Truce–Smiles Rearrangements by Strain Release: Harnessing Primary Alkyl Radicals for Metal-Free Arylation

Article abstract of DOI:10.1002/anie.202108240

The ring-opening of 3-aminocyclobutanone oximes enables easy generation of primary alkyl radicals, capable of undergoing an unprecedented strain-release, desulfonylative radical Truce–Smiles rearrangement, providing divergent access to valuable 1,3 diamin

Full text of DOI:10.1002/anie.202108240

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Accepted Article
Title: Truce-Smiles Rearrangements via Strain-Release: Harnessing
Primary Alkyl Radicals for Metal-Free Arylation
Authors: Michael Greaney, David M. Whalley, and Jayasree Seayad
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10.1002/anie.202108240
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COMMUNICATION
Truce-Smiles Rearrangements by Strain Release: Harnessing
Primary Alkyl Radicals for Metal-Free Arylation
David M. Whalley,[a,b] Jayasree Seayad,*[b] and Michael F. Greaney*[a]
Abstract: The ring-opening of 3-aminocyclobutanone oximes
enables easy generation of primary alkyl radicals, capable of
undergoing an unprecedented strain-release, desulfonylative radical
Truce-Smiles rearrangement, providing divergent access to valuable
1,3 diamines and unnatural β-amino acids. Characterized by mild
conditions and wide scope of migrating species, this protocol allows
the modular assembly of sp3-aryls under transition metal-free, room-
temperature conditions.
New methods for generating C(sp2)-C(sp3) bonds are in high
demand, to synthesize the complex arene structures fundamental
to pharmaceuticals and other functional molecules. The Truce-
Smiles rearrangement has become an increasingly important
transformation in this regard, harnessing carbon-centered anions
or radicals to create new arylation pathways via ipso-substitution,
often operating under simple, user-friendly conditions.[1] The
desulfonylative variant (Scheme 1A) is particularly powerful, as it
transforms readily available aryl sulfonamide substrates 1 into
high value arylethylamine aryl products 2-3 with no requirement
for stoichiometric arylmetals. The arylethylamine motif is
fundamental to drug design and widely exemplified in medicines
across numerous therapeutic areas (e.g. Scheme 1B).
For the radical variant of this reaction, which encompasses a
broader range of migrating arene groups, the majority of prior-art
has relied on one of two strategies for the generation of the key
Scheme 1. The radical Truce-Smiles rearrangement and proposed strain-
release arylation
carbon-centered radicals (Scheme 1C). First, the electrophilic
addition of open-shell species to an unsaturated species (e.g.
unactivated alkenes, Michael acceptors, styrenes, alkynes and
A new frontier for Truce-Smiles methodology would be the design
vinyl ureas) is a highly versatile approach to secondary alkyl
of a system that functionalizes inert C(sp3)-C(sp3) bonds, creating
radicals, which can then undergo the key aryl transfer from an
novel retrosynthetic disconnections for high value arene products.
