D3(BJ)/def2-QZVPP//IEFPCM(CH2Cl2)-B3LYP/6-31G(d),SDD) relative free energies (kcal/mol, italics)
for minima and TSSs involved in the Cu-promoted reaction of 1a and 2a. A selection of ion-pairs 12a-12e were generated by scanning the bonds
that form en route to the products. The energies for ion-pairs 12a-12e are based on optimized complexes. Geometries of ion-pairs 12a-12e, their
preceding zwitterion 11, and the recombination product 13a shown in ball-and-stick images are included to facilitate comparison of overall shapes.
For clarity in visual comparison, the enolate part of the ion-pair is highlighted in green and the indolyl part (highlighted in gray) is positioned the
same way for each structure above. The solvent cage (not modeled explicitly) is depicted in blue with dotted lines. (B) Reaction conditions for
radical probe experiment: indole 1q (0.16 mmol), benzyl diazoester 2a (1.2 equiv, added using syringe pump as 0.2 M solution in CH2Cl2 at a rate
of 2 mL/h), Cu(hfacac)2 (5 mol %), CH2Cl2, 23 °C. (C) Reaction conditions for crossover experiment: indole 1i (0.08 mmol, 0.5 equiv), indole 1r
(0.08 mmol, 0.5 equiv) benzyl diazoester 2a (1.2 equiv, added using syringe pump as 0.2 M solution in CH2Cl2 at a rate of 2 mL/h), Cu(hfacac)2
(5 mol %), CH2Cl2, 23 °C.
stereochemistry of the major diastereomer of products arising
from the [2,3]-rearrangement of indole-based onium ylides
such as 7 is consistent with a preference for an exo transition
state structure (8).4d Relative free energies calculated for the
exo and endo transition states predicted a lower energy barrier
for exo transition state 8 leading to the observed diastereomer
anti-4a.
For the copper-catalyzed ylide-formation/[1,2]-rearrange-
ment, we propose a mechanism that involves a stepwise
process (Figure 2A).4e,19 The preferential formation of the
[1,2]-rearrangement product 3a over the [2,3]-rearrangement
product 4a is an argument against pathways involving the early
dissociation of copper from the initially generated metal-
coordinated ylide 11, since metal-free [1,2] rearrangement is
predicted to have an extremely high barrier compared to that
of the [2,3]-rearrangement (see SI). On the basis of our
computational results, we favor an ion-pair fragmentation/
recombination pathway for the copper-catalyzed reactions.20
Other possible pathways were explored but were not consistent
with our experimental results (see SI for details). For example,
formation of simple radical-pairs cannot be ruled out on the
basis of our computational results, but our experimental data
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argues against it. Specifically, cyclopropane containing
substrate 1q reacted with diazoester 2a to yield the [1,2]-
rearrangement product 3q with the radical probe intact (Figure
2B).21,22
Scheme 2. Synthetic Derivatization of [2,3]-Rearrangement
Product
To gain insight into the key carbon−carbon bond formation
event in the copper-catalyzed reaction, we considered ion-pair
complexes (12a, 12b, 12c, 12d, and 12e) that could lead to
the [1,2]-rearrangement product 3a or the [2,3]-rearrange-
ment product diastereomers syn-4a and anti-4a with minimal
reorganization (Figure 2A).23 In principle, these ion-pairs
would be in equilibrium with each other and could recombine
to form copper-bound recombination products (e.g., 13a,
Figure 2A).24 However, recombination in a solvent cage is
expected to be faster than equilibration between ion-pairs.20g,25
Although a solvent cage was not explicitly modeled in our
calculations, the formation of ion-pairs in a solvent cage is
consistent with experimentally determined results. When
substrates 1i and 1r were simultaneously subjected to the
[1,2]-rearrangement conditions, we did not detect crossover
products 3s and 3a (Figure 2C).
We were able to find a transition state structure (TS12a
)
converting the ion-pair 12a to 13a, the Cu(hfacac)2-bound
experimentally observed product, with a 3.1 kcal/mol barrier.
Subsequent dissociation of Cu catalyst yields 3a. If 12a was
formed preferentially on the dissociation of the copper-
coordinated oxonium ylide 11, we propose that this ion-pair
could rapidly recombine to the experimentally observed
product (12a → 3a) before equilibration with other ion-
pairs. Comparisons of the various ion-pairs and metal-ylide
intermediate 11 do indeed reveal greater conformational
similarity between 11 and 12a than either 12b, 12c, 12d, or
12e (Figure 2A; see SI for details). We also investigated the
proposed stepwise ion-pair mechanism with other copper
catalysts (Cu(acac)2, CuCl2, Cu(hfacac)+, and Cu(acac)+), and
all qualitatively lead to similar results (see SI for details).
In summary, on the basis of our combined experimental and
computational data, we favor a mechanism for the rhodium-
promoted reaction where early catalyst dissociation occurs at
the ylide stage, and products are formed via a metal-free [2,3]-
sigmatropic rearrangement. For the copper-promoted reaction,
we favor a mechanism where a copper-coordinated ion-pair is
formed and rapidly recombines in a solvent cage to form the
observed [1,2]-rearrangement product.
