Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols with Aryl and Heteroaryl Iodides via Thiyl Radicals

Article abstract of DOI:10.1021/jacs.5b11244

Ni-catalyzed cross-couplings of aryl, benzyl, and alkyl thiols with aryl and heteroaryl iodides were accomplished in the presence of an Ir-photoredox catalyst. Highly chemoselective C-S cross-coupling was achieved versus competitive C-O and C-N cross-couplings. This C-S cross-coupling method exhibits remarkable functional group tolerance, and the reactions can be carried out in the presence of molecular oxygen. Mechanistic investigations indicated that the reaction proceeded through transient Ni(I)-species and thiyl radicals. Distinct from nickel-catalyzed cross-coupling reactions involving carbon-centered radicals, control experiments and spectroscopic studies suggest that this C-S cross-coupling reaction does not involve a Ni(0)-species.

Full text of DOI:10.1021/jacs.5b11244

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Communication
Photoredox Mediated Nickel Catalyzed Cross-Coupling of
Thiols With Aryl and Heteroaryl Iodides Via Thiyl Radicals
Martins Sunday Oderinde, Mathieu Frenette, Daniel W. Robbins, Brian Aquila, and Jeffrey W. Johannes
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11244 • Publication Date (Web): 21 Jan 2016
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Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols
With Aryl and Heteroaryl Iodides Via Thiyl Radicals
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Martins S. Oderinde,*† Mathieu Frenette,‡ Daniel W. Robbins,† Brian Aquila,† Jeffrey W. Johannes*†
†Chemistry Department (Oncology), AstraZeneca Pharmaceuticals LP, 35 Gatehouse Drive, Waltham, Massachusetts 02451,
United States
‡Département de Chimie, Université du Québec à Montréal, Montreal, Quebec, Canada, H2X 2J6
Supporting Information Placeholder
Scheme 1. Metalꢀcatalyzed CꢀO and CꢀS crossꢀcouplings
ABSTRACT: Niꢀcatalyzed crossꢀcouplings of aryl, benzyl and
alkyl thiols with aryl and heteroaryl iodides were accomplished in
the presence of an Irꢀphotoredox catalyst. Highly chemoselective
CꢀS crossꢀcoupling was achieved versus competitive CꢀO and Cꢀ
N crossꢀcouplings. This CꢀS crossꢀcoupling method exhibits reꢀ
markable functional group tolerance and the reactions can be carꢀ
ried out in the presence of molecular oxygen. Mechanistic invesꢀ
tigations indicated that the reaction proceeded through transient
Ni(I)ꢀspecies and thiyl radicals. Distinct from nickelꢀcatalyzed
crossꢀcoupling reactions involving carbonꢀcentred radicals, conꢀ
trol experiments and spectroscopic studies suggest that this CꢀS
crossꢀcoupling reaction does not involve a Ni(0)ꢀspecies.
