Organic Synthesis with N-Heterocyclic Carbenes of Indazole: Synthesis of Benzo(thio)imidates, Benzo[d][1,3]thiazines and Quinazoline-4-thiones

Article abstract of DOI:10.1002/ejoc.201500331

The N-heterocyclic carbenes of indazole, generated by deprotonation of indazolium salts, proved to be versatile starting materials for organic synthesis. They undergo ring-opening reactions to generate ketenimines which readily add thiols thus affording what are, to the best of our knowledge, the first examples of 2-anilinobenzothioimidates. Water converts the ring-opened intermediates into functionalized 2-anilinobenzamides which can be thionated with Lawesson's reagent and subsequently cyclized with formaldehyde and propionaldehyde, respectively, to give benzo[d][1,3]thiazines and quinazoline-4-thiones. The outcome of the cyclization depends upon the thiobenzamide substitution pattern.

Full text of DOI:10.1002/ejoc.201500331

FULL PAPER
DOI: 10.1002/ejoc.201500331
Organic Synthesis with N-Heterocyclic Carbenes of Indazole: Synthesis of
Benzo(thio)imidates, Benzo[d][1,3]thiazines and Quinazoline-4-thiones
Zong Guan,[a] Martin Nieger,[b] and Andreas Schmidt*[a]
Keywords: Nitrogen heterocycles / Carbenes / Ketene imines / Thioketones / Cyclization
The N-heterocyclic carbenes of indazole, generated by de-
protonation of indazolium salts, proved to be versatile start-
the ring-opened intermediates into functionalized 2-anilino-
benzamides which can be thionated with Lawesson’s reagent
ing materials for organic synthesis. They undergo ring-open- and subsequently cyclized with formaldehyde and propion-
ing reactions to generate ketenimines which readily add thi-
ols thus affording what are, to the best of our knowledge, the
first examples of 2-anilinobenzothioimidates. Water converts
aldehyde, respectively, to give benzo[d][1,3]thiazines and
quinazoline-4-thiones. The outcome of the cyclization de-
pends upon the thiobenzamide substitution pattern.
synthesis, the origin of which dates back into the 19th cen-
tury.[25] A copper catalyst is required to prepare thioimid-
ates from isocyanides.[26] Finally, the Beckmann rearrange-
ment can be modified in such a way that thioimidates are
formed.[27,28]
Introduction
Thioimidates (imidothioic acid esters, imidothioates)
constitute a relatively unknown class of compounds. Their
syntheses have been reviewed in 2005 by summarizing only
34 references.[1] Nevertheless, the synthetic potential of this
functional group has been demonstrated by the preparation
of several heterocyclic ring systems from suitable substi-
tuted thioimidates; among these are triazoles,[2] chiral
pyrrolidinones,[3] thiazoles,[4] pyrroles,[5] 3,4-dihydro-2H-
pyrroles,[6] pyrimidines,[7] dihydropyridines,[8] and 2-azabi-
cyclo[3.2.0]hept-2-enes.[9] Furthermore, N,NЈ-unsymmetri-
cally substituted 1,3-diketimines were prepared from
thioimidates.[10] Iminium salts of thioimidates were used for
aromatic thioether production proceeding by nucleophilic
aromatic substitution[11] or as precursors of azomethinyl-
ides for 1,3-dipolar cycloadditions.[12] Hitherto known
preparations of thioimidates are as follows (Scheme 1).
First, nucleophilic displacement of chloride from imidoyl
chlorides by thiols under phase-transfer conditions is a suit-
able method for the preparation of thioimidates, although
this procedure is rarely ever used.[1,13] A modification of
this procedure employs thallium(I)[14] or lithium salts of thi-
ols.[15] An alternative approach to the S-methyl derivatives
employs methylation of thioamides with methyl iodide or
dimethyl sulfate.[16–18] Nitriles can be coupled with thiols
under acidic[19–22] or basic conditions.[23,24] The former
mentioned reaction can be regarded as a modified Pinner
Scheme 1. Synthetic approaches to thioimidates.
Thioimidates are known to form E/Z-isomers in different
ratios depending on their substitution patterns and reaction
solvents. Their isomerism has been studied by dynamic
NMR spectroscopy,[29] and some E and Z isomers were also
isolated in pure form.[30] It was furthermore found that the
enthalpy difference between dialkylthioamides and corre-
sponding isomeric dialkylthioimidates is 2–3 kcal/mol in
favor of the amides.[31] (Scheme 2)
To the best of our knowledge, 2-anilinobenzothioimid-
ates have not been described before, as we were not able to
find any examples in the literature. In view of the synthetic
potential of N-heterocyclic carbenes of pyrazole[32–34] and
indazole,[34,35] we envisaged the first synthetic approach as
[a] Clausthal University of Technology, Institute of Organic
Chemistry,
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
E-mail: schmidt@ioc.tu-clausthal.de
http://www.ioc.tu-clausthal.de/abteilungen/
abteilung-prof-schmidt/
[b] University of Helsinki, Department of Chemistry,
Helsinki, Finland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500331.
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Organic Synthesis with N-Heterocyclic Carbenes of Indazole
able benzamides as precursors[40] which were subsequently
thionated,[41,42] to biologically active compounds.[43] Thion-
ations can be performed by P4S10/silicon oil,[44] aqueous
ammonium sulfide,[45] or polymer-supported thionation
reagents.[46] Alternative approaches incompatible with prep-
aration of benzamides as starting materials are addition re-
actions of aromatic Grignard reagents to isothiocyanates,[47]
and the reaction of imines[48] or amines with sulfur under
microwave conditions[49] which either fail or have never
been applied to the synthesis of 2-anilinothioamides. The
same is true for the hydrolysis of phosphorylated thiobenz-
amides,[50] preparations starting from aldehydes, benzotri-
azole, and unsubstituted thiobenzamide,[51] and substitu-
tion reactions of primary amines with benzocarbodithio-
esters.[52]
Scheme 2. Isomerism of thioimidates.
outlined in Scheme 3. We used indazolium salts I as proton-
ated precursors of the N-heterocyclic carbenes II (indazol-
3-ylidenes) which can be trapped as thiones or rhodium
complexes.[36] Alternatively, N-heterocyclic carbenes of
indazoles are available by decarboxylation of indazolium-3-
carboxylates.[37,38] The N-heterocyclic carbenes of indazole
are versatile starting materials for heterocycle synthesis.
Thus, under certain conditions, they dimerize to spiro com-
pounds[36] or undergo a ring-opening to the ketenimines III.
These readily rearrange to acridines[39] or undergo trapping
reactions with oxygen nucleophiles.[40] We therefore started
a project to explore their synthetic potential with sulfur nu-
cleophiles and aimed at the synthesis of the first representa-
tives of 2-anilinobenzothioimidates IV and 2-anilinobenzo-
thioamides V as shown in Scheme 3.
In support of our continued studies of N-heterocyclic
carbenes in heterocycle synthesis[36–40,53] we report here on
benzothioimidate as well as anthranilthioamide prepara-
tions that employ N-heterocyclic carbenes of indazole and
the conversion of the latter into the title ring systems.
Results and Discussion
Indazolium salts 1a–f were readily available by intramo-
lecular Buchwald–Hartwig reaction of 1-(2-bromobenzyl-
idene)-2-phenylhydrazine or by copper-catalyzed aryl cou-
pling of iodobenzenes with indazole, followed by methyl-
ation and anion exchange[39] Treatment of salts 1a–f with
tBuOK in toluene in the presence of 4-methylthiophenol
gave the p-tolyl N-methyl-2-(arylamino)benzothioimidates
2a–f (Scheme 4). At room temp., no reaction took place,
but on warming a color change to yellow indicated the for-
mation of the product. After a variation of the reaction
conditions we found that a temperature of 60 °C gave opti-
mal results. Since only one set of signals was visible in the
NMR spectra, the benzothioimidates appear to have
formed as single stereoisomers with respect to isomerism of
the imine bond. It can also be concluded from the NMR
resonance frequencies, that no Chapman-type rearrange-
ment to anthranilthioamides occurred under these condi-
Scheme 3. Synthetic approaches to thioimidates via N-heterocyclic
carbenes of indazole.
The synthesis of benzothioamides possessing amino
groups in the ortho position such as V (anthranilthioamides,
2-anilinothioamides) has seemingly been restricted to suit- Scheme 4. Synthesis of benzothioimidates from indazolium salts.
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Z. Guan, M. Nieger, A. Schmidt
FULL PAPER
tions. Thus, the 13C NMR chemical shifts of the imine
carbon atoms of 2a–f appear at δ = 162–164 ppm, whereas
the values for related 2-anilinothioamides (5a–f, see below)
can be detected considerably more downfield (i.e. between
195 ppm and 200 ppm in CDCl3, respectively). The reso-
nance frequencies of the N-methyl group of 2a–f can be
seen at δ = 3.57–3.61 ppm, whereas the amino group corre-
lates to signals at δ = 8.71–9.09 ppm in CDCl3, respectively.
The downfield shift of the latter moiety is indicative of a
hydrogen bond which is only possible in the Z isomer
(Scheme 4). A comparison with related E isomers is given
below.
