Synlett 2013; 24(1): 33-36
DOI: 10.1055/s-0032-1317690
letter
© Georg Thieme Verlag Stuttgart · New York

A Novel Approach to the Synthesis of α-Aminonitriles Using Triphenyl- phosphine Dibromide under Solvent-Free Conditions

Devdutt Chaturvedi*
a   Laboratory of Medicinal Chemistry, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow 226028, U. P., India   Fax: +91(522)2399610   Email: devduttchaturvedi@gmail.com   Email: dchaturvedi@lko.amity.edu
,
Amit K. Chaturvedi
b   Synthetic Research Laboratory, Department of Chemistry, B. S. A. P. G. College, Mathura 281004, U. P., India
,
Parmesh K. Dwivedi
a   Laboratory of Medicinal Chemistry, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow 226028, U. P., India   Fax: +91(522)2399610   Email: devduttchaturvedi@gmail.com   Email: dchaturvedi@lko.amity.edu
,
Nisha Mishra
b   Synthetic Research Laboratory, Department of Chemistry, B. S. A. P. G. College, Mathura 281004, U. P., India
› Author Affiliations
Further Information

Publication History

Received: 06 August 2012

Accepted after revision: 02 November 2012

Publication Date:
04 December 2012 (online)

 


Abstract

A quick and highly efficient, one-pot, three-component, solvent-free method for the synthesis of α-aminonitriles starting from the corresponding carbonyl compounds, amines, and trimethyl­isocyanide using triphenylphosphine dibromide, has been developed. Diverse α-aminonitriles have been synthesized in good to excellent yields (80–99%) using a range of aldehydes, ketones and amines.


#

α-Aminonitriles constitute a major class of naturally occurring compounds that display remarkable biological activities[ 1 ] (anticancer, antibacterial, antifungal, antibiotic, and antiviral) and also serve as efficient precursors for the synthesis of natural and unnatural α-amino acids.[ 2 ] They have also been widely used as essential building blocks in peptide and protein synthesis.[ 3 ] Their synthetic utility has further been applied as a versatile synthon for the syntheses of amides, diamines, and various kinds of structurally diverse nitrogen and sulfur heterocycles[ 4 ] such as imidazoles and thiadiazoles. Furthermore, their synthetic utility has also been extended through carbanion-induced nucleophilic attack on the α-carbon atom with a variety of electrophiles, offering the possibility of further synthetic transformations.[ 5 ]

Among the reported methods, nucleophilic addition of cyanide ion to imines (Strecker reaction) offers one of the most direct approaches to the synthesis of α-aminonitriles.[ 6 ] The cyanide sources used during the course of this reaction include HCN, KCN, TMSCN, (EtO)2P(O)CN, Et2AlCN, Bu3SnCN, MeCOCN, acetone cyanohydrin, acyl cyanides, ethyl cyanoformate, bis(dialkyl)amino­cyanoboranes, and K4[Fe(CN)6],[ 7 ] the majority of which are hazardous, toxic, and require harsh reaction conditions. In recent years, in the search for novel and efficient protocols for the synthesis of α-aminonitriles, a broad spectrum of metal complexes, Lewis acids, solid acids, bases, and organic catalysts have been developed to promote this reaction.[8] [9] The majority of these catalysts are only efficient for the synthesis of α-aminonitriles from active aldehydes and are not suitable for ketone substrates. Therefore, there is continuing interest in developing new, efficient and safer protocols employing mild reaction conditions.

In recent years, triphenylphosphine dibromide (Ph3PBr2) has emerged as a versatile reagent in organic synthesis.[ 10 ] Our group has been engaged in the development of novel and efficient synthetic methodologies.[ 11 ] In the present communication, we wish to report an efficient method for the synthesis of α-aminonitriles through reaction of the corresponding carbonyl compounds, amines, and ­TMSCN using a catalytic amount of triphenylphosphine dibromide (TPPDB) under solvent-free conditions.[ 12 ] Triphenylphosphine dibromide was synthesized by the reported procedure.[ 10 ]

To optimize the protocol, the reaction of an equimolar amount of aniline, benzaldehyde, and trimethysilylcyanide, using a catalytic amount of TPPDB, was studied in a range of anhydrous solvents (CH2Cl2, THF, Et2O, MeCN, DMF, MeNO2, and MeOH) at room temperature and the corresponding α-aminonitrile was isolated. The best yields (99%) of the desired α-aminonitrile were achieved using at least 10 mol% TPPDB in the absence of solvent (Scheme [1]).

