Diversity oriented efficient access of trisubstituted purines via sequential regioselective Mitsunobu coupling and SNAr based C6 functionalizations

Tetrahedron 69 (2013) 680e691

Contents lists available at SciVerse ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Diversity oriented efficient access of trisubstituted purines via sequential regioselective Mitsunobu coupling and SNAr based C6 functionalizations Atul Manvar y, Anamik Shah * National Facility for Drug Discovery, Department of Chemistry, Saurashtra University, Rajkot 360005, Gujarat, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 August 2012 Received in revised form 21 October 2012 Accepted 30 October 2012 Available online 6 November 2012

An efficient protocol for the syntheses of diverse 2,6,7- and 2,6,9-trisubstituted purines is reported starting from the guanine precursor, 2-amino-6-chloropurine nucleoside through subsequent regioselective, high yielding Mitsunobu coupling and nucleophilic substitutions at C6 with versatile primary and secondary amines. A wide range of 2,6,7- and 2,6,9-trisubstituted purines were accessible in good to excellent yields with remarkable functional group tolerance. Moreover, solvent-free, large scale synthesis of precursors 2 & 3 and facile preparation of organophosphorus side chains 4 & 5 were also accomplished with excellent yields. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Oxa-phosphonate ester Mitsunobu coupling SNAr reaction Purines

1. Introduction Purine pharmacophore has become an indispensable structural motif for the drug discovery. Arguably, purine-based skeletons are ubiquitous in versatile therapeutic areas as antimycobacterials, antimalarials, antivirals, cytostatic, agonists and antagonists of adenosine receptors, interferon inducers, and lineage-committed cell dedifferentiation, ligands of corticotropin-releasing hormone receptors, and as inhibitors of Hsp90 (heat shock protein), Src kinase, p38a MAP (Mitogen-activated protein) kinase, sulfotransferases, phosphodiesterases, CDK (cyclin-dependent kinases) etc.1 The novel ANP (acyclic nucleoside phosphonate) (S)-HPMPA, [(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine] and its potential as anti-DNA virus agent was first discovered by De Clercq and co-workers.2 Moreover, the anti-retrovirus activity of PMEA [9(2-phosphonomethoxyethyl)adenine] was also investigated.2 The in vitro and in vivo activity of PMEA against HIV (human immunodeficiency virus)3 and MSV (murine moloney sarcoma virus),4 are well documented. These motifs are known for their low toxicity and favorable pharmacokinetic properties. The ANPs are reverse

* Corresponding author. Tel.: þ91 281 2581013; fax: þ91 281 2589609; e-mail address: [email protected] (A. Shah). URL: http://www.chemdive.com/, https://sites.google.com/site/anamikkantilals hah/home y Present address: Centre for Synthesis & Chemical Biology, UCD-School of Chemistry & Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland. 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.10.079

transcriptase inhibitors and several ANPs have become drugs, e.g., Cidofovir, Adefovir, and Tenofovir are in clinical practice for HIV, CMV (cytomegalovirus), and HBV (hepatitis-B) viral infections.5 The ‘gold standard’ antiviral drug, Acyclovir [9-(2-hydroxyethoxymethyl)guanine] had been approved by FDA (Food and Drug Administration) in 1982 for the treatment of HSV-1 and 2 (herpes simplex virus) infections.6a Penciclovir is formulated as topical cream for the herpes labialis.6b (S)-DHPA [(S)-9-(2,3dihydroxypropyl)adenine]6cee is known to target SAHH (S-adenosylhomocysteine hydrolase) and also used for the treatment of herpes labialis. (R)-PMPDAP [(R)-9-(2-phosphonylmethoxypropyl)2,6-diaminopurine] is remarkably active against HBV at potency comparable to that of Tenofovir.6f (S)-HPMPA could be regarded as a hybrid of (S)-DHPA with a known antiviral candidate, phosphonoformic acid (PFA, Foscarnet). The ANPs are also inhibitors of PfHGXPRT (Plasmodium falciparum hypoxanthineeguaninee xanthine phosphoribosyltransferase).7 Very recently, 6-oxopurine,8 a novel N-branched ANP as a potent and selective inhibitors of human P. falciparum (Pf) and Plasmodium vivax (Pv) phosphoribosyltransferases have been discovered. Despite of their growing importance in drug discovery, there is considerable interest in synthesizing ANP containing nucleobase building blocks (Fig. 1).9 At present, two strategies for the syntheses of nucleobase analogs are existing (i) synthesis of nucleobase from corresponding amino precursors1 followed by installation of functional groups and (ii) transition metal-catalyzed functionalizations10a,b or baseassisted displacement10cef or Mitsunobu coupling.11 The second

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

O HN H2N

N

N O

H2N

N

OH

OH

NH2 N N

Tenofovir (R)-PMPA

O Me

O

HO

N O P OH H N N 2 OH

(R)-PMPDAP

N

P HO OH

HO (S)-DHPA

NH

N

N

O

N O P OH N OH

OH

HO

(S)-HPMPA

Me

N N Adefovir

O

O

O

NH2

N N

N

N

N

N

NH2

NH2 N

N

N

Penciclovir

NH2

N

N

HN OH

Acyclovir

N

NH2

O N

681

O P OH OH

O

N

HN R

O OH P O OH Cidofovir (S)-HPMPC

N

N

aza-ANPs R'

N

OH P OH O

Fig. 1. Structures of acyclic nucleosides/nucleotides possessing antiviral activities.

strategy is more straightforward and step-economical, which usually furnished with good to excellent yields. The nucleophilic substitutions (SNAr) on purines10c are generally accomplished with commercially available purines. The SNAr reaction of 6-halopurine derivatives with strong nucleophiles, such as PhONa, MeONa, MeSNa, and PhSNa etc. is relatively facile.12 On the contrary, the efficiency of poor leaving groups on purines could be enhanced by incorporation of versatile functionalities, for instance trimethylamine,13a N-methylpyrrolidine,13b pyridine,13c imidazole,13d 1hydroxybenzotriazole,13e 1,4-diazabicyclo[2.2.2] octane13f etc. Notably, the nucleophilic displacement of C2 halo group on purine usually requires several equivalents of nucleophiles, prolonged reaction time, and high temperature10c and thereby suffers from low atom economy. To this aid, microwave-assisted nucleophilic displacements14aeh of purines under solvent-, catalyst-, and ligandfree reaction conditions14g are especially appealing. Although, the functionalizations of purines at C6 frequently requires functional

reaction. The 1,3-dioxolane was heated in the presence of acetyl chloride at 80  C by employing Lewis-acid as a catalyst. Among the Lewis-acids screened, (e.g., BF3$OEt2, AlCl3, and ZnCl2), the ZnCl2 was proved to be an optimal, to afford 2-(chloromethoxy)ethyl acetate 2 in 92% yields after fractional distillation. The compound 3 was prepared by MichaeliseArbuzov phosphonate ester synthesis. We treat acetyl derivative 2 with triisopropylphosphite at 110  C for 3 h, afforded 2-(methoxy diisopropylphosphite)ethyl acetate 3 in 90% yields. On acid-catalyzed hydrolysis of 3 in methanol at 60  C, furnished alcohol 4 in noteworthy yields (89%). Finally, tosylation of alcohol 4 was accomplished in relatively mild conditions with 91% yields of compound 5. Thus, practical, large scale, high yield synthesis of bench stable oxa-phosphonate ester side chains 4 and 5 were achieved (Scheme 1). In literature, the synthesis of corresponding synthon, [diisopropyl-(2-chloroethoxy)-methylphosphonate],17 is reported utilizing expensive reagents, such as 1,3,5trioxane and 2-chloroethanol.18

Scheme 1. Reagents and conditions: (i) MeCOCl/ZnCl2, 80  C, 20 h (ii) P(OiPr)3, 110  C, 3 h (iii) MeOH/HCl, 60  C, 6 h (iv) TEA, p-TsCl/CH2Cl2, 15  C, 2 h.

group manipulations.15 While, the alkylation at N9 position of purine could be accomplished either by base-assisted displacement or Mitsunobu coupling, but regioselectivity is an issue in either case. Hence, we have envision for the search of practical, mild, stepeconomical, and high yield protocol for the preparation of hitherto unknown biologically useful 2,6,7- and 2,6,9-trisubstituted purines, which proceeds through site-selective Mitsunobu coupling and SNAr based C6 functionalizations as the key steps, on which we wish to report herein. 2. Results and discussion 2.1. Synthesis of phosphonate ester side chains Our synthetic strategy was started with a multi-step, large scale synthesis of organophosphorus side chain. At the outset, we focused on synthetically viable 1,3-dioxolane as an inexpensive16 and sustainable reagent as well as reaction media in the acetylation

2.2. Regioselective Mitsunobu coupling versus base-assisted alkylations Currently, three methodologies19 for the preparation of N-[2(phosphonomethoxy)ethyl] derivatives of 2-amino-6-chloropurine are existing (i) condensation of corresponding N-(2-hydroxyethyl) derivatives with dialkyl p-toluenesulfonyloxymethanephosphonates in the presence of strong base (ii) alkylation of 2-amino6-chloropurine with an appropriate organophosphorus side chains, and (iii) Mitsunobu coupling of the representative alcohol with nucleobases. The scope of first two strategies is rather limited due to the formation of competing N7 alkylated products in substantial amount. A variety of nucleobases alkylation with organophosphorus side chains and its limitations have already been reported.20 However, we became interested to assess the effectiveness of numerous bases in our envision alkylation of tosylate 5 with 2-amino6-chloropurine 6. Among the versatile bases, we have started with KOtBu in N,N-dimethylformamide (DMF) as a solvent (Table 1, entry

682

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

1). After 15 h heating at 90  C, only 12% alkylated purines were isolated having regioselectivity of 3/1 N9/N7. The effects of versatile acetate bases, such as KOAc, NaOAc, and CsOAc were probed utilizing DMF as a reaction media at 90  C (Table 1, entries 2e3, 11), which delivered 22%, 17%, and 24% alkylated purines, respectively, regardless of regioselectivity. To our delight, the regioisomeric

displacement. In an extensive review,21 we have highlighted the scope of Mitsunobu coupling in organic transformations. Particularly, the Mitsunobu reaction of versatile nucleobases22 with a wide range of alcohols and its site-selectivity has been extensively studied. The direct N9 functionalizations via Mitsunobu coupling of diisopropyl-(2-hydroxyethoxy)-methylphosphonate and 2-amino-

Table 1 Optimization by base assisted alkylation or regioselective Mitsunobu coupling for the synthesis of N7 and N9 isomers of purine

Entry

Method

Reagents and conditions

N9-isomer 8 Yielda (%)

N7-isomer 7 Yielda (%)

Regioselectivity N9/N7

Combined yieldsa (%)

1 2 3 4 5b 6 7 8b 9 10 11 12 13 14 15 16 17 18 19c 20d

A A A A A A A A A A A B B B B B B B B B

KOtBu/DMF, 90  C, 15 h KOAc/DMF, 90  C, 15 h NaOAc/DMF, 90  C, 15 h NaH/DMF, 90  C, 6 h NaH/DMF, 90  C, 6 h Li2CO3/DMSO, 90  C, 15 h Cs2CO3/DMF, 90  C, 6 h Cs2CO3/DMF, 90  C, 6 h Cs2CO3/DMA, 90  C, 6 h Cs2CO3/DMSO, 90  C, 6 h CsOAc/DMF, 90  C, 15 h Ph3P/DIAD, DMF, 0  C to rt, 12 h Ph3P/DIAD, DMF, 0  C to rt, 24 h Ph3P/DEAD, THF, rt, 24 h Ph3P/DEAD, PhMe/DCE (1:1), rt, 12 h Ph3P/DEAD, Dioxane, rt, 12 h Ph3P/DEAD, THF, 70  C, 12 h Ph3P/DIAD, THF, 70  C, 12 h Ph3P/DIAD, THF, 70  C, 12 h Ph3P/DIAD, THF, 70  C, 5 h

