Next Article in Journal
An Efficient Synthesis and Antibacterial Activity of Some Novel 3,4–Dihydropyrimidin-2-(1H)-Ones
Previous Article in Journal
The Investigations’ Importance in Conservation and Restoration of the National Cultural Heritage: Mobile Cultural Heritage and Historical Monuments
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Chemistry Proceedings
Volume 8
Issue 1
10.3390/ecsoc-25-11759
chemproc-logo
Submit to this Journal
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Proceeding Paper

Reaction of N-(tosylmethyl)ureas with NaCN: Synthetic and Mechanistic Aspects †

by
Anastasia A. Fesenko
and
Anatoly D. Shutalev
*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
†
Presented at the 25th International Electronic Conference on Synthetic Organic Chemistry, 15–30 November 2021; Available online: https://ecsoc-25.sciforum.net/.
Chem. Proc. 2022, 8(1), 54; https://doi.org/10.3390/ecsoc-25-11759
Published: 14 November 2021
(This article belongs to the Proceedings of The 25th International Electronic Conference on Synthetic Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
The reaction of NaCN with N-(tosylmethyl)ureas, prepared by condensation of urea with aldehydes and p-toluenesulfinic acid, was studied. Generally, this reaction afforded the corresponding α-ureido nitriles. Some mechanistic aspects of cyanide-anion amidoalkylation with N-(tosylmethyl)ureas were discussed based on DFT calculations.

1. Introduction

Nitriles of α-ureidocarboxylic acids are valuable derivatives of α-amino acids. They possess various biological properties, in particular fungicidal [1,2], antitumor [3], antihypertensive [4], and enzyme inhibitory activities [5,6,7,8,9]. These compounds also serve as starting materials for the preparation of hydantoins [10,11,12], imidazolidin-2-ones [13,14], 2,5-diaminooxazoles [15], 6-carboxydihydrouraciles [16], N-(1,2,4-triazol-3-yl)methyl- and N-(tetrazol-5-yl)methyl-substituted ureas [8,17,18,19], etc.
Nitriles of N(3)-substituted α-ureidocarboxylic acids can be readily prepared by reaction of α-aminonitriles with isocyanates [20,21,22]. In contrast, synthesis of α-ureidonitriles with unsubstituted ureido group (e.g., 1, Scheme 1) is still a challenge.
Described syntheses of compounds 1 generally involve formation of different C-N bonds. The most commonly used method is based on the reaction of α-aminonitriles with HNCO generated by the treatment of metal cyanates with acids [10,16,23,24,25,26,27,28]. Some representatives of these compounds were also prepared by reactions of α-aminonitriles or ketone cyanohydrines with urea [29,30,31], and 2-isocyanato-2-phenylbutanenitrile with ammonia [11]. However, these methods suffer from various disadvantages such as poor synthetic flexibility, formation of side products, moderate yields of the target products, difficulties in their isolation and purification, etc.
We hypothesized that ureido nitriles could be prepared in a straightforward fashion using C-C bond formation by reaction of appropriate amidoalkylating reagents with a cyanide source (Scheme 2). To the best of our knowledge, there are no reports on the synthesis of these nitriles according to the proposed method.
Previously, cyanation of some amidoalkylating reagents based on amides or carbamates has been described using alkali metal cyanides [32,33,34,35,36], K4Fe(CN)6 [37], ketone cyanohydrins in the presence of a base [38], or TMSCN in the presence of a Lewis acid [39,40,41,42] as a cyanide source. It should be noted that additional nucleophilic centers in ureido-based amidoalkylating reagents can affect the outcome of their cyanation. Based on the reported data and our experience [43], we chose NaCN as a cyanide source for our study.
The nature of the leaving group in amidoalkylating reagents plays an important role for successful amidoalkylation of nucleophiles. Previously, we found that the tosyl leaving group is one of choice for the preparation of urea-, thiourea-, and guanidine-based amidoalkylating reagents [44,45,46,47]. The reagents with tosyl group are readily available, stable and possess high reactivity.
Herein we report synthesis of N-(tosylmethyl)-substituted ureas and their reactions with sodium cyanide to give α-ureido nitriles. Some mechanistic aspects of cyanide-anion amidoalkylation with N-(tosylmethyl)ureas are suggested based on DFT calculations.

