Todd:The Lewis Acid-Catalysed Pictet-Spengler Formation of Substituted 1,2,3,4-Tetrahydroisoquinolines

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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

The Pictet-Spengler Reaction in Organic Synthesis and Nature (still not happy with this section)

The first example of the synthesis of tetrahydroisoquinoline (THIQ) from β-phenethylamine and formaldehyde was reported by Amé Pictet and Theodor Spengler in 1911.^[1] The reaction now known as the Pictet-Spengler (PS) reaction typically occurs via the condensation of a β-arylamine and an aldehyde or ketone to give an electrophilic iminium species that is subsequently attacked by the neighbouring aryl group (Scheme 1) (THIS SENTENCE IS TOO LONG).

Scheme 1: The typical Pictet-Spengler reaction based on the original synthesis of tetrahydroisoquinoline (blue).

The usefulness of the PS reaction is reflected by its application in Nature. A relatively recent discovery, the class of enzymes known as Pictet-Spenglerases are instrumental in the synthesis of strictosidine and nor-somethin, which are key intermediates in the biosynthesis of numerous plant alkaloids (Figure 1).^[2] The nonribosomalpeptidase...??

Figure 1: CHANGE THIS FIGURE

It should be unsurprising then, that the PS reaction is particularly useful in the synthesis of the tetrahydro-β-carboline and THIQ scaffolds typically associated with the plant alkaloids. Other notable variations include the acyl- and alkyl-PS reactions and the modified PS to give fused quinoxalines. The PS reaction is a powerful tool in the synthesis of complex, biologically active polycyclic heterocycles.[THIQ antibiotics, see waldmann for review, receptor ligand studies]
DO NOT DRIBBLE OFF HERE

Scheme 2: The tetrahydro-β-carboline, acyl-, alkyl- and quinoxaline Pictet-Spengler variations

The Limits of the Pictet-Spengler Reaction in Organic Synthesis (unsure if this title is appropriate for its content)

One apparent limitation to the PS reaction is the catalytic formation of non-activated THIQs. Ironically, the first PS formation of the THIQ scaffold appears to be the most difficult to produce catalytically via the PS route, at least by traditional homogenous catalytic methods. Two examples are known where the PS cyclisation of the unactivated β-phenethylamine with various aldehydes is effected by zeolite and acidic montomorillonite frameworks.^[D] Indeed(???), an example in Nature for the PS formation of the THIQ scaffold is yet to be found.

Recent reviews of the literature have revealed a lack of Lewis acid-catalysed asymmetric PS reactions.^{[2(iii), H]} Furthermore, there are no known examples of the asymmetric PS formation of the THIQ scaffold. Instead, the focus is on the organocatalysed asymmetric PS formation of tetrahydro-β-carbolines using catalysts such as the chiral thioureas[ref] and binapthyl-derived phosphoric acids.[ref]

There is also not much on the LA catalysed acyl-PS formation of THIQ. Even though the N-acylminium ion is supposed to be far more reactive than its iminium counterpart(?)....(Unsure if I should put stuff on the acyl-PS here or just put the 'intro' for it in the results section).

Still, there is precedent for the development of a catalytic asymmetric PS reaction to yield the THIQ scaffold. Rather than using chiral organocatalysts, as is the case with the synthesis of the tetrahydro-β-carboline moiety, the potential for the catalytic asymmetric formation to give the THIQ scaffold lies with Lewis acid catalysis. Cyclisation to give THIQ is difficult because the imines are rather unreactive (Jac04 mentions their low reactivity).

• Typical Lewis acid catalysts (PS)
  • 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.

Project Summary

While there are a number of known examples of (or for?) the Lewis acid-catalysed formation of the tetrahydro-β-carboline scaffold, the scope of the Lewis acid-catalysed formation of THIQ is limited. Three examples of the Lewis acid-catalysed PS reactions to give the THIQ scaffold involve the use of ytterbium(III) triflate,^[A] calcium hexafluoroisopropoxide^[B] and a gold(III) chloride-silver triflate combination.^[C]

The focus of this project was the development of an achiral Lewis acid-catalysed PS method for the formation of the THIQ scaffold that would be adaptable to an asymmetric model (Scheme 3). In order to minimise complications arising from the one-pot procedures using the aldehyde and arylamine starting materials, the corresponding isolatable imines were prepared for use as model substrates (Scheme 3, 1a-d).