9 15 12 53 50 24 51 52 55 42 18 47 50 50 34 52 60 65 67 80

3 7 5 13 7 14 14 7 12 13 6 5 5 6 6 6 4 3 3 Trace

3/1 2.1/1 2.4/1 4/1 7.1/1 1.7/1 3.6/1 7.4 4.6/1 3.2/1 3/1 9.4/1 10/1 8.3/1 5.6/1 8.6/1 15/1 21.6/1 22.3/1 >80/1

12 22 17 66 57 31 65 59 67 55 24 52 55 56 40 58 64 68 70 81

Reagents and conditions: unless otherwise mentioned, the reactions were carried out under N2 atmosphere. Method A: 2-amino-6-chloropurine 6 (1.0 mmol), tosylate 5 (1.2 mmol), base (1.0 mmol), anhydrous solvent (5.0 mL) at specified temperature and time. a Isolated yields after column chromatography. b 2-Amino-6-chloropurine 6 (1.0 mmol), tosylate 5 (1.2 mmol), base (0.5 mmol), anhydrous solvent (5.0 mL) was heated at 90  C, after 3 h a portion (0.5 mmol) of base was added and heated the reaction mass further 3 h. Method B: 2-amino-6-chloropurine 6 (1.0 mmol), alcohol 4 (1.05 mmol), Ph3P (1.05 mmol), and DEAD or DIAD (1.05 mmol) in anhydrous solvent (5.0 mL); DEAD: diethylazodicarboxylate; DIAD: diisopropylazodicarboxylate; DCE: 1,2-dichloroethane; DMA: N,N-dimethylacetamide. c Alcohol 4 (2.0 mmol), Ph3P (2.0 mmol), and DIAD (2.0 mmol). d One more equivalents of alcohol 4 (1.05 mmol), Ph3P (1.05 mmol), and DIAD (1.05 mmol) were added and the reaction mass was further heated at 70  C for 5 h.

purines were purified by column chromatography on alumina. Owing to poor yields and regioselectivity with a set of bases screened so far, we now became interested to examine the expected N9 alkylation utilizing NaH as a strong base in DMF at 90  C for 7 h (Table 1, entry 4). The reaction was proceeded efficiently with considerable increase in the yields (66%) with a regioselectivity of 4/1 N9/N7 purines. Among various carbonate bases screened (Table 1, entries 6e10), the significant yield improvement was observed with Cs2CO3, devoid of regioselectivity. The addition of NaH or Cs2CO3 in a two portions, did not improve the yields as well as site-selectivity (Table 1, entries 5 and 8). Surprisingly, however, neither the use of DMA nor DMSO as solvents in the presence of Cs2CO3 provided significant amounts of the desired products. Thus, a range of bases and solvent explored for this alkylation reaction gave inferior results. Consequently, we reasoned to focus on Mitsunobu coupling21 in our expected N9 coupling, which proceeds through sequential pathways of activation of alcohol by dialkylazodicarboxylate followed by nucleophilic

6-chloropurine nucleophile have been reported23 with a decent yield of N9 purine (45%) but no elaborative study was envisaged for the yield improvement. Presumably, the lowering of yields, due to the poor solubility of 2-amino-6-chloropurine in DMF at ambient temperature and competing alkylations. Hence, in the current paper, we aimed to investigate synthetically viable reaction parameters for the regioselective Mitsunobu coupling. We have initiated our envisioned Mitsunobu reaction in the presence of DMF utilizing Ph3P/DIAD as a redox system at ambient temperature for 12 h. Gratifyingly, we were able to isolate 52% products without obtaining satisfactory regioselectivity (Table 1, entry 12). Thus, in the next experiment we stirred the reaction mixture for 24 h at ambient temperature, but no dramatic yield improvement was noticed (Table 1, entry 13). Altering the solvent from DMF to the solvent of choice for the Mitsunobu reaction, non-polar THF and Ph3P/DEAD duet, almost comparable yields were isolated after 24 h (Table 1, entry 14). In either of the above experiments, we did not achieve remarkable N9 regioselectivity as well as yields. We then

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

probed the effects of co-solvents in our expected coupling (Table 1, entry 15), however, the 2-amino-6-chloropurine is poorly soluble in toluene/DCE mixture, which furnished with a modest yields (40%). By employing the 1,4-dioxane as a solvent, the reaction was proceeded at ambient temperature with 58% yields, but lack of regioselectivity (Table 1, entry 16). The 2-amino-6-chloropurine is poorly soluble in THF at room temperature, to improve its solubility the reaction mass was heated at 70  C. On refluxing in anhydrous THF in the presence of DEAD/PPh3 redox system, alcohol 4 was

683

secondary amines are comparatively facile, whereas the displacement of C2 halo group often demands excess of amine under harsh reaction conditions. In a search for the ideal reaction condition and suitable base, we have initiated optimization studies on a model reaction of N9 purine 8 (1.0 mmol) with primary amine nucleophile, benzylamine (1.05 mmol) in the presence of versatile bases and solvents at different temperatures enlisted in Table 2. On assessing a series of experiments, we have investigated the effectiveness of numerous

Table 2 Screening of bases and solvents in the SNAr reactions of N9 purinea

Entry

Solvent (s)

Base/equiv

GC yield (%)

T ( C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

DMSO DMF DMF DMA DMF/IPA (9:1) MeCN/NMP (1:1) NMP MeCN MeCN MeCN Acetone IPA n-Butanol Ethanol Ethanol MeCN t-AmOH

DIPEA/1.0 DIPEA/1.0 TEA/1.0 DIPEA/1.0 DIPEA/1.0 DIPEA/1.0 TEA/1.0 DIPEA/1.0 DIPEA/2.0 DIPEA/1.0 K2CO3/1.0 DIPEA/1.0 DIPEA/1.0 DIPEA/1.0 DABCO/1.0 DBU/1.0 DIPEA/1.0

65 64 61 67 77 75 69 90 90 21 45 79 83 79 72 65 71

100 100 100 100 80 80 80 80 80 rt 55 80 80 80 80 80 80

a b

(71)b (72)b (87)b (85)b

(81)b (77)b (68)b (62)b

Reagents and conditions: compound 9 (392 mg, 1.0 mmol), benzylamine (115 mL, 1.05 mmol), solvent (5 mL). The values in the parenthesis denotes the yields of the isolated products after column chromatography.

consumed within 6 h, while some of the 2-amino-6-chloropurine was remained unreacted on TLC. This observation could be attributed to the significant decomposition of the activated alcohol, which might be responsible for lowering of yields of the coupled products, nevertheless, we were pleased to isolate 64% of combined purines (Table 1, entry 17). Altering to DIAD/PPh3 as a reagent under reflux condition, we were able to isolate 68% purines in a ratio of 21.6/1 N9/N7. Despite the lower yields, we were able to suppress the formation of undesired N7 purine (Table 1, entry 18). By employing 2 mol equiv of alcohol and DIAD/Ph3P resulted into slightly improvement of the expected coupling product (Table 1, entry 19). In striking contrast, addition of one more round of alcohol 4 and DIAD/Ph3P, after 10 h of reaction time, we were delighted to isolate 81% N9 alkylated purine as a dominant product (Table 1, entry 20). Consequently, the current methodology was proved to be applicable to increase the regioselectivity and yields substantially in a highly efficient way of the Mitsunobu coupling. Thus, we accomplished mild, step-economical, and high yield synthesis of N9 alkylated purine via Mitsunobu reaction as a key step. 2.3. SNAr based nucleophilic substitutions on purines It is worth mentioning that because of their biological relevance, we reasoned to elaborate the scope of these purines via SNAr based C6 functionalizations on N7 and N9 isomers. The nucleophilic substitutions on nucleobases consisting C6 halo group with primary or

€ nig’s base, triethylamine, bases including amidines, such as Hu K2CO3, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicycloundec-7ene (DBU) in the nucleophilic substitution reaction. Among a set of € nig’s base was proved to be an optimal, which bases screened, Hu delivered good to excellent yields. In the next step, we would interest to probe an ideal solvent for this reaction. Among a set of alcoholic solvents employed, n-butanol gave better GC conversion and decent yields at 80  C (Table 2, entry 13). We have also examined the influence of polar solvents, such as DMSO, DMF, DMA, and NMP, unfortunately, neither of them furnished with significant conversion on GCeMS. Moreover, the use of co-solvents was ineffective to improve the reaction profile (Table 2, entries 5e6). Among a set of representative solvents examined, acetonitrile turned out to be the best solvent (Table 1, entry 8). No dramatic yield improvement was observed by using extra equivalents of € nig’s base (Table 2, entry 9). To our surprise, at ambient temHu perature the reaction proceeded with poor conversion (21%) (Table 1, entry 10). With optimized conditions in hand, we next explore the scope and generality of our protocol with a wide range of synthetically challenging amines (Scheme 2). Owing to its remarkable efficiency, the current methodology is proved to be applicable to functionalize the vast range of primary amine nucleophile, for example, n-propylamine, n-butylamine, ethane1,2-diamine, propane-1,2-diamine, n-octylamine, n-diisopropylamine, cyclohexylamine, and 2-amino-1-butanol. The C6 chloro SNAr reaction with above mentioned primary amine nucleophiles

684

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

Scheme 2. Scope of SNAr reaction of N9 purine with amines. Unless otherwise mentioned, the reactions were performed under N2 atmosphere. N9 purine 8 (392 mg, 1.0 mmol), amine (1.05 mmol), DIPEA (1.2 mmol), MeCN (5.0 mL).

were proceeded smoothly to deliver 77e92% yields. To our delight, the reaction was also tolerant to indole containing alkaloid tryptamine, which delivered 78% yields. Intrigued by above findings, we now became interested to utilize secondary amine nucleophiles in our reaction. Among versatile secondary amine nucleophiles probed, the nucleophilic displacement with piperazine derivatives (9b, 9e, 9h, 9i, and 9q) were proceeded smoothly to obtain corresponding C6 substituted purines with 81e91% yields. Gratifyingly, piperidine and morpholine were also efficiently installed at C6 with 87% and 82% yields, respectively (Scheme 2). The reaction time could be varied depending upon the reactivity of amines. To further demonstrate the significance of this methodology and to explore the substrate scope of bioactive purine heterocycle, we have also probed the C6 nucleophilic substitutions of N7 isomer of purine. The results are depicted in Scheme 3. Under preparative

conditions, a wide array of primary and secondary, including sterically hindered amines could be participated in the SNAr reaction of N7 purine with good to excellent yields and tolerated valuable functional groups. Thus, nucleophilic displacement reactions were broadly applicable to furnish hitherto unknown N7 analogs of purines. 3. Conclusion We have developed atom- and step-economical, practical, sustainable, and scalable synthesis of oxa-phosphonate ester side chain intermediates in excellent yields. Moreover, the attractive features of our methodology are remarkably mild, regioselective, and high yielding Mitsunobu coupling as well as base-assisted C6 nucleophilic displacements of N7 and N9 purine nucleosides. Our protocol could be applicable to expand the synthesis of

Scheme 3. Scope of SNAr reaction of N7 purine with amines. Unless otherwise mentioned, the reactions were performed under N2 atmosphere. N7 purine 7 (1.0 mmol), amine (1.05 mmol), DIPEA, (2.0 mmol), MeCN (5.0 mL).

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

indispensable biologically active purine nucleobases, which plays a significant role in the life processes.

685

(132.5 g, 89%). Anal. Calcd for C9H21O5P: C 45.00%, H 8.81%; found: C 45.09%, H 8.75%. 1H NMR (300 MHz, CDCl3): d 5.35 (br s, 1H), 4.79e4.73 (m, 2H), 3.82 (d, 4H), 3.74e3.71 (m, 4H), 1.34 (s, 12H).

4. Experimental 4.1. Materials and methods Unless otherwise stated, all reactions were carried out in predried glasswares under N2 atmosphere. Chemicals and solvents were purchased commercially. Solvents were dried and 1 or 2 amines were purified before using in the reactions.24 Yields refer to isolated compounds, estimated to be >95% pure as determined by 1 H NMR. TLC: MachereyeNagel, TLC plates AlugramÒ Sil G/UV254. Detection under UV light at 254 nm. Chromatography: separations were carried out on Merck Silica 60 (0.063e0.200 mm, 70e230 mesh ASTM). Melting points were determined in open capillary tubes with an Electrothermal-9200 melting point apparatus and are uncorrected. All IR spectra were recorded on Shimadzu FTIR-8400 using KBr disc techniques. The percentage transmittance is given in cm1. 1H and 13C NMR spectra were recorded on Bruker 300 and 400 MHz instruments using CDCl3 and D2O as the solvents with tetramethylsilane (TMS) as an internal standard. Chemical shifts were recorded in parts per million and coupling constants (J) are in Hertz. All mass spectra were recorded on Shimadzu GCeMS-QP2010 by EI technique. All elemental analysis was performed on EuroVector EA3000.