Powering such a transformation with a strong entropic driving
force would allow for milder reaction conditions to be employed,
appropriately disposed sulfonamide 4.[2] An innovative
development in this area was recently reported by Nevado and
co-workers, who demonstrated stereoselective aryl transfer using
negating the need for elevated reaction temperatures or strong
chiral sulfinamides.[2h] However, the applicability of these systems
chemical oxidants/reductants. A promising direction for this
is often constrained by structural limitations of the substrates and
chemistry is the ring opening of strained rings (e.g. 6, Scheme 2),
electronic compatibility of incoming radical coupling partners. The
which enables generation of alkyl radicals under mild conditions,
second major approach has been the single-electron reduction of
generally from commercially available cyclobutanone rings.[5]
alkyl / aryl halides and their equivalents (5), first demonstrated in
seminal work from Speckamp and Motherwell in the synthesis of
sp3-aryls and sp2 – sp2 biaryls using tin hydride chemistry.[3a-c]
Recent developments in photoredox catalysis have supplanted tin
reagents and transformed the scope of the reaction, but do
generally require the use of precious metal catalysts to perform
the initial reductions.[3e-g]
While the majority of Truce-Smiles radical arylations are set up
via these two approaches, recent advances have looked to
broaden the strategies employed in the field e.g. work by Studer
and co-workers showed how strong C-H bonds can be arylated
using the Truce-Smiles rearrangement through
hydrogen-atom-transfer (HAT) process.[4]
a radical
[a]
D. M. Whalley, Prof. M. F. Greaney
School of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: michael.greaney@manchester.ac.uk
Dr. J. Seayad,
Institute of Chemical and Engineering Sciences
8 Biomedical Grove, Neuros, #07-01 138665 (Singapore)
Scheme 2. Proposed metal-free, strain-release Truce-Smiles arylation and prior
art of Ni[6a] and Ni / Ir-catalyzed[6b,c] strain-release cross-coupling.
[b]
1
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Important prior art from the groups of Selander and Leonori has
shown how strain-release can be harnessed for arylation via
primary alkyl radicals 9, using stoichiometric organometallics as
coupling partners.[6] Whilst they both achieve efficient coupling
under mild conditions with an earth-abundant catalyst, the
reactions are intolerant of sterically demanding aryl species,
employ high catalytic loadings (20 mol% nickel catalyst) and often
use elevated temperatures or pyrophoric reagents. We hoped that
the Truce-Smiles rearrangement could address all three of these
shortcomings. In addition, the capture of unstabilized primary
radicals is uncommon[3e],[7] in Truce-Smiles systems, enhancing
the new reaction space we could explore with the proposed strain-
release system.
comparable yields. Interestingly, no deleterious ortho-addition or
dearomatization products were observed that can affect radical
aryl migration.[3b][11]
Entry[a]
Base
Solvent
% Yield[b]
We began our study with the functionalization of 3-
aminocyclobutanone hydrochloride 11;[8] two simple N-
functionalizations and the condensation of an O-aryl
hydroxylamine gave the bench-stable, Truce-Smiles starting
material 6, isolated via filtration in all cases (Scheme 3).
1
2
Et3N
MeCN
Acetone
THF
63
Et3N
Et3N
69
3
58
4
Et3N
DMSO
DCM
36
5
Et3N
72
6
TMEDA
DCM
70
7
DIPEA
DCM
64
8[c]
9
N-Me-pyrrolidine
-
DCM
79 (72)[d]
DCM
0
45
0
Scheme 3. Construction of the Truce-Smiles rearrangement starting material.
Ar = 2,4 dinitrophenyl.
10[e]
11[f]
DCM
N-Me-pyrrolidine
N-Me-pyrrolidine
DCM
We envisioned the use of a photoredox cycle, utilising an
inexpensive organic dye to generate the necessary nitrogen-
centered radical that could trigger the cyclobutanone ring-
opening.[9] Owing to our previous success with 2,6-diflurobenzene
as an effective migrating species, we elected to use it for the
optimization studies.[7a] After a survey of conditions, it was found
that green LEDs and Eosin Y afforded the desired fluorinated
arylethylamine product 7a in good yield without the need for
elevated temperatures. Furthermore, cyclic alkylamine bases
proved to be effective sacrificial reductants for the cycle,
outcompeting the more commonly used acyclic trialkyl amines
(DIPEA, TMEDA etc. see SI for details). The background
reactivity observed when the substrate was irradiated in the
absence of catalyst could be attributed to potential electron-donor
