A mild, one-pot Stadler-Ziegler synthesis of arylsulfides facilitated by photoredox catalysis in batch and continuous-flow

Article abstract of DOI:10.1002/anie.201303483

Visible advance: A mild, one-pot Stadler-Ziegler process for C-S bond formation has been developed. The method employs the photoredox catalyst [Ru(bpy)₃Cl₂]×6 H₂O irradiated with visible light. A variety of aryl-alkyl and diaryl sulfides were prepared from readily available arylamines and aryl/alkylthiols in good yields. The use of a photo microreactor led to a significant improvement with respect to safety and efficiency. Copyright

Full text of DOI:10.1002/anie.201303483

Angewandte
Chemie
Communications
Photoredox Catalysis
X. Wang,* G. D. Cuny,*
T. Noꢀl*
&&&& — &&&&
Visible advance: A mild, one-pot Stadler–
sulfides were prepared from readily
ꢀ
A Mild, One-Pot Stadler–Ziegler
Synthesis of Arylsulfides Facilitated by
Photoredox Catalysis in Batch and
Continuous-Flow
Ziegler process for C S bond formation
available arylamines and aryl/alkylthiols
in good yields. The use of a photo
microreactor led to a significant
improvement with respect to safety and
efficiency.
has been developed. The method
employs the photoredox catalyst [Ru-
(bpy)3Cl2]·6H2O irradiated with visible
light. A variety of aryl–alkyl and diaryl
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DOI: 10.1002/anie.201303483
Photoredox Catalysis
A Mild, One-Pot Stadler–Ziegler Synthesis of Arylsulfides Facilitated
by Photoredox Catalysis in Batch and Continuous-Flow**
Xiao Wang,* Gregory D. Cuny,* and Timothy Noꢀl*
Many aromatic molecules containing an aryl carbon–sulfur
bond display properties that afford them utility in a broad
array of fields, including pharmacology.[1–3] Transition metal-
catalyzed cross-coupling reactions are now among the most
[4]
ꢀ
important reaction classes for constructing aromatic C N
[5]
ꢀ
and C O bonds. However, the discovery of efficient
[6]
ꢀ
aromatic C S bond forming processes remains a challenge.
Several Pd-,[7a–c] Cu-,[7d,e] and Ni-catalyzed[7f] coupling reac-
tions of aryl halides (or boronic acids) and thiols have been
reported for generating arylsulfides (Scheme 1). Neverthe-
less, high reaction temperatures, the necessity of strong base,
as well as limited substrate scope and functional group
compatibility remain impediments of these approaches. In
addition, many of these methods also suffer from catalyst
poisoning by the sulfur-containing substrates and products.
ꢀ
A more traditional process to construct C S bonds is the
Stadler–Ziegler reaction,[8–10] in which arylamines are con-
verted to the corresponding diazonium salts and then allowed
to react with thiolates to yield arylsulfides. The broad scope
Scheme 1. Comparison of various methods for constructing aromatic
and efficiency of this reaction makes it attractive. In addition,
arylamines are usually more readily available and less
expensive than the corresponding arylhalides. Since the
pioneering work by Stadler[8] and later by Ziegler,[9] this
process has been applied extensively in industry for manu-
facturing arylsulfides.[11] Various modifications have also been
made to achieve improved yields and milder reaction
conditions.[12] However, these methods require multiple
steps including both preparation and isolation of the diazo-
ꢀ
C S bonds.
nium salts and preparation of the sodium thiolates prior to the
coupling step. More importantly, both the diazonium salts and
the subsequent intermediate diazosulfides are potentially
explosive, especially when heated.[13] Herein we report
a single-step, one-pot Stadler–Ziegler process facilitated by
photoredox catalysis for preparing a variety of aryl-alkyl and
diaryl sulfides at room temperature with minimum formation
of diazosulfides.
[*] Dr. X. Wang, Prof. Dr. G. D. Cuny
Harvard NeuroDiscovery Center, Harvard Medical School and
Brigham & Women’s Hospital
65 Landsdowne Street, Cambridge, MA 02139 (USA)
E-mail: xwang21@partners.org
To avoid the isolation of diazonium salts and to enhance
overall reaction efficiency, we envisioned combining the
diazotization and coupling steps in a one-pot protocol
(Scheme 1). Alkyl nitrites, which require only a catalytic
amount of organic acid to generate the reactive [NO]+
intermediate, were considered to replace sodium nitrite for
diazonium formation.[12d,14] For the sulfurous coupling frag-
ment, thiols would be used directly instead of thiolates.
