Synthesis of thiazolo[3,2-a]pyridines via an unusual Mannich-type cyclization

Article abstract of DOI:10.1080/10426507.2016.1224877

The Mannich-type reaction of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with 3-(1,3-benzodioxol-5-yl)-2-methylpropanal (ocean propanal) and p-toluidine afforded 7-aryl-2-(1,3-benzodioxol-5-ylmethyl)-2-methyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyridine-8-carbonitriles in modest (25–46%) yields. The structure of the key compound was confirmed by X-ray crystal structure analysis.

Full text of DOI:10.1080/10426507.2016.1224877

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis of thiazolo[3,2-a]pyridines via an
unusual Mannich-type cyclization
Victor V. Dotsenko, Ivan S. Bushmarinov, Alexander S. Goloveshkin, Elena A.
Chigorina, Konstantin A. Frolov & Sergey G. Krivokolysko
To cite this article: Victor V. Dotsenko, Ivan S. Bushmarinov, Alexander S. Goloveshkin, Elena
A. Chigorina, Konstantin A. Frolov & Sergey G. Krivokolysko (2016): Synthesis of thiazolo[3,2-
a]pyridines via an unusual Mannich-type cyclization, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2016.1224877
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1224877
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Synthesis of thiazolo[3,2-a]pyridines via an unusual Mannich-type cyclization
Victor V. Dotsenkoa,b*, Ivan S. Bushmarinovc, Alexander S. Goloveshkinc, Elena A. Chigorinad,
Konstantin A. Frolova and Sergey G. Krivokolyskoa
aDepartment of Chemistry and High Technologies, Kuban State University, Krasnodar 350040,
Russian Federation
bDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St., 355009
Stavropol, Russian Federation
cLaboratory for X-Ray Diffraction Studies, A.N. Nesmeyanov Institute of Organoelement
Compounds of Russian Academy of Sciences, Moscow 119991, Russian Federation
dLaboratory of Custom Organic Synthesis, State Enterprise IREA, Moscow 107076, Russian
Federation
* Corresponding author. E-mail: victor_dotsenko_@mail.ru
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Synthesis of thiazolo[3,2-a]pyridines via an unusual Mannich-type cyclization
Abstract
The Mannich-type reaction of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-
tetrahydropyridine-2-thiolates with 3-(1,3-benzodioxol-5-yl)-2-methylpropanal (ocean
propanal) and p-toluidine afforded 7-aryl-2-(1,3-benzodioxol-5-ylmethyl)-2-methyl-3-[(4-
methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitriles
in modest (25-46%) yields. The structure of the key compound was confirmed by X-ray
crystal structure analysis.
Keywords: thiazolo[3,2-a]pyridines; aminomethylation; Mannich reaction; X-ray studies;
bis(pyrid-2-yl)disulfides
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Introduction
3-Cyanopyridine-2(1H)-thiones and related thiolates are known as useful and versatile building
blocks in organic chemistry [1-10]. Recently it was shown that pyridine-2(1H)-thiones and
related thiolates easily react with primary amines and formaldehyde HCHO to give, depending
on the reaction conditions, stoichiometry and the nature of the reagents, a wide range of
heterocyclic systems including pyrido[1,2-a][1,3,5]triazines 1 [11,12], dipyridotetrazocines 2
[13], pyrido[2,1-b][1,3,5]thiadiazines 3-5 [14-22], diazabicyclo[3.3.1]non-3-enes 6 [21], 3,7-
diazabicyclo[3.3.1]nonanes 7 [23-25] or tetraazatricyclo[7.3.1.02,7]tridec-2-enes 8 [26-31]
(Scheme 1).
