Ru/Ni Dual Catalytic Desulfinative Photoredox Csp2-C sp3Cross-Coupling of Alkyl Sulfinate Salts and Aryl Halides

Article abstract of DOI:10.1021/acs.orglett.7b03280

A mild Ru/Ni dual catalytic desulfinative photoredox C_sp²-C_sp³ cross-coupling reaction of alkyl sulfinate salts with aryl halides has been developed. The optimized catalyst system, consisting of Ru(bpy)₃Cl₂, Ni(COD)₂, and DBU, smoothly mediates the coupling of a diverse set of secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl groups on pharmaceutical intermediates, and the C_sp²-C_sp³ cross-coupling reaction allowed the rapid synthesis of caseine kinase 1 inhibitor analogues via a parallel medicinal chemistry effort.

Full text of DOI:10.1021/acs.orglett.7b03280

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
2
3
Ru/Ni Dual Catalytic Desulfinative Photoredox Csp −Csp
Cross‑Coupling of Alkyl Sulfinate Salts and Aryl Halides
Thomas Knauber,*,† Ramalakshmi Chandrasekaran,† Joseph W. Tucker,† Jinshan Michael Chen,†
Matthew Reese,† Danica A. Rankic,† Neal Sach,‡ and Christopher Helal†
†Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States
‡Pfizer Worldwide Research and Development, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: A mild Ru/Ni dual catalytic desulfinative
2
3
photoredox Csp −Csp cross-coupling reaction of alkyl sulfinate
salts with aryl halides has been developed. The optimized
catalyst system, consisting of Ru(bpy)3Cl2, Ni(COD)2, and
DBU, smoothly mediates the coupling of a diverse set of
secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl
iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl
2
3
groups on pharmaceutical intermediates, and the Csp −Csp cross-coupling reaction allowed the rapid synthesis of caseine kinase
1δ inhibitor analogues via a parallel medicinal chemistry effort.
n increased fraction of Csp centers (Fsp )has been correlated
Awith the probability of human pharmaceutical agents
advancing through clinical development.1 Consequently, there
is a high interest in drug discovery in the development of broadly
applicable, robust, and concise procedures that allow the selective
tions,11 etherifications,12 thioetherificiations,13 and amination
reactions14 have been developed.
3
3
Inspired by the groundbreaking contributions, we engaged in
enabling photoredox technologies for applications in PMC. We
became particularly interested in metallaphotoredox reactions
that utilize alkyl radical precursors with low redox potentials
(E1/2ox < 1.00 V vs Ag/AgCl) and straightforward syntheses from
substrates that are already extensively used in drug discovery.
Alkyl sulfinate salts are diversely used in drug discovery, and
traditionally their nucleophilic reactivity is most frequently
exploited for the synthesis of pharmaceutically privileged
structural motifs such as sulfonamides, sulfones, and sulfonyl
fluorides (Scheme 1, top).15 In addition, Baran’s pioneering work
on desulfinative Minisci-type reactions demonstrated that alkyl
radical intermediates are efficiently generated by oxidizing alkyl
sulfinate salts with organic peroxides or electrochemically
(Scheme 1, middle) under reaction conditions that are
2
3
formation of Csp −Csp bonds from readily available, stable
starting materials. Also, the procedures should be amendable to
applications in parallel medicinal chemistry (PMC) for the rapid
preparation of chemical libraries which are a vital tool to explore
structure−activity relationships efficiently.
