C-H Imidation of 7-Deazapurines.

We developed and presented here a ferrocene-catalyzed C-H imidation of 7-deazapurines (pyrrolo[2,3-d]pyrimidines) with N-imidyl peroxyesters. The reactions occur regioselectively at position 8 in 7-deazapurines, leading to a series of 8-succinimido-, phtalimido-, or naphthalimido-7-deazapurine derivatives. Attempted hydrazinolysis of resulting 8-imidyl-7-deazapurines led to corresponding 8-amino-7-deazapurine, which was very unstable and quickly decomposed.

Introduction

Pyrrolo[2,3-d]pyrimidines (7-deazapurines)[1] are carba analogues of purine bases, which exert diversity of biological activities (for clarity and as reference to purines, the (7-deaza)purine nomenclature will be used in Results and Discussion, but the correct IUPAC names are given in the Experimental Section part). Several classes of substituted 7-deazapurine bases are inhibitors of protein kinases[2] and other enzymes,[3] resulting in therapeutically relevant biological effects. Also, many types of 7-deazapurine nucleosides were reported as anticancer agents.[4,5] Therefore, several synthetic approaches to diverse di-, tri-, or tetra-substituted 7-deazapurines were reported.[6] Introduction of a substituent onto the deazapurine scaffold can be achieved either through classical nucleophilic substitution or cross-coupling of a halogen or through C–H activation reactions.[7] In the recent years, our group and others reported C–H borylations,[8] aminations,[9] and phosphonations[10] which proceeded at position 8, whereas the Cu-catalyzed C–H sulfenylations proceeded at position 7.[11] On the other hand, the Ir-catalyzed C–H silylation of 6-aryl-7-deazapurines proceeded predominantly at the aryl group.[12] Therefore, we decided to study a complementary C–H imidation of 7-deazapurine bases to investigate the regioselectivity and possible use in the synthesis of new deazapurine derivatives for biological activity screening.

C–H imidations have been reported in the literature on several arene and heterocycle substrates using diverse reagents, such as N-fluorobenzenesulfonimide under Cu[13] or Ag catalysis,[14] as well as N-halophtalimide derivatives,[15] or N-bromosacharin[16] under photoredox catalysis. The most general seems to be the use of N-succinimidyl peroxyester (NSP)[17] under ferrocene catalysis. Therefore, we decided to use of the latter reagent for imidation of 7-deazapurines.

Results and Discussion

We selected 6-phenyl-9-benzyl-7-deazapurine 1a as a model compound to study its C–H imidation reaction with NSP[17]2a under ferrocene catalysis (Table ). The uncatalyzed reactions with 2 equiv of NSP gave only traces of the desired product 3a (entries 1 and 2). The reaction in the presence of 5 mol % of catalyst in dichloromethane (DCM) at 50 °C gave 3a in 12% yield (entry 3). An increase of the excess of NSP 2a to 2.5 or 2.75 equiv resulted in increased yields of 28 and 32%, respectively (entries 4 and 5). However, further increase of NSP to 3 and 5 equiv did not bring any improvement (entries 6 and 7, respectively). Next, we decided to test the influence of ferrocene catalyst loadings, and with a lower amount of 1 mol %, we observed a decrease of the reaction yield to 23%, whereas with a higher amount of 20 mol %, the yield remained the same (entries 8 and 9). We also tried alternative catalysts, for example, a more electron-rich ferrocene, Cu(I), Mn(III), Pd(II), or Rh2(esp)2, which all worked to a certain extent, but none of them brought any improvement (entries 10–14). Also, all attempts to use other solvents or higher temperature had no positive effect (entries 15–18). Finally, by tuning the reaction concentration, we obtained a slightly better (37%) yield of desired product 3a when performing the reaction in more diluted solution (entry 20). In most reactions, we also recovered ca. 30% of the unreacted starting material and the rest was an inseparable mixture of some highly polar compounds, presumably products of degradation. All other efforts to improve the yield by prolongation of the reaction time or by the use of additives were unsuccessful, and we used the best conditions (from entry 20) in further study.

