Decatungstate-Catalyzed C(sp3)-H Sulfinylation: Rapid Access to Diverse Organosulfur Functionality

Article abstract of DOI:10.1021/jacs.1c04722

Here we report the direct conversion of strong, aliphatic C(sp3)-H bonds into the corresponding alkyl sulfinic acids via decatungstate photocatalysis. This transformation has been applied to a diverse range of C(sp3)-rich scaffolds, including natural products and approved pharmaceuticals, providing efficient access to complex sulfur-containing products. To demonstrate the broad potential of this methodology for the divergent synthesis of pharmaceutically relevant molecules, procedures for the diversification of the sulfinic acid products into a range of medicinally relevant functional groups have been developed.

Full text of DOI:10.1021/jacs.1c04722

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Decatungstate-Catalyzed C(sp3)−H Sulfinylation: Rapid Access to
Diverse Organosulfur Functionality
Patrick J. Sarver, Noah B. Bissonnette, and David W. C. MacMillan*
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ABSTRACT: Here we report the direct conversion of strong, aliphatic C(sp3)−H bonds into the corresponding alkyl sulfinic acids
via decatungstate photocatalysis. This transformation has been applied to a diverse range of C(sp3)-rich scaffolds, including natural
products and approved pharmaceuticals, providing efficient access to complex sulfur-containing products. To demonstrate the broad
potential of this methodology for the divergent synthesis of pharmaceutically relevant molecules, procedures for the diversification of
the sulfinic acid products into a range of medicinally relevant functional groups have been developed.
ulfonamides, sulfones, and sulfides are widely employed
functional groups that are broadly found in modern
conversion of abundant functional groups, such as alcohols and
carboxylic acids, into a broad range of valuable products under
mild conditions.11 A number of recent studies have provided
further improvements to synthetic efficiency via photoredox
approaches to HAT-mediated C(sp3)−H functionalization.12
Among photo-HAT catalysts, the decatungstate anion
([W10O32]4−) has been widely investigated due to its ability
to catalytically cleave strong C−H bonds following excitation
with near-UV light.13 Given these uniquely valuable properties,
decatungstate has been utilized in a range of synthetically
valuable transformations,14 including oxidations,15 dehydro-
genations,16 fluorinations,17 conjugate additions,18 chromium-
mediated additions to aldehydes,19 and several novel metal-
laphotoredox reactions.20 Despite this scope of previous work,
methods for the formation of C(sp3)−S bonds via decatung-
state photocatalysis have not previously been reported.21
A depiction of our reaction design appears in Scheme 1.
Near-UV excitation of the decatungstate anion (1) followed by
rapid relaxation is known to afford the reactive excited state
*[W10O32]4− (2).13,22 Due to the electrophilic nature of the
oxygen-centered hole present in 2, selective HAT at the more
electron-rich β-position of cyclopentanone (3) would yield
alkyl radical 4 and reduced decatungstate ([W10O32]5−, 5).23
Rapid radical capture of 4 by sulfur dioxide (6) would then
generate sulfonyl radical 7, forming the key C(sp3)−S bond.
Based on literature precedent (kdisproportionation ≈ 105 M−1 s−1)24
and UV/vis studies of the reaction mixture at partial
conversion (Figure S6), the cycle would close via disproportio-
nation of 5 to afford doubly reduced decatungstate (8)
S
materials,1 agrochemicals,2 and pharmaceuticals.3 The impor-
tance of these ubiquitous motifs is underscored by their
abundance in bioactive molecules,4 with sulfur being more
commonly found than fluorine or phosphorus in approved
drugs.5 Despite the well-established importance of organo-
sulfur compounds and many advances in C−H functionaliza-
tion, there remain few catalytic technologies for the conversion
of C(sp3)−H bonds into alkylsulfonyl groups.6 Intriguingly,
recent studies involving alkyl sulfinates have instead focused on
the inverse transform, namely C(sp3)−SO2 bond cleavage via
the oxidative conversion of sulfinates to alkyl radicals with
concomitant extrusion of SO2.7 With this in mind, we
questioned whether this open-shell pathway might be reverse
engineered to selectively deliver the opposite transformation.
