Todd:Lewis Acid Catalysed Pictet-Spengler Reaction Model

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The Lewis Acid-Catalysed Pictet-Spengler formation of Substituted 1,2,3,4-Tetrahydroisoquinolines

This is an undergraduate project running from March-June 2012. Current plan of action here. Final document due: 17:00 +10 GMT (AEST), 15 June 2012.

Abstract

The Pictet-Spengler reaction is a useful carbon-carbon bond forming reaction. It is typically used in the synthesis of tetrahydroisoquinoline, tetrahydro-β-carboline and more recently, quinoxalines.

• Mini-summary
• Mini-conclusion

Introduction

NOTE: Will remain a bit of a mess until I can properly sort out what I'm trying to say

The Pictet-Spengler reaction is an intramolecular carbon-carbon bond forming reaction(...event?). It typically occurs via two-steps: the condensation of a β-arylamine with an aldehyde or ketone followed by nucleophilic attack of the resulting iminium species (Scheme X). This named reaction by Ame Pictet and Theodor Spengler in 1911. Amazingly, their The original reaction was first reported by Ame Pictet and Theodor Spengler in 1911 (Scheme 1).

Figure 1: The typical Pictet-Spengler reaction based on the original synthesis of tetrahydroisoquinoline from β-phenethylamine and formaldehyde. (NOTE: chemdraw is exporting my .png's strangely

It should be unsurprising then, the relatively recent discovery of a class of enzymes, termed Pictet-Spenglerases are instrumental in the synthesis of a number of plant alkaloids.[ref] PS in Nature Saframycin A. Pictet-Spenglerases: STR and NCS.

Figure X:

The usefulness of the Pictet-Spengler reaction in Nature is reflected in organic synthesis. hat the Pictet-Spengler reaction is particularly useful in the synthesis of the tetrahydro-β-carboline and tetrahydrioisoquinoline scaffolds typically associated with the plant alkaloids.

Notable variations of the original PS reaction include the formation of tetrahydro-β-carboline (though nature has been doing this long before we even started), the oxa-Pictet-Spengler, the acyl- and alkyl-PS, the spirocycle compounds and fused quinoxalines. All of these fall under the blanket named reaction. Efficient routes to lots of different potentially useful biologically active complex polycyclic heterocycles.<--fix this sentence.

Figure X: The tetrahydro-β-carboline, acyl-, alkyl- and quinoxaline Pictet-Spengler variations

The apparent limitations to the Pictet-Spengler reaction include catalytic formation of the non-activated tetrahydroisoquinolines. Ironically, the first synthetic example of the synthesis of the THIQ scaffold appears to be the most difficult to catalytically produce via the Pictet-Spengler route, at least by traditional homogenous catalytic methods. Indeed, an example in Nature for the PS formation of the THIQ scaffold is yet to be found.

A recent review of the literature has revealed a lack of Lewis acid catalysed asymmetric Pictet-Spengler reactions. Furthermore, there are no reports of the of the asymmetric Pictet-Spengler formation of the THIQ scaffold. Instead, most of the focus on the catalytic asymmetric Pictet-Spengler reaction uses tryptamine.

• The current scope of the catalytic (& asymmetric) Pictet-Spengler reaction. Lots of tryptamine but not much with THIQ.
• Few LA catalysed. No asymmetric LA catalysed.

Still, precedent exists for development of the catalytic asymmetric Pictet-Spengler reaction.<--sentence not so clear

• Typical LA catalysts (PS)
  • Aldimine selective - metal triflate catalysts. Lanthanoid Lewis acid-catalysts.
  • Studies of the Ln - Lewis acidity - Youn, Kobayashi, Stambuli, THIQ scaffold.
• Precedent for asymmetric: Friedel-Crafts using BOX ligands[Tang], Yb(OTf)3 catalysed PS from m-tyramines[Kobayashi], also Ca(HFIP)2 [Stambuli] and AuCl3/AgOTf [Youn]
  • But asymmetric first needs racemic model to... model.

The focus of this project was the development of......... Lewis acid-catalysed...from simple imines.......not widely explored THIQ (Scheme X).
Synthesis of the model imines as substrates for the cyclisation ubstrate materials were the corresponding imines. The reason: reaction less complicated. Minimising the amount of water in the reaction.

