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Stereocontrolled Oxidative Additionsupon 1,4-Dihydropyridines: Synthesisof Hexahydrofuro[2,3-b]pyridine andHexahydropyrano[2,3-b]pyridineDerivativesRakesh Kumar a , Dhiraj Kumar a & Ashok K. Prasad ba Department of Chemistry, Kirori Mal College, University of Delhi,Delhi, Indiab Department of Chemistry, Bio-organic Laboratory, University ofDelhi, Delhi, IndiaAccepted author version posted online: 13 Feb 2012.Version ofrecord first published: 08 Nov 2012.

To cite this article: Rakesh Kumar , Dhiraj Kumar & Ashok K. Prasad (2013): StereocontrolledOxidative Additions upon 1,4-Dihydropyridines: Synthesis of Hexahydrofuro[2,3-b]pyridine andHexahydropyrano[2,3-b]pyridine Derivatives, Synthetic Communications: An International Journal forRapid Communication of Synthetic Organic Chemistry, 43:4, 520-536

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STEREOCONTROLLED OXIDATIVE ADDITIONS UPON1,4-DIHYDROPYRIDINES: SYNTHESIS OFHEXAHYDROFURO[2,3-b]PYRIDINE ANDHEXAHYDROPYRANO[2,3-b]PYRIDINE DERIVATIVES

Rakesh Kumar,1 Dhiraj Kumar,1 and Ashok K. Prasad21Department of Chemistry, Kirori Mal College, University of Delhi,Delhi, India2Department of Chemistry, Bio-organic Laboratory, University of Delhi,Delhi, India

GRAPHICAL ABSTRACT

Abstract trans-a-Alkoxy-b-halotetrahydropyridines are synthesized in a very efficient

single step by stereocontrolled N-halosuccinimide (NXS)–promoted alcohol addition to

the enamine group in N-alkyl-1,4-dihydropyridines. These compounds are cyclized using

sodium cyanoborohydride in the presence of 2,20-azobis(2-methylpropionitrile), aza-

bisisobutyronitrile (AIBN) (cat.), and tributylstannane (cat.), affording hexahydro-

furo[2,3-b]pyridine and hexahydropyrano[2,3-b]pyridine derivatives. The cyclized

product undergoes ring-opening reaction by a nucleophile in the presence of Lewis acid

to afford highly functionalized tetrahydropyridines.

Keywords 1,4-Dihydropyridines; enamine; iminium ion reactions; radical cyclizations

Received April 26, 2011.

Address correspondence to Rakesh Kumar, Department of Chemistry, Kirori Mal College,

University of Delhi, Delhi 110 007, India. E-mail: rakeshkp@email.com

Synthetic Communications1, 43: 520–536, 2013

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397911.2011.603877

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INTRODUCTION

The widespread occurrence and different biological activities associated withnitrogen heterocyclic compounds have made them important targets for syntheticchemists.[1,2] The condensed derivatives of pyridines, especially in the form offuro[2,3-b]pyridines, which are structurally analogous to indoles and quinolines,[3]

play significant roles as bioactive molecules.[4] The furo[2,3-b]pyridine ring systemhas been claimed as antifungal, antibacterial, and potent herbicidal agents and asintegral components of cephalosporin and backbone of alkaloids isolated fromplants belonging to the Rutaceae family.[5–7]

The furopyridine derivative, cicletanine, is an antihypertensive drug with avasorelaxant effect and also has diuretic property.[8] In addition, the furopyridinemoiety has emerged as a useful pharmacophore in several therapeutic agents usedfor the treatment of skin disease and relief of intraocular pressure.[9] The develop-ment of new strategies that allow the synthesis of such nitrogen heterocycles is there-fore of great interest. Recent work from our laboratory has explored the use ofN-alkyl-1,4-dihydropyridines[10,11] 1 as versatile precursors for the formation offunctionalized tetrahydropyridines.[12–14] The precursor N-alkyl-1,4-dihydropyridine1 was prepared by sodium dithionite reduction of the corresponding pyridiniumsalt.[15] In this article we report stereocontrolled oxidative additions upon 1,4-dihydropyridines, leading to the formation of trans-2-alkoxy-3-halosubstitutedtetrahydropyridine 2, which undergoes radical cyclization, affording hexahydro-furo[2,3-b]pyridine and hexahydropyrano[2,3-b]pyridine derivatives 3. The cyclizedproduct 3a undergoes iminium ion reactions, such as addition of allyltributylsilanein the presence of BF3 �OEt2 to give functionalized tetrahydropyridine 4a.

RESULTS AND DISCUSSION

The nucleophilic character of the enamine moiety present in the 1,4-dihydro-pyridines of type 1 presents numerous synthetic opportunities. The most versatileapplication of such derivatives would be the simultaneous addition of an electrophileand a nucleophile to the enaminic double bond (Scheme 1). This process results inthe functionalization of the a- and b-positions of these substrates via the electrophilicaddition step to the more electron-rich b-position, triggering the subsequent additionof the nucleophile at the a-position.[16]

Treatment of starting1,4-dihydropyridines with alcohols (propargyl alcohol,2-butyn-1-ol, and 3-butyn-1-ol) in the presence of N-halosuccinimide (NXS)

Scheme 1. Reaction of N-alkyl-1,4-dihydropyridines 1 with an electrophile and a nucleophile.

REACTIONS OF 1,4-DIHYDROPYRIDINES 521

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afforded the trans-2-alkoxy-3-halosubstituted tetrahydropyridines 2 (Scheme 2,Table 1). The high levels of trans diastereoselectivity arises because the intermediateiodonium ion undergoes anti nucleophilic attack at the a-position.[17] The transfor-mations readily occur at 0 �C, and no side reaction was observed. The stereochem-istry of the product was ascertained by NMR methods (including homo- andhetero-correlation techniques). The small H2-H3 coupling constant (J¼ 1.0–2.28Hz) observed suggests a trans relationship between alkoxy group at C-2 andX-group at C-3 and a major conformation in which these substituents are axial.

Intramolecular radical cyclizations constitute a well-established strategy for theconstruction of five- and six-membered rings. Free-radical cyclization methods con-stitute one of the most powerful and versatile methods for the construction of cyclicsystems and have found extensive application in the synthesis of carbocycles and het-erocycles.[18] Radical cyclization reactions of trans-a-alkoxy-b-halotetrahydropyri-dines 2 using a sodium cyanoborohydride and catalytic tributylstannane systemafforded the bicyclic compounds 3 (Scheme 3 and Table 1).[19] The yields were mod-erate to good, except for the six-membered ring closures where the direct reductionpathway was strongly competitive (Table 1, entries 6, 9, and 10). The cyclizationswere highly regiospecific and stereospecific, with only the cis-fused products beingobtained. The cis-fused product was evident from the coupling constant of the vic-inal hydrogen atoms (J¼ 5.04–5.48Hz). The benzyl group at the nitrogen is axial,probably to relive steric congestion. The stereochemical assignments of compounds2a and 3a were based on the coupling constants in the 1H NMR spectra and by het-eronuclear correlation (HETCOR) and nuclear Overhauser effect spectroscopy(NOESY) experiments.

N-Acyliminium ion reactions have attracted considerable interest because theyare very useful in synthesis of nitrogen-containing heterocycles.[20] It is well knownthat a-alkoxyamines can promote the formation of iminium ions in the presenceof Lewis acids and, in this way, allow the introduction of substituent at the nitrogena-position through nucleophilic addition. More importantly these bicyclic com-pounds 3 can be utilized as iminium ion precursors in C–C bond-formingreactions.[21,22] For example, 7-benzyl-3-methylene-2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyridine-5-carbonitrile 3a is converted into 2-allyl-1-benzyl-3-(3-hydroxyprop-1-en-2-yl)-1,2,3,4-tetrahydropyridine-5-carbonitrile 4a on treatment with allyltribu-tylsilane in presence of BF3 �OEt2 (Scheme 4). The major diastereomer is thetrans-isomer,[23] as determined by NMR methods (coupling constant, HETCOR,

Scheme 2. Haloetherification of N-alkyl-1,4-dihydropyridines 1.

