The BF3·OEt2-assisted conversion of nitriles into thioamides with Lawesson's reagent

Article abstract of DOI:10.1055/s-0028-1083253

A method for the thiolysis of nitriles by applying Lawesson's reagent and facilitated by the addition of boron trifluoride-diethyl ether complex is reported. The method opens an easy access to primary thioamides. Aromatic, benzylic, and aliphatic nitriles were converted into the corresponding thioamides in high to quantitative yields (even in unfavorable cases, e.g., ortho-substitut-ed benzonitriles). The reaction was performed in 1,2-dimethoxyethane-tetrahydrofuran or toluene-diethyl ether solvent mixtures at 20-50°C, and exhibited considerable selectivity in the case of multifunctional nitrile substrates, such as cyanomethyl N-acetylphenylalaninate, benzoylacetonitrile, 4-cyanobenzamide, 4-acetylbenzonitrile, or pent-3-enenitrile. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083253

4012
PAPER
The BF3·OEt2-Assisted Conversion of Nitriles into Thioamides with
Lawesson’s Reagent
Conversionof
Nitriles
i
intoTh
c
ioamides
w
h
ith
L
awesso
a
n’s Reage
n
e
t
l Nagl,a,1 Claudia Panuschka,b,1 Andrea Barta,b Walther Schmid*a
a
Institute of Organic Chemistry, University of Vienna, Währingerstr. 38, 1090 Vienna, Austria
Fax +43(1)42779521; E-mail: walther.schmid@univie.ac.at
b
Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Dr. Bohrgasse 9, 1030 Vienna, Austria
Received 17 June 2008; revised 18 August 2008
Intending the preparation of sulfur analogues of cyano-
methyl esters of N-acetylated a-amino acids (e.g., used for
aminoacylations of adenosine mononucleotides15) we ini-
tially focussed on the thionylation reactions of these sub-
Abstract: A method for the thiolysis of nitriles by applying
Lawesson’s reagent and facilitated by the addition of boron trifluor-
ide–diethyl ether complex is reported. The method opens an easy
access to primary thioamides. Aromatic, benzylic, and aliphatic ni-
triles were converted into the corresponding thioamides in high to strates with Lawesson’s reagent. Remarkably,16 addition
quantitative yields (even in unfavorable cases, e.g., ortho-substitut-
of boron trifluoride–diethyl ether complex to the reaction
ed benzonitriles). The reaction was performed in 1,2-dimethoxy-
mixtures resulted in a significant increase in the
ethane–tetrahydrofuran or toluene–diethyl ether solvent mixtures at
susceptibility17 of the cyanomethyl moiety towards thio-
20–50 °C, and exhibited considerable selectivity in the case of mul-
lysis and led to exclusive and almost quantitative trans-
tifunctional nitrile substrates, such as cyanomethyl N-acetylphenyl-
formation of the nitrile group into the thioacetamide
moiety, leaving the amide function of the N-acetyl group
untouched. This pronounced nitrile activating effect was
observed for all types of nitrile substrates investigated.
The reaction system, Lawesson’s reagent–BF3·OEt2,
opened a simple and efficient route to primary thioamides.
alaninate, benzoylacetonitrile, 4-cyanobenzamide, 4-acetyl-
benzonitrile, or pent-3-enenitrile.
Key words: thioamides, nitriles, Lawesson’s reagent, Lewis acid
complex, sulfur-transferring reagents
The thiolysis of nitriles leading directly to thioamides re-
mains an attractive synthetic transformation.2 Thioamides
are versatile synthetic intermediates in the preparation of
heterocyclic compounds.3 Furthermore, thioamide-based
drugs are of increasing relevance in the treatment of mul-
tidrug-resistant tuberculosis.4 The thionation of nitriles,
amides, ketones, or esters has been known for a long time,
mostly utilizing hydrogen sulfide,5 ammonium and alka-
line sulfides,6 and phosphorus pentasulfide7 as sulfur-
transferring reagents. More recent approaches share the
methodological goal of overcoming the inconveniencies
of these methods due to the toxicity, malodorous proper-
ties, or moderate solubilities of these reagents. Especially,
diphenylphosphinodithioic acid,8 O,O-diethyl dithiophos-
phate,9 thioacetic acid,10 trimethylsilanethiolate,11 or 2,4-
bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-
disulfide12 (commonly known as Lawesson’s reagent;
L.R.) and its analogues have found application as alterna-
tives to phosphorus pentasulfide. Thionylations with
Lawesson’s reagent have become part of the standard rep-
ertoire of organic synthesis.13 The commercially available
reagent has been widely applied for the introduction of
sulfur to carbonyl, amide, and, with some restrictions,
ester functions. However, so far the thiolysis of nitriles
with Lawesson’s reagent has been restricted to a few spe-
cial cases (thionation of alkylidenemalonitriles).14
6
CSNH2
CN
L.R. (0.5–1.5 equiv)
5
1
BF3•OEt2 (2–12 equiv)
4
2
DME–THF or
toluene–Et2O
3
X
X
X = H
2-Br 3-Br 4-Br
2-OMe 3-OMe 4-OMe
2-NO2 3-NO2 4-NO2
4-CONH2 4-PhCO 4-MeCO
n = 0,1
n = 0,1
O
O
6
3
CN
CSNH2
3'
1'
L.R. (0.5–1.5 equiv)
5
4
1
2
2'
BF3•OEt2 (2–12 equiv)
DME–THF or
toluene–Et2O
X
X
X = H
X = H
n = 1 benzoylacetonitrile
n = 0 phenylacetonitrile
X = 2-Br n = 0 (2-bromophenyl)acetonitrile
Scheme 1 Examples for aromatic, benzylic, and homobenzylic
nitriles as substrates in thioamide formation reactions using the
L.R.–BF3·OEt2 system
Monosubstituted benzonitriles, homoaromatic phenylace-
tonitriles, and aliphatic nitriles were reacted with 0.5 to
1.5 equivalents of Lawesson’s reagent in the presence of
0 to 12 equivalents of boron trifluoride–diethyl ether com-
plex in different solvent mixtures (Table 1). Mixtures of
1,2-dimethoxyethane–tetrahydrofuran (2:1) and toluene–
diethyl ether (7:1) were found to be suitable media for the
transformation of nitriles into the corresponding primary
thioamides.
