Synthesis 2015; 47(01): 89-94
DOI: 10.1055/s-0034-1378898
paper
© Georg Thieme Verlag Stuttgart · New York

Formation of N-Heterocycles from 1,1-Diethoxy-5-hydroxyalk-3-yn-2-ones

Ingebjørg Nes
Department of Chemistry, University of Bergen, Allégt. 41, 5007 Bergen, Norway   Fax: +47(5)5589490   Email: leiv.sydnes@kj.uib.no
,
Leiv K. Sydnes*
Department of Chemistry, University of Bergen, Allégt. 41, 5007 Bergen, Norway   Fax: +47(5)5589490   Email: leiv.sydnes@kj.uib.no
› Author Affiliations
Further Information

Publication History

Received: 10 June 2014

Accepted after revision: 30 July 2014

Publication Date:
04 September 2014 (online)

 


Abstract

When treated with hydrazine, guanidine, and hydroxylamine, 1,1-diethoxy-5-hydroxyalk-3-yn-2-ones undergo Michael addition and give the corresponding β,β-disubstituted α,β-unsaturated olefinic ketones, which are unstable and undergo secondary reactions to form heterocyclic compounds. Hydrazine affords 3,5-disubstituted pyrazoles and hydroxylamine 5-hydroxy-4,5-dihydroisoxazoles in very good yields. Guanidine, however, furnishes complex reaction mixtures, which include the corresponding 2-aminopyrimidines. These results show that cyclization involves attack of the ketone moiety by the bisnucleophile reactive terminal group and not the hydroxyl group present in the starting material.


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Conjugated alkynones have become important intermediates in organic synthesis in recent years.[1] [2] [3] [4] [5] One reason is that such compounds react with nucleophiles in a Michael fashion and afford α,β-unsaturated alkenones as primary products, another is that the primary products may undergo subsequent reactions and form interesting compounds by secondary transformations.[5–7]

The outcome in a given case depends on the nature of the nucleophile and the properties of any additional reactive moiety present in the right position in the unsaturated ketone. The importance of these factors is illustrated by the outcome of reactions with two acetylenes, 1,1-diethoxybut-3-yn-2-one (1) and 1,1-diethoxy-5-hydroxyhex-3-yn-2-one (2b). When 1 is reacted with ammonia, the final product is (Z)-4-amino-1,1-diethoxybut-3-en-2-one, but when the nucleophile is switched to hydrazine, a bisnucleophile, the primary product reacts intramolecularly and furnishes 3-diethoxymethyl-1H-pyrazole (Scheme [1]).[5] Ketone 2b, however, contains one reactive group more than 1, that is, an OH group, and when 2b was treated with diethylamine the OH group reacts with the carbonyl group in the primary product and furnishes 4-diethylamino-2-diethoxymethyl-5-methylfuran (Scheme [2]).[8]

What would happen if 2b were treated with hydrazine or another bisnucleophile instead of a simple amine is, however, not obvious. The first step is supposed to be a conjugate addition leading to the corresponding β-substituted γ-hydroxy α,β-unsaturated olefinic ketone, but what the stereochemistry is going to become depends to a large extent on the hydrogen-bonding ability of the nucleophile residue relative to that of the OH group. If the OH and carbonyl groups end up Z to each other, a furan is expected, if not another heterocycle is anticipated. In principle, a third option is the formation of products due to intermolecular reactions, but from the results depicted in Schemes 1 and 2 that is unlikely.[5] Thus, the ultimate outcome is really determined by the competition in the first step. In order to get some insight into this competition, 2b and its analogues 2a and 2ce have been reacted with three bisnucleo­philes that are known to add very well to 1, namely, hydrazine, guanidine, and hydroxylamine,[5] [6] and the results obtained are reported here.

Zoom Image
Scheme 1
Zoom Image
Scheme 2

The study started by treating 2b with hydrazine, which is known to give pyrazoles when reacted with simple conjugated acetylenic ketones.[5] [6] Exploratory experiments, performed at room temperature and monitored by TLC and 1H NMR, revealed that 2b gave two products in a ratio, which varied with the reaction time in such a way that it was clear that the primary product was unstable and was gradually converted to a more stable secondary product. This was confirmed when the products were isolated; the stable product turned out to be 5-diethoxymethyl-3-(1-hydroxyethyl)pyrazole (3b) whereas the unstable compound was believed to be 5-diethoxymethyl-5-hydroxy-3-(1-hydroxyethyl)-4,5-dihydro-1H-pyrazole (Scheme [3]) because it decomposed fairly quickly and furnished 3b and water.[9] Apparently, the OH group cannot compete with the hydrazino moiety for the position Z to the carbonyl group in the addition reaction, and subsequent condensation leads to the formation of a pyrazole derivative.

Zoom Image
Scheme 3

Based on these findings, the reactions of 2 with hydrazine were carried out above room temperature (40 °C) and under these conditions, some 16–18 hours were required to consume all the starting material. In most cases, the corresponding pyrazole 3 was obtained in good yield (>80%); in fact the only exception was 5-diethoxymethyl-3-(hydroxy)(phenyl)methyl-1H-pyrazole (3d), which was obtained from 2d in 65% yield only (Table [1]). In all cases, the conjugate addition obviously must have furnished the corresponding β-hydrazino-γ-hydroxy α,β-unsaturated olefinic ketone with Z stereochemistry.