522 R. KUMAR, D. KUMAR, AND A. K. PRASAD

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Table

1.Structuresof1,4-dihyd

ropyridines

1,tetrahydropyridines

2,andhexahydrofuro[2,3-b]pyridineandhexahydropyrano[2,3-b]pyridinecompounds3

Entry

Dihydropyridine1

Alcohol=NXS

Tetrahydropyridine2

Yield

(%)a

Bicyclic

compound3

Yield

(%)a

1Propargylalcohol=NIS

82

80

2Propargylalcohol=NIS

74

62

3Propargylalcohol=NIS

62

58

4Propargylalcohol=NIS

53

52

52-Butyn-1-ol=NIS

57

75b

(Continued

)

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Table

1.Continued

Entry

Dihydropyridine1

Alcohol=NXS

Tetrahydropyridine2

Yield

(%)a

Bicyclic

compound3

Yield

(%)a

63-Butyn-1-ol=NIS

50

43c

72-Butyn-1-ol=NIS

58

71b

82-Butyn-1-ol=NIS

45

60b

93-Butyn-1-ol=NIS

57

48d

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10

3-Butyn-1-ol=NIS

55

46e

11

Propargylalcohol=NBS

60

70

12

Propargylalcohol=NBS

58

65

13

Propargylalcohol=NBS

57

55

14

Propargylalcohol=NCS

55

15

Propargylalcohol=NCS

53

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and NOESY experiments). The approach of nucleophile is from the less-hinderedface and dependent upon the size of the group present on C(3) in the intermediateiminium ion, 5. The assignment of the stereochemistry of 4a was based on the vicinalcoupling constant (Jvic) between H-C(2) and H-C(3). It was earlier concluded thatthe trans coupling is usually 0–1Hz, while for the corresponding cis-substitutedcompounds, Jvic, is �5Hz.[23]

CONCLUSION

In conclusion, we have demonstrated that bicyclic tetrahydropyridine 3 can beobtained by radical cyclization of trans-a-alkoxy-b-halotetrahydropyridines 2 usingsodium cyanoborohydride and catalytic tributylstannane protocols. The radical pre-cursors 2 are readily prepared by N-halosuccinimide-promoted haloetherification of1,4-dihydropydidines 1 (nonbiomemitic oxidation). The bicyclic adducts 3 are usefulprecursors for further transformations to form highly functionalized tetrahydor-pyridines. These results present interesting possibilities in the study of the chemicalreactivity of dihydropyridines, a class of compounds with a significant role in bio-chemistry and in natural product synthesis (e.g., alkaloids and azasugars).

Scheme 4. Ring-opening reaction of compound 3a, by allyltributylsilane in the presence of Lewis acid,

BF3 �OEt2.

Scheme 3. Free-radical cyclization of trans-a-alkoxy-b-halotetrahydropyrinines 2 to bicyclic compounds 3.

526 R. KUMAR, D. KUMAR, AND A. K. PRASAD

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EXPERIMENTAL

All reagents were of commercial grade and used as received. Solvents weredried and purified using standard techniques. 1H NMR (400MHz) and 13C NMR(100.5MHz) were recorded in CDCl3 on JNM ECX- 400P (Jeol, USA) spectrometerusing tetramethylsilane (TMS) as an internal standard. Chemical shifts are reportedin parts per million (ppm). Mass spectra were recorded on KC ESI 455-TOF massspectrometer. Infrared (IR) spectra were recorded on a Perkin-Elmer Fourier trans-form (FT)–IR spectrometer, with all compounds examined as films on a NaCl disk.Elemental analysis was performed with an Elementar Vario EL analyzer. These reac-tions were monitored by thin-layer chromatography (TLC), on aluminum platescoated with silica gel 60F254 (Merck). Ultraviolet (UV) radiation and iodine wereused as the visualizing agents. Column chromatography was performed on silicagel (100–200 mesh). All reactions were carried out under a nitrogen atmosphere.

Haloetherfication of Dihydropyridines 1 with Alkynols to PrepareCompounds 2a–2o

A solution of N-halosuccinimide (1.2 equiv.) and the alcohol (1.2 equiv.) in drydichloromethane (5ml) under nitrogen atmosphere was cooled to 0 �C. Startingdihydropyridine 1 (1.0 equiv.) in dry dichloromethane (3ml) was added dropwise,and the resulting mixture was stirred for 10min and then poured into a cold satu-rated aqueous solution of NaHCO3 (100ml). The mixture was extracted twice withdichloromethane (2� 50ml). The combined organic phase was dried over Na2SO4,and the solvent was removed in vacuo to yield the halo ether derivative, whichwas purified by column chromatography (SiO2, EtOAC=hexane) to afford purecompounds (2a–2o).

trans-1-Benzyl-3-iodo-2-(prop-2-ynyloxy)-1,2,3,4-tetrahydropyridine-5-carbonitrile (2a, Table 1, Entry 1). Compound 2a was obtained by the reaction ofN-iodosuccinimide and propargyl alcohol with dihydropyridine 1a as a colorless oil;Rf¼ 0.38 (20% EtOAc=80% hexane); IR (film): t 3287, 2920, 2194, 1633, 1423, 1371,1040, 991, 934 and 701 cm�1; 1H NMR (400MHz, CDCl3): d 7.36–7.34 (m, 5H, -Ph),6.76 (d, J¼ 1.6Hz, 1H, -NCH), 4.70 (s, d, J¼ 0.96Hz, 1H, -NCHO), 4.45–4.33 (m,3H, -CH2Ph and -CHI), 4.21–4.19 (m, 2H, -OCH2), 2.97–2.91 (m, 1H, -CH2), 2.51 (t,J¼ 2.24Hz, 1H, -C�CH) and 2.44–2.39 (m, 1H, -CH2);

13C NMR (100.5MHz,CDCl3): d 143.69 C(6), 135.0 C(ipso-ph), 128.81 C(m-ph), 128.72 C(o-ph), 128.42C(p-ph), 121.5 C(CN) 86.86 C(2), 78.66 C(�C), 75.91 C(HC�), 75.38 C(5), 57.67C(NCH2Ph), 55.48 C(OCH2), 27.86C(4) and 17.79C(3); MS (ESI): m=z¼ [MþH]þ

379.1. Anal. calcd. for C16H15IN2O: C, 50.81; H, 4.00; N, 7.41. Found: C, 50.80; H,3.98; N, 7.43.

trans-3-Iodo-1-methyl-2-(prop-2-ynyloxy)-1,2,3,4-tetrahydropyridine-5-carbonitrile (2b, Table 1, Entry 2). Compound 2b was obtained by the reaction ofN-iodosuccinimide and propargyl alcohol with dihydropyridine 1b as a colorless oil;Rf¼ 0.41 (20% EtOAc=80% hexane); IR (film): t 3285, 3058, 2920, 2191, 1633, 1351,1043 and 991 cm�1; 1H NMR (400MHz, CDCl3): d 6.70 (s, 1H, -NCH), 4.76 (s, 1H,-NCHO), 4.38 (s, 1H, -CHI), 4.26–4.24 (m, 2H, -OCH2), 3.12 (s, 3H, -NCH3),

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2.88–2.83 (m, 1H, -CH2), 2.54 (s, 1H, -C�CH) and 2.40 (d, J¼ 17.4Hz, 1H,-CH2);

13C NMR (100.5MHz, CDCl3): d 145.0 C(6), 121.4 C(CN), 89.44 C(2),87.66 C(�C), 78.51 C(HC�), 75.87 C(5), 55.21 C(OCH2), 42.58 C(NCH3), 27.48C(4) and 17.85 C(3); MS (ESI): m=z¼ [MþH]þ 303.4. Anal. calcd. for C10H11IN2O:C, 39.76; H, 3.67; N, 9.27. Found: C, 39.69; H, 3.66; N, 9.22.

