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One-pot synthesis of diverse N,N′-disubstituted guanidines from N-chlorophthalimide, isocyanides and amines via N-phthaloyl-guanidines

András Demjén ab, Anikó Angyal ab, János Wölfling b, László G. Puskás a and Iván Kanizsai *a
aAVIDIN Ltd, Alsó kikötő sor 11/D, Szeged, H-6726, Hungary. E-mail: i.kanizsai@avidinbiotech.com; Tel: (+36)-62-202-107
bDepartment of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary

Received 15th December 2017 , Accepted 1st March 2018

First published on 8th March 2018


Abstract

A sequential one-pot approach towards N,N′-disubstituted guanidines from N-chlorophthalimide, isocyanides and amines is reported. This strategy provides straightforward and efficient access to diverse guanidines in yields up to 81% through previously unprecedented N-phthaloylguanidines. This protocol also features wide substrate scope and mild conditions.


Introduction

The guanidine functionality is a privileged structure in many natural products, biochemical processes and pharmaceuticals, playing key roles in various biological functions.1 Moreover, guanidines also serve as valuable scaffolds in organocatalysis2 and precursors for the synthesis of heterocycles.3 The traditional synthesis of guanidines mainly relies on the addition of amines to carbodiimides,4 or utilizes thioureas (usually bearing electron-withdrawing substituents) in conjunction with thiophilic metal salts,5 Mukaiyama's reagent,6 coupling reagents,7 or other activating agents.8S-Oxidized thiourea derivatives9 and guanylating agents10 (such as S-methylisothioureas, pyrazole-1-carboximidamide and its derivatives, or triflyl guanidines) are also commonly employed. Beyond the well-known11 and recently12 developed approaches, a few isocyanide-based procedures have also been established, albeit each method exclusively affords N,N′,N′′-substituted guanidines.13

Looking at the synthetic toolbox for the assembly of N,N′-disubstituted guanidines, N-protected S-methylisothioureas are often used as starting materials; however, the techniques available for the derivatization of isothioureas lack the achievable diversity (Scheme 1a).14N,N′-Disubstituted guanidines can also be obtained from amines through cyanamides, but utilization of toxic cyanogen bromide and harsh conditions are required (Scheme 1b).15 The application of a commercially available guanylating reagent di(imidazole-1-yl)methanimine offers a more convenient access to N,N′-disubstituted guanidines through the stepwise displacement of its imidazole groups by amines (Scheme 1c).16 Besides the necessary isolation of intermediates, the nucleophilicity of amines can strongly affect the sequence of substitution and the yield of products, or even limit the achievable substitution pattern. Therefore, the development of a facile and general one-pot procedure for the synthesis of diverse N,N′-substituted guanidines is still highly desired.


image file: c7ob03109b-s1.tif
Scheme 1 Classical and new routes to N,N′-disubstituted guanidines.

Herein, we report a new approach for the synthesis of N,N′-disubstituted guanidines employing N-chlorophthalimide, isocyanides and amines as substrates in a sequential one-pot protocol (Scheme 1d).

Results and discussion

At the outset of the study, the model reaction of N-chlorophthalimide (1) with tert-butyl isocyanide (2a) and p-anisidine (4a) was investigated (Table 1). On the basis of literature information on the addition of analogous N-chloroamines to isocyanides,13a we presumed the need for the prior formation of the imidoyl chloride intermediate 3a, which can react with p-anisidine to furnish N-phthaloylguanidine 5a. Pleasingly, the addition of N-chlorophthalimide to tert-butyl isocyanide took place rapidly in dichloromethane at 0 °C with full conversion. However, further reaction with p-anisidine led to the desired guanidine 5a in only 12% HPLC yield, along with an unexpected side-product, which was identified as isoindolinone 6a (Table 1, entry 1). In order to optimize the reaction conditions, various solvents were tested (entries 1–15). Acetonitrile was found to be the best medium affording 5a in 75% HPLC yield, while non-polar solvents and ethers led to 6a predominantly. In order to avoid the formation of the urea-type product, anhydrous solvents were used; however, “wet” acetonitrile provided 5a in almost identical yield (entry 15). Decreasing the temperature gave 5a in lower yields, while elevated temperatures had no significant effect on the outcome of the reaction (entries 16–20). It is noteworthy, that the replacement of 1 with N-bromo- or N-iodophthalimide resulted in complex reaction mixtures and no trace of 5a or 6a.17
Table 1 Optimization of the model reactiona