(Scheme 1 here)
As was previously shown [14,15,20-22], easily available pyridine-2-thiolates 9 smoothly
react with HCHO and RNH2 under mild conditions without any catalyst to form pyrido[2,1-
b][1,3,5]thiadiazines 10 (Scheme 2). However, the Mannich reaction of thiolates 9 with other
aliphatic aldehydes (such as acetaldehyde) resulted in resinification, and the formation of deeply
colored complex mixtures, presumably owing to the side process of aldol-type condensations
which is competing with aminomethylation [22]. The only exception is the reaction of
compounds 9 with p-substituted anilines and isobutyraldehyde leading to the unusual Mannich
products, thiazolo[3,2-a]pyridines; this reaction was reported in our preliminary communication
[32]. In the reaction of thiolates 9 with aromatic aldehydes and benzyl amine, only
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benzylammonium salts 11 were isolated. No Mannich-type products were obtained when
thiolates 9 were reacted with amines and aromatic aldehydes [22].
(Scheme 2 here)
Results and Discussion
In the present paper we report on the unusual Mannich-type reaction of thiolates 9 with the
model amine, p-toluidine 12 and accessible α,α-disubstituted aldehyde – 3-(1,3-benzodioxol-5-
yl)-2-methylpropanal 13 (so-called “ocean propanal”). Surprisingly, when the reagents were
heated in EtOH under reflux, thiazolo[3,2-a]pyridines 14a-e were obtained in modest (25-46%)
yields (Scheme 3).
(Scheme 3 here)
The unusual fact of the formation of thiazolopyridine core in the aminomethylation
process clearly reveals the special character of the Mannich reaction of pyridine-2-thiolates with
α,α-disubstituted aldehydes and amines. A plausible mechanism has been suggested for the
reaction. One may assume that on the first step of the cascade process N-aminoalkylation take
place to form the intermediate 15 which can be oxidized by air to give disulfide intermediate 16.
The reaction didn’t proceed in the absence of air. Disulfide 16 can undergo an intramolecular S–
S bond cleavage to give thiazolopyridine 14 and thiolate 15. The latter upon the action of oxygen
gives disulfide 16 which reacts repeatedly to afford thiazolopyridine 14 and thiolate 15 and so
on. (Scheme 4).
(Scheme 4 here)
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Evidently, the structure of the aldehyde component is a crucial factor that determines the
specifics of the reaction: on the one hand, α,α-disubstituted aldehydes are able to form stable and
active enamide/enamine species, on the other – they almost cannot react by self-condensation to
form competing side products. The proposed mechanism was supported by the observation that
thiolates 9 [33] and related compounds (e.g., [34]) can be oxidized in air to form corresponding
2,2'-bis(pyridyl)disulfides 17. It is noteworthy that S–S bond in disulfides 17 could be easily
cleaved by C-nucleophiles [33]. One may suggest the alternative mechanism which is based on
the homolytic cleavage of disulfide bond. However, the homolysis of strong S–S bond with
dissociation energy of 55-75 kcal/mol usually requires more harsh conditions and higher
temperatures [35], therefore the homolytic mechanism should be excluded. Additional
supporting evidence for the proposed mechanism was obtained from the reaction of ocean
propanal and p-toluidine with 2,2'-bis(pyridyl)disulfide 17a which was obtained by the oxidation
of thiolate 9a with iodine [33]. Thiazolopyridine 14a was obtained in 38% yield (Scheme 5).
