Catalytic Acylcyanation of Imines with Acetylcyanide

acylcyanation - α-amino nitrile - Brønsted acid catalysis - organocatalysis - acetyl cyanide

The Strecker reaction of imines with HCN provides one of the most efficient methods for the preparation of α-amino nitriles, which are useful intermediates in the synthesis of α-amino acids. [1] However, the Strecker reaction has limitations in particular due to the volatile and highly toxic nature of HCN. In this regard, trimethylsilyl cyanide (TMSCN) offers certain advantages. However, due to its high toxicity and price, access to alternative cyanation reagents is desirable. For example, acyl cyanides are not only less toxic and readily available but also have already been used in the acylcyanation of carbonyl compounds. [2] Surprisingly however, while the reaction of acetyl cyanide and analogous α-oxonitriles with aldehydes and ketones has been studied extensively in recent years, its reaction with imines has been significantly less investigated. Thus in 1958, Dornow et al. first reported the reaction of acyl cyanides with imines and later described a triethylamine-catalyzed version. [3] Survey of the literature reveals that there are no other catalytic versions of this atom-economic yet rarely used approach to α-amino nitriles. [4]

Recently, Brønsted acid and hydrogen-bonding catalysis have emerged as powerful strategies for organocatalysis. [5] Inspired by these studies and realizing the potential of the acylcyanation of imines for the synthesis of α-amino acids, we were encouraged to investigate the catalytic addition of acyl cyanides to imines (Scheme [1] ).

Scheme 1 Catalytic acylcyanation of imines

Initial experiments focused on the examination of different catalysts for this transformation (Table [1] ). [6] While the highly acidic TFA (trifluoroacetic acid) did not give any conversion in dichloromethane (entry 1), moderately acidic phenylphosphinic acid 3a gave good conversion (entry 2). In the context of these studies we then found that the reaction cannot only be catalyzed by stronger, specific acid catalysts but also by hydrogen-bonding-type, general acid catalysts. [7]

Table 1 Catalytic Acylcyanation of Imine 1a

Entrya	Catalyst	mol%	Time (h)	Conv. (%)b
1	TFA	20	72	0
2	3a	20	24	90
3	3b	10	24	99
4	3b	2	24	98
5	3b	1	24	93
a All reactions were performed using 0.1 mmol of imine 1a and 0.15 mmol of acetyl cyanide (2). b Determined by GC.

We identified Schreiner’s thiourea catalyst 3b, in particular, to be highly efficient in promoting the reaction (entry 3). [8] In each instance, the reaction was carried out with 1.5 equivalents of acetyl cyanide. Decreasing the catalyst loading from 10 mol% to 2 mol% essentially preserved the conversion (entry 4). Reducing the catalyst loading to only 1 mol% reduced the yield somewhat (entry 5). [9] Consequently, either 2 mol% or 5 mol% of catalyst 3b was used in subsequent experiments.

Using dichloromethane as the solvent and thiourea 3b as the catalyst (2-5 mol%), we decided to explore the scope of this reaction (Table [2] ). It turned out that the selected reaction conditions are broadly useful for a variety of different substrates. Both aromatic aldimines (entries 1-4) with electron-donating or -withdrawing substituents, as well as heteroaromatic aldimines (entries 5 and 6), can be used with similar efficiencies. Furthermore, aliphatic branched, unbranched, and unsaturated aldimines can also be employed to give moderate to good yields (entries 7-10).

Table 2 Catalytic Acylcyanation of Various Imines

Entrya	R	Time (h)	Yield (%)b
1	Ph	24	88
2	4-MeOC6H4	24	84
3	4-ClC6H4	24	79
4	2-ClC6H4	24	83
5	2-Furyl	24	67
6	3-Pyridyl	24	96
7c	i-Pr	48	76
8c	t-Bu	48	64
9c	1-Cyclohexenyl	48	82
10c	t-BuCH2	48	81
a All reactions were performed using 2 mol% of the catalyst unless otherwise stated. b Yields of pure product after silica gel column chromatography. c 5 mol% of the catalyst.

Mechanistically, the reaction may proceed via an initial reaction of the imine with acetyl cyanide to form an acyl iminium-cyanide ion pair. Its recombination to product 4 may be urea-catalyzed.

