Efficient Synthesis of 2-Ureaguanines via the in situ Reactions of 2-Isocyanatopurines with Amines

Abstract

The synthesis of 2-ureaguanines is reported. The preparation involves a suitably protected intermediate, formation of a 2-isocyanatopurine and in situ trapping with a diverse range of amines followed by double deprotection. This is the first application of 2-isocyanatopurines for the synthesis of 2-ureaguanines.

Purines, and especially guanine derivatives, are of particular importance in the field of heterocyclic chemistry.[1] As constituents of oligonucleotides, purines have been widely studied in medicinal chemistry[2] and in supramolecular chemistry,[3] owing to their ability to form Watson–Crick[4] and Hoogsteen[5] base pairs. Although the synthesis of guanines modified at positions 2 and 6 has been studied extensively,[1] there are only a few examples of the preparation of 2-ureaguanines[6] and 2-ureapurines.[7] [8] Isocyanates such as phenyl isocyanate[7] and n-butyl isocyanate[8] have been used, but the reaction appeared to be very dependent on the isocyanate, and sometimes forcing conditions were required. The use of phenyl chloroformate has also been described to introduce cyclohexylamine derivatives[9] or ammonia.[10] To the best of our knowledge, however, there is no general method for the preparation of this class of compounds.

In the course of our research to access 2-ureaguanines and related compounds, we investigated several methods to functionalize the 2-amino group of purines. Although the reaction with isocyanates and related compounds emerged as the most straightforward toward this end, the low reactivity of the amino group of 2-aminopurines imposed the use of stronger electrophiles.[3] This lack of reactivity was confirmed in the reactions of guanine (1) or 2-amino-6-chloropurine (2) with several electrophiles under a variety of conditions (Scheme [1]).[11] This is not surprising since the 2-amino group donates its electron density to the purine system. Additionally, the imidazole nitrogen can also react under these conditions. In order to achieve insertion of diverse ureas at position 2 of purines, we turned our attention toward a more efficient method to generate 2-isocyanatopurines, which were expected to be more reactive and selective. Such compounds have already been used as intermediates for the insertion of carbamates at position 2,[12] and their preparation involved the use of triphosgene as the reagent, but they have not been used with amines. This appeared as a promising alternative to generate ureas from a diverse range of amines.

Initial results indicated that the imidazole moiety interfered with electrophiles such as triphosgene, thus this moiety was protected with a 2-tetrahydropyran (THP) group.[13] Although this group is not often used for purine protection, it can be easily cleaved under mild acidic conditions and suited our needs perfectly. It was inserted using standard Vorbrüggen conditions by employing 2-acetoxytetrahydropyran (3) as an electrophile (Scheme [2]). This method gave superior results in terms of purity compared to the direct reaction of 1 or 2 with 2,3-dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid (PTSA). The silylation of 1 with N,O-bis(trimethylsilyl)acetamide (BSA) in refluxing acetonitrile, followed by addition of 3 and trimethylsilyl trifluoromethanesulfonate (TMSOTf) allowed the isolation of a 1.7:1 mixture of N ⁹ (4) and N ⁷ (5) protected guanines, respectively, in a moderate 58% combined yield. Under the same conditions, protection of 2 occurred in 73% yield and regioisomer 6 was recovered as the major compound, the N ⁷ regioisomer 7 being only observed as traces (Scheme [2]).[14] The mixture of isomers 4 and 5 was then reacted with triphosgene in the presence of N,N-diisopropylethylamine (DIPEA) in tetrahydrofuran for one hour, followed by the addition of a methanolic solution of ammonia. After 16 hours at room temperature, only starting materials were recovered (Scheme [3]). The same was observed with aqueous methylamine.

In contrast, when compound 6 was reacted with triphosgene and N,N-diisopropylethylamine, followed by quenching with methanolic ammonia, urea 9 was isolated in 61% yield (Scheme [4]), however, when the intermediate isocyanate 8 was quenched with ethanolic methylamine, compound 10 was not observed. Instead, urea 11 was isolated in a good yield (70%), but only after reaction for five minutes at 0 °C. The same reaction performed with one equivalent of morpholine delivered only the double addition product after five minutes of reaction at 0 °C, as was observed by LC–MS.

Accordingly, protection of position 6 appeared to be necessary. As 6-O-alkyl groups can be cleaved under the same conditions as the tetrahydropyran moiety, the ethoxy (12) and benzyloxy (13) groups were selected (Scheme [5]). Compounds 12 and 13 were obtained in 81% and 93% yields, respectively, by reacting purine 6 with the corresponding alkoxide for four hours at room temperature. It is noteworthy that this reaction on an N⁹-protected 2-amino-6-chloropurine proceeded under mild conditions, whereas the 6-chloro substitution of unprotected 2-amino-6-chloropurine usually requires forcing conditions.[15]

With 6,9-diprotected guanines 12 and 13 in hand, the previous procedure was repeated with a wide range of amines (Table [1]). The use of ammonia, and primary and secondary amines gave moderate to good yields (53–81%) of products 14a–k. Piperidine gave a very satisfactory 81% yield of isolated 14k. Complete chemoselectivity was observed when 2-aminoethanol was used, to yield 53% of product 14i. In this case, no trace of the corresponding carbamate was evident by LC–MS. The use of tyramine led to urea 14l in 40% yield; whilst the use of hydrazine gave a complex mixture, and compound 14m was not observed by LC–MS.