Figure X:

The potency of Brønsted acids to effect the Pictet-Spengler cyclisation of the imine substrates was evaluated. Poor.
The LA most likely to effect the transformation were screened. It was found... ineffective... THIQ.
Adaptation of the model to the acyl-Pictet-Spengler. New, effective catalyst for...= * Bullet: Yb(OTf)3 effective catalyst in the acyl-Pictet Spengler. THIQ scaffold.

Results and Discussion

The first phase of the project required synthesis of the imine model substrates, which were easily prepared in excellent yield under very mild conditions (Scheme X, Table X).

Scheme X: Synthesis of the Pictet-Spengler model substrate imines.

Table X: Synthesis of the Pictet-Spengler model substrate imines.

//(THE REASON WHY I DID THE BA STUFF) The non-catalytic formation of the activated-THIQ is usually effected by Bronsted acids in superstoichometric amounts.[Coskun + Verma + Zheng] There is also lots of stuff on the Bronsted-acid catalyst formation of the THBC scaffold. Indeed, that's what all the asymmetric Pictet-Spengler literature describes: chiral Bronsted acid-catalysts. (Fix the last two sentences. They're horrendous.) It was appropriate to evaluate the properties and behaviour of the imines under these reaciton conditions. It also facilitated familiarisiation of reaction monitoring and handling of the substrate and expected products.
//(SUMMARY OF FAILURE) H-NMR indicated good conversion of substrate to product (Entry X). The attempts to effect the cyclisation of imines 1a using neat methanesulfonic acid and elevated temperatures were unsuccessful. A decent amount of 1b cyclisation was only effected using 50 equivalents of trifluoroacetic acid and reflux conditions. However, MSA mediated cyclisations of 1b were not attempted so it is unknown whether the pKa was noticably important - i.e. pKa MSA -1.9. pKa TFA 0.19.
zero conversion with catalytic loads.

Scheme X: Expected outcome for the...

Table X: Results of the Brønsted acid...

//(HOW I MEASURED REACTION PROGRESS AND RESULTS) The yields for the reaction were monitored by H-NMR of the crude product. * Poor conversion. Only able to monitor conversion by NMR<--describe how. The reaction progress for the Brønsted acid-mediated cyclisations was qualitatively monitored by thin layer chromatography (TLC). Surprisingly, the conditions required highly polar eluent (1:5, MeOH/DCM, v/v). Use of a ninhydrin stain allowed visualisation of the characteristic yellow secondary amine spot indicative of the formation of the THIQ product. Lit HNMR in CDCl3. Used DMSO to better see imine proton in dimethoxy substrates.
//(THE STUFF IS DIFFICULT TO HANDLE) Only qualitiative analyses of the reaction progress was possible. Purification of the THIQ 2b was unsuccessful. There was significant difficulty in purification of X. This sentiment was THIQ difficult to handle. Behaved unexpectedly on silica. Stambulli's comment.

//(...AND MOVING ON TO LA)

• (Move to stronger(?) Lewis acids. But why?. Choice of LA. Triflates + Yb(OTf)3. High LA. f13.)
  

//(BACK TO THE LA SCREEN) The project focus was on the Pictet-Spengler reaction in the presence of Lewis acids. The next stage was the screening of a number of LA with reputations of effectiveness. Copper(II)OTf is known to coordinate to BOX ligands. So that was used.[Tang 2009] As were Zn and Ag, just for comparison and to evaluate.

//(ON THE LNs AND LNOTfs) The trivalent lanthanoids are highly lewis acidic. The lanthanoid triflates are potent Lewis acids.The electron withdrawing effects of the triflate counterion is particularly effective at enhancing the LA. (Imamoto, 1999) In particular, the two most acidic Lanthanoid triflates are Ytterbium and Scandium(III). Yb(OTf)3 is less acidic than only Sc(OTf)3. Since the Yb(OTf)3 has already been shown to be an effective catalyst in the formation of THIQ scaffolds, this catalyst was chosen.