image file: c7ob03109b-u1.tif

Entry Solvent Temp.b Yield of
5a [%] 6a [%]
a Reaction conditions: N-Chlorophthalimide (0.25 mmol), anhydrous solvent (0.50 ml), t-butyl isocyanide (1.1 equiv.), 15 min, 0 °C, then p-anisidine (1.2 equiv.), 2 h. b Temperature after the addition of p-anisidine. c Yield was determined by HPLC (each product was calibrated). d Non-dried solvent was used.
1 CH2Cl2 r.t. 12 40
2 DMSO r.t. 0 0
3 MeOH r.t. 1 8
4 1,4-Dioxane r.t. 5 26
5 THF r.t. 7 32
6 Et2O r.t. 11 24
7 CHCl3 r.t. 16 30
8 Toluene r.t. 4 46
9 EtOAc r.t. 20 26
10 DMF r.t. 26 3
11 Acetone r.t. 45 18
12 CH3NO2 r.t. 48 8
13 IPA r.t. 66 10
14 MeCN r.t. 75 5
15 MeCNd r.t. 72 7
16 MeCN −40 °C 29 5
17 MeCN −20 °C 30 13
18 MeCN 0 °C 47 11
19 MeCN 40 °C 73 2
20 MeCN 60 °C 66 6


Interestingly, performing the reaction with aromatic isocyanide 2b under the optimized conditions failed to produce the corresponding guanidine 5b (Table 2, entry 1). However, application of an equimolar amount of base (KOtBu, DBU, Na2CO3 or tertiary aliphatic amine) in order to neutralize the liberated hydrogen chloride promoted the formation of 5b (Table 2, entries 7–12). Other bases were ineffective and gave access only to isoindolinone 6a (Table 2, entries 2–6). The best result was achieved when triethylamine was utilized, providing 5b in an acceptable 48% HPLC yield (Table 2, entry 12).

Table 2 The effect of base on the reaction performed with aromatic isocyanide 2b[thin space (1/6-em)]a

image file: c7ob03109b-u2.tif

Entry Base Yield of
5b [%] 6a [%]
a Reaction conditions: N-Chlorophthalimide (0.25 mmol), anhydrous MeCN (0.50 ml), 4-methoxyphenyl isocyanide (1.1 equiv.), 15 min, 0 °C, then base (1.0 equiv.) and p-anisidine (1.2 equiv.), r.t., 2 h. b Yield was determined by HPLC (each product was calibrated).
1 0 32
2 TMG 0 13
3 Proton Sponge 0 23
4 Pyridine 0 45
5 DMAP 0 46
6 N-Methylimidazole 0 48
7 KOtBu 1 16
8 DBU 2 13
9 Na2CO3 10 32
10 DABCO 39 28
11 DIPEA 47 41
12 NEt3 48 31


To investigate the scope of the reaction and the cleavability of the phthaloyl moiety, six structurally different N-phthaloylguanidines 5a–f were first synthesized by employing aliphatic (substrates 2a,c), benzylic (substrate 2d) or aromatic (substrates 2b,e) isocyanides and anilines bearing both electron-donating (substrates 4a,c) and electron-withdrawing groups (substrates 4b,d) (Table 3, entries 1–6). The reactions proceeded smoothly in the presence of triethylamine under the optimized conditions providing 5a–f in a non-protonated form in 28–68% isolated yields.18 To our delight, further treatment of 5a–f with methylhydrazine completely removed the phthaloyl group in all cases, leading to the desired N,N′-disubstituted guanidines 7a–f in excellent yields under mild conditions (Table 3, entries 1–6).19,20 Obtaining the products as hydrochloride salts facilitated the isolation procedure.

