Tetrahedron Letters 52 (2011) 1354–1358

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Tetrahedron Letters

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Stereoselective cascade reactions for construction of polyfunctionalisedoctahydroquinolines via [2C+2C+1C,1N] cyclisation

Ankita Rai, Atul K. Singh, Pankaj Singh, Lal Dhar S. Yadav ⇑Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India

a r t i c l e i n f o

Article history:Received 28 November 2010Revised 8 January 2011Accepted 16 January 2011Available online 20 January 2011

Keywords:OrganocatalysisStereoselective synthesisQuinolinesNitroalkenesCascade reaction[2+2+2] Annulation

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.01.079

⇑ Corresponding author. Tel.: +91 532 2500652; faxE-mail address: ldsyadav@hotmail.com (L.D.S. Yad

a b s t r a c t

A conceptually unifying approach for a highly enantio- and diastereoselective synthesis of polyfunction-alised octrahydroquinolines incorporating three contiguous chiral centres is reported. The synthesisinvolves diphenylprolinol silyl ether-catalysed Michael addition of 1,3-cyclohexanedione to nitroalkenesfollowed by potassium carbonate-promoted aza-Henry reaction with N-tosyl aldimines, intramolecularhemiaminalisation and dehydration reaction cascade in a one-pot operation.

� 2011 Elsevier Ltd. All rights reserved.

For a long time, the field of asymmetric catalysis was dominatedby metal and biocatalysis. Since the year 2000, the research area ofasymmetric organocatalysis has grown rapidly to become one ofthe most exciting current fields of organic chemistry.1 The applica-tion of organocatalysed cascade reactions mainly includes amine-catalysed cascade reactions.2 Organic synthesis has witnessed amajor revolution when proline and its derivative-based catalystsopened up a new horizon for asymmetric synthesis. A recurringfeature of the catalysts employed is the presence of a secondaryamine together with a source of protons within the same molecule.Among them, the enamine-iminium, iminium-enamine and enam-ine catalyses have turned out to be very powerful.3 In the presentwork, the enamine catalysis has been exploited, hence it should bementioned here that it was Enders et al. who, for the first time, em-barked on enamine activation of the first substrate to start a triplereaction cascade.4 Today, a number of examples of this catalysiscan be found in the literature.5

Recently, several research groups have synthesised numerouscarbocyclic compounds bearing multiple chiral carbons via enam-ine and/or iminium activation.4,6 However, only scarce reports areavailable on the application of this methodology to the synthesis ofchiral heterocycles.7

The design and realization of new organocatalytic, stereoselec-tive cascade reactions for stereoselectively installing multiple ste-

ll rights reserved.

: +91 532 2460533.av).

reogenic centres into organic molecules is a continuing challengeat the forefront of synthetic chemistry.8,9

Functionalised quinolines are common motifs found in naturalproducts and pharmaceuticals.10 In addition, they have utility inphotonic materials and redox switches.11 Numerous methods areavailable for the formation of quinoline and its derivatives suchas Skraup, Döbner–von Miller, Conrad–Limpach, Friedlaender andPfitzinger syntheses.12 Most of the methods reported for thesynthesis of octahydroquinolines involve mainly Diels–Alder ap-proach,13 cyclocondensation of substituted cyclohexene propio-nate,14 reactions of vinylallenes and imines,15 cycloaddition of 2-(N-acylamino)-1,3-dienes with N-phenylmaleimide,16 and imini-um ion based Diels–Alder approach.17 Recently, literature reportsa four component organocatalytic Hantzsch reaction for the syn-thesis of polyhydroquinolines.18 Very recently, an intramolecularDiels–Alder approach utilizing N-substituted oxazolone trienehas been reported for the synthesis of octahydroquinolines.19

Although octahydroquinoline alkaloids have received considerablesynthetic attention, organocatalysed enantioselective multicompo-nent synthetic strategy for the synthesis of octahydroquinolineshas not been explored so far.

Aliphatic nitro compounds have proven to be powerful syn-thetic tools because they facilitate the carbon–carbon bond-form-ing processes.20,21 but to the best of our knowledge, there is noreport on the synthesis of nitro derivatives of octahydroquinolines.