SYNTHESIS 2008, No. 24, pp 4012–4018
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x.
x
x
.
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0
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Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083253; Art ID: T10508SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Conversion of Nitriles into Thioamides with Lawesson’s Reagent
4013
Table 1 Influence of the Addition of BF3·OEt2 on the Conversion of Nitriles into Primary Thioamides by Lawesson’s Reagent for Different
Solvent Mixtures and Reaction Conditions
Entry
Nitrile
Product
Yield (%)a
No BF3·OEt2, BF3·OEt2
BF3·OEt2
No BF3·OEt2, BF3·OEt2
toluene–Et2Oe (12 equiv),
toluene–Et2Of
DME–THFb
(2 equiv),
(12 equiv),
DME–THFc
DME–THFd
1
2
benzonitrile
1
2
8
<1
5
61
18
54
<1
12
23
67
<5
53
<1
–
80
12
55
42g
8g
7
9
75
62
98
97
75
96
99
65
88
95
76
78
47i
92j
2-bromobenzonitrile
3-bromobenzonitrile
4-bromobenzonitrile
2-methoxybenzonitrile
3-methoxybenzonitrile
4-methoxybenzonitrile
2-nitrobenzonitrile
3-nitrobenzonitrile
4-nitrobenzonitrile
phenylacetonitrile
(2-bromophenyl)acetonitrile
pentanenitrile
3
3
14
17
4
4
4
5
5
5
2
6
6
12
15
<1
8
87
95
15
77
70
40
35
0
10
15
<1
13
8
7
7
8
8
9
9
10
11
12
13
14
10
11
12
13
14
3
–
–
–
–
–
–
0
0
pentanedinitrile
–
0
18h
0
a Yields of isolated thioamides.
b Conditions: nitrile (1 mmol), L.R. (0.5 mmol), DME–THF (2:1, 28 mL), 50 °C, 14 h.
c Conditions: nitrile (1 mmol), L.R. (0.5 mmol), BF3·OEt2 (2 mmol), DME–THF (2:1, 28 mL), r.t., 3 h.
d Conditions: nitrile (1 mmol), L.R. (1.5 mmol), BF3·OEt2 (12 mmol), DME–THF (2:1, 68 mL), 50 °C, 14 h (unless otherwise noted).
e Conditions: nitrile (1 mmol), L.R. (1.5 mmol), toluene–Et2O (10:1.5, 120 mL), 50 °C, 14 h.
f Conditions: nitrile (1 mmol), L.R. (1.5 mmol), BF3·OEt2 (12 mmol), toluene–Et2O (10:1.5, 120 mL), 50 °C, 14 h (unless otherwise noted).
g 50 °C, 36 h.
h 80 °C, 5 h, then r.t., 60 h.
i Conditions: nitrile (1 mmol), L.R. (1.5 mmol), BF3·OEt2 (24 mmol), toluene–Et2O (10:1.5, 120 mL), 50 °C, 36 h.
j Conditions: nitrile (1 mmol), L.R. (3 mmol), BF3·OEt2 (24 mmol), toluene–Et2O (10:1.5, 230 mL), 50 °C, 14 h.
Some aromatic nitriles show moderate reactivity towards nitriles were found to be unreactive towards Lawesson’s
Lawesson’s reagent, a fact that has to our knowledge not reagent (Table 1, entries 11–14).
been systematically investigated so far. In our control
The addition of boron trifluoride–diethyl ether complex to
experiments we treated a variety of methoxy, bromo, and
the reaction mixtures led to a significant increase in thio-
nitro derivatives of benzonitrile (Scheme 1) with
amide formation under even milder reaction conditions.
Lawesson’s reagent (see Table 1). Expectedly, after
Thus, when aromatic nitriles were reacted with 0.5 equiv-
workup we found only small amounts of thioamides in our
alents of Lawesson’s reagent in the presence of 2.0 equiv-
reaction mixtures after reaction times of 12 hours (at 50
alents of boron trifluoride–diethyl ether complex in 1,2-
°C). For the most reactive substrates, 3-bromobenzo-
dimethoxyethane–tetrahydrofuran (2:1) at room tempera-
nitrile, 3-methoxy- and 4-methoxybenzonitrile, and 3-
ture for three hours (Table 1, entries 1–10), substantial
nitrobenzonitrile, the yields of the corresponding thio-
amounts of thioamides were isolated from the reaction
mixtures (with exception of 4-bromo- and 4-nitrobenzo-
nitrile, Table 1, entries 4 and 10). While under these con-
ditions yields for the corresponding product thioamides
amides 3, 6, 7, 9 obtained were in the range of 10–15%
(Table 1, entries 3, 6, 7, 9). The lowest reactivities were
observed for ortho-substituted benzonitriles (Table 1, en-
tries 2, 5, 8). Essentially, the reactivities did not differ in
were only average for most aromatic nitriles, the different
1,2-dimethoxyethane–tetrahydrofuran to toluene–diethyl
reactivities of the chosen substrates towards thionylation
ether solvent mixtures. Recovery of unreacted nitriles
are reflected clearly: the meta-derivatives of bromo- and
(70–99%), complementing the molar fractions of isolated
nitrobenzonitrile, as well as 4-methoxy- and unsubstituted
thioamides, demonstrates the consistency of thioamide
benzonitrile (Table 1, entries 3, 9, 7, 1) gave 50–70%
yield and nitrile reactivity. Homoaromatic and aliphatic
yields of the corresponding thioamides. Generally, low
Synthesis 2008, No. 24, 4012–4018 © Thieme Stuttgart · New York