Scheme 3: Project outline for the PS formation of THIQs (2a-c and 3) from simple imines (1a-d)

The known literature describes the use of strong Brønsted acids in vast excess in PS syntheses of the activated-THIQ. It was appropriate to evaluate the capacity of strong Brønsted acids to effect the PS formation of the THIQ scaffold. It was found the ability of Brønsted acids to effect the PS cyclisation of the imine substrates to give the THIQ scaffold was poor unless present in vast excess or at high temperatures. The evaluation of the most promising Lewis acid catalysts revealed a similar ineffectiveness at inducing the PS formation of the THIQs 2b and 2c.
Adaptation of the model to the acyl-PS produced more promising results. (Stuff about the relative mildness of the acyl-PS?). The ytterbium(III) triflate Lewis acid-catalyst was found to be highly efficient at inducing the acyl-PS cyclisation of the activated THIQ scaffold. After minimal optimisation of the reaction conditions, the novel achiral Lewis acid PS reaction to give the THIQ scaffold under "nicer and better conditions than the literature results for the Au/Ag cat. reaction...."

Results and Discussion

Synthesis of the Model Substrate Materials and the Brønsted Acid-Mediated Cyclisations

The first phase of the project required synthesis of the imine model substrates, which were easily prepared in excellent yield (Scheme 4, Table 1). The condensation reactions of the arylamines with the corresponding aldehydes was facile. The nitro-substituted imines (1c and 1d) did not require post-reaction addition of a dehydrating agent but readily crystallised from the crude reaction mixtures.^[C1]

Scheme 4: Synthesis of the substrates for the Pictet-Spengler model.

Table 1: Results of the synthesis of the substrates for the Pictet-Spengler model.

The PS formation of activated-THIQs is typically effected by an excess of strong Brønsted acids and high temperatures.^[Gao] There is a lack of known catalytic examples of the PS reaction to give THIQs. In contrast, there is a plethora of examples describing the Brønsted acid-catalysed PS formation of the tetrahydro-β-carboline scaffold from tryptamine and various aryl- and alkyl-aldehydes. It was appropriate to evaluate the reactivity of the model imine substrates under the excess and catalytic Brønsted acid reaction conditions.

The attempts to effect the cyclisation of imine 1a using neat methanesulfonic acid and elevated temperatures were largely unsuccessful (Table 2, Entries 1-3). Of the activated imine, 1b, ¹H-NMR spectroscopic analysis indicated good conversion when a large excess of trifluoroacetic acid was used (Table 2, Entry 5). Lowering the acid load and increasing the reaction temperature resulted in moderate conversion. Under catalytic conditions, no conversion of 1b was observed after 5 days (Table 2, Entries 5-6).

Scheme 5: Expected outcome for the Brønsted Acid-mediated Pictet-Spengler cyclisations.

Table 2: Results of the Brønsted acid-mediated Pictet-Spengler cyclisations.

The conditions for monitoring the reaction by thin layer chromatography (TLC) required a highly polar eluent (1:5, methanol/dichloromethane, v/v). Use of a ninhydrin stain facilitated visualisation of the characteristic secondary amine, which appeared as a strong yellow spot, indicative of the THIQ formation. Conversion for the reaction attempts to give 2a and 2b were determined by ¹H-NMR spectroscopy of the crude products of known mass. The conversion and overall yield was calculated on the total mass of the isolated crude product and the relative peak integrals of the imine protons and the C1-THIQ protons (Figure X). A final comment on the HNMR in CDCl₃. Used DMSO to better see imine proton in dimethoxy substrates.

Figure X: ¹H-NMR of the...

Despite the considerable conversion, by ¹H-NMR spectroscopy of imine 1b to the corresponding THIQ (Table 2, Entry 5), no product was isolated. The high polarity of the substrates and products made in were difficulties in the chromatographic based assay techniques. The imine substrate materials did not behave as expected by TLC, often appearing as 2 or 3 spots, despite having clean NMR spectra. Stambulli The literature described recrystallisation and chromatographic methods for the separation of the compounds, however all attempts at these purification methods were unsuccessful.

Only qualitatively able to monitor conversion of imine 1d to 2c (by TLC and NMR). Yes there was conversion to product. But unable to compare imine peak (in the midst of a mass of peaks) with the C1 proton (clean). Did not have internal standard set up at this time. In addition to the difficulties with purification. So, able to say, yes there was THIQ formation - the extent? Unknown.

