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Phosphazene Superbase-mediated Regio- and Stereoselective Iodoaminocyclization of 2-(1Alkynyl)benzamides for the Synthesis of Isoindolin-1-ones Saurabh Mehta, and Dhirendra Brahmchari J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00452 • Publication Date (Web): 15 Apr 2019 Downloaded from http://pubs.acs.org on April 16, 2019
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The Journal of Organic Chemistry
Phosphazene Superbase-mediated Regio- and Stereoselective Iodoaminocyclization of 2-(1Alkynyl)benzamides for the Synthesis of Isoindolin-1-ones Saurabh Mehta,* and Dhirendra Brahmchari Department of Applied Chemistry, Delhi Technological University, Delhi, 110042 India
Abstract O NH2
R1 Y
R2
P4-t-Bu (1.0 equiv) E+ (3.0 equiv) R1 THF 25 °C, < 1min
E = I2, ICl, Br2, NBS, NIS R1 = H, OMe, NO2, F; R2 = H, alkyl, aryl, TMS, etc. Y = CH, N
Phosphazene
superbase
O
O R1 NH Y
NH
single step R2
E
65-97%
P4-t-Bu
Aristolactams
mediated
Easy to perform Fast reactions High yields Broad substrate scope Scalable Easy access to Aristolactams Overall a robust methodology
iodoaminocyclization
of
2-(1-
alkynyl)benzamides is reported. The reaction works under ambient conditions, and instantaneously results in the synthesis of isoindolin-1-ones in 65-97% yields, in a regio- and stereoselective manner. The exclusive formation of products with Z-geometry (across the exo C=C bond) has been confirmed through X-ray crystallography. The methodology also provides an easy access to Aristolactams, an important class of natural products. This has been successfully demonstrated by synthesizing two Aristolactam derivatives (including Cepharanone B).
Introduction Isoindolinones, also known as phathalimidines, are important nitrogenous compounds. This important heterocyclic scaffold is present in many pharmacologically important natural products such as Isoindolinomycin (Idm) (I),1 Lennoxamine (II),2
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Aristolactams (III),3 etc.4 (Figure 1). Additionally, several medicinally important synthetic compounds containing isoindolin-1-ones scaffold are also known, such as Chlortalidone (IV),5 Dopamine receptor ligand (S)-PD 172938 (V),6 Pagoclone (Cl-1043) (VI),7 Pazinaclone (VII),8 etc.9 (Figure 1).
Figure 1. Selected examples of natural (I-III) and synthetic (IV-VII) biologically active compounds with the isoindolin-1-one skeleton. Due to the medicinally privileged nature of isoindolinone scaffold, several synthetic organic as well as medicinal researchers have reported various interesting approaches for the synthesis of the isoindolin-1-ones.10-16 Also, various alkyne annulation reactions, such as metal-catalyzed annulations,17-20 base-mediated annulations,21-23 aza-conjugate additions,24,25 etc. have been extensively used for synthesizing a variety of isoindolinone derivatives. Electrophilic cyclization reactions of functionalized alkynes have emerged as very useful synthetic tools in organic chemistry.26-28 Over the years, we have been interested in developing novel strategies for the synthesis of heterocyclic and polyheterocyclic compounds through iodocyclization methodology.29,30 More particularly, we and others have studied the
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The Journal of Organic Chemistry
synthesis of isoindolinones and their regio-isomeric cyclic imidates, through the electrophilic cyclization reactions of o-alkynyl benzamides.31-35 In this context, it may be noted that Amide group (−CONH2) is known to be an ambident nucleophile.36-42 Further, it may be summarized that the cyclization of o-alkynyl benzamides in the absence of a base (using NIS in DCM),31 or in presence of weak base (using I2/ICl with NaHCO3 in MeCN),32-34 leads to the Ocyclization yielding the corresponding cyclic imidates (Scheme 1a). It may also be noted that some of these cyclic imidates were mis-characterized as isoindolinones and isoquinolones before32 and this was later corrected by us and also by Opatz et al.33,34 Furthermore, we later accomplished the N-cyclization for o-alkynyl benzamide substrates by using a stronger base n-BuLi with I2/ICl (Scheme 1b).35 Although the use of BuLi worked reasonably well, the scope of the methodology was found to be limited with respect to the substrate functionality, for example the substrates with trimethylsilyl (TMS) or bromo (-Br) groups did not yield the desired products. Also, the reaction yields were moderate in most cases. Moreover, n-BuLi being a highly reactive reagent, is difficult to handle, and is not a preferred choice of synthetic/industrial chemists. We believe that due to the ambident nature of the amide group, it is still a synthetic challenge to accomplish an efficient and regioselective N-cyclization for the alkynyl amides and related substrates.39-42 Moreover, we think that there is still scope for the development of a robust methodology for the synthesis of isoindolin-1-ones, especially one that allows further diversification, and possible extension to natural product synthesis. Therefore, we decided to develop a simple, straight-forward and efficient methodology for the iodoaminocyclization of o-alkynyl benzamides. We wondered if the use of an organic, nonnucleophilic superbase would be suitable for such iodocyclizations. One important class of such superbases is phosphazenes, which are very strong, metal free, non-nucleophilic bases.43-45 In this context, one member of the phosphazene superbase family, namely P4-t-Bu
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(Figure 2) is particularly established as an extremely strong (pKa = 42.7 in MeCN) and useful superbase in organic synthesis.46,47
Me2N NMe2 Me2N P N NMe2 Me2N
NMe2 P NMe2 N t-Bu P N N P NMe2 NMe2
Figure 2. Phosphazene Superbase P4-t-Bu. Upon a thorough search of the literature, we didn’t find any report of the use of a superbase in iodocyclization of functionally-substituted alkynes. Although we came across a few papers where Terada et al. reported superbase-catalyzed intramolecular cyclization of oalkynylphenyl ethers48 and o-alkynylbenzamides,49 however, no electrophiles (other than H+) were explored for that methodology. Also, in many cases mixtures of E/Z stereoisomers were obtained as a result of cyclization reaction of o-alkynylbenzamides (Scheme 1c).49 Therefore, we decided to explore the use of P4-t-Bu in halocyclization reactions, and here we report the results of our studies on superbase P4-t-Bu mediated stereo- and regioselective halocyclization reactions of 2-(1-alkynyl) benzamides (Scheme 1d). Scheme 1. Base-mediated Cyclizations of 2‑(1-Alkynyl)benzamides (a) Electrophilic Cyclization of 2‑(1-Alkynyl)benzamides yielding Cyclic Imidates33 O R1
NHR2 R3
I2/ICl NaHCO3 MeCN
NR2
NR2 R1
O
I
O
R1 R3
R3 I
Cyclic Imidates
(b) n-Butyl Lithium-mediated Iodocyclization of 2‑(1-Alkynyl)benzamides Generating isoindolin-1-ones35
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O NH2
R1
O
I2 or ICl BuLi/THF
R1
NH
0 °C, 30 min R2
I R2 38-94% isoindolin-1-ones
(c) P4-t-Bu Catalyzed Cyclization of o-Alkynylbenzamide forming isoindolinones49 O N H
R1
R3
O
P4-t-Bu
R2
(10 mol%)
R1
N R2
40°C solvent, 30-60 min
E/Z
R3
(d) Present work: P4-t-Bu mediated Stereoselective Electrophilic Cyclization of oAlkynylbenzamides O NH2
R1 Y
R2
P4-t-Bu (1.0 equiv) E+ (3.0 equiv) THF 25 °C,