We also tested other thiols and chose aryl-, heteroaryl-,
and alkylthiols with different steric demands and electronic
properties which were treated with 1a and 1c as model start-
ing materials. Indeed, the sterically hindered 2,4,6-triiso-
propylbenzenethiol gave 2-anilinobenzothioimidates 3a and
3b in good yields (Scheme 5). 4-Bromothiol converted 1a
smoothly into 3c. The ability of alkylthiols to undergo this
reaction was demonstrated by reaction of isopropylthiol
with indazolium salt 1a to produce 3d which was obtained
in moderate yield. However, the reaction of 2-naphthylthiol
with 1c suffered from relatively low yields. As an example of
a heteroarenethiol we chose benzo[d]thiazole-2-thiol which
converted indazolium salt 1c into benzothioimidate 3f. In
the NMR spectra of 3c, 3e, and 3f in CDCl3 only one set
of signals is observable. The N-H proton gave a resonance
frequency at approximately δ = 9.00 ppm which can be at-
tributed to the H-bonded proton of the Z isomer. The sig-
nals of the N-Me group were detected between 3.29 ppm
Scheme 5. Scope and limitations of the benzothioimidate forma-
tion.
1
(3f) and 3.60 ppm (3c, 3e) in the H NMR spectra taken in
CDCl3. For the case of sterically demanding substituents as
is the case for 3a,b as well as in isopropyl derivative 3d, a
second set of signals is visible which can be attributed to
the corresponding E isomers. The N-H resonance frequency
is shifted considerably upfield relative to the Z isomer and
appears at approximately δ = 5.75 ppm in CDCl3. Likewise,
the resonance frequencies of the N-Me groups are shifted
to higher field, as they were found in the range of 3.00 ppm
to 3.10 ppm, respectively. The ratio of E/Z isomers under
these conditions is 1:4 for 3a and 3d and 1:5 for 3b at room
temperature. These ratios remain almost unchanged, when
the spectra are measured in [D4]MeOH.
Figure 1. Molecular structure of benzothioimidate 3a (displace-
ment parameters are drawn at 50% probability level).
In order to gain knowledge about the isomers in the solid
state we performed single-crystal X-ray analysis of 3a. Re-
sults are shown in Figure 1. Suitable crystals were obtained
We next focused our interest on the synthesis of anthra-
by slow evaporation of a concentrated solution in CHCl3/ nilthioamides via N-heterocyclic carbenes of indazole. Gas-
MeOH. The imine bond adopts a Z configuration in the eous hydrogen sulfide gave only unsatisfactory results
single crystal. The C17–N16–C2–S1 moiety [crystallo- whereas the use of aqueous hydrogen sulfide gave the corre-
graphic numbering] is almost planar; a dihedral angle of sponding amides. Consequently, we envisaged a two-step
–2.6(3)° was measured. An H-bond is formed between the procedure for the synthesis of anthranilthioamides. There-
aniline group and the imine nitrogen atom [bond length fore, the indazolium salts 1a–f were deprotonated with
N9–H···N16 2.12(2) Å; bond angle 136(2)°]. As expected, 1.2 equiv. of tBuOK in toluene at 60 °C (Scheme 6). The in
the molecule is not planar since the phenylthiol ring is situ generated indazole-3-ylidenes were trapped with water
twisted from the plane of the imine bond. The correspond- to give target compounds 4a–f in good to excellent yields.
ing dihedral angle C2–S1–C18–C23 was found to be Subsequent reaction of anthranilamides 4a–f with Lawes-
72.6(2)°. Similarly, the aniline ring is twisted and the torsion sonЈs reagent afforded anthranilthioamides 5a–f in excellent
angle C8–N9–C10–C11 of 138.4(2)° was determined.
yields.
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Organic Synthesis with N-Heterocyclic Carbenes of Indazole
Figure 2. Molecular drawing of Z-N-[1-(p-tolyl)-1H-benzo[d][1,3]-
thiazin-4(2H)-ylidene]methanamine 6e (displacement parameters
are drawn at 50% probability level).
Scheme 6. Synthesis of anthranilthioamides.
Finally, we cyclized anthranilthioamides 5a–f with
propionaldehyde. In contrast to the reaction with formalde-
hyde, no reaction occurred in the presence of HCl in a two-
phase system with chloroform. Instead, small amounts
(1:200) of 50% sulfuric acid were necessary to catalyze the
reaction, whereas larger amounts of acid resulted in the for-
mation of decomposition products. Depending on the sub-
stitution pattern of the starting materials, two different
products were formed, either benzothiazine derivatives 7a–
d or quinazoline-4-thiones 7e–f, as slightly yellow com-
pounds, respectively (Scheme 8). The characteristic spectro-
scopic differences are as follows. The imine carbon atoms
of 7a–d appear at δ = 156.0 ppm in the 13C NMR spectra,
whereas the thiocarbonyl carbon atoms of 7e and 7f can be
detected at δ = 186.6 ppm in CDCl3, respectively. Corre-
lations between the N-CH3 carbon atom and the NCH(Et)-
N proton and vice versa are clearly visible in spectra of
We then attempted cyclization of anthranilthioamides
5a–f with formaldehyde and found that optimum results
were achieved if the reaction was performed in a two-phase
system of chloroform and aqueous 0.5 m HCl in the ratio
20:1 at 60 °C. Thus, we obtained N-[1-aryl-1H-benzo[d]-
[1,3]thiazin-4(2H)-ylidene]methanamines 6a–f in good to
very good yields as slightly yellow solids or oils (Scheme 7).
This method of preparing 6a,e,f gives considerably better
yields than reported. As an example, 6a was formed earlier
in 45% yield using ethanol as solvent, or in 15% yield by
reaction of benzo[d][1,3]thiazine-4(2H)-thione with methyl-
amine in benzene/ethanol mixtures. In this case, thioamide
5a was formed in 70% yield as the main product. The prod-
uct ratio was shifted to 80% in favor of 6a by changing the
solvent to anhydrous benzene.[54] To the best of our knowl-
edge, 6b,c,d are new compounds.
Scheme 7. Syntheses of benzo[d][1,3]thiazines.
Single crystals of 6e were obtained by slow crystallization
of a concentrated solution in MeOH. In the single crystals,
the imine bond adopts a Z configuration of the almost
planar C10–N9–C8–S1 moiety [crystallographic number-
ing], the dihedral angle of which is –4.4(4)°. As expected,
the thiazine moiety is not planar, and a torsion angle C2–
S1–C8–C7A –29.2(2)° was found [crystallographic number-
ing], see Figure 2.
Scheme 8. Syntheses of benzothiazines and quinazoline-4-thiones.
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Z. Guan, M. Nieger, A. Schmidt
FULL PAPER
tions were applied. For 3a the absolute structure was determined
by refinement of Parsons x-parameter.[57]
7e and 7f. In accordance with the assigned structures, the
corresponding correlations are not visible the benzo-
thiazines 7a–d.
3a: Colourless crystals, C29H36N2S, M = 444.66, crystal size
Thermal rearrangements of C2-unsubstituted 1H- 0.32ϫ0.20ϫ0.12 mm, orthorhombic, space group Pna21 (No. 33),
a = 18.0589(11) Å, b = 16.7842(10) Å, c = 8.3932(5) Å, V =
2544.0(3) Å3, Z = 4, ρ(calcd.) = 1.161 Mgm–3, F(000) = 960, μ =
1.249 mm 1, 18059 reflections (2θmax = 145.4°), 4552 unique [Rint
= 0.022], 293 parameters, 2 restraint, R1 [for 4532 IϾ2σ(I)] =
0.028, wR2 (all data) = 0.073, S = 1.06, largest diff. peak and hole
0.229 and –0.153 eÅ–3, x = 0.006(6).
benzo[d][1,3]thiazin-4(2H)-imines into 2,3-dihydroquin-
azoline-4(1H)-thiones at 200 °C over a period of 1 h have
been previously reported.[55] The outcome of the reaction
with propionaldehyde described here is very clearly gov-
erned by the electronic properties of the aniline ring.
6e: Colourless crystals, C16H16N2S, M = 268.37, crystal size
¯
0.20ϫ0.10ϫ0.03 mm, triclinic, space group P1 (No. 2), a =
6.7945(7) Å, b = 9.1927(18) Å, c = 12.1901(9) Å, α = 105.171(11)°,
β = 100.801(8)°, γ = 104.834(13)°, V = 683.45(17) Å3, Z = 2,
ρ(calcd.) = 1.304 Mgm–3, F(000) = 284, μ = 0.224 mm 1, 3508 re-
flections (2θmax = 50.6°), 2421 unique [Rint = 0.026], 174 param-
eters, R1 [for 1677 IϾ2σ(I)] = 0.060, wR2 (all data) = 0.159, S =
1.03, largest diff. peak and hole 0.260 and –0.314 eÅ–3.
