Synthesis and Synthetic Applications of Samarium Enolates of Unmasked Amides: Efficient Synthesis of 3-Aminoamides and 3-Amino-2-chloroamides

Abstract

Unprotected samarium acetamide and chloroacetamide enolates were prepared by treatment of iodoacetamide and dichloroacetamide with SmI₂. The addition of these samarium-based enolates to aldimines was efficiently performed affording 3-aminoamides and 3-amino-2-chloroamides in high yields. A mechanism is proposed to explain the synthesis and reactivity of samarium enolates of primary amides.

Lithium, magnesium, and other classical metal enolates are useful reagents in organic synthesis. Thus, syntheses of complex organic molecules in which enolates are not used are scarce. The high degree of utilization of such enolates can be explained as a consequence of their ready preparation and their ability to promote C-C bond-formation reactions with high selectivity under mild reaction conditions. However, in some cases, the synthetic applications of enolates are limited by their basic properties. For this reason, no reactions of enolates with compounds bearing acidic hydrogens (unless previous protection is performed) can be carried out. Hence, lithium or magnesium enolates derived from unmasked carboxylic acids or primary amides are not available. In general, two synthetic strategies are used to perform the reaction when enolates derived from unmasked carboxylic acids or primary amides are needed in a synthetic transformation: a) the most widely used synthetic method is to carry out the reaction with a protected carboxylic acid or amide enolate, followed by a deprotection reaction of the ester or amide function; and b) although dianionic species derived from acids or amides could be alternatively used, their synthetic applications are scarce, probably due to the low solubility of these dianions in organic solvents. [¹] Taking into account all these precedents, the preparation of less basic enolates and the synthesis of unprotected acid and amide enolates using other metals would be an alternative synthetic method of great interest in order to obviate the protection-deprotection protocols of the acid and amide functions.

Our group has previously reported the preparation of samarium acetic [²] and bromoacetic [³] acid enolates by the samarium diiodide promoted metalation [4] of iodoacetic and dibromoacetic acids, respectively. Very recently, we also reported a sequential synthesis of (E)-α,β-unsaturated primary amides with complete stereoselectivity reacting an unmasked samarium chloroacetamide enolate with aldehydes followed by a β-elimination process. [5]

Following on the study of the synthetic applications of these samarium enolates, reactions were performed with imines. Herein we report a new efficient strategy to access to 3-aminoamides by reaction of the samarium acetamide enolate with various aldimines. In a similar manner, 3-amino-2-chloroamides were formed by the addition of the samarium chloroacetamide enolate to imines. In all these cases the syntheses took place in high yields.

Recently we described, for the first time, the addition reaction of samarium ester or amide enolates to imines. [6] Due to their low basicity, samarium enolates [7] are a valuable alternative to classical lithium or magnesium enolates in addition reactions in which carbonyl compounds or imines are easily enolizable. These previous results prompted us to test the addition reaction of unprotected samarium acetamide enolates to imines. To perform the reaction under mild reaction conditions activated aldimines, such as N-tosylaldimines 2, [8] were employed. The best results were obtained treating a solution of iodoacet­amide 3 (0.4 mmol) and N-tosylaldimines (0.4 mmol) in THF (2 mL) with a 0.1 M solution of SmI₂ in THF (10 mL, 1 mmol) [9] for 3.5 hours at room temperature.

Table 1 Synthesis of 3-Aminoamides 1

Entry	1	R	Yield (%)a
1	1a	n-C7H15	81
2	1b	Cy	84
3	1c	s-Bu	72
4	1d	PhCH2CH2	77
5	1e	t-BuCH2CH(Me)CH2	78
a Isolated yield of pure compounds 1 after column chromatography based on compounds 2.

