Thanks, Murphy!

Note Sigma-Aldrich offers two products, including the desired hydridotetrakis-triphenylphosphine rhodium (I) but also the related tris-triphenylphosphine-carbonyl-rhodium hydride (I). The former, correct compound has CAS number 18284-36-1.

^ This is also incorrect. The primary tryptamines cannot be methylated to the tertiary amine using reductive methylation (as with tryptamine to DMT), but they can be methylated to the secondary amine because the iminium ion is never formed. - Enkidu

@ Enkidu - Thank you for the Picket Spengler references. I've read through them. I'm confused about your statement above. Was it based on the refs you posted? This is what jumped out at me

The reaction of tryptophan methyl ester (17) with benzaldehyde (18) in benzene at reflux resulted in the tetrahydro-P-carboline 20 in 90% yield. Conversely, the reaction of tryptamine (3) under the analogous conditions resulted only in the formation of the Schiffs base 50 in quantitative yield, as illustrated in Table 3. These results can be rationalized by examination of the PKa values of the two bases: tryptamine, PKa = tryptophan methyl ester, pKa = 7.29.59 The tryptophan methyl ester imine intermediate 19 is clearly more electrophilic than the imine 50, formed from tryptamine (3). In fact, even in the presence of small amounts of tryptophan or tryptophan methyl ester hydrochloride the tryptamine intermediate 50 failed to cyclize.

My interpretation of the reference is that the tryptamine imine is less prone to cyclization under aprotic non-acidic conditions, even with a long reflux. I was also under the impression that a secondary amine is even more reactive than a primary one and thus would form an imine more readily. Is there something I am missing, or misunderstanding? Sorry to be joining the conversation so late.

First, the mechanism needs to be considered.

"The Pictet-Spengler reaction has generally been thought to proceed via a spiroindolenine intermediate as shown in Scheme 8 (path A), although Casnatiso has shown that cyclization can occur by direct attack at position 2 of the indole (path B) when very reactive electrophiles are employed."



Therefore, the more the dipole moment is shifted toward the nitrogen, the more susceptible the carbon is to nucleophilic attack. The pKas of the imines are an indirect measure of electrophilic nature of the end of the imine containing the carbon. A Lewis acid is an electron acceptor; since the tryptophan methyl ester Schiff base has the lower pKa, it is more acidic and draws electron density away from the carbon, increasing its susceptibility to nucleophilic attack relative the the tryptamine Schiff base.

"These results can be rationalized by examination of the PKa values of the two [Schiff] bases: tryptamine, PKa = 10.2, tryptophan methyl ester, pKa = 7.29. The tryptophan methyl ester imine intermediate 19 is clearly more electrophilic...."



Here is the the short answer to your question, antibody2. When the Schiff base of a secondary amine is formed (as in the case of the N-methyl tryptamine Schiff base) or an imine is protonated, the nitrogen receives a positive formal charge. This moeity is called an iminium instead of an imine. Because the nitrogen is forced donate more than its desired share of electrons, its electrophilicity increases, and it draws electron density toward itself to an even greater extent than in the case of the tryptophan methyl ester Schiff base.  

When I said "cannot be methylated," I was probably speaking too strongly, because certain rxn conditions could limit the formation of the of unwanted cyclic product. For instance, the reason that STAB (edit: which apparently cannot be used on unprotected indoles) is used is because the reagent is not strong enough to quickly reduce the aldehyde or ketone, yet as soon as the iminium is formed, the hydride attacks the electrophilic carbon before the ring can, preempting cyclization.