Ambient-Temperature Newman-Kwart Rearrangement Mediated by Organic Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.5b11800

The Newman-Kwart rearrangement is perhaps the quintessential method for the synthesis of thiophenols from the corresponding phenol. However, the high thermal conditions required for the rearrangement of the requisite O-aryl carbamothioates often leads to decomposition. Herein, we present a general strategy for catalysis of O-aryl carbamothioates to S-aryl carbamothioates using catalytic quantities of a commercially available organic single-electron photooxidant. Importantly, this reaction is facilitated at ambient temperatures.

Full text of DOI:10.1021/jacs.5b11800

Communication
pubs.acs.org/JACS
Ambient-Temperature Newman−Kwart Rearrangement Mediated by
Organic Photoredox Catalysis
Andrew J. Perkowski,† Cole L. Cruz,† and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
bearing electron-donating functionality, which require higher
ABSTRACT: The Newman−Kwart rearrangement is
perhaps the quintessential method for the synthesis of
thiophenols from the corresponding phenol. However, the
high thermal conditions required for the rearrangement of
the requisite O-aryl carbamothioates often leads to
decomposition. Herein, we present a general strategy for
catalysis of O-aryl carbamothioates to S-aryl carbamo-
thioates using catalytic quantities of a commercially
available organic single-electron photooxidant. Impor-
tantly, this reaction is facilitated at ambient temperatures.
temperatures than more electron-deficient substrates due to an
intrinsically higher barrier to nucleophilic attack of sulfur on the
aromatic ring. Improvements upon the original procedures of
Newman and Kwart have primarily focused on modified
conditions to minimize deleterious side reactions, particularly
the use of microwave heating (Figure 2).9
here are a number of strategies for formation of carbon−
T
sulfur bonds on aromatic molecules,1 one efficient method
being the conversion of a phenol to a thiophenol known as the
Newman−Kwart rearangement (NKR).2,3 While the rearrange-
ment of O,O-diaryl carbonothioates to O,S-diaryl carbon-
othioates had been reported in 1930 by Schonberg, it was not
until 1966 that Newman and Karnes disclosed the thermal
rearrangement of O-aryl carbamothioates to S-aryl carbamo-
thioates, permitting the straightforward preparation of aryl
thiols from the corresponding aryl phenols in good yields
(Figure 1).4,5 Earlier that same year, Kwart and Evans reported
Figure 2. Development of conditions for O-aryl carbamothioate
rearrangement.
Attempts to catalyze the NKR have also been reported in the
literature, but are sparse. In Newman and Karnes’ initial
disclosure O-(pyridyl)carbamothioates rearranged at room
temperature when prepared as their hydrochloride salts.
Brooker et al. reported that boron trifluoride diethyl etherate
significantly lowered the temperature necessary for NKR of a
limited number of ortho-formyl substrates, but the catalytic
effect did not prove general.10 A more general method was
published in 2009 by Lloyd-Jones, wherein catalytic loadings of
palladium bis(tri-tert-butylphosphine) allowed for successful
NKR of a number of para-substituted substrates in toluene at
100 °C.11 The palladium-catalyzed method exhibits a similar
electronic trend to the thermal NKR with shorter reaction
times observed for substrates bearing electron-withdrawing
functionality, increased reaction times and catalyst loadings
necessary for substrates bearing electron-donating groups. An
alternate strategy for aryl carbon−sulfur bond synthesis also
makes use of palladium catalysis.12−14 Hartwig and co-workers
in particular have demonstrated the utility of Josiphos as a
ligand for the palladium catalyzed coupling of aryl halides and
pseudo-halides with a range of thiols, including triisopropylsilyl
thiol which can be deprotected to give the corresponding free
aryl thiol, or further elaborated to diaryl sulfides.15,16
Figure 1. Thermal NKR of O-aryl carbamothioate to S-aryl
carbamothioate.
a similar rearrangement in the vapor phase.6 The NKR
proceeds via ipso nucleophilic attack of the thiocarbonyl moiety
onto the aryl ring, traversing through a spirocyclic transition
state.7 To access this highly strained intermediate, the NKR
requires high temperatures regularly in excess of 200 °C,
sometimes above 300 °C, to proceed. Nevertheless, the NKR is
a widely used method for the synthesis of aryl thiols for a
variety of applications.8
Unfortunately, the high temperatures required to enact the
rearrangement often result in competitive decomposition
pathways leading to diminished yields. Rigorous exclusion of
moisture and oxygen is necessary to achieve optimal results.
