60
Acta Chim. Slov. 2015, 62, 60-71
DOI: 10.17344/acsi.2014.712
Scientific paper
A Four-step Synthesis of Novel (S)-1-(heteroaryl)-1-aminoethanes from (S)-Boc-alanine
Luka [enica,1 Nejc Petek,1 Uro{ Gro{elj1 and Jurij Svete1,2*
1 Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI - 1000 Ljubljana, Slovenia.
2 Centre of Excellence EN-FIST, Trg osvobodilne fronte 13, SI - 1000 Ljubljana, Slovenia
* Corresponding author: E-mail: jurij.svete@fkkt.uni-lj.si Tel.: +386j 1 2419 254. Fax.: +386j 1 2419 220
Received: 05-06-2014
Dedicated to Professor Branko Stanovnik, University of Ljubljana, on the occasion of his 75th anniversary.
Abstract
A series of (S)-1-(pyrimidin-4-yl)-, and regioisomeric (S)-1-(pyrazolo[1,5-a]pyrimidin-7-yl)-, and (S)-1-(pyrazolo[1,5-a]pyrimidin-5-yl)-1-aminoethanes were prepared by cyclisation of (S)-N-Boc-alanine-derived ynone with N,N-1,3-dinucleophiles, such as amidines and a-aminoazoles, followed by acidolytic removal of the Boc group. Stereoselective catalytic hydrogenation of (S)-1-(pyrazolo[1,5-a]pyrimidin-7-yl)-1-aminoethanes lead to saturation of the pyrimidine ring to afford ~4:1 mixture of diastereomeric 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidines. The structures of novel compounds were elucidated with NMR spectroscopy.
Keywords: Amines, amino acids, chirality, heterocycles, synthesis
1. Introduction
Nonracemic amines represent an important group of organic compounds, which found a widespread use in various applications. They are used as reagents and bases in organic synthesis, resolving agents, and chiral auxiliaries, ligands, and organocatalysts in asymmetric synthesis.1 Typical examples of synthetically useful enantiomerically pure alkylamines are (R)-1-phenylethylamine (1), amphe-
Figure 1. Examples of important chiral alkylamines 1-5.
tamine (2), (2S,5S)-5-benzyl-2-(tert-butyl) -3-methylimi-dazolidin-4-one (3), quinidine (4), and (1R,2R)-1,2-dia-minocyclohexane (5) (Figure 1).
In the last three decades, the studies on alkyl 2-sub-stituted 3-(dimethylamino)prop-2-enoates and related enaminones have shown, that they are useful and versatile reagents for the preparation of various dehydroalanine derivatives, heterocyclic systems, and natural product ana-logues.2,3 In extension, chiral cyclic enaminones derived from (S)-a-amino acids and (+)-camphor have been employed in the synthesis of functionalized heterocycles and heterocyclic analogues of peptides.2,4-7 Furthermore, ena-minones have also been successfully employed in a combinatorial synthesis of dehydroalanine derivatives8 and functionalized heterocycles.9
The usual way to prepare 3-(dimethylamino)prop-2-enoates and related enaminones comprise treatment of a suitably functionalized methylene compound with forma-mide acetal, e.g., with N,N-dimethylformamide dimethyl acetal or with bis(dimethylamino)-tert-butoxymethane (Bredereck's reagent).2,10 Alternative way of preparation proposed by Giacomelli and co-workers comprises treatment of Weinreb amides of a suitably protected a-amino acid with (trimethylsilyl)magnesium bromide followed by
reaction of the so formed silylynone with diethylamine. These enamino ketones were then used as the key-intermediates in the synthesis of chiral pyrazole-containing peptidomimetics11 and a-pyrazolylglycines.12 Later on, we also reported similar preparation of chiral enamino ke-tones from a-amino acids and their utilization in a two-step synthesis of 1-(heteroaryl)-2-phenyl-1-aminoethanes and 1-(heteroaryl)-1-aminopropan-2-ols.5 Another important example is ynone-based synthesis of chiral a-ami-noalkylpyrimidines using an enantioselective three-com-
13
ponent reaction.13
In continuation of our work in this field, we became interested in the Boc-a-amino acid derived ynones and enaminones again, as they turned out to be suitable precursors for the synthesis of vinylogous peptides14 and as chiral non-racemic dipolarophiles in regio- and stereo-selective 1,3-dipolar cycloadditions.15 As these reagents were available in sufficient amounts, we decided to further investigate their cyclisation reactions with N,N-1,3-dinucleophi-les leading to chiral non-racemic 1-(heteroaryl)-1-ethyla-mines. These novel primary amines are interesting as chi-ral bases, ligands, or organocatalysts in asymmetric applications. Furthermore, alkylamines bearing fluorescent azo-lo[a]pyrimidin-6-one residues could also be used in fluorescence-related applications, e.g. as fluorescent markers.
Herein, we report the results of this study, i.e. the synthesis and some transformations of novel pyrimidin-2-yl, pyrazolo[1,5-a]pyrimidin-5-yl, and pyrazolo[1,5-a] pyrimidin-7-yl substituted (S)-1-(heteroaryl)-1-aminoet-hanes.
2. Results and Discussion
The first reagent, (S)-tert-butyl (3-oxopent-4-yn-2-yl)carbamate (8) was prepared in two steps from commercially available (S)-Boc-alanine (6) via transformation into the corresponding Weinreb amide 716,17 and treatment with ethynylmagnesium bromide following the literature procedure.14 Quite expectedly,5,13 treatment of ynone 8 with simple amidines 10a-g furnished the corresponding tert-butyl (S)-(1-(5-substituted-pyrimidin-2-yl)ethyl)car-bamates 11a-g in 23-59% yields. The free 1-(pyrimidin-2-yl)-1-ethylamines 12a-d,g were then obtained by aci-dolytic removal of the Boc N-protecting group of 11a-d,g with 2 M HCl in EtOAc. In this manner, the free amines 12a-d,g were obtained in 79-89% yields upon simple evaporative workup (Scheme 1).
Reactions of 8 with unsymmetrical cyclic amidines, 3-aminopyrazoles 13a-c and methyl 5-amino-1#-1,2,4-triazole-3-carboxylate (13d), afforded two regioi-someric products, tert-butyl (S)-(1-(pyrazolo[1,5-a]pyrimidin-7-yl)ethyl)carbamates 14a-c and tert-butyl (S)-(1-(pyrazolo- [ 1,5-a]pyrimidin-5-yl)ethyl)carbama-tes 14'a-c and methyl (S)-7-(1-((tert-butoxycarbonyl)-amino)ethyl)[1,2,4]triazolo[1,5-a]pyrimidine-2-car-
Scheme 1. Synthesis of (S)-(1-(pyrimidin-2-yl)ethyl)carbamates 11a-g, and (S)-1-(pyrimidin-2-yl)-1-ethylamines 12a-d,g.
boxylate (14'd). Thus, treatment of 8 with 3-amino-1#-pyrazole (13a) and methyl 5-amino-1#-pyrazole-4-car-boxylate (13c) gave mixtures of the major 7-regioiso-mers 14a,c and the minor 5-regioisomers 14'a,c, which were separated by medium performance liquid chromatography (MPLC) to give isomerically pure compounds 14a ,c and 14'a,c in 11-54% yields. On the other hand, cyclisations of 8 with 3-amino-5-methyl-1#-pyrazole (13b) and methyl 5-amino-1#-1,2,4-triazole-3-car-boxylate (13d) furnished the corresponding products 14b and 14'd as the only regioisomers in 74% and 81% yield, respectively. Since known cyclisations of enami-nones with ambident nucleophiles generally proceed re-gioselectively,5 we reasoned that cyclisations of the corresponding enaminone reagent 9 with 3-aminopyrazoles 13 should be regioselective to produce the regioisomers 14, exclusively. (S,E)-tert-Butyl (5-(dimethylamino)-3-oxopent-4-en-2-yl)carbamate (9) was prepared from 8 and dimethylamine following the literature procedure.14 Indeed, treatment of enaminone 9 with 13a in the presence of one equivalent of HCl afforded 14a as the only isomer, though in somewhat lower yield (46% vs. 54% via the ynone 8). On the other hand, reaction of 9 with 13c produced the other regioisomer 14'c in poor yield. Treatment of 14a and 14b with 2 M HCl in EtOAc at room temperature furnished the corresponding free ami-
Scheme 2. Synthesis of tert-butyl (S)-(1-(pyrazolo[1,5-a]pyrimidin-7-yl)ethyl)carbamates 14a-c, their pyrazolo[1,5-a]pyrimidin-5-yl regioisomers 14'a,c,d, and the free amines 15a,b.
nes 15a and 15b in 94% and 47% yield, respectively (Scheme 2).
