How did this slip by the referees? Azomethine imines are not azomethine ylides

A recent paper by Xingwei Li and co-workers in Angewandte Chemie International Edition has some nice chemistry in it, but take a look at the title, “Rhodium(III)-catalyzed oxidative C-H functionalization of azomethine ylides.”  One might expect to see some azomethine ylides, right?  No, they are azomethine imines:

I suppose one could make the case that azomethine imines are a subset of azomethine ylides, but I’ve never seen it done.  What am I missing here?

[Edit:  Correspondence with Professor Li reveals his point of view:  “the structure can be called both azomethine ylides and azomethine imines,” (sic) and there “is not much difference,” (I strongly disagree on both counts) and “we simply want to emphasize the ylidic character of our substrate.”  Okay, I can understand wanting to emphasize that something is an ylide, but there’s no need to choose an incorrect name to do so.  Learning organic nomenclature is hard enough.  Enough said.  I’m now going to retire my Professor Pearson hat on this issue.]

[Edit: Here’s another paper from the same lab, still referring to azomethine imines as azomethine ylides.  Apparently the referees at Advanced Synthesis and Catalysis aren’t minding the store either.]

Synthesis of Kopsia lapidilecta alkaloids – The RCM approach takes a hit (retraction)

Let’s take a moment to appreciate the challenges of synthetic organic chemistry.  Not exactly stamping out widgets, is it?  Witness the recent retraction of an approach to the lundurine alkaloids from Steve Martin’s group (original Organic Letters paper here, retraction here).  Since the early days of RCM, Martin’s group has recognized its potential for the construction of alkaloids, but the presence of nitrogen atoms in RCM precursors can lead to problems.  Such may be the case here.

The Kopsia lapidilecta alkaloids

The Kopsia lapidilecta species of Asian flowering plants produces numerous alkaloids that bear the novel 5,6,12,13-tetrahydro-11a,13a-ethano-3H-pyrrolo[1′,2′:1,8]azocino[5,4-b]indole ring system.  Representative examples include lapidilectine B and lundurine B.

Synthetic efforts

Back at the University of Michigan, we became interested in making these alkaloids using our 2-azaallyl anion cycloaddition chemistry.  It was a war, but postdoc Ill Young Lee and Ph.D. student Patrick Stoy were up to the task.  The key step was the cycloaddition of the 2-azaallylanion shown with phenyl vinyl sulfide.  The resultant pyrrolidine cycloadduct was then converted on to lapidilectine B, completing the first total synthesis of any of the Kopsia lapidilecta alkaloids (JACS, JOC).

Martin’s group at Texas (link) and Sarpong’s group at Berkeley (link) have published approaches to the lundurines and lapidilectines, respectively, the former using RCM to make the central azocine core and the latter using an intramolecular electrophilic aromatic substitution approach.

Trouble with the RCM approach

Martin and co-workers reported a potentially simple way to access these alkaloids.  They carried out an RCM reaction on 24, which itself was made by an RCM assembly of the pyrroline ring.  The closure of the eight-membered ring was reported in 26% yield, producing 1.4 mg of 25.  A larger amount (12.9 mg) of 25 was then hydrogenated selectively to produce 26.  Their plan was to use this approach to make lundurine B. (Edit: Corrected yield of RCM.)


In a recent retraction, Martin has now withdrawn this work “on the basis that the RCM of 24 to give 25… is not reproducible; thus, the reduction of 25 to give 26… is also not reproducible.”  The wording of this sentence is curious to me, since the reproducibility of the reduction should not depend on the reproducibility of the RCM (the RCM product was used after purification), but nonetheless, this is a setback for this potentially powerful approach.

I hope the situation can be remedied.  Our synthesis of lapidilectine B was linear and involved a lot of steps, and I’d like to see the Martin or Sarpong approaches succeed; they have the potential to be considerably shorter.  I imagine there are other groups working on these alkaloids; they’re too beautiful to resist.  In my opinion.