Methyl trans-3-iodo-1-methyl-2-(prop-2-ynyloxy)-1,2,3,4-tetrahydro-pyridine-5-carboxylate (2c, Table 1, Entry 3). Compound 2c was obtained bythe reaction of N-iodosuccinimide and propargyl alcohol with dihydropyridine 1c

as a colorless oil; Rf¼ 0.40 (20% EtOAc=80% hexane); IR (film): t 3286, 2948,2922, 2856, 1681, 1633, 1440, 1296, 1176, 766 and 753 cm�1; 1H NMR (400MHz,CDCl3): d 7.25 (s, 1H, -NCH), 4.75 (d, J¼ 1.4Hz, 1H, -NCHO), 4.45 (d, J¼ 2.08Hz, 1H, -CHI), 4.23–4.22 (m, 2H, -OCH2), 3.67 (s, 3H, -OCH3), 3.13 (s, 3H,-NCH3), 3.11–3.08 (m, 1H, -CH2), 2.71–2.63 (m, 1H, -CH2) and 2.51 (t, J¼ 2.28Hz, 1H, -C�CH); 13C NMR (100.5MHz, CDCl3): d 168.10 C(C=O), 142.23 C(6),95.76 C(5), 88.29 C(2), 77.31 C(�C), 75.50 C(HC�), 54.96 C(OCH2), 50.95C(OCH3), 42.47 C(NCH3), 25.84 C(4) and 20.64 C(3); MS (ESI): m=z¼ [MþH]þ

336.09. Anal. calcd. for C11H14INO3: C, 39.42; H, 4.21; N, 4.18. Found: C, 39.35;H, 3.97; N, 4.15.

Methyl trans-1-benzyl-3-iodo-2-(prop-2-ynyloxy)-1,2,3,4-tetrahydropyr-idine-5-carboxylate (2d, Table 1, Entry 4). Compound 2d was obtained by thereaction of N-iodosuccinimide and propargyl alcohol with dihydropyridine 1d, asa colorless oil; Rf¼ 0.35 (20% EtOAc=80% hexane); IR (film): t 3030, 2949, 2927,1683, 1633, 1298, 1186, 1109, 1043, 934 and 699 cm�1; 1H NMR (400MHz, CDCl3):d 7.35–7.31 (m, 6H, -Ph and -NCH), 4.66 (d, J¼ 2.28Hz, 1H, -NCHO), 4.50–4.34(m, 3H, -CHI and -CH2Ph), 4.11–4.09 (m, 2H, -OCH2), 3.65 (s, 3H, -OCH3),2.77–2.76 (m, 2H, -CH2) and 2.48 (t, J¼ 2.28Hz, 1H, -C�CH); 13C NMR(100.5MHz, CDCl3): d 168.82 C(C=O), 141.92 C(6), 135.98 C(ipso-ph), 128.80C(m-ph), 128.28 C(o-ph), 96.27 C(5), 87.36 C(2), 79.49 C(�C), 75.73 C(HC�),57.70 C(NCH2Ph), 55.49 C(OCH2), 51.13 C(OCH), 26.32 C(4) and 20.47 C(3);MS (ESI): m=z¼ [MþH]þ 412.5. Anal. calcd. for C17H18INO3: C, 49.65; H, 4.41;N, 3.41. Found: C, 49.62; H, 4.40; N, 3.43.

trans-1-Benzyl-2-(but-2-ynyloxy)-3-iodo-1,2,3,4-tetrahydropyridine-5-carbonitrile (2e, Table 1, Entry 5). Compound 2e was obtained by the reaction ofN-iodosuccinimide and 2-butyn-1-ol with dihydropyridine 1a, as a colorless oil;Rf¼ 0.44 (20% EtOAc=80% hexane); IR (film): t 3062, 3030, 2918, 2854, 2195,1631, 1369, 1138, 1021 and 701 cm�1; 1H NMR (400MHz, CDCl3): d 7.39–7.33(m, 5H, Ph), 6.77 (d, J¼ 1.8Hz, 1H, -NCH), 4.71 (d, J¼ 1.16Hz, 1H, -NCHO),4.48–4.34 (m, 3H, -CH2Ph and -CHI), 4.14–4.13 (m, 2H, -OCH2), 3.0–2.93 (m,1H, -CH2), 2.46–2.41 (m, 1H, -CH2) and 1.85 (t, J¼ 2.28Hz, 3H, -C�C-CH3);

13CNMR (100.5MHz, CDCl3): d 143.82 C(6), 135.16 C(ipso-ph), 128.75 C(m-ph),128.69 C(o-ph), 128.34 C(p-ph), 121.42 C(CN), 86.32 C(2), 84.08 C(�C), 75.11C(CH3-C�), 74.09 C(5), 57.53 C(NCH2Ph), 56.12 C(OCH2), 27.92C(4), 18.18 C(3)and 3.59 C(CH3); MS (ESI): m=z¼ [MþH]þ 393.1. Anal. calcd. for C17H17IN2O:C, 52.06; H, 4.37; N, 7.14. Found: C, 52.1; H, 4.35; N, 7.12.

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trans-1-Benzyl-2-(but-3-ynyloxy)-3-iodo-1,2,3,4-tetrahydropyridine-5-carbonitrile (2f, Table 1, Entry 6). Compound 2f was obtained by the reaction ofN-iodosuccinimide and 3-butyn-1-ol with dihydropyridine 1a, as a colorless oil;Rf¼ 0.47 (20% EtOAc=80% hexane); IR (film): t 2920, 2850, 2194, 1715, 1628,1456, 1215 and 758 cm�1; 1H NMR (400MHz, CDCl3): d 7.37–7.35 (m, 5H, Ph),6.79 (d, J¼ 1.16Hz, 1H, -NCH), 4.49–4.33 (m, 4H, -NCHO, -CHI and -CH2Ph),3.60–3.50 (m, 2H, -OCH2), 3.19–2.96 (m, 1H, -CH2), 2.45–2.39 (m, 3H,-C�C-CH2

and -CH2) and 2.01 (t, J¼ 2.76Hz, 1H, -C�CH); 13C NMR (100.5MHz, CDCl3):d 143.87 C(6), 135.03 C(ipso-ph), 128.83 C(m-ph), 128.67 C(o-ph), 128.44 C(p-ph),121.39 C(CN), 86.06 C(2), 80.71 C(�C), 75.22 C(5), 69.98 C(HC�), 66.68C(OCH2), 57.75 C(NCH2Ph), 27.91 C(4), 20.22 C(�C-CH2) and 18.22 C(3); MS(ESI): m=z¼ [MþH]þ 393.2. Anal. calcd. for C17H17IN2O: C, 52.06; H, 4.37; N,7.14. Found: C, 52.15; H, 4.36; N, 7.11.

trans-2-(But-2-ynyloxy)-3-iodo-1-methyl-1,2,3,4-tetrahydropyridine-5-carbonitrile (2g, Table 1, Entry 7). Compound 2g was obtained by the reaction ofN-iodosuccinimide and 2-butyn-1-ol with dihydropyridine 1b, as a colorless oil;Rf¼ 0.42 (20% EtOAc=80% hexane); IR (film): t 2954, 2921, 2856, 2297, 2193,1633, 1407, 1346, 1197, 1149, 1019 and 926 cm�1; 1 H NMR (400MHz, CDCl3): d6.66 (d, J¼ 1.36Hz, 1H, -NCH), 4.69 (s, 1H, -NCHO), 4.34–4.32 (m, 1H, -CHI),4.18–4.15 (m, 2H, -OCH2), 3.07 (s, 3H, -NCH3), 2.83–2.78 (m, 1H, -CH2),2.37–2.32 (m, 1H, -CH2) and 2.84 (t, J¼ 2.28Hz, 1H, -C�C-CH3);

13C NMR(100.5MHz, CDCl3): d 144.24 C(6), 121.39 C(CN), 87.34 C(2), 83.92 C(�C),74.77 C(5), 73.87 C(CH3-C�), 55.84 C(OCH2), 42.38 C(NCH3), 27.58 C(4), 18.44C(3) and 3.52 C(CH3); MS (ESI): m=z¼ [MþH]þ 317.3. Anal. calcd. forC11H13IN2O: C, 41.79; H, 4.14; N, 8.86. Found: C, 41.75; H, 4.15; N, 8.81.