Table 1

Optimization of C–H Imidation Reaction of 6-Ph-9-Bn-7-Deazapurine (1a) with N-Succinimidyl Peroxyester (2a)a

entry	2a, equiv	catalyst, equiv	solvent	T, °C	yield, %
1	2.0		DCM	20	2
2	2.0		DCM	50	5
3	2.0	Cp2Fe (5%)	DCM	50	12
4	2.5	Cp2Fe (5%)	DCM	50	28
5	2.75	Cp2Fe (5%)	DCM	50	32
6	3.0	Cp2Fe (5%)	DCM	50	32
7	5.0	Cp2Fe (5%)	DCM	50	32
8	2.75	Cp2Fe (1%)	DCM	50	23
9	2.75	Cp2Fe (20%)	DCM	50	32
10	2.75	(Ph2Cp)2Fe (5%)	DCM	50	27
11	2.75	CuOAc (10%)	DCM	50	11
12	2.75	Mn(OAc)3 (10%)	DCM	50	5
13	2.75	Pd(OAc)2 (10%)	DCM	50	8
14	2.75	Rh2(esp)2 (5%)	DCM	50	21
15	2.75	Cp2Fe (5%)	DCE	70	27
16	2.75	Cp2Fe (5%)	THF	50	15
17	2.75	Cp2Fe (5%)	MeCN	80	11
18	2.75	Cp2Fe (5%)	TFE	50	16
19b	2.75	Cp2Fe (5%)	DCM	50	23
20c	2.75	Cp2Fe (5%)	DCM	50	37
21d	2.75	Cp2Fe (5%)	DCM	50	32

Reagents and conditions: for 0.1 mmol of 1a, 1 mL of DCM, under Ar, 5 h.

For 0.1 mmol of 1a, 0.2 mL of DCM.

For 0.1 mmol of 1a, 2 mL of DCM.

1 equiv of LiOBu as an additive.

With optimized reaction conditions in hand, our next step was to study the scope and limitations of the method. A series of diverse 6,9-disubstituted 7-deazapurines was tested in C–H imidation reactions (Scheme ).

Scheme 1

Preparative C−H Imidation of 7-Deazapurines

The reactions of 6-phenyl-, 6-methyl-, and 6-chloro-substituted deazapurines 1a–c proceeded smoothly, giving the desired products 3a–c in acceptable 30–37% yield. Next, we tested the tolerance of other protecting groups at position 9 of 7-deazapurine, and C–H imidation proceeded smoothly with (2-trimethylsilyl)-ethoxymethyl)-protected deazapurine to give imidated product 3d in acceptable 43% yield. Then, we tried C–H imidation of deazapurine 1a with bulkier peroxyesters 2b and 2c bearing phtalimidyl and naphtalimidyl groups. These reactions proceeded reasonably well to afford desired products 3e and 3f in 33–35% yields. On the other hand, the C–H imidation of the 9-benzyl-7-deazaadenine derivative 1e did not proceed, showing that the free amino group is not compatible with this reaction. Also, the attempted reaction of 9-unsubstituted 6-phenyl-7-deazapurine did not give product of imidation. We also tried other related heterocycles, that is, 9-benzyl-6-phenylpurine 4 or -6-phenyl-9-deazapurine 5, and we did not observe any reaction. The structure of 8-imidated-7-deazapurine 3a was confirmed by X-ray crystallography (Figure ).

Figure 1

ORTEP[18] view of 3a (CCDC 1814891) shown with 50% probability displacement ellipsoids.

Because the succinimide or phthalimide moieties often serve as the masked amino groups, we also attempted to cleave them to access 8-amino-7-deazapurines. The hydrazinolysis of 3a or 3e proceeded smoothly, but we were unable to isolate desired 8-amino product 6 in pure form because of the low stability and fast decomposition (Scheme ). 8-Amino-7-deazapurine 6 was brightly fluorescent, but the fluorescence disappeared within several minutes because of the decomposition of the compound. This observation is in accordance with previously reported low stability of related 8-methylamino-7-deazapurines under acidic conditions.[9] Apparently, the free amino function at position 8 of 7-deazapurines makes the molecule very unstable. Analogous 2-aminoindoles were also reported to be prone to protonation, tautomerization, and auto-oxidation.[19]

