Microwave-assisted synthesis of highly functionalized guanidines on
soluble polymer support
Chih-Hau Chen, Chieh-Li Tung, Chung-Ming Sun
⇑Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan, ROC
a r t i c l e
i n f o
Article history: Received 30 March 2012 Revised 10 May 2012 Accepted 15 May 2012 Available online 19 May 2012 Keywords:
Carbamate-protected guanidines Microwave irradiation Soluble polymer support
a b s t r a c t
An efficient method for the N,N0-di(Boc)-protected guanidines containing piperazine and homopiperazine
scaffolds has been developed under multi-step microwave irradiation. Followed by alkylation of carba-mate-protected guanidines with various alkyl halides is also explored. This protocol proceeds via depro-tonation of the acidic N-carbamate hydrogen of the guanidine by sodium hydride on soluble polymer support. In this manner, highly functionalized guanidines were obtained after cleavage from the support. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine com-ponents. In addition, the reaction is sufficiently simple workup by precipitation in each step to yield the substituted guanidines in high purity. In conjunction with microwave irradiation and soluble polymer support, this method provides an efficient route to access highly functionalized guanidines.
Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
Guanidines are one of the most privileged structural motifs fre-quently occurring in natural products,1and have been widely rec-ognized as useful building blocks for the synthesis of various biologically active compounds.2The compelling biological activi-ties of guanidine derivatives have been ascribed to their ability to recognize receptors by a variety of non-covalent interactions, including hydrogen-bonding, electrostatic, and
p
-stacking associa-tions.3As important variants, heterocycles substituted guanidines exhibit a broad range of intriguing biological activities such as cytotoxic,4antifungal,5antiviral,6antimicrobial,7anticancer,8and antimalarial4,5 activities. Saxitoxin (STX, Fig. 1), the causative agents of paralytic shellfish poisoning (PSP), is potent neurotoxins produced by dinoflagellates.9 Dragmacidin E was isolated from Spongosortes sp. and exhibited potent serine-threonine protein phosphatase inhibitory activity.10Ptilomycalin A displays promis-ing anticancer and antiviral activities.11Zanamivir was syntheti-cally derived influenza inhibitor.12 The tremendous therapeutic potential of this class of compounds has sparked our interest in the synthesis of guanidine with piperazine scaffold and their ana-log to further explore their bioana-logical application.13Compared to other heterocycles syntheses,14the synthetic approach to incorpo-rate guanidine moiety is limited.15Therefore, the development of a mild and efficient synthesis for the rapid construction of highly substituted guanidines is important. Methods wherein guanidines could be further functionalized with a variety of electrophiles togive a more highly substituted guanidine are referred to as a gua-nidinylation. There are very few methods that are employed for the further functionalization of protected guanidines. Batey and co-workers developed a phase-transfer catalyzed alkylation of guanidines for the synthesis of substituted guanidines.16The most commonly used method involves the reaction of guanidine with a primary or secondary alcohol under Mitsunobu conditions.17The advent of microwave-assisted organic synthesis has contributed significantly to the development of eco-compatible methodologies to save both energy and resources.18 The polyethylene glycol 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.074
⇑ Corresponding author.
E-mail address:[email protected](C.-M. Sun).
HN N OH OH H2N NH H N NH 2 O H2N O (+)-Saxitoxin (STX) 2X -N H OH N HN H2N NH N O H N Br dragmacin E N H N N H H H O O O ptilomycalin A 10 N O NH2 NH2 zanamivir HO HO OH H O COOH H N HN HN NH2 O
Figure 1. Various types of biologically active heterocycles containing guanidine frameworks.
Tetrahedron Letters 53 (2012) 3959–3962
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Tetrahedron Letters
support is suitable for energy dissipation with microwaves.19The incorporation of microwave irradiation with PEG supported organ-ic synthesis greatly accelerates the library synthesis and simplifies the purification steps in multistep organic synthesis. In this report, we present highly efficient guanylation and guanidinylation for the synthesis of highly substituted guanidines on soluble polymer sup-port under microwave irradiation.