a. Conventional methods utilizing thiolates
strong
base
S
X
"Pd"/"Cu"/"Ni"
up to 200
R
R1
R1
R-SH
R-S
+
C
b. This work: New strategy utilizing thiyl radicals
X
S
Ir(III)
"Ni"
R1
R
R-SH
+
R-S
R1
Light
weak base, 23
C
c. MacMillan's C-O coupling enabled by Ir/Ni dual-catalysis
X
O
Ir(III)/Ni
R
R1
R1
R-OH
+
weak base, 23
C
Nature employs thiyl radicals in a broad range of enzymatic proꢀ
cesses including the deoxygenation of ribonucleotides.1 The ease
in formation of thiyl radicals from thiols and their exceptional
reactivity make them extremely attractive for efficient and useful
radical reactions in organic synthesis.2 Some notable synthetic
applications of thiyl radicals include addition to unsaturated sysꢀ
tems,3 thiolꢀene reactions,4 thiolꢀyne reactions,5 radical cyclization
reactions,6 reduction processes,7 additionꢀfragmentation reacꢀ
tions,8a and hydrogen atom abstraction processes.8b However,
engaging thiyl radicals in a transitionꢀmetal catalyzed crossꢀ
coupling reactions with aryl halides to construct CꢀS bonds reꢀ
mains an elusive reaction in organic chemistry.2
The high frequency of CꢀS bonds in drugꢀmolecules across
many disease types such as cancer, HIV, and Alzheimer’s disease
necessitates the continued development of CꢀS bondꢀforming
reactions.9 Transitionꢀmetal catalyzed CꢀS crossꢀcoupling reacꢀ
tions of thiols with aryl halides generally rely on the conversion of
the thiols to their corresponding thiolates (Scheme 1a).10,11 The
strong coordination of thiolates to transitionꢀmetal catalysts often
leads to catalyst deactivation, thus requiring high catalyst loading,
specially designed ligands and/or high temperature to facilitate the
desired reaction.10,11 Furthermore, the high temperature and strong
base required for these reactions limit functional group tolerance.
Strategically, we reasoned that the utilization of thiyl radiꢀ
cals,12a in lieu of thiolates may eliminate the problem of catalyst
deactivation and deliver a more efficient CꢀS crossꢀcoupling reacꢀ
tion with the use of simple ancillary ligands. We also envisioned
that employing thiyl radicals could provide a highly chemoselecꢀ
tive reaction that operates at room temperature with broad funcꢀ
tional group tolerance.
Light
access to elusive reactivity makes the dualꢀcatalytic platform very
attractive.13 We recently undertook a mechanistic investigation
into the effect of oxygen on the Ir/Ni dualꢀcatalytic reactions deꢀ
veloped by the laboratories of Molander, Doyle, and MacMillan
involving carbonꢀcentered radicals.13a,b,14 Our investigations of
these systems prompted us to consider whether the photoredox
mediated dualꢀcatalysis could be used as a tool to form thiyl radiꢀ
cals and promote their crossꢀcoupling with aryl halides to form
carbonꢀsulfur bonds (Scheme 1b). MacMillan and colleagues
recently demonstrated that the Ir/Ni dualꢀcatalytic platform can be
extended to carbonꢀheteroatom crossꢀcoupling by elegantly deꢀ
veloping a new CꢀO crossꢀcoupling method (Scheme 1c).13d
Herein, we demonstrate that photogenerated thiyl radicals
from various thiols can engage in Niꢀcatalyzed crossꢀcouplings
with aryl and heteroaryl iodides to afford CꢀS bonds in a highly
chemoselective fashion under an Ir/Ni dualꢀcatalytic system.
From the outset, a principle concern in the development of
such a crossꢀcoupling method was identifying conditions wherein
the thiyl radicals can react selectively with a Niꢀspecies. In addiꢀ
tion, unlike the Niꢀcatalyzed crossꢀcouplings involving carbonꢀ
centered radicals,13a,b,14 the oxidation state of Ni that would proꢀ
mote the crossꢀcoupling involving heteroatom radicals was unꢀ
known. With these challenges in mind, we evaluated a number of
potential Irꢀphotoredox and Ni catalysts under various conditions
in the crossꢀcoupling of 4ꢀmethoxybenzyl thiol (1a) (pKa = 15.4,
for benzyl thiol)15a and 4ꢀiodotoluene (2a). The irradiation of a
reaction mixture containing 4ꢀmethoxybenzyl thiol (1a), 4ꢀ
iodotoluene
(2a),
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(IrꢀB),
The combination of a photoredox catalytic cycle with an orꢀ
ganometallic cycle has emerged as a powerful tool for crossꢀ
coupling reactions.13 The ability of the photoredox catalyst to
modulate transitionꢀmetal oxidation states, which allows easy
NiCl2·glyme, dtbbpy (4,4’ꢀdiꢀtertꢀbutylꢀ2,2’ꢀdipyridyl) and pyriꢀ
dine (pKa = 5.2)16 in MeCN with blueꢀLEDs for 24 hours at room
temperature in the presence of O2 gave the CꢀS crossꢀcoupled
product 3a in excellent conversion (Table 1, entry 1).