The formation of regioisomeric products 14 and 14' is explainable in the following way. 1,4-Addition of a heterocyclic amidine 13 to the ynone 8 (and similarly to the enaminone 9) can take place, either via the primary amino group (Path A), or via the ring NH group (Path B) to give the regioisomeric adducts 16 and 16'. Further cyclisation via addition of the other amino group leads to the bicyclic intermediates 17 and 17', which undergo elimination of water to furnish regioisomeric products 14 and 14'. Analogously, also formation of regioisomeric products 14a and 14'c from the enaminone reagent 9 can be explained by initial substitution of the dimethylamino group followed by cyclisation. Selective reaction of enaminones with the primary amino group of various non-symmetrical
cyclic amidines is well documented in the literature.2 The formation of the regioisomeric intermediate 16'a,c,d, on the other hand, is supported by the reactions of 8 with 5-amino-1#-1,2,4-triazole (13e) and 5-amino-1#-tetrazole (13f), which did not give the desired cyclisation products 14'e and 14'f, but rather the addition intermediates 16'e and 16'f in 55% and 26% yield, respectively (Scheme 3).
Finally, saturation of the pyrimidine ring of pyrazo-lo[1,5-a]pyrimidines 14a and 14c was carried out by catalytic hydrogenation. Reduction of 14a,c afforded ~4:1 mixtures of diastereomeric 4,5,6,7-tetrahydropyrazo-lo[1,5-a]pyrimidines 18a/18'a and 18c/18'c in 90% and 99% yield, respectively. Subsequent separation by MPLC furnished isomerically pure compounds, the major iso-mers 18a and 18c and the minor isomers 18'a and 18'c in 11-78% yields (Scheme 4).
Scheme 3. Regioselectivity of cyclisations of the reagents 8 and 9 with non-symmetrical cyclic amidines 13.
The structures of all novel compounds 11a-g, 12a-d,g, 14a-c, 14'a,c,d, 16e,f, 18a,c, and 18'a,c were determined by spectroscopic methods (1H NMR, 13C NMR, IR, MS, HRMS) and by elemental analyses for C, H, and N. Compounds 11d, 14b, 14'd, and 16'e,f were obtained in analytically pure form. On the other hand, compounds 11a-c,e-g, 12a-d,g, 14a,c, 14'a,c, 15a,b, 18a,c, and 18'a,c were not obtained in analytically pure form. Their identities were established by 1H NMR, 13C NMR, and HRMS.
The regiochemistry of compounds 14a-c and 14'a,c,d was established by 1H NMR on the basis of vicinal coupling constants, 3J5H-6H (compounds 14) and 3J6H-7H (compounds 14'). Thus, a small vicinal coupling constant, 3J5H-6H = 4.2 Hz, in compounds 14 was in agree-
ment with the literature data for 7-substituted pyrazo-lo[1,5-a]pyrimidines, whereas a larger vicinal coupling constant, 3J6H-7H = 7.2 Hz, in compounds 14' supported the pronounced CH=CH character and was in agreement with the literature data for 5-substituted pyrazolo[1,5-a]pyrimidines.1820 The 1H NMR data for compounds 14 were also in agreement with the literature data for closely related tert-butyl (S)-(2-phenyl-1-(pyrazolo[1,5-a]pyrimi-din-7-yl)ethyl)carbamate with its structure confirmed by X-ray analysis.5 Cyclization of 5-amino-1,2,4-triazole 13d (cf. Scheme 2) can take place, either at N(1), or at N(4) to give the isomeric 1,2,4-triazolo[1,5-a]pyrimidine 14'd or 1,2,4-triazolo[4,3-a]pyrimidine 14''d, respectively. The structure of 14'd was determined by HMBC spectroscopy. Correlation of H(7) with three carbon nuc-
Scheme 4. Stereoselective hydrogenation of compounds 14a and 14c.
lei, C(4a), C(5), and C(6), was in agreement with the proposed [1,5-a]-isomer 14'd. On the other hand, the corresponding H(5) in the [4,3-a]-isomer 14''d should correlate with four carbon nuclei, C(3), C(6), C(7), and C(8a) (Figure 2).
Unfortunately, we were not able to determine the absolute configuration of compounds 14b, 14'a,c,d, 18a,c, and 18'a,c, since numerous attempts to obtain suitable single crystals of compounds 14b, 14'a,c,d, 18a,c, and 18'a,c for X-Ray diffraction analysis were not successful.
3. Experimental
3. 1. General Methods
Melting points were determined on a Stanford Research Systems MPA100 OptiMelt automated melting point system. The NMR spectra were obtained on a Bru-ker Avance III UltraShield 500 plus at 500 MHz for 1H and 126 MHz for 13C, using CDCl3 and DMSO-d6 (with TMS as the internal standard) as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS spectrometer, IR spectra on a Bruker FTIR Alpha Platinum ATR spectrophotometer. Microanalyses were performed on a Perkin-Elmer CHN analyser 2400 II. Dry-vacuum flash chromatography (DVFC)21,22 was performed on silica gel (Fluka, Silica gel 60, particle size 35-70 |jm). Medium performance liquid chromatography
Figure 2. Structure determination by !H NMR and HMBC spectroscopy.
(MPLC) was performed on a Büchi Flash Chromatography System (Büchi Fraction Collector C-660, Büchi Pump Module C-605, Büchi Control Unit C-620) on silica gel (LiChroprep® Si 60, 15-25 pm), column dimensions: 23 X 460 mm, backpressure: 10 Bar, detection: UV (254 nm).
(S)-N-Boc-Alanine (6), N,0-dimethylhydroxyla-mine, CDI, ethynylmagnesium bromide, amidines 10a-g, aminopyrazoles 13a,b, methyl 5-amino-1#-1,2,4-triazole-3-carboxylate (13d), 5-amino-1#-1,2,4-triazole (13e), and 5-amino-1#-tetrazole (13f) (Sigma Aldrich) are commercially available. tert-Butyl (S)-1-[methoxy(methyl) amino]-1-oxopropan-2-yl)carbamate
(7),16	tert-butyl (S)-(3-oxopent-4-yn-2-yl)carbamate
(8),14,23	tert-butyl (S,£)-(5-(dimethylamino)-3-oxopent-4-en-2-yl)carbamate (9),14 and methyl 5-amino-1#-pyrazole-4-carboxylate (13c)24 were prepared following
the literature procedures.
3. 2. General procedure for the synthesis
of tert-butyl (S)-(1-(5-substituted
pyrimidin-2-yl) ethyl)carbamates 11a-f.
A mixture of amidine hydrochloride 10 (1.1 mmol), t-BuOK (112 mg, 1 mmol), and MeOH (5 mL) was stirred at r.t. for 15 min. The so formed suspension was added to a solution of ynone 8 (197 mg, 1 mmol) in EtOH (10 mL) and the mixture was stirred at r.t. for 72 h. In the case of free amidines 10, neutralisation with t-BuOK in MeOH was omitted. Volatile components were evaporated in vacuo and the residue was purified by DVFC (EtOAc/hexa-nes, 1:2). Fractions containing the product were combined and evaporated in vacuo to give 11.
The following compounds were prepared in this manner:
3. 2. 1. tert-Butyl (S)-(1-(pyrimidin-4-yl)ethyl) carbamate (11a).
Prepared from 8 (197 mg, 1 mmol) and formimidami-de acetate 10a (115 mg, 1.1 mmol). Yield: 52 mg (23%) of brownish oil; [a]D22 -0.8 (c 0.55, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.44 (9H, s, t-Bu); 1.46 (3H, d, J = 7.2 Hz, 4'-CH3); 4.82 (1H, p, J = 7.2 Hz, 4'-H); 5.48 (1H, br d, J = 8.6 Hz, NHBoc); 7.29 (1H, d, J = 5.2 Hz, 5-H); 8.68 (1H, d, J = 5.2 Hz, 6-H); 9.16 (1H, br d, J = 0.8 Hz, 2-H). 13C NMR (126 MHz, CDCl3): 5 21.8, 28.4, 50.8, 79.8, 118.3, 155.1, 157.2, 158.7, 170.3. m/z (ESI) = 224 (MH+). HRMS-ESI (m/z): [MH+] calcd for C11H18N3O2, 224.1394; found, 224.1386. IR (ATR) и 3227, 29776, 2929, 2859, 1703, 1581, 1553, 1468, 1356, 1366, 1299, 1267, 1247, 1171, 1105, 1073, 1056, 1019, 998, 870, 859, 782, 756, 731, 676, 611 cm-1.