Results and discussion
A synthetic route toward the highly functionalized Boc-guani-dines of piperazine and homopiperazine is described inScheme 1. Monohydroxyl functionalized PEG (MW 5000) was employed as a soluble support for a multistep synthetic sequence. PEG is allowed to react first with di-electrophile, 4-chloromethyl benzoyl chloride under basic condition. The formation of ester bond in a refluxing condition required 48 h in dichloromethane which was brought down to 10 min under open vessel microwave irradiation leading to polymer conjugates 2 (Scheme 1). Accordingly, PEG conjugate 2 was purified by precipitation with diethyl ether. The progress of the PEG supported reaction was directly monitored through reg-ular proton NMR spectroscopy without releasing the intermediate from the support. The piperazinyl and diazepanyl moiety are intro-duced to the immobilized benzyl chloride 2 by a nucleophilic sub-stitution reaction toward the targeted guanidine skeleton. This reaction was completed in 5 min in a microwave cavity at 100 °C. It took 16 h to complete in oil-based refluxing condition to afford polymer conjugate 3. It is noteworthy to mention that the nucleo-philic substitution with piperazine or diazepane did not cleave the ester bond of the polymer linkage site even under harsh micro-wave condition.
With the PEG attached benzyldiamine 3 in hand, we explored the viability and efficiency of the guanylation reaction with various
guanylating reagents comprising N,N0 -di-tert-butoxycarbonyl-1H-pyrazole-1-carboxamidine A,15aN,N0 -di-tert-butoxycarbonylthiou-rea B, N,N0-protected S-methylisothiourea C, triflylguanidine deriv-ative D, and bis-Boc-benzotriazole-carboxamidine E (Fig. 2).20The feasibility of these guanylating reagents was first attempted at room temperature. A comparison of the yields and purities of guanylation of the PEG linked cyclic diamines 3 with guanylating reagents A–E is shown inFigure 3. The desired guanylation adducts were unsuccessful in the case of agent A. However, guanylating re-agents B–E react efficiently with PEG immobilized benzylpiperi-zine and benzyldiazepane to afford Boc-protected guanidines in good yields and purities. The benzotriazole-based reagents E com-paratively analyzed and proved to be the most efficient one as the guanylating reagent which leads to a quantitative conversion of the PEG supported amines into the guanidines in excellent yield within 6 h at room temperature. The same transformation with guanylating reagent E is also performed in an open vessel micro-wave reactor which needed only 7 min to furnish the same product to show a substantial enhancement of the reaction efficiency. The reactivities of these guanylating reagents are proposed to be dependent on the properties of leaving groups that may enhance the electrophilicity of the amidine carbon.20cThe mechanism of the guanylation of 3 was speculated through a highly electrophilic intermediate, bis(Boc)carbodiimide.
The next challenge was the synthesis of substituted guanidine derivatives from PEG conjugate 4 through nucleophilic substitu-tion. To extend the scope of the present process, the PEG linked guanidine derivatives were planned to react with electrophiles to furnish extra scaffold diversity to provide highly substituted guani-dine derivatives. The NH alkylation of the PEG linked guaniguani-dine 4 is expected to be laborious. Since, the NH is hindered by the Boc func-tionality sterically and the nucleophilicity of the nitrogen may be dispersed by the guanidine due to resonance effect. PEG supported OH PEG pyridine, CH2Cl2 MW, 10 min O O PEG + Cl O Cl 1 Cl 2 + NH HN HN NH or O O PEG N 3 NH n n = 1, 2 + CH2Cl2 MW, 5 min O O PEG N 4 N n n = 1, 2 NBoc NHBoc RX, NaH, CH2Cl2 0°C, 3 h O O PEG N 5 N n n = 1, 2 NBoc NBoc R KCN, MeOH r.t. 12 hrs H3CO O N 6 N n n = 1, 2 NBoc NBoc R guanidinylating reagents A-E
Scheme 1. Synthesis of Boc-guanidine derivatives.