Methyl trans-2-(but-2-ynyloxy)-3-iodo-1-methyl-1,2,3,4-tetrahydropyri-dine-5-carboxylate (2h, Table 1, Entry 8). Compound 2h was obtained by thereaction of N-iodosuccinimide and 2-butyn-1-ol with dihydropyridine 1c, as a color-less oil; Rf¼ 0.45 (20% EtOAc=80% hexane); IR: (film) t 2921, 2223, 1676, 1633,1440, 1294, 1176, 1020, 931 and 752 cm�1; 1H NMR (400MHz, CDCl3): d 7.24 (s,1H, -NCH), 4.73 (s, 1H, -NCHO), 4.45�4.44 (m, 1H, -CHI), 4.25–4.18 (m, 2H,-OCH2), 3.67 (s, 3H, -OCH3), 3.12 (s, 3H, -NCH3), 2.71–2.67 (m, 2H, -CH2) and1.86 (s, 3H, -C�C-CH3);

13C NMR (100.5MHz, CDCl3): d 168.10 C(C=O),142.35 C(6), 95.41 C(5), 88.02 C(2), 83.60 C(�C), 74.20 C(HC�), 55.68 C(OCH2),50.85 C(OCH3), 42.36 C(NCH3), 25.86 C(4), 21.15 C(3) and 3.56 C(CH3); MS(ESI): m=z¼ [MþH]þ 350.0; Anal. calcd. for C12H16INO3: C, 41.28; H, 4.62; N,4.01. Found: C, 41.26; H, 4.57; N, 3.08.

trans-2-(But-3-ynyloxy)-3-iodo-1-methyl-1,2,3,4-tetrahydropyridine-5-carbonitrile (2i, Table 1, Entry 9). Compound 2i was obtained by the reaction ofN-iodosuccinimide and 3-butyn-1-ol with dihydropyridine 1b, as a colorless oil;Rf¼ 0.43 (20% EtOAc=80% hexane); IR (film): t 2918, 2850, 2189, 1632, 1343 and1058 cm�1; 1H NMR (400MHz, CDCl3): d 6.65 (s, 1H, -NCH), 4.33–4.29 (m, 2H,-NCHO and -CHI), 3.36–3.35 (m, 2H, -OCH2), 3.03 (s, 3H, -NCH3), 2.98–2.96(m, 1H, -CH2), 2.83–2.73 (m, 2H, -CH2 and -CH2-C�C) and 2.39–2.27 (m, 2H,-C�CH and -CH2-C�C); 13C NMR (100.5MHz, CDCl3): d 144.13 C(6), 121.32

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C(CN), 90.41 C(2), 89.34 C(�C), 73.93 C(5), 69.75 C(HC�), 55.84 C(OCH2), 42.58C(NCH3), 27.22 C(4), 19.93 C(�C-CH2) and 18.10C(3); MS (ESI): m=z¼ [MþH]þ

317.3. Anal. calcd. for C11H13IN2O: C, 41.79; H, 4.14; N, 8.86. Found: C, 41.85; H,4.13; N, 8.81.

Methyl trans-2-(but-3-ynyloxy)-3-iodo-1-methyl-1,2,3,4-tetrahydropyri-dine-5-carboxylate (2j, Table 1, Entry 10). Compound 2j was obtained by thereaction of N-iodosuccinimide and 3-butyn-1-ol with dihydropyridine 1c, as a color-less oil; Rf¼ 0.31 (20% EtOAc=80% hexane); IR (film) t 2918, 2850, 1736, 1676,1629, 1298 cm�1; 1H NMR (400MHz, CDCl3): d 7.24 (s, 1H, -NCH), 4.55 (d,J¼ 2.2Hz, 1H, -NCHO), 4.46–4.43 (m, 1H, -CHI), 3.69–3.63 (m, 5H, -OCH2 and-OCH3), 3.11 (s, 3H, -NCH3), 2.76–2.65 (m, 2H, -CH2), 2.46–2.42 (m, 2H, -CH2-C�C) and 2.0 (t, J¼ 2.96Hz, 1H, HC�C); 13C NMR (100.5MHz, CDCl3): d168.23 C(C=O), 142.64 C(6), 95.30 C(5), 90.50 C(2), 80.84 C(�C), 69.80 C(HC�),66.54 C(OCH2), 51.17 C(OCH3), 42.33 C(NCH3), 25.85 C(4), 21.22 C(�C-CH2)and 20.34 C(3); MS (ESI): m=z¼ [MþH]þ 350.2. Anal. calcd. for C12H16INO3: C,41.28; H, 4.62; N, 4.01. Found: C, 41.12; H, 4.53; N, 3.94.

trans-1-Benzyl-3-bromo-2-(prop-2-ynyloxy)-1,2,3,4-tetrahydropyridine-5-carbonitrile (2k, Table 1, Entry 11). Compound 2k was obtained by the reactionof N-bromosuccinimide and propargyl alcohol with dihydropyridine 1a, as a color-less oil; Rf¼ 0.39 (20% EtOAc=80% hexane); IR: (film) t 2924, 2194, 1631, 1420,1369, 1045 and 70 cm�1; 1H NMR (400MHz, CDCl3): d 7.33–7.25 (m, 5H, Ph),6.71 (s, 1H, -NCH), 4.62 (br s, 1H, -NCH-O), 4.43–4.31 (m, 2H, -CH2Ph),4.24–4.22 (m, 1H, -CHBr), 4.15–4.04 (m, 2H, -OCH2), 2.94–2.88 (m, 1H, -CH2),2.45 (t, J¼ 2.4Hz, 1H, -C�CH) and 2.43–2.38 (m, 1H, -CH2);

13C NMR(100.5MHz, CDCl3): d 143.62 C(6), 135.35 C(ipso-ph), 129.16 C(m-ph), 128.86C(o-ph), 128.48 C(p-ph), 121.29 C(CN) 85.55 C(2), 77.32 C(�C), 76.01 C(HC�),74.91 C(5), 57.76 C(NCH2Ph), 55.67 C(OCH2), 40.31 C(3) and 26.74 C(4); MS(ESI): m=z¼ [MþH]þ 332.1. Anal. calcd. for C16H15BrN2O: C, 58.02; H, 4.56; N,8.46. Found: C, 58.11; H, 4.55; N, 8.45.