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voltammetry (CV) of NiCl2·dtbbpy showed an irreversible two
Table 1. Irꢀphotoredox/Ni dualꢀcatalyzed CꢀS crossꢀcoupling:
Effect of reaction parameters
electron reduction peak (R1) corresponding to the NiII/Ni0 couple
at ꢀ1.34 V versus saturated calomel electrode (SCE) in MeCN
(Figure 1c). This reduction potential (R1) is similar to that reportꢀ
1
2
3
4
5
6
7
8
Ir-B (2 mol%),
NiCl2•glyme (10 mol%),
dtbbpy (15 mol%),
SH
S
I
red
ed for NiCl2·bpy (E1/2 [NiII/Ni0] = ꢀ1.36 V versus SCE in
+
pyridine (2 equiv.), MeCN,
34 W blue-LED, 24 h,
DMF),19 The quasiꢀreversible reduction peak observed at R2
(E1/2red = ꢀ1.88 V) can be ascribed to the Ni0/Ni0 couple.19 Since
the NiII/Ni0 couple reduction potentials of NiCl2·dtbbpy and
NiCl2·bpy complexes fall within the margin of error of the reducꢀ
tion potential of the reductant IrII (IrꢀB, E1/2red [IrIII/IrII] = ꢀ1.37 V
versus SCE in MeCN),20 it is difficult to accurately ascertain the
thermodynamic favorability/unfavorability of their reduction to
Ni(0)ꢀspecies. However, the fact that a reaction that does not proꢀ
O
O
1a
1.5 equiv.
2a
1.0 equiv.
3a
Not degassed
(Ir-B)
(Ir-A) Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(bpy)PF6
Entry
Variation from the standard conditionsa
Yield
(%)b
>95
NRc
NR
NR
<5d
<5
9
1
2
3
4
5
none
no light (dark)
no Ir(III)ꢀcatalyst
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12
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red
ceed with a Ni(0)ꢀspecies, proceeds with NiCl2·dppe (E1/2
no NiCl2•glyme and no dtbbpy
no pyridine
4ꢀbromotoluene instead of 4ꢀiodotoluene
IrꢀA instead of IrꢀB
[NiII/NiI] = ꢀ0.88 V and [NiI/Ni0] = ꢀ1.41 V versus SCE in
DMF/THF),21 which thermodynamically and kinetically should be
easily reduced to its Ni(I) oxidation state by IrII, supports that a
Ni(I)ꢀspecies is the active Niꢀspecies in this reaction. Therefore,
we hypothesize that the reduction of the Ni(II)ꢀcomplexes to their
corresponding Ni(I)ꢀspecies by IrII is thermodynamically and
kinetically facile.
6
7
30
8
9
26 W CFꢀlamp instead of 34 W blueꢀLEDs
IrꢀB with 34 W greenꢀLEDs
degassed
NR
NR
>95
>95
70
10
11
12
13
14
NiCl2•bpy instead of NiCl2•dtbbpy
NiCl2•dppe instead of NiCl2•dtbbpy
Ni(COD)2 instead of NiCl2•glyme
Ni(COD)2 and degassed
Finally, timeꢀresolved emission spectroscopy showed that the
excited state lifetime of 2.25 µs for *IrIII (the excited state of Irꢀ
B) as measured by its emission at 500 nm remains unchanged in
the presence of 0.2 M pyridine (see the supplementary inforꢀ
mation). From the steadyꢀstate emission quenching experiment, a
bimolecular rate constant of 7.6 x 105 Mꢀ1sꢀ1 was obtained for the
quenching reaction between *IrIII and 4ꢀmethoxybenzyl thiol
(1a). These experiments confirmed that the thiol (1a) quenches
the emission of *IrIII (Figure 1d) and the SternꢀVolmer analysis
gave an excellent linear regression (Figure 1d, inset).