More specifically, we considered the formation of alkyl radicals
from C−H bonds prior to SO2 trapping and subsequent
reduction, a pathway that if successful would generate C(sp3)-
rich, sulfonyl-containing adducts from simple aliphatic
substrates.
Given the current body of open shell coupling processes that
rely on the oxidative extrusion of sulfur dioxide to access alkyl
radicals, it is surprising to consider that previous kinetic8 and
synthetic9 studies support the feasibility of C(sp3) radical
capture by SO2 (effectively the inverse process to extrusion).
On this basis, we hypothesized that a sulfur dioxide alkyl
radical trapping mechanism might be readily married with
C(sp3)−H functionalization using a photo-HAT catalyst: a
pathway that would expand the range of potential sulfur-
containing feedstocks and, at the same time, provide a new
strategy for the divergent, late-stage functionalization of
pharmaceuticals. Herein, we report the successful execution
of these ideals and present a hydrogen atom transfer (HAT)-
sulfinylation protocol that employs aqueous sulfur dioxide,
light, and an inexpensive catalyst to rapidly deliver sulfones,
sulfonamides, and other sulfurous functionality (Figure 1).10
Advances in photoredox catalysis over the past decade have
facilitated the development of powerful methods for the
−
•
followed by single-electron reduction of 7 (Epa(RSO2 /RSO2 )
≈ 0.46 V in acetonitrile,25 0.8 V in water,26 both vs SCE for
Received: May 6, 2021
Published: June 23, 2021
https://doi.org/10.1021/jacs.1c04722
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© 2021 American Chemical Society
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Scheme 1. Proposed Photocatalytic Cycle and Initial
Conditions
chemistry setting, all experiments were performed using a
commercial integrated photoreactor30 including numerous
examples at gram-scale. While isolation of the crude alkyl
sulfinates was possible (e.g., 18, 36, S13), a one-pot procedure
to convert the intermediate sulfinic acid into the corresponding
benzyl sulfone was employed to facilitate convenient isolation
and characterization of the C(sp3)−S products. We first
examined a range of cyclic hydrocarbons bearing electron-
withdrawing groups such as sulfones (13, 64% yield),
carboxylic acids (14, 65% yield), and ketones (15 and 16, 49
and 70% yield, 57% and 58% selectivity, respectively). In all
cases, excellent selectivity was observed for the more electron-
rich, sterically accessible positions.23 Consistent with the
hydridic nature of tertiary C(sp3)−H bonds, 17 and 18 were
generated in good yield (72% and 57%, respectively) and
excellent tertiary selectivity despite the presence of weak (but
electron-poor) α-cyano31 and heterobenzylic32 C(sp3)−H
bonds.
We next turned our attention to medicinally relevant bicyclic
scaffolds. A tricyclic imide and brominated norbornane
derivative were sulfinylated at the most accessible, electron-
rich position as a single regioisomer in both cases (19 and 20,
86% and 62% yield, respectively). Heterobicyclic scaffolds also
proved to be effective substrates for this transformation, with a
bicylic amide affording the corresponding benzyl sulfone (21,
67% yield, 71% selectivity). This ability to efficiently and
selectively modify complex bicyclic scaffolds clearly illustrates
the benefits of C(sp3)−H functionalization-based approaches.
Figure 1. Development of a general C(sp3)−H sulfinylation.
related alkyl sulfinates) by 8 (E1/2red([W10O32]5−/[W10O32]6−)
= −1.48 V in acetonitrile,20a − 0.38 V in water,20b both vs
SCE) to afford the corresponding sulfinate (9). Under
sufficiently acidic conditions, subsequent protonation would
afford the sulfinic acid.27 An alternative radical chain
mechanism, in which sulfonyl radical 7 undergoes chain-
propagating HAT from 3 to afford the sulfinic acid product
and regenerate alkyl radical 4, appears unlikely based on
computed reaction barriers (ΔG‡calc > 22 kcal/mol, Table S9).
Our initial investigations began by irradiating a solution of
3,3-dimethylcyclohexanone (11) and sodium decatungstate
(NaDT, 10) in acetonitrile/water with PR160 40 W Kessil 390
nm lights in the presence of a range of convenient sulfur
dioxide surrogates. While commonly employed SO2 sources
such as DABSO28 and metabisulfite salts failed to generate the
corresponding sulfinic acid under a range of conditions, use of
inexpensive aqueous sulfur dioxide (“sulfurous acid,” 6 wt %
aq. SO2, $0.12/mmol)29 afforded the desired product (12) in
67% yield (Table S1). Importantly, control experiments
indicated that both decatungstate and light are required for
reactivity (Table S4).
