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 efficiently used in the synthesis of tetrahydroisoquinoline-, tetrahydro-β-carboline- and more recently, quinoxaline-derived moieties.

• Mini-summary
• Mini-conclusion

Introduction and Background

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

The Pictet-Spengler Reaction in Nature and Organic Synthesis

The first example of the synthesis of tetrahydroisoquinoline (THIQ) from phenethylamine and formaldehyde was reported by Ame Pictet and Theodor Spengler in 1911. Pictet and Spengler, in their original paper, proposed the carbon-carbon bond forming reaction could be a mimic of The so named Pictet-Spengler (PS) reaction has since been adapted for use in the organic synthesis of useful heterocycles. The reaction typically occurs via condensation of a β-arylamine with an aldehyde or ketone followed by nucleophilic attack on the resulting iminium species (Scheme X).

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 that 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.

THIQ Antitumor antiobiotics - analogues of

The reaction typically involves the intramolecular cyclisation via the condenNotable 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 acyl-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

(SOMETHING)

Recent reviews of the literature have revealed a lack of Lewis acid-catalysed asymmetric Pictet-Spengler reactions.[ref] Furthermore, there are no known examples 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 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. Two examples are known, where PS reaction of the the unactivated phenethylamine with various aldehydes is effected by montomorillonite and zeolite frameworks. Indeed, an example in Nature for the PS formation of the THIQ scaffold is yet to be found.

(SOMETHING)

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.
While most of the literature describes excess acid and harsh conditions to effect the cyclisation to give activated-THIQ, two notable examples exist for the Lewis acid-catalyst formation of THIQ.
Still, X the Brønsted acid effected PS reactions were attempted.

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

Synthesis of the Model Substrate Materials and Brønsted Acid Stuff

The first phase of the project required synthesis of the imine model substrates, which were easily prepared in excellent yield (Scheme X, Table X). The condensation reactions of the arylamines with the corresponding aldehydes was facile. The nitro-substituted imines did not require post-reaction addition of a dehydrating agent but readily crystallised from the crude reaction mixtures.[note]

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) There are no known examples in the literature of the Pictet-Spengler reaction to give unactivated THIQ from the The non-catalytic formation of the activated-THIQ is usually effected by strong Brønsted acids in vast excess.[Coskun + Verma + Zheng]. There is also lots of stuff on the Brønsted-acid catalyst formation of the THBC scaffold. Indeed, that is what all the asymmetric Pictet-Spengler literature describes: chiral Brønsted acid-catalysts. (Fix the last two sentences. They're horrendous.) It was appropriate to evaluate the properties and behaviour of the imines under these reaction conditions. It also facilitated familiarisiation of reaction monitoring and handling of the substrate and expected products (Table X).

The attempts to effect the cyclisation of imine 1a using neat methanesulfonic acid and elevated temperatures were unsuccessful (Table X). Poor conversion was observed in amount of 1b cyclisation was only effected using 50 equivalents of trifluoroacetic acid and reflux conditions. ¹H-NMR spectroscopic analysis indicated good conversion of substrate to product (Entry X).
The activated-imine.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 ¹H-NMR spectroscopy 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). Conditions required highly polar eluent (1:5, MeOH/DCM, v/v). Use of a ninhydrin stain facilitated 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.

The Lewis Acid-Catalyst 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.
• Strong Lewis acids - comment on stoichometric Brønsted acids usually employed
• Literature - Kobayashi and Stambuli.
  • The notable literature examples of the Lewis acid-catalysed Pictet-Spengler reactions to give the activated-THIQ. The catalysts employed were Yb(OTf)₃ and **Ca(HFIP)₂.[ref] The model system was very similar.
• Lanthanoids and LnOTfs
  • • The lanthanoid triflates are potent Lewis acids.[ref] In particular, Yb(III) with its f13 configuration. The triflate counterion is particularly effective at augmenting the Lewis acidity of the Ln(III) metals.(Imamoto, 1999)
  • Other MOTfs. MOTfs have already been incorporated in asymmteric catalysis.[Tang]

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.

• Therefore screen was of MOTfs including Yb(OTf)3 on the cyclisations of 1b and 1d - Greatest potential.
  • 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 A: The Lewis acid-catalyst screen for the PS formation of 2b and 2c

Scheme B: Related to Table X.

Table X: Results of the Yb(OTf)₃ catalysed PS formation of 2b

Under the conditions employed, the four metal triflates were ineffective at forming the Pictet-Spengler products (2a-b) from the corresponding imines (Scheme A). Starting material was recovered in all reactions. Like many examples of the PS formation of THIQ, the substrate materials in the template protocol were the aryl-amine and the aldehyde. Attempts to follow the literature more closely prompted re-screening of the Yb(OTf)₃ catalyst using the phenethylamine and benzaldehyde materials resulting in recovery of the corresponding 1b imine (Scheme B).

Stambuli reported similar yield for the Yb(OTf)₃ catalysed reaction from the m-tyramine substrate using a significantly altered method.[ref] The altered protocol, which involved substitution of dichloromethane (DCM) for toluene and an increase in reaction temperature (25 C to X C) was also attempted with the 1b substrate to no effect (Table X: Entry 2). The recovered material from the attempts at the Yb(OTf)₃ catalysed PS reaction from the phenethylamine and benzaldehyde starting materials resulted in the recovery of the corresponding imine (i.e. 1b). This suggested greater substrate specificity for the LA catalysed PS formation of the -oxy(?) substituted THIQ.