4.5. Synthesis of 2-{(isopropoxyphosphono)methoxy}-ethyl4-methylbenzenesulfonate (5) To a stirred solution of compound 4 (150 g, 0.62 mol) in dichloromethane (600 mL), triethylamine (103 mL, 0.74 mol) was added. The resulting solution was cooled to 15  C. A solution of ptoluenesulfonyl chloride (152.4 g, 0.8 mol) in 200 mL of dichloromethane was added dropwise. After the completion of addition, the reaction mixture was stirred for 2 h at ambient temperature. The progress of the reaction was checked by TLC (ethyl acetate/nhexane¼1/9). The reaction mass was washed with sodium bicarbonate (1100 mL) followed by water (3250 mL) and brine (2100 mL), dried over sodium sulfate. The solvent was removed in vacuo to leave the crude products. Finally, it was purified by silica gel column chromatography by using ethyl acetate/n-hexane as the eluents (224.1 g, 91%). Anal. Calcd for C16H27O7PS: C 48.72%, H 6.90%; found: C 48.80%, H 6.96%. 1H NMR (300 MHz, CDCl3): d 7.78 (d, J¼8.2 Hz, 2H), 7.35 (d, J¼8.3 Hz, 2H), 4.75e4.67 (m, 2H), 4.17e4.10 (m, 2H), 3.79 (t, 2H), 3.71 (d, J¼8.2 Hz, 2H), 2.44 (s, 3H), 1.35e1.23 (t, 12H).

4.2. Synthesis of 2-(chloromethoxy)ethyl acetate (2) To an oven dried flask equipped with mechanical stirrer, zinc chloride (5.0 g, 0.036 mol) and 1,3-dioxolane (250 g, 3.37 mol) were added under N2. The reaction mixture was stirred at ambient temperature for 30 min. To the reaction mass, acetyl chloride (317.9 g, 4.05 mol) was added dropwise over a period of 1 h. After the completion of addition, the reaction mixture was heated at 80  C for 1 h. The brown reaction mixture was cooled to ambient temperature and stirred for 20 h under N2. Finally, the product was collected by distillation at 75  C (4 mmHg) as colorless oil (473.7 g, 92%). Anal. Calcd for C5H9ClO3: C 39.36%, H 5.96%; found: C 39.44%, H 5.89%. 1H NMR (300 MHz, CDCl3): d 5.48 (s, 2H), 4.23 (t, 2H), 3.86 (t, 2H), 2.05 (s, 3H). 4.3. Synthesis of 2-(methoxy diisopropylphosphite)ethyl acetate (3) To an oven dried flask equipped with mechanical stirrer, compound 2 (200 g, 1.31 mol) was added and pre-heated at 110  C. To the reaction mass, triisopropylphosphite (272.9 g, 1.31 mol) was added dropwise and heated for 3 h at the same temperature. The 2chloropropane (bp¼36  C, 95 mL) was collected during the progress of reaction. Finally, the product was purified by distillation at 150  C (2 mmHg) to afford colorless oil (333 g, 90%). Anal. Calcd for C11H23O6P: C 46.81%, H 8.21%; found: C 46.89%, H 8.29%. 1H NMR (300 MHz, CDCl3): d 4.67e4.61 (m, 2H), 4.10 (d, J¼3.7 Hz, 2H), 3.66 (d, 4H), 1.94 (s, 3H), 1.23 (s, 6H), 1.21 (s, 6H). 4.4. Synthesis of diisopropyl-(2-hydroxyethoxy)methylphosphonate (4) To an oven dried flask, compound 3 (175 g, 0.062 mol) was added in methanol (500 mL) and stirred at ambient temperature. To a stirred reaction mass, concd HCl (12 mL) was added and it was refluxed for 6 h. After the completion of reaction as indicated by TLC (ethyl acetate/n-hexane¼1/9), methanol was removed in vacuo leaves the crude oil. A trace of water was removed with toluene as azeotrope on rotary evaporator for 6 h, afforded colorless oil

4.6. Synthesis of bis-(2-propyl)-7-[2-(phosphonomethoxy) ethyl]-2-amino-6-chloropurine (7) and bis-(2-propyl)-9-[2(phosphonomethoxy)ethyl]-2-amino-6-chloropurine (8) The title compounds were synthesized by Method A and Method B. 4.6.1. Representative procedure for alkylation (Method A). To an oven dried flask, N,N-dimethylformamide (5 mL), base (1.0 mmol), and 2-amino-6-chloropurine 6 (1.0 mmol) were added under N2 and stirred at ambient temperature. The tosylate 5 (1.2 mmol) was dissolved in DMF (2.5 mL) and it was added dropwise. The reaction mixture was heated at 90  C for an appropriate time as mentioned in Table 1. After completion of reaction as indicated by TLC (dichloromethane/methanol¼8.5/1.5), DMF was removed in vacuo and the product was dissolved in dichloromethane (30 mL), washed with water (210 mL), and brine (115 mL), dried over sodium sulfate. The solvent was removed at reduced pressure leaves the crude products, which was purified by column chromatography on alumina (dichloromethane/methanol: 98/2/95/5/90/10) as the eluents afforded N7 and N9 isomers of purines. The same methodology was adopted utilizing various bases depicted in Table 1, entries 1e11. 4.6.2. Representative procedure for Mitsunobu coupling (Method B). To an oven dried flask, 2-amino-6-chloropurine 6 (1.0 mmol), alcohol 4 (1.05 mmol), triphenylphosphine (1.05 mmol), and anhydrous DMF (5 mL) were added under N2. The reaction mixture was stirred at ambient temperature for 15 min. The dialkylazodicarboxylate (1.05 mmol) in DMF (2.5 mL) was added dropwise at same temperature. The reaction mixture was heated at specified temperature and time as depicted in Table 1. The progress of the reaction was checked by TLC (dichloromethane/methanol¼8.5/1.5). DMF was removed in vacuo and the solid mass was dissolved in dichloromethane (30 mL), washed with water (210 mL) and brine (115 mL), and dried over sodium sulfate. The solvent was removed at reduced pressure leaves the crude product, which was purified by column chromatography on alumina

686

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

(dichloromethane/methanol: 98/2/95/5/90/10) as the eluents afforded N7 and N9 isomers of purines. 4.6.3. {Bis(2-propyl)-7-[2-(phosphonomethoxy)ethyl]}-2-amino-6chloropurine (7). Mp¼150e151  C (lit. 152  C)17 as a yellow solid. [Anal. Calcd for C14H23ClN5O4P: C 42.90%, H 5.92%, N 17.88%; found: C 42.97%, H 5.98%, N 17.83%]; Rf¼0.41. 1H NMR (400 MHz, CDCl3): d 8.09 (s, 1H), 5.58 (br s, 2H, NH2 exchangeable), 4.72e4.64 (m, 2H), 4.56 (t, 2H), 3.97 (t, 2H), 3.73 (d, J¼8.0 Hz, 2H), 1.33e1.25 (m, 12H). 13 C NMR (100 MHz, CDCl3): d 164.2, 159.4, 149.5, 143.0, 115.7, 71.2 (JCeP¼10 Hz), 71.1, 66.8, 65.2, 23.9. IR (KBr disc): 3408, 2923, 1598, 1545, 1357, 1300, 1194, 1107, 985, 807 cm1. EI-MS: m/z 391 (Mþ, 2), 197 (19), 169 (22), 139 (79), 125 (29), 97 (63), 65 (16), 43 (100), 41 (35). 4.6.4. {Bis(2-propyl)-9-[2-(phosphonomethoxy)ethyl]}-2-amino-6chloropurine (8). Mp¼91e93  C (lit. 93  C)17 as a brown solid; [Anal. Calcd for C14H23ClN5O4P: C 42.90%, H 5.92%, N 17.88%; found: C 42.98%, H 5.95%, N 17.83%]; Rf¼0.30. 1H NMR (400 MHz, CDCl3): d 8.08 (s, 1H), 6.80 (br s, 2H, NH2 exchangeable), 4.50e4.45 (m, 2H), 4.23 (t, 2H), 3.87 (t, 2H), 3.77 (d, J¼8.4 Hz, 2H), 1.25e1.12 (d, 12H). 13 C NMR (100 MHz, CDCl3): d 160.2, 154.5, 149.6, 143.8, 123.6, 70.6 (JCeP¼10 Hz), 70.3, 65.8, 64.1, 24.15, 24.10, 24.04, 24.0. IR (KBr disc): 3361, 2930, 1614, 1561, 1374, 1353, 1315, 1228, 1104, 992, 787, 642 cm1. EI-MS: m/z 391 (Mþ, 10), 290 (20), 196 (100), 195 (60), 169 (56), 160 (27), 134 (32), 125 (19), 95 (28), 43 (73), 41 (25). 4.7. Representative procedure A for the syntheses of compounds (9aes) To a stirred solution of compound 8 (392 mg, 1.0 mmol) and DIPEA (209 mL, 1.2 mmol) in acetonitrile (5 mL), the corresponding 1 or 2 amine (1.05 mmol) was added dropwise at ambient temperature. After the completion of addition, the reaction mixture was heated at 80  C for specified time as depicted in Scheme 2. The reaction was monitored by TLC (dichloromethane/methanol¼9/1). After completion of the reaction, acetonitrile was removed in vacuo, and dichloromethane (30 mL) was added. The organic layer was washed with water (210 mL) and brine (110 mL), and dried over sodium sulfate. The solvent was removed in vacuo, leaves the crude products. Finally, it was purified by silica gel column chromatography using dichloromethane/methanol as the eluents. The compounds (9aes) were synthesized by above procedure. 4.7.1. Diisopropyl{2-[2-amino-6-(benzylamino)-9H-purine-9-yl]ethoxy}methylphosphonate (9a). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and benzylamine (115 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/3/95/5), yielded the title compound 9a (403 mg, 87%) as a yellow solid; [Anal. Calcd for C21H31N6O4P: C 54.54%, H 6.76%, N 18.17%; found: C 54.59%, H 6.81%, N 18.13%]; Rf¼0.37, mp¼94e96  C. 1H NMR (400 MHz, CDCl3): d 7.51 (s, 1H), 7.33e7.23 (m, 5H), 6.29 (br s, 1H, NH exchangeable), 4.93 (s, 2H), 4.77 (br s, 2H, NH2 exchangeable), 4.71e4.66 (m, 2H), 4.18 (t, 2H), 3.86 (t, 2H), 3.70 (d, J¼8.3 Hz, 2H), 1.30e1.25 (m, 12H). 13C NMR (100 MHz, CDCl3): d 159.9, 155.0, 151.1, 138.9, 138.1, 128.1, 127.6, 127.2, 114.1, 71.3 (JCeP¼10 Hz), 71.1, 66.7, 65.1, 42.8, 24.0, 23.98, 23.95, 23.90. IR (KBr disc): 3497, 3284, 3184, 2980, 1626, 1585, 1373, 1271, 1178, 1120, 910 cm1. EI-MS: m/z 462 (Mþ, 18), 283 (37), 240 (21), 163 (23), 135 (18), 106 (36), 91 (100), 43 (44). 4.7.2. Diisopropyl{2-[2-amino-6-(4-ethylpiperazine-1-yl)-9H-purine-9-yl]ethoxy}methylphosphonate (9b). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and 1-ethylpiperazine (133 mL, 1.05 mmol). Purification by column