Remarkable progress has been achieved in recent decades in
Ni-catalyzed Csp −Csp cross-coupling reactions.2 In particular,
merging Ni-catalyzed cross-coupling methods with photoredox
chemistry (metallaphotoredox)3 has introduced a powerful tool
for the selective construction of aryl−alkyl bonds, and diverse sets
of broadly available starting materials have been introduced as
alkyl radical precursors.4 The MacMillan and Doyle groups
spearheaded the development of Ir/Ni dual catalytic decarbox-
ylative metallaphotoredox reactions that utilize α-amino acids, α-
alkoxy carboxylic acids, and monoalkyl oxalates as radical
2
3
Scheme 1. Applications of Alkyl Sulfinate Salts in Medicinal
Chemistry
5
2
sources while the Molander group enabled photoredox Csp −
Csp cross-coupling reactions with potassium alkyl trifluorobo-
rates as radical precursors. The Csp −H bonds in the α-position
3
6
3
of tertiary amines and alkyl ethers have been selectively oxidized
under metallaphotoredox conditions, and the resulting radical
intermediates were subsequently cross-coupled with aryl
halides.7 The formation of transient silyl radical intermediates
allowed the development of a visible light-mediated cross-
electrophile coupling of alkyl bromides and aryl bromides.8
2
3
Particularly mild Ru/Ni-catalyzed photoredox Csp −Csp cou-
pling reactions have been achieved by the Molander and
Fensterbank groups by using ammonium catechol alkyl silicates9
which possess very low redox potentials as sources of alkyl
Received: October 20, 2017
radicals.10 In addition, photoredox Csp −Csp coupling reac-
3
3
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
significantly milder than required for the conversion of the
corresponding aliphatic carboxylic acids.16 Furthermore, sulfi-
nate salts have been used in transition-metal-catalyzed
trifluoromethylation reactions17 and in desulfinative biaryl
syntheses.18 In addition to their chemical properties, alkyl
sulfinate salts are bench-stable, nonvolatile solids which make
them easy to handle. Consequently, a broad range of operation-
ally simple protocols have been introduced to prepare alkyl
sulfinate salts from readily available precursors,19 and a diverse set
is meanwhile commercially available.
expected, only traces (<5%) of the product were detected with
photocatalysts having less oxidizing excited states, e.g., Ir(ppy)3
[E1/2red (IrIII*/IrII) = 0.36 V vs Ag/AgCl].
Encouraged, we set out to develop a catalyst system for a Ru/
Ni dual catalytic desulfinative metallaphotoredox reaction. We
chose sodium 4-tetrahydropyran sulfinate (2a) as a radical source
and 3-bromo quinoline (1a) as a pharmaceutically relevant N-
containing heterocycle. We sought to identify reaction conditions
by high-throughput experimentation (HTE). A set of 96 test
reactions were prepared in a N-filled glovebox, and each reaction
was run on 2 μmol scale and 0.02 M concentration using 20 mol
% of Ni(COD)2 and 5 mol % of Ru(bpy)3Cl2 (H2O)6. We chose
tert-amyl alcohol as solvent to solubilize 2a sufficiently, and we
expected the steric bulk of the alcohol to minimize the formation
of undesired 3-(tert-pentyloxy)quinoline.12 A set of 58 ligands
(25 mol %) and 38 bases (3.0 equiv) were investigated. 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) was used as a base in the
ligand screen, and 4,4′-di-tert-butyl-2,2′-bipyridine (dtbbpy) was
used as ligand in the base screen. The reaction vials were placed in
a 96-well plate, irradiated from the bottom with blue LEDlightfor
18 h at 25 °C, and the conversions were determined by UPLC.
The best result was obtained with a combination of 1,1,6,6-
tetramethylheptane-2,5-dione (TMHD) as ligand and DBU base.
The reaction conditions identified in the HTE screen worked
well outside of a glovebox on preparative scale (250 μmol and c =
0.5 M), and we isolated the desired product 3aa in 60% yield
(Table 1, entry 1) along with a Minisci-type side product 4 and
Herein we report the development of the first Ru/Ni dual
2
3
catalytic desulfinative metallaphotoredox Csp −Csp coupling
reaction of alkyl sulfinate salts and aryl halides and the application
of the procedure in PMC (Scheme 1, bottom). Initially, we
hypothesized that alkyl sulfinate salts could serve as radical
precursors in metallaphotoredox reactions. We envisaged a
catalytic cycle that relies on the generation of an alkyl radical
intermediate by single-electron oxidation of the sulfinate salt by
the excited triplet-state photocatalyst [PCn]* followed by
extrusion of SO2. The subsequently generated alkyl radical
species can intercept a Ni-catalyzed cycle following the
mechanism proposed by the groups of Molander and
Kozlowski.20
We started our investigation with inspiration by studies of the