The Lewis acid-catalysed acyl-Pictet-Spengler Reaction

The lack of progress prompted adaptation of the model system to the N-acyl PS variation. Only one (known) example of the LA catalysed acyl-Pictet-Spengler reaction of THIQ

//(SEGWAY TO ANOTHER ALTERNATIVE - THE aPS)

• why it is good.

Generation of the acyliminium in situ powerful results

• • 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 successful THIQ formed included the expected products (X and X) in this project, which made them ideal to template. 

The acyl-Pictet-Spengler reaction to give substituted, electron rich THIQs from corresponding imines is known to proceed in the presence of AuCl₃/AgOTf (Youn 2006). The model substrates and corresponding products included those used in this project. The AuCl₃/AgOTf represented an ideal starting point for the next stage in this project. With minimal adaptation, the literature results were reproduced (Table X, entry X). Following purification of the expected product, 3, by chromatography, 4-nitrobenzaldehyde (4) and N-(3,4-dimethoxyphenethyl)acetamide (5) were isolated. Another compound was isolated, the ¹H-NMR spectrum of which, suggested it corresponded to N-acetyl-N-(3,4-dimethoxyphenethyl)acetamide.
Application of the procedure with the non-acylated reaction imine resulted in no reaction. It was suspected the successful reaction was effected by the acyl group.

Scheme X

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

The ¹H-NMR spectroscopic analysis of the reaction by-products revealed sufficient separation of integrable peaks. Unlike monitoring of the conversion of the non-acyl-PS reactions Ideally, conversion was by use of tetrachloroethane as an internal standard and peak integrals of the aldehyde proton, the acyl or CH2 environment of 5 and either the stereogenic proton or the CX aromatic proton of 3d (Figure X).
The first attempts to gauge the yield by ¹H-NMR spectroscopy of the crude product in CDCl₃ were inconsistent with the isolated product yield. The spectroscopic analysis suggested a substrate to product conversion of 81%, while the isolated yield after chromatography was 51%. There were two problems associated with the spectroscopic assay: formation of a CDCl₃ insoluble white solid and peak interference by 2,6-lutidine. The nature of the assay relied on complete dissolution of the crude product into the CDCl₃ solvent. Incomplete dissolution of the crude product meant that comparison of the NMR spectrum with the added mass of the internal standard to the crude added product were non-comparable. Furthermore, the 2,6-lutidine signals were coincidental to the integrable peaks of interest.

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.

Future Work

• Optimising reaction conditions
• Screen other LAs in aPS.
• Asymmetric
• 1,1-disubstituted-1,2,3,4-THIQ - supposed to be difficult.
• UV-Vis
• NMR kinetics thing
• Brønsted acids
  • (catalysed?) acyl-PS
  • activated-THIQ under reflux conditions.
  • 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.
    

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.
  • Suggested 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 dried >2 hours at 130 °C then cooled under inert gas before use. 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, 24 mmol) was suspended in diethyl ether (50 mL). 2-(3,4-dimethoxyphenyl)ethanamine (4.0 mL, 25 mmol) 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 (8.0 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 1-phenyl-1,2,3,4-tetrahydroisoquinoline (2a)

(FIX THIS TABLE THE LAST ENTRY IS INCORRECT. SHOULD BE 6% YIELD - BY NMR).

Typical procedure (e.g. Entry 2): To a stirring solution of methanesulfonic acid (3.0 mL, 46 mmol) at 0 °C was added N-benzylidene-N-phenethylamine (1a) (0.48 g, 2.3 mmol). The now yellow solution was heated to 60 °C. After 30 minutes the solution had turned dark red. The reaction mixture was stirred at temperature for 68 hours. The mixture was poured over an ice water slurry (~15 mL) and made alkaline by the addition of sodium hydroxide solution (5 M), resulting in the formation of a white solid. The mixture was extracted with diethyl ether (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate and concentrated in vacuo to yield a brown oil (410 mg). ¹H-NMR of the indicated the isolated material was the 1a starting material.
In the case of entry 3, the yield was calculated by comparing the integrals of the 1a aldehydic proton (CDCl₃ δ X ppm) with the 2a CX proton (CDCl₃ δ X ppm).[ref] Relevant lab book entries: KAB20-2, KAB20-3, KAB20-4.

Brønsted acid synthesis of (2b)

Methanesulfonic Acid

Relevant lab book entry: KAB21-1.

Trifluoroacetic Acid

To a stirring solution of N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (1b) (1.9 g, 7.1 mmol) in toluene (40 mL) was added trifluoroacetic acid (30 mL, 0.36 mol). The dark yellow solution was refluxed for 22 hours. etc. etc. etc. ¹H-NMR of the isolated material confirmed the presence of 6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2b).[ref] Relevant lab book entries: KAB21-2, KAB21-3, KAB21-4.

Brønsted 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 (121 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 (MgSO₄) and concentrated under reduced pressure yielding a yellow oil (390 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 (MgSO₄) and concentrated under reduced pressure 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)

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