4014
M. Nagl et al.
PAPER
yields were found in the case of the ortho-substituted de- lents of Lawesson’s reagent and 12 equivalents of boron
rivatives 2-bromo-, 2-methoxy- and 2-nitrobenzonitrile trifluoride–diethyl ether complex. All aromatic nitriles
(Table 1, entries 2, 5, 8). Interestingly, only traces of tested were converted into the thioamides in high yields
products could be isolated from reaction mixtures of 4- (Table 1, entries 1–10). Benzylic nitriles and even aliphat-
bromo- and 4-nitrobenzonitrile after a reaction time of ic nitriles gave the corresponding thioamides in moderate
three hours at room temperature (Table 1, entries 4, 10). to good yields under these reaction conditions (Table 1,
Aliphatic nitriles also proved to be unreactive under these entries 11–14).
conditions (Table 1, entries 13, 14). High levels of recov-
The strong increase in reactivity of the nitrile function to-
ery of the unreacted nitrile substrate, regardless of the de-
wards Lawesson’s reagent by applying the Lewis acid
gree of conversion, indicated the high selectivity of the
complex boron trifluoride–diethyl ether complex was also
above transformations. Only traces of thioamides were
illustrated by a series of reactions with multifunctional
found in reaction mixtures devoid of boron trifluoride–
nitrile substrates (Table 2), showing functional groups
diethyl ether complex under otherwise similar reaction
such as ester, vinyl, carbonyl, and amide functionalities.
conditions (r.t., 3 h).
In analogy to certain aromatic nitriles, conventional thion-
ation of the cyanomethyl ester of N-acetyl-L-phenylala-
Increasing of the molar ratios of Lawesson’s reagent (up
to 1.5 equiv) and boron trifluoride–diethyl ether complex
nine with Lawesson’s reagent, without addition of boron
(up to 12 equiv) as well as raising the temperature (up to
trifluoride–diethyl ether complex, revealed the suscepti-
50 °C) and increasing the reaction time (up to 36 h) led to
bility of the nitrile function of the cyanohydrin moiety17
further improvements in conversions (with the exceptions
towards thiolysis. Due to partial thiolysis of the cyano-
methyl group, the N-acetylphenylalanine ester 15 was
present in the product mixtures (together with the cya-
nomethyl and 2-hydroxythioacetamide esters of N-thio-
of 2-bromobenzonitrile and 2-methoxybenzonitrile,
Table 1, entries 2 and 5). Generally, between 50% and
90% of the corresponding product thioamides were ob-
tained from the reaction mixtures (Table 1, entries 1–9).
acetylphenylalanine), albeit the yield for this product was
Even homoaromatic phenylacetonitriles (Scheme 1)
below 30%. However, addition of six equivalents of boron
showed average reactivity under these stoichiometric con-
trifluoride–diethyl ether complex to the reaction mixture
ditions (Table 1, entries 11, 12), for pentanedinitrile 18%
yielded 89% of monothioamide 15 as the sole product
(Table 2, entry 1), whereas the amide portion of the N-
acetyl group remained untouched. In the interesting case
conversion into the corresponding dithioamide 14 was ob-
served (Table 1, entry 14).
A more pronounced effect was obtained when using the of 4-cyanobenzamide (Table 2, entry 3) conventional
two-component solvent mixture toluene–diethyl ether thionation with Lawesson’s reagent in 1,2-dimethoxy-
(7:1), by treating the respective nitrile with 1.5 equiva- ethane–tetrahydrofuran (2:1) (i.e., without addition of
Table 2 Yields and Selectivity of Thionylations of Multifunctional Nitrile Substrates by the System Lawesson’s Reagent–BF3·OEt2
Entry Substrate
Product
Solventa
Stoichiometryb Temp (°C) Time (h) Yieldc (%)
O
O
H
H
S
N
N
1
15
A
1:0.8:6
40
4
89
O
O
CN
O
O
NH2
Ph
Ph
O
O
S
CN
2
3
16
17
B
A
1:1.0:12
1:0.7:24
20
20
14
3
75
73
NH2
CN
H2N
S
O
O
NH2
H2NOC
O
S
4
5
18
19
B
B
1:1.5:12
1:1.5:12
20
20
12
12
51
70
CN
CN
Ph
O
NH2
S
Ph
O
NH2
Me
NC
Me
6
7
20
21
A
B
1:1.5:12
1:1.5:12
55
20
14
14
62
45
H2NSC
COOMe
CSNH2
COOMe
CN
a Solvent A: DME–THF (2:1, 68 mL); solvent B: toluene–Et2O (7:1, 120 mL).
b Substrate (equiv)/L.R. (equiv)/BF3·OEt2 (equiv).
c Isolated yield (mol%).