Zoom Image
Scheme 1

It was subsequently observed that the desired α-amino­nitrile could be achieved without using TPPDB under solvent-free conditions; although the reaction took longer (4 h) and afforded a lower yield (92%). However, although acetophenone reacted with aniline and TMSCN using a catalytic amount of TPPDB to afford a high-yield of the desired α-aminonitrile under solvent-free conditions at room temperature (Table [1]), when this reaction was repeated without using TPPDB, the corresponding α-aminonitrile could not be achieved even after extended periods (4 h). When this reaction was repeated employing TPPDB without using TMSCN, the corresponding imine was obtained; without TPPDB no imine was observed. This implies a role for TPPDB in the generation of the corresponding imines in situ, particularly from ketones.

Table 1 Effect of Triphenylphosphine Dibromide on the Formation of α-Aminonitriles I

R1

R2

R3

Time

TPPDB (mol%)

Yield (%)

Ph

H

Ph

20 min

10

98

Ph

H

Ph

 4 h

absent

92

Ph

Me

Ph

25 min

10

98

Ph

Me

Ph

 4 h

absent

Comparing the catalytic activity of TPPBD with some reported catalysts such as I2, guanidine hydrochloride, and cellulose sulfuric acid for the synthesis of α-aminonitriles under solvent-free conditions, it was found that TPPDB was superior, achieving high yields of the desired products in shorter reaction times (Table [2]).

Table 2 Effect of Catalysts on the Formation of α-Aminonitriles I

R1

R2

R3

Time (h)

Catalyst (10 mol%)

Yield (%)

Ph

H

Ph

 4

I2

58

Ph

Me

Ph

 8

I2

52

Ph

H

Ph

 2

GuHCl

78

Ph

Me

Ph

 4

GuHCl

64

Ph

H

Ph

 2

cellulose sulfuric acid

66

Ph

Me

Ph

 4

cellulose sulfuric acid

53

Ph

H

Ph

25 min

TPPBD

98

Ph

Me

Ph

30 min

TPPBD

98

The scope of this reaction was further explored with a range of aliphatic and aromatic substituted aldehydes and ketones bearing electron-releasing and electron-withdrawing functionalities and primary aliphatic and aromatic amines having electron-releasing and electron-withdrawing functional groups. Best yields of the products were obtained when an electron-releasing group was present at the para-position of the aromatic aldehydes, ­ketones, and amines (Table [3]).

Table 3 Synthesis of α-Aminonitriles of General Formula I

Entry

R1

R2

R3

Time (min)

Yield (%)

Ref.

1

Ph

H

Ph

25

98

[ 8d ]

2

4-ClC6H4

H

Ph

25

97

[ 8m ]

3

4-O2NC6H4

H

Ph

30

94

[ 8i ]

4

4-BrC6H5

H

Ph

30

94

[ 9i ]

 5

3,4-Cl2C6H3

H

Ph

30

95

[ 9i ]

 6

4-FC6H4

H

Ph

35

91

[ 9b ]

 7

4-MeC6H4

H

Ph

30

90

[ 9a ]

 8

4-MeOC6H4

H

Ph

35

91

[ 9a ]

 9

3-pyridyl

H

Ph

30

89

[ 8i ]

10

C9H19

H

Ph

60

80

[ 8p ]

11

Et

H

Ph

60

89

[ 8q ]

12

Ph

H

4-MeC6H4

25

95

[ 8m ]

13

Ph

H

4-MeOC6H4

25

96

[ 8p ]

14

Ph

Me

Ph

30

98

[ 9b ]

15

Ph

Me

4-MeOC6H4

30

99

[ 8n ]

16

Ph

Me

4-ClC6H4

30

92

[ 8n ]

17

Ph

H

Bn

25

95

[ 9b ]

18

1-naphthyl

H

Ph

30

93

[ 8o ]

19

9-anthryl

H

Ph

35

91

[ 8r ]

20

c-Pr

H

Ph

30

90

[ 8o ]

21

Ph

Me

Bn

30

93

[ 9b ]

22

–(CH2)4

Ph

94

[ 8n ]

23

–(CH2)5

Ph

98

[ 8n ]

24

–(CH2)6

Ph

96

[ 9a ]

25

Ph

Et

Ph

30

92

[ 9b ]

26

Ph

Et

Bn

30

88

[ 9b ]

27

Ph

Ph

Ph

35

85

[ 9b ]

28

2-naphthyl

Me

Ph

35

84

[ 9b ]

29

i-Pr

Me

Ph

45

82

[ 9b ]

30

PhCH=CH

H

Ph

45

80

[ 9b ]

31

Ph

H

n-Bu

35

81

[ 8i ]

32

4-MeC6H4

H

n-Bu

35

83

33

c-Hex

H

Bn

35

81

34

c-Hex

H

Ph

35

80

35

n-Bu

n-Bu

Ph

45

86

[ 8r ]

36

2-naphthyl

Ph

Ph

50

83

[ 8r ]

37

4-O2NC6H4

Me

Ph

55

81

[ 9b ]

38

3-Me-2-HSC6H3

Me

Ph

55

83

[ 8o ]

39

3-pyridyl

Me

4-MeOC6H4

45

87

[ 8n ]

40

3,4-(OCH2O)C6H3

Me

4-MeOC6H4

50

82

[ 8n ]

In conclusion, we have developed a simple and efficient method for the synthesis of α-aminonitriles starting from their corresponding carbonyl compounds, amines, and trimethylsilyl cyanide, by employing a catalytic amount of TPPDB under solvent-free conditions.


