Inverting the Selectivity of the Newman-Kwart Rearrangement via One Electron Oxidation at Room Temperature

Article abstract of DOI:10.1021/acs.joc.8b01800

The discovery that the Newman-Kwart rearrangement can be performed at room temperature by action of a simple and readily available oxidant, cerium ammonium nitrate, is described. The conditions give clean conversion when using electron-rich aromatic subst

Full text of DOI:10.1021/acs.joc.8b01800

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Article
Inverting the selectivity of the Newman-Kwart rearrangement
via one electron oxidation at room temperature
Stephan K. Pedersen, Anne Ulfkjær, Madeleine N. Newman, Sarangki
Yogarasa, Anne U. Petersen, Theis Ivan Sølling, and Michael Pittelkow
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01800 • Publication Date (Web): 30 Aug 2018
Downloaded from http://pubs.acs.org on August 30, 2018
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The Journal of Organic Chemistry
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Inverting the selectivity of the Newman-Kwart rearrangement via
one electron oxidation at room temperature
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Stephan K. Pedersen, Anne Ulfkjær, Madeleine N. Newman, Sarangki Yogarasa, Anne U. Petersen,
Theis I. Sølling, and Michael Pittelkow*
Department of Chemistry, University of Copenhagen, Universitetsparken 5, DKꢀ2100 Copenhagen, Denmark
Supporting Information Placeholder
ꢀ Room temperature
ꢀ Ambient atmosphere
ꢀ Inexpensive Ce(IV) catalyst
ꢀ Electron donating groups
ꢀ Up to 99% yield
ꢀ 15 examples
ABSTRACT: Yes we CAN! The discovery that the NewmanꢀKwart rearrangement can be performed at room temperature by action
of a simple and readily available oxidant, cerium ammonium nitrate (CAN) is described. The conditions give clean conversion
when using electron rich aromatic substrates and the reactions are often quantitative. Computational studies support a reaction
mechanism where the Oꢀthiocarbamate is first oxidized to the radical cation, followed by nucleophilic attack by the ipso carbon of
the aromatic system.
Interestingly, a qualitative reversal of reactivity trend was
observed: electron rich aromatic substrates readily underwent
Introduction
NKR while electron deficient substrates were unreactive. This
is an important addition to the NKR.
The NewmanꢀKwart rearrangement (NKR) is the thermal
OAr → SAr rearrangement of aromatic thiocarbamates (Figure
1) and remains one of the most reliable ways of preparing
thiophenols from the corresponding phenol (3 steps).1ꢀ2 It has
found use across such diverse fields as molecular electronics,3
ligand synthesis,4 medicinal chemistry,5 dynamic combinatoriꢀ
al chemistry,6ꢀ7 along with the chemical industry.8ꢀ9 The generꢀ
ally accepted mechanism for the NKR involves nucleophilic
attack of the sulfur atom of the thiocarbamate functionality to
the ipsoꢀposition of the aromatic ring, which gives a cyclic
fourꢀmembered ring transition state (Figure 1A).10ꢀ11 The
rearrangement proceeds relatively smoothly, but at very high
temperatures (usually > 200 °C), making it unpractical for
substrates with thermally sensitive functional groups. Also
electron rich substrates, where even higher temperatures are
often needed, often prove unsuccessful due to significant
decomposition of the substrate.
Lately a series of developments have attracted renewed attenꢀ
tion to the NKR.12ꢀ14 A Pd catalyzed NKR was described
where the rearrangement proceeds at 100 °C using catalytic
Pd(tꢀBu3P)2 (Figure 1B).15 Here, substrates with electron withꢀ
drawing groups react faster than substrates with electron doꢀ
nating groups, nonetheless high yields were obtained for both
classes. Recently Nicewicz and coꢀworkers showed that the
NKR can proceed at room temperature using a photoꢀredox
catalyst (2,4,6ꢀtri(pꢀtolyl)pyrylium tetrafluoroborate) comꢀ
bined with irradiation by blue light (Figure 1C).16 The concept
of using transient generated radical cations to mediate the
NKR had previously been suggested by LloydꢀJones et. al.17
Figure 1. Highlights in the development of new conditions for the
NewmanꢀKwart rearrangement (NKR) and structures of the correꢀ
sponding transition states.
Photoꢀredox catalysis has gained increased popularity in the
last years,18ꢀ19 but it does come with certain drawbacks, i.e.
photolabile substrates are not compatible. Also, the exclusion
of oxygen is occasionally needed to avoid unwanted side
reactions, associated with the photocatalyst generating reactive
oxygen species.20 Finally, specialized equipment is needed for
the scale up of the reaction.
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tion kinetics of the thermal NKR changes from first to second
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Results and discussion
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order upon increasing concentration of substrate, but it has
been proven that the mechanism of the thermal reaction is
indeed intramolecular.10, 21 We observe no conversion at the
higher concentrations, even with excess of the oxidant added,
and even when conducting the reaction under an atmosphere
of O2. We do not have experimental evidence explaining this
phenomenon, but aggregation of the thiocarbamateꢀbased
reactants could contribute to the explanation, either as a neuꢀ
tral specie or as a mixedꢀvalence aggregate.
We were intrigued by the observations described by Niceꢀ
wicz and coꢀworkers and wondered if it would be possible to
choose a more commonplace chemical oxidant of sufficient
potency to match the oxidation strength of the photoꢀredox
catalyst, and thereby mediate the rearrangement. This would
potentially give a convenient and simple protocol for the NKR
without the use of a photoꢀredox catalyst or light (Figure 1D).