Table 3 Synthesis and hydrazinolysis of N-phthaloyl-guanidinesa,b

image file: c7ob03109b-u3.tif

Entry 2 R1 4 R2 5 Yieldc [%] 7 Yieldc [%]
a Reaction conditions for the synthesis of 5a–f: N-Chlorophthalimide (1.0 mmol), anhydrous MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C, 15 min, then Et3N (1.0 equiv.) and aniline (1.2 equiv.), r.t., 2 h. b Reaction conditions for the synthesis of 7a–f: Guanidine 5a–f (0.25 mmol), MeCN (0.5 ml), MeNHNH2 (1.5 equiv.), 40 °C, 2 h, then HCl/EtOH (3 equiv.), r.t., 15 min c Isolated yield (NMR yield in parenthesis). NMR yield was determined by 1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
1 2a t-Bu 4a 4-MeO 5a 68 (73) 7a 98 (99)
2 2b 4-MeOC6H4 4a 4-MeO 5b 31 (49) 7b 94 (98)
3 2b 4-MeOC6H4 4b 4-Br 5c 28 (44) 7c 96 (99)
4 2c c-Hex 4c 3,5-Me 5d 29 (64) 7d 96 (98)
5 2d Bn 4d 4-F 5e 48 (54) 7e 97 (99)
6 2e 4-FC6H4 4e H 5f 30 (47) 7f 96 (99)


Although 5a–f were readily formed, their isolation proved to be rather demanding and required individual chromatographic conditions (see the ESI for details). Therefore, we decided to combine the steps of the N,N′-disubstituted guanidine synthesis into a sequential one-pot three-step protocol and omit the isolation of N-phthaloylguanidine intermediates. First, the scope of the combined method with respect to the isocyanide reagent was evaluated, using 4a as an aniline input (Table 4). Gratifyingly, both aliphatic and benzylic, as well as aromatic isocyanides could be subjected to the reaction; however, their electronic nature had a notable impact on the overall yield of the products. Benzylic and aliphatic isocyanides (including the sterically hindered 1,1,3,3-tetramethylbutyl isocyanide) provided the best results (7a and 7g–i, 51–69% isolated yields), while aromatic isocyanides bearing electron-donating MeO or electron-withdrawing F substituents delivered the corresponding guanidine hydrochlorides 7b,j and 7k in moderate yields (33–48%).

Table 4 Scope of the one-pot three-step synthesis with respect to isocyanidea
a Reaction conditions: N-Chlorophthalimide (1.0 mmol), anhydrous MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C, 15 min, then Et3N (1.0 equiv.) and aniline (1.2 equiv.), r.t., 2 h, then MeNHNH2 (1.5 equiv.), 40 °C, 2 h. The products were isolated as hydrochloride salts. Isolated yield (NMR yield in parenthesis). NMR yield was determined by 1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
image file: c7ob03109b-u4.tif


Unfortunately, the strongly electron-deficient 4-nitrophenyl isocyanide was barely tolerated (7l, 22% isolated yield), while methyl isocyanoacetate, TosMIC and 2-isocyano- or 3-isocyanopyridine did not afford the desired products.

To further explore the generality of our protocol, various anilines were subjected to the one-pot reaction applying the previously utilized isocyanides (Table 5, entries 1–14). Interestingly, both electron-rich and electron-poor anilines were equally tolerated. The electronic effect of substituents was not significant, with the exception of the nitro group (substrate 4j, Table 5, entry 6). Even N-substituted anilines could be used, as exemplified by N-methylaniline (Table 5, entry 2). Guanidines derived from aliphatic and benzyl isocyanides were obtained in the highest yields (7d,e and 7m–r, up to 73% isolated yield), while aromatic isocyanides, especially with electron-withdrawing substituents, furnished the corresponding 7c,f and 7s–v products in lower yields ranging from 27 to 43%. These results suggest that the overall performance of our method principally depends on the reactivity of the isocyanide component.