(Scheme 5 here)
Presumably, the modest yields of thiazolopyridines 14 are due to the multi-step
mechanism of the reaction and competing side reactions. Since both ocean propanal 13 and
thiolates 9 are racemates, the products have three chiral centers and are isolated as a complex
mixture of diastereoisomers which cannot be easily separated. Compounds 14 are easily soluble
in Me2CO, EtOAc, DMSO and hot MeCN but sparingly soluble in alcohols. The structure of
1
compounds 14а-е was confirmed by H NMR, 13C APT NMR, IR, mass-spectrometry and
LCMS data. The analysis of NMR spectra of compounds 14 revealed a complex mixture
presumably due to the formation of diastereomers based on the presence of three stereogenic
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centers. In the IR spectra, the presence of a secondary amine moiety was confirmed by the
appearance of the intense and sharp absorption bands exhibited at ν 3330 cm-1. The IR spectra
also revealed the conjugated nitrile adsorption bands and lactam C=O bands. The mass spectra
showed peaks [М+H]+ and [М–ArNH2]+. Since it was difficult to elucidate the structure of
compounds 14 unequivocally from the spectral data, the structure of thiazolo[3,2-a]pyridine 14с
has been studied by X-ray single crystal methods (Fig. 1). The compound 14с is a racemate
(space group P21/c); the relative configuration of stereo centers was determined as 2R*, 3S*,
7R*. In the bicyclic core, the cycle N1-C5-C6-C7-C8=С8A has a sofa conformation with C6
lying 0.526(2) Å out of the plane of the remaining atoms (standard deviation 0.082 Å). The
fragment S1-C2-C3-N1-C8A has an envelope conformation with C3 out of the plane of the other
thiazole ring atoms by 0.520(2) Å. The lengths of bonds C–S & C–N have the expected [36]
values. In a crystal, molecules of 14с form centrosymmetric dimers, which are linked by
hydrogen bonds N3-H3…N2 (N3…N2 3.034(2) Å, N3-H3…N2 160.5(17)°).
(Figure 1 here)
In summary, we have demonstrated that the Mannich reaction of N-methylmorpholinium
4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-thiolates 9 with ocean propanal and p-
toluidine leads to the unexpected formation of functionalized thiazolo[3,2-a]pyridines. The
structures of the new compounds was unambiguously confirmed by spectral data and X-ray
analysis. As far as we know, the reaction demonstrates a new approach towards the construction
of thiazolo[3,2-a]pyridine ring system. Further studies to expand the scope of the reaction and
optimize the conditions are currently underway and will be published elsewhere.
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Experimental
The IR spectra were recorded on an IKS-29 (LOMO, USSR) instrument in Nujol mulls. NMR 1Н
spectra were recorded on a Bruker DPX-400 (400.4 MHz) and Bruker DRX-500 (500.07 MHz)
instruments in DMSO-d6 using TMS as an internal standard. NMR 13C and 13C APT spectra were
recorded on a Bruker DRX-500 (125.76 MHz) device in DMSO-d6 with TMS as an internal
standard. Mass spectra of compounds 14a-c (EI, 70 eV) were obtained on a МХ-1321
spectrometer by direct inlet. LCMS analysis for compound 14a was obtained on a PE SCIEX
API 150EX mass spectrometer (API–ES) following separation on a Shimadzu LC-10AD liquid
chromatography system with Waters XBridge C18 3.5 μm (4.6 × 150 mm) column, equipped
with Shimadzu SP D-10A UV-Vis detector (λmax 220 and 254 nm) and Sedex 75 ELSD detector.
C,H,N-analyses were performed on a Carlo Erba Strumentazione 1106 analyzer. The purity of all
obtained compounds was checked by TLC on Silufol® UV 254 plates (sorbent – Silpearl, large-
pore silicagel after Pitra with luminescent indicator for UV 254 on the aluminium foil, binder –
starch) in the acetone–hexane (1:1) system; spots were visualized with iodine vapors and UV
light. Ocean propanal 13 is commercially available reagent (Parchem). The Supplemental
1
13
Materials contains additional experimental details and sample H, C NMR, mass and LC-MS
spectra for compounds 14 (Figures S 1 – S 18).
Starting thiolates 9 were obtained by the known method [14,20,22,37,38] as follows: a
mixture of an aromatic aldehyde (0.05 mol), finely powdered cyanothioacetamide [39] (5.0 g,
0.05 mol), EtOH (35-40 mL) and 5-7 drops of N-methylmorpholine were stirred until
cyanothioacetamide had dissolved and yellow (or orange) crystalline 3-aryl-2-cyanoprop-2-
enethioamide started to precipitate. Then Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione)
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(7.5 g, 0.052 mol) and N-methylmorpholine (8.3 mL, 0.075 mol) were added, and the mixture
was gently refluxed for 2−4 h. The solution was evaporated to a syrup, whereupon it was treated
with acetone (50 mL). The light yellow (or beige) precipitate of the corresponding thiolate 9 was
filtered off and washed with cold EtOH and acetone. The compounds were used without further
purification.
