The preparation of methyl (E)- and (Z)-O-methylbenzothiohydroximates

Article abstract of DOI:10.1071/CH03218

A series of methyl (Z)-O-methylbenzothiohydroximates were prepared either by reaction of the corresponding (Z)-N-methoxybenzenecarboximidoyl bromides with potassium fluoride in dimethyl sulfoxide, or by reaction of N-methoxybenzamides with Lawesson's reag

Full text of DOI:10.1071/CH03218

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 549–552
The Preparation of Methyl (E)- and (Z)-O-Methylbenzothiohydroximates
James E. Johnson,A,C Diana C. Canseco,A and Jeffrey E. RoweB,C
A Department of Chemistry and Physics, Texas Woman’s University, Denton TX 76204-5859, USA.
B Department of Chemistry, La Trobe University, Bundoora VIC 3086, Australia.
C Authors to whom correspondence should be addressed (e-mail: F_Johnson@twu.edu, jeff.rowe@latrobe.edu.au).
A series of methyl (Z)-O-methylbenzothiohydroximates were prepared either by reaction of the corresponding
(Z)-N-methoxybenzenecarboximidoyl bromides with potassium fluoride in dimethyl sulfoxide, or by reaction of
N-methoxybenzamides with Lawesson’s reagent followed by alkylation. Irradiation of the Z isomers led to a
photostationary equilibrium containing mixtures of approx. 40% E and 60% Z, from which the E isomers were
isolated.
Manuscript received: 25 August 2003.
Final version: 17 December 2003.
X
X
OCH3
Introduction
C
N
C
N
Over several years we have studied nucleophilic substitution
at the carbon–nitrogen double bond and the mechanism of
the acid-catalyzed cis–trans isomerization in several related
systems (1–5)[1–5] (Scheme 1). This work has involved the
preparation of a large number of compounds, the most recent
being a series of imidoyl fluorides 2.[1] As part of this
work, several thiomethyl compounds 6 were isolated as by-
products, leadingustoconsiderthesecompoundsasasuitable
new series of compounds for our mechanistic studies. Theo-
retical calculations also suggested that it would be useful to
compare the acid-catalyzed isomerization of the thiomethyl
compounds 6 with the previously prepared methoxy deriva-
tives 4.[6] In this paper we report the preparation of a series
of methyl (E)- and (Z)-O-methylbenzothiohydroximates 6.
These compounds seem to be almost unknown in the chemi-
cal literature. Walter et al.[7] reported the preparation of 6Za
and 6Ea. The only other report was from Nagata et al.[8,9]
OCH3
a Yϭ 4-H
b Yϭ 4-NO2
c Yϭ 4-OMe
d Yϭ 4-Cl
Y-C6H4
Y-C6H4
1Z Xϭ Cl
2Z Xϭ F
3Z Xϭ Br
4Z Xϭ OCH3
5Z Xϭ CN
6Z Xϭ SCH3
7Z Xϭ SCH2CH3
8Z Xϭ SCH2C6H5
1E Xϭ Cl
2E Xϭ F
3E Xϭ Br
4E Xϭ OCH3
5E Xϭ CN
e Yϭ 4-Me
6E Xϭ SCH3
Scheme 1.
approximately 3 d at around 150◦C (Scheme 2). A black
viscous solution resulted after this long reaction time from
which the desired compounds could be extracted in fairly
low yields. Scheme 3 indicates a possible mechanism for the
conversion of the imidoyl fluorides 2Z into the thiomethyl
compounds. Recent work on nucleophilic substitution at
the carbon–nitrogen double bond[6] indicates that the flu-
oro compounds 2 are more reactive towards nucleophilic
substitution than any other compounds in this series, 1,3–5.