acceptor (EDA) complex reactivity, something that we, and others,
have previously reported as an effective strategy for Truce-Smiles
rearrangements.[2e][9b][10]
To study the scope of the reaction, we began by varying the
nitrogen protecting group of the optimized 2,6-difluorobenzene
system. We were pleased to find that the reaction proceeds
smoothly with both N-Ac and N-Boc substituents (example 7a and
7b, Scheme 4), enabling selectivity for further nitrogen
functionalization. We next studied the role of ortho-substitution in
the reaction by changing the fluorination pattern on the ring and
leaving one of the ortho positions unsubstituted (7c). ortho-
Substituents or heteroatoms are frequently observed in radical
Smiles arylations, to facilitate the radical ipso substitution.[2] We
were pleased to observed negligible adverse effect to the
efficiency of the reaction, even when scaled up to 1 mmol (entry
7d). Next we performed the rearrangement on an entirely
unsubstituted phenyl ring 7e and were delighted to again observe
Table 1. Optimisation of the strain-release initiated Truce-Smiles
rearrangement. [a] 0.05 mmol scale, 5 mol% Eosin Y, 2 eq of base, 0.10 M
concentration, 15 h [b] 1H NMR yield [c] 0.05 mmol scale, 5 mol% Eosin Y, 3
eq of base, 0.05 M concentration, 15 h [d] Isolated yield, 0.20 mmol scale [e] No
catalyst [f] No irradiation. Ar = 2,4-dinitrophenyl.
In agreement with other reports, this strain-release Truce-Smiles
rearrangement was capable of incorporating highly hindered
arene species such as 7f containing a mesityl ring, owing to the
spirocyclic nature of the radical intermediate.[12] This finding also
contrasts favorably with the more sterically-sensitive nickel-
catalyzed strain release arylation systems.[6]
The next series of examples systematically varied the ortho
substituent of the migrating phenyl ring, to observe the effect of
steric hinderance, functional group tolerance and comparative
efficiencies of the electron systems for the ipso substitution. First,
electron rich anisole rings could be migrated with reasonable
efficiency (7g), along with the bulkier and more electron-
withdrawing trifluoromethoxy group 7h. Trifluoromethyl and nitro
groups (7i and 7l) underwent the Truce-Smiles rearrangement in
good to excellent yields, along with the cyano (7j) and carboxy
ester (7k) derivatives, providing an array of compatible
functionality for further synthetic manipulation. Variation at the
para-position was also possible, with chloro-containing example
7m paving the way for possible cross-coupling reactions.
Alternatively, a biaryl group could be migrated directly as
demonstrated by example 7n. The electron rich 4-methoxyphenyl
ring also migrated in high yield (7o).
2
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10.1002/anie.202108240
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functionalizations, by converting the nitrile to an imino ether and
hydrolysing upon work-up to the methyl ester (14a – 14c).[15]
Product 14c is the -arylglycine backbone of the anti-diabetes
treatment Sitagliptin, and illustrates the potential of the reaction
for producing novel β-amino acid side chains.[16] By exploiting
commercially available arylsulfonyl chlorides, the reaction
obviates the requirement for stoichiometric organometallics which
can restrict arene substrate scope, providing a new pathway to
important β-amino acid and arylethylamine pharmacophores.
Scheme 5. Synthetic application of the products of the Truce-Smiles
rearrangement. 0.10 mmol Conditions A = NiCl2∙6H2O, NaBH4, Boc2O, MeOH
0℃ - r.t.. Conditions B: AcCl / DCM / MeOH 0℃ - r.t. overnight then sat. NaHCO3
solution 30 mins. [a] 0.20 mmol scale.
Lastly, the mechanism of the reaction was investigated (Scheme
6). Beginning with the control experiments reported in Table 1, it
was clear that the reaction required irradiation and base to yield
any product and absence of catalyst was detrimental to the
reaction yield (see Table 1, entries 9, 10 and 11). It is likely that
there is a degree of background reactivity of electron donor-
acceptor complexes, owing to the electron-poor nature of the O-
aryl oxime employed and the use of a trialkylamine reductant.[17]
The reduction potential of 2,4-dinitrophenyl oximes (-0.55 V vs
SCE) lies well within the reduction potential of excited state Eosin
Y (-1.11 V vs SCE).[18] Likewise, N-methylpyrrolidine has been
measured via cyclic voltammetry (+0.68 V vs SCE) allowing for
the photoredox cycle in Scheme 5 to be proposed.[9b][19]
Scheme 4. Scope of the Truce – Smiles rearrangement via strain-release.
