A four-step synthesis of novel (S)-1-(heteroaryl)-1-aminoethanes from (S)-Boc-alanine

Article abstract of DOI:10.17344/acsi.2014.712

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 α-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.

Full text of DOI:10.17344/acsi.2014.712

DOI: 10.17344/acsi.2014.712
Acta Chim. Slov. 2015, 62, 60–71
60
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, A{ker~eva 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.: +386 1 2419 254. Fax.: +386 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 α-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
tamine (2), (2S,5S)-5-benzyl-2-(tert-butyl) -3-methylimi-
dazolidin-4-one (3), quinidine (4), and (1R,2R)-1,2-dia-
1. Introduction
Nonracemic amines represent an important group of
organic compounds, which found a widespread use in va-
rious 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-
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 de-
rivatives, heterocyclic systems, and natural product ana-
logues.2,3 In extension, chiral cyclic enaminones derived
from (S)-α-amino acids and (+)-camphor have been em-
ployed in the synthesis of functionalized heterocycles and
heterocyclic analogues of peptides.2,4–7 Furthermore, ena-
minones have also been successfully employed in a com-
binatorial 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 treat-
ment of Weinreb amides of a suitably protected α-amino
acid with (trimethylsilyl)magnesium bromide followed by
Figure 1. Examples of important chiral alkylamines 1–5.
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Acta Chim. Slov. 2015, 62, 60–71
reaction of the so formed silylynone with diethylamine.
61
These enamino ketones were then used as the key-inter-
mediates in the synthesis of chiral pyrazole-containing
peptidomimetics11 and α-pyrazolylglycines.12 Later on,
we also reported similar preparation of chiral enamino ke-
tones from α-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 impor-
tant example is ynone-based synthesis of chiral α-ami-
noalkylpyrimidines using an enantioselective three-com-
ponent reaction.13
In continuation of our work in this field, we became
interested in the Boc-α-amino acid derived ynones and
enaminones again, as they turned out to be suitable precur-
sors 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 avai-
lable in sufficient amounts, we decided to further investi-
gate 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 appli-
cations. Furthermore, alkylamines bearing fluorescent azo-
lo[a]pyrimidin-6-one residues could also be used in fluo-
rescence-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.
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-1H-
pyrazole (13a) and methyl 5-amino-1H-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 chroma-
tography (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-1H-pyrazole
(13b) and methyl 5-amino-1H-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 cor-
responding 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 pre-
sence 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-
2. Results and Discussion
The first reagent, (S)-tert-butyl (3-oxopent-4-yn-2-
yl)carbamate (8) was prepared in two steps from commer-
cially available (S)-Boc-alanine (6) via transformation in-
to 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 amidi-
nes, 3-aminopyrazoles 13a–c and methyl 5-amino-1H-
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-
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Acta Chim. Slov. 2015, 62, 60–71
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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).
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-1H-1,2,4-triazole (13e) and 5-amino-1H-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 ca-
talytic 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).
The formation of regioisomeric products 14 and 14’
is explainable in the following way. 1,4-Addition of a he-
terocyclic 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’. Ana-
logously, also formation of regioisomeric products 14a
and 14’c from the enaminone reagent 9 can be explained
by initial substitution of the dimethylamino group follo-
wed by cyclisation. Selective reaction of enaminones with
the primary amino group of various non-symmetrical
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Acta Chim. Slov. 2015, 62, 60–71
63
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
ment with the literature data for 7-substituted pyrazo-
lo[1,5-a]pyrimidines, whereas a larger vicinal coupling
3
constant, J6H–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-
1
a]pyrimidines.18–20 The H 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, respecti-
vely. The structure of 14’d was determined by HMBC
spectroscopy. Correlation of H(7) with three carbon nuc-
1
form. Their identities were established by H 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 vici-
3
nal coupling constants, J5H–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-
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Acta Chim. Slov. 2015, 62, 60–71
64
Scheme 4. Stereoselective hydrogenation of compounds 14a and
14c.
lei, C(4a), C(5), and C(6), was in agreement with the pro-
posed [1,5-a]-isomer 14’d. On the other hand, the corres-
ponding 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) (Fi-
gure 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 sui-
table single crystals of compounds 14b, 14’a,c,d, 18a,c,
and 18’a,c for X-Ray diffraction analysis were not suc-
cessful.
