Synthesis of 3-aminopyrrolidines and piperidines from endocyclic enamine derivatives

TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 7007–7010

Pergamon

Synthesis of 3-aminopyrrolidines and piperidines from endocyclic enamine derivatives Marta R. P. Norton Matos,a,b Carlos A. M. Afonsoa and Robert A. Bateyb,* a

Departamento de Quı´mica, Centro de Quı´mica Fina e Biotecnologia, Faculdade de Cieˆncias e Tecnologia, Universidade Nova de Lisboa, 2825 -114 Monte de Caparica, Portugal b Department of Chemistry, 80 St. George Street, University of Toronto, Toronto, Ontario, Canada M5S 3H6 Received 14 July 2001; revised 31 July 2001; accepted 3 August 2001

Abstract—Reactions of endocyclic enecarbamates to form functionalized 3-aminopyrrolidines and piperidines are described. Iodoamination of N-acyl-2-pyrrolines followed by aziridination in methanol is an effective route to N-acyl-3-amino-2methoxypyrrolidines. Azidomethoxylation of endocyclic carbamates by ceric ammonium nitrate (CAN) in the presence of NaN3 and methanol gives 3-azido-2-methoxypiperidines and pyrrolidines. Formation and trapping of the N-acyliminium ions derived from these substrates under Lewis acidic conditions was also explored for the stereoselective preparation of 2-alkyl pyrrolidine and piperidine derivatives. © 2001 Published by Elsevier Science Ltd.

3-Aminopyrrolidines and 3-aminopiperidines constitute key structural units present in several bioactive molecules and have received increasing attention due to their interesting pharmacological properties.1 As part of a continuing interest in exploring new strategies for the functionalization of endocyclic enamine derivatives, we have become interested in the synthesis of such aminosubstituted nitrogen heterocycles.2 At the outset of our investigations we envisaged that reaction of an endocyclic enamine 1 through electrophilic amination at the b-position and nucleophilic attack at the a-position would provide an attractive multi-component strategy for the synthesis of N-heterocycle 2 (Fig. 1). An ideal reaction would achieve these transformations in a onepot manner, preferably with the three reactive components introduced simultaneously, and afford the adducts stereoselectively. There are considerable challenges to the introduction of a carbon based nucleophile at the a-position in this manner, since

competitive reaction of the nucleophile directly with the electrophilic amination reagent would be anticipated to occur. We now report preliminary results that address this issue using stepwise protocols for the preparation of N-heterocycles 2 that incorporate nitrogen functionality at the b-position. Two protocols have been investigated, both proceeding via formation of N-acyliminium ion precursors 3 which can then be elaborated to amino-substituted heterocycles 4 (Scheme 1). In the first protocol, iodocarbamaE n

E

n

N R

Nu

N R

Figure 1.

X n N R 1 n = 1, 2 R = Cbz

(a) or (b)

X

n N R

1

Nucleophile OMe

Lewis Acid

3

NH2

n N R

deprotect Nu

X = NHBoc (3a); NHCbz (3b); NHCO2Me (3c); N3 (3d)

Scheme 1. (a) Iodocarbamation followed by aziridination/methanolysis. (b) Azidomethoxylation. Keywords: N-acyliminium ions; N-heterocycles; enamines. * Corresponding author. Tel./fax: (+1)-416-978-5059; e-mail: [email protected] 0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd. PII: S 0 0 4 0 - 4 0 3 9 ( 0 1 ) 0 1 4 3 3 - 2