We commenced our investigations by exploring the direct
Stadler–Ziegler reaction between 4-methoxythiophenol (1)
and aniline (2). Preliminary results revealed that in the
presence of amyl nitrite and a catalytic amount of p-
toluenesulfonic acid monohydrate, 2 could be converted to
the phenyldiazonium salt in situ. This compound readily
reacted with 1 in MeCN at room temperature either in the
presence or absence of light to afford disulfide 4 and
diazosulfide 5. Interestingly, only trace amounts of the desired
diarylsulfide 3 were detected (Table 1, entries 1 and 2).
However, in the presence of the photoredox catalyst [Ru-
(bpy)3Cl2]·6H2O and visible light,[15,16] 3 was the predominant
Prof. Dr. G. D. Cuny
Department of Pharmacological and Pharmaceutical Sciences,
College of Pharmacy, University of Houston
549 A Science and Research Bldg 2, Houston, TX 77204 (USA)
E-mail: gdcuny@central.uh.edu
Dr. T. Noꢀl
Department of Chemical Engineering and Chemistry, Micro Flow
Chemistry & Process Technology, Eindhoven University of Tech-
nology, Den Dolech 2, 5612 AZ Eindhoven (The Netherlands)
E-mail: t.noel@tue.nl
[**] X.W. and G.D.C. thank the Harvard NeuroDiscovery Center for
financial support. T.N. would like to acknowledge financial support
from the Dutch Science Foundation for a VENI grant. The kind
donation of [Ru(bpy)3Cl2]·6H2O by Furuya Metal Co., Ltd. is
appreciated by T.N. We are grateful to Prof. Dennis P. Curran for his
valuable suggestions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303483.
2
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Table 1: The effects of light, catalyst and nitrite source on product
distribution in the photocatalytic Stadler-Ziegler reaction.[17]
Entry[a] Light[b] SET[c]
catalyst
Loading Nitrite
(mol%)
3
4
5
[%] [%] [%]
p
1
2
3
–
–
–
–
1.0
amylONO
amylONO
amylONO 59 30
1
2
26 68
28 62
ꢁ
p
[Ru(bpy)3Cl2]
·6H2O
9
4
5
6
7
ꢁ
[Ru(bpy)3Cl2]
·6H2O
[Ru(bpy)3Cl2]
·6H2O
[Ru(phen)3Cl2] 1.0
·6H2O
Cu2O
1.0
1.0
amylONO 30 68
3
p
tBuONO 86 12
tBuONO 77 17
1
2
p
p
0.5
tBuONO 62 35 <1
[a] LC yields were recorded, with Ph2O as an internal standard. [b] 20 W
fluorescent light bulb was used. [c] SET=single electron transfer,
bpy=2,2’-bipyridine, phen=phenanthroline.
Scheme 2. Substrate scope of the photocatalytic Stadler–Ziegler pro-
product. For example, when the phenyldiazonium salt was
generated in situ in the presence of a household 20 W
fluorescent light source and 1 mol% [Ru(bpy)3Cl2]·6H2O, 3
was produced in 59% yield after only 1 h (Table 1, entry 3).
Furthermore, when this reaction was conducted in the
absence of light irradiation, 3 was only produced in negligible
amounts (Table 1, entry 4). Further optimization showed that
tert-butylnitrite (tBuONO) was a better nitrite source, leading
cess.
technology provides reduced safety hazards and high sur-
face-to-volume ratios.[19] The latter is particularly advanta-
geous for photochemical syntheses since it allows for a homo-
geneous irradiation of the reaction medium.[20,21] An opera-
tionally simple microfluidic setup was assembled as shown in
Figure 1 and the reagents were introduced through a single
syringe pump into a visible light transparent capillary micro-
reactor (464 mL, PFA tubing, 500 mm inner diameter), which
was irradiated with blue LEDꢀs. By separating tert-butylnitrite
from other reagents, the diazonium intermediates are solely
generated in the microreactor and are immediately consumed
during the course of the reaction.
