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

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Notes to myself

Things that need doing

24/05/12 - Add full stops to the ends of the experimental paragraphs.

Need to cyclise and isolate all 4 THIQs. So far, have crude dimethoxy. Cyclise other dimethoxy (dimethoxy nitro) using same procedure. Then obtain yields for the reactions in neat MSA, 140C, 20 hours. MHT - Yes - find conditions that give you rac product in decent yield for one case, then use those conditions for the other imines. Once that's done, you think about changing the conditions.

Not quite sure where to put this


  • Currently stuck this in conc. - will prob have to move it later. "Address lack of non-electron rich PEAs (for homogenous but mention zeolite and clay)."


  • Cyclisation to give the 1-Ph-1,2,3,4-THIQ (i.e. KAB20) did not occur when the starting imine (KAB18) was stirred in neat methanesulfonic acid (4 h). It was expected the reaction would proceed at increased temperature under otherwise identical conditions given the Pictet-Spengler reaction to give PZQ (KAB3-X) under analogous conditions. <-- Put predecent in background, then describe result in R&D section(MHT)
  • Dimethoxy-phenyl (to give KAB21) did not cyclise in the presence of stoichiometric methanesulfonic acid (rt, 4 h). Result was expected given cyclisation to give dimethoxy PZQ analogues under similar conditions. Literature (2 ref. Bronsted acids.) procedures to produce the dimethoxy THIQs outlined harsh conditions (superstoichiometric TFA, toluene, reflux 2+ h). <-- Put predecent in background, then describe result in R&D section(MHT)
  • Found promising reference for the 10 mol% Yb(OTf)3 catalysed PS reaction to give hydroxy substituted THIQs [ref]. Put in background(MHT)

23/03/12 Need to note down CAS numbers for the imines.

Include this?

"Attempts at the recrystallisation of imines 1a-b were unsuccessful and the crude products were used without further purification." YES! Mention Stambuilli's oh-so-valuable-footnote.


23 Mar - SciFinder search turned up no NMR results for the imines KABX and KAB22-1. Recorded NMRs of compounds are close (spot on?) to the SciFinder predicted proton NMRs.

Noticed addition of lutidine in acyl-PS reactions --> Jacobsen and also in the AgOTf/AuCl3 rxns.

2 April - Assay conditions for the cyclisation of the dimethoxy nitro imine almost worked out (KAB24-2, under 2 eq TFA/toluene/110C). Just need to isolate final product to confirm formation of the expected THIQ.

2 April - So far all the imines have dramatically changed colour following addition of acid (MSA or TFA). Just regarding experiment KAB24-2 (with reference to TLCs): the starting material appeared to be consumed almost instantaneously, which may be related to the colour change during and immediately following the addition of acid. Disappearance of the starting material was accompanied by the appearance of a "comet" in the TLC. However, after the basic workup, TLC of the crude product indicated the presence of starting material and another spot (not the comet, which was absent - was the comet "quenched" back to starting material?). Sort of similar to KAB20-2 - very intense red reaction mixture formed, but only starting material was recovered. Difference with that reaction was that it didn't fade back to yellow. It just stayed a very dark red colour. (also see G+ post/comments)

4 April - Imines pKa DMSO 24, 2ndary amine, 5 membered ring pKa 44.

6 May - AuCl3/AgOTf catalysed acyl Pictet-Spengler reaction. Proceeded as expected (KAB26-1, KAB26-2 and KAB26-3).
Where to go next --> anhydrous, Yb(OTf)3 acyl-PS, BOX ligands, reduced temperature.

Solvents so far:
DCM (Kobayahsi 2005, Stambuli 2010).
DCE (Youn 2006)
toluene for tryptamines.



  • What the Pictet-Spengler reaction is.
    • Carbon-carbon bond forming reaction. Cyclisation.
    • Condensation of a aryl-amine with an aldehyde or ketone.
    • Original reaction.
  • PS in Nature
    • Pictet-Spenglerases: STR1 and NCS.
    • Saframycin
    • Useful for forming THBC and THIQ. Alkaloids.
    • Variations of the PS reaction.
      • Acyl (more recently = sulfenyliminium).
      • Tryptamine, thiophene, oxa.
      • Ketone - Spirocycle formation.
  • Limitations(?) for catalytic PS - non-electron rich. None currently identified in Nature and synthetically
  • Mini-lit-review
    • 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.
  • Typical LA catalysts (PS)
    • Aldimine selective - metal triflate catalysts. Lanthanoid Lewis acid-catalysts.
    • Studies of the Ln - Lewis acidity - Youn, Kobayashi, Stambuli, THIQ scaffold.
  • Precedent for asymmetric: Friedel-Crafts using BOX ligands[Tang], Yb(OTf)3 catalysed PS from m-tyramines[Kobayashi], also Ca(HFIP)2 [Stambuli] and AuCl3/AgOTf [Youn]
    • But asymmetric first needs racemic model to... model.
  • The focus of the project: model PS system on not widely explored THIQ.
  • What was found:
    • THIQ from simple imines using Bronsted acids (mediated). Not so good. Catalytically - negative.
    • Sentence on the choice of M(OTf)s. Lewis acids (catalytically). Negative.
    • N-acyl.
  • Bullet: Yb(OTf)3 effective catalyst in the acyl-Pictet Spengler. THIQ scaffold.

