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
First published on 8th March 2018
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.
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.
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).
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).
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.
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%).
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. |
---|
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.
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).
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.
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 | 10a | 81 (84) | |
2 | 2a | R1 = t-Bu | 8b | R2 = HO(CH2)5 | 10b | 80 (85) | |
3 | 2f | R1 = t-Octyl | 8c | R2 = C6H5(CH2)2 | 10c | 72 (78) | |
4 | 2f | R1 = t-Octyl | 8d | R2 = BocNH(CH2)4 | 10d | 55 (62) | |
5 | 2c | R1 = c-Hex | 8e | R2 = HCCCH2 | 10e | 44 (47) | |
6 | 2c | R1 = c-Hex | 8f | R2 = t-Bu | 10f | 64 (68) | |
7 | 2d | R1 = Bn | 8g | R2 = c-Hex | 10g | 71 (75) | |
8 | 2d | R1 = Bn | 8h | 10h | 53 (64) | ||
9 | 2b | R1 = 4-MeOC6H4 | 8g | R2 = c-Hex | 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).
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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