Our continuing interest in synthetic applications of nitroal-kenes22 and organocatalysis22d,23 to the synthesis of hetero-cycles prompted the development of one-pot enantio- and

O

R1

O2N

TsN

R2 NH

PhOTMS

Phcatalyst (S)-4a

N

R1

R2

NO2

TsK2CO3, 1,4-dioxane1

2

3 4a

O

O

rt, 17-26 h68-91% yield87-98% ee

5

Scheme 1. Synthesis of octahydroquinolines 5.

A. Rai et al. / Tetrahedron Letters 52 (2011) 1354–1358 1355

diastereoselective synthesis of polyfunctionalised octahydroquino-lines. The devised methodology involves a three-component dom-ino reaction following Michael, aza-Henry, hemiaminalization anddehydration sequence to afford the products 5 in moderate to goodyields (68–91%) with excellent enantioselectivities. During thisreaction sequence, three contiguous stereogenic centres are cre-ated with high stereoselectivity (Scheme 1).

Thus we focused our initial efforts on the screening of a range ofpyrrolidine-based catalysts 4a–e using 1,3-cyclohexanedione 1,nitrostyrene 2a and phenyl-N-tosyl-methanimine 3a as model sub-strates (Table 1). Of the catalysts tested, 4a was found to be thebest for triggering the reaction (Table 1, entries 2, 13–16) throughenamine catalysis. The reaction proceeds smoothly at rt, while at0 �C the yields were relatively lower (Table 1, entries 17 and 18).The optimum catalyst loading for 4a was found to be 20 mol % (Ta-ble 1, entry 2). When the amount of the catalyst decreased to15 mol % from 20 mol % relative to substrates, the yield of theproduct 5a reduced (Table 1, entries 1 and 2) but with 25 mol %

Table 1Optimization of the triple cascade reactiona

O

Ph

O2N

TsN

Ph catalyst (S)

base additive, s1

2a

3a

24 hO

NH O

NH

PhOTES

PhNH

PhOTMS

Ph

4a 4b 4c

Entry Catalyst 4 (mol %) Base additive (equiv)

1 4a (15) K2CO3 (0.5)2 4a (20) K2CO3 (0.5)3 4a (25) K2CO3 (0.5)4 4a (20) K2CO3 (0.5)5 4a (20) K2CO3 (0.5)6 4a (20) K2CO3 (0.5)7 4a (20) K2CO3 (1.0)8 4a (20) K2CO3 (0.2)9 4a (20) Na2CO3 (1.0)

10 4a (20) DABCO (1.0)11 4a (20) DBU (1.0)12 4a (20) Et3N (1.0)13 4b (20) K2CO3 (0.5)14 4c (20) K2CO3 (0.5)15 4d (20) K2CO3 (0.5)16 4e (20) K2CO3 (0.5)17 4e (20) K2CO3 (0.5)18 4a (20) K2CO3 (0.5)19 — K2CO3 (0.5)20 4a (20) —

a For experimental procedure, see Ref. 24.b Isolated yield of the product 5a.c All compounds gave C, H, N analyses within ±0.37% and satisfactory spectral (IR, 1Hd Determined by HPLC analysis on a chiral Eurocel column (250 � 4.6 mm, 5l).

of the catalyst no further improvement in the yield was observed(Table 1, entries 2 and 3). The reaction did not occur appreciablyin the absence of either a catalyst (Table 1, entry 19) or a base addi-tive (Table 1, entry 20). Next, we examined effects of solvents, andfound that the reaction catalysed by 4a produces product 5a inmoderate yields in aprotic nonpolar solvents (Table 1, entries 5and 6), whereas good yields were obtained in aprotic polar solvents(Table 1, entries 2 and 4), and 1,4-dioxane was found to be the bestsolvent (Table 1, entry 2).

The presence of a base is prerequisite for the success of the sub-sequent aza-Henry, hemiaminalization and dehydration reactions,hence the effect of base on these steps was investigated. Severalbases were examined, and it was found that bases like DABCO,DBU, Et3N gave poor yields (Table 1, entries 10–12). K2CO3 (0.5equiv) was found to be the best base additive (Table 1, entry 2)and decreasing its amount lowers the yield (Table 1, entry 8) butno further improvement in the yield was observed when 1 equivof K2CO3 was used (Table 1, entry 7).