Table 1 Formation of Ureas 14 ^a

Product	R1	R2R3NH	Yieldb
14a	Et	NH3 c	56%
14b	Et	MeNH2 d	58%
14c	Et	n-BuNH2	65%
14d	Et		72%
14e	Bn	NH3 b	71%
14f	Bn	MeNH2 c	78%
14g	Bn		54%
14h	Bn		54%
14i	Bn		53%
14j	Bn		66%
14k	Bn		81%
14l	Bn		40%
14m	Bn	N2H4	0%

^a Reaction conditions: (i) triphosgene, DIPEA, THF, 0 °C to r.t., 1 h; (ii) R¹R²NH, 0 °C to r.t., 1 h.

^b Yield of isolated product.

^c Used as a 7 M solution in MeOH, 20 equivalents.

^d Used as a 33% solution in EtOH, 20 equivalents.

With the protected 2-ureaguanines 14 in hand, we next turned our attention to the simultaneous deprotection of the 2-tetrahydropyranyl and 6-O-alkyl groups. Compounds 14a–l were dissolved in 1,4-dioxane, then a 10% aqueous solution of hydrochloric acid was added (Table [2]). After one hour at room temperature, LC–MS analyses showed that in all cases the tetrahydropyran moiety had been cleaved. With compounds 14a–d (R = Et), only intermediates 15a–d were observed, and continuous stirring did not lead to complete cleavage of the ethoxy group. Heating to reflux temperature appeared necessary to effect complete conversion of intermediates 15a–d, but was accompanied by some degradation of the final compound. Compounds 16a–c were recovered in moderate yields whereas compound 16d was completely degraded. With substrates 14e–l (R = Bn), LC–MS after one hour at room temperature indicated complete cleavage of the tetrahydropyran group as well as partial cleavage of the benzyl ether. Further stirring overnight at room temperature led to complete conversion into ureas 16e–i without any trace of degradation. The products were isolated by trituration in water, and in some cases, subsequent purification of the filtrate by preparative HPLC increased the yield above 70% (16e, 16h and 16i).

Table 2 Double Deprotection by Acidolysis^a

Product	R1	R2R3N-	Yield
16a	Et	-NH2	45%
16b	Et	-NHMe	31%
16c	Et	-NHn-Bu	44%
16d	Et		0%
16a	Bn	-NH2	56%
16b	Bn	-NHMe	53%
16d	Bn		37%
16e	Bn		76%
16f	Bn		56%
16g	Bn		40%
16h	Bn		71%
16i	Bn		82%

^a Reaction conditions: (i) HCl (10%), 1,4-dioxane, r.t., overnight.

In summary, we have reported a general methodology to prepare 2-ureaguanines. The simultaneous use of the 9-tetrahydropyranyl and 6-benzyloxy protective groups appeared to be the most suitable combination. Subsequent acidolysis of both protecting groups allowed straightforward recovery of the 2-ureaguanines by simple trituration. This procedure was also applicable to the preparation of 6-O-alkyl-2-ureaguanines.

All reactions were carried out under an Ar atmosphere. THF was distilled over Na with benzophenone. Thin-layer chromatography (TLC) was conducted with Merck KGA silica gel 60 F254 pre-coated plates and samples were made visual by exposure to UV light (254 nm). Flash chromatography was performed using normal phase silica (230–400 mesh, Merck KGA). Melting points were recorded on a Buchi apparatus and are uncorrected. ¹H NMR spectra were recorded on a Bruker spectrometer at 300 MHz and are reported relative to the deuterated solvent signals. ¹H NMR spectroscopic data are reported as follows: chemical shift (δ ppm), multiplicity (s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, quin: quintet, sext: sextet), integration and coupling constant (Hz). ¹³C NMR spectra were recorded on a Bruker spectrometer at 75 MHz. ¹³C NMR spectroscopic data are reported in terms of chemical shift (δ ppm). LC–MS spectra were recorded on a Waters Alliance 2695 HPLC apparatus using H₂O + 0.1% TFA and MeCN + 0.1% TFA as eluents, with detection at 254 nm; MS were recorded on a Waters Micromass ZQ2000 (electrospray) instrument. The purities of the final compounds were determined using a Dionex HPLC with a HILIC column (Inertsil Amide, purchased from GL Sciences), with a gradient made with MeCN and 10 mM ammonium formate buffer. Preparative HPLC was performed using Waters equipment (Autosampler 2707, Quaternary gradient module 2535, UV detector 2489, fraction collector WFCIII) using H₂O + 0.1% TFA and MeCN as eluents. Exact mass measurements (HRMS) were recorded on an electrospray quadrupole time-of-flight Maxis 3G from Bruker using positive mode.

Tetrahydro-2H-pyran-2-yl Acetate (3)

To a mixture of AcOH (5.6 mL, 97 mmol, 0.9 equiv) and PPTS (1 g) in CH₂Cl₂ (100 mL) at 0 °C was added dropwise 2,3-dihydrofuran (10 mL, 110 mmol, 1 equiv), and the mixture was stirred overnight from 0 °C to r.t. The mixture was then washed with sat. aq NaHCO₃ soln (3 × 50 mL) and brine (3 × 50 mL), dried over Na₂SO₄ and concentrated in vacuo to yield 13.3 g of 3 (92 mmol, 95%) as a yellowish colored liquid.