chromatography (dichloromethane/methanol: 100/99/1/97/ 3/95/5), yielded the title compound 9b (385 mg, 82%) as a colorless oil; [Anal. Calcd for C20H36N7O4P: C 51.16%, H 7.73%, N 20.88%; found: C 51.22%, H 7.78%, N 20.95%]; Rf¼0.25. 1H NMR (400 MHz, CDCl3): d 7.57 (s, 1H), 4.83 (br s, 2H, NH2 exchangeable), 4.78e4.61 (m, 2H), 4.47 (t, 2H), 3.90 (t, 2H), 3.58 (d, J¼7.8 Hz, 2H), 3.45 (s, 3H), 2.71 (m, 5H), 2.60 (q, 3H), 1.30e1.21 (m, 12H), 1.19 (t, 3H). 13C NMR (100 MHz, CDCl3): d 159.3, 156.2, 153.2, 137.5, 114.8, 71.7 (JCeP¼20 Hz), 71.3, 66.8, 65.1, 52.8, 52.7, 50.0, 47.2, 24.1, 11.3. IR (KBr disc): 3261, 3215, 2961, 1579, 1351, 1278, 1219, 1127, 918 cm1. EIMS: m/z 469 (Mþ, 19), 372 (95), 343 (55), 301 (33), 195 (30), 177 (49), 161 (21), 150 (100), 82 (33), 56 (21), 43 (44). 4.7.3. Diisopropyl{2-[2-amino-6-((2,4-dimethylpentane-3-yl) amino)-9H-purine-9-yl] ethoxy}methylphosphonate (9c). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and 3-amino-2,4-dimethylpentane (156 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/98/2/95/5), yielded the title compound 9c (362 mg, 77%) as a colorless oil; [Anal. Calcd for C21H39N6O4P: C 53.60%, H 8.35%, N 17.86%; found: C 53.66%, H 8.39%, N 17.89%]; Rf¼0.31. 1H NMR (400 MHz, CDCl3): d 7.55 (s, 1H), 4.91 (br s, 2H, NH2 exchangeable), 4.52e4.47 (m, 2H), 4.25 (t, 2H), 3.88 (t, 2H), 3.74 (d, J¼8.2 Hz, 2H), 2.29e2.21 (m, 2H), 1.27e1.13 (m, 12H), 1.01e0.97 (m, 12H). 13C NMR (100 MHz, CDCl3): d 159.7, 151.9, 143.8, 137.2, 115.2, 71.24 (JCeP¼8 Hz), 71.1, 70.5, 66.9, 65.5, 35.2, 24.12, 24.09, 24.01, 23.99, 17.26, 17.18, 17.12, 17.05. IR (KBr disc): 3419, 3319, 3238, 2986, 1649, 1571, 1357, 1269, 1165, 1129, 915 cm1. EI-MS: m/z 470 (Mþ, 13), 372 (33), 357 (23), 342 (25), 258 (100), 224 (41), 164 (32), 120 (19), 107 (25), 80 (18), 43 (21). 4.7.4. Diisopropyl{2-[2-amino-6-(piperidine-1-yl)-9H-purine-9-yl] ethoxy}methylphosphonate (9d). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and piperidine (104 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/95/5), yielded the title compound 9d (383 mg, 87%) as a yellow solid; [Anal. Calcd for C19H33N6O4P: C 51.81%, H 7.55%, N 19.08%; found: C 51.86%, H 7.58%, N 19.14%]; Rf¼0.29, mp¼96e98  C. 1H NMR (400 MHz, CDCl3): d 7.57 (s, 1H), 4.78 (br s, 2H, NH2 exchangeable), 4.73e4.65 (m, 3H), 4.29e4.15 (m, 5H), 3.92e3.87 (m, 3H), 3.72 (d, 2H), 1.65 (m, 5H), 1.30 (d, 6H), 1.27 (d, 6H). 13C NMR (100 MHz, CDCl3): d 159.1, 152.6, 143.1, 136.6, 114.4, 71.23 (JCeP¼13 Hz), 71.13, 66.7, 65.1, 46.0, 43.3, 42.8, 26.0, 24.8, 23.98, 23.95, 23.91. IR (KBr disc): 3336, 3217, 2976, 1645, 1568, 1371, 1278, 1188, 1101, 941 cm1. EI-MS: m/z 440 (Mþ, 23), 355 (16), 261 (93), 246 (100), 218 (16), 190 (30), 178 (22), 135 (16), 84 (19), 43 (33), 41 (18). 4.7.5. Diisopropyl{2-[2-amino-6-(piperazine-1-yl)-9H-purine-9-yl] ethoxy}methyl phosphonate (9e). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and piperazine (91 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/3/95/5), yielded the title compound 9e (402 mg, 91%) as a white solid; [Anal. Calcd for C18H32N7O4P: C 48.97%, H 7.31%, N 22.21%; found: C 48.95%, H 7.36%, N 22.16%]; Rf¼0.29, mp¼168e170  C. 1H NMR (400 MHz, CDCl3): d 7.61 (s, 1H), 4.80 (br s, 2H, NH2 exchangeable), 4.76e4.66 (m, 2H), 4.34 (m, 8H), 4.23 (t, 2H), 3.89 (t, 2H), 3.72 (d, J¼8.3 Hz, 2H), 1.32e1.27 (q, 12H). 13C NMR (400 MHz, CDCl3): d 159.1, 154.2, 152.9, 137.1, 114.7, 71.3 (JCeP¼10 Hz), 71.1, 66.8, 65.1, 45.0, 42.8, 24.5, 24.1, 23.97, 23.94. IR (KBr disc): 3295, 3235, 2987, 1578, 1387, 1281, 1215, 1119, 978 cm1. EI-MS: m/z 441 (Mþ, 39), 381 (100), 374 (40), 343 (51), 303 (67), 195 (21), 179 (35), 155 (22), 70 (19), 43 (52). 4.7.6. Diisopropyl{2-[2-amino-6-(diethylamino)-9H-purine-9-yl] ethoxy}methylphosphonate (9f).15b The representative procedure A

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

was followed using compound 8 (392 mg, 1.0 mmol) and diethylamine (109 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/95/5), yielded the title compound 9f (338 mg, 79%) as a white solid; [Anal. Calcd for C18H33N6O4P: C 50.46%, H 7.76%, N 19.61%; found: C 50.50%, H 7.76%, N 19.58%]; Rf¼0.35, mp¼104e106  C. 1H NMR (400 MHz, CDCl3): d 7.57 (s, 1H), 4.78 (br s, 2H, NH2 exchangeable), 4.72e4.64 (m, 2H), 4.21 (t, 2H), 3.92e3.87 (m, 6H), 3.71 (d, J¼8.3 Hz, 2H), 1.30e1.22 (m, 18H). 13C NMR (100 MHz, CDCl3): d 159.2, 154.0, 152.4, 136.8, 114.3, 71.3 (JCeP¼10 Hz), 71.1, 66.7, 65.1, 42.8, 42.4, 24.0, 23.98, 23.93, 23.8, 13.5. IR (KBr disc): 3406, 3333, 3230, 2978, 1643, 1579, 1377, 1249, 1178, 1141, 891 cm1. EI-MS: m/z 428 (Mþ, 45), 429 (MþHþ, 22), 399 (18), 315 (52), 249 (20), 234 (61), 219 (20), 205 (26), 191 (100), 177 (21), 163 (29), 135 (24), 43 (74). 4.7.7. Diisopropyl{2-[2-amino-(6-morpholino)-9H-purine-9-yl]ethoxy}methylphosphonate (9g). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and morpholine (91 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/3/95/5), yielded the title compound 9g (363 mg, 82%) as a white solid; [Anal. Calcd for C18H31N6O5P: C 48.86%, H 7.06%, N 18.99%; found: C 48.89%, H 7.09%, N 18.95%]; Rf¼0.39, mp¼110e112  C. 1H NMR (400 MHz, CDCl3): d 7.59 (s, 1H), 4.72e4.68 (m, 2H), 4.65 (br s, 2H, NH2 exchangeable), 4.23 (t, 6H), 3.88 (t, 2H), 3.80 (t, 4H), 3.71 (d, J¼8.4 Hz, 2H), 1.31 (d, 6H), 1.28 (d, 6H). 13C NMR (100 MHz, CDCl3): d 159.1, 154.2, 152.9, 137.2, 114.7, 71.3 (JCeP¼10 Hz), 71.1, 67.0, 66.8, 65.2, 24.07, 24.04, 24.01, 23.9. IR (KBr disc): 3396, 3335, 3223, 2976, 1645, 1583, 1356, 1251, 1174, 1109, 852, 829 cm1. EI-MS: m/z 442 (Mþ, 39), 263 (100), 248 (85), 233 (37), 217 (53), 203 (43), 190 (25), 163 (20), 135 (28), 43 (81), 41 (26). 4.7.8. Diisopropyl{2-[2-amino-6-(4-phenylpiperazine-1-yl)-9H-purine-9-yl]ethoxy}methylphosphonate (9h). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and 1-phenylpiperazine (170 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/95/5), yielded the title compound 9h (372 mg, 72%) as a white solid; [Anal. Calcd for C24H36N7O4P: C 55.70%, H 7.01%, N 18.94%; found: C 55.75%, H 7.07%, N 18.90%]; Rf¼0.28, mp¼100e102  C. 1H NMR (400 MHz, CDCl3): d 7.61 (s, 1H), 7.30e7.26 (m, 2H), 6.96 (d, 2H), 6.88 (t, 1H), 4.78 (br s, 2H, NH2 exchangeable), 4.72e4.67 (m, 2H), 4.38 (m, 4H), 4.22 (t, 2H), 3.88 (t, 2H), 3.71 (d, J¼8.2 Hz, 2H), 3.27 (t, 4H), 1.31e1.25 (m, 12H). 13C NMR (100 MHz, CDCl3): d 159.2, 154.1, 152.9, 151.2, 137.1, 129.1, 120.1, 116.4, 114.6, 71.22 (JCeP¼15 Hz), 71.13, 66.8, 65.1, 49.6, 44.7, 42.9, 24.08, 24.04, 24.01, 23.9. IR (KBr disc): 3392, 3333, 3223, 2976, 1643, 1570, 1348, 1242, 1153, 1101, 833, 786 cm1. EI-MS: m/z 517 (Mþ, 6), 372 (13), 337 (41), 218 (28), 205 (100), 163 (52), 139 (20), 120 (55), 77 (24), 42 (55), 41 (78). 4.7.9. Diisopropyl{2-[2-amino-6-(4-benzylpiperazine-1-yl)-9H-purine-9-yl]ethoxy}methylphosphonate (9i). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and 1-benzylpiperazine (185 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/95/5), yielded the title compound 9i (404 mg, 78%) as a white solid; [Anal. Calcd for C25H38N7O4P: C 56.49%, H 7.21%, N 18.44%; found: C 56.52%, H 7.28%, N 18.47%]; Rf¼0.29. 1H NMR (400 MHz, CDCl3): d 7.59 (s, 1H), 7.35e7.27 (m, 2H), 6.81 (d, 2H), 6.78 (t, 1H), 4.80 (br s, 2H, NH2 exchangeable), 4.75e4.69 (m, 2H), 4.32 (m, 4H), 4.19 (t, 2H), 4.11 (s, 2H), 3.89 (t, 2H), 3.72 (d, J¼8.2 Hz, 2H), 3.30 (t, 4H), 1.31e1.25 (m, 12H). 13C NMR (100 MHz, CDCl3): d 159.8, 155.3, 151.8, 151.1, 139.3, 129.3, 128.8, 127.7, 110.4, 71.5 (JCeP¼10 Hz), 71.11, 66.5, 65.2, 63.4, 53.2, 50.3, 47.1, 21.1, 24.07. IR (KBr disc): 3409, 3323, 3217, 2968, 1657, 1555, 1338, 1256, 1163, 1114, 876 cm1. EI-MS: m/z 531