2. Results and Discussion

Starting amidoalkylating reagents, N-(tosylmethyl)-substituted ureas were obtained by the method first described by Engberts et al. about 50 years ago [48]. The method involved condensation of amides with aldehydes and p-toluenesulfinic acid generated in situ by treatment of its sodium salt with HCOOH. Herein, we applied our convenient modification [44,45,46,47] of this method using p-toluenesulfinic acid itself. Thus, the three-component condensation of urea (1) (5 equiv.) with aromatic 2a-f or aliphatic aldehydes 2g-i (1 equiv.) and p-toluenesulfinic acid (3) (1 equiv.) readily proceeded in water at room temperature to give the corresponding N-(tosylmethyl)-substituted ureas 4a-i in excellent yields (Scheme 3, Table 1).
In our initial experiments with aliphatic aldehydes 2g-i, we found that some amount of the corresponding N,N′-bis(tosylmethyl)-substituted ureas formed along with the target products 4g-i. For example, use of 3 equivalents of urea in the condensation with butanal (2g) or 2-methylpropanal (2h) and sulfinic acid 3 afforded mixtures of 4g or 4h and the corresponding N,N′-bis-derivatives in a ratio of 99.5:0.5 and 98.5:1.5, respectively (entries 12 and 15). The amount of these N,N′-bis-derivatives increased to 17–20 mol% with prolonged reaction times (6.25–7.33 h) (entry 12 vs. entry 11, entry 15 vs. entry 14). Formation of N,N′-bis-derivatives was completely suppressed when 5 fold excess of urea was used. Under optimized conditions (Table 1, entries 1, 3–5, 10, 13, 16, and 17) with 5 equivalents of urea, the condensation with aliphatic aldehydes completed for 2 h and with aromatic ones for 20 h. The amount of N,N′-bis(tosylmethyl)-substituted ureas in the obtained products was less than 1 mol%.
Sulfones 4a-i precipitated from the reaction mixtures and, after completion the reactions, were isolated by filtration. According to 1H NMR spectroscopic data, the purity of crude products was excellent (>96%), therefore, they were used in the next step without additional purification. Generally, crystallization of sulfones 4a-i, especially alkyl-substituted ones 4g-i, from boiling solvents (or mixtures thereof) led to their partial decomposition. These compounds are rather unstable in solutions even at room temperature. For example, the 1H NMR spectrum of sulfone 4b in DMSO-d6 (5 min after dissolution) showed its 98% purity. After keeping this solution at room temperature for 70 h, a significant (about 50%) decomposition of 4b was observed, and among various products formed, 4-methylbenzaldehyde, p-toluenesulfinic acid and urea (each about 25 mol%) were identified. Similarly, sulfone 4a decomposed in DMSO-d6 solution at room temperature (about 40% after 73.5 h).
It is noteworthy that after addition of sulfinic acid 3 to a solution of an aliphatic aldehyde or an emulsion of aromatic aldehyde in water in all cases (with the exception of 2f), a coarse suspension formed. The precipitated solid was triturated to obtain a fine suspension followed by the addition of urea, otherwise the purity of isolated sulfone decreased. For large-scale sulfone preparation, the trituration may become laborious. Therefore, with aldehydes 2a,d,e the procedure was modified by the addition of EtOH (entries 2, 6, and 8) or HCOOH (entry 9) as a co-solvent. In these cases, the corresponding product 4 precipitated from the solution formed after adding all the reagents as a fine solid. Use of co-solvents had a very slight effect on the yield of sulfones 4a,d,e.
We found that N-(tosylmethyl)-substituted ureas 4 smoothly react with sodium cyanide in aprotic solvents to give the expected products of the tosyl group substitution, α-ureido nitriles 5 (Scheme 4).
Initially, we studied the reaction of sulfone 4b with NaCN in DMF with varying reagents ratio, temperature, and reaction time. We found that 4b reacted with NaCN (1.25 equiv.) at room temperature for 3 h to give cyanide 5b along with 7 mol% of a side product (Table 2, entry 4). The amount of the latter decreases with decreasing reaction time (entry 4 vs. entry 5), excess of NaCN (entry 6 vs. entry 7), and temperature (entry 5 vs. entry 6). Under the optimized conditions, the reaction of 4b with 1.1 equivalents of NaCN (DMF, 0 °C, 1 h) followed by precipitation of the product with water afforded cyanide 5b in 97% yield and >99% purity (entry 7).
Based on the experimental data (Table 2), we assume that the side product resulted from conversion of the initially formed cyanide 5b. Indeed, after keeping of a solution of the crude product containing 7 mol% of the byproduct (entry 4) in DMSO-d6 at room temperature for 6 days, the amount of the latter increased to 10 mol% (1H NMR data).
According to 1H NMR spectroscopic data, the structure of the side product was assigned as 4-iminohydantoin 6. Thus, the 1H NMR spectrum of compound 6 in DMSO-d6 showed two broad singlet signals at 10.44 and 8.07 ppm corresponding to protons of two NH groups, a multiplet in the range of 7.85–7.90 ppm due to two aromatic protons, and a singlet at 2.37 ppm corresponding to three protons of the methyl group. It is noteworthy that the chemical shifts of NH protons significantly differ (Δδ = 2.37 ppm), which proves very different environments of these protons.
Analogously, under the optimized conditions (DMF, 0 °C, 1 h), sulfones 4a,c-g,i reacted with NaCN (1.10–1.11 equiv.) to afford the corresponding α-ureido nitriles 5a,c-g,i in 69–100% yields (entries 1, 9–12, 14, and 17). Decrease in yields of 5f,g,i are explained by losses during isolation due to their higher solubility in water.
In contrast to 4a-g,i, the reaction of 4h with NaCN (1.12 equiv.) in DMF failed to give ureido nitrile 5h. The only isolated product (yield 10%) after dilution of the reaction mixture with water was isobutylidene diurea (entry 16), whose formation can be explained by relatively low rate of the tosyl group substitution in 4h caused by steric hindrance of the isopropyl group.
