[1,3]-Claisen rearrangement via removable functional group mediated radical stabilization

Article abstract of DOI:10.1021/acs.orglett.0c04109

A thermal O-to-C [1,3]-rearrangement of α-hydroxy acid derived enol ethers was achieved under mild conditions. The 2-aminothiophenol protection of carboxylic acids facilitates formation of the [1,3] precursor and its thermal rearrangement via stabilization of a radical intermediate. Experimental and theoretical evidence for dissociative radical pair formation, its captodative stability via aminothiophenol, and a unique solvent effect are presented. The aminothiophenol was deprotected from rearrangement products as well as after derivatization to useful synthons.

Full text of DOI:10.1021/acs.orglett.0c04109

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Letter
[1,3]-Claisen Rearrangement via Removable Functional Group
Mediated Radical Stabilization
Md Nirshad Alam, Soumya Ranjan Dash, Anirban Mukherjee, Satish Pandole, Udaya Kiran Marelli,
Kumar Vanka, and Pradip Maity*
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ABSTRACT: A thermal O-to-C [1,3]-rearrangement of α-hydroxy acid derived enol ethers was achieved under mild conditions.
The 2-aminothiophenol protection of carboxylic acids facilitates formation of the [1,3] precursor and its thermal rearrangement via
stabilization of a radical intermediate. Experimental and theoretical evidence for dissociative radical pair formation, its captodative
stability via aminothiophenol, and a unique solvent effect are presented. The aminothiophenol was deprotected from rearrangement
products as well as after derivatization to useful synthons.
he thermal [1,3]-rearrangement of O-alkyl enolates was
reported by Claisen in 1896,1 well before the famous
activation energy for thermal [1,3]-rearrangement via homo-
lytic bond cleavage. We envisioned that inexpensive biomass α-
hydroxy acids could be converted to derivative 5, which would
facilitate a mild 1,3-rearrangement for two reasons.6 First, the
enol ether conjugated with the three heteroatom lone pairs of
electrons is electron-rich and expected to be activated for a
homolytic bond cleavage (5 to 6).7 Second, the resulting α-
keto radical intermediate (III) should achieve enhanced
stability via a push−pull captodative effect.8 The extended
conjugations in captodatively stable radicals lead to polar-
ization and should enjoy a unique solvent stabilization for
further reduction in bond dissociation energy.9 Herein, we
report a facile and efficient thermal [1,3]-Claisen rearrange-
ment of α-hydroxy acid derivatives. The enhanced reactivity of
an intermediary enol ether and the stability of a subsequent
radical intermediate was achieved by the protection of the
carboxylic acid group with a removable 2-aminothiophenol for
its substrate independent reactivity. The reaction mechanism
and its efficiency are supported by both experiments and
computations.
T
[3,3]-Claisen sigmatropic rearrangement of O-allyl enolates in
1912.2 The [3,3]-rearrangement exhibits many essential
aspects of an ideal reaction, namely mild conditions and a
waste-free rearrangement for the regio- and stereoselective
synthesis of polyfunctionalized products.3 On the other hand,
although the thermal [1,3]-rearrangement is theoretically a
similar waste-free process, only a handful of reports have
appeared in the literature with very high-temperature require-
ments, narrow substrate scopes, and often poor yields. A
thermally allowed pericyclic pathway is presumably unattain-
able due to the constrained transition state with inversion at
the migrating center. The dissociative radical pair mechanism
for the reported methods is generally accepted and often
attributed to its inefficiency, substrate dependency, and the
dearth of examples (Figure 1a).4 The substrate dependency
with a narrow scope was exemplified by an accidental [1,3]
migration of highly substituted classes of ketene silyl ethers
discovered by the Shiina group.4q The thermal rearrangement
proceeds efficiently at 100 °C, but only with a fully substituted
C-3 carbon (R1, R2 ≠ H). On the other hand, other
dissociative radical pair rearrangements from highly reactive
starting materials that proceed under mild conditions such as
anionic [1,2]-Wittig and zwitterionic Stevens rearrangements
are efficient and synthetically valuable.5 A general and milder
radical [1,3]-Claisen rearrangement could, therefore, represent
an efficient and synthetically significant process.