n N R

Nu 4

Nu 2

M. R. P. Norton Matos et al. / Tetrahedron Letters 42 (2001) 7007–7010

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tion of 1 (n=1) is followed by ring-closure to an aziridine followed by ring-opening with methanol to yield 3a–c (X=NHCOOR) (Scheme 1). The second protocol utilizes azidomethoxylation of 1 (n=1 or n= 2) with ceric ammonium nitrate (CAN) in the presence of NaN3 and methanol for the preparation of 3d (X= N3) (Scheme 1). These compounds are useful precursors for N-acyliminium ion generation, providing a straightforward route to 2-substituted-3-aminopyrrolidines and piperidines 4. Iodine-promoted carbamate addition to the enecarbamate double bond in 1a occurs at low temperature affording trans/cis mixtures of 2-carbamate-3-iodopyrrolidines 5a–c in good yields3,4 (Table 1, entries 1–3). This transformation, initially attempted with N-iodosuccinimide (NIS), gave poor yields of the desired products (54% for 5a, 53% for 5b) due to competitive attack of succinimide on the electrophilic intermediate. Reaction with tosylsulfonamide gave a poor yield (32%) of the addition product 5d and partial decomposition was observed within a few days at 4°C (Table 1, entry 4). Attempts to introduce other nitrogen nucleophiles such as primary amines (allylamine and propargylamine), dialkylamines (N-methyl allylamine and Ncyclohexylamine), arylamines (aniline, N-acetyl aniline) and amides (acrylamide and trifluoroacetamide) failed to give stable addition products (with hydrolysis occuring on warming to room temperature). The pyrrolidine compounds 5a–5c undergo cyclization with NaN(SiMe3)2 in THF and methanol to give aziridine intermediates, which are ring-opened by methanol in situ affording inseparable diastereomeric mixtures of 3-carbamate-2-methoxypyrrolidines 6a–6c in good yields5 (Table 1, entries 1–3). The same transformation could also be accomplished in lower yields (59% for 6b, 60% for 6a) using KOH (0.1 M)/MeOH at 35°C for 5 h.6 Direct nucleophilic attack by carbon-centered nucleophiles on the aziridine intermediates formed the substituted pyrrolidines in poor yield and selectivity. Unfortunately, we were unable to apply the iodocarbamation method to the formation of isolable piperidines.

However, introduction of latent amino functionality through azidomethoxylation of endocyclic enecarbamates was possible (Scheme 2).7 Thus, treatment of a mixture of enecarbamate 1a or 1b with sodium azide and methanol with ceric ammonium nitrate (CAN) afforded 3-azido-2-methoxypyrrolidine 7a and piperidine 7b, respectively, as diastereomeric mixtures.8 Interestingly, and in contrast to the iodocarbamation protocol, the piperidine adduct 7b (n=2) was formed in much higher yields than the pyrrolidine adduct 7a (n=1). The reactivity of 2-methoxy-3-substituted-pyrrolidines and piperidines was further explored with BF3·OEt2mediated N-acyliminium ion reactions (Table 2). This transformation is useful for the preparation of 2-alkyl3-aminopyrrolidines and piperidines 8, which are potential precursors for natural product synthesis.1 The 3-NHBoc-pyrrolidine 6a gave, after reprotection of the free amine, only poor yields of the allylated product (Table 2, entry 1). However, the 3-NHCbz-pyrrolidine 6b afforded the 2-allyl, 2-cyano and 2-ethoxycarbonylmethylene derivatives in moderate to good yields and with moderate trans stereoselectivity9 (Table 2, entries 2–4). The observed trans-selectivity can be rationalized by a neighboring group effect which favors the trans nucleophilic attack. Similar attack of the 3-azido substrates 7a and 7b gave substituted products 8 in moderate yields and with high cis selectivity (Table 2, entries N3 n

NaN3 (1.5 eq.), CAN (3 eq.)

n

N Cbz

MeOH, MeCN, 0 oC to rt

N Cbz

1a (n = 1) 1b (n = 2)

OMe

7a (n = 1) 20% (d.r. = 30:70) 7b (n = 2) 71% (d.r. = 40:60)

Scheme 2.

Table 1. Examples of iodocarbamation of enecarbamate 1a followed by aziridination/methanolysis

N Cbz

THF, -78 oC, 10 min. step (i) 1a

NHR1

I

R1NH2, I2 (1.1 eq.)

MeOH, NaN(TMS)2 (1 eq.) N Cbz

NHR1

THF, -78 oC to rt step (ii)

5

N Cbz

OMe 6

Entry

R1NH2 (equiv.)

Product step (i)

Yield (%)a

d.r.b

Product step (ii)

Yield (%)a

d.r.b

1 2 3 4

BocNH2 (1.0) CbzNH2 (2.0) MeOCONH2 (2.0) TolSO2NH2 (2.0)

5a 5b 5c 5d

74 71 70 32c

72:28 77:23 73:27 69:31

6a 6b 6c

82 73 85

85:15 77:23 78:22

a

Yield of purified product (flash chromatography). Determined by 1H NMR. c Partial decomposition was observed within a few days at 4°C. b

M. R. P. Norton Matos et al. / Tetrahedron Letters 42 (2001) 7007–7010

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Table 2. Substitution of 6 and 7 with carbon-centered nucleophiles

