Intramolecular Homolytic Substitution Enabled by Photoredox Catalysis: Sulfur, Phosphorus, and Silicon Heterocycle Synthesis from Aryl Halides

Article abstract of DOI:10.1021/acs.orglett.9b01911

Aryl radical generation and manipulation constitutes a long-standing challenge in organic synthesis. Photocatalytic single-electron reduction of aryl halides has been established as a premier activation pathway to reach these intermediates. The current st

Full text of DOI:10.1021/acs.orglett.9b01911

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Intramolecular Homolytic Substitution Enabled by Photoredox
Catalysis: Sulfur, Phosphorus, and Silicon Heterocycle Synthesis
from Aryl Halides
,†,‡
Alberto F. Garrido-Castro,†,§ Noelia Salaverri,†,§ M. Carmen Maestro,*,† and Jose Aleman*
́
́
†
́
Department of Organic Chemistry, Universidad Autonoma de Madrid, Madrid 28049, Spain
‡
́
Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autonoma de Madrid, Madrid 28049, Spain
S
* Supporting Information
ABSTRACT: Aryl radical generation and manipulation
constitutes a long-standing challenge in organic synthesis.
Photocatalytic single-electron reduction of aryl halides has
been established as a premier activation pathway to reach
these intermediates. The current study integrates the
conceptual simplicity of the classical intramolecular homolytic
substitution with the practicality of the modern photocatalytic
approach. Predicated on an efficient metal-free dehalogenation
of aryl halides under mild organo-photoredox conditions,
sulfur, phosphorus, and silicon heteroatoms capture the C(sp2)-centered radical in an intramolecular fashion.
ryl synthons have continued to fulfill an incredibly valuable
role in organic chemistry for decades. Countless arylation
of new C−C or C−heteroatom bonds based on this strategy
remains markedly more appealing (Scheme 1, top). Intermo-
lecular versions of these events have proven to be quite
challenging, as superstoichiometric amounts of radical trapping
A
protocols based on two-electron reductions of aryl halides have
surfaced.1 Complementary to ionic chemistry, Single-Electron
Transfer (SET) reductive dehalogenation of aryl halides can give
access to C(sp2)-centered radicals. These species serve as
relevant intermediates in organic synthesis, and also feature a
reactivity profile which completes the general portfolio of
arylation methods.2 The most common reducing methods
employ either a hydride source to induce halide abstraction3 or
photochemical cleavage of the C(sp2)−X bond.4 The former
regularly hinges on stoichiometric amounts of toxic and unstable
metal-based H atom donors and radical initiators (such as
tributyltin hydride and AIBN, respectively). The latter has
traditionally enabled photolytic dehalogenation under highly
energetic light irradiation (λ < 300 nm), thus restricting
applicability and establishing a strict relationship between the
substrate and its photophysical properties.
Scheme 1. Photocatalytic Reductive Dehalogenations
(A−C): C(sp2)−Heteroatom Bonds in Relevant
Heterocycles
The recent renaissance of photochemistry has led to
transcendent developments, unlocking new bond constructions
based on newly identified photocatalysts capable of acting in the
visible or near-visible light end of the spectrum.5 In this regard,
the generation of C(sp2)-centered radicals has benefitted
greatly.6 Most precursors include an activating group that aids
the radical generation by lowering the reduction potential, e.g.,
aryl diazonium salts, diaryliodonium salts, or aryl sulfonyl
chlorides (>−1.0 V vs SCE). Alternatively, less-reactive aryl
halides present larger reduction potentials (<−1.5 V vs SCE),
although they remain the most convenient precursor due to
availability and stability.