The poor results of the Brønsted acid stuff was not entirely unexpected given the lack of precedent in the literature for the catalytic preparation of similar THIQ (and comments in footnotes...). Similar sentiments on the stability of the imines are reported, though more often than not, expressed as passing comments in footnotes.

The Lewis Acid-Catalyst Screen

The next phase of the project involved the evaluation of a number of Lewis acids with potential to effect the formation of the THIQ scaffold. Given the literature procedures for the formation of the THIQ scaffold using excess amounts of strong Brønsted acids, it was expected that strong Lewis acids would be required to effect the PS reaction under catalytic conditions.
The lanthanoid (Ln) triflates are potent Lewis acids. The triflate counterion is highly effective at augmenting the Lewis acidity of the Ln(III) metals.^[I] Ytterbium(III) in particular, with its f¹³ configuration, makes it one of the most Lewis acidic metals of the lanthanoid series.^[S] Metal triflates in general have also been described as selective at coordinating to aldimine nitrogens.^[I] Previous studies reporting highly selective asymmetric catalysis by combining Lewis acids with chrial bisoxazoline ligands in mechanistically similar reactions made them an attractive choice for evaluation in the screen given the overall goal for adaptation of the model to an asymmetric system (THIS SENTENCE IS TOO LONG).^[Tang]

• 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 screen to test the effectiveness of the.The screen was adapted from the conditions described by Kobayashi.[ref]
  

The conditions for the Lewis acid screen were adapted from the literature.^[A] Under the conditions employed, the four metal triflates were ineffective at forming the Pictet-Spengler products (2b-c) from the corresponding imines (Scheme 6). Starting material was recovered in all reactions.

Scheme 6: The Lewis acid-catalyst screen for the PS formation of 2b and 2c.

Yb(OTf)₃ is already established as a Lewis ..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. 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 7, Table 3).

Scheme 7: Related to Table 3.

Stambuli reported similar yield for the Yb(OTf)₃ catalysed reaction from the m-tyramine substrate using a significantly altered method (or should I call it 3-(2-aminoethyl)phenol and not bother putting another figure in?)).^[B] The altered protocol, which involved substitution of the dichloromethane (DCM) solvent for toluene and an increase in reaction temperature (25 °C to 110 °C) was also attempted with the phenethylamine and aldehyde substrates(Table 3: Entry 2). The recovered material from the attempts at the Yb(OTf)₃ catalysed PS reaction from the phenethylamine and benzaldehyde starting materials was identified, by ¹H-NMR spectroscopy as the corresponding imine 1b. The negative results suggested greater substrate specificity for the Lewis acid catalysed PS formation of the substituted THIQ.

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

The Lewis Acid-Catalysed Acyl-Pictet-Spengler Reaction

The lack of progress prompted adaptation of the model system to the N-acyl PS variation. The in situ generated N-acyliminium is a highly reactive species in comparison to the iminium in the normal PS. Consequently, Acyl-PS reactions are relatively mild. Nonetheless, there are limited known examples of the acyl-PS reaction effected catalytic Lewis acids.

One example of the Lewis acid-catalysed acyl-PS reaction to give the THIQ describes the catalyst combination of AuCl₃ and AgOTf.^[C] This reaction was an ideal starting point for the Lewis acid catalysed acyl-PS reaction, particularly due to the identical starting materials and expected products with this project.

With minimal adaptation, the cyclisation was effected with moderate yield (Scheme 8, Table 4: Entry 1). Presumably, the reduced yield in comparison to the reported yield was partially due to the use of HAuCl₄·3H₂O instead of AuCl₃. Following purification, the product, 3, and by-products, 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.

Scheme 8: The HAuCl₄·3H₂O/AgOTf catalysed acyl-PS reaction and associated by-products.

The procedure was performed in the absence of acylating conditions resulting in recover of the imine starting material, which was consistent with the literature.^[C]

Implementation of the Yb(OTf)₃ Lewis acid catalyst in a protocol adapted from the HAuCl₄·H₂O/AgOTf co-catalsyed reaction gave highly promising results (Scheme 9, Table X). Anhydrous conditions were employed 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. The extent of hydrolysis was minimised by reducing the initial reaction temperature.

Table 4: Results of the Lewis acid-catalysed acyl-PS reactions.

Scheme 9: The Yb(OTf)₃ catalysed acyl-PS formation of THIQ.

