CN110156641B - Synthesis method of substituted guanidine - Google Patents
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- CN110156641B CN110156641B CN201910594868.1A CN201910594868A CN110156641B CN 110156641 B CN110156641 B CN 110156641B CN 201910594868 A CN201910594868 A CN 201910594868A CN 110156641 B CN110156641 B CN 110156641B
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- C07—ORGANIC CHEMISTRY
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- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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Abstract
The invention provides a method for synthesizing substituted guanidine, which aims at the problem that heavy metal or complex oxidant is needed to be used in the traditional method for synthesizing the substituted guanidine. The synthesis method of the substituted guanidine has mild reaction conditions and high efficiency, and is expected to be applied to the later modification of drug molecules and natural products.
Description
Technical Field
The invention relates to a method for synthesizing substituted guanidine, belonging to the technical field of synthesis.
Background
Guanidine compounds are an important backbone in organic chemistry. The molecules not only exist in active natural product molecules and drug molecules widely, but also can be used as organic bases, small molecular catalysts, biological probes and the like to be applied to organic synthesis (chem.soc.rev.2014,43,3406). Because of this, the synthesis and preparation of guanidine compounds have been the focus of research for synthetic chemists.
Guanidine molecules can be obtained by reacting free amines with reactive intermediates such as thiourea, isourea, cyanamide or substituted imines. Among the many synthetic methods, the synthesis of substituted guanidines starting from N, N-di-tert-butoxycarbonylthiourea (Boc thiourea) is widely used in the synthesis of active natural product molecules as well as pharmaceutical molecules because of the easy preparation of the starting material and the easy removal of the Boc protecting group. In the early desulfurization of Boc thiourea, thiourea molecules were deprotonated by equivalent amounts of mercuric chloride or cupric chloride, followed by nucleophilic addition of the free amine to the resulting reactive intermediate and removal of the Boc protecting group by trifluoroacetic acid to allow the preparation of guanidines containing different substituents (Tetrahedron1997,53,5291). The disadvantage of this strategy is that the reaction requires the use of equivalent or excessive amounts of highly toxic mercury salts, which greatly limits the broad application of this strategy. In order to overcome the above disadvantages, new desulfurization reagents have been developed to replace the highly toxic mercury salts, which mainly include: cobalt chloride, TCT, PIDA, etc. (ARKIVOC 2005, 49). Nevertheless, Boc thiourea desulfurization suffers from the following disadvantages: 1. the reaction needs to use metal salt to easily introduce heavy metal ions into the product; 2. the desulfurization reagent has a complex structure and needs multi-step synthesis. 3. The reduction potential of the oxidant is relatively high, side reactions are easily caused, and the functional group tolerance is poor.
Disclosure of Invention
The invention aims to solve the technical problem that highly toxic heavy metals or iodine reagents with complex structures are required to be used in the desulfurization reaction in the prior art, and provides a method for preparing substituted guanidine by a thiourea desulfurization strategy with participation of iodine simple substances.
The synthesis method of the substituted guanidine comprises the following steps: firstly, dissolving free amine in a solvent at room temperature, and then sequentially adding N, N-di-tert-butoxycarbonylthiourea, an acid-binding agent and an iodine simple substance into a reaction system; stirring and reacting at 25 ℃, monitoring free amine by TLC, finishing the reaction after the free amine disappears, diluting the reaction system by ethyl acetate, washing by saturated saline solution, drying the obtained organic phase by anhydrous sodium sulfate, decompressing and concentrating, and separating the obtained crude product by column chromatography to obtain the substituted guanidine product.
A method for synthesizing substituted guanidine, the structural general formula of the substituted guanidine is as follows:
wherein the R group is alkyl, aryl, benzyl or allyl;
firstly, dissolving free amine in a solvent, and then sequentially adding N, N-di-tert-butoxycarbonylthiourea, an acid-binding agent and an iodine simple substance into a reaction system; stirring and reacting at 25 ℃, monitoring free amine by TLC (thin layer chromatography), finishing the reaction after the free amine disappears, diluting the reaction system with ethyl acetate, washing with saturated saline solution, drying the obtained organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the obtained crude product by column chromatography to obtain a substituted guanidine product; the acid-binding agent is triethylamine, sodium carbonate or 4-dimethylamino pyridine, and the solvent is ethyl acetate, ethanol or DMF; the molar ratio of the materials is as follows: free amine: n, N-di-tert-butoxycarbonylthiourea: iodine simple substance: and the acid-binding agent is 1.0: 1.0-1.5: 1.2:2.4, and the molar concentration of the free amine is 0.01-1.0M.