Synthetic Applications of Regiodivergent Rearrange-
ments. The products generated through the [2,3]-rearrange-
ment proved to be versatile substrates to access building blocks
that are potentially useful for the synthesis of complex
molecules (Scheme 2). For example, rearrangement product
4a can undergo ozonolysis to yield indoxyl product 14. In the
presence of acid, the rearrangement product 4a is rearomatized
to furnish 2,3-disubstituted indole 15. In the presence of an
electrophilic source of bromine, it is selectively converted to 3-
bromomethyl indole 16.
procedure converted benzylester 3a to the Weinreb amide 17.
Subsequent removal of the N-tosyl group provided N−H
indole 18 in 93% yield. To access the relative configuration for
the proposed structure of sorazolon B (21), we treated the
Weinreb amide 18 first with ethynylmagnesium bromide
followed by methylmagnesium bromide, which generated
tertiary alcohol 19 in 19:1 dr and 57% yield over the two
steps. The relative configuration of the major diastereomer,
which was confirmed by X-ray crystallography, was consistent
with a Cram chelation controlled addition of methylmagne-
sium bromide.27 Alcohol 19 was then converted to diol 20,
which was subjected to gold catalyzed 6-endo cyclization.28
Although the resulting tricyclic skeleton of 21 was consistent
with the proposed structure of sorazolon B, the NMR data of
our synthetic sample did not match the corresponding data for
the natural product.
We hypothesized that the relative configuration of the two
stereogenic centers in sorazolon B may have been misassigned.
To test this hypothesis, we switched the order of addition of
Grignard reagents to the Weinreb amide 18. An initial addition
of methylmagnesium bromide followed by a Cram chelation
controlled addition of ethynylmagnesium bromide yielded the
tertiary alcohol 22 in 9:1 dr. The relative configuration of the
major diastereomer was confirmed by X-ray crystallography.
The treatment of methyl ether 22 with bromodimethylborane
and 2-methyl-2-butene resulted in the formation of diol 23. In
the presence of Au(MeCN)SbF6 and JohnPhos, diol 23 was
converted to tricycle 24, which had spectroscopic data that
were identical with the data reported for sorazolon B in the
original isolation paper.26
To demonstrate the synthetic utility of the [1,2]-rearrange-
ment products, we incorporated this transformation into the
first total synthesis of the indole alkaloid sorazolon B, which
enabled a stereochemical reassignment of the natural product’s
structure that was reported in the original isolation paper
(Scheme 3).26 To commence the total synthesis, 3-
(methoxymethyl)-1-tosyl-1H-indole (1a) was coupled with
diazoester 2a under the [1,2]-rearrangement conditions to
furnish benzylester 3a in 82% yield and >95:5 rr. The efficiency
of the reaction was maintained on a gram scale. A two-step
CONCLUSION
■
We developed catalyst-controlled regiodivergent rearrange-
ments of onium-ylides derived from indole methyl ethers and
diazoesters. While a copper catalyst promotes a regioselective
[1,2]-rearrangement, a rhodium catalyst facilitates a regiose-
lective and diastereoselective [2,3]-rearrangement. We present
experimental and computational studies that support divergent
mechanistic pathways for the two rearrangement processes. We
also describe the synthetic utility of the two rearrangements by
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Scheme 3. Synthesis and Stereochemical Reassignment of ( )-Sorazolon B from [1,2]-Rearrangement Product
demonstrating the functional group tolerance and scope of the
reactions as well as the transformation of the rearrangement
products to several indole-containing products. Finally, we
applied the copper-catalyzed [1,2]-rearrangement in the first
total synthesis of the indole alkaloid sorazolon B, which
enabled the stereochemical reassignment of the natural
product.
Dean J. Tantillo − Department of Chemistry, University of
California, Davis, Davis, California 95616, United States;
orcid.org/0000-0002-2992-8844; Email: djtantillo@
ucdavis.edu
Authors
Vaishnavi N. Nair − Department of Biochemistry, The
University of Texas Southwestern Medical Center, Dallas,
Texas 75390-9038, United States
Volga Kojasoy − Department of Chemistry, University of
California, Davis, Davis, California 95616, United States
Croix J. Laconsay − Department of Chemistry, University of
California, Davis, Davis, California 95616, United States;
orcid.org/0000-0002-9244-1318
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00283.
Experimental details, characterization data, spectral data,
and computational results (PDF)
Wang Yeuk Kong − Department of Chemistry, University of
California, Davis, Davis, California 95616, United States
Accession Codes
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00283
CCDC 2057316−2057318 and 2068211 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
AUTHOR INFORMATION
The authors declare no competing financial interest.
■
Corresponding Authors
ACKNOWLEDGMENTS
Uttam K. Tambar − Department of Biochemistry, The
University of Texas Southwestern Medical Center, Dallas,
Texas 75390-9038, United States; orcid.org/0000-0001-
5659-5355; Email: uttam.tambar@utsouthwestern.edu
■
Financial support was provided to U.K.T by W. W. Caruth, Jr.