In summary, we have developed a new efficient and potentially useful variant of the Strecker reaction, the general Brønsted acid catalyzed acylcyanation of imines with acetyl cyanide as a new cyanide source. The operational simplicity, practicability, and mild reaction conditions render it an attractive approach for the generation of different N-acyl α-amino nitriles. Further studies in our laboratory aim at expanding the scope of the reaction to include ketimines and at developing an asymmetric catalytic version. [10]

Preparative Experiment for the Acylcyanation of Imines

The imine 1a (2.0 mmol) and catalyst 3b (2 mol%) were placed in a dry Schlenk flask. Then, dry CH₂Cl₂ (4 mL) was added to the ­mixture. The flask was cooled to 0 °C and stirred for 10 min. Acetyl cyanide (0.2 mL, 1.5 equiv) was added, and the mixture was stirred for 24 h at 0 °C. The mixture was directly subjected to silica gel column chromatography to give 464 mg (1.76 mmol, 88% yield) of the pure product 4a as a colorless liquid.

Acknowledgment

We thank Degussa, Merck, Saltigo, and Wacker for the donation of chemicals and support of our work and Novartis for a Young Investigator award to B.L. Our work was supported by the Max-Planck-Gesellschaft, the Deutsche Forschungsgemeinschaft (Priority Program 1179 Organocatalysis), and the Fonds der Chemischen Industrie.

References and Notes

For reviews, see:

1a Gröger H. Chem. Rev.  2003,  103:  2795 

1b Yet L. Angew. Chem. Int. Ed.  2001,  40:  875 

1c Spino C. Angew. Chem. Int. Ed.  2004,  43:  1764 

2a Tian J. Yamagiwa N. Matsunaga S. Shibasaki M. Angew. Chem. Int. Ed.  2002,  41:  3636 

2b Tian J. Yamagiwa N. Matsunaga S. Shibasaki M. Org. Lett.  2003,  5:  3021 

2c Yamagiwa N. Tian J. Matsunaga S. Shibasaki M. J. Am. Chem. Soc.  2005,  127:  3413 

2d Tian S.-K. Deng L. J. Am. Chem. Soc.  2001,  123:  6295 

2e Casas J. Baeza A. Sansano JM. Nájera C. Saá JM. Tetrahedron: Asymmetry  2003,  14:  197 

2f Belokon YN. Blacker AJ. Clutterbuck LA. North M. Org. Lett.  2003,  5:  4505 

2g Lundgren S. Wingstrand E. Penhoat M. Moberg C. J. Am. Chem. Soc.  2005,  127:  11592 

2h Belokon YN. Ishibashi E. Nombra H. North M. Chem. Commun.  2006,  16:  1775 

3a Dornow A. Lüpfert S. Chem. Ber.  1956,  89:  2718 

3b Dornow A. Lüpfert S. Chem. Ber.  1957,  90:  1780 

3c Dornow A, and Lüpfert S. inventors; US Patent  2849477. 

4a Gardent MJ. Delépine MM. C. R. Acad. Sci.  1958,  247:  2153 

4b Rai M. Krishan K. Singh A. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1978,  16:  834 

4c Sakamoto M. Akiyama Y. Furumi N. Ishii K. Tomimatsu Y. Date T. Chem. Pharm. Bull.  1983,  31:  2623 

For reviews, see:

5a Schreiner PR. Chem. Soc. Rev.  2003,  32:  289 

5b Akiyama T. Itoh J. Fuchibe K. Adv. Synth. Catal.  2006,  348:  999 

5c Taylor MS. Jacobsen EN. Angew. Chem. Int. Ed.  2006,  45:  1520 

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5e Pihko PM. Angew. Chem. Int. Ed.  2004,  43:  2062 

5f Connon SJ. Angew. Chem. Int. Ed.  2006,  45:  3909 

6

Under our reaction conditions using triethylamine as the catalyst only 4% conversion of imine 1a to product 4a was achieved.

7 Seayad J. List B. Org. Biomol. Chem.  2005,  3:  719 

8a Schreiner PR. Wittkopp A. Org. Lett.  2002,  4:  217 

8b Wittkopp A. Schreiner PR. Chem. Eur. J.  2003,  9:  407 

9

Even in the absence of catalyst, significant conversion (>30%) to the product was observed.

10

Using the chiral phosphoric acid catalyst 3,3′-bis[(2,4,6-tris(isopropyl)phenyl]-5,5′,6,6′,7,7′,8,8′-octahydro-1,1-binaphthyl hydrogen phosphate (10 mol%) at -40 °C, product 4a was obtained in 92% yield and 69:31 er.