We also studied the effect of solvent on the reaction of sulfones 4 with NaCN. Compound 4f smoothly reacted with NaCN in DMSO at room temperature to give cyanide 5f (entry 13). Reaction of 4a,b with NaCN (2 equiv.) slowly proceeded in MeCN at room temperature (several days), however, the corresponding cyanides 5a,b were isolated in good yields (entries 2 and 8). The rate of reaction between 4a and NaCN in MeCN significantly increased in the presence of 18-crown-6 (0.2 equiv.) to give 5a in 73% yield (entry 3). Interestingly, under similar conditions (MeCN, 18-crown-6), reaction of alkyl substituted sulfone 4g with NaCN failed to provide cyanide 5g (entry 15). The isolated product was very poorly soluble in common solvents including DMSO. According to 1H and 13C NMR spectroscopic data, this product mainly contained a heterocyclic compound resulting from the initially formed cyanide 5g. Unfortunately, we were not able to establish the structure of this compound unambiguously since its purification failed.
Despite numerous reports on α-amidoalkylation, detailed mechanism of this reaction has not been described [49,50,51,52,53,54,55,56,57,58]. It was postulated that amidoalkylating reagents with a good leaving group and derived from primary amides react with sufficiently basic nucleophiles via an elimination-addition mechanism (Scheme 5).
According to this mechanism, the first step of the reaction is transformation of amidoalkylating reagents into acylimines under the action of basic nucleophiles. Next, the acylimines rapidly react with nucleophiles to give the final products. It is noteworthy that in some cases, during the treatment of amidoalkylating reagents with weakly nucleophilic bases (DBU, Cs2CO3, etc.), the resulting acylimines were isolated and demonstrated high reactivity towards nucleophiles [59,60,61,62].
We performed a computational study of the reaction of sulfones 4a and 4j (R = Me in Scheme 3) with cyanide-anion in DMF solution at the DFT B3LYP/6-311++G(d,p) level of theory using the PCM solvation model. Special attention was put on calculations of thermodynamic and activation parameters for the transformation of 4a,j into the corresponding acylimines.
First, we calculated Cartesian coordinates and energies of the optimized geometries for the most stable conformers of compounds 4a,j (Figure 1, Table 3) considering that, according to 1H NMR spectroscopic data, sulfones 4a-i in DMSO-d6 solution exist in a conformation with anti-orientation of the vicinal NH and CH protons (3J = 10.2–10.8 Hz).
Table 3 shows that rotamer A is the most stable for both 4a and 4j, however, the differences in energy between the rotamers are relatively small (ΔE ≤ 0.90 kcal/mol). The calculations also demonstrate that the energy barriers separating the conformational isomers are very low and do not exceed 3 kcal/mol. It is noteworthy that for all three rotamers of 4a,j, the C-S bond is significantly longer (1.889–1.926 Ǻ) than that of alkyl sulfones (1.78 Ǻ) [63,64].
In contrast to compounds 4a and 4j, products of their NH deprotonation, the corresponding conjugated bases, were found to be unstable. According to the DFT calculations, the conjugated bases derived from rotamers A, B, C of 4a and rotamer B of 4j cannot exist in DMF solution and spontaneously transform into (E)-acylimines 7a,j via the C-S bond cleavage. Although the conjugated bases derived from rotamers A and C of 4j lie at energy minima, the energy barriers of their transformation into (E)-acylimine 7j in DMF solution are extremely low (ΔE# = 0.10 kcal/mol and ΔG# = 0.10 kcal/mol for A; ΔE# = 0.02 kcal/mol and ΔG# = −0.02 kcal/mol for C).
Next, we evaluated the role of the cyanide-anion in the conversion of conformer A of compounds 4a,j into the corresponding acylimines 7a,j in DMF solution (Scheme 6).
The calculations were started from the pre-reaction complexes I resulting from attack of the cyanide-anion on the proton of the NH group in 4a,j. We found that electronic energy barriers of the proton abstraction (via transition state TS1#) to give complexes of the conjugated bases of 4a,j with HCN (complexes II) are relatively low (ΔE# = 12.05 and 12.66 kcal/mol, respectively) (Figure 2 and Figure 3). The next step involves cleavage of the C-S bond in II (via transition state TS2#) to afford the post-reaction complexes of acylimines 7a,j with HCN and p-toluenesulfinate anion (complexes III). The electronic energy barriers of this step are very low (ΔE# = 0.14 and 0.98 kcal/mol, respectively). The IRC analysis demonstrated that the found transition states (TS1# and TS2#) connect the desired minima. Thus, the calculated electronic energy profiles for conversion of 4a,j into 7a,j under the action of CN-anion in DMF solution correspond to an E1cB mechanism.
It should be noted that, taking into account zero-point vibrational energies (ZPVE) and thermochemical corrections, the described reaction in DMF has only one transition state (TS1# for 4a → 7a and TS2# for 4j → 7j) with the Gibbs free energy barrier of 9.93 and 10.94 kcal/mol, respectively. These data prove that the intrinsic mechanism of the reaction is a synchronous E2-like pathway but not E1cB. In contrast to classical E2 elimination, the tosyl group and NH hydrogen are in a gauche orientation (the H-N-C-S dihedral angles for conformer A of 4a,j are 71.6 and 77.5°, respectively). The transition states of 4a → 7a and 4j → 7j transformations are significantly different. In the first case, it is close to the starting complex I, and in the second case, it is close to the final complex III. The transformation of 4a,j into 7a,j under the action of CN-anion is a thermodynamically favorable process with ΔG = −7.47 kcal/mol and ΔG = −5.14 kcal/mol in DMF, respectively (298 K, 1 atm).
We also performed the DFT calculations of the reaction between compound 4j and CN-anion in DMF via a SN1 partway involving initial heterolytic cleavage of the C-S bond. However, high activation barrier (>22 kcal/mol) of the heterolysis makes this mechanism unfavorable.
Obviously, the final step of the reaction between 4a,j and CN-anion involves nucleophilic addition of the nucleophile to acylimines 7a,j followed by protonation of the resulting conjugated bases of the target products with HCN.