This enhanced reactivity towards nucleophilic substitution
accounts for the slow conversion into the thiomethyl com-
pounds. Given the very vigorous conditions used to pre-
pare these compounds, the isomers isolated must be the
thermodynamically more stable isomers. Several compounds
reported here were prepared using this procedure. Sub-
sequently, a simpler method for preparing these thiomethyl
compounds was found. N-Methoxybenzamides were reacted
with Lawesson’s reagent,[11] leading to the (assumed) thio-
hydroxamic acids, which were not isolated, but immediately
methylated to give the desired compounds in excellent yields
(Scheme 2). Several compounds prepared by this method
are also reported here. This method gives access to a wide
Results and Discussion
In our earlier work on the preparation of the imidoyl fluorides
2Z[1] from the reaction of the corresponding bromo com-
pounds 3Z with potassium fluoride in dimethyl sulfoxide,
small amounts of the thiomethyl compounds 6Z were also
always present. 6Za and 6Ze were isolated and identified as
part of this earlier work.[1] Finger et al.[10] have also reported
the preparation of thiomethyl compounds during the prepara-
tion of fluoropyridines from the reaction of chloropyridines
with potassium fluoride in dimethyl sulfoxide.
Further work established that the fluoro compounds 2Z
were being converted into the corresponding thiomethyl com-
pounds under the reaction conditions used, and all that was
required to maximize the yields of the thiomethyl com-
pounds was to extend the reaction times from 10–12 h to
© CSIRO 2004
10.1071/CH03218
0004-9425/04/060549

550
J. E. Johnson, D. C. Canseco and J. E. Rowe
H3CS
Ar
E isomers predominated. For example, 4a gave an equilib-
rium distribution[12] of 83% E and 17% Z in an HCl/dioxan
solution at 39.5◦C. Intuitively, then, one might have predicted
that the E isomers would be the most stable for the thiomethyl
compounds 6. To definitively answer this question, the crys-
talline 4-nitro derivative 6Zb was prepared and the X-ray
crystal structure obtained, and was shown to have the Z
configuration.[13] The NMR spectra of these compounds 6
were not very helpful in assigning the configurations of the
isomers, but were sufficiently different to allow the com-
pounds to be grouped into two series, with the initially formed
compounds and more stable isomers always having the same
configuration as the 4-nitro compound and, therefore, the
Z configuration. The isomers formed on irradiation, which
by NMR also belong to a coherent series, must then have
the E configuration. For example, the SMe resonance was
at 15.0 0.2 ppm in the 13C spectra of the Z isomers and
at 14.2 ppm for the E isomers, and in the proton spectra, at
2.0–2.1 ppm in the Z isomers and around 2.4 ppm in the
E isomers.
C
N
OCH3
OCH3
6E
hn
Br
OCH3
F
OCH3
H3CS
Ar
KF
C
N
C
N
C
N
DMSO
Ar
Ar
3Z
2Z
6Z
dimethyl
sulfate
O
S
Lawesson’s
reagent
Ar
C
N
H
OCH3
Ar
C
N
H
OCH3
Scheme 2. The preparation of methyl (E and Z)-O-methyl-
benzothiohydroximates.
O
S
O
S
2H3C
CH3
ϩ
H3C
CH3
H3C
S
CH3
O
Conclusions
F
OCH3
CH3
F
OCH3
Preparation of the methyl (Z)-O-methylbenzothio-
hydroximates 6Z was achieved by two alternative synthetic
routes, either by reaction of the corresponding (Z)-N-
methoxybenzenecarboximidoyl bromides 3Z with potassium
fluoride in dimethyl sulfoxide, or by reaction of N-methoxy-
benzamides with Lawesson’s reagent followed by alkylation.
Irradiation of solutions of the Z isomers led to photostation-
ary mixtures containing both the Z and E isomers from which
the pure E isomers 6E were isolated.
C
ϪN
C
N
ϩ
H3C
S
CH3
Ar
ϩ
S
Ar
H3C
CH3
FϪ
H3C
S
OCH3
OCH3
ϩ
S
H3C
C
N
C
N
Ar
Ar
Scheme 3. A possible mechanism for the formation of the thiomethyl
compounds 6Z from the imidoyl fluorides.
Experimental
General Methods
Potassium fluoride was the spray-dried reagent from Aldrich. Photo-
chemical isomerization reactions were carried out in quartz tubes placed
in a Rayonet reactor, model RPR-100 (Southern New England Ultra-
violet Co.), fitted with 15 low-pressure lamps (254 nm). The 1H NMR
spectra were acquired at 300.13 MHz, and the 13C spectra at 75.47 MHz,
on either a Bruker Avance 300 spectrometer or a Varian Mercury
300 MHz spectrometer in deuterated chloroform. Low-resolution mass
spectra were obtained on a Varian Saturn 3 ion-trap GC-mass spectrom-
eter. New compounds gave a single spot by TLC analysis or a single
peak in the GC/MS, and showed the required numbers of carbons in the
13C NMR spectra. Elementary analyses of some compounds described
in this work were carried out by Midwest Microlab, Indianapolis, IN,
and the Campbell Microanalytical Laboratory, University of Otago.
variety of different alkyl derivatives, with the thioethyl 7Zb
and thiobenzyl 8Zb derivatives of compounds 6Zb being
included here as examples. Walter et al.[7] has also reported
the preparation of 6Za by methylation of the thiohydroxamic
acid.