Initially a range of single electron transfer (SET) oxidants
and their applicability in mediating the NKR of pꢀmethoxyꢀOꢀ
aryl thiocarbamate 1 at room temperature were tested. No
formation of the corresponding Sꢀaryl thiocarbamate 2 was
observed when treating 1 with readily available SET oxidants
such as 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀpꢀbenzoquinone (DDQ),
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With the optimal reaction conditions in hand the scope of
the CAN mediated NKR was established (Figure 2). As alꢀ
ready stated, the pꢀmethoxyꢀSꢀaryl thiocarbamate 2 was obꢀ
tained quantitative under the given conditions. Using the corꢀ
responding ethyl analogue 4 also gave full conversion. Movꢀ
ing to the more labile benzyl ether substituted 5 and allyl ether
6, clean conversions were observed for both substrates. The
allyl ether 6 serves as an excellent example of the applicability
of the presented methodology, as this compound would be
prone to Claisen rearrangement if subjected to the thermal
NKR conditions. Investigations of more electron deficient
systems, through addition of electron withdrawing groups in
the orthoꢀposition, as for nitro substituted 7 or formyl substiꢀ
tuted 8, showed that these substrates also successfully underꢀ
went rearrangement. Interestingly, the methylester substituted
substrate 13 lead to only 52% conversion. Changing the methꢀ
oxy group from the paraꢀ to the orthoꢀposition high yield was
retained affording 9 while the metaꢀposition (16) hampered
the rearrangement. Moving onto amino analogues, we found
that with a BOC protecting group as substituent (10), which is
thermally labile, high yield was obtained.22 With the Nꢀacetyl
group as substituent (11) full conversion to product was also
observed. Finally, we found that Sꢀ(naphthaleneꢀ1ꢀyl) dimeꢀ
thylcarbamothioate (12) could be obtained in high yields while
the 2ꢀnapthalene derivative 17 was not prone to the rearꢀ
rangement. The difference between the two naphthol subꢀ
strates is attributed to the increased electron density on the 1
position compared to the 2 position, allowing for only 12 to
rearrange under the presented conditions.23
(diacetoxyiodo)benzene
(PIDA),
and
[bis(trifluoroacetoxy)iodo]benzene (PIFA) in acetonitrile
(Table 1, entry 1ꢀ3). Instead formation of the oxygenated
product, carbamate 3, was solely observed. Interestingly, with
cerium ammonium nitrate (CAN) in acetonitrile, full converꢀ
sion of 1 to a mixture of products was observed. Thorough
investigation of the 1HꢀNMR spectrum of the reaction mixture
revealed trace formation of the rearranged product 2 (Table 1,
entry 4). Motivated by this observation, CAN was investigated
in a series of alternate polar solvents. Using DMF, as the
solvent, 17% conversion to the rearranged product 2 was
observed with no formation of 3 or any other byproducts (Taꢀ
ble 1, entry 5). Satisfactorily, using DMSO as the solvent led
to quantitative formation of 2 (Table 1, entry 6). Having estabꢀ
lished DMSO as an ideal solvent for the rearrangement DDQ,
PIDA and PIFA where reinvestigated. Nonetheless, no forꢀ
mation of 2 was observed (Table 1, entry 7ꢀ9).
Table 1. Optimization of the single electron transfer (SET)
oxidant and solvent for the oxidative NKR.[a]
[SET
oxidant]
Conversion to Conversion to
Entry Solvent
2[b]
3[b]
52
84
84
0
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
DMF
DDQ
PIDA
PIFA
CAN
CAN
0
0
0
Trace
17
0
DMSO CAN
DMSO DDQ
DMSO PIDA
DMSO PIFA
>99 (97)
0
0
0
0
0
22
27
[a]All reactions were conducted on a 0.1 mmol scale with 0.05
substrate concentration and 1.0 equiv. of oxidant.
M
[b]Determined by 1HꢀNMR analysis of the reaction mixture. Yield
of isolated product given within parentheses.
The rearrangement was found to be sensitive to substrate
concentration. At high concentrations (< 0.5 M) no conversion
was observed while more diluted conditions (> 0.05 M) gave
quantitative conversion (Supporting Information). These deꢀ
pendencies are consistent with the results by Nicewizc and coꢀ
workers.16 It has previously been discussed whether the reacꢀ
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Previous reports show that single electron oxidations, mediatꢀ
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ed by CAN, can be catalytic if done in the presence of molecuꢀ
lar oxygen, which oxidizes cerium(III) back to the active
cerium(IV).24ꢀ25 As a proof of principle we tested these condiꢀ
tions on the NKR of 1, using 50 mol% CAN under an atmosꢀ
phere of oxygen, and it was indeed found that the reaction
went to completion (Table 2, entry 1). The equivalents of
CAN could be lowered to 5 mol%, while still maintaining full
conversion (Table 2, entry 2ꢀ4). It was even found that the
rearrangement proceeded smoothly when simply run in an
open reaction flask showing how atmospheric oxygen is suffiꢀ
cient to reform the active cerium(IV) species (Table 2, entry
5). The reaction was also tested under a pure nitrogen atmosꢀ
phere with 10 mol% of CAN (Table 2, entry 6). Only 14%
conversion to product was observed. This rules out the termiꢀ
nal reductant of the oxidative NKR is Ce(IV) being reduced to
the active Ce(III) species. The fact that the conversion is highꢀ
er than the expected 10 % is attributed to leakage of oxygen in
to the system, either during the reaction or in the work up.