¹H NMR (300 MHz, CDCl₃): δ = 5.94 (m, 1 H), 3.94–3.86 (m, 1 H), 3.71–3.64 (m, 1 H), 2.09 (s, 3 H), 1.87–1.75 (m, 2 H), 1.68–1.60 (m, 4 H).

¹³C NMR (75 MHz, CDCl₃): δ = 165.1, 87.9, 58.6, 24.4, 20.1, 16.4, 13.9.

2-Amino-9-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-6H-purin-6-one (4) and 2-Amino-7-(tetrahydro-2H-pyran-2-yl)-1,7-dihydro-6H-purin-6-one (5)

To a suspension of guanine (2 g, 13.2 mmol, 1 equiv) in MeCN (200 mL) was added BSA (16.2 mL, 66 mmol, 5 equiv) and the mixture was heated at reflux temperature for 4 h under Ar. After cooling to r.t. and then to 0 °C, compound 3 (2.5 g, 17.2 mmol, 1.5 equiv) was added, followed by the dropwise addition of TMSOTf (3.6 mL, 19.8 mmol, 1.2 equiv), and the mixture was stirred overnight from 0 °C to r.t. The mixture was quenched by the addition of aq Na₂CO₃ soln (1 M) and then extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over Na₂SO₄ and concentrated in vacuo. Concentration of the aqueous phase followed by recrystallization of the solid residue from H₂O allowed recovery of another fraction of a mixture of 4 and 5. The combined fractions yielded 1.8 g (7.6 mmol, 58%) of a 1.7:1 mixture of 4 and 5 as a white solid.

¹H NMR (300 MHz, DMSO-d ₆): δ (major isomer) = 8.16 (s, 1 H), 6.18 (br s, 2 H), 5.75 (dd, J = 10.4 Hz, J = 2.5 Hz, 1 H), 4.01–3.97 (m, 1 H), 3.63–3.55 (m, 1 H), 2.12–1.87 (m, 3 H), 1.69–1.50 (m, 3 H).

¹H NMR (300 MHz, DMSO-d ₆): δ (minor isomer) = 7.87 (s, 1 H), 6.52 (br s, 2 H), 5.35 (dd, J = 11.3 Hz, J = 2.5 Hz, 1 H), 4.01–3.97 (m, 1 H), 3.63–3.55 (m, 1 H), 2.12–1.87 (m, 3 H), 1.69–1.50 (m, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ (major isomer) = 159.8, 154.3, 152.9, 140.8, 107.3, 83.1, 67.7, 30.6, 24.5, 22.5.

MS (ES): m/z = 235.8 [M + H]⁺.

6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-amine (6)

To a suspension of 2-amino-6-chloropurine (5 g, 29.5 mmol, 1 equiv) in MeCN (500 mL) was added BSA (21 mL, 85.9 mmol, 2.9 equiv) and the mixture was heated at reflux temperature for 4 h. After cooling to r.t. and then to 0 °C, compound 3 (6.3 g, 44.2 mmol, 1.3 equiv) was added, followed by the dropwise addition of TMSOTf­ (8 mL, 44.2 mmol, 1.5 equiv), and the mixture was stirred overnight from 0 °C to r.t. The mixture was quenched by the addition of aq Na₂CO₃ soln (1 M) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo. The crude residue was purified by silica gel chromatography (CH₂Cl₂–MeOH, 100:0 to 95:5) to yield 5.5 g of 6 as a beige solid (21.7 mmol, 73%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 8.33 (s, 1 H), 6.99 (br s, 2 H), 5.48 (dd, J = 11.0 Hz, J = 2.2 Hz, 1 H), 4.02–3.98 (m, 1 H), 3.66–3.57 (m, 1 H), 2.29–2.15 (m, 1 H), 1.97–1.89 (m, 2 H), 1.73–1.52 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.9, 153.5, 149.6, 140.9, 123.2, 80.8, 67.7, 29.7, 24.5, 22.5.

MS (ES): m/z = 253.7 (100%) [³⁵Cl, M + H]⁺, 255.7 (37%) [³⁷Cl, M + H]⁺.

6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-amine (12)

Na (291 mg, 12.7 mmol, 2.2 equiv) was dissolved in abs EtOH (100 mL), and 6 (1.46 g, 5.8 mmol, 1 equiv) was added in portions. The mixture was stirred at r.t. until completion of the reaction. The mixture was quenched by the addition of sat. aq NH₄Cl soln and then extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo, and the crude residue was purified by silica gel chromatography (CH₂Cl₂–MeOH, 100:0 to 95:5) to yield 1.23 g of 12 as a beige solid (4.7 mmol, 81%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 8.04 (s, 1 H), 6.44 (br s, 2 H), 5.45 (dd, J = 11.0 Hz, J = 2.2 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H), 4.01–3.97 (m, 1 H), 3.64–3.56 (m, 1 H), 2.24–2.11 (m, 1 H), 1.99–1.85 (m, 2 H), 1.75–1.52 (m, 3 H), 1.35 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 160.3, 159.9, 153.6, 137.3, 113.6, 80.4, 67.7, 61.5, 30.0, 24.5, 22.6, 14.5.

