In brief: Antaki's doctoral research developed a common ring-forming approach that could be applied across several cyclic amidines and 2-aminoheterocycles. Four related fused pyrimidine systems were published with V. Petrow in a single 1951 paper: pyrimido[2,1-b]benzothiazol-4-one, thiazolo[3,2-a]pyrimidin-5-one, pyrimido[2,1-b]benzoxazol-4-one, and pyrimido[1,2-a]benzimidazole (J. Chem. Soc., 1951, 551–555; DOI: 10.1039/JR9510000551). Three were presented as new ring systems in the thesis or the 1951 paper. The fourth was already known, but Antaki extended its substitution and fusion chemistry substantially.
| Record | Detail |
|---|---|
| Source paper | Antaki & Petrow, J. Chem. Soc. 1951, 551–555 |
| Thesis | H. B. F. Antaki, Contributions to the Chemistry of Heterocyclic Compounds, Queen Mary College, University of London, May 1950, Part I, Sections B–E |
| Common reaction principle | Condensation and ring closure using ethyl β-aminocrotonate with cyclic amidines or 2-aminoheterocycles |
| Thiazolo[3,2-a]pyrimidin-5-one | Recorded in the thesis as a previously undescribed ring system (the 1951 paper notes that only hydrogenated derivatives had been described earlier); ring closure obtained with ethyl β-aminocrotonate after earlier ethyl acetoacetate work had stopped at the acetoacetamido product |
| Pyrimido[2,1-b]benzothiazol-4-one | Described in the 1951 paper as a novel ring system; β-aminocrotonate gave ring closure where earlier ethyl acetoacetate work had produced acetoacetamido benzothiazoles |
| Pyrimido[2,1-b]benzoxazol-4-one | Recorded in the thesis as not previously reported; parent and a further annulated derivative prepared |
| Pyrimido[1,2-a]benzimidazole | Previously known system; Antaki extended it to new alkyl-substituted, annulated, and 4-imino derivatives |
In November 1950, H. Antaki and V. Petrow submitted a paper to the Journal of the Chemical Society describing a series of ring-closing condensations in which ethyl β-aminocrotonate proved "markedly superior" to ethyl acetoacetate. The work arose directly from Antaki's doctoral research completed earlier that year.
The pyrido[1,2-a]pyrimidin-4-one system — including its constitutional correction — is treated separately on this site. The same reaction principle was extended to other nitrogen-containing heterocycles, producing thiazolo-, benzothiazolo-, benzoxazolo-, and benzimidazolo-fused pyrimidine systems.
The work therefore formed a systematic test of whether a common condensation–cyclisation strategy could be transferred across different heterocyclic nuclei.
The thesis makes the logic of the programme particularly clear. Antaki had found that ethyl β-aminocrotonate could replace ethyl acetoacetate in ring closures involving an amidine-like residue. He then tested the same principle across a succession of heterocyclic amines.
The heterocyclic partner changed; the underlying ring-building strategy remained. The programme was applied to 2-aminopyridines, 2-aminothiazoles, 2-aminobenzothiazoles, 2-aminobenzoxazole, and 2-aminobenzimidazole. The products belonged to different fused heterocyclic families but arose from the same general synthetic reasoning.
A method-driven programme. The 1950–1951 work did not consist only of individual new ring systems. It also demonstrated that a common β-aminocrotonate-based condensation–cyclisation could be transferred across several heterocyclic nuclei.
The thiazolo[3,2-a]pyrimidin-5-one system was recorded in Antaki's 1950 thesis as a previously undescribed fused ring system and was subsequently published in the 1951 Antaki–Petrow paper, which notes that only hydrogenated derivatives had been described earlier.
Names used in the literature: thiazolo[3,2-a]pyrimidin-5-one; older literature: 4-keto-7:9-diazathianaphthen and 7:9-diazathianaphthen.
Antaki's thesis states:
"A 7:9-diazathianaphthen has not therefore been described in the literature, and previous attempts to obtain compounds of this type have been only partially successful."