Particularly challenging are O-aryl carbamothioate substrates
Received: November 10, 2015
Published: December 8, 2015
© 2015 American Chemical Society
15684
DOI: 10.1021/jacs.5b11800
J. Am. Chem. Soc. 2015, 137, 15684−15687

Journal of the American Chemical Society
Communication
a
The need to prepare a variety of aryl thiol and aryl disulfide
cocatalysts for use in our ongoing redox catalysis research
program initially prompted our interest in the NKR.17−20 We
hypothesized that single electron oxidation of the O-aryl
carbamothioate substrate should lower the barrier to
nucleophilic attack of sulfur upon the aryl ring and accelerate
rearrangement. Further examination of the NKR literature
brought our attention to electrospray ionization mass
spectrometry studies of O-aryl carbamothioates by Prabhakar
and co-workers which indicated significant O to S aryl
migration in situ.21 The authors proposed that single-electron
oxidation permitted the facile gas-phase rearrangement of the
substrates. This further bolstered our confidence that the NKR
could be amenable to cation radical acceleration in the solution
phase.
Table 2. Substrate Scope of Photoredox-Mediated NKR
We began our studies by irradiating solutions of O-(4-
methoxyphenyl) dimethylcarbamothioate (2a) with 1.0 mol %
2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate 1 using blue light
emitting diodes (LEDs). After 24 h, formation of S-(4-
methoxyphenyl) dimethylcarbamothioate (3a) was evident
(1H NMR), though appreciable amounts of 2a remained
(Table 1, entry 1). Additional solvents such as dichloromethane
Table 1. Optimization of Photoredox-Mediated NKR
a
entry
substrate
solvent
conc [M]
3:2
1
2
3
4
5
6
7
2a
2a
2a
2b
2b
2b
2c
CHCl3
DCM
0.5
1:2
0.5
>19:1
>19:1
1:9
MeCN
MeCN
MeCN
MeCN
0.5
0.5
0.12
0.06
0.03
1:3
>19:1
1:1
MeCN
a
1
Determined by analysis of crude H NMR spectra of the reaction
mixture.
and acetonitrile were tested (entries 2 and 3, respectively), and
complete conversion of 2a was observed after 24 h. Ease of
workup and purification led us to choose acetonitrile as the
optimal solvent. No appreciable side products were observed by
1H NMR analysis of the crude reaction mixture, and a silica
plug eluted with 19:1 hexanes/ethyl acetate was sufficient to
provide pure 3a. Additional optimization using the less
electron-rich 4-methyl-substituted 2b displayed an intriguing
concentration dependence, with more dilute conditions
resulting in dramatic rate increases (entries 4−6). The parent
O-phenyl dimethylcarbamothioate (2c) was sluggish to react
even under appreciably dilute conditions (entry 7).
Next, the scope of the reaction was investigated (Table 2A).
Given the observed concentration dependence, an optimum
concentration was sought that would afford 100% conversion
within 24 h. In general, more dilute conditions were observed
to accelerate rearrangement of all the substrates under
examination. The O-(2-methoxyphenyl) dimethylcarbamo-
thioate reacted competently to afford 3d in good yield.
Additional 2-methoxy-substituted substrates underwent smooth
rearrangement providing the propenyl-substituted 3e, allyl-
substituted 3f, bromo-substituted 3g, meta- and para-formyl-
a
Isolated yields, the average of two reactions at 100 mg scale of
b
c
substrate. 0.5 substrate concentration. 0.12 M substrate concen-
tration. 0.06 M substrate concentration. 0.03 M substrate
d
e
f
g
concentration with 48 h irradiation. 5 mol% 1. <15% conversion,
h
1H NMR No product detectable, H NMR.
1
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DOI: 10.1021/jacs.5b11800
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Journal of the American Chemical Society
Communication
substituted 3h and 3i, respectively, and the 4-methylester-
substituted 3j, all in nearly quantitative yields. The O-(2-
formyl-4-methoxyphenyl) dimethylcarbamothioate also rear-
ranges smoothly to give 3k in good isolated yield as does the O-
(2-formyl-6-methoxyphenyl) dimethylcarbamothioate 3l. Ben-
zyl protecting groups are also tolerated (3m) in good yield as
well as thermally sensitive Boc groups (3n). The corresponding
dimethylcarbamothioate of acetaminophen readily undergoes
the O−S rearrangement, giving the corresponding S-aryl
dimethylcarbamothioate 3o in excellent yield. Less electron-
rich groups can also be present, as evidenced by 4-propenyl-
substituted 3p, dihydrocinnamyl methyl ester derivative 3q, and
biphenyl 3r which all underwent rearrangement in good to
excellent yields (88−98%). It is worthy of note that 3p is
produced as >19:1 ratio of E:Z isomers, despite beginning with
a 1:9 E:Z ratio of the propenyl carbamothioate. Given this, it is
notable that the allyl group of 3f does not undergo any
detectable isomerization to the propenyl product 3e. We were
also pleased to find that a potassium trifluoroborate salt
substrate is capable of undergoing the redox-mediated NKR
(3s), providing a handle for further elaboration using cross
coupling techniques. Finally, sterically hindered substrates
derived from mesitol and ( )-α-tocopherol also reacted
efficiently, giving 3t and 3u, respectively.