A beautiful synthesis of (+)-pseudococaine

You might recall my fascination with cocaine (no, not for that reason), which culminated in a total synthesis of its enantiomer, (+)-cocaine, using our 2-azaallyl anion chemistry (Mans and Pearson, 2004, blog post here).  Davies and co-workers at Oxford have now published a short and elegant synthesis of (+)-pseudococaine, a diastereomer of natural (-)-cocaine.

The key step is a highly diastereoselective transannular iodoamination with concomitant N-debenzylation by iodide ion to produce the tropane skeleton:

It’s worth pointing out that intramolecular iodoamination reactions of simple primary and secondary amines can be problematic due to N-iodoamine formation and subsequent shenanigans, including potential post-cyclization aziridinium ion formation.  Davies’ reaction is well-behaved, since transannular iodoaminations are especially favorable, the amine is tertiary, and the product is not susceptible to aziridinium ion formation.

The cyclization precursor is made by a very nice sequence involving conjugate addition of a chiral lithium amide to an enoate with subsequent in situ trapping of the enolate by a diasteroselective aldol condensation (7% of the other aldol diastereomer is not shown).

Nice work!

On the regioselectivity of metal-catalyzed functionalizations of heteroaromatic C-H bonds

The direct functionalization of aromatic heterocycles at ring C-H bonds via transition metal-catalyzed processes has become a powerful alternative to electrophilic aromatic substitution.  Arylation, benzylation, alkenylation, and amination of aromatic heterocycles are possible, largely via palladium or copper catalysis.  There are hundreds of papers describing the functionalization of both five- and six-membered ring heteroaromatics, but here’s the rub:  How can one predict the regioselectivity of these reactions?  A recent paper by Daniel Ess and co-workers at BYU (Organic Letters) moves us closer to that goal.

Let’s say you’re in the drug discovery business and would like to snap a bunch of different arenes onto a core structure.  Where will they go?  Regioselectivity is often high (c.f. the example from Lapointe, Fagnou, and co-workers below), but how can we rationalize and predict the regioselectivity, especially in cases where there is no directing group present?

Ess and co-workers summarized the work that has been done so far on rationalizing the regioselectivity of these reactions.  I would also suggest looking at the Lapointe/Fagnou paper cited above, which focuses on the same issue.  C-H bond acidity, carbon center nucleophilicity, steric and stereoelectronic effects, activation-strain analysis, etc., have all been posited.  If you have the software, know-how, and patience to calculate the geometries and energies of all of the relevant transition states, go for it.  In that vein, I’ve shown an exemplary transition state from Ess’s (that’s a lot of esses!) paper below, which features the widely accepted six-membered ring CMD (concerted metalation-deprotonation) mechanism.  Shown is the transition state for the reaction of pyrazine-N-oxide with PhPd(PMe3)OAc.

But who wants to calculate transition states?  Well, Ess has uncovered an attractive shortcut:  He and his co-workers, upon noting that the CMD step is inherently endothermic and thus has a late transition state, postulated that all you really need to know are the relative thermodynamic stabilities of the palladium aryl intermediates.  After all, in a late transition state, the C-Pd bond is well along the way to being formed, so a higher C-Pd bond strength should be correspond to a lower TS energy.  Indeed, after adjusting for some hydrogen bonding effects in certain substrates, they found that the regioselectivity of fourteen out of fourteen examples were correctly rationalized by estimating the thermodynamic stability of the palladium aryl intermediates, a much easier task than TS calculation.

Ess and co-workers also proposed another way to get at this problem:

…the strongest C-H bond (in the substrate) will be preferentially activated since it will lead to the most stable Pd-C bond.  Indeed, for arenes and heteroarenes 1 – 14 the strongest C-H bond generally has the lowest activation energy.

Now the task becomes a “comprehensive thermodynamic analysis of palladium aryl bonding,” which “will be the subject of a future detailed study.”  Add in an understanding of C-H bond strength in heteroaromatics and these reactions will be even more attractive.

