Reaction of vicinal thieno[2,3-b]pyridine aminoamides with Lawesson's reagent

Article abstract of DOI:10.1007/s10593-013-1196-2

The reaction of vicinal thieno[2,3-b]pyridine aminoamides with Lawesson's reagent gave new condensed diazaphosphinine derivatives. The structure of the substituent at the amide nitrogen atom and the reagent ratio were found to affect the direction of this

Full text of DOI:10.1007/s10593-013-1196-2

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
REACTION OF VICINAL THIENO[2,3-b]PYRIDINE
AMINOAMIDES WITH LAWESSON'S REAGENT
V. M. Red'kin1, T. A. Stroganova1*, V. K. Vasilin1, and G. D. Krapivin1
The reaction of vicinal thieno[2,3-b]pyridine aminoamides with Lawesson's reagent gave new
condensed diazaphosphinine derivatives. The structure of the substituent at the amide nitrogen atom
and the reagent ratio were found to affect the direction of this reaction.
Keywords: 3-aminothieno[2,3-b]pyridinecarboxamides, diazaphosphinines, Lawesson's reagent, thionation.
Vicinal thieno[2,3-b]pyridine aminoamides are convenient starting compounds for the synthesis of
various condensed systems. The synthetic use of such compounds has been described in many articles and
reviews. Ring closure in the aminoamide is most often accomplished by reaction with an electrophile, which
may be either external or generated within the molecule itself during the reaction [1-8]. Reactions with an
external electrophile include the reaction of the aminoamides with carbonyl compounds [9-14], as well as with
carboxylic acids and their derivatives [15-18], etc. Despite the large variety of studies devoted to the formation
of condensed heterocycles using vicinal aminoamides, these compounds continue to remain at the focus of
attention.
We have studied the reaction of vicinal aminoamides with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithia-
diphosphetane 2,4-disulfide (Lawesson's reagent). The classical application of this reagent is for the thionation
of carbonyl compounds [19]. On the other hand, Lawesson's reagent may act as a dielectrophile, capable of
reacting with a substrate containing two nucleophilic sites, which leads to closure of a phosphorus heterocycle
[19-22]. Transformations of vicinal aminoamides, in particular anthranylamides, by the action of Lawesson's
reagent have been described in the literature [23, 24]. We have become interested in the behavior of
3-amino[2,3-b]pyridine-2-carboxamides in this reaction, since our studies of the chemical properties of such
compounds have shown that in some reactions their transformations differ from those of carbocyclic analogs
[25, 26].
R
R
NH2
N
H
N
R1
H
N
KOH
DMF
Cl
R1
+
S
1a–g
O
O
Me
N
H
S
Me
N
a–d,g R = CH2OМе, e,f R = Me; a R1 = Ph, b R1 = H, c R1 = 2-EtC6H4, d R1 = 2,5-Cl2C6H3,
e R1 = 5-methylfurfuryl, f,g R1 = t-Bu
_______
*To whom correspondence should be addressed, e-mail: tatka_s@mail.ru.
1Kuban State Technological University, 2 Moskovskaya St., Krasnodar 350072, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1817-1825, November, 2012.
Original article submitted July 22, 2011.
0009-3122/13/4811-1701©2013 Springer Science+Business Media New York
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TABLE 1. Physicochemical Characteristics of Compounds 1c,d, 2a-d,
4a,b, 5b, and 6a,b
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield, %
C
H
N
C19H21N3O2S
64.27
64.20
51.64
51.52
56.25
56.34
49.67
49.64
57.80
57.87
49.77
49.66
57.16
57.13
57.25
57.30
55.79
55.70
64.65
64.73
54.96
55.03
57.18
57.12
6.05
5.95
3.73
3.82
4.38
4.33
4.12
4.17
4.82
4.86
3.53
3.47
4.65
4.59
6.44
6.53
6.62
6.54
8.05
7.97
5.68
5.77
5.76
5.88
11.74
11.82
10.48
10.60
8.14
8.21
9.60
9.65
7.90
7.79
7.34
7.24
8.70
8.69
14.40
14.32
13.08
12.99
10.14
10.06
6.47
6.42
6.01
6.06
138-140
180-182
198-200
275-277
177-179
172-175
245-247
181-182
131-133
143-144
195-197
154-155
67
74
48
54
51
61
60
52
48
85
26
31
1c
1d
2a
2b
2c
2d
3
C17H15Cl2N3O2S
C24H22N3O2PS3
C18H18N3O2PS3
C26H26N3O2PS3
C24H20Cl2N3O2PS3
C23H22N3O3PS2
C14H19N3S2
4a
4b
5b
6a
6b
C15H21N3OS2
C15H22N2O3
C20H25N2O3PS2
C22H27N2O3PS2
In the present work, we used primary and secondary 3-aminothieno[2,3-b]pyridine amides 1a-g,
obtained using the earlier described procedure [27], as the starting compounds.
The reaction of pyridines 1a-d with Lawesson's reagent in a 1.0:1.3 molar ratio followed by column
chromatography gave diazaphosphininethione derivatives 2a-d, which are products of the amide carbonyl group
thionation and cyclization with participation of an external electrophile (Tables 1 and 2).
OMe
S
S
OMe
P
P
S
S
MeO
S
H
MeO
P
N
Lawesson's reagent
(1.3 equiv.)
R
N
1a–d
toluene, 
S
S
Me
N
2a–d
2 a R = Ph, b R = H, c R = 2-EtC6H4, d R = 2,5-Cl2C6H3
Heterocyclization leads to the formation of a diazaphosphinine ring containing an asymmetrical site,
namely, the chiral phosphorus atom giving rise to a pair of enantiomers. The presence of the phosphorus atom in
1
compounds 2a-d affects the multiplicity of the adjacent hydrogen atom signals in the H NMR spectra (Table
2). Thus, the signals of the p-methoxyphenyl group protons are double doublets with a typical ortho constant
3JH–H = 8.7-8.8 Hz and constants 3JP–H = 2.9 and 4JP–H = 14.0-15.0 Hz. The signal of the amine NH group is split
2
into a doublet with JP–H = 12.5 Hz (compound 2b) or appears as a broad singlet (compounds 2a,c,d) due to
coupling with the phosphorus atom. Splitting of the amide NH signal into a doublet with 2JP–H = 13.2 Hz is also
observed in the spectrum of diazaphosphininethione 2b, which is not substituted at the amide nitrogen atom.
The presence of the asymmetric phosphorus atom in thiones 2a-d is manifested as a change in the
1702

