Synthesis of azetidines
A straightforward synthesis of various 1,3-disubstituted azetidines has been accomplished via the alkylation of primary amines with in situ generated bis-triflates of 2-substituted-1,3-propanediols.
M. C. Hillier, C.-Y. Chen, J. Org. Chem., 2006, 71, 7885-7887.
A one-pot synthesis of nitrogen-containing heterocycles from alkyl dihalides and primary amines and hydrazines occurs under microwave irradiation via a simple and efficient cyclocondensation in an alkaline aqueous medium.
Y. Ju, R. S. Varma, J. Org. Chem., 2006, 71, 135-141.
A simple, efficient and general method has been developed for the synthesis of 1-arenesulfonylazetidines through a one-pot reaction of 1-arenesulfonylaziridines with dimethylsulfoxonium methylide, generated under microwave irradiation, using alumina as solid support.
S. Malik, U. K. Nadir, Synlett, 2008, 108-110.
An intramolecular amination of organoboronates provides azetidines, pyrrolidines, and piperidines via a 1,2-metalate shift of an aminoboron "ate" complex.
P. Xu, M. Zhang, B. Ingoglia, C. Allais, A.-M. R. Dechert-Schmitt, R. A. Singer, J. P. Morken, Org. Lett., 2021, 23, 3379-3383.
A direct alkylation of 1-azabicyclo[1.1.0]butane (ABB) with organometal reagents in the presence of Cu(OTf)2 rapidly provides bis-functionalized azetidines. This method allows for the preparation of azetidines bearing alkyl, allyl, vinyl, and benzyl groups. This catalyst system can also be used for the alkylation of aziridines.
R. Gianatassio, D. Kadish, Org. Lett., 2019, 21, 2060-2063.
A mechanistically distinct approach achieves Suzuki-Miyaura-type cross-couplings between alkyl iodides and aryl organoborons. This process requires a copper catalyst but the activation of the alkyl electrophile is based on the halogen-atom-transfer ability of α-aminoalkyl radicals to convert secondary alkyl iodides into the corresponding alkyl radicals that then couple with the boronate species.
Z. Zhang, B. Gˇrski, D. Leonori, J. Am. Chem. Soc., 2022, 144, 1758-1765.
Hiyama cross-coupling reactions of arylsilanes with 3-iodoazetidine provide various 3-arylazetidines in good yields und mild reaction conditions.
Z. Liu, N. Luan, L. Shen, J. Li, D. Zou, Y. Wu, Y. Wu, J. Org. Chem., 2019, 84, 12358-12365.
The high ring strain associated with azabicyclo[1.1.0]butane enables a modular construction of azetidines via generation of azabicyclo[1.1.0]butyl lithium followed by trapping with a boronic ester, N-protonation, and 1,2-migration with cleavage of the central C-N bond to relieve ring strain. Further functionalisations of the N-H azetidine and the boronic ester are reported.
A. Fawcett, A. Murtaza, C. H. U. Gregson, V. K. Aggarwal, J. Am. Chem. Soc., 2019, 141, 4573-4578.
Optically pure C2-symmetrical cyclic amines were efficiently synthesized from the corresponding diols obtained from an enantioselective borohydride reduction of diketones in the presence of a chiral β-ketoiminato cobalt(II) catalyst.
M. Sato, Y. Gunji, T. Ikeno, T. Yamada, Synthesis, 2004, 1434-1438.
Palladium-catalyzed intramolecular amination of unactivated C-H bonds at the γ and δ positions of picolinamide (PA) protected amine substrates enables the synthesis of azetidine, pyrrolidine, and indoline compounds. The method features relatively low catalyst loading, use of inexpensive reagents, convenient operating conditions and predictable selectivities.
G. He, Y. Zhao, S. Zhang, C. Lu, G. Chen, J. Am. Chem. Soc., 2012, 134, 3-6.
An efficient method to activate hydroxyl groups of amino alcohols has been developed, which avoids the use of toxic reagents and tolerates various functional groups. This strategy has been applied to the synthesis of functionalized p-methoxyphenyl-protected azetidines, pyrrolidines, and piperidines.
R. M. de Figueiredo, R. Fr÷hlich, M. Christmann, J. Org. Chem., 2006, 71, 4147-4154.
Easily accessible arylglycine derivatives were cyclized to azetidines by using commercially available (2-bromoethyl)sulfonium triflate in a simple and mild procedure, that offers a relatively broad scope.