Table 1 Synthesis of 5-Diethoxymethyl-1H-pyrazoles 3 from 2 and Hydrazine

2

R1, R2

3

Isolated yield (%)

2a

H, H

3a

94

2b

H, Me

3b

94

2c

H, i-Pr

3c

80

2d

H, Ph

3d

65

2e

Me, Me

3e

89

The formation of 3,5-disubstituted pyrazole derivatives 3 in high yields is interesting because such pyrazoles have been shown to form useful complexes with some transition metals.[10] The 1-hydroxyalkyl group is instrumental when P- and S-ligands are going to be incorporated, and by converting the acetal group in position 3 to the corresponding aldehyde other ligands can subsequently be introduced. This approach to expand the scope of pyrazole ligands will be investigated in due course.

Based on the results obtained for hydrazine, it was expected that also guanidine would afford the primary product with the Z-isomer and ultimately the corresponding 2-aminopyrimidine 4. However, this expectation was only partly fulfilled due to formation of a number of by-products, of which one could be isolated in a couple of cases. The best result was obtained when 1,1-diethoxy-5-hydroxyhex-3-yn-2-one (2b) was reacted and gave 2-amino-6-diethoxymethyl-4-(1-hydroxyethyl)pyrimidine (4b) in 48% yield along with 30% of 2-amino-6-diethoxymethyl-5,6-dihydro-4-(1-hydroxyethyl)-6-pyrimidinol (5b) (Scheme [4]).

Zoom Image
Scheme 4

Attempts to improve the yield by extending the reaction time and/or running the reaction at higher temperatures did not help; instead the number and total yield of by-products increased. The best results, summarized in Table [2], are indeed disappointing considering the fact that 2-amino-4-diethoxymethylpyrimidine was isolated in 95% yield when 1 was reacted with guanidine for just 45 minutes at room temperature.[5]

Table 2 Synthesis of 2-Amino-6-diethoxymethylpyrimidines 4 from 2 and Guanidine

2

R1, R2

Isolated yield (%)

4

5

2a

H, H

26

21

2b

H, Me

48

30

2c

H, i-Pr

30

 0

2d

H, Ph

trace

 0

2e

Me, Me

24

 0

Unlike hydrazine and guanidine, hydroxylamine does not give aromatic heterocycles at all when reacted with 2 under similar conditions. In every case, the only product was a derivative of 5-diethoxymethyl-5-hydroxy-3-hydroxy­methyl-4,5-dihydroisoxazole (6), which was easily isolated in better than 80% yield (Table [3]).

Table 3 Synthesis of 5-Diethoxymethyl-5-hydroxy-4,5-dihydro­isoxazoles 6 from 2 and Hydroxylamine

2

R1, R2

6

Isolated yield (%)

2a

H, H

2a

85

2b

H, Me

2b

88

2c

H, i-Pr

2c

82

2e

Me, Me

2e

87

The fact that hydroxylamine does not give aromatic products whereas hydrazine and guanidine do is interesting. These results clearly indicate that the aromaticity of isoxazoles is significantly less than that of pyrazoles and pyrimidines, and this is in complete accordance with empirical resonance energy values reported by Katritzky et al.[11] Dehydration of 2-isoxazoline 6 to form the corresponding isoxazole should therefore not be a favored reaction and this was indeed what was observed. When 6a and 6b were refluxed in aqueous acetone under acidic conditions (Dowex 50W) no product was detected (TLC and NMR) even after 11 hours, and 2-isoxazolines were recovered in quantitative yield. And when water elimination was attempted from 6b by azeotropic distillation in the presence of Dowex 50W only some of it reacted and gave a reaction mixture, which contained mainly unreacted 2-isoxazoline and from which no pure products were obtained.[12]

Melting points were determined on a Gallenkamp apparatus and are uncorrected. IR spectra were recorded on a Nicolet Impact 410 IR spectrophotometer, in most cases with the compound as a film between two NaCl plates. Standard abbreviations for denoting the intensities were used. NMR spectra were run on a Bruker Spectrospin DMX 400. Chemical shifts are reported downfield from TMS, the coupling constants are given in Hz, and standard abbreviations were used for denoting the multiplicities. TLC analyses of the reaction mixtures were performed with silica gel (60 F254) on aluminum sheets with mixtures of EtOAc and isomeric hexanes as the mobile phase. Flash chromatography was carried out with silica gel (230–400 mesh) as the stationary phase with mixtures of EtOAc and isomeric hexanes as the mobile phase. The eluent composition is given for each of the isolations described below. Mass spectra were obtained on a JEOL AccuTOF T100GC spectrometer operated in the DART+ mode at 10–15 eV.

3,3,4,4-Tetraethoxybut-3-yn-2-one (1) was synthesized as described in the literature. This was used to prepare the 5-substituted 1,1-diethoxy-5-hydroxypent-3-yn-2-ones 2af following published procedures.[3] [5] [7] The spectroscopic data were in agreement with those reported in the literature.