Endowed Scholarship, Welch Foundation (I-1748), National
Institutes of Health (R01GM102604), American Chemical
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Article
Lett. 1992, 33, 6193−6196. (g) Clark, J. S.; Krowiak, S. A.; Street, L. J.
Synthesis of Cyclic Ethers from Copper Carbenoids by Formation
and Rearrangement of Oxonium Ylides. Tetrahedron Lett. 1993, 34,
4385−4388. (h) West, F. G.; Eberlein, T. H.; Tester, R. W. O-Bridged
Medium Sized Rings via Bicyclic Oxonium Ylides. J. Chem. Soc., Perkin
Trans. 1 1993, 2857−2859. (i) West, F. G.; Naidu, B. N.; Tester, R.
W. Profound Catalyst Effects in the Generation and Reactivity of
Carbenoid-Derived Cyclic Ylides. J. Org. Chem. 1994, 59, 6892−6894.
(j) Doyle, M. P.; Ene, D. G.; Forbes, D. C.; Tedrow, J. S. Highly
Enantioselective Oxonium Ylide Formation and Stevens Rearrange-
ment Catalyzed by Chiral Dirhodium (II) Carboxamidates.
Tetrahedron Lett. 1997, 38, 4367−4370. (k) Li, Z.; Davies, H. M.
L. Enantioselective C-C Bond Formation by Rhodium-Catalyzed
Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement between
Donor/Acceptor Carbenoids and Allylic Alcohols. J. Am. Chem. Soc.
2010, 132, 396−401. (l) Li, Z.; Parr, B. T.; Davies, H. M. L. Highly
Stereoselective C-C Bond Formation by Rhodium-Catalyzed Tandem
Ylide Formation/[2,3]-Sigmatropic Rearrangement between Donor/
Acceptor Carbenoids and Chiral Allylic Alcohols. J. Am. Chem. Soc.
2012, 134, 10942−10946. (m) Doyle, M. P.; Forbes, D. C.;
Vasbinder, M. M.; Peterson, C. S. Enantiocontrol in the Generation
and Diastereoselective Reactions of Catalytically Generated Oxonium
and Iodonium Ylides. Metal-Stabilized Ylides as Reaction Inter-
mediates. J. Am. Chem. Soc. 1998, 120, 7653−7654. (n) Li, Z.;
Boyarskikh, V.; Hansen, J. H.; Autschbach, J.; Musaev, D. G.; Davies,
H. M. L. Scope and Mechanistic Analysis of the Enantioselective
Synthesis of Allenes by Rhodium-Catalyzed Tandem Ylide For-
mation/[2,3]-Sigmatropic Rearrangement between Donor/Acceptor
Carbenoids and Propargylic Alcohols. J. Am. Chem. Soc. 2012, 134,
15497−15504.
(5) Examples of catalytic ammonium, sulfonium, and iodonium ylide
rearrangements of aliphatic systems: (I) Ammonium (X = N) ylides:
(a) West, F. G.; Glaeske, K. W.; Naidu, B. N. One-Step Synthesis of
Tertiary α-Amino Ketones And α-Amino Esters from Amines and
Diazocarbonyl Compounds. Synthesis 1993, 1993, 977−980.
(b) West, F. G.; Naidu, B. N. New Route to Substituted Piperidines
via the Stevens [1,2]-Shift of Ammonium Ylides. J. Am. Chem. Soc.
1993, 115, 1177−1178. (c) Clark, J. S.; Hodgson, P. B. Intra-
molecular Generation and Rearrangement of Ammonium Ylides from
Copper Carbenoids: A General Method for the Synthesis of Cyclic
Amines. J. Chem. Soc., Chem. Commun. 1994, 2701−2702. (d) West,
F. G.; Naidu, B. N. Piperidines via Ammonium Ylide [1,2]-Shifts: A
Concise, Enantioselective Route to (−)-Epilupinine From Proline
Ester. J. Am. Chem. Soc. 1994, 116, 8420−8421. (e) Clark, J. S.;
Hodgson, P. B.; Goldsmith, M. D.; Street, L. J. Rearrangement of
ammonium ylides produced by intramolecular reaction of catalytically
generated metal carbenoids. Part 1. Synthesis of cyclic amines. J.