Reactions carried out on 0.20 mmol scale, isolated yields. [a] 0.10 mmol scale.
The reaction scope encompassed naphthalene (7p), fused
heteroarenes linked via the benzenoid (7q and 7r) or heteroarene
ring (7s), along with 2- and 3-substituted thiophenes (7t and 7u)
and furan (7v) forming the corresponding fused aryl/heteroaryl β-
amino nitrile derivatives. Collectively, the strain-release Truce-
Smiles exhibits a wide substrate scope[2][3]that includes a range of
oxygen, sulfur and nitrogen heterocycles in addition to a wide
range of functionalized phenyl rings capable of undergoing aryl
transfer in good to excellent yields.
After single-electron reduction of 6, fragmentation to iminyl radical
i and 2,4-dinitrophenolate. Intermediate i can then undergo a
entropically driven β-scission reaction to ring-open the
cyclobutanone ring, setting up the 1,5 alkyl radical / ipso position
necessary for the Truce-Smiles rearrangement (ii).[1] This key
alkyl radical species was trapped with TEMPO and detected by
HRMS (15). The resulting post-rearrangement amidyl radical iii
can then undergo a hydrogen atom transfer from the trialkylamine
base, giving the closed shell Smiles product 7.[20]
The amino nitriles presented in Scheme 4 offer numerous
possibilities for elaboration, with 1,3-diamines and β-amino acids,
in particular, being essential building blocks for pharmaceuticals
and natural products. The diamines are commonly accessed
through Mannich disconnections, reductions of pyrazolidines or
reduction of alkyl azides.[13] We applied Caddick’s one-pot nickel
boride reduction / Boc protection of the nitrile products to access
orthogonally protected 1,3 diamines, easily applicable to example
7s from the scope, giving 13 as the product (Scheme 5).[14] For β-
amino acids we could maintain the theme of room-temperature
In conclusion, we have described a new method for radical Truce-
Smiles rearrangement that proceeds at room temperature under
metal-free conditions. The reaction introduces a new design
element to Smiles arylation chemistry, that of strain-release,
which is effective for capturing unstable primary alkyl radical
intermediates. The process is capable of migrating a very wide
range of aryl and heteroaryl species, giving products that are
easily diversified to valuable β-amino acid and diamine products.
3
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Scheme 6. Proposed mechanism for the Eosin Y catalysed strain-release
Truce-Smiles rearrangement
Acknowledgements
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We thank the School of Chemistry (University of Manchester) and
[8] Boc-protected amine of 11 is commercially available from Fluorochem at a
current cost of £82/10g. Amine 11 is also commercialy available from
Fluorochem at a current cost of £123/10g. Accessed 09/06/21.
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A*STAR Singapore for funding. Dr Louise Natrajan (University of
Manchester) is thanked for assistance with photophysical
measurements.
Conflict of Interest
The authors declare no conflict of interest.
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Keywords: rearrangements • radicals • photoredox • arylation •
amino acids
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4
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Entry for the Table of Contents
The Truce-Smiles rearrangement has proven to be a powerful tool for the synthesis of new sp3-aryls via ipso substitution. The reaction
has been applied to the strain-release ring-opening of 3-aminocyclobutanone oximes, giving cyanide-free access to β-amino nitriles
under metal-free, room temperature conditions. The reaction displays a wide scope of migrating arenes as well as divergent access to
valuable 1,3-diamines and unnatural β-amino acids.
Institute and/or researcher Twitter usernames: @greaneygroup
5
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