Yield (%)b

cis:trans c

H2CCHCH2SiMe3

23d

23:77

6b, n=1, R%=NHCbz

H2CCHCH2SiMe3

60

24:76

3

6b, n=1, R%=NHCbz

Me3SiCN

52

30:70

4

6b, n=1, R%=NHCbz

CH2C(OTBDMS)OEt

80

15:85

5b

7a, n=1, R%=N3

CH2C(OTBDMS)OEt

49

88:12

6

7b, n=2, R%=N3

H2CCHCH2SiMe3

50

88:12

Entry

Substrate

Nucleophile

1

6a, n=1, R%=NHBoc

2

Major producta

a

The stereochemistry of the products were assigned by a combination of 1D-NMR and 2D-NMR NOESY experiments performed at 360 K in 1,1,2,2-tetrachloroethane-d2. b Yield of purified product (flash chromatography). c Determined by 1H NMR. d Product isolated after reprotection of the corresponding free amine.

5 and 6). This observed cis selectivity, in the absence of a neighboring group effect, is in accord with known N-acyliminium ion reactions.10 In summary, we have described synthetic routes for the preparation of 3-carbamate-2-methoxy-pyrrolidines 6a– 6c and 3-azido-2-methoxy-pyrrolidine 7a and piperidine 7b, starting from the endocyclic carbamates 1a and 1b. Stereoselective substitution of the 2-methoxy group in compounds 6 and 7 by carbon-based nucleophiles via

Lewis acid-promoted N-acyliminium ion reactions were also achieved.11 Whilst, the overall process to form 8 represents a formal 3-component coupling protocol, it is quite substrate dependent and does not allow for the introduction of all classes of amine functionality, and is consequently of limited utility for combinatorial library generation. Nevertheless, products 8 are potential precursors for the synthesis of bioactive molecules, and ongoing studies on the synthesis of 1-aminopyrrolizidines are under investigation.

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M. R. P. Norton Matos et al. / Tetrahedron Letters 42 (2001) 7007–7010

Acknowledgements This work was supported by the Fundac¸ a˜ o para a Cieˆ ncia e Tecnologia (FCT, project PRAXIS XXI PCEX/C/QUI/53/96 and a Ph.D. grant for M.N.M., ref. PRAXIS XXI BD/9040/96) and the National Science and Engineering Research Council (NSERC) of Canada. R.A.B. gratefully acknowledges the Ontario Government for additional support. We thank Dr. A. B. Young for mass spectroscopic analyses.

References 1. (a) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett. 1999, 40, 5071–5072; (b) Macdonald, S. J. F.; Belton, D. J.; Buckley, D. M.; Spooner, J. E.; Anson, M. S.; Harrison, L. A.; Mills, K.; Upton, R. J.; Dowle, M. D.; Smith, R. A.; Molloy, C. R.; Risley, C. J. Med. Chem. 1998, 41, 3919–3922; (c) Langlois, N.; Radom, M.-O. Tetrahedron Lett. 1998, 39, 857–860; (d) Owens, T. D.; Semple, J. E. Bioorg. Med. Chem. Lett. 1998, 8, 3683– 3688; (e) Christine, C.; Ikhiri, K.; Ahond, A.; Mourabit, A. A.; Poupat, C.; Potier, P. Tetrahedron 2000, 56, 1837– 1850; (f) Laschat, S.; Fro¨ hlich, R.; Wibbeling, B. J. Org. Chem. 1996, 61, 2829–2838; (g) Huang, P. Q.; Wang, S. L.; Zheng, H.; Fei, X. S. Tetrahedron Lett. 1997, 38, 271–272. 2. (a) Norton Matos, M. R. P.; Afonso, C. A. M.; McGarvey, T.; Lee, P.; Batey, R. A. Tetrahedron Lett. 1999, 40, 9189–9193; (b) Batey, R. A.; Simoncic, P.; Lin, D.; Smyj, R.; Lough, A. J. Chem. Commun. 1999, 651–652. 3. A similar transformation has been reported on dihydropyrans, using iodonium di-sym-collidine perchlorate [I(sym-Coll)2]ClO4 and benzenesulfonamide, providing stable iodosulfonamides in excellent yields: (a) Danishefsky, S. J.; Koseki, K.; Griffith, D. A.; Gervay, J.; Peterson, J. M.; McDonald, F. E.; Oriyama, T. J. Am. Chem. Soc. 1992, 114, 8331–8333; (b) Danishefsky, S. J.; Behar, V.; Randolph, J. T.; Lloyd, K. O. J. Am. Chem. Soc. 1995, 117, 5701–5711. 4. More recently, iodo trifluoracetamide pyran derivatives have been prepared in good yields using NIS and [I(symColl)2]ClO4 in the presence of trifluoracetamide: Erbeck, S.; Prinzbach, H. Tetrahedron Lett. 1997, 38, 2653–2656. 5. For an example of aziridination of N-tosyl-2-pyrroline, mediated by a manganese nitrido complex, to give Ntosyl-3-trifluoracetamide-2-methoxypyrrolidine, see: Sunose, M.; Anderson, K. M.; Orpen, A. G.; Gallagher, T.; Macdonald, S. J. F. Tetrahedron Lett. 1998, 39, 8885–8888. 6. For an example of conversion of 3-iodo-2-carbamates to aziridines using KOH/MeOH, see: Hassner, A.; Heathcock, C. J. Org. Chem. 1964, 29, 3640–3645.