With these optimal conditions established, the present strategywas followed for the synthesis of octahydroquinolines 5 (Table 2)in a one-pot procedure.24 The general utility of the present cascadeprocess was demonstrated across a range of substrates and resultsare summarized in Table 2. A series of nitroalkenes with a phenylgroup having either an electron-donating or electron-withdrawingsubstituent can be employed (Table 2, entries 1–4). Similarly, notonly imines of benzaldehyde and para-toluenesulfonamide butalso benzaldehyde possessing an electron-donating or electron-withdrawing substituent on the phenyl ring can be successfully

-4

N

Ph

Ph

NO2

Ts

olvent

5aSingle diastereomer

O

O

HNH

PhOH

PhNH N N

N Bn

4d 4e

Solvent Temp (�C) Yield (%)b,c eed

1,4-dioxane rt 71 931,4-dioxane rt 78 961,4-dioxane rt 78 96THF rt 67 94Toluene rt 56 91Hexane rt 52 961,4-dioxane rt 78 961,4-dioxane rt 70 921,4-dioxane rt 62 931,4-dioxane rt 41 941,4-dioxane rt 51 951,4-dioxane rt 39 951,4-dioxane rt 73 961,4-dioxane rt 70 961,4-dioxane rt 66 331,4-dioxane rt 68 921,4-dioxane 0 �C 66 901,4-dioxane 0 �C 72 961,4-dioxane rt — —1,4-dioxane rt — —

NMR, 13C NMR and EIMS) data.

Table 2Synthesis of functionalised octahydroquinolines via [2+2+2] annulation reactiona

OR1

O2N

TsN

R2

NH

PhOTMS

Phcatalyst (S)-4a N

R1

R2

NO2

TsK2CO3, 1,4-dioxane

1 2 3

4a

5

O

O

Entry R1 R2 Timeb (h) Product, Yieldc,d (%) ee (%)e

1 C6H5 C6H5 24 5a, 78 962 4-ClC6H4 C6H5 18 5b, 86 963 4-CH3C6H4 C6H5 22 5c, 76 944 4-(CH3O)C6H4 C6H5 21 5d, 79 915 C6H5 4-ClC6H4 20 5e, 88 906 4-ClC6H4 4-ClC6H4 17 5f, 91 877 4-CH3C6H4 4-ClC6H4 24 5g, 83 898 4-(CH3O)C6H4 4-ClC6H4 23 5h, 85 939 C6H5 4-CH3C6H4 26 5i, 75 87

10 4-ClC6H4 4-CH3C6H4 19 5j, 80 9011 4-CH3C6H4 4-CH3C6H4 25 5k, 68 9312 4-(CH3O)C6H4 4-CH3C6H4 24 5l, 73 9813 C6H5 4-(CH3O)C6H4 24 5m, 75 9514 4-ClC6H4 4-(CH3O)C6H4 23 5n, 89 9815 4-CH3C6H4 4-(CH3O)C6H4 25 5o, 80 8916 4-(CH3O)C6H4 4-(CH3O)C6H4 26 5p, 74 94

a For experimental procedure, see the Ref. 24.b Overall reaction time.c Isolated yield of purified products 5.d All compounds gave C, H, N analyses within ±0.37% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.e Determined by HPLC analysis on a chiral Eurocel column (250 � 4.6 mm, 5l).

R1

NN

O

TMSOPh2HCO

NH

PhOTMS

Ph

R1

NO2

Enamine-catalysedcycle

ONO2

TsNR2

catalyst (S)-4a

NO2

R1

ON R2

Ts

NO2

R1

N R2

Ts

K2CO3 1

2

3

Hemiaminalization

Michael reaction

Aza-Henry reaction

5

6

N

7

8

9

O

O

NO2

R1

OHN R2

Ts

HO

-H2O

O

O

O

O

O

10

NNO2

R1

O

TMSOPh2C

H2O

7'

TMSOPh2HC

H2O

R1

Scheme 2. Plausible mechanism for the formation of octahydroquinolines 5.

N

Ph

Ph

NO2

Ts

1 2

3456

7 8

HH

H

O

1H (d, J = 11.6 Hz)

1H (t, J = 11.1 Hz)

1H (d, J = 11.1 Hz)

Selected NOE Coupling constants

N

Ph

Ph

NO2

Ts

1 2

3456

7 8

HH

H

ONOE 10.6%

Figure 1. Determination of relative stereochemistry of 5a.

1356 A. Rai et al. / Tetrahedron Letters 52 (2011) 1354–1358

used to afford the corresponding octahydroquinolines 5 in consis-tently good yield with excellent enantioselectivity (Table 2).

