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Synthesis 2013; 45(21): 3029-3037
DOI: 10.1055/s-0033-1338524
paper
© Georg Thieme Verlag Stuttgart · New York

Regioselective Functionalization of Purine Derivatives at Positions 8 and 6 Using Hindered TMP-Amide Bases of Zn and Mg

François Crestey
,
Silvia Zimdars
,
Paul Knochel*
Further Information

Publication History

Received: 05 August 2013

Accepted: 09 August 2013

Publication Date:
02 September 2013 (online)

 
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Abstract

A broad range of purine derivatives were efficiently metalated at positions 8 and 6 using TMP-amide bases. This provided polysubstituted purines in good to very good yields after subsequent trapping of the zinc or magnesium intermediates with various electrophiles.


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Key words

purine derivatives - metalation - Negishi cross-coupling - magnesium - zinc

As a result of the large variety of biologically active compounds bearing a purine unit this scaffold became an important class of pharmacophores that has been extensively studied in the last decades.[2] Diverse combinatorial libraries of functionalized purines have been synthesized by direct C–H arylations[3] or heterocylizations.[4] Moreover, Pd- and Fe-mediated reactions can allow access to several simple 6,8-disubstituted and 2,6,8-trisubstituted purines.[5] In addition, the more challenging approach, that is, coupling of metalated purine derivatives with appropriate electrophiles, have been developed via magnesiation,[6] zincation,[7] or lithiation.[8] Recently, our group has described for the first time the successive and selective generation of magnesium and zinc organometallic intermediates at positions 6, 8, and 2 to furnish a large collection of novel and highly designed purine derivatives.[9] In the present work, we extend the study in the regioselective functionalization of purine scaffolds to the development of an efficient metalation protocol at positions 8 and 6 of a wide range of purine derivatives using hindered TMP-amide bases[10] (TMP = 2,2,6,6-tetramethylpiperidide).

First, the starting materials 1 used in this study were bearing a protecting group (PG) such as a methoxymethyl (MOM), a benzyl (Bn), or a 2,2,3,3-tetrahydropyranyl (THP) group (see Figure [1]). Thus, a selective deprotonation at position 8 using either zinc- or magnesium-amide bases generated a metalated species of type 2 as depicted in Scheme [1]. For example, purines 1a, 1i, and 1k were readily zincated by using TMPZnCl·LiCl[11] within 30 minutes at 25 °C. Subsequent trapping with iodine (1.2 equiv) provided the corresponding iodinated compounds 3a–c in 60–98% yields (Table [1], entries 1–3). Notably, if organomagnesium reagent TMPMgCl·LiCl[12] was used at –60 °C the yield was only slightly affected (entry 2). Bromination of purine 1i and 1j with 1,2-dibromo-1,1,2,2-tetrachloroethane proceeded under Barbier reaction conditions[13] at 0 °C using bisamide zinc base TMP2Zn·2MgCl2·2LiCl.[14] The 8-brominated compounds 3d and 3e were obtained after 15 minutes in 82% and 75% yield, respectively (entries 4, 5). Remarkably, using the same conditions as described above compound 1f was brominated to furnish the 2,6,8-trihalogenopurine 3f bearing three different halogens in 87% yield (entry 6). Similarly, derivative 1i reacted with S-phenyl benzenesulfonothioate under Barbier reaction conditions at 0 °C affording 8-phenylthiopurine 3g in 60% yield (entry 7). Copper(I)-catalyzed allylation[15] (10 mol% CuCN·2LiCl) of derivative 1f with 3-bromocyclohexene (–65 °C to 25 °C, 2 h) led to the allylated purine 3h in 84% yield (entry 8).

Zoom Image
Figure 1 Array of protected purines examined in the study
Zoom Image
Scheme 1 General reaction scheme for the selective metalation of purine derivatives of type 1 at position 8 and subsequent reaction with an electrophile: Reagents and conditions: (i) TMP-amide base; (ii) electrophile, 60–98%. See Table [1] for more details.

Table 1 Synthesis and Yields of Purine Derivatives of Type 3

Entry

SMa

Electrophile

Productb

1

1a

I2

3a (98)c

2

1i

I2

3b (80)c (84)d

3

1k

I2

3c (60)c

4

1i

(CCl2Br)2

3d (82)e

5

1j

(CCl2Br)2

3e (75)e

6

1f

(CCl2Br)2

3f (87)e

7

1i

PhSO2SPh

3g (60)e

8

1f

3h (84)f

a Starting material.

b Yield (%) of isolated analytically pure product is given in parentheses.

c 1) TMPZnCl·LiCl (1.1 equiv), 25 °C, 30 min; 2) I2 (1.2 equiv), 25 °C, 1 h.

d 1) TMPMgCl·LiCl (1.1 equiv), –60 °C, 15 min; 2) I2 (1.2 equiv), –60 °C, 2.5 h.

e 1) Electrophile (1 equiv), 0 °C, 5 min; 2) TMP2Zn·2MgCl2·2LiCl (1.2 equiv), 0 °C to 25 °C, 15 min.

f 1) ZnCl2 (1 equiv), 25 °C, 5 min; 2) TMPMgCl·LiCl (1.13 equiv), –65 °C, 30 min; 3) CuCN·2LiCl (0.1 equiv), 3-bromocyclohexene (1.4 equiv), –65 °C to 25 °C, 2 h.

As shown in Scheme [2], the 8-zincated intermediates of type 4 underwent Pd-catalyzed Negishi cross-coupling reactions[16] with Pd(dba)2 (2 mol%), (o-furyl)3P (4 mol%), and various aryl iodides (1.2 equiv) within a few hours (2–14 h) to afford the 8-arylated purines of type 5 in 48–97% yields. For example, purine 1c was readily metalated by using TMPZnCl·LiCl within 30 minutes at 25 °C. The organometallic intermediate reacted with either ethyl 4-iodobenzoate or 4-iodoanisole at 25 °C to provide the purine derivatives 5a and 5b in 97% and 61% yield, respectively (Table [2], entries 1, 2). Similarly, compound 1a furnished the 8-arylated 6-chloropurines 5c and 5d in 91% and 95% yield, respectively (entries 3, 4). Noticeably, derivative 5e was only detected in traces due to the deprotection of the THP group during the cross-coupling reaction. The unprotected arylated product was isolated instead in 75% yield (entry 5). Remarkably, functional groups like thioether and TMS are tolerated in position 2 during both the deprotonation and the Negishi cross-coupling reaction (entries 9–12). In the case of purine 1e, the cross-coupling reaction was performed at 45 °C for 14 hours leading to the trisubstituted purine 5l in 91% (entry 12). The same reaction was performed on 20 and 30 mmol scales furnishing the expected product 5l in 70% and 85% yield, respectively. Unfortunately attempts with aryl bromides or heteroaryl halides as electrophiles for the Negishi­ cross-coupling reaction failed.