//(SUBSTRATE CHOICE FOR THE LA SCREEN) The electron-rich model substrates 1b and 1d were most likely to undergo the cyclisation reaction. A scren to test teh effectiveness of the.The screen was adapted from the conditions described by Kobayashi.[ref]
The electron-rich model substrates 1b and 1d were most likely to undergo the cyclisation reaction. A scren to test teh effectiveness of the.The screen was adapted from the conditions described by Kobayashi.[ref]

Scheme X: The Lewis acid-catalyst screen for the PS formation of 2b and 2c

Scheme X

File:Newfig

Scheme X

//(SUMMARY OF FAILURE: 3-4 sentences) Under the conditions employed, the four metal triflates were ineffective at forming the Pictet-Spengler products (2a-b) from the corresponding imines (Scheme X).

//(SUGGESTIONS FOR FAILER AND ATTEMPTS TO FIX) It was thought the slight variations in substrates were responsible for the negative results. Like many examples of the PS formation of THIQ, the substrate materials in the template employed were the aryl-amine and the aldehyde (Scheme X). Attempts to reproduce the literature with minimal changes in procedure prompted re-screening of the Yb(OTf)₃ catalyst under analogous conditions (Scheme X). Stambuli reported similar yield for the transformation from the m-tyramine substrate using a significantly altered method (Scheme X). This was also attempted with the varied dimethoxyphenethylamine substrate to no effect.

• Substrate specific? Compare hydroxy + and Stambuli's replicated result with altered reaction conditions.

//(SEGWAY TO ANOTHER ALTERNATIVE - THE aPS)

• why it is good.
  • EWG should increase the reactivity of the inert imines.
  • LIt examples. 2 only (Youn and Jacobsen)
• Literature example of identical substrate and product.

//(REPRODUCING LIT.) The acyl-Pictet-Spengler reaction to give substituted, electron rich THIQs has been shown to be effected by the combination of AuCl₃/AgOTf and X and X.[ref] Generation of the acyliminium in situ powerful results The literature outcomes were easily reproduced with similar results (Table X).
The isolated by-products, following purification by chromatography of the acyl Pictet Spengler reaction included 4-nitrobenzaldehyde (1X), monoacelated dimethoxy PEA (X) and a suspected diacetylated dimethoxy phenethylamine.[fn] The literature procedure for the purification of the AuCl3/AgOTf aPS product involved separation silica gel column chromatography with no post-reaction work-up. Application of the procedure with the non acylated reaction imine ellicited no reaction.

//(MECH SUGGESTIONS?) It was (presumed) the combination of AuCl3/AgOTf resulted in the in situ formation of AuOTf following formation AgCl (ref?). Since the AuCl3/AgOTf effected no cyclisation in the non-acyl PS reaction, it was suspected the successful cyclisation was effected by the acyl group.

Scheme X

//(ADAPTATION TO YB. BECAUSE IT'S SUPPOSED TO BE AWESOME.) Moved to Yb(OTf)3 and implementatin of NMR assay. Given the high Lewis acidity of Yb(III), the acyl PS reaction was then attempted with the Yb(OTf)3 catalyst. The reaction conditions were adapted from the AuCl3/AgOTf procedure. Anhydrous conditions were employed to minimise Yb(OTf)3 poisoning by wate, competing hydrolysis reactions, and the generation of TfOH. The first attempts at the Yb(OTf)3 catalysed PS reaction suggested formation of rapid formation of the expected product and hydrolysis byproducts by TLC. Attempts to minimise competing hydrolysis reactions involved reduction of the reaction temperature.

//(CONCURRENT DEVELOPMENT OF NMR ASSAY) ¹H-NMR of isolated byproducts of the isolated reaction by products revealed sufficient peak separation. Different to previous monitoring of the conversion to non-acylated THIQ. DMSO was worse. Started with CDCl3, Ideally, conversion was by use of tetrachloroethane as an internal standard and peak integrals of the aldehydic proton, the acyl or CH2 environment of 5 and either the stereogenic proton or the CX aromatic proton of 3d.