<5
<5
aScale of reaction: 0.50 mmol of 4ꢀiodotoluene and 5 mL of 99.8%
MeCN (0.10 M). b%Conversion was determined by 1H NMR
c
spectroscopy with the aid of an internal standard. NR implies no
1
d
product was detected by H NMR spectroscopy. <5% implies trace
product was observed.
A series of control experiments established the importance of
light, Irꢀcatalyst, ligand, Niꢀcatalyst, and base on the reaction
yield (entries 1–5). Though the reaction did not proceed when an
aryl bromide was used in place of an aryl iodide (entry 6), the
chemoselectivity for aryl iodide over aryl bromide could be adꢀ
vantageous for orthogonal synthesis. In addition to the photoredox
catalyst IrꢀB, the Irꢀphotoredox catalyst Ir[dF(CF3)ppy]2(bpy)PF6
(IrꢀA) also mediated the reaction, albeit with lower efficiency
(entry 7). We found that the irradiation with blueꢀLEDs is essenꢀ
tial for the catalysis, as irradiation with either a white light (26 W
CFꢀlamp) or the greenꢀLEDs resulted in no reaction (entries 8 &
9). The crossꢀcoupling also proceeded efficiently in the absence of
O2 (entry 10). Regarding the competence of other simple bidenꢀ
tate ligands on Ni, the reaction proceeded with good efficiency
when either NiCl2·bpy (bpy = 2,2’ꢀbipyridine) or NiCl2·dppe
(dppe = 1,2ꢀbis(diphenylphosphino)ethane) precatalyst was used
(entries 11 & 12). Of significant mechanistic implication and
distinct from the Niꢀcatalyzed crossꢀcoupling reactions involving
carbonꢀcentered radicals,13a,b,14 this crossꢀcoupling reaction does
not proceed with Ni(0)ꢀprecatalyst, either in the presence or abꢀ
sence of O2 (entries 13 & 14). Instead, the dimerization of the
thiyl radicals to the corresponding disulfide was observed after 24
hours. The high efficiency of this CꢀS crossꢀcoupling reaction in
the presence of O2 could also be an indication that Ni(0)ꢀspecies is
not the active Niꢀspecies in this reaction.14 Ni(0)ꢀcomplexes are
generally incompatible with O2, and as a result, Ni(0)ꢀcatalyzed
reactions are generally carried out under anaerobic conditions.17
The generation of thiyl radicals from thiol (1a) in the presence
of the photoredox catalyst IrꢀB was experimentally supported by
trapping the thiyl radicals with olefin (4) and the thioether (5) was
obtained in good yield (Figure 1a).12 In addition, the use of 1,2ꢀ
bis(4ꢀmethoxybenzyl)disulfide (6) as the coupling partner with 4ꢀ
iodotoluene (2a) gave only trace CꢀS coupled product, which
implies that the reaction does not proceed through a disulfide
intermediate18 (Figure 1b).
Figure 1. (a) Trapping of the thiyl radicals with an olefin. (b)
Ruling out the involvement of disulfide. (c) The CV of
NiCl2·dtbbpy. (d) Steadyꢀstate emission quenching of *IrIII
with thiol (1a); (Inset) SternꢀVolmer analysis of the results
Trapping of the thiyl radicals with an olefin
a.
S
Ir-B (2 mol%),
SH
+
OH
34 W blue-LEDs, 24 h,
MeCN,
Not degassed
HO
O
5
4
1a
2.0 equiv.
O
1.0 equiv.
88% yield
Ruling out the involvement of disulfide
b.