Table 2 Synthesis and Yields of Purine Derivatives of Type 5

Entry

SMa

ArI

Productb

1

1c

5a (97)c

2

1c

5b (61)c

3

1a

5c (91)c

4

1a

5d (95)c

5

1k

5e (traces)d

6

1b

5f (58)c

7

1d

5g (62)c

8

1d

5h (71)c

9

1g

5i (48)c

10

1h

5j (85)c

11

1g

5k (52)c

12

1e

5l (91)e

a Starting material.

b Yield (%) of isolated analytically pure product is given in parentheses.

c Obtained by palladium-catalyzed cross-coupling reaction using Pd(dba)2 (2 mol%) and (o-furyl)3P (4 mol%) at 25 °C for 2–14 h.

d The deprotected product was obtained instead in 75% yield.

e Obtained by palladium-catalyzed cross-coupling reaction using Pd(dba)2 (2 mol%) and (o-furyl)3P (4 mol%) at 45 °C for 14 h.

Zoom Image
Scheme 2 General reaction scheme for the selective zincation of purine derivatives of type 1 at position 8 and subsequent Negishi cross-coupling reaction with an aryl iodide. Reagents and conditions: (i) TMPZnCl·LiCl (1.1 equiv), anhyd THF, 30 min, 25 °C; (ii) ArI (1.2 equiv), 48–97%. LiCl in 4 is omitted for clarity. See Table [2] for more details.

The deprotonation at position 6 of the purine scaffold was achieved with TMPMgCl·LiCl within 60 minutes at –20 °C leading to organomagnesium intermediates of type 6 as illustrated in Scheme [3]. Thus, after subsequent iodolysis purine derivatives 5a and 5b furnished the corresponding 6-iodopurines 7a and 7b in 70% and 60% yield, respectively (Table [3], entries 1, 2). Negishi cross-coupling reactions of compound 5a and 5b with iodobenzene and ethyl 4-iodobenzoate in the presence of Pd(dba)2 (2 mol%) and (o-furyl)3P (4 mol%) gave the 6,8-bisarylated products 7c and 7d in 55% and 63% yield, respectively (entries 3, 4). Particularly, starting from derivative 5i and using the same conditions described above a trisubstituted purine 7e was obtained in 53% yield.

Table 3 Synthesis and Yields of Purine Derivatives of Type 7

Entry

SMa

Electrophile

Productb

1

5a

I2

7a (70)

2

5b

I2

7b (60)

3

5a

7c (63)c

4

5b

7d (55)c

5

5i

7e (53)c

a Starting material.

b Yield (%) of isolated analytically pure product is given in parentheses.

c Transmetalation with ZnCl2 (1.3 equiv) then palladium-catalyzed cross-coupling reaction using Pd(dba)2 (2 mol%) and (o-furyl)3P (4 mol%) at 25 °C for 3–14 h.

Zoom Image
Scheme 3 General reaction scheme for the selective magnesiation of purine derivatives of type 5 at position 6 and subsequent reaction with an electrophile. Reagents and conditions: (i) TMPMgCl·LiCl (1.2 equiv), anhyd THF, 1 h, –20 °C; (ii) electrophile, 53–70%. LiCl in 6 is omitted for clarity. See Table [3] for more details.

In conclusion, a regioselective functionalization of a broad range of protected purine derivatives has been achieved successfully at positions 8 and 6 via zinc and magnesium intermediates providing a large variety of polysubstituted purines after subsequent trapping with various electrophiles. This study completes our previous work[9] by extending the scope of the purine scaffold and allows access now to a wide library of highly substituted compounds. Further studies concerning construction of new substituted derivatives are currently in progress.

All reactions were carried out under an argon atmosphere in flame-dried glassware. Syringes, which were used to transfer anhydrous solvents or reagents, were purged with argon prior to use. THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under N2. 2,2,6,6-Tetramethylpiperidine (TMPH) was distilled prior to use. Yields refer to isolated compounds estimated to be >95% pure as determined by 1H NMR spectroscopy (25 °C) and capillary GC. NMR spectra were recorded on Bruker ARX-200, AC-300, or WH-400 using CDCl3 as solvent. Standard abbreviations are used to indicate spin multiplicities. GC analyses were performed with instruments of type Hewlett-Packard 6890 or 5890 series II using a column of type HP 5. Column chromatography was performed using SiO2 (0.040–0.063 mm, 230–400 mesh ASTM) from Merck. Melting points were measured using a Büchi B-540 apparatus and are uncorrected. Mass spectra and high-resolution mass spectra (HRMS) were recorded on Finnigan MAT 95Q or Finnigan MAT 90 instrument using electron impact (EI); where otherwise noted electrospray ionization (ESI) was used. TMPZnCl·LiCl,[11] TMPMgCl·LiCl,[12] TMP2Zn·2MgCl2·2LiCl,[14] CuCN·2LiCl,[17] ZnCl2,[17] MOMCl solution in toluene[18] as well as purines 1a,[19] 1e,[9] 1i,[20] 1j,[21] and 1k [22] were prepared according to literature procedures. The freshly prepared TMP-amide bases were titrated­ prior to use at 25 °C with benzoic acid using 4-(phenylazo)diphenylamine as indicator.


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2-Chloro-9-(methoxymethyl)-9H-purine (1b)

A solution of MOMCl (30.0 mL, 2 M in toluene, 60 mmol, 2.3 equiv) was added dropwise to a solution of 2-chloro-9H-purine (4.0 g, 26 mmol, 1.0 equiv) and Et3N (7.2 mL, 52 mmol, 2 equiv) in DME (300 mL) at 25 °C. The mixture was stirred at this temperature for 3 h, and then quenched with K2CO3 (ca. 10 g) and H2O (200 mL). The aqueous layer was extracted with EtOAc (2 × 150 mL), then the combined organic layers were washed with H2O (200 mL) and brine (300 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using CH2Cl2–EtOH (20:1) as eluent to lead to purine 1b; yield: 3.0 g (58%); white solid; mp 113–115 °C.

1H NMR (CDCl3): δ = 9.01 (s, 1 H), 8.24 (s, 1 H), 5.61 (s, 2 H), 3.41 (s, 3 H).

13C NMR (CDCl3): δ = 155.0, 153.5, 150.4, 145.9, 132.9, 74.1, 57.5.

MS (70 eV): m/z (%) = 200 (7), 198 (20), 170 (24), 169 (15), 168 (84), 167 (36), 52 (5), 45 (100).

HRMS: m/z calcd for C7H7ClN4O: 198.0308; found: 198.0309.


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9-(Methoxymethyl)-9H-purine (1c)

t-BuONO (0.50 mL, 4 mmol, 2 equiv) was added to a solution of 9-(methoxymethyl)-9H-purin-6-amine (0.56 g, 2 mmol, 1 equiv) in anhydrous THF (10 mL) at 25 °C. The mixture was heated under reflux conditions for 3 h, then t-BuONO (0.50 mL, 4 mmol, 2 equiv) was added again, and the mixture stirred for further 3 h. After cooling to 25 °C, the solvents were removed in vacuo, and the crude material was purified by column chromatography using a gradient elution (CH2Cl2–MeOH, 100:0, then 100:1 to 30:1) to provide purine 1c; yield: 0.23 g (70%); pale yellow solid; mp 87–88 °C.