MS (ES): m/z = 263.8 [M + H]⁺.

6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-amine (13)

NaH (60% in oil, 790 mg, 19.7 mmol, 2.5 equiv) was added to a soln of benzyl alcohol (1.71 mL, 16.5 mmol, 2.1 equiv) in THF (50 mL), and the mixture was stirred at r.t. for 1 h. Compound 6 (2 g, 7.9 mmol, 1 equiv) was then added, and the mixture stirred at r.t. until completion of the reaction. The mixture was quenched with sat. aq NH₄Cl soln and extracted with EtOAc (3 × 25 mL). The combined organic extracts were then dried over Na₂SO₄ and concentrated in vacuo. The crude residue was purified by silica gel chromatography (CH₂Cl₂–MeOH, 100:0 to 95:5) to yield 2.40 g of 13 as a beige solid (7.4 mmol, 93%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 8.06 (s, 1 H), 7.51–7.48 (m, 2 H), 7.43–7.34 (m, 3 H), 6.54 (br s, 2 H), 5.49 (s, 2 H), 5.45 (dd, J = 11.0 Hz, J = 1.9 Hz, 1 H), 4.01–3.97 (m, 1 H), 3.65–3.60 (m, 1 H), 2.25–2.12 (m, 1 H), 1.98–1.85 (m, 2 H), 1.76–1.52 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 160.1, 159.8, 153.9, 137.6, 136.6, 128.5, 128.4, 128.1, 113.5, 80.5, 67.7, 66.9, 30.0, 24.5, 22.6.

MS (ES): m/z = 325.8 [M + H]⁺.

2-Ureapurines; General Procedure

To a soln of the 2-aminopurine (1 equiv) in THF (0.5 M) at 0 °C was added triphosgene (0.36 equiv) and DIPEA (3.5 equiv). The mixture was stirred for 30 min at 0 °C, then the ice bath was removed and the mixture was stirred for another 30 min, before again cooling to 0 °C. The amine (2 equiv) was then added, and the mixture was stirred for 1 h at 0 °C and at r.t. until completion of the reaction. EtOAc was added and the mixture was washed with brine (three times), dried Na₂SO₄ and concentrated in vacuo. The crude residue was purified by silica gel chromatography (CH₂Cl₂–MeOH, 100:0 to 95:5).

1-[6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]urea (9)

Prepared according to the general procedure starting from 200 mg of 6, yielding 143 mg of 9 as a white solid (61%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.89 (br s, 1 H), 8.63 (s, 1 H), 8.06 (br s, 1 H), 7.27–7.12 (m, 1 H), 5.72 (dd, J = 10.7 Hz, J = 2.2 Hz, 1 H), 4.03–3.99 (m, 1 H), 3.71–3.63 (m, 1 H), 2.26–2.16 (m, 1 H), 2.01–1.96 (m, 2 H), 1.80–1.57 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 154.1, 153.4, 151.7, 149.7, 143.7, 126.0, 81.4, 67.6, 29.6, 24.5, 22.2.

MS (ES): m/z = 296.8 (100%) [³⁵Cl, M + H]⁺, 298.8 (37%) [³⁷Cl, M + H]⁺.

1-Methyl-3-[6-(methylamino)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]urea (11)

Prepared according to the general procedure starting from 200 mg of 6, yielding 170 mg of 11 as a white solid (70%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.26 (q, J = 4.7 Hz, 1 H), 8.93 (br s, 1 H), 8.13 (s, 1 H), 7.92–7.91 (m, 1 H), 5.50 (d, J = 9.6 Hz, 1 H), 4.02–3.98 (m, 1 H), 3.67–3.59 (m, 1 H), 2.92 (d, J = 4.1 Hz, 3 H), 2.79 (d, J = 4.7 Hz, 3 H), 2.26–2.14 (m, 1 H), 1.98–1.90 (m, 2 H), 1.77–1.56 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 155.1, 154.7, 154.1, 137.2, 80.8, 67.6, 29.9, 27.0, 26.1, 24.6, 22.5.

MS (ES): m/z = 305.8 [M + H]⁺.

1-[6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]urea (14a)

Prepared according to the general procedure starting from 200 mg of 12, yielding 130 mg of 14a as a white solid (56%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.34 (br s, 1 H), 8.34 (s, 1 H), 8.29 (br s, 1 H), 7.04 (br s, 1 H), 5.61 (dd, J = 10.7 Hz, J = 1.9 Hz, 1 H), 4.54 (q, J = 7.1 Hz, 2 H), 4.02–3.98 (m, 1 H), 3.69–3.60 (m, 1 H), 2.28–2.16 (m, 1 H), 1.97–1.93 (m, 2 H), 1.78–1.56 (m, 3 H), 1.39 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 160.2, 154.7, 153.5, 151.8, 140.1, 116.0, 81.1, 67.6, 62.8, 29.8, 24.5, 22.4, 14.4.