A final note.  Focusing on the substrate alone is only part of the picture.  In the Lapointe/Fagnou work, conditions-based site-selectivity was also found to be important:



[EDIT: A follow-up to this post was published July 7, 2015, focusing on conditions-based regioselectivity.]

Fun new alkaloids: Let the synthesizing begin!

For the alkaloid lovers out there, here are a couple of new structures that made me say aloud, “Cool!”

Shi-Shan Yi and co-workers at the Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing) just reported (Organic Letters) the isolation and structure determination of several new alkaloids from Lycopodium japonicum including the two compounds lycojaponicumin B and C shown above.  (I’ve drawn them a bit differently; I can’t resist tinkering.)

Natural products that feature an isoxazolidine ring?  Nice.  There may be others… I haven’t checked.  Anyone?

How long will it take for someone to fire up the total synthesis machinery to make these?  And how long will it take for someone to say, “Hey, let’s employ an intramolecular 1,3-dipolar cycloaddition of a nitrone!” I’ll save everyone the trouble of disconnecting these alkaloids into the two obvious nitrone precursors by showing them here:

It’s possible that nature has already accomplished the first route.  The authors propose that lycojaponicumins B and C are produced biosynthetically from fawcettimine as shown below.

Let the synthesizing begin!

By the way… The Heterocyclist is relocating from Chicago to Raleigh this month, so things might be a bit quiet around here.

Blowing things up with heterocycles, featuring Werner E. Bachmann

You may have seen the recent article by Jyllian Kemsley (C&EN) on how authorities dealt with what they called the “largest cache of homemade explosives ever found in the U.S.”  (See also here and here.) George Djura Jakubec’s home was so infested with explosives and the chemicals used to make them that a firewall was built around the home so it could be burned down.

If you’ve ever looked at the structures of explosives (out of mere curiosity of course), you can’t help but appreciate the abundance of heterocycles.  Browsing Agrawal and Hodgson’s 2007 book entitled Organic Chemistry of Explosives (Wiley) reveals hundreds of explosive heterocycles.  Just for fun, let’s look at a couple, which will also give me a chance to touch on the accomplishments of one of my favorite chemists, Werner E. Bachmann from the University of Michigan.

HMTD, a peroxide

While Agrawal and Hodgson state that “no peroxide has found practical use as an explosive, a consequence of the weak oxygen-oxygen bond leading to poor thermal and chemical stability and a high sensitivity to impact,”  this hasn’t stopped terrorists and folks who like to make bombs at home. I can thus imagine the concern of the hazmat team when they found six quart-sized jars of hexamethylenetriperoxidediamine (HMTD) in Jakubec’s stash.  HMTD, made simply from hexamine and hydrogen peroxide in the presence of citric acid, is unstable and extremely dangerous to manufacture.

N-Nitroamines (Nitramines) and Werner E. Bachmann

Hexamine is also the starting material for two classic secondary explosives, RDX and HMX, shown above.  Secondary explosives are those that are rather stable compounds, requiring a primary explosive to get the ball rolling.

RDX (cyclonite, hexogen, Royal Demolition eXplosive, or cyclotrimethylenetrinitramine) is the most important military high explosive in the U.S.  It’s second to nitroglycerin among common explosives in strength and is a component of C-4 and Semtex.  It played a huge role in World War II, as we’ll see in a minute.

The most common method of its manufacture is the Bachmann process, where hexamine is nitrated in the presence of ammonium nitrate.  I must digress for a moment.  I got to know of Werner Bachmann’s accomplishments when I was at the University of Michigan, where he was a professor from 1925 until his untimely death in 1951.  The Department of Chemistry honored him annually with the Bachmann Lecture, where a distinguished organic chemist was invited to give a talk and attend a banquet.  Having introduced a few of the speakers, I had the chance to comment on Bachmann’s achievements in the opening remarks.