Table 5 Scope of the one-pot three-step synthesis with respect to anilinea

image file: c7ob03109b-u5.tif

Entry 2 R1 4 R2 R3 7 Yieldb [%]
a Reaction conditions: N-Chlorophthalimide (1.0 mmol), anhydrous MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C, 15 min, then Et3N (1.0 equiv.) and aniline (1.2 equiv.), r.t., 2 h, then MeNHNH2 (1.5 equiv.), 40 °C, 2 h. The products were isolated as hydrochloride salts. b Isolated yield (NMR yield in parenthesis). NMR yield was determined by 1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
1 2a t-Bu 4f H 2,4-F 7m 73 (78)
2 2a t-Bu 4g Me H 7n 66 (71)
3 2f t-Octyl 4h H 4-CF3 7o 55 (61)
4 2f t-Octyl 4i H 3-I 7p 64 (68)
5 2c c-Hex 4c H 3,5-Me 7d 56 (58)
6 2c c-Hex 4j H 4-Me-3-NO2 7q 35 (38)
7 2d Bn 4d H 4-F 7e 52 (54)
8 2d Bn 4k H 4-(NMe2) 7r 47 (51)
9 2b 4-MeOC6H4 4e H H 7s 42 (43)
10 2b 4-MeOC6H4 4b H 4-Br 7c 34 (42)
11 2g 3,4,5-MeOC6H2 4e H H 7t 43 (45)
12 2e 4-FC6H4 4e H H 7f 37 (39)
13 2e 4-FC6H4 4l H 4-CN 7u 27 (33)
14 2h 4-NO2C6H4 4e H H 7v 35 (37)


As an extension of the one-pot protocol towards N,N′-dialkylguanidines, we next surveyed the reaction of isobutylamine (8a) with 1 and 2a under standard conditions (Scheme 2). Surprisingly, no appreciable amount of guanidine 10a was produced and no trace of the expected intermediate 5g could be detected. Instead, compound 9a was isolated as the main product, presumably as a result of the subsequent reaction of 5g with an additional molecule of amine. Unfortunately, preventing the instantaneous ring-opening reaction by decreasing the temperature (−40 °C) was not successful. Nevertheless, we reasoned that product 9a might also be transformed to the desired N,N′-disubstituted guanidine 10a by a straightforward intramolecular cleavage. Our hypothesis was supported by the reaction mechanism of phthalimide deprotection with aliphatic amines.21 Indeed, simply heating 9a alone in refluxing acetonitrile for 10 h readily generated guanidine 10a in an almost quantitative yield (Scheme 2).


image file: c7ob03109b-s2.tif
Scheme 2 Unexpected ring-opening with aliphatic amine 8a.

Afterwards, a series of primary aliphatic and aralkyl amines were tested in a combined one-pot three-step manner (Table 6, entries 1–9). Intermediates 9a–i were formed smoothly by reacting 1 with isocyanides and amines under slightly modified conditions (2.2 equivalents of primary amine were used). Subsequent heating of the reaction mixtures at reflux temperature gave complete conversion of 9a–i within 10 h furnishing, in all cases, guanidine hydrochlorides in moderate to good yields (44–81%). We were pleased to find that bifunctional aliphatic amines, such as aminoalcohol 8b and Boc-protected diaminobutane 8d, were compatible with the protocol and provided the corresponding guanidines 10b and 10d in 80% and 55% isolated yields, respectively (Table 6, entries 2 and 4). Moreover, propargylamine (8e) and the sterically demanding tert-butylamine (8f) were also well tolerated (Table 6, entries 5 and 6). Alternatively, N-alkyl-N′-aryl guanidines are readily accessible from aromatic isocyanides as well, as demonstrated by the synthesis of 7h (Table 6, entry 9). Although their synthetic routes are somewhat different, it is noteworthy that aliphatic and aralkyl amines provided the corresponding guanidines generally in better yields compared to anilines (see the two complementary synthesis of 7h). This, most probably, is due to their higher nucleophilicity.