The first attempts to gauge the yield by NMR analysis of the crude product in CDCl3. Mention the 81% yield by NMR vs. 50% isolated product. Two problems with assay: Insoluble white solid in CDCl3. Therefore mass balance of NMR was wrong. And intereference of 2,6-lutidine peaks. The lutidine was easy to deal with - minimise presence by performing a mildly acidic acid work up. This made the insoluble bit worse, since there is Cl and some H+ in reaction mixture and I knew there was monoacetylated (from TLC).... adding acid made formation of suspected salt more pronounced. So added basic workup after acidic work up. Result --> Lutidine muted or removed and all of crude product goes into CDCl3.

• Byproducts only aldehyde + acetamide. Hydrolysis during reaction or workup? Unknown.

Error creating thumbnail: File with dimensions greater than 12.5 MP

Figure X

Once the NMR assay was worked out efforts to minimise hydrolysis were more efficient (<-- Does this make sense?). Allowed gauge of yield. Reducing temperature of reaction Increased scale slightly - hydrolysis went down. Where's the water coming from? Still unsure when the hydrolysis occured. Requires NMR studies.
Confirmed byproducts of Yb after column.[ref] Got 60% isolated yield from 7 mol% load. Doesn't matter when hydrolysis happens?
Probing the effectiveness of teh catalyst - 1 mol% load. NMR yield - X. Isolated yield, 77%.

Table X

Scheme X

• Pros to reaction
  • nicer to perform than gold. Potentially shorter reaction times.

• Downsides to the NMR assay:
  • Requires DRY crude product - can fix this by creating standard curves of TCE:Product and TCE:Aldehyde.
• Development of workup procedure. <--integrate above.

Conclusion

• Summary of what I just talked about.
• Comment on robustness(?) of model system.
• Acyl Pictet-Spengler + LA catalyst = happy, effective combination.
• What next?
  • Optimising reaction conditions - order of addition? Reaction time? Typically, the solvents used to effect Pictet-Spengler cyclisations are toluene, dichloromethane and dichloroethane.

88Suggested formation of iminium by Δ colour intensity. Possible UV-Vis monitoring of rxn? Kinetic NMR. See how far the catalyst can be pushed = increase temp, decrease load.

• • Evaluation of other MOTfs in acyl PS reaction (Esp. CuOTf2).
  • CuOTf2-BOX complexes for asymmetric.
  • enantioselective - pyBOX. Yb(OTf)3
  • PZQ?
• Limitations(?) for catalytic PS - non-electron rich. None currently identified in Nature and synthetically (for homogenous but mention zeolite and clay).
  • Acidic zeolite adsorbent has been shown to effect the cyclisation of non-electron rich β-phenethylamines with a variety of alkyl- and aryl- aldehydes and ketones. [Hell 2004]

Experimental

NMR specs. What CDCl₃ and DMSO-d₆ was used. All melting points were recorded using on a Standford Research Systems OptiMelt (ø = X mm, 90?? mm (pyrex?) capillaries, ramp rate 1 °C min^-1). Glassware used in anhydrous reactions were (or was?) dried >2 hours at 130 °C. All molecular sieves were microwave activated and cooled under nitrogen before immediate use.

N-benzylidene-2-phenylethanamine (1a)

To a stirring solution of benzaldehyde (4 mL, 40 mmol, 1 equiv.) in diethyl ether (10 mL) was slowly added 2-phenylethanamine (5 mL, 40 mmol, 1 equiv.). The clear yellow solution was stirred at room temperature for 5 hours, dried (MgSO₄) and concentrated in vacuo to yield a yellow oil that solidified on standing to give a yellow crystalline solid (8.3 g, 99%). M.p. 32.8-35.3 °C. ¹H-NMR (300 MHz; DMSO-d₆): δ 8.26 (s, 1H), 7.71 (dd, J = 6.6, 2.9 Hz, 2H), 7.45-7.16 (m, 10H), 3.81 (t, J = 7.3 Hz, 2H), 2.93 (t, J = 7.3 Hz, 2H). ¹³C-NMR (75 MHz; CDCl₃): δ 161.5, 139.9, 136.2, 130.6, 129.0, 128.6, 128.3, 128.1, 126.1, 63.2, 37.5. Relevant lab book entries: KAB18-1, KAB18-2.