Nicewicz group,21 and we decided to measure the half-potentials
E1/2ox of a set of alkyl sodium sulfinate salts by cyclic voltammetry
to select photocatalysts with matching redox potentials. The
cyclic voltammograms [c = 0.05 M, Et4NBF4 (0.10 M), scan rate:
90 mV/s] were acquired in aqueous solution at a glassy carbon
working electrode and Pt wire auxiliary electrode. The potentials
are reported relative to the Ag/AgCl reference electrode. The
selected sulfinates were surprisingly easy to oxidize, and the
measured oxidative half-potentials were E1/2ox (tBuCH2SO2Na)
= 0.58 V, E1/2ox (sodium 4-tetrahydropyran sulfinate) = 0.64 V,
and E1/2ox (tBuSO2Na) = 0.63 V, which are slightly lower than the
half-potentials of ammonium catechol silicates [E1/2ox = 0.83 V vs
Ag/AgCl for tetramethylammonium allyl bis(catecholo) silicate
in the presence of an equimolar amount of piperidine]22 and
significantly lower than the oxidative potentials of alkyl carboxylic
acids [E1/2ox (Cesium N-boc-prolinate) = 0.99 V vs Ag/AgCl]23
Table 1. Optimization of the Photoredox Ru/Ni Dual
Catalytic Desulfinative Cross-Coupling
a
entry
deviation from HTE conditions
HTE conditions
3aa [%] 4 [%]
b
1
60
0
<5
<5
0
2
3
4
5
6
7
no Ni(COD)2
no Ru(bpy)3Cl2·(H2O)6
no light or DBU
0
0
0
ox
and alkyl potassium trifluoroborates [E1/2 (potassium
no TMHD
41
13
39
50
43
71
84
10
10
12
0
cyclohexyltrifluoroborate) = 1.53 V vs Ag/AgCl].24 The half-
potentials of the tested sulfinate salts align perfectly with the
redox potential of Ru(bpy)3Cl2 [E1/2red (RuII*/RuI) = 0.82 V vs
Ag/AgCl electrode] which we used in the subsequent studies.
For the next step, we chose a photoredox conjugate addition
reaction25 to test our hypothesized radical generation via
photoredox catalysis. N-Cbz protected sodium 4-piperidinyl
sulfinate was selected as a radical precursor, and a solution in
methanol was irradiated with blue light in the presence of 8 mol %
of Ru(bpy)3Cl2·(H2O)6 (Scheme 2). An excess of methyl acrylate
was used to trap radical intermediates efficiently. The sulfinate
salt was fully consumed, and the desired product was isolated in
64% yield along with 19% of the proto-desulfinylated N-Cbz-
piperidine. Control experiments confirmed that the reaction can
be catalyzed by the more oxidizing Ir[dF(CF3)ppy]2(bpy)PF6 or
Ir[dF(CF3)ppy]2(dtbbpy)PF6 in comparable efficiency. As
dtbbpy as ligand
NiCl2·glyme as precatalyst
(tmeda)Ni(o-tolyl)Cl instead of Ni(COD)2
DMF as solvent
c
8
d
9
0
d
10
2a (3 equiv), DMF as solvent
2a (3 equiv), DMF as solvent, air
0
d
11
0
a
Reactions were performed on 0.25 mmol scale using anhydrous
b
conditions. Isolated yields are reported. Traces of 3-(tert-pentyloxy)-
quinoline detected. 20 mol %; tmeda: N,N,N′,N′-tetramethyl
ethylenediamine. 1 mol % Ru(bpy)3Cl2·(H2O)6.
c
d
<5% of 3-(tert-pentyloxy)quinoline. A series of control experi-
ments demonstrated that irradiation with blue LED light, the Ru-
photocatalyst, the Ni-catalyst, and DBU are essential for the
desulfinative coupling (Table 1, entries 2−4). We rationalize the
observation with DBU acting as an auxiliary ligand, which
prevents the formation of catalytically inactive sulfinate-Ni-
complexes (Table 1, entry 4).26 The presence of the weakly
coordinating ligand TMHD proved to be beneficial, and the
yields of 3aa diminished to 41% in absence of the ligand (Table 1,
entry 5). The use of 20 mol % of Ni(COD)2 proved to be optimal,
and lower catalyst loadings (5 mol %) resulted in a diminished
Scheme 2. Photoredox Desulfinative Conjugate Addition
B
DOI: 10.1021/acs.orglett.7b03280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield of 44%. Using NiCl2·glyme as a precatalyst led to a drop in
yield to 39% (Table 1, entry 7). The addition of 1,5-
cyclooctadiene as a stabilizing ligand for potential Ni0-
intermediates had no influence on the reaction outcome, and
3aa was obtained in 38% yield.27 Air-sensitive Ni(COD)2 can be
replaced with air-stable (tmeda)Ni(o-tolyl)Cl precatalyst, and
the desired product 3aa was obtained in 50% yield (Table 1 entry
8). The formation of 3aa was not observed when Ru(bpy)3Cl2
was replaced with substoichiometric (10 mol %)27 or excess
amounts (5.0 equiv) of tert-butyl hydrogen peroxide as a chemical
oxidant, and the starting materials were recovered along with
traces of 3,3′-biquinoline. The control experiments support our
mechanistic hypothesis and render a Ni-catalyzed desulfinative
radical chain reaction unlikely. The formation of the side
products 4 and 3-(tert-pentyloxy)quinoline was efficiently
suppressed by lowering the Ru-photocatalyst loading to 1 mol
% and using DMF as solvent (Table 1, entry 9). An improvement
in yield was obtained with 3 equiv of the sodium sulfinate 2a, and
the product 3aa was isolated in 71% yield (Table 1, entry 10).