1H NMR (CDCl3): δ = 9.17 (s, 1 H), 9.01 (s, 1 H), 8.24 (s, 1 H), 5.64 (s, 2 H), 3.38 (s, 3 H).

13C NMR (CDCl3): δ = 153.1, 148.8, 145.2, 133.8, 73.9, 57.3.

MS (70 eV): m/z (%) = 164 (8), 135 (11), 134 (100), 133 (38), 78 (5), 45 (86).

HRMS: m/z calcd for C7H8N4O: 164.0698; found: 164.0697.


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2,6-Dichloro-9-(methoxymethyl)-9H-purine (1d)[23]

A solution of MOMCl (7.50 mL, 2 M in toluene, 15 mmol, 1.5 equiv) was added dropwise to a solution of 2,6-dichloro-9H-purine (1.89 g, 10 mmol, 1.0 equiv) and K2CO3 (6.20 g, 45 mmol, 4.5 equiv) in DMF (20 mL) at 25 °C. The mixture was stirred at this temperature for 3 h, and then quenched with H2O (20 mL). The aqueous layer was extracted with EtOAc (2 × 40 mL), then the combined organic layers were washed with H2O (60 mL) and brine (60 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using a gradient elution (CH2Cl2–EtOH, 100:0 then 500:1 to 100:1) to provide purine 1d; yield: 0.86 g (37%); white solid; mp 126–127 °C.

1H NMR (CDCl3): δ = 8.27 (s, 1 H), 5.61 (s, 2 H), 3.41 (s, 3 H).

13C NMR (CDCl3): δ = 153.6, 152.1, 145.7, 130.6, 74.7, 57.6.

MS (70 eV): m/z (%) = 232 (9), 212 (9), 211 (12), 204 (40), 203 (20), 202 (62), 201 (21), 196 (12), 45 (100).

HRMS: m/z calcd for C7H6Cl2N4O: 231.9919; found: 231.9919.


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6-Chloro-2-iodo-9-(methoxymethyl)-9H-purine (1f)

A solution of I2 (0.95 g, 3.75 mmol, 1.5 equiv) in anhydrous THF (4 mL) was added dropwise to a solution of 6-chloro-9-(methoxymethyl)-2-(tributylstannyl)-9H-purine (1.22 g, 2.5 mmol, 1.0 equiv) in anhydrous THF (12 mL) at 25 °C. The mixture was stirred for 1 h, and then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), then the combined organic layers were washed with H2O (40 mL) and brine (60 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using pentane as eluent to furnish purine 1f; yield: 0.73 g (90%); pale yellow solid; mp 128–130 °C.

1H NMR (CDCl3): δ = 8.17 (s, 1 H), 5.60 (s, 2 H), 3.42 (s, 3 H).

13C NMR (CDCl3): δ = 152.9, 150.8, 145.0, 131.5, 117.2, 74.8, 57.7.

MS (70 eV): m/z (%) = 325 (9), 324 (28), 296 (33), 294 (100), 197 (7), 45 (16).

HRMS: m/z calcd for C7H6ClIN4O: 323.9275; found: 323.9252.


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9-(Methoxymethyl)-2-(trimethylsilyl)-9H-purine (1g)

Pd/C (0.25 g, 40 wt%) and ammonium formate (1.25 g, 19.8 mmol, 7.9 equiv) were successively added to a solution of purine 1e (0.68 g, 2.5 mmol, 1.0 equiv) in MeOH (5 mL) at 45 °C. When the reaction started proceeding (intensive bubbling), the mixture was stirred for further 30 min until the starting material was completely converted as monitored on TLC (EtOAc). The solution was filtered through a pad of Celite. The pad was washed several times with EtOH and the combined filtrates were concentrated in vacuo. The crude material was dissolved in CH2Cl2 (100 mL) and the remaining ammonium formate was filtered off. The solvent was removed in vacuo and the resulting crude material was purified by column chromatography using EtOAc as eluent to afford purine 1g; yield: 0.55 g (90%); pale yellow oil.

1H NMR (CDCl3): δ = 9.12 (s, 1 H), 8.14 (s, 1 H), 5.58 (s, 2 H), 3.32 (s, 3 H), 0.30 (s, 9 H).

13C NMR (CDCl3): δ = 174.6, 150.9, 147.1, 144.7, 132.3, 73.6, 57.5, –1.9.

HRMS (ESI): m/z calcd for C10H16N4OSi + H+: 237.1166; found: 237.1166.


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9-(Methoxymethyl)-2-[(4-methoxyphenyl)thio]-9H-purine (1h)

4-Methoxythiophenol (168 mg, 1.2 mmol, 1.2 equiv) was added to a solution of t-BuOK (224 mg, 2.0 mmol, 2 equiv) in NMP (2 mL) at 25 °C. The mixture was stirred for 5 min at 110 °C, then purine 1b (193 mg, 1.0 mmol, 1.0 equiv) was added, and the resulting mixture was heated for 1 h at this temperature. After cooling to 25 °C, EtOAc (30 mL) was added and the organic layer was washed with H2O (3 × 15 mL) and brine (15 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using pentane–EtOAc (1:2) as eluent to afford purine 1h; yield: 160 mg (53%); yellow oil.

1H NMR (CDCl3): δ = 8.87 (s, 1 H), 8.03 (s, 1 H), 7.55–7.50 (m, 2 H), 6.95–6.90 (m, 2 H), 5.37 (s, 2 H), 3.82 (s, 3 H), 3.23 (s, 3 H).

13C NMR (CDCl3): δ = 167.2, 160.6, 152.8, 149.1, 144.2, 137.2, 131.1, 120.7, 114.6, 73.7, 57.7, 55.4.

MS (70 eV): m/z (%) = 304 (5), 303 (17), 302 (100), 301 (88), 272 (6), 271 (19), 259 (7), 257 (23), 139 (7), 45 (27).

HRMS: m/z calcd for C14H14N4O2S: 302.0837; found: 302.0829.


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6-Chloro-8-iodo-9-(methoxymethyl)-9H-purine (3a)

Freshly prepared TMPZnCl·LiCl (0.92 mL, 1.2 M in THF, 1.1 mmol, 1.1 equiv) was added dropwise within 2 min to a solution of purine 1a (199 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (1.5 mL) at 25 °C. The mixture was stirred for 30 min, then a solution of I2 (305 mg, 1.2 mmol, 1.2 equiv) in anhydrous THF (4 mL) was added dropwise. The mixture was stirred for 1 h, and then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with Et2O (2 × 30 mL), then the combined organic layers were washed with H2O (40 mL) and brine (40 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using pentane–EtOAc (1:2) as eluent to furnish purine 3a; yield: 317 mg (98%); beige solid; mp 125–127 °C.