Chem. Soc., Perkin Trans. 1 2001, 3312−3324. (f) Clark, J. S.;
Hodgson, P. B.; Goldsmith, M. D.; Blake, A. J.; Cooke, P. A.; Street,
L. J. Rearrangement of ammonium ylides produced by intramolecular
reaction of catalytically generated metal carbenoids. Part 2. Stereo-
selective synthesis of bicyclic amines. J. Chem. Soc., Perkin Trans. 1
2001, 3325−3337. (g) Clark, J. S.; Middleton, M. D. Synthesis of
Novel α-Substituted and α,α-Disubstituted Amino Acids by
Rearrangement of Ammonium Ylides Generated from Metal
Carbenoids. Org. Lett. 2002, 4, 765−768. (h) Heath, P.; Roberts,
E.; Sweeney, J. B.; Wessel, H. P.; Workman, J. A. Copper(II)-
Catalyzed [2,3]-Sigmatropic Rearrangement of N-Methyltetrahydro-
Society Petroleum Research Fund (59177-ND1), Teva
Pharmaceuticals Marc A. Goshko Memorial Grant (60011-
TEV), and Sloan Research Fellowship. Financial support was
provided to V.N.N by Sarah and Frank McKnight Fund
Graduate Fellowship. Support from the National Science
Foundation (CHE-1856416 and XSEDE via CHE-030089) to
D.J.T. is gratefully acknowledged. We acknowledge Dr.
Vincent Lynch (Manager of the X-ray Diffraction Lab at UT
Austin) for the X-ray structural analysis and Dr. Hamid
Baniasadi (Director of the UT Southwestern Metabolomics
Core Facility) for the high resolution mass spectrometry. We
also thank our diverse group of lab members for creating an
environment that supports our scientific endeavors.
REFERENCES
■
(1) (a) Bru
̈
ckner, R. 2,3-Sigmatropic Rearrangements. In Compre-
hensive Organic Synthesis; Fleming, I., Ed.; Pergamon: Oxford, 1991;
pp 873−908. (b) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. [3,3]-
Sigmatropic rearrangements: recent applications in the total synthesis
of natural products. Chem. Soc. Rev. 2009, 38, 3133−3148.
(c) Seashore-Ludlow, B.; Somfai, P. Sigmatropic Rearrangements in
Stereoselective Synthesis; John Wiley & Sons: New York, 2013; pp
475−499. (d) Jones, A. C.; May, J. A.; Sarpong, R.; Stoltz, B. M.
Toward a Symphony of Reactivity: Cascades Involving Catalysis and
Sigmatropic Rearrangements. Angew. Chem., Int. Ed. 2014, 53, 2556−
2591. (e) Molecular Rearrangements in Organic Synthesis; Rojas, C. M.,
Ed.; John Wiley & Sons: New York, 2016.
(2) Reviews on catalytic onium ylide rearrangements: (a) Murphy,
G. K.; Stewart, C.; West, F. G. Intramolecular generation and
rearrangement of oxonium ylides: methodology studies and their
application in synthesis. Tetrahedron 2013, 69, 2667−2686.
(b) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Catalytic
enantioselective rearrangements and cycloadditions involving ylides
from diazo compounds. Chem. Soc. Rev. 2001, 30, 50−61. (c) West,
T. H.; Spoehrle, S. S. M.; Kasten, K.; Taylor, J. E.; Smith, A. D.
Catalytic Stereoselective [2,3]-Rearrangement Reactions. ACS Catal.
2015, 5, 7446−7479. (d) Murphy, G. K.; West, F. G. In Molecular
Rearrangements in Organic Synthesis; Rojas, C., Ed.; John Wiley Sons:
Hoboken, NJ, 2015; pp 497−538. (e) Sheng, Z.; Zhang, Z. K.; Chu,
C.; Zhang, Y.; Wang, J. Transition metal-catalyzed [2,3]-sigmatropic
rearrangements of ylides: An update of the most recent advances.
Tetrahedron 2017, 73, 4011−4022.
(3) (a) Books and reviews on classical non-catalytic onium ylide
rearrangements:Pine, S. H. In Organic Reactions; Dauben, W. G., Ed.;
Wiley: New York, 1970; Vol. 18 pp 403−464. (b) Nakai, T.; Mikami,
K. [2,3]-Wittig sigmatropic rearrangements in organic synthesis.
Chem. Rev. 1986, 86, 885−902. (c) Sweeney, J. B. Sigmatropic
rearrangements of ‘onium’ ylids. Chem. Soc. Rev. 2009, 38, 1027−
1038.
(4) Examples of catalytic oxonium ylide rearrangements of aliphatic
systems: (a) Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. Highly
Effective Catalytic Methods for Ylide Generation from Diazo
Compounds. Mechanism of the Rhodium- and Copper-Catalyzed
Reactions with Allylic Compounds. J. Org. Chem. 1981, 46, 5094−
5102. (b) Roskamp, E. J.; Johnson, C. R. Generation and
Rearrangements of Oxonium Ylides. J. Am. Chem. Soc. 1986, 108,
6062−6063. (c) Pirrung, M. C.; Werner, J. A. Intramolecular
Generation and [2,3]-Sigmatropic Rearrangement of Oxonium Ylides.
J. Am. Chem. Soc. 1986, 108, 6060−6062. (d) Doyle, M. P.; Bagheri,
V.; Harn, N. K. Facile catalytic methods for intermolecular generation
of allylic oxonium ylides and their stereoselective [2,3]-sigmatropic
rearrangement. Tetrahedron Lett. 1988, 29, 5119−5122. (e) Eberlein,
T. H.; West, F. G.; Tester, R. W. The Stevens [1,2]-Shift of Oxonium
Ylides: A Route to Substituted Tetrahydrofuranones. J. Org. Chem.