3-Aminoamides 1 prepared using this methodology are shown in Table  [¹] . [¹0] The reaction took place in high yields using linear, cyclic, or branched aliphatic aldimines. The observed difference in terms of yields (72-84%) is negligible. However, no reaction took place from aromatic aldimines, as a consequence of the pinacol coupling of the starting aromatic imines promoted by SmI₂. [¹¹]

After demonstrating that the formation and further addition reaction of unprotected samarium amide enolates to imines can be carried out, the diastereoselectivity of the addition was studied. Due to the synthetic possibilities of α-carbonyl compounds, we used the unprotected samarium chloroacetamide enolate. Thus, samarium chloroacet­amide enolate was readily prepared by metalation of the commercially available dichloroacetamide with SmI₂. In this case, the best results were obtained using SmI₂, generated in situ (from samarium powder and diiodomethane) [¹²] in the presence of the aldimine instead of using a previously generated samarium diiodide solution. Thus, diiodomethane (2.4 equiv) was added dropwise to a suspension of the corresponding imine 2 (1 equiv), dichloroacetamide 5 (1 equiv), and samarium powder (2.4 equiv) in 25 mL of THF at room temperature. After stirring for 3.5 hours, the corresponding 3-amino-2-chloro­amides 4 were obtained (Table  [²] ). [¹³]

Table 2 Synthesis of 3-Amino-2-chloroamides 4

Entry	4	R	dra	Yield (%)b
1	4a	n-C7H15	1.4:1	89
2	4b	Cy	1:1	92
3	4c	s-Bu	1.2:1:1	83
4	4d	PhCH2CH2	1.3:1	81
5	4e	t-BuCH2CH(Me)CH2	1.5:1.2:1	84
a Diastereomeric ratio (dr) was determined based on the data of the ¹H NMR spectra (300 MHz) of the crude reaction mixture. b Isolated yield of pure compounds 4 after column chromatography based on compounds 2.

Similarly to the synthesis of 3-aminoamides 1, the preparation of 3-amino-2-chloroamides 4 was general from aliphatic aldimines (linear, cyclic, branched) and no reaction took place with aromatic aldimines. Compounds 4 (Table  [²] ) were obtained in higher yields (10%) than amides 1 (Table  [¹] ). However, the diastereoselectivity of the process was poor (Table  [²] ). The relationship of dia­stereomers was determined based on the data of the ^¹H NMR spectra of the crude reaction mixture.

No differences were observed in the stereoisomeric ratio on compounds 4a and 4b when the reaction was performed using SmI₂ or Sm/CH₂I₂. In this latter case, the yield was also slightly higher than that obtained when SmI₂ was used (ca. 10%).

When the reaction was performed at 0 ˚C in order to improve the diastereoselectivity ratio of compounds 4, isolation of pinacol coupling of aldimine 2a (78%) was obtained including 3-amino-2-chloroamide 4a as a diastereomeric mixture.

To explain the synthesis of amides 1 and 4, unprotected samarium amide enolates 6 and 7 are proposed (Scheme  [¹] ). These enolates could be generated by metalation of iodoacetamide 3 or dichloroacetamide 5 with 2 equivalents of samarium diiodide. Although we have no direct evidence for the existence of these enolates, an alternative radical mechanism can be rejected taking into account that no differences were observed between the reactions performed in the presence or absence of AIBN. The higher stability of unprotected samarium amide enolates 6 and 7, in comparison to the corresponding lithium amide enolates, could be explained taking into account that, after the enolate formation, the C-samarium tautomeric form (I₂SmCH₂CONH₂) might completely be displaced to the most stable O-samarium tautomeric form [CH₂=C(NH₂)OSmI₂] according to the high oxophilic character exhibited by the Sm(III) ions. [¹4] Accordingly, no protonolysis of C-samarium bond would take place, and the addition reaction to imines would occur to afford the corresponding unprotected amides 1 or 4. On the contrary, in the case of lithium enolates, both tautomers could coexist, being the C-Li bond completely hydrolized and, for this reason, no aldolic addition reaction to imines would take place. An indirect support for this proposed mechanism is the synthesis of 3-hydroxy samarium enolates by treatment of the corresponding 2-chloro-3-hydroxyesters [¹5] or amides [¹6] with samarium diiodide. The elimination reaction of these intermediates afforded the corresponding α,β-unsaturated ester or amide, and the products derived from the hydrolysis of the enolate by the alcohol function were completely undetectable.