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Table 2. Screening of catalytic conditions for the oxidative
NKR.[a]
Entry Atmosphere Amount CAN [mol%] Conversion[b]
1
2
3
4
5
6
O2
50
10
5
>99
>99 (99)
98
O2
O2
O2
2
22
ambient
10
10
>99
14
[c]
N2
Figure 2. Substrate scope of the oxidative NKR.[a]
[a]All reactions were done on a 0.1 mmol scale with 0.05 M
substrate concentration. [b]Determined by 1HꢀNMR analysis of the
reaction mixture. [c] Additionally the solvent was sparged with N2.
Yield of isolated product given within parentheses.
[a]All reactions were done on a 0.25 mmol scale with 0.05 M
substrate concentration. [b]Yield of isolated product. [c]Conversion
1
is determined by HꢀNMR analysis of the reaction mixture. [d]No
product is detectable by 1HꢀNMR analysis.
To gain further insight to the mechanism, some mechanistic
studies were performed. A kinetic study of the rearrangement
of pꢀmethoxyꢀOꢀaryl thiocarbamate (1) showed how the oxiꢀ
dative NKR proceeds with first order kinetics, as the thermal
NKR,21 with a reaction rate constant, kobs, of 2.9ꢁ10ꢀ4 sꢀ1 (25 °C,
DMSO; Supporting Information). This is slightly faster than
The natural product derivative, Oꢀaryl thiocarbamate of
isoeugenol, undergoes oxidative NKR in a decent 49% conꢀ
version to yield substrate 14. Replacing the pꢀmethoxy subꢀ
stituent with a thioether functionality was also feasible and pꢀ
methylthioꢀSꢀaryl thiocarbamate (15) could be obtained, albeit
only in a 21% yield. Having an inductively electron donating
group in the paraꢀposition, as in the pꢀmethyl derivative 18,
no conversion was observed. This substrate rearranged sucꢀ
cessfully by Nicewicz and coꢀworkers method, thus highlightꢀ
ing a case where that protocol is advisable to use.16 For the
paraꢀsubstituted arylhalides (19) neither our nor the photoꢀ
redox catalyzed protocol provided the rearranged product.
Doing the reaction at elevated temperature, none of the arylꢀ
halides showed formation of the target NKR product. This
indicates the essentiality that the substrate should feature a
resonance electron donating substituent, either in the orthoꢀ or
para position increasing the nucleophilicity of the ipso carbon
on the aromatic ring.
the thermal NKR of pꢀnitroꢀOꢀarylthiocarbamate (kobs
=
2.1ꢁ10ꢀ4 sꢀ1, 160 °C, DMA).10
A crossꢀover experiment between pꢀmethoxyꢀOꢀaryl thioꢀ
carbamate (1) and its ethyl analogue 20 was conducted to
investigate whether the rearrangement is interꢀ or intramolecuꢀ
lar. The two nonꢀcrossover rearranged products 2 and 4
formed with comparable rates and in addition, to our satisfacꢀ
tion, we found that none of the crossover products were obꢀ
served (Figure 3, Supporting Information). Thus, under the
presented conditions, the rearrangement can be considered as
being solely intramolecular.
The rearrangement also proved successful at a larger scale.
For example, 5 grams of pꢀmethoxyꢀOꢀaryl thiocarbamate 1
gave analytically pure 2 in 95 % isolated yield.
3
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the reaction barrier. The high electronegativity of chlorine in
Page 4 of 8
1
2
3
4
19b counterbalances the electron releasing effect of the chloꢀ
rine lone pairs and thus the barrier is found to be too high to
make the oxidative NKR feasible, this being in agreement
with the experimental results.
Table 3. Comparison of G4MP2 calculated values of the
reaction barriers (ꢂE‡) and energies (ꢂrE) for selected
substrates undergoing either the thermal or the oxidative
NKR.[a]
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6
7
8
9
Figure 3. Crossꢀover experiment between 1 and 20 indicating the
oxidative NKR is intramolecular.
Thermal NKR
ꢂE‡
ꢂrE
[kJ/mol [kJ/mol [kJ/mol [kJ/mol
Oxidative NKR
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ꢂE‡
ꢂrE
Enꢀ
try
To further understand the underlying cause of reactivity obꢀ
served we turned to computational chemistry. The study was
performed on five Oꢀaryl thiocarbamates (2, 16, 19b, 21, and
22) and the results show a cyclic fourꢀmembered ring transiꢀ
tion state in both the oxidative and thermal NKR (Figure 4). A
charge analysis shows that the electron is removed from the
(nonꢀbonding) sulfur lone pair upon oxidation and the ionizaꢀ
tion potential values are similar for all substrates (Supporting
Information). This is supported experimentally by Nicewicz
and coꢀworkers,16 thus indicating that the oxidation indeed
takes place on sulfur.
Substrate
]
]
]
]
1
2
3
4
5
176.3
ꢀ52.1
37.0
ꢀ60.3
168.4
162.4
166.8
149.6
ꢀ46.1
ꢀ50.9
ꢀ46.5
ꢀ48.0
51.3
53.4
56.5
63.0
ꢀ24.8
ꢀ17.3
6.6
O
N
2.5
S
O2N
22
[a]For further information, see Supporting Information.