The thesis places this result against earlier work using ethyl acetoacetate. Antaki cites German Patent 607, 623, in which the reaction had stopped at the corresponding acetoacetamido thiazole rather than giving the fused system:
"This observation agrees with an earlier finding (German Patent 607, 623) that ethyl acetoacetate condenses with 2-amino thiazole to give only the 2-acetoacetamidothiazole."
Antaki then applied the β-aminocrotonate reaction developed in the preceding section. Direct reaction of ethyl 2-aminocrotonate with 2-aminothiazole gave the fused product:
"These observations have now been extended and the hitherto unknown 4-keto-6-methyl-7:9-diazathianaphthen (XI) obtained by the direct reaction of ethyl 2-amino-crotonate with 2-amino thiazole."
He contrasted the result directly with the earlier acetoacetate chemistry:
"In contrast to earlier work employing ethyl acetoacetate, facile ring closure occurred to give (XI) in good yield."
"4-Methyl-2-amino-thiazole behaved in the same way, 3:6-dimethyl-4-keto-7:9-diazathianaphthen being likewise obtained in rather poor yield."
The methyl-substituted thiazole therefore underwent the same overall ring-forming reaction, although the corresponding fused product was obtained in lower yield.
The thesis further examined reactions of the fused product itself. Nitration under strongly acidic conditions gave a mononitro derivative in poor yield, while treatment under different nitric-acid conditions could instead produce the nitrate salt. These experiments extended the derivative chemistry of the newly formed system.
The 5H-thiazolo[3,2-a]pyrimidin-5-one series continued to be used in later synthetic and structural studies. Andrew and Bradsher, reporting a new synthesis in 1967, noted that 5H-thiazolo[3,2-a]pyrimidin-5-ones had previously been prepared from 2-aminothiazoles with ethyl β-aminocrotonate and cited Antaki and Petrow's 1951 paper among the earlier methods.
Saint-Ruf and Silou subsequently studied the mass spectra of substituted 5H-thiazolo[3,2-a]pyrimidin-5-ones. Their reference list includes Antaki and Petrow's 1951 paper.
Dunwell and Evans later examined isomeric thiazolopyrimidinones and prepared 5H-thiazolo[3,2-a]pyrimidin-5-ones for comparison with the corresponding 7H-thiazolo[3,2-a]pyrimidin-7-one series. Antaki and Petrow's 1951 paper was cited as prior literature for the 5-one series.
D. W. Dunwell and D. Evans, Journal of the Chemical Society C, 1971, 2094–2097. DOI: 10.1039/J39710002094
Derivatives related to both the thiazolo[3,2-a]pyrimidinone and pyrimido[2,1-b]benzothiazolone systems later entered pharmaceutical patent research. Mead Johnson's US 4,223,031 (1980) covered tetrazole-substituted derivatives and cited Antaki and Petrow's 1951 paper among the earlier literature.
"Thiazolo[3,2-a]pyrimidinones and pyrimido[2,1-b]benzothiazolones have been previously described by Ogura, et al. … Antaki, et al., J. Chem. Soc., 551 (1951) … but none of those references discloses a 1H-tetrazol-5-yl substituted compound."
Janssen Pharmaceutica later investigated compounds in this ring family. Setoperone is a 2,3-dihydro derivative of the thiazolo[3,2-a]pyrimidin-5-one system, while ritanserin retains the aromatic 5H-thiazolo[3,2-a]pyrimidin-5-one framework. Both were investigated as serotonin S2 / 5-HT2 antagonists. In a 1986 account of Janssen's serotonin-antagonist programme, Kennis and colleagues discuss setoperone and ritanserin among compounds developed during this work (Kennis et al., Drug Development Research 1986, 8, 133–140).
The Mead Johnson patent provides a direct prior-art link to Antaki and Petrow's 1951 paper for the thiazolo[3,2-a]pyrimidinone ring system.
Later work has continued to investigate the broader thiazolo[3,2-a]pyrimidine scaffold family.