Scheme 2

Hydrazinolysis of 8-Imido-7-deazapurine Derivatives 3a, 3e

Conclusions

We explored ferrocene-catalyzed direct C–H imidations of 7-deazapurine nucleobases with several types of imidyl peroxyesters. The reactions proceeded with moderate yields, but regioselectively at position 8 of 7-deazapurines to give novel 6,9-disubstituted 8-imidyl-7-deazapurine bases. The method was applicable for 6-chloro-, 6-substituted and 9-protected deazapurines. On the other hand, the protocol was not compatible with deazaadenine, 9-unsubstituted 7-deazapurine, 9-deazapurine, and purine derivatives. The hydrazinolysis of 8-imidyl-7-deazapurines gave very unstable 8-amino-7-deazapurine, which quickly decomposed. The C–H imidation methodology complements the current toolbox of reactions for modification of the privileged deazapurine scaffold and could be used for the further synthesis of modified deazapurine heterocycles for biological activity screening.

Experimental Section

General

6-Chloro-7-deazapurine, 6-chloro-9-deazapurine, 6-chloro purine, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-1,8-naphthalimide, and tert-butyl α-bromoisobutyrate were purchased from commercial suppliers and used without any further purification. Compounds 1a–b, 1e, 1f, 5,[8a]1c,[9] and 1d(8b) were prepared according to reported procedures. Peroxyesters 2a–c(17) were prepared analogously to a reported procedure starting from N-hydroxyimides. Dry solvents were used as received from the supplier. All reactions were carried out under an argon atmosphere. All compounds were fully characterized by NMR, and spectra were recorded with a 500 MHz (499.8 or 500.0 MHz for 1H and 125.7 MHz for 13C) spectrometer. 1H and 13C resonances were assigned based on H,C-HSQC and H,C-HMBC spectra. The samples were measured in CDCl3, and chemical shifts (in ppm, δ-scale) are referenced to solvent signal in CDCl3 [δ (1H) = 7.26 ppm, δ (1H) = 77.0 ppm] or in [d6]DMSO [δ (1H) = 2.50 ppm, δ (1H) = 39.43 ppm]. Coupling constants (J) are given in hertz. High-performance flash column chromatography purifications were performed on KP-Sil columns. High-resolution (HR) mass spectra were measured on a LTQ Orbitrap XL spectrometer using the electrospray ionization (ESI) or electron impact ionization technique. IR spectra were recorded using the KBr method (wavenumbers are given in cm–1). Melting points were determined on a Kofler block and are uncorrected. X-ray diffraction experiment of single crystals was carried out by monochromatized Cu Kα radiation (λ = 1.54180 Å) at 180 K.

General Procedure for C–H Imidation of 7-Deazapurines

7-Deazapurine 1a–d (1.0 mmol), ferrocene (9.3 mg, 0.05 mmol), and perester 2a–c (2.75 mmol) were placed in a vial which was purged with argon. Then, degassed DCM (20 mL) was added, and the reaction mixture was heated to 50 °C and stirred for 5 h. Upon cooling, saturated Na2CO3 (25 mL) was added, followed by extraction with EtOAc (2 × 25 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The crude material was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc to afford the corresponding products.

1-(7-Benzyl-4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidine-2,5-dione (3a)

1a (285 mg, 1 mmol) and 2a (752 mg, 2.75 mmol) were used as starting compounds to give product 3a (142 mg, 37%) as brownish crystals after chromatography (50–60% of EtOAc in hexanes) and crystallization from EtOAc/hexane. mp 176–177 °C. 1H NMR (500 MHz, CDCl3): 2.56 (vbs, 4H, CH2–C4H4O2N), 5.52 (s, 2H, CH2-Ph), 6.84 (s, 1H, H-5), 7.10 (m, 2H, H-o-Bn), 7.26–7.34 (m, 3H, H-p,m-Bn), 7.49–7.58 (m, 3H, H-m,p-Ph), 8.10 (m, 2H, H-o-Ph), 9.06 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 28.19 (CH2–C4H4O2N), 46.11 (CH2-Ph), 100.59 (CH-5); 114.43 (C-4a), 126.94 (CH-o-Bn), 127.71 (C-6), 128.10 (CH-p-Bn), 128.81 (CH-m-Ph), 128.89 (CH-o-Ph), 128.92 (CH-m-Bn), 130.29 (CH-p-Ph), 135.82 (C-i-Bn), 137.66 (C-i-Ph), 151.39 (C-7a), 152.55 (CH-2), 158.34 (C-4), 174.76 (CO–C4H4O2N). IR (KBr): 3132, 2950, 1724, 1589, 1538, 1336, 1156, 946, 728, 692. HRMS (ESI): [M + H] calcd for C23H19N4O2, 383.1502; found, 383.1501.

