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Chemical Synthesis

(S)-(–)-5-(2-Pyrrolidinyl)-1H-tetrazole

Introduction

Organocatalysis provides convenient new methods to construct complex chiral compounds with operational simplicity and without the need for metals. (S)-(–)-5-(2-Pyrrolidinyl)-1H-tetrazole 684341 (Figure 1) is an isoster of L-proline with similar pKa, but anticipated greater solubility and reactivity in more lipophilic organic solvents. Originally synthesized for organocatalytic applications almost simultaneously by the groups of Arvidsson,1 Ley,2 and Yamamoto3 this reagent has proven very useful in a variety of reactions.

Figure 1

References:

  1. Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831.
  2. Hartikka, A.; Arvidsson, P. I. Eur. J. Org. Chem. 2005, 4287.
  3. Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43, 1983.

Mannich reactions

Pyrrolidinyltetrazole-mediated Mannich reactions provide efficient access to several highly important product types. For instance, α-amino acids were synthesized in excellent yields and stereoselectivities by the Mannich reaction as the key C–C-bond forming step (Scheme 1, Table 1). In contrast to the L-proline-catalyzed reaction, less polar solvents such as dichloromethane can be used while retaining similar selectivities.1,2


Scheme 1

R1, R2 Yield syn:anti ee
-(CH2)4- 65% >19:1 >99%
-(CH2)5- 59% >19:1 >99%
-(CH2)2- 74% >19:1 94%
H, Me 99% -a >99%
Me, Et 72% >19:1 >99%

Table 1

The Mannich reaction of phthaloyl protected amino ketone in N-methyl-2-pyrrolidone (NMP) exhibited excellent regioselectivity: enamine formation was favored at the less hindered side of the carbonyl group and generated protected 1,4-diamines in good yields and enantioselectivities (Scheme 2, Table 2). Interestingly, using L-proline as catalyst in this transformation furnished only trace amounts of the desired products.


Scheme 2

R1 Yield ee
CO2Et 88% 91%
4-O2N-C6H4 68% 97%
4-NC-C6H4 56% 95%
Ph 71% 77%

Table 2

References:

  1. Cobb, A. J. A.; Shaw.; M. M.; Ley, S. V. Synlett 2004, 558.
  2. Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
  3. Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III Org. Lett. 2006, 8, 2839.

Conjugate Additions

Pyrrolidinetetrazole 684341 catalyzes the asymmetric conjugate addition of malonates to a variety of enones in good-to-excellent yields and enantioselectivities.1 Following a series of experiments intended to determine the optimal reaction parameters, Ley and co-workers established the conditions shown below to be the most favorable (Scheme 1, Table 1). In contrast to other similar methods, these conditions permit the use of only a slight excess of the malonate and as low as 5 mol% of the organocatalyst, which allows for a more practical and easily scalable reaction.


Scheme 1

R1, R2 Yield ee
-(CH2)3- 87% 83%
Ph, Me 89% 84%
4-F3CC6H4, Me 84% 78%
4-HOC6H4-, Me 70% 64%
2-furanyl, Me 69% 81%
2-thienyl, Me 82% 84%

Table 1

The conjugate addition of nitroalkanes to cyclic and acyclic enones results in synthetically useful γ-nitro ketone adducts. Also in this case, pyrrolidinyltetrazole 684341 proved to be a versatile catalyst for the asymmetric 1,4-addition of a variety of nitroalkanes to cyclic and acyclic enones (Scheme 2, Table 2).2


Scheme 2

R1, R2 Yield ee
-(CH2)3- 64% 91%
-(CH2)2- 62% 80%
Ph, Et 78% 78%
2-thienyl, Me 61% 72%
CO2Me, Me 96% 82%
Pentyl, Me 44% 58%

Table 2

References:

  1. Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Commun. 2006, 66, and ref. cit. therein.
  2. Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem. Commun. 2005, 5346.

Products

Prod. No. Product Name Structure
684341  (S)-(–)-5-(2-Pyrrolidinyl)-1H-tetrazole