Using a larger excess of 2a did not improve the yield further. The
presence of air in the headspace of the reaction vial resulted in
another yield enhancement, which is in accordance to the
mechanistic studies of Oderinde et al.28 and allowed us to add
Ni(COD)2 to the reaction vessels under air. As a result of these
optimization efforts, 3aa was isolated in 84% yield (Table 1, entry
11).
Scheme 4. Scope of the Desulfinative Cross-Coupling with
Regard to Sodium Alkyl Sulfinates
a
Reactions were performed on 0.25 mmol scale using anhydrous
conditions unless otherwise reported. Isolated yields are reported.
salts 2b−h were successfully cross-coupled with 4-bromo
benzonitrile (1b) (Scheme 4).
Secondary sulfinates (2b−2f), the benzylic sulfinate 2g (71%),
and even primary sodium n-butane-1-sulfinate (2h) were
smoothly converted. Steric bulk proved to be detrimental, and
consequently traces of the desired product were detected with
sodium neopentyl sulfinate (<5%); no product was detected with
sodium tert-butane sulfinate (0%). Noteworthy, the azetidine
sulfinate 2c was well converted, but the separation of the desired
product 3bc from a small amount of nonconverted 1b was
surprisingly challenging, and 3bc was obtained in 30% yield.
Encouraged by the scope of the desulfinative photoredox
coupling, we investigated the transfer of the new method into a
reliable PMC protocol. We chose compound 4 as the
pharmaceutically relevant test substrate, as it serves as an
advanced intermediate for the synthesis of selective ATP-
competitive inhibitors of casein kinase 1δ, which is associated
with the regulation of the circadian rhythm.31 A stock solution of
the aryl bromide 4 and the catalyst system was prepared and
added to the reaction vials containing a set of 8 diverse sodium
alkyl sulfinates 5a−h (Scheme 5). The reactions (0.1 mmol scale)
With optimized reaction conditions in hand, we set out to
explore the scope of the desulfinative metallaphotoredox reaction
with regard to aryl halides (1a−p) (Scheme 3). Electron-deficient
Scheme 3. Scope of the Aryl and Heteroaryl Halides in Ru/Ni-
Catalyzed Desulfinative Cross-Coupling
Scheme 5. Preparation of Caseine Kinase 1δ Inihibitor
Analogues Using the Desulfinative Coupling in PMC
a
Reactions were performed on 0.25 mmol scale using aryl or
heteroaryl cross-coupling partners (X = Br) and anhydrous conditions
b
unless otherwise reported. Isolated yields are reported. Aryl iodide (X
= I) was used in place of aryl bromide.
aryl bromides (1b−f) and electron-neutral aryl iodides (1g−j)
were successfully coupled with 2a. Many pharmaceutically
important N-containing heterocycles, including pyridines (1m
and 1n), isoquinoline (1k), indole (1l), pyrimidine (1o), and
pyrazole (1p), were successfully converted, which are often
challenging in cross-coupling reactions because of coordination
of the basic N-atoms to the Ni-catalyst.29
Next, we attempted scaling up the reaction to 1 mmol, but
compound 3ba was isolated in 1% yield. The development of
elegant flow processes allowed the scaleup of photoredox
chemistry,30 but the development of such a protocol is beyond
the scope of this letter.
a
Reactions were performed on 0.1 mmol scale and anhydrous
conditions unless otherwise reported. Isolated yields from preparative
UPLC are reported.
were irradiated in parallel with visible blue light and purified by
semipreparative UPLC. The test library was highly successful,
and all the desired products 6a−h could be obtained in sufficient
amounts and high purity. Even 6h was isolated from the coupling
of sodium neopentyl sulfinate 5h.
