Intramolecular interception of the Newman-Kwart rearrangement by carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2020.152153

Instead of undergoing the Newman-Kwart rearrangement, thermally-promoted reactions of O-aryl dimethylthiocarbamates featuring ortho-carboxylic acid substituents result in the loss of carbonylsulfide and formation of N,N-dimethylsalicylamides in high yield

Full text of DOI:10.1016/j.tetlet.2020.152153

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular interception of the Newman-Kwart rearrangement
by carboxylic acids
Timothy A. Ablott a, Mitchell G. Fishburn a, David R. Turner b, Christopher Richardson a,
⇑
a School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
b School of Chemistry, Monash University, Clayton, VIC 3800, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Instead of undergoing the Newman-Kwart rearrangement, thermally-promoted reactions of O-aryl
dimethylthiocarbamates featuring ortho-carboxylic acid substituents result in the loss of carbonylsulfide
and formation of N,N-dimethylsalicylamides in high yields.
Received 17 April 2020
Revised 2 June 2020
Accepted 16 June 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Newman-Kwart rearrangement
Microwave-assisted synthesis
Metal-organic framework
Thermal reaction
Introduction
phenolic esters (1) and (2) in DMA solution and then selective
hydrolysis of the methyl esters (3) and (4) in aqueous hydroxide
We are pursuing a research program concerned with thermally-
promoted organic reactions in metal–organic frameworks [1–8].
Within this context, we became interested in the Newman-Kwart
rearrangement (NKR) [9]. This well-established reaction converts
O-aryl dialkylthiocarbamates to S-aryl dialkylthiocarbamates and
proceeds via an intramolecular pathway [10]. The NKR is a useful
tool as subsequent hydrolysis of the S-aryl dialkylthiocarbamate
unveils sulfhydryl groups and can be used, with proper planning,
in the synthesis of sulfur-containing heterocycles [11–13]. The
NKR shows good functional group tolerance with electron-with-
drawing groups and ortho-substituents on the phenyl ring often
proving advantageous. Microwave-assisted synthesis has opened
up the scope of this reaction as the purely thermally-promoted
NKR is effected at temperatures generally exceeding 200 °C [14,15].
We sought to extend our studies to the O-aryl dimethylthiocar-
bamate-functionalized terephthalic acids (5) and (6) shown in
Fig. 1 and we report herein their syntheses and thermal reactivity,
and those of their esterified precursors, in melts and microwave-
heated solutions.
at room temperature, as shown in Scheme 1. Compounds (3)-(6)
were characterized by 1H and 13C NMR spectroscopy (Figs. S1-S8,
ESI).
Compounds (3)-(6) were analyzed for their thermal properties
by simultaneous differential scanning calorimetry-thermogravi-
metric analysis (DSC-TGA) (Figs. S24-S36, ESI). Compound (3)
melted without decomposition and the exotherm around 245 °C
occurs without accompanying mass loss, consistent with a rear-
rangement reaction. At higher temperatures the sample vaporizes.
Heating (3) in a melt reaction at 240 °C for 20 min led to the isola-
tion of the expected Newman-Kwart product, dimethyl 2-
((dimethylcarbamoyl)thio)terephthalate (7), as the only product
in essentially quantitative yield.
The ethyl ester derivative of compound (4) [16–18] is known to
undergo the NKR giving the S-aryl diethylthiocarbamate derivative
in high yield by heating neat above 220 °C. The DSC-TGA of (4)
indicates the NKR ensues immediately upon the compound melt-
ing around 227 °C and completes rapidly. In our hands, this gives
the expected NKR product (9) as the only product in near quantita-
tive recovery upon isolation.
For comparison, microwave-assisted reactions were performed
on (3) and (4) at 240 °C for 10 min in DMF solutions (Scheme 2).
In contrast to the melt reaction, the solvothermal reaction of (3)
produced two compounds, which were separated by flash column
chromatography on silica gel. The expected NKR product (7) was
the more polar compound and the major component of the mix-
ture (64%). The less polar compound was isolated in 20% yield
Results and discussion
Diacids (5) and (6) were prepared by a standard reaction of
dimethylthiocarbamoyl chloride (dmtc-Cl) and DABCO with the
⇑
Corresponding author.