1-(7-Benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidine-2,5-dione (3b)

1b (243 mg, 1 mmol) and 2a (752 mg, 2.75 mmol) were used as starting compounds to give product 3b (102 mg, 30%) as yellowish crystals after chromatography (50–60% of EtOAc in hexanes) and crystallization from EtOAc/hexane. mp 229–230 °C. 1H NMR (500 MHz, CDCl3): 2.57 (vbs, 4H, CH2–C4H4O2N), 5.46 (s, 2H, CH2-Ph), 6.64 (s, 1H, H-5), 7.06 (m, 2H, H-o-Bn), 7.27–7.34 (m, 3H, H-p,m-Bn), 8.74 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 28.21 (CH2–C4H4O2N), 46.64 (CH2-Ph), 99.66 (CH-5), 116.23 (C-4a), 126.89 (CH-o-Bn), 127.93 (C-6), 128.31 (CH-p-Bn), 129.01 (CH-m-Bn), 135.25 (C-i-Bn), 150.71 (C-7a), 151.79 (CH-2), 152.83 (C-4), 174.50 (CO–C4H4O2N). IR (KBr): 3114, 3058, 1724, 1553, 1464, 1338, 1162, 940, 701, 597. HRMS (ESI): [M + H] calcd for C17H14N4O2Cl, 341.0799; found, 341.0799.

1-(7-Benzyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidine-2,5-dione (3c)

1c (223 mg, 1 mmol) and 2a (752 mg, 2.75 mmol) were used as starting compounds to give product 3c (99 mg, 31%) as a brownish solid after chromatography (80–90% of EtOAc in hexane). mp 190–200 °C. 1H NMR (500 MHz, DMSO-d6): 2.70 (s, 3H, CH3), 2.81 (s, 2 × 2H, H-4′,5′), 5.29 (s, 2H, CH2-Ph), 6.77 (s, 1H, H-5), 7.11 (m, 2H, H-o-Bn), 7.19–7.28 (m, 3H, H-m,p-Bn), 8.76 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 21.12 (CH3-4), 28.95 (CH2-4′,5′), 45.17 (CH2-Ph), 99.24 (CH-5), 116.31 (C-4a), 127.40 (CH-o-Bn), 127.72 (CH-p-Bn), 128.32 (C-6), 128.69 (CH-m-Bn), 136.86 (C-i-Bn), 149.04 (C-7a), 151.43 (CH-2), 159.47 (C-4), 176.70 (CO-1′,3′). IR (KBr): 3138, 2926, 1727, 1589, 1462, 1359, 1162, 896, 734, 695. HRMS (ESI): [M + Na] calcd for C18H16N4O2Na, 343.1165; found, 343.1157.

1-(4-Methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyrrolidine-2,5-dione (3d)

1d (279 mg, 1 mmol) and 2a (752 mg, 2.75 mmol) were used as starting compounds to give product 3d (172 mg, 43%) as brownish oil after chromatography (50–60% of EtOAc in hexane). 1H NMR (500 MHz, DMSO-d6): −0.12 (s, 9H, CH3Si), 0.76 (m, 2H, OCH2CH2Si), 2.90 (s, 4H, CH2CO), 3.33 (m, 2H, OCH2CH2Si), 4.07 (s, 3H, CH3O), 5.42 (s, 2H, NCH2O), 6.58 (s, −H, H-5), 8.53 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): −1.30 (CH3Si), 17.30 (OCH2CH2Si), 28.97 (CH2CO), 54.03 (CH3O), 65.48 (OCH2CH2Si), 70.46 (NCH2O), 98.45 (CH-5), 103.79 (C-4a), 126.27 (C-6), 151.29 (C-7a), 152.02(CH-2), 162.52 (C-4), 176.81 (CH2CO). IR (KBr): 2951, 1728, 1559, 1479, 1364, 1169, 1081, 837, 696. HRMS (ESI): [M + Na] calcd for C17H24N4O4NaSi, 399.1459; found, 399.1460.