1992, 57, 3479−3482. (f) Clark, J. S. Diastereoselective Synthesis of
2,5-Dialkyl Tetrahydrofuran-3-ones by a Copper-Catalysed Tandem
Carbenoid Insertion and Ylide Rearrangement Reaction. Tetrahedron
pyridinium Ylids. J. Org. Chem. 2003, 68, 4083−4086. (i) Sanco̧ n, J.;
Sweeney, J. B. Probing the Effect of Allylic Substitution on Cyclic
Ammonium Ylid Rearrangements. Synlett 2010, 2010, 664−666
Sulfonium (X = S) ylides. (j) Doyle, M. P.; Griffin, J. H.; Chinn, M.
S.; van Leusen, D. Rearrangements of Ylides Generated from
Reactions of Diazo Compounds with Allyl Acetals and Thioketals
by Catalytic Methods. Heteroatom Acceleration of the [2,3]-
Sigmatropic Rearrangement. J. Org. Chem. 1984, 49, 1917−1925.
(k) Aggarwal, V. K.; Ferrara, M.; Hainz, R.; Spey, S. E. [2,3]-
Sigmatropic rearrangement of allylic sulfur ylides derived from
trimethylsilyldiazomethane (TMSD). Tetrahedron Lett. 1999, 40,
9023
https://doi.org/10.1021/jacs.1c00283
J. Am. Chem. Soc. 2021, 143, 9016−9025

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
8923−8927. (l) Carter, D. S.; Van Vranken, D. L. Metal-Catalyzed
Ylide Formation and [2,3] Sigmatropic Rearrangement of Allyl
Sulfides with Trimethylsilyldiazomethane. Tetrahedron Lett. 1999, 40,
1617−1620. (m) Hock, K. J.; Mertens, L.; Hommelsheim, R.;
Spitzner, R.; Koenigs, R. M. Enabling iron catalyzed Doyle-Kirmse
rearrangement reactions with in situ generated diazo compounds.
Chem. Commun. 2017, 53, 6577−6580 (III) Iodonium (X = I) ylides:.
(n) Xu, B.; Tambar, U. K. Ligand-Controlled Regiodivergence in the
Copper-Catalyzed [2,3]- and [1,2]-Rearrangements of Iodonium
Ylides. J. Am. Chem. Soc. 2016, 138, 12073−12076. (o) Xu, B.;
Gartman, J. A.; Tambar, U. K. Copper-catalyzed [1,2]-rearrangements
of allylic iodides and aryl α-diazoacetates. Tetrahedron 2017, 73,
4150−4159. (p) Xu, B.; Tambar, U. K. Copper-Catalyzed Enantio-,
Diastereo-, and Regioselective [2,3]-Rearrangements of Iodonium
Ylides. Angew. Chem., Int. Ed. 2017, 56, 9868−9871.
(6) Catalytic aromatic rearrangements with sulfonium (X = S) ylides:
(a) Kennedy, A. R.; Taday, M. H.; Rainier, J. D. The Use of Sulfur
Ylides in the Synthesis of Substituted Indoles. Org. Lett. 2001, 3,
2407−2409. (b) Novikov, A. V.; Kennedy, A. R.; Rainier, J. D. Sulfur
Ylide-Initiated Thio-Claisen Rearrangements. The Synthesis of Highly
Substituted Indolines. J. Org. Chem. 2003, 68, 993−996. (c) Liao, M.;
Peng, L.; Wang, J. Rh(II)-Catalyzed Sommelet-Hauser Rearrange-
ment. Org. Lett. 2008, 10, 693−696. (d) Boyarskikh, V.; Nyong, A.;
Rainier, J. D. Highly Diastereoselective Sulfonium Ylide Rearrange-
ments to Quaternary Substituted Indolines. Angew. Chem., Int. Ed.
2008, 47, 5374−5377. (e) Li, Y.; Shi, Y.; Huang, Z.; Wu, X.; Xu, P.;
Wang, J.; Zhang, Y. Catalytic Thia-Sommelet-Hauser Rearrangement:
Application to the Synthesis of Oxindoles. Org. Lett. 2011, 13, 1210−
1213. (f) Li, S.-S.; Wang, J. Cu(I)/Chiral Bisoxazoline-Catalyzed
Enantioselective Sommelet-Hauser Rearrangement of Sulfonium
Ylides. J. Org. Chem. 2020, 85, 12343−12358 Catalytic aromatic
rearrangements with ammonium (X = N) ylides:. (g) Pan, C.; Guo,
W.; Gu, Z. Unusual biaryl torsional strain promotes reactivity in Cu-
catalyzed Sommelet-Hauser rearrangement. Chem. Sci. 2018, 9,
5850−5854.
(7) (a) Hansen, H. J.; Schmid, H. Aromatic Sigmatropic Rearrange-
ments. Chem. Br. 1969, 5, 111−116. (b) Murray, A. W. Molecular
rearrangements. Org. React. Mech. 2002, 487−615. (c) Snape, T. J. In
Aromatic Rearrangements in Which the Migrating Group Migrates to the
Aromatic Nucleus: An Overview; John Wiley & Sons, Inc.: 2015; pp
485−510.