Synthesis 2008, No. 24, 4012–4018 © Thieme Stuttgart · New York

PAPER
Conversion of Nitriles into Thioamides with Lawesson’s Reagent
4015
BF3·OEt2) led to isolation of 4-cyanothiobenzoamide18 as
single product after three hours at 50 °C (45%), as a result
of regioselective thionation of the aromatic amide moiety.
However, this regioselectivity was reversed when 24
equivalents of boron trifluoride–diethyl ether complex
were added to the reaction mixture; after three hours at
room temperature the monothio derivative 4-(thiocarbam-
oyl)benzamide (17) was isolated exclusively in high yield.
Cyanomethyl N-Acetyl-L-phenylalaninate (Table 2, Entry 1)
To a suspension of N-acetyl-L-phenylalanine (1.14 g, 5.5 mmol) in
anhyd MeCN (8 mL) under an argon atmosphere was added freshly
distilled Et3N (2.06 mL) to obtain a clear soln. The soln was cooled
on ice, chloroacetonitrile (1.46 mL, 19.5 mmol, 3.5 equiv) was add-
ed, and the mixture was stirred at 20 °C for 16 h (formation of a
white precipitate). CH2Cl2 (120 mL) was added and the mixture was
washed with 1 M NaHSO4. The aqueous phase was extracted with
another portion of CH2Cl2 (120 mL). The combined organic phases
were washed with brine and dried (MgSO4). After evaporation of
the solvent, the material obtained was dried in vacuo. The crude ma-
terial was pure enough for further transformations; white, feathery
crystals; yield: 1.2 g (89%).
High yields of the monothionylated products 18 and 19
were also found for 4-benzoyl- and 4-acetylbenzonitrile
(Table 2, entries 4 and 5). Selective conversion of the
nitrile group was also observed in the case of benzoyl-
acetonitrile (Table 2, entry 2): thioamide 16 was isolated
1H NMR (400 MHz, CDCl3): d = 7.36–7.13 (m, 5 HPh), 4.94–4.89
(ABX, 1 H, Hx2), 4.80–4.76 (d, J = 15.6 Hz, 1 H, COOCHA), 4.70–
as the main product in good yield as a 1:1 mixture of the 4.66 (d, J = 15.6 Hz, 1 H, COOCHB), 3.13 (ABX, 2 H, PhCH2), 1.98
corresponding keto and enol forms.19 No formation of
(s, 3 H, COCH3).
1,2,3-oxazaphosphorin-4-thione 2-sulfides20 was ob-
served.
13C NMR (100 MHz, CDCl3): d = 171.1, 170.6, 135.4, 129.9, 129.5,
127.9, 114.2, 53.5, 49.3, 37.9, 23.3.
Further examples of application of this method to func-
tionalized nitriles are the conversions of methyl cyano-
acetate and pent-3-enonitrile into the corresponding
thioamides (Table 2, entries 6 and 7), giving access to the
corresponding thioamides 20 and 21 in moderate yield.
4-Methoxythiobenzamide (7); Typical Procedure for Thiolysis
in DME–THF (2:1)
To a stirred soln of 4-methoxybenzonitrile (133 mg, 1.0 mmol) in
DME (6 mL) and THF (3 mL) was added, under an argon atmo-
sphere, BF3·OEt2 (1.50 mL, 12 mmol) followed by 0.025 M
Lawesson’s reagent in DME–THF (2:1) (60 mL, 1.5 mmol) [pre-
pared in an ultrasound cleaning bath at 50 °C]. The mixture was
stirred overnight at 50 °C. After 14 h, NaHCO3 (1.01 g, 12 mmol)
In summary, we have demonstrated that the addition of
boron trifluoride–diethyl ether complex to reaction mix-
tures of nitriles and Lawesson’s reagent promotes the di- was added and the mixture was stirred at r.t. for 20 min. After evap-
oration of the solvents the residue was dried in vacuo. The product
7 was purified by column chromatography (silica gel, PE–EtOAc,
1:1); yield: 159 mg (95%).
rect and smooth conversion of these substrates into their
corresponding thioamides, which were found to be inac-
cessible if boron trifluoride–diethyl ether complex was
omitted. High yields of thioamides were obtained even in
(2-Bromophenyl)thioacetamide (12); Typical Procedure for
the case of aliphatic nitriles or ortho-substituted aromatic
nitriles. The reaction shows remarkable compatibility
with a number of functional groups, such as benzoyl,
acetyl, ester, amide, and vinyl moieties. Thus, the boron
trifluoride–diethyl ether complex assisted conversion of
nitriles into thioamides by Lawesson’s reagent represents
a considerable expansion of the applicability of this wide-
ly used and versatile sulfur-transferring reagent.13
Thiolysis in Toluene–Et2O (10:1.5)
To a stirred soln of (2-bromophenyl)acetonitrile (197 mg, 1.0
mmol) in toluene (105 mL) and Et2O (15 mL) was added, under an
argon atmosphere, BF3·OEt2 (1.50 mL, 12 mmol) followed by solid
Lawesson’s reagent (606 mg, 1.5 mmol). The mixture was stirred at
50 °C overnight. After 14 h, NaHCO3 (1.01 g, 12 mmol) was added
and the mixture was stirred at r.t. for 20 min. After evaporation of
ca. 75% of the total solvent volume, DME (10 mL) was added, fol-
lowed by repeated evaporation of the solvent. The residue was dried
in vacuo. The product 12 was purified by column chromatography
(silica gel, PE–EtOAc, 1:1); yield: 180 mg (78%).