3. 2. 2. tert-Butyl (S)-(1-(2-methylpyrimidin-4-yl) ethyl)carbamate (11b).
Prepared from 8 (99 mg, 0.5 mmol) and acetimidami-de hydrochloride 10b (52 mg, 0.55 mmol). Yield: 36 mg (30%) of brownish oil; [a]D22 +0.6 (c 1.8, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.44 (3H, d, J = 7.2 Hz, 4'-Me); 1.45 (9H, s, t-Bu); 2.72 (3H, s, 2-Me); 4.76 (1H, p, J = 7.0 Hz, 4'-H); 5.61 (1H, br d, J = 7.3 Hz, NHBoc); 7.06 (1H, d, J = 5.1 Hz, 5-H); 8.57 (1H, d, J = 5.2 Hz, 6-H). 13C NMR (126 MHz, CDCl3): 5 22.1, 26.0, 28.4, 50.8, 79.7, 114.9, 155.1, 157.2, 168.0, 170.2. m/z (ESI) = 238 (MH+). HRMS-ESI (m/z): [MH+] calcd for C12H20N3O2, 238.1550; found, 238.1549. IR (ATR) и 3226, 2977, 2933, 1698, 1576, 1557, 1530, 1441, 1406, 1363, 1303, 1250, 1160, 1116, 1071, 1042, 1022, 999, 864, 842, 785, 733, 642, 629 cm-1.
3. 2. 3. tert-Butyl (S)-(1-(2-phenylpyrimidin-4-yl) ethyl)carbamate (11c).
Prepared from 8 (99 mg, 0.5 mmol) and benzimi-damide hydrochloride 10c (86 mg, 0.55 mmol). Yield: 47
mg (31%) of yellow oil; [a]D22 -4.2 (c 1.2, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.47 (9H, s, t-Bu); 1.52 (3H, d, J = 6.9 Hz, 4'-Me); 4.88 (1H, p, J = 7.2 Hz, 4'-H); 5.61 (1H, br d, J = 5.6 Hz, NHBoc); 7.14 (1H, d, J = 5.1 Hz, 5-H); 7.47-7.52 (3H, m, o,p-Ph); 8.44-8.49 (2H, m, m-Ph); 8.74 (1H, d, J = 5.1 Hz, 6-H). 13C NMR (126 MHz, CDCl3): 5 22.0, 28.4, 50.9, 79.7, 115.9, 128.2, 128.5, 130.81, 137.5, 155.2, 157.6, 164.3, 170.2. m/z (ESI) = 300 (MH+). HRMS-ESI (m/z): [MH+] calcd for C17H22N3O2, 300.1707; found, 300.1709. IR (ATR) и 3344, 2977, 2932, 1694, 1588, 1554, 1517, 1454, 1428, 1386, 1365, 1245, 1161, 1053, 1026, 845, 813, 760, 724, 696, 646 cm-1.
3. 2. 4. (S)-tert-butyl (1-(2-(3-nitrophenyl)
pyrimidin-4-yl)ethyl)carbamate (11d).
Prepared from 8 (197 mg, 1 mmol) and 3-nitroben-zimidamide hydrochloride 10d (222 mg, 1.1 mmol). Yield: 202 mg (59%) of yellowish crystals; m.p. 89-92 °C; [a]D22 -16.7 (c 0.55, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.47 (9H, s, t-Bu); 1.55 (3H, d, J = 7.0 Hz, 4'-Me); 43.91 (1H, p, J = 7.4 Hz, 4'-H); 5.41 (1H, br d, J = 8.0 Hz, NHBoc); 7.26 (1H, d, J = 5.5 Hz, 5-H); 7.68 (1H, t, J = 8.0 Hz, 6''-H); 8.32-8.37 (1H, m, 5''-H); 8.80 (1H, d, J = 5.0 Hz, 6-H); 8.83 (1H, d, J = 7.8 Hz, 4''-H); 9.32 (1H, t, J = 1.9 Hz, 2''-H). 13C NMR (126 MHz, CDCl3): 5 21.7, 28.4, 51.1, 80.0, 116.9, 123.3, 125.2, 129.5, 134.0, 139.3, 148.7, 155.2, 157.9, 162.2, 171.2. m/z (ESI) = 345 (MH+). HRMS-ESI (m/z): [MH+] calcd for C17H21N4O4, 345.1557; found, 345.1553. Anal. Calcd for C17H20N4O4MH2O: C 58.53, H 5.92, N 16.06. Found: C 581.87, H 5.84, N 15.83. IR (ATR) и 3363, 2977, 1682, 1587, 1568, 1553, 1510, 1460, 1398, 1366, 1346, 1295, 1248, 1158, 1098, 1056, 1000, 923, 899, 855, 832, 816, 801, 786, 760, 738, 698, 689, 639, 606 cm-1.
3. 2. 5. (S)-tert-butyl (1-(2-(3-aminophenyl)
pyrimidin-4-yl)ethyl)carbamate (11e).
Prepared from 8 (197 mg, 1 mmol) and 4-aminoben-zimidamide hydrochloride 10e (189 mg, 1.1 mmol). Yield: 160 mg (51%) of brown oil; [a]D22 -6.0 (c 0.5, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.46 (9H, s, t-Bu); 1.49 (3H, d, J = 7.4 Hz, CH3CH); 4.00 (2H, br s, NH2); 4.82 (1H, p, J = 7.2 Hz, 4'-H); 5.67 (1H, br d, J = 6.8 Hz, NHBoc); 6.75 (2H, d, J = 8.4 Hz, 2H of Ar); 7.00 (1H, d, J = 5.1 Hz, 5-H); 8.29 (2H, d, J = 8.5 Hz, 2H of Ar); 8.63 (1H, d, J = 5.0 Hz, 6-H). 13C NMR (126 MHz, CDCl3): 5 22.1, 28.4, 50.8, 79.6, 114.5, 114.6, 127.7, 129.8, 149.1, 155.3, 157.3, 164.4, 169.7. m/z (ESI) = 315 (MH+). HRMS-ESI (m/z): [MH+] calcd for C17H23N4O2, 315.1816; found, 315.1812. IR (ATR) и 34582 3368, 3215, 2974, 1682, 1627, 1605, 1579, 1553, 1520, 1450, 1422, 1388, 1365, 1333, 1300, 1244, 1167, 1060, 1008, 868, 836, 801, 755, 736, 675 cm-1.
3. 2. 6. tert-Butyl (S)-(1-(2-((1H-benzo[rf] imidazol- 2-yl)amino)pyrimidin-4-yl)ethyl) car-bamate (11f).
Prepared from 8 (99 mg, 0.5 mmol) and 1#-ben-zoMimidazole-2-carboximidamide hydrochloride 10f (98 mg, 0.55 mmol). Yield: 78 mg (44%) of brown oil; [a]D22 -18.9 (c 0.95, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.43 (9H, s, t-Bu); 1.53 (3H, d, J = 7.1 Hz, CH3CH); 4.82 (1H, br s, 4'-H); 5.38 (1H, br s, NHBoc); 6.88 31H, d, J = 5.1 Hz, 5-H); 7.18, 7.23, 7.45, and 7.89 (4H, 4 br s, 1:1:1:1, 4H of Ar); 8.56 (1H, br s, 6-H); 11.83 (1H, br s, NH); 1'(3')-H exchanged. 13C NMR (126 MHz, CDCl3): 5 28.4, 29.7, 50.9, 80.0, 110.2, 117.3, 120.8, 121.9, 131.6, 140.9, 149.4, 155.4, 158.8. m/z (ESI) = 355 (MH+). HRMS-ESI (m/z): [MH+] calcd for C18H23N6O2, 355.1877; found, 355.1874. IR (ATR) и 3343, 2976, 1684, 1643, 1606, 1555, 1511, 1457, 1435, 1393, 1365, 1319, 1271, 1245, 1163, 1061, 1006, 898, 861, 821, 795, 737, 693, 669, 608 cm-1.
3. 2. 7. tert-Butyl (S)-(1-(2-(1H-pyrazol-1-yl) pyrimidin-4-yl)ethyl)carbamate (11g).