1-[6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]-3-methylurea (14b)

Prepared according to the general procedure starting from 142 mg of 12, yielding 100 mg of 14b as a white solid (58%).

¹H NMR (300 MHz, CD₃OD): δ = 9.07 (q, J = 4.4 Hz, 1 H), 8.19 (s, 1 H), 5.64 (dd, J = 10.4 Hz, J = 2.2 Hz, 1 H), 4.54 (q, J = 7.1 Hz, 3 H), 4.12–4.08 (m, 1 H), 3.81–3.73 (m, 1 H), 2.95 (d, J = 4.4 Hz, 3 H), 2.08–1.66 (m, 6 H), 1.46 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CD₃OD): δ = 161.9, 157.5, 154.9, 152.6, 141.0, 117.4, 83.6, 69.5, 64.6, 31.7, 26.7, 26.1, 23.7, 14.7.

MS (ES): m/z = 320.8 [M + H]⁺.

1-Butyl-3-[6-ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)urea (14c)

Prepared according to the general procedure starting from 200 mg of 12, yielding 180 mg of 14c as a white solid (65%).

¹H NMR (300 MHz, CD₃OD): δ = 9.11 (t, J = 5.2 Hz, 1 H), 8.19 (s, 1 H), 5.59 (dd, J = 10.2 Hz, J = 2.5 Hz, 1 H), 4.53 (q, J = 7.1 Hz, 2 H), 4.12–4.08 (m, 1 H), 3.79–3.70 (m, 1 H), 3.37 (q, J = 6.6 Hz, 2 H), 2.18–2.04 (m, 4 H), 1.80–1.56 (m, 6 H), 1.46 (t, J = 7.1 Hz, 3 H), 0.98 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 160.2, 153.8, 153.5, 151.6, 140.0, 116.0, 81.4, 67.7, 62.8, 31.6, 24.5, 22.4, 19.7, 14.3, 13.7.

MS (ES): m/z = 362.9 [M + H]⁺.

N-[6-Ethoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)morpholine-4-carboxamide (14d)

Prepared according to the general procedure starting from 200 mg of 12, yielding 207 mg of 14d as a white solid (72%).

¹H NMR (300 MHz, CD₃OD): δ = 8.24 (s, 1 H), 5.77 (dd, J = 10.7 Hz, J = 2.2 Hz, 1 H), 4.59 (q, J = 6.9 Hz, 3 H), 4.11–4.07 (m, 1 H), 3.81–3.76 (m, 1 H), 3.73 (t, J = 4.9 Hz, 4 H), 3.57 (t, J = 4.9 Hz, 4 H), 2.15–2.02 (m, 3 H), 1.85–1.59 (m, 3 H), 1.45 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 160.0, 154.4, 154.1, 152.6, 139.9, 116.3, 80.8, 67.8, 66.1, 62.4, 46.8, 44.6, 29.9, 24.5, 22.5, 14.4.

MS (ES): m/z = 376.9 [M + H]⁺.

1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]urea (14e)

Prepared according to the general procedure starting from 250 mg of 13, yielding 200 mg of 14e as a white solid (71%).

¹H NMR (300 MHz, CD₃OD): δ = 8.19 (s, 1 H), 7.49–7.19 (m, 5 H), 5.61 (dd, J = 10.7 Hz, J = 2.5 Hz, 1 H), 5.51 (s, 2 H), 4.08–4.03 (m, 1 H), 3.75–3.68 (m, 1 H), 2.13–1.97 (m, 3 H), 1.76–1.55 (m, 3 H).

¹³C NMR (75 MHz, CD₃OD): δ = 161.7, 158.0, 154.8, 152.9, 141.2, 137.2, 129.5, 129.3, 117.5, 83.5, 70.0, 69.5, 31.7, 26.0, 23.7.

1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]-3-methylurea (14f)

Prepared according to the general procedure starting from 250 mg of 13, yielding 230 mg of 14f as a white solid (78%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.65 (br s, 1 H), 8.70 (q, J = 4.7 Hz, 1 H), 8.34 (s, 1 H), 7.57–7.54 (m, 2 H), 7.43–7.35 (m, 3 H), 5.64 (dd, J = 10.7 Hz, J = 1.9 Hz, 1 H), 5.58 (s, 2 H), 4.03–3.99 (m, 1 H), 3.72–3.64 (m, 1 H), 2.81 (d, J = 4.7 Hz, 3 H), 2.28–2.16 (m, 1 H), 1.98–1.94 (m, 2 H), 1.80–1.58 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.9, 154.5, 153.3, 151.8, 140.2, 136.1, 128.8, 128.5, 128.3, 116.0, 81.2, 67.9, 67.6, 29.7, 26.3, 24.6, 22.3.

MS (ES): m/z = 382.7 [M + H]⁺.

N-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]morpholine-4-carboxamide (14g)

Prepared according to the general procedure starting from 240 mg of 13, yielding 176 mg of 14g as a white solid (54%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.41 (br s, 1 H), 8.36 (s, 1 H), 7.56–7.53 (m, 2 H), 7.43–7.31 (m, 3 H), 5.61–5.54 (m, 3 H), 4.03–3.99 (m, 1 H), 3.67–3.59 (m + t, J = 4.9 Hz, 5 H), 3.44 (t, J = 4.9 Hz, 4 H), 2.31–2.19 (m, 1 H), 1.99–1.90 (m, 2 H), 1.78–1.57 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.8, 154.3, 154.0, 152.9, 140.1, 136.3, 128.8, 128.5, 128.2, 116.2, 80.9, 67.8, 67.6, 66.1, 44.7, 29.9, 24.5, 22.5.