To conclude, we have developed a room temperature NKR
for electron rich substrates. The use of CAN as the oxidant
and DMSO as the solvent provides a simple and convenient
approach that proved scalable and simple to reproduce using
standard equipment and chemicals. The mechanism is an
intramolecular rearrangement of a radical cation species,
which initially forms on the sulfur atom of the thiocarbamate.
As the thermal NKR can be understood as an intramolecular
nucleophilic aromatic substitution, the oxidative NKR is more
similar to that of an electrophilic aromatic substitution. This
satisfactorily explains the trend that thermal NKR proceeds
smoothly for electronꢀpoor aromatic systems, and why an
inversion of reactivity is observed for the oxidative NKR.
Figure 4. Schematic potential energy profile comparing the
G4MP2 calculated reaction coordinates for the thermal NKR
(blue) and the oxidative NKR (green). The reactant is set at 0
kJ/mol for each reaction, the energetic separation between the two
should in reality be the ionization energy of ∼ 750 kJ/mol.
The reaction barrier is significantly reduced when comparꢀ
ing the thermal and oxidative NKR (Table 3, Supporting Inꢀ
formation). The lower reaction barrier is a result of the fact
that sulfur is more easily accommodated by the aromatic ring
when the sulfur lone pair is ionized, i.e. a reversal takes place
compared to the neutral system where sulfur is more likely to
act as the nucleophile. These considerations are in agreement
with the experimental observations that the thermal NKR is
facilitated by electron withdrawing substituents, making the
ring more electrophilic whereas the oxidative NKR only proꢀ
ceeds when electron donating substituents are present to stabiꢀ
lize the positive charge that is introduced on the ring when the
ionized sulfur lone pair attacks. The thermochemical data in
Table 3 corroborates that the thermal rearrangement is faciliꢀ
tated by electron withdrawing groups. This is shown using the
4ꢀnitro substrate 22 as an example.
Current studies are ongoing to expand on the catalytic conꢀ
ditions as they would be an appealing alternative to the condiꢀ
tions that have been reported for the NKR thus far in the litꢀ
erature.
Experimental Section
Computational methods
The calculations were carried out with a fourth generation
composite method referred to as G4MP2 with the
GAUSSIAN09 suite of programs.26ꢀ27 G4MP2 theory is apꢀ
proximating a large basis set CCSD(T) single point calculation
on a B3LYP/6ꢀ31G(2df,p) geometry and is incorporating a soꢀ
called higher level correction that is derived by a fit to the
experimental values in the G3/05 test set with 454 experiꢀ
mental values.28 The average absolute derivation from the
For the oxidative NKR the lowest barrier is obtained when
an oxygen atom is present in the paraꢀposition (2). Moreover,
the substituent has to be in direct electronic contact with the
ipso position, i.e. the metaꢀsubstituted 16 does not decrease
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experimental test set values is 1.04 kcal molꢀ1, which places
13.6 mmol) were suspended in NMP (10 mL) and heated to 50
°C. To this clear reaction mixture N,Nꢀethylthiocarbamoyl
chloride (1.45 g, 10.5 mmol), dissolved in NMP (5 mL), was
added dropwise and the reaction mixture became turbid. The
reaction mixture was hereafter left standing at 50 °C for
5 hours before it was cooled down to 25 °C. After this, H2O
(50 mL) and CH2Cl2 (50 mL) were added to the mixture and
the phases were separated. The organic phase was washed
with 2 M NaOH (50 mL), H2O (2 × 50 mL), dried (Na2SO4)
and concentrated in vacuo to yield 20 as a white solid (1.63 g,
6.45 mmol, 61 %), mp. 67 ꢀ 68 °C. 1H NMR (500 MHz,
CDCl3, 298 K): δ = 6.96 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1
Hz, 2H), 4.02 (q, J = 7.0 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H),
3.68 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H), 1.33ꢀ1.31
(m, 6H). 13C NMR (125 MHz, CDCl3, 298 K): δ = 187.6,
156.8, 147.6, 123.6, 114.8, 63.9, 48.6, 44.3, 15.0, 13.7, 12.0.
LC/HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd. for C13H20NO2S
254.1209; Found 254.1219.
1
2
3
4
5
6
7
8
the G4MP2 results well within chemical accuracy of 10 kJ
molꢀ1. The transition structures for the reactions reported in
this work have been confirmed in each case by the calculation
of vibrational frequencies (one imaginary frequency) and an
intrinsic reaction coordinate analysis. Relative free energies
stated within the text correspond to G4MP2 values at 298.15
K.27
General methods
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All chemicals, unless otherwise stated, were purchased from
commercial suppliers and used as received. All solvents were
highꢀperformance liquid chromatography (HPLC) grade,
except solvents used for dry column vacuum chromatography,
which were technical grade. Solvents were degassed by bubꢀ
bling N2 through the solvent, while ultrasonicated for 20
minutes. All reactions were carried out under an anhydrous
nitrogen atmosphere unless otherwise stated.
O-(4-(Allyloxy)phenyl) N,N-dimethylthiocarbamate (6-
sm)
Analytical thin layer chromatography (TLC) was performed
on SiO2 60 F254 0.2 mm thick precoated TLC plates. Dry colꢀ
umn vacuum chromatography was performed using SiO2 (SI
1722, 60 Å, 15–40 ꢃm respectively). Melting points (m.p.) are
uncorrected.