1H NMR (CDCl3): δ = 8.71 (s, 1 H), 5.61 (s, 2 H), 3.42 (s, 3 H).

13C NMR (CDCl3): δ = 153.5, 152.3, 149.6, 133.7, 107.4, 76.0, 57.6.

MS (70 eV): m/z (%) = 323 (20), 296 (28), 295 (9), 294 (94), 292 (8), 197 (7), 169 (29), 168 (9), 167 (100), 77 (7), 45 (66).

HRMS: m/z calcd for C7H6ClIN4O: 323.9275; found: 323.9266.


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9-Benzyl-8-iodo-9H-purine (3b)[24]

Method A: Freshly prepared TMPZnCl·LiCl (0.92 mL, 1.2 M in THF, 1.1 mmol, 1.1 equiv) was added dropwise within 2 min to a solution of purine 1i (210 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (1.5 mL) at 25 °C. The mixture was stirred for 30 min, then a solution of I2 (305 mg, 1.2 mmol, 1.2 equiv) in anhydrous THF (4 mL) was added dropwise. The mixture was stirred for 1 h, and then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with CH2Cl2 (3 × 30 mL), then the combined organic layers were washed with H2O (40 mL) and brine (40 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using pentane–Et2O (1:9) as eluent to furnish purine 3b; yield: 270 mg (80%); white solid; mp 211–213 °C.

Method B: Freshly prepared TMPMgCl·LiCl (0.92 mL, 1.2 M in THF, 1.1 mmol, 1.1 equiv) was slowly added dropwise within 5 min to a solution of purine 1i (210 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (4 mL) at –60 °C. The mixture was stirred for 15 min, then a solution of I2 (305 mg, 1.2 mmol, 1.2 equiv) in anhydrous THF (3 mL) was added dropwise. The mixture was stirred for 2.5 h, and then quenched with sat. aq Na2S2O3 (10 mL). After workup and purification as described above, purine 3b was obtained as a white solid; yield: 284 mg (84%).

1H NMR (CDCl3): δ = 9.08 (s, 1 H), 8.95 (s, 1 H), 7.35–7.31 (m, 5 H), 5.48 (s, 2 H).

13C NMR (CDCl3): δ = 152.8, 147.1, 136.4, 134.7, 128.9, 128.5, 127.9, 108.3, 49.0.

MS (70 eV): m/z (%) = 337 (5), 336 (41), 335 (18), 210 (16), 209 (100), 208 (9), 104 (6), 92 (7), 91 (84), 65 (16).

HRMS: m/z calcd for C12H9IN4: 335.9872; found: 335.9859.


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6-Chloro-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3c)[25]

Freshly prepared TMPZnCl·LiCl (1.0 mL, 1.1 M in THF, 1.1 mmol, 1.1 equiv) was added dropwise within 2 min to a solution of purine 1k (239 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (1.5 mL) at 25 °C. The mixture was stirred for 30 min, then a solution of I2 (305 mg, 1.2 mmol, 1.2 equiv) in anhydrous THF (2 mL) was added dropwise. The mixture was stirred for 1 h, and then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with CH2Cl2 (3 × 30 mL), then the combined organic layers were washed with H2O (40 mL) and brine (40 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using CH2Cl2 as eluent to afford purine 3c; yield: 220 mg (60%); white solid; mp 143–145 °C.

1H NMR (CDCl3): δ = 8.68 (s, 1 H), 5.67 (dd, J = 11.4, 2.4 Hz, 1 H), 4.25–4.19 (m, 1 H), 3.79–3.71 (m, 1 H), 3.20–3.07 (m, 1 H), 2.20–2.13 (m, 1 H), 1.94–3.63 (m, 4 H).

13C NMR (CDCl3): δ = 152.5, 151.6, 149.5, 134.3, 106.6, 87.4, 69.3, 28.8, 24.6, 23.3.

MS (70 eV): m/z (%) = 282 (27), 281 (6), 280 (100), 245 (27), 127 (6), 118 (7), 99 (7), 91 (6), 85 (6).

HRMS: m/z calcd for C10H10ClIN4O: 363.9588; found: 363.9580.


#

Metalation at Position 8 of Purines Using TMP2Zn·2MgCl2·2LiCl as Base and Subsequent Quench with Electrophile; General Procedure 1 (GP1)

Freshly prepared TMP2Zn·2MgCl2·2LiCl (1.2 equiv) was added dropwise within 2 min to a solution of the desired purine (1.0 equiv) and the desired electrophile (1.0 equiv) in anhydrous THF (c = ca. 0.5 M) at 0 °C. The mixture was allowed to warm up to 25 °C over 15 min, and then quenched with sat. aq NH4Cl (10 mL). The aqueous layer was extracted with Et2O (3 × 20 mL), then the combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography.


#

9-Benzyl-8-bromo-9H-purine (3d)[26]

Starting from purine 1i (210 mg, 1.0 mmol), following GP1 and using 1,2-dibromo-1,1,2,2-tetrachloroethane as electrophile, the desired purine 3d was obtained after purification by column chromatography using a gradient elution (CH2Cl2–MeOH, 200:0, then 200:1 to 100:1); yield: 238 mg (82%); white solid; mp 130–131 °C.

1H NMR (CDCl3): δ = 9.05 (s, 1 H), 8.99 (s, 1 H), 7.37–7.31 (m, 5 H), 5.49 (s, 2 H).

13C NMR (CDCl3): δ = 152.9, 152.5, 147.2, 134.5, 134.3, 134.2, 129.0, 128.5, 127.9, 47.6.

MS (70 eV): m/z (%) = 290 (36), 289 (20), 288 (37), 287 (16), 209 (100), 92 (13), 91 (87), 65 (28).

HRMS: m/z calcd for C12H9BrN4: 288.0011; found: 287.9994.


#

9-Benzyl-8-bromo-6-chloro-9H-purine (3e)[27]

Starting from purine 1j (245 mg, 1.0 mmol), following GP1 and using 1,2-dibromo-1,1,2,2-tetrachloroethane as electrophile, the desired purine 3e was obtained after purification by column chromatography using a gradient elution (CH2Cl2–pentane, 5:1 to 7:1); yield: 240 mg (75%); white solid; mp 87–88 °C.

1H NMR (CDCl3): δ = 8.75 (s, 1 H), 7.36–7.31 (m, 5 H), 5.49 (s, 2 H).

13C NMR (CDCl3): δ = 152.2, 152.1, 149.5, 134.5, 134.1, 134.0, 129.0, 128.7, 128.0, 48.3.

MS (70 eV): m/z (%) = 324 (15), 323 (7), 322 (11), 245 (14), 244 (6), 243 (45), 92 (6), 91 (100), 65 (9).

