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 diasteroselective 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).
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.
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.
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):
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 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:
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.
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.
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 :
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.
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, 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.
Azaphiles, unite! Azaphobes, run! It’s time to delve into the synthesis of tetrazoles (review) in this two-part post. Whatever you think you know about making these hard-core heterocycles, I’ll wager you’ll still find something interesting here. Are you thinking that all tetrazoles are made with azide chemistry and thus you’ll lose a limb to an explosion? Read on.
Full disclosure: I love molecules with several nitrogens in a row. My graduate work involved adding organometallics to azides to produce triazenes and a good deal of my group’s research at the University of Michigan involved azides, triazoles, triazolines, etc. Good times.
When considering tetrazoles, most organic chemists will likely think first of 5-substituted tetrazoles, long known to be good carboxylic acid biomimetics/bioisosteres in the drug discovery endeavor, their acidity being much the same as those of carboxylic acids (see Meanwell’s excellent review). But there are other important types of tetrazoles that are nonacidic, e.g., disubstituted tetrazoles and fused bicyclic tetrazoles.
In the current post, we’ll consider making 5-substituted tetrazoles using azide chemistry. Online IR studies by the process R&D group at Merck Frosst are instructive in dealing with the dangers of hydrazoic acid.
In the next post, we’ll look at the tetrazole-azidoazomethine equilibrium for the synthesis of disubstituted and fused-bicyclic tetrazoles, where we’ll find that one can avoid sodium azide and hydrazoic acid issues entirely. Well, almost entirely.
5-Substituted tetrazoles – dealing with the dangers of hydrazoic acid
A popular procedure for making 5-substituted tetrazoles is the reaction of sodium azide with a nitrile, often in the presence of an ammonium salt. The example shown below is from Organic Syntheses (Novartis Process R&D and Ley’s group at Cambridge), providing the useful enantiocatalyst shown on an 80 mmol scale. The excess sodium azide was destroyed with sodium nitrite and sulfuric acid, which converts hydrazoic acid into nitrogen and nitrous oxide gases.
While the above procedure may be popular, any time you use sodium azide you should be thinking, “hydrazoic acid can be generated, it’s explosive and toxic, and I need to take the appropriate safety precautions.” That’s precisely what happened during some recent process R&D work at Merck Frosst on the steroyl-CoA desaturase inhibitor MK-8245. The discovery chemistry route used NaN3/pyridinium chloride as shown below, but the process group felt that the potential for significant amounts of hydrazoic acid generation was too high.
Armed with the ability to detect hydrazoic acid in the headspace above the reaction mixture using online IR, the Merck Frosst researchers surveyed alternatives. Sharpless’s zinc bromide procedure, proposed to minimize hydrazoic acid formation by control of the pH, led to a reading of 2000 ppm of HN3 in the headspace, which is below the detonation threshold of 15,000 ppm but was still felt to be undesirable. In their own survey of conditions, the Merck Frosst scientists found something quite new and significant: Reaction with sodium azide in the presence of a catalytic amount of zinc oxide in aqueous THF (pH 8) proceeded efficiently, and most notably, with only 2 ppm of HN3 in the headspace! They were able to make 7 kg of the tetrazole in one run in nearly quantitative yield. Nice!
I’d be remiss if I didn’t mention Bu3SnN3 and Me3SiN3/Cu(I) as sodium azide surrogates, sometimes used on large scale. Shown below is an application to valsartan (see here and here) with recycling of the tin by-products. The intermediate stannyl tetrazole and leftover Bu3SnN3 were converted with HCl to Bu3SnCl, which was then converted to the fluoride, which was removed by filtration and recycled to Bu3SnCl.
Next: The tetrazole-azidomethine equilibrium and its use in tetrazole synthesis.
It’s time for some “oldie-but-goodie” heterocyclic chemistry, namely the Knorr pyrrole synthesis. What’s left to be said about this venerable route to pyrroles? Well, I’d like to point out that it should probably be termed the Knorr pyrrole syntheses (plural). As usual with chemistry, things are more complex than they first appear.
Here’s the upshot: There are two fundamentally different pyrrole connectivities that are produced under the Knorr umbrella. Let’s look at what they are and then delve a little deeper into the connectivity that is often overlooked.
What is the conventional Knorr synthesis?