In conclusion, alkyl sulfinate salts which are frequently used in
medicinal chemistry for the generation of sulfonamide and
sulfone analogue libraries have been introduced as versatile, easy-
to-handle, and mild radical precursors in desulfinative Ru/Ni dual
Our attention then turned toward the scope of the sodium alkyl
sulfinates, and we selected a diverse set of commercially available
sulfinate salts (2b−h) as test substrates. The selected sulfinate
2
3
catalytic metallaphotoredox Csp −Csp coupling reactions. Initial
C
DOI: 10.1021/acs.orglett.7b03280
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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potentials of the substrate class and led to the development of a
mild catalyst system that uses inexpensive Ru(bpy)3Cl2 as a
photocatalyst. The optimized reaction conditions allow the
smooth coupling of a broad range of nonstabilized secondary and
primary sodium sulfinate salts with electron-rich aryl iodides,
electron-deficient aryl bromides, and pharmaceutically important
heteroaryl halides. The desulfinative metallaphotoredox reaction
marks an efficient strategy to functionalize advanced pharma-
ceutical intermediates in parallel as the rapid generation of casein
kinase 1δ inhibitors analogues.
́
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03280.
(13) (a) Oderinde, M. S.; Frenette, M.; Robbins, D. W.; Aquila, B.;
Johannes, J. W. J. Am. Chem. Soc. 2016, 138, 1760. (b) Jouffroy, M.; Kelly,
C. B.; Molander, G. A. Org. Lett. 2016, 18, 876.
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B.; Tentarelli, S.; Robbins, D. W.; Johannes, J. W. Angew. Chem., Int. Ed.
2016, 55, 13219. (b) Corcoran, E. B.; Pirnot, M. T.; Lin, S.; Dreher, S. D.;
DiRocco, D. A.; Davies, I. W.; Buchwald, S. L.; MacMillan, D. W. C.
Science 2016, 353, 279.
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Int. Ed. 2014, 53, 9430.
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Experimental procedures, characterizations, H and 13C
NMR spectra (PDF)
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thomas.knauber@pfizer.com.
ORCID
(17) (a) Li, Y.; Wu, L.; Neumann, H.; Beller, M. Chem. Commun. 2013,
49, 2628. (b) Li, Z.; Cui, Z.; Liu, Z.-Q. Org. Lett. 2013, 15, 406. (c) Ye, Y.;
Thomas Knauber: 0000-0002-3354-3322
Danica A. Rankic: 0000-0002-7326-8900
Christopher Helal: 0000-0002-9091-2091
Kunzi, S. A.; Sanford, M. S. Org. Lett. 2012, 14, 4979.
̈
(18) (a) Markovic, T.; Rocke, B. N.; Blakemore, D. C.; Mascitti, V.;
Willis, M. C. Chem. Sci. 2017, 8, 4437. (b) Sev
- Eur. J. 2013, 19, 2256.
́
igny, S.; Forgione, P. Chem.
Notes
The authors declare no competing financial interest.
(19) (a) Lenstra, D. C.; Vedovato, V.; Flegeau, E. F.; Maydom, J.; Willis,
M. C. Org. Lett. 2016, 18, 2086. (b) Shavnya, A.; Coffey, S. B.; Hesp, K.
D.; Ross, S. C.; Tsai, A. S. Org. Lett. 2016, 18, 5848. (c) Davies, A. T.;
Curto, J. M.; Bagley, S. W.; Willis, M. C. Chem. Sci. 2017, 8, 1233.
(d) Gianatassio, R.; Kawamura, S.; Eprile, C. L.; Foo, K.; Ge, J.; Burns, A.
C.; Collins, M. R.; Baran, P. S. Angew. Chem., Int. Ed. 2014, 53, 9851.
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ACKNOWLEDGMENTS
■
We thank Lara Czabaniuk (Amgen Inc.) for support and Dr.
Kevin Hesp (Pfizer Inc.), Dr. Hatice Yayla (Pfizer Inc.), Dr.
Martins Oderinde (Pfizer Inc.), and Dr. Anabella Villalobos
(Biogen Inc.) for fruitful discussions.
(21) Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Synlett 2016, 27, 714.
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DOI: 10.1021/acs.orglett.7b03280
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