HRMS: m/z calcd for C12H8BrClN4: 321.9621; found: 321.9617.


#

8-Bromo-6-chloro-2-iodo-9-(methoxymethyl)-9H-purine (3f)

Starting from purine 1f (325 mg, 1.0 mmol), following GP1 and using 1,2-dibromo-1,1,2,2-tetrachloroethane as electrophile, the desired purine 3f was obtained after purification by column chromatography using a gradient elution (EtOAc–pentane, 1:3 to 1:2); yield: 348 mg (87%); white solid; mp 144–146 °C.

1H NMR (CDCl3): δ = 5.60 (s, 2 H), 3.44 (s, 3 H).

13C NMR (CDCl3): δ = 153.8, 149.0, 134.3, 131.6, 117.1, 74.9, 57.8.

MS (70 eV): m/z (%) = 404 (16), 402 (13), 376 (12), 374 (48), 372 (35), 323 (15), 295 (13), 293 (40), 45 (100).

HRMS: m/z calcd for C7H5BrClIN4: 401.8380; found: 401.8376.


#

9-Benzyl-8-(phenylthio)-9H-purine (3g)

Starting from purine 1i (420 mg, 2.0 mmol), following GP1 (the base was added dropwise within 1.5 h) and using PhSO2SPh as electrophile, the desired purine 3g was obtained after purification by column chromatography using a gradient elution (CH2Cl2–MeOH, 400:1 to 100:1); yield: 380 mg (60%); white solid; mp 134–135 °C.

1H NMR (CDCl3): δ = 8.94 (s, 1 H), 8.93 (s, 1 H), 7.61–7.57 (m, 2 H), 7.46–7.41 (m, 3 H), 7.40–7.31 (m, 5 H), 5.50 (s, 2 H).

13C NMR (CDCl3): δ = 155.6, 153.5, 151.7, 145.7, 134.9, 134.3, 134.2, 129.9, 129.8, 129.0, 128.4, 128.0, 127.2, 46.5.

MS (70 eV): m/z (%) = 319 (17), 318 (83), 317 (54), 227 (7), 209 (30), 167 (39), 92 (7), 91 (100), 65 (12).

HRMS: m/z calcd for C18H14N4S: 318.0939; found: 318.0935.


#

6-Chloro-8-(cyclohex-2-en-1-yl)-2-iodo-9-(methoxymethyl)-9H-purine (3h)

A solution of ZnCl2 (1.0 mL, 1 M in THF, 1.0 mmol, 1.0 equiv) was added to a solution of purine 1f (325 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (1 mL) at 25 °C. The mixture was stirred for 5 min, then cooled to –65 °C prior to add freshly prepared TMPMgCl·LiCl (1.0 mL, 1.13 M in THF, 1.13 mmol, 1.13 equiv) dropwise within 2 min. The mixture was stirred for 30 min, then a solution of CuCN·2LiCl (0.1 mL, 1 M in THF, 0.1 mmol, 0.1 equiv) and 3-bromocyclohexene (225 mg, 1.4 mmol, 1.4 equiv) were successively added. The mixture was allowed to warm up to 25 °C over 2 h, and then quenched with sat. aq NH4Cl (10 mL). The aqueous layer was extracted with Et2O (3 × 20 mL), then the combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using pentane–Et2O (3:1) as eluent to furnish purine 3h; yield: 340 mg (84%); white solid; 102–104 °C.

1H NMR (CDCl3): δ = 6.06–5.99 (m, 1 H), 5.79–5.73 (m, 1 H), 5.60 (s, 2 H), 3.97–3.88 (m, 1 H), 3.40 (s, 3 H), 2.24–2.10 (m, 3 H), 2.08–1.94 (m, 2 H), 1.79–1.64 (m, 1 H).

13C NMR (CDCl3): δ = 161.8, 154.5, 149.0, 130.8, 130.8, 124.3, 115.7, 73.2, 57.4, 35.5, 28.1, 24.5, 21.2.

MS (70 eV): m/z (%) = 406 (13), 404 (39), 375 (13), 374 (28), 373 (19), 361 (28), 359 (23), 345 (14), 308 (15), 81 (14), 79 (14), 45 (100).

HRMS: m/z calcd for C13H14ClIN4O: 403.9901; found: 403.9892.


#

Negishi Cross-Coupling Reactions; General Procedure 2 (GP2)

Freshly prepared TMPZnCl·LiCl (1.1 M in THF, 1.1 equiv) was added dropwise within 2 min to a solution of desired purine derivative (1 equiv) in anhydrous THF (c = ca. 0.7 M) at 25 °C. The reaction mixture was stirred for 30 min prior to adding successively Pd(dba)2 (2 mol%), (o-furyl)3P (4 mol%), and the desired aryl iodide (1.2 equiv). After the completion of the reaction (checked by GC-analysis of reaction aliquots quenched with sat. aq NH4Cl, 2–14 h), the reaction mixture was quenched with sat. aq. NH4Cl (10 mL) The aqueous layer was extracted with CH2Cl2 (3 × 20 mL) and the combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The crude material was purified by column chromatography.


#

Negishi Cross-Coupling Reactions; General Procedure 3 (GP3)

The reaction was carried out as described above in GP2 except that the cross-coupling reaction was performed at 45 °C for 14 h.


#

Ethyl 4-[9-(Methoxymethyl)-9H-purin-8-yl]benzoate (5a)

Starting from purine 1c (0.82 g, 5.0 mmol), following GP2 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 5a was obtained after purification by column chromatography using EtOAc as eluent; yield: 1.51 g (97%); white solid; mp 117–119 °C.

1H NMR (CDCl3): δ = 9.34 (s, 1 H), 9.18 (s, 1 H), 8.24–8.19 (m, 4 H), 5.66 (s, 2 H), 4.43 (q, J = 7.2 Hz, 2 H), 3.60 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H).

13C NMR (CDCl3): δ = 165.7, 156.8, 154.4, 152.8, 147.7, 133.3, 133.1, 132.0, 130.1, 129.8, 73.5, 61.5, 57.9, 14.3.

MS (70 eV): m/z (%) = 312 (18), 283 (13), 282 (64), 281 (77), 267 (17), 253 (13), 209 (17), 133 (11), 45 (100).

HRMS: m/z calcd for C16H16N4O3: 312.1222; found: 312.1216.


#

9-(Methoxymethyl)-8-(4-methoxyphenyl)-9H-purine (5b)

Starting from purine 1c (164 mg, 1.0 mmol), following GP2 and using 4-iodoanisole as aryl iodide, the desired purine 5b was obtained after purification by column chromatography using Et2O as eluent; yield: 165 mg (61%); white solid; mp 164–166 °C.

1H NMR (CDCl3): δ = 9.10 (s, 1 H), 8.97 (s, 1 H), 8.09–8.04 (m, 2 H), 7.09–7.04 (m, 2 H), 5.62 (s, 2 H), 3.89 (s, 3 H), 3.59 (s, 3 H).