All reactions were performed in anhydrous solvents under an argon
atmosphere. THF, DME, Et2O, and toluene were distilled from K
and Na metal, respectively. MeCN was distilled from CaH2. PE re-
fers to petroleum ether (boiling range 60–95 °C). All reagents were
purchased from commercial sources and used without further puri-
fication. Lawesson’s reagent was purchased from Fluka. Nitrile
samples were purchased from Aldrich (4-methoxybenzonitrile from
Alfa Aesar). BF3·OEt2 (content ~48% BF3) was purchased from
Reaction conditions for different substrates (reaction time, temper-
ature, stoichiometry) and yields are listed in Tables 1 and 2. Prod-
ucts were purified by column chromatography (silica gel, PE–
EtOAc, 1:1), except otherwise noted. For atom labeling see
Scheme 1.
Thiobenzamide (1)
1
Merck and Aldrich. H and 13C NMR spectra were recorded in
Pale yellow coating of fan-shaped aggregated needles; mp 118–19
°C (Lit.2g 116–117 °C).
CDCl3 using a Bruker Avance 400 spectrometer. Products were
checked by 19F and 31P NMR spectroscopy for the absence of inor-
ganic impurities. Melting points of thioamides were determined on
a Leica Galen III melting point apparatus, after recrystallization
(CHCl3 or EtOAc unless otherwise noted). EI-MS spectra were
measured on a Finnigan MAT 8230 mass spectrometer, ESI-MS
spectra were measured on a Finnigan MAT 900S mass spectrome-
ter. NanoESI-MS and MS/MS measurements (MeOH–5% aq
HCO2H, 1:1) were carried out on a QSTAR Elite hybrid mass spec-
trometer (Applied Biosystems, CA).
NMR data are in agreement with literature data.28
2-Bromothiobenzamide (2)
Brown viscous oil.
1H NMR (400 MHz, CDCl3): d = 8.24 (br s, 1 H, CSNH), 7.58–7.56
(d, J = 7.6 Hz, 2 H, H3, H6), 7.36–7.32 (t, J = 7.7 Hz, 1 H, H5),
7.26–7.22 (t, J = 7.7 Hz, 1 H, H4).
13C NMR (100 MHz, CDCl3): d = 203.3 (s, CSNH2), 143.2 (s, C1),
133.6 (d, C3), 131.3 (d, C4), 130.0 (d, C6), 128.0 (d, C5), 117.5 (s,
C2).
MS (EI, 70 eV): m/z (%) = 135.9 (100), 214.7/216.7 (20/20) [M+].
Synthesis 2008, No. 24, 4012–4018 © Thieme Stuttgart · New York

4016
M. Nagl et al.
PAPER
3-Bromothiobenzamide (3)
Bright yellow needles; mp 120–21 °C.
(2-Bromophenyl)thioacetamide (12)
Colorless, shiny platelets; mp 145–148 °C.
1H NMR (400 MHz, CDCl3): d = 8.01 (d, J = 1.8 Hz, 1 H, H2),
7.81–7.78 (d, J = 7.8 Hz, 1 H, H6), 7.67–7.64 (d, J = 8.0 Hz, 1 H,
H4), 7.34–7.28 (t, J = 8.1, 7.8 Hz, 1 H, H5), 7.19 (br s, CSNH).
13C NMR (100 MHz, CDCl3): d = 201.4, 141.5, 135.1, 130.4, 130.4,
125.8, 123.0.
1H NMR (400 MHz, CDCl3): d = 7.55–7.53 (dd, J = 8.0 Hz, 1 H,
H3), 7.36–7.33 (dd, J = 7.6 Hz, 1 H, H6), 7.29–7.25 (t, J = 7.5 Hz,
1 H, H5), 7.15–7.11 (t, J = 7.6 Hz, 1 H, H4), 6.70 (br s, 1 H, CSNH),
4.17 (s, 2 H, H2¢).
13C NMR (100 MHz, CDCl3): d = 206.3, 135.5, 133.7, 132.2, 130.1,
128.6, 125.3, 52.2.
MS (EI, 70 eV): m/z (%) = 154.8/156.8 (13/11), 181.8/183.8 (50/
41), 214.7/216.7 (80/74) [M+].
MS (EI, 70 eV): m/z (%) = 150.0 (100), 168.9/170.9 (5/4), 194.9/
196.9 (6/6), 229/231 (<1) [M+].
4-Bromothiobenzamide (4)
MS (NanoESI-MS/MS, +850 V): m/z (%) = 150.0, 169.0/170.9,
Citreous needles; mp 131–35 °C (Lit.2b 138–142 °C).
213.0/214.9, 229.9/231.9 [M+].
NMR data are in agreement with literature data.2b
Anal. Calcd for C8H8BrNS: C, 41.75; H, 3.50; N, 6.08; S, 13.93.
Found: C, 41.90; H, 3.48; N, 6.05; S, 13.86.
2-Methoxythiobenzamide (5)
Yellow platelets; mp 105–108 °C.
Pentanethioamide (13)
Purified by column chromatography (PE–EtOAc, 2:1); white, waxy
solid; mp 40–45 °C.