1
Figure 2. Structure determination by H NMR and HMBC spec-
troscopy.
(MPLC) was performed on a Büchi Flash Chromato-
graphy System (Büchi Fraction Collector C-660, Büchi
Pump Module C-605, Büchi Control Unit C-620) on sili-
ca gel (LiChroprep® Si 60, 15–25 μm), column dimen-
sions: 23 × 460 mm, backpressure: 10 Bar, detection: UV
(254 nm).
(S)-N-Boc-Alanine (6), N,O-dimethylhydroxyla-
mine, CDI, ethynylmagnesium bromide, amidines
10a–g, aminopyrazoles 13a,b, methyl 5-amino-1H-
1,2,4-triazole-3-carboxylate (13d), 5-amino-1H-1,2,4-
triazole (13e), and 5-amino-1H-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,E)-(5-(dimethylamino)-3-oxopent-
4-en-2-yl)carbamate (9),14 and methyl 5-amino-1H-
pyrazole-4-carboxylate (13c)24 were prepared following
the literature procedures.
3. Experimental
3. 1. General Methods
Melting points were determined on a Stanford Re-
search Systems MPA100 OptiMelt automated melting
point system. The NMR spectra were obtained on a Bru-
1
ker Avance III UltraShield 500 plus at 500 MHz for H
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 per-
formed on silica gel (Fluka, Silica gel 60, particle size
35–70 μm). Medium performance liquid chromatography
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65
22
1
mg (31%) of yellow oil; [α]D –4.2 (c 1.2, CH2Cl2). H
NMR (500 MHz, CDCl3): δ 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): δ 22.0, 28.4, 50.9, 79.7, 115.9, 128.2,
128.5, 130.8, 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) υ
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. 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 va-
cuo 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. 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
3. 2. 1. tert-Butyl (S)-(1-(pyrimidin-4-yl)ethyl)
carbamate (11a).
22
1
Prepared from 8 (197 mg, 1 mmol) and formimidami-
°C; [α]D –16.7 (c 0.55, CH2Cl2). H NMR (500 MHz,
CDCl3): δ 1.47 (9H, s, t-Bu); 1.55 (3H, d, J = 7.0 Hz, 4’-
Me); 4.91 (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): δ 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
C17H20N4O4·¼H2O: C 58.53, H 5.92, N 16.06. Found: C
58.87, H 5.84, N 15.83. IR (ATR) υ 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.
de acetate 10a (115 mg, 1.1 mmol). Yield: 52 mg (23%) of
22
1
brownish oil; [α]D –0.8 (c 0.55, CH2Cl2). H NMR (500
MHz, CDCl3): δ 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): δ 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) υ 3227, 2976, 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; [α]D22 +0.6 (c 1.8, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ 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): δ 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) υ 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. 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).
22
Yield: 160 mg (51%) of brown oil; [α]D –6.0 (c 0.5,
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ 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): δ 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) υ 3458, 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. 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
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66
[ ]
3. 2. 6. tert-Butyl (S)-(1-(2-((1H-benzo d
Volatile components were evaporated in vacuo and the re-
sidue 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 eva-
porated 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:
imidazol- 2-yl)amino)pyrimidin-
4-yl)ethyl) car-bamate (11f).
Prepared from 8 (99 mg, 0.5 mmol) and 1H-ben-
zo[d]imidazole-2-carboximidamide hydrochloride 10f (98
22
mg, 0.55 mmol). Yield: 78 mg (44%) of brown oil; [α]D
1
–18.9 (c 0.95, CH2Cl2). H NMR (500 MHz, CDCl3): δ
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 (1H, 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): δ
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) υ 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. 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).
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 1H-pyrazo-
le-1-carboximidamide hydrochloride 10g (161 mg, 1.1
mmol). Yield: 72 mg (25%) of yellow oil; [α]D22 –12.3 (c
Prepared from 3-amino-1H-pyrazole 13a (91 mg,
1.1 mmol), and ynone 8 (197 mg, 1 mmol, G.P.A) or ena-
minone 9 (242 mg, 1 mmol, G.P.B), DVFC (EtOAc),
MPLC (EtOAc/hexanes, 1:1).