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3,5-Disubstituted 1H-pyrazoles 3 by Reaction of 2 with Hydrazine; General Procedure

The unsaturated ketone 2 (5.00 mmol) was dissolved in absolute EtOH (25.0 mL) and a 55% aq solution of hydrazine (0.3 g, 5.1 mmol) was slowly added to the stirred solution. The reaction mixture was heated to 40 °C and left stirring overnight. The EtOH was removed on a rotary evaporator and the crude product was purified using gradient flash chromatography with a mixture of hexanes, EtOAc, and MeOH to give the 3,5-disubstituted 1H-pyrazoles 3ae.


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5-Diethoxymethyl-3-hydroxymethyl-1H-pyrazole (3a)

The unsaturated ketone 2a (0.93 g, 4.99 mmol) was reacted with a 55% aq solution of hydrazine (0.30 g, 5.1 mmol) for 16 h. The title compound 3a was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as an orange-red oil; yield: 0.94 g (94%).

IR (ATR): 3592–3056 (br), 3143 (m), 3106 (m), 3028 (w), 2974 (s), 2930 (m), 2876 (m), 1632 (w), 1573 (w), 1444 (w), 1390 (w), 1371 (w), 1324 (m), 1291 (w), 1141 (s), 1096 (s), 1047 (s), 994 (s), 910 (m), 805 (s), 759 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.20–1.25 (m, 6 H), 3.52–3.74 (m, 4 H), 4.68 (s, 2 H), 5.61 (s, 1 H), 6.24 (s, 1 H); signals due to the OH and NH groups were not visible.

13C NMR (100 MHz, CDCl3): δ = 15.1 (2 C), 56.7, 61.3 (2 C), 96.9, 101.9, 146.9, 148.0.

HRMS (DART): m/z calcd for C7H11N2O2 + [M – EtO]+: 155.08205; found: 155.08212.


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5-Diethoxymethyl-3-(1-hydroxyethyl)-1H-pyrazole (3b)

The unsaturated ketone 2b (1.02 g, 5.09 mmol) was reacted with a 55% aq solution of hydrazine (0.3 g, 5.1 mmol) for 18 h. The title compound 3b was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as an orange-red oil; yield: 1.03 g (94%).

IR (ATR): 3577–3059 (br), 3143 (m), 3102 (m), 2974 (s), 2930 (m), 2882 (m), 1664 (w), 1571 (w), 1479 (w), 1445 (w), 1371 (m), 1322 (m), 1277 (m), 1149 (s), 1088 (s), 1050 (s), 991 (s), 892 (m), 804 (s), 735 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.20–1.25 (m, 6 H), 1.53 (d, J = 6.5 Hz, 3 H), 3.52–3.74 (m, 4 H), 4.97 (q, J = 6.5 Hz, 1 H), 5.60 (s, 1 H), 6.21 (s, 1 H); signals due to the OH and NH groups were not visible.

13C NMR (100 MHz, CDCl3): δ = 15.2 (2 C), 23.2, 61.4 (2 C), 63.4, 96.9, 100.2, 146.8, 152.6.

MS (EI+): m/z (%) = 169.1 (100, M+ – OEt).

HRMS (DART): m/z calcd for C10H19N2O3 + [M + H]+: 215.13856; found: 215.13155.


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5-Diethoxymethyl-3-(1-hydroxy-2-methylpropyl)-1H-pyrazole (3c)

The unsaturated ketone 2c (0.46 g, 2.02 mmol) was reacted with hydrazine (0.12 g, 2.06 mmol) for 16 h. The title compound 7c was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc– MeOH (85:15)] as a yellow to orange solid; yield: 0.39 g (80%). The obtained solid was recrystallized from hexane; mp 58–60 °C.

IR (ATR): 3595–3059 (br), 3141 (m), 3102 (m), 3028 (w), 2972 (s), 2930 (m), 2872 (m), 1707 (w), 1563 (w), 1469 (w), 1445 (w), 1384 (m), 1368 (m), 1323 (m), 1270 (w), 1148 (m), 1117 (s), 1094 (s), 1050 (s), 1010 (s), 910 (m), 805 (m), 736 (m), 702 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 0.90 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.7 Hz, 3 H), 1.23 (t, J = 7.0 Hz, 6 H), 1.97–2.05 (m, 1 H), 3.53–3.68 (m, 4 H), 4.55 (d, J = 6 Hz, 1 H), 5.62 (s, 1 H), 6.18 (s, 1 H); signals due to the OH and NH groups were not visible.

13C NMR (100 MHz, CDCl3): δ = 15.2 (2 C), 17.9, 18.8, 34.4, 61.2, 61.3, 73.0, 96.9, 101.0, 146.8, 150.6.

HRMS (DART): m/z calcd for C12H23N2O3 + [M + H]+: 243.17086; found 243.16509.


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5-Diethoxymethyl-3-(hydroxy)(phenyl)methyl-1H-pyrazole (3d)

The unsaturated ketone 2d (0.523 g, 1.99 mmol) was reacted with a 55% aq solution of hydrazine (0.12 g, 2.06 mmol) for 16 h. The title compound 3d was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as an orange oil; yield: 0.36 g (65%).