trans-3-Bromo-1-methyl-2-(prop-2-yn-1-yloxy)-1,2,3,4-tetrahydropyri-dine-5-carbonitrile (2l, Table 1, Entry 12). Compound 2l was obtained by thereaction of N-bromosuccinimide and propargyl alcohol with dihydropyridine 1b,as a colorless oil; Rf¼ 0.33 (20% EtOAc=80% hexane); IR (film): t 3247, 2193,1633, 1359, 1037, 937 and 673 cm�1; 1H NMR (400MHz, CDCl3): d 6.7 (s, 1H,-NCH), 4.68 (d, J¼ 1.36Hz, 1H, -NCHO), 4.27–4.23 (m, 3H, -CHBr and -OCH2),3.13 (s, 3H, -NCH3), 2.92–2.85 (m, 1H, CH2), 2.53 (t, J¼ 2.92Hz, 1H, -C�CH)and 2.45–2.41 (m, 1H, -CH2);

13C NMR (100.5MHz, CDCl3): d 144.23 C(6),121.3 C(CN), 86.24 C(2), 78.37 C(�C), 75.88 C(HC�), 74.64 C(5), 55.24C(OCH2), 42.51 C(NCH3), 40.44 C(3) and 26.40 C(4); MS (ESI): m=z¼ [MþH]þ

256.5. Anal. calcd. for C10H11BrN2O: C, 47.08; H, 4.35; N, 10.98. Found: C,47.05; H, 4.33; N, 10.95.

Methyl trans-3-bromo-1-methyl-2-(prop-2-yn-1-yloxy)-1,2,3,4-tetrahy-dropyridine-5-carboxylate (2m, Table 1, Entry 13). Compound 2m wasobtained by the reaction of N-bromosuccinimide and propargyl alcohol with dihy-dropyridine 1c, as a colorless oil; Rf¼ 0.48 (20% EtOAc=80% hexane); IR (film): t

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2949, 2925, 1683, 1633, 1302, 1186, 1059 and 757 cm�1; 1H NMR (400MHz,CDCl3): d 7.17 (s, 1H, -NCH), 4.81 (s, 1H, -NCHO), 4.51–4.33 (m, 3H, -OCH2

and -CHBr), 3.66 (s, 3H, -OCH3), 3.17 (s, 3H, -NCH3), 3.14 (br s, 2H, -CH2) and2.56 (t, J¼ 2.96Hz, 1H, -C�CH); 13C NMR (100.5MHz, CDCl3): d 167.09C(C=O), 141.6 C(6), 94.02 C(5), 90.43 C(2), 78.32 C(�C), 76.21 C(HC�), 57.4C(OCH2), 51.09 C(OCH3), 42.18 C(NCH3), 38.91 C(3) and 29.65 C(4); MS (ESI):m=z¼ [MþH]þ 289.1. Anal. calcd. for C11H14BrNO3: C, 45.85; H, 4.90; N, 4.86.Found: C, 45.88; H, 4.91; N, 4.88.

trans-3-Chloro-1-methyl-2-(prop-2-yn-1-yloxy)-1,2,3,4-tetrahydropyri-dine-5-carbonitrile (2n, Table 1, Entry 14). Compound 2n was obtained by thereaction of N-chlorosuccinimide and propargyl alcohol with dihydropyridine 1b, as acolorless oil; Rf¼ 0.46 (20% EtOAc=80% hexane); IR (film): t 3253, 2920, 2193,1634, 1358, 1105, 1039, 939, 704 and 679 cm�1; 1H NMR (400MHz, CDCl3): d6.7 (s, 1H, -NCH), 4.61 (d, J¼ 2.92Hz, 1H, -NCHO), 4.247–4.19 (m, 3H, -OCH2

and -CHCl), 3.14 (s, 3H, -NCH3), 2.76–2.71 (m, 1H, -CH2), 2.52 (t, J¼ 2.2Hz,1H, -C�CH) and 2.38–2.33 (m, 1H, -CH2);

13C NMR (100.5MHz, CDCl3): d144.26 C(6), 121.32 C(CN), 85.97 C(2), 78.32 C(�C), 75.85 C(HC�), 74.42 C(5),55.21 C(OCH2), 49.48 C(NCH3), 42.48 C(3) and 26.08 C(4); MS (ESI): m=z¼[MþH]þ 212.2. Anal. calcd. for C10H11ClN2O: C, 57.01; H, 5.26; N, 13.3. Found:C, 56.95; H, 5.28; N, 13.1.

trans-1-Benzyl-3-chloro-2-(prop-2-ynyloxy)-1,2,3,4-tetrahydropyridine-5-carbonitrile (2o, Table 1, Entry 15). Compound 2o was obtained by the reac-tion of N-chlorosuccinimide and propargyl alcohol with dihydropyridine 1a, as acolorless oil; Rf¼ 0.36 (20% EtOAc=80% hexane); IR (film): t 2917, 2194, 1708,1631, 1420, 1370 and 1048 cm�1; 1H NMR (400MHz, CDCl3): d 7.37–7.29 (m,5H, Ph), 6.77 (s, 1H, -NCH), 4.62 (br s, 1H, -NCH-O), 4.50–4.37 (m, 2H, -CH2Ph),4.31–4.21 (m, 2H, -CHCl), 4.17–4.10 (m, 2H, -OCH2), 2.85–2.79 (m, 1H, -CH2), 2.51(t, J¼ 2.72Hz, 1H, -C�CH) and 2.41–2.36 (m, 1H, -CH2);

13C NMR (100.5MHz,CDCl3): d 143.75 C(6), 135.58 C(ipso-ph), 128.74 C(m-ph), 128.42 C(o-ph), 128.18C(p-ph), 121.31 C(CN) 85.26 C(2), 77.32 C(�C), 76.15 C(HC�), 74.71 C(5), 57.82C(NCH2Ph), 55.63 C(OCH2), 49.52 C(3) and 26.47 C(4); MS (ESI): m=z¼ [MþH]þ

288.5. Anal. calcd. for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found: C, 67.11;H, 5.25; N, 9.72.

Radical Cyclizations to Prepare Bicyclic Compounds 3a–3j

Iodo- or bromoether derivative 2 (1.0 equiv.) in dry t-BuOH (3ml) was addeddropwise to a stirred mixture of NaCNBH3 (1.2 equiv.), Bu3SnH (0.05 equiv.), andAIBN (1.0 equiv.) in dry t-BuOH (10ml) under a nitrogen atmosphere at 80 �C.After refluxing for 1 h, the mixture was cooled to rt. Three portions of benzene(3� 15ml) were added, and the azeotropic mixture was removed under reducedpressure. The residue was taken up in dichloromethane (50ml) and filtered throughcelite. The solvent was removed in vacuo to yield the bicyclic derivative, which waspurified by column chromatography (SiO2, EtOAC=hexane) to afford pure com-pounds (3a–3j).

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7-Benzyl-3-methylene-2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyridine-5-carbonitrile (3a, Table 1, Entry 1). Compound 3a was obtained by cyclization ofcompound 2a, as a colorless oil; Rf¼ 0.51 (20% EtOAc=80% hexane); IR (film): t3031, 2926, 2866, 2190, 1633, 1495, 1421, 1375, 1054, 1027, 899 and 700 cm�1; 1HNMR (400MHz, CDCl3): d 7.34–7.19 (m, 5H, Ph), 6.79 (s, 1H, -NCH), 5.02 (brs, 2H, -CH2¼C), 4.84 (d, J¼ 5.04Hz, 1H, -NCHO), 4.42–4.20 (m, 4H, -CH2Phand -OCH2), 2.82–2.81 (m, 1H, -CH-C=C), 2.52–2.47 (m, 1H, -CH2) and 2.23(dd, J¼ 16.56, 8.48Hz, 1H, -CH2);

13C NMR (100.5MHz, CDCl3): d 146.82 C(3),146.06 C(6), 136.29 C(ipso-ph), 129.01 C(m-ph), 128.13 C(o-ph), 127.97 C(p-ph),122.38 C(CN), 105.58 C(CH2¼), 85.26 C(7a), 73.75 C(5), 68.53 C(2), 54.78C(NCH2Ph), 40.41 C(3a) and 22.60 C(4); MS (ESI): m=z¼ [MþH]þ 253.3. Anal.calcd. for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C, 77.15; H, 6.40; N,11.13. DEPT (400MHz, CDCl3): d 146.06(þ), 129.01(þ), 128.13(þ), 127.97(þ),105.58(�), 85.26(þ), 68.53(�), 54.78(�), 40.41(þ), 22.60(�).