687

(Mþ, 31), 400 (19), 372 (100), 258 (41), 193 (35), 164 (36), 148 (85), 134 (24), 121 (19), 94 (62), 43 (21). 4.7.10. Diisopropyl{2-[2-amino-6-(n-propylamino)-9H-purine-9-yl] ethoxy}methyl-phosphonate (9j). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and n-propylamine (86 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/3/95/5), yielded the title compound 9j (344 mg, 83%) as a white solid; [Anal. Calcd for C17H31N6O4P: C 49.27%, H 7.54%, N 20.28%; found: C 49.31%, H 7.55%, N 20.26%]; Rf¼0.30, mp¼110e112  C. 1H NMR (400 MHz, CDCl3): d 7.58 (s, 1H), 5.74 (br s, 1H, NH exchangeable), 4.93 (br s, 2H, NH2 exchangeable), 4.73e4.65 (m, 2H), 4.22 (t, 2H), 3.89 (d, 2H), 3.74e3.71 (q, J¼8.3 Hz, 2H), 3.53 (m, 2H), 1.67e1.60 (m, 2H), 1.35e1.24 (m, 12H), 0.97 (t, 3H). 13C NMR (100 MHz, CDCl3): d 159.9, 155.3, 143.1, 137.9, 114.1, 71.3 (JCeP¼10 Hz), 71.1, 66.7, 65.1, 42.8, 24.0, 23.97, 23.93, 23.8, 22.9, 11.3. IR (KBr disc): 3294, 3182, 3095, 2983, 1645, 1593, 1369, 1280, 1176, 1169, 910 cm1. EI-MS: m/z 414 (Mþ, 35), 235 (100), 220 (86), 191 (35), 178 (54), 150 (27), 135 (17), 43 (40). 4.7.11. Diisopropyl{2-[2-amino-6-(n-butylamino)-9H-purine-9-yl] ethoxy}methylphosphonate (9k). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and n-butylamine (104 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/97/3/95/5), yielded the title compound 9k (368 mg, 86%) as a white solid; [Anal. Calcd for C18H33N6O4P: C 50.46%, H 7.76%, N 19.61%; found: C 50.49%, H 7.80%, N 19.60%]; Rf¼0.29, mp¼92e94  C. 1H NMR (400 MHz, CDCl3): d 7.58 (s, 1H), 5.63 (br s, 1H, NH exchangeable), 4.90 (br s, 2H, NH2 exchangeable), 4.74e4.66 (m, 2H), 4.21 (t, 2H), 3.89 (t, 2H), 3.72 (d, J¼8.3 Hz, 2H), 3.56 (m, 2H), 1.64e1.56 (q, 2H), 1.45e1.36 (m, 2H), 1.31e1.26 (q, 12H), 0.93 (t, 3H). 13C NMR (100 MHz, CDCl3): d 160.4, 155.6, 150.7, 137.8, 114.1, 71.4 (JCeP¼10 Hz), 71.2, 66.8, 65.1, 42.8, 31.8, 24.06, 24.02, 23.98, 23.94, 19.9, 13.7. IR (KBr disc): 3302, 3190, 3095, 2983, 1647, 1593, 1369, 1284, 1176, 1109, 941 cm1. EI-MS: m/z 428 (Mþ, 30), 429 (MþHþ, 18), 249 (100), 234 (75), 205 (24), 191 (32), 178 (46), 150 (21), 135 (18), 43 (32). 4.7.12. Diisopropyl{2-[2-amino-6-(isopropylamino)-9H-purine-9-yl] ethoxy}methyl-phosphonate (9l). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and isopropylamine (90 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/95/5), yielded the title compound 9l (352 mg, 85%) as a colorless oil; [Anal. Calcd for C17H31N6O4P: C 49.27%, H 7.54%, N 20.28%; found: C 49.31%, H 7.59%, N 20.34%]; Rf¼0.39. 1H NMR (400 MHz, CDCl3): d 7.59 (s, 1H), 4.85 (br s, 2H, NH2 exchangeable), 4.45e4.39 (m, 2H), 4.26 (t, 2H), 3.85 (t, 2H), 3.76 (d, J¼8.3 Hz, 2H), 3.15 (m, 1H), 1.27e1.14 (m, 12H), 1.03 (q, 6H), 13C NMR (100 MHz, CDCl3): d 159.7, 156.7, 151.4, 139.2, 114.2, 71.17 (JCeP¼15 Hz), 71.05, 66.4, 65.4, 43.6, 27.2, 24.0. IR (KBr disc): 3279, 3247, 2982, 1569, 1389, 1271, 1226, 1132, 932 cm1. EI-MS: m/z 414 (Mþ, 25), 235 (85), 220 (100), 205 (67), 193 (22), 178 (43), 163 (19), 150 (29), 135 (32), 95 (16), 58 (50), 43 (85), 41 (47). 4.7.13. Diisopropyl{2-[6-(2-aminoethylamino)-2-amino-9H-purine9-yl]ethoxy}methylphosphonate (9m). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and 1,2-diaminoethane (71 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/97/ 3/95/5), yielded the title compound 9m (382 mg, 92%) as a colorless oil; [Anal. Calcd for C16H30N7O4P: C 46.26%, H 7.28%, N 23.60%; found: C 46.33%, H 7.29%, N 23.64%]; Rf¼0.49. 1H NMR (400 MHz, CDCl3): d 7.58 (s, 1H), 4.92 (br s, 2H, NH2 exchangeable), 4.48e4.45 (m, 2H), 4.26 (t, 2H), 3.88 (t, 2H), 3.76 (d, J¼8.2 Hz, 2H),

688

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

2.64 (s, 4H), 1.23e1.11 (m, 12H). 13C NMR (100 MHz, CDCl3): d 160.3, 155.4, 152.3, 139.6, 114.8, 71.2 (JCeP¼10 Hz), 71.0, 65.9, 65.0, 44.7, 44.2, 24.17, 24.14, 24.13, 24.09. IR (KBr disc): 3327, 3178, 3078, 2971, 1641, 1605, 1379, 1293, 1167, 1126, 956 cm1. EI-MS: m/z 415 (Mþ, 22), 372 (35), 357 (43), 258 (100), 224 (21), 164 (46), 148 (22), 139 (34), 91 (37), 43 (40). 4.7.14. Diisopropyl{2-[6-(2-(1H-indole-3-yl)ethylamino)-2-amino9H-purine-9-yl]ethoxy}methylphosphonate (9n). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and tryptamine (170 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol; 100/98/2/96/ 4/95/5), yielded the title compound 9n (401 mg, 78%) as a white solid; [Anal. Calcd for C24H34N7O4P: C 55.91%, H 6.65%, N 19.02%; found: C 55.97%, H 6.69%, N 19.06%]; Rf¼0.37, mp¼142e144  C. 1H NMR (400 MHz, CDCl3): d 8.39 (br s, 1H, NH exchangeable), 7.67 (d, J¼8.0 Hz, 1H), 7.51 (s, 1H), 7.38 (d, J¼8.0 Hz, 1H), 7.28 (s, 1H), 7.21 (t, 1H), 7.13 (t, 1H), 7.11 (s, 1H), 7.04 (d, 1H), 5.80 (s, 1H), 4.73e4.68 (m, 2H), 4.20 (t, 2H), 3.90 (t, 4H), 3.72 (d, J¼6.8 Hz, 2H), 3.11 (t, 2H), 1.32e1.21 (m, 12H). 13C NMR (100 MHz, CDCl3): d 160.0, 155.3, 138.0, 136.4, 127.3, 122.2, 121.9, 119.2, 118.7, 112.9, 111.2, 71.33 (JCeP¼15 Hz), 71.25, 71.21, 66.8, 65.2, 42.9, 24.07, 24.03, 24.0, 23.9. IR (KBr disc): 3556, 3460, 2978, 1633, 1599, 1356, 1251, 1211, 1120, 792 cm1. EI-MS: m/z 515 (MþHþ, 4), 373 (68), 301 (16), 289 (22), 193 (29), 178 (58), 150 (19), 130 (20), 44 (98). 4.7.15. Diisopropyl{2-[(6-cyclohexylamino)-2-amino-9H-purine-9yl]ethoxy}methyl-phosphonate (9o). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and cyclohexylamine (120 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/95/5), yielded the title compound 9o (332 mg, 73%) as a colorless oil; [Anal. Calcd for C20H35N6O4P: C 52.85%, H 7.76%, N 18.49%; found: C 52.91%, H 7.79%, N 18.54%]; Rf¼0.45, 1H NMR (400 MHz, CDCl3): d 7.57 (s, 1H), 5.51 (br s, 1H, NH exchangeable), 4.86 (br s, 2H, NH2 exchangeable), 4.74e4.66 (m, 2H), 4.21 (t, 2H), 4.19 (s, 1H), 3.88 (t, 2H), 3.71 (d, J¼8.3 Hz, 2H), 2.05 (d, 2H), 1.77e1.61 (m, 4H), 1.47e1.26 (m, 16H). 13C NMR (100 MHz, CDCl3): d 160.4, 154.9, 152.2, 138.2, 114.5, 71.7 (JCeP¼20 Hz), 71.5, 67.1, 65.2, 61.8, 43.2, 33.7, 26.0, 25.2, 24.4, 24.3, 24.2, 15.6. IR (KBr disc): 3281, 3225, 2980, 1567, 1380, 1273, 1216, 1104, 967 cm1. EI-MS: m/z 454 (Mþ, 47), 399 (21), 275 (65), 249 (23), 191 (20), 167 (33), 151 (43), 43 (41). 4.7.16. Diisopropyl{2-[2-amino-6-(n-octylamino)-9H-purine-9-yl] ethoxy}methylphosphonate (9p). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and n-octylamine (174 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/3/95/5), yielded the title compound 9p (388 mg, 80%) as a colorless oil; [Anal. Calcd for C22H41N6O4P: C 54.53%, H 8.53%, N 17.34%; found: C 54.58%, H 8.56%, N 17.30%]; Rf¼0.41. 1H NMR (400 MHz, CDCl3): d 7.61 (s, 1H), 4.59 (br s, 2H, NH2 exchangeable), 4.52e4.46 (m, 2H), 4.25 (t, 2H), 3.89 (t, 2H), 3.78 (t, J¼7.3 Hz, 2H), 3.49e3.45 (m, 2H), 1.66 (t, 2H), 1.35e1.22 (m, 22H), 0.88 (t, 2H). 13C NMR (100 MHz, CDCl3): d 160.9, 155.7, 152.5, 138.6, 115.7, 71.48 (JCeP¼7 Hz), 71.25, 68.7, 67.4, 40.9, 31.8, 29.6, 29.4, 29.3, 27.2, 24.0, 23.95, 23.91, 23.8, 22.6, 11.6. IR (KBr disc): 3281, 3189, 3106, 2975, 1655, 1589, 1371, 1265, 1185, 1161, 947 cm1. EI-MS: m/z 484 (Mþ, 50), 485 (MþHþ, 35), 399 (22), 315 (15), 305 (100), 290 (100), 247 (15), 233 (13), 205 (18), 192 (33), 178 (63), 163 (18), 150 (20), 135 (20), 43 (45), 41 (13). 4.7.17. Diisopropyl{2-[2-amino-6-(4-methylpiperazine-1-yl)-9H-purine-9-yl]ethoxy}methylphosphonate (9q). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol), 1methylpiperazine (105 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/