1H NMR and 13C NMR spectra were recorded at 500 MHz
and 125 MHz, respectively, using residual nonꢀdeuterated
4ꢀ(Allyloxy)phenol (1.00 g, 6.66 mmol) and DABCO (0.94 g,
8.38 mmol) were suspended in NMP (5 mL) and heated to 50
°C. To this clear reaction mixture N,Nꢀdimethylthiocarbamoyl
chloride (0.91 g, 7.32 mmol), dissolved in NMP (1 mL), was
added dropwise and the reaction mixture became turbid. The
reaction mixture was hereafter left standing at 50 °C for
3 hours before it was cooled down to 25 °C. After this, H2O
(15 mL) was added and the mixture was extracted with
CH2Cl2 (3 × 15 mL), dried (MgSO4) and concentrated in vacꢀ
uo. The crude product was purified by dry column vacuum
chromatography using a gradient of CH2Cl2 in heptane to yield
6-sm as a pale yellow oil (63.2 mg, 2.66 mmol, 40 %).
1H NMR (500 MHz, CDCl3, 298 K): δ = 6.97 (d, J = 9.1 Hz,
2H), 6.91 (d, J = 9.1 Hz, 2H), 6.06 (ddt, J = 17.3, 10.6, 5.3 Hz,
1H), 5.42 (dd, J = 17.3, 1.5 Hz, 1H), 5.29 (dd, J = 10.6, 1.5
Hz, 1H), 4.53 (dt, J = 5.3, 1.5 Hz, 2H), 3.45 (s, 3H), 3.33 (s,
3H). 13C NMR (125 MHz, CDCl3, 298 K): δ = 188.3, 156.4,
147.7, 133.2, 123.5, 117.7, 115.0, 69.2, 43.3, 38.7. LC/HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd. for C12H16NO2S 238.0896;
Found 238.0903.
solvent as the internal standard. All chemical shifts (δ) are
quoted in ppm and all coupling constants (J) are expressed in
Hertz (Hz). The following abbreviations are used for convenꢀ
ience in reporting the multiplicity for NMR resonances: s =
singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet,
and m = multiplet. Samples were prepared using CDCl3 or
DMSOꢀd6. Assignment of all 1H and 13C resonances was
achieved using standard 2D NMR techniques as 1Hꢀ1H COSY,
1Hꢀ13C HSQC, and 1Hꢀ13C HMBC.
HPLC analysis was performed on a UHPLC system coupled
to an diode array UV/Vis detector. Separations were achieved
using a C18 2.2 ꢃm 120 Å 2.1 × 100 mm column maintained
at 20 °C. The mobile phase solutions prepared with 0.1 %
HCOOH in the solvents. The water used as eluent was purified
by a Millipore system. LC/MS was carried out on a MicrOꢀ
TOFꢀQIIꢀsystem with ESIꢀsource with nebulizer 1.2 bar, dry
gas 8.0 L minꢀ1, dry temperature 200 °C, capillary −4500 V,
end plate offset −500 V, funnel 1 RF 200.0 Vpp, ISCID enerꢀ
gy 0.0 eV, funnel 2 RF 200.0 Vpp, hexapole RF 100.0 Vpp,
quadrupole ion energy 5.0 eV, low mass 100.00 m/z, collision
energy 8.0 eV, collision RF 100.0 Vpp, transfer time 80.0 ꢃs,
and pre puls storage 1.0 ꢃs. LC/HRMS samples were calibratꢀ
ed by an automated preꢀrun internal mass scale calibration of
the individual samples by injecting a sodium formate solution,
consisting of 10 mM NaOH(aq) in iꢀPrOH:H2O 1:1 v/v (+ 1 %
HCOOH).
Experimental procedures for the S-aryl thiocarbamates
Standard conditions for oxidative Newman-Kwart Rear-
rangement
Conditions
A
(CAN stoichiometric, N2 atmosphere)
The Oꢀaryl N,Nꢀdimethylthiocarbamate (1.0 equiv., 0.25
mmol) and CAN (1.0 equiv., 0.25 mmol) were dissolved in
DMSO (5.0 mL) and stirred at room temperature for 24 hours
under a nitrogen atmosphere. To the completed reaction mixꢀ
ture was added H2O (40 mL) and the solution was extracted
with Et2O (4 × 40 mL). The combined organic phase was
washed with H2O (40 mL), dried (MgSO4) and concentrated in
vacuo to give the rearranged product.
Experimental procedures for the O-aryl thiocarbamates
Compounds 1, 9-sm, 16-sm, 17-sm, 18-sm, 19a-sm, 19b-sm
and 19c-sm were synthesised according to the procedure pubꢀ
lished by Moseley et al.,12 while the compounds 5-sm, 8-sm,
10-sm, 11-sm, 12-sm, and 14-sm, were synthesised following
the protocol described by Perkowski et al.16 Similarly, 7-sm,29
13-sm,30 15-sm,31 and 19d-sm32 were synthesised following
previously reported literature procedures.
Conditions
B
(CAN
catalytic,
O2
atmosphere)
Identical to Conditions A, with the only alteration being the
amount of CAN is reduced to the desired equivalents (0.5 or
0.1 equiv.), and the reaction is performed under an oxygen
atmosphere.
Conditions
C
(CAN catalytic, ambient atmosphere)
O-(4-ethoxyphenyl)
N,N-diethylthiocarbamate
(20)
Identical to Conditions A, with the only alteration being the
amount of CAN is reduced to 0.1 equivalents, and the reaction
4ꢀEthoxyphenol (1.75 g, 11.5 mmol) and DABCO (1.53 g,
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is performed under ambient atmosphere, i.e. the reaction mixꢀ
ture is simply stirred in an open reaction flask.