The reaction optimisation process was made more efficient by establishing a spectroscopic assay of the crude products. ¹H-NMR spectroscopic analyses of the reaction product and by-products revealed sufficient separation of integrable peaks (Figure X). Unlike monitoring of the conversion of the non-acyl-PS reactions, conversion and yield were gauged by comparison of the hydrolysis THIQ product and the hydrolysis by-products. Ideally, conversion was by use of 1,1,2,2,-tetrachloroethane (CDCl₃ δ 5.97 ppm) as an internal standard and peak integrals of the aldehyde proton of 4, the acyl- or CH2 environment of 5 (Figure X, inset 2) and either the stereogenic proton or the aromatic proton of 3 (Figure X, inset 1).

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Figure X: Overlay of the acyl-PS THIQ product, 3 (black) and associated by-products, 4 (red) and 5 (blue).

The first attempts to gauge the yield by ¹H-NMR spectroscopy of the crude product (in CDCl₃) were inconsistent with the isolated product yield. 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: the presence 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 (see section 5.12). Incomplete dissolution of the crude product meant the mass of the crude product assayed and the mass of the internal standard were non-comparable by ¹H-NMR spectroscopy. Furthermore, the 2,6-lutidine signals were partially coincidental to the integrable peaks of interest.

A post-reaction work-up procedure was developed in order to address the problems with the ¹H-NMR assay. The 2,6-lutidine peaks were minimised by including a citric acid wash of the crude product. The presence of chloride in the crude reaction mixture exacerbated the formation of a suspected hydrochloride salt in subsequent attempts to dissolve the extracted product in CDCl₃. This was successfully resolved by implementing an alkaline wash following the acid-workup.

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%.

• 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.

The lack of imine reactivity in both the Yb(OTf)₃ catalysed and HAuCl₄·H₂O/AgOTf co-catalysed PS formation of the THIQ suggested the N-acyliminium intermediate was primarily responsible cyclisation. This makes sense because of the electron withdrawing properties N-acyliminium increasing the electrophilicity of the imine carbon.

Future Work

Due to time constraints, minimal optimisation of the Yb(OTf)₃ catalysed acyl-PS reaction was achieved. The and effects of solvent, reaction temperature, acylating agents and duration effects were not adequately explored. The primary solvents used in catalytic asymmetric PS reactions are toluene and dichloromethane, which are notably different from the polar acetonitrile that was used in the reactions.[ref] A screen the catalytic potential of other metal triflates in the acyl-PS reaction is necessary. While Yb(OTf)₃ may be one of the most Lewis acidic catalysts, the d-block transition metal triflates are more known to do the asymmetric thing. But there is also a report of Yb(III)-pyBOX complexes. On a similar note, the Brønsted acids in the acyl-PS the high Lewis acidity of the Yb(OTf)₃ catalyst in conjunction with the acyl-PS reaction...evaluation in the synthesis of the biologically active(?) 1,1-disubstituted activated THIQs, which includes the spirocyclic THIQs.

• Asymmetric

• 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. Evaluation of the achiral Brønsted acids in the acyl-PS reaction would also be appropriate.

• 1,1-disubstituted-1,2,3,4-THIQ - supposed to be difficult.
• NMR kinetics thing
• Brønsted acids
  • (catalysed?) acyl-PS

Conclusion

The Yb(OTf)₃ catalysed acyl-PS reaction is an efficient route to the dimethoxy substituted THIQ scaffold.

Strong Brønsted acids are ineffective at

• Summary of what I just talked about.
• Comment on robustness(?) of model system.
• Acyl Pictet-Spengler + Lewis acid catalyst = happy, effective combination.
  • Despite there not being many literature examples of the reaction.
• 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

The CDCl₃ and DMSO-d₆ solvents used in ¹H-NMR and ¹³C-NMR spectroscopic analyses were obtained from the Cambridge Isotope Laboratories. All melting points were recorded using on a Standford Research Systems OptiMelt (capillaries: ø = X-X mm, 90mm; 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 under reduced pressure to yield a yellow oil that solidified on standing to give a yellow crystalline solid (8.3 g, 99%). M.p. 33-35 °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 (MgSO₄) and concentrated under reduced pressure to yield a yellow oil that crystallised on standing (7.3 g, 90%). M.p. 31-33 °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. 71-72 °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 under reduced pressure 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. 123-124 °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)

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 (MgSO₄) and concentrated under reduced pressure 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 aldehyde proton (CDCl₃ δ X ppm) with the 2a C1 proton (CDCl₃ δ X ppm).[ref] Relevant lab book entries: KAB20-2, KAB20-3, KAB20-4.

