Regioselective Synthesis of 7,8-Dihydropyrrolo[1,2-a]pyrimidin-4(6H)-ones and 7,8-Dihydropyrrolo[1,2-a]pyrimidin-2(6H)-ones

Abstract

Annulated analogues of 5,6-dihydroxypyrimidine-4-carboxylate ester and 5,6-dihydroxypyrimidine-4-carboxylamide were synthesized. The intermediary homoallylic amines were subjected to a ring-closure reaction under different reaction conditions. A notable pH-dependency of the ring closure leading to regioisomeric tetrahydropyrrolo[1,2-a]pyrimidines was observed. Treatment with dimethyldioxirane and base led to 3-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidines while m-chloroperbenzoic acid or NBS afforded 3-hydroxy-2-oxo-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidines.

antiviral agents - bicyclic compounds - heterocycles - ­regioselectivity - ring closure

References and Notes

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12

Preliminary assignment of compounds 19 as the N3-alkylated products was based on the chemical shift of carbon signals of the pyrimidine core, not being consistent with data previously obtained from a variety of N1-alkylated pyrimidones (Pesci, S.; unpublished results); diagnostic ^¹³C NMR data of the major isomer 19b are reported in ref. 13 (refer to Figure  [³] for the numbering of the pyrimidine moiety).

13

trans -Methyl 3-(Benzoyloxy)-8-[( tert -butoxycarbonyl)-amino]-6-(hydroxymethyl)-2-oxo-2,6,7,8-tetrahydro-pyrrolo[1,2- a ]pyrimidine-4-carboxylate (19b) To a solution of methyl 5-(benzoyloxy)-2-({1-[(tert-butoxycarbonyl)amino]but-3-en-1-yl})-6-hydroxypyrimi-dine-4-carboxylate (17, 140 mg, 0.32 mmol) in CH₂Cl₂ (0.1 M), MCPBA (70%, 70 mg, 0.32 mmol) was added, and the suspension was stirred at r.t. After 1 h another equiv of MCPBA (70%, 70 mg, 0.32 mmol) was added, and the reaction mixture was stirred at r.t. for 36 h. Sodium thiosulfate was added, and the organic phase was separated and washed with aq NH₄HCO₃ (sat., 4×). The organic layer was dried over Na₂SO₄ and concentrated to dryness under reduced pressure. The product was purified by preparative RP-HPLC, and the two diastereomers were separated, using H₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The main diastereomer was obtained after lyophilization of the pooled product fractions (46%).
^¹H NMR (400 MHz, 300 K, CD₃CN): δ = 8.12 (d, J = 7.4 Hz, 2 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.4 Hz, 2 H), 5.76 (d, J = 6.7 Hz, 1 H), 5.05 (m, 1 H), 4.96 (m, 1 H), 3.79 (s, 3 H), 3.72 (dd, J = 12.2, 3.4 Hz, 1 H), 3.63 (m, 1 H), 2.50-2.36 (m, 2 H), 1.43 (s, 9 H). ^¹³C NMR (100 MHz, 300 K, CD₃CN): δ = 166.4 (C-6), 165.6 (C-2), 164.4, 161.2, 156.4, 135.9 (C-5), 135.3, 134.3 (C-4), 131.0, 129.9, 129.3, 80.5, 64.4, 62.6, 54.4, 53.6, 31.7, 28.5. MS: m/z = 537 [M + H]⁺.

14

trans - tert -Butyl-(5-hydroxyl)-4,6-dioxo-1,2,4,6,8,8a-hexahydro-7-oxa-3,8b-diazaacenaphthylen-2-yl) Carbamate (20) A solution of compound 19b (40 mg, 0.09 mmol) in MeOH (0.02 M) was stirred at 80 ˚C for 36 h. The solvent was evaporated under reduced pressure, and the product was purified by preparative RP-HPLC using H₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). ^¹H-^¹³C HMBC experiment performed on 20 showed the key heteronuclear correlations between OCH₂CH and C-2, C-4 of the pyrimidine core, while no correlation to C-6 was detected (see Figure  [³] for the numbering of the pyrimidine moiety), allowing the regiochemistry of the previous alkylation step to be assigned at N3. ^¹H NMR (500 MHz, 300 K, DMSO-d ₆): δ = 10.40 (br s, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 4.73 (m, 1 H), 4.70 (m, 1 H), 4.66 (m, 1 H), 4.42 (t, J = 10.9 Hz, 1 H), 2.27 (m, 1 H), 2.07 (m, 1 H), 1.39 (s, 9 H). ^¹³C NMR (100 MHz, 300 K, DMSO-d ₆): δ = 167.6 (C-6), 156.9, 155.9 (C-2), 154.8, 146.3 (C-5), 111.4 (C-4), 78.8, 70.0, 55.5, 53.3, 30.6, 28.1. MS: m/z = 324 [M + H]⁺.