1
1.2, CH2Cl2). H NMR (500 MHz, CDCl3): δ 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): δ 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) υ
3318, 2977, 1697, 1585, 1558, 1524, 1435, 1395, 1365,
1294, 1246, 1162, 1113, 1039, 946, 914, 842, 760, 733,
648 cm–1.
Major isomer 14a. Yield: 141 mg (54%, G.P.A) and
22
120 mg (46%, G.P.B) of yellowish oil; [α]D –63.7 (c
1
0.30, CH2Cl2). H NMR (500 MHz, CDCl3): δ 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): δ 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) υ
3326, 2977, 1691, 1614, 1514, 1454, 1391, 1366, 1330,
1294, 1244, 1160, 114, 1061, 1014, 992, 900, 862, 826,
775, 739, 636 cm–1.
3. 3. General procedures for the synthesis
Minor isomer 14’a. Yield: 28 mg (11%, G.P.A) of
[
]
of tert-butyl (S)-(1-(pyrazolo 1,5-a
pyrimidin-7-yl)ethyl)carbamates 14a–c,
22
yellowish crystals; m.p. 89–93 °C; [α]D –100.8 (c
0.35, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 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): δ 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) υ 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.
[
]
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.
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67
3. 3. 2. tert-Butyl (S)-(1-(2-methylpyrazolo
C15H21N4O4, 321.1557; found, 321.1556. IR (ATR) υ
3339, 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.
[
]
1,5-a pyrimidin-7-yl)ethyl)carbamate
(14b).
Prepared from ynone 8 (197 mg, 1 mmol) and 3-
amino-5-methyl-1H-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; [α]D22 –64.5 (c 0.45,
3. 3. 4. Methyl (S)-5-(1-((tert-butoxycarbonyl)
[
]
[
]
amino)ethyl) 1,2,4 triazolo 1,5-a pyrimidi
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ 1.44 (9H, s, t-
-ne-2-carboxylate (14’d).
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): δ 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, N
20.14. IR (ATR) υ 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.
Prepared from 8 (197 mg, 1 mmol) and methyl 5-
amino-1H-1,2,4-triazole-3-carboxylate (13d) (156 mg,
1.1 mmol), G.P.A, DVFC (EtOAc/hexanes, 1:2). Yield:
22
260 mg (81%) of white crystals; m.p. 191–195 °C; [α]D
–2.6 (c 0.50, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 1H
NMR (500 MHz, CDCl3): δ 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): δ 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
C14H19N5O4: C 52.33, H 5.96, N 21.79. Found: C, 51.90;
H, 5.63; N, 21.27. IR (ATR) υ 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. 3. Methyl (S)-7-(1-((tert-butoxycarbonyl)
[
]
amino)ethyl)pyrazolo 1,5-a pyrimidine-
3-carboxylate (14c) and methyl (S)-5
-(1-((tert-butoxycarbonyl)amino)ethyl)
[
]
pyrazolo 1,5-a pyrimidine-3-carboxylate
(14’c).
3. 3. 5. tert-butyl (S,E)-(5-(3-amino-4H-1,2,4-tria-
zol-4-yl)-3-oxopent-4-en-2-yl)carbamate
(16’e).
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).
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; [α]D22 –27.1 (c 0.20,
MeOH). 1H NMR (500 MHz, DMSO-d6): δ 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): δ 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 C12H20N5O3,
282.1561; found, 282.1567. Anal. Calcd for C12H19N5O3:
C 51.23, H 6.81, N 24.90. Found: C 50.80, H 6.65, N
24.54. IR (ATR) υ 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.
Major isomer 14c. Yield: 312 mg (32%, G.P.A) of
brownish oil; [α]D22 –30.9 (c 0.55, CH2Cl2). 1H NMR (500
MHz, CDCl3): δ 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): δ 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) υ
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
22
1
°C; [α]D –122.0 (c 0.40, CH2Cl2). H NMR (500 MHz,
CDCl3): δ 1.46 (9H, s, t-Bu); 1.57 (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): δ 21.4, 28.4, 51.3, 51.5, 79.8,
102.4, 108.1, 136.2, 147.2, 148.0, 155.3, 162.9, 166.0. m/z
(ESI) = 321 (MH+). HRMS–ESI (m/z): [MH+] calcd for
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; [α]D22 –37.7 (c 0.47,
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Acta Chim. Slov. 2015, 62, 60–71
68
MeOH). 1H NMR (500 MHz, DMSO-d6): δ 1.20 (3H, d, J
2251, 2076, 1622, 1577, 1508, 1439, 1397, 1297, 1202,
1098, 1043, 996, 930, 833, 728 cm–1.