#

Acknowledgment

The authors wish to thank the Pro-Vice Chancellor, and Dean, Research (Science and Technology) of Amity University, Lucknow for his constant encouragement and support.

  • References and Notes

    • 1a Undavia NK, Patwa BS, Navadiya HD, Jivani AR, Dave PN. Int. J. Chem. Sci. 2009; 7: 1019
    • 1b Mantri M, de Graaf O, van Veldhoven J, Goeblyoes A, von Frijtag Drabbe Künzel JK, Mulder-Krieger T, Link R, de Vries H, Beukers MW, Brussee J, Ijzerman AP. J. Med. Chem. 2008; 51: 4449
    • 1c Loeser R, Schilling K, Dimmig E, Guetschow M. J. Med. Chem. 2005; 48: 7688
    • 1d Ward YD, Thomson DS, Frye LL, Cywin CL, Morwick T, Emmanuel MJ, Zindell R, McNeil D, Bekkali Y, Giradot M, Hrapchak M, DeTuri M, Crane K, White D, Pav S, Wang Y, Hao M.-H, Grygon CA, Labadia ME, Freeman DM, Davidson W, Hopkins JL, Brown ML, Spero DM. J. Med. Chem. 2002; 45: 5471
    • 2a N’ajera C, Sansano JM. Chem. Rev. 2007; 107: 4584
    • 2b Zuend SJ, Coughlin MP, Lalonde MP, Jacobsen EN. Nature 2009; 461: 968
    • 3a Groger H. Chem. Rev. 2003; 103: 2795
    • 3b Shafran YM, Bakulev VA, Mokrushin VS. Russ. Chem. Rev. 1989; 58: 148
    • 3c Michaux J, Niel G, Campagne J.-M. Chem. Soc. Rev. 2009; 38: 2093
    • 4a Matier WL, Owens DA, Comer WT, Deitchman D, Ferguson H, Seidehamel RJ, Young JR. J. Med. Chem. 1973; 16: 901
    • 4b Ohfune Y, Shinada T. Eur. J. Org. Chem. 2005; 5127
    • 4c Friestad GK, Mathies AK. Tetrahedron 2007; 63: 2541
    • 4d Connon SJ. Angew. Chem. Int. Ed. 2008; 47: 1176
    • 5a Enders D, Shilvock JP. Chem. Soc. Rev. 2000; 29: 359
    • 5b Gembus V, Janvier S, Lecouve J.-P, Gloanec P, Marsais F, Levacher V. Eur. J. Org. Chem. 2010; 3583
    • 5c Yin B, Zhang Y, Xu L.-W. Synthesis 2010; 3583
    • 6a Strecker A. Justus Liebigs Ann. Chem. 1850; 75: 27
    • 6b Merino P, Marques-Lopez E, Tejero T, Herrera RP. Tetrahedron 2009; 65: 1219
    • 6c Pastori N, Gambarotti C, Punta C. Mini-Rev. Med. Chem. 2009; 6: 184
    • 6d Shibasaki M, Kanai M, Mita T. Org. React. 2008; 70: 1
    • 6e Wang J, Liu X, Feng X. Chem. Rev. 2011; 111: 6947
    • 7a Kobayashi S, Ishitani H. Chem. Rev. 1999; 99: 1069
    • 7b Bhanu Prasad BA, Bisai A, Singh VK. Tetrahedron Lett. 2004; 45: 9565
    • 7c Harusawa S, Hamada Y, Shioiri T. Tetrahedron Lett. 1979; 4663
    • 7d Nakamura S, Sato N, Sugimoto M, Toru T. Tetrahedron: Asymmetry 2004; 15: 1513
    • 7e Kantam ML, Mahendar K, Sreedhar B, Choudary BM. Tetrahedron 2008; 64: 3351
    • 7f Li Z, Ma Y, Xu J, Shi J, Cai H. Tetrahedron Lett. 2010; 51: 3922
    • 7g Cruz-Acosta F, Santos-exposito A, Armas P, Garcia-Tellado F. Chem. Commun. 2009; 6839
    • 7h Sipos S, Jablonkai I. Tetrahedron Lett. 2009; 50: 1844
    • 7i Abell JP, Yamamoto H. J. Am. Chem. Soc. 2009; 131: 15118
    • 7j Enders D, Shilvock JP. Chem. Soc. Rev. 2000; 29: 359
    • 8a De SK. J. Mol. Catal. A: Chem. 2005; 225: 169
    • 8b North M. Angew. Chem. Int. Ed. 2004; 43: 4126
    • 8c Murahashi SI, Komia N, Terai H, Nakae T. J. Am. Chem. Soc. 2003; 125: 15312