MS (ES): m/z = 438.8 [M + H]⁺.

1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]-3-(2-morpholinoethyl)urea (14h)

Prepared according to the general procedure starting from 250 mg of 13, yielding 200 mg of 14h as a white solid (54%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.66 (br s, 1 H), 8.81 (t, J = 5.2 Hz, 1 H), 8.36 (s, 1 H), 7.58–7.55 (m, 2 H), 7.43–7.36 (m, 3 H), 5.62–5.57 (m, 3 H), 4.04–4.00 (m, 1 H), 3.69–3.61 (m, 1 H), 3.51 (t, J = 4.4 Hz, 4 H), 3.37 (q, J = 6.3 Hz, 2 H), 2.47 (t, J = 6.3 Hz, 2 H), 2.38 (t, J = 4.4 Hz, 4 H), 2.29–2.17 (m, 1 H), 1.98–1.95 (m, 2 H), 1.74–1.58 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.9, 153.9, 153.3, 151.9, 140.3, 135.9, 128.9, 128.5, 128.4, 116.0, 81.2, 68.1, 67.7, 66.1, 57.9, 53.4, 36.5, 29.7, 24.5, 22.4.

1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]-3-(2-hydroxyethyl)urea (14i)

Prepared according to the general procedure starting from 250 mg of 13, yielding 167 mg of 14i as a white solid (53%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.67 (br s, 1 H), 9.27 (t, J = 5.2 Hz, 1 H), 8.36 (s, 1 H), 7.58–7.55 (m, 2 H), 7.44–7.36 (m, 3 H), 5.66 (dd, J = 10.7 Hz, J = 1.9 Hz, 1 H), 5.58 (s, 2 H), 4.97 (t, J = 4.9 Hz, 1 H), 4.01–3.97 (m, 1 H), 3.75–3.66 (m, 1 H), 3.57 (q, J = 5.2 Hz, 2 H), 3.36–3.31 (m, 2 H), 2.33–2.11 (m, 1 H), 1.97–1.91 (m, 2 H), 1.79–1.56 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 160.1, 154.0, 153.4, 151.6, 140.0, 136.0, 129.0, 128.5, 128.3, 115.8, 80.9, 68.0, 67.7, 60.1, 42.1, 30.0, 24.5, 22.4.

N-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]pyrrolidine-1-carboxamide (14j)

Prepared according to the general procedure starting from 250 mg of 13, yielding 170 mg of 14j as a white solid (66%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.04 (br s, 1 H), 8.35 (s, 1 H), 7.57–7.54 (m, 2 H), 7.43–7.35 (m, 3 H), 5.60–5.54 (m, 3 H), 4.02–3.99 (m, 1 H), 3.67–3.58 (m, 1 H), 3.43–3.39 (m, 4 H), 2.31–2.16 (m, 1 H), 1.95–1.90 (m, 2 H), 1.86–1.81 (m, 4 H), 1.75–1.57 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.7, 154.0, 152.9, 152.7, 140.1, 136.4, 128.8, 128.5, 128.2, 116.1, 80.8, 67.8, 67.5, 46.0, 30.0, 25.1, 25.0, 24.5, 22.5.

N-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]piperidine-1-carboxamide (14k)

Prepared according to the general procedure starting from 250 mg of 13, yielding 273 mg of 14k as a white solid (81%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.25 (br s, 1 H), 8.33 (s, 1 H), 7.56–7.53 (m, 2 H), 7.42–7.35 (m, 3 H), 5.57–5.53 (m, 3 H), 4.03–3.99 (m, 1 H), 3.67–3.58 (m, 1 H), 3.42–3.39 (m, 4 H), 2.32–2.16 (m, 1 H), 1.98–1.90 (m, 2 H), 1.76–1.43 (m, 9 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.7, 154.7, 153.8, 152.9, 139.9, 136.4, 128.8, 128.5, 128.2, 116.0, 80.8, 67.8, 67.5, 45.2, 29.9, 25.5, 24.5, 24.1, 22.5.

1-[6-(Benzyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl]-3-(4-hydroxyphenethyl)urea (14l)

Prepared according to the general procedure (using 5.4 equiv of DIPEA­) starting from 250 mg of 13, yielding 152 mg of 14l as a white solid (40%).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.67 (br s, 1 H), 9.18 (br s, 1 H), 8.90 (t, J = 5.8 Hz, 1 H), 8.33 (s, 1 H), 7.55–7.48 (m, 2 H), 7.43–7.36 (m, 3 H), 7.00 (d, J = 8.5 Hz, 2 H), 6.64 (d, J = 8.5 Hz, 2 H), 5.47 (s, 2 H), 5.43 (dd, J = 11.0 Hz, J = 1.9 Hz, 1 H), 3.99–3.95 (m, 1 H), 3.60–3.37 (m, 3 H), 2.72–2.67 (m, 2 H), 2.27–2.11 (m, 1 H), 1.93–1.90 (m, 2 H), 1.73–1.48 (m, 3 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.9, 155.7, 153.9, 153.3, 151.7, 140.2, 136.0, 129.6, 129.5, 128.9, 128.5, 128.4, 116.0, 115.2, 81.4, 67.9, 67.6, 41.4, 34.9, 29.6, 24.5, 22.3.