Conclusions
N-Heterocyclic carbenes of indazole are versatile starting
materials for organic and heterocyclic synthesis. The gener-
ation of the indazol-3-ylidenes by deprotonation of readily
available indazolium salts under mild conditions results in
ring-cleavage of the indazole N–N bond. Trapping of the
intermediary ketenimine with thiols results in the formation
of benzothioimidates, a hitherto, quite neglected class of
compounds. Trapping with water gives anthranilamides
which can easily be converted into the corresponding 2-
anilinobenzothioamides. These can be cyclized with form-
aldehyde and propionaldehyde, respectively, to give N-
[1-phenyl-1H-benzo[d][1,3]thiazin-4(2H)-ylidene]methan-
amines or quinazoline-4-thiones.
CCDC-1052378 (for 3a), and CCDC -1052379 (for 6e) contain the
crystallographic data for this article. Copies of the data can be ob-
tained free of charge on application to The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [Fax: int.code+(1223)336-
033; E-mail: deposit@ccdc.cam.ac.uk].
General Procedure for the Preparation of the Benzothioimidates 2a–
f: A solution of indazolium salt 1a–f (0.5 mmol), 4-methylthio-
phenol (0.5 mmol) and potassium tert-butoxide (0.6 mmol in
20 mL) of toluene was stirred 3 h at 60 °C. After evaporation of
the solvent in vacuo the crude reaction product was purified by
flash column chromatography (petroleum ether/ethyl acetate = 3:1)
and dried in vacuo.
p-Tolyl (Z)-N-Methyl-2-(phenylamino)benzimidothioate (2a): Yield
106 mg of a yellow oil, 64%. H NMR (400 MHz, CDCl3, TMS):
1
Experimental Section
δ = 8.89 (s, 1 H, PhNH-H), 7.57 (dd, J = 7.9, 1.5 Hz, 1 H, Ar-H),
7.30–7.26 (m, 2 H, Ar-H), 7.22 (dd, J = 8.3, 1.1 Hz, 1 H, Ar-H),
7.10–7.08 (m, 4 H, Ar-H), 7.02 (ddd, J = 8.3, 7.0, 1.5 Hz, 1 H, Ar-
H), 6.98–6.93 (m, 3 H, Ar-H), 6.61 (ddd, J = 7.9, 7.0, 1.1 Hz, 1 H,
Ar-H), 3.57 (s, 3 H, NMe), 2.24 (s, 3 H, PhMe) ppm. 13C NMR
(100 MHz, CDCl3, TMS): δ = 163.4, 143.0, 142.3, 137.4, 132.1,
132.0, 129.9, 129.8, 129.3, 129.2, 124.2, 121.7, 119.8, 118.5, 115.7,
General Considerations: Flash-chromatography was performed with
silica gel 60 (0.040–0.063 mm). Nuclear magnetic resonance
(NMR) spectra were obtained with a Bruker Avance 400 MHz and
Bruker Avance III 600 MHz. 1H NMR spectra were recorded at
400 MHz or 600 MHz. 13C NMR spectra were recorded at
100 MHz or 150 MHz, with the solvent peak or tetramethylsilane
used as the internal reference. Multiplicities are described by using
the following abbreviations: s = singlet, d = doublet, t = triplet, q
= quartet, and m = multiplet. FT-IR spectra were obtained using
a Bruker Alpha T equipped with a Platinum ATR unit. The mass
spectra were measured with a Varian 320 MS Triple Quad GC/MS/
MS with a Varian 450-GC. The electrospray ionization mass spec-
tra (ESIMS) were measured with an Agilent LCMSD series HP
1100 with APIES. Melting points are uncorrected and were deter-
mined with an apparatus according to Dr. Tottoli (Büchi), yields
are not optimized. The syntheses of starting materials 1a–c,[39]
1d,[36] 1e,[53] 1f[40] and 4a–f[40] have been described in our earlier
publications.
42.0, 21.1 ppm. IR (ATR): ν = 3019, 2916, 2853, 1587, 1571, 1490,
˜
1450, 1311, 1203, 1160, 997, 911, 832, 804, 741, 693, 637, 489 cm–1.
ESI-MS: m/z = 333.1 [M + H]+. HRESIMS: C21H21N2S: calcd.
333.1425, found 333.1426.
p-Tolyl
(Z)-2-[(2-Chlorophenyl)amino]-N-methylbenzimidothioate
(2b): Yield 156 mg of a yellow oil, 85%. 1H NMR (400 MHz,
CDCl3, TMS): δ = 9.09 (s, 1 H, PhNH-H), 7.53 (dd, J =
8.0, 1.5 Hz, 1 H, Ar-H), 7.37 (dd, J = 8.0, 1.5 Hz, 1 H, Ar-H), 7.29–
7.26 (m, 2 H, Ar-H), 7.13 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, Ar-H),
7.08–7.04 (m, 3 H, Ar-H), 6.91 (d, J = 8.0 Hz, 2 H, Ar-H), 6.83
(ddd,
J = 8.0, 7.4, 1.5 Hz, 1 H, Ar-H), 6.70 (ddd, J =
8.0, 7.4, 1.1 Hz, 1 H, Ar-H), 3.61 (s, 3 H, NMe), 2.23 (s, 3 H,
PhMe) ppm. 13C NMR (100 MHz, CDCl3, TMS): δ = 162.7, 141.0,
139.7, 137.5, 132.4, 131.8, 130.0, 129.7, 129.6, 128.9, 127.2, 126.4,
Crystal Structure Determinations: The single-crystal X-ray diffrac-
tion studies were carried out with a Bruker-D8 Venture dif-
fractometer with Photon100 detector at 123(2) K using Cu-Kα radi-
ation (λ = 1.54178 Å) (3a) and on an Agilent SuperNova dif-
fractometer with EOS detector at 173(2) K using Mo-Kα radiation
(λ = 0.71073 Å) (6e). Direct Methods (SHELXS-97)[56] were used
for structure solution and refinement was carried out using
123.2, 120.9, 120.0, 117.6, 116.6, 41.7, 21.1 ppm. IR (ATR): ν =
˜
3066, 3020, 2918, 1639, 1577, 1508, 1490, 1448, 1318, 1203, 1159,
1118, 1047, 999, 915, 803, 740, 490 cm–1. ESI-MS: m/z = 367.1 [M
+ H]+. HRESIMS: C21H20N2SCl: calcd. 367.1036, found 367.1041.
SHELXL-2013/2014a (full-matrix least-squares on F2). Non- p-Tolyl
(Z)-2-[(3-Chlorophenyl)amino]-N-methylbenzimidothioate
hydrogen atoms were refined anisotropically, hydrogen atoms were
localized by difference electron-density determination and refined
using a riding model [H(N) free]. Semi-empirical absorption correc-
(2c): Yield 141 mg of a yellow solid, 77%, m.p. 73–75 °C. 1H NMR
(400 MHz, CDCl3, TMS): δ = 8.71 (s, 1 H, PhNH-H), 7.54 (dd, J
= 8.0, 1.6 Hz, 1 H, Ar-H), 7.21 (dd, J = 8.3, 1.0 Hz, 1 H, Ar-H),
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Organic Synthesis with N-Heterocyclic Carbenes of Indazole
7.17 (t, J = 8.0 Hz, 1 H, Ar-H), 7.08–7.04 (m, 3 H, Ar-H), 7.00 (t,
isomer: δ = 7.38 (d, J = 8.0 Hz, 1 H, Ar-H), 7.31–7.27 (m, 3 H, Ar-
J = 2.0 Hz, 1 H, Ar-H), 6.94–6.88 (m, 4 H, Ar-H), 6.87 (ddd, J H), 7.23 (dd, J = 7.6, 1.5 Hz, 1 H, Ar-H), 7.12–7.08 (m, 4 H, Ar-
= 8.0, 7.0, 1.0 Hz, 1 H, Ar-H), 3.58 (s, 3 H, NMe), 2.24 (s, 3 H, H), 7.01–6.94 (m, 2 H, Ar-H), 5.75 (s, 1 H, PhNH-H), 3.74 (br. s,
PhMe) ppm. 13C NMR (100 MHz, CDCl3, TMS): δ = 164.0, 144.0,
141.6, 137.7, 134.9, 132.4, 131.9, 130.3, 130.0, 129.8, 128.7, 125.3,
2 H, iPr-H), 3.01 (s, 3 H, NMe), 2.93 (sept, J = 6.9 Hz, 1 H, iPr-
H), 1.29–1.26 (m, 18 H, iPr-H) ppm. 13C NMR (150 MHz, CDCl3,
TMS): Z isomer: 165.1, 151.7, 150.3, 142.5, 141.9, 131.1, 129.5,
129.2, 125.7, 121.7 (2C), 121.5, 120.0, 117.2, 114.5, 40.7, 34.2, 31.9,
121.1, 119.7, 118.4, 116.9 (2 C), 41.8, 21.1 ppm. IR (ATR): ν =
˜
3020, 2969, 2918, 2853, 1580, 1508, 1451, 1312, 1203, 1160, 1091,
993, 928, 903, 805, 730, 663, 491 cm–1. ESI-MS: m/z = 367.1 [M + 23.9, 23.8 ppm. E isomer: 165.3, 150.6, 150.3, 142.5, 139.7, 130.1,
H]+. HRESIMS: C21H20N2SCl: calcd. 367.1036, found 367.1035.
p-Tolyl (Z)-2-[(4-Bromophenyl)amino]-N-methylbenzimidothioate
129.5, 128.4, 125.7, 123.1, 121.8, 120.6, 118.7, 116.7, 114.5, 41.3,
34.3, 31.9, 23.9, 23.8 ppm. IR (ATR): ν = 2960, 2927, 2867, 1588,
˜
1512, 1454, 1381, 1307, 1154, 1060, 999, 919, 870, 751, 702, 627,
519 cm–1. MS: m/z = 444.2 [M]+. HRESIMS: C29H37N2S: calcd.