    • 8d Ranu BC, Dey SS, Hajra A. Tetrahedron 2002; 58: 2529
    • 8e Shen ZL, Ji SJ, Loh TP. Tetrahedron 2008; 64: 8159
    • 8f Narasimhulu M, Reddy TS, Mahesh KC, Reddy SM, Reddy AV, Venkateshwarlu Y. J. Mol. Catal. A: Chem. 2007; 264: 288
    • 8g De SK, Gibbs RA. Tetrahedron Lett. 2004; 45: 7407
    • 8h Royer L, De SK, Gibbs RA. Tetrahedron Lett. 2005; 46: 4595
    • 8i Karmakar B, Banerji J. Tetrahedron Lett. 2010; 51: 2748
    • 8j Mojtahedi MM, Abaee S, Alishiri T. Tetrahedron Lett. 2009; 50: 2322
    • 8k Paraskar S, Sudalai A. Tetrahedron Lett. 2006; 47: 5759
    • 8l Kobayashi S, Busujima T, Nagayama S. Chem. Commun. 1998; 981
    • 8m Martinez R, Ramon DJ, Yus M. Tetrahedron Lett. 2005; 46: 8471
    • 8n Zhang GW, Zheng DH, Nie J, Wang T, Ma JA. Org. Biomol. Chem. 2010; 8: 1399
    • 8o Ramesh S, Shivakumar K, Panja C, Arunanchalam PN, Lalitha A. Synth. Commun. 2010; 40: 3544
    • 8p Paraskar AS, Sudalai A. Tetrahedron Lett. 2006; 47: 5759
    • 8q Li Z, Ma Y, Xu J, Shi J, Cai H. Tetrahedron Lett. 2010; 51: 3922
    • 8r Wang J, Masui Y, Onaka M. Eur. J. Org. Chem. 2010; 1763
    • 9a Hajipour AR, Ghayeb Y, Sheikhan N. J. Iran. Chem. Soc. 2010; 7: 447
    • 9b Khan NH, Agrawal S, Kureshy RI, Abdi SH. R, Singh S, Suresh E, Jasra RV. Tetrahedron Lett. 2008; 49: 640
    • 9c Rafiee E, Rashidzadeh S, Joshaghani M, Chalabeh H, Afza K. Synth. Commun. 2008; 38: 2741
    • 9d Kantam ML, Mahender K, Sreedhar B, Choudhary BM. Tetrahedron 2008; 64: 3351
    • 9e Oskooie HA, Heravi MM, Sadnia A, Jannati F, Behbahani FK. Monatsh. Chem. 2008; 139: 27
    • 9f Arefi HA, Khaksar S, Shiroodi RK. J. Mol. Catal. A: Chem. 2007; 271: 142
    • 9g Shaabani A, Maleki A. Appl. Catal., A 2007; 331: 149
    • 9h Yadav JS, Reddy BV. S, Eeshwarain B, Srinivas M. Tetrahedron 2004; 60: 1767
    • 9i Rafiee E, Rashidzadeh S, Azad A. J. Mol. Catal. A: Chem. 2007; 261: 49
    • 9j Yadav JS, Reddy BV. S, Eshwaraiah B, Srinivas M, Vishnumurthy P. New J. Chem. 2003; 27: 462
    • 9k De SK. Synth. Commun. 2005; 35: 1577
    • 9l Shaabani A, Maleki A, Soudi MR, Mofakham H. Catal. Commun. 2009; 10: 945
    • 9m Niknam K, Saberi D, Sefat MN. Tetrahedron Lett. 2010; 51: 2959
    • 9n Kazemeini A, Azizi N, Saidi MR. Russ. J. Org. Chem. 2006; 42: 48
    • 9o Jarusiewicz J, Choe Y, Yoo KS, Park CP, Jung KW. J. Org. Chem. 2009; 74: 2873
    • 9p Karimi B, Maleki A, Elhamifar D, Clark JH, Hunt AJ. Chem. Commun. 2010; 46: 6947
    • 9q Khan NH, Saravanan S, Kureshy RI, Abdi SH. R, Bajaj HC. Tetrahedron: Asymmetry 2010; 21: 2076
    • 9r Sudhakar D, Rao VM, Suresh M, Rao CV. J. Chem. Res. 2010; 34: 12
    • 9s Karimi B, Maleki A. Chem. Commun. 2009; 5180
    • 10a Garima Synlett 2010; 1426
    • 10b Heck M.-P, Matt C, Wagner A, Toupet L, Mioskowski C. Eur. J. Org. Chem. 2010; 966
    • 10c Salome C, Kohn H. Tetrahedron 2009; 65: 456
    • 10d Bressy C, Alberico D, Lautens M. J. Am. Chem. Soc. 2005; 127: 13148
