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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

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 Amé Pictet and Theodor Spengler in 1911 (Pictet and Spengler 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 1).

Scheme 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

The usefulness of the PS reaction is reflected by its application in Nature. The class of enzymes known as Pictet-Spenglerases are instrumental in the synthesis of numerous plant alkaloids such as Saframycin A and X (Figure 1).[ref] A relatively recent discovery, these enzymes are...

PS in Nature Saframycin A. Pictet-Spenglerases: STR and NCS.

Figure 1: Natural molecules bearing the core THIQ (blue and red) PS product (<---FIX THIS CAPTION)

The PS reaction is particularly useful in the synthesis of the tetrahydro-β-carboline and THIQ scaffolds typically associated with the plant alkaloids.

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.

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

The Limits of the Pictet-Spengler Reaction in Organic Synthesis

One apparent limitation to the PS reaction is the catalytic formation of non-activated THIQs. Ironically, the first synthetic example for the preparation 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 unactivated phenethylamine with various aldehydes is effected by zeolite and acidic montomorillonite frameworks.[ref] 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.[ref] 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 and binapthyl-derived phosphoric acids.[ref]

Still, there is sufficient precedent for the development of a catalytic asymmetric PS reaction to yield the THIQ scaffold. Rather than the implementation of 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 lies with LA catalysis. (WHY??)

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

<--sentence not so clear

• Typical LA 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

The focus of this project was the development of an achiral Lewis acid-catalysed PS method? procedure? of the THIQ scaffold (Scheme 3). In order to minimise complications arising from the one-pot procedures using the aldehyde and arylamine starting materials, a ...... from the corresponding isolatable imines.

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

While most of the literature describes the use of strong Bronsted acids in vast excess and harsh conditions in the PS synthesis of the activated-THIQ, two notable examples exist for the Lewis acid-catalyst formation of THIQ. It was appropriate to evaluate the capacity of strong Bronsted acids to effect the PS formation of the THIQ scaffold. However, it was found that....
The significant proportion of examples for the asymmetric Bronsted acid-catalysed PS formation of tetrahydro-beta-scaffolds dictated the need for screening of achiral Bronsted acids in catalyytic PS reactions to give THIQ. It was found the potenchy of Bronsted acids to effect the PS cyclisation of the imine substrates to give the THIQ scaffold was poor.
The evaluation of the most promising LA catalysts revealed a similar ineffectiveness at inducing the PS cyclisation to give the activated THIQs. However, no screen was performed under non-catalytic conditions...
Adaptation of the model to the acyl-PS produced more promising results. 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 miminmal optimisation of the reaction conditions, the novel achiral LA 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 did not require post-reaction addition of a dehydrating agent but readily crystallised from the crude reaction mixtures.[note: 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.]

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-THIQ is typically effected by an excess of strong Brønsted acids and high temperatures.(Coskun + Verma + Zheng) The lack of known examples in the literature of the PS reaction to give unactivated-THIQs in the presence of catalytic amounts of strong Bronsted acid prompted evaluation. In contrast, there is a plethora of the catalytic Brønsted acid formation of the tetrahydro-beta-carboline scaffold from tryptamine and various aryl- and alkyl-aldehydes. Indeed, most of the known literature describes the asymmetric PS effected from the chiral Brønsted acid-catalysed condensation via the tryptamine starting material. It was appropriate to evaluate the properties and behaviour of the imines under similar catalytic Brønsted acid reaction conditions. Furthermore, evaluation of the Brønsted acid-mediated reactions...

The attempts to effect the cyclisation of imine 1a using neat methanesulfonic acid and elevated temperatures were largely unsuccessful (Table X). Poor conversion was observed in the cyclisation of 1a in amounts of trifluoroacetic acid less than using 50 equivalents and reflux conditions. Of the activated imine, 1b, ¹H-NMR spectroscopic analysis indicated good conversion of substrate to product (Entry X).

Scheme 5: Expected outcome for the...

Table 2: Results of the Brønsted acid...

The yields for the reaction were determined by ¹H-NMR spectroscopy of the crude products. In most cases no conversion was observed. The harshest reaction conditions employed in the PS reaction to give 1a resulted in poor conversion (Table X, entry X).

In the reactions of 1a-b to give 2a-b, conversion to give the THIQ product was qualtitatively gauged by thin layer chromatography (TLC) and approximately evaluated quantitatively by ¹H-NMR spectroscopic analyses of the crude products. The conditions for monitoring the reaction by TLC demanded a highly polar eluent (1:5, MeOH/DCM, 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. The conversion and overall yield was calculated based on total crude product mass isolated and the relative peak integrals of the imine proton and the C1 THIQ protons (~X ppm).

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 . 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.

• • Aldimine selective - metal triflate catalysts. Lanthanoid Lewis acid-catalysts.
• 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 6: The Lewis acid-catalyst screen for the PS formation of 2b and 2c

Scheme 7: Related to Table 3.

Table 3: 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 the dichloromethane (DCM) solvent for toluene and an increase in reaction temperature (25 °C to 110 °C) was also attempted with the 1b substrate to no effect (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 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

(...why aPS is good). The lack of progress prompted adaptation of the model system to the N-acyl PS variation, which is described to occur via the potent N-acyliminium intermediate. The presence of the electron withdrawing acyl group increases the electrophilicity of the imine carbon.... (mechanism stuff). (Should I mention this?) Furthermore, little in the field. Limited examples - Youn and Jacbonsen. ONe is organocatalysis to give THBC. Generation of the acyliminium in situ powerful results
The single known example of the LA catalysed acyl-Pictet-Spengler reaction to give the THIQ scaffold was effected by a combination of AuCl₃ and AgOTf.[ref] This reaction was an ideal starting point for the LA catalysed acyl-PS reaction, particularly due to the identical starting materials and expected products with 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, which was consistent with the literature.It was suspected the successful reaction was effected by the electron withdrawing acyl group.

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

Implementation of the Yb(OTf)₃ LA in the protocol for the HAuCl₄o AgOTf co-catalsyed reaction....
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 (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 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%. (* Byproducts only aldehyde + acetamide. Hydrolysis during reaction or workup? Unknown.) 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.
The inaccurate correlation of the spectroscopically calculated yield and the isolated yield meant that more work was required. The first step to cleaning up the ¹H-NMR was minimisation of the 2,6-lutidine peaks. Unfortunately, the presence of chlrode in the crude reaction mixture exacerbated the formatino of the supsected hydrochloride salt. This was successfully resolved by implementing an alkaline wash into the post-reaction work-up procedure.

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

Optimisation of the ¹H-NMR spectroscopic assay of the...

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: Results of the Lewis acid-catalysed acyl-PS reactions

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

The Yb(OTf)₃ catalysed acyl-PS reaction represents an efficient route to the activated THIQ scaffold.

• 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 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. 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. 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)

(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 (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.

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

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

Procedure 1 (Kobayashi 2006)

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 (Stambulli 2010)

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 2006)

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 (Youn 2006).
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. XX°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 ...

Tetrachloroethane (8 mg, X mmol) 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 signal integrated and number of protons. The ratio of integrals was compared to the mass ratio of crude product to tetrachloroethane.

References (arranged by date)

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