N-benzylidene-2-(3,4-dimethoxyphenyl)ethanamine (1b)

To a stirring solution of benzaldehyde (3.1 mL, 30 mmol, 1 equiv.) in diethyl ether (10 mL) was slowly added 2-(3,4-dimethoxyphenyl)ethanamine (5.0 mL, 30 mmol, 1 equiv.). The mixture was stirred at ambient temperature for 5 hours, diluted with diethyl ether (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield a yellow oil that crystallised on standing (7.3 g, 90%). M.p. X-X °C. ¹H-NMR (300 MHz; CDCl₃): δ 8.15 (s, 1H), 7.73 (dd, J = 6.7, 3.0 Hz, 2H), 7.43 (dt, J = 5.3, 2.6 Hz, 3H), 6.83-6.77 (m, 3H), 3.89-3.84 (m, 8H), 2.99 (t, J = 7.2 Hz, 2H). ¹³C-NMR (75 MHz; CDCl₃): δ 161.5, 148.7, 147.4, 136.2, 132.6, 130.6, 128.6, 128.0, 120.9, 112.6, 111.2, 77.6, 77.1, 76.7, 63.3, 55.89, 55.71, 37.0. Relevant lab book entries: KAB19-1, KAB19-2.

N-(4-nitrobenzylidene)-2-phenylethanamine (1c)

To a stirring suspension of 4-nitrobenzaldehyde (6.0 g, 40 mmol, 1 equiv.) in diethyl ether (40 mL) was slowly added 2-phenylethanamine (5.0 mL, 40 mmol, 1 equiv.). The mixture was stirred at room temperature for 1 hour before a yellowish solid precipitated. The mixture was concentrated under reduced pressure and the residue recrystallised from diethyl ether to afford the pure product as pale yellow needles. M.p. 70.6 - 71.1 °C. ¹H-NMR (300 MHz; CDCl₃): δ 8.25 (d, J = 8.7 Hz, 2H), 8.20 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.31-7.26 (m, 2H), 7.20-7.18 (m, 1H), 3.93 (t, J = 7.2 Hz, 2H), 3.04 (t, J = 7.3 Hz, 2H). ¹H-NMR (300 MHz; DMSO-d₆): δ 8.41 (s, 1H), 8.28 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 7.31-7.16 (m, 5H), 3.89 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H).¹³C-NMR (75 MHz; DMSO-d₆): δ 160.1, 149.0, 142.1, 140.1, 129.30, 129.26, 128.7, 126.5, 124.4, 62.4, 37.1. Relevant lab book entry: KAB22-1.

2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (1d)

4-Nitrobenzaldehyde (3.7 g, 23.5 mmol, 1 equiv.) was suspended in diethyl ether (50 mL). 2-(3,4-dimethoxyphenyl)ethanamine (4.0 mL, 24.5 mmol, 1 equiv.) was added dropwise, with stirring. The mixture was left to stir at ambient temperature for 6 hours resulting in the precipitation of a fine light yellow solid. The solvent was removed in vacuo to give the crude product as a fine, yellow powder (7.95 g, 103%). Recrystallisation of the crude product from ethanol (~200 mL) afforded the pure product as yellow needles (7.1 g, 23 mmol, 92%). M.p. 123.3-124.2 °C. ¹H-NMR (200 MHz; CDCl₃): δ 8.29-8.23 (m, 2H), 8.19 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 6.78-6.72 (m, 3H), 3.91 (td, J = 7.1, 1.1 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 2.99 (t, J = 7.1 Hz, 2H). ¹H-NMR (300 MHz; DMSO-d₆): δ 8.40 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.7 Hz, 2H), 6.84 (dd, J = 4.8, 3.3 Hz, 2H), 6.75 (dd, J = 8.2, 1.4 Hz, 1H), 3.86 (t, J = 7.1 Hz, 2H), 3.69 (d, J = 2.1 Hz, 6H), 2.90 (t, J = 7.2 Hz, 2H). ¹³C-NMR (75 MHz; DMSO-d₆): δ 160.0, 148.9, 147.6, 142.1, 132.5, 129.2, 124.4, 121.1, 113.3, 112.2, 62.7, 55.94, 55.80, 36.6. Relevant lab book entries: KAB23-1, KAB23-2.

Attempts at the synthesis of (2a)

Relevant lab book entries: KAB20-2, KAB20-3, KAB20-4.