445.2677, found 445.2677.
(2d): Yield 50 mg of a yellow solid, 24%, m.p. 103–105 °C. 1H
NMR (400 MHz, CDCl3, TMS): δ = 8.84 (s, 1 H, PhNH-H), 7.57
(dd, J = 8.0, 1.2 Hz, 1 H, Ar-H), 7.38–7.34 (m, 2 H, Ar-H), 7.17
(dd, J = 8.3, 1.0 Hz, 1 H, Ar-H), 7.08–7.02 (m, 3 H, Ar-H), 6.96–
6.93 (m, 2 H, Ar-H), 6.66 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H, Ar-H),
3.57 (s, 3 H, NMe), 2.25 (s, 3 H, PhMe) ppm. 13C NMR (100 MHz,
CDCl3, TMS): δ = 163.4, 142.3, 141.5, 137.5, 132.2 (2 C), 132.0,
129.9, 129.8, 129.0, 124.7, 120.9, 119.1, 116.0, 113.4, 41.9,
2,4,6-Triisopropylphenyl 2-[(3-Chlorophenyl)amino]-N-methylbenz-
imidothioate (3b): Yield 163 mg of a colorless solid, 68%, m.p. 69–
1
72 °C. H NMR (600 MHz, CDCl3, TMS): Z isomer: δ = 9.21 (s,
1 H, PhNH-H), 7.29 (d, J = 8.2 Hz, 1 H, Ar-H), 7.17 (t, J = 8.2 Hz,
1 H, Ar-H), 7.11 (t, J = 2.0 Hz, 1 H, Ar-H), 7.01–6.97 (m, 3 H,
Ar-H), 6.91–6.89 (m, 3 H, Ar-H), 6.42 (dd, J = 8.5, 7.6 Hz, 1 H,
Ar-H), 3.59 (s, 3 H, NMe), 3.53 (sept, J = 6.9 Hz, 2 H, iPr-H), 2.83
(sept, J = 6.9 Hz, 1 H, iPr-H), 1.21 (d, J = 6.9 Hz, 6 H, iPr-H),
1.14 (d, J = 6.9 Hz, 12 H, iPr-H) ppm. E isomer: δ = 7.39 (d, J =
8.2 Hz, 1 H, Ar-H), 7.35 (ddd, J = 8.2, 7.2, 1.4 Hz, 1 H, Ar-H),
7.24 (dd, J = 7.6, 1.2 Hz, 1 H, Ar-H), 7.19 (t, J = 8.2 Hz, 1 H, Ar-
H), 7.11–7.06 (m, 3 H, Ar-H), 6.93–6.88 (m, 3 H, Ar-H), 5.76 (s, 1
H, PhNH-H), 3.70 (br. s, 2 H, iPr-H), 2.98 (s, 3 H, NMe), 2.92
(sept, J = 6.9 Hz, 1 H, iPr-H), 1.31–1.23 (m, 18 H, iPr-H) ppm.
13C NMR (150 MHz, CDCl3, TMS): Z isomer: 165.1, 151.7, 150.4,
143.4, 141.4, 134.8, 131.1, 130.1, 129.5, 125.4, 122.5, 121.8, 121.0,
118.8, 118.1, 117.1, 115.3, 40.7, 34.2, 31.9, 23.9, 23.8 ppm. E iso-
mer: 165.0, 151.7, 150.7, 144.2, 138.5, 135.1, 130.4, 130.2, 128.5,
127.1, 122.8, 122.0, 121.2, 118.4, 118.1, 117.2, 115.7, 41.3, 34.3,
21.1 ppm. IR (ATR): ν = 3157, 3060, 3020, 2964, 2852, 1612, 1583,
˜
1520, 1478, 1387, 1310, 1001, 923, 803, 707, 658, 497, 474 cm–1.
ESI-MS: m/z = 411.0 [M + H]+. HRESIMS: C21H20N2SBr: calcd.
411.0531, found 411.0529.
p-Tolyl (Z)-N-Methyl-2-(p-tolylamino)benzimidothioate (2e): Yield
1
125 mg of a yellow oil, 72%. H NMR (400 MHz, CDCl3, TMS):
δ = 8.93 (s, 1 H, PhNH-H), 7.60 (dd, J = 7.9, 1.5 Hz, 1 H, Ar-H),
7.15–7.09 (m, 5 H, Ar-H), 7.02–6.98 (m, 3 H, Ar-H), 6.95 (d, J =
7.9 Hz, 2 H, Ar-H), 6.58 (ddd, J = 7.9, 7.0, 1.1 Hz, 1 H, Ar-H),
3.56 (s, 3 H, NMe-H), 2.32 (s, 3 H, NPhMe), 2.24 (s, 3 H,
SPhMe) ppm. 13C NMR (100 MHz, CDCl3, TMS): δ = 163.2,
143.9, 139.5, 137.3, 132.1, 131.9, 131.7, 130.0, 129.9, 129.8, 129.5,
123.4, 120.7, 117.8, 115.0, 42.0, 21.1, 20.8 ppm. IR (ATR): ν =
˜
3018, 2917, 2858, 1583, 1514, 1490, 1451, 1393, 1308, 1205, 1160,
999, 912, 752, 642, 517 cm–1. ESI-MS: m/z = 347.1 [M + H]+.
HRESIMS: C22H23N2S: calcd. 247.1582, found 247.1582.
31.9, 23.9, 23.8 ppm. IR (ATR): ν = 2960, 2926, 2864, 1581, 1514,
˜
1482, 1451, 1317, 993, 931, 904, 878, 755, 680, 656 cm–1. ESIMS:
m/z = 479.2 [M + H]+. HRESIMS: C29H36N2SCl: calcd. 479.2288,
found 479.2285.
p-Tolyl (Z)-2-[(4-Methoxyphenyl)amino]-N-methylbenzimidothioate
(2f): Yield 111 mg of a yellow oil, 61%. 1H NMR (400 MHz,
CDCl3, TMS): δ = 9.01 (s, 1 H, PhNH-H), 7.67 (dd, J =
8.0, 1.4 Hz, 1 H, Ar-H), 7.13–7.11 (m, 2 H, Ar-H), 7.09–7.06 (m,
2 H, Ar-H), 7.01–6.95 (m, 4 H, Ar-H), 6.90–6.86 (m, 2 H, Ar-H),
6.56 (ddd, J = 8.0, 6.6, 1.6 Hz, 1 H, Ar-H), 3.81 (s, 3 H, OMe-H),
3.57 (s, 3 H, NMe), 2.26 (s, 3 H, PhMe) ppm. 13C NMR (100 MHz,
CDCl3, TMS): δ = 163.0, 155.7, 145.2, 137.1, 135.0, 132.3, 131.6,
130.1, 129.8, 129.7, 123.8, 122.3, 117.1, 114.6, 114.0, 55.6, 42.0,
4-Bromophenyl
(Z)-N-Methyl-2-(phenylamino)benzimidothioate
(3c): Yield 127 mg of a yellow solid, 64%, m.p. 81–83 °C. 1H NMR
(400 MHz, CDCl3, TMS): δ = 8.96 (s, 1 H, PhNH-H), 7.58 (dd, J
= 8.0, 1.5 Hz, 1 H, Ar-H), 7.31–7.23 (m, 5 H, Ar-H), 7.10–7.03 (m,
5 H, Ar-H), 6.98 (tt, J = 7.4, 1.0 Hz, 1 H, Ar-H), 6.62 (ddd, J =
8.0, 7.0, 1.0 Hz, 1 H, Ar-H), 3.59 (s, 3 H, NMe) ppm. 13C NMR
(100 MHz, CDCl3, TMS): δ = 161.8, 143.3, 142.1, 133.2, 132.3,
132.1, 132.0, 130.3, 129.4, 123.5, 122.0, 121.4, 119.9, 118.6, 115.8,
21.1 ppm. IR (ATR): ν = 3033, 2907, 2832, 1571, 1507, 1450, 1295,
˜
1238, 1204, 1159, 1106, 1035, 993, 911, 803, 748, 664, 488 cm–1.
ESI-MS: m/z = 363.1 [M + H]+. HRESIMS: C22H23N2OS: calcd.
363.1531, found 363.1531.
42.2 ppm. IR (ATR): ν = 3349, 1609, 1571, 1503, 1445, 1390, 1302,
˜
1206, 1159, 1089, 1008, 988, 915, 865, 804, 746, 692, 664, 627, 486,
462 cm–1. ESI-MS: m/z
=
397.0 [M
+
H]+. HRESIMS:
C20H18N2SBr: calcd. 397.0374, found 397.0374.
