Organic &Biomolecular Chemistry

COMMUNICATION

Cite this: Org. Biomol. Chem., 2013, 11,3608

Received 13th February 2013,Accepted 24th April 2013

DOI: 10.1039/c3ob40320c

www.rsc.org/obc

Proline catalyzed sequential α-aminooxylation or-amination/reductive cyclization ofo-nitrohydrocinnamaldehydes: a high yield synthesisof chiral 3-substituted tetrahydroquinolines†

Varun Rawat, B. Senthil Kumar and Arumugam Sudalai*

A new sequential organocatalytic method for the synthesis of

chiral 3-substituted (X = OH, NH2) tetrahydroquinoline derivatives

(THQs) [ee up to 99%, yield up to 87%] based on α-aminooxy-

lation or -amination followed by reductive cyclization of o-nitro-

hydrocinnamaldehydes has been described. This methodology has

been efficiently demonstrated in the synthesis of two important

bioactive molecules namely (−)-sumanirole (96% ee) and 1-[(S)-

3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]-

propanone (92% ee).

Introduction

The 1,2,3,4-tetrahydroquinoline (THQ) is a very common struc-tural motif found in numerous biologically active natural pro-ducts and pharmacologically relevant therapeutic agents.1,2

For example, (−)-sumanirole (PNU-95666E, 1) is a selective andhigh affinity agonist at the dopamine D2 receptor subtype andhas proven to be a potential agent for the treatment of Parkin-son’s disease and restless leg syndrome.3 Also, 1-[(S)-3-(dimethy-lamino)-3,4-dihydro-6,7-dimethoxy quinolin-1(2H)-yl]propanone[(S)-903] 2 has recently been identified as a potentiallyinteresting positive inotropic agent,4 while (+)-duocarmycin D13 has exhibited potent antitumor activity (Fig. 1).5 Due tothe significance of these scaffolds in drug discovery and medi-cinal chemistry,6 the development of new methodologiesfor the synthesis of 3-substituted THQs derivatives continuesto be a very active field of research in recent years.7 A fewmethods are, however, reported in the literature for their syn-thesis, which include strategies involving oxidative aza-annula-tion of chiral amino acids,8 Rh-catalyzed reduction of chiralamino cinnamates,9 asymmetric epoxidation9 and dihydroxy-lation10 of alkenes and co-catalyzed reductive cyclization of

nitro cyclic sulfites.11 Use of expensive chiral startingmaterials, multi-step reaction sequences, use of protection anddeprotection of various functional groups and low overallyields are some of the limitations of the existing routes. In thisregard, an organocatalytic protocol that provides for theefficient synthesis of chiral 3-substituted THQs is highlydesirable.

Results and discussion

In recent years, it has been proven that proline-catalyzed directα-aminooxylation or -amination of aldehydes provides efficien-tly for the enantioselective synthesis of α-amino acid deriva-tives. Its sequential reactions have become one of the mostextensively studied organocatalytic reactions as well.12 Yet, fullsynthetic potential of the use of α-functionalized aldehydesthat are readily available in situ by this route in excellentenantioselectivity has not been realized. In continuation of ourwork on the utilization and application of these enantiomeri-cally-enriched α-functionalized aldehydes,13 we envisaged thatsequential trapping of α-aminooxylated or -aminated o-nitro-hydrocinnamaldehydes with Pd-catalyzed reductive cyclizationshould provide enantiomerically pure 3-hydroxy- or 3-aminatedTHQs respectively. We wish to report, in this note, that thissequential reaction of α-aminooxylation or -amination ofo-nitrohydrocinnamaldehydes followed by intramolecular cata-lytic hydrogenation indeed furnished 3-hydroxy- and 3-aminatedTHQs in good yields with excellent enantioselectivity(Scheme 1).

Fig. 1 Structures of some THQ containing bioactive molecules.