Bronsted acid synthesis of (2b)

Methanesulfonic Acid

Relevant lab book entry: KAB21-1.

Trifluoroacetic Acid

Relevant lab book entries: KAB21-2, KAB21-3, KAB21-4.

Bronsted acid synthesis of (2c)

Relevant lab book entries: KAB24-1, KAB24-2, KAB24-3, KAB24-4.

Procedure for the Lewis Acid-Catalyst Screen

Substrate stock solutions (0.20 M in dichloromethane) were prepared N-benzylidene-2-(3,4-dimethoxyphenyl)ethanamine (0.20 M) and 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine. Relevant lab book entry: KAB21-5, KAB21-6, KAB21-7, KAB21-8, KAB24-5, KAB24-6, KAB24-7 & KAB24-8.

Yb(OTf)₂ catalysed synthesis of 2c

Procedures were adapted from the literature.[Kobayashi 2006][Stambulli 2010]

Procedure 1

To a mixture of Yb(OTf)₃ (120.5 mg, 0.194 mmol, 0.2 equiv.) and microwave activated 3 Å powdered molecular sieves (~20 mg) was added dry dichloromethane (30 mL). Benzaldehyde (0.10 mL, 0.97 mmol, 1 equiv.) and 3,4-dimethoxyphenethylamine (0.16 mL, 0.97 mmol, 1 equiv.) were added. The reaction mixture was stirred under nitrogen for 24 hours. Saturated sodium bicarbonate solution (30 mL) was added to quench the reaction. The organic layer was separated and the alkaline aqueous fraction was extracted with ethyl acetate (3 × 50 mL). The organic fractions were combined, dried over magnesium sulfate and concentrated under reduced pressure yielding a yellow oil (392 mg, 150%). ¹H-NMR of the oil indicated the isolated product was a wet, 1:0.15 mixture of imine (1d) and 4-nitrobenzaldehyde (5). Relevant lab book entries: KAB25-1

Procedure 2

Relevant lab book entry: KAB25-2

HAuCl₄·3H₂O/AgOTf catalysed synthesis of 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (3) [Youn]

A solution of Gold(III) chloride trihydrate (31 mg, 0.079 mmol, 0.01 equiv.) and silver(I) trifluoromethanesulfonate (30 mg, 0.12 mmol, 0.02 equiv.) in acetonitrile (15 mL) was vigorously stirred at ambient temperature (~17 °C) for 1 hour. To the now yellow reaction mixture was added a pale yellow solution of 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (1d) (1.9 g, 6.1 mmol, 1 equiv.), acetyl chloride (0.40 mL, 6.1 mmol, 1 equiv.) and 2,6-lutidine (0.70 mL, 6.1 mmol, 1 equiv.) in acetonitrile (250 mL). The reaction mixture was stirred for 14 hours at ambient temperature (~12 °C), concentrated in vacuo and purified by silica gel column chromatography (50-100% ethyl acetate/hexane, v/v). The expected product (3d) was isolated (0.86 g, 41%) in addition to the byproducts,4 and 5. Relevant lab book entries: KAB26-1 & KAB26-2, KAB26-3, KAB26-10.
1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (3d)
M.p. 176.8 - 178.7 °C. Two amide rotamers (91:9). Signals corresponding to the major rotamer: ¹H-NMR (200 MHz; CDCl₃): δ 8.12 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 6.90 (s, 1H), 6.69 (s, 1H), 6.48 (s, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.74-3.70 (m, 1H), 3.42-3.27 (m, 1H), 2.95 (ddt, J = 15.9, 10.7, 5.2 Hz, 1H), 2.81-2.71 (m, 1H), 2.18 (s, 3H). Signals corresponding to the minor rotamer: ¹H-NMR (200 MHz; CDCl₃): δ 8.17 (s, 2H), 6.60 (s, 1H), 5.94 (s, 1H), 2.32 (s, 3H). Spectroscopic data matched those in the literature.[ref]
4-nitrobenzaldehyde (4)
M.p. 103.2 - 104.3 °C. ¹H-NMR (300 MHz; CDCl₃): δ 10.18 (s, 1H), 8.42 (d, J = 8.6 Hz, 2H), 8.10 (d, J = 8.5 Hz, 2H).¹³C-NMR (75 MHz; CDCl₃): δ 190.2, 140.0, 130.5, 124.3. Spectroscopic data matched those in the literature.[ref]
N-(3,4-dimethoxyphenethyl)acetamide (5)
M.p. °C. ¹H-NMR (300 MHz; CDCl₃): δ 6.82-6.79 (m, 1H), 6.74-6.71 (m, 2H), 5.66 (s, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.48 (q, J = 6.6 Hz, 2H), 2.76 (t, J = 7.0 Hz, 2H), 1.94 (s, 3H). ¹³C-NMR (75 MHz; CDCl₃): δ 170.1, 149.0, 147.7, 131.4, 120.6, 114.7, 111.9, 111.4, 55.91, 55.86, 40.8, 35.2, 23.3.