On the basis of the experimental results, a plausible mechanismfor the formation of polysubstituted octahydroquinolines is de-picted in Scheme 2. In the first step, the catalyst diphenylprolinoltrimethylsilyl ether ((S)-4a) activates the diketone 1 by enamineformation 6, which then selectively adds to nitroalkene 2 in a Mi-chael type reaction through a favourable transition state 7. In situ,hydrolysis of 7 forms nitroalkane 8 and liberates the catalyst (S)-4ato complete the catalytic cycle of the first step (Michael reaction).Potassium carbonate-catalysed aza-Henry reaction with 3 followedby hemiaminalization and dehydration furnishes 5. The presentreaction cascade forms a single diastereomer (as determined inthe crude isolates by 1H NMR spectroscopy) with a high enantiose-lectivity. The reason for the high stereoselectivity is the first

Michael addition, which is known to proceed with high diastereo-and enantioselectivity; clearly this selectivity is kept or enhancedin the subsequent steps via a sterically favourable interaction

A. Rai et al. / Tetrahedron Letters 52 (2011) 1354–1358 1357

between the imine 3 and nitroalkane 8 followed by intramolecularhemiaminalization and dehydration to afford 5. The possibility ofcontrolling the absolute configuration of up to three contiguousstereocentres on the octahydroquinoline ring offers a useful meth-odology for a short synthesis of differently substituted octahydro-quinoline derivatives in moderate to good yields with highdiastereo- and enantioselectivities (Table 2).

The relative stereochemistry of 5 was established by NOEexperiments and coupling constants (Fig. 1). The strong NOE be-tween 4-H and 2-H suggests that they are on the same face ofthe molecule, that is, cis to each other (Fig. 1). For example, inthe case of compound 5a, 10.6% NOE was observed between 4-Hand 2-H. Furthermore, the absence of any measurable NOE be-tween 2-H and 3-H indicates that 2-H and 3-H are disposed transto each other.

In summary, we have developed a highly enantio- and distereo-selective one-pot synthesis of polyfunctionalised octahydroquino-lines having three contiguous chiral centres. The protocol involvesdiphenylprolinol silyl ether-triggered coupling of 1,3-cyclohexane-dione, nitroalkenes and N-tosyl aldimines in a one-pot operation.Operational simplicity, ambient temperature and high stereoselec-tivity are the salient features of the present investigation whichopens up a new alternative to the existing procedures for synthesisof octahydroquinolines, especially for chiral ones.

Acknowledgements

We sincerely thank the CSIR, Govt. of India, for financial support(CSIR File No. 01/2396/10/EMR-II) and SAIF, Punjab University,Chandigarh, for providing microanalyses and spectra.

References and notes

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23. (a) Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Tetrahedron 2008, 64, 1420; (b)Yadav, L. D. S.; Rai, V. K.; Singh, S.; Singh, P. Tetrahedron Lett. 2010, 51, 1657; (c)Yadav, L. D. S.; Singh, S.; Rai, V. K. Synlett 2010, 240; (d) Singh, S.; Rai, V. K.;Singh, P.; Yadav, L. D. S. Synthesis 2010, 2957.

24. General procedure for the synthesis of compounds 5: To a stirred solution of thecatalyst diphenylprolinol trimethylsilyl ether 4a (20 mol %) and diketone 1(0.4 mmol) in 1,4-dioxane (1 mL) was added nitroalkene 2 (0.4 mmol). Afterstirring the reaction mixture for 7 h at rt, aldimine 3 (0.4 mmol), K2CO3

(0.2 mmol) and 1,4-dioxane (2 mL) were added and stirring at rt was continueduntil complete consumption of aldimine 3 (10–19 h) as indicated by TLC. Thesolvent was removed under reduced pressure and the residue was purified bysilica gel column chromatography [EtOAc-hexane (1:4) as eluent] to affordpure octahydroquinolines 5 in 68–91% yield and 87–98% ee (Table 2). Physicaldata of representative compounds 5.Compound 5a: White solid, yield 78%, mp 172–175 �C. IR (KBr) mmax 3598,2950, 1680, 1556, 1534, 1410, 1342, 1160, 1094, 852, 790, 745, 708, 605 cm�1.1H NMR (400 MHz; DMSO-d6) d: 1.10–1.76 (m, 6H), 2.42 (s, 3H), 4.93 (d, 1H,J = 11.6 Hz), 5.06 (d, 1H, J = 11.1 Hz), 5.91 (t, 1H, J = 11.1 Hz), 7.34 (d, 2H,J = 8.1 Hz), 7.45–7.75 (m, 10H), 7.72 (d, 2H, J = 8.5 Hz). 13C NMR (100 MHz,DMSO-d6) d: 20.1, 24.5, 25.8, 26.6, 35.2, 46.4, 90.8, 114.6, 125.2, 126.6, 127.4,128.3, 129.1, 130.8, 131.7, 132.6, 134.8, 139.5, 140.4, 141.5, 154.7, 198.4. EIMS(m/z) 502 (M+). Anal. Calcd for C28H26N2O5S: C, 66.91; H, 5.21; N, 5.57. Found:C, 66.61; H, 5.57; N, 5.35. ½a�20