15a Dalton DR. Jones DG. Tetrahedron Lett.  1967,  2875 

15b Dalton DR. Dutta VP. Jones DG. J. Am. Chem. Soc.  1968,  90:  5498 

16

cis - and trans -Methyl 3-(Benzoyloxy)-6-(bromomethyl)-8-[( tert -butoxycarbonyl)(methyl)amino] 2-Oxo-2,6,7,8-tetrahydropyrrolo[1,2- a ]pyrimidine-4-carboxylate (22) To a solution of methyl 5-(benzoyloxy)-2-({1-[(tert-butoxy-carbonyl)(methyl)amino]but-3-en-1-yl})-6-hydroxypyrimi-dine-4-carboxylate (18, 650 mg, 1.42 mmol) in DMSO (0.142 M), H₂O (2.84 mmol), and NBS (364 mg, 2.84 mmol) were added, and the solution was stirred at r.t. After 10 min H₂O was added, the aqueous phase was extracted with EtOAc, and the combined organic layers were dried over Na₂SO₄ and concentrated to dryness under reduced pressure. The product was purified by preparative RP-HPLC, and the two diastereomers were separated, using H₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The products were obtained after lyophilization of the pooled product fractions (60%; relative stereochemistry: undetermined). ^¹H-^¹³C HMBC experiments performed on both fractions showed the key heteronuclear correlations between BrCH₂CH and C-2, C-4 of the pyrimidine core (see Figure  [³] for the numbering of the pyrimidine moiety), while no correlation to C-6 was detected, allowing the regiochemi-stry of the alkylation to be assigned at N3. Both samples displayed two sets of broad proton signals at T = 300 K; exchange between the two rotamers was assessed by VT-^¹H NMR.
First fraction (mixture of two rotamers, ‘ra’ and ‘rb’; corresponding relative ratio 3:7): ^¹H NMR (600 MHz, 294 K, DMSO-d ₆): δ = 8.10-8.06 (m, 2 H), 7.78 (t, J = 7.3 Hz, 1 H), 7.62 (t, J = 7.3 Hz, 2 H), 5.63 (m, 0.3 H, ra), 5.31 (m, 0.7 H, rb), 5.26 (m, 0.3 H, ra), 5.13 (br s, 0.7 H, rb), 3.95-3.87 (m, 1 H), 3.84-3.73 (m, 1 H), 3.82 (s, 2.1 H, rb), 3.81 (s, 0.9 H, ra), 2.95 (s, 2.1 H, rb), 2.79 (s, 0.9 H, ra), 2.68-2.60 (m, 1 H), 2.56 (dd, J = 12.6, 9.4 Hz, 0.7 H, rb), 2.43 (dd, J = 12.7, 9.1 Hz, 0.3 H, ra), 1.42 (s, 2.7 H, rb), 1.26 (s, 6.3 H, ra). ^¹³C NMR (100 MHz, 294 K, DMSO-d ₆): δ = 164.3 (ra and rb, C-6), 164.2 (rb, C-2), 163.2 (ra, C-2), 162.8 (rb), 162.7 (ra), 159.6, 154.8 (ra), 153.6 (rb), 135.1 (ra, C-5), 134.9 (rb, C-5), 134.5, 131.5 (ra, C-4), 131.4 (rb, C-4), 129.9, 129.2, 127.7 (ra), 127.6 (rb), 79.8, 60.5 (ra), 60.2 (rb), 59.8 (rb), 57.8 (ra), 54.3 (ra), 54.1 (rb), 36.2 (rb), 35.8, 32.3 (ra), 30.9 (rb), 29.0 (ra), 27.9 (ra), 27.6 (rb). MS: m/z = 537 [M + H]⁺.
Second fraction: ^¹H NMR (500 MHz, 325 K, DMSO-d ₆):
δ = 8.07 (m, 2 H), 7.77 (t, J = 7.3 Hz, 1 H), 7.62 (t, J = 7.3 Hz, 2 H), 5.53 (t, J = 9.7 Hz, 1 H), 5.03 (m, 1 H), 3.88 (s, 3 H), 3.82 (dd, J = 11.7, 1.8 Hz, 1 H), 3.68 (m, 1 H), 2.84 (s, 3 H), 2.83 (m, 1 H), 2.10 (m, 1 H), 1.43 (s, 9 H). ^¹³C NMR (100 MHz, 325 K, DMSO-d ₆): δ = 163.5 (C-6), 162.7 (C-2), 162.5, 159.2, 154.6, 134.3 (C-5), 134.1, 131.3 (C-4), 129.6, 128.8, 127.5, 79.7, 59.4, 57.1, 53.9, 35.4, 31.4, 28.5, 27.7. MS: m/z = 537 [M + H]⁺.