In conclusion, we have demonstrated that samarium enolates derived from iodoacetamide and dichloroacetamide can be easily prepared and employed in organic synthesis. Both enolates are able to react with aldimines affording 3-amino and 3-amino-2-chloroamides in high yields.

Acknowledgment

We thank to Ministerio de Ciencia e Innovación (MICINN CTQ2007-61132) and Principado de Asturias (FICYT IB08-028) for financial support. C.C and N.A. thank MICINN and FICYT for a Juan de la Cierva contract and a predoctoral fellowship, respectively.

References and Notes

• For reviews of dianions of carboxylic acids, see:
• 1a Petragnani N. Yonashiro M. Synthesis  1982,  521 
• 1b Thompson CM. Green DLC. Tetrahedron  1991,  47:  4223 
  Search in Google Scholar
• 2 Concellón JM. Concellón C. J. Org. Chem.  2006,  71:  4428 
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• 3 Concellón JM. Concellón C. J. Org. Chem.  2006,  71:  1728 
  CrossrefPubMedSearch in Google Scholar
• To see reviews concerning the synthetic applications of SmI₂:
• 4a Soderquist JA. Aldrichimica Acta  1991,  24:  15 
  Search in Google Scholar
• 4b Molander GA. Chem. Rev.  1992,  92:  29 
  Search in Google Scholar
• 4c Molander GA. In Comprehensive Organic Synthesis   Vol. 1:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.251-282  
  Search in Google Scholar
• 4d Molander GA. In Organic Reactions   Paquette LA. John Wiley; New York: 1994.  p.211-367  
• 4e Molander GA. Harris CR. Chem. Rev.  1996,  96:  307 
  Search in Google Scholar
• 4f Molander GA. Harris CR. Tetrahedron  1998,  54:  3321 
  Search in Google Scholar
• 4g Krief A. Laval AM. Chem. Rev.  1999,  99:  745 
  Search in Google Scholar
• 4h Steel PG. J. Chem. Soc., Perkin Trans. 1  2001,  2727 
• 4i Kagan HB. Tetrahedron  2003,  59:  10351 
  Search in Google Scholar
• 4j Concellón JM. Rodríguez-Solla H. Chem. Soc. Rev.  2004,  33:  599 
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• 4k Concellón JM. Rodríguez-Solla H. Eur. J. Org. Chem.  2006,  1613 
• 4l Rudkin IM. Miller LC. Procter DJ. Organomet. Chem.  2008,  34:  19 
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• 4m Nicolau KC. Ellery SP. Chen JS. Angew. Chem. Int. Ed.  2009,  48:  7140 
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• 5 Concellón JM. Rodríguez-Solla H. Concellón C. Simal C. Alvaredo N. J. Org. Chem.  2010,  75:  3451 
  CrossrefSearch in Google Scholar
• 6a Concellón JM. Rodríguez-Solla H. Simal C. Adv. Synth. Catal.  2009,  351:  1238 
  Search in Google Scholar
• 6b Concellón JM. Rodríguez-Solla H. Simal C. del Amo V. García-Granda S. Díaz MR. Adv. Synth. Catal.  2009,  351:  2991 
  Search in Google Scholar
• 8 For the synthesis of N-tosylimines, see: Wang Y. Song J. Hong R. Li H. Deng L. J. Am. Chem. Soc.  2006,  128:  8156 
  CrossrefSearch in Google Scholar
• 9 The 0.1 M solution of samarium diiodide in THF was rapidly and readily prepared according to our reported method: Concellón JM. Rodríguez-Solla H. Bardales E. Huerta M. Eur. J. Org. Chem.  2003,  1775 
  Crossref
• 11 Enholm EJ. Forbes DC. Holub DP. Synth. Commun.  1990,  20:  981 
  CrossrefSearch in Google Scholar
• For other reactions promoted by in situ generated SmI₂, see:
• 12a Concellón JM. Rodríguez-Solla H. Huerta M. Pérez-Andrés JA. Eur. J. Org. Chem.  2002,  1839 
• 12b Concellón JM. Huerta M. Tetrahedron Lett.  2002,  43:  4943 
  Search in Google Scholar
• 13 General Procedure for the Synthesis of 3-Amino-2-chloroamides 4 Diiodomethane (2.4 equiv) was added dropwise to a suspension of the corresponding imine 2 (1.0 equiv), dichloroacetamide (1.0 equiv), and samarium powder (2.4 equiv) in THF (25 mL) at r.t. After stirring for 3.5 h at the same temperature, the corresponding 3-amino-2-choro-amides 4 were obtained after usual workup and purification by flash column chromatography (hexane-EtOAc = 3:1).
• 14 Molander GA. In Comprehensive Organic Synthesis   Vol. 1:  Trost BM. Fleming I. Schreiber SL. Pergamon; Cambridge: 1991.  p.252 
  Search in Google Scholar
• 15 Concellón JM. Pérez-Andrés JA. Rodríguez-Solla H. Angew. Chem. Int. Ed.  2000,  39:  2773 
  CrossrefSearch in Google Scholar
• 16 Concellón JM. Pérez-Andrés JA. Rodríguez-Solla H. Chem. Eur. J.  2001,  7:  3062 
  CrossrefSearch in Google Scholar