Therefore, SET reductive dehalogenation has been a main
target in the field of photocatalysis, yet the majority of the
findings merely report hydrogenation protocols.7 The formation
Received: June 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
agents are often required for adequate functionalization of the
aryl radical (Scheme 1A).8 Intriguingly, the intramolecular
variant has been less studied; only a short number of examples
restricted to C−C bond formation have been reported in the
literature (Scheme 1B).9 Nonetheless, the photocatalytic
intramolecular formation of C−heteroatom bonds has not
been described to the best of our knowledge (Scheme 1C),
although the heterocycles obtained through this synthetic route
represent highly relevant targets (Scheme 1, bottom). Through
careful evaluation of pioneering works in the field of the
intramolecular homolytic substitution (SHi),10 implementation
of a modern photocatalytic approach could serve as an ideal
activation pathway to help overcome previous limitations and
provide synthetic intermediates en route to these valuable
heterocyclic scaffolds (Scheme 1, bottom).11
although longer reaction times were required. Gratifyingly,
irradiation of PTH at a slightly more energetic wavelength (385
nm) led to full conversion of 1b and an 85% isolated yield of
product 3a after only 3 h (entry 7). Control experiments
confirmed that PTH, DIPEA, and light irradiation are necessary
for the reaction to take place (entries 8−9).
The nature of the leaving group (LG) was studied next, as
depicted in Scheme 2. tert-Butyl (tBu) had already been
a
Scheme 2. Evaluation of the Leaving Group in Sulfinamide 1
We thus identified a straightforward sulfur-based heterocycle
preparation to be an ideal starting point for our research.12 Initial
reductive dehalogenations were performed with brominated
sulfinamide 1a (Table 1). Several highly reducing organo-
a
Reaction conditions: 0.1 mmol scale using 1.0 equiv of sulfinamide 1,
5 mol % of PTH, and 2.5 equiv of DIPEA in 1.0 mL of MeCN for 3 h.
Isolated yields are indicated under each entry.
Table 1. Optimization of the Photocatalytic SHi
confirmed as a good LG throughout the optimization studies.
Furthermore, other alkyl chains such as isopropyl (1c) and n-
butyl (1d) displayed similar efficiency, yielding cyclic
sulfinamide 3a in equally impressive fashion. On the other
hand, irradiation of p-tolyl sulfinamide 1e under the present
conditions resulted in a decrease in yield,15 presumably due to
the higher bond dissociation energy associated to C(sp2)−S
bonds.16 This set of results indicates that the reaction behaves
similarly regardless of the alkyl substitution on the starting
sulfinamide. Thus, the rate-determining step of the reaction
should be the reductive dehalogenation of the aryl halide. In
addition, the stereochemical outcome of the reaction at the
sulfur atom was determined. When the reaction was carried out
with enantiopure sulfinamide (R)-1b (>99% ee), cyclic
sulfinamide (S)-3a was obtained without loss of enantiopurity
and complete inversion of configuration (>99% ee; see SI), in
accordance with an SHi mechanism.12,17 Consequently, tBu was
deemed a suitable LG stemming from Ellman’s accessible
sulfinamide, which is capable of enforcing exquisite stereo-
control on the reaction.
With the optimized conditions in hand, a host of structurally
diverse sulfinyl derivatives were subjected to the newly
developed photocatalytic protocol (Scheme 3). The reaction
was found to be amenable to electron-donating and electron-
withdrawing substitution on the aromatic ring, affording the
corresponding products in good yields (3b−3d). Impressively,
o-substitution on the aryl iodide was well tolerated (3d).
Conventional reductive dehalogenations have lacked selectivity
as a result of the highly reducing conditions often employed to
access radical intermediates. In this context, brominated
sulfinamides 1i and 1j provided a remarkable display of
chemoselectivity when subjected to irradiation at 420 nm,
observing exclusive cyclization at the iodinated positions, while
the bromide functionalities remained intact (3e and 3f).
Notably, indole- and quinoline-based iodides also underwent
efficient cyclization, delivering tricyclic heterocycles 3g and 3h
in good yields. Moreover, the presence of a stereogenic center at
the benzylic position did not alter the reaction outcome,
maintaining its stereochemical information at the benzyl site and
undergoing inversion of configuration at the sulfur atom (3i).18
hν
time
(h)
conversion
a
b
c
entry
X
photocatalyst
(nm)
(%)
1
2
3
4
5
6
1a PTH (2a)
365
365
365
540
450
420
385
385
−
3
3
3
16
16
16
3
3
3
44
0
1a Michler’s Ketone (2b)
1a Naph-PTH (2c)
1b Eosin Y (2d)
1b Rhodamine 6G (2e)
1b PTH
1b PTH
1b
1b PTH
22
49
52
58
d
e
7
>98 (85)
8
9
−
0
0
a
Reaction conditions: 0.1 mmol scale using 1.0 equiv of sulfinamide 1,
5 mol % of photocatalyst 2, and 2.5 equiv of DIPEA (iPr2EtN) in 1.0
b
mL of MeCN. 380 mW single LED. See Supporting Information for
c
detailed experimental setup. Determined by 1H NMR analysis of the
d
crude mixture. Absence of DIPEA results in <5% conversion.
