trans-2,5-Dimethylpyrrolidine

(racemate)

[62617-69-0; 39713-72-9]  · C6H13N  · trans-2,5-Dimethylpyrrolidine  · (MW 99.18) (2S,5S)

[117968-50-0] (2R,5R)

[62617-70-3] (.HCl, racemate)  · C6H14ClN  · trans-2,5-Dimethylpyrrolidine Hydrochloride  · (MW 135.64)

[114143-75-8; 4832-49-9] (.HCl, 2S,5S)

[138133-34-3] (.HCl, 2R,5R)

[70144-18-2]

(C2 symmetric chiral pyrrolidine,1 useful in optically active form as a chiral auxiliary in a variety of asymmetric reactions)

Physical Data: free amine: bp 102-103 °C; (2S,5S) [a]25D +10.6° (c 1.0, EtOH);2 (2R,5R) [a]25D -11.5° (c 1.0, EtOH).2 Hydrochloride: racemate mp 187-189 °C;3 (2S,5S) mp 200-201 °C,4 [a]25D -5.63° (c 0.67, CH2Cl2);4 (2R,5R) mp 200-203 °C,5 [a]25D +5.57° (c 1.18, CH2Cl2).5

Form Supplied in: colorless oil; commercially available as a mixture of (±)-trans and cis isomers (the mixture is not easily separated).6

Purification: the free amine can be purified by fractional distillation; the hydrochloride salt can be recrystallized from absolute ethanol and diethyl ether.

Handling, Storage, and Precautions: irritant; flammable. Use in a fume hood.

Synthesis.

Several routes are available for the synthesis of trans-2,5-dimethylpyrrolidine.2-9,22 Discussed below are preparative scale procedures for the synthesis of the pure trans compound in racemic and enantiomerically pure form.

The racemic hydrochloride salt can be prepared in four steps and 70% overall yield (eq 1).3 The synthesis is carried out on 2 mmol scale and starts with commercially available 5-hexen-2-one. The key step involves a mercury-catalyzed intramolecular amidomercuration to form the pyrrolidine ring. If desired, the racemate can be resolved via the salts of Mandelic Acid.2

Alternatively, an efficient synthesis of either antipode starting from D- or L-alanine has been reported (eq 2).9 The asymmetric synthesis conducted on 10 mmol scale involves a six-step sequence which incorporates the amidomercuration method.3 The enantiomerically pure product is isolated as its hydrochloride salt in 44% overall yield. Furthermore, an optimization of the capricious cuprate reaction which improves both the yield and reproducibility has been described.4

More recently, a four-step synthetic sequence which provides expedient access to the (-)-(R,R)-enantiomer in 42% overall yield has been reported.5 This route is convenient for large-scale preparation (0.2 mol scale), and is highlighted by an asymmetric Baker's Yeast reduction of 2,5-hexanedione. Subsequent mesylation, N,N-dialkylation, and deprotection provides the enantiomerically pure free pyrrolidine (eq 3). Alternatively, either enantiomer of the chiral pyrrolidine can be obtained in 15% overall yield from an isomeric mixture of 2,5-hexanediol, via a similar sequence in which (S)-a-methylbenzylamine is used as a chiral auxiliary.22 Also, an enantioselective route to either (2S,5S)- or (2R,5R)-hexanediol has been reported.23

Asymmetric Alkylations and Michael Additions.

Asymmetric alkylation of the cyclohexanone enamine derived from (+)-trans-2,5-dimethylpyrrolidine has been studied (eq 4).2 Alkylation with Iodomethane, n-propyl bromide, and Allyl Bromide afforded the corresponding 2-n-alkylcyclohexanones in yields of 50-80% and with enantiomeric purities of 66, 86, and 64%, respectively.

The lithium enolates from tetronic acid-derived vinylogous urethanes have been generated and their reactivity investigated with a variety of electrophiles (eq 5).10,11 The reactions proceed with excellent regio- and diastereoselectivity and a variety of alkylating agents can be utilized.

In the total synthesis of (-)-secodaphniphylline an asymmetric [1,4]-conjugate addition was used to establish relative and absolute stereocontrol.12 The lithium enolate of a trans-2,5-dimethylpyrrolidine-derived amide adds in a Michael fashion to a cyclic a,b-unsaturated ester, with subsequent enolate trapping, to afford the desired product in 64% yield and 92:8 diastereoselection (eq 6).

Asymmetric Radical Reactions.

Several reports have documented the utility of nonracemic trans-2,5-dimethylpyrrolidine as a chiral auxiliary in asymmetric radical reactions.13 For example, the addition of n-hexyl, cyclohexyl, and t-butyl radicals to the chiral acrylamide of 4-oxopentenoic acid provided four diastereomeric products resulting from a- and b-addition (eq 7).14 The isomers resulting from b-addition were formed with no diastereoselectivity; however, the isomers resulting from a-addition were formed in ratios of 16:1, 24:1, and 49:1. Unfortunately, the application of this chemistry is limited due to the poor regioselectivity in the addition and difficulty in removal of the chiral auxiliary.