E-mail address: chris_richardson@uow.edu.au (C. Richardson).
https://doi.org/10.1016/j.tetlet.2020.152153
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: T. A. Ablott, M. G. Fishburn, D. R. Turner et al., Intramolecular interception of the Newman-Kwart rearrangement by carboxylic
acids, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152153

2
T.A. Ablott et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. The structures of (5) and (6).
and identified as dimethyl 2-(methylthio)terephthalate (8) by sin-
gle crystal X-ray diffraction analysis (Fig. 2), with its bulk purity
established by 1H and 13C NMR spectroscopy (Figs. S9 and S10,
ESI). The most likely route for forming (8) is by cleavage of the
CAS bond in (7) and methylation under the reaction conditions.
We note that this product was observed in all microwave heated
reactions of (3) but usually in smaller proportions. Compound (9)
is produced efficiently and cleanly in 92% isolated yield from com-
pound (4) under these microwave conditions.
We determined the crystal structures of (3), (4), (7), (8) and (9)
by single crystal X-ray diffraction (CCDC Deposition Numbers
1988281–1988284) and show the molecular structures in Fig. 2.
A full molecule of (3) crystallizes in the asymmetric unit of the tri-
clinic space group P1̅. The ester group adjacent to the dimethylth-
iocarbamate group is inclined to the central phenyl ring with a
twist angle of 28.0(1)° forcing the dimethylthiocarbamate group
to be close to perpendicular (81.4(2)°) with the sulfur atom nicely
poised for the NKR at a distance of 2.976(1) Å from the ipso carbon
(Fig. S37, ESI). Compound (4) crystallizes with the molecule coinci-
dental to an inversion center in the space group P1̅ and therefore
has half a molecule in the asymmetric unit. The same general fea-
tures are seen in the structure of (4); the methyl esters take the
more coplanar conformation with respect to the central phenyl
ring (twist angles 28.6(3)°) compared to the dimethylthiocarba-
mate groups (79.33(5)°) and the sulfur atoms are positioned
2.968(1) Å from the ipso carbons (Fig. S37, ESI).
Fig. 2. The molecular structures of (3), (4), (8), and (9) determined from X-ray
crystallography. Ellipsoids shown at the 50% probability level.
The X-ray structure of (8) was determined from synchrotron
data [19]. The analysis revealed (8) crystallizes with two molecules
in the asymmetric unit of P21/c, of which one is shown in Fig. 2. All
non-hydrogen atoms adopt coplanar conformations with the cen-
spectrum of the material recovered from heating (5) to 230 °C
and holding for 20 min under nitrogen and subsequent MeOH/
H2O trituration showed that the major product was 2-hydrox-
yterephthalic acid, but also showed a second compound with a
phenolic signal typical of an ortho-hydroxy benzoic acid and two
broad signals for the methyl groups, suggestive of a tertiary amide.
The negative-mode ESI mass spectrum showed signals at 181 m/z
and 208 m/z assignable to 2-hydroxyterephthalic acid and 4-
(dimethylcarbamoyl)-3-hydroxybenzoic acid (10), respectively.
A proposed mechanism for the transformation from (5) to (10)
is shown in Scheme 3. The key step is the participation of the
neighbouring carboxylic acid group, precluding a NKR. This trans-
fers the dimethylthiocarbamoyl group to form an activated ester
that collapses at high temperature with expulsion of carbonylsul-
fide to the observed product. To the best of our knowledge this
transformation is unreported. As the mass loss in DSC-TGA is only
tral phenyl ring and the molecules stack with slipped p-p interac-
tions in the lattice. Compound (9) crystallizes in the space group
Pna21 with a full molecule in the asymmetric unit. The esters make
similar approximate twist angles of ~32° to the aromatic ring as
those seen in (4) but the twist angles between the aromatic ring
and the S-aryl dimethylthiocarbamate groups are much smaller
at ~50°. This may be attributable to the longer CAS bonds
(Caryl-S ~ 1.77 Å) relaxing steric constraints around the aromatic
nucleus.
