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Rapid, quantitative, solvent-free synthesis of medium-ring diaza heterocycles from diketene–acetone adduct and diamines Clifford S. Morrison, Jana B. Lampe, Tesia C. Kolodziejczyk  , Ronaldo J. Cavazos, Robby A. Petros Department of Chemistry, University of North Texas, 1155 Union Circle CB305070, Denton, TX 76203-5017, USA article info Article history: Received 29 July 2014 Revised 1 October 2014 Accepted 2 October 2014 Available online 8 October 2014 Keywords: Diaza heterocycles Diketene–acetone adduct Microwave-assisted synthesis Green chemistry abstract The synthesis of medium-ring heterocycles remains a challenge largely due to unfavorable energetic fac- tors. We are reporting syntheses of 7–9-member diaza heterocycles that go to completion in 5 min, require no solvents, and are quantitative with the only byproducts being acetone and water. The reaction products could be isolated in pure form by simply placing the mixture under vacuum. The reaction sequence possesses many of the hallmarks of a click reaction. Ó 2014 Elsevier Ltd. All rights reserved. Introduction The synthesis of medium-ring heterocycles remains a challenge largely due to unfavorable energetic factors. The use of microwave irradiation to overcome these barriers in the syntheses of this par- ticular class of compounds was reviewed recently. 1 While the meth- ods described were generally restricted to a single ring size, yields could be improved significantly through microwave irradiation. Here, we report a fortuitous re-discovery of a reaction sequence that has the potential to be applied quite broadly in the synthesis of het- erocycles of a variety of ring sizes. Our syntheses were carried out with no knowledge of an obscure previous report 2 detailing a subset of structures accessible via this methodology; however, the novelty of the reaction sequence itself was not what piqued our interest in the chemistry, but rather it was the remarkable efficiency of the reaction sequence that caught our attention. It should be noted that the reaction conditions reported here led to significantly higher yields under milder and more benign conditions and have been more generally applied to include a variety of ring sizes compared to previously reported similar methods. 2–8 The sequence was rapid, quantitative, atom economical, required no solvent or purification, and generated only benign byproducts, which are many of the hall- marks of a click reaction. Results Diketene–acetone adduct (1) and N,N-diethylethylenediamine (2a) were heated to 130 °C for 5 min under microwave irradia- tion under solvent-free conditions to form b-keto amide (3a) and acetone in quantitative yields (Fig. 1), the latter of which could be trivially removed under vacuum. The reaction sequence begins with a retro-Diels–Alder reaction of 1 known to occur upon heating above 80 °C. The diketene generated then under- goes nucleophilic attack by the amine to form a b-keto amide. 9 A variety of solvents, reaction times, and temperatures were investigated; however, none gave superior results to the opti- mized conditions reported. The acetoacetylation reaction was then coupled to a subsequent condensation reaction via bisnucleophilic amines resulting in the formation of heterocycles. Seven to nine member diaza heterocycles (3be) were readily prepared from both aliphatic and aromatic dia- mines (2be) using this methodology (Table 1). We compared the http://dx.doi.org/10.1016/j.tetlet.2014.10.007 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved. Corresponding author. Tel.: +1 940 369 8238; fax: +1 940 565 4318. E-mail address: [email protected] (R.A. Petros).  Present address: Department of Biochemistry, Augustana College, Rock Island, IL 61201, USA. Figure 1. Synthesis of 3a from diketene–acetone adduct and N,N-diethylethylene- diamine under solvent-free conditions. Tetrahedron Letters 55 (2014) 6547–6549 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Rapid, quantitative, solvent-free synthesis of medium-ring diaza heterocycles from diketene–acetone adduct and diamines

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Page 1: Rapid, quantitative, solvent-free synthesis of medium-ring diaza heterocycles from diketene–acetone adduct and diamines

Tetrahedron Letters 55 (2014) 6547–6549

Contents lists available at ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier .com/ locate/ tet le t

Rapid, quantitative, solvent-free synthesis of medium-ring diazaheterocycles from diketene–acetone adduct and diamines

http://dx.doi.org/10.1016/j.tetlet.2014.10.0070040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +1 940 369 8238; fax: +1 940 565 4318.E-mail address: [email protected] (R.A. Petros).