3/95/5), yielded the title compound 9q (369 mg, 81%) as a colorless oil; [Anal. Calcd for C19H34N7O4P: C 50.10%, H 7.52%, N 21.53%; found: C 50.15%, H 7.57%, N 21.50%]; Rf¼0.30, 1H NMR (400 MHz, CDCl3): d 7.58 (s, 1H), 4.74e4.66 (m, 2H), 4.62 (br s, 2H, NH2 exchangeable), 4.22 (t, 2H), 3.87 (t, 2H), 3.70 (d, J¼6.0 Hz, 2H), 2.51 (t, 5H), 2.33 (s, 3H), 2.19 (m, 3H), 1.31e1.26 (q, 12H). 13C NMR (100 MHz, CDCl3): d 159.6, 155.1, 153.2, 137.0, 114.9, 71.19 (JCeP¼10 Hz), 71.11, 66.4, 66.0, 57.1, 48.3, 47.1, 24.8, 24.1, 23.99, 23.94. IR (KBr disc): 3269, 3232, 2982, 1573, 1385, 1277, 1233, 1103, 957 cm1. EI-MS: m/z 455 (Mþ, 33), 385 (100), 372 (40), 343 (49), 301 (87), 193 (18), 178 (49), 163 (22), 70 (18), 43 (60). 4.7.18. Diisopropyl{2-[6-(3-aminopropylamino)-2-amino-9H-purine-9-yl]ethoxy}methylphosphonate (9r). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and 1,3-diaminopropane (88 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/ 4/95/5), yielded the title compound 9r (361 mg, 84%) as a white solid; [Anal. Calcd for C17H32N7O4P: C 47.54%, H 7.51%, N 22.83%; found: C 47.59%, H 7.55%, N 22.82%]; Rf¼0.40, mp¼119e120  C. 1H NMR (400 MHz, CDCl3): d 7.60 (s, 1H), 7.30 (br s, 1H, NH exchangeable), 5.64 (br s, 2H, NH2 exchangeable), 4.75e4.66 (m, 2H), 4.23 (t, 2H), 3.88 (t, 2H), 3.80 (d, J¼8.0 Hz, 2H), 3.74e3.64 (br s, 2H), 3.03 (s, 1H), 1.78 (br s, 1H), 1.31e1.27 (m, 14H). 13C NMR (100 MHz, CDCl3): d 160.4, 155.6, 150.7, 137.8, 114.1, 71.3 (JCeP¼10 Hz), 71.1, 66.8, 65.1, 42.8, 35.6, 29.9, 24.05, 24.01, 23.9, 23.8. IR (KBr disc): 3585, 3444, 2978, 1595, 1371, 1247, 1176, 1120 cm1. EI-MS: m/z 429 (Mþ, 12), 212 (40), 197 (54), 169 (56), 160 (22), 139 (44), 97 (37), 43 (100). 4.7.19. Diisopropyl{2-[6-(1-hydroxybutan-2-yl-amino)-2-amino-9Hpurine-9-yl]ethoxy}methylphosphonate (9s). The representative procedure A was followed using compound 8 (392 mg, 1.0 mmol) and 2-amino-1-butanol (99 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/ 4/94/6), yielded the title compound 9s (361 mg, 81%) as a white solid; [Anal. Calcd for C18H33N6O5P: C 48.64%, H 7.48%, N 18.91%; found: C 48.69%, H 7.53%, N 18.95%]; Rf¼0.37, mp¼115e116  C. 1H NMR (400 MHz, CDCl3): d 7.58 (s, 1H), 5.02 (br s, 2H, NH2 exchangeable), 4.50e4.44 (m, 2H), 4.22 (t, 2H), 3.86 (t, 2H), 3.75 (d, J¼7.9 Hz, 2H), 3.57 (q, 1H), 3.31 (q, 1H), 2.89 (br s, 1H, OH exchangeable), 2.76e2.71 (m, 1H), 1.36 (t, 2H), 1.25e1.11 (m, 12H), 0.96 (t, 3H). 13C NMR (100 MHz, CDCl3): d 159.4, 155.9, 151.3, 137.5, 114.3, 71.3 (JCeP¼10 Hz), 71.1, 67.2, 65.9, 65.7, 54.9, 27.2, 24.3, 24.2, 24.1, 23.99, 11.2. IR (KBr disc): 3405, 3267, 3245, 2989, 1567, 1387, 1295, 1227, 1145, 957 cm1. EI-MS: m/z 444 (Mþ, 40), 445 (MþHþ, 24), 414 (58), 399 (41), 391 (42), 371 (15), 329 (47), 212 (60), 197 (100), 196 (48), 169 (71), 160 (20), 139 (48), 123 (19), 97 (45), 43 (100), 41 (33).

4.8. Representative procedure B for the syntheses of compounds 10aem To a stirred solution of compound 7 (392 mg, 1.0 mmol) and DIPEA (357 mL, 2.0 mmol) in acetonitrile (5 mL), the corresponding base (1.05 mmol) was added dropwise at ambient temperature. After the completion of addition, the reaction mixture was heated at 80  C for specified time as depicted in Scheme 3. The reaction was monitored by TLC (dichloromethane/methanol: 9/1). After the completion of reaction, acetonitrile was removed in vacuo, and dichloromethane (30 mL) was added. The organic layer was washed with water (210 mL) and brine (110 mL), and dried over sodium sulfate. The solvent was removed in vacuo, leaves the crude product. Finally, it was purified by silica gel column chromatography using dichloromethane/methanol as the eluents. The compounds (10aem) were synthesized by above procedure.

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

4.8.1. Diisopropyl{2-[2-amino-6-(morpholino)-7H-purine-7-yl]ethoxy}methylphosphonate (10a). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and morpholine (91 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/95/5), yielded the title compound 10a (332 mg, 75%) as a white solid; [Anal. Calcd for C18H31N6O5P: C 48.86%, H 7.06%, N 18.99%; found: C 48.91%, H 7.10%, N 18.96%]; Rf¼0.33, mp¼129e130  C. 1H NMR (400 MHz, CDCl3): d 7.77 (s, 1H), 4.79 (br s, 2H, NH2 exchangeable), 4.50e4.39 (m, 2H), 4.14 (t, 2H), 3.68e3.60 (m, 6H), 3.44 (d, J¼7.9 Hz, 2H), 3.10 (s, 4H), 1.09e1.03 (q, 12H). 13C NMR (100 MHz, CDCl3): d 164.6, 159.7, 147.5, 135.8, 110.3, 72.0 (JCeP¼20 Hz), 71.7, 67.6, 67.4, 66.8, 65.4, 50.8, 47.2, 24.4, 24.3. IR (KBr disc): 3537, 2978, 1643, 1560, 1352, 1255, 1159, 1110, 879 cm1. EI-MS: m/z 442 (Mþ, 22), 263 (28), 247 (62), 233 (53), 220 (100), 190 (41), 177 (27), 162 (35), 135 (51), 43 (45). 4.8.2. Diisopropyl{2-[2-amino-6-(pyrrolidino)-7H-purine-7-yl]ethoxy}methylphosphonate (10b). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and pyrrolidine (88 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/3/95/5), yielded the title compound 10b (307 mg, 72%) as a colorless oil; [Anal. Calcd for C18H31N6O4P: C 50.70%, H 7.33%, N 19.71%; found: C 50.65%, H 7.36%, N 19.75%]; Rf¼0.43. 1H NMR (400 MHz, CDCl3): d 7.89 (s, 1H), 4.89 (br s, 2H, NH2 exchangeable), 4.51e4.35 (m, 2H), 4.42 (t, 2H), 3.91 (t, 2H), 3.71 (d, J¼7.9 Hz, 2H), 2.53 (m, 4H), 1.81 (m, 4H), 1.12e1.05 (m, 12H). 13C NMR (100 MHz, CDCl3): d 164.9, 160.5, 148.2, 137.3, 111.2, 71.7 (JCeP¼10 Hz), 71.5, 65.9, 64.7, 47.5, 25.6, 24.1, 23.97, 23.93, 23.90. IR (KBr disc): 3382, 3341, 3216, 2986, 1642, 1579, 1351, 1255, 1181, 1117, 862, 835 cm1. EI-MS: m/z 426 (Mþ, 33), 427 (MþHþ, 20), 411 (18), 247 (79), 231 (100), 219 (60), 204 (100), 176 (100), 162 (67), 149 (47), 135 (79), 95 (18), 70 (50), 43 (89), 41 (32). 4.8.3. Diisopropyl{2-[2-amino-6-(4-benzylpiperazine-1-yl)-7H-purine-7-yl]ethoxy}methylphosphonate (10c). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and 1-benzylpiperazine (185 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/ 4/92/8), yielded the title compound 10c (436 mg, 82%) as a colorless oil; [Anal. Calcd for C25H38N7O4P: C 56.49%, H 7.21%, N 18.44%; found: C 56.54%, H 7.26%, N 18.39%]; Rf¼0.31. 1H NMR (400 MHz, CDCl3): d 7.95 (s, 1H), 7.34 (d, 5H), 4.92 (br s, 2H, NH2 exchangeable), 4.68e4.62 (m, 2H), 4.34 (s, 2H), 3.84 (s, 2H), 3.64 (d, J¼7.8 Hz, 2H), 3.54 (s, 2H), 3.33 (s, 4H), 2.59 (s, 4H), 1.30e1.25 (m, 12H). 13C NMR (100 MHz, CDCl3): d 163.9, 159.3, 156.3, 147.0, 137.6, 129.1, 128.3, 127.3, 109.9, 100.0, 71.7 (JCeP¼10 Hz), 71.3, 66.9, 65.3, 62.9, 52.6, 49.9, 46.8, 24.0. IR (KBr disc): 3450, 3305, 3189, 2989, 1631, 1589, 1367, 1284, 1185, 1121, 927 cm1. EI-MS: m/z 531 (Mþ, 20), 385 (22), 372 (53), 343 (26), 301 (40), 193 (41), 177 (39), 163 (36), 150 (91), 91 (100). 4.8.4. Diisopropyl{2-[2-amino-6-(4-methylpiperazine-1-yl)-7H-purine-7-yl]ethoxy}methylphosphonate (10d). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol), 1methylpiperazine (105 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/ 4/95/5), yielded the title compound 10d (360 mg, 79%) as a yellow solid; [Anal. Calcd for C19H34N7O4P: C 50.10%, H 7.52%, N 21.53%; found: C 50.16%, H 7.56%, N 21.58%]; Rf¼0.25, mp¼121e123  C. 1H NMR (400 MHz, CDCl3): d 8.02 (s, 1H), 5.62 (br s, 2H, NH2 exchangeable), 4.69e4.61 (m, 2H), 4.27 (t, 2H), 3.90 (t, 2H), 3.74 (d, J¼6.9 Hz, 2H), 2.57 (t, 5H), 2.37 (s, 3H), 2.21 (m, 3H), 1.35e1.29 (q, 12H). 13C NMR (100 MHz, CDCl3): d 162.7, 160.1, 156.8, 148.1, 110.2, 71.7 (JCeP¼30 Hz), 71.2, 67.2, 65.7, 57.1, 46.9, 46.1, 23.99, 23.95, 23.92, 23.9. IR (KBr disc): 3255, 3226, 2980, 1568, 1373, 1284, 1213,