    • 10e Bartley DM, Coward JK. J. Org. Chem. 2005; 70: 6757
    • 10f Dormoy J.-R, Castro B. e-EROS Encyclopedia of Reagents for Organic Synthesis 2001;
    • 11a Chaturvedi D, Kumar A, Ray S. Tetrahedron Lett. 2003; 44: 7637
    • 11b Chaturvedi D, Ray S. Tetrahedron Lett. 2006; 47: 1307
    • 11c Chaturvedi D, Ray S. Tetrahedron Lett. 2007; 48: 149
    • 11d Chaturvedi D, Mishra N, Mishra V. Tetrahedron Lett. 2007; 48: 5043
    • 11e Chaturvedi D, Mishra N, Mishra V. Synthesis 2008; 355
    • 11f Chaturvedi D, Chaturvedi AK, Mishra N, Mishra V. Tetrahedron Lett. 2008; 49: 4886
    • 11g Chaturvedi AK, Chaturvedi D, Mishra N, Mishra V. J. Iran. Chem. Soc. 2010; 7: 702
    • 11h Chaturvedi AK, Chaturvedi D, Mishra N, Mishra V. J. Iran. Chem. Soc. 2011; 8: 396
  • 12 Synthesis of α-Aminonitriles; Typical Procedure: A mixture of aldehyde (1 mmol), amine (1 mmol), triphenylphosphine dibromide (10 mol%), and trimethylsilylcyanide (1.2 mmol) was stirred at room temperature until the reaction was complete (monitored by TLC). The reaction mixture was then extracted with EtOAc (×3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the crude product by chromatography on silica gel (60–120 mesh; petroleum ether–EtOAc, 5:1) gave the pure product. 2-Anilino-2-phenylacetonitrile (Table 3, Entry 1): Light-yellow solid; mp 85–86 °C; IR (CHCl3): 3368, 3055, 2233, 1602, 1502 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.03 (d, J = 9 Hz, 1 H), 5.41 (d, J = 9 Hz, 1 H), 6.76 (d, J = 9 Hz, 2 H), 6.90 (t, J = 6 Hz, 1 H), 7.30 (t, J = 9 Hz, 2 H), 7.44 (m, 3 H), 7.59 (m, 2 H); 13C NMR (75 MHz, CDCl3): δ = 49.8, 114.0, 118.1, 119.9, 127.0, 128.3, 129.4, 129.8, 133.6, 144.6; MS (ESI): m/z = 208.2 [M]+; Anal. Calcd for C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.80; H, 5.76; N, 13.47. 2-Anilino-2-(4-chlorophenyl)acetonitrile (Table 3, Entry 2): White solid; mp 96–98 °C; IR (CHCl3): 3365, 3055, 2235, 1603, 1504 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.02 (d, J = 6 Hz, 1 H), 5.41 (d, J = 9 Hz, 1 H), 6.75 (d, J = 9 Hz, 2 H), 6.92 (t, J = 6 Hz, 1 H), 7.28 (m, 2 H), 7.42 (d, J = 9 Hz, 2 H), 7.53 (d, J = 6 Hz, 2 H); 13C NMR (75 MHz, CDCl3): δ = 49.5, 114.2, 117.8, 120.4, 128.4, 129.2, 129.6, 132.8, 135.4, 144.3; MS (ESI): m/z = 242.1 [M]+; Anal. Calcd for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54; Found: C, 69.19; H, 4.63; N, 11.56. 2-Anilino-2-(4-nitrophenyl)acetonitrile (Table 3, Entry 3): Gummy solid; IR (CHCl3): 3381, 3063, 2225, 1601, 1550, 1502 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.08 (d, J = 9 Hz, 1 H), 5.57 (d, J = 9 Hz, 1 H), 6.68 (d, J = 9 Hz, 2 H), 6.78 (t, J = 8 Hz, 1 H), 7.29 (t, J = 9 Hz, 2 H), 7.8 (d, J = 9 Hz, 2 H), 8.1 (d, J = 9 Hz, 2 H); 13C NMR (75 MHz, CDCl3): δ = 49.8, 115.3, 118.0, 127.0, 127.7, 127.8, 128.6, 129.0, 133.8, 144.1, 145.0; MS (ESI): m/z = 276.2 [M + Na]+; Anal. Calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59; Found: C, 66.46; H, 4.40; N, 16.51.