S
Ir-B (2 mol%),
NiCl2•glyme (10 mol%),
dtbbpy (15 mol%),
I
S
2
+
pyridine (2 equiv.), MeCN,
34 W blue-LEDs, 24 h,
Not degassed
O
O
< 5% conversion
3a
6
2a
1.0 equiv.
1.5 equiv.
Based on these mechanistic data, a proposed mechanism for
the dualꢀcatalysis is depicted in Figure 2. Visibleꢀlight irradiation
of the heteroleptic IrIIIꢀphotocatalyst (IrꢀB) generates a longꢀlived
excited state *IrIII (2.25 µs). A single electron transfer (SET)
ox
oxidation of the thiol (E1/2 = +0.83 V versus SCE in MeCN for
red
benzyl thiol),12a,15 by the oxidizing photoexcited *IrIII (E1/2
[*IrIII/IrII] = +1.21 V versus SCE in MeCN),20 produces both the
In order to rationalize the dependence of this crossꢀcoupling
reaction on the oxidation state of the Niꢀprecatalyst, we carried
out electrochemical studies of NiCl2·dtbbpy in MeCN. The cyclic
thiol radical cation and IrII. The deprotonation of the highly
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Figure 2. Proposed mechanism for the CꢀS crossꢀcoupling
Table 2. Scope of aryl iodide coupling partner
1
2
3
4
5
6
7
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9
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acidic radical cation (pKa = 2.4 for benzyl thiol radical cation)15
by pyridine produces a thiyl radical (7). A SET reduction of the
NiCl2·dtbbpy (8) by IrII delivers a NiIꢀhalide (9). At this juncture,
a thiyl radical (7) rapidly intercepts the NiIꢀhalide (9) to form a
NiIIꢀspecies (10), which is reduced by IrII to a NiIꢀsulfide complex
(11) while concomitantly regenerating the IrIII. Oxidative addiꢀ
tion of an aryl iodide to the NiIꢀsulfide complex (11) delivers a
NiIIIꢀcomplex (12), which undergoes a facile reductive elimination
process18 to forge the CꢀS crossꢀcoupled product and reproduces a
NiIꢀhalide complex (9). We believe in addition to being the base,
pyridine also stabilizes the coordinatively unsaturated NiIꢀhalide
(9) and NiIꢀsulfide (11) complexes (see the supplementary inforꢀ
mation for the effects of other bases and more CV studies). The
preference for aryl iodide may be attributed to the inability of the
NiIꢀsulfide (11) to oxidatively add to the stronger aryl bromide
bond or the proclivity toward concerted oxidative addition.10d,22
With the optimized conditions in hand, we explored the scope
of this CꢀS crossꢀcoupling protocol. As envisioned, the scope of
the aryl iodide is very broad under these mild conditions (Table
2). A range of orthoꢀsubstituted aryl iodides bearing amino, methꢀ
oxy, fluoro and methyl groups engaged in the crossꢀcouplings to
forge CꢀS bonds in good yields (3bꢀ3e). However, ortho,orthoꢀ
dimethyliodobenzene failed to crossꢀcouple (3f), due to increased
steric hindrance. Aryl iodides containing functional groups for
orthogonal transformations such as organoboronate (3g), carboxꢀ
ylic acid (3h), primary amine (3i), aldehyde (3j), ketone (3k),
bromide (3l), nitrile (3m), and dimethyl (3n) all coupled with
complete chemoselectivity and high efficiencies to give products
in good to excellent yields. Heteroaromatic iodides, which are
common building blocks in the preparation of bioactive comꢀ
pounds, such as indole (3o), protected pyrazole (3p vs. 3q), pyriꢀ
dine (3r), pyrimidine (3s), and thiophene (3t), are all effective
electrophiles in this protocol.