The solvent is DMF or ethyl acetate.
The molar ratio of the materials is as follows: free amine: n, N-di-tert-butoxycarbonylthiourea: iodine simple substance: and the acid-binding agent is 1.0: 1.1-1.3: 1.2:2.4, and the concentration range of the free amine is 0.1-0.5M.
The invention has the beneficial effects that: the synthetic method of the substituted guanidine replaces the prior desulfurization reagents such as mercuric chloride, cobalt chloride, iodobenzene acetate and the like with an iodine simple substance which is economical, easy to obtain and relatively weak in oxidation capacity, and utilizes the electrophilicity of the iodine simple substance to enable the iodine simple substance to have desulfurization reaction with thiourea molecules, and then the generated active intermediate is attacked by free amine to realize the preparation of a series of guanidine with different substituent groups.
Detailed Description
The present invention will be described in further detail with reference to examples.
The following are examples given by the inventor, and it should be noted that these examples are preferred examples, and are mainly used for understanding the present invention, but the present invention is not limited to these examples.
Example 1
Preparation of N, N '-di-tert-butoxycarbonyl-N' -phenylguanidine
The structural formula is as follows:
aniline (19mg,0.2mmol) was dissolved in 3mL DMF solution at room temperature before adding NEt sequentially3(49mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to obtain N, N' -di-tert-butoxycarbonyl-N "-phenyl guanidine (61mg, 92% yield).1H NMR(500MHz,Chloroform–d)δ11.64(s,1H),10.32(s,1H),7.60(d,J＝7.9Hz,2H),7.32(t,J＝7.9Hz,2H),7.10(t,J＝7.4Hz,1H),1.53(s,9H),1.51(s,9H).13C NMR(126MHz,CDCl3)δ163.53,153.47,153.29,136.79,128.82,124.67,122.11,83.64,79.57,28.14,28.08.
The characterization data confirmed the preparation of N, N '-di-tert-butoxycarbonyl-N' -phenylguanidine.
Example 2
Preparation of N, N '-di-tert-butoxycarbonyl-N' - (4-methoxyphenyl) guanidine
The structural formula is as follows:
4-Methoxyaniline (25mg,0.2mmol) was dissolved in 3mL DMF solution at room temperature, after which NEt was added sequentially3(49mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). Drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and adding ethyl acetatePreparation of N, N' -di-tert-butoxycarbonyl-N ″ - (4-methoxyphenyl) guanidine (71mg, 98% yield) by column chromatography with petroleum ether (1: 9).1H NMR(500MHz,Chloroform–d)δ11.64(s,1H),10.18(s,1H),7.49(d,J＝9.0Hz,2H),6.85(d,J＝9.0Hz,2H),3.78(s,3H),1.53(s,9H),1.49(s,9H).13C NMR(126MHz,CDCl3) δ 163.61,156.75,153.57,153.31,129.78,123.78,114.01,83.47,79.36,55.41,28.17,28.04. confirmation from characterization data is the preparation of N, N' -di-tert-butoxycarbonyl-N "- (4-methoxyphenyl) guanidine.
Example 3
Preparation of N, N '-di-tert-butoxycarbonyl-N' -trifluoroethylguanidine
The structural formula is as follows:
trifluoroethylamine (20mg,0.2mmol) was dissolved in 3mL of DMF at room temperature before the addition of NEt in that order3(49mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using EA/PE ═ (1:9) to give N, N' -di-tert-butoxycarbonyl-N ″ -trifluoroethylguanidine (42mg, 61% yield).1H NMR(500MHz,Chloroform–d)δ11.50(s,1H),8.71(t,J＝5.9Hz,1H),4.39–3.90(m,2H),1.51(s,9H),1.51(s,9H)；13C NMR (126MHz, Chloroform-d) 163.15,156.56,153.03,123.91(q, J ═ 278.3Hz)83.88,79.86,41.87(q, J ═ 34.6Hz)28.18,28.00 the characterization data confirmed N, N' -di-tert-butoxycarbonyl-N "-trifluoroethylguanidine.