Brønsted acid synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (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 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (2c)

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

27/03/12. A suspension of KAB23-1 (610 mg, 1.94 mmol, 1 eq) in toluene (20 mL) was prepared before the slow addition of trifluoroacetic acid (6 mL, 78.4 mmol, 40 eq). The pale yellow suspension turned clear and orange-red immediately after the addition of TFA. The reaction mixture was reflux heated to 110 °C from 18:45. After 15 minutes, the reaction turned clear yellow. TLC indicated complete consumption of the starting material after 35 minutes (MeOH/DCM, 15%, v/v; ninhydrin stain). TLC of reaction mixture (30 min) The reaction mixture was promptly removed from the oil bath and allowed to cool.

28/03/12. After standing at rt for 13 hours, the reaction mixture was poured over ice then basified with NaOH (6 M), resulting in the brief formation of a white precipitate, which was presumably dissolved in the organic phase. The organic fraction was isolated and the aqueous fraction extracted with EtOAc (3 × 30 mL) then Et2O (50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB24-1 as a yellow paste, which showed signs of solidifying (~2 g wet). The crude product was put under a high vacuum for >7 hours, which solidified some of the product. The remainder was a paste.

Attempted to purify by silica gel column chromatography (5% MeOH/DCM). However collection of the first 10 fractions revealed product decomposition overnight (product had also went from a yellow solid to a brown gel). The product was taken no further. Experiment requires repeat.

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.

Attempts at the Yb(OTf)₃ catalysed synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (2c)

Procedure 1^[A]

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 2-(3,4-dimethoxyphenyl)ethanamine (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 spectroscopy 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^[B]

Relevant lab book entry: KAB25-2 To a mixture of Yb(OTf)₃ (120 mg, 0.194 mmol) and microwave activated 3 Å powdered molecular sieves (~20 mg) was added dry toluene (30 mL) under a nitrogen atmosphere. Benzaldehyde (0.10 mL, 0.97 mmol) and 2-(3,4-dimethoxyphenyl)ethanamine (0.16 mL, 0.97 mmol) were added. The reaction mixture was reflux heated to 110 °C for 96 hours. The mixture was made alkaline by the addition of saturated sodium bicarbonate solution. The organic layer was separated and the aqueous fraction was extracted with ethyl acetate (3 × 30 mL). The organic fractions were combined, dried (MgSO₄) and concentrated under reduced pressure to yield a yellow solid (360 mg, 130%). ¹H-NMR spectroscopy of the oil indicated the isolated product was mostly composed of imine 1b.

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

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 under reduced pressure 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. 177-179 °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.^[C]
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.^[C]

N-(3,4-dimethoxyphenethyl)acetamide (5)

M.p. 77-79 °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) was dried over microwave activated 3 Å 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 3 Å 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 entry: KAB26-11.

Typical procedure for the ¹H-NMR assays of the Yb(OTf)₃ catalysed acyl-Pictet-Spengler reactions

Tetrachloroethane (8.0 mg, 4.8 × 10^-5 mol) was added to a known amount of crude product (e.g. 10 mg). To the mixture was added CDCl₃. The peaks were integrated and normalised based on the integrated signal and number of protons. The number of moles of product or by-product was determined by comparing the ratio of integrals with the known moles of added tetrachloroethane. The amount in moles was converted to mass, which was then divided by the amount of crude product dissolved in the CDCl₃.

References

[1] Über die Bildung von Isochinolin-derivaten durch Einwirkung von Methylal auf Phenyl-äthylamin, Phenyl-alanin und Tyronsin, A. Pictet and T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030-2036. (DOI: 10.1002/cber.19110440309) Paper

[2] (i) Strictosidine Synthase: Mechanism of a Pictet−Spengler Catalyzing Enzyme, J. J. Maresh, L.-A. Giddings, A. Friedrich, E. A. Loris, S. Panjikar, B. L. Trout, J. Stöckigt, B. Peters and S. E. O'Connor, J. Am. Chem. Soc. 2007, 130, 710-723. (DOI: 10.1021/ja077190z) Paper; (ii) Reconstruction of the saframycin core scaffold defines dual Pictet-Spengler mechanisms, K. Koketsu, K. Watanabe, H. Suda, H. Oguri and H. Oikawa, Nat. Chem. Biol. 2010, 6, 408-410. (DOI: 10.1038/nchembio.365) Paper; (iii) The Pictet–Spengler Reaction in Nature and in Organic Chemistry, J. Stöckigt, A. P. Antonchick, F. Wu and H. Waldmann, Angew. Chem., Int. Ed. 2011, 50, 8538-8564. (DOI: 10.1002/anie.201008071) Paper

[3]

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[C1] Imine 1d showed trace amounts of the 4-nitrobenzaldhyde starting material, which promted recrystallisation of the pure imine from ethanol to yield the final product. Imine 1c required no further purification.

