Just a bit of sodium ethoxide does the trick …
The Knorr pyrazole synthesis, broadly defined, involves the condensation of hydrazines with 1,3-dielectrophiles, e.g., 1,3-diketones, beta-ketoesters, alpha-cyanoketones, beta-alkoxyacrylonitriles, alkoxymethylenemalonates, etc. When a nitrile electrophile is involved, an aminopyrazole typically results, producing compounds that are very useful in the pharmaceutical field. The first two equations in the general scheme below use hydrazine as the dinucleophile, but what happens when an unsymmetrically-substituted hydrazine is involved? Wouldn’t it be nice to be able to produce either the 3- or 5-aminopyrazole regioisomer in a selective fashion?
This problem has been kicking around the literature for a long time. The 5-aminopyrazole is generally the major product, leaving the 3-aminopyrazole as a useful-yet-expensive poor cousin. Much effort has been spent trying to rationalize and predict the outcome of these processes, so a recent paper from Fandrick, et al., from Boehringer Ingelheim is a most welcome arrival.
Heating the nitrile 3 with the alkyl-substituted hydrazine 4 in ethanol produces the 5-aminopyrazole 7, presumably through the adduct 5, a result that is consistent with the prior literature. At first glance, this should be rather surprising, since it is known that alkylhydrazines are more nucleophilic at the most substituted nitrogen, i.e., k1 should be larger than k2, thus producing adduct 6 and the 3-aminopyrazole 8. (Arylhydrazines are different; they are generally more nucleophilic on the unsubstituted nitrogen, though it depends on the nature of the arene.) Fandrick and co-workers proposed that 6 is indeed the kinetically-formed adduct, but its cyclization to 8 (under typical neutral conditions) is slower than isomerization to the more stable adduct 5, producing 7 instead.
In order to obtain the more rare and often desirable 3-aminopyrazole 8, Fandrick simply introduced sodium ethoxide to the mix with the idea that the kinetically favored 6 might be transformed to 8 before it can isomerize to 5. It worked, producing 3-aminopyrazoles with selectivities of up to 99:1 depending on the exact example.
Increasing the size of the alkyl group on the hydrazine should erode the selectivity for 8 in the kinetically-controlled ethoxide reaction, since the internal nitrogen of the hydrazine, while electronically more nucleophilic, is less accessible due to steric hindrance. Indeed, moving to cyclohexylhydrazine and then t-butylhydrazine leads to diminished and even reversed selectivities of 72:28 and 5:95 for 8:7. Under neutral thermodynamic conditions, cyclohexyl- and t-butylhydrazine gave >99:1 ratios of 7:8, as expected.
Arylhydrazines are known to highly favor 5-aminopyrazoles, which was supported by the current work when employing neutral (thermodynamic) conditions. Interestingly, reasonable quantities of 1-aryl-3-aminopyrazoles 8 were formed under kinetically-controlled (ethoxide) conditions. Hence, with phenylhydrazine, a 1:1 ratio of 8:7 was formed, indicating that a good deal of 6 was formed kinetically. Using the more electron-rich p-methoxyphenylhydrazine under kinetically controlled conditions produced even more of the 3-aminopyrazole, giving a 78:22 ratio of 8:7. This presumably reflects and increase in the nucleophilicity of the internal hydrazine nitrogen due to the resonance donating effect of the p-methoxy substituent.
Near-simultaneous reports of an interesting new pyrrole (and dihydropyrrole) synthesis have appeared recently from the labs of Frank Glorius (Westfälische Wilhelms-Universität Münster) and Naohiko Yoshikai (Nanyang Technologial University, Singapore). Optimization of the additives, solvent, and temperature led to essentially the same conditions from each laboratory. A balloon of oxygen is preferred: yields are much lower when air is used. A Heck-type mechanism is shown, but a Wacker-type mechanism involving nucleophilic attack of an enamine onto a Pd-complexed alkene could not be ruled out.
The scope of the reaction is decent, as indicated below. Failures include R3 = CF3 or cyclopropyl and R2 = Ph. N-Homoallylic and N-cinnamyl imines were also unsuccessful.