†Electronic supplementary information (ESI) available: Experimental details andspectral data of all the new compounds. See DOI: 10.1039/c3ob40320c

Chemical Engineering and Process Development Division, National Chemical

Laboratory, Pashan Road, Pune 411008, India. E-mail: a.sudalai@ncl.res.in;

Fax: +91-02025902676

3608 | Org. Biomol. Chem., 2013, 11, 3608–3611 This journal is © The Royal Society of Chemistry 2013

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As a model substrate, the α-aminooxylation reaction ofo-nitrohydrocinnamaldehyde 4a with nitrosobenzene as anoxygen source was carried out in the presence of L-proline(20 mol%) in CH3CN at −20 °C for 24 h to obtain α-aminooxyaldehydes in situ.14 Since α-aminooxy aldehydes are prone toracemization, it was immediately subjected to catalytic hydro-genation [10% Pd/C, (1 atm) H2] by distilling out CH3CNunder reduced pressure and adding MeOH into it, which gave3-hydroxy THQ 5a in 62% yield with moderate enantio-selectivity (82% ee). The low ee could possibly be due to theracemization occurring during the removal of CH3CN atslightly elevated temperature (45 °C).

Optimizing reaction parameters, therefore, were essentialin order to obtain high enantioselectivity. Thus, when a mixedsolvent system of CH3CN–MeOH (1 : 3) was used, 5a wasobtained in higher enantioselectivity (96% ee) with low yield(52%). In order to improve the yield, we performed severalexperiments to identify the most suitable condition by con-ducting experiments in several solvent systems (CHCl3, CH2Cl2and THF).

However, there was no significant improvement in yieldsobserved in each case. Finally, the best result (71% yield, 96%ee) for 5a was obtained when α-aminooxylation was carried outin DMSO and the intramolecular reductive cyclization done inMeOH in a sequential manner at ambient temperature (entry 7;Table 1).

At this point, we reasoned that α-amination of aldehydescould provide a direct access to 3-amino THQs under the reac-tion conditions. For example, α-amination of o-nitrohydro-cinnamaldehyde 4a with diisopropyl azodicarboxylate (DIAD)as an amine source in the presence of L-proline (10 mol%) as acatalyst in CH3CN was carried out using List’s protocol15 thatindeed gave the corresponding chiral α-aminated aldehydein situ. The removal of CH3CN under reduced pressure andsubsequently carrying out the reductive cyclization [Pd/C, H2

(1 atm), MeOH] afforded the desired 3-amino THQ 6a in highyield (85%) with low ee (60%). Several other solvents were alsoscreened simultaneously in order to improve the yield of theamination process, but with little success (yield 35–70%). Afterseveral experimentations, when α-amination was carried out inCH3CN and reductive cyclization in a solvent mixture ofCH3CN–MeOH (1 : 3), higher yield (82%) and enantioselectivity(90%) of 6a were realized (Table 1). Other amine sources likedi-tert-butyl and diethyl azodicarboxylate could be con-veniently employed under our reaction conditions16a givingthe desired 3-aminated THQs in high yields and enantio-selectivity; however, the reactions were not efficient in the case

when other commercially available L-proline based catalysts16b

were screened.With the optimized conditions in hand, we then turned our

attention to briefly investigate the scope of the reaction by sub-jecting several o-nitrohydrocinnamaldehydes 4a–e to a sequen-tial α-aminooxylation or -amination/reductive cyclizationprotocol. When subjected to L-proline catalyzed α-aminooxy-lation or -amination with 1 equiv. of PhNO or DIAD, severalo-nitrohydrocinnamaldehydes16c 4a–e gave the corresponding(R)-3-hydroxytetrahydroquinoline 5a–e (70–76%) or (R)-3-amino-tetrahydroquinoline 6a–e (80–87%) derivatives respectivelywith excellent enantioselectivities. Results of such studies arepresented in Table 2. For substrates with easily removablegroups like TBDPS, the corresponding 3-substituted THQswere obtained in excellent enantioselectivities (entry 5,Table 2).

Among the various applications of this sequential protocol,an enantioselective synthesis of (−)-sumanirole 1 and (S)-903 2seemed attractive to us due to their pharmacological impor-tance.17,18 For the synthesis of (−)-sumanirole 1, intermediate9 was prepared readily in three steps by following the presentprotocol starting from α,β-unsaturated ester 7, with an overallyield of 52.2%: (i) co-catalyzed chemoselective reduction of 7gave cinnamyl alcohol 8 (CoCl2·6H2O, iPr2NH, NaBH4, 85%);(ii) PCC oxidation of 8 smoothly afforded 4a in 85%;(iii) sequential protocol involving D-proline catalyzed α-aminooxy-lation followed by Pd/C catalyzed reductive cyclization of 4aunder H2 (1 atm) gave the corresponding annulated (3S)-hydroxy THQ 9. Amine functionality in 9 was then converted toits carbamate 10 (ClCO2Me, K2CO3, 98%). 10 was readily trans-formed into the corresponding azide 11 in two steps:

Scheme 1 Synthesis of chiral 3-substituted tetrahydroquinoline derivatives.