(8) (a) Xu, X.; Li, C.; Xiong, M.; Tao, Z.; Pan, Y. Hemin-catalyzed
sulfonium ylide formation and subsequently reactant-controlled
chemoselective rearrangements. Chem. Commun. 2017, 53, 6219−
6222. (b) Yang, Z.; Guo, Y.; Koenigs, R. M. Solvent-dependent,
rhodium catalysed rearrangement reactions of sulfur ylides. Chem.
Commun. 2019, 55, 8410−8413.
(9) Wang, J. In Comprehensive Organometallic Chemistry III;
Crabtree, R. H.; Mingos, D. M. P., Eds.; Elsevier: Oxford, U.K.,
2007; Vol. 11, pp 151−178.
(12) (a) Doyle, M. P. Metal Carbene Reactions from Dirhodium(II)
Catalysts. Top. Organomet. Chem. 2004, 13, 203−222. (b) Davies, H.
M. L.; Parr, B. T. Rhodium Carbenes. Wiley Ser. React. Intermed.
Chem. Biol. 2013, 7, 363−403.
(13) Select examples for the synthesis of 3-methyleneindolines:
(a) Burns, B.; Grigg, R.; Sridharan, V.; Worakun, T. Palladium
catalysed tandem cyclisation-anion capture processes. Hydride ion
capture by vinylpalladium species. Tetrahedron Lett. 1988, 29, 4325−
4328. (b) Zenner, J. M.; Larock, R. C. Palladium-Catalyzed,
Asymmetric Hetero- and Carboannulation of Allenes Using Func-
tionally-Substituted Aryl and Vinylic Iodides. J. Org. Chem. 1999, 64,
7312−7322. (c) Font, M.; Cendón, B.; Seoane, A.; Mascaren
̃
as, J. L.;
Gulías, M. Rhodium(III)-Catalyzed Annulation of 2-Alkenyl Anilides
with Alkynes Through C-H Activation: Direct Access to 2-Substituted
Indolines. Angew. Chem., Int. Ed. 2018, 57, 8255−8259. (d) Kondoh,
A.; Terada, M. Brønsted Base-Catalyzed Umpolung Intramolecular
Cyclization of Alkynyl Imines. Chem. - Eur. J. 2018, 24, 3998−4001.
(e) Li, X.; Zhou, B.; Yang, R.-Z.; Yang, F.-M.; Liang, R.-X.; Liu, R.-R.;
Jia, Y.-X. Palladium-Catalyzed Enantioselective Intramolecular Dear-
omative Heck Reaction. J. Am. Chem. Soc. 2018, 140, 13945−13951.
(14) When subjected to the [2,3]-rearrangement conditions, indole
3f proceeded to give a mixture of [2,3]:[1,2] rearrangement products.
We presume that the 2-methyl substituent hinders the [2,3]-
rearrangement that forms the fully substituted carbon center and
increases the propensity for the ylide to dissociate and generate the
competitive [1,2]-rearrangement product (see SI for details).
(15) (a) Becke, A. D. Density-Functional Thermochemistry. III. The
Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648−5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti
Correlation-Energy Formula into a Functional of the Electron
Density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−
789. (c) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping
Function in Dispersion Corrected Density Functional Theory. J.
Comput. Chem. 2011, 32, 1456−1465. (d) Hariharan, P. C.; Pople, J.
A. The Influence of Polarization Functions on Molecular Orbital
Hydrogenation Energies. Theor. Chim. Acta 1973, 28, 213−222.
(e) Igel-Mann, G.; Stoll, H.; Preuss, H. Pseudopotentials for Main
Group Elements (IIIa through VIIa). Mol. Phys. 1988, 65, 1321−
1328. (f) Hay, P. J.; Wadt, W. R. Ab Initio Effective Core Potentials
for Molecular Calculations. Potentials for the Transition Metal Atoms
Sc to Hg. J. Chem. Phys. 1985, 82, 270−283. (g) Goerigk, L.; Grimme,
S. Efficient and Accurate Double-Hybrid-Meta-GGA Density Func-
tionalsEvaluation with the Extended GMTKN30 Database for
General Main Group Thermochemistry, Kinetics, and Noncovalent
Interactions. J. Chem. Theory Comput. 2011, 7, 291−309. (h) Weigend,
F.; Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence
and quadruple zeta valence quality for H to Rn: Design and
assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297−3305.
(i) Weigend, F. Accurate Coulomb-fitting basis sets for H to Rn. Phys.
Chem. Chem. Phys. 2006, 8, 1057−1065. (j) Hellweg, A.; Hättig, C.;
Höfener, S.; Klopper, W. Optimized Accurate Auxiliary Basis Sets for
RI-MP2 and RI-CC2 Calculations for the Atoms Rb to Rn. Theor.
Chem. Acc. 2007, 117, 587−597. (k) Chmela, J.; Harding, M. E.