For a recent review on samarium enolates, see ref. 4l.

General Procedure for the Synthesis of 3-Aminoamides 1 A solution of iodoacetamide 3 (0.4 mmol) and the corresponding N-tosylaldimine 2 (0.4 mmol) in THF (2 mL) was treated with a 0.1 M solution of SmI₂ in THF (10 mL, 1 mmol). After 3.5 h at r.t. the reaction mixture was quenched with HCl (1.0 M, 20 mL). Usual workup and purification by flash column chromatography (hexane-EtOAc, 3:1) afforded pure compounds 1.

References and Notes

• For reviews of dianions of carboxylic acids, see:
• 1a Petragnani N. Yonashiro M. Synthesis  1982,  521 
• 1b Thompson CM. Green DLC. Tetrahedron  1991,  47:  4223 
  Search in Google Scholar
• 2 Concellón JM. Concellón C. J. Org. Chem.  2006,  71:  4428 
  CrossrefSearch in Google Scholar
• 3 Concellón JM. Concellón C. J. Org. Chem.  2006,  71:  1728 
  CrossrefPubMedSearch in Google Scholar
• To see reviews concerning the synthetic applications of SmI₂:
• 4a Soderquist JA. Aldrichimica Acta  1991,  24:  15 
  Search in Google Scholar
• 4b Molander GA. Chem. Rev.  1992,  92:  29 
  Search in Google Scholar
• 4c Molander GA. In Comprehensive Organic Synthesis   Vol. 1:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.251-282  
  Search in Google Scholar
• 4d Molander GA. In Organic Reactions   Paquette LA. John Wiley; New York: 1994.  p.211-367  
• 4e Molander GA. Harris CR. Chem. Rev.  1996,  96:  307 
  Search in Google Scholar
• 4f Molander GA. Harris CR. Tetrahedron  1998,  54:  3321 
  Search in Google Scholar
• 4g Krief A. Laval AM. Chem. Rev.  1999,  99:  745 
  Search in Google Scholar
• 4h Steel PG. J. Chem. Soc., Perkin Trans. 1  2001,  2727 
• 4i Kagan HB. Tetrahedron  2003,  59:  10351 
  Search in Google Scholar
• 4j Concellón JM. Rodríguez-Solla H. Chem. Soc. Rev.  2004,  33:  599 
  Search in Google Scholar
• 4k Concellón JM. Rodríguez-Solla H. Eur. J. Org. Chem.  2006,  1613 
• 4l Rudkin IM. Miller LC. Procter DJ. Organomet. Chem.  2008,  34:  19 
  Search in Google Scholar
• 4m Nicolau KC. Ellery SP. Chen JS. Angew. Chem. Int. Ed.  2009,  48:  7140 
  Search in Google Scholar
• 5 Concellón JM. Rodríguez-Solla H. Concellón C. Simal C. Alvaredo N. J. Org. Chem.  2010,  75:  3451 
  CrossrefSearch in Google Scholar