13C NMR (CDCl3): δ = 162.1, 156.8, 154.1, 152.3, 147.2, 133.6, 131.4, 120.9, 114.5, 73.2, 57.6, 55.5.

MS (70 eV): m/z (%) = 270 (100), 240 (61), 239 (94), 227 (18), 226 (11), 225 (25), 209 (10), 134 (11), 133 (12), 45 (81).

HRMS: m/z calcd for C14H14N4O2: 270.1117; found: 270.1109.


#

Ethyl 4-[6-Chloro-9-(methoxymethyl)-9H-purin-8-yl]benzoate (5c)

Starting from purine 1a (199 mg, 1.0 mmol), following GP2 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 5c was obtained after purification by column chromatography using pentane–EtOAc (5:1) as eluent; yield: 317 mg (91%); white solid; mp 142–144 °C.

1H NMR (CDCl3): δ = 8.77 (s, 1 H), 8.21–8.18 (m, 4 H), 5.63 (s, 2 H), 4.42 (q, J = 7.3 Hz, 2 H), 3.58 (s, 3 H), 1.42 (t, J = 7.3 Hz, 3 H).

13C NMR (CDCl3): δ = 165.7, 155.7, 154.2, 152.2, 150.6, 132.9, 132.0, 131.1, 130.0, 129.8, 73.9, 61.5, 57.8, 14.3.

MS (70 eV): m/z (%) = 348 (15), 346 (39), 317 (34), 316 (50), 315 (92), 314 (97), 300 (20), 286 (10), 271 (12), 243 (14), 45 (100).

HRMS: m/z calcd for C16H15ClN4O3: 346.0833; found 346.0823.


#

6-Chloro-9-(methoxymethyl)-8-(4-methoxyphenyl)-9H-purine (5d)

Starting from purine 1a (1.19 g, 6.0 mmol), following GP2 and using 4-iodoanisole as aryl iodide, the desired purine 5d was obtained after purification by column chromatography using a gradient elution (EtOAc–pentane, 1:1 to 2:1); yield: 1.74 g (95%); white solid; mp 157–159 °C.

1H NMR (CDCl3): δ = 8.74 (s, 1 H), 8.10 (d, J = 8.6 Hz, 2 H), 7.07 (d, J = 9.1 Hz, 2 H), 5.63 (s, 2 H), 3.91 (s, 3 H), 3.59 (s, 3 H).

13C NMR (CDCl3): δ = 162.3, 157.0, 154.4, 151.5, 149.6, 131.6, 131.1, 120.3, 114.5, 73.9, 57.7, 55.5.

MS (70 eV): m/z (%) = 306 (29), 305 (16), 304 (100), 276 (11), 275 (16), 274 (35), 273 (39), 261 (13), 259 (12), 45 (65).

HRMS: m/z calcd for C14H13ClN4O2: 304.0727; found: 304.0721.


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Ethyl 4-[2-Chloro-9-(methoxymethyl)-9H-purin-8-yl]benzoate (5f)

Starting from purine 1b (199 mg, 1.0 mmol), following GP2 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 5f was obtained after purification by column chromatography using pentane–EtOAc (4:1) as eluent; yield: 200 mg (58%); white solid; mp 142–143 °C.

1H NMR (CDCl3): δ = 9.02 (s, 1 H), 8.25–8.23 (m, 2 H), 8.20–8.18 (m, 2 H), 5.62 (s, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 3.61 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).

13C NMR (CDCl3): δ = 165.7, 156.4, 155.6, 154.7, 149.8, 133.1, 132.4, 132.0, 130.2, 129.7, 73.4, 61.5, 57.8, 14.3.

MS (70 eV): m/z (%) = 348 (17), 346 (48), 318 (24), 317 (41), 316 (59), 315 (79), 301 (16), 287 (13), 271 (14), 243 (21), 45 (100).

HRMS: m/z calcd for C16H15ClN4O3: 346.0833; found: 346.0824.


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Ethyl 4-[2,6-Dichloro-9-(methoxymethyl)-9H-purin-8-yl]benzoate (5g)

Starting from purine 1d (1.4 g, 6.0 mmol), following GP2 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 5g was obtained after purification by column chromatography using pentane–EtOAc (2:1) as eluent; yield: 1.4 g (62%); beige solid; mp 149–151 °C.

1H NMR (CDCl3): δ = 8.25–8.18 (m, 4 H), 5.61 (s, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 3.61 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).

13C NMR (CDCl3): δ = 165.7, 156.4, 155.5, 153.1, 151.4, 133.3, 131.6, 130.3, 130.1, 129.9, 74.0, 61.5, 58.0, 14.3.

MS (70 eV): m/z (%) = 382 (13), 380 (19), 352 (13), 351 (20), 350 (21), 349 (26), 335 (6), 274 (5), 45 (100).

HRMS: m/z calcd for C16H14Cl2N4O3: 380.0443; found: 380.0437.


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2,6-Dichloro-9-(methoxymethyl)-8-(4-methoxyphenyl)-9H-purine (5h)[23]

Starting from purine 1d (2.33 g, 10.0 mmol), following GP2 and using 4-iodoanisole as aryl iodide, the desired purine 5h was obtained after purification by column chromatography using CH2Cl2 as eluent; yield: 2.40 g (71%); white solid; mp 179–181 °C.

1H NMR (CDCl3): δ = 8.08–8.03 (m, 2 H), 7.06–7.02 (m, 2 H), 5.57 (s, 2 H), 3.89 (s, 3 H), 3.59 (s, 3 H).

13C NMR (CDCl3): δ = 162.4, 157.6, 155.7, 152.2, 150.1, 131.6, 130.3, 120.0, 114.6, 74.0, 57.8, 55.5.

MS (70 eV): m/z (%) = 340 (22), 338 (34), 310 (11), 309 (10), 308 (17), 307 (12), 295 (6), 293 (6), 133 (11), 45 (100).

HRMS: m/z calcd for C14H12Cl2N4O2: 338.0337; found: 338.0327.


#

9-(Methoxymethyl)-8-[3-(trifluoromethyl)phenyl]-2-(trimethylsilyl)-9H-purine (5i)

Starting from purine 1g (1.90 g, 8.0 mmol), following GP2 and using 1-iodo-3-(trifluoromethyl)benzene as aryl iodide, the desired purine 5i was obtained after purification by column chromatography using pentane–EtOAc (3:1) as eluent; yield: 1.45 g (48%); white solid; mp 135–136 °C.

1H NMR (CDCl3): δ = 9.27 (s, 1 H), 8.46 (br s, 1 H), 8.36–8.34 (m, 1 H), 7.85–7.83 (m, 1 H), 7.73–7.69 (m, 1 H), 5.69 (s, 2 H), 3.64 (s, 3 H), 0.44 (s, 9 H).