Prepared from 8 (197 mg, 1 mmol) and Ш-pyrazo-le-1-carboximidamide hydrochloride 10g (161 mg, 1.1 mmol). Yield: 72 mg (25%) of yellow oil; [a]D22 -12.3 (c 1.2, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.44 (9H, s, t-Bu); 1.52 (3H, d, J = 7.0 Hz, CH3CH); 4.88 (1H, p, J = 6.8 Hz, 4'-H); 5.47 (1H, br d, J = 6.1 Hz, NHBoc); 6.50 (1H, dd, J = 2.5, 1.7 Hz, 4''-H); 7.19 (1H, d, J = 5.0 Hz, 5-H); 7.84 (1H, d, J = 0.8 Hz, 3''-H); 8.62 (1H, d, J = 2.7 Hz, 5''-H); 8.70 (1H, d, J = 5.0 Hz, 6-H). 13C NMR (126 MHz, CDCl3): 5 21.5, 28.4, 51.0, 79.9, 108.6, 115.4, 129.3, 143.7, 155.1, 155.8, 159.3, 173.1. m/z (ESI) = 290 (MH+). HRMS-ESI (m/z): [MH+] calcd for C14H20N5O2, 290.1612; found, 290.1609. IR (ATR) и 3318, 2977, 1697, 1585, 1558, 1524, 1435, 1395, 1365, 1294, 1246, 1162, 1113, 1039, 946, 914, 842, 760, 733, 648 cm-1.
3. 3. General procedures for the synthesis of tert-butyl (S)-(1-(pyrazolo[1,5-a] pyrimidin-7-yl)ethyl)carbamates 14a-c, tert-butyl (S)-(1-(pyrazolo[1,5-a] pyrimidin-5-yl)ethyl)carbamates 14'a,c,d, tert-butyl (S,E)-(5-(5-amino-1H -1,2,4-triazol-1-yl)-3-oxopent-4-en-2-yl) carbamate (16'e) and tert-butyl (S,E) -(5-(5-amino-1H-tetrazol-1-yl)-3 -oxopent -4-en-2-yl)carbamate (16'f).
General procedure A. Aminoazole 13 (1.1 mmol) was added to a solution of ynone 8 (197 mg, 1 mmol) in EtOH (10 mL) and the mixture was stirred at r.t. for 72 h.
Volatile components were evaporated in vacuo and the residue was purified by DVFC (EtOAc/hexanes). Fractions containing the product were combined and evaporated in vacuo to give 14/14'. Mixtures of regioisomers 14a/14'a and 14c/14'c were separated by MPLC (EtOAc/hexanes). Fractions containing the product were combined and evaporated in vacuo to give isomerically pure compounds 14a, 14c, 14'a, and 14'c.
General procedure B. Enaminone 9 (242 mg, 1 mmol) was dissolved in EtOH (10 mL), aminoazole hydrochloride 13 (1.1 mmol) was added, and the mixture was stirred at 50 °C for 72 h. Volatile components were evaporated in vacuo and the residue was purified by DVFC (EtOAc/hexanes, 1:2) to give 14, 14', and 16'.
The following compounds were prepared in this manner:
3. 3. 1. (S)-tert-butyl (1-(pyrazolo[1,5-a]
pyrimidin-7-yl)ethyl)carbamate (14a) and (S)-tert-butyl (1-(pyrazolo[1,5-a] pyrimidin-5-yl)ethyl)carbamate (14'a).
Prepared from 3-amino-1#-pyrazole 13a (91 mg, 1.1 mmol), and ynone 8 (197 mg, 1 mmol, G.P.A) or enaminone 9 (242 mg, 1 mmol, G.P.B), DVFC (EtOAc), MPLC (EtOAc/hexanes, 1:1).
Major isomer 14a. Yield: 141 mg (54%, G.P.A) and 120 mg (46%, G.P.B) of yellowish oil; [a]D22 -63.7 (c 0.30, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.43 (9H, s, t-Bu); 1.67 (3H, d, J = 7.2 Hz, 7'-Me); 5.43 (1H, p, J = 7.6 Hz, 7'-H); 6.16 (1H, br d, J = 8.5 Hz, NHBoc); 6.73 (1H, br d, J = 2.4 Hz, 3-H); 6.80 (1H, d, J = 4.1 Hz, 6-H); 8.15 (1H, br d, J = 2.4 Hz, 2-H); 8.47 (1H, d, J = 4.3 Hz,
5-H).	13C NMR (126 MHz, CDCl3): 5 18.5, 28.3, 47.6, 80.0, 96.7, 104.1, 144.4, 149.2, 149.2, 149.5, 154.9. m/z (ESI) = 263 (MH+). HRMS-ESI (m/z): [MH+] calcd for C13H19N4O2, 263.1503; found, 263.1502. IR (ATR) и 3326, 29772 1691, 1614, 1514, 1454, 1391, 1366, 1330, 1294, 1244, 1160, 114, 1061, 1014, 992, 900, 862, 826, 775, 739, 636 cm-1.
Minor isomer 14'a. Yield: 28 mg (11%, G.P.A) of yellowish crystals; m.p. 89-93 °C; [a]D22 -100.8 (c 0.35, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.46 (9H, s, t-Bu); 1.51 (3H, d, J = 6.9 Hz, 5'-Me); 4.89 (1H, p, J = 7.2 Hz, 5'-H); 5.71 (1H, br d, J = 7.5 Hz, NHBoc); 6.62 (1H, br d, J = 2.3 Hz, 3-H); 6.79 (1H, d, J = 7.2 Hz,
6-H);	8.10 (1H, d, J = 2.0 Hz, 2-H); 8.62 (1H, d, J = 7.2 Hz, 7-H). 13C NMR (126 MHz, CDCl3): 5 21.6, 28.4, 51.0, 79.7, 96.3, 106.2, 135.3, 145.3, 147.9, 155.2, 162.0. m/z (ESI) = 263 (MH+). HRMS-ESI (m/z): [MH+] calcd for C13H19N4O2, 263.1503; found, 263.1501. IR (ATR) и 3365, 2962, 2930, 2860, 1717, 1681, 1617, 1511, 1455, 1411, 1364, 1326, 1311, 1296, 1266, 1247, 1161, 1116, 1060, 1019, 1001, 907, 858, 809, 783, 766, 731, 636 cm-1.
3. 3. 2. tert-Butyl (S)-(1-(2-methylpyrazolo
[1,5-a]pyrimidin-7-yl)ethyl)carbamate (14b).
Prepared from ynone 8 (197 mg, 1 mmol) and 3-amino-5-methyl-1#-pyrazole 13b (107 mg, 1.1 mmol), G.P.A, DVFC (EtOAc/hexanes, 1:2). Yield: 205 mg (74%) of white crystals; m.p. 100-105 °C; [a]D22 -64.5 (c 0.45, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.44 (9H, s, t-Bu); 1.66 (3H, d, J = 7.1 Hz, 7'-Me); 2.53 (3H, s, 2-Me); 5.35 (1H, p, J = 7.3 Hz, 7'-H); 6.09 (1H, br d, J = 9.2 Hz, NHBoc); 6.49 (1H, s, 3-H); 6.68 (1H, d, J = 4.2 Hz, 6-H); 8.37 (1H, br d, J = 4.2 Hz, 5-H). 13C NMR (126 MHz, CDCl3): 5 14.8, 18.7, 28.3, 47.8, 80.0, 95.9, 103.4, 148.6, 149.0, 150.0, 154.8, 154.9. m/z (ESI) = 277 (MH+). HRMS-ESI (m/z): [MH+] calcd for C14H21N4O2, 277.1659; found, 277.1656. Anal. Calcd for C14H20N4O2: C 60.85, H 7.30, N 20.28. Found: C 61.11, H 7.58, IN 20.14. IR (ATR) и 3352, 2984, 2933, 1682, 1616, 1549, 1519, 1478, 1417, 1393, 1367, 1352, 1331, 1300, 1266, 1248, 1211, 1160, 1112, 1076, 1059, 1020, 862, 847, 822, 780, 736, 666, 628 cm-1.
3. 3. 3. Methyl (S)-7-(1-((tert-butoxycarbonyl) amino)ethyl)pyrazolo[1,5-a]pyrimidme-3-carboxylate (14c) and methyl (S)-5 -(1-((tert-butoxycarbonyl)amino)ethyl) pyrazolo[1,5-a]pyrimidine-3-carboxylate (14'c).