3.1 Hz, 1H), 3.88 (s, 3H), 3.16 (bs, 3H), 3.02 (bs, 3H).
The analytic data is in accordance with the literature.16
1
2
3
4
5
6
7
8
9
S-(2-Methoxyphenyl) N,N-dimethylcarbamothioate (9)
Yield: 0.049 g, 0.233 mmol, 93 % (Conditions A), 0.050 g,
S-(4-Methoxyphenyl) N,N-dimethylcarbamothioate (2)
0.238
mmol,
95
%
(Conditions
C).
Yield: 0.052 g, 0.248 mmol, 99 % (Conditions A), 0.052 g,
0.248 mmol, 99 % (Conditions B), 0.052 g, 0.248 mmol, 99 %
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.46 (dd, J = 7.5, 1.8
Hz, 1H), 7.40 (ddd, J = 8.2, 7.5, 1.8 Hz, 1H), 7.00 – 6.94 (m,
2H), 3.87 (s, 3H), 3.13 (bs, 3H), 3.01 (bs, 3H).
The analytic data is in accordance with the literature.12
(Conditions
C).
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.40 (d, J = 8.9 Hz,
2H), 6.91 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.07 (bs, 3H), 3.02
(bs,
3H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The analytic data is in accordance with the literature.12
tert-Butyl
(4-((N,N-
dimethylcarbamoyl)thio)phenyl)carbamate (10)
S-(4-Ethoxyphenyl) N,N-diethylcarbamothioate (4)
Yield: 0.073 g, 0.245 mmol, 98
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.39 (bs, 4H), 6.53
(bs, 1H), 3.05 (bs, 6H), 1.52 (s, 9H).
The analytic data is in accordance with the literature.16
% (Conditions A).
After the general work up described under Conditions A, the
title compound is obtained as yellow oil.
Yield: 0.063 g, 0.248 mmol. 99 % (Conditions A), 0.063 g,
a
0.248
mmol,
99
%
(Conditions
C).
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.39 (d, J = 8.8 Hz,
2H), 6.89 (d, J = 8.8 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.42
(q, J = 7.1 Hz, 4H), 1.41 (t, J = 7.0 Hz, 3H), 1.28 (bs, 3H),
1.16 (bs, 3H). 13C NMR (125 MHz, CDCl3, 298 K): δ = 166.5,
159.9, 137.4, 119.3, 115.1, 63.6, 42.3 (2×C), 14.8, 13.9, 13.3.
S-(4-Acetamidophenyl) N,N-dimethylcarbamothioate (11)
Yield: 0.059 g, 0.248 mmol, 99
% (Conditions A).
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.49 (d, J = 8.2 Hz,
2H), 7.41 – 7.39 (m, 3H), 3.09 (bs, 3H), 3.03 (bs, 3H), 2.15 (s,
3H).
LC/HRMS
(ESIꢀTOF)
m/z:
[M+H]+
Calcd.
for
The analytic data is in accordance with the literature.16
C13H20NO2S254.1209; Found 254.1216.
S-(Naphthalen-1-yl) N,N-dimethylcarbamothioate (12)
S-(4-(Benzyloxy)phenyl) N,N-dimethylcarbamothioate (5)
Yield: 0.053 g, 0.228 mmol, 91
% (Conditions A).
Yield: 0.050 g, 0.223 mmol, 89
% (Conditions A).
1H NMR (500 MHz, CDCl3, 298 K): δ = 8.32 (d, J = 8.4 Hz,
1H), 7.93 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.78
(d, J = 7.1 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.52 – 7.47 (m,
2H), 3.24 (bs, 3H), 3.02 (bs, 3H).
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.46 – 7.35 (m, 6H),
7.33 (t, J = 7.0 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H),
3.07 (bs, 3H), 3.03 (bs, 3H).
The analytic data is in accordance with the literature.16
The analytic data is in accordance with the literature.16
S-(4-(allyloxy)phenyl) N,N-dimethylcarbamothioate (6)
Methyl
2-((N,N-dimethylcarbamoyl)thio)-5-
After the general work up, the title compound is obtained as a
pale yellow oil. Yield: 0.057 g, 0.240 mmol, 96 % (Conditions
methoxybenzoate (13)
Conversion: 52 % (Conditions A).
A), 0.054 g, 0.228 mmol, 91
%
(Conditions C).
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.42 (d, J = 8.8 Hz,
2H), 6.95 (d, J = 8.8 Hz, 2H), 6.07 (ddt, J = 17.3, 10.5, 5.3 Hz,
1H), 5.44 (dd, J = 17.3, 1.5 Hz, 1H), 5.32 (dd, J = 10.5, 1.5
Hz, 1H), 4.57 (dt, J = 5.3, 1.5 Hz, 2H), 3.08 (bs, 3H), 3.04 (bs,
3H). 13C NMR (125 MHz, CDCl3, 298 K): δ = 167.8, 159.7,
137.4, 133.1, 119.7, 118.0, 115.5, 69.0, 37.0 (2×C).
LC/HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd. for C12H16NO2S
238.0896; Found 238.0898.
The product is isolated as a mixture of starting material and
product.
The analytic data is in accordance with the literature.30
(E)-S-(2-Methoxy-4-(prop-1-en-1-yl)phenyl)
dimethylcarbamothioate (14)
N,N-
Conversion: 49 % (Conditions A).
The product is isolated as a mixture of starting material and
product.