Isolated yield after flash chromatography. DIPEA = N,N-diisopropyl-
ethylamine, PTH = 10-phenylphenothiazine, Naph-PTH = 10-(1-
naphthyl)phenothiazine.
e
photocatalysts5d,13 (entries 1−3) and solvents (see Supporting
Information (SI) for detailed optimization studies) were tested
̈
in the presence of a sacrificial electron donor (Hunig’s base,
DIPEA). Irradiation at near-visible light (365 nm) of PTH 2a as
a photocatalyst (5 mol %) in MeCN yielded the best results,
albeit resulting in moderate formation of sulfinamide 3a (entry
1, 44% conversion). In spite of the extensive efforts made to
optimize this reaction, bromo-derivative 1a displayed moderate
reactivity.14 Therefore, iodinated sulfinamide 1b was subjected
to numerous photocatalysts, reaching improved conversions
with organic dyes Eosin Y 2d (entry 4) and Rhodamine 6G 2e
(entry 5), and PTH (entry 6), under visible light irradiation,
B
DOI: 10.1021/acs.orglett.9b01911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of the Photocatalytic SHi with Sulfinyl
Derivatives 1
Scheme 4. (A) Scope of the Photocatalytic SHi with
a
a
Phosphites 4 ; (B) Scope of the Photocatalytic SHi with Silyl
b
Ethers 6
a
Reaction conditions: 0.1 mmol scale using 1.0 equiv of phosphite 4,
a
20 mol % of PTH and 2.5 equiv of DIPEA in 1.0 mL of MeCN for 16
h. Isolated yields are indicated under each entry. Reaction
conditions: 0.1 mmol scale using 1.0 equiv of silyl ether 6, 5 mol %
of PTH, and 2.5 equiv of DIPEA in 1.0 mL of MeCN. Yields
determined by 1H NMR using PhMe as internal standard, and
reaction times are indicated under each entry.
Reaction conditions: 0.1 mmol scale using 1.0 equiv of sulfinyl
b
derivative 1, 5 mol % of PTH, and 2.5 equiv of DIPEA in 1.0 mL of
MeCN for 3 h. Isolated yields are indicated under each entry.
b
c
Reaction performed on a 1.0 mmol scale. Reaction mixture
d
e
irradiated for 6 h. Reaction mixture irradiated at 420 nm. Yield
determined by 1H NMR using PhMe as internal standard.
f
1
Determined by H NMR.
An additional challenge surfaced when the formation of six-
membered cyclic sulfinamide 3j was attempted. The unsub-
stituted starting material (1n, R′′ = H) features an N−H bond
capable of engaging in a 1,5-Hydrogen Atom Transfer (HAT)
event with the C(sp2)-radical, leading to undesired hydro-
genation over cyclization. Nevertheless, this issue was bypassed
upon N-alkylation of the open sulfinamide (1o, R′′ = Me),
affording cyclic N-methyl sulfinamide 3j. Lastly, the method was
also successfully implemented in the preparation of other
heterocycles in excellent yields such as five- and six-membered
sultines (3k and 3l) and five-membered cyclic sulfoxide (3m).
Encouraged by the generality and efficiency of this photo-
catalytic system throughout the synthesis of different sulfur-
based heterocycles, we wondered if this protocol could be
expanded further. Phosphorus and silicon have showcased the
ability to participate in SHi processes,19 although it remains
largely unexplored under photocatalytic conditions. Conse-
quently, phosphites 4 (Scheme 4A) and silyl ethers 6 (Scheme
4B) were quickly identified as intriguing candidates.