If you were to consult a reference source or ask someone to describe “the Knorr pyrrole synthesis,” you’d probably find something like this:
The Knorr is usually considered to be the condensation of an α-aminocarbonyl compound with another carbonyl compound, typically an active methylene compound such as a β-ketoester, in the fashion shown above, generally proceeding by (i) condensation of the amine with the other carbonyl compound and (ii) an intramolecular aldol (Knoevenagel) condensation. Using an organizational system that I employ in my heterocyclic chemistry course, it’s a [3+2]-a,c approach, i.e., it makes the bonds at the “a” and “c” faces of the pyrrole by combining a three-atom component and a two-atom component.
Getting specific, one of my favorite examples is Hamby and Hodges’ 1993 work at Parke-Davis, featuring a Weinreb amide approach to the α-aminocarbonyl compound and reductive deprotection to the amine in the presence of the β-ketoester:
Most [3+2]-a,c Knorr examples produce pyrroles with an electron-withdrawing group (EWG) at the 3-position, but there are examples without it.
The Fischer-Fink variant of the Knorr pyrrole synthesis
If you look a bit further into the Knorr synthesis, you find examples that I would classify as [3+2]-a,d variants. Here, the α-aminocarbonyl compound contributes two pyrrole atoms rather than three; the other carbonyl compound (typically a 1,3-diketone) contributes three atoms rather than two. These reactions proceed by (i) condensation of the amine with the other carbonyl compound to form bond a and (ii) an intramolecular aldol condensation to form bond d. If the amine bears two electron-withdrawing groups (as it does in much of the early work), one is lost during the reaction.
This variant of the Knorr synthesis is perhaps best termed the Fischer-Fink variant after the discoverers of traces of these compounds in traditional Knorr syntheses that employ ethyl acetoacetate (H. Fischer and E. Z. Fink, Hoppe-Seyler’s Z. Physiol. Chem. 1944, 280, 290 and 1948, 283, 152 and this link).
It was Kleinspehn in 1955 who figured how to obtain a majority of the [3+2]-a,d connectivity: simply use diethyl malonate rather than ethyl acetoacetate. Paine and Dolphin later improved Kleinspehn’s method by preforming the amine rather than carrying out an oxime reduction in situ. The Paine/Dolphin method is notable in that it works regioselectively with unsymmetrical 1,3-diketones and has found wide application in porphyrin synthesis.
Let’s look at a couple of my favorite examples of the Fischer-Fink variant of the Knorr pyrrole synthesis.
Elliott and co-workers at BioCryst used an α-cyano aldehyde rather than a 1,3-diketone, producing a 2-carboxy-3-aminopyrrole, an intermediate in their synthesis of some PNP-inhibitory pyrrolopyrimidinones (9-deazaguanines):
Prashad and co-workers in the process group at Novartis later used the Elliott chemistry to prepare a related PNP-inhibitor. Both the BioCryst and Novartis groups used cyanamide as the cycloguanidinylating agent to produce the pyrrolopyrimidinones, a method that can be traced back to the work of my early mentor Robert McKee at UNC-CH, the subject one of my earlier posts.
The Fiesselmann-type modification of the Fischer-Fink variant
Okay, that’s a mouthful, but I think it’s worth treating this [3+2]-a,d method separately. In the Fischer-Fink chemistry, a 2-aminomalonate is used, one of the esters being lost in the cyclization reaction. Starting in the 1980s, examples began to appear where a simple glycinate is used; the second ester is omitted. Thus, the condensation of simple α-amino esters with 1,3-diketones or their equivalents produces 2-carboxypyrroles as shown in the following example by Mataka (Synthesis, 1983, 157-159):
As far as I can tell, there isn’t a standard way to refer to these reactions. They remind me of the Fiesselmann thiophene synthesis, which involves the condensation of α-mercaptoacetates with 1,3-diketones and their equivalents, so I’ll call these Fiesselmann-type modifications of the Fischer-Fink variant of the Knorr pyrrole synthesis.
Here are a few more examples of the Fiesselmann-type pyrrole syntheses. Note the complementary regiochemistry of the last two examples.
The greater Knorr synthesis umbrella produces two basic connectivities resulting from [3+2]-a,c or [3+2]-a,d constructions.
Knorr-o-philes please weigh in.
[Jan. 21, 2012: Edited Fischer-Fink citation to include earlier work.]