3. Conclusions

In summary, we have shown that the reaction of N-(tosylmethyl)-substituted ureas, prepared by condensation of urea with aromatic or aliphatic aldehydes and p-toluenesulfinic acid, with sodium cyanide depends on the reaction conditions. Under optimized conditions (DMF, 0 °C, 1 h), N-(tosylmethyl)ureas smoothly reacted with NaCN (1.10–1.10 equiv.) to give α-ureido nitriles. According to DFT computational data, the first step of cyanide-anion amidoalkylation with N-(tosylmethyl)ureas involves the formation of the corresponding N-acylimines under the action of CN-anion via E2-like pathway.

Author Contributions

Synthetic investigation, writing–original draft preparation, A.A.F.; methodology, software, writing–original draft preparation, A.D.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was financially supported by the Russian Foundation for Basic Research (Grant No. 20-03-00928).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data available on request.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Schulze, W.; Klepel, M.; Jumar, A.; Lehmann, H.; Braemer, B. N-cyanoalkylurea derivatives as fungicides. Chem. Abstr. 1987, 106, 4685. [Google Scholar]
  2. Ohishi, T.; Kato, T.; Ozaki, T.; Kameda, N.; Itooka, E.; Fujinami, A. Cyanourea fungicides. Chem. Abstr. 1975, 83, 142996. [Google Scholar]
  3. Nieper, H.A.; Koehler, F. Cytostatic α-cyanobenzyl derivatives. Chem. Abstr. 1984, 100, 96704. [Google Scholar]
  4. Schwing, G.W.; Price, W.A., Jr.; Smith, D.H., Jr. Ureidonitrile, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel. Chem. Abstr. 1980, 92, 22091. [Google Scholar]
  5. Löser, R.; Schilling, K.; Dimmig, E.; Guetschow, M. Interaction of Papain-like Cysteine Proteases with Dipeptide-Derived Nitriles. J. Med. Chem. 2005, 48, 7688–7707. [Google Scholar] [CrossRef]
  6. Salvati, M.E.; Finlay, H.; Harikrishnan, L.S.; Jiang, J.; Johnson, J.A.; Kamau, M.G.; Lawrence, R.M.; Miller, M.M.; Qiao, J.X.; Wang, T.C.; et al. Heterocyclic CETP inhibitors. Chem. Abstr. 2011, 154, 259401. [Google Scholar]
  7. Giuliano, C.; Rubio, S.G.; Daina, A.; Guainazzi, A.; Pietra, C. p-Substituted Asymmetric Ureas and Medical Uses Thereof. Chem. Abstr. 2015, 163, 412148. [Google Scholar]
  8. Takahashi, H.; Watanabe, H.; Fujii, K.; Shibasaki, M.; Kawashima, M.; Kamiya, M.; Ohata, K. Urea derivative or pharmacologically acceptable salt thereof. Chem. Abstr. 2016, 166, 39993. [Google Scholar]
  9. Luengo, J.; Vaddi, K. Selective inhibitors of protein arginine methyltransferase 5 (PRMT5). Chem. Abstr. 2017, 168, 100879. [Google Scholar]
  10. Moore, J.E. 1-Substituted-3-polyhaloalkylthio hydantoin fungicides. Chem. Abstr. 1987, 106, 98089. [Google Scholar]
  11. Knabe, J.; Wunn, W. Racem. und optisch aktive Hydantoine aus disubstituierten Cyanessigsäuren. Arch. Pharm. 1980, 313, 538–543. [Google Scholar] [CrossRef]
  12. Herbst, R.M.; Johnson, T.B. Researches on hydantoins. xlix. a new rearrangement leading to the formation of 4-aminohydantoin derivatives. J. Am. Chem. Soc. 1930, 52, 3676–3680. [Google Scholar] [CrossRef]
  13. Mas-Roselló, J.; Okoh, M.; Clayden, J. Enantioselectively functionalised phenytoin derivatives by auxiliary-directed N to C aryl migration in lithiated α-amino nitriles. Chem. Commun. 2018, 54, 10985–10988. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Ackermann, J.; Amrein, K.; Hunziker, D.; Kuhn, B.; Mayweg, A.V.; Neidhart, W.; Takahashi, T. Imidazolone and imidazolidinone derivatives as 11B-HSD1 inhibitors for the treatment of diabetes. Chem. Abstr. 2008, 148, 495950. [Google Scholar]
  15. Cook, A.H.; Hunter, G.D. Studies in the azole series. Part XXXIII. The interaction of α-amino-nitriles and alkyl or aryl isocyanates. J. Chem. Soc. 1952, 3789–3796. [Google Scholar] [CrossRef]
  16. Husbands, S.; Fraser, W.; Suckling, C.J.; Wood, H.C. Latent inhibitors part 11. The synthesis of 5-spirocyclopropyl dihydroorotic acid. Tetrahedron 1995, 51, 865–870. [Google Scholar] [CrossRef]