689

1118, 936 cm1. EI-MS: m/z 455 (Mþ, 8), 385 (22), 372 (56), 343 (31), 301 (56), 193 (42), 177 (42), 163 (36), 150 (100), 135 (16), 70 (28), 43 (52). 4.8.5. Diisopropyl{2-[2-amino-6-(4-phenylpiperazine-1-yl)-7H-purine-7-yl]ethoxy}methylphosphonate (10e). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and 1phenylpiperazine (170 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/ 4/94/6), yielded the title compound 10e (404 mg, 78%) as a white solid; [Anal. Calcd for C24H36N7O4P: C 55.70%, H 7.01%, N 18.94%; found: C 55.77%, H 7.05%, N 18.90%]; Rf¼0.38, mp¼129e130  C. 1H NMR (400 MHz, CDCl3): d 7.99 (s, 1H), 7.31e7.27 (m, 2H), 6.97 (d, J¼7.9 Hz, 2H), 6.90 (t, 1H), 4.95 (br s, 2H, NH2 exchangeable), 4.69e4.61 (m, 2H), 4.40 (t, 2H), 3.87 (t, 2H), 3.65 (d, J¼8.0 Hz, 2H), 3.47 (t, 4H), 3.32 (t, 4H), 1.33e1.24 (m, 12H). 13C NMR (100 MHz, CDCl3): d 164.0,159.3,156.3,151.0,147.1,129.2,120.3,116.3,110.0, 71.6 (JCeP¼10 Hz), 71.3, 66.9, 65.3, 50.1, 49.0, 46.8, 29.6, 24.0. IR (KBr disc): 3385, 3341, 3215, 2985, 1645, 1579, 1338, 1235, 1157, 1109, 835, 786 cm1. EI-MS: m/z 517 (Mþ, 21), 502 (19), 385 (73), 372 (82), 343 (67), 301 (90), 283 (21), 205 (21), 193 (50), 177 (45), 163 (67), 150 (100), 132 (33), 104 (40), 95 (21), 77 (22), 43 (44), 41 (20). 4.8.6. Diisopropyl{2-[2-amino-6-(4-ethylpiperazine-1-yl)-7H-purine-7-yl]ethoxy}methylphosphonate (10f). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and 1-ethylpiperazine (133 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/ 4/95/5), yielded the title compound 10f (357 mg, 76%) as a colorless oil; [Anal. Calcd for C20H36N7O4P: C 51.16%, H 7.73%, N 20.88%; found: C 51.21%, H 7.78%, N 20.85%]; Rf¼0.25. 1H NMR (400 MHz, CDCl3): d 7.97 (s, 1H), 4.96 (br s, 2H, NH2 exchangeable), 4.70e4.62 (m, 2H), 4.35 (t, 2H), 3.86 (t, 2H), 3.65 (d, J¼8.0 Hz, 2H), 3.40 (s, 3H), 2.64 (m, 5H), 2.52 (q, 3H), 1.33e1.26 (m, 12H), 1.15 (t, 3H). 13C NMR (100 MHz, CDCl3): d 163.9, 159.3, 156.2, 147.0, 109.8, 71.7 (JCeP¼10 Hz), 71.4, 66.9, 65.3, 52.4, 52.2, 49.7, 46.9, 24.0, 11.7. IR (KBr disc): 3275, 3225, 2967, 1577, 1363, 1299, 1201, 1139, 911 cm1. EIMS: m/z 469 (Mþ, 11), 385 (17), 372 (50), 343 (25), 301 (43), 193 (44), 177 (40), 163 (28), 150 (100), 84 (37), 56 (23), 43 (40). 4.8.7. Diisopropyl{2-[2-amino-6-(n-octylamino)-7H-purine-7-yl] ethoxy}methylphosphonate (10g). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and n-octylamine (174 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/94/6), yielded the title compound 10g (354 mg, 73%) as a white solid; [Anal. Calcd for C22H41N6O4P: C 54.53%, H 8.53%, N 17.34%; found: C 54.59%, H 8.58%, N 17.33%]; Rf¼0.23, mp¼139e141  C. 1H NMR (400 MHz, CDCl3): d 7.65 (s, 1H), 6.01 (br s, 1H, NH exchangeable), 4.68e4.62 (m, 4H), 4.38 (t, 2H), 4.03 (t, 2H), 3.74 (d, J¼7.2 Hz, 2H), 3.53e3.48 (m, 2H), 1.65 (t, 2H), 1.36e1.20 (m, 22H), 0.88 (t, 3H). 13C NMR (100 MHz, CDCl3): d 159.8, 158.3, 152.4, 139.4, 117.3, 71.4 (JCeP¼10 Hz), 71.1, 67.4, 65.7, 40.9, 31.8, 29.6, 29.4, 29.3, 27.2, 24.0, 23.95, 23.91, 23.8, 22.6, 11.6. IR (KBr disc): 3593, 3271, 3177, 2979, 1639, 1603, 1385, 1255, 1195, 1149, 924 cm1. EI-MS: m/z 484 (Mþ, 39), 399 (25), 385 (35), 343 (21), 305 (65), 289 (96), 262 (41), 191 (40), 177 (41), 163 (44), 150 (83), 135 (30), 95 (22), 43 (100), 41 (40). 4.8.8. Diisopropyl{2-[2-amino-6-(n-propylamino)-7H-purine-7-yl] ethoxy}methyl-phosphonate (10h). The representative procedure B was followed using compound 7 (392 mg, 1.3 mmol) and n-propylamine (86 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/97/3/95/5), yielded the title compound 10h (336 mg, 81%) as a yellow solid; [Anal. Calcd for C17H31N6O4P: C 49.27%, H 7.54%, N 20.28%; found: C 49.32%, H 7.59%, N 20.33%]; Rf¼0.29, mp¼124e125  C. 1H NMR (400 MHz,

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691

CDCl3): d 7.66 (s, 1H), 6.18 (s, 1H), 5.06 (br s, 2H, NH2 exchangeable), 4.68e4.61 (m, 2H), 4.42 (t, 2H), 4.00 (t, 2H), 3.72 (d, J¼7.6 Hz, 2H), 3.46 (q, 2H), 1.67 (q, 2H), 1.30e1.18 (m, 12H), 0.98 (t, 3H). 13C NMR (100 MHz, CDCl3): d 160.4, 159.4, 152.1, 143.4, 107.4, 73.2, 71.4 (JCeP¼10 Hz), 67.3, 65.6, 42.6, 23.98, 23.91, 23.87, 23.83, 22.7, 11.6. IR (KBr disc): 3291, 3179, 3099, 2987, 1649, 1589, 1375, 1281, 1180, 919 cm1. EI-MS: m/z 414 (Mþ, 30), 385 (19), 343 (18), 301 (25), 235 (57), 219 (100), 192 (60), 177 (19), 163 (35), 150 (55), 135 (20), 43 (64), 41 (23). 4.8.9. Diisopropyl{2-[2-amino-6-(n-butylamino)-7H-purine-7-yl] ethoxy}methylphosphonate (10i). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and n-butylamine (104 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/94/6), yielded the title compound 10i (334 mg 78%) as a yellow solid; [Anal. Calcd for C18H33N6O4P: C 50.46%, H 7.76%, N 19.61%; found: C 50.55%, H 7.81%, N 19.58%]; Rf¼0.30, mp¼128e130  C. 1H NMR (400 MHz, CDCl3): d 7.64 (s, 1H), 6.03 (br s, 1H, NH exchangeable), 4.77 (br s, 2H, NH2 exchangeable), 4.68e4.63 (m, 2H), 4.39 (t, 2H), 4.01 (t, 2H), 3.74 (d, J¼7.2 Hz, 2H), 3.51 (q, 2H), 1.63 (q, 2H), 1.45e1.39 (m, 2H), 1.30e1.20 (m, 12H), 0.97 (t, 3H). 13C NMR (100 MHz, CDCl3): d 160.4, 159.6, 152.1, 143.1, 107.6, 73.2 (JCeP¼10 Hz), 71.4, 67.3, 65.7, 40.6, 31.7, 29.6, 24.0, 23.9, 23.85, 23.81, 20.2, 13.9. IR (KBr disc): 3319, 3181, 3081, 2985, 1649, 1595, 1371, 1289, 1177, 1113, 949 cm1. EIMS: m/z 428 (Mþ, 35), 385 (26), 343 (24), 301 (29), 249 (62), 233 (100), 206 (60), 191 (25), 177 (31), 163 (41), 150 (55), 135 (24), 108 (13), 95 (19), 43 (64), 41 (29). 4.8.10. Diisopropyl{2-[2-amino-6-(benzylamino)-7H-purine-7-yl] ethoxy}methylphosphonate (10j). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and benzylamine (115 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/99/1/97/3/95/5), yielded the title compound 10j (356 mg, 77%) as a yellow solid; [Anal. Calcd for C21H31N6O4P: C 54.54%, H 6.76%, N 18.17%; found: C 54.59%, H 6.70%, N 18.15%]; Rf¼0.35, mp¼131e133  C. 1H NMR (400 MHz, CDCl3): d 7.65 (s, 1H), 7.37e7.21 (m, 5H), 6.68 (br s, 1H, NH exchangeable), 5.09 (br s, 2H, NH2 exchangeable), 4.66e4.52 (m, 2H), 4.39 (t, 2H), 3.95 (t, 2H), 3.68 (s, 2H), 3.53 (d, J¼7.2 Hz, 2H), 1.27e1.22 (m, 12H). 13C NMR (100 MHz, CDCl3): d 162.3, 161.5, 141.1, 129.2, 128.1, 127.1, 108.0, 72.1 (JCeP¼15 Hz), 71.0, 68.9, 68.1, 42.0, 24.1. IR (KBr disc): 3491, 3278, 3179, 2983, 1630, 1588, 1375, 1278, 1175, 1123, 912 cm1. EI-MS: m/z 462 (Mþ, 25), 335 (21), 245 (27), 163 (31), 149 (19), 101 (32), 91 (100), 43 (30). 4.8.11. Diisopropyl{2-[2-amino-6-(isopropylamino)-7H-purine-7-yl] ethoxy}methyl-phosphonate (10k). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and isopropylamine (90 mL, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/4/95/5), yielded the title compound 10k (327 mg, 79%) as a yellow solid; [Anal. Calcd for: C17H31N6O4P: C 49.27%, H 7.54%, N 20.28%; found: C 49.33%, H 7.58%, N 20.33%]; Rf¼0.29, mp¼125e127  C. 1H NMR (400 MHz, CDCl3): d 7.89 (s, 1H), 5.01 (br s, 2H, NH2 exchangeable), 4.51e4.45 (m, 2H), 4.27 (t, 2H), 3.82 (t, 2H), 3.79 (d, J¼7.9 Hz, 2H), 3.09 (m, 1H), 1.31e1.20 (m, 12H), 0.99 (q, 6H). 13C NMR (100 MHz, CDCl3): d 163.2, 160.0, 151.9, 144.3, 109.3, 72.12 (JCeP¼5 Hz), 71.9, 67.2, 65.9, 43.3, 26.7, 24.16, 24.04, 24.0, 23.9. IR (KBr disc): 3291, 3225, 2974, 1579, 1376, 1245, 1209, 1149, 947 cm1. EI-MS: m/z 414 (Mþ, 37), 389 (21), 239 (43), 229 (100), 211 (50), 175 (23), 150 (29), 135 (32), 55 (34), 43 (85). 4.8.12. Diisopropyl{2-[6-(2-(1H-indole-3-yl)ethylamino)-2-amino7H-purine-7-yl] ethoxy}methylphosphonate (10l). The representative procedure B was followed using compound 7 (392 mg,