  • References and Notes

    • 1a Undavia NK, Patwa BS, Navadiya HD, Jivani AR, Dave PN. Int. J. Chem. Sci. 2009; 7: 1019
    • 1b Mantri M, de Graaf O, van Veldhoven J, Goeblyoes A, von Frijtag Drabbe Künzel JK, Mulder-Krieger T, Link R, de Vries H, Beukers MW, Brussee J, Ijzerman AP. J. Med. Chem. 2008; 51: 4449
    • 1c Loeser R, Schilling K, Dimmig E, Guetschow M. J. Med. Chem. 2005; 48: 7688
    • 1d Ward YD, Thomson DS, Frye LL, Cywin CL, Morwick T, Emmanuel MJ, Zindell R, McNeil D, Bekkali Y, Giradot M, Hrapchak M, DeTuri M, Crane K, White D, Pav S, Wang Y, Hao M.-H, Grygon CA, Labadia ME, Freeman DM, Davidson W, Hopkins JL, Brown ML, Spero DM. J. Med. Chem. 2002; 45: 5471
    • 2a N’ajera C, Sansano JM. Chem. Rev. 2007; 107: 4584
    • 2b Zuend SJ, Coughlin MP, Lalonde MP, Jacobsen EN. Nature 2009; 461: 968
    • 3a Groger H. Chem. Rev. 2003; 103: 2795
    • 3b Shafran YM, Bakulev VA, Mokrushin VS. Russ. Chem. Rev. 1989; 58: 148
    • 3c Michaux J, Niel G, Campagne J.-M. Chem. Soc. Rev. 2009; 38: 2093
    • 4a Matier WL, Owens DA, Comer WT, Deitchman D, Ferguson H, Seidehamel RJ, Young JR. J. Med. Chem. 1973; 16: 901
    • 4b Ohfune Y, Shinada T. Eur. J. Org. Chem. 2005; 5127
    • 4c Friestad GK, Mathies AK. Tetrahedron 2007; 63: 2541
    • 4d Connon SJ. Angew. Chem. Int. Ed. 2008; 47: 1176
    • 5a Enders D, Shilvock JP. Chem. Soc. Rev. 2000; 29: 359
    • 5b Gembus V, Janvier S, Lecouve J.-P, Gloanec P, Marsais F, Levacher V. Eur. J. Org. Chem. 2010; 3583
    • 5c Yin B, Zhang Y, Xu L.-W. Synthesis 2010; 3583
    • 6a Strecker A. Justus Liebigs Ann. Chem. 1850; 75: 27
    • 6b Merino P, Marques-Lopez E, Tejero T, Herrera RP. Tetrahedron 2009; 65: 1219
    • 6c Pastori N, Gambarotti C, Punta C. Mini-Rev. Med. Chem. 2009; 6: 184
    • 6d Shibasaki M, Kanai M, Mita T. Org. React. 2008; 70: 1
    • 6e Wang J, Liu X, Feng X. Chem. Rev. 2011; 111: 6947
    • 7a Kobayashi S, Ishitani H. Chem. Rev. 1999; 99: 1069
    • 7b Bhanu Prasad BA, Bisai A, Singh VK. Tetrahedron Lett. 2004; 45: 9565
    • 7c Harusawa S, Hamada Y, Shioiri T. Tetrahedron Lett. 1979; 4663
    • 7d Nakamura S, Sato N, Sugimoto M, Toru T. Tetrahedron: Asymmetry 2004; 15: 1513
    • 7e Kantam ML, Mahendar K, Sreedhar B, Choudary BM. Tetrahedron 2008; 64: 3351
    • 7f Li Z, Ma Y, Xu J, Shi J, Cai H. Tetrahedron Lett. 2010; 51: 3922
    • 7g Cruz-Acosta F, Santos-exposito A, Armas P, Garcia-Tellado F. Chem. Commun. 2009; 6839
    • 7h Sipos S, Jablonkai I. Tetrahedron Lett. 2009; 50: 1844
    • 7i Abell JP, Yamamoto H. J. Am. Chem. Soc. 2009; 131: 15118
    • 7j Enders D, Shilvock JP. Chem. Soc. Rev. 2000; 29: 359
    • 8a De SK. J. Mol. Catal. A: Chem. 2005; 225: 169
    • 8b North M. Angew. Chem. Int. Ed. 2004; 43: 4126
    • 8c Murahashi SI, Komia N, Terai H, Nakae T. J. Am. Chem. Soc. 2003; 125: 15312
    • 8d Ranu BC, Dey SS, Hajra A. Tetrahedron 2002; 58: 2529
    • 8e Shen ZL, Ji SJ, Loh TP. Tetrahedron 2008; 64: 8159