Results and Discussion

  • Imine synthesis.
    • Why imines? Lit uses aldehyde and amine. Less complicated. Less stuff in cyclisation reactions. Plus - v. easy to make.
  • Bronsted acid mediated cycliations - because lit. trend in BA catalysed reactions (even though it's tryptamine).
    • All literature describes harsh conditions.
    • Attempted neat MSA - based on PZQ results. Did not proceed. Possibly a results of non-acylated?
  • Poor conversion. Only able to monitor conversion by NMR. THIQ difficult to handle. Behaved unexpectedly on silica.
    • Zero conversion under catalytic and stoichiometric (double check stoich.) acid loads.
  • Move to stronger(?) Lewis acids. But why?. Choice of LA. Triflates + Yb(OTf)3. High LA. f13.
  • Screen of catalysts (4 x MOTf) - no conversion in all cases.
  • Focussed on the Yb(OTf)3 - adapted conditions from literature. Attempts to optimise reaction conditions. Zero conversion.
    • Substrate specific? Compare hydroxy + and Stambuli's replicated result with altered reaction conditions.
  • Move to acyl-Pictet-Spengler.
    • Why change to acyl?
      • Inertness of the imines.
      • Acyl EWG increase Nuc of imine.
    • Literature for dimethoxy THIQ - Youn. AuCl3/AgOTf. Gold triflate? Lit results (pretty much) reproduced. Requirement of lutidine - reaction still proceeds, however yield is reduced. Also suspect formation of salts that complicated work up. Lutidine has high affinity for HCl [check ref].
    • Byproducts isolated from reaction.
  • Adapted conditions to Yb(OTf)3 catalysed - easier to handle than AuCl3/AgOTf. V. strong LA.
  • Describe the choice of Yb in more detail... Move back to Yb based on positive result of Au.
    • Byproducts only aldehyde + acetamide. Hydrolysis during reaction or workup? Unknown.
    • Development of NMR assay to aid screening process <-- integrate above somewhere.
    • Development of workup procedure.
    • Best result (unoptimised) - 1 mol% Yb cat. 77% isolated yield. Compare to 7 mol% 30 min. 60% isolated yield.

Conclusion (and Future Work?)

  • 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? 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?
    • Address lack of non-electron rich PEAs (for homogenous but mention zeolite and clay).

Page before revamp

Bronsted Acid Mediated and Catalysed Cyclisations

Attempts at the Bronsted acid-mediated cyclisation of imines (3) to give the racemic THIQ (4).
R1=H, R2=H - KAB20-2 KAB20-3 KAB20-4
R1=OMe, R2=H - KAB21-1 KAB21-2
R1=OMe, R2 = NO2 - KAB24-1KAB24-2KAB24-3KAB24-4

Scheme X


Cyclisation to give the 1-Ph-1,2,3,4-THIQ (i.e. KAB20) did not occur when the starting imine (KAB18) was stirred in neat methanesulfonic acid (4 h). It was expected the reaction would proceed at increased temperature under otherwise identical conditions given the Pictet-Spengler reaction to give PZQ (KAB3-X) under analogous conditions.

Initial procedures for the cyclisation to give the dimethoxy THIQs (KAB21 and KAB24) from the starting imines (KAB18 and KAB23) were adapted from Verma (2005) and Zheng (2006) - i.e. TFA/reflux.<ref>

First attempt at the achiral catalytic PS reaction (KAB24-4) resulted in negligible conversion after 72 hours (110 °C). Another attempt KAB21-4 (50 mol% TFA) for comparison.

Lewis Acid-Catalyst Screen (KAB21-5, KAB21-6, KAB21-7, KAB21-8, KAB24-5, KAB24-6, KAB24-7 & KAB24-8

Scheme X

Screen unsuccessful - possibly a result of the setup (low volume, MS, stirring problems). In all cases, starting material was recovered. No product. Confirmed by NMR.

Attempt to reproduce similar results to the Kobayshi paper --> KAB25-1. Yb(OTf)3 (20 mol%), DCM, rt. SM: Benzaldehyde and dimethoxy phenethylamine. At 3 hours: formation of imine, some iminium (by TLC). 24 hours: No product. Imine and some benzaldehyde (by NMR) following workup.

Difficulty in reproducing results described by Kobayashi 2005. Experiment had been repeated by Stambulli 2010, with slightly altered conditions (DCM, rt --> PhMe, 100C) to obtain a similar yield (51%).

Experiment was repeated in toluene, 110 °C (2 attempts, KAB25-2 & KAB25-3). No product after 4 days. Possibly requires hydroxy substituted phenethylamine derivative starting material --> deprotonation. Bronsted/Lewis acid co-catalysed?

Possibility of catalyst poisoning by H2O. Additional attempt using imine starting product (Scheme X). Crude NMR contained peaks corresponding to benzaldehyde and the imine starting material.

Scheme X

Scheme X


AuCl3/AgOTf catalysed acyl Pictet-Spengler reaction (Scheme X).[Ref] Proceeded as expected (KAB26-1, KAB26-2 and KAB26-3). Purification of KAB26-2 and KAB26-3 by silica gel column chromatography. Recovered p-nitrobenzaldehyde, N-acetyl-N-(3,4-dimethoxyphenethyl)acetamide and N-(3,4-dimethoxyphenethyl)acetamide. KAB26-1 crystallised on standing (Not pure...yet).

Scheme X

Yb(OTf)3 catalysed acyl Pictet-Spengler reaction (Scheme X).
KAB26-4 Also testing quantitative NMR using 1,1,2,2-tetrachloroethane internal standard. KAB26-5 KAB26-6 KAB26-7 KAB26-8