� Present address: Department of Biochemistry, Augustana College, Rock Island, IL61201, USA.

Figure 1. Synthesis of 3a from diketene–acetone adduct and N,N-diethylediamine under solvent-free conditions.

Clifford S. Morrison, Jana B. Lampe, Tesia C. Kolodziejczyk �, Ronaldo J. Cavazos, Robby A. Petros ⇑Department of Chemistry, University of North Texas, 1155 Union Circle CB305070, Denton, TX 76203-5017, USA

a r t i c l e i n f o

Article history:Received 29 July 2014Revised 1 October 2014Accepted 2 October 2014Available online 8 October 2014

Keywords:Diaza heterocyclesDiketene–acetone adductMicrowave-assisted synthesisGreen chemistry

a b s t r a c t

The synthesis of medium-ring heterocycles remains a challenge largely due to unfavorable energetic fac-tors. We are reporting syntheses of 7–9-member diaza heterocycles that go to completion in 5 min,require no solvents, and are quantitative with the only byproducts being acetone and water. The reactionproducts could be isolated in pure form by simply placing the mixture under vacuum. The reactionsequence possesses many of the hallmarks of a click reaction.

� 2014 Elsevier Ltd. All rights reserved.

Introduction

The synthesis of medium-ring heterocycles remains a challengelargely due to unfavorable energetic factors. The use of microwaveirradiation to overcome these barriers in the syntheses of this par-ticular class of compounds was reviewed recently.1 While the meth-ods described were generally restricted to a single ring size, yieldscould be improved significantly through microwave irradiation.Here, we report a fortuitous re-discovery of a reaction sequence thathas the potential to be applied quite broadly in the synthesis of het-erocycles of a variety of ring sizes. Our syntheses were carried outwith no knowledge of an obscure previous report2 detailing a subsetof structures accessible via this methodology; however, the noveltyof the reaction sequence itself was not what piqued our interest inthe chemistry, but rather it was the remarkable efficiency of thereaction sequence that caught our attention. It should be noted thatthe reaction conditions reported here led to significantly higheryields under milder and more benign conditions and have beenmore generally applied to include a variety of ring sizes comparedto previously reported similar methods.2–8 The sequence was rapid,quantitative, atom economical, required no solvent or purification,and generated only benign byproducts, which are many of the hall-marks of a click reaction.

Results

Diketene–acetone adduct (1) and N,N-diethylethylenediamine(2a) were heated to 130 �C for 5 min under microwave irradia-tion under solvent-free conditions to form b-keto amide (3a)and acetone in quantitative yields (Fig. 1), the latter of whichcould be trivially removed under vacuum. The reaction sequencebegins with a retro-Diels–Alder reaction of 1 known to occurupon heating above 80 �C. The diketene generated then under-goes nucleophilic attack by the amine to form a b-keto amide.9

A variety of solvents, reaction times, and temperatures wereinvestigated; however, none gave superior results to the opti-mized conditions reported.

The acetoacetylation reaction was then coupled to a subsequentcondensation reaction via bisnucleophilic amines resulting in theformation of heterocycles. Seven to nine member diaza heterocycles(3b–e) were readily prepared from both aliphatic and aromatic dia-mines (2b–e) using this methodology (Table 1). We compared the

thylene-

Page 2: Rapid, quantitative, solvent-free synthesis of medium-ring diaza heterocycles from diketene–acetone adduct and diamines

Figure 2. Possible tautomeric structures for 3b.

Table 1Products obtained from the reaction of diketene–acetone adduct with variousaminesa

Entry Amine Product Yieldb (%)

1H2N(CH2)2NEt2

2aNH

O O

3a

Et2N100

2H2N(CH2)2NH2

2b NH

NHO

3b

100 (88)c

3H2N(CH2)3NH2

2cHN

NHO

3c

97 (89)c

4H2N(CH2)4NH2

2dNH

HNO

3d

100 (96)c

5

NH2

NH22e N

H

NH

O

3e

100

a Performed with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (5 mmol) and the corre-sponding amine (5 mmol) heated for 5 min at 130 �C under microwave irradiation.

b Isolated yield.c Yields from conventional heating for 5 min.