boronate ester 4a showed diminished reactivity, as did 3-
methoxy-substituted 4b, both achieving low conversion under
the standard conditions (Table 2B). Substrates with alkenyl or
aryl substitution ortho to the O-carbamothioate moiety also
proved recalcitrant (4c−4e), regardless of the presence of an
additional beneficial substituent (Table 2C). The rearrange-
ment was also inhibited by sterically large ortho substituents (4f,
4g). As previously discussed, 2-naphthyl-derived 4h did not
rearrange, nor did the 5,6,7,8-tetrahydronaphthyl analogue 4i.
Monosubstituted haloarenes also give little to no rearrange-
ment, regardless of halide identity or position (4j−4m).
Substrates bearing a single electron-donating substituent meta
to the O-carbamothioate afforded trace amounts of rearranged
product (4n, TBDPS = tert-butyldiphenylsilyl, 4o), suggesting a
strict electronic requirement for rearrangement (for example
see 3a, 3d compared to 4b).
Further analysis of 2a and 3a by cyclic voltammetry (CV)
gave several irreversible oxidation waves (Figure 5). Qual-
Unfortunately, O-(2-naphthyl) dimethylcarbamothioate (4i)
failed to give appreciable rearrangement, while the regio-
isomeric O-(1-naphthyl) dimethylcarbamothioate (2v) was a
competent candidate providing 3v in excellent yield (Figure 3).
Figure 3. Photoredox-mediated rearrangement of 2v.22 aIsolated yield,
the average of two reactions at 100 mg scale of substrate.
Intriguingly, the propensity toward rearrangement under
thermal NKR conditions is reversed, with O-(2-naphthyl)
dimethylcarbamothioate undergoing O to S aryl migration at
285 °C, while 2v does not undergo rearrangement under
thermal conditions.22
We chose O-(2,4,6-trimethylphenyl) dimethylcarbamo-
thioate (2t) as a representative substrate to assess the suitability
of this protocol using a flow apparatus (Figure 4). No
Figure 5. Cyclic voltammograms for 2a, 3a, and 5. All values are in V
vs SCE.
itatively, the traces for 2a and 3a appear similar except for an
irreversible oxidation wave with Ep/2 = +1.1 V present in the
CV trace for 2a but absent for 3a. For comparison, substrate 5
which cannot undergo rearrangement, exhibits an oxidation
wave nearly identical to 2a at +1.1 V. These data suggest that
oxidation of the thiocarbonyl moiety, rather than the arene, is
likely involved in the rearrangement. This is in agreement with
previous work carried out in our laboratory on the cyclization
of thioamides onto pendant alkenes.20
Given these observations, we propose the mechanism
depicted in Scheme 1 for the redox-mediated NKR. Excitation
of 1 by the blue LEDs followed by single electron oxidation of
2 by 1* affords sulfur-centered cation radical 6 and the
Figure 4. Large scale synthesis of 3t using a flow reactor and
commercially available triphenylpyrylium tetrafluoroborate (TPT).
precautions were taken to exclude moisture or oxygen and
we employed commercially available triphenylpyrylium tetra-
fluoroborate as catalyst. Using the optimized conditions, 21.5 g
of 2t underwent smooth rearrangement to 3t after 82 h. After
chromatography, the desired product was isolated in a 91%
yield providing 19.7 g of 3t.
Despite the success of this system, there are substitution
patterns for which rearrangement was not observed. Aryl
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Journal of the American Chemical Society
Communication
(3) Zonta, C.; De Lucchi, O.; Volpicelli, R.; Cotarca, L. In Sulfur-
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Accelerated NKR
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In conclusion, we present a method for the ambient
temperature NKR. This represents a dramatic reduction in
reaction temperature relative to the traditional thermal NKR
and even palladium-catalyzed methods. The transformation is
enabled via organic redox catalysis using easily prepared, and
even commercially available, triarylpyrylium salts. This reaction
exhibits complementary reactivity relative to the thermal NKR,
with more facile reactivity observed for more electron-rich
substrates. Tolerance toward a number of functional and
protecting groups was also demonstrated, in addition to
amenability to scale-up of the reaction using flow chemistry.
Studies to further elucidate the mechanism of the reaction, so
as to expand the utility and substrate scope, are planned.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b11800.
■
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Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*nicewicz@unc.edu
■
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Author Contributions
†A.J.P. and C.L.C. contributed equally.
́
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by the David and Lucile
Packard Foundation.
■
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DOI: 10.1021/jacs.5b11800
J. Am. Chem. Soc. 2015, 137, 15684−15687