We started our exploration with the protection of the
carboxylic acid with 1,2-phenylenediamine, 2-aminophenol,
Received: December 12, 2020
Published: January 14, 2021
We reasoned that a reactive enol ether and stable
corresponding α-keto radical intermediate would reduce the
https://dx.doi.org/10.1021/acs.orglett.0c04109
© 2021 American Chemical Society
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Table 1. Thermal Rearrangement for α-Hydroxy Acid
a
Derivatives
entry
X
MeY
base
solvent
time (h) yield (%)
b
1
NMe
O
S
S
S
S
S
S
S
S
S
S
S
MeOTf
MeOTf
MeOTf
MeOTf
MeOTf
MeOTf
Me2SO4
MeI
MeOTf
MeOTf
MeOTf
MeOTf
MeOTf
MeOTf
DBU
DBU
DBU
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
PhMe
PhMe
DCE
24
24
24
8
8
16
8
ND
ND
22
90
92
<5
40
27
69
69
77
72
79
86
b
2
c
3
4
5
6
7
K2CO3
KHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
d
8
8
9
16
16
12
12
10
10
10
11
12
13
14
THF
DMF
DMA
S
a
Conditions: All reactions were performed on a 0.2 mmol scale with
1.5 equiv of MeY and 2 equiv of bases in 2 mL of solvent (0.1 M) at
Figure 1. Thermal [1, 3]-Claisen rearrangements
b
c
d
50 °C. rt−100 °C. rt. N-Methylation step at 0−40 °C.
and 2-aminothiophenol, respectively. The protected acid
derivatives were O-benzylated (3), followed by N-methylation
with methyl triflate in a minimum amount of DCM for their
clean formation of the corresponding salts (4; see Supporting
Information (SI) for details).10 The formation of a [1,3]
precursor enol ether (5) and its proposed rearrangement were
studied via an operationally simple treatment of weak base
DBU in situ at room temperature followed by warming. DMSO
was chosen as the solvent to study the rearrangement with an
anticipation that a compatible polar solvent would reduce the
activation energy further by stabilizing the captodative radical
(III), leading to a facile or faster product formation.9
Carboxylic acid derivatives of 1,2-phenylenediamine and 2-
aminophenol (3a″, 3a′) led to the smooth formation of N-
methyl salts (4a″, 4a′; see SI), but failed to rearrange at
ambient temperature followed by decomposition at higher
temperature (entries 1, 2). With 2-aminothiophenol derivative
3a, we were delighted to observe the partial formation of [1,3]-
rearrangement product 6a (∼22%) at room temperature
(Table 1, entry 3). The rate of thermal rearrangement
increased substantially at 50 °C for its completion in 8 h to
form the [1,3] product in 90% yield (entry 4). With 3a, we
screened other bases and alkylating reagents to find both DBU
and K2CO3 as efficient bases and methyl triflate as the optimal
alkylating agent in DMSO (entries 5−8). As anticipated, the
rearrangement in less polar solvents such as toluene was slower
and afforded a lower yield (69%, entry 9). Other solvents were
screened for their effect on the rearrangement (entries 10−14)
which showed DMSO as the best solvent with yields and rate
of rearrangement roughly following the solvent polarity.
Figure 2. Substrate scope. Reaction conditions: Methyl triflate (0.3
mmol) was added to the substrate (0.2 mmol) and K2CO3 (0.4
mmol) in 1 mL of DCM (0.2 M) at 0 °C for 12 h, followed by
a
addition of DMSO (2 mL, 0.1 M) and heating at 50 °C for 8 h. Up
to 100 °C after DMSO addition.
generality of migrating groups was tested next with R1 as alkyl
groups. A broad variety of substituents on the phenyl ring of
the migrating benzyl were equally effective. For example,
fluoro, chloro, and bromo at C-4 with either methyl or isobutyl
as R1 rearranged to form corresponding products (6i−k) in
With the development of a mild and efficient rearrangement
condition, we explored the substrate scope to find its
generality. Different α-hydroxyacid derivatives with alkyl,
benzyl, and aryl groups (R1) were efficient for the synthesis
of various alkyl and aryl ketones (Figure 2, 6a−h). The
good yields. With R1
=
iBu, ortho-, meta-, and para-
chlorobenzyl substituents were tested to examine electronic
and steric effects. Both para- and meta- resulted in similar high
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yields (6k, 6l), while ortho- led to slightly diminished product
formation (6m). Electron-donating groups at C-4 such as
methyl and methoxy (6o−q) were found to be effective.
