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Oxidative NHC-Catalysis for the Generation of Imidoyl Azoliums: Synthesis of Benzoxazoles Atanu Patra, Anjima James, Tamal Kanti Das, and Akkattu T. Biju J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02598 • Publication Date (Web): 29 Oct 2018 Downloaded from http://pubs.acs.org on October 29, 2018
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The Journal of Organic Chemistry
Oxidative NHC-Catalysis for the Generation of Imidoyl Azoliums: Synthesis of Benzoxazoles Atanu Patra,† Anjima James,† Tamal Kanti Das,† and Akkattu T. Biju*,‡ †Organic
Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411008, India
‡Department
of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India E-mail:
[email protected] N XH R
Ar
N BF4 N Ph
(20 mol %)
XH Ar
X R
Ar
KOt-Bu (20 mol %) N oxidant (1.0 equiv) X = O, S DMSO, 30 °C, 12 h (+) mild conditions (+) 26 examples (+) up to 99% yield
N
N
N
Ph N N
via.
ABSTRACT: N-Heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of aldimines generated from 2-amino phenols and aromatic aldehydes leading to the synthesis of 2arylbenzoxazoles under mild conditions is presented. The reaction proceeds via the generation of the aza-Breslow intermediates from imines and NHC, which under oxidative conditions forms the key imidoyl azoliums and a subsequent intramolecular cyclization furnishes the product. The reaction tolerates a broad range of functional groups and the products are formed in generally good yields. One of the unconventional ways of forging carbon-carbon and carbon-heteroatom bonds and thereby construction of new or existing molecules is by using N-heterocyclic carbene (NHC) organocatalysis.1 The underlying principle behind many of these reactions is the remarkable ability of NHCs to reverse the normal mode of reactivity of electrophiles (the umpolung concept).2,3 In majority cases, the electrophiles used are aldehydes, and the reactions proceed via the generation of nucleophilic Breslow intermediates (acyl anion equivalents).4 Two important transformations proceeding via the umpolung of aldehydes are benzoin reaction and the Stetter reaction. Intriguingly, catalysis using this concept employing NHCs has been extended to the umpolung of Michael acceptors5 and aldimines.6,7 NHCs are also useful for catalyzing 1
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transformations, which proceed in the normal way without polarity reversal.8 One such intermediate is the activated carboxylate generated from suitably substituted aldehydes and NHCs, which can undergo redox esterification to furnish functionalized esters.9 In 2010, Studer and co-workers demonstrated the NHC-catalyzed oxidation of aldehydes to esters using the bisquinone oxidant developed by Kharasch and Joshi.10a,11 These reactions proceed via the initial generation of the Breslow intermediate from aldehyde and NHC followed by the two electron oxidation using bisquinone to form the key acyl azolium intermediate, and a subsequent acylation to form the ester product (Scheme 1, eq 1). In the context of our interest in the NHC-catalyzed transformations in general12 and umpolung of aldimines triggered by NHCs in particular,6a,6b we envisioned that aldimines could be converted into analogous imidoyl azoliums by the addition of NHC to imines followed by the two electron oxidation of the initially formed aza-Breslow intermediate (eq 2). Herein, we report the synthesis of 2-arylbenzoxazoles by the NHC-catalyzed intramolecular cyclization of aldimines generated from 2-amino phenols and aromatic aldehydes proceeding under oxidative conditions. Notably, benzoxazole moiety is found is various biologically active natural products and marketed drugs.13 Scheme 1. NHC-Catalyzed Generation of Acyl Azoliums and Imidoyl Azoliums NHC-catalyzed oxidative esterification of aldehydes (Studer) Y O R
Ar H
OH
N
Y = S, NR1
O Y
R Ar
[O]
N
Y
R Ar
Breslow intermediate
HOR2
N
O OR2 (1)
R
Acyl azolium
NHC-catalyzed oxidative generation of imidoyl azoliums (this work) Ar N
XH Ar N X = O, S
Y
Ar N
XH Ar N H
[O]
Y
aza-Breslow intermediate
XH Ar N
Ar N
X N
Ar (2)
Y Imidoyl azolium
2
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The Journal of Organic Chemistry
Encouraged by our recent findings on NHC-catalyzed umpolung of imines,6a,6b the present studies were initiated by treating the aldimine 1a with the carbene generated from the triazolium salt 3 using KOt-Bu under oxidative conditions using bisquinone 411 in DMF at 30 °C. Interestingly, under these conditions, the expected 2-aryl benzoxa-zole 2a was formed in 72% yield (Table 1, entry 1). The reactions performed using NHC generated from other commonly used triazolium salts 5-7 returned reduced yields of 2a (entries 2-4).14 KOt-Bu was found to be the optimal base for this annulation as the reactions carried out using other organic and inorganic bases furnished low yields of 2a (entries 5-8). The screening of different solvents for this transformation revealed that 1,4-dioxane, toluene and CH2Cl2 are inefficient for this oxidative annulation (entries 9-11), whereas DMSO provided an improvement in yield to 86% (entry 12). With the high yield of 2a obtained in DMSO, we then performed a series of control experiments to confirm the role of both carbene and oxidant in this transformation at 30 °C.15 The reaction afforded only 7% of 2a when performed in the absence of the triazolium salt 3 (entry 13). Moreover, in the absence of 3 and KOt-Bu, the reaction did not proceed at all at 30 °C and 60 °C (entries 14, 15). In addition, the presence of triazolium salt and the oxidant were essential for this reaction (entry 16). These experiments (entries 13-16; repeated four times) confirms the involvement of both NHC and oxidant. The use of excess oxidant reduced the yield of 2a to 51% (entry 17). Furthermore, employing air as the oxidant afforded only 8% yield of 2a and the use of DDQ furnished 51% of 2a (entries 18, 19).
3
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Table 1. Optimization of the Reaction Conditionsa O
N BF 4 N N Ph 3 (20 mol %)
OH Ph
KOt-Bu (20 mol %) 4 (1.5 equiv) DMF, 12 h, 30 °C
N 1a
t-Bu O Ph N 2a
variation of standard conditionsa none 5 instead of 3 6 instead of 3 7 instead of 3 DBU instead of KOt-Bu DIPEA instead of KOt-Bu K2CO3 instead of KOt-Bu Cs2CO3 instead of KOt-Bu 1,4-dioxane instead of DMF toluene instead of DMF CH2Cl2 instead of DMF DMSO instead of DMF no 3 no 3 and KOt-Bu no 3 and KOt-Bu, run at 60 °C no 3 and 4 2.0 equiv 4 instead of 1.5 equiv air as an oxidant 8 instead of 4
a Standard
t-Bu
t-Bu 4 O
"Standard conditions"
entry 1 2 3 4 5 6 7 8 9 10 11 12 13c,d 14c,d 15c,d 16c,d 17c 18c 19c
t-Bu
yield of 2a (%)b 72 51 64