Pyrimido[2,1-b]benzothiazol-4-one was described by H. Antaki and V. Petrow in 1951 as a novel ring system, and Antaki's 1950 doctoral thesis documents the same ring system in the preceding year. Later sources credit them with its first synthesis (below). The scaffold was subsequently developed in both academic and pharmaceutical research.
Names used in the literature: pyrimido[2,1-b]benzothiazol-4-one; 4H-pyrimido[2,1-b]benzothiazol-4-one; older literature: 1:11-diaza-9-thiafluorene.
The 1951 paper explicitly describes it as a "novel ring system" (p. 553). Condensation of 2-aminobenzothiazole with the β-aminocrotonate reagent gave the fused thiafluorene system, and substituted benzothiazoles were used to prepare a series of related products.
The thesis compares the β-aminocrotonate reaction with earlier benzothiazole chemistry using ethyl acetoacetate.
"Previous attempts (German Patent 603, 623) to condense 2-amino benzothiazole, its 3-methyl and 6-ethoxy derivatives with ethyl acetoacetate gave only 2-acetoacetamido benzothiazoles."
The β-aminocrotonate reaction instead gave the fused pyrimido[2,1-b]benzothiazolone system and was subsequently applied to a series of substituted benzothiazoles.
The thesis and the 1951 paper show that the reaction was explored across several substituted benzothiazole starting materials. The resulting fused products included acetamido-, amino-, carbethoxy-, chloro-, and ethoxy-substituted members of the diaza-thiafluorene series. The thesis also records further reactions interconverting some of these derivatives, including hydrolysis of an acetamido compound to the corresponding amino derivative.
This derivative series documents the same methodological feature seen in Thesis Section B: the reaction was used as a general route into a fused-ring family while substitution on the starting heterocycle was carried through into the final system.
A 1991 review devoted to condensed thiazolo[3,2-a]pyrimidine systems placed the Antaki–Petrow work at the beginning of its account of the tricyclic series. Babu, Ramana and Ramadas wrote (p. 144):
"Antaki and Petrow reported the first synthesis of a tricyclic thiazolopyrimidinone"
The review identifies the product as 2-methyl-4-oxo-benzothiazolo[3,2-a]pyrimidine and describes its preparation by condensation of 2-aminobenzothiazole with ethyl β-aminocrotonate. A later section of the same review states that Antaki and Petrow first reported the synthesis of a tetracyclic thiazolopyrimidinone (compound 89, p. 156). The 1951 paper itself reports a naphtho-fused analogue, compound (VIII), made from 2-aminonaphtho(2′:1′-4:5)thiazole (p. 553), the same starting amine named in the review.
B. Ramesh Babu, D. V. Ramana & S. R. Ramadas, Synthesis of Condensed Thiazolo-[3,2-a]pyrimidine Systems, Sulfur Reports 1991, 11(1), 143–165. DOI: 10.1080/01961779108048764
Later academic groups developed pyrimido[2,1-b]benzothiazole chemistry during the following decades, including Gompper and co-workers, Galasko and co-workers, Dunwell and co-workers, and Alaimo.
Ciba Ltd. cited Antaki and Petrow's 1951 paper in US 3,538,086 (1970), covering pharmacologically active pyrimido[2,1-b]benzothiazole and benzoxazole derivatives investigated for antiviral and antifungal properties.
Pfizer subsequently stated explicitly in US 4,041,163 (1977):
"The pyrimido[2,1-b]benzothiazole ring system was first reported by Antaki, et al., J. Chem. Soc., 551 (1951)."
The same 1951 paper was later cited directly in additional pharmaceutical patent programmes, including Mead Johnson's US 4,223,031 and Roussel-Uclaf's US 4,762,840.
Pyrimido[2,1-b]benzothiazole derivatives remain present in modern medicinal and synthetic chemistry.
Pyrimido[2,1-b]benzoxazol-4-one was described by Antaki and Petrow in 1951; Antaki's 1950 doctoral thesis records it as a ring system not hitherto reported.