Gratifyingly, electron-deficient groups such as trifluoromethyl
at C-3 (6r) and cyano (6s) at C-4 (6m) were also well
tolerated. C-2 substituted heteroaromatic furan (6n) and
thiophene (6o) also led to the rearranged product under the
optimized reaction conditions in good yields. α-Substituted
benzyl groups were tested next for their thermal [1,3]
migration. The rearrangements with tertiary migrating groups
proceeded at a faster rate than the secondary benzyl to furnish
products in good overall yields with low to moderate
diastereoselectivities. The 1-phenylethyl group migrated with
a 79% yield and 1.7:1 diastereomeric ratio, and 1-β-
naphthylethyl rearranged to 67% product with 2.3:1 diaster-
eoselectivity. Interestingly, the 1-phenylcyclopropyl ethyl
group migrated efficiently (yield 75%, dr = 2:1) without any
ring-opening product.11 The low diastereoselectivities in these
products might be a combination of poor d.r. of in situ formed
[1,3] precursors and dissociative nature of the rearrangement.
A 1,1-bisphenylmethane (6y) also migrated efficiently to yield
71% of the rearranged product. Alkyl groups such as methyl,
ethyl, and isopropyl as the migrating group remained
unreactive under the optimized reaction conditions, and
heating at higher temperature led to a complex reaction
mixture, presumably via multiple air oxidation paths.12
Scheme 1. Mechanistic Experiments
With the establishment of a broad substrate scope for the
thermal [1,3]-rearrangement protocol, we next conducted
mechanistic studies on this facile migration. First, a radical trap
reaction with TEMPO was conducted to obtain direct
evidence for a bis-radical path. A 1 equiv amount of TEMPO
did not alter the product formation significantly, although we
detected a TEMPO trapped benzyl radical by HRMS analysis
of the crude reaction mixture. Increasing the TEMPO to 5
equiv led to a lowering of yield for the [1,3] product (58%)
along with 18% isolated TEMPO trapped product (Scheme
1A). Next, we carried out a crossover experiment with 3a and
3i (Scheme 1B), which mainly resulted in intramolecular
products 6a and 6i along with ∼10% total cross-products 6b
and 6h. The partial trapping of radicals via TEMPO and a
minor amount of crossover product formation indicate a
solvent cage recombination of bis-radical intermediates. To
further distinguish between radical versus ionic paths, we
compared the rate of rearrangement for the 4-cyanobenzyl
migrating group to the parent benzyl group (Scheme 1C). The
4-cyano substituent is expected to reduce the rate of the ionic
reaction13 while accelerating the radical reaction path.14 The
thermal rearrangement (Scheme 2A). The fact that our
substrates rearrange effectively at a lower temperature indicates
further stabilization via solvent on the captodatively stable
radical III. To estimate the relative solvent effects, we first
determined the ΔG’s in solvents with an increasing dielectric
constant for these three α-keto radicals. The calculations show
a considerably higher magnitude of stabilization (5.0 vs 1.8 vs
1.3 kcal/mol from gas-phase to DMSO) for radical III over
radical II and I. The origin of this solvent stabilization was
attributed to their polarization which was examined via spin
densities for radical II and III in different solvents (Scheme
2B) using the SMD solvation model.9,16 The computations
show that the reduction in spin density at radical carbon in a
higher polarity solvent was greater in magnitude for our system
(III) compared to the α-ester radical II. Conversely, the spin
density on electron donor nitrogen in III increased
significantly, while no significant change was observed on α-
carbons of II. Both the spin density distribution and ΔG
calculation in different solvents shows our captodatively stable
radical III was more polarizable than a typical α-keto radical
and exerted higher stabilization in polar solvents. The solvent
effect was tested experimentally, which showed a 1.6-fold rate
enhancement in DMSO compared to toluene at 40 °C. We
observed significant spin density on sulfur (0.12), which is
indicative of its superior effect on radical III stabilization and
success over other carboxylic acid protecting groups tested.