General Procedure for the Preparation of the Benzothioimidates
3a–f: A solution of indazolium salt 1a or 1c (0.5 mmol), thiol
(0.5 mmol) and potassium tert-butoxide (0.6 mmol in 20 mL of tol-
uene) was stirred 3 h at 60 °C. After evaporation of the solvent
in vacuo the crude reaction product was purified by flash column
chromatography (petroleum ether/ethyl acetate = 3:1) and dried in
vacuo.
Isopropyl N-Methyl-2-(phenylamino)benzimidothioate (3d): Yield
1
67 mg of a yellow solid, 47%, m.p. 57–59 °C. H NMR (400 MHz,
CDCl3, TMS): Z-isomer: δ = 8.60 (s, 1 H, PhNH-H), 7.65 (dd, J =
8.0, 1.5 Hz, 1 H, Ar-H), 7.37 (dd, J = 8.0, 1.0 Hz, 1 H, Ar-H), 7.30–
7.23 (m, 2 H, Ar-H), 7.19 (ddd, J = 8.0, 7.0, 1.5 Hz, 1 H, Ar-H),
7.13–7.11 (m, 2 H, Ar-H), 6.95 (tt, J = 7.4, 1.0 Hz, 1 H, Ar-H),
6.86 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H, Ar-H), 3.52 (s, 3 H, NMe),
3.23 (sept, J = 6.8 Hz, 1 H, iPr-H), 1.16 (d, J = 6.8 Hz, 6 H, iPr-
2,4,6-Triisopropylphenyl N-Methyl-2-(phenylamino)benzimidothio-
ate (3a): Yield 156 mg of a colorless solid, 70%, m.p. 105–108 °C.
1H NMR (600 MHz, CDCl3, TMS): Z isomer: δ = 9.11 (s, 1 H, H) ppm. E isomer: δ = 7.30–7.23 (m, 4 H, Ar-H), 7.09–7.07 (m, 3
PhNH-H), 7.31–7.27 (m, 3 H, Ar-H), 7.14 (dd, J = 8.4, 1.1 Hz, 2 H, Ar-H), 6.99–6.91 (m, 2 H, Ar-H), 5.74 (s, 1 H, PhNH-H), 3.83
H, Ar-H), 7.01–6.94 (m, 3 H, Ar-H), 6.92 (s, 2 H, Ar-H), 6.36 (ddd, (sept, J = 6.8 Hz, 1 H, iPr-H), 3.11 (s, 3 H, NMe), 1.38 (d, J =
J = 8.2, 7.0, 1.0 Hz, 1 H, Ar-H), 3.59 (s, 3 H, NMe), 3.57 (sept, J 6.8 Hz, 6 H, iPr-H) ppm. 13C NMR (100 MHz, CDCl3, TMS): Z
= 6.9 Hz, 2 H, iPr-H), 2.83 (sept, J = 6.9 Hz, 1 H, iPr-H), 1.21 (d, isomer: 165.6, 142.3, 142.2, 131.2, 129.9, 129.3, 124.7, 121.7, 119.6,
J = 6.9 Hz, 6 H, iPr-H), 1.15 (d, J = 6.9 Hz, 12 H, iPr-H) ppm. E 118.9, 116.2, 41.5, 38.7, 24.0 ppm. E isomer: 161.3, 142.4, 140.9,
Eur. J. Org. Chem. 2015, 4710–4719
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4715

Z. Guan, M. Nieger, A. Schmidt
FULL PAPER
130.2, 129.4, 129.3, 125.4, 121.8, 120.3, 119.0, 117.1, 53.0, 37.3,
1035, 943, 741, 523, 489 cm–1. MS: m/z = 276.1 [M]+. HRESIMS:
23.0 ppm. IR (ATR): ν = 2964, 2927, 1658, 1586, 1574, 1509, 1495,
C14H13N2SClNa: calcd. 299.0386, found 299.0381.
˜
1449, 1305, 1241, 1154, 1091, 1000, 749, 695, 637, 506 cm–1. ESI-
MS: m/z = 285.1 [M + H]+. HRESIMS: C17H21N2S: calcd.
285.1425, found 285.1425.
2-[(3-Chlorophenyl)amino]-N-methylbenzothioamide (5c): Yield
116 mg of a yellow solid, 84%, m.p. 96–98 °C. 1H NMR (400 MHz,
[D6]DMSO): δ = 10.37 (d, J = 4.7 Hz, 1 H, MeNH-H), 8.26 (s, 1
H, PhNH-H), 7.34–7.26 (m, 3 H, Ar-H), 7.20 (dd, J = 8.3, 8.0 Hz,
1 H, Ar-H), 7.01 (ddd, J = 7.4, 7.2, 1.4 Hz, 1 H, Ar-H), 6.97 (dd,
J = 2.2, 2.1 Hz, 1 H, Ar-H), 6.92 (dd, J = 8.3, 2.2 Hz, 1 H, Ar-H),
6.83 (dd, J = 8.0, 2.1 Hz, 1 H, Ar-H), 3.04 (d, J = 4.7 Hz, 3 H,
NMe) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 196.5, 145.1,
138.3, 133.5, 133.4, 130.6, 129.9, 128.5, 121.4, 119.7, 119.4, 116.0,
Naphthalen-2-yl (Z)-2-[(3-Chlorophenyl)amino]-N-methylbenzimido-
thioate (3e): Yield 68 mg of a yellow oil, 34%. 1H NMR (600 MHz,
CDCl3, TMS): δ = 8.98 (s, 1 H, PhNH-H), 7.72–7.70 (m, 1 H, Ar-
H), 7.67–7.65 (m, 2 H, Ar-H), 7.60–7.57 (m, 2 H, Ar-H), 7.44–7.40
(m, 2 H, Ar-H), 7.20–7.16 (m, 3 H, Ar-H), 7.05 (t, J = 2.0 Hz, 1
H, Ar-H), 6.99 (ddd, J = 8.5, 7.0, 1.3 Hz, 1 H, Ar-H), 6.91 (d, J =
8.1 Hz, 2 H, Ar-H), 6.62 (t, J = 7.5 Hz, 1 H, Ar-H), 3.62 (s, 3 H,
NMe) ppm. 13C NMR (150 MHz, CDCl3, TMS): δ = 162.6, 143.8,
141.8, 134.9, 133.4, 132.0, 131.9, 130.7, 130.3, 130.1, 130.0, 129.0,
128.6, 127.6, 127.3, 126.6, 126.4, 125.1, 121.2, 119.6, 118.4, 117.0,
115.3, 32.6 ppm. IR (ATR): ν = 3249, 3189, 3049, 2962, 2932, 1583,
˜
1514, 1462, 1408, 1300, 1238, 1161, 1109, 1073, 1032, 942, 847,
784, 746, 697, 687, 676, 545, 527, 443 cm–1. MS: m/z = 276.1 [M]+.
HRESIMS: C14H13N2SClNa: calcd. 299.0386, found 299.0390.
116.7, 42.2 ppm. IR (ATR): ν = 3053, 2965, 2903, 2851, 1579, 1500,
˜
2-[(4-Bromophenyl)amino]-N-methylbenzothioamide (5d): Yield
128 mg of a yellow solid, 80%, m.p. 158–160 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 10.39 (d, J = 4.5 Hz, 1 H, MeNH-H),
8.30 (s, 1 H, PhNH-H), 7.38–7.34 (m, 2 H, Ar-H), 7.32–7.23 (m, 3
H, Ar-H), 6.98–6.93 (m, 3 H, Ar-H), 3.06 (d, J = 4.5 Hz, 3 H,
NMe) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 196.4, 142.4,
139.1, 132.4, 131.7, 129.9, 128.4, 120.7, 119.2, 118.4, 111.2,
1479, 1451, 1313, 1204, 1160, 1074, 993, 927, 891, 848, 743, 682,
474 cm–1. MS: m/z = 402.2 [M]+. HRESIMS: C24H20N2SCl: calcd.
403.1036, found 403.1036.
Benzo[d]thiazol-2-yl (Z)-2-[(3-Chlorophenyl)amino]-N-methylbenz-
imidothioate (3f): Yield 104 mg of a yellow solid, 51%, m.p. 193–
196 °C. 1H NMR (600 MHz, CDCl3, TMS): δ = 11.08 (s, 1 H,
PhNH-H), 7.58 (dd, J = 7.8, 1.5 Hz, 1 H, Ar-H), 7.44 (dd, J =
8.6, 1.0 Hz, 1 H, Ar-H), 7.38–7.33 (m, 3 H, Ar-H), 7.32–7.28 (m,
2 H, Ar-H), 7.24 (dd, J = 8.1, 2.0 Hz, 1 H, Ar-H), 7.09 (ddd, J =
7.9, 2.0, 1.0 Hz, 1 H, Ar-H), 6.92 (dd, J = 8.0, 1.5 Hz, 1 H, Ar-H),
32.6 ppm. IR (ATR): ν = 3345, 3253, 3162, 3084, 3033, 2956, 2929,
˜
2888, 1579, 1505, 1485, 1460, 1357, 1317, 1282, 1253, 1165, 1069,
942, 829, 743, 604, 494 cm–1. MS: m/z = 320.0 [M]+. HRESIMS:
C14H14N2SBr: calcd. 321.0061, found 321.0067.