condition for A: 1.2 eq. of A in CH2Cl2(r.t.; 8 h)
condition for B: 1.2 eq. of B and 1.2 eq. DICDI in CH2CI2(r.t.; 18 h)
condition for C: 1.2 eq. of C, 2 eq of HgCI2and 3 eq. of Et3N in CH2CI2(r.t.; 40 h)
condition for D: 1.2 eq. of D, and 3 eq. of Et3N in CH2CI2(r.t.; 10 h)
condition for E: 1.2 eq. of E, and 3 eq. of Et3N in CH2Cl2(r.t.; 6 h or MW; 7 min)
N BocN NHBoc N A BocHN S NHBoc B BocN S NHBoc CH3 C N BocHN NHBoc S F3C O O D N N N NHBoc BocN E
Figure 2. Reagents and conditions for the synthesis of N,N0-diprotected guanidines.
guanidine 4 was treated with sodium hydride and electrophiles in dichloromethane. Gratifyingly, polymer supported substituted guanidine conjugate 5 was obtained in 3 h through deprotonation and nucleophilic substitution. It is worth to mention that the ester functionality of the electrophiles remains intact under the strongly basic condition during the nucleophilic substitution (entries 6d, 6f, 6j, and 6l). Compared with previous reports,16,17we have demon-strated the guanidinylation protocol that is compatible with a wide range of substrates and additional phase-transfer-catalysts or cou-pling reagents are not needed. The cleavage of the polymer support from compound 5 was carried out by using a 1% potassium cyanide solution in methanol. The polymer was precipitated out by addi-tion of a cold ether soluaddi-tion and the filtrates were concentrated to obtain polymer-free substituted guanidine derivatives 6 with high purities and yields (Table 1).21The results summarized in
Ta-ble 1show some representative examples to demonstrate the suc-cessful access of guanidinylation and N-alkylation to the substituted Boc-guanidine derivatives with manifold appendages. In current synthetic approach, we have successfully integrated the advantages of PEG with microwave synthesis to afford a rapid synthesis of substituted Boc-guanidine derivatives with high puri-ties and yields.
Conclusion
An efficient method for the alkylation of N-dicarbamate-pro-tected guanidines using a variety of alkyl halides has been ex-plored. Under this procedure, the acidic N-carbamate hydrogen is deprotonated using basic conditions and subsequently alkylation to yield highly functionalized guanidines. This protocol provides Figure 3. Yields and purities of isolated N,N0-diprotected guanidines 6 upon
reaction of (i) PEG immobilized benzylpiperizine and (ii) PEG immobilized benzyldiazepane with guanylating reagents A–E.
Table 1
Synthesis of substituted guanidine derivatives
Entry Amine RX HPLC purityc
(%) Isolate yielda (%) 6a HN NH Br 91 82 6b HN NH Br 95 86 6c HN NH Br 97 87 6d HN NH Cl OCH3 O 79 71 6e HN NH Br 93 84 6f NH HN Br OCH3 O 97 87 6g HN NH Br 91 82 6h HN NH Br 89 80 6i HN NH Br 97 87 6j HN NH Cl OCH3 O 69 (29)b 62 6k HN NH Br 88 79 6l HN NH Br OCH3 O 92 83 a
Yields were determined on weight of purified samples. b
The yields in the parentheses represent unreacted starting material. c
HPLC purities were determined with crude samples.
an alternate method for the alkylation of protected guanidines from those currently utilized. In addition, the need for stoichiome-tric amounts of costly reactive coupling reagents is circumvented. An attractive feature of this methodology is that few byproducts are generated and at the end of the reaction, simple workup fol-lowed by filtration gives high yields of the desired products. The efficiency of parallel synthesis was greatly enhanced by combining the advantages of microwave synthesis and a soluble polymer support.