Table 6 One-pot three-step synthesis of N,N′-disubstituted guanidines from aliphatic and aralkyl aminesa

image file: c7ob03109b-u6.tif

Entry 2   8   Product   Yieldb [%]
a Reaction conditions: N-Chlorophthalimide (1.0 mmol), anhydrous MeCN (2.0 ml), isocyanide (1.1 equiv.), 0 °C, 15 min, then Et3N (1.0 equiv.) and amine (2.2 equiv.), r.t., 2 h, then reflux, 10 h. The products were isolated as hydrochloride salts. b Isolated yield (NMR yield in parenthesis). NMR yield was determined by 1H-NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
1 2a R1 = t-Bu 8a R2 = i-Bu image file: c7ob03109b-u7.tif 10a 81 (84)
2 2a R1 = t-Bu 8b R2 = HO(CH2)5 image file: c7ob03109b-u8.tif 10b 80 (85)
3 2f R1 = t-Octyl 8c R2 = C6H5(CH2)2 image file: c7ob03109b-u9.tif 10c 72 (78)
4 2f R1 = t-Octyl 8d R2 = BocNH(CH2)4 image file: c7ob03109b-u10.tif 10d 55 (62)
5 2c R1 = c-Hex 8e R2 = HCCCH2 image file: c7ob03109b-u11.tif 10e 44 (47)
6 2c R1 = c-Hex 8f R2 = t-Bu image file: c7ob03109b-u12.tif 10f 64 (68)
7 2d R1 = Bn 8g R2 = c-Hex image file: c7ob03109b-u13.tif 10g 71 (75)
8 2d R1 = Bn 8h image file: c7ob03109b-u14.tif image file: c7ob03109b-u15.tif 10h 53 (64)
9 2b R1 = 4-MeOC6H4 8g R2 = c-Hex image file: c7ob03109b-u16.tif 7h 66 (70)


Based on the above results and observations, a plausible mechanism is proposed (Scheme 3). In the first step, N-chlorophthalimide 1 undergoes α-addition to isocyanide to form imidoyl chloride B through nitrilium species A. Then, nucleophilic attack of the amine takes place, which can occur either on the imidoyl carbon to provide guanidine products (route A), or on the carbonyl carbon to give intermediate C (route B). The subsequent rearrangement of C results in isoindolone D along with an isocyanate by-product. Finally, D undergoes tautomerization to afford the more stable22 isoindolinone 6. To support the mechanism, the formation of isocyanate was confirmed by control experiments and a representative example of B was also isolated (see the ESI for details).


image file: c7ob03109b-s3.tif
Scheme 3 Proposed reaction mechanism.

Conclusions

In conclusion, we have developed a new and efficient synthesis of N,N′-disubstituted guanidines from readily available N-chlorophthalimide, isocyanides and amines in a sequential one-pot manner. The reactions proceed through the formation of N-phthaloylguanidines, which represent a novel class of guanidines. This operationally simple method tolerates both aromatic and aliphatic substrates in all possible combinations, providing general and diverse access to N-alkyl-N′-aryl, N-aryl-N′-aryl and N-alkyl-N′-alkyl guanidines with broad substrate scope.