  17. De Simone, A.; Georgiou, C.; Ioannidis, H.; Gupta, A.A.; Juárez-Jiménez, J.; Doughty-Shenton, D.; Blackburn, E.A.; Wear, M.A.; Richards, J.P.; Barlow, P.N.; et al. A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors. Chem. Sci. 2019, 10, 542–547. [Google Scholar] [CrossRef] [Green Version]
  18. Yun, W. Piperidine analogs as glycogen synthase activators. Chem. Abstr. 2011, 154, 588717. [Google Scholar]
  19. Luo, G.; Chen, L.; Degnan, A.P.; Dubowchik, G.M.; Macor, J.E.; Tora, G.O.; Chaturvedula, P.V. Heterocyclic anti-migraine agents. Chem. Abstr. 2005, 143, 78091. [Google Scholar]
  20. Coussanes, G.; Gaus, K.; O’Sullivan, A.C. The Synthesis of Ketone-Derived Enamides by Elimination of HCN from Cyanoamides. Eur. J. Org. Chem. 2016, 2016, 4176–4188. [Google Scholar] [CrossRef]
  21. Labrie, F.; Singh, S.M.; Labrecque, R.; Ciobanu, L.C. Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety. Chem. Abstr. 2015, 163, 132721. [Google Scholar]
  22. Ventosa-Andrés, P.; Vera, J.A.G.; García-López, M.T.; Herranz, R. Solvent-Free Synthesis of α-Amino Nitrile-Derived Ureas. Org. Lett. 2013, 15, 632–635. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Alker, D.; Campbell, S.F.; Cross, P.E.; Burges, R.A.; Carter, A.J.; Gardiner, D.G. Long-acting dihydropyridine calcium antagonists. 5. Synthesis and structure-activity relationships for a series of 2-[[(N-substituted-heterocyclyl)ethoxy]methyl]-1,4-dihydropyridine calcium antagonists. J. Med. Chem. 1990, 33, 1805–1811. [Google Scholar] [CrossRef] [PubMed]
  24. Vitali, R.A.; Jacob, T.A.; Chemerda, J.M. Analogs of Methyldopa and Dopa. Hydantoic Acids and Hydantoins. J. Med. Chem. 1964, 7, 379–381. [Google Scholar] [CrossRef]
  25. Smith, L.H.; Yates, P. The Synthesis of 4-Amino-2(3H)-oxo-5-imidazolecarboxamide. J. Am. Chem. Soc. 1954, 76, 6080–6084. [Google Scholar] [CrossRef]
  26. Rigler, H.E.; Henze, H.R. Synthesis of Compounds with Hypnotic Properties. I. Alkoxymethylhydantoins. J. Am. Chem. Soc. 1936, 58, 474–477. [Google Scholar] [CrossRef]
  27. Biltz, H.; Slotta, K. Über die Herstellung von Hydantoinen. J. Prakt. Chem. 1926, 113, 233–267. [Google Scholar] [CrossRef]
  28. Read, W.T. Researches on hydantoins. synthesis of the soporific, 4,4-phenylethyl-hydantoin(nirvanol). J. Am. Chem. Soc. 1922, 44, 1746–1755. [Google Scholar] [CrossRef] [Green Version]
  29. Wendelin, W.; Schramm, H.-W. Über die Reaktionen von Guanidin bzw. Harnstoff mit Cyanhydrinen. Chem. Mon. 1981, 112, 853–866. [Google Scholar] [CrossRef]
  30. Pinner, A.; Lifschütz, J. Ueber die Einwirkung von Harnstoff auf Cyanhydrine. Eur. J. Inorg. Chem. 1887, 20, 2351–2358. [Google Scholar] [CrossRef] [Green Version]
  31. Zhou, X.; Zhang, H. Schiff base metal manganese complex and preparation method and application thereof. Chem. Abstr. 2016, 165, 283533. [Google Scholar]
  32. Yan, H.; Oh, J.S.; Lee, J.; Song, C.E. Scalable organocatalytic asymmetric Strecker reactions catalysed by a chiral cyanide generator. Nat. Commun. 2012, 3, 1212. [Google Scholar] [CrossRef] [Green Version]
  33. Reingruber, R.; Baumann, T.; Dahmen, S.; Bräse, S. Use of the Chiral Pool—Practical Asymmetric Organocatalytic Strecker Reaction with Quinine. Adv. Synth. Catal. 2009, 351, 1019–1024. [Google Scholar] [CrossRef]
  34. Ooi, T.; Uematsu, Y.; Fujimoto, J.; Fukumoto, K.; Maruoka, K. Advantage of in situ generation of N-arylsulfonyl imines from α-amide sulfones in the phase-transfer-catalyzed asymmetric Strecker reaction. Tetrahedron Lett. 2007, 48, 1337–1340. [Google Scholar] [CrossRef]
  35. Banphavichit, V.; Chaleawlertumpon, S.; Bhanthumnavin, W.; Vilaivan, T. A Convenient Synthesis of N-Boc-Protected α-Aminonitriles from α-Amidosulfones. Synth. Commun. 2004, 34, 3147–3160. [Google Scholar] [CrossRef]
  36. Katritzky, A.R.; Urogdi, L. Benzotriazole-assisted synthesis of α-acylaminonitriles and a conceptually novel method for peptide elongation. J. Chem. Soc. Perkin Trans. 1 1990, 1, 1853–1857. [Google Scholar] [CrossRef]