MS (ES): m/z = 488.8 [M + H]⁺.

Double Deprotection; General Procedure

To a soln of the protected urea 14a–l (1 equiv) in 1,4-dioxane (1 M) was added an aq soln of HCl (10%, 1 M), and the mixture was stirred at r.t. (R = Bn) or at reflux temperature (R = Et) until LC–MS showed that the double deprotection was complete. The mixture was concentrated in vacuo, and the solid residue triturated with H₂O. When required, purification by preparative HPLC on a C-18 column was performed.

1-(6-Oxo-6,9-dihydro-1H-purin-2-yl)urea (16a)

Prepared according to the general procedure starting from 130 mg of 14a or 200 mg of 14e, yielding 37 mg (R = Et, 45%) or 59 mg (R = Bn, 56%) of 16a as a white solid (100% purity).

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 12.47 (br s, 1 H), 10.43 (br s, 1 H), 8.86 (s, 1 H), 7.34 (br s, 1 H), 6.92 (br s, 1 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 156.3, 152.6, 150.3, 149.9, 138.1, 111.7.

HRMS (ES): m/z [M + Na]⁺ calcd for C₆H₆N₆O₂Na: 217.0444; found: 217.0444.

1-Methyl-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea (16b)

Prepared according to the general procedure starting from 100 mg of 14b or 230 mg of 14f, yielding 20 mg (R = Et, 31%) or 66 mg (R = Bn, 53%) of 16b as a white solid (97% purity).

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 12.39 (br s, 1 H), 10.55 (br s, 1 H), 8.87 (s, 1 H), 7.36 (q, J = 4.7 Hz, 1 H), 2.72 (d, J = 4.7 Hz, 3 H).

HRMS (ES): m/z [M + Na]⁺ calcd for C₇H₈N₆O₂Na: 231.0601; found: 231.0601

1-Butyl-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea (16c)

Prepared according to the general procedure starting from 180 mg of 14c, yielding 55 mg (44%) of 16c as a brown solid.

Mp >250 °C.

¹H NMR (300 MHz, 10% NaOD–D₂O): δ = 7.27 (s, 1 H), 2.81 (t, J = 6.9 Hz, 2 H), 1.10 (quin, J = 6.9 Hz, 2 H), 0.91 (sext, J = 7.1 Hz, 2 H), 0.44 (t, J = 7.1 Hz, 3 H).

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₀H₁₄N₆O₂Na: 273.1070; found: 273.1075.

N-(6-Oxo-6,9-dihydro-1H-purin-2-yl)morpholine-4-carboxamide (16d)

Prepared according to the general procedure starting from 176 mg of 14g, yielding 39 mg (37%) of 16d as a white solid (98% purity).

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 12.62 (br s, 1 H), 10.59 (br s, 1 H), 8.93 (s, 1 H), 3.62–3.59 (m, 4 H), 3.53–3.50 (m, 4 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 154.8, 152.7, 150.5, 150.1, 138.5, 112.1, 65.8, 44.4.

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₀H₁₂N₆O₃Na: 287.0863; found: 287.0871.

1-(2-Morpholinoethyl)-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea (16e)

Prepared according to the general procedure starting from 200 mg of 14h, yielding 96 mg (76%) of 16e as a white solid (97% purity).

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 11.81 (br s, 1 H), 10.48 (br s, 1 H), 10.22 (br s, 1 H), 7.98 (s, 1 H), 7.77 (br s, 1 H), 3.95 (br s, 2 H), 3.76 (br s, 2 H), 3.59–3.49 (m, 4 H), 3.25–3.11 (m, 4 H).

HRMS (ES): m/z [M + H]⁺ calcd for C₁₂H₁₈N₇O₃Na: 308.1466; found: 308.1466.

1-(2-Hydroxyethyl)-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea (16f)

Prepared according to the general procedure starting from 167 mg of 14i, yielding 53 mg (56%) of 16f as a white solid (99% purity).

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 11.84 (br s, 1 H), 9.72 (br s, 1 H), 7.97 (s, 1 H), 7.26 (br s, 1 H), 4.86 (br s, 1 H), 3.47 (t, J = 5.5 Hz, 2 H), 3.22 (q, J = 5.5 Hz, 2 H).

HRMS (ES): m/z [M + Na]⁺ calcd for C₈H₁₀N₆O₃Na: 261.0707; found: 261.0706.

N-(6-Oxo-6,9-dihydro-1H-purin-2-yl)pyrrolidine-1-carboxamide (16g)

Prepared according to the general procedure starting from 172 mg of 14j, yielding 40 mg (40%) of 16g as a white solid (99% purity).

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 12.97 (br s, 1 H), 10.36 (br s, 1 H), 8.97 (s, 1 H), 3.46–3.38 (m, 4 H), 1.85 (br s, 4 H).

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₀H₁₂N₆O₂Na: 271.0914; found: 271.0917.