The photocatalytic Stadler–Ziegler reaction between 4-
methoxythiophenol (1) and aniline (2) was conducted in
continuous flow under otherwise similar experimental con-
ditions as described for the batch experiments. The formation
of segmented gas–liquid flow served as an indication for the
loss of nitrogen from the diazonium intermediates and,
therefore, progress of the reaction was qualitatively moni-
tored (Figure 1c). The short length scale in the microreactor
provides increased photon flux. This results in a significant
acceleration of the direct Stadler–Ziegler reaction; full
conversion could be obtained within 15 s residence time
(Scheme 3). In total 13.2 mmol of 3a per hour can be
synthesized in continuous flow, which represents a 78-fold
improvement when compared to the corresponding batch
experiment. As can be seen from Scheme 3, all three reactions
could be completed within 15 s.
to an increased yield of
3 to 85% (entry 5). [Ru-
(phen)3Cl2]·6H2O also proved effective, affording 3 in 77%
yield (entry 6). However, copper(I) oxide, a commonly used
single electron transfer (SET) catalyst in the Sandmeyer and
related reactions, gave a lower yield of 3 (entry 7).
Once the optimal conditions were established, the sub-
strate scope of this transformation was explored (Scheme 2).
Reactions of coupling components with meta- and para-
substituents provided good to excellent yields of the arylsul-
fides. In these cases, the electronic property of the substitu-
ents had little impact on the product yields. Ortho-substituted
reactants generally led to slightly diminished yields (3d, g, h),
depending on the size of the substituent. Alkylthiols exhibited
similar reactivities as compared to arylthiols (3m, n). N-
heterocyclic reactants resulted in somewhat lower product
yields (3j, k, l). Notably, the compatibility of aryl halides in
this transformation makes it a suitable complement to the
existing Ullmann-type cross-coupling reactions (3e, f, g, h). In
the case where both OH and SH groups were presented, the
S-thiolation product (3b) predominated.
To further address the safety concerns associated with the
diazonium intermediates, a continuous-flow protocol was
developed.[18] Due to its small dimensions, microreactor
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cantly decreased amount of 4 and 5 observed under the
photoredox conditions (entry 3) may reflect a more efficient
SETroute over the SRN1/SRN2 processes. Initially, we surmised
that the [Ru(bpy)3Cl2]·6H2O catalyst facilitates the overall
transformation in favor of the desired sulfide product,
2+
through the oxidative quenching of *Ru(bpy)3 by either
the diazonium salt (Scheme 4, pathway A),[16b,23] the diazo-
sulfide (Scheme 4, pathway B), or the disulfide (Scheme 4,
pathway C).[24,25]
Figure 1. a) Schematic representation of the microfluidic setup used
for the continuous-flow synthesis of arylsulfides through a photocata-
lytic Stadler–Ziegler reaction. b) Picture of the capillary microreactor
irradiated with blue LED light. More details about the photomicror-
eactor assembly can be found in the Supporting Information. c) Seg-
mented gas–liquid flow at the outlet of the photo microreactor.
Scheme 4. Possible mechanisms for the photocatalytic Stadler–Ziegler
reaction.
To explore the mechanistic details, experiments in Table 1,
entries 3 and 4 were performed with quantification of differ-
ent species at multiple time points (Figure 2). Initially, the
reaction was protected from light, during which the amounts
of diazosulfide 5 and disulfide 4 accumulated and stabilized at
a maximum level after 1 h, with 5 as the predominant species.
After 1 h, the reaction was irradiated with light.[26] The sulfide
product 3 started to form rapidly, while 5 was consumed at
approximately the same rate. Monitoring the reaction
revealed that the maximum yield of 3 was approached at
Scheme 3. Formation of biarylsulfides through a photocatalytic
Stadler–Ziegler reaction in continuous-flow.
The traditional Stadler–Ziegler reaction is well known for
its complicated set of possible mechanisms.[12] Normally, it has
been proposed to proceed through a SRN1 chain mechanis-
m,[11a,12b,22] or in some cases, a SRN2 mechanism.[12c] In those
mechanisms, with loss of nitrogen, the diazosulfide can
generate the sulfide product using the sulfide radical anion
as a single electron transfer reagent (SRN1 and SRN2), and/or
a disulfide by radical dimerization (SRN2). In the absence of
photoredox catalyst (Table 1, entries 1 and 2), disulfide 4 was
observed along with the unconsumed diazosulfide 5, which
might indicate an inefficient SRN2 mechanism. The signifi-
Figure 2. HPLC yields of sulfide 3, disulfide 4, and diazosulfide 5 over
time (0–5 h).