7-Methyl-3-methylene-2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyridine-5-carbonitrile (3b, Table 1, Entry 2). Compound 3b was obtained by cyclization ofcompound 2b, as a colorless oil; Rf¼ 0.55 (20% EtOAc=80% hexane); IR (film): t3008, 2922, 2853, 2188, 1637, 1335, 1054, 1022 and 750 cm�1; 1H NMR(400MHz, CDCl3): d 6.64 (s, 1H, -NCH), 5.03 (br s, 2H, -CH2¼C), 4.81 (d,J¼ 5.04Hz, 1H, -NCHO), 4.37–4.35 (m, 2H, -OCH2), 2.92 (s, 3H, -NCH3),2.84–2.82 (m, 1H, -CH-C¼), 2.53–2.47 (m, 1H, -CH2) and 2.26–2.16 (m, 1H,-CH2);

13C NMR (100.5MHz, CDCl3): d 146.66 C(3), 146.55 C(6), 122.34 C(CN),105.47 C(CH2¼), 86.95 C(7a), 72.87 C(5), 68.30 C(2), 40.37 C(3a), 38.57C(NCH3) and 23.06 C(4); MS (ESI): m=z¼ [MþH]þ 177.1. Anal. calcd. forC10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C, 68.14; H, 6.85; N, 15.92.

Methyl 7-methyl-3-methylene-2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyri-dine-5-carboxylate (3c, Table 1, Entry 3). Compound 3c was obtained by cycliza-tion of compound 2c, as a colorless oil; Rf¼ 0.52 (20% EtOAc=80% hexane); IR(film): t 3078, 2947, 2918, 2852, 1682, 1633, 1269, 1186, 1171, 1054, 967 and763 cm�1; 1H NMR (400MHz, CDCl3): d 7.20 (s, 1H, -NCH), 4.97–4.94 (m, 2H,-CH2¼C), 4.82 (d, J¼ 5.48Hz, 1H, -NCH-O),4.38–4.28 (m, 2H, -OCH2), 3.63 (s,3H, -OCH3), 2.92 (s, 3H, -NCH3), 2.85–2.82 (m, 1H, -CH-C=C), 2.52 (dd,J¼ 16.28, 6.44Hz, 1H, -CH2) and 2.35 (dd, J¼ 16.52, 5.48Hz, 1H, -CH2);

13CNMR (100.5MHz, CDCl3): d 168.5 C(C=O), 147.56 C(3), 145.23 C(6), 104.76C(CH2¼), 93.69 C(5), 87.68 C(7a), 68.43 C(2), 50.76C(OCH3), 40.99 C(3a), 38.50C(NCH3) and 20.64 C(4); MS (ESI): m=z¼ [MþH]þ 210.3. Anal. calcd. forC11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.13; H, 7.25; N, 6.65.

Methyl 7-benzyl-3-methylene-2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyri-dine-5-carboxylate (3d, Table 1, Entry 4). Compound 3d was obtained by cycli-zation of compound 2d, as a colorless oil; Rf¼ 0.49 (20% EtOAc=80% hexane); IR(film): t 3063, 3029, 2947, 2850, 1682, 1627, 1180, 1154, 964 and 699 cm�1; 1HNMR (400MHz, CDCl3): d 7.29–7.16 (m, 6H, Ph and -NCH), 4.94–4.90 (m, 2H,-CH2¼C), 4.85 (d, J¼ 5.04Hz, 1H, -NCHO), 4.43–4.18 (m, 4H, -CH2Ph and-OCH2), 3.61 (s, 3H, -OCH3), 2.78–2.77 (m, 1H, -CH-C=C), 2.50 (dd, J¼ 16.72,6.4Hz, 1H, -CH2), 2.36 (dd, J¼ 16.72, 5.48Hz, 1H, -CH2);

13C NMR

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(100.5MHz, CDCl3): d 169.12 C(C=O), 147.65 C(3), 144.47 C(6), 136.83 C(ipso-ph),128.72 C(m-ph), 127.25 C(o-ph), 127.68 C(p-ph), 104.75 C(CH2¼), 94.57 C(5), 85.63C(7a), 68.54 C(2), 54.70 C(OCH3), 50.78 C(NCH2Ph), 40.91 C(3a) and 20.73 C(4);MS (ESI): m=z¼ [MþH]þ 286.1. Anal. calcd. for C17H19NO3: C, 71.56; H, 6.71;N, 4.91. Found: C, 71.55; H, 6.72; N, 4.95.

7-Benzyl-3 (E and Z)-ethylidene-2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyri-dine-5-carbonitrile (3e, Table 1, Entry 5). Compound 3f was obtained by cycliza-tion of compound 2e, as a colorless oil; Rf¼ 0.54 (20% EtOAc=80% hexane); IR(film): t 3061, 3030, 2919, 2857, 2192, 1634, 1432, 1376, 1030, 737 and 699 cm�1;1H NMR (400MHz, CDCl3): d 7.36 (br s, 5H, Ph), 7.23 (br s, 5H, Ph), 6.91 (s,1H, -NCH), 6.80 (s, 1H, -NCH), 5.38 (s, 2H, -CHCH3), 4.82 (s, 1H, -NCHO),4.67 (s, 1H, -NCHO), 4.53–4.13 (m, 8H, -CH2Ph and -OCH2), 2.75 (s, 1H,-CH-C=C), 2.60 (s, 1H, -CH-C=C), 2.48–1.94 (m, 4H, -CH2), 1.69 (br s, 3H-CH3)and 1.59 (br s, 3H.�CH3);

13C NMR (100.5MHz, CDCl3): d 145.82, 145.45,139.45, 137.86, 136.25, 128.87, 128.83, 127.75, 122.85, 122.01, 116.33, 115.88,86.36, 85.19, 76.18, 73.78, 66.59, 66.49, 57.02, 54.69, 39.72, 34.75, 22.77, 22.59,14.59 and 14.37; MS (ESI): m=z¼ [MþH]þ 267.2. Anal. calcd. for C17H18N2O: C,76.66; H, 6.81; N, 10.52. Found: C, 76.65; H, 6.80; N, 10.51.

8-Benzyl-4-methylene-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]pyri-dine-6-carbonitrile (3f, Table 1, Entry 6). Compound 3f was obtained by cycli-zation of compound 2f, as a colorless oil; Rf¼ 0.53 (20% EtOAc=80% hexane); IR(film): t 2920, 2851, 2190, 1622, 1424, 1369, 1052 and 700 cm�1; 1H NMR(400MHz, CDCl3): d 7.30–7.29 (m, 5H, Ph), 6.71 (s, 1H, -NCH), 4.81–4.77 (m,2H, CH2¼C), 4.35–4.16 (m, 5H, -NCHO, -CH2Ph and -OCH2), 2.96–2.93 (m,1H, -CH-C=C), 2.47–2.45 (m, 2H, -CH2-C=C) and 2.14–2.10 (m, 2H, -CH2);

13CNMR (100.5MHz, CDCl3): d 148.12 C(4), 145.34 C(7), 136.33 C(ipso-ph), 128.86C(m-ph), 128.03 C(o-ph), 127.72 C(p-ph), 121.77 C(CN), 111.95 C(CH2¼), 84.66C(8a), 74.9 C(6), 67.12 C(2), 56.52 C(NCH2Ph), 41.36 C(4a), 22.94 C(3) and 20.69C(5); MS (ESI): m=z¼ [MþH]þ 267.3. Anal. calcd. for C17H18N2O: C, 76.66; H,6.81; N, 10.52. Found: C, 76.75; H, 6.82; N, 10.53.