IR (ATR): 3592–3048 (br), 3143 (m), 3104 (m), 3063 (m), 3028 (m), 2974 (s), 2932 (m), 2881 (m), 1663 (w), 1603 (w), 1565 (w), 1493 (w), 1479 (w), 1452 (m), 1391 (w), 1371 (w), 1323 (m), 1139 (s), 1096 (s), 1045 (s), 1021 (s), 984 (s), 911 (m), 804 (s), 698 cm–1 (s).

1H NMR (400 MHz, CDCl3): δ = 1.17 (dt, J = 7.0, 1.1 Hz, 6 H), 5.43–3.66 (m, 4 H), 5.48 (s, 1 H), 5.83 (s, 1 H), 6.00 (s, 1 H), 7.22–7.36 (m, 5 H); signals due to the OH and NH groups were not visible.

13C NMR (100 MHz, CDCl3): δ = 15.1 (2 C), 61.3 (2 C), 69.7, 96.6, 101.9, 126.7 (2 C), 127.7, 128.4 (2 C), 142.4, 146.3, 151.6.

MS (EI+): m/z (%) = 231.2 (100, M+ – OEt).

HRMS (DART): m/z calcd for C15H21N2O3 + [M + H]+: 277.15521; found: 277.15892.


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3-Diethoxymethyl-5-(1-hydroxy-1-methylethyl)-1H-pyrazole (3e)

The unsaturated ketone 2e (0.22 g, 1.03 mmol) was reacted with a 55% aq solution of hydrazine (0.062 g, 1.06 mmol) for 18 h. The title compound 3e was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as a yellow semi-solid; yield: 0.21 g (89%).

IR (ATR): 3584–3006 (br), 3137 (m), 3100 (m), 2974 (s), 2930 (m), 2878 (m), 1683 (m), 1457 (m), 1377 (m), 1364 (m), 1327 (m), 1281 (m), 1207 (m), 1153 (s), 1116 (s), 1090 (s), 1050 (s), 995 (s), 961 (s), 909 (m), 845 (m), 807 (m), 770 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.0 Hz, 6 H), 1.54 (s, 6 H), 3.48–3.64 (m, 4 H), 5.54 (s, 1 H), 6.13 (s, 1 H); signals due to the OH and NH groups were not visible.

13C NMR (100 MHz, CDCl3): δ = 15.2 (2 C), 30.8 (2 C), 61.3 (2 C), 69.1, 97.1, 99.5, 147.5, 155.2.

MS (EI+): m/z (%) = 183.2 (45, [M – OEt]+).

HRMS (DART): m/z calcd for C11H21N2O3 + [M + H]+: 229.15521; found: 229.14924.


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2,4,6-Trisubstituted Pyrimidines 4 by Reaction of 2 with Guanidine; General Procedure

A 60% suspension of NaH in mineral oil (0.046 g, 1.15 mmol) was dissolved in EtOH (2.50 mL) and left stirring for 15 min before guanidine hydrochloride (0.105 g, 1.10 mmol) dissolved in EtOH (1.0 mL) was added to the solution. After stirring for 30 min, the unsaturated ketone 2 (1.00 mmol) was added to the solution with some additional EtOH (1.5 mL). The reaction mixture was left stirring overnight at r.t. The solvent was removed on a rotary evaporator and the residue was dissolved in CH2Cl2 (10 mL), and H2O was added (10 mL). The organic layer was separated from the aqueous phase and the aqueous phase was then extracted with CH2Cl2 (3 × 8 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated on a rotary evaporator. The crude product was purified using gradient flash chromatography with a mixture of hexanes, EtOAc, and MeOH to give a 2,4,6-trisubstituted pyrimidine 4 and in two cases also a 6-pyrimidinol 5.


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2-Amino-6-diethoxymethyl-4-hydroxymethylpyrimidine (4a) and 2-Amino-6-diethoxymethyl-5,6-dihydro-4-hydroxymethyl-6-pyrimidinol (5a)

The unsaturated ketone 2a (0.93 g, 4.99 mmol) was reacted with guanidine hydrochloride (0.48 g, 5.02 mmol) for 15 h. The crude product was purified by gradient flash chromatography ([hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] affording pyrimidine 4a as a yellowish solid, which was recrystallized from EtOH; yield: 0.30 g (26%): Further, the pyrimidinol derivative 5a was isolated as a slightly yellow liquid; yield: 0.26 g (21%).


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4a

Mp 120–123 °C.

IR (ATR): 3438 (m), 3304 (m), 3280–2990 (br), 2971 (s), 3929 (m), 2887 (s), 2840 (m), 1641 (s), 1568 (s), 1478 (m), 1456 (m), 1436 (m), 1392 (m), 1375 (m), 1347 (m), 1324 (m), 1308 (m), 1233 (m), 1125 (s), 1102 (s), 1056 (s), 1032 (s), 1006 (m), 981 (m), 952 (m), 905 (m), 848 (m), 836 (m), 809 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.0 Hz, 6 H), 3.41 (br s, 1 H, OH), 3.55–3.71 (m, 4 H), 4.61 (s, 2 H), 5.12 (br s, 2 H, NH2), 5.22 (s, 1 H), 6.83 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.2 (2 C), 62.0 (2 C), 63.5, 100.9, 104.6, 162.5, 167.4, 170.2.

MS (DART): m/z (%) = 228 (100, [M + H]+).