In addition, we investigated a diverse set of thiols to further
highlight the versatility of this method (Table 3). We found that a
wide range of thiols are effective coupling partners including
thiophenols (13a and 13b), simple and functionalized alkyl thiols
(13c and 13d). Interestingly, NꢀBocꢀcysteine undergoes only the
CꢀS crossꢀcoupling reaction without any decarboxylative CꢀC
bond formation13b,14 to give 13e in good yield. Thiols bearing βꢀ
electronꢀdeficient groups are also competent substrates in this
transformation and they coupled with high efficiency (13f, 13g
and 13h). Notably, secondary and tertiary thiols also gave the
desired thioethers in good to moderate yields (13i, 13j and 13k).
To further demonstrate the high level of chemoselectivity
obtained under this catalytic system for CꢀS bond formation over
Table 3. Scope of thiol coupling partner
CꢀN and CꢀO bonds formation, we conducted a series of competiꢀ
tion experiments. Under our conditions, no crossꢀcoupling reacꢀ
tion occurred between either 4ꢀmethoxybenzyl alcohol and 4ꢀ
iodotoluene (2a) or 4ꢀmethoxybenzyl amine and 4ꢀiodotoluene
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Scheme 2. (a). Chemoselective CꢀS bond formation. (b) Priꢀ
mary and secondary thiols competition reaction
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(2a) (see supplementary information). Similarly, a reaction mixꢀ
ture containing a 1:1 ratio of 4ꢀmethoxybenzyl alcohol and 4ꢀ
methoxybenzyl thiol as competitive nucleophiles in the presence
of 4ꢀiodotoluene (2a) gave exclusively the CꢀS crossꢀcoupled
product with no CꢀO bond formation13d (Scheme 2a). Futhermore,
consistent with the effects of radical stability, a secondary thiol
(1j) gave twice as much crossꢀcoupled product (13i:13m = 2:1) in
a competition reaction with a primary thiol (1m) (Scheme 2b). It
is noteworthy that MacMillan’s CꢀO coupling method operates
under a unique set of conditions and different mechanism.13d
In conclusion, we have developed a mild, highly chemoselecꢀ
tive, and robust photoinduced Niꢀcatalyzed method for the crossꢀ
coupling of aryl, benzyl and alkyl thiols with a wide array of funcꢀ
tionalized aryl and heteroaryl iodides. To the best of our
knowledge, this study is the first method that allows thiyl radicals
or any heteroatom radical to engage in a transitionꢀmetal cataꢀ
lyzed crossꢀcoupling reactions with iodoarenes. The ability of the
catalytic system to operate with high efficiency in the presence of
molecular oxygen further enhances the practical utility of this
method. Control experiments and spectroscopic studies indicated
that this reaction does not involve a Ni(0)ꢀspecies but is catalyzed
by a transient Ni(I)ꢀspecies. With this method, we have expanded
on the utilities of thiyl radicals and developed a versatile CꢀS
crossꢀcoupling method that should find widespread application in
organic synthesis.
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ASSOCIATED CONTENT
Supporting Information
Additional experimental and electrochemical studies. Experiꢀ
mental procedures, characterization data and spectra for all new
compounds. This material is available free of charge via the Interꢀ
net at http://pubs.acs.org.
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Lett. 2013, 4, 2535.
AUTHOR INFORMATION
Corresponding Authors
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1954, 50, 918.
*Emails: martins.oderinde@astrazeneca.com;
jeffrey.johannes@astrazeneca.com
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(19). (a) Zhao, P. Luo, Y.ꢀW. Xue, T. Zhang, A.ꢀJ. Lu, J.ꢀX. Chin. J.
Chem. 2006, 24, 877.
We thank Professor Mohammad Movassaghi (MIT) for helpful
discussions and Ngoc Duc Trinh (UQAM) for help with electroꢀ
chemical measurements. M. S. Oderinde thanks AstraZeneca
(Oncology and Innovative Medicine) for the innovation and
achievement award. M. S. Oderinde also thanks the Natural
Sciences and Engineering Research Council of Canada (NSERC)
for a fellowship award.
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