Table 1 Optimization studies for proline-catalyzed α-aminooxylation or -amin-ation/reductive cyclization of o-nitrohydrocinnamaldehyde (4a)

Entry S1 S2

Product (5a) Product (6a)

Yieldc

(%)eed

(%)Yieldc

(%)eed

(%)

1 CH3CN MeOH 62 82 85 602e CH3CN CH3CN–MeOH 52 96 82 903e CH2Cl2 CH2Cl2–MeOH 35 nd 65 nd4 CH2Cl2 MeOH 39 nd 70 755 THF MeOH 15 nd 35 nd6 CHCl3 MeOH 30 nd 45 nd7 f DMSO MeOH 71 96 — —

a Condition A: L-proline (20 mol%), o-nitrohydrocinnamaldehyde(5 mmol), PhNO (5 mmol), 15 min. b Condition B: L-proline (10 mol%),o-nitrohydrocinnamaldehyde (5.5 mmol), iPrCO2NvNCO2iPr(5 mmol), 3 h. c Isolated yield after column chromatography. d eedetermined by chiral HPLC analysis. e Solvent ratio S2 (1 : 3). f Reactionwas carried out at 25 °C for 10 min followed by ether extraction. nd =not determined.

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mesylation (MsCl, Et3N) and treatment of mesylate with anazide anion (NaN3, DMF, 93%). When selective azidation of 11at the C-8 position was attempted via an ortho-lithiation proto-col (sec-BuLi, TsN3), only a complex reaction mixture wasobtained. Alternately, regioselective nitration of 11 at the C-8position was carried out successfully in two steps: (i) bromina-tion (Br2, AcOH, 95%) of azido carbamate 11; (ii) subsequentregiospecific nitration of 12 (NaNO3, TFA, 95%) gave the keyintermediate 13 with an overall yield of 42.6% and 96% ee. Asthe conversion of 13 to 1 has been reported previously in foursteps, this work thus constitutes a formal synthesis of 1(Scheme 2).17

Additionally, a concise enantioselective synthesis of (S)-9032 was undertaken to demonstrate the direct application of theα-amination/reductive cyclization protocol in synthesis. Thus,

14 was prepared using D-proline as a catalyst and di-tert-butylazodicarboxylate as an amine source by following the opti-mized conditions. THQ 14 was subsequently acylated to givethe corresponding amide 15 followed by Boc deprotection togive hydrazine 16. Its hydrogenolysis under RANEY® Nireduction conditions and subsequent reductive methylation(HCHO, HCO2H) afforded 2 in 65% yield and 92% ee(Scheme 3).

Conclusion

In conclusion, we have described, for the first time, a novelorganocatalyzed sequential strategy for the construction ofchiral 3-substituted THQs in high yields. Although twodifferent catalysts (L-proline, 10% Pd/C) were used for the reac-tion, the protocol is convenient to carry out under milder con-ditions with excellent enantioselectivity. We believe that thisstrategy will find wide applications in the synthesis of opticallypure 3-substituted tetrahydroquinoline derivatives 5 and 6 (X =–OH, –NH2) owing to the flexible nature of synthesis of substi-tuted o-nitrohydrocinnamaldehydes and the ready availabilityof both enantiomers of proline.

Acknowledgements

We thank CSIR, UGC and DST, New Delhi (sanction no. SR/S1/OC-67/2010) for financial support. The authors also thankDr V. V. Ranade, Head, CE-PD for his constant encouragementand support.

References

1 For reviews see: D. L. Boger, C. W. Boyce, R. M. Garbaccioand J. A. Goldberg, Chem. Rev., 1997, 97, 787.

2 T. Yasuzawa, K. Muroi, M. Ichimura, I. Takahashi,T. Ogawa, K. Takahashi, H. Sano and Y. Saitoh, Chem.Pharm. Bull., 1995, 43, 378 and references cited therein.