The first event in the DSC-TGA trace of (5) is melting at 220 °C,
and this is accompanied by a rapid mass loss of 23% (Figs. S25 and
S26, ESI) and the evident smell of carbonylsulfide (calculated 22%
by mass). The broad endothermic mass loss that follows at higher
temperatures indicates vaporization of the sample. The 1H NMR
Scheme 1. Reaction conditions and yields for the synthesis of (5) and (6).
Please cite this article as: T. A. Ablott, M. G. Fishburn, D. R. Turner et al., Intramolecular interception of the Newman-Kwart rearrangement by carboxylic
acids, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152153

T.A. Ablott et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Scheme 2. Reaction conditions and yields for the microwave reactions of (3) and (4).
Scheme 3. Proposed mechanism for the transformation of (5) to (10).
consistent with the loss of carbonylsulfide, we rationalized the for-
mation of 2-hydroxyterephthalic acid, which requires further mass
loss, from acidolysis of some product during the melt reaction uti-
lizing the free carboxylic acid functionality in (10). Indeed, quanti-
tative crude recoveries were obtained when the reaction was
repeated on 2-((dimethylcarbamothioyl)oxy)benzoic acid and
2-((dimethylcarbamothioyl)oxy)-5-methoxybenzoic acid giving
2-hydroxy-N,N-dimethylbenzamide [20] and 2-hydroxy-5-meth-
oxy-N,N-dimethylbenzamide [21] respectively (Figs. S28–S33, ESI).
Similarly, heating (6) saw the rapid loss of 33% mass upon melt-
ing at ~200 °C in DSC-TGA, matching that expected for the loss of
two molar equivalents of carbonylsulfide (32%) (Figs. S34 and
S35, ESI) and pure material could be recovered in near quantitative
yield after trituration and filtration. The 1H NMR spectrum of the
product contained signals expected for 2,5-dihydroxy-N1,N1,N4,
N4-tetramethylterephthalamide (11) (Fig. S15, ESI). Crystallization
from hot DMSO furnished crystals suitable for single crystal X-ray
diffraction and the analysis confirmed the structure and showed
(11) (CCDC Deposition Number 1988285) crystallizes in the space
group P21/n with half a molecule in the asymmetric unit (Fig. 3).
There is a considerable twist angle of 62.00(5)° from the amide
group to the plane of the central phenyl ring as a result of the
ortho-hydroxyl groups. The crystal structure features a two-dimen-
sional polymeric hydrogen bonding pattern, which accounts for the
extremely low solubility of this compound in common organic sol-
vents and in water. Each molecule of (11) connects to four other
molecules in the sheet structure via short contacts (1.784(1) Å)
between phenoxyl proton donors and carbonyl oxygen acceptors
in neighbouring molecules (Fig. 3). The singular other report of this
compound described its expedient preparation from 2,5-dihydrox-
yterephthalic acid and DMF in the presence of P2O5 [22].
Conclusion
We have found that carboxylic acids positioned ortho to O-aryl
dimethylthiocarbamate groups intercepts NKR chemistry in high
temperature thermal processes and provide an expeditious and
previously unreported synthesis of salicyldimethylamides.
Declaration of Competing Interest
Fig. 3. The molecular structure of (11) with ellipsoids shown at the 50% probability
level (top); and a view of the two-dimensional hydrogen bonding pattern in the
structure where, for clarity, only hydrogen atoms involved in the polymeric donor-
acceptor interactions are shown (bottom).
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Please cite this article as: T. A. Ablott, M. G. Fishburn, D. R. Turner et al., Intramolecular interception of the Newman-Kwart rearrangement by carboxylic
acids, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152153

4
T.A. Ablott et al. / Tetrahedron Letters xxx (xxxx) xxx
[7] M.R. Bryant, A.D. Burrows, C.J. Kepert, P.D. Southon, O.T. Qazvini, S.G. Telfer, C.
Acknowledgments
Richardson, Cryst. Growth Des. 17 (2017) 2016–2023.