6.87 (dd,
J = 7.9, 1.0 Hz, 1 H, Ar-H), 6.68 (ddd, J =
N-Methyl-2-(p-tolylamino)benzothioamide (5e): Yield 118 mg of a
8.0, 7.0, 1.0 Hz, 1 H, Ar-H), 3.29 (s, 3 H, NMe) ppm. 13C NMR
(150 MHz, CDCl3, TMS): δ = 187.2, 151.3, 146.2, 142.4, 139.8,
134.9, 132.4, 130.3, 130.0, 128.5, 127.5, 125.4, 123.1, 121.9, 121.7,
1
yellow solid, 92%, m.p. 118–120 °C. H NMR (600 MHz, CDCl3,
TMS): δ = 8.27 (s, 1 H, PhNH-H), 7.83 (br. s, 1 H, MeNH-H),
7.22–7.16 (m, 3 H, Ar-H), 7.09 (d, J = 8.1 Hz, 2 H, Ar-H), 7.02–
7.01 (m, 2 H, Ar-H), 6.77 (ddd, J = 7.4, 7.2, 1.4 Hz, 1 H, Ar-H),
3.27 (d, J = 4.9 Hz, 3 H, NMe), 2.30 (s, 3 H, PhMe) ppm. 13C
NMR (150 MHz, CDCl3, TMS): δ = 199.2, 142.7, 139.3, 132.0,
130.8, 129.9, 129.3, 126.8, 120.6, 119.0, 116.2, 32.9, 20.8 ppm. IR
120.1, 118.3, 114.4, 114.3, 112.5, 38.4 ppm. IR (ATR): ν = 3141,
˜
3079, 3059, 1626, 1577, 1520, 1483, 1450, 1309, 1286, 1254, 1162,
1140, 1108, 1077, 1023, 994, 931, 904, 860, 804, 762, 748, 661,
629, 537, 496 cm–1. MS: m/z
=
409.1 [M]+. HRESIMS:
C21H16N3S2ClNa: calcd. 432.0372, found 432.0370.
(ATR): ν = 3351, 3288, 3164, 3023, 2955, 2929, 1587, 1511, 1462,
˜
General Procedure for the Preparation of the Benzothioamides 5a–
f: A solution of corresponding benzamide 4a–f[40] (0.5 mmol) and
Lawesson’s reagent (0.6 mmol in 20 mL of toluene) was stirred 3 h
at 60 °C. After evaporation of the solvent in vacuo the crude reac-
tion product was purified by flash column chromatography (petro-
leum ether/ethyl acetate = 3:1) and dried in vacuo.
1356, 1322, 1258, 1211, 1167, 1038, 941, 878, 806, 744, 603,
499 cm–1. MS: m/z = 256.2 [M]+. HRESIMS: C15H17N2S: calcd.
257.1112, found 257.1114.
2-[(4-Methoxyphenyl)amino]-N-methylbenzothioamide (5f): Yield
127 mg of a yellow solid, 93%, m.p. 122–123 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.26 (s, 1 H, PhNH-H), 7.86 (s, 1 H,
MeNH-H), 7.17–7.13 (m, 2 H, Ar-H), 7.07 (d, J = 8.8 Hz, 2 H,
Ar-H), 7.03 (d, J = 8.2 Hz, 1 H, Ar-H), 6.85 (d, J = 8.8 Hz, 2 H,
Ar-H), 6.72 (dd, J = 7.8, 7.3 Hz, 1 H, Ar-H), 3.78 (s, 3 H, OMe),
3.28 (d, J = 3.8 Hz, 3 H, NMe) ppm. 13C NMR (150 MHz,
CDCl3): δ = 199.0, 155.8, 144.0, 134.7, 131.0, 128.2, 126.7, 123.7,
N-Methyl-2-(phenylamino)benzothioamide (5a): Yield 103 mg of a
yellow solid, 85%, m.p. 176–178 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 10.43 (d, J = 4.5 Hz, 1 H, MeNH-H), 8.36 (s, 1 H,
PhNH-H), 7.27–7.23 (m, 5 H, Ar-H), 7.03 (dd, J = 8.4, 1.0 Hz, 2
H, Ar-H), 6.92–6.87 (m, 2 H, Ar-H), 3.08 (d, J = 4.5 Hz, 3 H,
NMe) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 196.5, 142.4,
140.1, 131.1, 129.9, 129.2, 128.1, 120.9, 119.7, 118.0, 117.0,
118.2, 115.1, 114.7, 55.6, 32.9 ppm. IR (ATR): ν = 3158, 3035,
˜
2952, 2928, 2891, 2829, 1595, 1574, 1511, 1459, 1360, 1320, 1285,
1240, 1035, 938, 806, 741, 604 cm–1. MS: m/z = 272.2 [M]+. HRES-
IMS: C15H16N2OSNa: calcd. 295.0881, found 295.0875.
32.5 ppm. IR (ATR): ν = 3309, 3158, 3039, 3014, 2958, 2930, 2895,
˜
1587, 1569, 1505, 1455, 1362, 1287, 1212, 1148, 1075, 1024, 753,
695, 464 cm–1. MS: m/z = 242.1 [M]+. HRESIMS: C14H15N2S:
calcd. 243.0956, found 243.0956.
General Procedure for the Preparation of the Benzothiazine 6a–f:
A solution of 0.5 mmol of the benzothioamide 5a–f (0.5 mmol),
formaldehyde (0.1 mL) and 0.5 m HCl (1 mL in 20 mL of chloro-
form) was stirred 3 h at 60 °C and neutralized with sodium carb-
onate. After evaporation of the solvent in vacuo the crude reaction
product was purified by flash column chromatography (petroleum
ether/ethyl acetate = 3:1) and dried in vacuo.
2-[(2-Chlorophenyl)amino]-N-methylbenzothioamide (5b): Yield
127 mg of a yellow solid, 92%, m.p. 113–115 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 10.56 (d, J = 4.5 Hz, 1 H, MeNH-H),
8.64 (s, 1 H, PhNH-H), 7.44 (dd, J = 8.0, 1.4 Hz, 1 H, Ar-H), 7.37–
7.31 (m, 2 H, Ar-H), 7.29–7.18 (m, 3 H, Ar-H), 7.02 (ddd, J =
7.6, 6.0, 2.0 Hz, 1 H, Ar-H), 6.89 (ddd, J = 8.2, 7.0, 1.8 Hz, 1 H,
Ar-H), 3.10 (d, J = 4.5 Hz, 3 H, NMe) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 195.9, 139.1, 138.7, 132.2, 130.0, 129.9, 127.8,
(Z)-N-[1-Phenyl-1H-benzo[d][1,3]thiazin-4(2H)-ylidene]methanamine
(6a): Yield 116 mg of a yellow oil, 91%. 1H NMR (600 MHz,
127.7, 121.8, 121.3, 121.1, 118.4, 116.4, 32.5 ppm. IR (ATR): ν = CDCl3, TMS): δ = 8.24 (dd, J = 8.2, 1.6 Hz, 1 H, Ar-H), 7.31–7.25
˜
3281, 3255, 3209, 3062, 2960, 2928, 1585, 1515, 1456, 1317, 1255,
(m, 3 H, Ar-H), 7.10–7.04 (m, 4 H, Ar-H), 7.00 (dd, J = 8.2, 1.0 Hz,
4716
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4710–4719

Organic Synthesis with N-Heterocyclic Carbenes of Indazole
1 H, Ar-H), 5.07 (s, 2 H, CH2-H), 3.35 (s, 3 H, NMe) ppm. 13C 7.07–7.04 (m, 2 H, Ar-H), 7.01 (ddd, J = 8.1/7.0/1.2 Hz, 1 H, Ar-
NMR (150 MHz, CDCl3, TMS): δ = 157.4, 146.3, 144.5, 130.7,
129.4, 127.1, 126.7, 123.8, 123.3, 123.2, 122.0, 52.0, 41.0 ppm. IR
H), 6.88–6.86 (m, 3 H, Ar-H), 4.99 (s, 2 H, CH2-H), 3.80 (s, 3 H,
OMe), 3.38 (s, 3 H, NMe) ppm. 13C NMR (150 MHz, CDCl3,
(ATR): ν = 3061, 2924, 2846, 1636, 1588, 1493, 1475, 1353, 1276, TMS): δ = 157.5, 156.4, 145.5, 139.8, 130.7, 126.9, 125.7, 124.9,
˜
1153, 1009, 912, 746, 693, 614 cm–1. MS: m/z = 254.1 [M]+. HRES-
122.8, 122.1, 114.7, 55.5, 52.8, 41.0 ppm. IR (ATR): ν = 3011, 2957,
˜
IMS: C15H15N2S: calcd. 255.0956, found 255.0957.
2920, 2908, 2835, 1588, 1506, 1478, 1449, 1393, 1323, 1280, 1032,
1004, 835, 759, 700, 547, 526 cm–1. ESI-MS: m/z = 285.0 [M +
H]+. HRESIMS: C16H17N2OS: calcd. 285.1062, found 285.1060.