1H NMR (400 MHz, CDCl3):31 d = 7.40 (br s, 1 H, CSNH), 2.62–
2.58 (t, J = 7.6 Hz, 2 H, H2), 1.69–1.61 (tt, J = 7.6, 7.4 Hz, 2 H, H3),
1.35–1.24 (tq, J = 7.4, 7.2 Hz, 2 H, H4), 0.87–0.83 (t, J = 7.2 Hz, 3
H, H5).
1H NMR (400 MHz, CDCl3): d = 9.06 (br s, 1 H, CSNH), 8.64–8.61
(dd, J = 8.0 Hz, 1 H, H6), 8.35 (br s, 1 H, CSNH), 7.49–7.44 (t,
J = 8.0 Hz, 1 H, H4), 7.10–7.03 (t, J = 7.16 Hz, 1 H, H5), 6.97–6.95
(d, J = 8.44 Hz, 1 H, H3), 3.96 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 199.5, 156.7, 136.7, 134.1, 125.4,
121.6, 111.9, 56.5.
MS (EI, 70 eV): m/z (%) = 106.0 (72), 107.0 (19), 134.0 (100),
13C NMR (100 MHz, CDCl3): d = 209.7 (s, CSNH2), 44.8 (t, C2),
31.3 (t, C3), 22.4 (t, C4), 16.5 (t, C5).
166.9 (81) [M+].
MS (EI, 70 eV): m/z (%) = 117.0 (85) [M+].
3-Methoxythiobenzamide (6)
Dark yellow viscous oil.
Pentanebis(thioamide) (14)
1H NMR (400 MHz, CDCl3): d = 7.38–7.40 (dd, J = 1.8 Hz, 1 H,
H2), 7.30–7.28 (dd, J = 7.3 Hz, 1 H, H6), 7.25–7.20 (t, J = 8.0 Hz,
1 H, H5), 6.99–6.96 (dd, J = 8 Hz, 1 H, H4), 3.78 (s, 3 H, OCH3).
Purified by column chromatography (PE–EtOAc, 2:1); yellow coat-
ing of fan-shaped aggregated needles; mp 98–102 °C (Lit.23 120–
121 °C, dec.).
13C NMR (100 MHz, CDCl3): d = 203.0, 159.9, 141.0, 129.9, 118.7,
118.5, 113.4, 55.9.
1H NMR (400 MHz, CDCl3): d = 2.98–2.95 (t, J = 6.0 Hz, 4 H, H2,
H4), 1.98–1.89 (quint, J = 6.2 Hz, 2 H, H3).
MS (EI, 70 eV): m/z (%) = 107.0 (17), 134.0 (89), 151.0 (16), 166.9
13C NMR (100 MHz, CDCl3): d = 204.2 (s, 2 CSNH2), 40.7 (t, C2,
C4), 20.4 (t, C3).
(100) [M+].
MS (NanoESI-MS/MS, +850 V): m/z (%) = 130.0, 145.0, 162.1
4-Methoxythiobenzamide (7)
[M+], 163.1 [M + H]+.
Pale yellow coating of fan-shaped aggregated needles; mp 144–148
°C (Lit.8a,21 145–147 to 148–149 °C).
2-Amino-2-thioxoethyl N-Acetyl-L-phenylalaninate (15)
Purified by column chromatography (PE–EtOAc, 1:4); white, feath-
ery crystalline solid; mp 137–140 °C.
NMR data are in agreement with literature data.29
2-Nitrothiobenzamide (8)
Pale yellow, crystalline solid; mp 99–104 °C.
1H NMR (400 MHz, CDCl3): d = 7.95–7.92 (d, J = 8.1 Hz, 1 H,
H6), 7.59–7.55 (t, J = 7.4 Hz, 1 H, H5), 7.47–7.44 (m, 2 H, H3, H4),
7.05 (br s, 1 H, CSNH).
13C NMR (100 MHz, CDCl3):30 d = 201.5, 145.8, 138.3, 133.5,
130.5, 128.9, 125.1.
MS (ESI, 4 kV, MeOH–MeCN): m/z (%) = 180.9 [M – H]–.
1H NMR (400 MHz, CDCl3): d = 7.34–7.12 (m, 5 HPh), 5.11–5.07
(d, J = 16.7 Hz, 1 H, COOCHA), 4.86–4.81 (d, J = 16.7 Hz, 1 H,
COOCHB), 4.56–4.51 (ABX, 1 H, Hx2), 3.18–3.06 (ABX, 2 H,
PhCH2), 1.98 (s, 3 H, COCH3).
13C NMR (100 MHz, CDCl3): d = 200.6 (s, CSNH2), 172.0 (s, NH-
COMe), 170.9 (s, CO2CH2), 135.6 (s, CPh), 129.5 (d), 129.3 (d),
128.1 (d) (CHPh), 69.0 (t, OCH2), 55.2 (d, NHCHCO2), 37.3 (t,
PhCH2), 23.2 (q, COCH3).
MS (NanoESI-MS/MS, +850 V): m/z (%) = 120.1, 162.1, 208.1,
3-Nitrothiobenzamide (9)
281.2 [M + H]+.
Orpiment yellow, granular power; mp 124–28 °C.
NMR data are in agreement with literature data.29
Anal. Calcd for C13H16N2O3S: C, 55.69; H, 5.75; N, 9.99; S, 11.44.
Found: C, 55.53; H, 5.89; N, 9.85; S, 11.37.
4-Nitrothiobenzamide (10)
2-Benzoylthioacetamide (16)
Yellow, crystalline powder; mp 154–157 °C (Lit.2b,8a,22b 156–159
°C to 159–161 °C).