The analytic data is in accordance with the literature.16
S-(4-Methoxy-2-nitrophenyl) N,N-dimethylcarbamothioate
(7)
S-(4-(methylthio)phenyl)
N,N-dimethylcarbamothioate
Yield: 0.063g, 0.248 mmol, 99
%
(Conditions A).
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.56 (d, J = 8.7 Hz,
1H), 7.44 (d, J = 2.8 Hz, 1H), 7.11 (dd, J = 8.7, 2.8 Hz, 1H),
3.88 (s, 3H), 3.10 (bs, 3H), 3.01 (bs, 3H).
(15)
Conversion: 21 % (Conditions A).
The product is isolated as a mixture of starting material and
product.
The analytic data is in accordance with the literature.31
The analytic data is in accordance with the literature.29
S-(2-Formyl-4-methoxyphenyl)
dimethylcarbamothioate (8)
N,N-
Analytical data for the rearrangement of 16, 17, 18, 19a, 19b,
19c, and 19d were compared with the literature and it was
concluded that no conversion had occurred.12, 32
Yield: 0.057 g, 0.240 mmol, 96
%
(Conditions A).
1H NMR (500 MHz, CDCl3, 298 K): δ = 10.33 (s, 1H), 7.54
(d, J = 3.1 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.13 (dd, J = 8.5,
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The Journal of Organic Chemistry
Temperatures through Palladium Catalysis. Angew. Chem. Int.
Ed. 2009, 48, 7612ꢀ7615.
ASSOCIATED CONTENT
Supporting Information
1
2
3
4
5
6
7
8
16. Perkowski, A. J.; Cruz, C. L.; Nicewicz, D. A. Ambientꢀ
Temperature Newman–Kwart Rearrangement Mediated by
Organic Photoredox Catalysis. J. Am. Chem. Soc. 2015, 137,
15684ꢀ15687.
17. LloydꢀJones, G. C.; Moseley, J. D.; Renny, J. S. Mechanism and
Application of the NewmanꢀKwart O→S Rearrangement of Oꢀ
Aryl Thiocarbamates. Synthesis 2008, 2008, 661ꢀ689.
18. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes:
Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322ꢀ
5363.
Spectral characterisation data, determination of the rate constant
and crossover studies, as well as a description of the theoretical
calculations. The Supporting Information is available free of
charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
9
*Eꢀmail: pittel@chem.ku.dk
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19. Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
Chem. Rev. 2016, 116, 10075ꢀ10166.
20. Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran, D. P.; Rueping, M.
Oxygen Switch in VisibleꢀLight Photoredox Catalysis: Radical
Additions and Cyclizations and Unexpected C–CꢀBond Cleavage
Reactions. J. Am. Chem. Soc. 2013, 135, 1823ꢀ1829.
21. Gilday, J. P.; Lenden, P.; Moseley, J. D.; Cox, B. G. The
Newman−Kwart Rearrangement: A Microwave Kinetic Study. J.
Org. Chem. 2008, 73, 3130ꢀ3134.
22. Shaker, M.; Park, B.; Lee, J.ꢀH.; kim, W.; Trinh, C. K.; Lee, H.ꢀ
J.; Choi, J. w.; Kim, H.; Lee, K.; Lee, J.ꢀS. Synthesis and organic
field effect transistor properties of isoindigo/DPPꢀbased polymers
containing a thermolabile group. RSC Advances 2017, 7, 16302ꢀ
16310.
23. Amou, S.; Takeuchi, K.; Asai, M.; Niizeki, K.; Okada, T.; Seino,
M.; Haba, O.; Ueda, M. Synthesis of regiocontrolled polymer
having 2ꢀnaphthol unit by CuClꢀamine catalyzed oxidative
coupling polymerization. J. Polym. Sci., Part A: Polym. Chem.
1999, 37, 3702ꢀ3709.
24. Dhakshinamoorthy, A.; Pitchumani, K. Clayꢀsupported ceric
ammonium nitrate as an effective, viable catalyst in the oxidation
of olefins, chalcones and sulfides by molecular oxygen. Catal.
Commun. 2009, 10, 872ꢀ878.
25. Nair, V.; Deepthi, A. Cerium(IV) Ammonium NitrateA Versatile
SingleꢀElectron Oxidant. Chem. Rev. 2007, 107, 1862ꢀ1891.
26. Curtiss, L. A.; Redfern, P. C.; Raghavachari, K. Gaussianꢀ4
theory using reduced order perturbation theory. J. Chem. Phys.
2007, 127, 124105.
27. Gaussian 09, Revision A.02 and D.01, M. J. Frisch, G. W.
Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H.
Nakatsuji, X. Li, M. Caricato, A. Marenich, J. Bloino, B. G.
Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz,
A. F. Izmaylov, J. L. Sonnenberg, D. WilliamsꢀYoung, F. Ding,
F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T.
Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega,
G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E.
Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W.
Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B.
Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.
28. Curtiss, L. A.; Redfern, P. C.; Raghavachari, K. Gaussianꢀ4
theory. J. Chem. Phys. 2007, 126, 084108.
29. Maeda, K.; Okamoto, H.; Shinkai, H. Sꢀ(2ꢀ(Acylamino)phenyl)
2,2ꢀdimethylpropanethioates as CETP inhibitors. Bioorg. Med.
Chem. Lett. 2004, 14, 2589ꢀ2591.