3 R. F. Heier, L. A. Dolak, J. N. Duncan, D. K. Hyslop,M. F. Lipton, I. J. Martin, M. A. Mauragis, M. F. Piercey,N. F. Nichols, P. J. K. D. Schreur, M. W. Smith andM. W. Moon, J. Med. Chem., 1997, 40, 639.

Table 2 L-Proline-catalyzed sequential α-aminooxylation or -amination/reduc-tive cyclization of o-nitro hydrocinnamaldehyde (4a–e)

Entry Substrates 4a–e

Products (5a–e) Products (6a–e)

Yieldc

(%)eed

(%)Yieldc

(%)eed

(%)

1 R = R1 = H 71 96 82 902 R = R1 = OMe 76 98 85 903 R,R1 = –O–CH2–O– 75 94 87 914 R = O-pentyl; R1 = OMe 72 96 81 915 R = OTBDPS; R1 = OMe 70 99 80 90

a Condition A: L-proline (20 mol%), o-nitrohydrocinnamaldehyde(5 mmol), nitroso benzene (5 mmol), DMSO (20 mL), 10 min, thenether extraction followed by H2 (1 atm), 10% Pd/C (5 wt%), MeOH(20 mL). bCondition B: L-proline (10 mol%), o-nitrohydro-cinnamaldehyde (5.5 mmol), iPrCO2NvNCO2iPr (5 mmol),CH3CN (10 mL), 3 h, followed by H2 (1 atm), 10% Pd/C (5 wt%), MeOH(30 mL). c Isolated yields of THQ-3-ol. d ee determined by chiral HPLCanalysis.

Scheme 2 Formal synthesis of (−)-sumanirole (1).

Scheme 3 Total synthesis of [(S)-903] (2).

Communication Organic & Biomolecular Chemistry

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4 Y. Ito, K. Ishida, S. Okada and M. Murakami, Tetrahedron,2004, 60, 9075.

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6 W. C. Van Voorhis, K. L. Rivas, P. Bendale, L. Nallan,C. Hornéy, L. K. Barrett, K. D. Bauer, B. P. Smart, S. Ankala,O. Hucke, C. L. M. J. Verlinde, D. Chakrabarti,C. Strickland, K. Yokoyama, F. K. Buckner, A. D. Hamilton,D. K. Williams, L. J. Lombardo, D. Floyd and M. H. Gelb,Antimicrob. Agents Chemother., 2007, 3659.

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8 For review, see: A. K. Lawrence and K. Gademann, Syn-thesis, 2008, 331.

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11 A. R. Jagdale, R. S. Reddy and A. Sudalai, Org. Lett., 2009,11, 803.

12 For a review of proline-catalyzed asymmetric reactions, see:B. List, Tetrahedron, 2002, 58, 5573.

13 B. S. Kumar, V. Venkataramasubramanian andA. Sudalai, Org. Lett., 2012, 14, 2468 and referencescited therein.

14 Y. Hayashi, J. Yamaguchi, K. Hibino and M. Shoj, Tetra-hedron Lett., 2003, 44, 8293.

15 B. List, J. Am. Chem. Soc., 2002, 124, 5656.16 (a) A complex mixture was observed when dibenzyl azo-

dicarboxylate was used for this sequential protocol; (b) Useof (S)-α,α-diarylprolinol silyl ether as a modified prolinecatalyst was found to be less effective for the reaction;(c) ArX (X = Cl, Br, I) were found to undergo dehalogenationunder the present protocol of reductive cyclization.Further, attempts to prepare substrates with other electron-withdrawing groups (F, –CN, –CO2Et) on the aryl ring wereunsuccessful due to lengthy sequence of reactions invol-ving formation of undesired regioisomers.

17 F. Macé, A. N. Ngo, M. Pauvert, H. Dentel, M. Evain,S. Collet and A. Guingant, Eur. J. Org. Chem., 2012, 4240and references cited therein.

18 A. R. Jagdale, R. S. Reddy and A. Sudalai, Tetra-hedron: Asymmetry, 2009, 20, 335 and references citedtherein.

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