HRMS (DART): m/z calcd for C10H18N3O3 + [M + H]+: 228.13482; found: 228.13457.


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5a (Mixture of Diastereomers)

IR (ATR): 3597–3313 (br), 2974 (s), 3931 (m), 2883 (m), 1482 (w), 1444 (m), 1391 (w), 1368 (w), 1274 (w), 1235 (w), 1158 (s), 1109 (s), 1051 (s), 1006 (s), 970 (s), 945 (s), 908 (m), 848 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.17–1.25 (m, 6 H), 2.15 (d, J = 13.4 Hz, 1 H), 2.37 (d, J = 13.4 Hz, 1 H), 3.44–3.82 (m, 4 H), 3.79 (d, J = 9.3 Hz, 1 H), 4.06 (d, J = 9.3 Hz, 1 H), 4.38 (s, 1 H); signals due to the OH and NH2 groups were not visible.

13C NMR (100 MHz, CDCl3): δ = 15.42, 15.45, 15.48, 42.0, 58.0, 58.4, 64.6, 64.9, 72.1, 103.6, 105.8, 108.3.

MS (DART): m/z (%) = 229 (100, [M + H – H2O]+).

HRMS (DART): m/z calcd for C10H19N3O3 + [M + H – HO]+: 229.14264; found: 229.14367.


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2-Amino-6-diethoxymethyl-4-(1-hydroxyethyl)pyrimidine (4b) and 2-Amino-6-diethoxymethyl-5,6-dihydro-4-(1-hydroxyethyl)-6-pyrimidinol (5b)

The unsaturated ketone 2b (0.60 g, 3.00 mmol) was reacted with guanidine hydrochloride (0.34 g, 3.60 mmol) for 17 h. The crude product was purified by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] affording pyrimidine 4b as a pale yellow solid, which was recrystallized from EtOH; yield: 0.35 g (48%). Further, the pyrimidinol derivative 5b was isolated as as a colorless liquid; yield: 0.23 g (30%).


#

4b

Mp 94–95 °C.

IR (ATR): 3314 (s), 3184 (s), 2975 (s), 3930 (s), 2930 (m), 2840 (m), 1637 (m), 1563 (s), 1469 (m), 1443 (m), 1401 (m), 1384 (m), 1328 (m), 1300 (m), 1218 (w), 1165 (m), 1125 (s), 1056 (s), 1032 (s), 1005 (m), 952 (m), 909 (m), 876 (m), 851 (m), 831 (m), 801 (m), 785 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 6.8 Hz, 6 H), 1.46 (d, J = 6.6 Hz, 3 H), 3.55–3.71 (m, 4 H), 3.96 (br s, 1 H, OH), 4.69 (q, J = 6.6 Hz, 1 H), 5.21 (br s, 2 H, NH2), 5.22 (s, 1 H), 6.84 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.1 (2 C), 23.3, 61.8, 61.9, 68.6, 100.8, 103.7, 162.5, 167.5, 174.1.

MS (DART+): m/z (%) = 242 (100, [M + H]+).

HRMS (DART+): m/z calcd for C11H20N3O3 + [M + H]+: 242.15047; found: 242.15145.


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5b (Mixture of Diastereomers)

IR (ATR): 3595–3335 (br), 2975 (s), 3932 (m), 2883 (m), 1482 (w), 1444 (m), 1390 (m), 1326 (m), 1286 (w), 1157 (s), 1112 (s), 1050 (s), 987 (s), 917 (m), 853 (m), 734 cm–1 (w).

1H NMR (400 MHz, CDCl3): δ = 1.13–1.30 (m, 9 H), 1.61 (s, 1 H, NH/OH), 2.09 and 2.23 (2 d in an approximate ratio of 2:1, J = 13.1 and 13.9 Hz, respectively, 1 H), 2.41 and 2.45 (2 d in an approximate ratio of 2:1, J = 13.1 and 13.9 Hz, respectively, 1 H), 3.42–3.82 (m, 4 H), 4.06 (s, 1 H, NH/OH), 4.11 and 4.36 (2 q in an approximate ratio of 1:2, J = 6.6 and 6.5 Hz, respectively, 1 H), 4.31 (s, 1 H, NH/OH), 4.38 (s, 1 H); signals due to OH or NH2 protons were not detected.

13C NMR (100 MHz, CDCl3): δ = 15.05, 15.09, 15.13, 15.2, 15.3, 17.2, 17.7, 39.6, 40.3, 56.8, 57.2, 58.2, 58.8, 64.3, 64.9, 65.0, 77.9, 79.4, 103.3, 103.6, 103.9, 104.0, 107.6, 108.4.

MS (DART+): m/z (%) = 215 (100, [M + H – OEt]+).

HRMS (DART+): m/z calcd for C9H17N3O3 + [M + H – OEt]+: 215.12699; found: 215.12602.


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2-Amino-6-diethoxymethyl-4-(1-hydroxy-2-methylpropyl)pyrimidine (4c)

The unsaturated ketone 2c (0.24 g, 1.05 mmol) was reacted with guanidine hydrochloride (0.12 g, 1.26 mmol) for 3 h. The title compound 4c was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as a yellow solid after recrystallization from EtOAc; yield: 0.086 g (30%); mp 120–121 °C.