17

cis - and trans - tert -Butyl-(5-hydroxy)-4,6-dioxo-2,4,6,7,8,8a-hexahydro-1 H -3,7,8b-triazaacenaphthylen-2-yl) methyl carbamate (24) To a solution of compound 22 (mixture of diastereomers, crude material; 761 mg, 1.42 mmol) in DMF (0.5 M) NaN₃ (185 mg, 2.84 mmol) was added, and the solution was stirred at r.t. After 48 h the solution was concentrated to dryness under reduced pressure. To the residue in MeOH (0.142 M) was added Pd/C (10%, 80 mg), and the reaction mixture was stirred at r.t. After 16 h the suspension was filtered over Celite, and the filtrate was concentrated to dryness under reduced pressure. The product was purified by preparative RP-HPLC, using a gradient of H₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The product was obtained after lyophilization of the pooled product fractions (46% over three steps). Four sets of NMR signals were detectable, corresponding to the two (1:1) diastereomers ‘cis’/‘trans’ (each one as a mixture of rotamers, indicated as ‘ra,rb’ for the ‘cis’-isomer, ‘rc,rd’ for the ‘trans’-isomer). Determination of the relative stereochemistry (‘cis’, ‘trans’) and assessment of the exchange between the two sets of signals from each stereoisomer were performed combining results from ^¹H-^¹H NOESY and ROESY experiments at different temperatures.
‘trans’-Isomer ^¹H NMR (500 MHz, 300 K, DMSO-d ₆): δ = 10.22 (br s, 1 H), 8.75 (br s, 1 H), 5.58 (br t, J = 9.2 Hz, 0.25 H, ra), 5.15 (br s, 0.25 H, rb), 5.09 (br s, 0.25 H, rc), 5.00 (br s, 0.25 H, rd), 4.62 (br s, 0.50 H, rc,rd), 4.28 (br s, 0.50 H, ra,rb), 3.70-3.56 (m, 1 H), 3.49 (t, J = 12.2 Hz, 0.25 H, ra), 3.39 (t, J = 11.9 Hz, 0.75 H, rb,rc,rd), 2.82 (s, 0.75 H), 2.80 (s, 1.5 H), 2.70 (s, 1.5 H), 2.70 (s, 0.75 H), 2.66 (m, 0.25 H, rb), 2.54 (m, 0.25 H, ra), 2.40-2.30 (m, 0.5 H, rc,rd), 2.24-2.14 (m, 0.5 H, rc,rd), 2.02 (m, 0.25 H, rb), 1.98 (m, 0.25 H, ra), 1.44 (s, 2.25 H), 1.39 (s, 2.25 H), 1.31-1.28 (br, s, 4.5 H). ^¹³C NMR (100 MHz, 300 K, DMSO-d ₆): δ = 166.6, 161.6, 161.4, 156.0, 155.8, 155.3, 154.9, 154.0, 143.7, 143.6, 115.5, 115.3, 115.1, 79.8, 79.6, 60.1 (rb), 59.9 (rd), 59.7 (rc), 58.1 (ra), 56.7 (rc,rd), 52.8 (ra,rb), 44.1, 43.9, 43.8 (ra), 33.3, 30.7, 30.0 (rb), 29.4 (rc,rd), 28.8 (ra), 27.9. MS: m/z = 337 [M + H]⁺.