Ultraviolet irradiation of benzene solutions of the Z iso-
mers, 6Z, gave a photostationary mixture of the E and Z
isomers with an approximately 40 : 60 (E/Z) mixture of the
two isomers. The E isomers were separated from the Z iso-
mers by column chromatography. This separation of the E
isomers from mixtures containing higher concentrations of
the Z isomers was difficult, leading to poor yields of the pure
E isomers.
Preparation of Methyl ( Z)-O-Methylbenzothiohydroximates 6 from
the Equivalent Imidoyl Bromide and KF
Walter[7] used dipole moment measurements to predict
which of his isomers was the Z and which was the E isomer.
In our previous work,[2,3] we have found this method to be
extremelyunreliableinpredictingtheconfigurationofsimilar
isomers. Where possible, we have confirmed our assignments
by X-ray crystal structure analysis.[2,3] The NMR spectra are
usually sufficiently different to also help in the assignment of
the configuration in similar isomers.[1] In the halogen deriva-
tives 1–3, the most stable isomers were always found to have
the Z configuration, while for the methoxy derivatives 4, the
Methyl ( Z)-O-Methylbenzothiohydroximate 6Za[1,7]
(Z)-N-Methoxybenzenecarboximidoyl bromide (20.6 g, 0.096 mol) and
spray-dried potassium fluoride (25.80 g, 0.43 mol) in dry DMSO
(365 mL) were heated and stirred at 150◦C for 59 h. Nitrogen gas was
purged through the system during this period. On cooling, saturated
sodium chloride solution (400 mL) was added and the organic products
were extracted into ether. The ether solution was washed with saturated
sodium chloride solution, dried (MgSO4), and the solvent removed by
evaporation. The crude product was purified by fractional distillation
yielding an oil which solidified on cooling (3.40 g, 20%). δH (300 MHz,
CDCl3) 2.02 (3H, s, SCH3), 4.03 (3H, s, OCH3), 7.40 (5H, s, ArH).

Preparation of Methyl (E)- and (Z)-O-Methylbenzothiohydroximates
551
δC (75.5 MHz, CDCl3) 14.9 (SCH3), 62.4 (OCH3), 128.4 (CH), 128.6
(CH), 129.3 (CH), 132.4 (C), 155.4 (C).
after recrystallization from hexane/dichloromethane (4 : 1) (83%), mp
62–63◦C (Found: C 59.6, H 4.9, N 9.3. C15H14N2O3S requires C 59.6,
H 4.7, N 9.3%). δH (300 MHz, CDCl3) 3.92 (2H, s, SCH2), 4.07 (3H,
s, OCH3), 7.07 (2H, m, ArH), 7.20 (3H, m, ArH), 7.61 (2H, d, J 8.9,
ArH), 8.15 (2H, d, J 8.9, ArH). δC (75.5 MHz, CDCl3) 36.3 (SCH2),
62.9 (OCH3), 123.4 (CH), 127.4 (CH), 128.4 (CH), 128.5 (CH), 129.3
(CH), 136.4 (C), 139.9 (C), 148.1 (C), 150.2 (C).
The following compounds were also prepared by a similar method:
Methyl ( Z)-4-methoxy-O-methylbenzothiohydroximate 6Zc
This compound was obtained as a colourless liquid (11%) (Found:
C 56.8, H 6.2, N 6.6, S 15.1. C10H13NO2S requires C 56.9, H 6.2,
N 6.6, S 15.2%). δH (300 MHz, CDCl3) 2.07 (3H, s, SCH3), 3.83 (3H,
s, OCH3), 4.03 (3H, s, OCH3), 6.93 (2H, d, J 9.1, ArH), 7.36 (2H, d,
J 9.1, ArH). δC (75.5 MHz, CDCl3) 15.1 (SCH3), 55.3 (OCH3), 62.4
(OCH3), 113.9 (CH), 124.9 (C), 130.0 (CH), 155.2 (C), 160.4 (C).