13C NMR (CDCl3): δ = 174.7, 154.4, 153.0, 146.7, 132.8 (q, 3 J C,F = 1 Hz), 132.1, 131.7 (q, 2 J C,F = 33 Hz), 129.7, 129.6, 127.7 (q, 3 J C,F = 4 Hz), 126.7 (q, 3 J C,F = 4 Hz), 123.7 (q, 1 J C,F = 272 Hz), 73.1, 57.9, –1.8.

HRMS (ESI): m/z calcd for C17H19F3N4OSi + H+: 381.1353; found: 381.1350.


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9-(Methoxymethyl)-8-(4-methoxyphenyl)-2-[(4-methoxyphenyl)thio]-9H-purine (5j)

Starting from purine 1h (302 mg, 1.0 mmol), following GP2 and using 4-iodoanisole as aryl iodide, the desired purine 5j was obtained after purification by column chromatography using a gradient elution (EtOAc–pentane, 1:1 to 8:1); yield: 345 mg (85%); orange solid; mp 150–152 °C.

1H NMR (CDCl3): δ = 8.86 (s, 1 H), 7.99 (d, J = 8.6 Hz, 2 H), 7.57 (d, J = 8.6 Hz, 2 H), 7.02 (d, J = 9.1 Hz, 2 H), 6.96 (d, J = 8.6 Hz, 2 H), 5.35 (s, 2 H), 3.86–3.85 (m, 6 H), 3.35 (s, 3 H).

13C NMR (CDCl3): δ = 166.0, 161.8, 160.4, 155.5, 154.9, 147.5, 137.2, 131.1, 130.7, 121.0, 120.8, 114.5, 114.4, 73.2, 57.7, 55.3, 55.3.

MS (70 eV): m/z (%) = 409 (40), 408 (100), 407 (79), 363 (39), 69 (36), 57 (52), 55 (47), 44 (48), 43 (35), 41 (44).

HRMS: m/z calcd for C21H20N4O3S: 408.1256; found: 408.1252.


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Ethyl 4-[9-(Methoxymethyl)-2-(trimethylsilyl)-9H-purin-8-yl]benzoate (5k)[9]

Starting from purine 1g (236 mg, 1.0 mmol), following GP2 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 5k was obtained after purification by column chromatography using pentane–EtOAc (9:1) as eluent; yield: 200 mg (52%); white solid; mp 179–180 °C.

1H NMR (CDCl3): δ = 9.24 (s, 1 H), 8.20 (s, 4 H), 5.67 (s, 2 H), 4.40 (q, J = 7.2 Hz, 2 H), 3.60 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H), 0.41 (s, 9 H).

13C NMR (CDCl3): δ = 174.7, 165.8, 154.8, 153.0, 146.8, 132.9, 132.6, 132.2, 130.0, 129.6, 73.1, 61.4, 57.9, 14.3, –1.8.

MS (70 eV): m/z (%) = 384 (79), 383 (25), 369 (61), 351 (30), 350 (30), 338 (25), 337 (100), 89 (36), 73 (24), 45 (31).

HRMS: m/z calcd for C19H24N4O3Si: 384.1618; found: 384.1620.


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Ethyl 4-[6-Chloro-9-(methoxymethyl)-2-(trimethylsilyl)-9H-purin-8-yl]benzoate (5l)[9]

Starting from purine 1e (271 mg, 1.0 mmol), following GP3 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 5l was obtained after purification by column chromatography using hexane–EtOAc (10:1) as eluent; yield: 380 mg (91%); white solid; mp 121–122 °C. The reaction was performed also on 20 and 30 mmol scales furnishing the desired purine 5l in 70% and 85% yield, respectively.

1H NMR (CDCl3): δ = 8.20 (s, 4 H), 5.65 (s, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.60 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H), 0.40 (s, 9 H).

13C NMR (CDCl3): δ = 175.3, 165.8, 154.9, 153.5, 149.5, 132.8, 132.3, 130.0, 129.9, 129.8, 73.8, 61.4, 58.0, 14.3, –1.9.

MS (70 eV): m/z (%) = 418 (55), 404 (100), 389 (64), 388 (51), 384 (100), 374 (72), 93 (57), 57 (46), 45 (83), 43 (56).

HRMS: m/z calcd for C19H23ClN4O3Si: 418.1228; found: 418.1225.


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Ethyl 4-[6-Iodo-9-(methoxymethyl)-9H-purin-8-yl]benzoate (7a)

A solution of purine 5a (312 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added dropwise within 3 min to freshly prepared TMPMgCl·LiCl (1.3 mL, 0.94 M in THF, 1.2 mmol, 1.2 equiv) at –20 °C. The reaction mixture was stirred for 1 h prior to add a solution of I2 (1.00 g, 3.9 mmol, 3.9 equiv) in anhydrous THF (2 mL). The resulting mixture was allowed to warm up to 0 °C over 3 h, and then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), then the combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using pentane–EtOAc (1:1) as eluent to furnish purine 7a; yield: 306 mg (70%); beige solid; mp 152–154 °C.

1H NMR (CDCl3): δ = 8.68 (s, 1 H), 8.24–8.20 (m, 4 H), 5.61 (s, 2 H), 4.44 (q, J = 7.3 Hz, 2 H), 3.59 (s, 3 H), 1.44 (t, J = 7.1 Hz, 3 H).

13C NMR (CDCl3): δ = 165.7, 155.1, 152.2, 150.5, 138.1, 133.0, 132.1, 130.1, 129.9, 121.6, 73.8, 61.5, 57.8, 14.3.

MS (70 eV): m/z (%) = 439 (14), 438 (62), 409 (17), 408 (100), 407 (88), 393 (17), 239 (11), 238 (14), 221 (11), 207 (16), 45 (70).

HRMS: m/z calcd for C16H15IN4O3: 438.0189; found: 438.0182.


#

6-Iodo-9-(methoxymethyl)-8-(4-methoxyphenyl)-9H-purine (7b)

A solution of purine 5b (270 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added dropwise within 3 min to freshly prepared TMPMgCl·LiCl (1.3 mL, 0.94 M in THF, 1.2 mmol, 1.2 equiv) at –20 °C. The reaction mixture was stirred for 1 h prior to add a solution of I2 (1.00 g, 3.9 mmol, 3.9 equiv) in anhydrous THF (2 mL). The resulting mixture was allowed to warm up to 0 °C over 3 h. and then quenched with sat. aq Na2S2O3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), then the combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography using pentane–Et2O (1:1) as eluent to furnish purine 7b; yield: 238 mg (60%); beige solid; mp 156–158 °C.

1H NMR (CDCl3): δ = 8.63 (s, 1 H), 8.10–8.08 (m, 2 H), 7.08–7.06 (m, 2 H), 5.59 (s, 2 H), 3.90 (s, 3 H), 3.58 (s, 3 H).

13C NMR (CDCl3): δ = 162.3, 156.3, 151.6, 150.6, 138.1, 131.7, 120.3, 120.2, 114.5, 73.9, 57.7, 55.5.