  37. Hu, X.; Li, R.; Li, Z. Conversion of N-Benzyloxycarbonylamino- and N-Tosylamino-Benzyl Phenylsulfones by Green Strecker Reactions to α-Aminobenzyl Nitriles Using Potassium Hexacyanoferrate(II). J. Chem. Res. 2014, 38, 432–436. [Google Scholar] [CrossRef]
  38. Herrera, R.P.; Sgarzani, V.; Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A. Phase Transfer Catalyzed Enantioselective Strecker Reactions of α-Amido Sulfones with Cyanohydrins. J. Org. Chem. 2006, 71, 9869–9872. [Google Scholar] [CrossRef]
  39. Oba, M.; Koguchi, S.; Nishiyama, K. Stereoselective Synthesis of 3,4-Dihydroxylated Prolines and Prolinols Starting fromL-Tartaric Acid. J. Heterocycl. Chem. 2014, 51, 237–243. [Google Scholar] [CrossRef]
  40. Kadam, S.T.; Thirupathi, P.; Kim, S.S. Synthetic application of in situ generation of N-acyliminium ions from α-amido p-tolylsulfones for the synthesis of α-amino nitriles. Tetrahedron 2010, 66, 1684–1688. [Google Scholar] [CrossRef]
  41. Das, B.; Damodar, K.; Shashikanth, B.; Srinivas, Y.; Kalavathi, I. A Mild and Efficient Catalytic Strecker Reaction of N-Alkoxycarbonylamino Sulfones with Trimethylsilyl Cyanide Using Indium(III) Chloride: A Facile Synthesis of α-Aminonitriles. Synlett 2008, 2008, 3133–3136. [Google Scholar] [CrossRef]
  42. Harding, K.E.; Liu, L.T.; Farrar, D.G.; Coleman, M.T.; Tansey, S.K. Preparation of AcyclicN-Acyl-N,O-acetals by Decarboxylation ofN-Protected α-Amino Acids and Studies of Asymmetric Amidoalkylation with Trimethylsilyl Cyanide. Synth. Commun. 1991, 21, 1409–1417. [Google Scholar] [CrossRef]
  43. Shutalev, A.D. Reaction of α-(thio)amidoalkylation in the synthesis of α-cyano-substituted cyclic (thio)ureas and dithiocarbamates. Chem. Heterocycl. Compd. 1993, 29, 1192–1199. [Google Scholar] [CrossRef]
  44. Fesenko, A.A.; Grigoriev, M.S.; Shutalev, A.D. Nucleophile-Mediated Ring Expansion of 5-Acyl-substituted 4-Mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones in the Synthesis of 7-Membered Analogues of Biginelli Compounds and Related Heterocycles. J. Org. Chem. 2017, 82, 8085–8110. [Google Scholar] [CrossRef]
  45. Fesenko, A.A.; Shutalev, A.D. Synthesis of γ-Azido-β-ureido Ketones and Their Transformation into Functionalized Pyrrolines and Pyrroles via Staudinger/aza-Wittig Reaction. J. Org. Chem. 2013, 78, 1190–1207. [Google Scholar] [CrossRef]
  46. Shutalev, A.D.; Fesenko, A.A. 4-Hydroxy-4-methyl-5-tosylhexahydropyrimidin-2-imines: Synthesis and different dehydration pathways. Tetrahedron 2011, 67, 6883–6888. [Google Scholar] [CrossRef]
  47. Fesenko, A.A.; Cheshkov, D.A.; Shutalev, A.D. Synthesis of diethyl 2-thioxo-1,2,3,4-tetrahydro- and hexahydropyrimidine-5-phosphonates. Mendeleev Commun. 2008, 18, 51–53. [Google Scholar] [CrossRef]
  48. Meijer, H.; Tel, R.M.; Strating, J.; Engberts, J.B.F.N. Mannich-type condensation reactions of sulfinic acids with aldehydes and nitrogen bases: Part. VI. The use of ureas, thioureas and thiobenzamide. Recl. Trav. Chim. 1973, 92, 72–82. [Google Scholar] [CrossRef]
  49. Zaugg, H.E.; Martin, W.B. α-Amidoalkylations at Carbon. Org. React. 1965, 14, 52–269. [Google Scholar]
  50. Zaugg, H.E. Recent Synthetic Methods Involving Intermolecular α-Amidoalkylation at Carbon. Synthesis 1970, 1970, 49–73. [Google Scholar] [CrossRef]
  51. Zaugg, H.E. α-Amidoalkylation at Carbon: Recent Advances—Part I. Synthesis 1984, 1984, 85–110. [Google Scholar] [CrossRef]
  52. Zaugg, H.E. Synthesis α-Amidoalkylation at Carbon: Recent Advances—Part II. Synthesis 1984, 1984, 181–212. [Google Scholar] [CrossRef]
  53. Speckamp, W.; Moolenaar, M.J. New Developments in the Chemistry of N-Acyliminium Ions and Related Intermediates. Tetrahedron 2000, 56, 3817–3856. [Google Scholar] [CrossRef]
  54. Maryanoff, B.E.; Zhang, H.-C.; Cohen, J.H.; Turchi, A.I.J.; Maryanoff, C.A. Cyclizations of N-Acyliminium Ions. Chem. Rev. 2004, 104, 1431–1628. [Google Scholar] [CrossRef]
  55. Petrini, M. α-Amido Sulfones as Stable Precursors of Reactive N-Acylimino Derivatives. Chem. Rev. 2005, 105, 3949–3977. [Google Scholar] [CrossRef]
  56. Mazurkiewicz, R.; Październiok-Holewa, A.; Adamek, J.; Zielińska, K. α-Amidoalkylating Agents: Structure, Synthesis, Reactivity and Application. Adv. Heterocycl. Chem. 2014, 111, 43–94. [Google Scholar]