4
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4 h when diazosulfide 5 was undetectable.[17] These results
suggest that diazosulfide 5 is a reactive, photo-labile inter-
mediate in the catalytic cycle (Scheme 4, pathway B). The
amount of disulfide 4 remained largely constant, thus it is less
likely to be a major reactive intermediate. From these results,
we can conclude that the reaction mainly proceeds through
pathway B. Other minor and competing mechanisms, includ-
ing SRN1 and SRN2, are less pronounced under our photo-
catalytic conditions. Further mechanistic studies of this
reaction are in progress.
raphy eluting with petroleum ether or hexanes and 0–10% ethyl
acetate.
Received: April 24, 2013
Published online: && &&, &&&&
ꢀ
Keywords: C S bond formation · microflow chemistry ·
one-pot processes · visible-light photoredox catalysis
.
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In conclusion, a novel one-pot Stadler–Ziegler process to
ꢀ
form C S bonds has been developed that operates under mild
reaction conditions. By employing the photoredox catalyst
[Ru(bpy)3Cl2]·6H2O irradiated with visible light, arylsulfides
can be prepared from readily available arylamines and aryl/
alkylthiols in good yields. Notably, the process eliminates the
need for diazonium salt isolation and minimizes formation of
diazosulfides, both of which are potential explosion hazards.
To further address the safety concerns associated with
diazonium species, a scalable continuous-flow protocol was
developed. The use of microreactors led to an improved
irradiation of the reaction medium, which resulted in
significant accelerations (full conversion within 15 s residence
time) when compared to its batch counterpart.
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Experimental Section
General batch reaction procedure:[18] In a 40 mL clear glass vial with
PTFE septum (from I-Chem) punched with a disposable syringe
needle (for venting N2), photoredox catalyst [Ru(bpy)3Cl2]·6H2O
(0.010 mmol) was added to a mixture of thiol (1.0 mmol), amine
(1.3 mmol), and TsOH·H2O (0.015 mmol) in MeCN (7.0 mL) at room
temperature. The catalyst normally dissolves completely in 5 min
upon stirring. Under visible light generated by a 20 W fluorescent
bulb, tert-butylnitrite (2.0 mmol) was slowly added to the mixture.
The reaction was monitored by TLC and HPLC, and was stopped
after 5 to 16 h. For safety concern, water (0.10–0.20 mL) was added to
the reaction mixture to moisturize any unconsumed diazonium salt.
Silica gel (0.50–1.0 g) was next added and then the mixture was
concentrated. The wet silica gel was loaded onto a flash column
eluting with cyclohexane/EtOAc (100:0 to 4:1) to give the desired
arylsulfide. The silica gel was also moistened with a half column
volume of water before disposal.
General continuous-flow procedure: An oven-dried volumetric
flask (10.0 mL) was charged with TsOH·H2O (8.8 mg, 0.046 mmol)
and [Ru(bpy)3Cl2]·6H2O (22.4 mg, 0.030 mmol). The vessel was fitted
with a septum and purged with argon. Next, thiol (3.0 mmol) and
aniline (3.9 mmol) were added through a syringe and acetonitrile was
added to make the solution volume 10 mL. A second oven-dried
volumetric flask (10.0 mL) was fitted with a septum and purged with
argon. tert-Butylnitrite (720 mL, 6 mmol) was added through a syringe
and acetonitrile was added to make the solution volume 10 mL. These
two solutions were loaded in 10 mL BD Discardit II plastic syringes
and fitted to a single syringe pump. The different solutions were
introduced into the photo microreactor device, as described in
Figure 1a, with the appropriate flow rates to provide the different
residence times. When exiting the photo microreactor, the reaction
was collected in a vial, which was covered in aluminum foil. Typically,
each experiment is preceded by a flush of four reactor volumes in
order to ensure steady-state data collection. Next, a sample was
collected in order to obtain exactly 1.5 mmol of product. The organic
phase was concentrated in vacuo and purified by column chromatog-
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[21] For a review on the combination of photoredox catalysis and
continuous-flow microreactors: T. Noꢃl, X. Wang, V. Hessel,
Chim Oggi 2013, 31(3), 10.
[26] For an experiment of monitoring the reaction under light from
the beginning, see the Supporting Information.
6
www.angewandte.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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