3-(E and Z)-Ethylidene-7-methyl-2,3,3a,4,7,7a-hexahydrofuro[2,3-b]-pyridine-5-carbonitrile (3g, Table 1, Entry 7). Compound 3g was obtained bycyclization of compound 2g, as a colorless oil; Rf¼ 0.45 (20% EtOAc=80% hexane);IR (film): t 3056, 2919, 2855, 2189, 1735, 1637, 1368, 1031 and 818 cm�1; 1H NMR(400MHz, CDCl3): d 6.75 (s, 1H, -NCH), 6.61 (s, 1H, -NCH), 5.36–5.33 (m, 2H,-C=CHCH3), 4.75 (d, J¼ 5.04Hz, 1H, -NCHO), 4.56 (d, J¼ 4.12Hz, 1H, -NCHO),4.36–4.11(m, 4H, -OCH2), 3.06 (s, 3H, -NCH3), 2.90 (s, 3H, -NCH3), 2.74–2.70 (m,1H, -CH-C=C), 2.61–2.55 (m, 1H, -CH-C=C), 2.44–2.38 (m, 1H, -CH2), 2.31–2.23(m, 1H, -CH2), 2.15–2.10 (m, 1H, -CH2), 1.90-1.83 (m,1H, -CH2), 1.67-1.66 (m,3H, -CH3) and 1.55–1.54 (m, 3H, -CH3);

13C NMR (100.5MHz, CDCl3): d146.49, 146.03, 139.42, 137.88, 122.47, 121.86, 116.41, 115.85, 88.06, 87.03, 75.24,72.88, 66.48, 41.07, 39.78, 38.64, 34.86, 22.72, 22.32, 14.53 and 14.35; MS (ESI):m=z¼ [MþH]þ 191.3. Anal. calcd. for C11H14N2O: C, 69.45; H, 7.42; N, 14.73.Found: C, 69.44; H, 7.46; N, 14.71.

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Methyl 3-(E and Z)-ethylidene-7-methyl-2,3,3a,4,7,7a-hexahydro-furo[2,3-b]pyridine-5-carboxylate (3h, Table 1, Entry 8). Compound 3h wasobtained by cyclization of compound 2h, as a colorless oil; Rf¼ 0.43 (20%EtOAc=80% hexane); IR (film): t 2923, 2853, 1683, 1633, 1270, 1171, 1031 and761 cm�1; 1H NMR (400MHz, CDCl3): d 7.30 (s, J¼ 2.2Hz, 1H, -NCH), 7.17 (s,1H, -NCH), 5.32–5.29 (m, 2H, -C=CHCH3), 4.76 (d, J¼ 5.12Hz, 1H, -NCHO),4.58 (d, J¼ 3.68Hz, 1H, -NCHO), 4.40–4.13 (m, 4H, -OCH2), 3.65 (s, 3H,-OCH3), 3.63 (s, 3H, -OCH3), 3.09 (s, 3H, -NCH3), 2.93 (s, 3H, -NCH3),2.75–2.45 (m, 4H, -CH-C=C and -CH2), 2.29 (dd, J¼ 16Hz, 5.12Hz, 1H, -CH2),1.76–1.73 (m, 1H, -CH2), 1.70-1.67 (m, 3H, -CH3) and 1.53–1.51 (m, 3H, -CH3);13C NMR (100.5MHz, CDCl3): d 168.76, 168.31, 145.09, 144.52, 140.43, 138.72,115.55, 115.07, 96.46, 93.89, 88.83, 87.82, 66.76, 66.68, 50.76, 50.66, 41.09, 40.46,38.59, 35.61, 20.95, 20.66, 14.56 and 14.38; MS (ESI): m=z¼ [MþH]þ 224.1. Anal.calcd. for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.45; H, 7.68; N, 6.26.

8-Methyl-4-methylene-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]pyri-dine-6-carbonitrile (3i, Table 1, Entry 9). Compound 3i was obtained by cycli-zation of compound 2i, as a colorless oil; Rf¼ 0.5 (20% EtOAc=80% hexane); IR(film): t 2924, 2853, 2186, 1633, 1348, 1053 and 704 cm�1; 1H NMR (100.5MHz,CDCl3): d 6.64 (s, 1H, -NCH), 4.82 (d, J¼ 16.12Hz, 2H, CH2¼C), 4.14 (s, 1H,-NCHO), 3.43–3.40 (m, 2H, -OCH2), 2.97 (s, 3H, -NCH3), 2.81–2.80 (m, 1H,-CH-C=C), 2.46–2.43 (m, 2H, -CH2-C=C) and 2.12–2.10 (m, 2H, -CH2);

13CNMR (400MHz, CDCl3): d 147.59 C(4), 144.01 C(7), 121.74 C(CN), 111.62C(CH2¼), 86.10 C(8a), 75.02 C(6), 66.9 C(2), 42.44 C(NCH3), 30.65 C(4a), 21.16C(3) and 20.55 C(5); MS (ESI): m=z¼ [MþH]þ 191.4. Anal. calcd. forC11H14N2O: C, 69.45; H, 7.42; N, 14.73. Found: C, 69.44; H, 7.51; N, 14.71. Thecorresponding reduced product 1-methyl-1,4,5,6-tetrahydropyridine-3-carbonitrilewas obtained as a colorless oil; Rf¼ 0.47 (20% EtOAc=80% hexane); IR (film): t2934, 2853, 2181, 1633, 1409, 1138 and 918 cm�1; 1H NMR (400MHz, CDCl3): d6.66 (s, 1H, -NCH), 3.01–2.99 (m, 2H, -NCH2), 2.84 (s, 3H, -NCH3), 2.15–2.12(m, 2H, -CH2), 1.83–1.80 (m, 2H, -CH2-CCN); 13C NMR: (100.5MHz, CDCl3): d147.69 C(2), 123.60 C(CN), 72.08 C(3), 46.97 C(6), 42.56 C(CH3), 21.27 C(5) and20.67 C(4); MS (ESI): m=z¼ [MþH]þ 123.2. Anal. calcd. for C7H10N2; C, 68.82;H, 8.25; N, 22.93. Found: C, 68.83; H, 8.20; N, 22.85.

Methyl 8-methyl-4-methylene-3,4,4a,5,8,8a-hexahydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (3j, Table 1, Entry 10). Compound 3j was obtainedby cyclization of compound 2j, as a colorless oil; Rf¼ 0.48 (20% EtOAc=80% hex-ane); IR (film): t 2925, 2852, 1681, 1622, 1553, 1185, 1064 and 760 cm�1; 1HNMR (400MHz, CDCl3): d 7.29 (s, 1H, -NCH), 4.83 (d, J¼ 16.24Hz, 2H,CH2¼C), 4.19 (s, 1H, -NCHO), 3.66–3.64 (m, 5H, -OCH2 and -OCH3), 3.02 (s,3H, -NCH3), 2.61–2.53 (m, 1H, -CH-C=C), 2.50–2.35 (m, 3H, -CH2-C=C and-CH2) and 2.32–2.29 (m, 1H, -CH2);

13C NMR (100.5MHz, CDCl3): d 168.49C(C=O), 146.58 C(4), 143.93 C(7), 110.86 C(CH2¼), 96.57 C(6), 87.02 C(8a),67.09 C(2), 50.75 C(OCH3), 47.63 C(NCH3), 41.82 C(4a), 21.19 C(3) and 19.58C(s); MS (ESI): m=z¼ [MþH]þ 224.4. Anal. calcd. for C12H17NO3: C, 64.55; H,7.67; N, 6.27. Found: C, 64.54; H, 7.66; N, 6.21.