6548 C. S. Morrison et al. / Tetrahedron Letters 55 (2014) 6547–6549

effects of microwave versus conventional heating (entries 2–4),which can have a substantial impact on reaction progression insome cases.7 In our experiments, slightly lower yields wereobtained under conventional heating at short reaction times, butoverall the products obtained were quite similar indicating noattributable effects specific to microwave irradiation.

The products were analyzed by NMR where 13C and 1H NMRrevealed the presence of at least two of the four possible tautomericforms of 3b (Fig. 2). The structure of the predominate form was

Figure 3. Potential sites for int

assigned with the aid of several 1D- and 2D-NMR experiments(see Supplementary data). Presumably, the initially formed cyclicimine tautomerizes to the a,b-unsaturated form due to extendedp conjugation in the latter. Extended heating of 3b led to furthertautomerization and redistribution between species. This dynamicprocess was observed for each of the cyclization products and is thesubject of ongoing studies.

Discussion

We first utilized diketene–acetone adduct as a convenientsource of diketene10 while synthesizing a b-keto amide (Fig. 1)that was an intermediate in what is an otherwise straightforwardsynthesis of a tyrosine kinase inhibitor.11 Our interest was inexploring the inhibitor as a potential cargo for our nanoparticledelivery vectors.12–15 As we began optimizing the reaction, wefound that the product could be obtained in quantitative yieldby simply heating the two starting materials neat for as little as5 min under microwave irradiation. We hypothesized that theb-keto amide could be induced to undergo a subsequent intramo-lecular condensation reaction to synthesize cyclic imines if a dia-mine was used as the nucleophile. Indeed, 7–9 memberheterocycles were readily prepared from 1,2-, 1,3-, and 1,4-dia-mines using this methodology, which was somewhat surprisinggiven the relative difficulty of preparing such ring systems andthe limited number of known synthetic routes.1 The reactionproved to be quantitative (>97% isolated yields) making it highlyattractive for the synthesis of a variety of substituted heterocycleswith potential biological properties. Other similar methods havebeen reported for the reactions of diamines with 1,3-dicarbonylcontaining compounds,16 such as b-keto esters;6–8 however, thosemethods generally result in lower yields, require solvents, and/orlonger reaction times.

In our experiments, slightly lower yields were obtained underconventional heating at short reaction times; however, at 15 minno discernible difference was observed between the two heatingmethods. The slight decrease in yields observed at short reactiontime was not due to the formation of additional products, butrather incomplete conversion of the starting materials. Substitu-tion could theoretically be introduced in both the diamine sub-strate as well as at the two positions of 1 through knownreactions (Fig. 3) to generate a variety of diaza heterocycles. Aparticularly attractive subset of privileged17 structures that areaccessible via this synthetic methodology is benzodiazepines.Reaction of an aromatic amine, o-phenylene diamine (2e), with1 under the conditions outlined above did indeed lead to quanti-tative formation of the analogous cyclized product (3e), whichwas the main focus of a previous report utilizing diketene–ace-tone adduct discussed above.2 Benzene ring fusion in 3e is atC2–C3 of the diazepine ring making it structurally unique fromthe bonding motif most commonly encountered in diazepinesemployed as psychotropic drugs where benzene ring fusion isfound at C5–C6 or C6–C7.18 A number of pharmacologicallyactive dibenzodiazepines19 do, however, possess this motif mak-ing 3e and its derivatives attractive candidates for further psy-chotropic studies.

roducing substituents in 1.

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C. S. Morrison et al. / Tetrahedron Letters 55 (2014) 6547–6549 6549

Conclusions

In summary, a synthetic methodology that allows for quantita-tive synthesis of b-keto amides and biologically relevant medium-ring diaza heterocycles that is superior to other known methodsis reported herein. Diazepines, diazocines, and diazonines were allprepared from diketene acetone adduct and diamines by simpleheating under solvent-free conditions. The methodology provedto be remarkably efficient and little effort was required for productpurification. The heat source (microwave vs conventional) had littleeffect on reaction products or reaction time. The major product ofeach of the cyclization reactions was not the expected cyclic imine,but rather an ene-amine tautomer that was identified via 13C and 1HNMR. While these reactions were conducted using diamines, a vari-ety of other bi-nucleophilic species should react similarly allowingaccess to N-, O-, or S-containing heterocycles of varying ring size.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.007.

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