MS (70 eV): m/z (%) = 397 (15), 396 (100), 366 (21), 365 (23), 269 (12), 239 (11), 238 (9), 197 (7), 133 (12), 45 (30).

HRMS: m/z calcd for C14H13IN4O2: 396.0083; found: 396.0074.


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Negishi Cross-Coupling Reactions; General Procedure 4 (GP4)

A solution of the desired purine derivative in anhydrous THF (c = ca. 0.1 M) was added dropwise within 3 min to freshly prepared TMPMgCl·LiCl (0.94 M in THF, 1.2 equiv) at –20 °C. The reaction mixture was stirred for 1 h prior to add a solution of ZnCl2 (1 M in THF, 1.3 equiv). The resulting reaction mixture was allowed to warm up to 25 °C over 30 min, then Pd(dba)2 (2 mol%), (o-furyl)3P (4 mol%), and the desired aryl iodide (1.3 equiv) were successively added. After the completion of the reaction (checked by GC-analysis of reaction aliquots quenched with sat. aq NH4Cl, 3–14 h), the reaction mixture was quenched with sat. aq NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL) and the combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The crude material was purified by column chromatography.


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Ethyl 4-[9-(Methoxymethyl)-6-phenyl-9H-purin-8-yl]benzoate (7c)

Starting from purine 5a (312 mg, 1.0 mmol), following GP4 and using 4-iodobenzene as aryl iodide, the desired purine 7c was obtained after purification by column chromatography using pentane–EtOAc (5:1) as eluent; yield: 245 mg (63%); beige solid; mp 156–157 °C.

1H NMR (CDCl3): δ = 9.07 (s, 1 H), 8.94–8.92 (m, 2 H), 8.28–8.23 (m, 4 H), 7.61–7.43 (m, 3 H), 5.68 (s, 2 H), 4.45 (q, J = 7.0 Hz, 2 H), 3.62 (s, 3 H), 1.45 (t, J = 7.1 Hz, 3 H).

13C NMR (CDCl3): δ = 165.8, 155.1, 154.7, 154.2, 152.4, 135.2, 132.8, 132.6, 131.2, 130.5, 130.0, 129.9, 129.8, 128.7, 73.4, 61.4, 57.6, 14.3.

MS (70 eV): m/z (%) = 388 (26), 359 (9), 358 (46), 357 (100), 343 (10), 329 (13), 285 (6), 209 (9), 45 (23).

HRMS: m/z calcd for C22H20N4O3: 388.1535; found: 388.1529.


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Ethyl 4-[9-(Methoxymethyl)-8-(4-methoxyphenyl)-9H-purin-6-yl]benzoate (7d)

Starting from purine 5b (270 mg, 1.0 mmol), following GP4 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 7d was obtained after purification by column chromatography using pentane–EtOAc (3:1) as eluent; yield: 230 mg (55%); beige solid; mp 158–159 °C.

1H NMR (CDCl3): δ = 9.05–9.01 (m, 3 H), 8.24–8.22 (m, 2 H), 8.18–8.14 (m, 2 H), 7.12–7.08 (m, 2 H), 5.68 (s, 2 H), 4.43 (q, J = 7.0 Hz, 2 H), 3.92 (s, 3 H), 3.62 (s, 3 H), 1.44 (t, J = 7.1 Hz, 3 H).

13C NMR (CDCl3): δ = 166.3, 162.1, 156.4, 155.6, 151.7, 151.7, 139.5, 132.1, 131.5, 131.1, 129.8, 129.7, 121.0, 114.5, 73.4, 61.1, 57.5, 55.5, 14.3.

MS (70 eV): m/z (%) = 419 (21), 418 (86), 389 (9), 388 (43), 387 (100), 373 (17), 359 (15), 315 (9), 300 (9), 159 (8), 45 (28).

HRMS: m/z calcd for C23H22N4O4: 418.1641; found 418.1640.


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Ethyl 4-{9-(Methoxymethyl)-8-[3-(trifluoromethyl)phenyl]}-2-(trimethylsilyl)-9H-purin-6-yl)benzoate (7e)

Starting from purine 5i (380 mg, 1.0 mmol), following GP4 and using ethyl 4-iodobenzoate as aryl iodide, the desired purine 7e was obtained after purification by column chromatography using pentane–CH2Cl2 (5:4) as eluent; yield: 280 mg (55%); beige solid; mp 148–149 °C.

1H NMR (CDCl3): δ = 9.10–9.06 (m, 2 H), 8.52 (br s, 1 H), 8.45–8.42 (m, 1 H), 8.27–8.23 (m, 2 H), 7.87–7.84 (m, 1 H), 7.76–7.71 (m, 1 H), 5.72 (s, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 3.66 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H), 0.49 (s, 9 H).

13C NMR (CDCl3): δ = 174.0, 166.5, 154.6, 153.9, 150.8, 140.4, 133.0 (q, 4 J C,F = 1 Hz), 131.9, 131.7 (q, 2 J C,F = 33 Hz), 130.0, 129.8, 129.7, 129.7, 129.6, 127.5 (q, 3 J C,F = 4 Hz), 126.8 (q, 3 J C,F = 4 Hz), 123.8 (q, 1 J C,F = 272 Hz), 73.2, 61.1, 57.8, 14.3, –1.7.

HRMS (ESI): m/z calcd for C26H27F3N4O3Si + H+: 529.1877; found: 529.1872.


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Acknowledgment

We thank the European Research Council (ERC-227763) for financial support as well as Rockwood Lithium GmbH (Frankfurt), Evonik AG (Hanau), W. C. Heraeus GmbH (Hanau), and BASF AG (Ludwigshafen) for the generous gift of chemicals. We also acknowledge­ Dr. Vladimir Malakhov and Christelle Pecceu for their helpful supports.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
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Figure 1 Array of protected purines examined in the study
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Scheme 1 General reaction scheme for the selective metalation of purine derivatives of type 1 at position 8 and subsequent reaction with an electrophile: Reagents and conditions: (i) TMP-amide base; (ii) electrophile, 60–98%. See Table [1] for more details.
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Scheme 2 General reaction scheme for the selective zincation of purine derivatives of type 1 at position 8 and subsequent Negishi cross-coupling reaction with an aryl iodide. Reagents and conditions: (i) TMPZnCl·LiCl (1.1 equiv), anhyd THF, 30 min, 25 °C; (ii) ArI (1.2 equiv), 48–97%. LiCl in 4 is omitted for clarity. See Table [2] for more details.
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Scheme 3 General reaction scheme for the selective magnesiation of purine derivatives of type 5 at position 6 and subsequent reaction with an electrophile. Reagents and conditions: (i) TMPMgCl·LiCl (1.2 equiv), anhyd THF, 1 h, –20 °C; (ii) electrophile, 53–70%. LiCl in 6 is omitted for clarity. See Table [3] for more details.