    • 8f Narasimhulu M, Reddy TS, Mahesh KC, Reddy SM, Reddy AV, Venkateshwarlu Y. J. Mol. Catal. A: Chem. 2007; 264: 288
    • 8g De SK, Gibbs RA. Tetrahedron Lett. 2004; 45: 7407
    • 8h Royer L, De SK, Gibbs RA. Tetrahedron Lett. 2005; 46: 4595
    • 8i Karmakar B, Banerji J. Tetrahedron Lett. 2010; 51: 2748
    • 8j Mojtahedi MM, Abaee S, Alishiri T. Tetrahedron Lett. 2009; 50: 2322
    • 8k Paraskar S, Sudalai A. Tetrahedron Lett. 2006; 47: 5759
    • 8l Kobayashi S, Busujima T, Nagayama S. Chem. Commun. 1998; 981
    • 8m Martinez R, Ramon DJ, Yus M. Tetrahedron Lett. 2005; 46: 8471
    • 8n Zhang GW, Zheng DH, Nie J, Wang T, Ma JA. Org. Biomol. Chem. 2010; 8: 1399
    • 8o Ramesh S, Shivakumar K, Panja C, Arunanchalam PN, Lalitha A. Synth. Commun. 2010; 40: 3544
    • 8p Paraskar AS, Sudalai A. Tetrahedron Lett. 2006; 47: 5759
    • 8q Li Z, Ma Y, Xu J, Shi J, Cai H. Tetrahedron Lett. 2010; 51: 3922
    • 8r Wang J, Masui Y, Onaka M. Eur. J. Org. Chem. 2010; 1763
    • 9a Hajipour AR, Ghayeb Y, Sheikhan N. J. Iran. Chem. Soc. 2010; 7: 447
    • 9b Khan NH, Agrawal S, Kureshy RI, Abdi SH. R, Singh S, Suresh E, Jasra RV. Tetrahedron Lett. 2008; 49: 640
    • 9c Rafiee E, Rashidzadeh S, Joshaghani M, Chalabeh H, Afza K. Synth. Commun. 2008; 38: 2741
    • 9d Kantam ML, Mahender K, Sreedhar B, Choudhary BM. Tetrahedron 2008; 64: 3351
    • 9e Oskooie HA, Heravi MM, Sadnia A, Jannati F, Behbahani FK. Monatsh. Chem. 2008; 139: 27
    • 9f Arefi HA, Khaksar S, Shiroodi RK. J. Mol. Catal. A: Chem. 2007; 271: 142
    • 9g Shaabani A, Maleki A. Appl. Catal., A 2007; 331: 149
    • 9h Yadav JS, Reddy BV. S, Eeshwarain B, Srinivas M. Tetrahedron 2004; 60: 1767
    • 9i Rafiee E, Rashidzadeh S, Azad A. J. Mol. Catal. A: Chem. 2007; 261: 49
    • 9j Yadav JS, Reddy BV. S, Eshwaraiah B, Srinivas M, Vishnumurthy P. New J. Chem. 2003; 27: 462
    • 9k De SK. Synth. Commun. 2005; 35: 1577
    • 9l Shaabani A, Maleki A, Soudi MR, Mofakham H. Catal. Commun. 2009; 10: 945
    • 9m Niknam K, Saberi D, Sefat MN. Tetrahedron Lett. 2010; 51: 2959
    • 9n Kazemeini A, Azizi N, Saidi MR. Russ. J. Org. Chem. 2006; 42: 48
    • 9o Jarusiewicz J, Choe Y, Yoo KS, Park CP, Jung KW. J. Org. Chem. 2009; 74: 2873
    • 9p Karimi B, Maleki A, Elhamifar D, Clark JH, Hunt AJ. Chem. Commun. 2010; 46: 6947
    • 9q Khan NH, Saravanan S, Kureshy RI, Abdi SH. R, Bajaj HC. Tetrahedron: Asymmetry 2010; 21: 2076
    • 9r Sudhakar D, Rao VM, Suresh M, Rao CV. J. Chem. Res. 2010; 34: 12
    • 9s Karimi B, Maleki A. Chem. Commun. 2009; 5180
    • 10a Garima Synlett 2010; 1426
    • 10b Heck M.-P, Matt C, Wagner A, Toupet L, Mioskowski C. Eur. J. Org. Chem. 2010; 966
    • 10c Salome C, Kohn H. Tetrahedron 2009; 65: 456
    • 10d Bressy C, Alberico D, Lautens M. J. Am. Chem. Soc. 2005; 127: 13148
    • 10e Bartley DM, Coward JK. J. Org. Chem. 2005; 70: 6757