Preparation of the E Isomers by Photoisomerization of the Z Isomers
Methyl (E)-4-chloro-O-methylbenzothiohydroximate 6Ed
Methyl (Z)-4-chloro-O-methylbenzothiohydroximate (2.9 g) in ben-
zene (50 mL) was placed in 13 cm quartz tubes and irradiated in a
Rayonet photochemical reactor (254 nm) for 5.5 h. Analysis of the
benzene solution by GC/MS indicated a mixture of Z and E isomers
in a ratio of 60 : 40. This benzene solution was extracted with 10%
sodium carbonate solution before drying the benzene solution (MgSO4)
and removing the solvent by evaporation. The isomers were separated
by column chromatography on silica gel (90 : 10 hexane/chloroform)
leading first to the E isomer (0.25 g, 9%) and then to the Z isomer
(0.74 g, 26%).
For the E isomer (Found: C 50.3, H 4.7, Cl 16.7, N 6.6, S 14.6.
C9H10ClNOS requires C 50.1, H 4.7, Cl 16.4, N 6.5, S 14.9%). δH
(300 MHz, CDCl3) 2.41 (3H, s, SCH3), 3.87 (3H, s, OCH3), 7.35 (2H,
d, J 8.6, ArH), 7.45 (2H, d, J 8.6, ArH). δC (75.5 MHz, CDCl3) 14.2
(SCH3), 62.3 (OCH3), 128.3 (CH), 129.7 (CH), 130.9 (C), 135.4 (C),
154.0 (C).
Methyl ( Z)-4-chloro-O-methylbenzothiohydroximate 6Zd
This compound was obtained as a pale yellow solid (16%), mp 30–31◦C
(Found: C 50.1, H 4.7, Cl 16.7, N 6.5, S 14.7. C9H10ClNOS requires
C 50.1, H 4.7, Cl 16.4, N 6.5, S 14.9%). δH (300 MHz, CDCl3) 2.08
(3H, s, SCH3), 4.04 (3H, s, OCH3), 7.40 (4H, s, ArH). δC (75.5 MHz,
CDCl3) 15.1 (SCH3), 62.6 (OCH3), 128.8 (CH), 130.0 (CH), 131.1 (C),
135.5 (C), 154.2 (C).
Preparation of Alkyl ( Z)-O-Methylbenzothiohydroximates Using
Lawesson’s Reagent
Methyl ( Z)-4-methoxy-O-methylbenzothiohydroximate 6Zc
N,4-Dimethoxybenzamide (0.64 g, 3 mmol) and Lawesson’s reagent[12]
(1.22 g, 3 mmol) in benzene (16 mL) were heated at reflux and stirred
for 12 h under an atmosphere of nitrogen. On cooling, ether (16 mL)
was added, the mixture was filtered, and the solvent was removed by
evaporation.
This crude product and sodium hydroxide (0.18 g, 4.6 mmol) were
dissolved by warming in water (10 mL) and ethanol (16 mL). On cool-
ing the solution to room temperature, dimethyl sulfate (0.38 mL, 0.60 g.
4.0 mmol) was added and the resulting solution stirred at room temper-
ature for 3 h. The ethanol was removed by evaporation. The product was
extracted into CH2Cl2, the CH2Cl2 solution was washed with water,
dried, and the solvent was removed by evaporation to give a reddish
oil. This oil was purified by dry column chromatography on silica using
CH2Cl2/hexane (1 : 1) as the eluting solvent, yielding the product as an
oil (0.62 g, 82%). δC (75.5 MHz, CDCl3) 15.0 (SCH3), 55.3 (OCH3),
62.4 (OCH3), 114.0 (CH), 125.0 (C), 130.1 (CH), 155.3 (C), 160.5 (C).