30. Sugiyama, H.; Yoshida, M.; Mori, K.; Kawamoto, T.; Sogabe, S.;
Takagi, T.; Oki, H.; Tanaka, T.; Kimura, H.; Ikeura, Y. Synthesis
and Structure Activity Relationship Studies of Benzothieno[3,2ꢀ
b]furan Derivatives as a Novel Class of IKKβ Inhibitors. Chem.
Pharm. Bull. 2007, 55, 613ꢀ624.
ACKNOWLEDGMENT
We gratefully acknowledge support from the Danish Council for
Independent Research (DFF – 4181ꢀ00206).
REFERENCES
1. Newman, M. S.; Karnes, H. A. The Conversion of Phenols to
Thiophenols via Dialkylthiocarbamates. J. Org. Chem. 1966, 31,
3980ꢀ3984.
2. Kwart, H.; Evans, E. R. The Vapor Phase Rearrangement of
Thioncarbonates and Thioncarbamates. J. Org. Chem. 1966, 31,
410ꢀ413.
3. Błaszczyk, A.; Chadim, M.; Hänisch, C. v.; Mayor, M. Synthesis
of Macrocyclic Molecular Rods as Potential Electronic Devices.
Eur. J. Org. Chem. 2006, 2006, 3809ꢀ3825.
4. Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.; Jones, P.
G.; Hopf, H. A novel entry into a new class of cyclophane
derivatives: synthesis of (±)ꢀ[2.2]paracyclophaneꢀ4ꢀthiol.
Tetrahedron Lett. 2001, 42, 373ꢀ376.
5. Hori, M.; Ban, M.; Imai, E.; Iwata, N.; Suzuki, Y.; Baba, Y.;
Morita, T.; Fujimura, H.; Nozaki, M.; Niwa, M. Novel
nonnarcotic analgesics with an improved therapeutic ratio.
Structureꢀactivity relationships of 8ꢀ(methylthio)ꢀ and 8ꢀ
(acylthio)ꢀ1,2,3,4,5,6ꢀhexahydroꢀ2,6ꢀmethanoꢀ3ꢀbenzazocines. J.
Med. Chem. 1985, 28, 1656ꢀ1661.
6. Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Selection and
Amplification of Hosts From Dynamic Combinatorial Libraries
of Macrocyclic Disulfides. Science 2002, 297, 590ꢀ593.
7. Sørensen, A.; Rasmussen, B.; Agarwal, S.; SchauꢀMagnussen,
M.; Sølling, T. I.; Pittelkow, M. Conversion of Phenols into
Selenophenols: Seleno Newman–Kwart Rearrangement. Angew.
Chem. Int. Ed. 2013, 52, 12346ꢀ12349.
8. Lin, S.; Moon, B.; Porter, K. T.; Rossman, C. A.; Zennie, T.;
Wemple, J. A Continuous Procedure for Preparation of paraꢀ
Functionalized Aromatic Thiols Using NewmanꢀKwart
Chemistry. Org. Prep. Proced. Int. 2000, 32, 547ꢀ555.
9. Dallinger, D.; Lehmann, H.; Moseley, J. D.; Stadler, A.; Kappe,
C. O. ScaleꢀUp of MicrowaveꢀAssisted Reactions in a Multimode
BenchꢀTop Reactor. Org. Process Res. Dev. 2011, 15, 841ꢀ854.
10. Burns, M.; LloydꢀJones, G. C.; Moseley, J. D.; Renny, J. S. The
Molecularity of the Newman−Kwart Rearrangement. J. Org.
Chem. 2010, 75, 6347ꢀ6353.
11. Miyazaki, K. The thermal rearrangement of thionocarbamates to
thiolcarbamates. Tetrahedron Lett. 1968, 9, 2793ꢀ2798.
12. Moseley, J. D.; Sankey, R. F.; Tang, O. N.; Gilday, J. P. The
NewmanꢀKwart rearrangement reꢀevaluated by microwave
synthesis. Tetrahedron 2006, 62, 4685ꢀ4689.
13. Moseley, J. D.; Lenden, P. A high temperature investigation
using microwave synthesis for electronically and sterically
disfavoured substrates of the NewmanꢀKwart rearrangement.
Tetrahedron 2007, 63, 4120ꢀ4125.
14. Hoffmann, I.; Schatz, J. Microwaveꢀmediated NewmanꢀKwart
rearrangement in water. RSC Advances 2016, 6, 80692ꢀ80699.
15. Harvey, J. N.; Jover, J.; LloydꢀJones, G. C.; Moseley, J. D.;
Murray, P.; Renny, J. S. The Newman–Kwart Rearrangement of
OꢀAryl Thiocarbamates: Substantial Reduction in Reaction
31. Perjessy, A.; Jones, R. G.; McClair, S. L.; Wilkins, J. M. Infrared
spectra and transmission of electronic effects in substituted
phenyl
N,Nꢀdimethylcarbamates
and
Sꢀphenyl
N,Nꢀ
dimethylthiocarbamates. J. Org. Chem. 1983, 48, 1266ꢀ1271.
7
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32. Wang, C.; Batsanov, A. S.; Bryce, M. R.; Sage, I. An Improved
Synthesis
and
Structural
Characterisation
of
2ꢀ(4ꢀ
The
1
2
3
4
Acetylthiophenylethynyl)ꢀ4ꢀnitroꢀ5ꢀphenylethynylaniline:
Molecule Showing High Negative Differential Resistance (NDR).
Synthesis 2003, 2003, 2089ꢀ2095.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
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44
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46
47
48
49
50
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57
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59
60
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