It’s really worth reading a biographical memoir of Bachmann (pdf) by the famous heterocyclic chemist Robert C. Elderfield, also from the University of Michigan, published by the National Academy of Sciences.

An exerpt:

In the summer of 1940 the National Defense Research Committee was established and in the fall of that year a group of organic chemists, most of whom were ignorant of the chemistry of explosives, met in Roger Adams’s residence in Urbana, Illinois, to discuss how they could best contribute to the budding war effort. Among the neophytes was Werner Bachmann and among the topics discussed was how best to manufacture and use a high explosive known in this country as Cyclonite and in England as RDX. The potential military value of RDX as the most powerful of the nonatomic high explosives had already been appreciated. However, in this country there was no knowledge at the time as to how it could be used safely and no practical process for its manufacture. It subsequently developed that the British had largely solved the problem of the use of the explosive and had developed a fairly satisfactory batch process for its manufacture. To Bachmann was assigned the problem of devising a more efficient and economical manufacturing process.

In some respects Bachmann’s achievement in discovering an efficient new method for preparing RDX testifies most eloquently to the amazing versatility and experimental technique of this extraordinary chemist. He had no previous experience in the chemistry of explosives, and was best known for his elegant syntheses of complicated molecules such as the sex hormones. When Bachmann first learned that his assignment under the NDRC program was to be the development of a practical method for the large-scale manufacture of the highly sensitive RDX, he records that his “heart sank.”

In January of 1941, J. C. Sheehan, who had just completed his doctoral thesis with Bachmann, began work on a novel approach to the synthesis of RDX. In the conventional British process for making RDX, hexamethylenetetramine is treated with 98-100 percent nitric acid, as is shown in equation (1).

C6H12N4 + 3 HNO3 –> C3H6O6N6 + 3 HCHO + NH3       (1)

This direct nitration method suffers from at least two serious disadvantages: large excesses of nitric acid must be employed for optimum yield, and one half of the equivalent of formaldehyde is lost, principally through oxidation by the nitric acid. Thus, the maximum amount of RDX possible is one mole from one mole of hexamethylenetetramine, and the actual yield is considerably less. In 1940 Bachmann learned that Ross and Schiessler at McGill University had obtained RDX from formaldehyde, ammonium nitrate, and acetic anhydride in the absence of nitric acid, but no details of their experiments were available. Although equation (2) is undoubtedly an oversimplification of the reaction, it occurred to Bachmann and Sheehan to attempt utilization of the by-products of the nitrolysis to obtain a second mole of RDX. In this way, if two moles of ammonium nitrate and six moles of acetic anhydride were present during the nitrolysis of hexamethylenetetramine, then two moles of RDX might be obtainable from one mole of hexamethylenetetramine.

C6H12N4 + 4 HNO3 + 2 NH4NO3 + 6 (CH3CO)2O –> RDX + 12 CH3CO2H     (2)

Although exploratory experiments were discouraging and frequently led to spectacular “fume-offs,” from a few reactions a small amount of RDX was obtained. After each experiment, Bachmann, who personally spent long hours in the laboratory, would carefully and ingeniously design a variation in the experimental conditions until finally, after literally dozens of experiments, the reaction conditions which permitted control of the process were worked out and a consistent yield of RDX was obtained. A memorable occasion was the day on which Bachmann and Sheehan isolated more than 100 percent yield of RDX based upon one mole of hexamethylenetetramine to demonstrate conclusively that a “combination” process was prevailing. The enthusiastic encouragement given by Roger Adams and J. B. Conant was most heartening in the early phase of the work. It now became important to adapt the process for relatively large-scale use. A number of scaled-up reactions were carried out involving quantities as large as several kilograms. Owing to the hazardous nature of the reaction these experiments were conducted on Sunday mornings and at other times when the University buildings were sparsely occupied.