2-(7-Benzyl-4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)isoindoline-1,3-dione (3e)

1a (285 mg, 1 mmol) and 2b (884 mg, 2.75 mmol) were used as starting compounds to give product 3e (151 mg, 35%) as brownish crystals after chromatography (50–60% of EtOAc in hexanes) and crystallization from EtOAc/hexane. mp 139–140 °C. 1H NMR (500 MHz, DMSO-d6): 5.47 (s, 2H, CH2Ph), 7.03 (m, 2H, o-Bn), 7.12–7.16 (m, 3H, m-Bn, p-Bn), 7.23 (s, 1H, H-5), 7.56–7.64 (m, 3H, m-Ph, p-Ph), 7.93–8.01 (m, 4H, H-4′,H-5′,H-6′,H-7′), 8.16 (m, 2H, o-Ph), 9.01 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 45.43 (CH2Ph), 100.96 (CH-5), 113.98 (C-4a), 124.31 (CH-4′,CH-7′), 127.21 (CH-o-Bn), 127.75 (CH-p-Bn), 128.69 (CH-m-Bn), 128.98 (CH-o-Ph), 129.29 (C-6), 129.34 (CH-m-Ph), 131.02 (CH-p-Ph), 131.63 (C-3a′,C-7a′), 135.60 (CH-5′,CH-6′), 136.71 (C-i-Bn), 137.02 (C-i-Ph), 150.89 (C-7a), 152.11 (CH-2), 156.71 (C-4), 166.75 (C=O). IR (KBr): 3120, 2944, 1723, 1574, 1512, 1328, 1101, 943, 726, 691. HRMS (ESI): [M + H] calcd for C27H19N4O2, 431.1502; found, 431.1503.

2-(7-Benzyl-4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3f)

1a (143 mg, 0.5 mmol) and 2c (511 mg, 1.375 mmol) were used as starting compounds to give product 3f (79 mg, 33%) as a yellowish solid after chromatography (50–60% of EtOAc in hexane). mp 181–182 °C. 1H NMR (500 MHz, DMSO-d6): 5.42 (s, 2H, CH2-Ph), 7.05–7.12 (m, 5H, H-o,m,p-Bn), 7.19 (s, 1H, H-5), 7.54–7.62 (m, 3H, H-m,p-Ph), 7.92 (dd, 2H, J5′,6′ = 8.3 Hz, J5′,4′ = 7.3 Hz, H-5′,8′), 8.18 (m, 2H, H-o-Ph), 8.49 (dd, 2H, J4′,5′ = 7.3 Hz, J4′,6′ = 1.3 Hz, H-4′,9′), 8.56 (dd, 2H, J6′,5′ = 8.3 Hz, J6′,4′ = 1.3 Hz, H-6′,7′), 8.98 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 45.38 (CH2-Ph), 99.96 (CH-5), 114.10 (C-4a), 122.10 (C-3′a,9′a), 127.36 (CH-p-Bn), 127.51 (CH-5′,8′), 127.58 (CH-o-Bn), 128.32 (CH-m-Bn), 128.78 (CH-o-Ph), 128.30 (C-9′b), 129.15 (CH-m-Ph), 130.63 (CH-p-Ph), 131.45 (CH-4′,9′), 131.72 (C-6′a), 132.90 (C-6), 135.36 (CH-6′,7′), 136.75 (C-i-Bn), 137.47 (C-i-Ph), 150.79 (C-7a), 150.86 (CH-2), 156.35 (C-4), 163.80 (CO-1′,3′). IR (KBr): 3064, 2977, 2358, 1685, 1583, 1347, 1324, 1183, 782, 698. HRMS (ESI): [M + H] calcd for C31H21N4O2, 481.1659; found, 481.1659.

7-Benzyl-4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-amine (6)

3a or 3e (0.2 mmol) was placed in a vial which was purged with argon, followed by addition of methanol (1 mL). Then, hydrazine hydrate (50% solution in water) (0.04 mL, 0.6 mmol) was added dropwise and stirred for 1 h. Product 6 was detectable by thin-layer chromatography, crude NMR, and HR mass spectrometry but was not isolated in pure form because of a very low stability and fast decomposition. HRMS (ESI): [M + H] calcd for C19H17N4, 301.1447; found, 301.1447.