(Z)-N-[1-(2-Chlorophenyl)-1H-benzo[d][1,3]thiazin-4(2H)-ylidene]-
methanamine (6b): Yield 123 mg of a yellow oil, 85%. 1H NMR
(600 MHz, CDCl3, TMS): δ = 8.28 (dd, J = 8.2, 1.6 Hz, 1 H, Ar-
General Procedure for the Preparation of the Compounds 7a–f: A
H), 7.48 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-H), 7.23–7.15 (m, 3 H, Ar- solution of benzothioamide 5a–f (0.5 mmol), propionaldehyde
H), 7.09 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-H), 7.02 (ddd, J =
8.2, 7.0, 1.2 Hz, 1 H, Ar-H), 6.66 (dd, J = 8.2, 1.2 Hz, 1 H, Ar-H),
(0.1 mL) and 50% sulfuric acid (0.1 mL in 20 mL of chloroform)
was stirred 3 h at 60 °C and neutralized with sodium carbonate.
4.99 (s, 2 H, CH2-H), 3.41 (s, 3 H, NMe) ppm. 13C NMR After evaporation of the solvent in vacuo the crude reaction prod-
(150 MHz, CDCl3, TMS): δ = 157.5, 145.4, 143.4, 131.0, 130.9 (7),
uct was purified by flash column chromatography (petroleum ether/
130.8, 129.0, 127.9, 126.9, 126.8 (6), 125.2, 122.2, 122.1, 51.5,
ethyl acetate = 3:1) and dried in vacuo.
41.0 ppm. IR (ATR): ν = 3061, 2928, 1636, 1584, 1515, 1476, 1363,
˜
(Z)-N-[2-Ethyl-1-phenyl-1H-benzo[d][1,3]thiazin-4(2H)-ylidene]-
methanamine (7a): Yield 90 mg of a yellow solid, 64%, m.p. 140–
142 °C. 1H NMR (600 MHz, CDCl3, TMS): δ = 8.22 (dd, J =
8.1, 1.6 Hz, 1 H, Ar-H), 7.29–7.26 (m, 3 H, Ar-H), 7.99 (ddd, J =
1316, 1258, 1034, 947, 915, 743, 643, 585, 487 cm–1. MS: m/z =
288.1 [M]+. HRESIMS: C15H14N2SCl: calcd. 289.0566, found
289.0557.
(Z)-N-[1-(3-Chlorophenyl)-1H-benzo[d][1,3]thiazin-4(2H)-ylidene]- 8.1, 7.3, 1.1 Hz, 1 H, Ar-H), 7.05–7.02 (m, 3 H, Ar-H), 7.00 (dd, J
methanamine (6c): Yield 111 mg of a yellow oil, 77%. 1H NMR
(400 MHz, CDCl3, TMS): δ = 8.24 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-
= 8.2, 1.1 Hz, 1 H, Ar-H), 5.03 (dd, J = 9.3, 6.3 Hz, 1 H, NCHS-
H), 3.35 (s, 3 H, NMe), 2.13–2.06 (m, 1 H, CH2-H), 1.98–1.91
H), 7.32 (ddd, J = 8.1, 7.0, 1.6 Hz, 1 H, Ar-H), 7.20 (t, J = 8.1 Hz, (m, 1 H, CH2-H), 1.08 (t, J = 7.3 Hz, 3 H, CMe) ppm. 13C NMR
1 H, Ar-H), 7.16 (ddd, J = 8.0, 7.0, 1.3 Hz, 1 H, Ar-H), 7.05–7.02
(m, 2 H, Ar-H), 6.99 (ddd, J = 8.1, 2.1, 1.0 Hz, 1 H, Ar-H), 6.92 127.4, 126.3, 125.8, 123.3, 123.1, 122.2, 67.0, 40.9, 31.1, 12.0 ppm.
(ddd, J = 8.1, 2.1, 1.0 Hz, 1 H, Ar-H), 5.06 (s, 2 H, CH2-H), 3.34 IR (ATR): ν = 3311, 3161, 3038, 3014, 2960, 2929, 1587, 1570,
(150 MHz, CDCl3, TMS): δ = 156.4, 148.3, 141.4, 131.0, 129.4,
˜
(s, 3 H, NMe) ppm. 13C NMR (100 MHz, CDCl3, TMS): δ = 157.0, 1506, 1456, 1362, 1310, 1255, 1163, 1037, 942, 753, 695, 574,
147.6, 143.7, 135.2, 130.9, 130.4, 127.4, 127.3, 124.4, 124.3, 122.9,
4 7 5 c m – 1 . E S I - M S : m / z = 2 8 3 [ M + H ] + . H R E S I M S :
121.3, 119.3, 51.7, 41.1 ppm. IR (ATR): ν = 3063, 3011, 2930, 1685,
C17H18N2SNa: calcd. 305.1088, found 305.1088.
˜
1636, 1586, 1475, 1453, 1289, 1190, 1111, 1039, 980, 917, 866, 748,
643, 616, 440 cm–1. ESI-MS: m/z = 289.0 [M + H]+. HRESIMS:
C15H14N2SCl: calcd. 289.0566, found 289.0568.
(Z)-N-[1-(2-Chlorophenyl)-2-ethyl-1H-benzo[d][1,3]thiazin-4(2H)-yl-
idene]methanamine (7b): Yield 104 mg of a yellow solid, 66%, m.p.
120–124 °C. H NMR (600 MHz, CDCl3, TMS): δ = 8.18 (dd, J =
1
(Z)-N-[1-(4-Bromophenyl)-1H-benzo[d][1,3]thiazin-4(2H)-ylidene]- 8.1, 1.5 Hz, 1 H, Ar-H), 7.37 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-H), 7.16
methanamine (6d): Yield 153 mg of a yellow oil, 92%. 1H NMR
(400 MHz, CDCl3, TMS): δ = 8.24 (dd, J = 8.2, 1.6 Hz, 1 H, Ar-
H), 7.41–7.37 (m, 2 H, Ar-H), 7.29 (ddd, J = 8.2, 7.2, 1.6 Hz, 1 H,
Ar-H), 7.13 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H, Ar-H), 7.00 (dd, J =
8.2, 1.2 Hz, 1 H, Ar-H), 6.95–6.92 (m, 2 H, Ar-H), 5.04 (s, 2 H,
CH2-H), 3.34 (s, 3 H, NMe) ppm. 13C NMR (100 MHz, CDCl3,
(ddd, J = 8.1, 7.1, 1.5 Hz, 1 H, Ar-H), 7.08 (ddd, J =
7.7, 7.6, 1.6 Hz, 1 H, Ar-H), 7.03 (ddd, J = 8.0, 7.6, 1.6 Hz, 1 H,
Ar-H), 6.99 (ddd, J = 8.1, 7.1, 1.2 Hz, 1 H, Ar-H), 6.89 (d, J =
7.7 Hz, 1 H, Ar-H), 6.68 (d, J = 8.1 Hz, 1 H, Ar-H), 4.72 (dd, J =
9.5, 5.5 Hz, 1 H, NCHS-H), 3.35 (s, 3 H, NMe), 2.16 (ddq, J =
5.5, 14.0, 7.4 Hz, 1 H, CH2-H), 1.93 (ddq, J = 9.5, 14.0, 7.4 Hz, 1
TMS): δ = 157.1, 145.5, 144.0, 132.4, 130.9, 127.3, 127.2, 124.2, H, CH2-H), 1.00 (t, J = 7.4 Hz, 3 H, CMe) ppm. 13C NMR
124.0, 123.2, 115.7, 51.9, 41.1 ppm. IR (ATR): ν = 3059, 2925,
(150 MHz, CDCl3, TMS): δ = 156.6, 145.2, 143.0, 131.3, 130.9,
˜
1582, 1485, 1450, 1392, 1353, 1269, 1201, 1156, 1108, 1070, 1038,
1005, 820, 744, 493 cm–1. MS: m/z = 332.0 [M]+. HRESIMS:
C15H14N2SBr: calcd. 333.0061, found 333.0060.
130.8, 129.0, 127.8, 126.8, 126.4, 126.1, 125.2, 123.0, 67.3, 40.9,
30.5, 11.5 ppm. IR (ATR): ν = 3063, 2964, 2929, 2873, 1582, 1515,
˜
1474, 1293, 1147, 1009, 940, 742, 457 cm–1. ESI-MS: m/z = 317.1
[M + H]+. HRESIMS: C17H18N2SCl: calcd. 317.0879, found
317.0880.