Yb(OTf)₃ catalysed synthesis of 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (3)

The acetonitrile (HPLC grade, something 190?) was dried over microwave activated 3A molecular sieves (2.5-5.0 mm, 30 %(w/v)) for >24 hours. All glassware was ovendried (130 °C) for >2 hours prior to use. 2,6-lutidine was dried over 3A molecular sieves (diameter, 2.5-5.0 mm, 50 %(w/v)).

Procedure 1

2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (X g, X mmol, 1 equiv.) was dissolved in anhydrous acetonitrile (X mL). Relevant lab book entries: KAB26-4

Procedure 2

- Added citric acid workup. Relevant lab book entry: KAB26-5

Procedure 3

Acetonitrile/liquid N2 bath. KAB26-6 KAB26-7 KAB26-9

Procedure 4

To a mixture of 3 Å molecular sieves (~30 g) in dry acetonitrile (160 mL), under nitrogen, was added 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (1.50 g, 4.77 mmol, 1 equiv.). Once dissolved, the mixture was cooled in a brine ice bath. Acetyl chloride (0.34 mL, 4.8 mmol, 1 equiv.) and 2,6-lutidine (0.55 mL, 4.8 mmol, 1 equiv.) were added, dropwise. Yb(OTf)₃ (0.034 g, 0.048 mmol, 0.01 equiv.) was added. Thereaction mixture was allowed to warm to ambient temperature (~12 °C) and stirred under argon for 23 hours. The mixture was filtered through a bed of Celite, eluting with ethyl acetate (~50 mL). The filtrate was washed with saturated sodium bicarbonate solution (40 mL). The aqueous layer was extracted with ethyl acetate (3 × 40 mL). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to yield a yellow oil that partially crystallised on standing (1.8 g, 106%). The crude product was dissolved in hot methanol, dry loaded onto a silica gel column (ø = 6.5 cm, 15 cm) and purified by chromatography (70-100% ethyl acetate/hexane) yielding the expected product as a yellow powder (1.3 g, 77%). Relevant lab book entries: KAB26-11.

Typical procedure for the ¹H-NMR Assays

Tetrachloroethane (

References (arranged by date)

• Ueber die Bildung von Isochinolin-derivaten durch Einwirkung von Methylal auf Phenyl-aethylamin, Phenyl-alanin und Tyronsin, A. Pictet and T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030-2036. Paper
• Evaluation of the relative Lewis acidities of lanthanoid(III) compounds by tandem mass spectrometry, H. Tsuruta, K. Yamaguchi, T. Imamoto, Chemical Communications 1999, 1703-1704. Paper
• Highly efficient Lewis acid-catalysed Pictet-Spengler reactions discovered by parallel screening, N. Srinivasan, A. Ganesan, Chemical Communications 2003, 916. DOI: 10.1039/B212063A Paper
• One-step preparation of 1-substituted tetrahydroisoquinolines via the Pictet–Spengler reaction using zeolite catalysts, Adrienn Hegedus and Zoltan Hell, TetLett 2004 45, 8553–8555. DOI: 10.1016/j.tetlet.2004.09.097 Paper
  
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• Development of the Pictet-Spengler Reaction Catalyzed by AuCl3/AgOTf, S. W. Youn, The Journal of Organic Chemistry 2006 71(6), 2521-2523. DOI: 10.1021/jo0524775 Paper
  
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