multiplicity of the prochiral methylene signals. The signal of the protons of the distant methylene group of the
methoxymethyl substituent appears as a pair of doublets with geminal coupling constant J = 14.0-14.7 Hz
(Table 2).
In order to confirm the structure of these products, we carried out an X-ray diffraction structural
analysis of thione 2a.
The six-membered phosphadiazine ring in thione 2a had a flattened "distorted sofa" conformation, in
which the N(2), N(3) nitrogen atoms and the C(6), C(7), and C(8) carbon atoms formed the planar base of the
sofa (plane 1, the mean deviation of these atoms from the plane was 0.0203 Å). The phosphorus atom deviated
from this plane by 0.2709 Å and formed the "back of the sofa" with the adjacent nitrogen atoms (plane 2). The
angle between the planes 1 and 2 was 14.1°. The planar thienopyridine fragment (plane 3) was nearly coplanar
with the plane 1; the angle between these planes did not exceed 2.6°.
The tetracoordinated phosphorus atom had a distorted tetrahedral bond arrangement. The distortions
were apparently due to the different sizes of the adjacent atoms, in particular, the sulfur atom: valence angles
S(2)–P(1)–C(15), S(2)–P(1)–N(2), and S(2)–P(1)–N(3) were extended to ~114°. On the other hand, the valence
angles N(2)–P(1)–N(3), N(2)–P(1)–C(15), and C(15)–P(1)–N(3) are reduced to 100.03(6), 107.44(6), and
105.25(6)°, respectively.
Fig. 1. General view of the thione 2a molecule.
We should note the P(1)–C(15) bond length of 1.7844(14) Å is much greater than the P(1)–N(2) and
P(1)–N(3) phosphorus–nitrogen bond lengths, which are equal to 1.7235(12) and 1.6702(12) Å, respectively. The
P(1)–S(2) bond length is 1.9230(5) Å.
We also note the arrangement of the phenyl substituents relative to the phosphadiazine ring. The
methoxyphenyl substituent is virtually perpendicular to plane 2, so that it eclipses the exocyclic P(1)–S(2) bond
(the S(2)–P(1)–C(15)–C(16) dihedral angle is only 6.1°). The C(9)···C(14) phenyl substituent (plane 4) is
perpendicular to plane 1, so the angle between the planes 1 and 4 is exactly 90°.
Further investigation showed that the use of a smaller amount of Lawesson's reagent (0.7 mol per mol of
aminoamide) gave the diazaphosphinin-2-one 3 as the major product (Tables 1 and 2).
1703