Specific examples are shown below:
Interested in having a short course on Heterocyclic Chemistry at your company?
In late 2011, I put together a new two-day short course entitled “Heterocyclic Chemistry – A Drug-Oriented Approach” to present at companies. In a nutshell, it’s an intensive, preparatively-oriented course on the synthesis of the types of molecules encountered in the pharma and agricultural endeavors. There is a heavy focus on practical, proven methodology that people actually use. I keep it updated with lots of current chemistry.
Beyond the two days of instruction at your company, participants are left with a great resource: A book of over 500 slides of information, nicely organized, well-referenced, and containing many specifics on the best ways to make heterocycles.
I’m booking courses for 2013 and early 2014. Learn more by checking out the course web site, where you’ll find more on what the course covers. You can also download a two-page summary of the course to pass around to your colleagues. If you know of other chemists who might be interested in the course, I’d appreciate passing this along. You can reach me at will at pearsonchemsolutions dot com.
Here’s a process that I think needs continued attention from the synthetic community: Making saturated nitrogen heterocycles from simple N-alkylamines by intramolecular CH amination reactions. There’s a lot of great chemistry out there for related process where there is an electron-withdrawing group attached to the nitrogen within the tether (vide infra), but let’s focus on N-alkyl groups. With all the activity on CH functionalization chemistry in general, I hope this reaction will become routine at some point. Let’s take a look at some recent work in this area.
The Hoffmann-Löffler-Freytag reaction – An medicinal chemistry application
To exemplify the need for such a reaction, consider the compounds shown below, appearing in a recent J. Med. Chem. paper by McClure and coworkers at Pfizer. The diazatricyclodecane (or diazaadamantane) heterocycles in the dotted boxes were proposed as conformationally restricted piperidines that might make good agonists of G-protein-coupled receptor 119.
The Pfizer group settled on a Hoffmann-Löffler-Freytag (HLF) reaction to form the heterocycle. In their initial work, they were unable to reproduce Rassat’s route to such diazatricyclodecanes (JACS 1974), which involved heating the N-bromoamine in acid. Switching to the N-chloroamine led to only 14% of the desired compound accompanied by 40% of an elimination product involving the N-benzyl group.
Ultimately, forgoing the protecting group was fruitful. N-Chlorination of the primary amine shown below was followed by photolysis with a 450 W mercury lamp to provide multigram quantities of the crude cyclization product. Acylation followed by demethylation of the other amino group provided the key diazatricyclodecane for their studies.
One curious bit is the chlorination reaction: The authors do not state how many equivalents of t-butylhypochlorite are used. This seems rather important, since primary amines are well-known to form dichloroamines. I’ve contacted to authors, so hopefully we’ll know soon whether they were dealing with the monochloroamine or the dichloroamine. [Update: Dr. McClure responded that 1.2 equivalents of t-BuOCl were used.]
The Pfizer compounds did not pan out, so we’ll never know if their process research wizards would be able to employ the HLF route in a scaleup setting, but I imagine it would be an uphill battle. If photochemistry is ruled out, I imagine the “acid and heat” HLF would have to be sorted out somehow.
Now it’s easy to see why a more modern CH functionalization reaction with a catalytic transition metal would be useful, right?
Toward a practical intramolecular CH functionalization reaction
This seems like an excellent strategy, and I look forward to seeing where this research will go. How about metal-free, light-free, halogen-free versions? There’s a worthy goal!
Finally, I’d be remiss if I didn’t mention the extensive work in the literature on intramolecular aminations using nitrenoids that are substituted by strong electron-withdrawing groups (DuBois, Sanford, Davies, White, Lebel, Panek, and others, leading reference here). It’s a bit different from what we’re talking about here, since the electron-withdrawing group ends up in the tether, making cyclic sulfamates, carbamates, and the like.
By the way, if you’re interested in this topic, you might also look at some nice recent work by Tom Driver at UIC, who is using aryl azides as the nitrogen source for metal-catalyzed intramolecular CH aminations. His paper is also a good entry to the literature of CH aminations in general.
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):
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.]