Example 4
N, N '-di-tert-butoxycarbonyl-N' -cyclohexylguanidine
The structural formula is as follows:
cyclohexylamine (20mg,0.2mmol) was dissolved in 3mL DMF at room temperature before adding NEt sequentially3(49mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to give N, N' -di-tert-butoxycarbonyl-N "-cyclohexylguanidine (64mg, 94% yield).1H NMR(500MHz,Chloroform–d)δ11.54(s,1H),8.31(s,1H),4.33–3.86(m,1H),2.18–1.89(m,2H),1.50(s,9H),1.49(s,9H),1.74–1.18(m,8H)；13C NMR(126MHz,CDCl3) δ 163.86,155.23,153.29,82.75,78.90,48.51,32.73,28.31,28.07,27.98,25.50,24.36. confirmation from characterization data is N, N' -di-tert-butoxycarbonyl-N "-cyclohexylguanidine.
Example 5
N, N '-Di-tert-butoxycarbonyl-N' -cyclopentylguanidine
The structural formula is as follows:
at room temperature, cyclopentylamine (17mg,0.2mmol) was dissolved in 3mL DMF solution, followed by the sequential addition of NEt3(49mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to give N, N' -di-tert-butoxycarbonyl-N "-cyclopentylguanidine (54mg, 82% yield).1H NMR(500MHz,Chloroform–d)δ11.51(s,1H),8.35(d,J＝7.9Hz,1H),4.94–4.04(m,1H),2.22–1.97(m,2H),1.77–1.66(m,2H),1.62–1.55(m,1H),1.50(s,9H),1.49(s,9H),1.48–1.41(m,3H)；13C NMR(126MHz,CDCl3) δ 163.77,155.61,153.36,82.88,79.07,52.04,33.16,28.38,28.11,28.03,23.62, the characterization data confirmed N, N' -di-tert-butoxycarbonyl-N "-cyclopentylguanidine.
Example 6
Preparation of N, N '-di-tert-butoxycarbonyl-N' -cyclopropylguanidine
The structural formula is as follows:
cyclopropylamine (12mg,0.2mmol) was dissolved in 3mL DMF solution at room temperature, after which NEt was added in sequence3(49mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to give N, N' -di-tert-butoxycarbonyl-N "-cyclopropylguanidine (46mg, 77% yield).1H NMR(500MHz,Chloroform–d)δ11.52(s,1H),8.31(s,1H),3.09–2.96(m,1H),1.52(s,9H),1.48(s,9H),0.89–0.76(m,2H),0.64–0.53(m,2H).13C NMR(126MHz,CDCl3) δ 163.63,157.24,153.20,83.02,79.31,28.27,28.01,23.72,6.83. it was confirmed from the characterization data that it was N, N' -di-tert-butoxycarbonyl-N "-cyclopropylguanidine.
Example 7
Preparation of N, N '-di-tert-butoxycarbonyl-N' -benzylguanidine
The structural formula is as follows:
benzylamine (22mg,0.2mmol) was dissolved in 3mL DMF at room temperature, after which NEt was added sequentially3(49mg,0.48mmol), N, N' -Boc thiourea(66mg,0.24mmol),I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to give N, N' -di-tert-butoxycarbonyl-N "-benzylguanidine (35mg, 50% yield).1H NMR(500MHz,Chloroform–d)δ11.55(s,1H),8.58(t,J＝5.2Hz,1H),7.53–7.00(m,5H),4.63(d,J＝5.1Hz,2H),1.52(s,9H),1.48(s,9H)；13C NMR(126MHz,CDCl3) δ 163.62,156.11,153.19,137.26,128.74,127.80,127.60,83.15,79.38,45.05,28.32,28.07. it is confirmed from the characterization data that it is N, N' -di-tert-butoxycarbonyl-N "-benzylguanidine.
Example 8
Preparation of N, N '-di-tert-butoxycarbonyl-N' -benzylguanidine
The structural formula is as follows:
benzylamine (22mg,0.2mmol) was dissolved in 3mL ethyl acetate solution at room temperature, after which NEt was added sequentially3(49mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to obtain N, N' -di-tert-butoxycarbonyl-N "-benzylguanidine (38mg, 54% yield).