Prepared from methyl 5-amino-1H-pyrazole-4-car-boxylate 13c (423 mg, 3.3 mmol), and ynone 8 (591 mg, 3 mmol, G.P.A) or enaminone 9 (727 mg, 3 mmol, G.P.B), DVFC (EtOAc), MPLC (EtOAc/hexanes, 1:1).
Major isomer 14c. Yield: 312 mg (32%, G.P.A) of brownish oil; [a]D22 -30.9 (c 0.55, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.42 (9H, s, t-Bu); 1.68 (3H, d, J = 7.1 Hz, 7'-Me); 3.98 (3H, s, OMe); 5.43 (1H, p, J = 7.8 Hz, 7'-H); 5.73 (1H, br s, NHBoc); 6.99 (1H, d, J = 4.2 Hz, 6-H); 8.62 (1H, s, 2-H); 8.76 (1H, d, J = 4.4 Hz, 5-H). 13C NMR (126 MHz, CDCl3): 5 18.6, 28.3, 47.7, 51.8, 80.5, 102.8, 106.2, 147.5, 148.2, 151.0, 152.8, 154.7, 163.0. m/z (ESI) = 321 (MH+). HRMS-ESI (m/z): [MH+] calcd for C15H21N4O4, 321.1557; found, 321.1558. IR (ATR) и 3341, 2979, 2248, 1692, 1618, 1549, 1514, 1486, 1453, 1367, 1323, 1281, 1249, 1226, 1161, 1112, 1088, 1062, 1009, 969, 909, 861, 835, 802, 784, 758, 728, 645 cm-1.
Minor isomer 14'c. Yield: 110 mg (11%, G.P.A) and 72 mg (8%, G.P.B) of yellowish crystals; m.p. 102-106 °C; [a]D22 -122.0 (c 0.40, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.46 (9H, s, t-Bu); 1.577 (3H, d, J = 7.0 Hz, 5'-Me); 3.94 (3H, s, OMe); 4.99 (1H, p, J = 6.9 Hz, 5'-H); 5.82 (1H, d, J = 5.6 Hz, NHBoc); 7.04 (1H, d, J = 7.2 Hz, 6-H); 8.55 (1H, s, 2-H); 8.70 (1H, d, J = 7.1 Hz, 7-H). 13C NMR (126 MHz, CDCl3): 5 21.4, 28.4, 51.3, 51.5, 79.8, 102.4, 108.1, 136.2, 14732, 148.0, 155.3, 162.9, 166.0. m/z (ESI) = 321 (MH+). HRMS-ESI (m/z): [MH+] calcd for
C15H21N4O4, 321.1557; found, 321.1556. IR (ATR) и 33539, 2983, 1685, 1624, 1542, 1521, 1476, 1447, 1411, 1365, 1318, 1293, 1248, 1226, 1198, 1164, 1104, 1067, 1052, 1004, 938, 905, 866, 824, 782, 690, 633 cm-1.
3. 3. 4. Methyl (S)-5-(1-((tert-butoxycarbonyl)
amino)ethyl)[1,2,4]triazolo[1,5-a]pyrimidi -ne-2-carboxylate (14'd).
Prepared from 8 (197 mg, 1 mmol) and methyl 5-amino-№-1,2,4-triazole-3-carboxylate (13d) (156 mg, 1.1 mmol), G.P.A, DVFC (EtOAc/hexanes, 1:2). Yield: 260 mg (81%) of white crystals; m.p. 191-195 °C; [a]D22 -2.6 (c 0.50, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1H NMR (500 MHz, CDCl3): 5 1.44 (9H, s, t-Bu); 1.57 (3H, d, J = 7.0 Hz, 5'-Me); 4.09 (3H, s, OMe); 5.04 (1H, p, J = 7.3 Hz, 5'-H); 5.61(1H, br d, J = 7.9 Hz, NHBoc); 7.30 (1H, d, J = 7.1 Hz, 6-H); 8.86 (1H, d, J = 7.0 Hz, 7-H). 13C NMR (126 MHz, CDCl3): 5 21.2, 28.3, 51.4, 53.3, 80.1, 110.7, 136.3, 155.0, 155.3, 157.5, 160.3, 170.7. m/z (ESI) = 322 (MH+). HRMS-ESI (m/z): [MH+] calcd for C14H20N5O4, 322.1510; found, 322.1508. Anal. Calcd for C^H^O^ C 52.33, H 5.96, N 21.79. Found: C, 51.90; H, 5.63; N 21.27. IR (ATR) и 3379, 3083, 2982, 1732, 1682, 1627, 1510, 1474, 1387, 1367, 1333, 1303, 1245, 1217, 1163, 1059, 1022, 998, 970, 948, 861, 844, 782, 761, 743, 717, 656 cm-1.
3. 3. 5. tert-butyl (S,£M5-(3-amino-4tf-1,2,4-tria-zol-4-yl)-3-oxopent-4-en-2-yl)carbamate (16'e).
Prepared from 8 (99 mg, 0.5 mmol) and 13e (98 mg, 0.5 mmol) and , General Procedure A. Yield: 72 mg (55%) of white crystals; m.p. 188-191 °C; [a]D22 -27.1 (c 0.20, MeOH). 1H NMR (500 MHz, DMSO-d6D: 5 1.18 (3H, d, J = 7.2 Hz, CH3CH); 1.38 (9H, s, t-Bu); 4.18 (1H, p, J = 7.3 Hz, CHCH3); 6.66 (1H, d, J = 13.2 Hz, CH=CHN); 7.33 (1H, d, J = 7.4 Hz, NHBoc); 7.35 (2H, b s, NH2); 7.62 (1H, s, 5-H); 8.15 (1H, d, J = 13.3 Hz, CH=CHN). 13C NMR (126 MHz, DMSO-d6): 5 16.2, 28.2, 54.4, 78.1, 108.5, 133.9, 152.3, 155.2, 156.9, 199.0. m/z (ESI) = 282 (MH+). HRMS-ESI (m/z): [MH+] calcd for C12H29N5O3, 282.1561; found, 282.1567. Anal. Calcd for C^H^N^: C 51.23, H 6.81, N 24.90. Found: C 50.80, H 6.65, IN 24.54. IR (ATR) и 3357, 3119, 2980, 1683, 1610, 1516, 1456, 1428, 1389, 1366, 1310, 1290, 1251, 1201, 1168, 1081, 1055, 1027, 957, 888, 856, 817, 780, 742, 695, 640,
625 cm-1.
3. 3. 6. tert-butyl (S,E)-(5-(5-amino-1H-tetrazol-1 -yl)-3-oxopent-4-en-2-yl)carbamate (16'f).
Prepared from 8 (99 mg, 0.5 mmol) and 13f (98 mg, 0.5 mmol), General Procedure A. Yield: 36 mg (26%) of yellowish crystals; m.p. 144-147 °C; [a]D22 -37.7 (c 0.47,
MeOH). 1H NMR (500 MHz, DMSO-d6): 5 1.20 (3H, d, J = 7.2 Hz, CH3CH); 1.38 (9H, s, t-Bu); 4.22 (1H, p, J = 7.2 Hz, CHCH3); 7.03 (1H, d, J = 13.8 Hz, CH=CHN); 7.43 (1H, d, J = 7.1 Hz, NHBoc); 7.65 (2H, br s, NH2); 8.13 (1H, d, J = 13.8 Hz, CH=CHN). 13C NMR (126 MHz, DMSO-d6): 5 15.8, 28.1, 54.6, 78.3, 112.8, 130.6, 155.3, 155.4, 198.6. m/z (ESI) = 283 (MH+). HRMS-ESI (m/z): [MH+] calcd for C11H19N6O2, 283.1513; found, 283.1504. Anal. Calcd for C11H18N6O3: C 46.80, H 6.43, N 29.77. Found: C 46.35, H (5.15, NN 30.04. IR (ATR) и 3353, 3152, 2980, 2143, 1682, 1618, 1592, 1516, 1455, 1390, 1366, 1311, 1252, 1161, 1112, 1048, 991, 959, 856, 780, 701, 626 cm-1.
3. 4. General procedure for the synthesis of (S)-1-(pyrimidin-2-yl)-1-ethylaminium chlorides 12a-d,g and (S)-1-(pyrazolo [1,5-a]pyrimidin-7-yl)-1-ethylaminium chlorides 15a,b.
2 M HCl in ethyl acetate (1 mL, 2 mmol) was added to a stirred solution of 11 or 14 (0.2 mmol) in ethyl acetate (5 mL) and the mixture was stirred at r.t. for 3 h. Volatile components were evaporated to give the crude products 12 and 15.