Phosphonate esters hold an important role in pharmaceutical
chemistry, serving as the corresponding prodrug of biologically
active phosphonic acids, such as tenofovir or fosmidomycin.20
Among the multiple synthetic routes which grant access to these
prized organophosphorus compounds, phosphites have been
described to undergo SHiconcurrent with oxidation from
P(III) to P(V)delivering these Arbuzov-type products.21 In
this regard, a series of phosphites were evaluated (see SI for
detailed studies). Iodinated derivatives proved difficult to work
with due to background photolytic cleavage of the C−I bond,
leading to hydrogenated byproduct formation.22 Given this lack
of control, focus shifted to bromo-derivatives in an attempt to
harness the aryl radical generation in a milder way. To our
delight, homobenzylic phosphite 4a was successfully debromi-
nated to afford the hexacyclic phosphonate 5a (Scheme 4A), for
which an increase in catalyst loading (20 mol %) and reaction
time (16 h) was essential. Subsequently, a brief structural scope
evaluation was conducted on this system. Electron-donating
substitution (4b) and the chloride functionality (4c) were
tolerated, affording phosphonates 5b and 5c in synthetically
useful yields.23
Silyl groups represent a useful functionality in organic
synthesis. They can act as “placeholders” for further
functionalizations, including alcohol formation via oxidation
and Hiyama-type cross-couplings with electrophiles.24 Accord-
ingly, the expansion of this photocatalytic reaction to achieve
C(sp2)−Si bond formation could be valuable (Scheme 4B).
Tris(trimethylsilyl)-substituted silyl ethers 6 were selected as
precursors, since the TMS group is known to be a good LG in
SHi reactions.25 Iodinated starting materials proved unstable
once again, so aryl bromides were employed instead. We were
pleased to find that the reaction worked well under the standard
photocatalytic conditions (5 mol % of PTH, short reaction
times) with the less-reactive bromine-substituted ring 6a,
affording cyclic silyl ether 7a in good yield. In this case,
electron-rich and electron-poor aromatic rings could be studied,
providing swift formation of products 7b and 7c, respectively.
C
DOI: 10.1021/acs.orglett.9b01911
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Letter
Finally, chloro-derivative 7d was readily accessed under these
mild conditions.
homolytic substitution at the different heteroatoms studied
under this protocol.
A plausible mechanism for the photocatalytic SHi reaction is
represented in Scheme 5. First, the photocatalyst (PTH) reaches
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
Scheme 5. Mechanistic Proposal for the Photocatalytic SHi
ACS Publications website at DOI: 10.1021/acs.orglett.9b01911.
General experimental procedures, optimization studies,
compound synthesis and characterization data, mecha-
nistic studies, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: carmen.maestro@uam.es.
*E-mail: jose.aleman@uam.es.
ORCID
Alberto F. Garrido-Castro: 0000-0001-7262-7986
M. Carmen Maestro: 0000-0002-5639-9714
its highly reducing excited state (Ered PTH•+/PTH* = −2.1 V vs
SCE)5d,13 upon absorption of light. The photoexcited catalyst
would then engage in an SET event with the corresponding aryl
halide (Ered ca. −1.5 to −2.0 V vs SCE),6c,14a generating the
anion radical of the substrate through an oxidative quenching
pathway. Stern−Volmer quenching studies have shown the
inability of trialkylamines to quench PTH*. Therefore, the
excited catalyst is interacting with the aryl halide13 (see SI).
Ensuing mesolytic cleavage of the C(sp2)−X bond results in the
release of a halide anion (X−) and formation of the aryl
radical.14a At this point, the SHi process should become strictly
substrate-dependent, as the aryl radical interacts with each
heteroatom in a different manner:
́
́
Jose Aleman: 0000-0003-0164-1777
Author Contributions
§A.F.G.-C. and N.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the Spanish Government
(CTQ2015-64561-R and RTI2018-095038-B-I00), and “Co-
munidad de Madrid” and European Structural Funds (S2018/
NMT-4367).
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