Thiazolo[3,2-a]pyridine-8-carbonitriles 14a-e (General procedure). p-Toluidine 12 (330 mg,
3.08 mmol) and ocean propanal 13 (1.7 mL, 10.2 mmol) were added to the suspension of thiolate
9a-e (2.4 mmol) in the mixture of EtOH (12 mL) and water (2 mL). The mixture was heated
under reflux for 10-15 h. The heavy red oil formed was separated by decantation and then
dissolved in boiling n-BuOH (20 mL). The solution was left to stand at 25 °C in a loosely
stoppered flask. The crystalline solid which slowly (1-3 months) precipitate from the solution
was filtered off and recrystallized from either BuOH or i-PrOH–MeCN. Compounds 14a-c were
obtained as colorless crystals, compounds 14d,e – as yellow viscous oils.
Synthesis of thiazolo[3,2-a]pyridine 5а from disulfide 17a. To the solution of ocean propanal 13
(1.7 mL, 10.2 mmol), p-toluidine 12 (300 mg, 3.08 mmol) and 0.3 mL (2.73 mmol) of N-
methylmorpholine in 96% EtOH (15 mL), 0.62 g (1.2 mmol) of disulfide 17а (0.62 g, 1.2 mmol)
were added. The mixture were heated under reflux for 20 h, the precipitated yellowish solid was
filtered off and recrystallized from BuOH to give 490 mg (38%) of thiazolo[3,2-a]pyridine 14a.
The physical data and spectra are in agreement with the data obtained for the sample of 14a
prepared from thiolate 9a.
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2-(1,3-Benzodioxol-5-ylmethyl)-7-(4-methoxyphenyl)-2-methyl-3-[(4-methylphenyl)amino]-5-
oxo-2,3,6,7-tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitrile 14a, mixture of diastereomers.
White crystalline solid, yield was 46% (n-BuOH). IR spectrum (nujol): 3330 (NH), 2195 (C≡N),
1680 (C=О) cm-1. 1Н NMR (400 MHz, DMSO-d6), δ 1.41-1.53 (m, 3Н, 2-СН3), 2.12-2.15 (m,
3H, ArMe), 2.29-2.42 (m, 1H, cis-H-6), 2.84-2.94 (m, 1H, 2-СН2Ar), 3.04-3.12 (m, 1H, 2-
СН2Ar), 3.16-3.26 (m, 1H, trans-H-6), 3.69-3.75 (m, 3H, OCH3), 3.85-3.92 (m, 1H, Н-7), 5.93-
6.04 (m, 3H, Н-3 & ОСН2О signals overlapped), 6.25 (d, ~0.32Н, 3J =9.4, NH), 6.36 (d, ~0.36Н,
3
3
3J =10.7, NH), 6.47 (d, ~0.22Н, J =11.0, NH), 6.67-6.95 (m, 9H, H Ar), 7.08 (d, ~1.23H, J
3
=8.3, H Ar), 7.16 (d, ~0.71H, J =8.3, H Ar). LCMS, m/z (ES-API): 1080.3 [2М+H]+, 540.8
[М+H]+, 433.6 [M-ArNH2]+. MS (EI, 70 eV) m/z (I, %): 539 [М]+ (22), 280 (23), 135 [3,4-
(OCH2O)-C6H3CH2]+ (100), 118 (24), 107 (14). Anal. Calcd for C31H29N3O4S: C 69.00; H 5.42;
N 7.79. M = 539.66. Found: C 69.31; H 5.54; N 7.65.