The following compounds were prepared in this manner:
3. 4. 1. (S)-1-(Pyrimidin-4-yl)-1-ethylaminium chloride (12a).
Prepared from 11a (8 mg, 0.04 mmol). Yield: 5 mg (79%) of brownish oil; [a]D22 +15.6 (c 0.20, MeOH). 1H NMR (500 MHz, DMSO-d6): 5 1.55 (3H, d, J = 6.9 Hz, 4'-Me); 4.58 (1H, p, J = 6.46 Hz, 4'-H); 7.77 (1H, dd, J = 5.3, 1.3 Hz, 5-H); 8.77 (3H, br s, NH3+); 8.92 (1H, d, J = 5.2 Hz, 6-H); 9.29 (1H, br d, J = 1.3 Hz, 2-H). 13C NMR (126 MHz, DMSO-d6): 5 20.2, 50.5, 120.1, 158.9, 159.1, 167.1. m/z (ESI) = 124 (M+). HRMS-ESI (m/z): [M+] calcd for C6H10N3, 124.0869; found, 124.0866. IR (ATR) и 2927, 2858, 1-720, 1627, 1580, 1505, 1463, 1386, 1266, 1246, 1155, 1116, 1101, 1019, 842, 790, 730 cm-1.
3. 4. 2. (S)-1-(2-Methylpyrimidin-4-yl)-1
-ethylaminium chloride (12b).
Prepared from 11b (36 mg, 0.1 mmol). Yield: 16 mg
(84%) of yellowish oil; [a]D22 +8.9 (c 0.70, MeOH). 1H
NMR (500 MHz, DMSO-d6): 5 1.54 (3H, d, J = 6.9 Hz,
4'-Me); 2.71 (3H, s, 2-Me); 4.51 (1H, p, J = 6.1 Hz, 4'-
H); 7.64 (1H, d, J = 5.3 Hz, 5-H); 8.84 (1H, d, J = 5.3 Hz,
6-H); 8.85 (3H, br s, NH3+). 13C NMR (126 MHz, DMSO-
d6): 5 20.2, 26.3, 50.7, 117.1, 158.1, 167.6, 168.0. m/z
(IESI) = 138 (M+). HRMS-ESI (m/z): [M+] calcd for
C7H12N3, 138.1026; found, 138.1028. IR (ATR) и 2916,
2251, 2076, 1622, 1577, 1508, 1439, 1397, 1297, 1202, 1098, 1043, 996, 930, 833, 728 cm-1.
3. 4. 3. (S)-1-(2-Phenylpyrimidin-4-yl) -1-ethylaminium chloride (12c).
Prepared from 11c (37 mg, 0.12 mmol). Yield: 23 mg (82%) of yellowish oil; [a]D22 +7.9 (c 1.1, MeOH). 1H NMR (500 MHz, DMSO-d6): 5 1.63 (3H, d, J = 6.8 Hz, 4'-Me); 4.63 (1H, p, J = 6.4 Hz, 4'-H); 7.54-7.60 (3H, m, 3H of Ar); 7.66 (1H, d, J = 5.1 Hz, 5-H); 8.59 (2H, dd, J = 7.5, 2.3 Hz, 2H of Ar); 8.94 (3H, br s, NH3+); 8.99 (1H, d, J = 5.1 Hz, 6-H). 13C NMR (126 MHz, DMSO-d6): 5 20.2, 50.7, 117.9, 129.2, 129.6, 132.2, 137.7, 159.4, 164.0, 167.5. m/z (ESI) = 200 (M+). HRMS-ESI (m/z): [M+] calcd for C12H14N3, 200.1182; found, 200.1184. IR (ATR) и 2875, 19973, 1588, 1559, 1499, 1460, 1427, 1389, 1373, 1198, 1175, 1129, 1098, 1081, 1069, 1025, 991, 940, 909, 844, 816, 762, 723, 694, 646 cm-1.
3. 4. 4. (S)-1-(2-(3-Nitrophenyl)pyrimidin-4-yl) -1-ethylaminium chloride (12d).
Prepared from 11d (13 mg, 0.04 mmol). Yield: 10 mg (89%) of yellowish crystals; m.p. 214-220 °C; [a]D22 -22.4 (c 0.40, MeOH). 1H NMR (500 MHz, DMSO-d6): 5 1.64 (3H, d, J = 6.9 Hz, CH3CH); 4.72 (1H, p, J = 6.1 Hz, CHCH3); 7.76 (1H, d, J = 5.2 Hz, 5-H); 7.92 (1H, t, J = 8.0 Hz, 5''-H); 8.46 (1H, ddd, J = 8.2, 2.3, 0.8 Hz 4''-H); 8.89 (3H, br s, NH3+); 9.04 (1H, dt, J = 7.8, 1.3 Hz, 6''-H); 9.09 (1H, d, J = 5.1 Hz, 6-H); 9.32 (1H, t, J = 2.0 Hz, 2''-H). 13C NMR (126 MHz, DMSO-d6): 5 20.1, 50.5, 119.0, 123.4, 126.7, 131.5, 135.3, 139.3, 149.4, 159.8, 162.0, 167.9. m/z (ESI) = 245 (M+). HRMS-ESI (m/z): [M+] calcd for C12H13N4O2, 245.1033; found, 245.1035. IR (ATR) и 2977, 2847, 2016, 1967, 1684, 1587, 1557, 1528, 1481, 1426, 1393, 1348, 1247, 1194, 1168, 1141, 1099, 1062, 993, 926, 907, 887, 844, 826, 801, 738, 699, 682, 645, 616 cm-1.
3. 4. 5. (S)-1-(2-(Lff-Pyrazol-1-yl)pyrimidin-4-yl)-1-ethylaminium chloride (12g).
Prepared from 11g (72 mg, 0.25 mmol). Yield: 47 mg (84%) of brownish oil; [a]D22 +7.1 (c 1.8, MeOH). 1H NMR (500 MHz, DMSO-d6): 5 1.62 (3H, d, J = 6.8 Hz, 4'-Me); 4.65 (1H, p, J = 5.9 Hz, 4'-H); 6.67 (1H, dd, J = 2.7, 1.6 Hz, 4''-H); 7.67 (1H, d, J = 5.1 Hz, 5-H); 7.92 (1H, d, J = 1.5 Hz, 3''-H); 8.95 (1H, d, J = 5.1 Hz, 6-H); 8.99 (3H, br s, NH3+); 9.06 (1H, d, J = 2.7 Hz, 5''-H). 13C NMR (126 MHz, DMSO-d6): 5 20.1, 50.5, 109.9, 117.4, 131.5, 144.6, 155.8, 161.3, 169.4. m/z (ESI) = 190 (M+). HRMS-ESI (m/z): [M+] calcd for C9H12N5, 190.1087; found, 190.1084. IR (ATR) и 2823, 1589, 1561, 1523, 1467, 1439, 1393, 1344, 1220, 1166, 1100, 1069, 1043, 992, 947, 902, 835, 809, 703, 648, 606 cm-1.
3. 4. 6. (S)-1-(Pyrazolo[1,5-a]pyrimidin-7-yl) -1-ethylaminium chloride (15a).
Prepared from 14a (40 mg, 0.15 mmol). Yield: 28 mg (94%) of yellowish oil; [a]D22 +8.0 (c 1.4, MeOH). 1H NMR (500 MHz, DMSO-d6): 5 1.73 (3H, d, J = 6.8 Hz, 7'-Me); 5.19 (1H, p, J = 6.2 Hz, 7'-H); 6.89 (1H, d, J = 2.4 Hz, 3-H); 7.43 (1H, d, J = 4.3 Hz, 6-H); 8.36 (1H, d, J = 2.4 Hz, 2-H); 8.70 (1H, d, J = 4.3 Hz, 5-H); 9.30 (3H, br d, J = 4.4 Hz, NH3+). 13C NMR (126 MHz, DMSO-d6): 5 17.6, 45.8, 98.0, 106.4, 145.7, 146.6, 149.3, 150.6. m/z (ESI) = 163 (M+). HRMS-ESI (m/z): [M+] calcd for C8H11N4, 163.0978; found, 163.0979. IR (ATR) и 2858, 2084, 1721, 1617, 1543, 1456, 1373, 1310, 1269, 1245, 1176, 1117, 1021, 995, 903, 821, 776, 742, 634 cm-1.