1.0 mmol) and tryptamine (170 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/ 2/96/4/92/8), yielded the title compound 10l (366 mg, 71%) as yellow solid; [Anal. Calcd for C24H34N7O4P: C 55.91%, H 6.65%, N 19.02%; found: C 55.97%, H 6.72%, N 19.06%]; Rf¼0.36, mp¼139e140  C. 1H NMR (400 MHz, CDCl3): d 8.41 (br s, 1H, NH exchangeable), 7.91 (s, 1H), 7.59 (d, J¼7.8 Hz, 1H), 7.32 (d, J¼7.9 Hz, 1H), 7.32 (s, 1H), 7.25 (t, 1H), 7.11 (s, 1H), 7.07 (t, 1H), 7.00 (d, 1H), 5.80 (s, 1H), 4.77e4.62 (m, 2H), 4.22 (t, 2H), 3.89 (t, 4H), 3.68 (d, J¼6.8 Hz, 2H), 3.15 (t, 2H), 1.35e1.20 (m, 12H). 13C NMR (100 MHz, CDCl3): d 163.2, 161.1, 153.5, 141.6, 137.2, 128.5, 123.4, 121.3, 119.3, 118.9, 112.9, 111.6, 110.2, 72.4 (JCeP¼20 Hz), 71.9, 67.9, 66.6, 43.5, 31.1, 24.21, 24.15, 24.09, 24.05. IR (KBr disc): 3512, 3441, 2965, 1653, 1617, 1367, 1239, 1221, 1147, 929, 792 cm1. EI-MS: m/z 515 (Mþ, 11), 398 (75), 299 (17), 275 (28), 199 (34), 178 (58), 145 (29), 43 (100). 4.8.13. Diisopropyl{2-[2-amino-6-(cyclohexylamino)-7H-purine-7yl]ethoxy}methyl-phosphonate (10m). The representative procedure B was followed using compound 7 (392 mg, 1.0 mmol) and cyclohexylamine (120 mg, 1.05 mmol). Purification by column chromatography (dichloromethane/methanol: 100/98/2/96/ 4/95/5), yielded the title compound 10m (368 mg, 81%) as a white solid; [Anal. Calcd for C20H35N6O4P: C 52.85%, H 7.76%, N 18.49%; found: C 52.89%, H 7.81%, N 18.54%]; Rf¼0.28, mp¼142e143  C. 1H NMR (400 MHz, CDCl3): d 7.63 (s, 1H), 5.79 (d, J¼7.1 Hz, 1H), 4.72 (br s, 2H, NH2 exchangeable), 4.70e4.59 (m, 2H), 4.35 (t, 2H), 4.07 (t, 3H), 3.74 (d, J¼6.1 Hz, 2H), 2.07 (m, 2H), 1.78e1.65 (m, 3H), 1.49e1.37 (m, 2H), 1.29 (d, 8H), 1.21 (d, 7H). 13C NMR (100 MHz, CDCl3): d 161.8, 160.1, 151.6, 143.9, 107.8, 73.2 (JCeP¼15 Hz), 71.8, 67.8, 65.6, 49.3, 47.6, 33.6, 26.1, 25.3, 24.35, 24.31, 24.2. IR (KBr disc): 3278, 3239, 2979, 1561, 1377, 1289, 1217, 1122, 955 cm1. EI-MS: m/z 454 (Mþ, 20), 275 (40), 259 (70), 232 (38), 193 (24), 177 (30), 150 (100), 43 (41), 41 (20). Acknowledgements The authors are thankful to ‘National Facility for Drug Discovery through New Chemical Entities (NCEs) Development and Instrumentation Support to Small Manufacturing Pharma Enterprise’ under Drugs and Pharmaceutical Research Support (DPRS) project jointly funded by DST (India), Gujarat Industries Commissionerate (Government of Gujarat), and Saurashtra University, Rajkot (India). References and notes 1. (a) Legraverend, M.; Grieison, D. S. Bioorg. Med. Chem. 2006, 14, 3987; (b) Baldwin, S. A. Curr. Pharm. Design 2007, 13, 569; (c) Ducati, R. G.; Breda, A.; Basso, L. A.; Santos, D. S. Curr. Med. Chem. 2011, 18, 1258; (d) Burnstock, G. Nat. Rev. Drug Discov. 2008, 7, 575; (e) Taldone, T.; Gabriela, D. Curr. Top. Med. Chem. 2009, 9, 1436; (f) Carlsson, J.; Yoo, L.; Gao, Z.-G.; Irwin, J. J.; Shoichet, B. K.; , Jacobson, K. A. J. Med. Chem. 2010, 53, 3748; (g) Zatloukal, M.; Jorda, R.; Gucky  , V.; Adamcova , H.; Krystof, V.; kov a, E.; Voller, J.; Pospísil, T.; Malínkova T.; Rezníc Strnad, M. Eur. J. Med. Chem. 2012, http://dx.doi.org/10.1016/j.ejmech.2012.06. 036. , A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P. C. 2. (a) De Clercq, E.; Holy Nature 1986, 323, 464; (b) De Clercq, E.; Sakuma, T.; Baba, M.; Pauwels, R.; , A. Antiviral Res. 1987, 8, 261; (c) De Clercq, E. Balzarini, J.; Rosenberg, I.; Holy Med. Res. Rev. 2012, 32, 765; (d) Lee, W. A.; Martin, J. S. Antiviral Res. 2006, 71, 254; (e) De Clercq, E. J. Med. Chem. 2010, 53, 1438. , 3. Pauwels, R.; Balzarini, J.; Schols, D.; Baba, M.; Desmyter, J.; Rosenberg, I.; Holy A.; De Clercq, E. Antimicrob. Agents Chemother. 1988, 32, 1025. , A.; Pauwels, R.; 4. Balzarini, J.; Naesens, L.; Herdewijn, P.; Rosenberg, I.; Holy Baba, M.; Johns, D. G.; De Clercq, E. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 332.  , D.; Holy , A.; Dra , M.; Baszczyn  ski, O.; De Jersey, J.; 5. Cesnek, M.; Hockova cínsky Keough, D. T.; Guddat, L. W. Bioorg. Med. Chem. 2012, 20, 1076. 6. (a) De Clercq, E. Antiviral Res. 2005, 67, 56 and references cited therein; (b) Boyd, M. R.; Bacon, T. H.; Sutton, D.; Cole, M. Antimicrob. Agents Chemother. 1987, 31, 1238; (c) Elion, G. B.; Furman, P. A.; Fyfe, J. A.; De Miranda, P.; Beauchamp, L.; Schaeffer, H. J. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 5716; (d) Schaeffer, H. J.; Beauchamp, L.; De Miranda, P.; Elion, G. B.; Bauer, D. J.; Collins, P. Nature , A. Science 1978, 272, 583; (e) De Clercq, E.; Descamps, J.; De Somer, P.; Holy 1978, 200, 563; (f) Ying, C.; De Clercq, E.; Neyts, J. J. Viral Hepatitis 2000, 7, 79. ˇ

690

A. Manvar, A. Shah / Tetrahedron 69 (2013) 680e691 7. Donaldson, T.; Kim, K. Curr. Drug Targets 2010, 10, 191. 8. Hockova, D.; Keough, D. T.; Janeba, Z.; Wang, T.-H.; De Jersey, J.; Guddat, L. W. J. Med. Chem. 2012, 55, 6209. , A. Nat. Rev. Drug Discov. 2005, 4, 928. 9. De Clercq, E.; Holy 10. (a) Hocek, M. Eur. J. Org. Chem. 2003, 245; (b) Strouse, J. J.; Jeselnik, M.; Arterburn, J. B. Acta Chim. Slov. 2005, 52, 187; (c) Legraverend, M. Tetrahedron 2008, 64, 8585; (d) Chang, Y.-T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.; Kwon, S.; Norman, T. C.; Sarohia, R.; Leost, M.; Meijer, M.; Schultz, P. G. Chem. Biol. 1999, 6, 361; (e) Ran, C.; Dai, Q.; Harvey, R. G. J. Org. Chem. 2005, 70, 3724; (f) Lakshman, M. K.; Kumar, A.; Balchandran, R.; Day, B. W.; Andrei, G.; Snoeck, R.; Balzarini, J. J. Org. Chem. 2012, 77, 5870. 11. (a) Mitsunobu, O. Synthesis 1981, 1, 1; (b) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127. 12. (a) Kofoed, T.; Hansen, H. F.; érum, H.; Koch, T. J. Pept. Sci. 2001, 7, 402; (b) Hamden, M. R.; Wyatt, P. G. Tetrahedron Lett. 1990, 31, 2185; (c) Roggen, H.; Charnock, C.; Gundersen, L. L. Tetrahedron 2009, 65, 5199; (d) Veliz, E. A.; Beal, P. A. J. Org. Chem. 2001, 66, 8592; (e) Nair, V.; Turner, G. A.; Chamberlain, S. D. J. Am. Chem. Soc. 1987, 109, 7224. € hlhausen, U.; Wa €ngler, B.; Schirrmacher, E.; Reinhard, 13. (a) Schirrmacher, R.; Mu J.; Nagel, G.; Kaina, B.; Piel, M.; Wiebler, M.; Rosch, F. Tetrahedron Lett. 2002, 43, 6301; (b) Pauly, G. T.; Loktionova, N. A.; Fang, Q.; Vankayala, S. L.; Guida, W. C.; Pegg, A. E. J. Med. Chem. 2008, 51, 7144; (c) Fathi, R.; Goswami, B.; Kung, P. P.; Gaffney, B. L.; Jones, R. A. Tetrahedron Lett. 1990, 31, 319; (d) Janeba, Z.; Lin, X.; Robins, M. J. Nucleosides, Nucleotides Nucleic Acids 2004, 23, 137; (e) Bae, S.; Lakshman, M. K. J. Org. Chem. 2008, 73, 1311; (f) Lembicz, N. K.; Grant, S.; Clegg, W.; Griffin, R. J.; Heath, S. L.; Golding, B. T. J. Chem. Soc. 1997, 1, 185. 14. (a) Guo, H.-M.; Xin, P.-Y.; Niu, H.-Y.; Wang, D.-C.; Jiang, Y.; Qu, G.-R. Green Chem. 2010, 12, 2131; (b) Lanver, A.; Schmalz, H. G. Molecules 2005, 10, 508; (c) Guo, H.-M.; Zhang, Y.; Niu, H.-Y.; Wang, D.-C.; Chu, Z.-L.; Qu, G.-R. Org. Biomol. Chem. 2011, 9, 2605; (d) Niu, H.-Y.; Xia, C.; Qu, G.-R.; Wu, S.; Jiang, Y.; Jin, X.; Guo, H.M. Chem.dAsian J. 2012, 7, 45; (e) Takvorian, A. G.; Combs, A. P. J. Comb. Chem. 2004, 6, 171; (f) Qu, G.-R.; Zhang, Z.-G.; Geng, M.-W.; Xia, R.; Zhao, L.; Guo, H.M. Synlett 2007, 721; (g) Qu, G.-R.; Zhao, L.; Wang, D.-C.; Wu, J.; Guo, H.-M.

15. 16. 17.

18. 19.

20.

21. 22.

23. 24.

691

Green Chem. 2008, 10, 287; (h) Qu, G.-R.; Wu, J.; Wu, Y.-Y.; Zhang, F.; Guo, H.-M. Green Chem. 2009, 11, 760; (i) Qu, G.-R.; Zhang, H.-L.; Niu, H.-Y.; Xue, Z.-K.; Lv, X.-X.; Guo, H.-M. Green Chem. 2012, 14, 1877. (a) Elion, G. B.; Burgi, E.; Hitchings, G. H. J. Am. Chem. Soc. 1952, 74, 411; (b) Fu, R.; Xu, X.; Dang, Q.; Bai, X. J. Org. Chem. 2005, 70, 10810. The SigmaeAldrich price of 1 L 1,3-dioxolane is 61.2 Euro. , A.; Gu € nter, J.; Dvora kova, H.; Masojídikov (a) Holy a, M.; Andrei, G.; Snoeck, R.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1999, 42, 2064; (b) Horejsí, K.; , A. Bioorg. Med. Chem. Andrei, G.; De Clercq, E.; Snoeck, R.; Pohl, R.; Holy 2006, 14, 8057. The SigmaeAldrich prices of 1,3,5-trioxane and 2-chloroethanol are 25 g (22 Euro) and 250 g (29 Euro), respectively. , A.; Rosenberg, I.; Dvora kova, H. Collect. Czech. Chem. Commun. 1989, (a) Holy 54, 2190; (b) Yu, K. L.; Bronson, J. J.; Yang, H.; Patick, A.; Alam, A.; Brankovan, V.; Datema, R.; Hitchcock, M. J. M.; Martin, J. C. J. Med. Chem. 1992, 35, 2958. (a) Bronson, J. J.; Ghazzouli, I.; Hitchcock, M. J. M.; Web, R. R., II; Martin, J. C. J. Med. Chem. 1989, 32, 1457; (b) Choi, J.-R.; Cho, D.-G.; Roh, K. Y.; Hwang, J.-T.; Ahn, S.; Jang, H. S.; Cho, W.-Y.; Kim, K. W.; Cho, Y.-G.; Kim, J.; Kim, Y.-Z. J. Med. , D.; Holy , A.; Masojídikova , M.; Andrei, G.; Chem. 2004, 47, 2864; (c) Hockova Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2003, 46, 5064. Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551. (a) Lu, W.; Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. J. Org. Chem. 2007, 72, 5012; (b) Fletcher, S.; Shahani, V. M.; Gunning, P. T. Tetrahedron Lett. liz, E. A.; 2009, 50, 4258; (c) Fletcher, S. Tetrahedron Lett. 2010, 51, 2948; (d) Ve Beal, P. A. Tetrahedron Lett. 2006, 47, 3153; (e) Fletcher, S.; Shahani, V. M.; Lough, A. J.; Gunning, P. T. Tetrahedron 2010, 66, 4621; (f) Yin, X.-Q.; Li, W.-K.; Scheneller, S. W. Tetrahedron Lett. 2006, 47, 9187; (g) Lucas, B.; Rosen, N.; Chiosis, G. J. Comb. Chem. 2001, 3, 518; (h) Guo, H.-M.; Wu, Y.-Y.; Niu, H.-Y.; Wang, D.-C.; Qu, G.-R. J. Org. Chem. 2010, 75, 3863. Fu, X. Z.; Jiang, S. H.; Xin, J.; Yang, Y. S.; Ji, R. Y. Chin. Chem. Lett. 2007, 18, 817. Armarego, W. L. F.; Pervin, D. D. Purification of Laboratory Chemicals, 4th ed.; Butterworth Heinemann: 2000.