• 6a Concellón JM. Rodríguez-Solla H. Simal C. Adv. Synth. Catal.  2009,  351:  1238 
  Search in Google Scholar
• 6b Concellón JM. Rodríguez-Solla H. Simal C. del Amo V. García-Granda S. Díaz MR. Adv. Synth. Catal.  2009,  351:  2991 
  Search in Google Scholar
• 8 For the synthesis of N-tosylimines, see: Wang Y. Song J. Hong R. Li H. Deng L. J. Am. Chem. Soc.  2006,  128:  8156 
  CrossrefSearch in Google Scholar
• 9 The 0.1 M solution of samarium diiodide in THF was rapidly and readily prepared according to our reported method: Concellón JM. Rodríguez-Solla H. Bardales E. Huerta M. Eur. J. Org. Chem.  2003,  1775 
  Crossref
• 11 Enholm EJ. Forbes DC. Holub DP. Synth. Commun.  1990,  20:  981 
  CrossrefSearch in Google Scholar
• For other reactions promoted by in situ generated SmI₂, see:
• 12a Concellón JM. Rodríguez-Solla H. Huerta M. Pérez-Andrés JA. Eur. J. Org. Chem.  2002,  1839 
• 12b Concellón JM. Huerta M. Tetrahedron Lett.  2002,  43:  4943 
  Search in Google Scholar
• 13 General Procedure for the Synthesis of 3-Amino-2-chloroamides 4 Diiodomethane (2.4 equiv) was added dropwise to a suspension of the corresponding imine 2 (1.0 equiv), dichloroacetamide (1.0 equiv), and samarium powder (2.4 equiv) in THF (25 mL) at r.t. After stirring for 3.5 h at the same temperature, the corresponding 3-amino-2-choro-amides 4 were obtained after usual workup and purification by flash column chromatography (hexane-EtOAc = 3:1).
• 14 Molander GA. In Comprehensive Organic Synthesis   Vol. 1:  Trost BM. Fleming I. Schreiber SL. Pergamon; Cambridge: 1991.  p.252 
  Search in Google Scholar
• 15 Concellón JM. Pérez-Andrés JA. Rodríguez-Solla H. Angew. Chem. Int. Ed.  2000,  39:  2773 
  CrossrefSearch in Google Scholar
• 16 Concellón JM. Pérez-Andrés JA. Rodríguez-Solla H. Chem. Eur. J.  2001,  7:  3062 
  CrossrefSearch in Google Scholar

For a recent review on samarium enolates, see ref. 4l.

General Procedure for the Synthesis of 3-Aminoamides 1 A solution of iodoacetamide 3 (0.4 mmol) and the corresponding N-tosylaldimine 2 (0.4 mmol) in THF (2 mL) was treated with a 0.1 M solution of SmI₂ in THF (10 mL, 1 mmol). After 3.5 h at r.t. the reaction mixture was quenched with HCl (1.0 M, 20 mL). Usual workup and purification by flash column chromatography (hexane-EtOAc, 3:1) afforded pure compounds 1.