3. 4. 7. (S)-1-(2-Methylpyrazolo[1,5-a]pyrimidin -7-yl)-1-ethylaminium chloride (15b).
Prepared from 14b (52 mg, 0.2 mmol). Yield: 20 mg (47%) of yellowish oil; [a]D22 +16.5 (c 0.40, MeOH). 1H NMR (500 MHz, DMSO-d6): 5 1.72 (3H, d, J = 6.8 Hz, 7'-Me); 2.51 (3H, s, 2-Me); 5.16 (1H, p, J = 6.5 Hz, 7'-H); 6.68 (1H, s, 3-H); 7.30 (1H, d, J = 4.4 Hz, 6-H); 8.62 (1H, d, J = 4.4 Hz, 5-H); 9.21 (3H, br d, J = 4.4 Hz, NH3+). 13C NMR (126 MHz, DMSO-d6): 5 15.4, 17.5, 45.6, 97.2, 105.5, 146.0, 149.9, 150.2, 155.2. m/z (ESI) = 321 (M+). HRMS-ESI (m/z): [M+] calcd for C9H13N4, 177.1135; found, 177.1134. IR (ATR) и 2848, 1611, 1572, 1534, 1483, 1405, 1343, 1249, 1208, 1152, 998, 777, 738 cm-1.
3. 5. Catalytic hydrogenation of pyrazolo
[1,5-a]pyrimidines 14a and 14'c.
Synthesis of 4,5,6,7-tetrahydropyrazolo
[1,5-a]pyrimidines 18 and 18'.
A mixture of pyrazolo[1,5-a]pyrimidine 14 (0.5 mmol), MeOH (30 mL), and 10% Pd-C (15 mg) was hydrogenated under 3 Bar of H2 at r.t. for 16 h. The catalyst was removed by filtration through a glass-sintered funnel, washed with MeOH (10 mL), and the combined filtrate was evaporated in vacuo to give 18/18'. The mixture of isomers 18 and 18' was first purified by DVFC (EtOAc). The combined eluate was evaporated in vacuo to give the purified mixture of diastereomers 18 and 18', which were separated by MPLC (EtOAc/hexanes, 1:1). Fractions containing the products were combined and evaporated in vacuo to give isomerically pure compounds 18 and 18'.
The following compounds were prepared in this manner:
3. 6. 1. tert-Butyl (7S,7'S)-1-((4,5,6,7-tetrahydrop-yra- zolo[1,5-a]pyrimidin-7-yl)ethyl)-car-bamate (18a) and its (7tf ,7'S)-isomer 18'a.
Prepared from 14a (131 mg, 0.5 mmol). Yield: 120 mg (90%) of reddish oil, 18a:18'a = 80:20.
Data for the major isomer 18a. Yield: 55 mg (41%) of reddish oil; [a]D22 -1.4 (c 0.70, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.00 (3H, d, J = 6.8 Hz, 7'-Me); 1.46 (9H, s, t-Bu); 1.98 (1H, br dtd, J = 3.9, 10.3, 13.6 Hz, 1H of 6-Ha); 2.14 (1H, br dddd, J = 3.1, 5.1, 8.3, 13.6 Hz, 6-Hb); 3.24 (1H, br td, J = 11.0, 2.8 Hz, 5-Ha); 3.34 (1H, br dt, J = 11.5, 4.5 Hz, 5-Hb); 4.01 (1H, br p, J = 6.8 Hz, 7'-H); 4.11 (1H, br s, 4-H); 4.27 (1H, br tdd, J = 1.7, 5.7, 8.2 Hz, 7-H); 5.34 (1H, br d, J = 2.0 Hz, 3-H); 6.59 (1H, d, J = 9.8 Hz, NHBoc); 7.25 (1H, br d, J = 2.0 Hz, 2-H). 13C NMR (126 MHz, CDCl3): 5 15.0, 26.7, 28.5, 39.3, 49.9, 59.1, 79.0, 86.4, 138.7, 146.5, 155.5. m/z (ESI) = 267 (MH+). HRMS-ESI (m/z): [MH+] calcd for C13H23N4O2, 267.1816; found, 267.1816. IR (ATR) и 3339, 2976, 2934, 1687, 1578, 1499, 1450, 1391, 1363, 1340, 1293, 1242, 1162, 1083, 1061, 1045, 1026, 990, 923, 886, 846, 729, 631 cm-1.
Data for the minor isomer 18'a. Yield: 17 mg (13%) of reddish oil; [a]D22 -24.2 (c 0.25, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.36 (3H, d, J = 77.0 Hz, 7'-Me); 1.39 (9H, s, t-Bu)3 2.11 and 2.15 (2H, 2 br dddd, J = 4.1, 4.6, 8.9, 13.6 Hz, 6-Ha and 6-Hb); 3.28 (1H, ddd, J = 3.9, 6.9, 11.2 Hz, 5-Ha); 3.40 (1H, ddd, J = 3.6, 8.7, 11.9 Hz, 5-Hb); 4.06 and 4.13 (3H, 2 br s, 2:1, 7'-H, 4-H, and 7-H); 5.12 (1H, br s, NHBoc); 5.33 (1H, br d, J = 2.0 Hz, 3-H); 7.26 (1H, br d, J = 2.0 Hz, 2-H). 13C NMR (126 MHz, CDCl3): 5 19.4, 25.3, 28.4, 37.8, 49.8, 58.1, 79.2, 86.2, 139.0, 145.5, 155.7. m/z (ESI) = 267 (MH+). HRMS-ESI (m/z): [MH+] calcd for C13H23N4O2, 267.1816; found, 267.1818. IR (ATR) и 33230, 2975, 2932, 1689, 1579, 1518, 1452, 1391, 1364, 1293, 1245, 1162, 1062, 988, 923, 872, 729 cm-1.
3. 6. 2. Methyl (5S,5'S)-5-(1-((tert-butoxycar-
bonyl)amino)ethyl)-4,5,6,7-tetrahydrop-yrazolo-[1,5-a]pyrimidine-3-carboxylate (18c) and its (5tf,5'S)-isomer 18'c.
Prepared from 14c (320 mg, 1 mmol). Yield: 322 mg (99%) of yellowish oil; 18c: 18'c = 84:16.
Data for the major isomer 18c. Yield: 254 mg (78%) of colourless resin; [a]D22 -0.3 (c 0.70, CH2Cl2). 1H NMR (500 MHz, CDCl3): 5 1.06 (3H, d, J = 6.7 Hz, 7'-Me); 1.46 (9H, s, t-Bu); 1.98-2.08 (1H, m, 6-Ha); 2.09-2.18 (1H, m, 6-Hb); 3.32-3.41 (1H, m, 5-Ha); 3.45-3.52 (1H, m, 5-Hb); 3.78 (3H, s, OMe); 3.99-4.08 (1H, br m, 7'-H); 4.17-4.24 (1H, br m, 7-H); 5.81 (1H, br s, 4-H); 6.12 (1H, br d, J = 9.8 Hz; NHBoc); 7.187.58 (1H, s, 2-H). 13C NMR (126 MHz, CDCl3): 5 15.6, 25.4, 28.4, 37.7, 49.4, 50.7, 58.9, 79.4, 93.5, 139.1, 149.3, 155.4, 164.6. m/z (ESI) = 325 (MH+). HRMS-ESI (m/z): [MH+] calcd for C15H25N4O4, 325.1870; found, 325.1863. IR (ATR) и 3369, 2977, 2249, 1680, 1599, 1541, 1501, 1443, 1391, 1365, 1339, 1287, 1235, 1212, 1163, 1125, 1086, 1061, 1027, 990, 939, 919, 846, 807, 779, 729, 646 cm-1.
Data for the minor isomer 18'c. Yield: 36 mg (11%) of colourless resin; [a] D22 +2.0 (c 0.35, CH2Cl2). 1H NMR
(500 MHz, CDCl3): 5 1.34 (3H, d, J = 5.4 Hz, 7'-Me); 1.31 (9H, s, t-Bu); 2.05-2.15 (2H, m, 6-CH2); 3.40 (1H, dtd, J =
12.2,	5.1, 2.6 Hz, 5-Ha); 3.48 (1H, br dddd, J = 13.3, 8.4, 4.8, 1.6 Hz, 5-Hb); 3.70 (3H, s, OMe); 3.95-4.06 (1H, br p, J = 6.0 Hz, 7-H); 4.09 (1H, br p, J = 5.4 Hz, 7'-H); 4.88 (1H, br d, J = 5.4 Hz, NHBoc); 5.85 (1H, br s, 4-H); 7.57 (1H, s, 2-H). 13C NMR (126 MHz, CDCl3): 5 19.3, 24.3,
28.3,	36.4, 49.6, 50.7, 57.9, 79.5, 93.3, 139.4, 148.6, 155.5, 164.7. m/z (ESI) = 325 (MH+). HRMS-ESI (m/z): [MH+] calcd for C15H25N404, 325.1870; found, 325.1868. IR (ATR) и 3350, 2975, 1(578, 1599, 1540, 1442, 1391, 1364, 1289, 1232, 1212, 1163, 1082, 1061, 981, 938, 925, 870, 807, 778, 734, 697 cm-1.