Acknowledgments
The authors thank the National Science Council of Taiwan for the financial assistance and the authorities of the National Chiao Tung University for providing the laboratory facilities. This Letter is particularly supported by ‘Aim for the Top University Plan’ of the National Chiao Tung University and Ministry of Education,Tai-wan, ROC.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 05.074.
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21. General procedures for synthesis of 6: (All microwave experiments performed in CEM discover microwave system at the frequency of 2450 Hz and 0–300 W power in open vessel system.) The polymer support (PEG 5000; 10.0 g, 1.0 equiv, 2.0 mmol) in toluene (25 mL) was treated with 4-(chloromethyl) benzoyl chloride 1 (567.0 mg, 1.5 equiv, 3.0 mmol) in toluene (25 mL) and pyridine (791.0 mg, 5.0 equiv, 10.0 mmol) under microwave irradiation at 200 W for 10 min to afford amide 2. The reaction mixture was diluted with slow addition of excess cold ether (50 mL). The precipitated amide conjugate was filtered through a fritted funnel, washed with ether, and then dried. Piperazine (4.31 g, 5.0 equiv, 50.0 mmol) or Homopiperazine (5.01 g, 5.0 equiv, 50.0 mmol) were added to a solution of 2 (10.31 g, 1.0 equiv, 2.0 mmol) in dichloromethane. The reaction mixture was stirred under microwave irradiation at 120 W for 5 min and after completion; the reaction mixture was passed through a thin layer of celite to remove salt. The solution was concentrated by rotary evaporation and diluted with slow addition of an excess of cold ether. The precipitated conjugate was filtered through a fritted funnel and washed with ether to afford 3. N,N0 -di-tert-butoxycarbonyl-1H-benzo[d][1,2,3]triazole-1-carboximidamide (0.47 g, 1.3 equiv, 1.3 mmol) was added to a solution of 3 (5.20 g, 1.0 equiv, 1.0 mmol) in dichloromethane (30 mL). After stirring for 10 min, triethylamine (0.30 g, 3.0 equiv, 3.0 mmol) was added and it was treated under microwave irradiations at 150 W for 7 min. The solution was concentrated by rotary evaporation and diluted with slow addition of an excess of cold ether. The precipitated guanidine conjugate was filtered through a fritted funnel and washed with ether to afford 4. To a solution of 4 (1.09 g, 1.0 equiv, 0.2 mmol) and alkyl halide (3.0 equiv, 0.6 mmol) in dichloromethane (10 mL) under nitrogen, sodium hydride (0.024 g, 5.0 equiv, 1.0 mmol) was added and the reaction mixture was stirred at 0 °C for 3 h. After completion, the reaction mixture was washed with cold ether. The precipitate was filtered and dried well to furnish the PEG bound quanidine 5 in excellent yield. To a solution of 5 in methanol (10 mL), KCN (0.1 g) was added and stirred for 48 h. After the quenching procedure, the crude products 6 were obtained. The filtrate was dried and subjected to HPLC analysis which depicts high purity. The title compounds 6 were obtained in good to excellent overall yield after column chromatography purification. Compound 6e:1 H NMR (300 MHz, CDCl3) d 7.91 (d, J = 8.4 Hz, 2H), 7.81 (m, 4H), 7.49 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 5.25 (b, 1H), 3.89 (m, 4H), 3.07 (m, 6H), 2.63 (b, 2H), 2.05 (b, 2H), 1.55 (s, 9H), 1.48 (s, 9H);13 C NMR (75 MHz, CDCl3) d 167.3, 160.0, 154.1, 152.8, 134.2, 133.7, 133.4, 130.0, 129.3, 129.1, 128.8, 128.4, 128.0, 127.7, 126.7, 126.6, 115.8, 115.0, 82.3, 79.9, 62.6, 52.5, 51.4, 28.8, 28.6; IR (neat): 2922, 2851, 1721; MS (FAB-MS) m/z: 617 (M+H)+ ; HRMS : calcd for C35H44N4O6m/z : 616.3261; found 617.3341 (M+H)+.