Finally, we demonstrated the removal of the 2-amino-
thiophenol from the [1,3] rearranged products. Several
reported S,N-acetal deprotection reagents were unsuccessful,
but AgNO3 at 60 °C afforded the desired products 8 in 55−
64% yield.17 Optimization with various silver salts led to
cleaner deprotection with AgBF4 in MeCN/H2O (3:1) at 60
°C for 2 h to the diketone products with various C-2
1
kinetic experiments via H NMR monitoring in DMSO-d6 at
40 °C resulted in a 3.5 times faster reaction with the 4-cyano
substrate, further supporting the radical mechanism (see SI for
details).
To compare the relative energy required for thermal radical
pair [1,3]-rearrangements, we calculated the ΔG associated
with the bond dissociation step for Claisen,1 Shiina,4g and our
system using DFT (ωB97XD/6-31+G(d,p)) (Scheme 2).9,15
We chose the migrating group as benzyl for all three systems to
correlate the effect of α-ketyl radical stability (I, II, and III) on
the bond dissociation step. The gas-phase ΔG for the
homolytic cleavage of the Claisen system is 34.3 kcal/mol,
consistent with the very high temperature for its rearrange-
ment. For the fully substituted Shiina system, the ΔG is 12.9
kcal/mol, while for our 2-aminothiophenol protected system
the ΔG is 13.0 kcal/mol, in line with their unusually facile
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Scheme 2. Captodative Stability and Solvent Effects
Scheme 3. Derivatization of [1,3] Products
for facile reaction and provide evidence for further solvent
stabilization. The S,N-acetal of the rearrangement products
and their derivatives were deprotected efficiently with good
yields for the synthesis of 1,2-diketones, as well as an
unsymmetrical α-hydroxy ketone and α,β-unsaturated ketone.
We are currently exploring the possibility of stereotranslation
from chiral substrates via stereoretentive [1,3]-rearrangements.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04109.
Experimental details; characterization of compounds;
Computational studies; NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds S1−2, S4−5, S7−8, S11−15, all 3 and 6,
4b, 4s, 8a−c, 9, 10 (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Pradip Maity − Organic Chemistry Division, CSIR-National
Chemical Laboratory, Pune 411008, India; orcid.org/
0000-0001-8493-3171; Email: p.maity@ncl.res.in
Authors
Md Nirshad Alam − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India; orcid.org/0000-0003-1076-
7013
Soumya Ranjan Dash − Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, India; Physical and
Material Chemistry Division, CSIR-National Chemical
Laboratory, Pune 411008, India
substituted rearranged products (8a−c) (Scheme 3). We also
took advantage of the regioselectively protected diketone
products to modify the unprotected ketone to an alcohol and
alkene followed by deprotection to obtain selectively one
regioisomer of the α-hydroxy alcohol 9 and α,β-unsaturated
ketone 10, respectively.18
In conclusion, inexpensive, stable, and naturally abundant α-
hydroxy acids were converted to 2-aminothiophenol derived
enol ether precursors for their thermal [1,3]-rearrangements
under ambient conditions. The aminothiophenol derivative of
carboxylic acids led to protection, enol ether formation, and
most importantly radical stabilization for mild and general
thermal [1,3]-rearrangements. Good to excellent yields were
achieved with both alkyl and aryl α-hydroxy acids and a large
variety of migrating groups. Mechanistic studies support a
dissociative radical pair mechanism and solvent cage
recombination. Computational studies support our hypothesis
Anirban Mukherjee − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India
Satish Pandole − Organic Chemistry Division, CSIR-National
Chemical Laboratory, Pune 411008, India
Udaya Kiran Marelli − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India; orcid.org/0000-0003-0466-
6611
Kumar Vanka − Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, India; Physical and
893
https://dx.doi.org/10.1021/acs.orglett.0c04109
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Material Chemistry Division, CSIR-National Chemical
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Laboratory, Pune 411008, India; orcid.org/0000-0001-
7301-7573
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the SERB (EMR/2015/
000711 and CRG/2019/001065). Md.N.A. thanks UGC for a
fellowship. The support from central analytical facility, NCL is
greatly acknowledged. The support and the resources provided
by “PARAM Brahma Facility” under the National Super-
computing Mission, Government of India at the Indian
Institute of Science Education and Research (IISER) Pune
are gratefully acknowledged.
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