Experimental section

General procedure for the one-pot synthesis of guanidines 7a–v

To a cooled suspension of N-chlorophthalimide (1.0 mmol, 182 mg) in anhydrous acetonitrile (2 mL) isocyanide (1.1 mmol) was added and stirred at 0 °C for 15 min. Then triethylamine (1.0 mmol, 140 μL) and subsequently the corresponding aniline (1.2 mmol) were added and the reaction mixture was allowed to warm to room temperature. After stirring for 2 h, methylhydrazine (1.5 mmol, 79 μL) was added, and the stirring was continued at 40 °C for 2 h. Then the reaction mixture was poured into aqueous NaOH solution (30 mL, 1 M) and extracted with chloroform (4 × 50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo until complete removal of the solvent and triethylamine. The residue was purified by flash column chromatography on neutral alumina (RediSep Rf; EtOAc[thin space (1/6-em)]:[thin space (1/6-em)]hexanes 0[thin space (1/6-em)]:[thin space (1/6-em)]100–100[thin space (1/6-em)]:[thin space (1/6-em)]0 gradient, then eluent switch to methanol[thin space (1/6-em)]:[thin space (1/6-em)]chloroform 0[thin space (1/6-em)]:[thin space (1/6-em)]100–1[thin space (1/6-em)]:[thin space (1/6-em)]10 gradient) to afford the pure guanidine base, which was then treated with HCl in ethanol (1 M, 2–3 equiv.) and stirred at room temperature for 15 min. Finally, evaporation to dryness followed by trituration with n-hexane or diisopropyl ether or diethyl ether (if necessary) gave pure guanidine hydrochlorides 7a–v.

General procedure for the one-pot synthesis of guanidines 10a–h

To a cooled suspension of N-chlorophthalimide (1.0 mmol, 182 mg) in anhydrous acetonitrile (2 mL) isocyanide (1.1 mmol) was added and stirred at 0 °C for 15 min. Then triethylamine (1.0 mmol, 140 μL) and subsequently primary amine (2.2 mmol) were added and the mixture was warmed to room temperature. After stirring for 2 h, the reaction mixture was warmed to reflux temperature and the stirring was continued for 10 h. Then the reaction mixture was poured into aqueous NaOH solution (30 mL, 1 M) and extracted with chloroform (4 × 50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo until the complete removal of the solvent and triethylamine. The residue was purified by flash column chromatography on neutral alumina (RediSep Rf; EtOAc[thin space (1/6-em)]:[thin space (1/6-em)]hexanes 0[thin space (1/6-em)]:[thin space (1/6-em)]100–100[thin space (1/6-em)]:[thin space (1/6-em)]0 gradient, then eluent switch to methanol[thin space (1/6-em)]:[thin space (1/6-em)]chloroform 0[thin space (1/6-em)]:[thin space (1/6-em)]100–1[thin space (1/6-em)]:[thin space (1/6-em)]10 gradient) to afford the pure guanidine base, which was then treated with HCl in ethanol (1 M, 2–3 equiv.) and stirred at room temperature for 15 min. Finally, evaporation to dryness followed by trituration with n-hexane or diisopropyl ether or diethyl ether (if necessary) gave pure guanidine hydrochlorides 10a–h.

Conflicts of interest

There are no conflicts to declare.

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  17. Application of NCS led to the corresponding succinimidyl analogue of 5a, however, in lower isolated yield (51%). On the other hand, no desired product was observed by means of NBS or NIS.
  18. In order to evaluate the effectiveness of the isolation procedures, NMR yields obtained from crude reaction mixtures are also shown.
  19. It should be noted that similar efficiencies were observed when hydrazine monohydrate was utilized, but the separation of the byproduct phthalhydrazide from N,N′-disubstituted guanidines was tedious.
  20. The succinimidyl analogue of 5a (see ref. 17) could not be transformed to the desired N,N′-disubstituted guanidine 7a by hydrazinolysis (MeNHNH2, MeCN) even at reflux temperature.
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Footnote

Electronic supplementary information (ESI) available: Experimental procedures, mechanistic study, compound characterization data and copies of NMR spectra. See DOI: 10.1039/c7ob03109b

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