= 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): δ 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 6.15, N 30.04. IR (ATR) υ 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. 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; [α]D22 +7.9 (c 1.1, MeOH). 1H
NMR (500 MHz, DMSO-d6): δ 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): δ 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+] cal-
cd for C12H14N3, 200.1182; found, 200.1184. IR (ATR) υ
2875, 1973, 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. 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.
3. 4. 4. (S)-1-(2-(3-Nitrophenyl)pyrimidin-4-yl)
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 aceta-
te (5 mL) and the mixture was stirred at r.t. for 3 h. Volati-
le components were evaporated to give the crude products
12 and 15.
-1-ethylaminium chloride (12d).
Prepared from 11d (13 mg, 0.04 mmol). Yield: 10
22
mg (89%) of yellowish crystals; m.p. 214–220 °C; [α]D
1
–22.4 (c 0.40, MeOH). H NMR (500 MHz, DMSO-d6):
The following compounds were prepared in this
manner:
δ 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,
3. 4. 1. (S)-1-(Pyrimidin-4-yl)-1-ethylaminium
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): δ 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) υ 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.
chloride (12a).
Prepared from 11a (8 mg, 0.04 mmol). Yield: 5 mg
22
1
(79%) of brownish oil; [α]D +15.6 (c 0.20, MeOH). H
NMR (500 MHz, DMSO-d6): δ 1.55 (3H, d, J = 6.9 Hz,
4’-Me); 4.58 (1H, p, J = 6.4 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): δ 20.2, 50.5, 120.1, 158.9, 159.1,
167.1. m/z (ESI) = 124 (M+). HRMS–ESI (m/z): [M+] cal-
cd for C6H10N3, 124.0869; found, 124.0866. IR (ATR) υ
2927, 2858, 1720, 1627, 1580, 1505, 1463, 1386, 1266,
1246, 1155, 1116, 1101, 1019, 842, 790, 730 cm–1.
3. 4. 5. (S)-1-(2-(1H-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; [α]D22 +7.1 (c 1.8, MeOH). 1H
NMR (500 MHz, DMSO-d6): δ 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);
3. 4. 2. (S)-1-(2-Methylpyrimidin-4-yl)-1
-ethylaminium chloride (12b).
Prepared from 11b (36 mg, 0.1 mmol). Yield: 16 mg
22
1
(84%) of yellowish oil; [α]D +8.9 (c 0.70, MeOH). H
NMR (500 MHz, DMSO-d6): δ 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,
8.99 (3H, br s, NH3 ); 9.06 (1H, d, J = 2.7 Hz, 5’’-H). 13C
+
NMR (126 MHz, DMSO-d6): δ 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) υ 2823, 1589, 1561, 1523,
1467, 1439, 1393, 1344, 1220, 1166, 1100, 1069, 1043,
992, 947, 902, 835, 809, 703, 648, 606 cm–1.
6-H); 8.85 (3H, br s, NH3 ). 13C NMR (126 MHz, DMSO-
+
d6): δ 20.2, 26.3, 50.7, 117.1, 158.1, 167.6, 168.0. m/z
(ESI) = 138 (M+). HRMS–ESI (m/z): [M+] calcd for
C7H12N3, 138.1026; found, 138.1028. IR (ATR) υ 2916,
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69
[
]
3. 4. 6. (S)-1-(Pyrazolo 1,5-a pyrimidin-7-yl)
Data for the major isomer 18a. Yield: 55 mg (41%)
of reddish oil; [α]D22 –1.4 (c 0.70, CH2Cl2). 1H NMR (500
MHz, CDCl3): δ 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): δ 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) υ 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%)
-1-ethylaminium chloride (15a).
Prepared from 14a (40 mg, 0.15 mmol). Yield: 28
mg (94%) of yellowish oil; [α]D22 +8.0 (c 1.4, MeOH). 1H
NMR (500 MHz, DMSO-d6): δ 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): δ
+
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) υ 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).