IR (ATR): 3426 (m), 3294 (m), 3270–3000 (br), 2967 (m), 3930 (m), 2881 (s), 1630 (s), 1563 (s), 1470 (m), 1403 (m), 1370 (m), 1317 (s), 1252 (w), 1227 (w), 1125 (s), 1056 (s), 1014 (s), 983 (m), 924 (w), 901 (w), 871 (m), 841 (m), 783 (m), 730 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 0.77 (d, J = 6.8 Hz, 3 H), 1.03 (d, J = 6.9 Hz, 3 H), 1.23 (t, J = 7.0 Hz, 6 H), 1.97–2.05 (m, 1 H), 3.53–3.68 (m, 4 H), 3.90 (br s, 1 H, OH), 4.40 (d, J = 3.6 Hz, 1 H), 5.22 (s, 1 H), 5.34 (br s, 2 H, NH2), 6.79 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.3 (2 C), 15.8, 19.7, 34.5, 62.0 (2 C), 76.6, 101.0, 105.4, 162.2, 167.2, 172.3.

MS (DART+): m/z (%) = 270 (100, [M + H]+).

HRMS (DART+): m/z calcd for C13H24N3O3 + [M + H]+: 270.18177; found: 270.18313.


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2-Amino-6-diethoxymethyl-4-(1-hydroxyisopropyl)pyrimidine (4e)

The unsaturated ketone 2e (0.22 g, 1.03 mmol) was reacted with guanidine hydrochloride (0.16 g, 1.67 mmol) for 15 h. The title compound 4e was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as a yellow solid, which was recrystallized from EtOH; yield: 0.064 g (24%), mp 80–83 °C.

IR (ATR): 3362 (m), 3311 (m), 3184 (m), 2976 (m), 3927 (m), 2878 (m), 1638 (m), 1567 (s), 1455 (m), 1444 (m), 1381 (m), 1357 (m), 1330 (m), 1313 (m), 1177 (s), 1023(s), 1054 (s), 1025 (s), 982 (m), 967 (m), 944 (m), 900 (w), 852 (m), 821 (m), 804 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.0 Hz, 6 H), 1.46 (s, 6 H), 3.55–3.70 (m, 4 H), 4.56 (br s, 1 H, OH), 5.21 (s, 1 H), 5.33 (br s, 2 H, NH2), 6.89 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.3 (2 C), 30.0 (2 C), 62.3 (2 C), 71.6, 101.3, 103.0, 162.0, 168.0, 176.8.

MS (EI+): m/z (%) = 211.2 (45, [M + H – OEt]+).

HRMS (DART+): m/z calcd for C12H22N3O3 + [M + H]+: 256.18177; found: 256.18313.


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4,5-Dihydroisoxazoles 6 by Reaction of 2 with Hydroxylamine; General Procedure

The unsaturated ketone 2 (1.00 mmol) was dissolved in EtOH (5.0 mL) and a 50 wt% aq solution of hydroxylamine (0.07 g, 1.06 mmol) was slowly added to the solution. The reaction mixture was stirred at r.t. for 1.5 h. The EtOH was removed on a rotary evaporator and the crude product was purified using gradient flash chromatography with a mixture of hexanes, EtOH, and MeOH to give the 3,5-disubstituted 4,5-dihydroisoxazoles 6.


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5-Diethoxymethyl-5-hydroxy-3-hydroxymethyl-4,5-dihydro­isoxazole (6a)

The unsaturated ketone 2a (0.93 g, 4.94 mmol) was reacted with a 50 wt% aq solution of hydroxylamine (0.34 g, 5.15 mmol). The title compound was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as an orange liquid; yield: 0.92 g (85%).

IR (ATR): 3629–3020 (br), 2977 (m), 3932 (m), 2881 (m), 1628 (w), 1446 (m), 1410 (m), 1372 (m), 1334 (m), 1198 (m), 1164 (m), 1056 (s), 998 (s), 896 (s), 862 (s), 820 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.21–1.28 (m, 6 H), 2.96 (d, J = 18.2 Hz, 1 H), 3.23 (d, J = 18.2 Hz, 1 H), 3.59–3.85 (m, 4 H), 4.40 (d, J = 14.4 Hz, 1 H), 4.43 (d, J = 14.4 Hz, 1 H), 4.58 (s, 1 H); signals due to the OH groups were missing.

13C NMR (100 MHz, CDCl3): δ = 15.3 (2 C), 42.0, 57.8, 64.7, 64.8, 102.0, 107.7, 160.1.

HRMS (DART+): m/z calcd for C9H18NO5 + [M + H]+: 219.11850; found: 220.11842.


#

5-Diethoxymethyl-5-hydroxy-3-(1-hydroxyethyl)-4,5-dihydro­isoxazole (6b)

The unsaturated ketone 2b (1.05 g, 5.24 mmol) was reacted with a 50 wt% aq solution of hydroxylamine (0.34 g, 5.15 mmol) and 6b was isolated as an inseparable mixture of diastereomers by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15) as a yellow liquid; yield: 1.06 g (88%).

IR (ATR): 3620–3067 (br), 2976 (m), 3930 (m), 2884 (m), 1622 (w), 1446 (m), 1398 (m), 1371 (m), 1323 (m), 1202 (m), 1165 (m), 1059 (s), 984 (s), 895 (s), 854 (s), 815 cm–1 (m).