D +24 (c 0.60, THF). The enantiomeric excess wasdetermined to be 97% by HPLC on a chiral Eurocel column (250 � 4.6 mm, 5l),k = 225 nm, (i-PrOH/hexane) (10:90), 1 mL/min; tR = 5.7 min (minor),tR = 6.5 min (major). Compound 5e: White solid, yield 88%, mp 181–182 �C.IR (KBr) mmax 3602, 2945, 2815, 1685, 1550, 1538, 1414, 1339, 1162, 1091, 850,796, 749, 712, 601 cm�1. 1H NMR (400 MHz; DMSO-d6) d: 1.06–1.78 (m, 6H),2.40 (s, 3H), 4.94 (d, 1H, J = 11.7 Hz), 5.05 (d, 1H, J = 11.3 Hz), 5.93 (t, 1H,J = 11.3 Hz), 7.30 (d, 2H, J = 8.1 Hz), 7.65–7.70 (m, 2H), 7.72 (d, 2H, J = 8.3 Hz),7.66–7.71 (m, 5H), 8.10–8.17(m, 2H). 13C NMR (100 MHz, DMSO-d6) d: 19.2,24.1, 25.7, 45.8, 90. 7, 114.9, 124.5, 126.0, 127.2, 128.1, 129.4, 130.2,131.1,132.9, 134.6, 136.8, 138.4, 139.5, 141.9, 154.2, 198.2. EIMS (m/z) 536(M+). Anal. Calcd for C28H25ClN2O5S: C, 62.62; H, 4.69; N, 5.22. Found: C, 62.91;H, 4.32; N, 5.53. ½a�20

D +22 (c 0.60, THF). The enantiomeric excess wasdetermined to be 91% by HPLC on a chiral Eurocel column (250 � 4.6 mm,5l), k = 225 nm, (i-PrOH/hexane) (10:90), 1 mL/min; tR = 5.6 min (minor),tR = 7.4 min (major). Compound 5m: White solid, yield 75%, mp 189–191 �C.IR (KBr) mmax 3592, 2941, 1680, 1552, 1539, 1407, 1345, 1158, 1096, 858, 797,741, 706, 606 cm�1. 1H NMR (400 MHz; DMSO-d6) d: 1.09–1.72 (m, 6H), 2.42(s, 3H), 3.85 (s, 3H), 4.91 (d, 1H, J = 11.5 Hz), 5.09 (d, 1H, J = 11.3 Hz), 5.95 (t,1H, J = 11.3 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.66–7.68 (m, 2H), 7.74 (d, 2H,

1358 A. Rai et al. / Tetrahedron Letters 52 (2011) 1354–1358

J = 8.2 Hz), 7.61–7.69 (m, 5H), 8.01–8.03 (m, 2H). 13C NMR (100 MHz, DMSO-d6) d: 20.6, 24.3, 25.4, 26.2, 36.8, 46.1, 54.2, 89.4, 112.8, 114.5, 124.6, 126.4,127.5, 128.9, 129.9, 130.7, 132.1, 135.6, 138.4, 140.8, 152.2, 158.4, 198.1. EIMS(m/z) 532 (M+). Anal. Calcd for C29H28N2O6S: C, 65.40; H, 5.30; N, 5.26. Found:

C, 65.72; H, 5.51; N, 4.99. ½a�20D +19 (c 0.60, THF). The enantiomeric excess was

determined to be 94% by HPLC on a chiral Eurocel column (250 � 4.6 mm, 5l),k = 225 nm, (i-PrOH/hexane) (10:90), 1 mL/min; tR = 6.7 min (minor),tR = 7.8 min (major).