Names used in the literature: pyrimido[2,1-b]benzoxazol-4-one; 4H-pyrimido[2,1-b]benzoxazol-4-one; older literature: 1:11-diaza-9-oxafluorene.
The thesis states:
"The 1:11-diaza-9-oxafluorene ring system has not hitherto been reported in the literature, but has now been successfully prepared by the application of the reaction outlined in sections A and B to 2-aminobenzoxazole."
The wording explicitly describes the benzoxazole result as an application of the reaction developed in the preceding thesis sections. The novelty therefore lay both in the previously unreported ring system and in transfer of the same synthetic principle to a new heterocyclic nucleus.
The thesis also records extension beyond the simple methyl-substituted parent system. Condensation of 2-aminobenzoxazole with an ethyl cyclohexanone carboxylate produced a further annulated diaza-oxafluorene derivative in which an additional saturated ring was fused onto the pyrimidine system.
The experiment extended the programme from simple substitution to further annulation of the fused system.
Ciba Ltd.'s US 3,538,086 (1970) covered both benzothiazole and benzoxazole members of the family and cited Antaki and Petrow's 1951 paper.
Riker Laboratories later obtained US 4,476,130 (filed 1982, granted 1984), covering 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzoxazol-4-one as an antiallergic compound.
Pyrimido[1,2-a]benzimidazole differed historically from the three systems above because the basic ring system was already known before Antaki began his work. His contribution was therefore not the first report of the parent scaffold but a substantial extension of its synthetic chemistry within the same programme.
Names used in the literature: pyrimido[1,2-a]benzimidazole; older literature: 1:11-diazacarbazole (thesis) and 1:9:11-triazafluorene (1951 paper).
Antaki's thesis reviewed earlier syntheses by Crippa and Perroncito, Morgan and Stewart, Ochiai and Yanai, Petrow and Saper, and Henecka. He then used the system as another test of how widely the condensation chemistry could be extended.
The thesis states:
"It has now been found that 2-substituted ethyl acetoacetates react with 2-aminobenzimidazole to give the corresponding 2-methyl-3-alkyl-4-keto-1:11-diazacarbazoles."
The experimental section of the 1951 paper (p. 555) records the 3-ethyl, 3-n-propyl and 3-isopropyl analogues, extending substitution at the 3-position beyond the compounds available through the earlier routes reviewed in the thesis.
Antaki also used cyclic β-ketoesters to enlarge the system further. Ethyl cyclohexanone-2-carboxylate reacted with 2-aminobenzimidazole to give the cyclotetramethylene-fused product. The thesis describes it as:
"the first representative of this type of compound to be prepared"
Ethyl cyclopentanone-2-carboxylate "behaved in the same way", giving the corresponding cyclotrimethylene-fused analogue in good yield. The two reactions document an extension from simple substitution to construction of additional fused saturated rings.
The programme was then extended beyond β-ketoesters themselves. Antaki showed that 2-aminocrotononitrile and 2-phenyl-2-aminoacrylonitrile could undergo related transformations with 2-aminobenzimidazole. Instead of the usual 4-keto products, these reactions gave corresponding 4-imino derivatives.
The thesis therefore documents three separate dimensions of development within this already known ring system: new alkyl substitution, additional ring fusion, and replacement of the usual 4-oxo functionality by 4-imino analogues.
Nearly seventy years later, researchers at Takeda Pharmaceutical reported 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as a new class of CRF-1 receptor antagonists (Kojima et al., Bioorganic & Medicinal Chemistry 2018, 26, 2229–2250). Their programme arose from Takeda's own 2-anilinobenzimidazole series. Among several conformationally constrained systems examined, the tetrahydropyrimido[1,2-a]benzimidazole series was selected for further development.
DOI: 10.1016/j.bmc.2018.01.020
A 2021 computational follow-up study modelled the structure–activity relationships of the same series using QSAR, molecular docking and molecular-dynamics simulation.