1704

1705

This result confirms a previous finding by Jesberger et al. [19], that the initial step of the reaction is
closure of the diazaphosphinine ring. Then, thionation of the amide carbonyl group is accomplished by means of
excess Lawesson's reagent.
OMe
S
Lawesson's reagent
H
Me
N
(0.7 equiv.)
P
N
1e
N
toluene, 
O
O
S
Me
Me
3
The multiplet formed by the prochiral protons of the furfuryl fragment methylene group is an interesting
1
feature of the H NMR spectrum of compound 3, along with the above-mentioned splitting of the
methoxyphenyl substituent and amino group NH proton signals, which are characteristic for diazaphosphinines.
Coupling with the close-lying phosphorus atom (JP–H = 6.6 Hz, Table 2) is seen in addition to geminal coupling
(2J = 15.4 Hz).
An interesting observation was made when the reaction was carried out with aminoamides 1f,g, which
have a bulky tert-butyl substituent at the amide group nitrogen atom. In this case, only thionation of the amide
carbonyl group occurred, without heterocyclization.
R
NH2
Lawesson's reagent
(1.3 equiv.)
H
N
Bu
-t
1f,g
toluene, 
S
4a,b
S
Me
N
4 a R = Ме, b R = CH2OМе
We assumed that a steric factor, namely, the presence of a bulky substituent at the amide nitrogen atom,
hindered the cyclization reaction. In order to check this hypothesis, an analogous reaction was carried out for
two vicinal aromatic aminoamides, namely, N-tert-butylanthranylamide 5a and N-cyclohexylanthranylamide
5b. However, the corresponding diazaphosphininethione derivatives 6a,b were formed in these reactions.
H S
N
Lawesson's reagent
(1.3 equiv.)
NH2
MeO
MeO
MeO
MeO
P
OMe
H
N
S
N
toluene, 
R
R
O
5a,b
6a,b
5, 6 a R = t-Bu, b R = cyclohexyl
The yields of these compounds after separation of the reaction mixture by column chromatography were
26 and 31%, respectively (Tables 1 and 2). A similar result was described by Lawesson [24], who refluxed
N-cyclohexylanthranylamide with Lawesson's reagent in benzene, obtaining a diazaphosphininethione in 20%
yield. The rather low yields of the reaction products were probably a consequence of steric hindrance.
In the case of thienopyridines 1f,g, the course of the reaction was affected not only by the steric bulk of
the substituent at the amide nitrogen atom, but also by the reduced nucleophilicity of the amino group nitrogen
atom attached to the thienopyridine fragment.
1706