  57. Wu, P.; Nielsen, T.E. Scaffold Diversity from N-Acyliminium Ions. Chem. Rev. 2017, 117, 7811–7856. [Google Scholar] [CrossRef]
  58. Marcantoni, E.; Palmieri, A.; Petrini, M. Recent synthetic applications of α-amido sulfones as precursors of N-acylimino derivatives. Org. Chem. Front. 2019, 6, 2142–2182. [Google Scholar] [CrossRef]
  59. Lillo, V.J.; Mansilla, J.; Saá, J.M. Organocatalysis by Networks of Cooperative Hydrogen Bonds: Enantioselective Direct Mannich Addition to Preformed Arylideneureas. Angew. Chem. Int. Ed. 2016, 55, 4312–4316. [Google Scholar] [CrossRef]
  60. Lillo, V.J.; Mansilla, J.; Saá, J.M. The role of proton shuttling mechanisms in solvent-free and catalyst-free acetalization reactions of imines. Org. Biomol. Chem. 2018, 16, 4527–4536. [Google Scholar] [CrossRef]
  61. Davis, T.A.; Vilgelm, A.E.; Richmond, A.; Johnston, J.N. Preparation of (−)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale. J. Org. Chem. 2013, 78, 10605–10616. [Google Scholar] [CrossRef] [Green Version]
  62. Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. Heterobimetallic Transition Metal/Rare Earth Metal Bifunctional Catalysis: A Cu/Sm/Schiff Base Complex for Syn-Selective Catalytic Asymmetric Nitro-Mannich Reaction. J. Am. Chem. Soc. 2010, 132, 4925–4934. [Google Scholar] [CrossRef]
  63. Rudolph, F.A.M.; Fuller, A.L.; Slawin, A.M.Z.; Bühl, M.; Aitken, R.A.; Woollins, J.D. The X-ray Structures of Sulfones. J. Chem. Crystallogr. 2009, 40, 253–265. [Google Scholar] [CrossRef]
  64. Sands, D.E. The crystal structure of dimethyl sulfone. Z. Kristallogr. 1963, 119, 245–251. [Google Scholar] [CrossRef]
Chemproc 08 00054 sch001 550
Scheme 1. Described synthesis of α-ureido nitriles with unsubstituted ureido group.
Scheme 1. Described synthesis of α-ureido nitriles with unsubstituted ureido group.
Chemproc 08 00054 sch001
Chemproc 08 00054 sch002 550
Scheme 2. Straightforward approach to ureido nitriles.
Scheme 2. Straightforward approach to ureido nitriles.
Chemproc 08 00054 sch002
Chemproc 08 00054 sch003 550
Scheme 3. Three-component condensation of urea with aldehydes and p-toluenesulfinic acid.
Scheme 3. Three-component condensation of urea with aldehydes and p-toluenesulfinic acid.
Chemproc 08 00054 sch003
Chemproc 08 00054 sch004 550
Scheme 4. Synthesis of α-ureido nitriles 5a-i by the reaction of N-(tosylmethyl)ureas 4a-i with sodium cyanide.
Scheme 4. Synthesis of α-ureido nitriles 5a-i by the reaction of N-(tosylmethyl)ureas 4a-i with sodium cyanide.
Chemproc 08 00054 sch004
Chemproc 08 00054 sch005 550
Scheme 5. Postulated mechanism of α-amidoalkylation under basic conditions.
Scheme 5. Postulated mechanism of α-amidoalkylation under basic conditions.
Chemproc 08 00054 sch005
Chemproc 08 00054 g001 550
Figure 1. Newman projections of the most stable conformers of compounds 4a and 4j along the C-S bond.
Figure 1. Newman projections of the most stable conformers of compounds 4a and 4j along the C-S bond.
Chemproc 08 00054 g001
Chemproc 08 00054 sch006 550
Scheme 6. Plausible pathway for the transformation of 4a,j (conformer A) into acylimines 7a,j under the action of cyanide-anion.
Scheme 6. Plausible pathway for the transformation of 4a,j (conformer A) into acylimines 7a,j under the action of cyanide-anion.
Chemproc 08 00054 sch006
Chemproc 08 00054 g002 550
Figure 2. Calculated electronic (a) and Gibbs free energy (b) profiles for the transformation of 4a (conformer A) into acylimine 7a under the action of cyanide-anion in DMF solution (1 atm, 298 K). The relative energies are given in kcal/mol. A view of the transition state TS1# with selected bond lengths is presented.
Figure 2. Calculated electronic (a) and Gibbs free energy (b) profiles for the transformation of 4a (conformer A) into acylimine 7a under the action of cyanide-anion in DMF solution (1 atm, 298 K). The relative energies are given in kcal/mol. A view of the transition state TS1# with selected bond lengths is presented.