The RDX prepared by the new process was at first considerably more sensitive to impact than was RDX from the direct nitrolysis reaction. At one point an urgent telegram was received from the U.S. Bureau of Mines Laboratory in Bruceton, Pennsylvania, reporting that an RDX sample submitted to them for evaluation was highly sensitive and should be handled with extreme care. This sensitivity was later traced to the presence of impurities, in particular to a small amount of a high-melting substance termed HMX (HM—high melting), and to a lesser extent to an impurity termed BSX (BS—Bachmann and Sheehan).

In the early phase of this work the armed services showed little interest in RDX as a military explosive, but during the summer of 1941 Admiral Blandy, then Chief of the Bureau of Ordnance, after consultation with top scientists of the Office of Scientific Research and Development, recognized the potentialities of RDX for use in rockets, torpedoes, and aerial bombs. The greater explosive power as compared to TNT (RDX has 150 percent of the power of TNT on a weight basis; on a volume basis, which is important for certain applications, RDX is approximately twice as powerful by virtue of its greater density) offered tremendous potential advantages. In addition, its markedly greater brisance, or shattering power, made RDX the ideal explosive for use in shaped charges, the principle behind the bazooka.

Several companies undertook the development of the new combination process, but the efforts of Tennessee Eastman were the most successful. At Kingsport, Tennessee, the largest munitions plant in the world was constructed to produce RDX by the new process on ten continuous production lines. It has been reported (Scientists against Time by James Phinney Baxter, 3d) that RDX was produced in this way at the rate of 360 tons per day. The production of RDX by the direct nitration process would not only have been considerably more expensive but would have involved much larger quantities of critically short corrosion-resistant materials for handling the nitric acid. It has been estimated that the saving to the government in plant cost alone was over two hundred million dollars.

The contribution of RDX to Allied success in the Second World War can scarcely be overestimated. Although RDX was considered too sensitive to fire from conventional artillery, it found wide application in rocket heads, in the 12,000-pound “Tallboys,” in block-busters, and in the torpedoes which sank the “unsinkable” German battleship Tirpitz. Thus Bachmann, the very prototype of the unassuming scientist, was able to make an outstanding contribution to his country’s and to the free world’s victory by bringing to bear his extraordinary scientific prowess, his imagination, and his perfection in laboratory technique.

Simultaneously with and subsequent to his work on RDX he also carried on important investigations on the oxynitration of benzene as a route to picric acid and on various aspects of the penicillin problem. The strain created by these wartime researches and the effort devoted to them undoubtedly contributed to the serious undermining of his health.

In recognition of his services Bachmann was the recipient of the Naval Ordnance Award in 1945, and in 1948 he was granted the Presidential Certificate of Merit by the United States government and the King’s Medal by the British government.

The strain and effort of the war years finally took their toll and, with his health undermined, Werner Bachmann died of heart failure at the age of forty-nine on March 22, 1951.

Although Bachmann’s career was a relatively short one, he published over one hundred and fifty papers, featuring such accomplishments as the first total synthesis of a steroidal sex hormone (equilinen), the Gomberg-Bachmann reaction for the synthesis of biaryls from aryl diazonium ions, and some pivotal early work in the synthesis of penicillin.  John C. Sheehan, a Ph.D. student of Bachmann’s who worked on the RDX project, went on to accomplish the first synthesis of penicillin V as a faculty member at MIT.

One more thing.  If you enjoy watching explosions in slow motion, especially seeing shock waves, check it out (fast forward to 2:42 for the good stuff):

Tetrazole synthesis, Part II: Harnessing the tetrazole-azidoazomethine equilibrium

Welcome to the second part of our Tour de Tetrazoles. In Part I, we saw that tetrazoles, particularly 5-substituted versions, are often made from nitriles and an azide source. Toxic and explosive hydrazoic acid can be formed in this chemistry, but we saw that there are ways to minimize its production.

Now let’s take a look at another general approach to tetrazoles, namely the concerted electrocyclic ring-closure of azidoazomethines. This chemistry will allow us to access a variety of tetrazoles, including fused-bicyclic versions, often under azide-free (and hydrazoic acid-free) conditions.