Kumar, S.; Kumar, N.; Sharma, C. S.; Mishra, S. S. Iranian Journal of Pharmaceutical Research 2021, 20(2), 22–34. DOI: 10.22037/ijpr.2020.113746.14464
Read together, Thesis Sections B–E document a programme broader than the preparation of several individual heterocycles. The same general reaction principle was repeatedly transferred to different starting nuclei and then extended through substitution, annulation and functional-group variation.
The thiazole series tested the reaction with a substituted heterocyclic partner. The benzothiazole work developed a family of substituted products. The benzoxazole work transferred the method to an oxygen-containing analogue and extended it to a further annulated system. The benzimidazole work examined alkyl substitution, additional ring fusion and replacement of the usual carbonyl product by imino analogues.
This systematic structure is visible more fully in the doctoral thesis than in the compressed 1951 journal paper. The paper established the published record; the thesis preserves the experimental breadth and reasoning behind it.
One 1951 paper, arising directly from Antaki's 1950 doctoral research, brought together four fused pyrimidine systems beyond the pyrido[1,2-a]pyrimidin-4-one treated elsewhere on this site. Three were presented as new ring systems in the thesis or the 1951 paper. The fourth was an established system whose substitution, fusion and functional-group chemistry Antaki extended substantially.
Their later histories differed. Some were developed by later academic groups, and some entered patent programmes that cite the 1951 paper.
The common feature is the original synthetic programme itself: a transferable ring-forming strategy applied systematically across several heterocyclic nuclei rather than a set of unrelated preparations.
Antaki, H. B. F. Contributions to the Chemistry of Heterocyclic Compounds. PhD thesis, Queen Mary College, University of London, May 1950. Part I, Sections B–E.
Antaki, H.; Petrow, V. New syntheses of heterocyclic compounds. Part XII. The condensation of ethyl β-aminocrotonate with some cyclic amidines. J. Chem. Soc. 1951, 551–555. DOI: 10.1039/JR9510000551
Gompper, R. et al. Chemische Berichte 1962, 95, 2871–2880.
Andrew, H. F.; Bradsher, C. K. A New Synthesis of Thiazolo[3,2-a]pyrimidinones. J. Heterocycl. Chem. 1967, 4, 577–581. DOI: 10.1002/jhet.5570040419
Galasko, G. et al. Journal of the South African Chemical Institute 1969, 22, 121–127.
Dunwell, D. W.; Evans, D. The Reactions of 2-Aminothiazoles and 2-Aminobenzothiazoles with Propiolic Acid and its Esters. J. Chem. Soc. C 1971, 2094–2097. DOI: 10.1039/J39710002094
Alaimo, R. J. Journal of Heterocyclic Chemistry 1973, 10, 769.
Ciba Ltd., US 3,538,086 (1970).
Pfizer Inc., US 4,041,163 (1977).
Saint-Ruf, G.; Silou, T. 2-Aminothiazole Derivatives. III. Mass Spectra of Some 5H-Thiazolo[3,2-a]pyrimidin-5-ones. J. Heterocycl. Chem. 1979, 16, 1535–1539. DOI: 10.1002/jhet.5570160803
Mead Johnson & Company, US 4,223,031 (1980).
Riker Laboratories, Inc., US 4,476,130 (1984).
Roussel-Uclaf, US 4,762,840 (1988).
Babu, B. R.; Ramana, D. V.; Ramadas, S. R. Synthesis of Condensed Thiazolo-[3,2-a]pyrimidine Systems. Sulfur Reports 1991, 11(1), 143–165. DOI: 10.1080/01961779108048764
Kojima, T. et al. Bioorg. Med. Chem. 2018, 26, 2229–2250. DOI: 10.1016/j.bmc.2018.01.020
Kumar, S.; Kumar, N.; Sharma, C. S.; Mishra, S. S. Iran. J. Pharm. Res. 2021, 20(2), 22–34. DOI: 10.22037/ijpr.2020.113746.14464
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