Purified by column chromatography (PE–EtOAc, 1:2); yellow crys-
talline powder ; mp 124–128 °C (Lit.24 133 °C). Mixture of keto (K)
and enol forms (E) (1:1) in CDCl3. (Orange solid from CDCl3 soln).
1H NMR (400 MHz, CDCl3): d = 14.59 [s, 1 H, OH (E)], 8.81 (br s,
1 H, CSNH), 8.04–8.01 [d, J = 8.5 Hz, 2 H, H2, H6 (K)], 7.80–7.78
[d, J = 7.0 Hz, 2 H, H2, H6 (E)], 7.72 (br s, 1 H, CSNH), 7.66–7.62
[t, J = 7.4 Hz, 1 H, H4 (E)], 7.53–7.41 [m, 5 H, H3, H5 (K + E), H4
NMR data are in agreement with literature data.29
Phenylthioacetamide (11)
Colorless needles; mp 94–96 °C (Lit.2g,5a,8a,22 94–96 °C to 99–100
°C).
NMR data are in agreement with literature data.29
Synthesis 2008, No. 24, 4012–4018 © Thieme Stuttgart · New York

PAPER
Conversion of Nitriles into Thioamides with Lawesson’s Reagent
4017
(K)], 6.50 (br s, 1 H, CSNH), 6.07 [s, 1 H, C(OH)=CH (E)], 4.49 [s,
2 H, COCH2 (K)].
References
(1) These authors contributed equally.
13C NMR (100 MHz, CDCl3): d = 199.9 [s, CSNH2 (E)], 195.9 [s,
CO (K)], 194.6 [s, CSNH2 (K)], 171.9 [s, C(OH)=C (E)], 135.8 [s,
C1 (K)], 134.9 [s, C1 (E)], 134.4 [d, C4 (E)], 131.4 [d, C4 (K)],
128.9 (d), 128.7 (d) [C3, C5 (K + E)], 128.6 [d, C2, C6 (K)], 126.2
[d, C2, C6 (E)], 96.3 [d, C(OH)=CH (E)], 51.8 [t, COCH2 (K)].
(2) (a) Goswami, S.; Maity, A. C.; Das, N. K. J. Sulfur Chem.
2007, 28, 233. (b) Kaboudin, B.; Elhamifar, D. Synthesis
2006, 224. (c) Boys, M. L.; Downs, V. L. Synth. Commun.
2006, 36, 295. (d) Manaka, A.; Masakazu, S. Synth.
Commun. 2005, 35, 761. (e) Bagley, M. C.; Chapaneri, K.;
Glover, C.; Merritt, E. A. Synlett 2004, 2615. (f) Crane, L.
J.; Anastassiadou, M.; Stigliani, J. L.; Baziard-Mouysset, G.;
Payard, M. Tetrahedron 2004, 60, 5325. (g) Liboska, R.;
Zyka, D.; Bobek, M. Synthesis 2002, 1649.
MS (NanoESI-MS/MS, +850 V): m/z (%) = 77.0, 105.0, 146.1,
163.0, 180.0 [M + H]+.
4-(Thiocarbamoyl)benzamide (17)
(3) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
(4) (a) Wang, F.; Langley, R.; Gulten, G.; Dover, L. G.; Besra,
G. S.; Jabobs, W. R. Jr.; Sacchettini, J. C. J. Exp. Med. 2007,
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517. (c) Fairfull, A. E. S.; Lowe, J. L.; Peak, D. A. J. Chem.
Soc. 1952, 742.
Purified by column chromatography (PE–EtOAc, 1:2); crystalline,
‘fluorescent yellow’ powder; mp 225–26 °C (nitrobenzene) (Lit.25
224–225 °C).
1H NMR data are in agreement with literature data.25
13C NMR (150 MHz, CD3OD):26 d = 203.0 (s, CSNH2), 171.4 (s,
CONH2), 144.3 (s, C1), 137.2 (s, C4), 128.4 (d, C2, C6), 128.4 (d,
C3, C5).
MS (EI, 70 eV): m/z (%) = 146.0 (25), 147.0 (24), 164.0 (15), 180.0
(22) [M+].
(6) Ralston, A. W.; Vander Wal, R. J.; McCorkle, M. R. J. Org.
Chem. 1939, 4, 68.
MS (ESI, 4 kV, MeOH–MeCN): m/z (%) = 179.1 [M – H]–.
(7) Brillon, D. Synth. Commun. 1992, 22, 1397.
(8) (a) Benner, S. A. Tetrahedron Lett. 1981, 22, 1851.
(b) Pudovik, A. N.; Cherkasov, R. A.; Sudakova, T. M.;
Evstaf’ev, G. I. Dokl. Akad. Nauk SSSR 1973, 211, 113.
(c) LaMattina, J. L.; Mularski, C. J. J. Org. Chem. 1986, 51,
413.
4-Benzoylthiobenzamide (18)
Purified by column chromatography (PE–EtOAc, 3:2); lime yellow,
crystalline powder; mp 145–150 °C.
NMR data are in agreement with literature data.32
(9) (a) Zabirov, N. G.; Shamsevaleev, F. M.; Cherkasov, R. A.
Zh. Obshch. Khim. 1992, 62, 71. (b) Yousif, N. M.
Tetrahedron 1989, 45, 4599. (c) Shabana, R.; Meyer, H. J.;
Lawesson, S. O. Phosphorus Sulfur Relat. Elem. 1985, 25,
297.