2-(1,3-Benzodioxol-5-ylmethyl)-7-(2-ethoxyphenyl)-2-methyl-3-[(4-methylphenyl)amino]-5-oxo-
2,3,6,7-tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitrile 14b, mixture of diastereomers.
Colorless crystals, yield was 35% (i-PrOH : MeCN = 3 : 1). IR spectrum (nujol): 3330 (NH),
1
3
2190 (C≡N), 1685 (C=О) cm-1. Н NMR (500 MHz, DMSO-d6), δ 1.31 (t, J=6.8, 3Н,
OCH2СН3), 1.42 (s, ~1.8Н, 2-СН3), 1.49 (s, ~1.2Н, 2-СН3), 2.11 (s, ~1.8Н, ArСН3), 2.14 (s,
~1.2Н, ArСН3), 2.39-2.44 (m, 1Н, cis-H-6), 2.84-2.94 (m, 1Н, 2-СН2Ar), 3.05-3.12 (m, 1Н, 2-
СН2Ar), 3.19-3.26 (m, 1Н, trans-H-6), 4.01-4.06 (m, 2Н, OCH2CH3), 4.12-4.19 (m, 1H, Н-7),
3
5.93-6.05 (m, 3Н, Н-3 & ОСН2О signals overlapped), 6.32 (d, ~0.6Н, J=10.9, NH), 6.43 (d,
~0.4Н, 3J=10.9, NH), 6.73–6.97 (m, 9H, H-Ar), 7.07 (d, 1H, 3J=7.3, H-Ar), 7.17-7.21 (m, 1H, H-
Ar). 13C NMR (126 МHz, DMSO-d6), δ 14.4, 19.8, 20.0, 20.03, 27.1, 33.0, 36.3, 40.4, 46.5, 60.9,
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62.1, 63.2, 74.8, 76.8, 79.6, 80.7, 100.8, 100.9, 106.8, 107.8, 108.2, 109.9, 110.8, 111.8, 113.8,
114.4, 118.6, 120.4, 122.7, 123.7, 125.9, 126.3, 126.8, 126.9, 127.7, 128.6, 129.01, 129.04,
129.6, 130.4, 143.4, 143.7, 146.2, 146.3, 146.8, 147.2, 153.0, 153.7, 155.2, 165.6, 166.2. 13C
NMR APT (126 МHz, DMSO-d6), δ 14.4*, 19.8*, 19.96*, 20.0*, 27.1*, 33.0*, 36.3, 46.5, 60.9,
62.1, 63.2, 74.8*, 76.8*, 79.6, 80.7, 100.8, 107.8*, 108.2*, 109.9*, 110.8*, 111.8*, 113.8*,
114.8*, 118.5, 120.4*, 122.7*, 123.7*, 125.9, 126.3, 126.8*, 126.9*, 127.65, 128.6*, 129.0*,
129.6, 130.4, 143.4, 143.7, 146.2, 146.3, 146.8, 147.2, 153.0, 153.7, 155.2, 165.6, 166.2.
*Signals with the opposite phase. LCMS, m/z (ES-API): 447.0 [M-ArNH2]+, 552.2 [M-H]–. MS
(EI, 70 eV) m/z (I, %): 553 [М]+ (12), 280 (12), 135 [3,4-(OCH2O)-C6H3CH2]+ (100), 118 (23),
91 (12). Anal. Calcd for C32H31N3O4S: C, 69.42; H, 5.64; N, 7.59. M=553.69 Found: C, 69.51;
H, 5.71; N, 7.55.