With optimized conditions in hand, we sought to evaluate
the scope of this new C(sp3)−S bond-forming reaction (Table
1). To ensure uniformity and applicability within a medicinal
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a
Table 1. Scope of C(sp)3−H Sulfinylation
a
All yields are isolated. Performed with substrate (1.0 equiv, 0.5 mmol), SO2 (2.0−4.0 equiv, 6 wt % aq.), and NaDT (1 mol %) in acetonitrile/
water, irradiating for 4−8 h with 365 nm LEDs followed by addition of NaHCO3 (1.5−2.0 equiv), EtOH (1 mL), and BnBr (1.2−1.5 equiv),
b
c
d
1
stirring at room temperature for 16 h. See SI for complete experimental details. Yield of crude sodium sulfinate by H NMR. 11:1 dr. 5:1 dr.
3.9:1 dr (major), > 20:1 dr (minor). 1:1 dr. >20:1 dr. 5 mol % NaDT.
e
f
g
h
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a
Table 2. Sulfinylation of Natural Product and Pharmaceutical Substrates and One-Pot Diversification of Alkyl Sulfinates
a
b
c
d
e
f
g
All yields are isolated. See SI for complete experimental details. >20:1 dr. 6.0:1 dr. 6.5:1 dr. 9.1:1 dr. 5.0:1 dr. 11:1 dr.
Given the acidic nature of the aqueous SO2 employed under
complete regioselectivity (23 and 24, 66% and 60% yield,
our optimized conditions, we hypothesized that adding an
additional equivalent of this reagent should enable direct
functionalization of unprotected amines. Protonation of
amines renders the adjacent C(sp3)−H bonds both stronger
and less hydridic, enabling selective abstraction of distal C−H
bonds.15a,33 Thus, pyrrolidine was sulfinylated under our
standard conditions to afford the expected β−benzyl sulfone as
a single regioisomer (22, 50% yield). Excellent selectivity was
observed in the case of amines bearing tertiary C(sp3)−H
bonds, with 4-methylpiperidine and isobutylamine affording
the corresponding C(sp3)−S products in good yields and
respectively). By further increasing the amount of aqueous
SO2, trans-1,2-cyclohexanediamine was selectively function-
alized at the position furthest from the amines (25, 55% yield,
single regioisomer). Bicyclic amines were also effective
substrates for this transformation, with nortropanone and a
[2.2.1] bicycle functionalized at the most sterically accessible,
electron-rich positions (26 and 27, 33% and 54% yield,
respectively, single regioisomer and 74% selectivity, respec-
tively).
Finally, this reaction was applied to an electronically diverse
range of benzylic substrates. While the relatively low benzylic
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C−H bond dissociation energies render the initial HAT step
facile, the stability of the resultant radical led us to initially
question the favorability of its reaction with sulfur dioxide.
Gratifyingly, toluene derivatives were highly effective in this
transformation, producing the expected benzylic sulfinic acids
in good yields across a broad range of aryl functionality (28−
33, 67−82% yield), including ortho substitution (33, 81%
yield). Despite greater stabilization of the resultant radical,
secondary benzylic substrates also performed well in this
transformation (34 and 35, 74% and 46% yield, respectively).
Notably, many of these benzylic substrates contain protic
functional groups, such as sulfonamides (30), amides (32 and
33), and boronic acids (35), which prove problematic for
traditional approaches requiring a strong base or organo-
metallic nucleophiles.34 Further investigation revealed that
heterobenzylic substrates were also effective in this reaction,
with selectivity observed for functionalization at the (hetero)-
benzylic C−H bonds (36 and 37, 58% and 56% yield,
respectively).