18 Adam W. Hadjiarapoglu L. Smerz A. Chem. Ber.  1991,  124:  227 

19

cis - and trans -Methyl 3-(Benzoyloxy)-8-[( tert -butoxy-carbonyl)(methyl)amino]-6-(hydroxymethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a ]pyrimidine-2-carboxy-late (27a and 27b) To a solution of methyl 5-(benzoyloxy)-2-({1-[(tert-butoxy-carbonyl)(methyl)amino]but-3-en-1-yl})-6-hydroxypyrimi-dine-4-carboxylate (18, 0.44 mmol) was added dimethyldi-oxirane (freshly prepared, solution in acetone, 6 mL), and the solution was stirred at r.t. in the dark. After 4 h Cs₂CO₃ (1.29 mmol) was added, and the reaction mixture was stirred at r.t. for 2 h. Then the solvent was evaporated, EtOAc was added, and the organic layer was washed with H₂O, dried over Na₂SO₄, and concentrated to dryness under reduced pressure. The product was purified by preparative RP-HPLC, and the two diastereomers were separated using H₂O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The products were obtained after lyophilization of the pooled product fractions (50%). ^¹H-^¹³C HMBC experiments performed on 27 showed on both diastereomers the key heteronuclear correlations between HOCH₂CH and C-2, C-6 of the pyrimidine core (see Figure  [³] for the numbering of the pyrimidine moiety), while no correlation to C-4 was detected, allowing the regiochemistry of the alkylation to be assigned at N1. Determination of the relative stereochemistry (‘cis’, ‘trans’) and assessment of the exchange between the two sets of signals observed for each stereoisomer were performed combining results from ^¹H-^¹H NOESY and ROESY experiments at different temperatures.
‘trans’-Isomer (mixture of two rotamers ra,rb; corresponding relative ratio = 7:3): ^¹H NMR (600 MHz, 294 K, DMSO-d ₆): δ = 8.80 (d, J = 7.3 Hz, 2 H), 7.79 (t, J = 7.3 Hz, 1 H), 7.63 (t, J = 7.3 Hz, 2 H), 5.72 (t, J = 8.9 Hz, 0.3 H), 5.09 (br s, 0.7 H), 4.71 (d, J = 9.5 Hz, 0.7 H), 4.68 (d, J = 9.5 Hz, 0.3 H), 3.91-3.85 (m, 1 H), 3.75 (s, 2.1 H), 3.74 (s, 0.9 H), 3.61 (d, J = 11.4 Hz, 0.3 H), 3.58 (d, J = 11.4 Hz, 0.7 H), 2.95 (s, 2.1 H), 2.76 (s, 0.9 H), 2.60-2.44 (m, 1.4 H), 2.51-2.34 (m, 0.6 H), 1.44 (s, 0.9 H), 1.24 (s, 2.1 H). ^¹³C NMR (100 MHz, 294 K, DMSO-d ₆): δ = 163.2, 162.9, 161.7 (ra, C-2), 160.5 (rb, C-2), 155.8 (ra and rb, C-6), 154.9 (rb), 153.7 (ra), 143.4 (ra, C-4), 142.9 (rb, C-4), 136.6 (rb, C-5), 136.1 (ra, C-5), 134.6, 129.9, 129.2, 127.7, 79.8 (rb), 79.7 (ra), 61.4 (ra), 60.2, 59.4, 59.1 (rb), 52.9, 35.5 (ra), 31.5 (rb), 29.7 (ra), 28.0(rb), 27.6 (ra,rb). MS: m/z = 474 [M + H]⁺.
‘cis’-Isomer (mixture of two rotamers ra,rb; corresponding relative ratio = 1:1): ^¹H NMR (600 MHz, 294 K, DMSO-d ₆): δ = 8.08 (d, J = 7.3 Hz, 2 H), 7.78 (t, J = 7.3 Hz, 1 H), 7.63 (t, J = 7.3 Hz, 2 H), 5.63 (t, J = 8.8 Hz, 0.5 H, ra), 5.27 (s, br, 0.5 H, rb), 4.52 (s, br, 0.5 H, ra) 4.47 (s, br, 0.5 H, rb), 4.23 (d, J = 10.1 Hz, 0.5 H, ra), 4.12 (m, 0.5 H, rb), 3.76 (m, 0.5 H, rb), 3.74 (s, 3 H), 3.59 (d, J = 10.1 Hz, 0.5 H, ra), 2.80 (s, 1.5 H, rb), 2.76 (s, 1.5 H, ra), 2.61 (m, 0.5 H, rb), 2.55 (m, 0.5 H, ra), 2.22 (m, 0.5 H, rb), 2.18 (m, 0.5 H, ra), 1.45 (s, 4.5 H, ra,rb), 1.34 (s, 4.5 H, rb,ra). ^¹³C NMR (100 MHz, 294 K, DMSO-d ₆): δ = 163.1, 163.0, 160.8 (rb, C-2), 160.4 (ra, C-2), 156.8 (ra), 156.6 (rb), 155.0 (ra, C-6), 154.2 (rb, C-6), 142.6 (ra and rb, C-4), 136.7 (ra, C-5), 136.4 (rb, C-5), 134.6, 129.9, 129.2, 127.7, 79.8, 60.4 (rb), 60.2 (ra), 58.9 (rb), 58.7 (rb), 58.5 (ra), 57.0(ra), 52.9, 31.6 (rb), 30.7 (ra), 28.0, 27.0(rb), 25.4 (ra). MS: m/z = 474 [M + H]⁺ _.