(Z)-N-[1-(p-Tolyl)-1H-benzo[d][1,3]thiazin-4(2H)-ylidene]methan-
amine (6e): Yield 108 mg of a yellow solid, 81%, m.p. 93–94 °C. 1H
NMR (600 MHz, CDCl3, TMS): δ = 8.24 (dd, J = 8.2, 1.6 Hz, 1
H, Ar-H), 7.24 (ddd, J = 8.3, 6.9, 1.6 Hz, 1 H, Ar-H), 7.11 (d, J =
8.5 Hz, 2 H, Ar-H), 7.05 (ddd, J = 8.1, 7.1, 1.2 Hz, 1 H, Ar-H),
6.98 (d, J = 8.5 Hz, 2 H, Ar-H), 6.95 (dd, J = 8.2, 1.2 Hz, 1 H, Ar-
(Z)-N-[1-(3-Chlorophenyl)-2-ethyl-1H-benzo[d][1,3]thiazin-4(2H)-yl-
idene]methanamine (7c): Yield 106 mg of a yellow oil, 67 %. 1H
NMR (600 MHz, CDCl3, TMS): δ = 8.22 (dd, J = 8.2, 1.6 Hz, 1
H, Ar-H), 7.32 (ddd, J = 8.2, 7.2, 1.6 Hz, 1 H, Ar-H), 7.19–7.14
H), 5.03 (s, 2 H, CH2-H), 3.35 (s, 3 H, NMe), 2.31 (s, 3 H, (m, 2 H, Ar-H), 7.02–6.97 (m, 3 H, Ar-H), 6.89 (ddd, J =
PhMe) ppm. 13C NMR (150 MHz, CDCl3, TMS): δ = 157.6, 145.0,
144.0, 133.2, 130.7, 130.0, 127.1, 126.5, 123.5, 122.8, 122.5, 52.4,
8.2, 2.3, 0.9 Hz, 1 H, Ar-H), 5.03 (dd, J = 9.3, 6.3 Hz, 1 H, NCHS-
H), 3.34 (s, 3 H, NMe), 2.09–2.02 (m, 1 H, CH2-H), 1.96–1.89
(m, 1 H, CH2-H), 1.07 (t, J = 7.3 Hz, 3 H, CMe) ppm. 13C NMR
(150 MHz, CDCl3, TMS): δ = 155.8, 149.5, 140.4, 135.0, 131.1,
41.1, 20.8 ppm. IR (ATR): ν = 2912, 2846, 1599, 1587, 1560, 1508,
˜
1476, 1449, 1423, 1389, 1356, 1321, 1301, 1274, 1204, 1136, 1116,
1094, 1041, 1008, 970, 908, 821, 712, 612, 539 cm–1. ESI-MS: m/z 130.2, 127.8, 126.5, 126.0, 124.2, 122.8, 121.6, 119.6, 66.5, 40.9,
= 269.0 [M + H]+. HRESIMS: C16H17N2S: calcd. 269.1112, found
269.1111.
31.0, 11.9 ppm. IR (ATR): ν = 3176, 3053, 2963, 2929, 1583, 1511,
˜
1463, 1355, 1253, 1092, 1074, 1036, 748, 682, 485, 439 cm–1. MS:
m/z = 316.1 [M]+. HRESIMS: C17H18N2SCl: calcd. 317.0879,
found 317.0877.
(Z)-N-[1-(4-Methoxyphenyl)-1H-benzo[d][1,3]thiazin-4(2H)-yl-
idene]methanamine (6f): Yield 131 mg of a yellow solid, 92%, m.p.
1
107–110 °C. H NMR (600 MHz, CDCl3, TMS): δ = 8.25 (dd, J = (Z)-N-[1-(4-Bromophenyl)-2-ethyl-1H-benzo[d][1,3]thiazin-4(2H)-yl-
8.1/1.6 Hz, 1 H, Ar-H), 8.22 (ddd, J = 8.2/7.0/1.6 Hz, 1 H, Ar-H), idene]methanamine (7d): Yield 83 mg of a yellow oil, 46 %. 1H
Eur. J. Org. Chem. 2015, 4710–4719
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4717

Z. Guan, M. Nieger, A. Schmidt
FULL PAPER
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K. H. Park, W. J. Marshall, J. Org. Chem. 2005, 70, 2075–2081.
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204–205.
A. Padwa, G. Haffmanns, T. Miguel, J. Org. Chem. 1984, 49,
3314–3322.
NMR (600 MHz, CDCl3, TMS): δ = 8.21 (dd, J = 8.1, 1.6 Hz, 1
H, Ar-H), 7.35–7.38 (m, 2 H, Ar-H), 7.30 (ddd, J = 8.2, 7.0, 1.6 Hz,
1 H, Ar-H), 7.13 (ddd, J = 8.1, 7.0, 1.0 Hz, 1 H, Ar-H), 6.98 (dd,
J = 8.2, 1.0 Hz, 1 H, Ar-H), 6.89–6.91 (m, 2 H, Ar-H), 4.97 (dd, J
= 9.3, 6.3 Hz, 1 H, SCHN-H), 3.34 (s, 3 H, NMe), 2.10–2.02 (m, 1
H, CH2-H), 1.96–1.89 (m, 1 H, CH2-H), 1.06 (t, J = 7.3 Hz, 3 H,
CMe) ppm. 13C NMR (150 MHz, CDCl3, TMS): δ = 156.0, 147.6,
140.9, 132.4, 131.3, 127.8, 126.6, 126.0, 124.1, 123.7, 115.7, 67.0,
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J. E. Rowe, Synthesis 1980, 114–115.
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G. Kjellin, J. Sandström, Acta Chem. Scand. 1973, 27, 209–
217.
41.0, 31.1, 12.1 ppm. IR (ATR): ν = 3263, 3168, 3037, 2956, 2889,
˜
[16]
[17]
1580, 1506, 1486, 1461, 1358, 1319, 1038, 1006, 942, 746, 684 cm–1.
ESI-MS: m/z = 361.0 [M + H]+. HRESIMS: C17H18N2SBr: calcd.
361.0374, found 361.0374.
H. Yoshida, S. Sogame, S. Bando, S. Nakajima, T. Ogata, K.
Matsumoto, Bull. Chem. Soc. Jpn. 1983, 56, 3849–3850.
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[18]
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[20]
2-Ethyl-3-methyl-1-(p-tolyl)-2,3-dihydro-quinazoline-4(1H)-thione
1
(7e): Yield 68 mg of a yellow solid, 46%, m.p. 96–99 °C. H NMR
(400 MHz, CDCl3, TMS): δ = 8.43 (dd, J = 8.1, 1.5 Hz, 1 H, Ar-
H), 7.25 (ddd, J = 8.1, 7.1, 1.5 Hz, 1 H, Ar-H), 7.04 (d, J = 8.2 Hz,
2 H, Ar-H), 6.98 (ddd, J = 8.1, 7.1, 1.2 Hz, 1 H, Ar-H), 6.93–6.89
(m, 3 H, Ar-H), 4.96 (dd, J = 8.6, 6.0 Hz, 1 H, NCHN-H), 3.48 (s,
3 H, NMe), 2.25 (s, 3 H, PhMe), 1.83–1.67 (m, 2 H, CH2-H), 0.99
(t, J = 7.4 Hz, 3 H, CMe) ppm. 13C NMR (100 MHz, CDCl3,
[21]
[22]
[23]
[24]
TMS): δ = 186.6, 144.7, 138.2, 133.9, 132.5, 132.1, 130.1, 127.5, [25]
[26]
122.2, 122.1, 121.1, 81.3, 43.0, 25.1, 20.8, 10.3 ppm. IR (ATR): ν
˜
= 2965, 2923, 2873, 1646, 1600, 1568, 1475, 1378, 1251, 1146, 1082,
914, 809, 758, 675, 644, 507 cm–1. ESI-MS: m/z = 319.2 [M +
Na]+. HRESIMS: C18H21N2S: calcd. 297.1425, found 297.1419.
[27]
[28]
K. Maruoka, T. Miyazaki, M. Ando, Y. Matsumura, S. Sakane,
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182.
2-Ethyl-1-(4-methoxyphenyl)-3-methyl-2,3-dihydroquinazoline-
4(1H)-thione (7f): Yield 84 mg of a yellow solid, 54%, m.p. 107–
110 °C. 1H NMR (400 MHz, CDCl3, TMS): δ = 8.43 (dd, J =
8.2, 1.5 Hz, 1 H, Ar-H), 7.23 (ddd, J = 8.2, 7.2, 1.5 Hz, 1 H, Ar-
H), 6.98–6.93 (m, 3 H, Ar-H), 6.82–6.76 (m, 3 H, Ar-H), 4.87 (dd,
J = 8.5, 6.0 Hz, 1 H, NCHN-H), 3.72 (s, 3 H, OMe), 3.48 (s, 3 H,
NMe), 1.82–1.67 (m, 2 H, CH2-H), 0.99 (t, J = 7.4 Hz, 3 H,
CMe) ppm. 13C NMR (100 MHz, CDCl3, TMS): δ = 186.6, 156.8,
140.6, 138.9, 132.6, 132.1, 127.1, 124.6, 121.9, 120.7, 114.8, 81.8,
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P. Beak, J.-K. Lee, J. M. Zeigler, J. Org. Chem. 1978, 43, 1536–
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55.6, 43.0, 25.2, 10.3 ppm. IR (ATR): ν = 2962, 2930, 2902, 2873,
˜
2829, 1563, 1538, 1498, 1472, 1371, 1238, 1217, 1142, 1030, 830,
813, 791, 763, 672, 643 cm–1. ESI-MS: m/z = 313.1 [M + H]+.
HRESIMS: C18H21N2OS: calcd. 313.1375, found 313.1376.
[36]
[37]
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Acknowledgments
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Dr. Gerald Dräger, University of Hannover, Germany is gratefully
acknowledged for measuring the HRMS spectra.
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