7. For an example of CAN-mediated azidomethoxylation of alkenes, see: Chavan, S. P.; Subbarao, Y. T. Tetrahedron Lett. 1999, 40, 5073–5074. 8. Fujimoto, K.; Tokuda, Y.; Matsubara, Y.; Maekawa, H.; Mizuno, T.; Nishiguchi, I. Tetrahedron Lett. 1995, 36, 7483–7486. 9. For a similar example of trans selectivity in Nacyliminium reactions, see: Macdonald, S. J. F.; Clarke, G. D. E.; Dowle, M. D.; Harrison, L. A.; Hodgson, S. T.; Inglis, G. G. A.; Johnson, M. R.; Shah, P.; Upton, R. J.; Walls, S. B. J. Org. Chem. 1999, 64, 5166–5175. 10. (a) Chiesa, M. V.; Manzoni, L.; Scolastico, C. Synlett 1996, 441–443; (b) Ungureaunu, I.; Bologa, C.; Chayer, S.; Mann, A. Tetrahedron Lett. 1999, 40, 5315–5318. 11. All new compounds were characterized by IR, 1H, 13C NMR and HRMS. Typical procedures: representative iodocarbamation: A solution of iodine (254 mg, 1 mmol) in dry THF (5 ml) was added dropwise to a stirred solution of N-(benzyloxy)carbonyl-2-pyrroline 1a (n=1) (203 mg, 1 mmol) and tert-butyl carbamate (119 mg, 1 mmol) in dry THF (5 ml) at −78°C and under nitrogen. The resulting mixture was stirred for 10 min and then poured into a cold saturated aqueous solution of NaHCO3 and diethyl ether. The aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 30:70 EtOAc:hexane) afforded 5a (332 mg, 74%) as an orange foam; Rf=0.46 (30:70 EtOAc:hexane). For entries 2–4 further purification is required to remove the excess R1NH2. Representative aziridination: A solution of NaN(SiMe3)2 in THF (0.5 M, 1.46 ml, 0.73 mmol) was added dropwise to a stirred solution of 5a (298 mg, 0.67 mmol) in dry THF (7 ml) and dry methanol (0.35 ml) at −78°C under nitrogen. The mixture was stirred for 5 min at −78°C and then allowed to reach rt. A saturated aqueous solution of NaHCO3 and diethyl ether was then added, and the organic layer separated and the aqueous layer extracted with diethyl ether. The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 30:70 EtOAc:hexane) afforded 6a (184 mg, 82%) as a clear oil; Rf=0.30 (20:80 EtOAc:hexane). Representative azido methoxylation: CAN (5.82 g, 10.5 mmol) dissolved in acetonitrile (50 ml) was added dropwise to a cooled (ice-bath) mixture of sodium azide (0.34 g, 5.25 mmol) and 1b (n=2) (0.76 g, 3.5 mmol) in dry acetonitrile (35 ml) and dry methanol (6 ml) under nitrogen. The mixture was gradually brought to rt and stirred overnight. Water and diethyl ether were added and the organic layer separated and washed with ice-cold water. The aqueous layer was extracted once again with diethyl ether, the combined organic layers dried (Na2SO4) and the solvent was removed in vacuo. Purification by column chromatography (SiO2, 10:90 EtOAc:hexane) afforded 7b (0.69 g, 69%) as a clear oil; Rf=0.65 (20:80 EtOAc:hexane).