1H NMR (400 MHz, CDCl3): δ = 1.06–1.14 (m, 6 H), 1.25 and 1.30 (2 d in an approximate 3:2 ratio, J = 6.6 Hz, 3 H), 2.79 and 2.82 (2 d in an approximate 2:3 ratio, J = 18.0 Hz, 1 H), 3.15 (d, J = 18.0 Hz, 1 H), 3.40 and 4.30 (2 br s, 1 H, OH), 3.50–3.70 (m, 4 H), 4.42 and 4.44 (2 s, 1 H), 4.50 and 4.59 (2 q in an approximate 2:3 ratio, J = 6.4 Hz, 1 H), 5.25 and 5.51 (2 br s, 1 H, OH).

13C NMR (100 MHz, CDCl3): δ = 15.0, 15.1, 20.4, 20.5, 19.5, 40.9, 63.1, 63.6, 64.3, 64.4, 64.5, 64.7, 101.8, 107.4, 107.5, 162.9, 163.0.

MS (DART+): m/z (%) = 234 (100, [M + H]+).

HRMS (DART+): m/z [M + H]+ calcd for C10H20NO5 +: 234.13415; found 234.13423.


#

5-Diethoxymethyl-5-hydroxy-3-(1-hydroxy-2-methylpropyl)-4,5-dihydroisoxazole (6c)

The unsaturated ketone 2c (0.23 g, 1.01 mmol) was reacted with a 50 wt% aq solution of hydroxylamine (0.07 g, 1.06 mmol). The title compound was isolated as an inseparable mixture of diastereomers by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc (85:15)] as a white solid, which was recrystallized from EtOAc; yield: 0.22 g (82%); mp 88–90 °C.

IR (ATR): 3511–3210 (br), 2976 (m), 2959 (m), 3933 (m), 2875 (m), 1622 (w), 1472 (m), 1447 (w), 1409 (m), 1370 (w), 1338 (m), 1241 (w), 1217 (m), 1164 (m), 1106 (m), 1069 (s), 1049 (s), 1028 (s), 1005 (s), 923 (w), 873 (s), 830 cm–1 (s).

1H NMR (400 MHz, CDCl3): δ = 0.84, 0.95, 0.99, and 1.03 (4 d in an approximate 2:1:1:2 ratio, J = 6.8 Hz, 6 H), 1.17–1.27 (m, 6 H), 1.76–1.91 (m, 1 H), 2.83, 2.98, 3.17, and 3.21 (4 d in an approximate 1:2:2:1 ratio, J = 18.4, 18.0, 18.0, and 18.4 Hz, 2 H), 3.51 (br s, 1 H, OH), 3.55–3.82 (m, 4 H), 4.22 (d, J = 6.8 Hz, 1 H), 4.53 and 4.57 (2 s in an approximate ratio of 2:1, 1 H), 4.23 and 4.86 (2 br s, 1 H, OH).

13C NMR (100 MHz, CDCl3): δ = 15.31, 15.35, 17.5, 18.4, 18.6, 32.1, 32.4, 40.2, 41.5, 64.4, 64.7, 64.9, 65.0, 73.0, 73.2, 102.1, 107.3, 107.7, 161.8, 162.1.

HRMS (DART+): m/z calcd for C12H24NO5 + [M + H]+: 234.13415; found: 234.13423.


#

5-Diethoxymethyl-5-hydroxy-3-(1-hydroxyisopropyl)-4,5-dihydroisoxazole (6e)

The unsaturated ketone 2e (0.22 g, 1.03 mmol) was reacted with a 50 wt% aq solution of hydroxylamine (0.07 g, 1.06 mmol). The title compound was isolated by gradient flash chromatography [hexanes–EtOAc (70:30), EtOAc–MeOH (85:15)] as a yellow solid, which was recrystallized from EtOAc; yield: 0.22 g (87%); mp 60–62 °C.

IR (ATR): 3553–3198 (br), 2976 (m), 2932 (m), 3933 (m), 2902 (w), 2886 (m), 1617 (w), 1456 (m), 1372 (m), 1330 (m), 1254 (m), 1223 (m), 1176 (m), 1063 (s), 1008 (s), 995 (m), 962 (m), 923 (m), 876 (s), 831 cm–1 (s).

1H NMR (400 MHz, CDCl3): δ = 1.16–1.23 (m, 6 H), 1.40 (s, 3 H), 1.46 (s, 3 H), 2.95 (2 d, J = 18.2 Hz, 1 H), 3.23 (2 d, J = 18.2 Hz, 1 H), 3.57–3.79 (m, 4 H), 4.52 (s, 1 H); signals due to the OH groups were missing.

13C NMR (100 MHz, CDCl3): δ = 15.3 (2 C), 27.9, 28.0, 41.0, 64.4, 64.8, 69.4, 102.0, 107.9, 165.3.

HRMS (DART+): m/z calcd for C11H22NO5 + [M + H]+: 248.14980; found: 248. 14965.


#
#

Acknowledgment

Financial support from the Munin Foundation is acknowledged with considerable appreciation. Thanks are also due to Dr. Bjarte Holmelid for skilful recording of the mass spectra.