N-(6-Oxo-6,9-dihydro-1H-purin-2-yl)piperidine-1-carboxamide (16h)

Prepared according to the general procedure starting from 273 mg of 14k, yielding 115 mg (71%) of 16h as a white solid.

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 12.78 (br s, 1 H), 10.51 (br s, 1 H), 8.93 (s, 1 H), 3.50–3.47 (m, 4 H), 1.59–1.50 (m, 6 H).

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₁H₁₄N₆O₂Na: 285.1070; found: 285.1077.

1-(4-Hydroxyphenethyl)-3-(6-oxo-6,9-dihydro-1H-purin-2-yl)urea (16i)

Prepared according to the general procedure starting from 152 mg of 14l, yielding 80 mg (82%) of 16i as a white solid (95% purity).

Mp >250 °C.

¹H NMR (300 MHz, DMSO-d ₆): δ = 12.09 (br s, 1 H), 10.08 (br s, 1 H), 9.22 (br s, 1 H), 8.41 (s, 1 H), 7.26 (t, J = 5.5 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.70 (d, J = 8.5 Hz, 2 H), 3.34 (q, J = 6.9 Hz, 2 H), 2.66 (t, J = 6.9 Hz, 2 H).

HRMS (ES): m/z [M + Na]⁺ calcd for C₁₄H₁₄N₆O₃Na: 337.1020; found: 337.1022.

Acknowledgment

This work was supported financially by the ministère du Développement Économique, de l’innovation et des Exportations du Québec­. Financial support from the MITACS program in the form of a scholarship to A.L.R. is gratefully acknowledged.

• References

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• References

• 1 Joule JA, Mills K. Heterocyclic Chemistry . 5th ed. Wiley; Oxford: 2010: 515-538 and 629–644
  Search in Google Scholar
• 2a Huryn DM, Okabe M. Chem. Rev. 1992; 92: 1745
  CrossrefSearch in Google Scholar
• 2b Babu PA, Narasu ML, Srinivas K. ARKIVOC 2007; (ii): 247
  Search in Google Scholar
• 3a Lena S, Masiero S, Pieraccini S, Spada GP. Mini Rev. Org. Chem. 2008; 5: 262
  CrossrefSearch in Google Scholar
• 3b Lena S, Masiero S, Pieraccini S, Spada GP. Chem. Eur. J. 2009; 15: 7792
  CrossrefSearch in Google Scholar
• 3c Park T, Zimmerman SC. J. Am. Chem. Soc. 2006; 128: 14236
  CrossrefSearch in Google Scholar
• 4 Watson JD, Crick FH. Nature 1953; 171: 737
  CrossrefSearch in Google Scholar
• 5 Hoogsteen K. Acta Crystallogr. 1963; 16: 907
  CrossrefSearch in Google Scholar
• 6 Jones AS, Warren JH. Tetrahedron 1970; 26: 791
  CrossrefSearch in Google Scholar
• 7 Martin AM, Butler RS, Ghivirigia I, Giessert RE, Abboud KA, Castellano RK. Chem. Commun. 2006; 4413
• 8 Park T, Todd EM, Nakashima S, Zimmerman SC. J. Am. Chem. Soc. 2005; 127: 18133
  CrossrefSearch in Google Scholar
• 9 Seio K, Kurohagi S, Kodama E, Masaki Y, Tsunoda H, Ohkubo A, Sekine M. Org. Biomol. Chem. 2012; 10: 994
  CrossrefSearch in Google Scholar
• 10 Sasami T, Odawara Y, Ohkubo A, Sekine M, Seio K. Tetrahedron Lett. 2007; 48: 5325
  CrossrefSearch in Google Scholar
• 11 NB: In schemes 1 and 2, compounds 1, 4 and 5 are depicted as the enol form for convenience; however, it should be kept in mind that this form is in equilibrium with the keto form.
• 12a Adebambo KF, Zanoli S, Thomas MG, Cancio R, Howarth NM, Maga G. ChemMedChem 2007; 2: 1405
  CrossrefSearch in Google Scholar
• 12b Debaene F, Winssinger N. Org. Lett. 2003; 5: 4445
  CrossrefSearch in Google Scholar
• 13 Robins RK, Godefroi EF, Taylor EC, Lewis LR, Jackson A. J. Am. Chem. Soc. 1961; 83: 2574
  CrossrefSearch in Google Scholar
• 14 The correct structure of 6 was assumed based on NOESY experiments with 14, which showed no correlation between the protons of the THP ring and those of the benzyl group (see Supporting Information).
• 15a Huang L.-K, Cherng Y.-C, Cheng Y.-R, Jang J.-P, Chao Y.-L, Cherng Y.-J. Tetrahedron 2007; 63: 5323
  CrossrefSearch in Google Scholar
• 15b Qu G.-R, Wu J, Wu Y.-Y, Zhang F, Guo H.-M. Green Chem. 2009; 11: 760
  CrossrefSearch in Google Scholar
• 15c Guo H.-M, Xin P.-Y, Niu H.-Y, Wang D.-C, Jiang Y, Qu G.-R. Green Chem. 2010; 12: 2131
  CrossrefSearch in Google Scholar

• Supplementary Material