Example 9
Preparation of N, N '-di-tert-butoxycarbonyl-N' -benzylguanidine
The structural formula is as follows:
benzylamine (22mg,0.2mmol) was dissolved in 3mL DMF solution at room temperature, followed by the addition of potassium carbonate (66mg,0.48mmol), N, N' -Boc thiourea (66mg,0.24mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to obtain N, N' -di-tert-butoxycarbonyl-N "-benzylguanidine (40mg, 57% yield).
Example 10
Preparation of N, N '-di-tert-butoxycarbonyl-N' -benzylguanidine
The structural formula is as follows:
benzylamine (22mg,0.2mmol) was dissolved in 3mL DMF solution at room temperature, followed by the addition of 4-dimethylaminopyridine (59mg,0.48mmol), N, N' -Boc-thiourea (66mg,0.24mmol), I in that order2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to obtain N, N' -di-tert-butoxycarbonyl-N "-benzylguanidine (30mg, 43% yield).
Example 11
Preparation of N, N '-di-tert-butoxycarbonyl-N' -benzylguanidine
The structural formula is as follows:
benzylamine (22mg,0.2mmol) was dissolved in 3mL DMF at room temperature, followed by the addition of carbonic acidPotassium (66mg,0.48mmol), N, N' -Boc thiourea (66mg,0.26mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to give N, N' -di-tert-butoxycarbonyl-N "-benzylguanidine (39mg, 55% yield).
Example 12
Preparation of N, N '-di-tert-butoxycarbonyl-N' -benzylguanidine
The structural formula is as follows:
benzylamine (22mg,0.2mmol) was dissolved in 1mL DMF solution at room temperature, followed by the addition of potassium carbonate (66mg,0.48mmol), N, N' -Boc thiourea (66mg,0.26mmol), I2(61mg,0.24 mmol). After the addition was complete, the reaction was allowed to continue at 25 ℃ until TLC showed complete conversion of starting material. Thereafter, the reaction solution was diluted with ethyl acetate (50mL) and washed three times with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography using ethyl acetate/petroleum ether (1:9) to give N, N' -di-tert-butoxycarbonyl-N "-benzylguanidine (28mg, 40% yield).
Claims (3)
1. A method for synthesizing substituted guanidine, the structural general formula of the substituted guanidine is as follows:
wherein the R group is alkyl, aryl, benzyl or allyl;
firstly, dissolving free amine in a solvent, and then sequentially adding N, N-di-tert-butoxycarbonylthiourea, an acid-binding agent and an iodine simple substance into a reaction system; stirring and reacting at 25 ℃, monitoring free amine by TLC (thin layer chromatography), finishing the reaction after the free amine disappears, diluting the reaction system with ethyl acetate, washing with saturated saline solution, drying the obtained organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the obtained crude product by column chromatography to obtain a substituted guanidine product; the acid-binding agent is triethylamine, sodium carbonate or 4-dimethylamino pyridine, and the solvent is ethyl acetate, ethanol or DMF; the molar ratio of the materials is as follows: free amine: n, N-di-tert-butoxycarbonylthiourea: iodine simple substance: and the acid-binding agent is 1.0: 1.0-1.5: 1.2:2.4, and the molar concentration of the free amine is 0.01-1.0M.
2. The method of synthesizing a substituted guanidine according to claim 1, wherein the solvent is DMF or ethyl acetate.
3. The method for synthesizing substituted guanidine according to claim 1, wherein the molar ratio of the materials is: free amine: n, N-di-tert-butoxycarbonylthiourea: iodine simple substance: and the acid-binding agent is 1.0: 1.1-1.3: 1.2:2.4, and the concentration range of the free amine is 0.1-0.5M.
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Non-Patent Citations (3)
| Title |
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| Copper（II） chloride promoted transformation of amine into guanidines and asymmetrical N,N’-disubstituted guanidines;Brendan Kelly et al.;《Tetrahedron Letters》;20130523;第54卷;第3982-3984页 * |
| Iodine-Mediated Guanidine Formation through Arylsulfonyl-Activated Thioureas;Cuiying Qin et al.;《Synlett》;20091231;第000A-000D页 * |
| Synthesis of 2-Amino 3-Substituted Quinazolin-4(3H)-one Derivatives via Iodine-Mediated Guanidinylation of Pbf-Activated Thiourea;Jizhen Li et al.;《Journal of Heterocyclic Chemistry》;20131231;第50卷;第304-308页 * |
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