    • 10f Dormoy J.-R, Castro B. e-EROS Encyclopedia of Reagents for Organic Synthesis 2001;
    • 11a Chaturvedi D, Kumar A, Ray S. Tetrahedron Lett. 2003; 44: 7637
    • 11b Chaturvedi D, Ray S. Tetrahedron Lett. 2006; 47: 1307
    • 11c Chaturvedi D, Ray S. Tetrahedron Lett. 2007; 48: 149
    • 11d Chaturvedi D, Mishra N, Mishra V. Tetrahedron Lett. 2007; 48: 5043
    • 11e Chaturvedi D, Mishra N, Mishra V. Synthesis 2008; 355
    • 11f Chaturvedi D, Chaturvedi AK, Mishra N, Mishra V. Tetrahedron Lett. 2008; 49: 4886
    • 11g Chaturvedi AK, Chaturvedi D, Mishra N, Mishra V. J. Iran. Chem. Soc. 2010; 7: 702
    • 11h Chaturvedi AK, Chaturvedi D, Mishra N, Mishra V. J. Iran. Chem. Soc. 2011; 8: 396
  • 12 Synthesis of α-Aminonitriles; Typical Procedure: A mixture of aldehyde (1 mmol), amine (1 mmol), triphenylphosphine dibromide (10 mol%), and trimethylsilylcyanide (1.2 mmol) was stirred at room temperature until the reaction was complete (monitored by TLC). The reaction mixture was then extracted with EtOAc (×3), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the crude product by chromatography on silica gel (60–120 mesh; petroleum ether–EtOAc, 5:1) gave the pure product. 2-Anilino-2-phenylacetonitrile (Table 3, Entry 1): Light-yellow solid; mp 85–86 °C; IR (CHCl3): 3368, 3055, 2233, 1602, 1502 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.03 (d, J = 9 Hz, 1 H), 5.41 (d, J = 9 Hz, 1 H), 6.76 (d, J = 9 Hz, 2 H), 6.90 (t, J = 6 Hz, 1 H), 7.30 (t, J = 9 Hz, 2 H), 7.44 (m, 3 H), 7.59 (m, 2 H); 13C NMR (75 MHz, CDCl3): δ = 49.8, 114.0, 118.1, 119.9, 127.0, 128.3, 129.4, 129.8, 133.6, 144.6; MS (ESI): m/z = 208.2 [M]+; Anal. Calcd for C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.80; H, 5.76; N, 13.47. 2-Anilino-2-(4-chlorophenyl)acetonitrile (Table 3, Entry 2): White solid; mp 96–98 °C; IR (CHCl3): 3365, 3055, 2235, 1603, 1504 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.02 (d, J = 6 Hz, 1 H), 5.41 (d, J = 9 Hz, 1 H), 6.75 (d, J = 9 Hz, 2 H), 6.92 (t, J = 6 Hz, 1 H), 7.28 (m, 2 H), 7.42 (d, J = 9 Hz, 2 H), 7.53 (d, J = 6 Hz, 2 H); 13C NMR (75 MHz, CDCl3): δ = 49.5, 114.2, 117.8, 120.4, 128.4, 129.2, 129.6, 132.8, 135.4, 144.3; MS (ESI): m/z = 242.1 [M]+; Anal. Calcd for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54; Found: C, 69.19; H, 4.63; N, 11.56. 2-Anilino-2-(4-nitrophenyl)acetonitrile (Table 3, Entry 3): Gummy solid; IR (CHCl3): 3381, 3063, 2225, 1601, 1550, 1502 cm–1; 1H NMR (300 MHz, CDCl3): δ = 4.08 (d, J = 9 Hz, 1 H), 5.57 (d, J = 9 Hz, 1 H), 6.68 (d, J = 9 Hz, 2 H), 6.78 (t, J = 8 Hz, 1 H), 7.29 (t, J = 9 Hz, 2 H), 7.8 (d, J = 9 Hz, 2 H), 8.1 (d, J = 9 Hz, 2 H); 13C NMR (75 MHz, CDCl3): δ = 49.8, 115.3, 118.0, 127.0, 127.7, 127.8, 128.6, 129.0, 133.8, 144.1, 145.0; MS (ESI): m/z = 276.2 [M + Na]+; Anal. Calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59; Found: C, 66.46; H, 4.40; N, 16.51.

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Scheme 1