2-(1,3-Benzodioxol-5-ylmethyl)-7-(2-furyl)-2-methyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-
tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitrile 14с, mixture of diastereomers. Sand-
colored crystals, yield was 25% (i-PrOH : MeCN = 2 : 1). IR spectrum (nujol): 3330 (NH), 2195
1
(C≡N), 1680 (C=О) cm-1. Н NMR (500 MHz, DMSO-d6), δ 1.38 (s, ~2.7Н, 2-СН3), 1.50* (s,
2
~0.3Н, c, 2-СН3), 2.06-2.16 (m, 3Н, ArСН3); 2.56 (br.d, 1Н, J=16.3, cis-H-6), 2.85 (dd, 1Н,
3
2
2J=16.3, J=6.8, trans-H-6), 3.05 and 3.08 (both are d, each 1H, J=13.3, 2-СН2Ar), 4.02-4.03
(m, 1H, Н-7), 6.00-6.02 (m, 3Н, signals of Н-3 & ОСН2О overlapped), 6.13-6.15 (m, 1Н, furyl
3
Н-4), 6.23 (d, 1Н, J=10.4, NH), 6.31-6.33 (m, 1Н, furyl Н-3), 6.70–6.76 (m, 3H, H Ar), 6.84–
6.89 (m, 4H, H Ar), 7.47-7.49 (m, ~0.9Н, furyl Н-5), 7.60-7.62* (m, ~0.1Н, furyl Н-5). *The
observed signals of minor diastereomers. 13C NMR (126 MHz, DMSO-d6), δ 19.7, 20.0, 32.6,
34.9, 46.5, 61.1, 75.0, 78.3, 100.9, 105.8, 107.86, 110.5, 110.8, 113.8, 118.4, 123.8, 126.0, 129.1,
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13
129.6, 142.7, 143.8, 146.2, 146.9, 153.1, 154.0, 165.2. C NMR APT (126 MHz, DMSO-d6), δ
19.7** (Ме), 20.0** (Ме), 32.6** (С-7), 34.9 (С-6), 46.5 (СН2Ar), 61.1 (OCH2O), 75.0** (C-
3), 78.3 (C-8), 100.9 (C-2), 105.8** (HC-Ar), 107.8** (HC-Ar), 110.4** (HC-Ar), 110.8**
(HC-Ar), 113.8** (HC-Ar), 118.4 (C≡N), 123.8** (HC-Ar), 125.9 (C-Ar), 129.1** (HC-Ar),
129.5 (C-Ar), 142.7** (furyl C-5), 143.7 (furyl С-2), 146.2 (С-Ar), 146.9 (C-Ar), 153.1 (C-8a or
C-Ar), 153.9 (C-Ar or С-8а), 165.2 (С=О). **Signals with the opposite phase. LCMS, m/z (ES-
API): 501.1 [M+H]+, 393.0 [M-ArNH2]+, 498.0 [M-H]–. MS (EI, 70 eV) m/z (I, %): 499 [М]+
(18), 280 (18), 135 [3,4-(OCH2O)-C6H3CH2]+ (100), 118 (21), 107 (14), 91 (12), 77 (10). Anal.
Calcd for C28H25N3O4S: C 67.32; H 5.04; N 8.41. M=499.59. Found: C, 67.53; H, 5.15; N, 8.40.
2-(1,3-Benzodioxol-5-ylmethyl)-7-(4-bromophenyl)-2-methyl-3-[(4-methylphenyl)amino]-5-oxo-
2,3,6,7-tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitrile 14d, mixture of diastereomers. The
compound 14d was obtained as yellow viscous oil in 27% yield after double recrystallization of
crude product from n-BuOH. IR spectrum (nujol): 3330 (NH), 2190 (C≡N), 1680 (C=О) cm-1.
1Н NMR (400 MHz, DMSO-d6), δ 1.40-1.53 (m, 3Н, 2-СН3), 2.10-2.16 (m, 3Н, ArСН3), 4.11-
4.15 (m, 1H, Н-7), 6.00-6.05 (m, 3Н, Н-3 & ОСН2О overlapped), 6.25-6.28 (m, 1Н, NH), 6.67-
6.95 (m, 7H, H Ar), 7.16-7.20 (m, 2H, H Ar), 7.55-7.60 (m, 2H, H Ar). Anal. Calcd for
C30H26BrN3O3S: C 61.23; H 4.45; N 13.58. M=588.53. Found: C, 61.44; H, 4.68; N, 13.44.