Similar results have been achieved in the addition of chiral amide radicals to activated alkenes.13 For instance, a chiral amide radical, derived from (-)-trans-2,5-dimethylpyrrolidine, adds in a 1,4-fashion to ethyl acrylate in 35% yield and with 12:1 diastereoselectivity (eq 8).15 Unfortunately, substantial amounts of higher oligomers are also formed. The radical telomerization of chiral acrylamides to afford nonracemic lower-order telomers (n = 1-5) has also been described.16

Asymmetric Pericyclic Reactions.

Several reports illustrate the utility of trans-2,5-dimethylpyrrolidine as a chiral auxiliary in asymmetric Claisen-type rearrangements,17 [4 + 2],18,19 and [2 + 2] cycloaddition reactions.20 The enantioselective Claisen-type rearrangement of N,O-ketene acetals derived from trans-2,5-dimethylpyrrolidine has been studied.17 For example, the rearrangement of the N,O-ketene acetal, formed in situ by the reaction of N-propionyl-trans-(2S,5S)-dimethylpyrrolidine with (E)-crotyl alcohol, affords the [3,3]-rearrangement product in 50% yield and 10:1 diastereoselectivity (eq 9).

Carbamoyl nitroso dienophiles, derived from chiral pyrrolidines, have been generated and their reactivity with cyclohexadiene investigated.18 Using (-)-trans-2,5-dimethylpyrrolidine as the auxiliary, the [4 + 2] cycloadduct is isolated in 82% yield and with 98% diastereomeric excess (eq 10). Similarly, chiral ynamine dienophiles have been utilized in asymmetric [4 + 2] cycloadditions with a,b-unsaturated nitroalkenes to afford cyclic nitronic esters.19 The resulting esters subsequently undergo a rapid [1,3]-rearrangement to afford chiral cyclic nitrones in moderate yield and high diastereoselectivity (eq 11).

An asymmetric, thermal [2 + 2] cycloaddition of keteniminium salts derived from trans-2,5-dimethylpyrrolidine has been employed in the synthesis of prostaglandins.20 An intramolecular [2 + 2] cycloaddition affords a cis-fused bicyclic system which is then further transformed into a common prostaglandin intermediate (eq 12).

Miscellaneous.

trans-2,5-Dimethylpyrrolidine has been utilized as a chiral auxiliary for an asymmetric iodolactonization in the total synthesis of (±)-pleurotin and (±)-dihydropleurotin.21 The reaction affords the desired lactone in 47% yield and only 30% enantiomeric excess.

Related Reagents.

trans-2,5-Bis(methoxymethyl)pyrrolidine.


1. Whitesell, J. K. CRV 1989, 89, 1581.
2. Whitesell, J. K.; Felman JOC 1977, 42, 1663.
3. Harding, K. E.; Burks, S. R. JOC 1981, 46, 3920.
4. Yamazaki, T.; Gimi, R.; Welch, J. T. SL 1991, 573.
5. Short, R. P.; Kennedy, R. M.; Masamune, S. JOC 1989, 54, 1755.
6. House, H. O.; Lee, L. F. JOC 1976, 41, 863.
7. Dervan, P. B.; Uyehara, T. JACS 1976, 98, 2003.
8. Gagné, M. R.; Stern, C. L.; Marks, T. J. JACS 1992, 114, 275.
9. Schlessinger, R. H.; Iwanowicz, E. J. TL 1987, 28, 2083.
10. Schlessinger, R. H.; Iwanowicz, E. J.; Springer, J. P. JOC 1986, 51, 3070.
11. Schlessinger, R. H.; Iwanowicz, E. J.; Springer, J. P. TL 1988, 29, 1489.
12. Heathcock, C. H.; Stafford, J. A. JOC 1992, 57, 2566.
13. Porter, N. A.; Giese, B.; Curran, D. P. ACR 1991, 24, 296.
14. Porter, N. A.; Scott, D. M.; Rosenstein, I. J.; Giese, B.; Veit, V.; Zeitz, H. G. JACS 1991, 113, 1791.
15. Porter, N. A.; Swann, E.; Nally, J.; McPhail, A. T. JACS 1990, 112, 6740.
16. Porter, N. A.; Breyer, R.; Swann, E.; Nally, J.; Pradhan, J.; Allen, T.; McPhail, A. T. JACS 1991, 113, 7002.
17. Yamazaki, T.; Welch, J. T.; Plummer, J. S.; Gimi, R. H. TL 1991, 32, 4267.
18. Defoin, A.; Brouillard-Poichet, A.; Streith, J. HCA 1991, 74, 103.
19. Elburg, P. A.; Honig, G. W. N.; Reinhoudt, D. N. TL 1987, 28, 6397.
20. Chen, L.-Y.; Ghosez, L. TA 1991, 2, 1181.
21. Hart, D. J.; Huang, H.-C.; Krishnamurthy, R.; Schwartz, T. JACS 1989, 111, 7507.
22. Mariël, E. Z.; Meetsma, A.; Feringa, B. L. TA 1993, 4, 2163.
23. Burk, M. J.; Feaster, J. E.; Harlow, R. L. TA 1991, 2, 569.

Lawrence R. Marcin

University of Illinois at Urbana-Champaign, IL, USA



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