Scheme 2. Computational Study of Radical Addition to SO2
To demonstrate the utility of this methodology for late-stage
functionalization, natural products and pharmaceuticals were
converted to the corresponding sulfinates in a single step
(Table 2). Notably, natural amino acids leucine and GABA
afforded the corresponding benzyl sulfones in synthetically
useful yields and excellent selectivity (38 and 39, 58% and 24%
yield, respectively, 91% selective and single regioisomer,
respectively). The monoterpenoid fenchone was functionalized
with good selectivity for the most electron-rich, sterically
accessible C−H bond (40, 56% yield, 63% selectivity), and
pregabalin was converted to the corresponding benzyl sulfone
with excellent regioselectivity for the tertiary position (41, 54%
yield, 85% selectivity). Finally, two drugs bearing benzylic C−
H bonds, celecoxib and prilocaine, were derivatized with
complete selectivity observed for functionalization at the
benzylic position (42 and 43, 70% and 73% yield,
respectively).
As an illustration of the broad utility of this platform for the
synthesis of diverse organosulfur compounds, a range of one-
pot procedures for the divergent functionalization of tricyclic
imide 44 were developed. As shown in Table 2, the sulfinic
acid intermediate was successfully converted to a range of alkyl
sulfone derivatives (45−47, 56−93% yield). Introduction of
heteroatoms also proved facile, with the corresponding sulfonic
acid (48, 82% yield), primary sulfonamide (49, 65% yield),
sulfonyl fluoride (50, 66% yield), and sulfonyl chloride (51,
57% yield) all generated with good efficiency. Additionally,
two-pot protocols were developed for the conversion of
celecoxib to a diverse range of sulfonamides via the
intermediacy of a sulfonyl chloride, generated via chlorination
of the C−H sulfinylation product without intermediate
purification. Alkyl amines (52 and 53, 62% and 53% yield,
respectively), anilines (54, 56% yield), and N-heterocycles (55,
31% yield) all reacted to afford the desired sulfonamide
products.
continuous increase in energy, possibly indicating a barrierless
process (Figure S7). In order to further investigate the nature
of the C−S bond-forming step, we calculated the transition
state energies for the addition of a series of stabilized radicals
(e.g., benzylic) into SO2 in the gas phase, conditions under
which sulfonyl radical formation is predicted to be markedly
less favorable than in the presence of polar solvent.
Remarkably, however, low barriers to radical capture with
SO2 were determined (7.5 and 6.8 kcal/mol for primary and
secondary benzylic, respectively), consistent with the observed
efficiencies in experiments involving aliphatic radicals and
sulfur dioxide.
In summary, we have developed a perfectly atom-
economical protocol for the photocatalytic conversion of
C(sp3)−H bonds into the corresponding alkyl sulfinic acids,
thereby enabling unprecedented access to a broad array of
valuable organosulfur products. Furthermore, these studies
clearly illustrate the importance of sulfur dioxide as an efficient
reagent for the formation of C−S bonds from a diverse range
of aliphatic radicals and, as such, should inform the
development of related transformations that proceed via this
key elementary step.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04722.
Experimental and characterization data, UV/vis and
computational studies, and spectral data (PDF)
As a preliminary investigation into the mechanism of this
transformation, we computationally studied the coupling of a
range of alkyl radicals with sulfur dioxide (Scheme 2). Notably,
with aliphatic radicals, a significant negative free energy of
reaction was observed for this trapping in water ((U)-
ωB97XD/6-31+G(d,p), SMD solvent model). Moreover,
efforts to identify a transition state in the case of unstabilized
aliphatic radicals proved unsuccessful, with stretching of the
C−S bond of the sulfonyl radical product resulting in a
AUTHOR INFORMATION
■
Corresponding Author
David W. C. MacMillan − Merck Center for Catalysis at
Princeton University, Princeton, New Jersey 08544, United
States; orcid.org/0000-0001-6447-0587;
Email: dmacmill@princeton.edu
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Authors
Patrick J. Sarver − Merck Center for Catalysis at Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0001-7227-8966
Noah B. Bissonnette − Merck Center for Catalysis at
Princeton University, Princeton, New Jersey 08544, United
States; orcid.org/0000-0001-6892-5040
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04722
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support provided by the
National Institute of General Medical Sciences (NIGMS), the
NIH (under Award R35GM134897-01), the Princeton
Catalysis Initiative, and kind gifts from Merck, Janssen, BMS,
Genentech, Celgene, and Pfizer. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of NIGMS. P.J.S. thanks Bristol-Myers Squibb
for a graduate fellowship.
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