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Nucleophilic Substitution of 3a via Iminium Ion Formation:Synthesis of 4a

BF3 �OEt2 (2 equiv) was added to a stirred solution of the bicyclic compound3a (1 equiv.) and allyltributylsilane (2 equiv.) in dichloromethane (10ml) at 0 �C.The resulting mixture was stirred at rt for 2 h. Saturated aqueous solution ofNaHCO3(100ml) was then added. The mixture was extracted twice with dichloro-methane (2� 50ml). The combined phase were dried over Na2SO4, and the solventwas removed under vacuum to yield the 2,3-dialkylsubstitutedtetrahydropyridinederivative, which was purified by column chromatography (SiO2, EtOAC=hexane)to afford pure compound 4a.

2-Allyl-1-benzyl-3-(3-hydroxyprop-1-en-2-yl)-1,2,3,4-tetrahydropyridine-5-carbonitrile (4a). Compound 4a was obtained as a colorless oil; Rf¼ 0.27 (50%EtOAc=50% hexane); IR (film): t 3416, 2923, 2856, 2183, 1622, 1367, 1029 and700 cm�1; 1H NMR (400MHz, CDCl3): d 7.32–7.18 (m, 5H, -Ph), 6.85 (s, 1H,-NCH), 5.74–5.72 (m, 1H, -CH2-CH=CH2), 5.15–4.98 (m, 4H, -CH=CH2 andC=CH2), 4.31–4.24 (m, 2H, -OCH2), 3.73–3.66 (m, 2H, -NCH2Ph), 3.2 (s, 1H,-OH), 2.50–2.35 (m, 3H, -NCH-CH2, -CH=C and -CH2), 2.19–2.08 (m, 2H,-C=CH-CH2) and 1.82 (m, 1H, -CH2);

13C NMR (100.5MHz, CDCl3): d 148.02C(C=CH2), 145.62 C(6), 136.20 C(ipso-ph), 133.63 C(CH=CH2), 128.59 C(m-ph),128.22 C(o-ph), 127.68 C(p-ph), 123.31 C(CN), 118.63 C(CH2¼CH), 111.68C(CH2¼C), 71.38 C(5), 65.48 C(OCH2), 58.35 C(2), 55.39 C(NCH2Ph), 36.80C(3), 33.73 C(CH2) and 22.25 C(4); MS (ESI): m=z¼ [MþH]þ 295.3. Anal. calcd.for C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.53; H, 7.51; N, 9.56.

ACKNOWLEDGMENT

We thank the University Grant Commission (UGC), New Delhi, for financialsupport.

REFERENCES

1. Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turch, I. J.; Maryanoff, C. A. Cyclizationsof N-acyliminium ions. Chem. Rev. 2004, 104, 1431–1628.

2. Nadin, A. Saturated nitrogen heterocycles J. Chem. Soc., Perkin Trans. 1 1998, 3493–3515.

3. Shiotani, S.; Morita, H.; Inoue, M.; Ishida, T.; Iitaka, Y.; Itai, A. Furopyridine, II:Bromination and nitration of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]-, and furo[3,2-c]pyri-dine. J. Heterocycl. Chem. 1984, 21, 725–736.

4. Ledoussal, B.; Bouzard, D.; Coroneos, E. Potent non-6-fluoro-substituted quinolone anti-bacterials: Synthesis and biological activity. J. Med. Chem. 1992, 35, 198–200.

5. Clive, D. L. J.; Huang, X. Model studies and first synthesis of the antifungal and antibac-terial agent cladobotryal. J. Org. Chem. 2004, 69, 1872–1879.

6. Ramesh, D.; Chandrashekhar, C.; Vaidya, V. P. Synthesis of novel naphtha[2,1-b]furo[3,2-b]pyridine derivatives as potential antimicrobial agents. Indian J. Chem. 2008,47B, 753–758.

7. Grindson, M. F. The Alkaloids; Academic Press: New York, 1979; vol. 17, p. 145.

REACTIONS OF 1,4-DIHYDROPYRIDINES 535

Dow

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3

8. Chabrier, P. E.; Guinot, P.; Tarrade, T.; Auguet, M. C.; Clostre, F.; Etienne, A.; Esanu,A.; Braquet, P. Cardiovascular Drug Reviews; Raven Press: New York, 1988, vol. 6,pp. 166–179.

9. VanSickle, A. P.; Rapoport, H. Azapsoralens: Synthesis of 8-azapsoralens. J. Org. Chem.1990, 55, 895–901.

10. Lavilla, R.; Gullon, F.; Baron, X.; Bosch, J. Nonbiomimetic oxidations of dihydropyri-dines. Chem. Commun. 1997, 213–214.

11. Lavilla, R.; Baron, X.; Coll, O.; Gullon, F.; Masdeu, C.; Bosch, J. Nonbiomimetic oxida-tions of dihydropyridines. J. Org. Chem. 1998, 63, 10001–10005.

12. Lavilla, R.; Coll, O.; Kumar, R.; Bosch, J. Electrophilic oxidative additions upon1,4-dihydropyridines. J. Org. Chem. 1998, 63, 2728–2730.

13. Lavilla, R.; Kumar, R.; Coll, O.; Masdeu, C.; Bosch, J. Vicinal diamination of 1,4-dihy-dropyridines. Chem. Commun. 1998, 2715–2716.

14. Lavilla, R.; Kumar, R.; Coll, O.; Masdeu, C.; Spada, A.; Bosch, J.; Espinosa, E.; Molins,E. Introduction of heteroatom-based substituents into 1,4-dihydropyridines by means of ahalogen-mediated, oxidative protocol: Diamination, sulfonylation, sulfinylation,bis-sulfanylation, and halo-phosphonylation processes. Chem. Eur. J. 2000, 6, 1763–1772.

15. Brewster, M. E.; Simay, A.; Czako, K.; Winwood, D.; Farag, H.; Bodor, N. Reactivity ofbiologically important reduced pyridines, 4: Effect of substitution on ferricyanide-mediated oxidation rates of various 1,4-dihydropyridines. J. Org. Chem. 1989, 54,3721–3726.

16. Correia, C. R. D.; Caroll, P. J.; Sugisaki, C. H. Differential oxidation of endocyclic ene-carbamate: Synthesis of cyclic b-hydroxy-a-amino acids. Tetrahedron Lett. 1998, 39,3413–3416.

17. Hoffman, H. M. R.; Albrecht, U.; Wartchow, R. Stereocontrolled construction of 6 � 5 � 6and 5 � 5 � 6 ring systems by radical tandem cyclization. Angew. Chem. Int. Ed. 1992, 31,910–913.

18. Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academ-ic: London, 1992.

19. Stork, G.; Sher, M. A. Catalytic tin system for trapping of radicals from cyclization reac-tions: Regio- and stereocontrolled formation of two adjacent chiral centers. J. Am. Chem.Soc. 1986, 108, 303–304.

20. Kim, S. H.; Kim, H. G.; Choo, H.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Chung, B. Y.; Cho,Y. S. N-Acyliminium ion cyclizations of trimethylsilylmethylallenes. Tetrahedron Lett.2006, 47, 6353–6356.

21. Speckamp, W. N.; Moolenaar, M. J. New developments in the chemistry ofN-acyliminium ions and related intermediates. Tetrahedron 2000, 56, 3817–3856.

22. Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Cyclizationsof N-acyliminium ions. Chem. Rev. 2004, 104, 1431–1628.

23. Thaning, M.; Wistrand, L.-G. A short enantiodinergent synthesis of the Geissman–Waisslactone. J. Org. Chem. 1990, 55, 1406–1408.

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