Thus, we have studied the reaction of vicinal thieno[2,3-b]pyridine aminoamides, as well as
anthranylamides with Lawesson's reagent, leading to the formation of a new heterocyclic system, namely,
dihydropyrido[3',2':4,5]thieno[3,2-d][1,2,3]diazaphosphinine 2-sulfide. The initial reaction step was found to be
closure of the diazaphosphinine ring, and not thionation of the amide carbonyl group. Steric factors, such as the
bulky substituent at the amide nitrogen atom, and also the reduced nucleophilicity of the amino group were
shown to affect the composition of the products formed.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker AM-300 spectrometer (300 MHz) in DMSO-d6 with
TMS as internal standard. The electron impact mass spectra were recorded on a Kratos MS-30 mass
spectrometer at 70 eV. The elemental analysis was carried out on a Flash EA 1112 CHN analyzer. The melting
points were determined on a Stuart SMP 30 AC Melting Point Apparatus. Thin layer chromatography was
carried out on Silufol UV-254 and Sorbpolimer Sorbfil plates with development by iodine and bromine vapor.
Sorbpolimer KSK silica gel (50-100 μm) was used for column chromatography. The eluent was selected
individually for each case.
Aminopyridines 1a-g were obtained according to our previous procedure [27] by reacting the
corresponding 3-cyanopyridine-2-thione (10 mmol) and N-substituted chloroacetamide (10 mmol) in DMF in
the presence of potassium hydroxide.
3-Amino-4-(methoxymethyl)-6-methyl-N-phenylthieno[2,3-b]pyridine-2-carboxamide (1a). Yield
2.42 g (74%). Cream-colored crystals; mp 181-182°С (mp 180-181°С [26]). Spectral data matched the literature
values [26].
3-Amino-4-(methoxymethyl)-6-methylthieno[2,3-b]pyridine-2-carboxamide (1b). Yield 2.06 g
(82%). White powder; mp 191-192°С (mp 190-191°С [26]). Spectral data matched the literature data [26].
3-Amino-4,6-dimethyl-N-[(5-methyl-2-furyl)methyl]thieno[2,3-b]pyridine-2-carboxamide
(1e).
Yield 2.48 g (79%). Cream-colored crystals; mp 98-99°С (mp 97-99°С [7]). Spectral data matched the literature
data [7].
3-Amino-N-(tert-butyl)-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide (1f). Yield 2.21 g (80%).
Colorless crystals; mp 176-177°С (mp 176-177°С [7]). Spectral data matched the literature data [7].
3-Amino-N-(tert-butyl)-4-methoxymethyl-6-methylthieno[2,3-b]pyridine-2-carboxamide (1g). Yield
2.24 g (73%). White powder; mp 182-183°С (mp 181-183°С [7]). Spectral data matched the literature data [7].
Aminoamides 5a,b were prepared according to our previous procedure [7], by the reaction of
2-nitroveratric acid chloride (8 mmol) and the corresponding amine (8 mmol) in acetonitrile in the presence of
triethylamine, with subsequent reduction of the resultant nitroamides with hydrazine hydrate and Raney nickel
in ethanol.
2-Amino-N-(tert-butyl)-4,5-dimethoxybenzamide (5a). Yield 1.67 g (83%). Colorless crystals; mp
62-63°С (mp 62-63°С [7]). Spectral data matched the literature data [7].
2-Amino-N-cyclohexyl-4,5-dimethoxybenzamide (5b) was obtained as colorless crystals. The yield,
melting point, and spectral data for benzamide 5b are given in Tables 1 and 2.
Reaction of Aminoamides 1a-d,f,g and 5a,b with Lawesson's Reagent at Molar Ratio of 1.0:1.3
(General Method). A mixture of aminoamide 1a-d,f,g or compound 5a,b (3.0 mmol) and Lawesson's reagent
(1.58 g, 3.9 mmol) in toluene (20 ml) was heated at reflux until the starting aminoamide was completely
consumed (0.5-2.0 h). The reaction mixture was cooled. In the case of aminoamides 1a-d,f,g, the precipitate that
formed was collected by filtration and separated by column chromatography to give compounds 2a-d and 4a,b
as bright-yellow crystals. In the case of aminoamides 5a,b, the reaction mixture was evaporated to dryness at
reduced pressure and column chromatography of the residue gave bright-yellow crystals of products 6a,b. The
eluent in each case was individually selected. The yields, melting points, and spectral data for 2a-d, 4a,b, and
6a,b are given in Tables 1 and 2.
1707

Reaction of Aminoamide 1e with Lawesson's Reagent at Molar Ratio of 1.0:0.7. The reaction was
carried out analogously, using aminoamide 1e (0.945 g, 3.0 mmol) and Lawesson's reagent (0.850 g,
2.1 mmol). The reaction time was 1.5 h. The product 2e was isolated by column chromatography (eluted with
3:5 EtOAc–petroleum ether) from the residue obtained upon evaporation of the reaction mixture. The yield,
melting point, and spectral data of diazaphosphininone 2e are given in Tables 1 and 2.
X-ray Diffraction Structural Analysis of Diazaphosphininone 2a. Orange triclinic prisms of compound
2a were obtained by crystallization from aqueous DMF. A crystal with dimensions 0.60×0.40×0.35 mm was
used for the study. The unit cell parameters were as follows: a 9.4955(3), b 10.4156(4), c 13.7627(8),
α 98.2170(10)°, β 96.6860(10)°, γ 116.0020(10)°, V 1186.02 Å3, d 1.433 g/cm3, space group P1, Z 2. The unit
cell parameters and intensities of 5680 independent reflections with I > 3σ(I) were obtained on an automatic
Bruker APEX II CCD diffractometer using MoKα radiation, β-filter, and θ/2θ scanning to 28°. The structure
was solved by the direct method using the SHELXL-97 software package [28] and refined anisotropically
(isotropically for the hydrogen atoms) to R1 = 0.0308 and wR2 = 0.0798 (I > 2σ(I)). The results of the X-ray
diffraction study were deposited at the Cambridge Crystallographic Data Center (CCDC deposit 856221).
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