Supporting Information

  • References

    • 1a Bergmann ED, Ginsburg D, Pappo R. Org. React. 1959; 10: 179
    • 1b Perlmutter P. Conjugate Addition Reactions in Organic Synthesis. Pergamon; Oxford: 1992
    • 1c Rossiter BE, Swingle NM. Chem. Rev. 1992; 92: 771
    • 2a Bol’shedvorskaya RL, Vereshchagin LI. Russ. Chem. Rev. 1973; 42: 225
    • 2b Posner GH. Org. React. 1972; 19: 1
    • 2c Tomioka K. Synthesis 1990; 541
    • 2d Gaunt MJ, Snedon HF, Hewitt PR, Orsins P, Hook DF, Ley SV. Org. Biomol. Chem. 2003; 1: 15
    • 2e Valdersnes S, Apeland I, Flemmen G, Sydnes LK. Helv. Chim. Acta 2012; 95: 2099
    • 3a Kvernenes OH, Sydnes LK. Org. Synth. 2005; 83: 184
    • 3b Kvernenes OH, Sydnes LK, Holmelid B, Kvernenes OH, Sandberg M, Hodne M, Bakstad E. Tetrahedron 2007; 63: 4144
    • 4a Sydnes LK, Holmelid B, Valdersnes S, Sengee M, Boman K. Jordanian J. Chem. 2007; 2: 105 ; Chem. Abstr. 2009, 152, 37057
    • 4b Sydnes LK, Valdersnes S. Pure Appl. Chem. 2007; 79: 2137
  • 6 Fustero S, Sánchez-Roselló M, Barrio P, Simón-Fuentes A. Chem. Rev. 2011; 111: 6984
  • 7 Sydnes LK, Holmelid B, Sengee M, Hanstein M. J. Org. Chem. 2009; 74: 3430
  • 8 Erdenebileg U, Høstmark I, Polden K, Sydnes LK. J. Org. Chem. 2014; 79: 1213
  • 9 Although two tautomeric forms are possible for pyrazoles 3, only one has been shown.
  • 10 Grotjahn DB, Van S, Combs D, Lev DA, Schneider C, Rideout M, Meyer C, Hernandez G, Mejardo L. J. Org. Chem. 2002; 67: 9200
  • 11 Chapman AV, Cook MJ, Katritzky AR, Abraham MH, Danil de Namor AF, Dumont L, Reisse J. Tetrahedron 1978; 34: 1571
  • 12 Reimlinger H, Vandewalle JJ. M. Justus Liebigs Ann. Chem. 1969; 720: 117

  • References

    • 1a Bergmann ED, Ginsburg D, Pappo R. Org. React. 1959; 10: 179
    • 1b Perlmutter P. Conjugate Addition Reactions in Organic Synthesis. Pergamon; Oxford: 1992
    • 1c Rossiter BE, Swingle NM. Chem. Rev. 1992; 92: 771
    • 2a Bol’shedvorskaya RL, Vereshchagin LI. Russ. Chem. Rev. 1973; 42: 225
    • 2b Posner GH. Org. React. 1972; 19: 1
    • 2c Tomioka K. Synthesis 1990; 541
    • 2d Gaunt MJ, Snedon HF, Hewitt PR, Orsins P, Hook DF, Ley SV. Org. Biomol. Chem. 2003; 1: 15
    • 2e Valdersnes S, Apeland I, Flemmen G, Sydnes LK. Helv. Chim. Acta 2012; 95: 2099
    • 3a Kvernenes OH, Sydnes LK. Org. Synth. 2005; 83: 184
    • 3b Kvernenes OH, Sydnes LK, Holmelid B, Kvernenes OH, Sandberg M, Hodne M, Bakstad E. Tetrahedron 2007; 63: 4144
    • 4a Sydnes LK, Holmelid B, Valdersnes S, Sengee M, Boman K. Jordanian J. Chem. 2007; 2: 105 ; Chem. Abstr. 2009, 152, 37057
    • 4b Sydnes LK, Valdersnes S. Pure Appl. Chem. 2007; 79: 2137
  • 6 Fustero S, Sánchez-Roselló M, Barrio P, Simón-Fuentes A. Chem. Rev. 2011; 111: 6984
  • 7 Sydnes LK, Holmelid B, Sengee M, Hanstein M. J. Org. Chem. 2009; 74: 3430
  • 8 Erdenebileg U, Høstmark I, Polden K, Sydnes LK. J. Org. Chem. 2014; 79: 1213
  • 9 Although two tautomeric forms are possible for pyrazoles 3, only one has been shown.
  • 10 Grotjahn DB, Van S, Combs D, Lev DA, Schneider C, Rideout M, Meyer C, Hernandez G, Mejardo L. J. Org. Chem. 2002; 67: 9200
  • 11 Chapman AV, Cook MJ, Katritzky AR, Abraham MH, Danil de Namor AF, Dumont L, Reisse J. Tetrahedron 1978; 34: 1571
  • 12 Reimlinger H, Vandewalle JJ. M. Justus Liebigs Ann. Chem. 1969; 720: 117

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Scheme 1
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Scheme 2
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Scheme 3
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Scheme 4