Chemproc 08 00054 g002
Chemproc 08 00054 g003 550
Figure 3. Calculated electronic (a) and Gibbs free energy (b) profiles for the transformation of 4j (conformer A) into acylimine 7j under the action of cyanide-anion in DMF solution (1 atm, 298 K). The relative energies are given in kcal/mol. A view of the transition state TS2# with selected bond lengths is presented.
Figure 3. Calculated electronic (a) and Gibbs free energy (b) profiles for the transformation of 4j (conformer A) into acylimine 7j under the action of cyanide-anion in DMF solution (1 atm, 298 K). The relative energies are given in kcal/mol. A view of the transition state TS2# with selected bond lengths is presented.
Chemproc 08 00054 g003
Table
Table 1. Synthesis of N-(tosylmethyl)-substituted ureas 4a-i a.
Table 1. Synthesis of N-(tosylmethyl)-substituted ureas 4a-i a.
EntryAldehyde (R)1:2:3 Molar RatioSolventTime (h)ProductYield (%) b
12a (Ph)5:1:1H2O204a94
22a (Ph)5:1:125% aq EtOH204a94
32b (4-MeC6H4)5:1:1H2O204b97
42c (4-EtC6H4)5:1:1H2O204c98
52d (4-MeOC6H4)5:1:1H2O204d97
62d (4-MeOC6H4)5:1:125% aq EtOH244d96
72e (3,4-(MeO)2C6H3)5:1:1H2O244e97
82e (3,4-(MeO)2C6H3)5:1:125% aq EtOH244e98
92e (3,4-(MeO)2C6H3)5:1:121% aq HCOOH244e99
102f (fur-2-yl)5:1:1H2O204f96
112g (Pr)3:1:1H2O6.254g c89
122g (Pr)3:1:1H2O24g d94
132g (Pr)5:1:1H2O24g96
142h (i-Pr)3:1:1H2O7.334h e80
152h (i-Pr)3:1:1H2O2.44h f88
162h (i-Pr)5:1:1H2O24h90
172i (Bu)5:1:1H2O24i91
a At room temperature. b Isolated yield. c Product contains 17 mol% of N,N′-di(1-tosylbut-1-yl)urea. d Product contains 0.5 mol% of N,N′-di(1-tosylbut-1-yl)urea. e Product contains 20 mol% of N,N′-di(2-methyl-1-tosylprop-1-yl)urea. f Product contains 1.5 mol% of N,N′-di(2-methyl-1-tosylprop-1-yl)urea.
Table
Table 2. Reaction N-(tosylmethyl)ureas 4a-i with sodium cyanide.
Table 2. Reaction N-(tosylmethyl)ureas 4a-i with sodium cyanide.
Entry4REquiv. of NaCNReaction ConditionsProductYield (%) a
14aPh1.10DMF, 0 °C, 1 h5a83
24aPh2.00MeCN, rt, 73 h5a81
3 b4aPh1.51MeCN, rt, 9.75 h5a73
44b4-MeC6H41.25DMF, rt, 3 h5b c85
54b4-MeC6H41.22DMF, rt, 1 h5b d91
64b4-MeC6H41.21DMF, 0 °C, 1 h5b e92
74b4-MeC6H41.10DMF, 0 °C, 1 h5b97
84b4-MeC6H42.00MeCN, rt, 113 h5b97
94c4-EtC6H41.11DMF, 0 °C, 1 h5c100
104d4-MeOC6H41.11DMF, 0 °C, 1 h5d96
114e3,4-(MeO)2C6H31.11DMF, 0 °C, 1 h5e95
124ffur-2-yl1.10DMF, 0 °C, 1 h5f75
134ffur-2-yl1.12DMSO, rt, 1 h5f69
144gPr1.10DMF, 0 °C, 1 h5g69
15 b4gPr1.52MeCN, rt, 8.67 h5g0 f
164hi-Pr1.12DMF, 0 °C, 1 h5h0 g
174iBu1.10DMF, 0 °C, 1 h5i71
a Isolated yield. b In the presence of 18-crown-6 (0.2 equiv.). c Along with 7 mol% of 6. d Along with 3 mol% of 6. e Along with 2 mol% of 6. f An unidentified compound along with some unidentified impurities were isolated. g Isobutylidene diurea in 10% yield was isolated.
Table
Table 3. Relative electronic energy (ΔE), Gibbs free energy (ΔG), C-S and C-N bond lengths in N-C-S fragment for three rotamers of compounds 4a and 4j in DMF solution a.
Table 3. Relative electronic energy (ΔE), Gibbs free energy (ΔG), C-S and C-N bond lengths in N-C-S fragment for three rotamers of compounds 4a and 4j in DMF solution a.
Parameter4a4j
ABCABC
ΔE, kcal/mol0.000.490.900.000.510.70
ΔG, kcal/mol0.000.810.360.000.421.35
C-S, Ǻ1.9071.9151.9261.8891.9031.896
C-N, Ǻ1.4251.4251.4201.4241.4221.423
a The DFT B3LYP/6-311++G(d,p) calculations were used (298 K, 1 atm).
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Fesenko, A.A.; Shutalev, A.D. Reaction of N-(tosylmethyl)ureas with NaCN: Synthetic and Mechanistic Aspects. Chem. Proc. 2022, 8, 54. https://doi.org/10.3390/ecsoc-25-11759

AMA Style

Fesenko AA, Shutalev AD. Reaction of N-(tosylmethyl)ureas with NaCN: Synthetic and Mechanistic Aspects. Chemistry Proceedings. 2022; 8(1):54. https://doi.org/10.3390/ecsoc-25-11759

Chicago/Turabian Style

Fesenko, Anastasia A., and Anatoly D. Shutalev. 2022. "Reaction of N-(tosylmethyl)ureas with NaCN: Synthetic and Mechanistic Aspects" Chemistry Proceedings 8, no. 1: 54. https://doi.org/10.3390/ecsoc-25-11759

Article Metrics

Back to TopTop