S. P. Fritz, J. F. Moya, M. G. Unthank, E. M. McGarrigle, V. K. Aggarwal, Synthesis, 2012, 44, 1584-1590.
A simple and robust one-pot nucleophilic addition-ring contraction of α-bromo N-sulfonylpyrrolidinones gives α-carbonylated N-sulfonylazetidines in the presence of potassium carbonate. Various nucleophiles, such as alcohols, phenols or anilines, have been efficiently incorporated into the azetidine derivatives. A monobromination of cheap and easily available N-sulfonyl-2-pyrrolidinone derivatives is also described.
N. Kern, A.-S. Felten, J.-M. Weibel, P. Pale, A. Blanc, Org. Lett., 2014, 16, 6104-6107.
Diversely substituted N-aryl-2-cyanoazetidines can be prepared in high yields from β-amino alcohols in enantiomerically pure form through a three-step sequence involving copper-catalyzed N-arylation, N-cyanomethylation of the secondary aniline, and one-pot mesylation followed by ring closure induced by a base. This method gives access to azetidines with a predictable and adjustable substitution pattern and also with predictable diastereoselectivity.
P. Quinodoz, B. Drouillat, K. Wright, J. Marrot, F. Couty, J. Org. Chem., 2016, 81, 2899-2910.
A relay catalysis strategy enables a [3 + 1]-annulation reaction between cyclopropane 1,1-diester and aromatic amines via lewis acid-catalyzed nucleophilic ring opening of cyclopropane 1,1-diester with aromatic amine and (hypo)iodite-catalyzed C-N bond formation. This reaction provides biologically important azetidines and tetrahydroquinolines.
J.-Q. Han, H.-H. Zhang, P.-F. Xu, Y.-C. Luo, Org. Lett., 2016, 18, 5212-5215.
N-Tosyl-3-halo-3-butenylamines underwent efficient Ullmann-type coupling to afford 2-alkylideneazetidines, which could be readily converted to the corresponding β-lactams by oxidation with O3.
H. Lu, C. Li, Org. Lett., 2006, 8, 5365-5367.
The reaction of alkynyl ketones with N-tosylimines catalyzed by Bu3P at room temperature in toluene gives highly functionalized 3-pyrrolines in very good yields. When DMAP was used in place of Bu3P as catalyst to facilitate the cycloaddition, completely substituted azetidines were produced in moderate yields in CH2Cl2.
L-G. Meng, P. Cai, Q. Guo, S. Xue, J. Org. Chem., 2008, 73, 8491-8496.
Under selected conditions, the Zr-catalyzed reaction of EtMgCl with imines produces C,N-dimagnesiated compounds, which can be further trapped with electrophiles. The overall transformation provides a new route to bifunctional or cyclic nitrogen-containing compounds such as 1-azaspirocyclic γ-lactams, pyrrolidines and azetidines.
V. Gandon, P. Bertus, J. Szymoniak, Synthesis, 2002, 1115-1120.
tert-Butyl hypoiodite is a mild and powerful reagent for the cyclization of N-alkenylamides leading to various N-heterocycles. N-alkenylsulfonamides gave three- to six-membered saturated N-heterocycles in good yields, whereas alkenylbenzamide derivatives afforded N-, O- or N-, S-heterocycles.
S. Minakata, Y. Morino, Y. Oderaotoshi, M. Komatsu, Org. Lett., 2006, 8, 3335-3337.
Thermal and silver-catalyzed [2+2] cycloadditions of imines to methylenecyclopropane derivatives gave 2-alkoxyazetidines, which are versatile building blocks for the synthesis of various other compounds such as α-cyclopropanated β-amino acids.
T. Nishimura, Y. Yasuhara, T. Hayashi, Angew. Chem. Int. Ed., 2006, 45, 5164-5166.
Functionalized 2-(sulfonylimino)-4-(alkylimino)azetidine derivatives were prepared in good to excellent yields via a copper-catalyzed multicomponent reaction of readily available terminal alkynes, sulfonyl azides, and carbodiimides without the assistance of a base under very mild conditions.
X. Xu, D. Cheng, J. Li, H. Guo, J. Yan, Org. Lett., 2007, 9, 1585-1587.