The tetrazole-azidoazomethine equilibrium

Azidoazomethines, also known as imidoyl azides, can undergo a concerted electrocyclization reaction to tetrazoles:

The tetrazole-azidoazomethine equilibrium

The position of the equilibrium depends on the nature of the substituents: electron-withdrawing groups on the azomethine nitrogen favor the open form, whereas hydrogen and normal organic substituents favor the tetrazole (leading reference and theoretical studies).

Fascinating, but there’s more: This equilibrium is an excellent entry point for tetrazole synthesis. Anything you can do to make the azidoazomethine will, with the right substituents, lead to the tetrazole.

Accessing azidoazomethines, and thus tetrazoles

If you can make the azidoazomethine, you’ll get the tetrazole. So, how does one make azidoazomethines? There are two primary methods, namely (1) the use of an activated amide to acylate sodium azide and, (2) the diazotization of amidrazones, themselves available by acylation of hydrazine with an activated amide:

Routes to azidoazomethines

Notice that the amidrazone method doesn’t require sodium azide or its equivalents, prompting some to call this an “azide-free” method.  A word of caution, though: It’s conceivable that the azidoazomethine could eliminate azide, so hydrazoic acid may still be lurking.  Use caution.

Example: Azidoazomethines (and thus tetrazoles) by Duncia’s method

John Duncia at du Pont reported a nice way to access azidoazomethines (and thus tetrazoles) from amides and TMSN3 using diethyl azodicarboxylate and triphenylphosphine. Shown below is a more recent application of Duncia’s method by discovery chemists Li, Tino, and co-workers at Bristol-Myers Squibb, who synthesized BMS-317180, a GHS agonist.

BMS discovery route using Duncia's method for tetrazole synthesis

The Process R&D group at BMS later felt that the issues of high exothermicity, TMSN3 safety, and PPh3PO removal warranted another approach to the tetrazole for scale-up.

Example: Azidoazomethines (and thus tetrazoles) from amidrazone diazotization

The BMS process group ultimately decided to avoid azide chemistry altogether by using amidrazone diazotization chemistry. Hydrazinolysis of the oxazoline shown below gave an amidrazone that was then diazotized to give the azidoazomethine (not shown) and thus the tetrazole on a 40 kg scale.  Superb.

BMS's Process for Tetrazole Synthesis on Large Scale

By the way, you can also make 5-substituted tetrazoles from amidrazones, though it’s not as common as the nitrile/azide method discussed in Part I of this post. Here’s an example :

Amidrazone route to 5-substituted tetrazoles

Fused bicyclic tetrazoles: An ideal application of the azidoazomethine-tetrazole equilibrium

Azidoazomethines where the azomethine (imine) is part of a ring, e.g. 2-azidopyridines and 4-azidopyrimidines, undergo electrocyclization to provide fused bicyclic tetrazoles. Historically, this is where the azidoazomethine-tetrazole chemistry began, with work by Bülow (1909; azidopyrimidines), Benson (1954, azidopyrimidines), Boyer (1959, azidopyridines), and McKee (1962, azidopyrimidines). The following example is from McKee’s lab at UNC and Montgomery’s lab at SRI (see also here). Both the azide and diazotization methods were used successfully.

McKee and Montgomery fused tetrazole synthesis

Finally, remember that the position of the azidoazomethine-tetrazole equilibrium depends on the electron density around the tetrazole? McKee used that knowledge to develop a new purine synthesis: Converting the above amine (electron donor) to the imidate shown below (electron acceptor) caused the azidoazomethine-tetrazole equilibrium to shift to favor the latter, which upon heating gave a purine. There’s some great stuff in the old literature.

McKee Purine Synthesis by shifting the tetrazole-azidoazomethine equilibrium

McKee, by the way, was the professor that got me interested in heterocyclic chemistry… see an earlier post for that story.

I hope you’ve enjoyed this Tour de Tetrazoles. I know there are some tetrazole experts out there, so please share some of your knowledge in the Comments.