Optimized Auxiliary Basis Sets for Density Fitted Post-Hartree-Fock
Calculations of Lanthanide Containing Molecules. Mol. Phys. 2018,
116, 1523−1538.
(16) (a) Hock, K. J.; Koenigs, R. M. Enantioselective [2,3]-
Sigmatropic Rearrangements: Metal-Bound or Free Ylides as Reaction
Intermediates? Angew. Chem., Int. Ed. 2017, 56, 13566−13568.
(b) Zhang, Z.; Sheng, Z.; Yu, W.; Wu, G.; Zhang, R.; Chu, W.-D.;
Zhang, Y.; Wang, J. Catalytic asymmetric trifluoromethylation via
enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides.
Nat. Chem. 2017, 9, 970−976. (c) Harrison, J. G.; Gutierrez, O.; Jana,
N.; Driver, T. G.; Tantillo, D. J. Mechanism of Rh2(II)-Catalyzed
Indole Formation: The Catalyst Does Not Control Product
Selectivity. J. Am. Chem. Soc. 2016, 138, 487−490. (d) Nickerson,
L. A.; Bergstrom, B. D.; Gao, M.; Shiue, Y.-S.; Laconsay, C. J.;
Culberson, M. R.; Knauss, W. A.; Fettinger, J. C.; Shaw, J. T.; Tantillo,
D. J. Enantioselective synthesis of isochromans and tetrahydroisoqui-
(10) (a) Kochanowska-Karamyan, A. J.; Hamann, M. T. Marine
Indole Alkaloids: Potential New Drug Leads for the Control of
Depression and Anxiety. Chem. Rev. 2010, 110, 4489−4497.
(b) Kaushik, N.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.; Verma,
A.; Choi, E. Biomedical Importance of Indoles. Molecules 2013, 18,
6620−6662. (c) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of
the Structural Diversity, Substitution Patterns, and Frequency of
Nitrogen Heterocycles Among U. S. FDA Approved Pharmaceuticals.
J. Med. Chem. 2014, 57, 10257−10274.
(11) (a) Doyle, M. P. Catalytic Methods for Metal Carbene
Transformations. Chem. Rev. 1986, 86, 919−939. (b) Liu, L.; Zhang,
J. Gold-catalyzed transformations of α-diazocarbonyl compounds:
selectivity and diversity. Chem. Soc. Rev. 2016, 45, 506−516.
(c) DeAngelis, A.; Panish, R.; Fox, J. M. Rh-Catalyzed Intermolecular
Reactions of α-Alkyl-α-Diazo Carbonyl Compounds with Selectivity
Over β-Hydride Migration. Acc. Chem. Res. 2016, 49, 115−127.
(d) Zhao, X.; Zhang, Y.; Wang, J. Recent developments in copper-
catalyzed reactions of diazo compounds. Chem. Commun. 2012, 48,
10162−10173.
9024
https://doi.org/10.1021/jacs.1c00283
J. Am. Chem. Soc. 2021, 143, 9016−9025

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
nolines by C-H insertion of donor/donor carbenes. Chem. Sci. 2020,
11, 494−498. (e) Laconsay, C. J.; Tantillo, D. J. Metal Bound or Free
Ylides as Reaction Intermediates in Metal-Catalyzed [2,3]-Sigma-
tropic Rearrangements? It Depends. ACS Catal. 2021, 11, 829−839.
(f) Li, F.; Pei, C.; Koenigs, R. M. Rhodium-catalyzed cascade
reactions of triazoles with organoselenium compounds - a combined
experimental and mechanistic study. Chem. Sci. 2021, 12, 6362−6369.
(17) In addition, when two distinct substrates were simultaneously
subjected to the [2,3]-rearrangement conditions, no crossover
products were detected (see SI for details). These observations are
consistent with a metal-free symmetry-allowed, concerted, and
unimolecular process.
supramolecular cages with microwave microfluidics. Commun. Chem.
2019, 2, 54.
(26) Karwehl, S.; Jansen, R.; Huch, V.; Stadler, M. Sorazolons,
Carbazole Alkaloids from Sorangium cellulosum Strain Soce375. J. Nat.
Prod. 2016, 79, 369−375.
(27) (a) Cram, D. J.; Elhafez, F. A. A. Studies in Stereochemistry. X.
The Rule of ‘ Steric Control of Asymmetric Induction” in the
Syntheses of Acyclic Systems. J. Am. Chem. Soc. 1952, 74, 5828−5835.
(b) Reetz, M. T. Chelation or Non-Chelation Control in Addition
Reactions of Chiral α- and β- Alkoxy Carbonyl Compounds [New
Synthetic Methods (44)]. Angew. Chem., Int. Ed. Engl. 1984, 23, 556−
569. (c) Mengel, A.; Reiser, O. Around and beyond Cram’s Rule.
Chem. Rev. 1999, 99, 1191−1223.