The following compounds were prepared by a similar method:
The following compounds were also prepared by a similar method:
Methyl ( E)-O-methylbenzothiohydroximate 6Ea
This compound was obtained as an oil (11%) (Found: C 56.6, H 6.0,
N 7.7, S 17.4. C9H11NOS requires C 59.6, H 6.1, N 7.7, S 17.7%). δH
(300 MHz, CDCl3) 2.41 (3H, s, SCH3), 3.87 (3H, s, OCH3), 7.38 (3H,
m, ArH), 7.48 (2H, m, ArH). δC (75.5 MHz, CDCl3) 14.2 (SCH3), 62.2
(OCH3), 128.1 (CH), 128.2 (CH), 129.5 (CH), 132.7 (C), 155.2 (C).
Methyl ( E)-4-methoxy-O-methylbenzothiohydroximate 6Ec
This compound was obtained as a solid (11%), mp 41.5–42.5◦C (Found:
C 56.7, H 6.2, N 6.4, S 15.0. C10H13NO2S requires C 56.9, H 6.2, N
6.6, S 15.2%). δH (300 MHz, CDCl3) 2.39 (3H, s, SCH3), 3.81 (3H,
s, OCH3), 3.87 (3H, s, OCH3), 6.90 (2H, d, J 9.1, ArH), 7.51 (2H, d,
J 9.1, ArH). δC (75.5 MHz, CDCl3) 14.2 (SCH3), 55.2 (OCH3), 62.1
(OCH3), 113.4 (CH), 124.8 (C), 129.9 (CH), 154.7 (C), 160.2 (C).
Methyl ( Z)-O-methylbenzothiohydroximate 6Za
This compound was obtained as an oil (61%). δC (75.5 MHz, CDCl3)
14.8 (SCH3), 62.4 (OCH3),128.5 (CH), 128.7 (CH), 129.4 (CH), 132.5
(C), 155.5 (C).
Methyl ( E)-O,4-dimethylbenzothiohydroximate 6Ee
This compound was obtained as an oil (11%) (Found: C 61.7, H 6.8,
N 7.1, S 16.3. C10H13NOS requires C 61.5, H 6.7, N 7.2, S 16.4%).
δH (300 MHz, CDCl3) 2.36 (3H, s, ArCH3), 2.40 (3H, s, SCH3), 3.87
(3H, s, OCH3), 7.19 (2H, d, J 8.0, ArH), 7.41 (2H, d, J 8.0, ArH). δC
(75.5 MHz, CDCl3) 14.2 (SCH3), 21.5 (ArCH3), 62.1 (OCH3), 128.1
(CH), 128.7 (CH), 129.7 (C), 139.6 (C), 155.2 (C).
Methyl ( Z)-O-methyl-4-nitrobenzothiohydroximate 6Zb
This compound was obtained as an off-white crystalline solid after
recrystallization from hexane/dichloromethane (4 : 1) (60%), mp 113–
114◦C. The reaction with Lawesson’s reagent in the first step only took
3 h. δC (75.5 MHz, CDCl3) 15.2 (SCH3), 63.0 (OCH3), 123.8 (CH),
129.7 (CH), 139.3 (C), 148.3 (C), 152.7 (C).
Acknowledgments
Ethyl ( Z)-O-methyl-4-nitrobenzothiohydroximate 7Zb
The Minority Biomedical Research Support Program of the
National Institutes of Health (NIH-MBRS Grant GM08256),
the RobertA. Welch Foundation, and theTexasWoman’s Uni-
versity Research Enhancement Program supported this work.
J.E.R. thanks the Texas Woman’s University for hospitality
during the completion of part of this work.
This compound was prepared using diethyl sulfate in place of dimethyl
sulfate. Compound 7Zb was obtained as a colourless crystalline solid
after recrystallization from hexane/dichloromethane (4 : 1) (88%), mp
75–76◦C (Found: C 50.1, H 5.3, N 11.6. C10H12N2O3S requires C 50.0,
H 5.0, N 11.7%). δH (300 MHz, CDCl3) 1.13 (3H, t, J 7.4,–CH2CH3),
2.66 (2H, q, J 7.4, SCH2CH3) 4.06 (3H, s, OCH3), 7.73 (2H, d, J 8.7,
ArH), 8.23 (2H, d, J 8.7,ArH). δC (75.5 MHz, CDCl3) 15.1 (CH3), 26.5
(SCH2), 62.9 (OCH3), 123.7 (CH), 129.4 (CH), 140.0 (C), 148.3 (C),
151.3 (C).
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