[I] Evaluation of the relative Lewis acidities of lanthanoid(III) compounds by tandem mass spectrometry, H. Tsuruta, K. Yamaguchi and T. Imamoto, Chem. Commun. 1999, 1703-1704. (DOI: 10.1039/A905569J) Paper

[Gan] Highly efficient Lewis acid-catalysed Pictet-Spengler reactions discovered by parallel screening, N. Srinivasan and A. Ganesan, Chem. Commun. 2003, 916-917. (DOI: 10.1039/B212063A) Paper

[A] Catalytic Pictet-Spengler reactions using Yb(OTf)₃, K. Manabe, D. Nobutou and S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158. (DOI: 10.1016/j.bmc.2005.05.018) Paper

[C] Development of the Pictet-Spengler Reaction Catalyzed by AuCl₃/AgOTf, S. W. Youn, J. Org. Chem 2006, 71, 2521-2523. (DOI: 10.1021/jo0524775) Paper

[S] Principal properties (PPs) for lanthanide triflates as Lewis-acid catalysts, C. G. Fortuna, G. Musumarra, M. Nardi, A. Procopio and G. Sindona, S. Scirè, J. Chemom. 2006, 20, 418-424. (DOI: 10.1002/cem.1016) Paper

[Tang] Trisoxazoline/Cu(II)-catalyzed asymmetric intramolecular Friedel-Crafts alkylation reaction of indoles, J.-L. Zhou, M.-C. Ye, X.-L. Sun and Y. Tang, Tetrahedron 2009 65, 6877-6881. (DOI: 10.1016/j.tet.2009.06.071) Paper

[B] Calcium-Promoted Pictet-Spengler Reactions of Ketones and Aldehydes, M. J. V. Eynden, K. Kunchithapatham and J. P. Stambuli, J. Org. Chem. 2010, 75, 8542-8549. (DOI: 10.1021/jo1019283) Paper

[D] (i) Pictet-Spengler condensation reactions catalyzed by a recyclable H(+)-montmorillonite as a heterogeneous Brønsted acid, Wang, Y., Z. Song, et al. Science China-Chemistry 2010, 53(8), 562-568. (DOI: 10.1007/s11426-010-0073-4) Paper; (ii) One-step preparation of 1-substituted tetrahydroisoquinolines via the Pictet–Spengler reaction using zeolite catalysts, A. Hegedüs and Z. Hell, TetLett 2004, 45, 8553–8555. (DOI: 10.1016/j.tetlet.2004.09.097) Paper

[Jac04] Highly Enantioselective Catalytic Acyl-Pictet-Spengler Reactions, M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558-10559. (DOI: 10.1021/ja046259p) Paper

[H] Badiola, K. A., Robertson, M. N., Tarselli, M. A., Todd, M. H. 2012, The Catalytic, Asymmetric Pictet-Spengler Reaction wiki, openwetware, 9 June 2012, http://openwetware.org/wiki/Todd:Catalytic%2C_Asymmetric_Pictet-Spengler_Reaction.

[Gao] (i) Synthesis of carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potential PET AMPA receptor ligands, M. Gao, D. Kong, A. Clearfield, Q.-H. Zheng, Bioorg. Med. Chem. Lett. 2006, 16, 2229-2233. (DOI: 10.1016/j.bmcl.2006.01.042) Paper; (ii) Synthesis of stable azomethine ylides by the rearrangement of 1,3-dipolar cycloadducts of 3,4-dihydroisoquinoline-2-oxides with DMAD, N. Coşkun and S. Tunçman, Tetrahedron 2006, 62, 1345-1350. (DOI: 10.1016/j.tet.2005.11.040) Paper; (iii) Synthesis, antibacterial activity and QSAR studies of 1,2-disubstituted-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines, R. K. Tiwari, D. Singh, J. Singh, A. K. Chhillar, R. Chandra and A. K. Verma, Eur. J. Med. Chem. 2006, 41, 40-49. (DOI: 10.1016/j.ejmech.2005.10.010) Paper