[8] M.R. Bryant, T.A. Ablott, S.G. Telfer, L. Liu, C. Richardson, CrystEngComm 21
(2019) 60–64.
[9] G.C. Lloyd-Jones, J.D. Moseley, J.S. Renny, Synthesis 2008 (2008) 661–689.
[10] M. Burns, G.C. Lloyd-Jones, J.D. Moseley, J.S. Renny, J. Org. Chem. 75 (2010)
6347–6353.
[11] L.K.A. Rahman, R.M. Scrowston, J. Chem. Soc., Perkin Trans. 1 (1983) 2973–
2977.
[12] P. Rodighiero, G. Pastorini, A. Chilin, A. Marotto, J. Het. Chem. 35 (1998) 847–
852.
T.A.A. and M.G.F. acknowledge the Australian Government for
Australian Government Research Training Program Awards. C.R.
thanks the University of Wollongong for financial support. This
research was undertaken in part using the MX2 beamline at the
Australian Synchrotron, part of ANSTO, and made use of the
Australian Cancer Research Foundation (ACRF) detector.
[13] H. Meier, A. Mayer, Angew. Chem. Int. Ed. Engl. 33 (1994) 465–467.
[14] J.D. Moseley, P. Lenden, Tetrahedron Lett. 63 (2007) 4120–4125.
[15] J.D. Moseley, R.F. Sankey, O.N. Tang, J.P. Gilday, Tetrahedron Lett. 62 (2006)
4685–4689.
[16] L. Field, P.R. Engelhardt, J. Org. Chem. 35 (1970) 3647–3655.
[17] L. Vial, R.F. Ludlow, J. Leclaire, R. Pérez-Fernández, S. Otto, J. Am. Chem. Soc.
128 (2006) 10253–10257.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152153.
[18] P.T. Skowron, M. Dumartin, E. Jeamet, F. Perret, C. Gourlaouen, A. Baudouin, B.
Fenet, J.V. Naubron, F. Fotiadu, L. Vial, J. Leclaire, J. Org. Chem. 81 (2016) 654–
661.
References
[19] D. Aragao, J. Aishima, H. Cherukuvada, R. Clarken, M. Clift, N.P. Cowieson, D.J.
Ericsson, C.L. Gee, S. Macedo, N. Mudie, S. Panjikar, J.R. Price, A. Riboldi-
Tunnicliffe, R. Rostan, R. Williamson, T.T. Caradoc-Davies, J. Synchrotron Rad.
25 (2018) 885–891.
[1] A.D. Burrows, C. Frost, M.F. Mahon, C. Richardson, Angew. Chem. Int. Ed. 47
(2008) 8482–8486.
[2] A.D. Burrows, C.G. Frost, M.F. Mahon, C. Richardson, Chem. Commun. (2009)
4218–4220.
[20] W. Ali, S.K. Rout, S. Guin, A. Modi, A. Banerjee, B.K. Patel, Adv. Synth. Catal. 357
(2015) 515–522.
[21] S. Mavel, N. Meheux, D. Guilloteau, P. Emond, Bioorg. Med. Chem. 18 (2010)
236–241.
[3] A.D. Burrows, L.C. Fisher, D. Hodgson, M.F. Mahon, N.F. Cessford, T. Düren, C.
Richardson, S.P. Rigby, CrystEngComm 14 (2012) 188–192.
[4] A.D. Burrows, S.O. Hunter, M.F. Mahon, C. Richardson, Chem. Commun. 49
(2013) 990–992.
[5] M.R. Bryant, C. Richardson, CrystEngComm 17 (2015) 8858–8863.
[6] T.A. Ablott, M. Turzer, S.G. Telfer, C. Richardson, Cryst. Growth Des. 16 (2016)
7067–7073.
[22] H. Schindlbauer, Monatsh. Chem. 99 (1968) 1799–1807.
Please cite this article as: T. A. Ablott, M. G. Fishburn, D. R. Turner et al., Intramolecular interception of the Newman-Kwart rearrangement by carboxylic
acids, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152153