2-(1,3-Benzodioxol-5-ylmethyl)-7-(4-benzyloxy-3-methoxyphenyl)-2-methyl-3-[(4-
methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitrile 14e,
mixture of diastereomers. The compound 14e was obtained as viscous oil in 25% yield after
double recrystallization of crude product from n-BuOH. IR spectrum (nujol): 3330 (NH), 2195
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1
(C≡N), 1680 (C=О) cm-1. Н NMR (400 MHz, DMSO-d6), δ 1.40-1.50 (m, 3Н, 2-СН3), 2.13-
2.17 (m, 3Н, ArСН3), 3.72-3.75 (3H, m, OMe), 4.09-4.15 (m, 1H, Н-7), 4.99-5.03 (m, 2H,
PhCH2O), 5.97-6.05 (m, 3Н, Н-3 & ОСН2О overlapped), 6.25-6.30 (m, 1Н, NH), 6.60-7.45 (m,
15H, H Ar). Anal. Calcd for C38H35N3O5S: C 70.68; H 5.46; N 6.51. M=645.78. Found: C,
70.49; H, 5.63; N, 6.48.
X-ray
studies
of
2-(1,3-benzodioxol-5-ylmethyl)-7-(2-furyl)-2-methyl-3-[(4-methyl-
phenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitrile 14с. Single
crystals of 14c (C28H25N3O4S) were obtained by recrystallization from i-PrOH–MeCN mixture
(2:1). X-ray diffraction studies were performed on a Bruker APEX II CCD diffractometer at 100
K. The structure was solved by charge flipping method (olex2.solve) and refined by the least
squares technique using Olex2 [40] software package and SHELXL 2014/7 program. Crystals of
compound 14c are monoclinic, C28H25N3O4S (M =499.57), space group P21/c (No 14),
a =10.099(6) Å, b =13.104(8) Å, c =18.303(10) Å, β = 90.754(13)°, V = 2422(2) Å3, Z = 4, T =
100 K, μ(MoKα) = 0.175 mm-1, Dcalc = 1.370 g/cm3, 26667 reflections were collected (3.822° ≤
2Θ ≤ 66.262°), of which 8871 were independent (Rint = 0.0376, Rsigma = 0.0479). The final
probability factors were: R1 = 0.0470 (I > 2σ(I)), wR2 = 0.1196 (all reflections). The full
crystallographic data has been placed at the Cambridge Crystallographic Data Center as deposit
CCDC 1056696. Additional X-ray data collection parameters and selected bond lengths and
angles are found in Tables S 1 – S 8 (Supplemental Materials).
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Acknowledgements
V.V.D. is grateful for financial support by Russian Ministry of Education and Science (State
Assignment to Higher Education Institutions, project No. 547).
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A shortened version of the title to be used as the running head is required (no more than 50
characters) should be supplied:
Mannich-type synthesis of thiazolo[3,2-a]pyridines
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Scheme 1. The aminomethylation of pyridine-2(1H)-thiones and related species. X = electron-
withdrawing group (CN, COOMe, COOEt).
Scheme 2. The aminomethylation of thiolates 9 (NMM = N-methylmorpholine).
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Scheme 3. The reaction of thiolates 9 with ocean propanal and p-toluidine.
Ar = 4-MeOC6H4 (а); Ar = 2-EtOC6H4 (b); Ar = 2-furyl (c); Ar = 4-BrC6H4 (d); Ar = 4-BnO-3-
MeOC6H3 (e).
Scheme 4. Proposed mechanism for the formation of thiazolopyridines 14.
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Scheme 5. Synthesis of thiazolopyridine 14a from disulfide 17a.
Figure 1. The structure of compound 14c. Vibrational ellipsoids are shown at the 50%
probability level.
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