4. Conclusions
Novel (S)-N-Boc-1-(heteroaryl)-1-ethylamines 11, 14, and 14' were prepared by cyclocondensation of (S)-N-Boc-alanine (6)-derived ynone 8 with amidines 10 and a-aminoazoles 13. Acidolytic removal of the Boc N-protec-ting group then furnished the free amines 12 and 15 in moderate yields over two steps. Reactions of 8 with nonsymmetrical cyclic amidines 13 were generally not regio-selective and gave mixtures of isomeric products 14 and 14'. Since 14 and 14' were separable by chromatography, this lack of regioselectivity can also be advantageous, due to increase of diversity of the products. Catalytic hydroge-nation of (S)-tert-butyl (1-(pyrazolo[1,5-a]pyrimidin-7-yl)ethyl)carbamates 14 was quite stereoselective to furnish the corresponding 4,5,6,7-tetrahydro derivatives as separable mixtures of diastereomers 18 and 18' in a ratio of 4:1. In summary, the present method allows a short and simple synthesis of various (S)-1-(heteroaryl)-1-ethylami-nes from commercially available a-amino acids. The title compounds could be useful generally as chiral non-race-mic amines and ligands in asymmetric applications, whereas (S)-1-(pyrazolo[1,5-a]pyrimidinyl)-1-ethylamines are additionally applicable in fluorescence-related applications.
5. Acknowledgement
The financial support from the Slovenian Research Agency through grant P1-0179 is gratefully acknowledged.
6. References
1. J. Mulzer, in: G. Helmchem (Ed.): Basic Principles of EPC Synthesis in Stereoselective Synthesis, Houben-Weyl Methods of Organic Chemistry, 4th edn., Georg Thieme Verlag, Stuttgart, Germany, 1996, Vol. 1, p. 75-146.
2.	B. Stanovnik, J. Svete, Chem. Rev. 2004, 104, 2433-2480. http://dx.doi.org/10.1021/cr020093y
3.	B. Stanovnik, J. Svete, Mini-Rev. Org. Chem. 2005, 2, 211224.
http://dx.doi.org/10.2174/1570193054368864
4.	J. Svete, Monatsh. Chem. 2004, 135, 629-647. http://dx.doi.org/10.1007/s00706-003-0133-y
5.	S. Pirc, D. Bevk, A. Golobic, B. Stanovnik, J. Svete, Helv. Chim. Acta 2006, 89, 30-44. http://dx.doi.org/10.1002/hlca.200690010
6.	J. Wagger, U. Grošelj, A. Meden, J. Svete, B. Stanovnik, Tetrahedron 2008, 64, 2801-2815. http://dx.doi.org/10.1016/j.tet.2008.01.045
7.	U. Grošelj, D. Bevk, R. Jakše, A. Meden, B. Stanovnik, J. Svete, Tetrahedron: Asymmetry 2006, 17, 1217-1237. http://dx.doi.org/10.1016/j.tetasy.2006.04.014
8.	P. Čebašek, J. Wagger, D. Bevk, R. Jakše, J. Svete, B. Stanovnik, J. Comb. Chem. 2004, 6, 356-362. http://dx.doi.org/10.1021/cc034066c
9.	P. Čebašek, D. Bevk, S. Pirc, B. Stanovnik, J. Svete, J. Comb. Chem. 2006, 8, 95-102. http://dx.doi.org/10.1021/cc050073k
10.	U. Grošelj, M. Žorž, A. Golobic, B. Stanovnik, J. Svete Tetrahedron 2013, 69, 11092-11108.
11.	L. De Luca, M. Falorini, G. Giacomelli, A. Porcheddu, Tetrahedron Lett. 1999, 40, 8701-8704. http://dx.doi.org/10.1016/S0040-4039(99)01847-X
12.	L. De Luca, G. Giacomelli, A. Porcheddu, A. M. Spannedda, M. Falorini, Synthesis 2000, 1295-1298. http://dx.doi.org/10.1055/s-2000-6426
13.	H. Dube, N. Gommermann, P. Knochel Synthesis 2004, 2015-2025.
14.	L. Senica, U. Grošelj, M. Kasunic, D. Kocar, B. Stanovnik, J. Svete, Eur. J. Org. Chem. 2014, 3067-3071. http://dx.doi.org/10.1002/ejoc.201402033
15.	E. Pušavec, J. Mirnik, L. Senica, U. Grošelj, B. Stanovnik, J. Svete Z. Naturforsch. 2014, 69b, 615-626.
16.	D. J. Wilson, C. Shi, B. P. Duckworth, J. M. Muretta, U. Ma-njunatha, Y. Y. Sham, D. D. Thomas, C. C. Aldrich, Anal. Biochem. 2011, 416, 27-38. http://dx.doi.org/10.1016/j.ab.2011.05.003
17.	T. Morwick, M. Hrapchak, M. DeTuri, S. Campbell, Org. Lett. 2002, 4, 2665-2668. http://dx.doi.org/10.1021/ol020092s
18.	A. C. Regan, in: J. Cossy (Ed.): Pyrazolo[1,5-a]pyrimidine (74), A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor (Eds.): Comprehensive heterocyclic chemistry III, vol 11, Elsevier Science Ltd., Oxford, UK, 2008, pp. 577-577, and references cited therin.
19.	M. H. Elnagdi, M. R. H. Elmoghayar, G. E. H. Elgemeie, Adv. Heterocycl. Chem. 1987, 41, 319-376. http://dx.doi.org/10.1016/S0065-2725(08)60164-6
20.	S. Ahmetaj, N. Velikanje, U. Grošelj,-I. Sterbal, B. Prek, A. Golobic, D. Kocar, G. Dahmann, B. Stanovnik, J. Svete, Mol. Divers. 2013, 17, 731-743. http://dx.doi.org/10.1007/s11030-013-9469-3
21.	L. M. Harwood, C. J. Moody, ''Dry Flash' column chromatography, in: Experimental organic chemistry, principles and practice, Blackwell Science, Oxford, 1989, p. 185-188.
22.	L. M. Harwood, Aldrichim. Acta 1985, 18, 25-25.
23.	T. L. Cupps, R. H. Boutin, H. Rapoport, J. Org. Chem. 1985, 50, 3972-3979.
http://dx.doi.org/10.1021/jo00221a004
24. T. J. Nitz, K. Salzwedel, C. Finnegan, C. Wild, S. Brunton, S. Flanagan, C. Montalbetti, T. S. Coulter, M. Kimber, F. Ma-garaci, D. Johnston, Alpha-unsubstituted arylmethylpipera-zine pyrazolo[1,5-a]pyrimidine amide derivatives as antire-troviral agents and their preparation and use in the treatment of HIV-associated diseases. WO Patent Number 2008134 035, date of patent November 6, 2008.
Povzetek
(S)-terc-butil (3-oksopent-4-in-2-il)karbamat, pripravljen v dveh stopnjah iz (S)-N-Boc-alanina, smo ciklizirali z različnimi N,N-1,3-dinukleofili, kot so amidini in a-aminoazoli ter tako po acidolitski odstranitvi Boc skupine sintetizirali seriji (S)-1-(pirimidin-4-il)- in regioizomernih (S)-1-(pirazolo[1,5-a]pirimidin-7-il)- in (S)-1-(pirazolo[1,5-a]pir-imidin-5-il)-1-aminoetanov. Stereoselektivno katalitsko hidrogeniranje (S)-1-(pirazolo[1,5-a]pirimidin-7-il)-1-aminoetanov je vodilo do nasičenja pirimidinskega obroča in nastanka zmesi diastereomernih 4,5,6,7-tetrahidropirazo-lo[1,5-a]pirimidinov v razmerju 4:1. Strukture vseh novih spojin so bile pojasnjene z NMR spektroskopijo.