22
1
of reddish oil; [α]D –24.2 (c 0.25, CH2Cl2). H NMR
(500 MHz, CDCl3): δ 1.36 (3H, d, J = 7.0 Hz, 7’-Me);
1.39 (9H, s, t-Bu); 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): δ 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) υ 3320, 2975, 2932, 1689, 1579,
1518, 1452, 1391, 1364, 1293, 1245, 1162, 1062, 988,
923, 872, 729 cm–1.
Prepared from 14b (52 mg, 0.2 mmol). Yield: 20 mg
22
1
(47%) of yellowish oil; [α]D +16.5 (c 0.40, MeOH). H
NMR (500 MHz, DMSO-d6): δ 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): δ 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) υ 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
3. 6. 2. Methyl (5S,5’S)-5-(1-((tert-butoxycar-
bonyl)amino)ethyl)-4,5,6,7-tetrahydrop-
[
]
1,5-a pyrimidines 18 and 18’.
[
]
yrazolo- 1,5-a pyrimidine-3-carboxylate
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 con-
taining the products were combined and evaporated in va-
cuo to give isomerically pure compounds 18 and 18’.
The following compounds were prepared in this
manner:
(18c) and its (5R,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; [α]D22 –0.3 (c 0.70, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ 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): δ 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) υ
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; [α]D22 +2.0 (c 0.35, CH2Cl2). 1H NMR
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 (7R,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.
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(500 MHz, CDCl3): δ 1.34 (3H, d, J = 5.4 Hz, 7’-Me); 1.31
2. B. Stanovnik, J. Svete, Chem. Rev. 2004, 104, 2433–2480.
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3. B. Stanovnik, J. Svete, Mini-Rev. Org. Chem. 2005, 2, 211–
224.
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4. J. Svete, Monatsh. Chem. 2004, 135, 629–647.
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5. S. Pirc, D. Bevk, A. Golobi~, B. Stanovnik, J. Svete, Helv.
Chim. Acta 2006, 89, 30–44.
(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): δ 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 C15H25N4O4, 325.1870; found, 325.1868.
IR (ATR) υ 3350, 2975, 1678, 1599, 1540, 1442, 1391,
1364, 1289, 1232, 1212, 1163, 1082, 1061, 981, 938, 925,
870, 807, 778, 734, 697 cm–1.
http://dx.doi.org/10.1002/hlca.200690010
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trahedron 2008, 64, 2801–2815.
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7. U. Gro{elj, D. Bevk, R. Jak{e, 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. ^eba{ek, J. Wagger, D. Bevk, R. Jak{e, J. Svete, B. Sta-
novnik, J. Comb. Chem. 2004, 6, 356–362.
http://dx.doi.org/10.1021/cc034066c
9. P. ^eba{ek, D. Bevk, S. Pirc, B. Stanovnik, J. Svete, J.
Comb. Chem. 2006, 8, 95–102.
http://dx.doi.org/10.1021/cc050073k
10. U. Gro{elj, M. @or`, A. Golobi~, B. Stanovnik, J. Svete Te-
trahedron 2013, 69, 11092–11108.
11. L. De Luca, M. Falorini, G. Giacomelli, A. Porcheddu, Te-
trahedron Lett. 1999, 40, 8701–8704.
http://dx.doi.org/10.1016/S0040-4039(99)01847-X
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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.
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Svete, Eur. J. Org. Chem. 2014, 3067–3071.
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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 α-
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 non-
symmetrical 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 fur-
nish 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 α-amino acids. The title
compounds could be useful generally as chiral non-race-
mic amines and ligands in asymmetric applications, whe-
reas (S)-1-(pyrazolo[1,5-a]pyrimidinyl)-1-ethylamines
are additionally applicable in fluorescence-related appli-
cations.
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.
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Lett. 2002, 4, 2665–2668.
5. Acknowledgement
http://dx.doi.org/10.1021/ol020092s
The financial support from the Slovenian Research
Agency through grant P1-0179 is gratefully acknowled-
ged.
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.
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Povzetek
(S)-terc-butil (3-oksopent-4-in-2-il)karbamat, pripravljen v dveh stopnjah iz (S)-N-Boc-alanina, smo ciklizirali z
razli~nimi N,N-1,3-dinukleofili, kot so amidini in α-aminoazoli ter tako po acidolitski odstranitvi Boc skupine sinte-
tizirali 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 nasi~enja pirimidinskega obro~a 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.
[enica et al.: A Four-step Synthesis of Novel ...

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