(28) Ferrer, C.; Echavarren, A. M. Gold-Catalyzed Intramolecular
Reaction of Indoles with Alkynes: Facile Formation of Eight-
Membered Rings and an Unexpected Allenylation. Angew. Chem.,
Int. Ed. 2006, 45, 1105−1109.
(18) Other stepwise mechanisms were considered and cannot be
definitively ruled out, including a fragmentation/recombination
pathway (see SI).
(19) (a) Ollis, W. D.; Rey, M.; Sutherland, I. O.; Closs, G. L. The
Mechanism of Stevens Rearrangement. J. Chem. Soc., Chem. Commun.
1975, 543−545. (b) Chantrapromma, K.; Ollis, W. D.; Sutherland, I.
O. Radical-coupling Products Derived from Ammonium Ylides.
Competing [1,2], [1,3], and [1,4] Anionic Rearrangements. J.
Chem. Soc., Chem. Commun. 1978, 670−671. (c) Heard, G. L.;
Frankcombe, K. E.; Yates, B. F. A. Theoretical Study of the Stevens
Rearrangement of Methylammonium Methylide and Methylammo-
nium Formylmethylide. Aust. J. Chem. 1993, 46, 1375−1388. (d) Liu,
Z.; Jin, X.; Dang, Y. Mechanistic Studies of Copper(I)-Catalyzed
Stereoselective [2,3]- Sigmatropic Rearrangements of Diazoesters
with Allylic Iodides/ Sulfides. ACS Catal. 2021, 11, 691−702.
(20) (a) Hogen-Esch, T. E.; Smid, J. Studies of Contact and Solvent-
Separated Ion Pairs of Carbanions. I. Effect of Temperature, and
Solvent. J. Am. Chem. Soc. 1966, 88, 307−318. (b) Roy, S.; Baer, M.
D.; Mundy, C. J.; Schenter, G. K. Marcus Theory of Ion-Pairing. J.
Chem. Theory Comput. 2017, 13, 3470−3477. (c) Macchioni, A. Ion
Pairing in Transition-Metal Organometallic Chemistry. Chem. Rev.
2005, 105, 2039−2073. (d) Brak, K.; Jacobsen, E. N. Asymmetric
Ion-Pairing Catalysis. Angew. Chem., Int. Ed. 2013, 52, 534−561.
(e) Chen, Y.; Liu, Y.; Li, Z.; Dong, S.; Liu, X.; Feng, X. Tandem
Insertion-[1,3]-Rearrangement: Highly Enantioselective Construction
of α-Aminoketones. Angew. Chem. 2020, 132, 8129−8133. (f) Yao, L.;
Ishihara, K. Enantioselective [1,3] O-to-C Rearrangement: Dearoma-
tization of Alkyl 2-Allyloxy/Benzyloxy-1/3-Naphthoates Catalyzed by
a Chiral π-Cu(II) Complex. Chem. Sci. 2019, 10, 2259−2263.
(g) Tsuji, Y.; Richard, J. P. Reactions of Ion-Pair Intermediates of
Solvolysis. Chem. Rec. 2005, 5, 94−106.
(21) Bowry, V. W.; Lusztyk, J.; Ingold, K. U. Calibration of a New
Horologery of Fast Radical “Clocks”. Ring-Opening Rates for Ring-
and α-Alkyl-Substituted Cyclopropylcarbinyl Radicals and for the
Bicyclo[2.1.0]pent-2-yl Radical. J. Am. Chem. Soc. 1991, 113, 5687−
5698.
(22) We do note, however, that some ion-pairs appear to have
diradical character (see SI).
(23) Computed relative free energies of ion-pairs 12a-12e with
respect to the reactants were calculated using PWPB95-D3(BJ)/def2-
QZVPP//IEFPCM(CH2Cl2)-B3LYP/6-31G(d),SDD, which is used
to more accurately capture dispersion effects, but the accuracy of the
computed energies is limited because explicit solvent was not
included.
(24) de Azambuja, F.; Yang, M. H.; Feoktistova, T.; Selvaraju, M.;
Brueckner, A. C.; Grove, M. A.; Koley, S.; Cheong, P. H. Y.; Altman,
R. A. Connecting remote C-H bond functionalization and
decarboxylative coupling using simple amines. Nat. Chem. 2020, 12,
489−496.
(25) (a) Fang, Y.; Powell, J. A.; Li, E.; Wang, Q.; Perry, Z.; Kirchon,
A.; Yang, X.; Xiao, Z.; Zhu, C.; Zhang, L.; Huang, F.; Zhou, H.-C.
Catalytic Reactions within the Cavity of Coordination Cages. Chem.
Soc. Rev. 2019, 48, 4707−4730. (b) Stelson, A. C.; Hong, C. M.;
Groenenboom, M. C.; Little, C. A. E.; Booth, J. C.; Orloff, N. D.;
Bergman, R. G.; Raymond, K. N.; Schwarz, K. A.; Toste, F. D.; Long,
C. J. Measuring ion-pairing and hydration in variable charge
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https://doi.org/10.1021/jacs.1c00283
J. Am. Chem. Soc. 2021, 143, 9016−9025