4-Acetylthiobenzamide (19)
Yellow, crystalline powder; mp 170–73 °C (Lit.27 180–181 °C).
NMR data are in agreement with literature data.26
(10) Gauthier, J. Y.; Lebel, H. Phosphorus, Sulfur Silicon Relat.
Elem. 1994, 95, 325.
(11) Shiao, M. J.; Lai, L. L.; Ku, W. S.; Lin, P. Y.; Hwu, J. R.
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(12) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson,
S.-O. Bull. Soc. Chim. Belg. 1978, 87, 223.
(13) (a) Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107,
5210. (b) Cherkasov, R. A.; Kutyrev, G. A.; Pudovik, A. N.
Tetrahedron 1985, 41, 2567. (c) Cava, M. P.; Levinson, M.
I. Tetrahedron 1985, 41, 5061.
Methyl 3-Amino-3-thioxopropanoate (20)
Amber oil.
1H NMR (400 MHz, CDCl3): d = 8.80 (br s, 1 H, CSNH), 8.10 (br
s, 1 H, CSNH), 3.86 (s, 2 H, CH2), 3.77 (s, 3 H, COOCH3).
13C NMR (100 MHz, CDCl3): d = 199.2 (s, CSNH2), 170.3 (s,
COOMe), 53.1 (q, COOCH3), 47.9 (t, CH2)
MS (EI, 70 eV): m/z (%) = 73.9 (27), 74.9 (16), 101.9 (24), 132.9
(100) [M+].
(14) (a) Mohamed, N. R.; Kamel, E. M.; Erian, A. W.; Nada, A.
A. Egypt. J. Chem. 2003, 46, 873. (b) Abdel-Malek, H. A.
Heterocycl. Commun. 2003, 9, 457. (c) Abd El Rahman, N.
M. Heterocycl. Commun. 2002, 8, 465. (d) Khidre, M. D.;
Yakout, El.-S. M. A.; Mahran, M. R. H. Phosphorus, Sulfur
Silicon Relat. Elem. 1998, 133, 119. (e) Deng, S. L.; Chen,
R. Y. Synthesis 2002, 2527.
(15) (a) Panuschka, C. Ph. D. Thesis; University of Vienna:
Austria, 2007. (b) Dorner, S.; Panuschka, C.; Schmid, W.;
Barta, A. Nucleic Acids Res. 2003, 31, 6536.
(16) (a) On the BF3·OEt2-mediated conversion of nitriles into
amides, see: Hauser, C. R.; Hoffenberg, D. S. J. Org. Chem.
1955, 20, 1448. (b) on the BF3·OEt2-promoted conversion
of nitriles into esters, see: Jayachitra, G.; Yasmeen, N.;
Srinivasa Rao, K.; Ralte, S. L.; Srinivasan, R.; Singh, A. K.
Synth. Commun. 2003, 33, 3461.
Pent-3-enethioamide (21)
Purified by column chromatography (PE–EtOAc, 1:2); white felted
needles; mp 59–64 °C.
1H NMR (400 MHz, CDCl3): d = 7.20 (br s, 1 H, CSNH), 5.78–5.64
(dq, J = 15.3, 6.2 Hz, 1 H, H4vinyl), 5.62–5.50 (ddt, J = 15.3, 6.7, 1.3
Hz, 1 H, H3vinyl), 3.46–3.43 (d, J = 6.8 Hz, 2 H, H2), 1.78–1.75 (dd,
J = 6.2, 1.2 Hz, 3 H, H5)
13C NMR (100 MHz, CDCl3): d = 208.5 (s, C1), 132.4 (d, C3),
125.0 (d, C4), 49.3 (t, C2), 18.4 (q, C1).
MS (EI, 70 eV): m/z (%) = 99.9 (14), 114.9 (70) [M+].
Acknowledgment
Dr. C. Panuschka was supported by a research program of the Fonds
zur Förderung der wissenschaftlichen Forschung (FWF Projekt
Nummer P16523-B11 to Andrea Barta). The authors would like to
thank Ing. Susanne Felsinger and Dr. Hanspeter Kählig (Inst.
Organ. Chem., Univ. of Vienna) for NMR spectra and valuable dis-
cussions, Dr. Edina Csaszar (Max F. Perutz Laboratories, Dept. of
Biochemistry) for NanoESI-MS mass spectra, Ing. Peter
Unteregger and Dr. Eberhard Lorbeer (Inst. Organ. Chem., Univ. of
Vienna) for EI and ESI mass spectra and for valuable discussions.
(17) LaMattina, J. L.; Mularski, C. J. J. Org. Chem. 1986, 51,
413.
(18) NMR spectroscopic data of 4-cyanothiobenzamide: 1H
NMR (400 MHz, CDCl3): d = 7.21 (s, CSNH), 7.70 (d,
J = 8.4 Hz, 2 H, H2, H6), 7.76 (s, CSNH), 7.93 (d, J = 8.5
Hz, 2 H, H3, H5). 13C NMR (400 MHz, CDCl3): d = 115.5
(s, CCN), 118.3 (s, CN), 127.8 (d, CHCCSNH2), 132.7 (d,
CHCCN), 143.3 (s, CCSNH2), 201.0 (s, CSNH2).
Synthesis 2008, No. 24, 4012–4018 © Thieme Stuttgart · New York

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M. Nagl et al.
PAPER
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Synthesis 2008, No. 24, 4012–4018 © Thieme Stuttgart · New York